Skin test concentrations for systemically administered drugs -- an ENDA/EAACI Drug Allergy Interest Group position paper

NARCIS (Netherlands)

Brockow, K.; Garvey, L. H.; Aberer, W.; Atanaskovic-Markovic, M.; Barbaud, A.; Bilo, M. B.; Bircher, A.; Blanca, M.; Bonadonna, B.; Campi, P.; Castro, E.; Cernadas, J. R.; Chiriac, A. M.; Demoly, P.; Grosber, M.; Gooi, J.; Lombardo, C.; Mertes, P. M.; Mosbech, H.; Nasser, S.; Pagani, M.; Ring, J.; Romano, A.; Scherer, K.; Schnyder, B.; Testi, S.; Torres, M.; Trautmann, A.; Terreehorst, I.

2013-01-01

Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable

Maximum permissible concentration (MPC) values for spontaneously fissioning radionuclides

International Nuclear Information System (INIS)

Ford, M.R.; Snyder, W.S.; Dillman, L.T.; Watson, S.B.

1976-01-01

The radiation hazards involved in handling certain of the transuranic nuclides that exhibit spontaneous fission as a mode of decay were reaccessed using recent advances in dosimetry and metabolic modeling. Maximum permissible concentration (MPC) values in air and water for occupational exposure (168 hr/week) were calculated for 244 Pu, 246 Cm, 248 Cm, 250 Cf, 252 Cf, 254 Cf, /sup 254m/Es, 255 Es, 254 Fm, and 256 Fm. The half-lives, branching ratios, and principal modes of decay of the parent-daughter members down to a member that makes a negligible contribution to the dose are given, and all daughters that make a significant contribution to the dose to body organs following inhalation or ingestion are included in the calculations. Dose commitments for body organs are also given

Using Potentiometric Free Drug Sensors to Determine the Free Concentration of Ionizable Drugs in Colloidal Systems

DEFF Research Database (Denmark)

Tran, Thuy; Chakraborty, Anjan; Xi, Xi

2018-01-01

The present study investigates the use of free drug sensors (FDS) to measure free ionized drug concentrations in colloidal systems, including micellar solutions, emulsions, and lipid formulations during in vitro lipolysis. Diphenhydramine hydrochloride (DPH) and loperamide hydrochloride (LOP) wer...

Maximum flow approach to prioritize potential drug targets of Mycobacterium tuberculosis H37Rv from protein-protein interaction network.

Science.gov (United States)

Melak, Tilahun; Gakkhar, Sunita

2015-12-01

In spite of the implementations of several strategies, tuberculosis (TB) is overwhelmingly a serious global public health problem causing millions of infections and deaths every year. This is mainly due to the emergence of drug-resistance varieties of TB. The current treatment strategies for the drug-resistance TB are of longer duration, more expensive and have side effects. This highlights the importance of identification and prioritization of targets for new drugs. This study has been carried out to prioritize potential drug targets of Mycobacterium tuberculosis H37Rv based on their flow to resistance genes. The weighted proteome interaction network of the pathogen was constructed using a dataset from STRING database. Only a subset of the dataset with interactions that have a combined score value ≥770 was considered. Maximum flow approach has been used to prioritize potential drug targets. The potential drug targets were obtained through comparative genome and network centrality analysis. The curated set of resistance genes was retrieved from literatures. Detail literature review and additional assessment of the method were also carried out for validation. A list of 537 proteins which are essential to the pathogen and non-homologous with human was obtained from the comparative genome analysis. Through network centrality measures, 131 of them were found within the close neighborhood of the centre of gravity of the proteome network. These proteins were further prioritized based on their maximum flow value to resistance genes and they are proposed as reliable drug targets of the pathogen. Proteins which interact with the host were also identified in order to understand the infection mechanism. Potential drug targets of Mycobacterium tuberculosis H37Rv were successfully prioritized based on their flow to resistance genes of existing drugs which is believed to increase the druggability of the targets since inhibition of a protein that has a maximum flow to

The maximum ground level concentration of air pollutant and the effect of plume rise on concentration estimates

International Nuclear Information System (INIS)

Mayhoub, A.B.; Azzam, A.

1991-01-01

The emission of an air pollutant from an elevated point source according to Gaussian plume model has been presented. An elementary theoretical treatment for both the highest possible ground-level concentration and the downwind distance at which this maximum occurs for different stability classes has been constructed. The effective height release modification was taken into consideration. An illustrative case study, namely, the emission from the research reactor in Inchas, has been studied. The results of these analytical treatments and of the derived semi-empirical formulae are discussed and presented in few illustrative diagrams

Toward the establishment of standardized in vitro tests for lipid-based formulations. 2. The effect of bile salt concentration and drug loading on the performance of type I, II, IIIA, IIIB, and IV formulations during in vitro digestion.

Science.gov (United States)

Williams, Hywel D; Anby, Mette U; Sassene, Philip; Kleberg, Karen; Bakala-N'Goma, Jean-Claude; Calderone, Marilyn; Jannin, Vincent; Igonin, Annabel; Partheil, Anette; Marchaud, Delphine; Jule, Eduardo; Vertommen, Jan; Maio, Mario; Blundell, Ross; Benameur, Hassan; Carrière, Frédéric; Müllertz, Anette; Pouton, Colin W; Porter, Christopher J H

2012-11-05

The LFCS Consortium was established to develop standardized in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental mechanisms that underlie LBF performance. In this publication, the impact of bile salt (sodium taurodeoxycholate, NaTDC) concentration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during in vitro digestion testing has been explored and a common driver of the potential for drug precipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, increasing NaTDC concentrations increased the digestion of the most lipophilic LBFs and promoted lipid (and drug) trafficking from poorly dispersed oil phases to the aqueous colloidal phase (AP(DIGEST)). High NaTDC concentrations showed some capacity to reduce drug precipitation, although, at NaTDC concentrations ≥3 mM, NaTDC effects on either digestion or drug solubilization were modest. In contrast, increasing drug load had a marked impact on drug solubilization. For LBFs containing long-chain lipids, drug precipitation was limited even at drug loads approaching saturation in the formulation and concentrations of solubilized drug in AP(DIGEST) increased with increased drug load. For LBFs containing medium-chain lipids, however, significant precipitation was evident, especially at higher drug loads. Across all formulations a remarkably consistent trend emerged such that the likelihood of precipitation was almost entirely dependent on the maximum supersaturation ratio (SR(M)) attained on initiation of digestion. SR(M) defines the supersaturation "pressure" in the system and is calculated from the maximum attainable concentration in the AP(DIGEST) (assuming zero precipitation), divided by the solubility of the drug in the colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not occur, a

Soil and Water Assessment Tool model predictions of annual maximum pesticide concentrations in high vulnerability watersheds.

Science.gov (United States)

Winchell, Michael F; Peranginangin, Natalia; Srinivasan, Raghavan; Chen, Wenlin

2018-05-01

Recent national regulatory assessments of potential pesticide exposure of threatened and endangered species in aquatic habitats have led to increased need for watershed-scale predictions of pesticide concentrations in flowing water bodies. This study was conducted to assess the ability of the uncalibrated Soil and Water Assessment Tool (SWAT) to predict annual maximum pesticide concentrations in the flowing water bodies of highly vulnerable small- to medium-sized watersheds. The SWAT was applied to 27 watersheds, largely within the midwest corn belt of the United States, ranging from 20 to 386 km 2 , and evaluated using consistent input data sets and an uncalibrated parameterization approach. The watersheds were selected from the Atrazine Ecological Exposure Monitoring Program and the Heidelberg Tributary Loading Program, both of which contain high temporal resolution atrazine sampling data from watersheds with exceptionally high vulnerability to atrazine exposure. The model performance was assessed based upon predictions of annual maximum atrazine concentrations in 1-d and 60-d durations, predictions critical in pesticide-threatened and endangered species risk assessments when evaluating potential acute and chronic exposure to aquatic organisms. The simulation results showed that for nearly half of the watersheds simulated, the uncalibrated SWAT model was able to predict annual maximum pesticide concentrations within a narrow range of uncertainty resulting from atrazine application timing patterns. An uncalibrated model's predictive performance is essential for the assessment of pesticide exposure in flowing water bodies, the majority of which have insufficient monitoring data for direct calibration, even in data-rich countries. In situations in which SWAT over- or underpredicted the annual maximum concentrations, the magnitude of the over- or underprediction was commonly less than a factor of 2, indicating that the model and uncalibrated parameterization

Influence of drugs of abuse and alcohol upon patients admitted to acute psychiatric wards: physician's assessment compared to blood drug concentrations.

Science.gov (United States)

Mordal, Jon; Medhus, Sigrid; Holm, Bjørn; Mørland, Jørg; Bramness, Jørgen G

2013-06-01

In acute psychiatric services, rapid and accurate detection of psychoactive substance intake may be required for appropriate diagnosis and intervention. The aim of this study was to investigate the relationship between (a) drug influence as assessed by physicians and (b) blood drug concentrations among patients admitted to acute psychiatric wards. We also explored the possible effects of age, sex, and psychotic symptoms on physician's assessment of drug influence. In a cross-sectional study, the sample comprised 271 consecutive admissions from 2 acute psychiatric wards. At admission, the physician on call performed an overall judgment of drug influence. Psychotic symptoms were assessed with the positive subscale of the Positive and Negative Syndrome Scale. Blood samples were screened for a wide range of psychoactive substances, and quantitative results were used to calculate blood drug concentration scores. Patients were judged as being under the influence of drugs and/or alcohol in 28% of the 271 admissions. Psychoactive substances were detected in 56% of the blood samples. Altogether, 15 different substances were found; up to 8 substances were found in samples from 1 patient. Markedly elevated blood drug concentration scores were estimated for 15% of the patients. Physician's assessment was positively related to the blood drug concentration scores (r = 0.52; P < 0.001), to symptoms of excitement, and to the detection of alcohol, cannabis, and amphetamines. The study demonstrates the major impact of alcohol and drugs in acute psychiatric settings and illustrates the challenging nature of the initial clinical assessment.

Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis

Science.gov (United States)

Heinrichs, M. Tobias; Nikolaishvili, Ketino; Sabulua, Irina; Bablishvili, Nino; Gogishvili, Shota; Avaliani, Zaza; Tukvadze, Nestani; Little, Brent; Bernheim, Adam; Read, Timothy D.; Guarner, Jeannette; Derendorf, Hartmut; Peloquin, Charles A.; Blumberg, Henry M.; Vashakidze, Sergo

2017-01-01

ABSTRACT Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed using ex vivo lung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary (n = 6 patients), mass-like (n = 3 patients), or consolidative (n = 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 μg/ml. The median lung tissue free pyrazinamide concentration was 20.96 μg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis (R = −0.66, P = 0.04) and acid-fast bacilli (R = −0.75, P = 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens. PMID:28373198

Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis.

Science.gov (United States)

Kempker, Russell R; Heinrichs, M Tobias; Nikolaishvili, Ketino; Sabulua, Irina; Bablishvili, Nino; Gogishvili, Shota; Avaliani, Zaza; Tukvadze, Nestani; Little, Brent; Bernheim, Adam; Read, Timothy D; Guarner, Jeannette; Derendorf, Hartmut; Peloquin, Charles A; Blumberg, Henry M; Vashakidze, Sergo

2017-06-01

Improved knowledge regarding the tissue penetration of antituberculosis drugs may help optimize drug management. Patients with drug-resistant pulmonary tuberculosis undergoing adjunctive surgery were enrolled. Serial serum samples were collected, and microdialysis was performed using ex vivo lung tissue to measure pyrazinamide concentrations. Among 10 patients, the median pyrazinamide dose was 24.7 mg/kg of body weight. Imaging revealed predominant lung lesions as cavitary ( n = 6 patients), mass-like ( n = 3 patients), or consolidative ( n = 1 patient). On histopathology examination, all tissue samples had necrosis; eight had a pH of ≤5.5. Tissue samples from two patients were positive for Mycobacterium tuberculosis by culture (pH 5.5 and 7.2). All 10 patients had maximal serum pyrazinamide concentrations within the recommended range of 20 to 60 μg/ml. The median lung tissue free pyrazinamide concentration was 20.96 μg/ml. The median tissue-to-serum pyrazinamide concentration ratio was 0.77 (range, 0.54 to 0.93). There was a significant inverse correlation between tissue pyrazinamide concentrations and the amounts of necrosis ( R = -0.66, P = 0.04) and acid-fast bacilli ( R = -0.75, P = 0.01) identified by histopathology. We found good penetration of pyrazinamide into lung tissue among patients with pulmonary tuberculosis with a variety of radiological lesion types. Our tissue pH results revealed that most lesions had a pH conducive to pyrazinamide activity. The tissue penetration of pyrazinamide highlights its importance in both drug-susceptible and drug-resistant antituberculosis treatment regimens. Copyright © 2017 American Society for Microbiology.

Plasma vs heart tissue concentration in humans - literature data analysis of drugs distribution.

Science.gov (United States)

Tylutki, Zofia; Polak, Sebastian

2015-03-12

Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Can fluconazole concentrations in saliva be used for therapeutic drug monitoring?

NARCIS (Netherlands)

Koks, C. H.; Crommentuyn, K. M.; Hoetelmans, R. M.; Mathôt, R. A.; Beijnen, J. H.

2001-01-01

The saliva/plasma concentration ratio of fluconazole was investigated in 22 HIV-1-infected individuals with an oropharyngeal Candida infection to determine whether saliva fluconazole concentrations could provide useful information for therapeutic drug monitoring in this population. Steady-state

Hypnosis control based on the minimum concentration of anesthetic drug for maintaining appropriate hypnosis.

Science.gov (United States)

Furutani, Eiko; Nishigaki, Yuki; Kanda, Chiaki; Takeda, Toshihiro; Shirakami, Gotaro

2013-01-01

This paper proposes a novel hypnosis control method using Auditory Evoked Potential Index (aepEX) as a hypnosis index. In order to avoid side effects of an anesthetic drug, it is desirable to reduce the amount of an anesthetic drug during surgery. For this purpose many studies of hypnosis control systems have been done. Most of them use Bispectral Index (BIS), another hypnosis index, but it has problems of dependence on anesthetic drugs and nonsmooth change near some particular values. On the other hand, aepEX has an ability of clear distinction between patient consciousness and unconsciousness and independence of anesthetic drugs. The control method proposed in this paper consists of two elements: estimating the minimum effect-site concentration for maintaining appropriate hypnosis and adjusting infusion rate of an anesthetic drug, propofol, using model predictive control. The minimum effect-site concentration is estimated utilizing the property of aepEX pharmacodynamics. The infusion rate of propofol is adjusted so that effect-site concentration of propofol may be kept near and always above the minimum effect-site concentration. Simulation results of hypnosis control using the proposed method show that the minimum concentration can be estimated appropriately and that the proposed control method can maintain hypnosis adequately and reduce the total infusion amount of propofol.

Influence of the composition of radionuclide mixtures on the maximum permissible concentration

International Nuclear Information System (INIS)

Schillinger, K.; Schuricht, V.

1975-08-01

By dividing radionuclides according to their formation mechanisms it is possible to assess the influence of separate partial mixtures on the maximum permissible concentration (MPC) of the total mixture without knowing exactly their contribution to the total activity. Calculations showed that the MPC of a total mixture of unsoluble radionuclides, which may occur in all fields of peaceful uses of nuclear energy, depends on the gastrointestinal tract as the critical organ and on the composition of the fission product mixture. The influence of fractionation on the MPC can be reglected in such a case, whereas in case of soluble radionuclides this is not possible

Suspended particle and drug ingredient concentrations in hospital dispensaries and implications for pharmacists' working environments.

Science.gov (United States)

Inaba, Ryoichi; Hioki, Atsushi; Kondo, Yoshihiro; Nakamura, Hiroki; Nakamura, Mitsuhiro

2016-03-01

The aim of this study was to assess the present status of working environments for pharmacists, including the concentrations of suspended particles and suspended drug ingredients in dispensaries. We conducted a survey on the work processes and working environment in 15 hospital dispensaries, and measured the concentrations of suspended particles and suspended drug ingredients using digital dust counter and high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS), respectively. Of 25 types of powdered drugs that were frequently handled in the 15 dispensaries surveyed, 11 could be quantitatively determined. The amounts of suspended particles were relatively high, but below the reference value, in three dispensaries without dust collectors. The sedative-hypnotic drug zopiclone was detected in the suspended particles at one dispensary that was not equipped with dust collectors, and the antipyretic and analgesic drug acetaminophen was detected in two dispensaries equipped with dust collectors. There was no correlation between the daily number of prescriptions containing powdered drugs and the concentration of suspended particles in dispensaries. On the basis of the suspended particle concentrations measured, we concluded that dust collectors were effective in these dispensaries. However, suspended drug ingredients were detected also in dispensaries with dust collectors. These results suggest that the drug dust control systems of individual dispensaries should be properly installed and managed.

Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs

DEFF Research Database (Denmark)

Prahl, Julie B; Johansen, Isik S; Cohen, Arieh S

2014-01-01

OBJECTIVES: To study 2 h plasma concentrations of the first-line tuberculosis drugs isoniazid, rifampicin, ethambutol and pyrazinamide in a cohort of patients with tuberculosis in Denmark and to determine the relationship between the concentrations and the clinical outcome. METHODS: After 6......-207 days of treatment (median 34 days) 2 h blood samples were collected from 32 patients with active tuberculosis and from three patients receiving prophylactic treatment. Plasma concentrations were determined using LC-MS/MS. Normal ranges were obtained from the literature. Clinical charts were reviewed...... failure occurred more frequently when the concentrations of isoniazid and rifampicin were both below the normal ranges (P = 0.013) and even more frequently when they were below the median 2 h drug concentrations obtained in the study (P = 0.005). CONCLUSIONS: At 2 h, plasma concentrations of isoniazid...

Influence of drug concentration on the diffusion parameters of caffeine

Science.gov (United States)

Mustapha, R.Ben; Lafforgue, C.; Fenina, N.; Marty, J.P.

2011-01-01

Background and Objectives: In the fields of the pharmaceutical and cosmetic industries and in toxicology, the study of the skin penetration of molecules is very interesting. Various studies have considered the impact of different physicochemical drug characteristics, skin thickness, and formulations, on the transition from the surface of the skin to the underlying tissues or to the systemic circulation; however, the influence of drug concentration on the permeation flux of molecules has rarely been raised. Our study aims to discover the influence of caffeine concentration in a formulation on the percutaneous penetration from gels, as a result of different dose applications to polysulfate membrane and human skin. Materials and Methods: For this purpose, three identical base gels were used at 1, 3, and 5% of caffeine, to evaluate the effect of the concentration of caffeine on in vitro release through the synthetic membrane and ex vivo permeation through the human skin, using diffusion FranzTM cells. Results: The diffusion through the epidermal tissue was significantly slower than through the synthetic membrane, which recorded an increase of flux with an increase in the concentration of caffeine. The skin permeation study showed that diffusion depended not only on the concentration, but also on the deposited amount of gel. Nevertheless, for the same amount of caffeine applied, the flux was more significant from the less concentrated gel. Conclusion: Among all the different concentrations of caffeine examined, 1% gel of caffeine applied at 5 mg / cm2 showed the highest absorption characteristics across human skin. PMID:21572649

MAK and BAT values list 2017. Maximum permissible concentrations at the place of work and biological tolerance values for working materials

International Nuclear Information System (INIS)

2017-01-01

The MAK and BAT values list 2017 includes the maximum permissible concentrations at the place of work and biological tolerance values for working materials. The following working materials are covered: carcinogenic working materials, sensitizing materials and aerosols. The report discusses the restriction of exposure peaks, skin resorption, MAK (maximum working place concentration) values during pregnancy, germ cell mutagens and specific working materials. Importance and application of BAT (biological working material tolerance) values, list of materials, carcinogens, biological guide values and reference values are also included.

MAK and BAT values list 2016. Maximum permissible concentrations at the place of work and biological tolerance values for working materials

International Nuclear Information System (INIS)

2016-01-01

The MAK and BAT values list 2016 includes the maximum permissible concentrations at the place of work and biological tolerance values for working materials. The following working materials are covered: carcinogenic working materials, sensitizing materials and aerosols. The report discusses the restriction of exposure peaks, skin resorption, MAK (maximum working place concentration) values during pregnancy, germ cell mutagens and specific working materials. Importance and application of BAT (biological working material tolerance) values, list of materials, carcinogens, biological guide values and reference values are also included.

Use of MICRAS code on the evaluation of the maximum radionuclides concentrations due to transport/migration of decay chain in groundwaters

International Nuclear Information System (INIS)

Aquino Branco, O.E. de

1995-01-01

This paper presents a methodology for the evaluation of the maximum radionuclides concentrations in groundwaters, due to the transport/migration of decay chains. Analytical solution of the equations system is difficult, even if only three elements of the decay chain are considered. Therefore, a numerical solution is most convenient. An application of the MICRAS code, developed to assess maximum concentrations of each radionuclide, starting with the initial concentrations, is presented. The maximum concentration profile for 226 Ra, calculated using MICRAS, is compared with the results obtained through an analytical and a numerical model. The fitness of results is considered good. Simplified models, like the one represented by the application of MICRAS, are largely employed in the section in the selection and characterization of sites for radioactive wastes repositories and in studies of safety evaluation for the same purpose. A detailed analysis of the transport/migration of contaminants in aquifers requires a large quantify of data from the site and from the installation as well, which makes this analysis expensive and inviable during the preliminary phases of the studies. (author). 6 refs, 1 fig, 1 tab

Development and Evaluation of Chronotherapeutic Drug Delivery ...

African Journals Online (AJOL)

Conclusion: The developed system is capable of releasing the drug after a 4-h lag period. However ... concentration would be at its maximum level, ... spheronizer (Caleva MBS, UK)operating at .... capsules show that the color intensity of the.

MAK and BAT values list 2015. Maximum permissible concentrations at the place of work and biological tolerance values for working materials

International Nuclear Information System (INIS)

2015-01-01

The book on the MAK (maximum permissible concentrations at the place of work) and BAT (biological tolerance values for working materials) value list 2015 includes the following chapters: (a) Maximum permissible concentrations at the place of work: definition, application and determination of MAT values, list of materials; carcinogenic working materials, sensibilizing working materials, aerosols, limiting the exposition peaks, skin resorption, MAK values during pregnancy, germ cell mutagens, specific working materials; (b) Biological tolerance values for working materials: definition and application of BAT values, list of materials, carcinogenic working materials, biological guide values, biological working material reference values.

MAK and BAT values list 2014. Maximum permissible concentrations at the place of work and biological tolerance values for working materials

International Nuclear Information System (INIS)

2014-01-01

The book on the MAK (maximum permissible concentrations at the place of work) and BAT (biological tolerance values for working materials) value list 2014 includes the following chapters: (a) Maximum permissible concentrations at the place of work: definition, application and determination of MAT values, list of materials; carcinogenic working materials, sensibilizing working materials, aerosols, limiting the exposition peaks, skin resorption, MAK values during pregnancy, germ cell mutagens, specific working materials; (b) Biological tolerance values for working materials: definition and application of BAT values, list of materials, carcinogenic working materials, biological guide values, biological working material reference values.

[Estimation of maximum acceptable concentration of lead and cadmium in plants and their medicinal preparations].

Science.gov (United States)

Zitkevicius, Virgilijus; Savickiene, Nijole; Abdrachmanovas, Olegas; Ryselis, Stanislovas; Masteiková, Rūta; Chalupova, Zuzana; Dagilyte, Audrone; Baranauskas, Algirdas

2003-01-01

Heavy metals (lead, cadmium) are possible dashes which quantity is defined by the limiting acceptable contents. Different drugs preparations: infusions, decoctions, tinctures, extracts, etc. are produced using medicinal plants. The objective of this research was to study the impurities of heavy metals (lead, cadmium) in medicinal plants and some drug preparations. We investigated liquid extracts of fruits Crataegus monogyna Jacq. and herbs of Echinacea purpurea Moench., tinctures--of herbs Leonurus cardiaca L. The raw materials were imported from Poland. Investigations were carried out in cooperation with the Laboratory of Antropogenic Factors of the Institute for Biomedical Research. Amounts of lead and cadmium were established after "dry" mineralisation using "Perkin-Elmer Zeeman/3030" model electrothermic atomic absorption spectrophotometer (ETG AAS/Zeeman). It was established that lead is absorbed most efficiently after estimation of absorption capacity of cellular fibers. About 10.73% of lead crosses tinctures and extracts, better cadmium--49.63%. Herbs of Leonurus cardiaca L. are the best in holding back lead and cadmium. About 14.5% of lead and cadmium crosses the tincture of herbs Leonurus cardiaca L. We estimated the factors of heavy metals (lead, cadmium) in the liquid extracts of Crataegus monogyna Jacq. and Echinacea purpurea Moench., tincture of Leonurus cardiaca L. after investigations of heavy metals (lead, cadmium) in drugs and preparations of it. The amounts of heavy metals (lead, cadmium) don't exceed the allowable norms in fruits of Crataegus monogyna Jacq., herbs of Leonurus cardiaca L. and Echinacea purpurea Moench. after estimation of lead and cadmium extraction factors, the maximum of acceptable daily intake and the quantity of drugs consumption in day.

A comparison of muscle activity in concentric and counter movement maximum bench press.

Science.gov (United States)

van den Tillaar, Roland; Ettema, Gertjan

2013-01-01

The purpose of this study was to compare the kinematics and muscle activation patterns of regular free-weight bench press (counter movement) with pure concentric lifts in the ascending phase of a successful one repetition maximum (1-RM) attempt in the bench press. Our aim was to evaluate if diminishing potentiation could be the cause of the sticking region. Since diminishing potentiation cannot occur in pure concentric lifts, the occurrence of a sticking region in this type of muscle actions would support the hypothesis that the sticking region is due to a poor mechanical position. Eleven male participants (age 21.9 ± 1.7 yrs, body mass 80.7 ± 10.9 kg, body height 1.79 ± 0.07 m) conducted 1-RM lifts in counter movement and in pure concentric bench presses in which kinematics and EMG activity were measured. In both conditions, a sticking region occurred. However, the start of the sticking region was different between the two bench presses. In addition, in four of six muscles, the muscle activity was higher in the counter movement bench press compared to the concentric one. Considering the findings of the muscle activity of six muscles during the maximal lifts it was concluded that the diminishing effect of force potentiation, which occurs in the counter movement bench press, in combination with a delayed muscle activation unlikely explains the existence of the sticking region in a 1-RM bench press. Most likely, the sticking region is the result of a poor mechanical force position.

Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration.

Directory of Open Access Journals (Sweden)

Donghee Park

Full Text Available Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with

Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration.

Science.gov (United States)

Park, Donghee; Song, Gillsoo; Jo, Yongjun; Won, Jongho; Son, Taeyoon; Cha, Ohrum; Kim, Jinho; Jung, Byungjo; Park, Hyunjin; Kim, Chul-Woo; Seo, Jongbum

2016-01-01

Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa) causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with microbubbles depends on the

An introduction to predictive modelling of drug concentration in anaesthesia monitors.

Science.gov (United States)

DeCou, J; Johnson, K

2017-01-01

A significant amount of anaesthetists' work involves the prediction of drug effects and interactions to produce a smooth general anaesthetic that minimises drug side effects and promotes rapid emergence. Successfully managing this process requires a basic understanding of drug effects, experience and inevitably some guesswork, since it is difficult (and in some cases impossible) to anticipate all relevant patient and surgical factors. Although data are generally available to allow calculation of plasma drug and effect site concentrations, this is often difficult to apply in complex clinical contexts, particularly when multiple drug types are used. In recent years, manufacturers have developed and incorporated into anaesthetic workstations technologies that use drug pharmacodynamic and pharmacokinetic data to predict drug effects and interactions. Such systems can predict the duration and effects of drugs during anaesthesia and assist the anaesthetist to understand complex drug interactions. With this information available, different drug types, doses and combinations may be tailored in a scientific way to maximise useful effects whilst minimising overdose and side-effects, particularly in high-risk patients. Examples are used to illustrate how such systems can be used in practice, and how drug effects and interactions can be simulated to "rehearse" an anaesthetic before any drugs are actually administered. At present only a small number of anaesthetic workstations use this technology, and as yet they are not able to manage all drugs used in anaesthetic practice. However, such systems have the potential to help anaesthetists manage the complexity of their work, and to provide information on predicted drug effects in a way that is useful and relevant to both experienced anaesthetists and trainees. © 2017 The Association of Anaesthetists of Great Britain and Ireland.

Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug-Drug Interactions.

Science.gov (United States)

Weiss, Johanna; Gajek, Thomas; Köhler, Bruno Christian; Haefeli, Walter Emil

2016-02-24

Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug-drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug-drug interactions.

The frequency of drugs among Danish drivers before and after the introduction of fixed concentration limits

DEFF Research Database (Denmark)

Steentoft, Anni; Simonsen, Kirsten Wiese; Linnet, Kristian

2010-01-01

Until July 2007, the driving under the influence of drugs (DUID) legislation in Denmark was based on impairment, evaluated on the basis of a clinical investigation and toxicological analyses, but in 2007 fixed concentration limits were introduced into the Danish traffic legislation. The objective...... for this study was to investigate the prevalence of medication and illicit drugs among Danish drivers before and after 2007.......Until July 2007, the driving under the influence of drugs (DUID) legislation in Denmark was based on impairment, evaluated on the basis of a clinical investigation and toxicological analyses, but in 2007 fixed concentration limits were introduced into the Danish traffic legislation. The objective...

Maximum neutron flux in thermal reactors

International Nuclear Information System (INIS)

Strugar, P.V.

1968-12-01

Direct approach to the problem is to calculate spatial distribution of fuel concentration if the reactor core directly using the condition of maximum neutron flux and comply with thermal limitations. This paper proved that the problem can be solved by applying the variational calculus, i.e. by using the maximum principle of Pontryagin. Mathematical model of reactor core is based on the two-group neutron diffusion theory with some simplifications which make it appropriate from maximum principle point of view. Here applied theory of maximum principle are suitable for application. The solution of optimum distribution of fuel concentration in the reactor core is obtained in explicit analytical form. The reactor critical dimensions are roots of a system of nonlinear equations and verification of optimum conditions can be done only for specific examples

The Impact of Serum Drug Concentration on the Efficacy of Imipramine, Pregabalin and their Combination in Painful Polyneuropathy

DEFF Research Database (Denmark)

Sindrup, Søren Hein; Holbech, Jakob Vormstrup; Bach, Flemming W

2017-01-01

OBJECTIVE: The serum concentration-effect relation was explored for first line drugs in neuropathic pain and aimed to determine if efficacy could be increased. METHODS: Data from a randomized, placebo-controlled, cross-over trial on imipramine, pregabalin and their combination in painful...... polyneuropathy were used. Treatment periods were of 4 weeks' duration, outcome was the weekly median of daily pain rated by a 0-10 numeric scale, and drug concentrations were determined by high-performance liquid chromatography. RESULTS: In 47 patients pain was reduced -1.0 (95% CI -1.5:-0.6) by imipramine, -0.......178). There was no correlation between drug concentration and pain reduction for imipramine (r= 0.17, P=0.247), whereas there was a marginally, positive correlation for pregabalin (r=0.28, P=0.057). There was no interaction between treatment and concentration classes (imipramine

Pharmacokinetic equivalence study of nonsteroidal anti-inflammatory drug etoricoxib

Directory of Open Access Journals (Sweden)

Tjandrawinata RR

2018-04-01

Full Text Available Raymond R Tjandrawinata,1 Arini Setiawati,2 Dwi Nofiarny,1 Liana W Susanto,1 Effi Setiawati3 1Dexa Laboratories of Biomolecular Sciences Unit, Dexa Medica Group, Cikarang, West Java, Indonesia; 2Department of Pharmacology and Therapeutics, Medical Faculty, University of Indonesia, Jakarta, Indonesia; 3Bioavailability and Bioequivalence Laboratory Unit, PT Equilab International, Jakarta, Indonesia Purpose: The current study aimed to evaluate whether a generic product of etoricoxib 120 mg film-coated tablet (the test drug was bioequivalent to the reference product (Arcoxia® film-coated tablet 120 mg.Methods: This was a randomized, open-label, two-sequence, crossover study under fasting condition, with a 14-day washout period, involving 26 healthy adult male and female subjects. Blood samples were taken and analyzed for plasma concentrations of etoricoxib (Chemical Abstracts Service [CAS] 202409-33-4 using a high-pressure liquid chromatography–ultraviolet detector (HPLC-UV system capable of measuring etoricoxib concentrations ranging from 5.00 to 5002.90 ng/mL, with the lowest limit of quantitation of 5.00 ng/mL. A noncompartmental method was used to determine the pharmacokinetic parameters of a single-dose administration of the drug, including the area under plasma concentration–time curve from time zero to the time of last observed concentration (AUC0-t, the area under plasma concentration–time curve from time zero to infinity (AUC0-∞, the maximum plasma concentration (Cmax, the time to reach the maximum plasma concentration (tmax, and the terminal half-life (t½.Results: After a single-dose administration of etoricoxib 120 mg film-coated tablet, the mean (SD values for the AUC0-72h and Cmax of the test drug were 45913.42 (13142.19 ng·h/mL and 3155.93 (752.81 ng/mL, respectively; the values for the reference drug were 44577.20 (13541.85 ng⋅h/mL and 2915.13 (772.81 ng/mL, respectively. The geometric mean ratios (90% CIs of the test

Flexing the PECs: Predicting environmental concentrations of veterinary drugs in Canadian agricultural soils.

Science.gov (United States)

Kullik, Sigrun A; Belknap, Andrew M

2017-03-01

Veterinary drugs administered to food animals primarily enter ecosystems through the application of livestock waste to agricultural land. Although veterinary drugs are essential for protecting animal health, their entry into the environment may pose a risk for nontarget organisms. A means to predict environmental concentrations of new veterinary drug ingredients in soil is required to assess their environmental fate, distribution, and potential effects. The Canadian predicted environmental concentrations in soil (PECsoil) for new veterinary drug ingredients for use in intensively reared animals is based on the approach currently used by the European Medicines Agency for VICH Phase I environmental assessments. The calculation for the European Medicines Agency PECsoil can be adapted to account for regional animal husbandry and land use practices. Canadian agricultural practices for intensively reared cattle, pigs, and poultry differ substantially from those in the European Union. The development of PECsoil default values and livestock categories representative of typical Canadian animal production methods and nutrient management practices culminates several years of research and an extensive survey and analysis of the scientific literature, Canadian agricultural statistics, national and provincial management recommendations, veterinary product databases, and producers. A PECsoil can be used to rapidly identify new veterinary drugs intended for intensive livestock production that should undergo targeted ecotoxicity and fate testing. The Canadian PECsoil model is readily available, transparent, and requires minimal inputs to generate a screening level environmental assessment for veterinary drugs that can be refined if additional data are available. PECsoil values for a hypothetical veterinary drug dosage regimen are presented and discussed in an international context. Integr Environ Assess Manag 2017;13:331-341. © 2016 Her Majesty the Queen in Right of Canada

Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations.

Science.gov (United States)

Ji, Yuan; Schaid, Daniel J; Desta, Zeruesenay; Kubo, Michiaki; Batzler, Anthony J; Snyder, Karen; Mushiroda, Taisei; Kamatani, Naoyuki; Ogburn, Evan; Hall-Flavin, Daniel; Flockhart, David; Nakamura, Yusuke; Mrazek, David A; Weinshilboum, Richard M

2014-08-01

Citalopram (CT) and escitalopram (S-CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S-CT and their metabolites in MDD patients treated with CT or S-CT. Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms (SNPs) were modelled as additive allelic effects. Genome-wide significant associations were observed for S-CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10(-9) ) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10(-16) ), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation. In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S-CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors. © 2014 The British Pharmacological Society.

Study of homeopathic drugs on seed germination and fungal growth

International Nuclear Information System (INIS)

Hanif, A.; Dawar, S.

2016-01-01

In vitro, seeds of mungbean, sunflower, okra and mashbean were treated with homeopathic drugs namely Arnica montana and Thuja occidentalis (30C) were evaluated against root rot fungi. Different concentrations like 100, 75 and 50% v/v were tested to investigate seeds germination and inhibition of root rot fungi such as Fusarium oxysporum, Rhizoctonia solani and Macrophomina phaseolina. Results indicated that treated seeds of mungbean, sunflower, okra and mashbean with pure homeopathic drugs (100% v/v) by A. montana and T. occidentalis (30C) showed complete germination (100%), greater root length and excellent inhibition of root infecting pathogens. However, tested seeds treated with 75 and 50% v/v concentrations (prepared from 30C) by homeopathic drugs, respectively recorded significant increase in germination, root length and maximum zone of inhibition. (author)

40 CFR Table C-1 to Subpart C of... - Test Concentration Ranges, Number of Measurements Required, and Maximum Discrepancy Specification

Science.gov (United States)

2010-07-01

... Measurements Required, and Maximum Discrepancy Specification C Table C-1 to Subpart C of Part 53 Protection of... Reference Methods Pt. 53, Subpt. C, Table C-1 Table C-1 to Subpart C of Part 53—Test Concentration Ranges..., June 22, 2010, table C-1 to subpart C was revised, effective Aug. 23, 2010. For the convenience of the...

Considerations for effect site pharmacokinetics to estimate drug exposure: concentrations of antibiotics in the lung.

Science.gov (United States)

Rodvold, Keith A; Hope, William W; Boyd, Sara E

2017-10-01

Bronchoalveolar lavage (BAL) and microdialysis have become the most reliable and relevant methods for measuring lung concentrations of antibiotics, with the majority of BAL studies involving either healthy adult subjects or patients undergoing diagnostic bronchoscopy. Emphasis on the amount of drug that reaches the site of infection is increasingly recognized as necessary to determine whether a dose selection will translate to good clinical outcomes in the treatment of patients with pneumonia. Observed concentrations and/or parameters of exposure (e.g. area-under-the-curve) need to be incorporated with pharmacokinetic-pharmacodynamic indices so that rational dose selection can be identified for specific pathogens and types of pneumonic infection (community-acquired vs hospital-acquired bacterial pneumonia, including ventilator-associated bacterial pneumonia). Although having measured plasma or lung concentration-time data from critically ill patients to incorporate into pharmacokinetic-pharmacodynamic models is very unlikely during drug development, it is essential that altered distribution, augmented renal clearance, and renal or hepatic dysfunction should be considered. Notably, the number of published studies involving microdialysis and intrapulmonary penetration of antibiotics has been limited and mainly involve beta-lactam agents, levofloxacin, and fosfomycin. Opportunities to measure in high-resolution effect site spatial pharmacokinetics (e.g. with MALDI-MSI or PET imaging) and in vivo continuous drug concentrations (e.g. with aptamer-based probes) now exist. Going forward these studies could be incorporated into antibiotic development programs for pneumonia in order to further increase the probability of candidate success. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

Science.gov (United States)

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

2017-09-01

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

Serum concentrations of psychotropic drugs in neonates as a PROgnOstic Factor for admission to the neonatology ward and withdrawal symptoms: PROOF-1.

Science.gov (United States)

Sparla, Shirley C A; Coppens, Hans; Evers, Inge M; Stramrood, Claire A I; Pasker-de Jong, Pieternel C M; van der Westerlaken, Monique M L; Hogeman, Paul H G; Malingré, Mirte M

2017-05-01

The aim is to determine whether serum drug concentrations obtained from the neonate's umbilical cord can be used as a prognostic factor for admission to the neonatology ward and the occurrence of withdrawal symptoms. A retrospective observational monocenter cohort study was carried out among pregnant women using psychotropic drugs and their baby. Binary logistic regression was used for the multivariate analysis. Of the 186 neonates included, 22.6% (n=42) were admitted to the neonatology ward, 6.5% (n=12) because of withdrawal. Among women with therapeutic concentrations of psychotropic medication, 22.0% (n=5) of the neonates had withdrawal symptoms. When comparing neonates with therapeutic versus undetectable drug concentrations, an odds ratio of 3.1 (95% confidence interval: 1.1-8.6) was found for admission to the neonatology ward and an odds ratio of 20.5 (95% confidence interval: 2.2-186.1) for the occurrence of withdrawal symptoms. Therapeutic concentrations of psychotropic drugs in neonates' umbilical cord blood correspond with higher odds for admission to the neonatology ward and the occurrence of withdrawal symptoms compared with neonates with undetectable drug concentrations. The measurement of drug concentrations in the neonate may contribute toward the general clinical assessment of the physician to predict the necessity of admission to the neonatology ward and the risk of withdrawal symptoms.

An inert 3D emulsification device for individual precipitation and concentration of amorphous drug nanoparticles.

Science.gov (United States)

Lorenz, T; Bojko, S; Bunjes, H; Dietzel, A

2018-02-13

Nanosizing increases the specific surface of drug particles, leading to faster dissolution inside the organism and improving the bioavailability of poorly water-soluble drugs. A novel approach for the preparation of drug nanoparticles in water using chemically inert microfluidic emulsification devices is presented in this paper. A lithographic fabrication sequence was established, allowing fabrication of intersecting and coaxial channels of different depths in glass as is required for 3D flow-focusing. Fenofibrate was used as a model for active pharmaceutical ingredients with very low water solubility in the experiments. It was dissolved in ethyl acetate and emulsified in water, as allowed by the 3D flow-focusing geometry. In the thread formation regime, the drug solution turned into monodisperse droplets of sizes down to below 1 μm. Fast supersaturation occurs individually in each droplet, as the disperse phase solvent progressively diffuses into the surrounding water. Liquid antisolvent precipitation results in highly monodisperse and amorphous nanoparticles of sizes down to 128 nm which can be precisely controlled by the continuous and disperse phase pressure. By comparing optically measured droplet sizes with particle sizes by dynamic light scattering, we could confirm that exactly one particle forms in every droplet. Furthermore, a downstream on-chip concentration allowed withdrawal of major volumes of only the continuous phase fluid which enabled an increase of particle concentration by up to 250 times.

Isoflurane minimum alveolar concentration reduction by fentanyl.

Science.gov (United States)

McEwan, A I; Smith, C; Dyar, O; Goodman, D; Smith, L R; Glass, P S

1993-05-01

Isoflurane is commonly combined with fentanyl during anesthesia. Because of hysteresis between plasma and effect site, bolus administration of fentanyl does not accurately describe the interaction between these drugs. The purpose of this study was to determine the MAC reduction of isoflurane by fentanyl when both drugs had reached steady biophase concentrations. Seventy-seven patients were randomly allocated to receive either no fentanyl or fentanyl at several predetermined plasma concentrations. Fentanyl was administered using a computer-assisted continuous infusion device. Patients were also randomly allocated to receive a predetermined steady state end-tidal concentration of isoflurane. Blood samples for fentanyl concentration were taken at 10 min after initiation of the infusion and before and immediately after skin incision. A minimum of 20 min was allowed between the start of the fentanyl infusion and skin incision. The reduction in the MAC of isoflurane by the measured fentanyl concentration was calculated using a maximum likelihood solution to a logistic regression model. There was an initial steep reduction in the MAC of isoflurane by fentanyl, with 3 ng/ml resulting in a 63% MAC reduction. A ceiling effect was observed with 10 ng/ml providing only a further 19% reduction in MAC. A 50% decrease in MAC was produced by a fentanyl concentration of 1.67 ng/ml. Defining the MAC reduction of isoflurane by all the opioids allows their more rational administration with inhalational anesthetics and provides a comparison of their relative anesthetic potencies.

Drug Concentration Thresholds Predictive of Therapy Failure and Death in Children With Tuberculosis: Bread Crumb Trails in Random Forests.

Science.gov (United States)

Swaminathan, Soumya; Pasipanodya, Jotam G; Ramachandran, Geetha; Hemanth Kumar, A K; Srivastava, Shashikant; Deshpande, Devyani; Nuermberger, Eric; Gumbo, Tawanda

2016-11-01

 The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown.  Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables.  Among the 143 children with known outcomes, there was high between-child variability of isoniazid, rifampin, and pyrazinamide concentrations: 110 (77%) completed therapy, 24 (17%) failed therapy, and 9 (6%) died. The main predictors of therapy failure or death were a pyrazinamide peak concentration <38.10 mg/L and rifampin peak concentration <3.01 mg/L. The relative risk of these poor outcomes below these peak concentration thresholds was 3.64 (95% confidence interval [CI], 2.28-5.83). Isoniazid had concentration-dependent antagonism with rifampin and pyrazinamide, with an adjusted odds ratio for therapy failure of 3.00 (95% CI, 2.08-4.33) in antagonism concentration range. In regard to death alone as an outcome, the same drug concentrations, plus z scores (indicators of malnutrition), and age <3 years, were highly ranked predictors. In children <3 years old, isoniazid 0- to 24-hour area under the concentration-time curve <11.95 mg/L × hour and/or rifampin peak <3.10 mg/L were the best predictors of therapy failure, with relative risk of 3.43 (95% CI, .99-11.82).  We have identified new antibiotic target concentrations, which are potential biomarkers associated with treatment failure and death in children with tuberculosis. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Towards a better prediction of peak concentration, volume of distribution and half-life after oral drug administration in man, using allometry.

Science.gov (United States)

Sinha, Vikash K; Vaarties, Karin; De Buck, Stefan S; Fenu, Luca A; Nijsen, Marjoleen; Gilissen, Ron A H J; Sanderson, Wendy; Van Uytsel, Kelly; Hoeben, Eva; Van Peer, Achiel; Mackie, Claire E; Smit, Johan W

2011-05-01

It is imperative that new drugs demonstrate adequate pharmacokinetic properties, allowing an optimal safety margin and convenient dosing regimens in clinical practice, which then lead to better patient compliance. Such pharmacokinetic properties include suitable peak (maximum) plasma drug concentration (C(max)), area under the plasma concentration-time curve (AUC) and a suitable half-life (t(½)). The C(max) and t(½) following oral drug administration are functions of the oral clearance (CL/F) and apparent volume of distribution during the terminal phase by the oral route (V(z)/F), each of which may be predicted and combined to estimate C(max) and t(½). Allometric scaling is a widely used methodology in the pharmaceutical industry to predict human pharmacokinetic parameters such as clearance and volume of distribution. In our previous published work, we have evaluated the use of allometry for prediction of CL/F and AUC. In this paper we describe the evaluation of different allometric scaling approaches for the prediction of C(max), V(z)/F and t(½) after oral drug administration in man. Twenty-nine compounds developed at Janssen Research and Development (a division of Janssen Pharmaceutica NV), covering a wide range of physicochemical and pharmacokinetic properties, were selected. The C(max) following oral dosing of a compound was predicted using (i) simple allometry alone; (ii) simple allometry along with correction factors such as plasma protein binding (PPB), maximum life-span potential or brain weight (reverse rule of exponents, unbound C(max) approach); and (iii) an indirect approach using allometrically predicted CL/F and V(z)/F and absorption rate constant (k(a)). The k(a) was estimated from (i) in vivo pharmacokinetic experiments in preclinical species; and (ii) predicted effective permeability in man (P(eff)), using a Caco-2 permeability assay. The V(z)/F was predicted using allometric scaling with or without PPB correction. The t(½) was estimated from

Polar drug residues in sewage and natural waters in the state of Rio de Janeiro, Brazil.

Science.gov (United States)

Stumpf, M; Ternes, T A; Wilken, R D; Rodrigues, S V; Baumann, W

1999-01-12

The drug residues of lipid regulators, anti-inflammatories and some drug metabolites have been detected in raw sewage, treated waste water and river water in the state of Rio de Janeiro, Brazil. These residues are mainly derived from humans via excretion. The median concentrations in the effluents of sewage treatment plants (STPs) of most drugs investigated in this study ranged from 0.1 to 1 microgram/l. The removal rates of individual drugs during passage through a Brazilian STP varied from 12 to 90%. As a consequence of the incomplete removal of these residues during passage through a STP, rivers were also found to be contaminated. Median concentrations ranged from between 0.02 and 0.04 microgram/l in river water, whereas the maximum values were observed to be up to 0.5 microgram/l.

Prevalence and sunlight photolysis of controlled and chemotherapeutic drugs in aqueous environments

International Nuclear Information System (INIS)

Lin, Angela Yu-Chen; Lin, Yen-Ching; Lee, Wan-Ning

2014-01-01

This study addresses the occurrences and natural fates of chemotherapeutics and controlled drugs when found together in hospital effluents and surface waters. The results revealed the presence of 11 out of 16 drugs in hospital effluents, and the maximum detected concentrations were at the μg L −1 level in the hospital effluents and the ng L −1 level in surface waters. The highest concentrations corresponded to meperidine, morphine, 5-fluorouracil and cyclophosphamide. The sunlight photolysis of the target compounds was investigated, and the results indicated that morphine and codeine can be significantly attenuated, with half-lives of 0.27 and 2.5 h, respectively, in natural waters. Photolysis can lower the detected environmental concentrations, also lowering the estimated environmental risks of the target drugs to human health. Nevertheless, 5-fluorouracil and codeine were found to have a high risk quotient (RQ), demonstrating the high risks of directly releasing hospital wastewater into the environment. - Highlights: • High occurrence of chemotherapeutics and controlled substances in aqueous systems. • Photolysis lowers the detected concentrations of morphine and codeine. • 5-fluorouracil and codeine in hospital effluents have high risk quotients. - Chemotherapeutics and controlled drugs occur at significant levels in hospital effluents and surface waters. Natural sunlight photolysis reduces their environmental occurrence

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

NARCIS (Netherlands)

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

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

Does the placebo effect modulate drug bioavailability? Randomized cross-over studies of three drugs.

Science.gov (United States)

Hammami, Muhammad M; Yusuf, Ahmed; Shire, Faduma S; Hussein, Rajaa; Al-Swayeh, Reem

2017-05-23

Medication effect is the sum of its drug, placebo, and drug*placebo interaction effects. It is conceivable that the interaction effect involves modulating drug bioavailability; it was previously observed that being aware of caffeine ingestion may prolong caffeine plasma half-life. This study was set to evaluate such concept using different drugs. Balanced single-dose, two-period, two-group, cross-over design was used to compare the pharmacokinetics of oral cephalexin, ibuprofen, and paracetamol, each described by its name (overt) or as placebo (covert). Volunteers and study coordinators were deceived as to study aim. Drug concentrations were determined blindly by in-house, high performance liquid chromatography assays. Terminal-elimination half-life (t ½ ) (primary outcome), maximum concentration (C max ), C max first time (T max ), terminal-elimination-rate constant (λ), area-under-the-concentration-time-curve, to last measured concentration (AUC T ), extrapolated to infinity (AUC I ), or to T max of overt drug (AUC Overttmax ), and C max /AUC I were calculated blindly using standard non-compartmental method. Covert-vs-overt effect on drug pharmacokinetics was evaluated by analysis-of-variance (ANOVA, primary analysis), 90% confidence interval (CI) using the 80.00-125.00% bioequivalence range, and percentage of individual pharmacokinetic covert/overt ratios that are outside the +25% range. Fifty, 30, and 50 healthy volunteers (18%, 10%, and 6% females, mean (SD) age 30.8 (6.2), 31.4 (6.6), and 31.2 (5.4) years) participated in 3 studies on cephalexin, ibuprofen, and paracetamol, respectively. Withdrawal rate was 4%, 0%, and 4%, respectively. Eighteen blood samples were obtained over 6, 10, and 14 h in each study period of the three drugs, respectively. ANOVA showed no significant difference in any pharmacokinetic parameter for any of the drugs. The 90% CIs for AUC T , AUC I , C max , AUC Overttmax , and C max /AUC I were within the bioequivalence range, except

Maximum permissible concentration of radon {sup 222}Rn in air; La concentration maximale admissible du radon 222 dans l'air

Energy Technology Data Exchange (ETDEWEB)

Hamard, J; Beau, P G; Ergas, A [Commissariat a l' Energie Atomique, Fontenay-aux-Roses (France). Centre d' Etudes Nucleaires, departement de la protection sanitaire, service d' hygiene atomique

1968-09-01

In order to verify the validity of the values proposed for the maximum permissible concentration of {sup 222}Rn in air, one can either approach the problem: - by epidemiological studies tending to determine the relation dose-effect both quantitatively and qualitatively; - or by choosing a lung model and clearance constants allowing a more accurate determination of the delivered dose and the localisation of the more severely irradiated portions of the bronchial tree. The radon MPC have been calculated using the model and the respiration constants set up by the I.C.R.P. Task Group on Lung dynamics. Two cases have been considered, i.e. when the radon daughter products behave as soluble materials and as insoluble ones. The values which have been found have been compared with those given up to now by several national and international bodies. (authors) [French] Deux voies d'approche peuvent etre empruntees pour verifier la validite des valeurs proposees pour la concentration maximale admissible du radon 222 dans l'air: - etudes epidemiologiques tendant a preciser qualitativement et quantitativement la relation dose-effet; - choix d'un modele pulmonaire et de constantes d'epuration permettant une determination plus precise de la dose delivree et la localisation des segments de l'arbre pulmonaire les plus irradies. Les auteurs ont utilise pour le calcul de la CMA du radon le modele et les constantes respiratoires proposees par le Task Group on Lungs dynamics de la C.I.P.R. On a pris en consideration le cas ou les descendants du radon se comportent comme des substances solubles et celui ou ils se comportent comme des substances insolubles. Les valeurs trouvees sont comparees a celles proposees jusqu'alors par divers organismes nationaux et internationaux. (auteurs)

Effects of drugs in subtoxic concentrations on the metabolic fluxes in human hepatoma cell line Hep G2

International Nuclear Information System (INIS)

Niklas, Jens; Noor, Fozia; Heinzle, Elmar

2009-01-01

Commonly used cytotoxicity assays assess the toxicity of a compound by measuring certain parameters which directly or indirectly correlate to the viability of the cells. However, the effects of a given compound at concentrations considerably below EC 50 values are usually not evaluated. These subtoxic effects are difficult to identify but may eventually cause severe and costly long term problems such as idiosyncratic hepatotoxicity. We determined the toxicity of three hepatotoxic compounds, namely amiodarone, diclofenac and tacrine on the human hepatoma cell line Hep G2 using an online kinetic respiration assay and analysed the effects of subtoxic concentrations of these drugs on the cellular metabolism by using metabolic flux analysis. Several changes in the metabolism could be detected upon exposure to subtoxic concentrations of the test compounds. Upon exposure to diclofenac and tacrine an increase in the TCA-cycle activity was observed which could be a signature of an uncoupling of the oxidative phosphorylation. The results indicate that metabolic flux analysis could serve as an invaluable novel tool for the investigation of the effects of drugs. The described methodology enables tracking the toxicity of compounds dynamically using the respiration assay in a range of concentrations and the metabolic flux analysis permits interesting insights into the changes in the central metabolism of the cell upon exposure to drugs.

Comparison of Active Drug Concentrations in the Pulmonary Epithelial Lining Fluid and Interstitial Fluid of Calves Injected with Enrofloxacin, Florfenicol, Ceftiofur, or Tulathromycin

Science.gov (United States)

Foster, Derek M.; Martin, Luke G.; Papich, Mark G.

2016-01-01

Bacterial pneumonia is the most common reason for parenteral antimicrobial administration to beef cattle in the United States. Yet there is little information describing the antimicrobial concentrations at the site of action. The objective of this study was to compare the active drug concentrations in the pulmonary epithelial lining fluid and interstitial fluid of four antimicrobials commonly used in cattle. After injection, plasma, interstitial fluid, and pulmonary epithelial lining fluid concentrations and protein binding were measured to determine the plasma pharmacokinetics of each drug. A cross-over design with six calves per drug was used. Following sample collection and drug analysis, pharmacokinetic calculations were performed. For enrofloxacin and metabolite ciprofloxacin, the interstitial fluid concentration was 52% and 78% of the plasma concentration, while pulmonary fluid concentrations was 24% and 40% of the plasma concentration, respectively. The pulmonary concentrations (enrofloxacin + ciprofloxacin combined) exceeded the MIC90 of 0.06 μg/mL at 48 hours after administration. For florfenicol, the interstitial fluid concentration was almost 98% of the plasma concentration, and the pulmonary concentrations were over 200% of the plasma concentrations, exceeding the breakpoint (≤ 2 μg/mL), and the MIC90 for Mannheimia haemolytica (1.0 μg/mL) for the duration of the study. For ceftiofur, penetration to the interstitial fluid was only 5% of the plasma concentration. Pulmonary epithelial lining fluid concentration represented 40% of the plasma concentration. Airway concentrations exceeded the MIC breakpoint for susceptible respiratory pathogens (≤ 2 μg/mL) for a short time at 48 hours after administration. The plasma and interstitial fluid concentrations of tulathromcyin were lower than the concentrations in pulmonary fluid throughout the study. The bronchial concentrations were higher than the plasma or interstitial concentrations, with over 900

Comparison of Active Drug Concentrations in the Pulmonary Epithelial Lining Fluid and Interstitial Fluid of Calves Injected with Enrofloxacin, Florfenicol, Ceftiofur, or Tulathromycin.

Directory of Open Access Journals (Sweden)

Derek M Foster

Full Text Available Bacterial pneumonia is the most common reason for parenteral antimicrobial administration to beef cattle in the United States. Yet there is little information describing the antimicrobial concentrations at the site of action. The objective of this study was to compare the active drug concentrations in the pulmonary epithelial lining fluid and interstitial fluid of four antimicrobials commonly used in cattle. After injection, plasma, interstitial fluid, and pulmonary epithelial lining fluid concentrations and protein binding were measured to determine the plasma pharmacokinetics of each drug. A cross-over design with six calves per drug was used. Following sample collection and drug analysis, pharmacokinetic calculations were performed. For enrofloxacin and metabolite ciprofloxacin, the interstitial fluid concentration was 52% and 78% of the plasma concentration, while pulmonary fluid concentrations was 24% and 40% of the plasma concentration, respectively. The pulmonary concentrations (enrofloxacin + ciprofloxacin combined exceeded the MIC90 of 0.06 μg/mL at 48 hours after administration. For florfenicol, the interstitial fluid concentration was almost 98% of the plasma concentration, and the pulmonary concentrations were over 200% of the plasma concentrations, exceeding the breakpoint (≤ 2 μg/mL, and the MIC90 for Mannheimia haemolytica (1.0 μg/mL for the duration of the study. For ceftiofur, penetration to the interstitial fluid was only 5% of the plasma concentration. Pulmonary epithelial lining fluid concentration represented 40% of the plasma concentration. Airway concentrations exceeded the MIC breakpoint for susceptible respiratory pathogens (≤ 2 μg/mL for a short time at 48 hours after administration. The plasma and interstitial fluid concentrations of tulathromcyin were lower than the concentrations in pulmonary fluid throughout the study. The bronchial concentrations were higher than the plasma or interstitial concentrations

Parallel monitoring of plasma and intraluminal drug concentrations in man after oral administration of fosamprenavir in the fasted and fed state.

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Brouwers, Joachim; Tack, Jan; Augustijns, Patrick

2007-10-01

The purpose of this study was to explore the feasibility of linking the pharmacokinetic profile of a drug with its gastrointestinal behavior by simultaneously monitoring plasma and intraluminal drug concentrations. Fosamprenavir, a phosphate ester prodrug of the poorly water-soluble HIV-inhibitor amprenavir, was selected as model compound. A single tablet of fosamprenavir (Telzir) was administered to 5 volunteers in the fasted and fed state (simulated by intake of a nutritional drink). Gastric and duodenal fluids were aspirated in function of time and characterized with respect to the concentration of (fos)amprenavir, inorganic phosphate and pH. In parallel, blood samples were collected and analyzed for amprenavir. The observed plasma concentration-time profiles suggested a food-induced delay in the absorption of amprenavir: in the fed state, mean tmax increased by more than 150 min compared to the fasted state. A similar delay was seen in the duodenal appearance of fosamprenavir (concentrations in mM-range) and, after dephosphorylation, amprenavir (concentrations below 160 microM). This observation could be related to the behavior of fosamprenavir in the stomach. In the fasted state, gastric dissolution of fosamprenavir started immediately, resulting in a Cmax of 4 +/- 2 mM after 43 +/- 15 min; however, in the fed state, the fosamprenavir concentration remained below 20 microM for the first 90 min after drug intake. The postponed gastric dissolution may be attributed to a food-induced delay in tablet disintegration. For the first time, the pharmacokinetic profile of a drug was monitored in parallel with its gastrointestinal concentrations. The observed food effect in the plasma concentration-time profile of amprenavir after intake of its phosphate ester prodrug could be related to a food-induced delay in gastric dissolution of fosamprenavir.

Effect of Chinese traditional medicine anti-fatigue prescription on the concentration of the serum testosterone and cortisol in male rats under stress of maximum intensive training

International Nuclear Information System (INIS)

Dong Ling; Si Xulan

2008-01-01

Objective: To study the effect of chinese traditional medicine anti-fatigue prescription on the concentration of the serum testosterone (T) and cortisol (C) in male rats under the stress of maximum intensive training. Methods: Wistar male rat models of stress under maximum intensity training were established (n=40) and half of them were treated with Chinese traditional medicine anti-fatigue prescription twenty undisturbed rats served as controls. Testosterone and cortisol serum levels were determined with RIA at the end of the seven weeks' experiment. Results: Maximum intensive training would cause the level of the serum testosterone lowered, the concentration of the cortisol elevated and the ratio of T/C reduced. The serum T levels and T/C ratio were significantly lower and cortisol levels significantly higher in the untreated models than those in the treated models and controls (P<0.01). The levels of the two hormones were markedly corrected in the treated models with no significantly differences from those in the controls. However, the T/C ratio was still significantly lower than that in the controls (P <0.05) due to a relatively slightly greater degree of reduction of T levels. Conclusion: Anti-fatigue prescription can not only promote the recovery of fatigue after the maximum intensive training but also strengthen the anabolism of the rats. (authors)

[Scientific basis in the setting of residue limits for veterinary drugs in food of animal origin taking into account the presence of their metabolites].

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Mitsumori, K

1993-01-01

Maximum residue level (MRL) for veterinary drugs in food of animal origin has been proposed by FAO/WHO, as a new evaluation procedure taking into account the presence of metabolites for the regulation of veterinary drug residues. The MRL is the maximum concentration of residue resulting from the use of a veterinary drug that is recommended to be legally permitted as acceptable in a food. It is established from the Acceptable Daily Intake (ADI) obtained from the data of toxicological studies, the residue concentration of the drug when used according to good practice in the use of veterinary drugs, and the lowest level consistent with the practical analytical methods available for routine residue analysis. Among the veterinary drugs, some chemicals contain a large amount of bound residues that are neither extractable from tissues by the analytical method identical with that used in parent chemicals. Especially, the bioavailable residues which are probably absorbed when the food is ingested are of great toxicological concern. In this case, the FAO/WHO recommends that the MRL can be established after the calculation of daily intake of residues of toxicological concern by the addition of both the extractable and bioavailable bound residues.

42 CFR 50.504 - Allowable cost of drugs.

Science.gov (United States)

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false Allowable cost of drugs. 50.504 Section 50.504... APPLICABILITY Maximum Allowable Cost for Drugs § 50.504 Allowable cost of drugs. (a) The maximum amount which may be expended from program funds for the acquisition of any drug shall be the lowest of (1) The...

Comparison of changes in the extracellular concentration of noradrenaline in rat frontal cortex induced by sibutramine or d-amphetamine: modulation by α2-adrenoceptors

Science.gov (United States)

Wortley, K E; Hughes, Z A; Heal, D J; Stanford, S C

1999-01-01

The effects of sibutramine (0.25–10 mg kg−1, i.p.) on extracellular noradrenaline concentration in the frontal cortex of halothane-anaesthetized rats were compared with those of d-amphetamine (1–3 mg kg−1, i.p.) using in vivo microdialysis. The role of presynaptic α2-adrenoceptors in modulating the effects of these drugs on extracellular noradrenaline concentration were also investigated by pretreating rats with the selective α2-adrenoceptor antagonist, RX821002.Sibutramine induced a gradual and sustained increase in extracellular noradrenaline concentration. The dose-response relationship was described by a bell-shaped curve with a maximum effect at 0.5 mg kg−1. In contrast, d-amphetamine induced a rapid increase in extracellular noradrenaline concentration, the magnitude of which paralleled drug dose.Pretreatment with the α2-adrenoceptor antagonist, RX821002 (dose 3 mg kg−1, i.p.) increased by 5 fold the accumulation of extracellular noradrenaline caused by sibutramine (10 mg kg−1) and reduced the latency of sibutramine to reach its maximum effect from 144–56 min.RX821002-pretreatment increased by only 2.5 fold the increase in extracellular noradrenaline concentration caused by d-amphetamine alone (10 mg kg−1) and had no effect on the latency to reach maximum.These findings support evidence that sibutramine acts as a noradrenaline uptake inhibitor in vivo and that the effects of this drug are blunted by indirect activation of presynaptic α2-adreno-ceptors. In contrast, the rapid increase in extracellular noradrenaline concentration induced by d-amphetamine is consistent with this being mainly due to an increase in Ca2+-independent release of noradrenaline. PMID:10482917

Food-Drug Interactions

Directory of Open Access Journals (Sweden)

Arshad Yar Khan

2011-03-01

Full Text Available The effect of drug on a person may be different than expected because that drug interacts with another drug the person is taking (drug-drug interaction, food, beverages, dietary supplements the person is consuming (drug-nutrient/food interaction or another disease the person has (drug-disease interaction. A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. These interactions may occur out of accidental misuse or due to lack of knowledge about the active ingredients involved in the relevant substances. Regarding food-drug interactions physicians and pharmacists recognize that some foods and drugs, when taken simultaneously, can alter the body's ability to utilize a particular food or drug, or cause serious side effects. Clinically significant drug interactions, which pose potential harm to the patient, may result from changes in pharmaceutical, pharmacokinetic, or pharmacodynamic properties. Some may be taken advantage of, to the benefit of patients, but more commonly drug interactions result in adverse drug events. Therefore it is advisable for patients to follow the physician and doctors instructions to obtain maximum benefits with least fooddrug interactions. The literature survey was conducted by extracting data from different review and original articles on general or specific drug interactions with food. This review gives information about various interactions between different foods and drugs and will help physicians and pharmacists prescribe drugs cautiously with only suitable food supplement to get maximum benefit for the patient.

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

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

2004-09-01

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

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

Science.gov (United States)

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

2012-01-01

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

Monoglyceride-based self-assembling copolymers as carriers for poorly water-soluble drugs.

Science.gov (United States)

Rouxhet, L; Dinguizli, M; Latere Dwan'isa, J P; Ould-Ouali, L; Twaddle, P; Nathan, A; Brewster, M E; Rosenblatt, J; Ariën, A; Préat, V

2009-12-01

To develop self-assembling polymers forming polymeric micelles and increasing the solubility of poorly soluble drugs, amphiphilic polymers containing a hydrophilic PEG moiety and a hydrophobic moiety derived from monoglycerides and polyethers were designed. The biodegradable copolymers were obtained via a polycondensation reaction of polyethylene glycol (PEG), monooleylglyceride (MOG) and succinic anhydride (SA). Polymers with molecular weight below 10,000 g/mol containing a minimum of 40 mol% PEG and a maximum of 10 mol% MOG self-assembled spontaneously in aqueous media upon gentle mixing. They formed particles with a diameter of 10 nm although some aggregation was evident. The critical micellar concentration varied between 3x10(-4) and 4x10(-3) g/ml, depending on the polymer. The cloud point (> or = 66 degrees C) and flocculation point (> or = 0.89 M) increased with the PEG chain length. At a 1% concentration, the polymers increased the solubility of poorly water-soluble drug candidates up to 500-fold. Drug solubility increased as a function of the polymer concentration. HPMC capsules filled with these polymers disintegrated and released model drugs rapidly. Polymer with long PEG chains had a lower cytotoxicity (MTT test) on Caco-2 cells. All of these data suggest that the object polymers, in particular PEG1000/MOG/SA (45/5/50) might be potential candidates for improving the oral biopharmaceutical performance of poorly soluble drugs.

SU-F-19A-08: Optimal Time Release Schedule of In-Situ Drug Release During Permanent Prostate Brachytherapy

International Nuclear Information System (INIS)

Cormack, R; Ngwa, W; Makrigiorgos, G; Tangutoori, S; Rajiv, K; Sridhar, S

2014-01-01

Purpose: Permanent prostate brachytherapy spacers can be used to deliver sustained doses of radiosentitizing drug directly to the target, in order to enhance the radiation effect. Implantable nanoplatforms for chemo-radiation therapy (INCeRTs) have a maximum drug capacity and can be engineered to control the drug release schedule. The optimal schedule for sensitization during continuous low dose rate irradiation is unknown. This work studies the optimal release schedule of drug for both traditional sensitizers, and those that work by suppressing DNA repair processes. Methods: Six brachytherapy treatment plans were used to model the anatomy, implant geometry and calculate the spatial distribution of radiation dose and drug concentrations for a range of drug diffusion parameters. Three state partial differential equations (cells healthy, damaged or dead) modeled the effect of continuous radiation (radiosensitivities α,β) and cellular repair (time tr) on a cell population. Radiosensitization was modeled as concentration dependent change in α,β or tr which with variable duration under the constraint of fixed total drug release. Average cell kill was used to measure effectiveness. Sensitization by means of both enhanced damage and reduced repair were studied. Results: Optimal release duration is dependent on the concentration of radiosensitizer compared to the saturation concentration (csat) above which additional sensitization does not occur. Long duration drug release when enhancing α or β maximizes cell death when drug concentrations are generally over csat. Short term release is optimal for concentrations below saturation. Sensitization by suppressing repair has a similar though less distinct trend that is more affected by the radiation dose distribution. Conclusion: Models of sustained local radiosensitization show potential to increase the effectiveness of radiation in permanent prostate brachytherapy. INCeRTs with high drug capacity produce the greatest

Inhibitory effects of drugs on the metabolic activity of mouse and human aldehyde oxidases and influence on drug-drug interactions.

Science.gov (United States)

Takaoka, Naoki; Sanoh, Seigo; Okuda, Katsuhiro; Kotake, Yaichiro; Sugahara, Go; Yanagi, Ami; Ishida, Yuji; Tateno, Chise; Tayama, Yoshitaka; Sugihara, Kazumi; Kitamura, Shigeyuki; Kurosaki, Mami; Terao, Mineko; Garattini, Enrico; Ohta, Shigeru

2018-04-17

As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug-drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC 50 values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O 6 -benzylguanine as substrates. 17β-Estradiol, menadione, norharmane and raloxifene exhibited marked differences in inhibitory effects between the human and mouse AOX isoforms when the phthalazine substrate was used. Some of the compounds tested exhibited substrate-dependent differences in their inhibitory effects. Docking simulations with human AOX1 and mouse AOX3 were conducted for six representative inhibitors. The rank order of the minimum binding energy reflected the order of the corresponding IC 50 values. We also evaluated the potential DDI between an AOX substrate (O 6 -benzylguanine) and an inhibitor (hydralazine) using chimeric mice with humanized livers. Pretreatment of hydralazine increased the maximum plasma concentration (C max ) and the area under the plasma concentration-time curve (AUC 0-24 ) of O 6 -benzylguanine compared to single administration. Our in vitro data indicate species-specific and substrate-dependent differences in the inhibitory effects on AOX activity. Our in vivo data demonstrate the existence of a DDI which may be of relevance in the clinical context. Copyright © 2018 Elsevier Inc. All rights reserved.

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

Science.gov (United States)

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

2012-02-01

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

Fixed drug eruption: topical provocation and subsequent phenomena

Energy Technology Data Exchange (ETDEWEB)

Mahboob, A; Haroon, T S [Shaikh Zayed FPGMI, Lahore (Pakistan). Dept. of Dermatology; Haroon, T S [King Edward Medical Univ., Lahore (Pakistan). Dept. of Dematology; Iqbal, Z; Iqbal, F [Shaikh Zayed FPGMI, Lahore (Pakistan). Dept. of Medicine

2006-12-15

To determine the usefulness of topical provocation in detecting the incriminated drug causing fixed eruption. Three hundred and five, clinically diagnosed cases of Fixed Drug Eruption (FDE) of either gender and of any age were subjected to topical provocation with different drugs by using concentration of 1% (n=203), 2% (n=210) and 5% (n=235) in white soft paraffin. Drug ointment of one strength was applied one at a time on normal skin of flexor surface of right or left forearm. The effects of tests on involved and uninvolved skin were observed for 48 hours. The changes in lesions like erythema, hyperpigmentation, itching, burning or appearance of new lesion were considered a positive response. In case of no change, the patients (n=5) were subjected to oral provocation test, by giving half to full therapeutic dose of the suspected drug depending upon the severity of the initial attack. A patient who exhibited see-sawing phenomenon with 5% metamizole TPT was given oral challenge with same drug. Control topical tests were repeated in equal number of normal persons with various drug ointments and in patients of FDE with white soft paraffin on normal and affected skin. One hundred and thirty-seven patients were males and one hundred and sixty-eight patients were females. Maximum number of patients belonged to third decade. With 1% drug preparations 12 out of 316, with 2% drug preparations 28 out of 422 and with 5% drug preparations, 312 out of 523 TPTs were positive. The comparison revealed a highly significant association (Chi-square 448.1 and p<0.000) among various strengths of preparations and positive response. Sulphamethoxazole was found to be the most commonly incriminated cause of FDE applied in 5% concentration yielded sensitivity rate of 91% compared to 4% with lower concentrations. Positive patch test was also observed with oxytetracycline. Five patients who were given oral provocation with different drugs were found to be positive to tinidazole, dapsone

Fixed drug eruption: topical provocation and subsequent phenomena

International Nuclear Information System (INIS)

Mahboob, A.; Haroon, T.S.; Haroon, T.S.; Iqbal, Z.; Iqbal, F.

2006-01-01

To determine the usefulness of topical provocation in detecting the incriminated drug causing fixed eruption. Three hundred and five, clinically diagnosed cases of Fixed Drug Eruption (FDE) of either gender and of any age were subjected to topical provocation with different drugs by using concentration of 1% (n=203), 2% (n=210) and 5% (n=235) in white soft paraffin. Drug ointment of one strength was applied one at a time on normal skin of flexor surface of right or left forearm. The effects of tests on involved and uninvolved skin were observed for 48 hours. The changes in lesions like erythema, hyperpigmentation, itching, burning or appearance of new lesion were considered a positive response. In case of no change, the patients (n=5) were subjected to oral provocation test, by giving half to full therapeutic dose of the suspected drug depending upon the severity of the initial attack. A patient who exhibited see-sawing phenomenon with 5% metamizole TPT was given oral challenge with same drug. Control topical tests were repeated in equal number of normal persons with various drug ointments and in patients of FDE with white soft paraffin on normal and affected skin. One hundred and thirty-seven patients were males and one hundred and sixty-eight patients were females. Maximum number of patients belonged to third decade. With 1% drug preparations 12 out of 316, with 2% drug preparations 28 out of 422 and with 5% drug preparations, 312 out of 523 TPTs were positive. The comparison revealed a highly significant association (Chi-square 448.1 and p<0.000) among various strengths of preparations and positive response. Sulphamethoxazole was found to be the most commonly incriminated cause of FDE applied in 5% concentration yielded sensitivity rate of 91% compared to 4% with lower concentrations. Positive patch test was also observed with oxytetracycline. Five patients who were given oral provocation with different drugs were found to be positive to tinidazole, dapsone

MAK and BAT values list 2017. Maximum permissible concentrations at the place of work and biological tolerance values for working materials; MAK- und BAT-Werte-Liste 2017. Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte

Energy Technology Data Exchange (ETDEWEB)

NONE

2017-08-01

The MAK and BAT values list 2017 includes the maximum permissible concentrations at the place of work and biological tolerance values for working materials. The following working materials are covered: carcinogenic working materials, sensitizing materials and aerosols. The report discusses the restriction of exposure peaks, skin resorption, MAK (maximum working place concentration) values during pregnancy, germ cell mutagens and specific working materials. Importance and application of BAT (biological working material tolerance) values, list of materials, carcinogens, biological guide values and reference values are also included.

Usefulness of saliva for measurement of 3,4-methylenedioxymethamphetamine and its metabolites: correlation with plasma drug concentrations and effect of salivary pH.

Science.gov (United States)

Navarro, M; Pichini, S; Farré, M; Ortuño, J; Roset, P N; Segura, J; de la Torre, R

2001-10-01

Saliva is an alternative biologic matrix for drugs-of-abuse testing that offers the advantages of noninvasive, rapid, and easy sampling. We studied the excretion profile of 3,4-methylenedioxymethamphetamine (MDMA) and its metabolites in both saliva and plasma, as well the effect of the drug on salivary pH. Saliva and plasma samples were obtained from eight healthy MDMA consumers after ingestion of a single 100-mg dose of the drug. Concentrations of MDMA and its main metabolites, 3,4-methylenedioxyamphetamine (MDA) and 4-hydroxy-3-methoxymethamphetamine (HMMA), in saliva and plasma were measured by gas chromatography-mass spectrometry. Apparent pharmacokinetic parameters for MDMA in saliva were estimated, and the saliva-to-plasma ratio at each time interval was calculated and correlated with salivary pH. MDMA, MDA, and HMMA were detected in saliva. Salivary concentrations of MDMA were 1728.9-6510.6 microg/L and peaked at 1.5 h after drug intake. This was followed by a progressive decrease, with a mean concentration of 126.2 microg/L at 24 h. The saliva-to-plasma ratio was 32.3-1.2, with a peak of 18.1 at 1.5 h after drug administration. Salivary pH seemed to be affected by MDMA administration; pH values decreased by 0.6 units (mean pH values of 6.9 and 6.8 at 1.5 and 4 h after drug administration vs predose pH of 7.4). Measurement of MDMA in saliva is a valuable alternative to determination of plasma drug concentrations in both clinical and toxicologic studies. On-site testing is also facilitated by noninvasive and rapid collection of salivary specimens.

Spatiotemporal modeling of PM2.5 concentrations at the national scale combining land use regression and Bayesian maximum entropy in China.

Science.gov (United States)

Chen, Li; Gao, Shuang; Zhang, Hui; Sun, Yanling; Ma, Zhenxing; Vedal, Sverre; Mao, Jian; Bai, Zhipeng

2018-05-03

Concentrations of particulate matter with aerodynamic diameter Bayesian Maximum Entropy (BME) interpolation of the LUR space-time residuals were developed to estimate the PM 2.5 concentrations on a national scale in China. This hybrid model could potentially provide more valid predictions than a commonly-used LUR model. The LUR/BME model had good performance characteristics, with R 2  = 0.82 and root mean square error (RMSE) of 4.6 μg/m 3 . Prediction errors of the LUR/BME model were reduced by incorporating soft data accounting for data uncertainty, with the R 2 increasing by 6%. The performance of LUR/BME is better than OK/BME. The LUR/BME model is the most accurate fine spatial scale PM 2.5 model developed to date for China. Copyright © 2018. Published by Elsevier Ltd.

Applicability of a Single Time Point Strategy for the Prediction of Area Under the Concentration Curve of Linezolid in Patients

DEFF Research Database (Denmark)

Srinivas, Nuggehally R; Syed, Muzeeb

2016-01-01

Background and Objectives: Linezolid, a oxazolidinone, was the first in class to be approved for the treatment of bacterial infections arising from both susceptible and resistant strains of Gram-positive bacteria. Since overt exposure of linezolid may precipitate serious toxicity issues......, therapeutic drug monitoring (TDM) may be required in certain situations, especially in patients who are prescribed other co-medications. Methods: Using appropriate oral pharmacokinetic data (single dose and steady state) for linezolid, both maximum plasma drug concentration (Cmax) versus area under the plasma...... concentration–time curve (AUC) and minimum plasma drug concentration (Cmin) versus AUC relationship was established by linear regression models. The predictions of the AUC values were performed using published mean/median Cmax or Cmin data and appropriate regression lines. The quotient of observed and predicted...

Prevalence of alcohol and other drugs and the concentrations in blood of drivers killed in road traffic crashes in Sweden.

Science.gov (United States)

Ahlner, Johan; Holmgren, Anita; Jones, Alan Wayne

2014-03-01

Drunk or drug-impaired drivers represent a major public health and societal problem worldwide. Because over 95% of drivers killed on the roads in Sweden are autopsied, reliable information is available about the use of alcohol and/or other drug before the crash. This retrospective 4-year study (2008-2011) used a forensic toxicology database (TOXBASE) to evaluate the concentrations of alcohol and other drugs in blood samples from drivers killed in road-traffic crashes. The mean age of all victims (N = 895) was 48 ± 20 years, and the majority were male (86%). In 504 drivers (56%), the results of toxicological analysis were negative and these victims were older; mean age (± SD) 47 ± 20 years, than alcohol positive cases (35 ± 14 years) and illicit drug users (34 ± 15 years). In 21% of fatalities, blood-alcohol concentration (BAC) was above the statutory limit for driving (0.2 g/L), although the median BAC was appreciably higher (1.72 g/L). Illicit drugs (mainly amphetamine and cannabis) were identified in ~7% of victims, either alone (2.5%), together with alcohol (1.8%) or a prescription drug (2%). The psychoactive prescription drugs identified were mainly benzodiazepines, z-hypnotics and tramadol, which were found in the blood of 7.6% of crash victims. The high median BAC in fatally-injured drivers speaks strongly towards alcohol-induced impairment as being responsible for the crash. Compared with alcohol, the prevalence of illicit and psychoactive prescription drugs was fairly low despite a dramatic increase in the number of drug-impaired drivers arrested by the police after a zero-tolerance law was introduced in 1999.

Use of homeopathic drugs in combination with fertilizers for the control of root rot fungi

International Nuclear Information System (INIS)

Hanif, A.; Dawar, S.

2015-01-01

This study was conducted to evaluate the fungicidal effectiveness of homeopathic drugs in combination with fertilizers on the growth production and controlling of root rot fungi. Seeds treated with homeopathic drugs in addition of phosphorous and nitrogen fertilizers as soil amendment showed significant inhibitory effect on fungal growth as well as improved the plant growth. Remarkable control of root infecting fungi was shown by the seeds treated with Thuja occidentalis and Arnica montana at rate of 75 percentage v/v concentration and soil amended with urea at rate of 0.1 percentage w/w but greater increased in plant growth was observed by urea at rate of 0.01 percentage in the tested plants viz. mung bean, mash bean, sunflower and okra. Whereas, when A. montana and T. occidentalis at rate of 75 percentage v/v concentration along with the addition of DAP at rate of 0.01 and 0.1 percentage w/w respectively showed maximum suppression of Fusarium spp, R. solani and M. phaseolina and enhanced the plant height and weight followed by A. montana and T. occidentalis at rate of 50 percentage v/v concentration respectively showed a maximum control of root rot fungi and also strengthened the crop plant for better growth. (author)

Selection of suitable mineral acid and its concentration for biphasic dilute acid hydrolysis of the sodium dithionite delignified Prosopis juliflora to hydrolyze maximum holocellulose.

Science.gov (United States)

Naseeruddin, Shaik; Desai, Suseelendra; Venkateswar Rao, L

2016-02-01

Two grams of delignified substrate at 10% (w/v) level was subjected to biphasic dilute acid hydrolysis using phosphoric acid, hydrochloric acid and sulfuric acid separately at 110 °C for 10 min in phase-I and 121 °C for 15 min in phase-II. Combinations of acid concentrations in two phases were varied for maximum holocellulose hydrolysis with release of fewer inhibitors, to select the suitable acid and its concentration. Among three acids, sulfuric acid in combination of 1 & 2% (v/v) hydrolyzed maximum holocellulose of 25.44±0.44% releasing 0.51±0.02 g/L of phenolics and 0.12±0.002 g/L of furans, respectively. Further, hydrolysis of delignified substrate using selected acid by varying reaction time and temperature hydrolyzed 55.58±1.78% of holocellulose releasing 2.11±0.07 g/L and 1.37±0.03 g/L of phenolics and furans, respectively at conditions of 110 °C for 45 min in phase-I & 121 °C for 60 min in phase-II. Copyright © 2015 Elsevier Ltd. All rights reserved.

Incentives for orphan drug research and development in the United States.

Science.gov (United States)

Seoane-Vazquez, Enrique; Rodriguez-Monguio, Rosa; Szeinbach, Sheryl L; Visaria, Jay

2008-12-16

The Orphan Drug Act (1983) established several incentives to encourage the development of orphan drugs (ODs) to treat rare diseases and conditions. This study analyzed the characteristics of OD designations, approvals, sponsors, and evaluated the effective patent and market exclusivity life of orphan new molecular entities (NMEs) approved in the US between 1983 and 2007. Primary data sources were the FDA Orange Book, the FDA Office of Orphan Drugs Development, and the US Patent and Trademark Office. Data included all orphan designations and approvals listed by the FDA and all NMEs approved by the FDA during the study period. The FDA listed 1,793 orphan designations and 322 approvals between 1983 and 2007. Cancer was the main group of diseases targeted for orphan approvals. Eighty-three companies concentrated 67.7% of the total orphan NMEs approvals. The average time from orphan designation to FDA approval was 4.0 +/- 3.3 years (mean +/- standard deviation). The average maximum effective patent and market exclusivity life was 11.7 +/- 5.0 years for orphan NME. OD market exclusivity increased the average maximum effective patent and market exclusivity life of ODs by 0.8 years. Public programs, federal regulations, and policies support orphan drugs R&D. Grants, research design support, FDA fee waivers, tax incentives, and orphan drug market exclusivity are the main incentives for orphan drug R&D. Although the 7-year orphan drug market exclusivity provision had a positive yet relatively modest overall effect on effective patent and market exclusivity life, economic incentives and public support mechanisms provide a platform for continued orphan drug development for a highly specialized market.

Adequate plasma drug concentrations suggest that amoxicillin can be administered by continuous infusion using elastomeric pumps.

Science.gov (United States)

Arensdorff, Lyne; Boillat-Blanco, Noémie; Decosterd, Laurent; Buclin, Thierry; de Vallière, Serge

2017-09-01

Elastomeric pumps can be useful for the administration of antibiotics in the outpatient setting. To determine amoxicillin degradation in elastomeric pumps, as well as the effectiveness of amoxicillin treatment administered by elastomeric pumps. Antibiotic degradation was measured in elastomeric pumps filled with 6 g of amoxicillin in 240 mL of NaCl 0.9% by drawing samples at 12 h intervals when stored in the fridge for 48 h and when worn around the waist for 24 h. Subsequently nine patients were treated with continuous infusions of 8 or 12 g of amoxicillin per day. Plasma amoxicillin concentrations were measured on each visit to the outpatient parenteral antibiotic therapy unit. Clinical outcome was verified 3 months after the end of treatment. Amoxicillin degradation in elastomeric pumps reached 10% after 48 h in the fridge and an additional 30% when worn around the waist for 24 h. Mean plasma drug concentrations achieved with 12 g of amoxicillin per day were 18.5 mg/L (95% CI 13.5-23.5), which is largely above the MIC of amoxicillin-susceptible bacteria. Nine patients treated for various complicated infections were cured and had no unexpected adverse effects. Adequate plasma drug concentrations and favourable clinical outcomes suggest that amoxicillin can be administered by continuous infusion using elastomeric pumps. This treatment modality does not fulfil formal requirements regarding pharmaceutical stability, but the resulting safety impact in patients is probably limited. Therapeutic drug monitoring and a close clinical follow-up are recommended if this route of administration is chosen. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Reduced antituberculosis drug concentrations in HIV-infected patients who are men or have low weight: implications for international dosing guidelines.

Science.gov (United States)

McIlleron, Helen; Rustomjee, Roxana; Vahedi, Mahnaz; Mthiyane, Thuli; Denti, Paolo; Connolly, Catherine; Rida, Wasima; Pym, Alexander; Smith, Peter J; Onyebujoh, Philip C

2012-06-01

Reduced antituberculosis drug concentrations may contribute to unfavorable treatment outcomes among HIV-infected patients with more advanced immune suppression, and few studies have evaluated pharmacokinetics of the first-line antituberculosis drugs in such patients given fixed-dose combination tablets according to international guidelines using weight bands. In this study, pharmacokinetics were evaluated in 60 patients on 4 occasions during the first month of antituberculosis therapy. Multilevel linear mixed-effects regression analysis was used to examine the effects of age, sex, weight, drug dose/kilogram, CD4(+) lymphocyte count, treatment schedule (5 versus 7 days/week), and concurrent antiretrovirals (efavirenz plus lamivudine plus zidovudine) on the area under the concentration-time curve from 0 to 12 h (AUC(0-12)) of the respective antituberculosis drugs and to compare AUC(0-12)s at day 8, day 15, and day 29 with the day 1 AUC(0-12). Median (range) age, weight, and CD4(+) lymphocyte count were 32 (18 to 47) years, 55.2 (34.4 to 98.7) kg, and 252 (12 to 500)/μl. For every 10-kg increase in body weight, the predicted day 29 AUC(0-12) increased by 14.1% (95% confidence interval [CI], 7.5, 20.8), 14.1% (95% CI, -0.7, 31.1), 6.1% (95% CI, 2.7, 9.6) and 6.0% (95% CI, 0.8, 11.3) for rifampin, isoniazid, pyrazinamide, and ethambutol, respectively. Males had day 29 AUC(0-12)s 19.3% (95% CI, 3.6, 35.1) and 14.0% (95% CI, 5.6, 22.4) lower than females for rifampin and pyrazinamide, respectively. Level of immune suppression and concomitant antiretrovirals had little effect on the concentrations of the antituberculosis agents. As they had reduced drug concentrations, it is important to review treatment responses in patients in the lower weight bands and males to inform future treatment guidelines, and revision of doses in these patients should be considered.

Cost-effectiveness of routine measuring of serum drug concentrations and anti-drug antibodies in treatment of rheumatoid arthritis patients with TNF-α blockers

Directory of Open Access Journals (Sweden)

Laine J

2016-04-01

Full Text Available Juha Laine,1 T Sakari Jokiranta,2,3 Kari K Eklund,4,5 Merja Väkeväinen,1 Kari Puolakka6 1Pfizer Oy, Helsinki, 2United Medix Laboratories Ltd, Espoo, 3Research Programs Unit, Immunobiology, 4Department of Rheumatology, University of Helsinki, 5Helsinki University Central Hospital, Helsinki, 6Department of Medicine, South Karelia, Finland Abstract: Monitoring of anti-drug antibodies (ADAbs or serum concentrations of biologicals in treatment of rheumatoid arthritis could provide an explanation for a loss of efficacy and help in the choice of subsequent medication. Current clinical practices do not generally include such monitoring of tumor necrosis factor (TNF-α blockers on a routine basis. The main aims of this study were to estimate the probabilities of optimal and nonoptimal treatment decisions if infliximab or adalimumab drug trough level (DL and ADAbs are tested or not in rheumatoid arthritis, and to model cost-effectiveness of performing such monitoring on a routine basis. Data on DLs and ADAbs concentrations were obtained in Finland from clinically requested monitoring analyses of 486 and 1,137 samples from patients on adalimumab and infliximab, respectively. DL was within the target range in 42% of samples from adalimumab- and 50.4% of infliximab-treated patients. ADAbs were detected in approximately 20% and 13.5% of samples from adalimumab- and infliximab-treated patients, respectively. ADAbs were found in 52.3% and 41.3% of those with low adalimumab or infliximab DLs, respectively. The monitoring data were incorporated into probabilities for making the optimal treatment decision. Economic impact of clinical decision-making was modeled in a short-term (3–6 months scenario with 100 hypothetical patients. In the model, the combined measurement of DLs and ADAbs was cost-saving compared to the nontesting scenario when the monitoring results affected the treatment decision in at least 2–5 of 100 patients, a proportion which is easily

Plasma dispositions and concentrations of ivermectin in eggs following treatment of laying hens.

Science.gov (United States)

Cirak, V Y; Aksit, D; Cihan, H; Gokbulut, C

2018-05-01

To determine the plasma disposition and concentrations of ivermectin (IVM) in eggs produced by laying hens following S/C, oral and I/V administration. Twenty-four laying hens, aged 37 weeks and weighing 1.73 (SD 0.12) kg were allocated to three groups of eight birds. The injectable formulation of IVM was administered either orally, S/C, or I/V, at a dose of 0.2 mg/kg liveweight, following dilution (1:5, v/v) with propylene glycol. Heparinised blood samples were collected at various times between 0.25 hours and 20 days after drug administration. Eggs produced by hens were also collected daily throughout the study period. Samples of plasma and homogenised egg were analysed using HPLC. Maximum concentrations of IVM in plasma and mean residence time of IVM were lower after oral (10.2 (SD 7.2) ng/mL and 0.38 (SD 0.14) days, respectively) than after S/C (82.9 (SD 12.4) ng/mL and 1.05 (SD 0.24) days, respectively) administration (pV administration, and until 15 days after S/C administration. Peak concentrations of IVM were 15.7, 23.3 and 1.9 µg/kg, observed 2, 5 and 4 days after I/V, S/C and oral administration, respectively. The low plasma bioavailability of IVM observed after oral administration in laying hens could result in lower efficacy or subtherapeutic plasma concentrations, which may promote the development of parasitic drug resistance. Due to high IVM residues in eggs compared to the maximum residue limits for other food-producing animal species, a withdrawal period should be necessary for eggs after IVM treatment in laying hens.

A conductance maximum observed in an inward-rectifier potassium channel

OpenAIRE

1994-01-01

One prediction of a multi-ion pore is that its conductance should reach a maximum and then begin to decrease as the concentration of permeant ion is raised equally on both sides of the membrane. A conductance maximum has been observed at the single-channel level in gramicidin and in a Ca(2+)-activated K+ channel at extremely high ion concentration (> 1,000 mM) (Hladky, S. B., and D. A. Haydon. 1972. Biochimica et Biophysica Acta. 274:294-312; Eisenmam, G., J. Sandblom, and E. Neher. 1977. In ...

Effects of the summer holiday season on UV filter and illicit drug concentrations in the Korean wastewater system and aquatic environment.

Science.gov (United States)

Kim, Ki Yong; Ekpeghere, Kalu Ibe; Jeong, Hee-Jin; Oh, Jeong-Eun

2017-08-01

Seasonal variations in the concentrations of eight ultraviolet (UV) filters and 22 illicit drugs including their metabolites in the Korean aquatic environment were investigated. Seawater samples from three beaches, water samples from two rivers, and influents and effluents from three wastewater treatment plants were analyzed. The UV filter concentrations in the seawater, river water, and effluent samples were 39.4-296, 35.4-117, and 6.84-51.1 ng L -1 , respectively. The total UV filter concentrations in the seawater samples were 1.9-4.4 times higher at the peak of the holiday season than outside the peak holiday season. An environmental risk assessment showed that ethylhexyl methoxy cinnamate (EHMC) could cause adverse effects on aquatic organisms in the seawater at the three beaches during the holiday period. Seven of the 22 target illicit drugs including their metabolites were detected in the wastewater influent samples, and the total illicit drug concentrations in the influent samples were 0.08-65.4 ng L -1 . The estimated daily consumption rates for cis-tramadol (Cis-TRM), methamphetamine (MTP), meperidine (MEP), and codeine (COD) were 25.7-118.4, 13.8-36.1, 1.36-12.6, and 1.75-8.64 mg d -1 (1000 people) -1 , respectively. In popular vacation area, the illicit drug consumption rates (Cis-TRM, MTP and MEP) were 1.6-2.6 times higher at the peak of the summer holiday season than at the beginning of the summer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Transferosomes - A vesicular transdermal delivery system for enhanced drug permeation

Directory of Open Access Journals (Sweden)

Reshmy Rajan

2011-01-01

Full Text Available Transdermal administration of drugs is generally limited by the barrier function of the skin. Vesicular systems are one of the most controversial methods for transdermal delivery of active substances. The interest in designing transdermal delivery systems was relaunched after the discovery of elastic vesicles like transferosomes, ethosomes, cubosomes, phytosomes, etc. This paper presents the composition, mechanisms of penetration, manufacturing and characterization methods of transferosomes as transdermal delivery systems of active substances. For a drug to be absorbed and distributed into organs and tissues and eliminated from the body, it must pass through one or more biological membranes/barriers at various locations. Such a movement of drug across the membrane is called as drug transport. For the drugs to be delivered to the body, they should cross the membranous barrier. The concept of these delivery systems was designed in an attempt to concentrate the drug in the tissues of interest, while reducing the amount of drug in the remaining tissues. Hence, surrounding tissues are not affected by the drug. In addition, loss of drug does not happen due to localization of drug, leading to get maximum efficacy of the medication. Therefore, the phospholipid based carrier systems are of considerable interest in this era.

MAK and BAT values list 2015. Maximum permissible concentrations at the place of work and biological tolerance values for working materials; MAK- und BAT-Werte-Liste 2015. Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte

Energy Technology Data Exchange (ETDEWEB)

NONE

2015-11-01

The book on the MAK (maximum permissible concentrations at the place of work) and BAT (biological tolerance values for working materials) value list 2015 includes the following chapters: (a) Maximum permissible concentrations at the place of work: definition, application and determination of MAT values, list of materials; carcinogenic working materials, sensibilizing working materials, aerosols, limiting the exposition peaks, skin resorption, MAK values during pregnancy, germ cell mutagens, specific working materials; (b) Biological tolerance values for working materials: definition and application of BAT values, list of materials, carcinogenic working materials, biological guide values, biological working material reference values.

MAK and BAT values list 2014. Maximum permissible concentrations at the place of work and biological tolerance values for working materials; MAK- und BAT-Werte-Liste 2014. Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte

Energy Technology Data Exchange (ETDEWEB)

NONE

2014-11-01

The book on the MAK (maximum permissible concentrations at the place of work) and BAT (biological tolerance values for working materials) value list 2014 includes the following chapters: (a) Maximum permissible concentrations at the place of work: definition, application and determination of MAT values, list of materials; carcinogenic working materials, sensibilizing working materials, aerosols, limiting the exposition peaks, skin resorption, MAK values during pregnancy, germ cell mutagens, specific working materials; (b) Biological tolerance values for working materials: definition and application of BAT values, list of materials, carcinogenic working materials, biological guide values, biological working material reference values.

MAK and BAT values list 2013. Maximum permissible concentrations at the place of work and biological tolerance values for working materials; MAK- und BAT-Werte-Liste 2013. Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte

Energy Technology Data Exchange (ETDEWEB)

NONE

2013-08-01

The book on the MAK (maximum permissible concentrations at the place of work) and BAT (biological tolerance values for working materials) value list 2013 includes the following chapters: (a) Maximum permissible concentrations at the place of work: definition, application and determination of MAT values, list of materials; carcinogenic working materials, sensibilizing working materials, aerosols, limiting the exposition peaks, skin resorption, MAK values during pregnancy, germ cell mutagens, specific working materials; (b) Biological tolerance values for working materials: definition and application of BAT values, list of materials, carcinogenic working materials, biological guide values, biological working material reference values.

Pushing concentration of stationary solar concentrators to the limit.

Science.gov (United States)

Winston, Roland; Zhang, Weiya

2010-04-26

We give the theoretical limit of concentration allowed by nonimaging optics for stationary solar concentrators after reviewing sun- earth geometry in direction cosine space. We then discuss the design principles that we follow to approach the maximum concentration along with examples including a hollow CPC trough, a dielectric CPC trough, and a 3D dielectric stationary solar concentrator which concentrates sun light four times (4x), eight hours per day year around.

Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

Directory of Open Access Journals (Sweden)

Fang Zheng

Full Text Available A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC value in brain (denoted by AUC2(∞ required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞. The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

Modeling of pharmacokinetics of cocaine in human reveals the feasibility for development of enzyme therapies for drugs of abuse.

Science.gov (United States)

Zheng, Fang; Zhan, Chang-Guo

2012-01-01

A promising strategy for drug abuse treatment is to accelerate the drug metabolism by administration of a drug-metabolizing enzyme. The question is how effectively an enzyme can actually prevent the drug from entering brain and producing physiological effects. In the present study, we have developed a pharmacokinetic model through a combined use of in vitro kinetic parameters and positron emission tomography data in human to examine the effects of a cocaine-metabolizing enzyme in plasma on the time course of cocaine in plasma and brain of human. Without an exogenous enzyme, cocaine half-lives in both brain and plasma are almost linearly dependent on the initial cocaine concentration in plasma. The threshold concentration of cocaine in brain required to produce physiological effects has been estimated to be 0.22±0.07 µM, and the threshold area under the cocaine concentration versus time curve (AUC) value in brain (denoted by AUC2(∞)) required to produce physiological effects has been estimated to be 7.9±2.7 µM·min. It has been demonstrated that administration of a cocaine hydrolase/esterase (CocH/CocE) can considerably decrease the cocaine half-lives in both brain and plasma, the peak cocaine concentration in brain, and the AUC2(∞). The estimated maximum cocaine plasma concentration which a given concentration of drug-metabolizing enzyme can effectively prevent from entering brain and producing physiological effects can be used to guide future preclinical/clinical studies on cocaine-metabolizing enzymes. Understanding of drug-metabolizing enzymes is key to the science of pharmacokinetics. The general insights into the effects of a drug-metabolizing enzyme on drug kinetics in human should be valuable also in future development of enzyme therapies for other drugs of abuse.

Determination of safety margins for whole blood concentrations of alcohol and nineteen drugs in driving under the influence cases.

Science.gov (United States)

Kristoffersen, Lena; Strand, Dag Helge; Liane, Veronica Horpestad; Vindenes, Vigdis; Tvete, Ingunn Fride; Aldrin, Magne

2016-02-01

Legislative limits for driving under the influence of 20 non-alcohol drugs were introduced in Norway in February 2012. Per se limits corresponding to blood alcohol concentrations (BAC) of 0.2g/kg were established for 20 psychoactive drugs, and limits for graded sanctions corresponding to BACs of 0.5 and 1.2g/kg were determined for 13 of these drugs. This new legislation made it possible for the courts to make sentences based on the analytical results, similar to the situation for alcohol. To ensure that the reported concentration is as least as high as the true concentration, with a 99% safety level, safety margins had to be calculated for each of the substances. Diazepam, tetrahydrocannabinol (THC) and alcohol were used as model substances to establish a new model for estimating the safety margins. The model was compared with a previous used model established several years ago, by a similar yet much simpler model, and they were found to be in agreement. The measurement uncertainties depend on the standard batch used, the work list and the measurements' replicate. A Bayesian modelling approach was used to determine the parameters in the model, using a dataset of 4700 diazepam positive specimens and 5400 THC positive specimens. Different safety margins were considered for low and high concentration levels of diazepam (≤2μM (0.6mg/L) and >2μM) and THC (≤0.01μM (0.003mg/L) and >0.01μM). The safety margins were for diazepam 19.5% (≤2μM) and 34% (>2μM), for THC 19.5% (≤0.01μM) and 24.9% (>0.01μM). Concentration dependent safety margins for BAC were based on a dataset of 29500 alcohol positive specimens, and were in the range 10.4% (0.1g/kg) to 4.0% (4.0g/kg) at a 99% safety level. A simplified approach was used to establish safety margins for the compounds amphetamine, MDMA, methamphetamine, alprazolam, phenazepam, flunitrazepam, clonazepam, nitrazepam, oxazepam, buprenorphine, GHB, methadone, ketamine, cocaine, morphine, zolpidem and zopiclone. The

Anticancer drugs in Portuguese surface waters - Estimation of concentrations and identification of potentially priority drugs.

Science.gov (United States)

Santos, Mónica S F; Franquet-Griell, Helena; Lacorte, Silvia; Madeira, Luis M; Alves, Arminda

2017-10-01

Anticancer drugs, used in chemotherapy, have emerged as new water contaminants due to their increasing consumption trends and poor elimination efficiency in conventional water treatment processes. As a result, anticancer drugs have been reported in surface and even drinking waters, posing the environment and human health at risk. However, the occurrence and distribution of anticancer drugs depend on the area studied and the hydrological dynamics, which determine the risk towards the environment. The main objective of the present study was to evaluate the risk of anticancer drugs in Portugal. This work includes an extensive analysis of the consumption trends of 171 anticancer drugs, sold or dispensed in Portugal between 2007 and 2015. The consumption data was processed aiming at the estimation of predicted environmental loads of anticancer drugs and 11 compounds were identified as potentially priority drugs based on an exposure-based approach (PEC b > 10 ng L -1 and/or PEC c > 1 ng L -1 ). In a national perspective, mycophenolic acid and mycophenolate mofetil are suspected to pose high risk to aquatic biota. Moderate and low risk was also associated to cyclophosphamide and bicalutamide exposition, respectively. Although no evidences of risk exist yet for the other anticancer drugs, concerns may be associated with long term effects. Copyright © 2017 Elsevier Ltd. All rights reserved.

maximum neutron flux at thermal nuclear reactors

International Nuclear Information System (INIS)

Strugar, P.

1968-10-01

Since actual research reactors are technically complicated and expensive facilities it is important to achieve savings by appropriate reactor lattice configurations. There is a number of papers, and practical examples of reactors with central reflector, dealing with spatial distribution of fuel elements which would result in higher neutron flux. Common disadvantage of all the solutions is that the choice of best solution is done starting from the anticipated spatial distributions of fuel elements. The weakness of these approaches is lack of defined optimization criteria. Direct approach is defined as follows: determine the spatial distribution of fuel concentration starting from the condition of maximum neutron flux by fulfilling the thermal constraints. Thus the problem of determining the maximum neutron flux is solving a variational problem which is beyond the possibilities of classical variational calculation. This variational problem has been successfully solved by applying the maximum principle of Pontrjagin. Optimum distribution of fuel concentration was obtained in explicit analytical form. Thus, spatial distribution of the neutron flux and critical dimensions of quite complex reactor system are calculated in a relatively simple way. In addition to the fact that the results are innovative this approach is interesting because of the optimization procedure itself [sr

Postmortem Blood Concentrations of R- and S-Enantiomers of Methadone and EDDP in Drug Users: Influence of Co-Medication and P-glycoprotein Genotype

DEFF Research Database (Denmark)

Buchard, Anders; Linnet, Kristian; Johansen, Sys Stybe

2010-01-01

We investigated toxicological and pharmacogenetic factors that could influence methadone toxicity using postmortem samples. R- and S-methadone were measured in femoral blood from 90 postmortem cases, mainly drug users. The R-enantiomer concentrations significantly exceeded that of the S-enantiome......We investigated toxicological and pharmacogenetic factors that could influence methadone toxicity using postmortem samples. R- and S-methadone were measured in femoral blood from 90 postmortem cases, mainly drug users. The R-enantiomer concentrations significantly exceeded that of the S...

Maximum neutron flux in thermal reactors; Maksimum neutronskog fluksa kod termalnih reaktora

Energy Technology Data Exchange (ETDEWEB)

Strugar, P V [Institute of Nuclear Sciences Boris Kidric, Vinca, Beograd (Yugoslavia)

1968-07-01

Direct approach to the problem is to calculate spatial distribution of fuel concentration if the reactor core directly using the condition of maximum neutron flux and comply with thermal limitations. This paper proved that the problem can be solved by applying the variational calculus, i.e. by using the maximum principle of Pontryagin. Mathematical model of reactor core is based on the two-group neutron diffusion theory with some simplifications which make it appropriate from maximum principle point of view. Here applied theory of maximum principle are suitable for application. The solution of optimum distribution of fuel concentration in the reactor core is obtained in explicit analytical form. The reactor critical dimensions are roots of a system of nonlinear equations and verification of optimum conditions can be done only for specific examples.

A new application of micellar liquid chromatography in the determination of free ampicillin concentration in the drug-human serum albumin standard solution in comparison with the adsorption method.

Science.gov (United States)

Stępnik, Katarzyna E; Malinowska, Irena; Maciejewska, Małgorzata

2016-06-01

The determination of free drug concentration is a very important issue in the field of pharmacology because only the unbound drug fraction can achieve a pharmacological effect. Due to the ability to solubilize many different compounds in micellar aggregates, micellar liquid chromatography (MLC) can be used for direct determination of free drug concentration. Proteins are not retained on the stationary phase probably due to the formation of protein - surfactant complexes which are excluded from the pores of stationary phase. The micellar method is simple and fast. It does not require any pre-preparation of the tested samples for analysis. The main aim of this paper is to demonstrate a completely new applicability of the analytical use of MLC concerning the determination of free drug concentration in the standard solution of human serum albumin. The well-known adsorption method using RP-HPLC and the spectrophotometric technique was applied as the reference method. The results show that the free drug concentration value obtained in the MLC system (based on the RP-8 stationary phase and CTAB) is similar to that obtained by the adsorption method: both RP-HPLC (95.83μgmL(-1), 79.86% of free form) and spectrophotometry (95.71μgmL(-1), 79.76%). In the MLC the free drug concentration was 93.98μgmL(-1) (78.3%). This indicates that the obtained results are within the analytical range of % of free ampicillin fraction and the MLC with direct sample injection can be treated like a promising method for the determination of free drug concentration. Copyright © 2016 Elsevier B.V. All rights reserved.

Venetoclax (ABT-199) Might Act as a Perpetrator in Pharmacokinetic Drug–Drug Interactions

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Weiss, Johanna; Gajek, Thomas; Köhler, Bruno Christian; Haefeli, Walter Emil

2016-01-01

Venetoclax (ABT-199) represents a specific B-cell lymphoma 2 (Bcl-2) inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR) cells. We therefore scrutinized its drug–drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs) was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1), breast cancer resistance protein (BCRP), and organic anion transporting polypeptides (OATPs)) was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug–drug interactions. PMID:26927160

Drug-Target Kinetics in Drug Discovery.

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Tonge, Peter J

2018-01-17

The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood-brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This Review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The Review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

Linezolid Trough Concentrations Correlate with Mitochondrial Toxicity-Related Adverse Events in the Treatment of Chronic Extensively Drug-Resistant Tuberculosis.

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Song, Taeksun; Lee, Myungsun; Jeon, Han-Seung; Park, Yumi; Dodd, Lori E; Dartois, Véronique; Follman, Dean; Wang, Jing; Cai, Ying; Goldfeder, Lisa C; Olivier, Kenneth N; Xie, Yingda; Via, Laura E; Cho, Sang Nae; Barry, Clifton E; Chen, Ray Y

2015-11-01

Long-term linezolid use is limited by mitochondrial toxicity-associated adverse events (AEs). Within a prospective, randomized controlled trial of linezolid to treat chronic extensively drug-resistant tuberculosis, we serially monitored the translational competence of mitochondria isolated from peripheral blood of participants by determining the cytochrome c oxidase/citrate synthase activity ratio. We compared this ratio with AEs associated with mitochondrial dysfunction. Linezolid trough concentrations were determined for 38 participants at both 600 mg and 300 mg doses. Those on 600 mg had a significantly higher risk of AE than those on 300 mg (HR 3·10, 95% CI 1·23-7 · 86). Mean mitochondrial function levels were significantly higher in patients before starting linezolid compared to their concentrations on 300 mg (P = 0·004) or 600 mg (P linezolid trough concentrations were associated with lower mitochondrial function levels (Spearman's ρ = - 0.48; P = 0.005). Mitochondrial toxicity risk increased with increasing linezolid trough concentrations, with all patients with mean linezolid trough > 2 μg/ml developing an AE related to mitochondrial toxicity, whether on 300 mg or 600 mg. Therapeutic drug monitoring may be useful to prevent the development of mitochondrial toxicity associated with long-term linezolid use.

Maximum a posteriori Bayesian estimation of mycophenolic Acid area under the concentration-time curve: is this clinically useful for dosage prediction yet?

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Staatz, Christine E; Tett, Susan E

2011-12-01

This review seeks to summarize the available data about Bayesian estimation of area under the plasma concentration-time curve (AUC) and dosage prediction for mycophenolic acid (MPA) and evaluate whether sufficient evidence is available for routine use of Bayesian dosage prediction in clinical practice. A literature search identified 14 studies that assessed the predictive performance of maximum a posteriori Bayesian estimation of MPA AUC and one report that retrospectively evaluated how closely dosage recommendations based on Bayesian forecasting achieved targeted MPA exposure. Studies to date have mostly been undertaken in renal transplant recipients, with limited investigation in patients treated with MPA for autoimmune disease or haematopoietic stem cell transplantation. All of these studies have involved use of the mycophenolate mofetil (MMF) formulation of MPA, rather than the enteric-coated mycophenolate sodium (EC-MPS) formulation. Bias associated with estimation of MPA AUC using Bayesian forecasting was generally less than 10%. However some difficulties with imprecision was evident, with values ranging from 4% to 34% (based on estimation involving two or more concentration measurements). Evaluation of whether MPA dosing decisions based on Bayesian forecasting (by the free website service https://pharmaco.chu-limoges.fr) achieved target drug exposure has only been undertaken once. When MMF dosage recommendations were applied by clinicians, a higher proportion (72-80%) of subsequent estimated MPA AUC values were within the 30-60 mg · h/L target range, compared with when dosage recommendations were not followed (only 39-57% within target range). Such findings provide evidence that Bayesian dosage prediction is clinically useful for achieving target MPA AUC. This study, however, was retrospective and focussed only on adult renal transplant recipients. Furthermore, in this study, Bayesian-generated AUC estimations and dosage predictions were not compared

SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

International Nuclear Information System (INIS)

Soltani, M; Bazmara, H; Sefidgar, M; Subramaniam, R; Rahmim, A

2015-01-01

Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm 3 , were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm 3 , was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm 3 , the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic tumors is not

SU-D-201-04: Study On the Impact of Tumor Shape and Size On Drug Delivery to Pancreatic Tumors

Energy Technology Data Exchange (ETDEWEB)

Soltani, M [ohns Hopkins University School of Medicine, Baltimore, Maryland, and KNT university, Tehran (Iran, Islamic Republic of); Bazmara, H [KNT university, Tehran (Iran, Islamic Republic of); Sefidgar, M [IKI University, Qazvin (Iran, Islamic Republic of); Subramaniam, R; Rahmim, A [Johns Hopkins University School of Medicine, Baltimore, MD (United States)

2015-06-15

Purpose: Drug delivery to solid tumors can be expressed physically using transport phenomena such as convection and diffusion for the drug of interest within extracellular matrices. We aimed to carefully model these phenomena, and to investigate the effect of tumor shape and size on drug delivery to solid tumors in the pancreas. Methods: In this study, multiple tumor geometries as obtained from clinical PET/CT images were considered. An advanced numerical method was used to simultaneously solve fluid flow and solute transport equations. Data from n=45 pancreatic cancer patients with non-resectable locoregional disease were analyzed, and geometrical information from the tumors including size, shape, and aspect ratios were classified. To investigate effect of tumor shape, tumors with similar size but different shapes were selected and analyzed. Moreover, to investigate effect of tumor size, tumors with similar shapes but different sizes, ranging from 1 to 77 cm{sup 3}, were selected and analyzed. A hypothetical tumor similar to one of the analyzed tumors, but scaled to reduce its size below 0.2 cm{sup 3}, was also analyzed. Results: The results showed relatively similar average drug concentration profiles in tumors with different sizes. Generally, smaller tumors had higher absolute drug concentration. In the hypothetical tumor, with volume less than 0.2 cm{sup 3}, the average drug concentration was 20% higher in comparison to its counterparts. For the various real tumor geometries, however, the maximum difference between average drug concentrations was 10% for the smallest and largest tumors. Moreover, the results demonstrated that for pancreatic tumors the shape is not significant. The negligible difference of drug concentration in different tumor shapes was due to the minimum effect of convection in pancreatic tumors. Conclusion: In tumors with different sizes, smaller tumors have higher drug delivery; however, the impact of tumor shape in the case of pancreatic

Green Pharmaceutical Analysis of Drugs Coformulated with Highly Different Concentrations Using Spiking and Manipulation of Their Ratio Spectra.

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Ayoub, Bassam M

2017-07-01

Introducing green analysis to pharmaceutical products is considered a significant approach to preserving the environment. This method can be an environmentally friendly alternative to the existing methods, accompanied by a validated automated procedure for the analysis of a drug with the lowest possible number of samples. Different simple spectrophotometric methods were developed for the simultaneous determination of empagliflozin (EG) and metformin (MT) by manipulating their ratio spectra in their application on a recently approved pharmaceutical combination, Synjardy tablets. A spiking technique was used to increase the concentration of EG in samples prepared from the tablets to allow for the simultaneous determination of EG with MT without prior separation. Validation parameters according to International Conference on Harmonization guidelines were acceptable over a concentration range of 2-12 μg/mL for both drugs using derivative ratio and ratio subtraction coupled with extended ratio subtraction. The optimized methods were compared using one-way analysis of variance and proved to be suitable as ecofriendly approaches for industrial QC laboratories.

Triple-component nanocomposite films prepared using a casting method: Its potential in drug delivery

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Sadia Gilani

2018-04-01

Full Text Available The purpose of this study was to fabricate a triple-component nanocomposite system consisting of chitosan, polyethylene glycol (PEG, and drug for assessing the application of chitosan–PEG nanocomposites in drug delivery and also to assess the effect of different molecular weights of PEG on nanocomposite characteristics. The casting/solvent evaporation method was used to prepare chitosan–PEG nanocomposite films incorporating piroxicam-β-cyclodextrin. In order to characterize the morphology and structure of nanocomposites, X-ray diffraction technique, scanning electron microscopy, thermogravimetric analysis, and Fourier transmission infrared spectroscopy were used. Drug content uniformity test, swelling studies, water content, erosion studies, dissolution studies, and anti-inflammatory activity were also performed. The permeation studies across rat skin were also performed on nanocomposite films using Franz diffusion cell. The release behavior of films was found to be sensitive to pH and ionic strength of release medium. The maximum swelling ratio and water content was found in HCl buffer pH 1.2 as compared to acetate buffer of pH 4.5 and phosphate buffer pH 7.4. The release rate constants obtained from kinetic modeling and flux values of ex vivo permeation studies showed that release of piroxicam-β-cyclodextrin increased with an increase in concentration of PEG. The formulation F10 containing 75% concentration of PEG showed the highest swelling ratio (3.42±0.02 in HCl buffer pH 1.2, water content (47.89±1.53% in HCl buffer pH 1.2, maximum cumulative drug permeation through rat skin (2405.15±10.97 μg/cm2 in phosphate buffer pH 7.4, and in vitro drug release (35.51±0.26% in sequential pH change mediums, and showed a significantly (p<0.0001 higher anti-inflammatory effect (0.4 cm. It can be concluded from the results that film composition had a particular impact on drug release properties. The different molecular weights of PEG have a

Drug ratio-dependent antagonism: a new category of multidrug resistance and strategies for its circumvention.

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Harasym, Troy O; Liboiron, Barry D; Mayer, Lawrence D

2010-01-01

A newly identified form of multidrug resistance (MDR) in tumor cells is presented, pertaining to the commonly encountered resistance of cancer cells to anticancer drug combinations at discrete drug:drug ratios. In vitro studies have revealed that whether anticancer drug combinations interact synergistically or antagonistically can depend on the ratio of the combined agents. Failure to control drug ratios in vivo due to uncoordinated pharmacokinetics could therefore lead to drug resistance if tumor cells are exposed to antagonistic drug ratios. Consequently, the most efficacious drug combination may not occur at the typically employed maximum tolerated doses of the combined drugs if this leads to antagonistic ratios in vivo after administration and resistance to therapeutic effects of the drug combination. Our approach to systematically screen a wide range of drug ratios and concentrations and encapsulate the drug combination in a liposomal delivery vehicle at identified synergistic ratios represents a means to mitigate this drug ratio-dependent MDR mechanism. The in vivo efficacy of the improved agents (CombiPlex formulations) is demonstrated and contrasted with the decreased efficacy when drug combinations are exposed to tumor cells in vivo at antagonistic ratios.

Limits to anaerobic energy and cytosolic concentration in the living cell

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Paglietti, A.

2015-11-01

For many physical systems at any given temperature, the set of all states where the system's free energy reaches its largest value can be determined from the system's constitutive equations of internal energy and entropy, once a state of that set is known. Such an approach is fraught with complications when applied to a living cell, because the cell's cytosol contains thousands of solutes, and thus thousands of state variables, which makes determination of its state impractical. We show here that, when looking for the maximum energy that the cytosol can store and release, detailed information on cytosol composition is redundant. Compatibility with cell's life requires that a single variable that represents the overall concentration of cytosol solutes must fall between defined limits, which can be determined by dehydrating and overhydrating the cell to its maximum capacity. The same limits are shown to determine, in particular, the maximum amount of free energy that a cell can supply in fast anaerobic processes, starting from any given initial state. For a typical skeletal muscle in normal physiological conditions this energy, i.e., the maximum anaerobic capacity to do work, is calculated to be about 960 J per kg of muscular mass. Such energy decreases as the overall concentration of solutes in the cytosol is increased. Similar results apply to any kind of cell. They provide an essential tool to understand and control the macroscopic response of single cells and multicellular cellular tissues alike. The applications include sport physiology, cell aging, disease produced cell damage, drug absorption capacity, to mention the most obvious ones.

Pharmacokinetics of a concentrated buprenorphine formulation in red-tailed hawks (Buteo jamaicensis).

Science.gov (United States)

Gleeson, Molly D; Guzman, David Sanchez-Migallon; Knych, Heather K; Kass, Philip H; Drazenovich, Tracy L; Hawkins, Michelle G

2018-01-01

OBJECTIVE To determine the pharmacokinetics and sedative effects of 2 doses of a concentrated buprenorphine formulation after SC administration to red-tailed hawks (Buteo jamaicensis). ANIMALS 6 adult red-tailed hawks. PROCEDURES Concentrated buprenorphine (0.3 mg/kg, SC) was administered to all birds. Blood samples were collected at 10 time points over 24 hours after drug administration to determine plasma buprenorphine concentrations. After a 4-week washout period, the same birds received the same formulation at a higher dose (1.8 mg/kg, SC), and blood samples were collected at 13 time points over 96 hours. Hawks were monitored for adverse effects and assigned agitation-sedation scores at each sample collection time. Plasma buprenorphine concentrations were quantified by liquid chromatography-tandem mass spectrometry. RESULTS Mean time to maximum plasma buprenorphine concentration was 7.2 minutes and 26.1 minutes after administration of the 0.3-mg/kg and 1.8-mg/kg doses, respectively. Plasma buprenorphine concentrations were > 1 ng/mL for mean durations of 24 and 48 hours after low- and high-dose administration, respectively. Mean elimination half-life was 6.23 hours for the low dose and 7.84 hours for the high dose. Mean agitation-sedation scores were higher (indicating some degree of sedation) than the baseline values for 24 hours at both doses. No clinically important adverse effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE Concentrated buprenorphine was rapidly absorbed, and plasma drug concentrations considered to have analgesic effects in other raptor species were maintained for extended periods. Most birds had mild to moderate sedation. Additional studies are needed to evaluate the pharmacodynamics of these doses of concentrated buprenorphine in red-tailed hawks.

Radiation Synthesis and Characterization of Polyvinyl alcohol/Acrylic acid Hydrogel and its Amoxicillin drug Delivery application

International Nuclear Information System (INIS)

El kelesh, N.A.; Ismail, S.A.; Abd El Wahab, S.Y.

2012-01-01

Polyvinyl alcohol /Acrylic acid based hydrogels can be synthesized by Gamma radiation technique using 60 Co irradiation cell at irradiation dose rate 1.8 Gray/second. The optimum conditions of hydrogel preparation takes place at different factors such as composition ratios of PVA/AAc, different comonomer concentration and different irradiation doses resulting in hydrogel with maximum gel percent as it obtained 98%. The structures of hydrogels were characterized by FTIR analysis. The results can be confirmed the expected structures as well as free radical copolymerization. According to the swelling studies, hydrogels with high content of AAc gave relatively high swelling percent. The hydrogel showed a super adsorbent with swelling capacity 10320 %. Water diffusion into such prepared hydrogel showed a non-Fickian type where a Fickian number was 0.77. This hydrogel was used for the adsorption of amoxicillin drug from their aqueous solutions. The factors affected on the uptake conditions such as ph, time and initial feed concentration on the amoxicillin adsorption capacity of hydrogel was studied depending on Freundlish model of adsorption isotherm.. It was observed that the interaction between drug and ionic comonomers was enhanced in alkaline medium and high initial feed concentration of the drug. The ability of the hydrogel and the affinity of the drug to be adsorbed can be cleared by determining the empirical constants n and k respectively from the logarithmic form of Freundlish equation. The recovery of drug was also investigated in different ph values to study the suitable condition of drug release as drug delivery system.

Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance

International Nuclear Information System (INIS)

Hembruff, Stacey L; Laberge, Monique L; Villeneuve, David J; Guo, Baoqing; Veitch, Zachary; Cecchetto, Melanie; Parissenti, Amadeo M

2008-01-01

Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7 DOX-2 ), epirubicin (MCF-7 EPI ), paclitaxel (MCF-7 TAX-2 ), or docetaxel (MCF-7 TXT ). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of

Venetoclax (ABT-199 Might Act as a Perpetrator in Pharmacokinetic Drug–Drug Interactions

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Johanna Weiss

2016-02-01

Full Text Available Venetoclax (ABT-199 represents a specific B-cell lymphoma 2 (Bcl-2 inhibitor that is currently under development for the treatment of lymphoid malignancies. So far, there is no published information on its interaction potential with important drug metabolizing enzymes and drug transporters, or its efficacy in multidrug resistant (MDR cells. We therefore scrutinized its drug–drug interaction potential in vitro. Inhibition of cytochrome P450 enzymes (CYPs was quantified by commercial kits. Inhibition of drug transporters (P-glycoprotein (P-gp, ABCB1, breast cancer resistance protein (BCRP, and organic anion transporting polypeptides (OATPs was evaluated by the use of fluorescent probe substrates. Induction of drug transporters and drug metabolizing enzymes was quantified by real-time RT-PCR. The efficacy of venetoclax in MDR cells lines was evaluated with proliferation assays. Venetoclax moderately inhibited P-gp, BCRP, OATP1B1, OATP1B3, CYP3A4, and CYP2C19, whereas CYP2B6 activity was increased. Venetoclax induced the mRNA expression of CYP1A1, CYP1A2, UGT1A3, and UGT1A9. In contrast, expression of ABCB1 was suppressed, which might revert tumor resistance towards antineoplastic P-gp substrates. P-gp over-expression led to reduced antiproliferative effects of venetoclax. Effective concentrations for inhibition and induction lay in the range of maximum plasma concentrations of venetoclax, indicating that it might act as a perpetrator drug in pharmacokinetic drug–drug interactions.

Plasma Drug Concentrations of Orally Administered Rosuvastatin in Hispaniolan Amazon Parrots (Amazona ventralis).

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Beaufrère, Hugues; Papich, Mark G; Brandão, João; Nevarez, Javier; Tully, Thomas N

2015-03-01

Atherosclerotic diseases are common in pet psittacine birds, in particular Amazon parrots. While hypercholesterolemia and dyslipidemia have not definitely been associated with increased susceptibility to atherosclerosis in parrots, these are important and well-known risk factors in humans. Therefore statin drugs such as rosuvastatin constitute the mainstay of human treatment of dyslipidemia and the prevention of atherosclerosis. No pharmacologic studies have been performed in psittacine birds despite the high prevalence of atherosclerosis in captivity. Thirteen Hispaniolan Amazon parrots were used to test a single oral dose of 10 mg/kg of rosuvastatin with blood sampling performed according to a balanced incomplete block design over 36 hours. Because low plasma concentrations were produced in the first study, a subsequent pilot study using a dose of 25 mg/kg in 2 Amazon parrots was performed. Most plasma samples for the 10 mg/kg dose and all samples for the 25 mg/kg dose had rosuvastatin concentration below the limits of quantitation. For the 10 mg/kg study, the median peak plasma concentration and time to peak plasma concentration were 0.032 μg/mL and 2 hours, respectively. Our results indicate that rosuvastatin does not appear suitable in Amazon parrots as compounded and used at the dose in this study. Pharmacodynamic studies investigating lipid-lowering effects of statins rather than pharmacokinetic studies may be more practical and cost effective in future studies to screen for a statin with more ideal properties for potential use in psittacine dyslipidemia and atherosclerotic diseases.

Development, optimization and evaluation of surfactant-based pulmonary nanolipid carrier system of paclitaxel for the management of drug resistance lung cancer using Box-Behnken design.

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Kaur, Prabhjot; Garg, Tarun; Rath, Goutam; Murthy, R S Rayasa; Goyal, Amit K

2016-07-01

In the present study, nanostructured lipid carriers (NLCs) along with various surfactants loaded with paclitaxel (PTX) were prepared by an emulsification technique using a Box-Behnken design. The Box-Behnken design indicated that the most effective factors on the size and PDI were at high surfactant concentration (1.5%), low lipids ratio (6:4) and medium homogenization speed (6000 rpm). Among all the formulations, Tween 20-loaded NLCs show least particle size compared to Tween 80 and Tween 60. Entrapment efficiency of Tween 20, Tween 80 and Tween 60-loaded formulations were 82.40, 85.60 and 79.78%, respectively. Drug release of Tween 80, Tween 20 and Tween 60-loaded NLCs is 64.9, 62.3 and 59.7%, respectively (within 72 h). Maximum cellular uptake was observed with Tween 20 formulation on Caco-2 cell lines. Furthermore, spray drying of resultant NLCs was showed good flow properties and was selected for drug delivery to deeper airways. In-vivo studies demonstrated the better localization of drug within the lungs using different surfactant-based pulmonary delivery systems. From this study, we have concluded that delivering drugs through pulmonary route is advantageous for local action in lungs as maximum amount of drug concentration was observed in lungs. The surfactants could prove to be beneficial in treating drug resistance lung cancer by inhibiting P-gp efflux in the form of nano lipidic carriers.

Spatio-temporal observations of the tertiary ozone maximum

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V. F. Sofieva

2009-07-01

Full Text Available We present spatio-temporal distributions of the tertiary ozone maximum (TOM, based on GOMOS (Global Ozone Monitoring by Occultation of Stars ozone measurements in 2002–2006. The tertiary ozone maximum is typically observed in the high-latitude winter mesosphere at an altitude of ~72 km. Although the explanation for this phenomenon has been found recently – low concentrations of odd-hydrogen cause the subsequent decrease in odd-oxygen losses – models have had significant deviations from existing observations until recently. Good coverage of polar night regions by GOMOS data has allowed for the first time to obtain spatial and temporal observational distributions of night-time ozone mixing ratio in the mesosphere.

The distributions obtained from GOMOS data have specific features, which are variable from year to year. In particular, due to a long lifetime of ozone in polar night conditions, the downward transport of polar air by the meridional circulation is clearly observed in the tertiary ozone maximum time series. Although the maximum tertiary ozone mixing ratio is achieved close to the polar night terminator (as predicted by the theory, TOM can be observed also at very high latitudes, not only in the beginning and at the end, but also in the middle of winter. We have compared the observational spatio-temporal distributions of the tertiary ozone maximum with that obtained using WACCM (Whole Atmosphere Community Climate Model and found that the specific features are reproduced satisfactorily by the model.

Since ozone in the mesosphere is very sensitive to HO_x concentrations, energetic particle precipitation can significantly modify the shape of the ozone profiles. In particular, GOMOS observations have shown that the tertiary ozone maximum was temporarily destroyed during the January 2005 and December 2006 solar proton events as a result of the HO_x enhancement from the increased ionization.

A two-dimensional mathematical model of percutaneous drug absorption

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Kubota K

2004-06-01

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

Underlying mechanism of drug-drug interaction between pioglitazone and gemfibrozil: Gemfibrozil acyl-glucuronide is a mechanism-based inhibitor of CYP2C8.

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Takagi, Motoi; Sakamoto, Masaya; Itoh, Tomoo; Fujiwara, Ryoichi

2015-08-01

While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug-drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the kinact and K'app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min(-1) and 57.3 μM, respectively. In this study, the kobs, in vivo value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo. The kobs, in vivo values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min(-1) and 0.0051 min(-1), respectively. The kobs, in vivo value of gemfibrozil was 0.0060 min(-1), which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo. Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Parametric characteristics of a solar thermophotovoltaic system at the maximum efficiency

International Nuclear Information System (INIS)

Liao, Tianjun; Chen, Xiaohang; Yang, Zhimin; Lin, Bihong; Chen, Jincan

2016-01-01

Graphical abstract: A model of the far-field TPVC driven by solar energy, which consists of an optical concentrator, an absorber, an emitter, and a PV cell and is simply referred as to the far-field STPVS. - Highlights: • A model of the far-field solar thermophotovoltaic system (STPVS) is established. • External and internal irreversible losses are considered. • The maximum efficiency of the STPVS is calculated. • Optimal values of key parameters at the maximum efficiency are determined. • Effects of the concentrator factor on the performance of the system are discussed. - Abstract: A model of the solar thermophotovoltaic system (STPVS) consisting of an optical concentrator, a thermal absorber, an emitter, and a photovoltaic (PV) cell is proposed, where the far-field thermal emission between the emitter and the PV cell, the radiation losses from the absorber and emitter to the environment, the reflected loss from the absorber, and the finite-rate heat exchange between the PV cell and the environment are taken into account. Analytical expressions for the power output of and overall efficiency of the STPVS are derived. By solving thermal equilibrium equations, the operating temperatures of the emitter and PV cell are determined and the maximum efficiency of the system is calculated numerically for given values of the output voltage of the PV cell and the ratio of the front surface area of the absorber to that of the emitter. For different bandgaps, the maximum efficiencies of the system are calculated and the corresponding optimum values of several operating parameters are obtained. The effects of the concentrator factor on the optimum performance of the system are also discussed.

Evaluation of optimized bronchoalveolar lavage sampling designs for characterization of pulmonary drug distribution.

Science.gov (United States)

Clewe, Oskar; Karlsson, Mats O; Simonsson, Ulrika S H

2015-12-01

Bronchoalveolar lavage (BAL) is a pulmonary sampling technique for characterization of drug concentrations in epithelial lining fluid and alveolar cells. Two hypothetical drugs with different pulmonary distribution rates (fast and slow) were considered. An optimized BAL sampling design was generated assuming no previous information regarding the pulmonary distribution (rate and extent) and with a maximum of two samples per subject. Simulations were performed to evaluate the impact of the number of samples per subject (1 or 2) and the sample size on the relative bias and relative root mean square error of the parameter estimates (rate and extent of pulmonary distribution). The optimized BAL sampling design depends on a characterized plasma concentration time profile, a population plasma pharmacokinetic model, the limit of quantification (LOQ) of the BAL method and involves only two BAL sample time points, one early and one late. The early sample should be taken as early as possible, where concentrations in the BAL fluid ≥ LOQ. The second sample should be taken at a time point in the declining part of the plasma curve, where the plasma concentration is equivalent to the plasma concentration in the early sample. Using a previously described general pulmonary distribution model linked to a plasma population pharmacokinetic model, simulated data using the final BAL sampling design enabled characterization of both the rate and extent of pulmonary distribution. The optimized BAL sampling design enables characterization of both the rate and extent of the pulmonary distribution for both fast and slowly equilibrating drugs.

Magnetocaloric effect in magnetothermally-responsive nanocarriers for hyperthermia-triggered drug release

International Nuclear Information System (INIS)

Li Jianbo; Qu Yang; Ren Jie; Yuan Weizhong; Shi Donglu

2012-01-01

The magnetocaloric effects and lower critical solution temperature (LCST) were investigated in a magnetothermally-responsive nanocarrier for magnetothermal drug release under alternating magnetic field (AMF). The Mn 0.2 Zn 0.8 Fe 2 O 4 nanoparticles with low T c were dispersed in a polymeric matrix consisting of N-Isopropyl acrylamide (NIPAAm) and N-hydroxymethyl acrylamide (HMAAm). The magnetocaloric effects and LCST of the nanocarriers were characterized by using high-resolution electron transmission microscopy, thermogravimetric analyses, and vibrating sample magnetometer. The maximum self-heating temperature of 42.9 °C was achieved by optimizing the Mn 0.2 Zn 0.8 Fe 2 O 4 concentration in the polymer matrix. By adjusting the NIPAAm to HMAAm ratio, the LCST was controlled at an ideal level of 40.1 °C for efficient thermosensitive drug delivery. Magnetothermally responsive drug release of Doxorubicin, an anticancer drug, was significantly enhanced by application of an external AMF on the nanocarriers. The cytotoxicity experimental results in vitro show good biocompatibility and efficient therapeutic effects in cancer treatment. (paper)

Lapatinib Plasma and Tumor Concentrations and Effects on HER Receptor Phosphorylation in Tumor.

Directory of Open Access Journals (Sweden)

Neil L Spector

Full Text Available The paradigm shift in cancer treatment from cytotoxic drugs to tumor targeted therapies poses new challenges, including optimization of dose and schedule based on a biologically effective dose, rather than the historical maximum tolerated dose. Optimal dosing is currently determined using concentrations of tyrosine kinase inhibitors in plasma as a surrogate for tumor concentrations. To examine this plasma-tumor relationship, we explored the association between lapatinib levels in tumor and plasma in mice and humans, and those effects on phosphorylation of human epidermal growth factor receptors (HER in human tumors.Mice bearing BT474 HER2+ human breast cancer xenografts were dosed once or twice daily (BID with lapatinib. Drug concentrations were measured in blood, tumor, liver, and kidney. In a randomized phase I clinical trial, 28 treatment-naïve female patients with early stage HER2+ breast cancer received lapatinib 1000 or 1500 mg once daily (QD or 500 mg BID before evaluating steady-state lapatinib levels in plasma and tumor.In mice, lapatinib levels were 4-fold higher in tumor than blood with a 4-fold longer half-life. Tumor concentrations exceeded the in vitro IC90 (~ 900 nM or 500 ng/mL for inhibition of HER2 phosphorylation throughout the 12-hour dosing interval. In patients, tumor levels were 6- and 10-fold higher with QD and BID dosing, respectively, compared to plasma trough levels. The relationship between tumor and plasma concentration was complex, indicating multiple determinants. HER receptor phosphorylation varied depending upon lapatinib tumor concentrations, suggestive of changes in the repertoire of HER homo- and heterodimers.Plasma lapatinib concentrations underestimated tumor drug levels, suggesting that optimal dosing should be focused on the site of action to avoid to inappropriate dose escalation. Larger clinical trials are required to determine optimal dose and schedule to achieve tumor concentrations that maximally

Maximum entropy decomposition of quadrupole mass spectra

International Nuclear Information System (INIS)

Toussaint, U. von; Dose, V.; Golan, A.

2004-01-01

We present an information-theoretic method called generalized maximum entropy (GME) for decomposing mass spectra of gas mixtures from noisy measurements. In this GME approach to the noisy, underdetermined inverse problem, the joint entropies of concentration, cracking, and noise probabilities are maximized subject to the measured data. This provides a robust estimation for the unknown cracking patterns and the concentrations of the contributing molecules. The method is applied to mass spectroscopic data of hydrocarbons, and the estimates are compared with those received from a Bayesian approach. We show that the GME method is efficient and is computationally fast

Efficiency of autonomous soft nanomachines at maximum power.

Science.gov (United States)

Seifert, Udo

2011-01-14

We consider nanosized artificial or biological machines working in steady state enforced by imposing nonequilibrium concentrations of solutes or by applying external forces, torques, or electric fields. For unicyclic and strongly coupled multicyclic machines, efficiency at maximum power is not bounded by the linear response value 1/2. For strong driving, it can even approach the thermodynamic limit 1. Quite generally, such machines fall into three different classes characterized, respectively, as "strong and efficient," "strong and inefficient," and "balanced." For weakly coupled multicyclic machines, efficiency at maximum power has lost any universality even in the linear response regime.

Spectrophotometric Method for the Determination of Two Coformulated Drugs with Highly Different Concentrations. Application on Vildagliptin and Metformin Hydrochloride

Science.gov (United States)

Zaazaa, H. E.; Elzanfaly, E. S.; Soudi, A. T.; Salem, M. Y.

2016-03-01

A new smart simple validated spectrophotometric method was developed for the determination of two drugs one of which is in a very low concentration compared to the other. The method is based on spiking and dilution then simple mathematical manipulation of the absorbance spectra. This method was applied for the determination of a binary mixture of vildagliptin and metformin hydrochloride in the ratio 50:850 in laboratory prepared mixtures containing both drugs in this ratio and in pharmaceutical dosage form with good recoveries. The developed method was validated according to ICH guidelines and can be used for routine quality control testing.

Control of drug releasing from biodegradable polymer drug delivery system by gamma-ray irradiation

International Nuclear Information System (INIS)

Yoshioka, Sumie; Aso, Yukio; Kojima, Shigeo

1999-01-01

In order to introduce the drug to the target organ, we developed a gel to control the drug releasing velocity by response to change of temperature by means of γ-ray irradiation to gelatin-GMA modified dextran mixture aqueous solution. A certain level of molecular weight of drug is necessary. The response to the temperature (change of drug releasing velocity) was affected by the concentration of gelatin and the modification rate of GMA. The Higuchi equation was applied to the releasing of β-galactosidase from gelatin-dextran gel and the releasing velocity was calculated. The releasing velocity decreased with increasing GMA modification rate at 37degC and 15degC. The releasing velocity of β-galactosidase decreased with increasing the concentration of gelatin at 15degC, but the velocity increased with increasing the concentration at 37degC. These results indicated that the good drug releasing conditions are obtained by controlling the GMA modification rate and the concentration of gelatin. (S.Y.)

Gemfibrozil concentrations are significantly decreased in the presence of lopinavir-ritonavir.

Science.gov (United States)

Busse, Kristin H; Hadigan, Colleen; Chairez, Cheryl; Alfaro, Raul M; Formentini, Elizabeth; Kovacs, Joseph A; Penzak, Scott R

2009-10-01

The objective of this study was to determine the influence of a 2-week course of lopinavir-ritonavir on the pharmacokinetics of the triglyceride-lowering agent, gemfibrozil. The study was conducted as an open label, single-sequence pharmacokinetic study in healthy human volunteers. Gemfibrozil pharmacokinetic parameter values were compared using a Student t test after a single 600-mg dose was administered to healthy volunteers before and after 2 weeks of lopinavir-ritonavir (400/100 mg) twice daily. Fifteen healthy volunteers (eight males) completed the study. All study drugs were generally well tolerated and no subjects withdrew participation. The geometric mean ratio (90% confidence interval) for gemfibrozil area under the plasma concentration-time curve after 14 days of lopinavir-ritonavir compared with baseline was 0.59 (0.52, 0.67) (P gemfibrozil area under the plasma concentration-time curve after lopinavir-ritonavir (range, -6% to -74%). The geometric mean ratios for gemfibrozil apparent oral clearance and maximum concentration were 1.69 (1.41, 1.97) and 0.67 (0.49, 0.86) after 14 days of lopinavir-ritonavir versus baseline, respectively (P Gemfibrozil elimination half-life did not change after lopinavir-ritonavir administration (P = 0.60). Lopinavir-ritonavir significantly reduced the systemic exposure of gemfibrozil by reducing gemfibrozil absorption. Clinicians treating HIV-infected patients with hypertriglyceridemia should be aware of this drug interaction.

Drug-drug interactions in prescriptions for hospitalized elderly with Acute Coronary Syndrome

Directory of Open Access Journals (Sweden)

Tiago Aparecido Maschio de Lima

2017-11-01

Full Text Available The objective was to determine the rate of potential drug-drug interactions in prescriptions for elderly diagnosed with Acute Coronary Syndrome in a teaching hospital. This is an exploratory, descriptive study that analyzed 607 prescriptions through databases to identify and classify the interactions based on intensity (major, moderate or minor, the mechanism (pharmacokinetic or pharmacodynamics and documentation relevance. We detected 10,162 drug-drug interactions, distributed in 554 types of different combinations within the prescribed drugs, and 99% of prescriptions presented at least one and a maximum of 53 interactions; highlighting the prevalence of major and moderates ones. There was a correlation between the number of drug-drug interactions and the number of prescribed drugs and the hospitalization time. This study contributes for the delimitation of a prevalence pattern in drug-drug interactions in prescriptions for Acute Coronary Syndrome, besides subsidizing the importance of the effective implementation of the Clinical Pharmacy in teaching hospitals.

Human drug metabolism: an introduction

National Research Council Canada - National Science Library

Coleman, Michael D

2010-01-01

... metabolism and its impact on patient welfare. After underlining the relationship between efficacy, toxicity and drug concentration, the book then considers how metabolizing systems operate and how they impact upon drug concentration...

Aggregation and phase separation behavior of an amphiphilic drug promazine hydrochloride under the influence of inorganic salts and ureas

Energy Technology Data Exchange (ETDEWEB)

Rub, Malik Abdul, E-mail: malikrub@gmail.com [Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Chemistry Department, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Asiri, Abdullah M.; Azum, Naved; Khan, Anish; Khan, Aftab Aslam Parwaz; Khan, Sher Bahadar; Rahman, Mohammed M. [Center of Excellence for Advanced Materials Research, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Chemistry Department, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Kabir-ud-Din [Department of Chemistry, Aligarh Muslim University, Aligarh 202002 (India)

2013-12-20

Highlights: • Aggregation and clouding behavior of PMZ-additive (salts/ureas) mixtures have been investigated. • Both urea and thiourea, at low concentrations, decrease the cmc but, at high concentrations, increase it. • However, ΔH{sub m}° for pure drug/drug–additive systems is negative at low temperature and positive at higher temperature. • The ΔS{sub m}° values are positive, their magnitude being more at T = 303.15 K and above. - Abstract: Self-association and phase separation phenomena of an amphiphilic phenothiazine drug promazine hydrochloride (PMZ) in the absence and presence of inorganic salts (NaF, NaCl and NaBr) and ureas (urea and thiourea) have been investigated in the present study. By the increase in temperature the critical micelle concentration (cmc) of drug PMZ first increases then decreases. Maximum cmc values were obtained at 303.15 K in presence or absence of additives (salts/ureas). Decrease in cmc occurs by the addition of the inorganic salts which is explained on the basis of nature and ion size. Ureas (urea and thiourea) decreased the cmc at low concentration; however, at higher concentrations, increase in cmc was observed with both the additives. Increasing inorganic salt concentrations caused an increase in the cloud point (CP) of PMZ, whereas urea decreased the CP. Significant thermodynamic parameters were also evaluated and discussed.

Aggregation and phase separation behavior of an amphiphilic drug promazine hydrochloride under the influence of inorganic salts and ureas

International Nuclear Information System (INIS)

Rub, Malik Abdul; Asiri, Abdullah M.; Azum, Naved; Khan, Anish; Khan, Aftab Aslam Parwaz; Khan, Sher Bahadar; Rahman, Mohammed M.; Kabir-ud-Din

2013-01-01

Highlights: • Aggregation and clouding behavior of PMZ-additive (salts/ureas) mixtures have been investigated. • Both urea and thiourea, at low concentrations, decrease the cmc but, at high concentrations, increase it. • However, ΔH m ° for pure drug/drug–additive systems is negative at low temperature and positive at higher temperature. • The ΔS m ° values are positive, their magnitude being more at T = 303.15 K and above. - Abstract: Self-association and phase separation phenomena of an amphiphilic phenothiazine drug promazine hydrochloride (PMZ) in the absence and presence of inorganic salts (NaF, NaCl and NaBr) and ureas (urea and thiourea) have been investigated in the present study. By the increase in temperature the critical micelle concentration (cmc) of drug PMZ first increases then decreases. Maximum cmc values were obtained at 303.15 K in presence or absence of additives (salts/ureas). Decrease in cmc occurs by the addition of the inorganic salts which is explained on the basis of nature and ion size. Ureas (urea and thiourea) decreased the cmc at low concentration; however, at higher concentrations, increase in cmc was observed with both the additives. Increasing inorganic salt concentrations caused an increase in the cloud point (CP) of PMZ, whereas urea decreased the CP. Significant thermodynamic parameters were also evaluated and discussed

Influence of tiamulin concentration in feed on its bioavailability in piglets.

Science.gov (United States)

Riond, J L; Schreiber, F; Wanner, M

1993-01-01

Tiamulin pharmacokinetic parameters were determined in 8 2-month-old male improved Swiss Landrace piglets after intake of 2,000 mg/kg feed, 500 mg/kg feed, 12.5 mg/ml aqueous solution administered via a stomach tube and 180 mg/kg feed offered ad libitum. In all cases, the total tiamulin dose received was 10 mg/kg body weight (bw) per day. For the 2,000 mg/kg and 500 mg/kg treatments, animals were restrictively fed a commercial mix in amounts corresponding to 3-fold their maintenance requirement of digestible energy. The piglets first individually received the amount of medicated feed and immediately thereafter the rest of the daily ration. The highest tiamulin serum concentrations (Cmax), the largest area under the curve (AUC0-->infinity), the largest absorption rate constant (Ka), and the shortest time at which the maximum serum concentration occurred (tmax) were obtained after administration via stomach tube followed in the respective order by the 2,000 mg/kg, 500 mg/kg and 180 mg/kg treatments. Ad libitum feeding of the medicated mix at 180 mg/kg failed to provide tiamulin serum concentration above minimum inhibitory concentrations (MIC) of some representative microorganisms. In conclusion, tiamulin concentration in medicated feed strongly influences its rate and extent of absorption and consequently serum concentrations. Larger tiamulin concentration in feed enhances its bioavailability. The common practice adopted by national regulatory agencies for the registration of a new drug is to conduct pharmacokinetic studies after administration agencies for the registration of a new drug is to conduct pharmacokinetic studies after administration via a stomach tube. This practice should be reevaluated because this mode of administration does not correspond to that in routine use.

Secondary poisoning of cadmium, copper and mercury: implications for the Maximum Permissible Concentrations and Negligible Concentrations in water, sediment and soil

NARCIS (Netherlands)

Smit CE; van Wezel AP; Jager T; Traas TP; CSR

2000-01-01

De betekenis van doorvergiftiging voor de Maximum Toelaatbaar Risiconiveau's (MTRs) en Verwaarloosbaar Risiconiveau's (VRs) van cadmium, koper en kwik in water, sediment en bodem is geevalueerd. Veldgegevens met betrekking tot de accumulatie van deze elementen door vissen, mosselen en

Prediction of Drug-Drug Interactions with Bupropion and Its Metabolites as CYP2D6 Inhibitors Using a Physiologically-Based Pharmacokinetic Model.

Science.gov (United States)

Xue, Caifu; Zhang, Xunjie; Cai, Weimin

2017-12-21

The potential of inhibitory metabolites of perpetrator drugs to contribute to drug-drug interactions (DDIs) is uncommon and underestimated. However, the occurrence of unexpected DDI suggests the potential contribution of metabolites to the observed DDI. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model for bupropion and its three primary metabolites-hydroxybupropion, threohydrobupropion and erythrohydrobupropion-based on a mixed "bottom-up" and "top-down" approach and to contribute to the understanding of the involvement and impact of inhibitory metabolites for DDIs observed in the clinic. PK profiles from clinical researches of different dosages were used to verify the bupropion model. Reasonable PK profiles of bupropion and its metabolites were captured in the PBPK model. Confidence in the DDI prediction involving bupropion and co-administered CYP2D6 substrates could be maximized. The predicted maximum concentration (C max ) area under the concentration-time curve (AUC) values and C max and AUC ratios were consistent with clinically observed data. The addition of the inhibitory metabolites into the PBPK model resulted in a more accurate prediction of DDIs (AUC and C max ratio) than that which only considered parent drug (bupropion) P450 inhibition. The simulation suggests that bupropion and its metabolites contribute to the DDI between bupropion and CYP2D6 substrates. The inhibitory potency from strong to weak is hydroxybupropion, threohydrobupropion, erythrohydrobupropion, and bupropion, respectively. The present bupropion PBPK model can be useful for predicting inhibition from bupropion in other clinical studies. This study highlights the need for caution and dosage adjustment when combining bupropion with medications metabolized by CYP2D6. It also demonstrates the feasibility of applying the PBPK approach to predict the DDI potential of drugs undergoing complex metabolism, especially in the DDI involving inhibitory

Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.

Science.gov (United States)

Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Conery, Annie L; Kim, Wooseong; Jayamani, Elamparithi; Kwon, Bumsup; Ausubel, Frederick M; Mylonakis, Eleftherios

2015-01-01

Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections.

Maximum entropy estimation of a Benzene contaminated plume using ecotoxicological assays

International Nuclear Information System (INIS)

Wahyudi, Agung; Bartzke, Mariana; Küster, Eberhard; Bogaert, Patrick

2013-01-01

Ecotoxicological bioassays, e.g. based on Danio rerio teratogenicity (DarT) or the acute luminescence inhibition with Vibrio fischeri, could potentially lead to significant benefits for detecting on site contaminations on qualitative or semi-quantitative bases. The aim was to use the observed effects of two ecotoxicological assays for estimating the extent of a Benzene groundwater contamination plume. We used a Maximum Entropy (MaxEnt) method to rebuild a bivariate probability table that links the observed toxicity from the bioassays with Benzene concentrations. Compared with direct mapping of the contamination plume as obtained from groundwater samples, the MaxEnt concentration map exhibits on average slightly higher concentrations though the global pattern is close to it. This suggest MaxEnt is a valuable method to build a relationship between quantitative data, e.g. contaminant concentrations, and more qualitative or indirect measurements, in a spatial mapping framework, which is especially useful when clear quantitative relation is not at hand. - Highlights: ► Ecotoxicological shows significant benefits for detecting on site contaminations. ► MaxEnt to rebuild qualitative link on concentration and ecotoxicological assays. ► MaxEnt shows similar pattern when compared with concentrations map of groundwater. ► MaxEnt is a valuable method especially when quantitative relation is not at hand. - A Maximum Entropy method to rebuild qualitative relationships between Benzene groundwater concentrations and their ecotoxicological effect.

Pharmacokinetics of a self-microemulsifying drug delivery system of tacrolimus.

Science.gov (United States)

von Suesskind-Schwendi, Marietta; Gruber, Michael; Touraud, Didier; Kunz, Werner; Schmid, Christof; Hirt, Stephan W; Lehle, Karla

2013-07-01

This study evaluated the pharmacokinetics of tacrolimus (Tac) in a novel self-microemulsifying drug delivery system (SMEDDS) for improved oral administration. SMEDDS Tac consisted of ethyl oleate as the oily phase, Solutol HS 15 as the surfactant and glycofurol as the co-surfactant and contained 0.5mg/mL tacrolimus. Blood and tissue concentrations of tacrolimus from two study groups (oral application of SMEDDS Tac and Prograf®) were determined using ELISA technique following tacrolimus administration in rats. There was no difference between area under the whole blood concentration-time curve in the SEDDM Tac group and the Prograf® group. Maximum concentrations of the drug were three times higher (P<0.05) in the SEDDM Tac group accompanied by a 3-fold earlier peak time. Elimination half-life was significantly lower in the SEDDM Tac group. Application of SMEDDS Tac increased tissue accumulation. Already after 15 min, Tac levels of small intestine, liver, kidney, spleen, heart and bone marrow were significantly higher in the SMEDDS Tac group than in the Prograf® group (P<0.05). However, the Tac concentration in the kidney was significantly lower in the SMEDDS Tac group. Formulation of SMEDDS did not affect blood-brain barrier function. The SMEDDS is a potentially useful method for a local delivery of Tac to target organs. The selection of the optimum SMEDDS Tac composition might have advantage as an alternative oral dosage form for Tac. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Comparison of concentrations of drugs between blood samples with and without fluoride additive-important findings for Δ9-tetrahydrocannabinol and amphetamine.

Science.gov (United States)

Wiedfeld, Christopher; Krueger, Julia; Skopp, Gisela; Musshoff, Frank

2018-02-17

Fluoride is a common stabilizing agent in forensic toxicology to avoid the frequent problem of degradation of drugs in blood samples especially described for cocaine. In cases only samples with addition of fluoride are available, it is a crucial question if also concentrations of common drugs other than cocaine (amphetamines, opiates and cannabinoids) are affected by fluoride. So far, there are only rare literature data available on discrepant results especially for Δ 9 -tetrahydrocannabinol (THC). In this study, comparative analysis of positive tested paired routine plasma/serum samples (n = 375), collected at the same time point (one device with and one without fluoride), was carried out with special focus on cannabinoids. Samples were measured with validated routine liquid chromatography-tandem mass spectrometry methods for THC, 11-hydroxy-THC (THC-OH), 11-nor-9-carboxy-THC (THC-COOH), cocaine, benzoylecgonine, ecgonine methyl ester, morphine, codeine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine, 3,4-methylenedioxyamphetamine, and 3,4-methylenedioxyethylamphetamine, and results were statistically evaluated. Beside the expected stabilization effect on cocaine and the consequently reduced concentration of ecgonine methyl ester in fluoride samples, benzoylecgonine was elevated compared to respective samples without fluoride. Most importantly, new findings were significantly reduced mean concentrations of THC (- 17%), THC-OH (- 17%), and THC-COOH (- 22%) in fluoride samples. Mean amphetamine concentration was significantly higher in samples with the additive (+ 6%). For the other amphetamine type of drugs as well as for morphine and codeine, no significant differences could be seen. Whenever specified thresholds have been set, such as in most European countries, the use of different blood sample systems may result in a motorist being differently charged or prosecuted. The findings will support forensic toxicologists at the

Influence of aliphatic amides on the temperature of maximum density of water

International Nuclear Information System (INIS)

Torres, Andrés Felipe; Romero, Carmen M.

2017-01-01

Highlights: • The addition of amides decreases the temperature of maximum density of water suggesting a disruptive effect on water structure. • The amides in aqueous solution do not follow the Despretz equation in the concentration range considered. • The temperature shift Δθ as a function of molality is represented by a second order equation. • The Despretz constants were determined considering the dilute concentration region for each amide solution. • Solute disrupting effect of amides becomes smaller as its hydrophobic character increases. - Abstract: The influence of dissolved substances on the temperature of the maximum density of water has been studied in relation to their effect on water structure as they can change the equilibrium between structured and unstructured species of water. However, most work has been performed using salts and the studies with small organic solutes such as amides are scarce. In this work, the effect of acetamide, propionamide and butyramide on the temperature of maximum density of water was determined from density measurements using a magnetic float densimeter. Densities of aqueous solutions were measured within the temperature range from T = (275.65–278.65) K at intervals of 0.50 K in the concentration range between (0.10000 and 0.80000) mol·kg −1 . The temperature of maximum density was determined from the experimental results. The effect of the three amides is to decrease the temperature of maximum density of water and the change does not follow the Despretz equation. The results are discussed in terms of solute-water interactions and the disrupting effect of amides on water structure.

Pharmacokinetics of Second-Line Antituberculosis Drugs after Multiple Administrations in Healthy Volunteers.

Science.gov (United States)

Park, Sang-In; Oh, Jaeseong; Jang, Kyungho; Yoon, Jangsoo; Moon, Seol Ju; Park, Jong Sun; Lee, Jae Ho; Song, Junghan; Jang, In-Jin; Yu, Kyung-Sang; Chung, Jae-Yong

2015-08-01

Therapeutic drug monitoring (TDM) of second-line antituberculosis drugs would allow for optimal individualized dosage adjustments and improve drug safety and therapeutic outcomes. To evaluate the pharmacokinetic (PK) characteristics of clinically relevant, multidrug treatment regimens and to improve the feasibility of TDM, we conducted an open-label, multiple-dosing study with 16 healthy subjects who were divided into two groups. Cycloserine (250 mg), p-aminosalicylic acid (PAS) (5.28 g), and prothionamide (250 mg) twice daily and pyrazinamide (1,500 mg) once daily were administered to both groups. Additionally, levofloxacin (750 mg) and streptomycin (1 g) once daily were administered to group 1 and moxifloxacin (400 mg) and kanamycin (1 g) once daily were administered to group 2. Blood samples for PK analysis were collected up to 24 h following the 5 days of drug administration. The PK parameters, including the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve during a dosing interval at steady state (AUCτ), were evaluated. The correlations between the PK parameters and the concentrations at each time point were analyzed. The mean Cmax and AUCτ, respectively, for each drug were as follows: cycloserine, 24.9 mg/liter and 242.3 mg · h/liter; PAS, 65.9 mg/liter and 326.5 mg · h/liter; prothionamide, 5.3 mg/liter and 22.1 mg · h/liter; levofloxacin, 6.6 mg/liter and 64.4 mg · h/liter; moxifloxacin, 4.7 mg/liter and 54.2 mg · h/liter; streptomycin, 42.0 mg/liter and 196.7 mg · h/liter; kanamycin, 34.5 mg/liter and 153.5 mg · h/liter. The results indicated that sampling at 1, 2.5, and 6 h postdosing is needed for TDM when all seven drugs are administered concomitantly. This study indicates that PK characteristics must be considered when prescribing optimal treatments for patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT02128308.). Copyright © 2015, American Society for

Maximum permissible concentrations and negligible concentrations for phthalates (dibutylphthalate and di(2-ethylhexyl)phthlate), with emphasis on endocrine disruptive properties

NARCIS (Netherlands)

Wezel AP van; Posthumus R; Vlaardingen P van; Crommentuijn T; Plassche EJ van de; CSR

This report presents maximal permissible concentrations (MPCs) and negligible concentrations (NCs) are derived for di-n-butylphthalate (DBP) and di(2-ethylhexyl)phthalate (DEHP). Phthalates are often mentioned as suspected endocrine disrupters. Data with endpoints related to the endocrine or

Comparison of direct sampling and brochoalveolar lavage for determining active drug concentrations in the pulmonary epithelial lining fluid of calves injected with enrofloxacin or tilmicosin.

Science.gov (United States)

Foster, D M; Sylvester, H J; Papich, M G

2017-12-01

Antibiotic distribution to interstitial fluid (ISF) and pulmonary epithelial fluid (PELF) was measured and compared to plasma drug concentrations in eight healthy calves. Enrofloxacin (Baytril ® 100) was administered at a dose of 12.5 mg/kg subcutaneously (SC), and tilmicosin (Micotil ® 300) was administered at a dose of 20 mg/kg SC. PELF, sampled by two different methods-bronchoalveolar lavage (BAL) and direct sampling (DS)-plasma, and ISF were collected from each calf and measured for tilmicosin, enrofloxacin and its metabolite ciprofloxacin by HPLC. Pharmacokinetic analysis was performed on the concentrations in each fluid, for each drug. The enrofloxacin/ciprofloxacin concentration as measured by AUC in DS samples was 137 ± 72% higher than in plasma, but in BAL samples, this value was 535 ± 403% (p enrofloxacin/ciprofloxacin concentrations collected by DS were significantly different than those collected by BAL, but the tilmicosin concentrations were not significantly different between the two methods. Concentrations of enrofloxacin/ciprofloxacin exceeded the MIC values for bovine respiratory disease pathogens but tilmicosin did not reach MIC levels for these pathogens in any fluids. © 2017 John Wiley & Sons Ltd.

Preparation of Simvastatin Hydrogel through Arginine Addition for Drug Delivery System

Directory of Open Access Journals (Sweden)

Rosyida Niswati Fathmah

2018-01-01

Full Text Available Simvastatin is a lipid lowering agent which has been used recently as drug delivery system for stimulating bone regeneration. Because of low therapeutic efficacy and bioavailability, it is necessary to deliver simvastatin by local administration e.g. by hydrogel system. However, simvastatin has very poor solubility which restricts to prepare hydrogel formulation. The aim of this study is to improve solubility of simvastatin with arginine as co-solvent for developing a controlled released drug delivery system by loading simvastatin into gelatin hydrogel. The solubility study was performed by addition of an excess mass of simvastatin into the specified molar solutions of the arginine. All conical flasks were placed in a mechanical water bath shaker at the temperature of 25, 40, and 50 °C and shaken for a maximum period of 72 hours. The drug concentration was analyzed by UV/Visible spectroscopy at 238 nm. The hydrogel was prepared by a dehydrothermal method. The results showed that simvastatin solubility increases with increasing arginine concentrations and temperature. Characterizations showed a successful preparation of simvastatin-loaded gelatin hydrogel. The arginine simvastatin hydrogel and the gelatin hydrogel (as a blank exhibited a comparable swelling index (ca. 6.5. Furthermore, microparticles of the material show a narrow particle size distribution in the range between 150-250 μm.

Comparison of Plasma, Saliva, and Hair Levetiracetam Concentrations.

Science.gov (United States)

Karaś-Ruszczyk, Katarzyna; Kuczyńska, Julita; Sienkiewicz-Jarosz, Halina; Kurkowska-Jastrzębska, Iwona; Bienkowski, Przemyslaw; Restel, Magdalena; Samochowiec, Jerzy; Mierzejewski, Pawel

2017-06-01

Previous findings revealed high correlations between serum/plasma and saliva levetiracetam concentrations, indicating saliva as an alternative matrix for monitoring levetiracetam therapy. Levetiracetam concentration in the hair, which could reflect long-term drug exposure and patients' compliance, has not been systematically tested, as yet. The aim of this study was to determine the correlation between plasma, saliva, and hair levetiracetam concentrations in 47 patients with epilepsy. Plasma, saliva, and hair levetiracetam concentrations were measured by liquid chromatography-tandem mass spectrometry with positive ionization. Levetiracetam saliva and plasma concentrations were highly correlated (r = 0.93). Plasma concentrations were not influenced by sex, age, and other concomitant antiepileptic drugs. Levetiracetam hair concentrations correlated with plasma concentrations (r = 0.36) but not daily dose (mg/kg). Drug hair concentrations were not influenced by hair color or treatment (dyed). The results tend to indicate that saliva may be a reliable alternative to plasma for monitoring levetiracetam concentrations. Levetiracetam can also be detected in human hair.

Differential mechanism of Escherichia coli Inactivation by (+)-limonene as a function of cell physiological state and drug's concentration.

Science.gov (United States)

Chueca, Beatriz; Pagán, Rafael; García-Gonzalo, Diego

2014-01-01

(+)-limonene is a lipophilic antimicrobial compound, extracted from citrus fruits' essential oils, that is used as a flavouring agent and organic solvent by the food industry. A recent study has proposed a common and controversial mechanism of cell death for bactericidal antibiotics, in which hydroxyl radicals ultimately inactivated cells. Our objective was to determine whether the mechanism of Escherichia coli MG1655 inactivation by (+)-limonene follows that of bactericidal antibiotics. A treatment with 2,000 μL/L (+)-limonene inactivated 4 log10 cycles of exponentially growing E. coli cells in 3 hours. On one hand, an increase of cell survival in the ΔacnB mutant (deficient in a TCA cycle enzyme), or in the presence of 2,2'-dipyridyl (inhibitor of Fenton reaction by iron chelation), thiourea, or cysteamine (hydroxyl radical scavengers) was observed. Moreover, the ΔrecA mutant (deficient in an enzyme involved in SOS response to DNA damage) was more sensitive to (+)-limonene. Thus, this indirect evidence indicates that the mechanism of exponentially growing E. coli cells inactivation by 2,000 μL/L (+)-limonene is due to the TCA cycle and Fenton-mediated hydroxyl radical formation that caused oxidative DNA damage, as observed for bactericidal drugs. However, several differences have been observed between the proposed mechanism for bactericidal drugs and for (+)-limonene. In this regard, our results demonstrated that E. coli inactivation was influenced by its physiological state and the drug's concentration: experiments with stationary-phase cells or 4,000 μL/L (+)-limonene uncovered a different mechanism of cell death, likely unrelated to hydroxyl radicals. Our research has also shown that drug's concentration is an important factor influencing the mechanism of bacterial inactivation by antibiotics, such as kanamycin. These results might help in improving and spreading the use of (+)-limonene as an antimicrobial compound, and in clarifying the controversy about

Effect of intravenous drug administration mode on drug distribution in a tumor slab: a finite Fourier transform analysis.

Science.gov (United States)

Subramaniam, B; Claudius, J S

1990-03-08

Cancer therapy using chemotherapeutic drugs frequently involves injection of the drug into the body through some intravenous mode of administration, viz, continuous (drip) infusion or single/multiple bolus injection(s). An understanding of the effect of the various modes of administration upon tumor penetration of drug is essential to rational design of drug therapy. This paper investigates drug penetration into a model tumor of slab geometry (between two capillaries) in which the overall transport rate of drug is limited by intra-tumor transport characterized by an effective diffusion coefficient. Employing the method of Finite Fourier Transforms (FFT), analytical solutions have been obtained for transient drug distribution in both the plasma and the tumor following three modes of administration, viz, continuous infusion, single bolus injection and equally-spaced equal-dose multiple bolus injections, of a given amount of drug. The qualitative trends exhibited by the plasma drug distribution profiles are consistent with reported experimental studies. Two concepts, viz, the dimensionless decay constant and the plasma/tumor drug concentration trajectories, are found to be particularly useful in the rational design of drug therapy. The dimensionless decay constant provides a measure of the rate of drug decay in the plasma relative to the rate of drug diffusion into the tumor and is thus characteristic of the tumor/drug system. The magnitude of this parameter dictates the choice of drug administration mode for minimizing drug decay in the plasma while simultaneously maximizing drug transport into the tumor. The concentration trajectories provide a measure of the plasma drug concentration relative to the tumor drug concentration at various times following injection. When the tumor drug concentration exceeds the plasma drug concentration, the drug will begin to diffuse out of the tumor. Knowledge of the time at which this diffusion reversal occurs is especially useful

Effect of a therapeutic maximum allowable cost (MAC) program on the cost and utilization of proton pump inhibitors in an employer-sponsored drug plan in Canada.

Science.gov (United States)

Mabasa, Vincent H; Ma, Johnny

2006-06-01

Therapeutic maximum allowable cost (MAC) is a managed care intervention that uses reference pricing in a therapeutic class or category of drugs or an indication (e.g., heartburn). Therapeutic MAC has not been studied in Canada or the United States. The proton pump inhibitor (PPI) rabeprazole was used as the reference drug in this therapeutic MAC program based on prices for PPIs in the province of Ontario. No PPI is available over the counter in Canada. To evaluate the utilization and anticipated drug cost savings for PPIs in an employer-sponsored drug plan in Canada that implemented a therapeutic MAC program for PPIs. An employer group with an average of 6,300 covered members, which adopted the MAC program for PPIs in June 2003, was compared with a comparison group comprising the book of business throughout Canada (approximately 5 million lives) without a PPI MAC program (non-MAC group). Pharmacy claims for PPIs were identified using the first 6 characters of the generic product identifier (GPI 492700) for a 36-month period from June 1, 2002, through May 31, 2005. The primary comparison was the year prior to the intervention (from June 1, 2002, through May 31, 2003) and the first full year following the intervention (June 1, 2004, through May 31, 2005). Drug utilization was evaluated by comparing the market share of each of the PPIs for the 2 time periods and by the days of PPI therapy per patient per year (PPPY) and days of therapy per prescription (Rx). Drug cost was defined as the cost of the drug (ingredient cost), including allowable provincial pharmacy markup but excluding pharmacy dispense fee. Cost savings were calculated from the allowed drug cost per claim, allowed cost per day, and allowed cost PPPY. (All amounts are in Canadian dollars.) The MAC intervention group experienced an 11.7% reduction in the average cost per day of PPI drug therapy, from 2.14 US dollars in the preperiod to 1.89 US dollars in the postperiod, compared with a 3.7% reduction in

Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat

Science.gov (United States)

Lilius, T O; Jokinen, V; Neuvonen, M S; Niemi, M; Kalso, E A; Rauhala, P V

2015-01-01

Background and Purpose The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal. Experimental Approach Morphine minipumps (6 mg·day–1) induced tolerance during 5 days in Sprague–Dawley rats, after which s.c. ketamine (10 mg·kg–1) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3-glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry. Key Results In morphine-naïve rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine-treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed. Conclusions and Implications The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans. PMID:25297798

Pharmacokinetics and Safety of DW1029M, a Botanical Drug for the Treatment of Diabetic Nephropathy, Following Single Doses in Healthy Subjects.

Science.gov (United States)

Kim, Yunjeong; Jeon, Ji-Young; Kim, Eun-Young; Lim, Cheol-Hee; Jang, Hwan Bong; Kim, Min-Gul

2017-09-01

DW1029M is a botanical extract of Morus albalinne root bark and Puerariae radix that is used for the treatment of diabetic nephropathy. This study evaluated the safety and pharmacokinetics of DW1029M following its administration in healthy Korean subjects. We conducted a randomized, open-label, single-dose, crossover phase 1 clinical study. During each period, subjects received 300, 600, or 1200 mg oral doses of DW1029M. Plasma concentrations of puerarin, daidzin, and daidzein were analyzed using a liquid chromatography-tandem mass spectrometry. Six healthy male subjects completed the study. The maximum concentration of the drug in the plasma (C max ) and area under the plasma drug concentration-time curve to the last measurable concentration (AUC last ) for puerarin, daidzin, and daidzein were assessed after oral administration of DW1029M. No serious adverse events or clinically or statistically significant adverse events associated with any of the drug levels were observed. The results of the measurement of vital signs, electrocardiogram, laboratory tests, and physical examinations indicated that no clinically significant changes occurred during this study. The DW1029M tablet was safe and well tolerated over a single dose range of 300-1200 mg. This pharmacokinetic study of a botanical drug may aid in the development of DW1029M. © 2017, The American College of Clinical Pharmacology.

Relation between CYP2D6 Genotype, Phenotype and Therapeutic Drug Concentrations among Nortriptyline and Venlafaxine Users in Old Age Psychiatry

NARCIS (Netherlands)

Berm, E; Kok, R.; Hak, E; Wilffert, B

2016-01-01

Objectives: To determine relations between drug concentrations and the cytochrome P450-CYP2D6 genotype or phenotype among elderly patients treated with nortriptyline or venlafaxine. Methods: A post-hoc analysis of a clinical trial was performed. Patients were grouped into phenotypes according to the

Optimization of Drug Delivery by Drug-Eluting Stents.

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Franz Bozsak

Full Text Available Drug-eluting stents (DES, which release anti-proliferative drugs into the arterial wall in a controlled manner, have drastically reduced the rate of in-stent restenosis and revolutionized the treatment of atherosclerosis. However, late stent thrombosis remains a safety concern in DES, mainly due to delayed healing of the endothelial wound inflicted during DES implantation. We present a framework to optimize DES design such that restenosis is inhibited without affecting the endothelial healing process. To this end, we have developed a computational model of fluid flow and drug transport in stented arteries and have used this model to establish a metric for quantifying DES performance. The model takes into account the multi-layered structure of the arterial wall and incorporates a reversible binding model to describe drug interaction with the cells of the arterial wall. The model is coupled to a novel optimization algorithm that allows identification of optimal DES designs. We show that optimizing the period of drug release from DES and the initial drug concentration within the coating has a drastic effect on DES performance. Paclitaxel-eluting stents perform optimally by releasing their drug either very rapidly (within a few hours or very slowly (over periods of several months up to one year at concentrations considerably lower than current DES. In contrast, sirolimus-eluting stents perform optimally only when drug release is slow. The results offer explanations for recent trends in the development of DES and demonstrate the potential for large improvements in DES design relative to the current state of commercial devices.

Pharmacokinetic-Pharmacodynamic (PKPD) Analysis with Drug Discrimination.

Science.gov (United States)

Negus, S Stevens; Banks, Matthew L

2016-08-30

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

MAK- and BAT values list 2003. Maximum permissible concentrations at the place of work and biological tolerance values for working materials; MAK- und BAT-Werte-Liste 2003. Maximale Arbeitsplatzkonzentrationen und Biologische Arbeitsstofftoleranzwerte

Energy Technology Data Exchange (ETDEWEB)

NONE

2003-07-01

The importance, application and derivation of the maximum concentrations at the workplace is explained. A material's list contains the presently valid maximum concentration values supplemented by a list of materials for which no such values were determined as yet. Furthermore there is a list of working materials clearly identified as carcinogenic, and of working materials with a sensitizing effect, aerosols and some specific working materials are discussed. Finally, the importance and the application of biological tolerance values is explained, supplemented by a materials list. (orig.) [German] In der vorliegenden neuesten Ausgabe werden erneut Bedeutung, Benutzung und Ableitung der MAK-Werte (maximale Arbeitsplatzkonzentrationen) erlaeutert. Eine Stoffliste enthaelt die derzeit gueltigen MAK-Werte, ergaenzt durch eine Aufzaehlung von Stoffen, fuer die noch keine MAK-Werte aufgestellt werden koennen. Es folgt eine Auflistung der Arbeitsstoffe, die bereits eindeutig als krebserregend ausgewiesen wurden, sowie der sensibilisierenden Arbeitsstoffe, Aerosole und einige besondere Arbeitsstoffe. Abschliessend wird die Bedeutung und Benutzung der BAT-Werte erlaeutert, ergaenzt durch eine Stoffliste. (orig.)

Vaginal drug distribution modeling.

Science.gov (United States)

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

2015-09-15

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

2004 list of MAK (maximum work place concentration) and BAT (biological workplace tolerance) values; MAK- und BAT-Werte-Liste 2004

Energy Technology Data Exchange (ETDEWEB)

NONE

2004-07-01

The MAK value (maximum workplace concentration) is the highest permissible concentration of a working material occurring in the ambient air of the workplace as a gas or vapour or in suspended form which according to the present state of knowledge does not, in general, impair the health of or pose an unreasonable molestation (for example through repulsive odour) to employees even in the case of repeated, long-term exposure, that is as a rule 8 hours daily, assuming an average working week of no more than 40 hours. As a rule, MAK values are quoted as average values over a time period of up to one working day or shift. They are primarily defined in consideration of effect characteristics of the substances in question, but also - as far as possible - of the practical conditions attending the work processes or the exposure patterns which they entail. This is done on the basis of scientifically founded criteria of health protection, not on whether providing such protection is technically or economically feasible. In addition, substances are assessed in terms of carcinogenicity, sensitising effects, any contribution to systemic toxicity following cutaneous resorption, hazards for pregnancy and germ cell mutagenicity and are classified or marked accordingly. The Commission's procedures in assessing substances with respect to these criteria are described in corresponding sections of the MAK and BAT list of values, in the ''Toxicological and occupational medical explanations of MAK values'' and in scientific journals.

Plasma drug concentrations and clinical effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in horses sedated with detomidine.

Science.gov (United States)

Vainionpää, Mari H; Raekallio, Marja R; Pakkanen, Soile A E; Ranta-Panula, Ville; Rinne, Valtteri M; Scheinin, Mika; Vainio, Outi M

2013-05-01

To investigate plasma drug concentrations and the effect of MK-467 (L-659'066) on sedation, heart rate and gut motility in horses sedated with intravenous (IV) detomidine. Experimental randomized blinded crossover study. Six healthy horses. Detomidine (10 μg kg(-1) IV) was administered alone (DET) and in combination with MK-467 (250 μg kg(-1) IV; DET + MK). The level of sedation and intestinal sounds were scored. Heart rate (HR) and central venous pressure (CVP) were measured. Blood was collected to determine plasma drug concentrations. Repeated measures anova was used for HR, CVP and intestinal sounds, and the Student's t-test for pairwise comparisons between treatments for the area under the time-sedation curve (AUCsed ) and pharmacokinetic parameters. Significance was set at p Detomidine-induced intestinal hypomotility was prevented by MK-467. AUCsed was significantly higher with DET than DET + MK, but maximal sedations scores did not differ significantly between treatments. MK-467 lowered the AUC of the plasma concentration of detomidine, and increased its volume of distribution and clearance. MK-467 prevented detomidine induced bradycardia and intestinal hypomotility. MK-467 did not affect the clinical quality of detomidine-induced sedation, but the duration of the effect was reduced, which may have been caused by the effects of MK-467 on the plasma concentration of detomidine. MK-467 may be useful clinically in the prevention of certain peripheral side effects of detomidine in horses. © 2013 The Authors. Veterinary Anaesthesia and Analgesia © 2013 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

A REVIEW ON OSMOTIC DRUG DELIVERY SYSTEM

OpenAIRE

Harnish Patel; Upendra Patel; Hiren Kadikar; Bhavin Bhimani; Dhiren Daslaniya; Ghanshyam Patel

2012-01-01

Conventional oral drug delivery systems supply an instantaneous release of drug, which cannot control the release of the drug and effective concentration at the target site. This kind of dosing pattern may result in constantly changing, unpredictable plasma concentrations. Drugs can be delivered in a controlled pattern over a long period of time by the process of osmosis. Osmotic devices are the most promising strategy based systems for controlled drug delivery. They are the most reliable con...

A mechanistic framework for in vitro-in vivo extrapolation of liver membrane transporters: prediction of drug-drug interaction between rosuvastatin and cyclosporine.

Science.gov (United States)

Jamei, M; Bajot, F; Neuhoff, S; Barter, Z; Yang, J; Rostami-Hodjegan, A; Rowland-Yeo, K

2014-01-01

The interplay between liver metabolising enzymes and transporters is a complex process involving system-related parameters such as liver blood perfusion as well as drug attributes including protein and lipid binding, ionisation, relative magnitude of passive and active permeation. Metabolism- and/or transporter-mediated drug-drug interactions (mDDIs and tDDIs) add to the complexity of this interplay. Thus, gaining meaningful insight into the impact of each element on the disposition of a drug and accurately predicting drug-drug interactions becomes very challenging. To address this, an in vitro-in vivo extrapolation (IVIVE)-linked mechanistic physiologically based pharmacokinetic (PBPK) framework for modelling liver transporters and their interplay with liver metabolising enzymes has been developed and implemented within the Simcyp Simulator(®). In this article an IVIVE technique for liver transporters is described and a full-body PBPK model is developed. Passive and active (saturable) transport at both liver sinusoidal and canalicular membranes are accounted for and the impact of binding and ionisation processes is considered. The model also accommodates tDDIs involving inhibition of multiple transporters. Integrating prior in vitro information on the metabolism and transporter kinetics of rosuvastatin (organic-anion transporting polypeptides OATP1B1, OAT1B3 and OATP2B1, sodium-dependent taurocholate co-transporting polypeptide [NTCP] and breast cancer resistance protein [BCRP]) with one clinical dataset, the PBPK model was used to simulate the drug disposition of rosuvastatin for 11 reported studies that had not been used for development of the rosuvastatin model. The simulated area under the plasma concentration-time curve (AUC), maximum concentration (C max) and the time to reach C max (t max) values of rosuvastatin over the dose range of 10-80 mg, were within 2-fold of the observed data. Subsequently, the validated model was used to investigate the impact of

Raltegravir cerebrospinal fluid concentrations in HIV-1 infection.

Directory of Open Access Journals (Sweden)

Aylin Yilmaz

2009-09-01

Full Text Available Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF and plasma in subjects receiving antiretroviral treatment regimens containing this drug.Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma.Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0. The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180. CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations.Approximately 50% of the CSF specimens exceeded the IC(95 levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.

Raltegravir cerebrospinal fluid concentrations in HIV-1 infection.

Science.gov (United States)

Yilmaz, Aylin; Gisslén, Magnus; Spudich, Serena; Lee, Evelyn; Jayewardene, Anura; Aweeka, Francesca; Price, Richard W

2009-09-01

Raltegravir is an HIV-1 integrase inhibitor currently used in treatment-experienced HIV-1-infected patients resistant to other drug classes. In order to assess its central nervous system penetration, we measured raltegravir concentrations in cerebrospinal fluid (CSF) and plasma in subjects receiving antiretroviral treatment regimens containing this drug. Raltegravir concentrations were determined by liquid chromatography tandem mass spectrometry in 25 paired CSF and plasma samples from 16 HIV-1-infected individuals. The lower limit of quantitation was 2.0 ng/ml for CSF and 10 ng/ml for plasma. Twenty-four of the 25 CSF samples had detectable raltegravir concentrations with a median raltegravir concentration of 18.4 ng/ml (range, <2.0-126.0). The median plasma raltegravir concentration was 448 ng/ml (range, 37-5180). CSF raltegravir concentrations correlated with CSF:plasma albumin ratios and CSF albumin concentrations. Approximately 50% of the CSF specimens exceeded the IC(95) levels reported to inhibit HIV-1 strains without resistance to integrase inhibitors. In addition to contributing to control of systemic HIV-1 infection, raltegravir achieves local inhibitory concentrations in CSF in most, but not all, patients. Blood-brain and blood-CSF barriers likely restrict drug entry, while enhanced permeability of these barriers enhances drug entry.

Verification of average daily maximum permissible concentration of styrene in the atmospheric air of settlements under the results of epidemiological studies of the children’s population

Directory of Open Access Journals (Sweden)

М.А. Zemlyanova

2015-03-01

Full Text Available We presented the materials on the verification of the average daily maximum permissible concentration of styrene in the atmospheric air of settlements performed under the results of own in-depth epidemiological studies of children’s population according to the principles of the international risk assessment practice. It was established that children in the age of 4–7 years when exposed to styrene at the level above 1.2 of threshold level value for continuous exposure develop the negative exposure effects in the form of disorders of hormonal regulation, pigmentary exchange, antioxidative activity, cytolysis, immune reactivity and cytogenetic disbalance which contribute to the increased morbidity of diseases of the central nervous system, endocrine system, respiratory organs, digestion and skin. Based on the proved cause-and-effect relationships between the biomarkers of negative effects and styrene concentration in blood it was demonstrated that the benchmark styrene concentration in blood is 0.002 mg/dm3. The justified value complies with and confirms the average daily styrene concentration in the air of settlements at the level of 0.002 mg/m3 accepted in Russia which provides the safety for the health of population (1 threshold level value for continuous exposure.

Functional Maximum Autocorrelation Factors

DEFF Research Database (Denmark)

Larsen, Rasmus; Nielsen, Allan Aasbjerg

2005-01-01

MAF outperforms the functional PCA in concentrating the interesting' spectra/shape variation in one end of the eigenvalue spectrum and allows for easier interpretation of effects. Conclusions. Functional MAF analysis is a useful methods for extracting low dimensional models of temporally or spatially......Purpose. We aim at data where samples of an underlying function are observed in a spatial or temporal layout. Examples of underlying functions are reflectance spectra and biological shapes. We apply functional models based on smoothing splines and generalize the functional PCA in......\\verb+~+\\$\\backslash\\$cite{ramsay97} to functional maximum autocorrelation factors (MAF)\\verb+~+\\$\\backslash\\$cite{switzer85,larsen2001d}. We apply the method to biological shapes as well as reflectance spectra. {\\$\\backslash\\$bf Methods}. MAF seeks linear combination of the original variables that maximize autocorrelation between...

Biodegradable drug-eluting nanofiber-enveloped implants for sustained release of high bactericidal concentrations of vancomycin and ceftazidime: in vitro and in vivo studies

Directory of Open Access Journals (Sweden)

Hsu YH

2014-09-01

Full Text Available Yung-Heng Hsu,1,2 Dave Wei-Chih Chen,1 Chun-Der Tai,3 Ying-Chao Chou,1,2 Shih-Jung Liu,2 Steve Wen-Neng Ueng,1 Err-Cheng Chan4 1Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Guishan Township, 2Department of Mechanical Engineering, Chang Gung University, Guishan Township, 3Graduate Institute of Medical Mechatronics, Chang Gung University, Guishan Township, 4School of Medical Technology, Chang Gung University, Guishan Township, Taiwan Abstract: We developed biodegradable drug-eluting nanofiber-enveloped implants that provided sustained release of vancomycin and ceftazidime. To prepare the biodegradable nanofibrous membranes, poly(D,L-lactide-co-glycolide and the antibiotics were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol. They were electrospun into biodegradable drug-eluting membranes, which were then enveloped on the surface of stainless plates. An elution method and a high-performance liquid chromatography assay were employed to characterize the in vivo and in vitro release rates of the antibiotics from the nanofiber-enveloped plates. The results showed that the biodegradable nanofiber-enveloped plates released high concentrations of vancomycin and ceftazidime (well above the minimum inhibitory concentration for more than 3 and 8 weeks in vitro and in vivo, respectively. A bacterial inhibition test was carried out to determine the relative activity of the released antibiotics. The bioactivity ranged from 25% to 100%. In addition, the serum creatinine level remained within the normal range, suggesting that the high vancomycin concentration did not affect renal function. By adopting the electrospinning technique, we will be able to manufacture biodegradable drug-eluting implants for the long-term drug delivery of different antibiotics. Keywords: biodegradable nanofiber-enveloped plates, electrospinning, antibiotics, release characteristics

Pharmacokinetic Variability of Drugs Used for Prophylactic Treatment of Migraine

DEFF Research Database (Denmark)

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

2017-01-01

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

Effects of Spray-Drying and Choice of Solid Carriers on Concentrations of Labrasol® and Transcutol® in Solid Self-Microemulsifying Drug Delivery Systems (SMEDDS

Directory of Open Access Journals (Sweden)

Christopher Wai-Kei Lam

2013-01-01

Full Text Available Solid self-microemulsifying drug delivery systems (SMEDDS have been used increasingly for improving the bioavailability of hydrophobic drugs. Labrasol® and Transcutol® are used widely as surfactant and solubilizer in the formulation of solid SMEDDS. We investigated the effects of spray-drying and the use of different solid carriers on concentrations of Labrasol® and Transcutol® in solid SMEDDS with scutellarin as the formulated drug. Liquid and gas chromatography tandem mass spectrometry (LC-MS and GC-MS methods were developed for measuring low concentrations of Labrasol® and Transcutol®. In the preparation of solid SMEDDS, lactose, hydroxypropylmethyl cellulose (HPMC and microcrystalline cellulose (MCC were used as solid carriers. Judging from the retention ratios of Labrasol® and Transcutol®, the droplet size of solid SMEDDS increased after spray-drying of liquid SMEDDS, and concentrations of these excipients decreased after the solidifying procedure. In such reduction, Lactose and HPMC were found to preserve Labrasol® and Transcutol® better than MCC during spray-drying, and the resultant droplet sizes were smaller than that of MCC. Labrasol® and Transcutol® showed good thermal stability at 60 °C degree for 10 days. It can be concluded that spray-drying could increase the droplet size of solid SMEDDS and decreased the concentration of Labrasol® and Transcutol® therein, while water-soluble solid carriers could preserve Labrasol® and Transcutol® better than insoluble carriers in the solid SMEDDS.

Herb-drug interactions.

Science.gov (United States)

Fugh-Berman, A

2000-01-08

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

Refractometry for quality control of anesthetic drug mixtures.

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Stabenow, Jennifer M; Maske, Mindy L; Vogler, George A

2006-07-01

Injectable anesthetic drugs used in rodents are often mixed and further diluted to increase the convenience and accuracy of dosing. We evaluated clinical refractometry as a simple and rapid method of quality control and mixing error detection of rodent anesthetic or analgesic mixtures. Dilutions of ketamine, xylazine, acepromazine, and buprenorphine were prepared with reagent-grade water to produce at least 4 concentration levels. The refraction of each concentration then was measured with a clinical refractometer and plotted against the percentage of stock concentration. The resulting graphs were linear and could be used to determine the concentration of single-drug dilutions or to predict the refraction of drug mixtures. We conclude that refractometry can be used to assess the concentration of dilutions of single drugs and can verify the mixing accuracy of drug combinations when the components of the mixture are known and fall within the detection range of the instrument.

Approximate maximum parsimony and ancestral maximum likelihood.

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Alon, Noga; Chor, Benny; Pardi, Fabio; Rapoport, Anat

2010-01-01

We explore the maximum parsimony (MP) and ancestral maximum likelihood (AML) criteria in phylogenetic tree reconstruction. Both problems are NP-hard, so we seek approximate solutions. We formulate the two problems as Steiner tree problems under appropriate distances. The gist of our approach is the succinct characterization of Steiner trees for a small number of leaves for the two distances. This enables the use of known Steiner tree approximation algorithms. The approach leads to a 16/9 approximation ratio for AML and asymptotically to a 1.55 approximation ratio for MP.

Relationship between self-reported adherence, antiretroviral drug concentration measurement and self-reported symptoms in patients treated for HIV-1 infection.

Science.gov (United States)

Fabbiani, Massimiliano; Di Giambenedetto, Simona; Cingolani, Antonella; Fanti, Iuri; Colafigli, Manuela; Tamburrini, Enrica; Cauda, Roberto; Navarra, Pierluigi; De Luca, Andrea; Murri, Rita

2016-01-01

The aim of the study was to explore relationships between self-reported adherence, antiretroviral drug concentration measurement (TDM) and self-reported symptoms. We systematically administered to human immunodeficiency (HIV)-infected outpatients a questionnaire evaluating measures of self-reported adherence (missing doses during last week, deviations from the prescribed timing of therapy, self-initiated discontinuations for > 24 or 48 h, exhausting drugs and present sense of how patients are taking therapy) and a panel of referred symptoms (a symptom score was built summing self-reported scores for each listed symptom). We selected patients who completed the questionnaire and also had a TDM (mainly reflecting adherence in the past few days or weeks), thus comparing these two tools as measures of adherence. A total of 130 patients (64.6% males, median age 44 years, 76.2% with HIV RNA HIV RNA symptom score was associated with a lower self-reported adherence and with a higher proportion of undetectable drug levels. Self-reported adherence and TDM showed a correlation and seemed to be comparable tools for adherence estimation. Self-reported symptoms were associated with lower adherence and undetectable drug levels.

Target concentration intervention: beyond Y2K.

Science.gov (United States)

Holford, N H

2001-01-01

Target concentration intervention (TCI) is proposed as an alternative conceptual strategy to therapeutic drug monitoring (TDM). It is argued that the idea of a therapeutic range has limited the interpretation of measured drug concentrations and diminished the anticipated clinical benefit to patients by use of an oversimplified pharmacodynamic model. TCI on the other hand embraces pharmacokinetic and pharmacodynamic concepts and uses the idea of a target effect and associated target concentration to make rational individual dose decisions.

STUDY ON MAXIMUM SPECIFIC SLUDGE ACIVITY OF DIFFERENT ANAEROBIC GRANULAR SLUDGE BY BATCH TESTS

Institute of Scientific and Technical Information of China (English)

无

2001-01-01

The maximum specific sludge activity of granular sludge from large-scale UASB, IC and Biobed anaerobic reactors were investigated by batch tests. The limitation factors related to maximum specific sludge activity (diffusion, substrate sort, substrate concentration and granular size) were studied. The general principle and procedure for the precise measurement of maximum specific sludge activity were suggested. The potential capacity of loading rate of the IC and Biobed anaerobic reactors were analyzed and compared by use of the batch tests results.

Gemfibrozil Concentrations are Significantly Decreased in the Presence of Lopinavir/ritonavir

Science.gov (United States)

Busse, Kristin H.; Hadigan, Colleen; Chairez, Cheryl; Alfaro, Raul M.; Formentini, Elizabeth; Kovacs, Joseph A.; Penzak, Scott R.

2009-01-01

Objective: To determine the influence of a two-week course of lopinavir-ritonavir on the pharmacokinetics of the triglyceride-lowering agent, gemfibrozil. Methods: The study was conducted as an open label, single-sequence pharmacokinetic study in healthy human volunteers. Gemfibrozil pharmacokinetic parameter values were compared using a students t test after a single 600 mg dose was administered to healthy volunteers before, and after two weeks of lopinavir-ritonavir (400/100 mg) twice daily. Results: Fifteen healthy volunteers (8 males) completed the study. All study drugs were generally well-tolerated and no subjects withdrew participation. The geometric mean ratio (GMR, 90% CI) for gemfibrozil area under the plasma concentration-time curve (AUC0-∞) after 14 days of lopinavir-ritonavir compared to baseline was 0.59 (0.52, 0.67) (P gemfibrozil AUC0-∞ after lopinavir-ritonavir (range: −6% to −74%). The GMRs for gemfibrozil apparent oral clearance (Cl/F) and maximum concentration (Cmax) were 1.69 (1.41, 1.97) and 0.67 (0.49, 0.86) after 14 days of lopinavir-ritonavir versus baseline, respectively (P Gemfibrozil elimination half-life did not change after lopinavir-ritonavir administration (P = 0.60). Conclusion: Lopinavir/ritonavir significantly reduced the systemic exposure of gemfibrozil by reducing gemfibrozil absorption. Clinicians treating HIV-infected patients with hypertriglyceridemia should be aware of this drug interaction. PMID:19648824

Evaluation of Amoxicillin & Cephalexin concentrations in dental alveolar sockets after tooth extraction

Directory of Open Access Journals (Sweden)

Fakhraei AH.

2005-06-01

Full Text Available Statement of Problem: One of the most important complications after tooth extraction and oral and maxillofacial surgery is transient bacteraemia and prescription of prophylactic antibiotic is necessary to prevent postoperative infections in immunocompromised patients. Purpose: The aim of this study was the evaluation of cephalexin and amoxicillin concentrations in dental alveolar sockets following tooth extraction. Materials and Methods: In this interventional study, 80 healthy patients subjected to tooth extraction were divided into two groups. Each group received 1 gr amoxicillin or cephalexin and teeth were extracted 30-60-90-120-180 minutes after antibiotic intake. Blood sampling was performed immediately after extraction and concentrations of two antibiotics were measured in microbiology laboratory. ANOVA test and Post-hoc (Duncan test were used for statistical analysis with P<0.05 as the limit of significance. Results: The maximum serum concentration was 10.1006 μg/ml for amoxicillin at 120 minutes and 41.5467 μg/ml for cephalexin at 90 minutes after drug intake. The minimum inhibitory concentration (MIC of cephalexin and amoxicillin for Streptococcus sanguis was 2 μg/ml and 1 μg/ml respectively. Conclusion: The mean concentration for amoxicillin was 10 times and for cephalexin was 20 times higher than MIC.

21 CFR 131.115 - Concentrated milk.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Concentrated milk. 131.115 Section 131.115 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION MILK AND CREAM Requirements for Specific Standardized Milk and Cream § 131.115...

[Evaporation of selected cytotoxic drugs and permeation of protective gloves--research into the occupational risks of health care personnel handling hazardous cytotoxic drugs (CYTO project)].

Science.gov (United States)

Dolezalová, L; Odráska, P; Gorná, L; Prudilová, M; Vejpustková, R; Bláha, L

2009-01-01

The CYTO project studies an important aspect of healthcare provision -long-term occupational exposure, both threshold and below-threshold, to chemical agents with carcinogenic and mutagenic properties, with the major focus on antineoplastic drugs.This contribution presents experimental results from the first stages of the project's experimental work, i.e. an evaluation of the physico-chemical characteristics of cytostatic agents (evaporation) and an investigation into protective glove permeation. In co-operation with IUTA (Institut für Energie- und Umwelttechnik e.V., Duisburg, Germany), the vapour pressure of paclitaxel, doxorubicin and dacarbazine was measured following OECD guideline No. 104: Vapour pressure curve--vapour pressure balance. Furthermore, the evaporation of cytostatic drugs was examined in actual laboratory conditions by monitoring the airborne concentration using the passive sampling technique. Besides the evaporation of selected drugs, the permeation of cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil and paclitaxel through different types of gloves (vinyl, latex, nitrile) was assessed. Although our experiments showed relatively slow evaporation of the evaluated cytostatic drugs (the highest pressure in paclitaxel was 0.024 Pa), equilibrium concentrations may go up to milligrams per cubic metre. Nevertheless, analytical measurements of airborne contamination did not confirm these concentration levels. The glove permeation experiments with cytostatics showed good resistance of nitrile gloves (which were impermeable to all five drugs). Other materials should be avoided while handling cytostatic agents (e.g. maximum permeation of cyclophosphamide through latex was 19 microg/sq cm/hr). Although the volatility of cytostatic agents is low, it cannot be neglected considering the chronic character of exposure. However, in order to estimate actual occupational exposure, future research should focus on the development of sensitive analytical

Interaction of cephalosporin drugs with dodecyltrimethylammonium Bromide

International Nuclear Information System (INIS)

Hoque, Md. Anamul; Hossain, Mohammed Delwar; Khan, Mohammed Abdullah

2013-01-01

Highlights: • We carry out the interaction of cephalosporin drugs with DTAB conductometrically. • We examine the effect of drugs on the critical micelle concentration of DTAB. • Three critical micelle concentrations are obtained for drug- DTAB system. • Electrostatic and hydrophobic interactions between drugs and DTAB are proposed. • Drug supported micelle formation of DTAB is much favoured in aq. solution of K 2 SO 4 . -- Abstract: The interaction of three cephalosporin drugs namely cefadroxyl monohydrate (CFM), cephalexin monohydrate (CLM) and cephradine monohydrate (CDM) with dodecyltrimethylammonium Bromide (DTAB) has been carried out by conductance measurements in aqueous medium and in aqueous solution of K 2 SO 4 salt over temperature range of (303.15 to 318.15) K. For pure DTAB and drug-DTAB systems, three critical micelle concentrations were obtained. The third critical micelle concentration (c ∗ 3 ) indicates that the spherical micelle turns into rod shape that is sphere to rod transition. The c ∗ values of DTAB are changed due to the addition of cephalosporin drugs. In addition, the change of the values of c ∗ 1 , c ∗ 2 and c ∗ 3 with increase of the concentration of drugs indicate the presence of interaction between drug and DTAB. The c ∗ values indicate that micellization for the cephalosporins-surfactant systems in water follow the order: CFM-surfactant ∗ values for the cephalosporins - DTAB systems in aqueous K 2 SO 4 are lower in magnitude than those in pure water and the values decrease with increase of the concentrations of K 2 SO 4 at a particular temperature. A significant decrease of c ∗ values in the presence of K 2 SO 4 for cephalosporins-DTAB systems indicates that drug supported ionic micelle formation is much favoured in aqueous K 2 SO 4 solution compared to that in pure water. For cephalosporin-DTAB systems, ΔG 0 m values are negative which indicate that the drugs mediated ionic micelle formation processes are

Drugs in breast milk.

Science.gov (United States)

Hervada, A R; Feit, E; Sagraves, R

1978-09-01

The amount of drug excreted into breast milk is dependent upon the lipid solubility of the medication, the mechanism of transport, the degree of ionization, and change in plasma pH. The higher the lipid solubility, the greater the concentration in human milk. The majority of drugs are transported into mammary blood capillaries by passive diffusion. The rest are transported by reverse pinocytosis. Once the drug has entered the epithelial cells of breast tissue, the drug molecules are excreted into the human milk by active transport, passive diffusion, or apocrine secretion. The amount of free (active) drug available for transport depends on the degree of protein binding the plasma pH. Another factor affecting excretion of drugs is the time when breast feeding occurs. In the 1st few days of life, when colostrum is present, water-soluble drugs pass through the breast more easily than afterwards when milk is produced. Then lipid-soluble drugs cross in higher concentrations. The effect on nursing infants is dependent on the amount excreted into the milk, the total amount absorbed by the infant, and the toxicity of the drug. The use of the following drugs in breast feeding mothers is reviewed: anticoagulants, antihypertensives and diuretics, antimicrobials, drugs affecting the central nervous system (alcohol, chloral hydrate, meprobamate, lithium, and aspirin), marijuana, other drugs (antihistamines, atropine, ergot alkaloids, laxatives, nicotine, iodides, propylthiouracil, theophylline), hormones (insulin, thyroxine, and oral contraceptives), and radiopharmaceuticals.

Determination of As, Cd, Hg and Pb in continuous use drugs and excipients by plasma-based techniques in compliance with the United States Pharmacopeia requirements

Science.gov (United States)

da Silva, Caroline Santos; Pinheiro, Fernanda Costa; do Amaral, Clarice Dias Britto; Nóbrega, Joaquim Araújo

2017-12-01

Some inorganic impurities are toxic to human health even when present at low concentrations and therefore must be carefully monitored in products as continuous use drugs. This work aimed the development of a simple microwave-assisted digestion procedure for different types of drugs and excipients and the analytical determination of elemental impurities according to the new regulations of the United States Pharmacopeia (USP) 232 and 233 using inductively coupled plasma optical emission spectrometry (ICP-OES) or inductively coupled plasma mass spectrometry (ICP-MS). Eight drugs samples and two excipients of different brands were microwave-assisted digested with inverse aqua regia. Addition and recovery experiments were performed according to J values, once permissible daily exposure value is specific for each element and estimated according to the maximum daily dose of drug indicated by the label. Samples were spiked with values of 1.5J in order to check accuracies for As, Cd, Hg, and Pb. Recoveries obtained by ICP-OES ranged from 75 to 148% and for ICP-MS ranged from 74 to 120%. The limits of detection for ICP-OES ranged from 0.4 to 17 mg kg- 1 and for ICP-MS from 7.4 to 41.6 μg kg- 1. Both analytical methods were adequate in terms of accuracies and sensitivities. Considering the maximum daily dose, all drugs samples and excipients contained As, Cd, Hg and Pb below the maximum limits stipulated by USP since all of them presented contents below respective limits of detection.

Enhanced drug delivery capabilities from stents coated with absorbable polymer and crystalline drug

OpenAIRE

Carlyle, Wenda C.; McClain, James B.; Tzafriri, Abraham R.; Bailey, Lynn; Zani, Brett G.; Markham, Peter M.; Stanley, James R.L.; Edelman, Elazer R.

2012-01-01

Current drug eluting stent (DES) technology is not optimized with regard to the pharmacokinetics of drug delivery. A novel, absorbable-coating sirolimus-eluting stent (AC-SES) was evaluated for its capacity to deliver drug more evenly within the intimal area rather than concentrating drug around the stent struts and for its ability to match coating erosion with drug release. The coating consisted of absorbable poly-lactide-co-glycolic acid (PLGA) and crystalline sirolimus deposited by a dry-p...

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care.

Science.gov (United States)

Koegelenberg, C F N; Nortje, A; Lalla, U; Enslin, A; Irusen, E M; Rosenkranz, B; Seifart, H I; Bolliger, C T

2013-04-05

There is a paucity of data on the pharmacokinetics of fixed-dose combination enteral antituberculosis treatment in critically ill patients. To establish the pharmacokinetic profile of a fixed-dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol given according to weight via a nasogastric tube to patients admitted to an intensive care unit (ICU). We conducted a prospective, observational study on 10 patients (mean age 32 years, 6 male) admitted to an ICU and treated for tuberculosis (TB). Serum concentrations of the drugs were determined at eight predetermined intervals over 24 hours by means of high-performance liquid chromatography. The therapeutic maximum plasma concentration (Cmax) for rifampicin at time to peak concentration was achieved in only 4 patients, whereas 2 did not achieve therapeutic Cmax for isoniazid. No patient reached sub-therapeutic Cmax for pyrazinamide (6 were within and 4 above therapeutic range). Three patients reached sub-therapeutic Cmax for ethambutol, and 6 patients were within and 1 above the therapeutic range. Patients with a sub-therapeutic rifampicin level had a higher mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score (p=0.03) and a lower estimated glomerular filtration rate (GFR) (p=0.03). A fixed-dose combination tablet, crushed and mixed with water, given according to weight via a nasogastric tube to patients with TB admitted to an ICU resulted in sub-therapeutic rifampicin plasma concentrations in the majority of patients, whereas the other drugs had a more favourable pharmacokinetic profile. Patients with a sub-therapeutic rifampicin concentration had a higher APACHE II score and a lower estimated GFR, which may contribute to suboptimal outcomes in critically ill patients. Studies in other settings have reported similar proportions of patients with 'sub-therapeutic' rifampicin concentrations.

Concentration of trace metals in boreholes in the Ankobra Basin, Ghana

International Nuclear Information System (INIS)

Kortasi, B. K.

2006-01-01

Analysis of trace metals in ground water from the Ankobra basin revealed high levels of iron, manganese and aluminium. Approximately 40% of boreholes had total iron concentration exceeding 1000 μ 1 -1 (maximum WHO permissible limit). Aluminium concentration varied from 0.1 μ to 2510 μ 1 -1 with a median value of 10.0 μ 1 -1 . Approximately 20% of the boreholes had aluminium concentration exceeding the WHO maximum acceptable limit (200 μ 1 -1 ) for drinking water. Manganese concentration was in the range 6-2510 μ 1 -1 with a median of 356 μ 1 -1 . Roughly 25% of the boreholes had manganese concentrations higher that 500 μ 1 -1 , which is the WHO maximum acceptable limit for drinking water. The concentrations of mercury was higher than 1.0 μ 1 -1 (WHO maximum acceptable limit) in 60% of the boreholes during the rainy season but below detection limit in the dry season, suggesting anthropogenic origin for mercury in the groundwater. Other trace metals that occurred, but in insignificant concentration in the boreholes, include lead, arsenic, nickel and selenium. Most of the boreholes with high trace metal concentrations were located in and around the Bawdie-Bogoso-Prestea area. (au)

Drug: D08821 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D08821 Drug Concentrated human red blood cells; Red cells concentrates -leukocytes... reduced (RCC-LR) (TN); Irradiated red cells concentrates -leukocytes reduced (Ir-RCC-LR) (TN) ... PubChem: 96025504 ...

Drug adsorption to plastic containers and retention of drugs in cultured cells under in vitro conditions.

Science.gov (United States)

Palmgrén, Joni J; Mönkkönen, Jukka; Korjamo, Timo; Hassinen, Anssi; Auriola, Seppo

2006-11-01

Loss of drug content during cell culture transport experiment can lead to misinterpretations in permeability analysis. This study analyses drug adsorption to various plastic containers and drug retention in cultured cells under in vitro conditions. The loss of various drugs to polystyrene tubes and well plates was compared to polypropylene and glass tubes both in deionised water and buffer solution. In cellular uptake experiments, administered drugs were obtained from cultured cells by liquid extraction. Samples were collected at various time points and drug concentrations were measured by a new HPLC-MS/MS method. Acidic drugs (hydrochlorothiazide, naproxen, probenicid, and indomethacin) showed little if any sorption to all tested materials in either water or buffer. In the case of basic drugs, substantial loss to polystyrene tubes and well plates was observed. After 4.5 h, the relative amount remaining in aqueous test solution stored in polystyrene tubes was 64.7 +/- 6.8%, 38.4 +/- 9.1%, 31.9 +/- 6.7%, and 23.5 +/- 6.1% for metoprolol, medetomidine, propranolol, and midazolam, respectively. Interestingly, there was no significant loss of drugs dissolved in buffer to any of the tested materials indicating that buffer reduced surficial interaction. The effect of drug concentration to sorption was also tested. Results indicated that the higher the concentration in the test solution the lower the proportional drug loss, suggesting that the polystyrene contained a limited amount of binding sites. Cellular uptake studies showed considerable retention of drugs in cultured cells. The amounts of absorbed drugs in cellular structures were 0.45%, 4.88%, 13.15%, 43.80%, 23.57% and 11.22% for atenolol, metoprolol, medetomidine, propranolol, midazolam, and diazepam, respectively. Overall, these findings will benefit development and validation of further in vitro drug permeation experiments.

Variable Linezolid Exposure in Intensive Care Unit Patients-Possible Role of Drug-Drug Interactions.

Science.gov (United States)

Töpper, Christoph; Steinbach, Cathérine L; Dorn, Christoph; Kratzer, Alexander; Wicha, Sebastian G; Schleibinger, Michael; Liebchen, Uwe; Kees, Frieder; Salzberger, Bernd; Kees, Martin G

2016-10-01

Standard doses of linezolid may not be suitable for all patient groups. Intensive care unit (ICU) patients in particular may be at risk of inadequate concentrations. This study investigated variability of drug exposure and its potential sources in this population. Plasma concentrations of linezolid were determined by high-performance liquid chromatography in a convenience sample of 20 ICU patients treated with intravenous linezolid 600 mg twice daily. Ultrafiltration applying physiological conditions (pH 7.4/37°C) was used to determine the unbound fraction. Individual pharmacokinetic (PK) parameters were estimated by population PK modeling. As measures of exposure to linezolid, area under the concentration-time curve (AUC) and trough concentrations (Cmin) were calculated and compared with published therapeutic ranges (AUC 200-400 mg*h/L, Cmin 2-10 mg/L). Coadministered inhibitors or inducers of cytochrome P450 and/or P-glycoprotein were noted. Data from 18 patients were included into the PK evaluation. Drug exposure was highly variable (median, range: AUC 185, 48-618 mg*h/L, calculated Cmin 2.92, 0.0062-18.9 mg/L), and only a minority of patients had values within the target ranges (6 and 7, respectively). AUC and Cmin were linearly correlated (R = 0.98), and classification of patients (underexposed/within therapeutic range/overexposed) according to AUC or Cmin was concordant in 15 cases. Coadministration of inhibitors was associated with a trend to higher drug exposure, whereas 3 patients treated with levothyroxine showed exceedingly low drug exposure (AUC ∼60 mg*h/L, Cmin linezolid is highly variable and difficult to predict in ICU patients, and therapeutic drug monitoring seems advisable. PK drug-drug interactions might partly be responsible and should be further investigated; protein binding appears to be stable and irrelevant.

Optimal Control of Polymer Flooding Based on Maximum Principle

Directory of Open Access Journals (Sweden)

Yang Lei

2012-01-01

Full Text Available Polymer flooding is one of the most important technologies for enhanced oil recovery (EOR. In this paper, an optimal control model of distributed parameter systems (DPSs for polymer injection strategies is established, which involves the performance index as maximum of the profit, the governing equations as the fluid flow equations of polymer flooding, and the inequality constraint as the polymer concentration limitation. To cope with the optimal control problem (OCP of this DPS, the necessary conditions for optimality are obtained through application of the calculus of variations and Pontryagin’s weak maximum principle. A gradient method is proposed for the computation of optimal injection strategies. The numerical results of an example illustrate the effectiveness of the proposed method.

High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs

Energy Technology Data Exchange (ETDEWEB)

Roy, Caroline; Gagné, Valérie; Fernandes, Maria J.G.; Marceau, François, E-mail: francois.marceau@crchul.ulaval.ca

2013-07-15

Many cationic drugs are concentrated in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping), with an ensuing vacuolar and autophagic cytopathology. In solid tissues, there is evidence that phagocytic cells, e.g., histiocytes, preferentially concentrate cationic drugs. We hypothesized that peripheral blood leukocytes could differentially take up a fluorescent model cation, quinacrine, depending on their phagocytic competence. Quinacrine transport parameters were determined in purified or total leukocyte suspensions at 37 °C. Purified polymorphonuclear leukocytes (PMNLs, essentially neutrophils) exhibited a quinacrine uptake velocity inferior to that of lymphocytes, but a consistently higher affinity (apparent K{sub M} 1.1 vs. 6.3 μM, respectively). However, the vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine transport or initiated its release in either cell type. PMNLs capture most of the quinacrine added at low concentrations to fresh peripheral blood leukocytes compared with lymphocytes and monocytes (cytofluorometry). Accumulation of the autophagy marker LC3-II occurred rapidly and at low drug concentrations in quinacrine-treated PMNLs (significant at ≥ 2.5 μM, ≥ 2 h). Lymphocytes contained more LAMP1 than PMNLs, suggesting that the mass of lysosomes and late endosomes is a determinant of quinacrine uptake V{sub max}. PMNLs, however, exhibited the highest capacity for pinocytosis (uptake of fluorescent dextran into endosomes). The selectivity of quinacrine distribution in peripheral blood leukocytes may be determined by the collaboration of a non-concentrating plasma membrane transport mechanism, tentatively identified as pinocytosis in PMNLs, with V-ATPase-mediated concentration. Intracellular reservoirs of cationic drugs are a potential source of toxicity (e.g., loss of lysosomal function in phagocytes). - Highlights: • Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion

High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs

International Nuclear Information System (INIS)

Roy, Caroline; Gagné, Valérie; Fernandes, Maria J.G.; Marceau, François

2013-01-01

Many cationic drugs are concentrated in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping), with an ensuing vacuolar and autophagic cytopathology. In solid tissues, there is evidence that phagocytic cells, e.g., histiocytes, preferentially concentrate cationic drugs. We hypothesized that peripheral blood leukocytes could differentially take up a fluorescent model cation, quinacrine, depending on their phagocytic competence. Quinacrine transport parameters were determined in purified or total leukocyte suspensions at 37 °C. Purified polymorphonuclear leukocytes (PMNLs, essentially neutrophils) exhibited a quinacrine uptake velocity inferior to that of lymphocytes, but a consistently higher affinity (apparent K M 1.1 vs. 6.3 μM, respectively). However, the vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine transport or initiated its release in either cell type. PMNLs capture most of the quinacrine added at low concentrations to fresh peripheral blood leukocytes compared with lymphocytes and monocytes (cytofluorometry). Accumulation of the autophagy marker LC3-II occurred rapidly and at low drug concentrations in quinacrine-treated PMNLs (significant at ≥ 2.5 μM, ≥ 2 h). Lymphocytes contained more LAMP1 than PMNLs, suggesting that the mass of lysosomes and late endosomes is a determinant of quinacrine uptake V max . PMNLs, however, exhibited the highest capacity for pinocytosis (uptake of fluorescent dextran into endosomes). The selectivity of quinacrine distribution in peripheral blood leukocytes may be determined by the collaboration of a non-concentrating plasma membrane transport mechanism, tentatively identified as pinocytosis in PMNLs, with V-ATPase-mediated concentration. Intracellular reservoirs of cationic drugs are a potential source of toxicity (e.g., loss of lysosomal function in phagocytes). - Highlights: • Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion trapping

Predicting the effect of cytochrome P450 inhibitors on substrate drugs: analysis of physiologically based pharmacokinetic modeling submissions to the US Food and Drug Administration.

Science.gov (United States)

Wagner, Christian; Pan, Yuzhuo; Hsu, Vicky; Grillo, Joseph A; Zhang, Lei; Reynolds, Kellie S; Sinha, Vikram; Zhao, Ping

2015-01-01

The US Food and Drug Administration (FDA) has seen a recent increase in the application of physiologically based pharmacokinetic (PBPK) modeling towards assessing the potential of drug-drug interactions (DDI) in clinically relevant scenarios. To continue our assessment of such approaches, we evaluated the predictive performance of PBPK modeling in predicting cytochrome P450 (CYP)-mediated DDI. This evaluation was based on 15 substrate PBPK models submitted by nine sponsors between 2009 and 2013. For these 15 models, a total of 26 DDI studies (cases) with various CYP inhibitors were available. Sponsors developed the PBPK models, reportedly without considering clinical DDI data. Inhibitor models were either developed by sponsors or provided by PBPK software developers and applied with minimal or no modification. The metric for assessing predictive performance of the sponsors' PBPK approach was the R predicted/observed value (R predicted/observed = [predicted mean exposure ratio]/[observed mean exposure ratio], with the exposure ratio defined as [C max (maximum plasma concentration) or AUC (area under the plasma concentration-time curve) in the presence of CYP inhibition]/[C max or AUC in the absence of CYP inhibition]). In 81 % (21/26) and 77 % (20/26) of cases, respectively, the R predicted/observed values for AUC and C max ratios were within a pre-defined threshold of 1.25-fold of the observed data. For all cases, the R predicted/observed values for AUC and C max were within a 2-fold range. These results suggest that, based on the submissions to the FDA to date, there is a high degree of concordance between PBPK-predicted and observed effects of CYP inhibition, especially CYP3A-based, on the exposure of drug substrates.

Does drug price-regulation affect healthcare expenditures?

Science.gov (United States)

Ben-Aharon, Omer; Shavit, Oren; Magnezi, Racheli

2017-09-01

Increasing health costs in developed countries are a major concern for decision makers. A variety of cost containment tools are used to control this trend, including maximum price regulation and reimbursement methods for health technologies. Information regarding expenditure-related outcomes of these tools is not available. To evaluate the association between different cost-regulating mechanisms and national health expenditures in selected countries. Price-regulating and reimbursement mechanisms for prescription drugs among OECD countries were reviewed. National health expenditure indices for 2008-2012 were extracted from OECD statistical sources. Possible associations between characteristics of different systems for regulation of drug prices and reimbursement and health expenditures were examined. In most countries, reimbursement mechanisms are part of publicly financed plans. Maximum price regulation is composed of reference-pricing, either of the same drug in other countries, or of therapeutic alternatives within the country, as well as value-based pricing (VBP). No association was found between price regulation or reimbursement mechanisms and healthcare costs. However, VBP may present a more effective mechanism, leading to reduced costs in the long term. Maximum price and reimbursement mechanism regulations were not found to be associated with cost containment of national health expenditures. VBP may have the potential to do so over the long term.

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

Directory of Open Access Journals (Sweden)

Jessica M Conway

2014-08-01

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

Entropy concentration and the empirical coding game

NARCIS (Netherlands)

Grünwald, P.D.

2008-01-01

We give a characterization of maximum entropy/minimum relative entropy inference by providing two 'strong entropy concentration' theorems. These theorems unify and generalize Jaynes''concentration phenomenon' and Van Campenhout and Cover's 'conditional limit theorem'. The theorems characterize

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

Science.gov (United States)

Avtar, Ram; Tandon, Deepti

2008-10-02

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

Zeolites: promising candidates for drug delivery systems (DDSs)

OpenAIRE

Vilaça, Natália; Amorim, Ricardo; Baltazar, Fátima; Fonseca, António Manuel; Neves, Isabel C.

2012-01-01

[Excerpt] The aim of controlled drug delivery systems (DDSs) is to administer the necessary amount of drug safely and effectively to specific sites in the human body and to regulate the temporal drug profile for maximum therapeutic benefits.[1] Zeolites are crystalline aluminosilicates solids with very regular microporous structures and they have been recently considered for medical use due to their biological properties and stability in biological environments.[1,2] The large variety in ...

Maximum permissible dose

International Nuclear Information System (INIS)

Anon.

1979-01-01

This chapter presents a historic overview of the establishment of radiation guidelines by various national and international agencies. The use of maximum permissible dose and maximum permissible body burden limits to derive working standards is discussed

Evaluation of Flexible Tacrolimus Drug Concentration Monitoring Approach in Patients Receiving Extended-Release Once-Daily Tacrolimus Tablets.

Science.gov (United States)

Philosophe, Benjamin; Leca, Nicolae; West-Thielke, Patricia M; Horwedel, Timothy; Culkin-Gemmell, Christine; Kistler, Kristin; Stevens, Daniel R

2018-02-20

The majority of United States kidney transplant patients are treated with tacrolimus, a drug effective in preventing graft rejection, but with a narrow therapeutic range, necessitating close monitoring to avoid increased risks of transplant rejection or toxicity if the tacrolimus concentration is too low or too high, respectively. The trough drug concentration tests are time sensitive; patients treated on a twice-daily basis have blood draws exactly 12 hours after their previous dose. The schedule's rigidity causes problems for both patients and health care providers. Novel once-daily tacrolimus formulations such as LCPT (an extended-release tablet by Veloxis Pharmaceuticals, Inc., Cary, North Carolina) have allowed for blood draws on a once-daily basis; however, even that schedule can be restrictive. Results from tests taken either before or after that 24-hour target time may be discarded, or worse, may lead to inappropriate dose changes. Data from ASTCOFF, a phase 3B pharmacokinetic clinical trial (NCT02339246), demonstrated that the unique pharmacokinetic curve of LCPT may allow for a therapeutic monitoring window that extends for 3 hours before or after the 24-hour monitoring target. Furthermore, important tools to help clinicians interpret these levels, such as formulas to estimate the 24-hour trough level if an alternative monitoring time is used, were constructed from these data. These study results give treating clinicians access to data that allow them to safely use and monitor LCPT in their patients and expand the body of evidence surrounding differentiation and practical application of the novel LCPT tacrolimus formulation. © 2018, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Interdependence of initial cell density, drug concentration and exposure time revealed by real-time impedance spectroscopic cytotoxicity assay

DEFF Research Database (Denmark)

Caviglia, Claudia; Zor, Kinga; Canepa, Silvia

2015-01-01

We investigated the combined effect of the initial cell density (12 500, 35 000, 75 000, and 100 000 cells cm−2) and concentration of the anti-cancer drug doxorubicin on HeLa cells by performing timedependent cytotoxicity assays using real-time electrochemical impedance spectroscopy. A correlation...... between the rate of cell death and the initial cell seeding density was found at 2.5 μM doxorubicin concentration, whereas this was not observed at 5 or 100 μM. By sensing the changes in the cell–substrate interaction using impedance spectroscopy under static conditions, the onset of cytotoxicity...... was observed 5 h earlier than when using a standard colorimetric end-point assay (MTS) which measures changes in the mitochondrial metabolism. Furthermore, with the MTS assay no cytotoxicity was observed after 15 h of incubation with 2.5 μM doxorubicin, whereas the impedance showed at this time point cell...

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

Science.gov (United States)

Poulin, Patrick

2015-07-01

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

Concentration dependence of biotransformation in fish liver S9: Optimizing substrate concentrations to estimate hepatic clearance for bioaccumulation assessment.

Science.gov (United States)

Lo, Justin C; Allard, Gayatri N; Otton, S Victoria; Campbell, David A; Gobas, Frank A P C

2015-12-01

In vitro bioassays to estimate biotransformation rate constants of contaminants in fish are currently being investigated to improve bioaccumulation assessments of hydrophobic contaminants. The present study investigates the relationship between chemical substrate concentration and in vitro biotransformation rate of 4 environmental contaminants (9-methylanthracene, pyrene, chrysene, and benzo[a]pyrene) in rainbow trout (Oncorhynchus mykiss) liver S9 fractions and methods to determine maximum first-order biotransformation rate constants. Substrate depletion experiments using a series of initial substrate concentrations showed that in vitro biotransformation rates exhibit strong concentration dependence, consistent with a Michaelis-Menten kinetic model. The results indicate that depletion rate constants measured at initial substrate concentrations of 1 μM (a current convention) could underestimate the in vitro biotransformation potential and may cause bioconcentration factors to be overestimated if in vitro biotransformation rates are used to assess bioconcentration factors in fish. Depletion rate constants measured using thin-film sorbent dosing experiments were not statistically different from the maximum depletion rate constants derived using a series of solvent delivery-based depletion experiments for 3 of the 4 test chemicals. Multiple solvent delivery-based depletion experiments at a range of initial concentrations are recommended for determining the concentration dependence of in vitro biotransformation rates in fish liver fractions, whereas a single sorbent phase dosing experiment may be able to provide reasonable approximations of maximum depletion rates of very hydrophobic substances. © 2015 SETAC.

Local drug delivery - the early Berlin experience: single drug administration versus sustained release.

Science.gov (United States)

Speck, Ulrich; Scheller, Bruno; Rutsch, Wolfgang; Laule, Michael; Stangl, Verena

2011-05-01

Our initial investigations into restenosis inhibition by local drug delivery were prompted by reports on an improved outcome of coronary interventions, including a lower rate of target lesion revascularisation, when the intervention was performed with an ionic instead of non-ionic contrast medium. Although this was not confirmed in an animal study, the short exposure of the vessel wall to paclitaxel dissolved in contrast agent or coated on balloons proved to be efficacious. A study comparing three methods of local drug delivery to the coronary artery in pigs indicated the following order of efficacy in inhibiting neointimal proliferation: paclitaxel-coated balloons > sirolimus-eluting stents, sustained drug release > paclitaxel in contrast medium. Cell culture experiments confirmed that cell proliferation can be inhibited by very short exposure to the drug. Shorter exposure times require higher drug concentrations. Effective paclitaxel concentrations in porcine arteries are achieved when the drug is dissolved in contrast medium or coated on balloons. Paclitaxel is an exceptional drug in that it stays in the treated tissue for a long time. This may explain the long-lasting efficacy of paclitaxel-coated balloons, but does not disprove the hypothesis that the agent blocks a process initiating long-lasting excessive neointimal proliferation, which occurs early after vessel injury.

The analysis of a trace amount of elements in crude drugs

International Nuclear Information System (INIS)

Wakayama, I.; Akagawa, J.; Yase, Y.; Yoshida, S.; Sasajima, Kazuhisa

2001-01-01

The concentrations and the pharmacological actions of iron and zinc in nearly 30 kinds of crude drugs of Chinese medicine are studied using the neutron activation analysis, quantitatively. The quantitative analytical results are also compared with the semi-quantitative analytical results of iron and zinc obtained by particle induced X-ray emission spectroscopy. The crude drugs with higher iron concentration were almost drugs for the mentality. The crude drugs with highest zinc concentration were also the drugs for the mentality. (H. Katsuta)

Preparation and controlled release of mesoporous MCM-41/propranolol hydrochloride composite drug.

Science.gov (United States)

Zhai, Qing-Zhou

2013-01-01

This article used MCM-41 as a carrier for the assembly of propranolol hydrochloride by the impregnation method. By means of chemical analysis, powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy and low-temperature N(2) adsorption-desorption at 77 K, the characterization was made for the prepared materials. The propranolol hydrochloride guest assembly capacity was 316.20 ± 0.31 mg/g (drug/MCM-41). Powder XRD test results indicated that during the process of incorporation, the frameworks of the MCM-41 were not destroyed and the crystalline degrees of the host-guest nanocomposite materials prepared still remained highly ordered. Characterization by SEM and TEM showed that the composite material presented spherical particle and the average particle size of composite material was 186 nm. FT-IR spectra showed that the MCM-41 framework existed well in the (MCM-41)-propranolol hydrochloride composite. Low-temperature nitrogen adsorption-desorption results at 77 K showed that the guest partially occupied the channels of the molecular sieves. Results of the release of the prepared composite drug in simulated body fluid indicated that the drug can release up to 32 h and its maximum released amount was 99.20 ± 0.11%. In the simulated gastric juice release pattern of drug, the maximum time for the drug release was discovered to be 6 h and the maximum cumulative released amount of propranolol hydrochloride was 45.13 ± 0.23%. The drug sustained-release time was 10 h in simulated intestinal fluid and the maximum cumulative released amount was 62.05 ± 0.13%. The prepared MCM-41 is a well-controlled drug delivery carrier.

Color corrected Fresnel lens for solar concentration

International Nuclear Information System (INIS)

Kritchman, E.M.

1979-01-01

A new linear convex Fresnel lens with its groove side down is described. The design philosophy is similar to the highly concentrating two focal Fresnel lens but including a correction for chromatic aberration. A solar concentration ratio as high as 80 is achieved. For wide acceptance angles the concentration nears the theoretical maximum. (author)

Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats.

Science.gov (United States)

Kosasa, T; Kuriya, Y; Matsui, K; Yamanishi, Y

1999-09-10

The effects of oral administration of the centrally acting acetylcholinesterase (AChE) inhibitors, donepezil hydrochloride (donepezil: E2020: (+/-)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride), tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and ENA-713 (rivastigmine: (S)-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate), which have been developed for the treatment of Alzheimer's disease, on the extracellular acetylcholine concentration in the hippocampus of rats were evaluated by using a microdialysis technique without adding cholinesterase inhibitor to the perfusion solution. We also compared the inhibition of brain AChE and the brain concentrations of these drugs. Donepezil at 2.5 mg/kg and tacrine at 5 mg/kg showed significant effects for more than 6 h. At these doses, the maximum increases were observed at about 1.5 h after administration of donepezil, and at about 2 h with tacrine, and were 499% and 422% of the pre-level, respectively. ENA-713 produced significant effects at doses of 0.625, 1.25 and 2.5 mg/kg, which lasted for about 1, 2 and 4 h, respectively. The maximum increases produced by these doses at about 0.5 h after administration were 190, 346 and 458% of the pre-level, respectively. The time courses of brain AChE inhibition with donepezil at 2.5 mg/kg, tacrine at 10 mg/kg and ENA-713 at 2.5 mg/kg were mirror images of the extracellular acetylcholine-increasing action at the same doses. The time courses of the brain concentrations of drugs after oral administration of donepezil at 2.5 mg/kg and tacrine at 10 mg/kg were consistent with those of brain AChE inhibition at the same doses, and there was a linear relation between these parameters. Brain concentration of ENA-713 at 2.5 mg/kg was below the limit of quantification at all time points measured. These results suggest that oral administration of donepezil, tacrine and ENA-713 increases acetylcholine concentration in the

Potential drug-drug interactions with direct oral anticoagulants in elderly hospitalized patients.

Science.gov (United States)

Forbes, Heather L; Polasek, Thomas M

2017-10-01

To determine the prevalence and nature of potential drug-drug interactions (DDIs) with direct oral anticoagulants (DOACs) in elderly hospitalized patients. This was a retrospective observational study. Inclusion criteria were: aged over 65 years; taking apixaban, rivaroxaban or dabigatran; and admitted to the Repatriation General Hospital between April 2014 and July 2015. A list of clinically relevant 'perpetrator' drugs was compiled from product information, the Australian Medicines Handbook, the Australian National Prescribing Service resources, and local health network guidelines. The prevalence and nature of potential DDIs with DOACs was determined by comparing inpatient drug charts with the list of perpetrator drugs. There were 122 patients in the study with a mean age of 82 years. Most patients had nonvalvular atrial fibrillation and were taking DOACs to prevent thrombotic stroke (83%). Overall, 45 patients (37%) had a total of 54 potential DDIs. Thirty-five patients had potential pharmacodynamic DDIs with antidepressants, nonsteroidal anti-inflammatory drugs and antiplatelets (35/122, 29%). Nineteen patients had potential pharmacokinetic DDIs (19/122, 16%). Of these, 68% (13/19) were taking drugs that increase DOAC plasma concentrations (amiodarone, erythromycin, diltiazem or verapamil) and 32% (6/19) were taking drugs that decrease DOAC plasma concentrations (carbamazepine, primidone or phenytoin). There were no cases of patients taking contraindicated interacting drugs. Potential DDIs with DOACs in elderly hospital inpatients are relatively common, particularly interactions that may increase the risk of bleeding. The risk-benefit ratio of DOACs in elderly patients on polypharmacy should always be carefully considered.

Time to reach tacrolimus maximum blood concentration,mean residence time, and acute renal allograft rejection: an open-label, prospective, pharmacokinetic study in adult recipients.

Science.gov (United States)

Kuypers, Dirk R J; Vanrenterghem, Yves

2004-11-01

The aims of this study were to determine whether disposition-related pharmacokinetic parameters such as T(max) and mean residence time (MRT) could be used as predictors of clinical efficacy of tacrolimus in renal transplant recipients, and to what extent these parameters would be influenced by clinical variables. We previously demonstrated, in a prospective pharmacokinetic study in de novo renal allograft recipients, that patients who experienced early acute rejection did not differ from patients free from rejection in terms of tacrolimus pharmacokinetic exposure parameters (dose interval AUC, preadministration trough blood concentration, C(max), dose). However, recipients with acute rejection reached mean (SD) tacrolimus T(max) significantly faster than those who were free from rejection (0.96 [0.56] hour vs 1.77 [1.06] hours; P clearance nor T(1/2) could explain this unusual finding, we used data from the previous study to calculate MRT from the concentration-time curves. As part of the previous study, 100 patients (59 male, 41 female; mean [SD] age, 51.4 [13.8] years;age range, 20-75 years) were enrolled in the study The calculated MRT was significantly shorter in recipients with acute allograft rejection (11.32 [031] hours vs 11.52 [028] hours; P = 0.02), just like T(max) was an independent risk factor for acute rejection in a multivariate logistic regression model (odds ratio, 0.092 [95% CI, 0.014-0.629]; P = 0.01). Analyzing the impact of demographic, transplantation-related, and biochemical variables on MRT, we found that increasing serum albumin and hematocrit concentrations were associated with a prolonged MRT (P calculated MRT were associated with a higher incidence of early acute graft rejection. These findings suggest that a shorter transit time of tacrolimus in certain tissue compartments, rather than failure to obtain a maximum absolute tacrolimus blood concentration, might lead to inadequate immunosuppression early after transplantation.

Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile

International Nuclear Information System (INIS)

Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes; Hilber, Karlheinz; Sandtner, Walter

2013-01-01

The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Na v 1.5 sodium and Ca v 1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on ion channels are a potential

Performance investigation of a concentrating photovoltaic/thermal system with transmissive Fresnel solar concentrator

International Nuclear Information System (INIS)

Feng, Chaoqing; Zheng, Hongfei; Wang, Rui; Ma, Xinglong

2016-01-01

Highlights: • A common design method of a cycloidal transmissive Fresnel solar concentrator was presented. • The gallium arsenide high concentrated solar was used as the receiver. • High efficiency of electric generating could be achieved at noon. • Fresnel solar concentrator was studied and compared in hazy weather and clear weather. - Abstract: A design method of a cycloidal transmissive Fresnel solar concentrator which can provide a certain width focal line was presented in this study. Based on the optical principle of refraction, the dimensions of each wedge-shaped element of Fresnel lens are calculated. An optical simulation has been done to obtain the optical efficiency of the concentrator for different tracking error and axial incidence angle. It has been found that about 80% of the incident sunlight can still be gathered by the absorber when the tracking error is within 0.7°. When the axial angle of incidence is within 10°, it almost has no influence to the receiving rate. The concentrating photovoltaic/thermal system with transmissive Fresnel solar concentrator has been designed in this paper. Take the gallium arsenide high concentrated battery as the receiver, experimental research about cylindrical Fresnel concentrating photovoltaic/thermal system is undertaken in the real sky. Main parameters are tested such as the temperature distribution on receiver, electric energy and thermal energy outputs of concentrating photovoltaic/thermal system, the efficiency of multipurpose utilization of electric and heat, and so on. The test results in clear weather show that maximum electric generating efficiency is about 18% at noon, the maximum heat receiving rate of cooling water is about 45%. At noon time (11:00–13:00), the total efficiency of thermal and electricity can reach more than 55%. Performance of this concentrating photovoltaic/thermal system with transmissive Fresnel solar concentrator is studied and compared in two types typical weather, hazy

The Effect of Alcoholic Extract of Physalis alkekengi on Serum Concentration of Thyroid Hormones in Rats

Directory of Open Access Journals (Sweden)

Shahnaz Shekar-Foroosh

2012-05-01

Full Text Available Background: There are different factors which are effective on maintaining homeostasis, especially by pituitary-thyroid axis hormones. The objective of this study was to examine the effect of Physalis alkekengi plant extract belonging to Solanaceae family on the concentration of the pituitary-thyroid axis hormones.Materials and Methods: This study was conducted on five groups (n=10 of male Wistar rats (with mean weight 210±5g. The control group did not receive any substances, while the reference group received 0.2 ml normal saline daily and the experimental groups received maximum (0.4 g/kg, moderate (0.2 g/kg, and minimum (0.1 g/kg intraperitoneal (IP doses of the alcoholic extract for 14 days. At the end of this period, blood samples were drawn and the results were analyzed by SPSS-11.5 software.Results: The results of statistical analysis showed significant increases in plasma concentrations of thyroxin (T4 and triiodothyronine (T3 in the maximum dose group (p<0.05 with no significant changes in plasma concentrations of thyroid-stimulating hormone (TSH.Conclusion: Increases in T3 and T4 levels with no changes in TSH concentration indicate hyperthyroidism euthyroidism in which the levels of thyroid hormones increase while the amount of TSH remains constant. These changes could be due to plasma proteins increase including albumin, which are probably induced by physaline and alkaloids existing in Physalis alkekengi. So, these drug doses do not seem to bring about pathological changes in the pituitary-thyroid axis.

Drug loading into porous calcium carbonate microparticles by solvent evaporation.

Science.gov (United States)

Preisig, Daniel; Haid, David; Varum, Felipe J O; Bravo, Roberto; Alles, Rainer; Huwyler, Jörg; Puchkov, Maxim

2014-08-01

Drug loading into porous carriers may improve drug release of poorly water-soluble drugs. However, the widely used impregnation method based on adsorption lacks reproducibility and efficiency for certain compounds. The aim of this study was to evaluate a drug-loading method based on solvent evaporation and crystallization, and to investigate the underlying drug-loading mechanisms. Functionalized calcium carbonate (FCC) microparticles and four drugs with different solubility and permeability properties were selected as model substances to investigate drug loading. Ibuprofen, nifedipine, losartan potassium, and metronidazole benzoate were dissolved in acetone or methanol. After dispersion of FCC, the solvent was removed under reduced pressure. For each model drug, a series of drug loads were produced ranging from 25% to 50% (w/w) in steps of 5% (w/w). Loading efficiency was qualitatively analyzed by scanning electron microscopy (SEM) using the presence of agglomerates and drug crystals as indicators of poor loading efficiency. The particles were further characterized by mercury porosimetry, specific surface area measurements, differential scanning calorimetry, and USP2 dissolution. Drug concentration was determined by HPLC. FCC-drug mixtures containing equivalent drug fractions but without specific loading strategy served as reference samples. SEM analysis revealed high efficiency of pore filling up to a drug load of 40% (w/w). Above this, agglomerates and separate crystals were significantly increased, indicating that the maximum capacity of drug loading was reached. Intraparticle porosity and specific surface area were decreased after drug loading because of pore filling and crystallization on the pore surface. HPLC quantification of drugs taken up by FCC showed only minor drug loss. Dissolution rate of FCC loaded with metronidazole benzoate and nifedipine was faster than the corresponding FCC-drug mixtures, mainly due to surface enlargement, because only small

21 CFR 169.176 - Concentrated vanilla extract.

Science.gov (United States)

2010-04-01

... content of ethyl alcohol is not less than 35 percent by volume. (b) The specified name of the food is... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Concentrated vanilla extract. 169.176 Section 169.176 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

Direct binding of radioiodinated monoclonal antibody to tumor cells: significance of antibody purity and affinity for drug targeting or tumor imaging

International Nuclear Information System (INIS)

Kennel, S.J.; Foote, L.J.; Lankford, P.K.; Johnson, M.; Mitchell, T.; Braslawsky, G.R.

1983-01-01

For MoAb to be used efficiently for drug targeting and tumor imaging, the fraction of antibody binding to tumor cells must be maximized. The authors have studied the binding of 125 I MoAb in three different tumor systems. The fraction of antibody that could be bound to the cell surface was directly proportional to the antibody purity. The affinity constant also limits the fraction of antibody that can bind to cells at a given antigen concentration. Rearrangement of the standard expression for univalent equilibrium binding between two reactants shows that in antigen excess, the maximum fraction of antibody that can bind =Ka[Ag total]/1 + Ka[Ag total]. Binding data using four different MoAb with three cell systems confirm this relationship. Estimates for reasonable concentrations of tumor antigens in vivo indicate that antibodies with binding constants less than 10 8 M -1 are not likely to be useful for drug targeting or tumor imaging

A Kinetic Model to Explain the Maximum in alpha-Amylase Activity Measurements in the Presence of Small Carbohydrates

NARCIS (Netherlands)

Baks, T.; Janssen, A.E.M.; Boom, R.M.

2006-01-01

The effect of the presence of several small carbohydrates on the measurement of the -amylase activity was determined over a broad concentration range. At low carbohydrate concentrations, a distinct maximum in the -amylase activity versus concentration curves was observed in several cases. At higher

Energy-Efficient Algorithm for Sensor Networks with Non-Uniform Maximum Transmission Range

Directory of Open Access Journals (Sweden)

Yimin Yu

2011-06-01

Full Text Available In wireless sensor networks (WSNs, the energy hole problem is a key factor affecting the network lifetime. In a circular multi-hop sensor network (modeled as concentric coronas, the optimal transmission ranges of all coronas can effectively improve network lifetime. In this paper, we investigate WSNs with non-uniform maximum transmission ranges, where sensor nodes deployed in different regions may differ in their maximum transmission range. Then, we propose an Energy-efficient algorithm for Non-uniform Maximum Transmission range (ENMT, which can search approximate optimal transmission ranges of all coronas in order to prolong network lifetime. Furthermore, the simulation results indicate that ENMT performs better than other algorithms.

Drug poisoning deaths in Sweden show a predominance of ethanol in mono-intoxications, adverse drug-alcohol interactions and poly-drug use.

Science.gov (United States)

Jones, A W; Kugelberg, F C; Holmgren, A; Ahlner, J

2011-03-20

Over a 10-year period (1998-2007) all deaths in Sweden classified by forensic pathologists as fatal drug poisonings (N = 6894) were retrieved from a toxicology database (TOXBASE) belonging to the National Board of Forensic Medicine. The deaths were further classified as suicides N = 2288 (33%), undetermined N = 2260 (33%) and accidental N = 2346 (34%). The average age (± SD) of all victims was 49.1 ± 15.9 years and men 47.4 ± 15.6 years were 5-year younger than women 52.2 ± 15.8 years (p intoxications) was found in 22% of all poisoning deaths (p intoxication deaths were mostly ethanol-related (N = 976) and the mean and median blood-alcohol concentration (BAC) was 3.06 g/L and 3.10 g/L, respectively. The BAC decreased as the number of additional drugs in blood increased from 2.15 g/L with one drug to 1.25 g/L with 6 or more drugs. The mean (median) concentrations of non-alcohol drugs in mono-intoxication deaths were morphine (N = 93) 0.5mg/L (0.2mg/L), amphetamine (N = 39) 2.0mg/L (1.2mg/L), dextropropoxyphene (N = 33) 3.9 mg/L (2.9 mg/L), dihydro-propiomazine (N = 32) 1.6 mg/L (1.0mg/L) and 7-amino-flunitrazepam (N = 28), 0.4 mg/L (0.3mg/L). Elevated blood morphine in these poisoning deaths mostly reflected abuse of heroin as verified by finding 6-monoacetyl morphine (6-MAM) in the blood samples. When investigating drug poisoning deaths a comprehensive toxicological analysis is essential although the results do not reveal the extent of prior exposure to drugs or the development of pharmacological tolerance. The concentrations of drugs determined in post-mortem blood are one element in the case. The autopsy report, the police investigation, the findings at the scene and eye-witness statements should all be carefully considered when the cause and manner of death are determined. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Study on drug resistance of mycobacterium tuberculosis in patients with pulmonary tuberculosis by drug resistance gene detecting

International Nuclear Information System (INIS)

Wang Wei; Li Hongmin; Wu Xueqiong; Wang Ansheng; Ye Yixiu; Wang Zhongyuan; Liu Jinwei; Chen Hongbing; Lin Minggui; Wang Jinhe; Li Sumei; Jiang Ping; Feng Bai; Chen Dongjing

2004-01-01

To investigate drug resistance of mycobacterium tuberculosis in different age group, compare detecting effect of two methods and evaluate their the clinical application value, all of the strains of mycobacterium tuberculosis were tested for resistance to RFP, INH SM PZA and EMB by the absolute concentration method on Lowenstein-Jensen medium and the mutation of the rpoB, katG, rpsL, pncA and embB resistance genes in M. tuberculosis was tested by PCR-SSCP. In youth, middle and old age group, the rate of acquired drug resistance was 89.2%, 85.3% and 67.6% respectively, the gene mutation rate was 76.2%, 81.3% and 63.2% respectively. The rate of acquired drug resistance and multiple drug resistance in youth group was much higher than those in other groups. The gene mutation was correlated with drug resistance level of mycobacterium tuberculosis. The gene mutation rate was higher in strains isolated from high concentration resistance than those in strains isolated from low concentration resistance. The more irregular treatment was longer, the rate of drug resistance was higher. Acquired drug resistance varies in different age group. It suggested that surveillance of drug resistence in different age group should be taken seriously, especially in youth group. PCR - SSCP is a sensitive and specific method for rapid detecting rpoB, katG, rpsL, pncA and embB genes mutations of MTB. (authors)

Exercise treatment for drug abuse -a Danish pilot study

DEFF Research Database (Denmark)

Roessler, Kirsten Kaya

2010-01-01

AIMS: The paper presents a recent Danish programme using exercise to alter the behaviour and body image of drug addicts. METHODS: 38 participants (23 male and 15 female) took part in groups three times per week for a minimum of two to a maximum of six months. Self-reported data combined with the ......AIMS: The paper presents a recent Danish programme using exercise to alter the behaviour and body image of drug addicts. METHODS: 38 participants (23 male and 15 female) took part in groups three times per week for a minimum of two to a maximum of six months. Self-reported data combined...

Quantitative PET Imaging in Drug Development: Estimation of Target Occupancy.

Science.gov (United States)

Naganawa, Mika; Gallezot, Jean-Dominique; Rossano, Samantha; Carson, Richard E

2017-12-11

Positron emission tomography, an imaging tool using radiolabeled tracers in humans and preclinical species, has been widely used in recent years in drug development, particularly in the central nervous system. One important goal of PET in drug development is assessing the occupancy of various molecular targets (e.g., receptors, transporters, enzymes) by exogenous drugs. The current linear mathematical approaches used to determine occupancy using PET imaging experiments are presented. These algorithms use results from multiple regions with different target content in two scans, a baseline (pre-drug) scan and a post-drug scan. New mathematical estimation approaches to determine target occupancy, using maximum likelihood, are presented. A major challenge in these methods is the proper definition of the covariance matrix of the regional binding measures, accounting for different variance of the individual regional measures and their nonzero covariance, factors that have been ignored by conventional methods. The novel methods are compared to standard methods using simulation and real human occupancy data. The simulation data showed the expected reduction in variance and bias using the proper maximum likelihood methods, when the assumptions of the estimation method matched those in simulation. Between-method differences for data from human occupancy studies were less obvious, in part due to small dataset sizes. These maximum likelihood methods form the basis for development of improved PET covariance models, in order to minimize bias and variance in PET occupancy studies.

Comparison of the Force-, Velocity- and Power-Time Curves Between the Concentric-Only and Eccentric-Concentric Bench Press Exercises.

Science.gov (United States)

Pérez-Castilla, Alejandro; Comfort, Paul; McMahon, John J; Pestaña-Melero, Francisco Luis; García-Ramos, Amador

2018-01-17

The aim of this study was to compare the temporal and mechanical variables between the concentric-only and eccentric-concentric bench press (BP) variants. Twenty-one men (age: 22.0±4.2 years, body mass: 73.4±7.7 kg, height: 177.2±8.0 cm; one-repetition maximum [1RM]: 1.12±0.12 kg⋅kg) were evaluated during the concentric-only and eccentric-concentric BP variants using 80% 1RM. Temporal (concentric phase duration, propulsive phase duration, and time to reach the maximum values of force, velocity, and power) and mechanical variables (force, velocity, and power), determined using a linear velocity transducer, were compared between both BP variants. All temporal variables were significantly lower during the eccentric-concentric BP compared to the concentric-only BP (P velocity and power were significantly higher for the eccentric-concentric BP compared to the concentric-only BP (all P velocity (ES: 0.40) and power (ES: 0.41). The stretch-shortening cycle (i.e., eccentric-concentric BP) mainly enhanced force production at the early portion of the concentric phase, but this potentiation effect gradually reduced over the latter part of the movement. Finally, force was higher for the concentric-only BP during 49% of the concentric phase duration. These results suggest that both BP variants should be included during resistance training programs in order to optimize force output at different points of the concentric phase.

Dissolution rate enhancement of the poorly water-soluble drug Tibolone using PVP, SiO2, and their nanocomposites as appropriate drug carriers.

Science.gov (United States)

Papadimitriou, Sofia; Bikiaris, Dimitrios

2009-09-01

Creation of immediate release formulations for the poorly water-soluble drug Tibolone through the use of solid dispersions (SDs). SD systems of Tibolone (Tibo) with poly(vinylpyrrolidone) (PVP), fumed SiO(2) nanoparticles, and their corresponding ternary systems (PVP/SiO(2)/Tibo) were prepared and studied in order to produce formulations with enhanced drug dissolution rates. The prepared SDs were characterized by the use of differential scanning calorimetry and wide-angle X-ray diffractometry techniques. Also dissolution experiments were performed. From the results it was concluded that PVP as well as SiO(2) can be used as appropriate carriers for the amorphization of Tibo, even when the drug is used at high concentrations (20-30%, w/w). This is due to the evolved interactions taking place between the drug and the used carriers, as was verified by Fourier transform infrared spectroscopy. At higher concentrations the drug was recrystallized. Similar are the observations on the ternary PVP/SiO(2)/Tibo SDs. The dissolution profiles of the drug in PVP/Tibo and SiO(2)/Tibo SDs are directly dependent on the physical state of the drug. Immediately release rates are observed in SD with low drug concentrations, in which Tibo was in amorphous state. However, these release profiles are drastically changed in the ternary PVP/SiO(2)/Tibo SDs. An immediate release profile is observed for low drug concentrations and an almost sustained release as the concentration of Tibo increases. This is due to the weak interactions that take place between PVP and SiO(2), which result in alterations of the characteristics of the carrier (PVP/SiO(2) nanocomposites). Immediate release formulation was created for Tibolone as well as new nanocomposite matrices of PVP/SiO((2)), which drastically change the release profile of the drug to a sustained delivery.

The Female Genital Tract Microbiome Is Associated With Vaginal Antiretroviral Drug Concentrations in Human Immunodeficiency Virus-Infected Women on Antiretroviral Therapy.

Science.gov (United States)

Donahue Carlson, Renee; Sheth, Anandi N; Read, Timothy D; Frisch, Michael B; Mehta, C Christina; Martin, Amy; Haaland, Richard E; Patel, Anar S; Pau, Chou-Pong; Kraft, Colleen S; Ofotokun, Igho

2017-11-15

The female genital tract (FGT) microbiome may affect vaginal pH and other factors that influence drug movement into the vagina. We examined the relationship between the microbiome and antiretroviral concentrations in the FGT. Over one menstrual cycle, 20 human immunodeficiency virus (HIV)-infected women virologically suppressed on tenofovir (TFV) disoproxil fumarate/emtricitabine and ritonavir-boosted atazanavir (ATV) underwent serial paired cervicovaginal and plasma sampling for antiretroviral concentrations using high-performance liquid chromatography-tandem mass spectrometry. Analysis of 16S ribosomal RNA gene sequencing of cervicovaginal lavage clustered each participant visit into a unique microbiome community type (mCT). Participants were predominantly African American (95%), with a median age of 38 years. Cervicovaginal lavage sequencing (n = 109) resulted in a low-diversity mCT dominated by Lactobacillus (n = 40), and intermediate-diversity (n = 28) and high-diversity (n = 41) mCTs with abundance of anaerobic taxa. In multivariable models, geometric mean FGT:plasma ratios varied significantly by mCT for all 3 drugs. For both ATV and TFV, FGT:plasma was significantly lower in participant visits with high- and low-diversity mCT groups (all P < .02). For emtricitabine, FGT:plasma was significantly lower in participant visits with low- vs intermediate-diversity mCT groups (P = .002). Certain FGT mCTs are associated with decreased FGT antiretroviral concentrations. These findings are relevant for optimizing antiretrovirals used for biomedical HIV prevention in women. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Last Glacial Maximum CO2 and d13C successfully reconciled

NARCIS (Netherlands)

Bouttes, N.; Paillard, D.; Roche, D.M.V.A.P.; Brovkin, V.; Bopp, L.

2011-01-01

During the Last Glacial Maximum (LGM, ∼21,000 years ago) the cold climate was strongly tied to low atmospheric CO2 concentration (∼190 ppm). Although it is generally assumed that this low CO2 was due to an expansion of the oceanic carbon reservoir, simulating the glacial level

The maximum theoretical performance of unconcentrated solar photovoltaic and thermoelectric generator systems

DEFF Research Database (Denmark)

Bjørk, Rasmus; Nielsen, Kaspar Kirstein

2017-01-01

The maximum efficiency for photovoltaic (PV) and thermoelectric generator (TEG) systems without concentration is investigated. Both a combined system where the TEG is mounted directly on the back of the PV and a tandem system where the incoming sunlight is split, and the short wavelength radiation...

Concentration of metals in fishes from Thane and Bassein creeks of Bombay, India

Digital Repository Service at National Institute of Oceanography (India)

Krishnamurti, A.J.; Nair, V.R.

-58% to the total metals accumulated. Maximum concentration of all metals was found either in liver or in alimentary canal with lowest level in muscle tissue. Though metal accumulation was found to be species specific maximum concentrations were found in bottom...

The impact of preparation parameters on typical attributes of chitosan-heparin nanohydrogels: particle size, loading efficiency, and drug release.

Science.gov (United States)

Shahbazi, Mohammad-Ali; Hamidi, Mehrdad

2013-11-01

Today, developing an optimized nanoparticle (NP) preparation procedure is of paramount importance in all nanoparticulate drug delivery researches, leading to expanding more operative and clinically validated nanomedicines. In this study, a one-at-a-time experimental approach was used for evaluating the effect of various preparation factors on size, loading, and drug release of hydrogel NPs prepared with ionotropic gelation between heparin and chitosan. The size, loading efficiency (LE) and drug release profile of the NPs were evaluated when the chitosan molecular weight, chitosan concentration, heparin addition time to chitosan solution, heparin concentration, pH value of chitosan solution, temperature, and mixing rate were changed separately while other factors were in optimum condition. The results displayed that size and LE are highly influenced by chitosan concentration, getting an optimum of 63 ± 0.57 and 75.19 ± 2.65, respectively, when chitosan concentration was 0.75 mg/ml. Besides, heparin addition time of 3 min leaded to 74.1 ± 0.79 % LE with no sensible effect on size and release profile. In addition, pH 5.5 showed a minimum size of 63 ± 1.87, maximum LE of 73.81 ± 3.13 and the slowest drug release with 63.71 ± 3.84 % during one week. Although LE was not affected by temperature, size and release reduced to 63 ± 0 and 74.21 ± 1.99% when temperature increased from 25°C to 55°C. Also, continuous increase of mixer rate from 500 to 3500 rpm resulted in constant enhancement of LE from 58.3 ± 3.6 to 74.4 ± 2.59 as well as remarkable decrease in size from 148 ± 4.88 to 63 ± 2.64.

Concentration of trace metals in boreholes in the Ankobra Basin, Ghan

African Journals Online (AJOL)

Roughly 25% of the boreholes had manganese concentration higher than 500 mg l-1, which is the WHO maximum acceptable limit for drinking water. The concentration of mercury was higher than 1.0 mg l-1 (WHO maximum acceptable limit) in 60% of the boreholes during the rainy season but below detection limit in the dry ...

Pharmacokinetic drug-drug interaction between erlotinib and paracetamol: A potential risk for clinical practice.

Science.gov (United States)

Karbownik, Agnieszka; Szałek, Edyta; Sobańska, Katarzyna; Grabowski, Tomasz; Wolc, Anna; Grześkowiak, Edmund

2017-05-01

Erlotinib is a tyrosine kinase inhibitor available for the treatment of non-small cell lung cancer. Paracetamol is an analgesic agent, commonly used in cancer patients. Because these drugs are often co-administered, there is an increasing issue of interaction between them. The aim of the study was to investigate the effect of paracetamol on the pharmacokinetic parameters of erlotinib, as well as the influence of erlotinib on the pharmacokinetics of paracetamol. The rabbits were divided into three groups: the rabbits receiving erlotinib (I ER ), the group receiving paracetamol (II PR ), and the rabbits receiving erlotinib+paracetamol (III ER+PR ). A single dose of erlotinib was administered orally (25mg) and was administered intravenously (35mg/kg). Plasma concentrations of erlotinib, its metabolite (OSI420), paracetamol and its metabolites - glucuronide and sulphate were measured with the validated method. During paracetamol co-administration we observed increased erlotinib maximum concentration (C max ) and area under the plasma concentration-time curve from time zero to infinity (AUC 0-∞ ) by 87.7% and 31.1%, respectively. In turn, erlotinib lead to decreased paracetamol AUC 0-∞ by 35.5% and C max by 18.9%. The mean values of paracetamol glucuronide/paracetamol ratios for C max were 32.2% higher, whereas paracetamol sulphate/paracetamol ratios for C max and AUC 0-∞ were 37.1% and 57.1% lower in the II PR group, when compared to the III ER+PR group. Paracetamol had significant effect on the enhanced plasma exposure of erlotinib. Additionally, erlotinib contributed to the lower concentrations of paracetamol. Decreased glucuronidation and increased sulphation of paracetamol after co-administration of erlotinib were also observed. Copyright © 2017. Published by Elsevier B.V.

Therapeutic drug monitoring: how to improve drug dosage and patient safety in tuberculosis treatment

Directory of Open Access Journals (Sweden)

Giovanni Sotgiu

2015-03-01

Full Text Available In this article we describe the key role of tuberculosis (TB treatment, the challenges (mainly the emergence of drug resistance, and the opportunities represented by the correct approach to drug dosage, based on the existing control and elimination strategies. In this context, the role and contribution of therapeutic drug monitoring (TDM is discussed in detail. Treatment success in multidrug-resistant (MDR TB cases is low (62%, with 7% failing or relapsing and 9% dying and in extensively drug-resistant (XDR TB cases is even lower (40%, with 22% failing or relapsing and 15% dying. The treatment of drug-resistant TB is also more expensive (exceeding €50 000 for MDR-TB and €160 000 for XDR-TB and more toxic if compared to that prescribed for drug-susceptible TB. Appropriate dosing of first- and second-line anti-TB drugs can improve the patient's prognosis and lower treatment costs. TDM is based on the measurement of drug concentrations in blood samples collected at appropriate times and subsequent dose adjustment according to the target concentration. The ‘dried blood spot’ technique offers additional advantages, providing the rationale for discussions regarding a possible future network of selected, quality-controlled reference laboratories for the processing of dried blood spots of difficult-to-treat patients from reference TB clinics around the world.

Identification of intestinal loss of a drug through physiologically based pharmacokinetic simulation of plasma concentration-time profiles.

Science.gov (United States)

Peters, Sheila Annie

2008-01-01

Despite recent advances in understanding of the role of the gut as a metabolizing organ, recognition of gut wall metabolism and/or other factors contributing to intestinal loss of a compound has been a challenging task due to the lack of well characterized methods to distinguish it from first-pass hepatic extraction. The implications of identifying intestinal loss of a compound in drug discovery and development can be enormous. Physiologically based pharmacokinetic (PBPK) simulations of pharmacokinetic profiles provide a simple, reliable and cost-effective way to understand the mechanisms underlying pharmacokinetic processes. The purpose of this article is to demonstrate the application of PBPK simulations in bringing to light intestinal loss of orally administered drugs, using two example compounds: verapamil and an in-house compound that is no longer in development (referred to as compound A in this article). A generic PBPK model, built in-house using MATLAB software and incorporating absorption, metabolism, distribution, biliary and renal elimination models, was employed for simulation of concentration-time profiles. Modulation of intrinsic hepatic clearance and tissue distribution parameters in the generic PBPK model was done to achieve a good fit to the observed intravenous pharmacokinetic profiles of the compounds studied. These optimized clearance and distribution parameters are expected to be invariant across different routes of administration, as long as the kinetics are linear, and were therefore employed to simulate the oral profiles of the compounds. For compounds with reasonably good solubility and permeability, an area under the concentration-time curve for the simulated oral profile that far exceeded the observed would indicate some kind of loss in the intestine. PBPK simulations applied to compound A showed substantial loss of the compound in the gastrointestinal tract in humans but not in rats. This accounted for the lower bioavailability of the

Managing Drug-Drug Interaction Between Ombitasvir, Paritaprevir/Ritonavir, Dasabuvir, and Mycophenolate Mofetil.

Science.gov (United States)

Lemaitre, Florian; Ben Ali, Zeineb; Tron, Camille; Jezequel, Caroline; Boglione-Kerrien, Christelle; Verdier, Marie-Clémence; Guyader, Dominique; Bellissant, Eric

2017-08-01

No drug-drug interaction study has been conducted to date for the combination of ombitasvir, paritaprevir/ritonavir, dasabuvir (3D), and mycophenolic acid (MPA). We here report the case of a hepatitis C virus-infected patient treated with 3D and MPA for vasculitis. In light of the threat of drug-drug interaction, the concentration of MPA was measured before, during, and 15 days after the end of the 3D treatment. Similar values were found at all 3 time points, thus indicating that there is probably no need to adapt MPA dosage to 3D.

Long-term variation of outdoor radon equilibrium equivalent concentration

Energy Technology Data Exchange (ETDEWEB)

Hoetzl, H. [GSF-Forschungszentrum fuer Umwelt und Gesundheit, Inst. fuer Strahlenschutz, Oberschleissheim (Germany); Winkler, R. [GSF-Forschungszentrum fuer Umwelt und Gesundheit, Inst. fuer Strahlenschutz, Oberschleissheim (Germany)

1994-10-01

Long-term variation of outdoor radon equilibrium equivalent concentration was investigated from 1982 to 1992 at a semi-natural location 10 km north of Munich, southern Germany. For this period the continuous measurement yielded a long-term average of 8.6 Bq.m{sup -3} (arithmetic mean) and 6.9 Bq.m{sup -3} (geometric mean), from which an average annual effective dose of 0.14 mSv due to outdoor radon can be derived. A long-term trend of the radon concentration was not detectable over the whole period of observation. However, by time series analysis, a long-term cyclic pattern was identified with two maxima (1984-1986, 1989-1991) and two minima (1982-1983, 1987-1988). The seasonal pattern is characterized by an autumn maximum and an early summer minimum. On average, the seasonal maximum in October was found to be higher by a factor of 2 than the June minimum. The diurnal variation of the radon concentration shows a maximum in the early morning and a minimum in the afternoon. On average, this maximum is a factor of 2 higher than the minimum. In the long term a seasonal pattern was observed for diurnal variation, with an average diurnal maximum to minimum ratio of 1.5 in winter compared with 3.5 in the summer months. The radon concentration is correlated with a meteorological parameter (stagnation index) which takes into account horizontal and vertical exchange processes and the wash-out of aerosols in the lower atmosphere. (orig.)

Long-term variation of outdoor radon equilibrium equivalent concentration

International Nuclear Information System (INIS)

Hoetzl, H.; Winkler, R.

1994-01-01

Long-term variation of outdoor radon equilibrium equivalent concentration was investigated from 1982 to 1992 at a semi-natural location 10 km north of Munich, southern Germany. For this period the continuous measurement yielded a long-term average of 8.6 Bq.m -3 (arithmetic mean) and 6.9 Bq.m -3 (geometric mean), from which an average annual effective dose of 0.14 mSv due to outdoor radon can be derived. A long-term trend of the radon concentration was not detectable over the whole period of observation. However, by time series analysis, a long-term cyclic pattern was identified with two maxima (1984-1986, 1989-1991) and two minima (1982-1983, 1987-1988). The seasonal pattern is characterized by an autumn maximum and an early summer minimum. On average, the seasonal maximum in October was found to be higher by a factor of 2 than the June minimum. The diurnal variation of the radon concentration shows a maximum in the early morning and a minimum in the afternoon. On average, this maximum is a factor of 2 higher than the minimum. In the long term a seasonal pattern was observed for diurnal variation, with an average diurnal maximum to minimum ratio of 1.5 in winter compared with 3.5 in the summer months. The radon concentration is correlated with a meteorological parameter (stagnation index) which takes into account horizontal and vertical exchange processes and the wash-out of aerosols in the lower atmosphere. (orig.)

The moving-window Bayesian maximum entropy framework: estimation of PM(2.5) yearly average concentration across the contiguous United States.

Science.gov (United States)

Akita, Yasuyuki; Chen, Jiu-Chiuan; Serre, Marc L

2012-09-01

Geostatistical methods are widely used in estimating long-term exposures for epidemiological studies on air pollution, despite their limited capabilities to handle spatial non-stationarity over large geographic domains and the uncertainty associated with missing monitoring data. We developed a moving-window (MW) Bayesian maximum entropy (BME) method and applied this framework to estimate fine particulate matter (PM(2.5)) yearly average concentrations over the contiguous US. The MW approach accounts for the spatial non-stationarity, while the BME method rigorously processes the uncertainty associated with data missingness in the air-monitoring system. In the cross-validation analyses conducted on a set of randomly selected complete PM(2.5) data in 2003 and on simulated data with different degrees of missing data, we demonstrate that the MW approach alone leads to at least 17.8% reduction in mean square error (MSE) in estimating the yearly PM(2.5). Moreover, the MWBME method further reduces the MSE by 8.4-43.7%, with the proportion of incomplete data increased from 18.3% to 82.0%. The MWBME approach leads to significant reductions in estimation error and thus is recommended for epidemiological studies investigating the effect of long-term exposure to PM(2.5) across large geographical domains with expected spatial non-stationarity.

The moving-window Bayesian Maximum Entropy framework: Estimation of PM2.5 yearly average concentration across the contiguous United States

Science.gov (United States)

Akita, Yasuyuki; Chen, Jiu-Chiuan; Serre, Marc L.

2013-01-01

Geostatistical methods are widely used in estimating long-term exposures for air pollution epidemiological studies, despite their limited capabilities to handle spatial non-stationarity over large geographic domains and uncertainty associated with missing monitoring data. We developed a moving-window (MW) Bayesian Maximum Entropy (BME) method and applied this framework to estimate fine particulate matter (PM2.5) yearly average concentrations over the contiguous U.S. The MW approach accounts for the spatial non-stationarity, while the BME method rigorously processes the uncertainty associated with data missingnees in the air monitoring system. In the cross-validation analyses conducted on a set of randomly selected complete PM2.5 data in 2003 and on simulated data with different degrees of missing data, we demonstrate that the MW approach alone leads to at least 17.8% reduction in mean square error (MSE) in estimating the yearly PM2.5. Moreover, the MWBME method further reduces the MSE by 8.4% to 43.7% with the proportion of incomplete data increased from 18.3% to 82.0%. The MWBME approach leads to significant reductions in estimation error and thus is recommended for epidemiological studies investigating the effect of long-term exposure to PM2.5 across large geographical domains with expected spatial non-stationarity. PMID:22739679

Pharmacokinetics, efficacy prediction indexes and residue depletion of antibacterial drugs.

Directory of Open Access Journals (Sweden)

Arturo Anadón

2016-06-01

Full Text Available Pharmacokinetics behaviour of the antibacterial in food producing animals, provides information on the rates of absorption and elimination, half-life in plasma and tissue, elimination pathways and metabolism. The dose and the dosing interval of the antimicrobial can be justified by considering the pharmacokinetic/pharmacodynamic (PK/PD relationship, if established, as well as the severity of the disease, whereas the number of administrations should be in line with the nature of the disease. The target population for therapy should be well defined and possible to identify under field conditions. Based on in vitro susceptibility data, and target animal PK data, an analysis for the PK/PD relationship may be used to support dose regimen selection and interpretation criteria for a clinical breakpoint. Therefore, for all antibacterials with systemic activity, the MIC data collected should be compared with the concentration of the compound at the relevant biophase following administration at the assumed therapeutic dose as recorded in the pharmacokinetic studies. Currently, the most frequently used parameters to express the PK/PD relationship are Cmax/MIC (maximum serum concentration/MIC, %T > MIC (fraction of time in which concentration exceeds MIC and AUC/MIC (area under the inhibitory concentration– time curve/MIC. Furthermore, the pharmacokinetic parameters provide the first indication of the potential for persistent residues and the tissues in which they may occur. The information on residue depletion in food-producing animals, provides the data on which MRL recommendations will be based. A critical factor in the antibacterial medication of all food-producing animals is the mandatory withdrawal period, defined as the time during which drug must not be administered prior to the slaughter of the animal for consumption. The withdrawal period is an integral part of the regulatory authorities’ approval process and is designed to ensure that no

Gentile statistics with a large maximum occupation number

International Nuclear Information System (INIS)

Dai Wusheng; Xie Mi

2004-01-01

In Gentile statistics the maximum occupation number can take on unrestricted integers: 1 1 the Bose-Einstein case is not recovered from Gentile statistics as n goes to N. Attention is also concentrated on the contribution of the ground state which was ignored in related literature. The thermodynamic behavior of a ν-dimensional Gentile ideal gas of particle of dispersion E=p s /2m, where ν and s are arbitrary, is analyzed in detail. Moreover, we provide an alternative derivation of the partition function for Gentile statistics

Target mediated drug disposition with drug-drug interaction, Part II: competitive and uncompetitive cases.

Science.gov (United States)

Koch, Gilbert; Jusko, William J; Schropp, Johannes

2017-02-01

We present competitive and uncompetitive drug-drug interaction (DDI) with target mediated drug disposition (TMDD) equations and investigate their pharmacokinetic DDI properties. For application of TMDD models, quasi-equilibrium (QE) or quasi-steady state (QSS) approximations are necessary to reduce the number of parameters. To realize those approximations of DDI TMDD models, we derive an ordinary differential equation (ODE) representation formulated in free concentration and free receptor variables. This ODE formulation can be straightforward implemented in typical PKPD software without solving any non-linear equation system arising from the QE or QSS approximation of the rapid binding assumptions. This manuscript is the second in a series to introduce and investigate DDI TMDD models and to apply the QE or QSS approximation.

Long-term measurement of radon concentration in the family house

International Nuclear Information System (INIS)

Muellerova, M.; Holy, K.

2009-01-01

The aim of this report was monitored the family house with radon concentration above radon limit for inhabited areas during one year. We were studied radon concentration changes in different rooms this house. Knowledge concerning of variations of radon activity concentration in family house were obtained. Daily variations show a maximum in the morning and a minimum in the afternoon. The seasonal variations show a minimum in spring months (March -April) and a maximum in early autumn (September). The radon concentration in the upstairs room was similar but ten-times lower than radon concentration in the downstairs room. In next period, the obtained results will be analysed in detail and different model describing the behaviour of radon in indoor air will be tested too. (authors)

Drug-drug interactions as a determinant of elevated lithium serum levels in daily clinical practice

NARCIS (Netherlands)

Wilting, [No Value; Movig, KL; Moolenaar, M; Hekster, YA; Brouwers, [No Value; Heerdink, ER; Nolen, WA; Egberts, AC

Objective: Lithium is a drug with a narrow therapeutic window. Concomitantly used medication is a potentially influencing factor of lithium serum concentrations. We conducted a multicentre retrospective case-control study with the aim of investigating lithium-related drug interactions as

The influence of drug distribution and drug-target binding on target occupancy : The rate-limiting step approximation

NARCIS (Netherlands)

Witte, de W.E.A.; Vauquelin, G.; Graaf, van der P.H.; Lange, de E.C.M.

2017-01-01

The influence of drug-target binding kinetics on target occupancy can be influenced by drug distribution and diffusion around the target, often referred to as "rebinding" or "diffusion-limited binding". This gives rise to a decreased decline of the drug-target complex concentration as a result of a

Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes.

Science.gov (United States)

Jeong, Hyunyoung

2010-06-01

Medication use during pregnancy is prevalent, but pharmacokinetic information of most drugs used during pregnancy is lacking in spite of known effects of pregnancy on drug disposition. Accurate pharmacokinetic information is essential for optimal drug therapy in mother and fetus. Thus, understanding how pregnancy influences drug disposition is important for better prediction of pharmacokinetic changes of drugs in pregnant women. Pregnancy is known to affect hepatic drug metabolism, but the underlying mechanisms remain unknown. Physiological changes accompanying pregnancy are probably responsible for the reported alteration in drug metabolism during pregnancy. These include elevated concentrations of various hormones such as estrogen, progesterone, placental growth hormones and prolactin. This review covers how these hormones influence expression of drug-metabolizing enzymes (DMEs), thus potentially responsible for altered drug metabolism during pregnancy. The reader will gain a greater understanding of the altered drug metabolism in pregnant women and the regulatory effects of pregnancy hormones on expression of DMEs. In-depth studies in hormonal regulatory mechanisms as well as confirmatory studies in pregnant women are warranted for systematic understanding and prediction of the changes in hepatic drug metabolism during pregnancy.

Influence of multidrug resistance and drug transport proteins on chemotherapy drug metabolism.

Science.gov (United States)

Joyce, Helena; McCann, Andrew; Clynes, Martin; Larkin, Annemarie

2015-05-01

Chemotherapy involving the use of anticancer drugs remains an important strategy in the overall management of patients with metastatic cancer. Acquisition of multidrug resistance remains a major impediment to successful chemotherapy. Drug transporters in cell membranes and intracellular drug metabolizing enzymes contribute to the resistance phenotype and determine the pharmacokinetics of anticancer drugs in the body. ATP-binding cassette (ABC) transporters mediate the transport of endogenous metabolites and xenobiotics including cytotoxic drugs out of cells. Solute carrier (SLC) transporters mediate the influx of cytotoxic drugs into cells. This review focuses on the substrate interaction of these transporters, on their biology and what role they play together with drug metabolizing enzymes in eliminating therapeutic drugs from cells. The majority of anticancer drugs are substrates for the ABC transporter and SLC transporter families. Together, these proteins have the ability to control the influx and the efflux of structurally unrelated chemotherapeutic drugs, thereby modulating the intracellular drug concentration. These interactions have important clinical implications for chemotherapy because ultimately they determine therapeutic efficacy, disease progression/relapse and the success or failure of patient treatment.

Designing generalized conic concentrators for conventional optical systems

Science.gov (United States)

Eichhorn, W. L.

1985-01-01

Generalized nonimaging concentrators can be incorporated into conventional optical systems in situations where flux concentration rather than imaging is required. The parameters of the concentrator for maximum flux concentration depend on the design of the particular optical system under consideration. Rationale for determining the concentrator parameters is given for one particular optical system and the procedure used for calculation of these parameters is outlined. The calculations are done for three concentrators applicable to the optical system.

Ultrasound mediated nanoparticle drug delivery

Science.gov (United States)

Mullin, Lee B.

. Ultrasound parameters are optimized to achieve maximum cell internalization of molecules and increased nanoparticle delivery to a cell layer on a coverslip. In-vivo studies demonstrate the possibility of using a lower dose of paclitaxel to slow tumor growth rates, increase doxorubicin concentration in tumor tissue, and enhance tumor delivery of fluorescent molecules through treatments that combine nanoparticles with ultrasound and microbubbles.

Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: A study to assess the drug's cardiac ion channel profile

Energy Technology Data Exchange (ETDEWEB)

Koenig, Xaver; Kovar, Michael; Rubi, Lena; Mike, Agnes K.; Lukacs, Peter; Gawali, Vaibhavkumar S.; Todt, Hannes [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Hilber, Karlheinz, E-mail: karlheinz.hilber@meduniwien.ac.at [Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna (Austria); Sandtner, Walter [Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna (Austria)

2013-12-01

The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licenced as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Na{sub v}1.5 sodium and Ca{sub v}1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias. - Highlights: • We study effects of anti-addiction drug ibogaine on ionic currents in cardiomyocytes. • We assess the cardiac ion channel profile of ibogaine. • Ibogaine inhibits hERG potassium, sodium and calcium channels. • Ibogaine’s effects on

Sodium Carboxymethyl Cellulose Using Acrylamide and Acrylic Acid and Investigation of Drug Delivery Properties

Directory of Open Access Journals (Sweden)

Mahdi Geramipour

2016-07-01

Full Text Available Hydrogels are three-dimensional polymer networks that can absorb and retain a huge amount of aqueous fluids even under certain pressure, but do not dissolve in water. They are responsive to environmental stimulants such as pH and ionic strength of the solution. In this study, a series of novel sodium carboxymethyl cellulose-based hydrogel nanocomposites were synthesized using acrylamide comonomer in the presence of iron magnetic as crosslinker and acrylic acid ammonium persulfate (APS comonomer as initiator. All reaction variables affecting the water absorbency of the hydrogel nanocomposite including the concentration of crosslinking agent and initiator, and comonomers ratio were optimized in order to achieve the maximum absorption capacity. The experimental data showed that the hydrogel nanocomposite exhibited improved swelling capacity compared to the nanoparticel-free hydrogel. In addition, optimized hydrogel nanocomposite showed a good water uptake ability and the equilibrium swelling capacity was achieved within the initial 10 min. In examining the quality of the synthesized hydrogel nanocomposite, the amount of absorption in saline solutions of different concentrations was measured. Furthermore, the swelling behavior of hydrogel nanocomposite in solutions with different pH values was evaluated. The chemical structure of the hydrogel nanocomposites was characterized by means of transmission electron microscopy (TEM, scanning electron microscopy (SEM, vibrating sample magnetometry (VSM, thermogravimetry analysis (TGA, derivative thermogravimetry (DTG and Fourier transform infrared spectroscopy (FTIR. In order to study the drug delivery and drug release behavior, the release of sodium diclofenac as a model drug from synthesized hydrogel nanocomposite was examined in two acidic and basic buffer environments. The results indicated that this hydrogel nanocomposite may be an appropriate alternative for drug release processes in human body.

Applying tracer techniques to NPP liquid effluents for estimating the maximum concentration of soluble pollutants in a man-made canal

International Nuclear Information System (INIS)

Varlam, Carmen; Stefanescu, Ioan; Varlam, Mihai; Raceanu, Mircea; Enache, Adrian; Faurescu, Ionut; Patrascu, Vasile; Bucur, Cristina

2006-01-01

-October 2002. We established tritium level and tritium concentrations significant for the edge and the tail of tritiated wastewater evacuations. We obtained unit-peak-attenuation (UPA) curve as related to different mixing times using three locations in which we measured tracer-response curves. The UPA curve, along with the time-of travel curves, provides a ready means of predicting maximum soluble contaminant levels that could be experienced at any location in the investigated area. (authors)

Intracellular Drug Bioavailability: Effect of Neutral Lipids and Phospholipids.

Science.gov (United States)

Treyer, Andrea; Mateus, André; Wiśniewski, Jacek R; Boriss, Hinnerk; Matsson, Pär; Artursson, Per

2018-06-04

Intracellular unbound drug concentrations are the pharmacologically relevant concentrations for targets inside cells. Intracellular drug concentrations are determined by multiple processes, including the extent of drug binding to intracellular structures. The aim of this study was to evaluate the effect of neutral lipid (NL) and phospholipid (PL) levels on intracellular drug disposition. The NL and/or PL content of 3T3-L1 cells were enhanced, resulting in phenotypes (in terms of morphology and proteome) reminiscent of adipocytes (high NL and PL) or mild phospholipidosis (only high PL). Intracellular bioavailability ( F ic ) was then determined for 23 drugs in these cellular models and in untreated wild-type cells. A higher PL content led to higher intracellular drug binding and a lower F ic . The induction of NL did not further increase drug binding but led to altered F ic due to increased lysosomal pH. Further, there was a good correlation between binding to beads coated with pure PL and intracellular drug binding. In conclusion, our results suggest that PL content is a major determinant of drug binding in cells and that PL beads may constitute a simple alternative to estimating this parameter. Further, the presence of massive amounts of intracellular NLs did not influence drug binding significantly.

Population Exposure to Phthalate-Containing Drugs

DEFF Research Database (Denmark)

Broe, Anne; Ennis, Zandra Nymand; Pottegård, Anton

2017-01-01

Phthalates are known endocrine disruptors. Not commonly recognised, phthalates are used as excipients in a number of drug formulations. We aimed to describe the sale of phthalate-containing drugs in Denmark from 2004 to 2015. National data on annual sale of medications (tablets only) were accessed...... from medstat.dk. Data from the Danish Medicines Agency on phthalate content per tablet were merged with data on total sale for each active substance and drug formulation. We used the 'defined daily dose' (DDD) as the unit of sale and calculated the total amount of phthalate (mg) dispensed per 1......,000 inhabitants. Specific tablet content was compared with the maximum daily exposure limits defined by regulatory agencies for diethylphthalate (DEP) and dibutylphthalate (DBP) of 4.0 and 0.01 mg/kg/day, respectively. Use of phthalate-containing drugs in Denmark was common. We found 154 drug products containing...

Studies of atmospheric pollutants concentration factors from La Reina reactor

International Nuclear Information System (INIS)

Vera, I.; Alegria, E.

1983-01-01

Results of an atmospheric diffusion model for pollutant gases re shown, in which the nuclear reactor of the La Reina Nuclear Centre is considered as the emitting source. The model uses a gaussian shape steady state cloud of concentration of pollutants and actual topographical and meteorological statistics data os the zone. Expected and maximum probable concentration factors are computed in a polar lattice in 16 wind directions. It was found that peaks for expected concentration factors and maximum probable concentration factors at ground level fall within the N and ESE directions at distances where hills or mountains reach the emitted cloud. A discussion of the practical value of these calculations is given. (Author)

Studies of atmospheric pollutants concentration factors from La Reina reactor

Energy Technology Data Exchange (ETDEWEB)

Vera, I; Alegria, E [Comision Chilena de Energia Nuclear, Santiago. Div. de Seguridade Nuclear y Radioproteccion

1983-11-01

Results of an atmospheric diffusion model for pollutant gases are shown, in which the nuclear reactor of the La Reina Nuclear Centre is considered as the emitting source. The model uses a gaussian shape steady state cloud of concentration of pollutants and actual topographical and meteorological statistics data of the zone. Expected and maximum probable concentration factors are computed in a polar lattice in 16 wind directions. It was found that peaks for expected concentration factors and maximum probable concentration factors at ground level fall within the N and ESE directions at distances where hills or mountains reach the emitted cloud. A discussion of the practical value of these calculations is given.

Postmortem Femoral Blood Concentrations of Risperidone

DEFF Research Database (Denmark)

Linnet, Kristian; Johansen, Sys Stybe

2014-01-01

Postmortem femoral blood concentrations of the antipsychotic drug risperidone and the active metabolite 9-hydroxyrisperidone were determined by an achiral LC-MS/MS method in 38 cases. The cause of death was classified as unrelated to risperidone in 30 cases, in which the sum of the concentration ...

Problems in the regulatory policy of the drug market

Science.gov (United States)

Miziara, Nathália Molleis; Coutinho, Diogo Rosenthal

2015-01-01

OBJECTIVE Analyze the implementation of drug price regulation policy by the Drug Market Regulation Chamber. METHODS This is an interview-based study, which was undertaken in 2012, using semi-structured questionnaires with social actors from the pharmaceutical market, the pharmaceuticals industry, consumers and the regulatory agency. In addition, drug prices were compiled based on surveys conducted in the state of Sao Paulo, at the point of sale, between February 2009 and May 2012. RESULTS The mean drug prices charged at the point of sale (pharmacies) were well below the maximum price to the consumer, compared with many drugs sold in Brazil. Between 2009 and 2012, 44 of the 129 prices, corresponding to 99 drugs listed in the database of compiled prices, showed a variation of more than 20.0% in the mean prices at the point of sale and the maximum price to the consumer. In addition, many laboratories have refused to apply the price adequacy coefficient in their sales to government agencies. CONCLUSIONS The regulation implemented by the pharmaceutical market regulator was unable to significantly control prices of marketed drugs, without succeeding to push them to levels lower than those determined by the pharmaceutical industry and failing, therefore, in its objective to promote pharmaceutical support for the public. It is necessary reconstruct the regulatory law to allow market prices to be reduced by the regulator as well as institutional strengthen this government body. PMID:26083945

Herbal drug patenting in India: IP potential.

Science.gov (United States)

Sahoo, Niharika; Manchikanti, Padmavati; Dey, Satya Hari

2011-09-01

Herbal drugs are gaining worldwide prominence due to their distinct advantages. Developing countries have started exploring the ethnopharmacological approach of drug discovery and have begun to file patents on herbal drugs. The expansion of R&D in Indian herbal research organizations and presence of manufacturing units at non-Indian sites is an indication of the capability to develop new products and processes. The present study attempts to identify innovations in the Indian herbal drug sector by analyzing the patenting trends in India, US and EU. Based on key word and IPC based search at the IPO, USPTO, Esp@cenet and WIPO databases, patent applications and grant in herbal drugs by Indian applicants/assignees was collected for the last ten years (from 1st January 2001 to 31st October 2010). From this collection patents related to human therapeutic use only were selected. Analysis was performed to identify filing trends, major applicants/assignees, disease area and major plant species used for various treatments. There is a gradual increase in patent filing through the years. In India, individual inventors have maximum applications and grants. CSIR, among research organizations and Hindustan Unilever, Avesthagen, Piramal Life Science, Sahajanand Biotech and Indus Biotech among the companies have the maximum granted patents in India, US and EU respectively. Diabetes, cancer and inflammatory disorders are the major areas for patenting in India and abroad. Recent patents are on new herbal formulations for treatment of AIDS, hepatitis, skin disorders and gastrointestinal disorders. A majority of the herbal patents applications and grants in India are with individual inventors. Claim analysis indicates that these patents include novel multi-herb compositions with synergistic action. Indian research organizations are more active than companies in filing for patents. CSIR has maximum numbers of applications not only in India but also in the US and EU. Patents by research

Development and validation of a general approach to predict and quantify the synergism of anti-cancer drugs using experimental design and artificial neural networks.

Science.gov (United States)

Pivetta, Tiziana; Isaia, Francesco; Trudu, Federica; Pani, Alessandra; Manca, Matteo; Perra, Daniela; Amato, Filippo; Havel, Josef

2013-10-15

The combination of two or more drugs using multidrug mixtures is a trend in the treatment of cancer. The goal is to search for a synergistic effect and thereby reduce the required dose and inhibit the development of resistance. An advanced model-free approach for data exploration and analysis, based on artificial neural networks (ANN) and experimental design is proposed to predict and quantify the synergism of drugs. The proposed method non-linearly correlates the concentrations of drugs with the cytotoxicity of the mixture, providing the possibility of choosing the optimal drug combination that gives the maximum synergism. The use of ANN allows for the prediction of the cytotoxicity of each combination of drugs in the chosen concentration interval. The method was validated by preparing and experimentally testing the combinations with the predicted highest synergistic effect. In all cases, the data predicted by the network were experimentally confirmed. The method was applied to several binary mixtures of cisplatin and [Cu(1,10-orthophenanthroline)2(H2O)](ClO4)2, Cu(1,10-orthophenanthroline)(H2O)2(ClO4)2 or [Cu(1,10-orthophenanthroline)2(imidazolidine-2-thione)](ClO4)2. The cytotoxicity of the two drugs, alone and in combination, was determined against human acute T-lymphoblastic leukemia cells (CCRF-CEM). For all systems, a synergistic effect was found for selected combinations. © 2013 Elsevier B.V. All rights reserved.

Effect of Na2SO3 concentration to drug loading and drug release of ascorbic acid in chitosan edible film as drug delivery system membrane

Directory of Open Access Journals (Sweden)

Kistriyani Lilis

2018-01-01

Full Text Available Chitosan is a type of carbohydrate compounds produced from waste marine products, in particular the class of shrimp, crabs and clams. Chitosan is often process into edible films and utilized for food packaging also has potential as a membrane for drug delivery system. Drug loading and drug release can be controlled by improve the characteristics of the membrane by adding crosslinker. The purpose of this research is to study the effect of addition of crosslinker to the rate of loading and release of ascorbic acid in the chitosan edible film. Na2SO3 was used as crosslinker. Two grams of chitosan was dissolved into 100 ml of distilled water. Acetic acid and plasticizer were added in the solution then heated at 50°C. Na2SO3 solution with mass various of Na2SO3 dissolved, 01026 0.3; and 0.5 grams were added about 30 mL to make edible film. The analysis include of drug loading, drug release and tensile strength. The result showed that the loading of edible film with crosslinker 0.15 g; 0.3 g; and 0.5 g respectively were 60.98 ppm; 52.53 ppm; and 40.88 ppm, meanwhile for the release with crosslinker 0.15 g; 0.3 g; and 0.5 g respectively were 3.78 ppm; 5.72 ppm; and 5.97 ppm.

Grapefruit and drug interactions.

Science.gov (United States)

2012-12-01

Since the late 1980s, grapefruit juice has been known to affect the metabolism of certain drugs. Several serious adverse effects involving drug interactions with grapefruit juice have been published in detail. The components of grapefruit juice vary considerably depending on the variety, maturity and origin of the fruit, local climatic conditions, and the manufacturing process. No single component accounts for all observed interactions. Other grapefruit products are also occasionally implicated, including preserves, lyophylised grapefruit juice, powdered whole grapefruit, grapefruit seed extract, and zest. Clinical reports of drug interactions with grapefruit juice are supported by pharmacokinetic studies, each usually involving about 10 healthy volunteers, in which the probable clinical consequences were extrapolated from the observed plasma concentrations. Grapefruit juice inhibits CYP3A4, the cytochrome P450 isoenzyme most often involved in drug metabolism. This increases plasma concentrations of the drugs concerned, creating a risk of overdose and dose-dependent adverse effects. Grapefruit juice also inhibits several other cytochrome P450 isoenzymes, but they are less frequently implicated in interactions with clinical consequences. Drugs interacting with grapefruit and inducing serious clinical consequences (confirmed or very probable) include: immunosuppressants, some statins, benzodiazepines, most calcium channel blockers, indinavir and carbamazepine. There are large inter-individual differences in enzyme efficiency. Along with the variable composition of grapefruit juice, this makes it difficult to predict the magnitude and clinical consequences of drug interactions with grapefruit juice in a given patient. There is increasing evidence that transporter proteins such as organic anion transporters and P-glycoprotein are involved in interactions between drugs and grapefruit juice. In practice, numerous drugs interact with grapefruit juice. Although only a few

Application of Hill's equation for estimating area under the concentration-time curve (AUC) and use of time to AUC 90% for expressing kinetics of drug disposition.

Science.gov (United States)

Cheng, Hsien C

2009-01-01

Half life and its derived pharmacokinetic parameters are calculated on an assumption that the terminal phase of drug disposition follows a constant rate of disposition. In reality, this assumption may not necessarily be the case. A new method is needed for analyzing PK parameters if the disposition does not follow a first order PK kinetic. Cumulative area under the concentration-time curve (AUC) is plotted against time to yield a hyperbolic (or sigmoidal) AUC-time relationship curve which is then analyzed by Hill's equation to yield AUC(inf), time to achieving AUC50% (T(AUC50%)) or AUC90% (T(AUC90%)), and the Hill's slope. From these parameters, an AUC-time relationship curve can be reconstructed. Projected plasma concentration can be calculated for any time point. Time at which cumulative AUC reaches 90% (T(AUC90%)) can be used as an indicator for expressing how fast a drug is cleared. Clearance is calculated in a traditional manner (i.v. dose/AUC(inf)), and the volume of distribution is proposed to be calculated at T(AUC50%) (0.5 i.v. dose/plasma concentration at T(AUC50%)). This method of estimating AUC is applicable for both i.v. and oral data. It is concluded that the Hill's equation can be used as an alternative method for estimating AUC and analysis of PK parameters if the disposition does not follow a first order kinetic. T(AUC90%) is proposed to be used as an indicator for expressing how fast a drug is cleared from the system.

A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.

Science.gov (United States)

Pawluk, Shane Ashley; Roels, Craig Allan; Wilby, Kyle John; Ensom, Mary H H

2015-04-01

Medications indicated for helminthes and other parasitic infections are frequently being used in mass populations in endemic areas. Currently, there is a lack of guidance for clinicians on how to appropriately manage drug interactions when faced with patients requiring short-term anthelmintic therapy with albendazole or mebendazole while concurrently taking other agents. The objective of this review was to systematically summarize and evaluate published literature on the pharmacokinetics of albendazole or mebendazole when taken with other interacting medications. A search of MEDLINE (1946 to October 2014), EMBASE (1974 to October 2014), International Pharmaceutical Abstracts (1970 to October 2014), Google, and Google Scholar was conducted for articles describing the pharmacokinetics of albendazole or mebendazole when given with other medications (and supplemented by a bibliographic review of all relevant articles). Altogether, 17 articles were included in the review. Studies reported data on pharmacokinetic parameters for albendazole or mebendazole when taken with cimetidine, dexamethasone, ritonavir, phenytoin, carbamazepine, phenobarbital, ivermectin, praziquantel, diethylcarbamazine, azithromycin, and levamisole. Cimetidine increased the elimination half-life of albendazole and maximum concentration (Cmax) of mebendazole; dexamethasone increased the area under the plasma concentration-time curve (AUC) of albendazole; levamisole decreased the Cmax of albendazole; anticonvulsants (phenytoin, phenobarbital, carbamazepine) decreased the AUC of albendazole; praziquantel increased the AUC of albendazole; and ritonavir decreased the AUC of both albendazole and mebendazole. No major interactions were found with ivermectin, azithromycin, or diethylcarbamazine. Future research is required to clarify the clinical relevance of the interactions observed.

21 CFR 146.150 - Canned concentrated orange juice.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Canned concentrated orange juice. 146.150 Section... Fruit Juices and Beverages § 146.150 Canned concentrated orange juice. (a) Canned concentrated orange... labeling of ingredients prescribed for frozen concentrated orange juice by § 146.146, except that it is not...

A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers.

Science.gov (United States)

Kim, Anhye; Lim, Kyoung Soo; Lee, Howard; Chung, Hyewon; Yoon, Seo Hyun; Yu, Kyung-Sang; Cho, Joo-Youn; Jang, In-Jin; Chung, Jae-Yong

2016-07-01

Prolongation of the QT interval on an ECG is a surrogate marker for predicting the proarrhythmic potential of a drug under development. The aim of this study was to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine immediate release (IR) and escitalopram, in healthy individuals. This was a randomized, open-label, 4×4 Williams crossover study, with four single-dose treatments [placebo, 400 mg moxifloxacin (positive control), 20 mg escitalopram, and 100 mg quetiapine IR], conducted in 40 healthy volunteers. Serial blood samples for pharmacokinetics and ECG were collected. Individually, RR-corrected QTc intervals (QTcI) and placebo-adjusted changes from baseline values of QTcI (ΔΔQTcI) were evaluated. Lower-bound values of the one-sided 95% confidence interval for ΔΔQTcI of moxifloxacin with more than 5 ms confirmed the sensitivity of the assay. The maximum upper bound 95% confidence interval for the ΔΔQTcI of quetiapine IR and escitalopram was 13.7 and 10.5 ms, with mean estimates of 10.2 and 6.9 ms, respectively. Peak effects of moxifloxacin and quetiapine IR on ΔΔQTcI were observed at approximately time to maximum concentration (Tmax), whereas that of escitalopram was observed 3 h after Tmax. The concentration-ΔΔQTcI relationships of quetiapine IR and escitalopram were relatively flat, as compared with that of moxifloxacin. The results demonstrated the validity of trial methodology and that quetiapine IR and escitalopram caused QT prolongation in healthy individuals. In addition, hysteresis of escitalopram-induced QTc prolongation. These results indicate that higher doses of these drugs could lead to greater QT prolongation in a dose-response manner.

REMOVAL AND CONCENTRATION OF URANIUM FROM WASTE MINE

Directory of Open Access Journals (Sweden)

Elizângela Augusta Santos

2011-01-01

Full Text Available The use of leaching agents, such as sodium citrate and ammonium carbonate, were assessed for the extraction of uranium from one mining residue containing 0.25% U. Concentration techniques such as precipitation and ion exchange were employed to recover the uranium from the leaching liquor. Leaching results showed maximum uranium extraction of about 40% for both reagents. The use 10 mol L-1 NaOH to precipitate the uranium from the leach liquor leads to a recovery of 62%; what was considered not satisfactory. In view of this, resins were used to concentrate the uranium from the liquor and the metal loading obtained at pH 3.9 was higher for the resin DOWEX RPU, whose maximum loading maximum capacity was 148.3 mg g-1, compared to 126.9 mg g-1 presented by the resin IRA 910 U.

Maximum Mass of Hybrid Stars in the Quark Bag Model

Science.gov (United States)

Alaverdyan, G. B.; Vartanyan, Yu. L.

2017-12-01

The effect of model parameters in the equation of state for quark matter on the magnitude of the maximum mass of hybrid stars is examined. Quark matter is described in terms of the extended MIT bag model including corrections for one-gluon exchange. For nucleon matter in the range of densities corresponding to the phase transition, a relativistic equation of state is used that is calculated with two-particle correlations taken into account based on using the Bonn meson-exchange potential. The Maxwell construction is used to calculate the characteristics of the first order phase transition and it is shown that for a fixed value of the strong interaction constant αs, the baryon concentrations of the coexisting phases grow monotonically as the bag constant B increases. It is shown that for a fixed value of the strong interaction constant αs, the maximum mass of a hybrid star increases as the bag constant B decreases. For a given value of the bag parameter B, the maximum mass rises as the strong interaction constant αs increases. It is shown that the configurations of hybrid stars with maximum masses equal to or exceeding the mass of the currently known most massive pulsar are possible for values of the strong interaction constant αs > 0.6 and sufficiently low values of the bag constant.

Evaluation of the external radiation exposure dosimetry and calculation of maximum permissible concentration values for airborne materials containing 18F, 15O, 13N, 11C and 133Xe

International Nuclear Information System (INIS)

Piltingsrud, H.V.; Gels, G.L.

1985-01-01

To better understand the dose equivalent (D.E.) rates produced by airborne releases of gaseous positron-emitting radionuclides under various conditions of cloud size, a study of the external radiation exposure dosimetry of these radionuclides, as well as negatron, gamma and x-ray emitting 133Xe, was undertaken. This included a calculation of the contributions to D.E. as a function of cloud radii, at tissue depths of 0.07 mm (skin), 3 mm (lens of eye) and 10 mm (whole body) from both the particulate and photon radiations emitted by these radionuclides. Estimates of maximum permissible concentration (MPC) values were also calculated based on the calculated D.E. rates and current regulations for personnel radiation protection (CFR84). Three continuous air monitors, designed for use with 133Xe, were evaluated for applications in monitoring air concentrations of the selected positron emitters. The results indicate that for a given radionuclide and for a cloud greater than a certain radius, personnel radiation dosimeters must respond acceptably to only the photon radiations emitted by the radionuclide to provide acceptable personnel dosimetry. For clouds under that radius, personnel radiation dosimeters must also respond acceptably to the positron or negatron radiations to provide acceptable personnel dosimetry. It was found that two out of the three air concentration monitors may be useful for monitoring air concentrations of the selected positron emitters

Cosmic shear measurement with maximum likelihood and maximum a posteriori inference

Science.gov (United States)

Hall, Alex; Taylor, Andy

2017-06-01

We investigate the problem of noise bias in maximum likelihood and maximum a posteriori estimators for cosmic shear. We derive the leading and next-to-leading order biases and compute them in the context of galaxy ellipticity measurements, extending previous work on maximum likelihood inference for weak lensing. We show that a large part of the bias on these point estimators can be removed using information already contained in the likelihood when a galaxy model is specified, without the need for external calibration. We test these bias-corrected estimators on simulated galaxy images similar to those expected from planned space-based weak lensing surveys, with promising results. We find that the introduction of an intrinsic shape prior can help with mitigation of noise bias, such that the maximum a posteriori estimate can be made less biased than the maximum likelihood estimate. Second-order terms offer a check on the convergence of the estimators, but are largely subdominant. We show how biases propagate to shear estimates, demonstrating in our simple set-up that shear biases can be reduced by orders of magnitude and potentially to within the requirements of planned space-based surveys at mild signal-to-noise ratio. We find that second-order terms can exhibit significant cancellations at low signal-to-noise ratio when Gaussian noise is assumed, which has implications for inferring the performance of shear-measurement algorithms from simplified simulations. We discuss the viability of our point estimators as tools for lensing inference, arguing that they allow for the robust measurement of ellipticity and shear.

Reduction of Nicardipine-Related Phlebitis in Patients with Acute Stroke by Diluting Its Concentration.

Science.gov (United States)

Kawada, Kei; Ohta, Tsuyoshi; Tanaka, Koudai; Miyamoto, Norifumi

2018-03-05

Nicardipine is frequently used in the treatment of hypertension for patients with acute stroke; however, its dosing is complicated by a high risk of phlebitis. In the present study, we examined whether restricting nicardipine concentration under a specific value could reduce the incidence of nicardipine-related phlebitis in patients with acute stroke. Intravenous nicardipine-related phlebitis was retrospectively analyzed. From July 2015, a simple proposition was made to dilute maximum intravenous nicardipine concentration to lower than 130 µg/mL. The maximum intravenous nicardipine concentration and the incidence of phlebitis were compared between patients treated from July 2014 to June 2015 (preproposition group) and patients treated from July 2015 to June 2016 (postproposition group). A total of 300 patients (preproposition group, 138; postproposition group, 162) were included. The postproposition group demonstrated significantly lower maximum intravenous nicardipine concentration (in µg/mL, 76.9, 47.6-104.5 versus 130.4, 69.8-230.8; P phlebitis (9.9%, 16/162 vs. 30%, 42/138; P phlebitis, which indicated the usefulness of the proposition to dilute maximum intravenous nicardipine concentration to lower than 130 µg/mL. The simple and appropriate proposition about nicardipine administration lowered maximum nicardipine concentration and reduced the incidence of nicardipine-related phlebitis in patients with acute stroke. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Development of a Video-Microscopic Tool To Evaluate the Precipitation Kinetics of Poorly Water Soluble Drugs: A Case Study with Tadalafil and HPMC.

Science.gov (United States)

Christfort, Juliane Fjelrad; Plum, Jakob; Madsen, Cecilie Maria; Nielsen, Line Hagner; Sandau, Martin; Andersen, Klaus; Müllertz, Anette; Rades, Thomas

2017-12-04

Many drug candidates today have a low aqueous solubility and, hence, may show a low oral bioavailability, presenting a major formulation and drug delivery challenge. One way to increase the bioavailability of these drugs is to use a supersaturating drug delivery strategy. The aim of this study was to develop a video-microscopic method, to evaluate the effect of a precipitation inhibitor on supersaturated solutions of the poorly soluble drug tadalafil, using a novel video-microscopic small scale setup. Based on preliminary studies, a degree of supersaturation of 29 was chosen for the supersaturation studies with tadalafil in FaSSIF. Different amounts of hydroxypropyl methyl cellulose (HPMC) were predissolved in FaSSIF to give four different concentrations, and the supersaturated system was then created using a solvent shift method. Precipitation of tadalafil from the supersaturated solutions was monitored by video-microscopy as a function of time. Single-particle analysis was possible using commercially available software; however, to investigate the entire population of precipitating particles (i.e., their number and area covered in the field of view), an image analysis algorithm was developed (multiparticle analysis). The induction time for precipitation of tadalafil in FaSSIF was significantly prolonged by adding 0.01% (w/v) HPMC to FaSSIF, and the maximum inhibition was reached at 0.1% (w/v) HPMC, after which additional HPMC did not further increase the induction time. The single-particle and multiparticle analyses yielded the same ranking of the HPMC concentrations, regarding the inhibitory effect on precipitation. The developed small scale method to assess the effect of precipitation inhibitors can speed up the process of choosing the right precipitation inhibitor and the concentration to be used.

Curcumin drug delivery by vanillin-chitosan coated with calcium ferrite hybrid nanoparticles as carrier.

Science.gov (United States)

Kamaraj, Sriram; Palanisamy, Uma Maheswari; Kadhar Mohamed, Meera Sheriffa Begum; Gangasalam, Arthanareeswaran; Maria, Gover Antoniraj; Kandasamy, Ruckmani

2018-04-30

The aim of the present investigation is the development, optimization and characterization of curcumin-loaded hybrid nanoparticles of vanillin-chitosan coated with super paramagnetic calcium ferrite. The functionally modified vanillin-chitosan was prepared by the Schiff base reaction to enhance the hydrophobic drug encapsulation efficiency. Calcium ferrite (CFNP) nano particles were added to the vanillin modified chitosan to improve the biocompatibility. The vanillin-chitosan-CFNP, hybrid nanoparticle carrier was obtained by ionic gelation method. Characterizations of the hybrid materials were performed by XRD, FTIR, 1 H NMR, TGA, AFM and SEM techniques to ensure the modifications on the chitosan material. Taguchi method was applied to optimize the drug (curcumin) encapsulation efficiency by varying the drug to chitosan-vanillin, CFNP to chitosan-vanillin and TPP (sodium tripolyphospate) to chitosan-vanillin ratios. The maximum encapsulation efficiency was obtained as 98.3% under the conditions of 0.1, 0.75 and 1.0 for the drug to chitosan-vanillin, CFNP to chitosan-vanillin and TPP to chitosan-vanillin ratios, respectively. The curcumin release was performed at various pH, initial drug loading concentrations and magnetic fields. The drug release mechanism was predicted by fitting the experimental kinetic data with various drug release models. The drug release profiles showed the best fit with Higuchi model under the most of conditions. The drug release mechanism followed both non-Fickian diffusion and case II transport mechanism for chitosan, however the non-Fickian diffusion mechanism was followed for the vanillin modified chitosan. The biocompatibility of the hybrid material was tested using L929 fibroblast cells. The cytotoxicity test was performed against MCF-7 breast cancer cell line to check the anticancer property of the hybrid nano carrier with the curcumin drug. Copyright © 2018 Elsevier B.V. All rights reserved.

21 CFR 146.145 - Orange juice from concentrate.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Orange juice from concentrate. 146.145 Section 146... Juices and Beverages § 146.145 Orange juice from concentrate. (a) Orange juice from concentrate is the food prepared by mixing water with frozen concentrated orange juice as defined in § 146.146 or with...

Seasonal variation in heavy metal concentration in mangrove foliage

Digital Repository Service at National Institute of Oceanography (India)

Untawale, A.G.; Wafar, S.; Bhosle, N.B.

Seasonal variation in the concentration of some heavy metals in the leaves of seven species of mangrove vegetation from Goa, revealed that maximum concentration of iron and manganese occurs during the monsoon season without any significant toxic...

Continuous measurements of outdoor radon concentrations

International Nuclear Information System (INIS)

Iida, T.; Ikebe, Y.; Suzuki, K.; Ueno, K.; Komura, K.; Kato, I.; Jin Yihe

1993-01-01

The authors studied and developed an electrostatic 222 Rn monitor and have measured continuously outdoor radon ( 222 Rn) concentrations at Nagoya University since 1985. Four 222 Rn monitors were newly constructed to measure outdoor 222 Rn concentrations at other locations. The 222 Rn concentrations at Nagoya and Kasugai show a clear diurnal variation in autumn, and a seasonal pattern of a spring-summer minimum and a autumn-winter maximum. The results at Toki are the same pattern as that at Nagoya except spring. The concentrations at Kanazawa show a slight seasonal variation. A clear diurnal variation is observed in summer. (4 figs.)

The Therapeutic Utility of Employment in Treating Drug Addiction: Science to Application

OpenAIRE

Silverman, Kenneth; Holtyn, August F.; Morrison, Reed

2016-01-01

Research on a model Therapeutic Workplace has allowed for evaluation of the use of employment in the treatment of drug addiction. Under the Therapeutic Workplace intervention, adults with histories of drug addiction are hired and paid to work. To promote drug abstinence or adherence to addiction medications, participants are required to provide drug-free urine samples or take prescribed addiction medications, respectively, to gain access to the workplace and/or to maintain their maximum rate ...

The impact of cancer drug wastage on economic evaluations.

Science.gov (United States)

Truong, Judy; Cheung, Matthew C; Mai, Helen; Letargo, Jessa; Chambers, Alexandra; Sabharwal, Mona; Trudeau, Maureen E; Chan, Kelvin K W

2017-09-15

The objective of this study was to determine the impact of modeling cancer drug wastage in economic evaluations because wastage can result from single-dose vials on account of body surface area- or weight-based dosing. Intravenous chemotherapy drugs were identified from the pan-Canadian Oncology Drug Review (pCODR) program as of January 2015. Economic evaluations performed by drug manufacturers and pCODR were reviewed. Cost-effectiveness analyses and budget impact analyses were conducted for no-wastage and maximum-wastage scenarios (ie, the entire unused portion of the vial was discarded at each infusion). Sensitivity analyses were performed for a range of body surface areas and weights. Twelve drugs used for 17 indications were analyzed. Wastage was reported (ie, assumptions were explicit) in 71% of the models and was incorporated into 53% by manufacturers; this resulted in a mean incremental cost-effectiveness ratio increase of 6.1% (range, 1.3%-14.6%). pCODR reported and incorporated wastage for 59% of the models, and this resulted in a mean incremental cost-effectiveness ratio increase of 15.0% (range, 2.6%-48.2%). In the maximum-wastage scenario, there was a mean increase in the incremental cost-effectiveness ratio of 24.0% (range, 0.0%-97.2%), a mean increase in the 3-year total incremental budget costs of 26.0% (range, 0.0%-83.1%), and an increase in the 3-year total incremental drug budget cost of approximately CaD $102 million nationally. Changing the mean body surface area or body weight caused 45% of the drugs to have a change in the vial size and/or quantity, and this resulted in increased drug costs. Cancer drug wastage can increase drug costs but is not uniformly modeled in economic evaluations. Cancer 2017;123:3583-90. © 2017 American Cancer Society. © 2017 American Cancer Society.

Therapeutic drug monitoring of isoniazid and rifampicin during anti-tuberculosis treatment in Auckland, New Zealand.

Science.gov (United States)

Maze, M J; Paynter, J; Chiu, W; Hu, R; Nisbet, M; Lewis, C

2016-07-01

There is uncertainty as to the optimal therapeutic concentrations of anti-tuberculosis drugs to achieve cure. To characterise the use of therapeutic drug monitoring (TDM), and identify risk factors and outcomes for those with concentrations below the drug interval. Patients treated for tuberculosis (TB) who had rifampicin (RMP) or isoniazid (INH) concentrations measured between 1 January 2005 and 31 December 2012 were studied retrospectively. Matched concentrations and drug dosing time were assessed according to contemporary regional drug intervals (RMP > 6 μmol/l, INH > 7.5 μmol/l) and current international recommendations (RMP > 10 μmol/l, INH > 22 μmol/l). Outcomes were assessed using World Health Organization criteria. Of 865 patients, 121 had concentrations of either or both medications. RMP concentrations were within the regional drug intervals in 106/114 (93%) and INH in 91/100 (91%). Concentrations were within international drug intervals for RMP in 76/114 (67%) and INH in 53/100 (53%). Low weight-based dose was the only statistically significant risk factor for concentrations below the drug interval. Of the 35 patients with low concentrations, 21 were cured, 9 completed treatment and 5 transferred out. There were no relapses during follow-up (mean 66.5 months). There were no clinically useful characteristics to guide use of TDM. Many patients had concentrations below international therapeutic intervals, but were successfully treated.

Determination of the maximum MGS mounting height : phase II detailed analysis with LS-DYNA.

Science.gov (United States)

2012-12-01

Determination of the maximum Midwest Guardrail System (MGS) mounting height was performed in two phases. : Phase I concentrated on crash testing: two full-scale crash tests were performed on the MGS with top-rail mounting heights : of 34 in. (864 mm)...

Trace elements in natural drugs determined by INAA

International Nuclear Information System (INIS)

Chen Kehshaw; Tseng Chialiang; Lin Tehsien

1993-01-01

Natural drugs are widely used for diuretic, phlegm elimination and stomach invigoration purposes. Seventy-five of the most common remedies used by Chinese people have been subjected to trace element survey analysis by instrumental neutron activation. Within this large number of different natural products, fourteen trace elements (K, Sc, Cr, Fe, Co, Zn, Br, Rb, Cs, La, Sm, Eu, Au and Th) are commonly detected. Among these elements, Fe had the highest concentration followed by Zn, and Rb, Sm, Eu and Au were found to have the lowest concentrations. Although the three groups of natural drugs exhibit a widely different therapeutic action, the concentration ranges of the fourteen elements were very similar. While this suggests no apparent specific role for the trace elements in the drug function, parallels are drawn between the known drug related functions of Rb, Zn, Br, Fe, Co and K and the levels of elements found in the natural drugs. It is concluded that the various natural drugs also provide human benefits through supplements of essential elements such as Fe, Zn, Cr, Sc, Rb and Co. (author) 13 refs.; 5 tabs

The Therapeutic Utility of Employment in Treating Drug Addiction: Science to Application.

Science.gov (United States)

Silverman, Kenneth; Holtyn, August F; Morrison, Reed

2016-06-01

Research on a model Therapeutic Workplace has allowed for evaluation of the use of employment in the treatment of drug addiction. Under the Therapeutic Workplace intervention, adults with histories of drug addiction are hired and paid to work. To promote drug abstinence or adherence to addiction medications, participants are required to provide drug-free urine samples or take prescribed addiction medications, respectively, to gain access to the workplace and/or to maintain their maximum rate of pay. Research has shown that the Therapeutic Workplace intervention is effective in promoting and maintaining abstinence from heroin, cocaine and alcohol and in promoting adherence to naltrexone. Three models could be used to implement and maintain employment-based reinforcement in the treatment of drug addiction: A Social Business model, a Cooperative Employer model, and a Wage Supplement model. Under all models, participants initiate abstinence in a training and abstinence initiation phase (Phase 1). Under the Social Business model, Phase 1 graduates are hired as employees in a social business and required to maintain abstinence to maintain employment and/or maximum pay. Under the Cooperative Employer model, cooperating community employers hire graduates of Phase 1 and require them to maintain abstinence to maintain employment and/or maximum pay. Under the Wage Supplement Model, graduates of Phase 1 are offered abstinence-contingent wage supplements if they maintain competitive employment in a community job. Given the severity and persistence of the problem of drug addiction and the lack of treatments that can produce lasting effects, continued development of the Therapeutic Workplace is warranted.

Effect of adeturone on the concentration of endogenous sulfhydryl groups in mouse spleen and liver

International Nuclear Information System (INIS)

Pantev, T.; Bychvarova, K.

1981-01-01

Levels of endogenous sulfhydryl groups (total, protein, and non-protein) in mouse liver and spleen were studied for response to the radioprotective drug Adeturone (AET adenosine triphosphate) as recorded at various time intervals (5 - 90 min) following administration of a 300 mg/kg b.w. dose. Spleen sulfhydryl concentration levels tended to elevation, with the peak effect noted at 45 min post-treatment. In the liver, augmentation was observed only for non-protein sylfhydryl groups, at 10 and 15 min post-treatment (time intervals when Adeturone affords maximum protection against radiation); at the 60 min, however, there was a statistically reliable drop. The findings indicate that Adeturone treatment produces response patterns of opposite directions in liver and spleen endogenous thiols. (A.B.)

Formulation and Optimization of Multiparticulate Drug Delivery System Approach for High Drug Loading.

Science.gov (United States)

Shah, Neha; Mehta, Tejal; Gohel, Mukesh

2017-08-01

The aim of the present work was to develop and optimize multiparticulate formulation viz. pellets of naproxen by employing QbD and risk assessment approach. Mixture design with extreme vertices was applied to the formulation with high loading of drug (about 90%) and extrusion-spheronization as a process for manufacturing pellets. Independent variables chosen were level of microcrystalline cellulose (MCC)-X 1 , polyvinylpyrrolidone K-90 (PVP K-90)-X 2 , croscarmellose sodium (CCS)-X 3 , and polacrilin potassium (PP)-X 4 . Dependent variables considered were disintegration time (DT)-Y 1 , sphericity-Y 2 , and percent drug release-Y 3 . The formulation was optimized based on the batches generated by MiniTab 17 software. The batch with maximum composite desirability (0.98) proved to be optimum. From the evaluation of design batches, it was observed that, even in low variation, the excipients affect the pelletization property of the blend and also the final drug release. In conclusion, pellets with high drug loading can be effectively manufactured and optimized systematically using QbD approach.

Drug-drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer.

Science.gov (United States)

Park, Gab-Jin; Bae, Soo Hyeon; Park, Wan-Su; Han, Seunghoon; Park, Min-Ho; Shin, Seok-Ho; Shin, Young G; Yim, Dong-Seok

2017-01-01

A microdose drug-drug interaction (DDI) study may be a valuable tool for anticipating drug interaction at therapeutic doses. This study aimed to compare the magnitude of DDIs at microdoses and regular doses to explore the applicability of a microdose DDI study. Six healthy male volunteer subjects were enrolled into each DDI study of omeprazole (victim) and known perpetrators: fluconazole (inhibitor) and rifampin (inducer). For both studies, the microdose (100 μg, cold compound) and the regular dose (20 mg) of omeprazole were given at days 0 and 1, respectively. On days 2-9, the inhibitor or inducer was given daily, and the microdose and regular dose of omeprazole were repeated at days 8 and 9, respectively. Full omeprazole pharmacokinetic samplings were performed at days 0, 1, 8, and 9 of both studies for noncompartmental analysis. The magnitude of the DDI, the geometric mean ratios (with perpetrator/omeprazole only) of maximum concentration (C max ) and area under the curve to the last measurement (AUC t ) of the microdose and the regular dose were compared. The geometric mean ratios in the inhibition study were: 2.17 (micro) and 2.68 (regular) for C max , and 4.07 (micro), 4.33 (regular) for AUC t . For the induction study, they were 0.26 (micro) and 0.21 (regular) for C max , and 0.16 (micro) and 0.15 (regular) for AUC t . There were no significant statistical differences in the magnitudes of DDIs between microdose and regular-dose conditions, regardless of induction or inhibition. Our results may be used as partial evidence that microdose DDI studies may replace regular-dose studies, or at least be used for DDI-screening purposes.

Measured density and calculated baricity of custom-compounded drugs for chronic intrathecal infusion.

Science.gov (United States)

Hejtmanek, Michael R; Harvey, Tracy D; Bernards, Christopher M

2011-01-01

To minimize the frequency that intrathecal pumps require refilling, drugs are custom compounded at very high concentrations. Unfortunately, the baricity of these custom solutions is unknown, which is problematic, given baricity's importance in determining the spread of intrathecally administered drugs. Consequently, we measured the density and calculated the baricity of clinically relevant concentrations of multiple drugs used for intrathecal infusion. Morphine, clonidine, bupivacaine, and baclofen were weighed to within 0.0001 g and diluted in volumetric flasks to produce solutions of known concentrations (morphine 1, 10, 25, and 50 mg/mL; clonidine 0.05, 0.5, 1, and 3 mg/mL; bupivacaine 2.5, 5, 10, and 20 mg/mL; baclofen 1, 1.5, 2, and 4 mg/mL). The densities of the solutions were measured at 37°C using the mechanical oscillation method. A "best-fit" curve was calculated for plots of concentration versus density for each drug. All prepared solutions of clonidine and baclofen were hypobaric. Higher concentrations of morphine and bupivacaine were hyperbaric, whereas lower concentrations were hypobaric. The relationship between concentration and density is linear for morphine (r > 0.99) and bupivacaine (r > 0.99) and logarithmic for baclofen (r = 0.96) and clonidine (r = 0.98). This is the first study to examine the relationship between concentration and density for custom drug concentrations commonly used in implanted intrathecal pumps. We calculated an equation that defines the relationship between concentration and density for each drug. Using these equations, clinicians can calculate the density of any solution made from the drugs studied here.

Therapeutic drug monitoring of atypical antipsychotic drugs

Directory of Open Access Journals (Sweden)

Grundmann Milan

2014-12-01

Full Text Available Schizophrenia is a severe psychiatric disorder often associated with cognitive impairment and affective, mainly depressive, symptoms. Antipsychotic medication is the primary intervention for stabilization of acute psychotic episodes and prevention of recurrences and relapses in patients with schizophrenia. Typical antipsychotics, the older class of antipsychotic agents, are currently used much less frequently than newer atypical antipsychotics. Therapeutic drug monitoring (TDM of antipsychotic drugs is the specific method of clinical pharmacology, which involves measurement of drug serum concentrations followed by interpretation and good cooperation with the clinician. TDM is a powerful tool that allows tailor-made treatment for the specific needs of individual patients. It can help in monitoring adherence, dose adjustment, minimizing the risk of toxicity and in cost-effectiveness in the treatment of psychiatric disorders. The review provides complex knowledge indispensable to clinical pharmacologists, pharmacists and clinicians for interpretation of TDM results.

Melanin targeting for intracellular drug delivery: Quantification of bound and free drug in retinal pigment epithelial cells.

Science.gov (United States)

Rimpelä, Anna-Kaisa; Hagström, Marja; Kidron, Heidi; Urtti, Arto

2018-05-31

Melanin binding affects drug distribution and retention in pigmented ocular tissues, thereby affecting drug response, duration of activity and toxicity. Therefore, it is a promising possibility for drug targeting and controlled release in the pigmented cells and tissues. Intracellular unbound drug concentrations determine pharmacological and toxicological actions, but analyses of unbound vs. total drug concentrations in pigmented cells are lacking. We studied intracellular binding and cellular drug uptake in pigmented retinal pigment epithelial cells and in non-pigmented ARPE-19 cells with five model drugs (chloroquine, propranolol, timolol, diclofenac, methotrexate). The unbound drug fractions in pigmented cells were 0.00016-0.73 and in non-pigmented cells 0.017-1.0. Cellular uptake (i.e. distribution ratio Kp), ranged from 1.3 to 6300 in pigmented cells and from 1.0 to 25 in non-pigmented cells. Values for intracellular bioavailability, F ic , were similar in both cells types (although larger variation in pigmented cells). In vitro melanin binding parameters were used to predict intracellular unbound drug fraction and cell uptake. Comparison of predictions with experimental data indicates that other factors (e.g. ion-trapping, lipophilicity-related binding to other cell components) also play a role. Melanin binding is a major factor that leads to cellular uptake and unbound drug fractions of a range of 3-4 orders of magnitude indicating that large reservoirs of melanin bound drug can be generated in the cells. Understanding melanin binding has important implications on retinal drug targeting, efficacy and toxicity. Copyright © 2017. Published by Elsevier B.V.

Understanding release kinetics of biopolymer drug delivery microcapsules for biomedical applications

International Nuclear Information System (INIS)

Desai, Salil; Perkins, Jessica; Harrison, Benjamin S.; Sankar, Jag

2010-01-01

Drug delivery and dosage concentrations are considered as major focal points in conventional as well as battlefield emergency medicine. The concept of localizing drug delivery via microcapsules is an evolving field to confine the adverse side effects of high concentration drug doses. This paper focuses on understanding release kinetics through biopolymer microcapsules for time-dependent drug release. Calcium alginate microcapsules were manufactured using a direct-write inkjet technique. Rhodamine 6G was used as the release agent to observe the release kinetics from calcium alginate beads in distilled water. A design of experiments was constructed to compare the effect of the microcapsule diameter and different concentrations of calcium chloride (M) and sodium alginate (%, w/v) solutions on the release kinetics profiles of the microcapsules. This research gives insight to identify favorable sizes of microcapsules and concentrations of sodium alginate and calcium chloride solutions for controlled release behavior of drug delivery microcapsules.

Hydrophobic Drug-Loaded PEGylated Magnetic Liposomes for Drug-Controlled Release

Science.gov (United States)

Hardiansyah, Andri; Yang, Ming-Chien; Liu, Ting-Yu; Kuo, Chih-Yu; Huang, Li-Ying; Chan, Tzu-Yi

2017-05-01

Less targeted and limited solubility of hydrophobic-based drug are one of the serious obstacles in drug delivery system. Thus, new strategies to enhance the solubility of hydrophobic drug and controlled release behaviors would be developed. Herein, curcumin, a model of hydrophobic drug, has been loaded into PEGylated magnetic liposomes as a drug carrier platform for drug controlled release system. Inductive magnetic heating (hyperthermia)-stimulated drug release, in vitro cellular cytotoxicity assay of curcumin-loaded PEGylated magnetic liposomes and cellular internalization-induced by magnetic guidance would be investigated. The resultant of drug carriers could disperse homogeneously in aqueous solution, showing a superparamagnetic characteristic and could inductive magnetic heating with external high-frequency magnetic field (HFMF). In vitro curcumin release studies confirmed that the drug carriers exhibited no significant release at 37 °C, whereas exhibited rapid releasing at 45 °C. However, it would display enormous (three times higher) curcumin releasing under the HFMF exposure, compared with that without HFMF exposure at 45 °C. In vitro cytotoxicity test shows that curcumin-loaded PEGylated magnetic liposomes could efficiently kill MCF-7 cells in parallel with increasing curcumin concentration. Fluorescence microscopy observed that these drug carriers could internalize efficiently into the cellular compartment of MCF-7 cells. Thus, it would be anticipated that the novel hydrophobic drug-loaded PEGylated magnetic liposomes in combination with inductive magnetic heating are promising to apply in the combination of chemotherapy and thermotherapy for cancer therapy.

Tacrolimus concentration/dose ratio as a therapeutic drug monitoring strategy: The influence of gender and comedication

Directory of Open Access Journals (Sweden)

Rančić Nemanja

2015-01-01

Full Text Available Background/Aim. A combination of tacrolimus and other drugs such as corticosteroids has been commonly used immunosuppresive regimens. On the other hand, there is a growing body of evidence that male and female may differ in their response to the equal drug treatment. The aim of the study was to estimated the use of tacrolimus concentration/dose (C/D ratio for the assessment of the influence of gender differences and comedication on tacrolimus exposure in renal transplant recipients. Methods. This prospective case series study included 54 patients, in which the unit of monitoring was outpatient examination (1,872 of the renal transplant patients. The patients were monitored in the period 2010-2014, starting one month after the transplantation. Tacrolimus trough concentrations (TTC were measured by chemiluminescence microparticles immunoassay. Results. TTC and the tacrolimus C/D ratio were significantly lower in the females comparing with the males. Contrary to the males, in the females a significant increase of the tacrolimus daily dose (TDD per body weight and TTC, along with the corticosteroid dose increase, was not accompanied by any significant changes in the tacrolimus C/D ratio; in different corticosteroid doses faster elimination of tacrolimus was found with the exception of the doses > 0.25 mg/kg. In the patients treated with proton pump inhibitors, mainly with pantoprazole TDD per body weight and TTC were significantly higher, while the tacrolimus C/D ratio was significantly lower compared to the patients without this treatment. In the patients treated with calcium channel blockers, TDD per body weight was significantly lower (particularly with amlodipine while the tacrolimus C/D ratio was higher compared to the patients who were not treated by them. Conclusion. A lower tacrolimus exposure was detected in females in comparison to males. When gender differences were considered in the context of different corticosteroid doses, faster

The tolerance efficiency of Panicum maximum and Helianthus annuus in TNT-contaminated soil and nZVI-contaminated soil.

Science.gov (United States)

Jiamjitrpanich, Waraporn; Parkpian, Preeda; Polprasert, Chongrak; Laurent, François; Kosanlavit, Rachain

2012-01-01

This study was designed to compare the initial method for phytoremediation involving germination and transplantation. The study was also to determine the tolerance efficiency of Panicum maximum (Purple guinea grass) and Helianthus annuus (Sunflower) in TNT-contaminated soil and nZVI-contaminated soil. It was found that the transplantation of Panicum maximum and Helianthus annuus was more suitable than germination as the initiate method of nano-phytoremediation potting test. The study also showed that Panicum maximum was more tolerance than Helianthus annuus in TNT and nZVI-contaminated soil. Therefore, Panicum maximum in the transplantation method should be selected as a hyperaccumulated plant for nano-phytoremediation potting tests. Maximum tolerance dosage of Panicum maximum to TNT-concentration soil was 320 mg/kg and nZVI-contaminated soil was 1000 mg/kg in the transplantation method.

Maximum Acceleration Recording Circuit

Science.gov (United States)

Bozeman, Richard J., Jr.

1995-01-01

Coarsely digitized maximum levels recorded in blown fuses. Circuit feeds power to accelerometer and makes nonvolatile record of maximum level to which output of accelerometer rises during measurement interval. In comparison with inertia-type single-preset-trip-point mechanical maximum-acceleration-recording devices, circuit weighs less, occupies less space, and records accelerations within narrower bands of uncertainty. In comparison with prior electronic data-acquisition systems designed for same purpose, circuit simpler, less bulky, consumes less power, costs and analysis of data recorded in magnetic or electronic memory devices. Circuit used, for example, to record accelerations to which commodities subjected during transportation on trucks.

Drug-Loaded Microspheres for the Treatment of Liver Cancer: Review of Current Results

International Nuclear Information System (INIS)

Kettenbach, Joachim; Stadler, Alfred; Katzler, Isabella v.; Schernthaner, Ruediger; Blum, Melanie; Lammer, Johannes; Rand, Thomas

2008-01-01

Transarterial chemoembolization (TACE) involves the emulsification of a chemotherapeutic agent in a viscous drug carrier, delivered intra-arterially to liver tumor for maximum effect. TACE reduces arterial inflow, diminishes washout of the chemotherapeutic agent, and decreases systemic exposure. Despite evidence of some clinical success with TACE, a new type of microspheres with drug-eluting capabilities may offer a precisely controlled and sustainable release of the chemotherapeutic agent into the tumor bed. In animal trials tumor necrosis (approaching 100%) was greatest at 7 days, with significantly lower plasma concentrations of doxorubicin than in control animals treated with doxorubicin intra-arterially. Clinically, drug-eluting microspheres loaded with doxorubicin, either at 75 mg/m 2 or at a fixed dose of 150 mg, were used recently and no severe disorders of the hepatic function were observed postprocedure, while a substantial reduction of the fetoprotein levels occurred. An interim analysis of the first 15 patients from the Hong Kong group at 3 months showed an objective response rate of 61.54% and 53.84% according to EASL criteria and RECIST criteria, respectively, and a survival rate of 93.3%. In this paper we present how to use microspheres loaded with doxorubicin and review their clinical value and preliminary performance for treatment of unresectable liver cancer

Effects of low concentrations of Regorafenib and Sorafenib on human HCC cell AFP, migration, invasion and growth in vitro

Science.gov (United States)

Carr, Brian Irving; D’Alessandro, Rosalba; Refolo, Maria Grazia; Iacovazzi, Palma Aurelia; Lippolis, Catia; Messa, Caterina; Cavallini, Aldo; Correale, Mario; Di Carlo, Antonio

2012-01-01

Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multi-kinase inhibitors, Regorafenib (Stivarga) and Sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.1–1µM drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multi-kinase inhibitor concentrations thus modulate several aspects of HCC cell biology. PMID:23169148

Neutron spectra unfolding with maximum entropy and maximum likelihood

International Nuclear Information System (INIS)

Itoh, Shikoh; Tsunoda, Toshiharu

1989-01-01

A new unfolding theory has been established on the basis of the maximum entropy principle and the maximum likelihood method. This theory correctly embodies the Poisson statistics of neutron detection, and always brings a positive solution over the whole energy range. Moreover, the theory unifies both problems of overdetermined and of underdetermined. For the latter, the ambiguity in assigning a prior probability, i.e. the initial guess in the Bayesian sense, has become extinct by virtue of the principle. An approximate expression of the covariance matrix for the resultant spectra is also presented. An efficient algorithm to solve the nonlinear system, which appears in the present study, has been established. Results of computer simulation showed the effectiveness of the present theory. (author)

Maximum Power from a Solar Panel

Directory of Open Access Journals (Sweden)

Michael Miller

2010-01-01

Full Text Available Solar energy has become a promising alternative to conventional fossil fuel sources. Solar panels are used to collect solar radiation and convert it into electricity. One of the techniques used to maximize the effectiveness of this energy alternative is to maximize the power output of the solar collector. In this project the maximum power is calculated by determining the voltage and the current of maximum power. These quantities are determined by finding the maximum value for the equation for power using differentiation. After the maximum values are found for each time of day, each individual quantity, voltage of maximum power, current of maximum power, and maximum power is plotted as a function of the time of day.

[Ozone concentration distribution of urban].

Science.gov (United States)

Yin, Yong-quan; Li, Chang-mei; Ma, Gui-xia; Cui, Zhao-jie

2004-11-01

The increase of ozone concentration in urban is one of the most important research topics on environmental science. With the increase of nitrogen oxides and hydrogen-carbon compounds which are exhausted from cars, the ozone concentration in urban is obviously increased on sunlight, and threat of photochemistry smog will be possible. Therefore, it is very important to monitor and study the ozone concentration distribution in urban. The frequency-distribution, diurnal variation and monthly variation of ozone concentration were studied on the campus of Shandong University during six months monitoring. The influence of solar radiation and weather conditions on ozone concentration were discussed. The frequency of ozone concentration less than 200 microg/m3 is 96.88%. The ozone concentration has an obvious diurnal variation. The ozone concentration in the afternoon is higher than in the morning and in the evening. The maximum appears in June, when it is the strong solar radiation and high air-temperature. The weather conditions also influence the ozone concentration. The ozone concentration in clear day is higher than in rainy and cloudy day.

Modelling the encapsulation of the anticancer drug cisplatin into carbon nanotubes

International Nuclear Information System (INIS)

Hilder, Tamsyn A; Hill, James M

2007-01-01

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

Anesthetic drug wastage in the operation room: A cause for concern

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Kapil Chaudhary

2012-01-01

Full Text Available Context: The cost of anesthetic technique has three main components, i.e., disposable supplies, equipments, and anesthetic drugs. Drug budgets are an easily identifiable area for short-term savings. Aim: To assess and estimate the amount of anesthetic drug wastage in the general surgical operation room. Also, to analyze the financial implications to the hospital due to drug wastage and suggest appropriate steps to prevent or minimize this wastage. Settings and Design: A prospective observational study conducted in the general surgical operation room of a tertiary care hospital. Materials and Methods: Drug wastage was considered as the amount of drug left unutilized in the syringes/vials after completion of a case and any ampoule or vial broken while loading. An estimation of the cost of wasted drug was made. Results: Maximal wastage was associated with adrenaline and lignocaine (100% and 93.63%, respectively. The drugs which accounted for maximum wastage due to not being used after loading into a syringe were adrenaline (95.24%, succinylcholine (92.63%, lignocaine (92.51%, mephentermine (83.80%, and atropine (81.82%. The cost of wasted drugs for the study duration was 46.57% (Rs. 16,044.01 of the total cost of drugs issued/loaded (Rs. 34,449.44. Of this, the cost of wastage of propofol was maximum being 56.27% (Rs. 9028.16 of the total wastage cost, followed by rocuronium 17.80% (Rs. 2856, vecuronium 5.23% (Rs. 840, and neostigmine 4.12% (Rs. 661.50. Conclusions: Drug wastage and the ensuing financial loss can be significant during the anesthetic management of surgical cases. Propofol, rocuronium, vecuronium, and neostigmine are the drugs which contribute maximally to the total wastage cost. Judicious use of these and other drugs and appropriate prudent measures as suggested can effectively decrease this cost.

A facile doxorubicin-dichloroacetate conjugate nanomedicine with high drug loading for safe drug delivery.

Science.gov (United States)

Yang, Conglian; Wu, Tingting; Qin, Yuting; Qi, Yan; Sun, Yu; Kong, Miao; Jiang, Xue; Qin, Xianya; Shen, Yaqi; Zhang, Zhiping

2018-01-01

Doxorubicin (DOX) is an effective chemotherapeutic agent but severe side effects limit its clinical application. Nanoformulations can reduce the toxicity while still have various limitations, such as complexity, low drug loading capability and excipient related concerns. An amphiphilic conjugate, doxorubicin-dichloroacetate, was synthesized and the corresponding nanoparticles were prepared. The in vitro cytotoxicity and intracellular uptake, in vivo imaging, antitumor effects and systemic toxicities of nanoparticles were carried out to evaluate the therapeutic efficiency of tumor. Doxorubicin-dichloroacetate conjugate can self-assemble into nanoparticles with small amount of DSPE-PEG 2000 , leading to high drug loading (71.8%, w/w) and diminished excipient associated concerns. The nanoparticles exhibited invisible systemic toxicity and high maximum tolerated dose of 75 mg DOX equiv./kg, which was 15-fold higher than that of free DOX. It also showed good tumor targeting capability and enhanced antitumor efficacy in murine melanoma model. This work provides a promising strategy to simplify the drug preparation process, increase drug loading content, reduce systemic toxicity as well as enhance antitumor efficiency.

Can medical students calculate drug doses? | Harries | Southern ...

African Journals Online (AJOL)

... with calculations when the drug concentration was expressed either as a ratio or a percentage. Conclusion: Our findings support calls for the standardised labelling of drugs in solution and for dosage calculation training in the medical curriculum. Keywords: drug dosage calculations, clinical competence, medication errors

Markers of anthropogenic contamination: A validated method for quantification of pharmaceuticals, illicit drug metabolites, perfluorinated compounds, and plasticisers in sewage treatment effluent and rain runoff.

Science.gov (United States)

Wilkinson, John L; Swinden, Julian; Hooda, Peter S; Barker, James; Barton, Stephen

2016-09-01

An effective, specific and accurate method is presented for the quantification of 13 markers of anthropogenic contaminants in water using solid phase extraction (SPE) followed by high performance liquid chromatography (HPLC) tandem mass spectrometry (MS/MS). Validation was conducted according to the International Conference on Harmonisation (ICH) guidelines. Method recoveries ranged from 77 to 114% and limits of quantification between 0.75 and 4.91 ng/L. A study was undertaken to quantify the concentrations and loadings of the selected contaminants in 6 sewage treatment works (STW) effluent discharges as well as concentrations in 5 rain-driven street runoffs and field drainages. Detection frequencies in STW effluent ranged from 25% (ethinylestradiol) to 100% (benzoylecgonine, bisphenol-A (BPA), bisphenol-S (BPS) and diclofenac). Average concentrations of detected compounds in STW effluents ranged from 3.62 ng/L (ethinylestradiol) to 210 ng/L (BPA). Levels of perfluorinated compounds (PFCs) perfluorooctanoic acid (PFOA) and perfluorononanoic acid (PFNA) as well as the plasticiser BPA were found in street runoff at maximum levels of 1160 ng/L, 647 ng/L and 2405 ng/L respectively (8.52, 3.09 and 2.7 times more concentrated than maximum levels in STW effluents respectively). Rain-driven street runoff may have an effect on levels of PFCs and plasticisers in receiving rivers and should be further investigated. Together, this method with the 13 selected contaminants enables the quantification of various markers of anthropogenic pollutants: inter alia pharmaceuticals, illicit drugs and their metabolites from humans and improper disposal of drugs, while the plasticisers and perfluorinated compounds may also indicate contamination from industrial and transport activity (street runoff). Copyright © 2016 Elsevier Ltd. All rights reserved.

Magnetic concentration of iron-titanium ore with vanadium concentrate from campo Alegre de Lourdes - Bahia, Brazil

International Nuclear Information System (INIS)

Delgado, O.; Silva, F.T. da; Ogasawara, T.; Soares, G.F.

1988-01-01

The feasibility studies of magnetic concentration of the Campo Alegre de Lourdes ore were carried out, trying to obtain a maximum recovery of vanadium. As a consequence of the complex nature of the ore, mainly due to the presence of ilmenite as a exolutions in the interior of hematite/martite particles, it was not possible to separate the hematite-ilmenite eficiently, wich would be necessary for obtaining a high grade vanadium concentrate with low titanium content. (author) [pt

Evaluation of the Presence and Levels of Enrofloxacin, Ciprofloxacin, Sulfaquinoxaline and Oxytetracycline in Broiler Chickens after Drug Administration.

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de Assis, Débora Cristina Sampaio; da Silva, Guilherme Resende; Lanza, Isabela Pereira; Ribeiro, Ana Cláudia Dos Santos Rossi; Lana, Ângela Maria Quintão; Lara, Leonardo José Camargos; de Figueiredo, Tadeu Chaves; Cançado, Silvana de Vasconcelos

2016-01-01

The depletion times of enrofloxacin and its metabolite ciprofloxacin as well as sulfaquinoxaline and oxytetracycline were evaluated in broiler chickens that had been subjected to pharmacological treatment. The presence and residue levels of these drugs in muscle tissue were evaluated using an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method that was validated in this work. The results showed the presence of all antimicrobial residues; however, the presence of residues at concentrations higher than the drugs' maximum residue limit (MRL) of 100 μg kg-1 was found only during the treatment period for oxytetracycline and until two days after discontinuation of the medication for enrofloxacin, ciprofloxacin and sulfaquinoxaline. It was concluded that the residues of all antimicrobials were rapidly metabolized from the broiler muscles; after four days of withdrawal, the levels were lower than the limit of quantification (LOQ) of the method for the studied analytes.

Effect of glycine, DL-alanine and DL-2-aminobutyric acid on the temperature of maximum density of water

International Nuclear Information System (INIS)

Romero, Carmen M.; Torres, Andres Felipe

2015-01-01

Highlights: • Effect of α-amino acids on the temperature of maximum density of water is presented. • The addition of α-amino acids decreases the temperature of maximum density of water. • Despretz constants suggest that the amino acids behave as water structure breakers. • Despretz constants decrease as the number of CH 2 groups of the amino acid increase. • Solute disrupting effect becomes smaller as its hydrophobic character increases. - Abstract: The effect of glycine, DL-alanine and DL-2-aminobutyric acid on the temperature of maximum density of water was determined from density measurements using a magnetic float densimeter. Densities of aqueous solutions were measured within the temperature range from T = (275.65 to 278.65) K at intervals of T = 0.50 K over the concentration range between (0.0300 and 0.1000) mol · kg −1 . A linear relationship between density and concentration was obtained for all the systems in the temperature range considered. The temperature of maximum density was determined from the experimental results. The effect of the three amino acids is to decrease the temperature of maximum density of water and the decrease is proportional to molality according to Despretz equation. The effect of the amino acids on the temperature of maximum density decreases as the number of methylene groups of the alkyl chain becomes larger. The results are discussed in terms of (solute + water) interactions and the effect of amino acids on water structure

A high content screening assay to predict human drug-induced liver injury during drug discovery.

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Persson, Mikael; Løye, Anni F; Mow, Tomas; Hornberg, Jorrit J

2013-01-01

Adverse drug reactions are a major cause for failures of drug development programs, drug withdrawals and use restrictions. Early hazard identification and diligent risk avoidance strategies are therefore essential. For drug-induced liver injury (DILI), this is difficult using conventional safety testing. To reduce the risk for DILI, drug candidates with a high risk need to be identified and deselected. And, to produce drug candidates without that risk associated, risk factors need to be assessed early during drug discovery, such that lead series can be optimized on safety parameters. This requires methods that allow for medium-to-high throughput compound profiling and that generate quantitative results suitable to establish structure-activity-relationships during lead optimization programs. We present the validation of such a method, a novel high content screening assay based on six parameters (nuclei counts, nuclear area, plasma membrane integrity, lysosomal activity, mitochondrial membrane potential (MMP), and mitochondrial area) using ~100 drugs of which the clinical hepatotoxicity profile is known. We find that a 100-fold TI between the lowest toxic concentration and the therapeutic Cmax is optimal to classify compounds as hepatotoxic or non-hepatotoxic, based on the individual parameters. Most parameters have ~50% sensitivity and ~90% specificity. Drugs hitting ≥2 parameters at a concentration below 100-fold their Cmax are typically hepatotoxic, whereas non-hepatotoxic drugs typically hit based on nuclei count, MMP and human Cmax, we identified an area without a single false positive, while maintaining 45% sensitivity. Hierarchical clustering using the multi-parametric dataset roughly separates toxic from non-toxic compounds. We employ the assay in discovery projects to prioritize novel compound series during hit-to-lead, to steer away from a DILI risk during lead optimization, for risk assessment towards candidate selection and to provide guidance of safe

21 CFR 146.146 - Frozen concentrated orange juice.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Frozen concentrated orange juice. 146.146 Section... Fruit Juices and Beverages § 146.146 Frozen concentrated orange juice. (a) Frozen concentrated orange juice is the food prepared by removing water from the juice of mature oranges as provided in § 146.135...

Quantitative analysis of microbicide concentrations in fluids, gels and tissues using confocal Raman spectroscopy.

Directory of Open Access Journals (Sweden)

Oranat Chuchuen

Full Text Available Topical vaginal anti-HIV microbicides are an important focus in female-based strategies to prevent the sexual transmission of HIV. Understanding microbicide pharmacokinetics is essential to development, characterization and implementation of efficacious microbicide drug delivery formulations. Current methods to measure drug concentrations in tissue (e.g., LC-MS/MS, liquid chromatography coupled with tandem mass spectrometry are highly sensitive, but destructive and complex. This project explored the use of confocal Raman spectroscopy to detect microbicide drugs and to measure their local concentrations in fluids, drug delivery gels, and tissues. We evaluated three candidate microbicide drugs: tenofovir, Dapivirine and IQP-0528. Measurements were performed in freshly excised porcine buccal tissue specimens, gel vehicles and fluids using two Horiba Raman microscopes, one of which is confocal. Characteristic spectral peak calibrations for each drug were obtained using serial dilutions in the three matrices. These specific Raman bands demonstrated strong linear concentration dependences in the matrices and were characterized with respect to their unique vibrational signatures. At least one specific Raman feature was identified for each drug as a marker band for detection in tissue. Sensitivity of detection was evaluated in the three matrices. A specific peak was also identified for tenofovir diphosphate, the anti-HIV bioactive product of tenofovir after phosphorylation in host cells. Z-scans of drug concentrations vs. depth in excised tissue specimens, incubated under layers of tenofovir solution in a Transwell assay, showed decreasing concentration with depth from the surface into the tissue. Time-dependent concentration profiles were obtained from tissue samples incubated in the Transwell assay, for times ranging 30 minutes - 6 hours. Calibrations and measurements from tissue permeation studies for tenofovir showed good correlation with gold

Quantitative Analysis of Microbicide Concentrations in Fluids, Gels and Tissues Using Confocal Raman Spectroscopy

Science.gov (United States)

Chuchuen, Oranat; Henderson, Marcus H.; Sykes, Craig; Kim, Min Sung; Kashuba, Angela D. M.; Katz, David F.

2013-01-01

Topical vaginal anti-HIV microbicides are an important focus in female-based strategies to prevent the sexual transmission of HIV. Understanding microbicide pharmacokinetics is essential to development, characterization and implementation of efficacious microbicide drug delivery formulations. Current methods to measure drug concentrations in tissue (e.g., LC-MS/MS, liquid chromatography coupled with tandem mass spectrometry) are highly sensitive, but destructive and complex. This project explored the use of confocal Raman spectroscopy to detect microbicide drugs and to measure their local concentrations in fluids, drug delivery gels, and tissues. We evaluated three candidate microbicide drugs: tenofovir, Dapivirine and IQP-0528. Measurements were performed in freshly excised porcine buccal tissue specimens, gel vehicles and fluids using two Horiba Raman microscopes, one of which is confocal. Characteristic spectral peak calibrations for each drug were obtained using serial dilutions in the three matrices. These specific Raman bands demonstrated strong linear concentration dependences in the matrices and were characterized with respect to their unique vibrational signatures. At least one specific Raman feature was identified for each drug as a marker band for detection in tissue. Sensitivity of detection was evaluated in the three matrices. A specific peak was also identified for tenofovir diphosphate, the anti-HIV bioactive product of tenofovir after phosphorylation in host cells. Z-scans of drug concentrations vs. depth in excised tissue specimens, incubated under layers of tenofovir solution in a Transwell assay, showed decreasing concentration with depth from the surface into the tissue. Time-dependent concentration profiles were obtained from tissue samples incubated in the Transwell assay, for times ranging 30 minutes - 6 hours. Calibrations and measurements from tissue permeation studies for tenofovir showed good correlation with gold standard LC-MS/MS data

X-ray Spectroscopy for Quality Control of Chemotherapy Drugs

International Nuclear Information System (INIS)

Greaves, E. D.; Barros, H.; Bermudez, J.; Sajo-Bohus, L.; Angeli-Greaves, M.

2007-01-01

We develop a method, employing Compton peak standardization and the use of matrix-matched spiked samples with Total Reflection X-ray Fluorescence (TXRF), for the determination of platinum plasma concentrations of patients undergoing chemotherapy with Pt-bearing drugs. Direct blood plasma analysis attains Pt detection limits of 70 ng/ml. Measurement results of prescribed drug doses are compared to achieved blood Pt concentrations indicating a lack of expected correlations. Direct analysis of Pt-containing infused drugs from a variety of suppliers indicates cases of abnormal concentrations which raises quality control issues. We demonstrate the potential usefulness of the method for pharmacokinetic studies or for routine optimization and quality control of Pt chemotherapy treatments

Emerging Frontiers in Drug Delivery.

Science.gov (United States)

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

2016-01-27

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

Prediction of clearance, volume of distribution and half-life by allometric scaling and by use of plasma concentrations predicted from pharmacokinetic constants: a comparative study.

Science.gov (United States)

Mahmood, I

1999-08-01

Pharmacokinetic parameters (clearance, CL, volume of distribution in the central compartment, VdC, and elimination half-life, t1/2beta) predicted by an empirical allometric approach have been compared with parameters predicted from plasma concentrations calculated by use of the pharmacokinetic constants A, B, alpha and beta, where A and B are the intercepts on the Y axis of the plot of plasma concentration against time and alpha and beta are the rate constants, both pairs of constants being for the distribution and elimination phases, respectively. The pharmacokinetic parameters of cefpiramide, actisomide, troglitazone, procaterol, moxalactam and ciprofloxacin were scaled from animal data obtained from the literature. Three methods were used to generate plots for the prediction of clearance in man: dependence of clearance on body weight (simple allometric equation); dependence of the product of clearance and maximum life-span potential (MLP) on body weight; and dependence of the product of clearance and brain weight on body weight. Plasma concentrations of the drugs were predicted in man by use of A, B, alpha and beta obtained from animal data. The predicted plasma concentrations were then used to calculate CL, VdC and t1/2beta. The pharmacokinetic parameters predicted by use of both approaches were compared with measured values. The results indicate that simple allometry did not predict clearance satisfactorily for actisomide, troglitazone, procaterol and ciprofloxacin. Use of MLP or the product of clearance and brain weight improved the prediction of clearance for these four drugs. Except for troglitazone, VdC and t1/2beta predicted for man by use of the allometric approach were comparable with measured values for the drugs studied. CL, VdC and t1/2beta predicted by use of pharmacokinetic constants were comparable with values predicted by simple allometry. Thus, if simple allometry failed to predict clearance of a drug, so did the pharmacokinetic constant

Controlled-release, pegylation, liposomal formulations: new mechanisms in the delivery of injectable drugs.

Science.gov (United States)

Reddy, K R

2000-01-01

To review recent developments in novel injectable drug delivery mechanisms and outline the advantages and disadvantages of each. A MEDLINE (1995-January 2000) search using the terms polyethylene glycol, liposomes, polymers, polylactic acid, and controlled release was conducted. Additional references were identified by scanning bibliographies. All articles were considered for inclusion. Abstracts were included only if they were judged to add critical information not otherwise available in the medical literature. A number of systems that alter the delivery of injectable drugs have been developed in attempts to improve pharmacodynamic and pharmacokinetic properties of therapeutic agents. New drug delivery systems can be produced either through a change in formulation (e.g., continuous-release products, liposomes) or an addition to the drug molecule (e.g., pegylation). Potential advantages of new delivery mechanisms include an increased or prolonged duration of pharmacologic activity, a decrease in adverse effects, and increased patient compliance and quality of life. Injectable continuous-release systems deliver drugs in a controlled, predetermined fashion and are particularly appropriate when it is important to avoid large fluctuations in plasma drug concentrations. Encapsulating a drug within a liposome can produce a prolonged half-life and a shift of distribution toward tissues with increased capillary permeability (e.g., tumors, infected tissue). Pegylation provides a method for modification of therapeutic proteins to minimize many of the limitations (e.g., poor stability, short half-life, immunogenicity) associated with these agents. Pegylation of therapeutic proteins is an established process with new applications. However, not all pegylated proteins are alike, and each requires optimization on a protein-by-protein basis to derive maximum clinical benefit. The language required to describe each pegylated therapeutic protein must be more precise to accurately

Interaction of charged amphiphilic drugs with phosphatidylcholine vesicles studied by NMR

International Nuclear Information System (INIS)

Eriksson, L.E.G.

1987-01-01

Small unilamellar vesicles from egg phosphatidylcholine in NaCl solutions were exposed to some amphiphilic pharmaca. The aromatic drugs (chlorpromazine, dibucaine, tetracaine, imipramine and propranolol) were in their cationic form of the amines. By 1 H- and 31 P-NMR the membrane signals were observed. In particular, the N-methyl choline proton signals were followed upon drug addition. The intrinsic chemical shift difference (0.02 ppm) between the inner (upfield) and outer choline signals was influenced by the drug concentration. Packing properties of the lipid head groups and ring current shift probably contributed. At very high drug concentration, the vesicles are destroyed. A transformation into a micellar state with a high sample viscosity took place in a narrow concentration range of drug. The anion effects of Cl - were studied from the 35 Cl-NMR linewidth at 9.8 and 39.1 MHz. A continuous increase in the signal linewidth followed upon drug addition to the vesicles. Only chlorpromazine produced a broadening in the absence of vesicles (NaCl blank). The linewidth reflected a critical micelle concentration of this drug around 7 mM in 0.1 M NaCl. The 35 Cl-NMR experiments demonstrated the existence of an anionic counterion effect. This phenomenon should be accounted for when quantitatively analysing drug-membrane interactions in electrostatic terms. (Auth.)

Fabrication of drug nanoparticles by evaporative precipitation of nanosuspension.

Science.gov (United States)

Kakran, M; Sahoo, N G; Li, L; Judeh, Z; Wang, Y; Chong, K; Loh, L

2010-01-04

Evaporative precipitation of nanosuspension (EPN) was used to fabricate nanoparticles of a poorly water-soluble antimalarial drug, artemisinin (ART), with the aim of enhancing its dissolution rate. We investigated the nanoparticle fabrication of ART via a full factorial experimental design considering the effects of drug concentration and solvent to antisolvent ratio on the physical, morphological and dissolution properties of ART. Characterization of the original ART powder and EPN prepared ART nanoparticles was carried out by scanning electron microscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD) and dissolution tester. DSC and XRD studies suggested that the crystallinity of EPN prepared ART nanoparticles decreased with increasing drug concentration and ratio of solvent to antisolvent. The particle diameters of EPN prepared ART nanoparticles were found to be 100-360 nm. The dissolution of EPN prepared ART nanoparticles markedly increased as compared to the original ART powder. A percent dissolution surface-response model was used to elucidate the significant and direct relationships between drug concentration and solvent to antisolvent ratio on one hand and percent dissolution on the other hand. The best dissolution percent was found to be 75.9%, at the drug concentration of 15 mg/mL and solvent to antisolvent ratio (by volume) of 1:20.

Temperature of maximum density and excess thermodynamics of aqueous mixtures of methanol

Energy Technology Data Exchange (ETDEWEB)

González-Salgado, D.; Zemánková, K. [Departamento de Física Aplicada, Universidad de Vigo, Campus del Agua, Edificio Manuel Martínez-Risco, E-32004 Ourense (Spain); Noya, E. G.; Lomba, E. [Instituto de Química Física Rocasolano, CSIC, Calle Serrano 119, E-28006 Madrid (Spain)

2016-05-14

In this work, we present a study of representative excess thermodynamic properties of aqueous mixtures of methanol over the complete concentration range, based on extensive computer simulation calculations. In addition to test various existing united atom model potentials, we have developed a new force-field which accurately reproduces the excess thermodynamics of this system. Moreover, we have paid particular attention to the behavior of the temperature of maximum density (TMD) in dilute methanol mixtures. The presence of a temperature of maximum density is one of the essential anomalies exhibited by water. This anomalous behavior is modified in a non-monotonous fashion by the presence of fully miscible solutes that partly disrupt the hydrogen bond network of water, such as methanol (and other short chain alcohols). In order to obtain a better insight into the phenomenology of the changes in the TMD of water induced by small amounts of methanol, we have performed a new series of experimental measurements and computer simulations using various force fields. We observe that none of the force-fields tested capture the non-monotonous concentration dependence of the TMD for highly diluted methanol solutions.

Evaluation of Pterin, a Promising Drug Candidate from Cyanide Degrading Bacteria.

Science.gov (United States)

Mahendran, Ramasamy; Thandeeswaran, Murugesan; Kiran, Gopikrishnan; Arulkumar, Mani; Ayub Nawaz, K A; Jabastin, Jayamanoharan; Janani, Balraj; Anto Thomas, Thomas; Angayarkanni, Jayaraman

2018-06-01

Pterin is a member of the compounds known as pteridines. They have the same nucleus of 2-amino-4-hydroxypteridine (pterin); however, the side-chain is different at the position 6, and the state of oxidation of the ring may exist in different form viz. tetrahydro, dihydro, or a fully oxidized form. In the present study, the microorganisms able to utilize cyanide, and heavy metals have been tested for the efficient production of pterin compound. The soil samples contaminated with cyanide and heavy metals were collected from Salem steel industries, Tamil Nadu, India. Out of 77 isolated strains, 40 isolates were found to utilize sodium cyanate as nitrogen source at different concentrations. However, only 13 isolates were able to tolerate maximum concentration (60 mM) of sodium cyanate and were screened for pterin production. Among the 13 isolates, only 1 organism showed maximum production of pterin, and the same was identified as Bacillus pumilus SVD06. The compound was extracted and purified by preparative high-performance liquid chromatography and analyzed by UV/visible, FTIR, and fluorescent spectrum. The antioxidant property of the purified pterin compound was determined by cyclic voltammetry. In addition, antimicrobial activity of pterin was also studied which was substantiated by antagonistic activity against Escherichia coli, and Pseudomonas aeruginosa. Besides that the pterin compound was proved to inhibit the formation of biofilm. The extracted pterin compounds could be proposed further not only for antioxidant and antimicrobial but also for its potency to aid as anticancer and psychotic drugs in future.

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

Directory of Open Access Journals (Sweden)

Malcolm J. Reid

2011-12-01

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

Time required to achieve maximum concentration of amikacin in synovial fluid of the distal interphalangeal joint after intravenous regional limb perfusion in horses.

Science.gov (United States)

Kilcoyne, Isabelle; Nieto, Jorge E; Knych, Heather K; Dechant, Julie E

2018-03-01

OBJECTIVE To determine the maximum concentration (Cmax) of amikacin and time to Cmax (Tmax) in the distal interphalangeal (DIP) joint in horses after IV regional limb perfusion (IVRLP) by use of the cephalic vein. ANIMALS 9 adult horses. PROCEDURES Horses were sedated and restrained in a standing position and then subjected to IVRLP (2 g of amikacin sulfate diluted to 60 mL with saline [0.9% NaCl] solution) by use of the cephalic vein. A pneumatic tourniquet was placed 10 cm proximal to the accessory carpal bone. Perfusate was instilled with a peristaltic pump over a 3-minute period. Synovial fluid was collected from the DIP joint 5, 10, 15, 20, 25, and 30 minutes after IVRLP; the tourniquet was removed after the 20-minute sample was collected. Blood samples were collected from the jugular vein 5, 10, 15, 19, 21, 25, and 30 minutes after IVRLP. Amikacin was quantified with a fluorescence polarization immunoassay. Median Cmax of amikacin and Tmax in the DIP joint were determined. RESULTS 2 horses were excluded because an insufficient volume of synovial fluid was collected. Median Cmax for the DIP joint was 600 μg/mL (range, 37 to 2,420 μg/mL). Median Tmax for the DIP joint was 15 minutes. CONCLUSIONS AND CLINICAL RELEVANCE Tmax of amikacin was 15 minutes after IVRLP in horses and Cmax did not increase > 15 minutes after IVRLP despite maintenance of the tourniquet. Application of a tourniquet for 15 minutes should be sufficient for completion of IVRLP when attempting to achieve an adequate concentration of amikacin in the synovial fluid of the DIP joint.

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

Science.gov (United States)

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

2012-10-01

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

Sample preparation composite and replicate strategy for assay of solid oral drug products.

Science.gov (United States)

Harrington, Brent; Nickerson, Beverly; Guo, Michele Xuemei; Barber, Marc; Giamalva, David; Lee, Carlos; Scrivens, Garry

2014-12-16

In pharmaceutical analysis, the results of drug product assay testing are used to make decisions regarding the quality, efficacy, and stability of the drug product. In order to make sound risk-based decisions concerning drug product potency, an understanding of the uncertainty of the reportable assay value is required. Utilizing the most restrictive criteria in current regulatory documentation, a maximum variability attributed to method repeatability is defined for a drug product potency assay. A sampling strategy that reduces the repeatability component of the assay variability below this predefined maximum is demonstrated. The sampling strategy consists of determining the number of dosage units (k) to be prepared in a composite sample of which there may be a number of equivalent replicate (r) sample preparations. The variability, as measured by the standard error (SE), of a potency assay consists of several sources such as sample preparation and dosage unit variability. A sampling scheme that increases the number of sample preparations (r) and/or number of dosage units (k) per sample preparation will reduce the assay variability and thus decrease the uncertainty around decisions made concerning the potency of the drug product. A maximum allowable repeatability component of the standard error (SE) for the potency assay is derived using material in current regulatory documents. A table of solutions for the number of dosage units per sample preparation (r) and number of replicate sample preparations (k) is presented for any ratio of sample preparation and dosage unit variability.

21 CFR 146.154 - Concentrated orange juice with preservative.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 2 2010-04-01 2010-04-01 false Concentrated orange juice with preservative. 146... Canned Fruit Juices and Beverages § 146.154 Concentrated orange juice with preservative. (a) Concentrated orange juice with preservative complies with the requirements for composition and labeling of optional...

Surfactants enhance recovery of poorly soluble drugs during microdialysis sampling

DEFF Research Database (Denmark)

Koplin, Sebastian; Kumpugdee-Vollrath, Mont; Bauer-Brandl, Annette

2017-01-01

Aim of this project was to investigate the applicability of a recently developed in vitro microdialysis-sampling approach in connection with a dissolution-/permeation (D/P) system, especially the impact of surfactants within the perfusion fluid. The D/P-system is based on side-by-side chambers...... drug-dissolution (-release) and drug permeation. Furthermore, it should allow quantification of the unbound (free) drug concentration. In the first step, it was assessed, if the addition of the anionic surfactant sodium dodecyl sulphate (SDS) to the perfusate of the microdialysis system affects...... celecoxib, i.e. the fraction of drug, which is not associated with taurocholate surfactant micelles. In buffer, the measured concentrations matched the overall CXB concentrations. By the use of SDS-containing perfusates microdialysis sampling enabled reliable quantification of minute amounts of free CXB...

Cell culture media impact on drug product solution stability.

Science.gov (United States)

Purdie, Jennifer L; Kowle, Ronald L; Langland, Amie L; Patel, Chetan N; Ouyang, Anli; Olson, Donald J

2016-07-08

To enable subcutaneous administration of monoclonal antibodies, drug product solutions are often needed at high concentrations. A significant risk associated with high drug product concentrations is an increase in aggregate level over the shelf-life dating period. While much work has been done to understand the impact of drug product formulation on aggregation, there is limited understanding of the link between cell culture process conditions and soluble aggregate growth in drug product. During cell culture process development, soluble aggregates are often measured at harvest using cell-free material purified by Protein A chromatography. In the work reported here, cell culture media components were evaluated with respect to their impact on aggregate levels in high concentration solution drug product during accelerated stability studies. Two components, cysteine and ferric ammonium citrate, were found to impact aggregate growth rates in our current media (version 1) leading to the development of new chemically defined media and concentrated feed formulations. The new version of media and associated concentrated feeds (version 2) were evaluated across four cell lines producing recombinant IgG4 monoclonal antibodies and a bispecific antibody. In all four cell lines, the version 2 media reduced aggregate growth over the course of a 12 week accelerated stability study compared with the version 1 media, although the degree to which aggregate growth decreased was cell line dependent. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:998-1008, 2016. © 2016 American Institute of Chemical Engineers.

Chitosan microspheres in novel drug delivery systems.

Science.gov (United States)

Mitra, Analava; Dey, Baishakhi

2011-07-01

The main aim in the drug therapy of any disease is to attain the desired therapeutic concentration of the drug in plasma or at the site of action and maintain it for the entire duration of treatment. A drug on being used in conventional dosage forms leads to unavoidable fluctuations in the drug concentration leading to under medication or overmedication and increased frequency of dose administration as well as poor patient compliance. To minimize drug degradation and loss, to prevent harmful side effects and to increase drug bioavailability various drug delivery and drug targeting systems are currently under development. Handling the treatment of severe disease conditions has necessitated the development of innovative ideas to modify drug delivery techniques. Drug targeting means delivery of the drug-loaded system to the site of interest. Drug carrier systems include polymers, micelles, microcapsules, liposomes and lipoproteins to name some. Different polymer carriers exert different effects on drug delivery. Synthetic polymers are usually non-biocompatible, non-biodegradable and expensive. Natural polymers such as chitin and chitosan are devoid of such problems. Chitosan comes from the deacetylation of chitin, a natural biopolymer originating from crustacean shells. Chitosan is a biocompatible, biodegradable, and nontoxic natural polymer with excellent film-forming ability. Being of cationic character, chitosan is able to react with polyanions giving rise to polyelectrolyte complexes. Hence chitosan has become a promising natural polymer for the preparation of microspheres/nanospheres and microcapsules. The techniques employed to microencapsulate with chitosan include ionotropic gelation, spray drying, emulsion phase separation, simple and complex coacervation. This review focuses on the preparation, characterization of chitosan microspheres and their role in novel drug delivery systems.

Effect of the anticarcinogenic drug 6-mercaptopurine on mineral metabolism

International Nuclear Information System (INIS)

Amemiya, K.

1987-01-01

The effect of 6-mercaptopurine (6-MP) on mineral metabolism was investigated using rats and mice. A single 6-mercaptopurine injection in pregnant rats on day 11 of gestation proved to be highly teratogenic. At term, fetuses from 6-MP injected dams had lower livers zinc concentrations than non-injected or vehicle injected controls while dams showed no differences in liver zinc. Fetuses from dams injected with 6-MP and fed supplemental levels of zinc had a lower frequency of malformations and had higher hepatic zinc concentrations than fetuses from dams fed less zinc with drug injection. Non-pregnant mice injected with 6-MP had higher zinc concentrations compared to controls. In addition, iron, copper and calcium concentrations were higher in the livers of 6-MP injected mice than in controls, indicating that the drug affected several elements. Hepatic concentrations of metallothionein (MT) were also elevated in 6-MP injected mice, suggesting that the change in zinc concentrations associated with drug administration was the result of a drug induction of MT. Dams injected with 6-MP on day 13 of pregnancy had livers which retained more of an absorbed dose of 65 zinc than non-injected dams. Plasma from these drug injected dams also retained less of the absorbed dose than control dams. In contrast, day 14 from dams injected with 6-MP, retained less of an absorbed dose than control embryos

Population pharmacokinetics and limited sampling strategy for first-line tuberculosis drugs and moxifloxacin

NARCIS (Netherlands)

Magis-Escurra, C.; Later-Nijland, H. M. J.; Alffenaar, J. W. C.; Broeders, J.; Burger, D. M.; van Crevel, R.; Boeree, M. J.; Donders, A. R. T.; van Altena, R.; van der Werf, T. S.; Aarnoutse, R. E.

Therapeutic drug monitoring (TDM) of tuberculosis (TB) drugs currently focuses on peak plasma concentrations, yet total exposure [area under the 24-h concentration-time curve (AUC(0-24))] is probably most relevant to the efficacy of these drugs. We therefore assessed population AUC(0-24) data for

Investigations on the viscoelastic performance of pressure sensitive adhesives in drug-in-adhesive type transdermal films.

Science.gov (United States)

Wolff, Hans-Michael; Irsan; Dodou, Kalliopi

2014-08-01

We aimed to investigate the effect of solubility parameter and drug concentration on the rheological behaviour of drug-in-adhesive films intended for transdermal application. Films were prepared over a range of drug concentrations (5%, 10% and 20% w/w) using ibuprofen, benzoic acid, nicotinic acid and lidocaine as model drugs in acrylic (Duro-Tak 87-4287 and Duro-Tak 87900A) or silicone (Bio-PSA 7-4301 and Bio-PSA 7-4302) pressure sensitive adhesives (PSAs). Saturation status of films was determined using light microscopy. Viscoelastic parameters were measured in rheology tests at 32°C. Subsaturated films had lower viscoelastic moduli whereas saturated films had higher moduli than the placebo films and/or a concentration-dependent increase in their modulus. Saturation concentration of each drug in the films was reflected by decreasing/increasing viscoelastic patterns. The viscoelastic windows (VWs) of the adhesive and drug-in-adhesive films clearly depicted the effect of solubility parameter differences, molar concentration of drug in the adhesive film and differences in PSA chemistry. Drug solubility parameters and molar drug concentrations have an impact on rheological patterns and thus on the adhesive performance of tested pressure sensitive adhesives intended for use in transdermal drug delivery systems. Use of the Flory equation in its limiting form was appropriate to predict drug solubility in the tested formulations.

Refillable and magnetically actuated drug delivery system using pear-shaped viscoelastic membrane

KAUST Repository

So, Hongyun

2014-07-01

We report a refillable and valveless drug delivery device actuated by an external magnetic field for on-demand drug release to treat localized diseases. The device features a pear-shaped viscoelastic magnetic membrane inducing asymmetrical deflection and consecutive touchdown motion to the bottom of the dome-shaped drug reservoir in response to a magnetic field, thus achieving controlled discharge of the drug. Maximum drug release with 18 ± 1.5 μg per actuation was achieved under a 500 mT magnetic flux density, and various controlled drug doses were investigated with the combination of the number of accumulated actuations and the strength of the magnetic field.

Comparison of tritium concentrations in rainwater, simulated infiltrating water, and groundwater

International Nuclear Information System (INIS)

Ishii, Yoshiyuki; Saito, Masaaki; Imaizumi, Hiroshi; Kato, Norio; Kitaoka, Koichi

2014-01-01

The tritium concentration in initial groundwater(i.e., freshly infiltrating rainwater) is necessary for groundwater dating. We collected simulated infiltrating water as the initial groundwater and examined its characteristics for tritium concentration. First, in Tokyo, the tritium concentration of simulated infiltrating water was compared with that of rainwater, atmospheric moisture, groundwater, spring water, and sap water. While rainwater, atmospheric moisture, and simulated infiltrating water remarkably changed month-to-month or with every rainfall event, groundwater and spring water were nearly constant throughout the year. Second, we collected the simulated infiltrating water monthly at four sampling sites widely dispersed across Japan(i.e., Sapporo, Niigata, Tokyo, and Matsuyama) from 2004 to 2010. Sapporo and Niigata showed high tritium concentrations as compared with the relatively low concentrations in Tokyo and Matsuyama. These results indicate that we can obtain annual maximum and minimum concentrations at each site, and that we can estimate the tritium concentration in initial groundwater at each site by using a mixing model composed of these maximum and minimum concentrations. (author)

Amount of self-reported illicit drug use compared to quantitative hair test results in community-recruited young drug users in Amsterdam

NARCIS (Netherlands)

Welp, Esther A. E.; Bosman, Ingrid; Langendam, Miranda W.; Totté, Maja; Maes, Robert A. A.; van Ameijden, Erik J. C.

2003-01-01

To assess the dose-effect relationship between self-reported drug intake and the concentration of drugs and/or their metabolites in hair and to examine factors that may mediate this relationship. A cohort study among young drug users (YDU) in Amsterdam, the Netherlands, which began in July 2000. At

Therapeutic drug monitoring of aminoglycosides in neonates

NARCIS (Netherlands)

Touw, Daniël J; Westerman, Elsbeth M; Sprij, Arwen J

2009-01-01

The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations, therefore, therapy with aminoglycosides in adults is usually guided by therapeutic drug monitoring. Dosing regimens in adults have evolved from multiple daily dosing to

Sucralfate significantly reduces ciprofloxacin concentrations in serum.

OpenAIRE

Garrelts, J C; Godley, P J; Peterie, J D; Gerlach, E H; Yakshe, C C

1990-01-01

The effect of sucralfate on the bioavailability of ciprofloxacin was evaluated in eight healthy subjects utilizing a randomized, crossover design. The area under the concentration-time curve from 0 to 12 h was reduced from 8.8 to 1.1 micrograms.h/ml by sucralfate (P less than 0.005). Similarly, the maximum concentration of ciprofloxacin in serum was reduced from 2.0 to 0.2 micrograms/ml (P less than 0.005). We conclude that concurrent ingestion of sucralfate significantly reduces the concentr...

Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.

Science.gov (United States)

Lee, Kwang-Hun; Liapi, Eleni A; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A; Ventura, Veronica Prieto; Geschwind, Jean-Francois H

2010-06-01

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

International Nuclear Information System (INIS)

Lee, Kwang-Hun; Liapi, Eleni A.; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A.; Ventura, Veronica Prieto; Geschwind, Jean-Francois H.

2010-01-01

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

The frequency of drugs in randomly selected drivers in Denmark

DEFF Research Database (Denmark)

Simonsen, Kirsten Wiese; Steentoft, Anni; Hels, Tove

is the Danish legal limit. The percentage of drivers positive for medicinal drugs above the Danish legal concentration limit was 0.4%; while, 0.3% of the drivers tested positive for one or more illicit drug at concentrations exceeding the Danish legal limit. Tetrahydrocannabinol, cocaine, and amphetamine were...... the most frequent illicit drugs detected above the limit of quantitation (LOQ); while, codeine, tramadol, zopiclone, and benzodiazepines were the most frequent legal drugs. Middle aged men (median age 47.5 years) dominated the drunk driving group, while the drivers positive for illegal drugs consisted......Introduction Driving under the influence of alcohol and drugs is a global problem. In Denmark as well as in other countries there is an increasing focus on impaired driving. Little is known about the occurrence of psychoactive drugs in the general traffic. Therefore the European commission...

Tacrolimus interaction with nafcillin resulting in significant decreases in tacrolimus concentrations: A case report.

Science.gov (United States)

Wungwattana, Minkey; Savic, Marizela

2017-04-01

Tacrolimus (TAC) is subject to many drug interactions as a result of its metabolism primarily via CYP450 isoenzyme 3A4. Numerous case reports of TAC and CYP3A4 inducers and inhibitors have been described including antimicrobials, calcium channel antagonists, and antiepileptic drugs. We present the case of a 13-year-old patient with cystic fibrosis and a history of liver transplantation, where subtherapeutic TAC concentrations were suspected to be a result of concomitant TAC and nafcillin (NAF) therapy. The observed drug interaction occurred on two separate hospital admissions, during both of which the patient exhibited therapeutic TAC concentrations prior to exposure to NAF, a CYP3A4 inducer. Upon discontinuation of NAF, TAC concentrations recovered in both instances. This case represents a drug-drug interaction between TAC and NAF that has not previously been reported to our knowledge. Despite the lack of existing reports of interaction between these two agents, this case highlights the importance of therapeutic drug monitoring and assessing for any potential drug-drug or drug-food interactions in patients receiving TAC therapy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

40 CFR 1042.140 - Maximum engine power, displacement, power density, and maximum in-use engine speed.

Science.gov (United States)

2010-07-01

... cylinders having an internal diameter of 13.0 cm and a 15.5 cm stroke length, the rounded displacement would... 40 Protection of Environment 32 2010-07-01 2010-07-01 false Maximum engine power, displacement... Maximum engine power, displacement, power density, and maximum in-use engine speed. This section describes...

Credal Networks under Maximum Entropy

OpenAIRE

Lukasiewicz, Thomas

2013-01-01

We apply the principle of maximum entropy to select a unique joint probability distribution from the set of all joint probability distributions specified by a credal network. In detail, we start by showing that the unique joint distribution of a Bayesian tree coincides with the maximum entropy model of its conditional distributions. This result, however, does not hold anymore for general Bayesian networks. We thus present a new kind of maximum entropy models, which are computed sequentially. ...

Continuous protein concentration via free-flow moving reaction boundary electrophoresis.

Science.gov (United States)

Kong, Fanzhi; Zhang, Min; Chen, Jingjing; Fan, Liuyin; Xiao, Hua; Liu, Shaorong; Cao, Chengxi

2017-07-28

In this work, we developed the model and theory of free-flow moving reaction boundary electrophoresis (FFMRB) for continuous protein concentration for the first time. The theoretical results indicated that (i) the moving reaction boundary (MRB) can be quantitatively designed in free-flow electrophoresis (FFE) system; (ii) charge-to-mass ratio (Z/M) analysis could provide guidance for protein concentration optimization; and (iii) the maximum processing capacity could be predicted. To demonstrate the model and theory, three model proteins of hemoglobin (Hb), cytochrome C (Cyt C) and C-phycocyanin (C-PC) were chosen for the experiments. The experimental results verified that (i) stable MRBs with different velocities could be established in FFE apparatus with weak acid/weak base neutralization reaction system; (ii) proteins of Hb, Cyt C and C-PC were well concentrated with FFMRB; and (iii) a maximum processing capacity and recovery ratio of Cyt C enrichment were 126mL/h and 95.5% respectively, and a maximum enrichment factor was achieved 12.6 times for Hb. All of the experiments demonstrated the protein concentration model and theory. In contrast to other methods, the continuous processing ability enables FFMRB to efficiently enrich diluted protein or peptide in large volume solution. Copyright © 2017 Elsevier B.V. All rights reserved.

Maximum total organic carbon limit for DWPF melter feed

International Nuclear Information System (INIS)

Choi, A.S.

1995-01-01

DWPF recently decided to control the potential flammability of melter off-gas by limiting the total carbon content in the melter feed and maintaining adequate conditions for combustion in the melter plenum. With this new strategy, all the LFL analyzers and associated interlocks and alarms were removed from both the primary and backup melter off-gas systems. Subsequently, D. Iverson of DWPF- T ampersand E requested that SRTC determine the maximum allowable total organic carbon (TOC) content in the melter feed which can be implemented as part of the Process Requirements for melter feed preparation (PR-S04). The maximum TOC limit thus determined in this study was about 24,000 ppm on an aqueous slurry basis. At the TOC levels below this, the peak concentration of combustible components in the quenched off-gas will not exceed 60 percent of the LFL during off-gas surges of magnitudes up to three times nominal, provided that the melter plenum temperature and the air purge rate to the BUFC are monitored and controlled above 650 degrees C and 220 lb/hr, respectively. Appropriate interlocks should discontinue the feeding when one or both of these conditions are not met. Both the magnitude and duration of an off-gas surge have a major impact on the maximum TOC limit, since they directly affect the melter plenum temperature and combustion. Although the data obtained during recent DWPF melter startup tests showed that the peak magnitude of a surge can be greater than three times nominal, the observed duration was considerably shorter, on the order of several seconds. The long surge duration assumed in this study has a greater impact on the plenum temperature than the peak magnitude, thus making the maximum TOC estimate conservative. Two models were used to make the necessary calculations to determine the TOC limit

Air Pollution Modelling to Predict Maximum Ground Level Concentration for Dust from a Palm Oil Mill Stack

Directory of Open Access Journals (Sweden)

Regina A. A.

2010-12-01

Full Text Available The study is to model emission from a stack to estimate ground level concentration from a palm oil mill. The case study is a mill located in Kuala Langat, Selangor. Emission source is from boilers stacks. The exercise determines the estimate the ground level concentrations for dust to the surrounding areas through the utilization of modelling software. The surround area is relatively flat, an industrial area surrounded by factories and with palm oil plantations in the outskirts. The model utilized in the study was to gauge the worst-case scenario. Ambient air concentrations were garnered calculate the increase to localized conditions. Keywords: emission, modelling, palm oil mill, particulate, POME

A phase I trial to evaluate the safety and pharmacokinetics of low-dose methotrexate as an anti-malarial drug in Kenyan adult healthy volunteers

Directory of Open Access Journals (Sweden)

Oyoo George O

2011-03-01

Full Text Available Abstract Background Previous investigations indicate that methotrexate, an old anticancer drug, could be used at low doses to treat malaria. A phase I evaluation was conducted to assess the safety and pharmacokinetic profile of this drug in healthy adult male Kenyan volunteers. Methods Twenty five healthy adult volunteers were recruited and admitted to receive a 5 mg dose of methotrexate/day/5 days. Pharmacokinetics blood sampling was carried out at 2, 4, 6, 12 and 24 hours following each dose. Nausea, vomiting, oral ulcers and other adverse events were solicited during follow up of 42 days. Results The mean age of participants was 23.9 ± 3.3 years. Adherence to protocol was 100%. No grade 3 solicited adverse events were observed. However, one case of transiently elevated liver enzymes, and one serious adverse event (not related to the product were reported. The maximum concentration (Cmax was 160-200 nM and after 6 hours, the effective concentration (Ceff was Conclusion Low-dose methotraxate had an acceptable safety profile. However, methotrexate blood levels did not reach the desirable Ceff of 250-400-nM required to clear malaria infection in vivo. Further dose finding and safety studies are necessary to confirm suitability of this drug as an anti-malarial agent.

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

Directory of Open Access Journals (Sweden)

Yvonne Paulley

2010-01-01

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

Microencapsulation of protein drugs for drug delivery: strategy, preparation, and applications.

Science.gov (United States)

Ma, Guanghui

2014-11-10

Bio-degradable poly(lactide) (PLA)/poly(lactide-glycolide) (PLGA) and chitosan microspheres (or microcapsules) have important applications in Drug Delivery Systems (DDS) of protein/peptide drugs. By encapsulating protein/peptide drugs in the microspheres, the serum drug concentration can be maintained at a higher constant value for a prolonged time, or injection formulation can be changed to orally or mucosally administered formulation. PLA/PLGA and chitosan are most often used in injection formulation and oral formulation. However, in the preparation and applications of PLA/PLGA and chitosan microspheres containing protein/peptide drugs, the problems of broad size distribution and poor reproducibility of microspheres, and deactivation of protein during the preparation, storage and release, are still big challenges. In this article, the techniques for control of the diameter of microspheres and microcapsules will be introduced at first, then the strategies about how to maintain the bioactivity of protein drugs during preparation and drug release will be reviewed and developed in our research group. The membrane emulsification techniques including direct membrane emulsification and rapid membrane emulsification processes were developed to prepare uniform-sized microspheres, the diameter of microspheres can be controlled from submicron to 100μm by these two processes, and the reproducibility of products can be guaranteed. Furthermore, compared with conventional stirring method, the big advantages of membrane emulsification process were that the uniform microspheres with much higher encapsulation efficiency can be obtained, and the release behavior can be adjusted by selecting microsphere size. Mild membrane emulsification condition also can prevent the deactivation of proteins, which frequently occurred under high shear force in mechanical stirring, sonification, and homogenization methods. The strategies for maintaining the bioactivity of protein drug were

Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients.

Science.gov (United States)

Hertz, Daniel L; Speth, Kelly A; Kidwell, Kelley M; Gersch, Christina L; Desta, Zeruesenay; Storniolo, Anna Maria; Stearns, Vered; Skaar, Todd C; Hayes, Daniel F; Henry, N Lynn; Rae, James M

2017-10-01

The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n = 200, LET n = 200). Thirty (7.6%) patients (EXE n = 13, LET n = 17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p > 0.05). Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

Maximum Quantum Entropy Method

OpenAIRE

Sim, Jae-Hoon; Han, Myung Joon

2018-01-01

Maximum entropy method for analytic continuation is extended by introducing quantum relative entropy. This new method is formulated in terms of matrix-valued functions and therefore invariant under arbitrary unitary transformation of input matrix. As a result, the continuation of off-diagonal elements becomes straightforward. Without introducing any further ambiguity, the Bayesian probabilistic interpretation is maintained just as in the conventional maximum entropy method. The applications o...

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

Science.gov (United States)

Williamson, Beth; Riley, Robert J

2017-12-01

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

Concentrations of trimethoprim and sulphadoxine in tissues from goats and a cow

Energy Technology Data Exchange (ETDEWEB)

Nielsen, P; Rasmussen, F [Kongelige Veterinaer- og Landbohoejskole, Copenhagen (Denmark)

1975-01-01

The concentration of trimethoprim and sulphadoxine in plasma and tissue from goats and a cow have been determined after a single intravenous injection. Furthermore, the concentration of the two drugs and their metabolites in plasma and tissues have been determined after continuous intravenous infusion for 2 1/2 - 3 hrs. Trimethoprim was present in all tissues but brain at higher concentrations than in plasma while the concentration of sulphadoxine in the different tissues were lower than in plasma. The highest concentration of the 2 drugs and their metabolites was found in the kidney. The distribution pattern of trimethoprim and sulphadoxine was similar in cow and goats.

Concentrations of trimethoprim and sulphadoxine in tissues from goats and a cow

International Nuclear Information System (INIS)

Nielsen, P.; Rasmussen, F.

1975-01-01

The concentration of trimethoprim and sulphadoxine in plasma and tissue from goats and a cow have been determined after a single intravenous injection. Furthermore, the concentration of the two drugs and their metabolites in plasma and tissues have been determined after continuous intravenous infusion for 2 1/2 - 3 hrs. Trimethoprim was present in all tissues but brain at higher concentrations than in plasma while the concentration of sulphadoxine in the different tissues were lower than in plasma. The highest concentration of the 2 drugs and their metabolites was found in the kidney. The distribution pattern of trimethoprim and sulphadoxine was similar in cow and goats. (author)

Effects of different photoperiods and concentrations of phosphate on ...

African Journals Online (AJOL)

The maximum growth rates were observed in the group treated with 2 fold PO4 concentration. The strategy of growth in this species may depend on nitrogen fixation, when other algae were nitrogen limited and fast PO4 uptake even if very low concentration is available. Key words: Cyanobacteria, Cylindrospermopsis ...

Concentration and solidification of liquid radioactive wastes. Laboratory studies

International Nuclear Information System (INIS)

Nuche Vazquez, F.; Lora Soria, F. de

1969-01-01

Bench scale runs on concentration of intermediate level radioactive wastes, and incorporation of the concentrates in asphalt, are described. The feasibility of the process has been demonstrated, with a maximum incorporation of 60 percent of salts into the asphaltic matrix and a volume reduction factor of 10. (Author) 14 refs

Can the genotype or phenotype of two polymorphic drug metabolising cytochrome P450-enzymes identify oral lichenoid drug eruptions?

DEFF Research Database (Denmark)

Kragelund, Camilla; Hansen, Claus; Reibel, Jesper

2010-01-01

Lichenoid drug eruptions (LDE) in the oral cavity are adverse drug reactions (ADR) that are impossible to differentiate from oral lichen planus (OLP) as no phenotypic criteria exist. Impaired function of polymorphic cytochrome 450-enzymes (CYPs) may cause increased plasma concentration of some...

Illicit drugs and the environment--a review.

Science.gov (United States)

Pal, Raktim; Megharaj, Mallavarapu; Kirkbride, K Paul; Naidu, Ravi

2013-10-01

Illicit drugs and their metabolites are the latest group of emerging pollutants. Determination of their concentration in environment (such as water bodies, soil, sediment, air) is an indirect tool to estimate the community level consumption of illicit drug and to evaluate potential ecotoxicological impacts from chronic low level exposure. They enter the wastewater network as unaltered drugs and/or their active metabolites by human excretion after illegal consumption or by accidental or deliberate disposal from clandestine drug laboratories. This article critically reviews the occurrence and concentration levels of illicit drugs and their metabolites in different environmental compartments (e.g., wastewater, surface waters, groundwater, drinking water, and ambient air) and their potential impact on the ecosystem. There is limited published information available on the presence of illicit drugs in the environment, reports are available mainly from European countries, UK, USA, and Canada but there is a lack of information from the remainder of the world. Although the environmental concentrations are not very high, they can potentially impact the human health and ecosystem functioning. Cocaine, morphine, amphetamine, and MDMA have potent pharmacological activities and their presence as complex mixtures in water may cause adverse effect on aquatic organisms and human health. However, there is no current regulation demanding the determination of occurrence of these emerging pollutants in treated wastewater, surface water, drinking water, or atmosphere. Thus, critical investigation on distribution pattern of this new group of emerging contaminant and their potential harmful impact on our environment needs immediate attention. Copyright © 2012. Published by Elsevier B.V.

Self-microemulsifying drug delivery system for improving the bioavailability of huperzine A by lymphatic uptake

Directory of Open Access Journals (Sweden)

Fang Li

2017-05-01

Full Text Available Huperzine A (Hup-A is a poorly water-soluble drug with low oral bioavailability. A self-microemulsifying drug delivery system (SMEDDS was used to enhance the oral bioavailability and lymphatic uptake and transport of Hup-A. A single-pass intestinal perfusion (SPIP technique and a chylomicron flow-blocking approach were used to study its intestinal absorption, mesenteric lymph node distribution and intestinal lymphatic uptake. The value of the area under the plasma concentration–time curve (AUC of Hup-A SMEDDS was significantly higher than that of a Hup-A suspension (P<0.01. The absorption rate constant (Ka and the apparent permeability coefficient (Papp for Hup-A in different parts of the intestine suggested a passive transport mechanism, and the values of Ka and Papp of Hup-A SMEDDS in the ileum were much higher than those in other intestinal segments. The determination of Hup-A concentration in mesenteric lymph nodes can be used to explain the intestinal lymphatic absorption of Hup-A SMEDDS. For Hup-A SMEDDS, the values of AUC and maximum plasma concentration (Cmax of the blocking model were significantly lower than those of the control model (P<0.05. The proportion of lymphatic transport of Hup-A SMEDDS and Hup-A suspension were about 40% and 5%, respectively, suggesting that SMEDDS can significantly improve the intestinal lymphatic uptake and transport of Hup-A.

Weighted Maximum-Clique Transversal Sets of Graphs

OpenAIRE

Chuan-Min Lee

2011-01-01

A maximum-clique transversal set of a graph G is a subset of vertices intersecting all maximum cliques of G. The maximum-clique transversal set problem is to find a maximum-clique transversal set of G of minimum cardinality. Motivated by the placement of transmitters for cellular telephones, Chang, Kloks, and Lee introduced the concept of maximum-clique transversal sets on graphs in 2001. In this paper, we study the weighted version of the maximum-clique transversal set problem for split grap...

Selective serotonin reuptake inhibitors and venlafaxine in pregnancy: Changes in drug disposition.

Directory of Open Access Journals (Sweden)

Andreas Austgulen Westin

Full Text Available Pregnancy may cause changes in drug disposition. The clinical consequences may be profound and even counterintuitive; in some cases pregnant women may need more than twice their usual drug dose in order to maintain therapeutic drug levels. For antidepressants, evidence on drug disposition in pregnancy is scarce. The aim of this study was to determine the effects of pregnancy on serum levels of selective serotonin reuptake inhibitors (SSRIs and venlafaxine in a large and naturalistic patient material, in order to provide tentative dose recommendations for pregnant women.Using patient data from two routine therapeutic drug monitoring (TDM services in Norway with linkage to the national birth registry, dose-adjusted serum drug concentrations of SSRIs and venlafaxine during pregnancy were compared to the women's own baseline (non-pregnant values, using a linear mixed model.Overall, the TDM databases contained 196,726 serum concentration measurements from 54,393 women. After data linkage and drug selection (SSRIs or venlafaxine only, we identified 367 analyses obtained from a total of 290 pregnancies in 281 women, and 420 baseline observations from the same women. Serum concentrations in the third trimester were significantly lower than baseline for paroxetine (-51%; 95% confidence interval [CI], -66%, -30%; p<0.001, fluvoxamine (-56%; CI, -75%, -23%; p = 0.004 and citalopram (-24%; CI, -38%, -7%; p = 0,007, and higher than baseline for sertraline (+68%; CI, +37%, +106%; p<0.001. For escitalopram, fluoxetine and venlafaxine concentrations did not change significantly.For paroxetine and fluvoxamine the pronounced decline in maternal drug serum concentrations in pregnancy may necessitate a dose increase of about 100% during the third trimester in order to maintain stable concentrations. For fluoxetine, venlafaxine, citalopram, escitalopram and sertraline, the present study indicates that dose adjustments are generally not necessary during pregnancy.

Reference Brain/Blood Concentrations of Citalopram, Duloxetine, Mirtazapine and Sertraline

DEFF Research Database (Denmark)

Nedahl, Michael; Johansen, Sys Stybe; Linnet, Kristian

2018-01-01

Postmortem blood samples may not accurately reflect antemortem drug concentrations, as the levels of some drugs increase due to postmortem redistribution (PMR). The brain has been suggested as an alternative sampling site. The anatomically secluded site of the brain limits redistribution and prol.......85), whereas the median citalopram/N-desmethylcitalopram ratio was higher in brain (9.1) than blood (4.1). The results of this study may serve as reference concentrations in brain for forensic cases....

Maximum power demand cost

International Nuclear Information System (INIS)

Biondi, L.

1998-01-01

The charging for a service is a supplier's remuneration for the expenses incurred in providing it. There are currently two charges for electricity: consumption and maximum demand. While no problem arises about the former, the issue is more complicated for the latter and the analysis in this article tends to show that the annual charge for maximum demand arbitrarily discriminates among consumer groups, to the disadvantage of some [it

Quantitation of methylglyoxal bis(guanylhydrazone) in blood plasma and leukemia cells of patients receiving the drug.

Science.gov (United States)

Seppänen, P; Alhonen-Hongisto, L; Siimes, M; Jänne, J

1980-11-15

Methylglyoxal bis(guanylhydrazone), a cytostatic compound which apparently interferes with the metabolism and/or functions of the natural polyamines (spermidine and spermine), was effectively taken up by cultured human lymphocytic leukemia cells, rapidly resulting in the formation of a concentration gradient of up to 1,000-fold across the cell membrane in cells grown in the presence of micromolar concentrations of the drug. For an anti-proliferative effect on the leukemia cells, an intracellular concentration of more than 0.5 mM was required. The uptake of methylglyoxal bis(guanylhydrazone) was critically dependent on the growth rate of the leukemia cells. Low intracellular concentrations of the drug were present in cells growing slowly, whereas in rapidly dividing cells the intracellular concentration of the drug approached 5mM. When given as repeated intravenous infusions to two leukemic children, methylglyoxal bis(guanylhydrazone) exhibited sharp and transient peaks of plasma concentration, the drug having an apparent half-life in plasma of only 1-2 h. However, as in cultured cells, the drug was rapidly concentrated in the leukemia cells, reaching concentrations that were distinctly anti-proliferative. In contrast to the rapid disappearance of methylglyoxal bis(guanylhydrazone) from plasma, the circulation leukemia cells retained the drug for a period of several days with only minimal decrease in the initial concentrations. Methylglyoxal bis(guanylhydrazone) was given to the patients for 1 to 2 months as intravenous infusions, the timing of which was determined by regular assays of the drug concentrations in the leukemia cells. In agreement with the results obtained with the cultured cells, and intracellular concentration of about 0.5 to 1mM was apparently required for growth-inhibitory action to occur. Regular determination of the cellular drug concentrations indicated that methylglyoxal bis(quanylhydrazone) could be given as weekly infusions. This treatment

Physicochemical characterization of in situ drug-polymer nanocomplex formed between zwitterionic drug and ionomeric material in aqueous solution

Energy Technology Data Exchange (ETDEWEB)

Salamanca, Constain H., E-mail: chsalamanca@icesi.edu.co [Pharmaceutical physical chemistry laboratory, Department of Pharmacy, Faculty of Natural Sciences, ICESI University, Cali (Colombia); Castillo, Duvan F.; Villada, Juan D. [Pharmaceutical physical chemistry laboratory, Department of Pharmacy, Faculty of Natural Sciences, ICESI University, Cali (Colombia); Rivera, Gustavo R. [SIT Biotech GmbH, BMZ 2 Otto-Hahn-Str. 15, 44227 Dortmund (Germany)

2017-03-01

Biocompatible polymeric materials with the potential to form functional structures, in association with different therapeutic molecules, in physiological media, represent a great potential for biological and pharmaceutical applications. Therefore, here the formation of a nano-complex between a synthetic cationic polymer and model drug (ampicillin trihydrate) was studied. The formed complex was characterized by size and zeta potential measurements, using dynamic light scattering and capillary electrophoresis. Moreover, the chemical and thermodynamically stability of these complexes were studied. The ionomeric material, here referred as EuCl, was obtained by equimolar reaction between Eudragit E and HCl. The structural characterization was carried out by potentiometric titration, FTIR spectroscopy, and DSC. The effect of pH, time, polymer concentration and ampicillin/polymer molar ratio over the hydrodynamic diameter and zeta potential were established. The results show that EuCl ionomer in aqueous media presents two different populations of nanoparticles; one of this tends to form flocculated aggregates in high pH and concentrations, by acquiring different conformations in solution by changing from a compact to an extended conformation. Moreover, the formation of an in situ interfacial polymer-drug complex was demonstrated, this could slightly reduce the hydrolytic degradation of the drug while affecting its solubility, mainly under acidic conditions. - Highlights: • The EuCl ionomer in aqueous media presents two different populations of nanoparticle, corresponding to proximally 15 nm and 150 nm. • The EuCl ionomer in aqueous media may form different structure depending on the pH and polymer concentration, which tends to form flocculated aggregates in high pH and concentrations. • The formation of an in situ interfacial polymer-drug complex was demonstrated, which could slightly reduce the hydrolytic degradation of the drug and affecting its solubility in

Drug interactions: volatile anesthetics and opioids.

Science.gov (United States)

Glass, P S; Gan, T J; Howell, S; Ginsberg, B

1997-09-01

Multiple drugs are used to provide anesthesia. Volatile anesthetics are commonly combined with opioids. Several studies have demonstrated that small doses of opioid (i.e., within the analgesic range) result in a marked reduction in minimum alveolar concentration (MAC) of the volatile anesthetic that will prevent purposeful movement in 50% of patients at skin incision). Further increases in opioid dose provide only a further small reduction in MAC. Thus, a ceiling effect of the opioid is observed at a MAC value of the volatile anesthetic equal to its MAC awake. Recovery from anesthesia when an opioid is combined with a volatile anesthetic is dependent on the rate of decrease of both drugs to their respective concentrations that are associated with adequate spontaneous ventilation and awakening. Through an understanding of the pharmacodynamic interaction of volatile anesthetics with opioids and the pharmacokinetic processes responsible for the recovery from drug effect, optimal dosing schemes can thus be developed. A review of these pharmacodynamic and pharmacokinetic principles that will allow clinicians to administer drugs to provide a more optimal anesthetic is provided.

Wet microcontact printing (µCP) for micro-reservoir drug delivery systems

International Nuclear Information System (INIS)

Lee, Hong-Pyo; Ryu, WonHyoung

2013-01-01

When micro-reservoir-type drug delivery systems are fabricated, loading solid drugs in drug reservoirs at microscale is often a non-trivial task. This paper presents a simple and effective solution to load a small amount of drug solution at microscale using ‘wet’ microcontact printing (µCP). In this wet µCP, a liquid solution containing drug molecules (methylene blue and tetracycline HCl) dissolved in a carrier solvent was transferred to a target surface (drug reservoir) by contact printing process. In particular, we have investigated the dependence of the quantity and morphology of transferred drug molecules on the stamp size, concentration, printing times, solvent types and surfactant concentration. It was also found that the repetition of printing using a non-volatile solvent such as polyethylene glycol (PEG) as a drug carrier material actually increased the transferred amount of drug molecules in proportion to the printing times based on asymmetric liquid bridge formation. Utilizing this wet µCP, drug delivery devices containing different quantity of drugs in micro-reservoirs were fabricated and their performance as controlled drug delivery devices was demonstrated. (paper)

Nonlinearities in Drug Release Process from Polymeric Microparticles: Long-Time-Scale Behaviour

Directory of Open Access Journals (Sweden)

Elena Simona Bacaita

2012-01-01

Full Text Available A theoretical model of the drug release process from polymeric microparticles (a particular type of polymer matrix, through dispersive fractal approximation of motion, is built. As a result, the drug release process takes place through cnoidal oscillations modes of a normalized concentration field. This indicates that, in the case of long-time-scale evolutions, the drug particles assemble in a lattice of nonlinear oscillators occur macroscopically, through variations of drug concentration. The model is validated by experimental results.

Thin-source concentration dependent diffusion

International Nuclear Information System (INIS)

Eng, G.

1978-01-01

The diffusion of (Ca ++ ) in NaCl has been measured for various diffusion times and for the temperature range (575 0 to 775 0 C), using a thin-source of 45 Ca tracer, rectangular geometry, and serial sectioning. The pre-diffusion surface concentration was approximately 3 x 10 16 (Ca)-atoms/cm 2 , which, for an average penetration depth of 100 to 300 μm, produces a maximum (post-diffusion) impurity concentration comparable to or greater than the intrinsic cation vacancy concentration. The high-temperature function closely matches the D 0 (T) function obtained from low impurity concentration experiments. The lower-temperature function, combined with the sudden failure of the D(C) = D 0 (1 + [C] + 0.5[C] 2 ) function at these lower temperatures, indicates the onset of a second diffusion process, one which would operate only at extremely high impurity concentrations. This low-temperature behavior is shown to be consistent with a breakdown of the conditions assumed for vacancy equilibrium

Kinetics of ethanol production by immobilized Kluyveromyces marxianus cells at varying sugar concentrations of Jerusalem artichoke juice

Energy Technology Data Exchange (ETDEWEB)

Bajpai, P.; Margaritis, A.

1987-08-01

Kinetics of ethanol fermentation at varying sugar concentrations of Jerusalem artichoke tuber extract has been studied using Kluyveromyces marxianus cells immobilized in calcium alginate gel beads. A maximum ethanol concentration of 111 g/l was achieved at an initial sugar concentration of 260 g/l in 20 hours, when the immobilized cell concentration in the calcium alginate beads was 53.3 g dry wt./l bead volume. Ethanol yield remained almost unaffected by initial sugar concentration up to 250 g/l and was found to be about 88% of the theoretical. Maximum rate of ethanol production decreased from 22.5 g ethanol/l/h to 10.5 g ethanol/l/h while the maximum rate of total sugars utilization decreased from 74.9 g sugars/l/h to 28.5 g sugars/l/h as the initial substrate concentration was increased from 100 to 300 g/l. The concentration of free cells in the fermentation broth was low.

Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine.

Science.gov (United States)

Paine, Mary F; Widmer, Wilbur W; Pusek, Susan N; Beavers, Kimberly L; Criss, Anne B; Snyder, Jennifer; Watkins, Paul B

2008-04-01

We previously established furanocoumarins as mediators of the interaction between grapefruit juice (GFJ) and the model CYP3A4 substrate felodipine in healthy volunteers using a GFJ devoid of furanocoumarins. It remains unclear whether furanocoumarins mediate drug-GFJ interactions involving CYP3A4 substrates that are also P-glycoprotein substrates. The effects of furanocoumarin-free GFJ on drug disposition were further characterized by using the dual CYP3A4/P-glycoprotein substrate cyclosporine. By randomized crossover design, 18 healthy volunteers received cyclosporine (5 mg/kg) with 240 mL orange juice (control), GFJ, or furanocoumarin-free GFJ. Blood was collected over 24 h. Juice treatments were separated by > or = 1 wk. The effects of diluted extracts of each juice and of purified furanocoumarins on [3H]cyclosporine translocation in Caco-2 cells were then compared. The median (range) dose-corrected cyclosporine area under the curve and the maximum concentration with GFJ (P or = 0.50), were significantly higher than those with orange juice [15.6 (6.7-33.5) compared with 11.3 (4.8-22.0) x 10(-3) h/L and 3.0 (1.6-5.8) compared with 2.4 (1.1-3.1) mL(-1), respectively]. The median time to reach maximum concentration and terminal elimination half-life were not significantly different between the juices (2-3 and 7-8 h, respectively; P > or = 0.08). Relative to vehicle, the GFJ extract, orange juice extract, and purified furanocoumarins partially increased apical-to-basolateral and decreased basolateral-to-apical [3H]cyclosporine translocation in Caco-2 cells, whereas the furanocoumarin-free GFJ extract had negligible effects. Reanalysis of the clinical juices identified polymethoxyflavones as candidate P-glycoprotein inhibitors in orange juice but not in GFJ. Furanocoumarins mediate, at least partially, the cyclosporine-GFJ interaction in vivo. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and P-glycoprotein.

Analysis of abused drugs by selected ion monitoring: quantitative comparison of electron impact and chemical ionization

International Nuclear Information System (INIS)

Foltz, R.L.; Knowlton, D.A.; Lin, D.C.K.; Fentiman, A.F. Jr.

1975-01-01

A comparison was made of the relative sensitivities of electron impact and chemical ionization when used for selected ion monitoring analysis of commonly abused drugs. For most of the drugs examined chemical ionization using ammonia as the reactant gas gave the largest single m/e ion current response per unit weight of sample. However, if maximum sensitivity is desired it is important to evaluate electron impact and chemical ionization with respect to both maximum response and degree of interference from background and endogenous materials

Lack of cross-reactivity of Ambien (zolpidem) with drugs in standard urine drug screens.

Science.gov (United States)

Piergies, A A; Sainati, S; Roth-Schechter, B

1997-04-01

To determine in healthy volunteers (men and women; 18 to 40 years old) the potential cross-reactivity of Ambien (zolpidem) and/or its metabolites with drugs that are screened by the Syva EMIT II and the Abbott ADx urine drug screens assays. Open-label, fixed-treatment sequence of 1 night each of treatment with zolpidem (10 mg) and temazepam (15 mg). Clinical Pharmacology Unit within a teaching hospital. Over a 24-hour period, presence or absence of positive results on the Syva EMIT II or the Abbott ADx urine drug assay system, each performed at two different laboratory assay sites. Following ingestion of zolpidem, no subject had any positive response in either laboratory to the Syva EMIT II or the Abbott ADx urine drug screen assays at 0, 4, 8, 12, and 24 hours postdose. During the same time period, all subjects had measurable zolpidem plasma concentrations at 1.5 and 8 hours postdose, with mean concentrations of 115.2 ng/mL and 30.1 ng/mL, respectively (in agreement with its half-life of 2.5 hours). The positive response rate at 10 hours after ingestion of Restoril (temazepam) among the four laboratory/assay combinations ranged from 36.8% to 73.7%, a range that is within the reported response rates for these tests. These data indicate that zolpidem will not cross-react in standard urine drug screens with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines.

[Studies on antimicrobial concentrations of flomoxef in serum, pelvic dead space exudate, and pelvic organs/tissues].

Science.gov (United States)

Obata, T; Koishi, K; Sasaki, J; Eguchi, M; Yamamoto, Y

1987-10-01

To women undergoing radical and total hysterectomy, flomoxef (FMOX, 6315-S) in a dose of 2 g was administered by intravenous drip infusion over 1 hour and drug concentrations in serum and pelvic dead space exudate as well as pelvic organs/tissues were determined over time. The following results were obtained: 1. Serum concentrations of FMOX after intravenous infusion showed the peak value of 92.86 +/- 17.05 micrograms/ml at the end of infusion and then gradually decreased to 29.00 +/- 10.49 micrograms/ml in 1 hour and 1.16 +/- 1.08 micrograms/ml in 6 hours. 2. Concentrations in pelvic dead space exudate, which were 6.54 +/- 3.21 micrograms/ml at the end of intravenous infusion, gradually increased to 31.28 +/- 12.69 micrograms/ml in 30 minutes, and the peak of 35.21 +/- 13.29 micrograms/ml in 1 hour. Exudate concentrations gradually decreased to 11.10 +/- 6.64 micrograms/ml at 6 hours after infusion. 3. The serum concentration at the ligature of uterine artery was 103.21 +/- 51.69 micrograms/ml. Among concentrations in pelvic organ/tissues 37.17 +/- 18.20 micrograms/ml in uterine cervix was the highest, followed by 35.77 +/- 7.68 micrograms/g in portio vaginalis, 26.35 +/- 14.15 micrograms/g in tube, 21.62 +/- 12.15 micrograms/g in ovary, 20.56 +/- 9.82 micrograms/g in myometrium, and 16.45 +/- 8.10 micrograms/g in endometrium, in this order. 4. From an analysis of the two-compartment model, the maximum serum concentration was 92.81 micrograms/ml, which was very high. The time of 50% reduction of concentration in beta phase was 1.21 hours. In the pelvic dead space exudate, the maximum concentration was 32.38 micrograms/ml and the time of 50% reduction was 2.44 hours. The AUC was 147 micrograms.hr/ml in serum and 201 micrograms.hr/ml in the pelvic dead space. The shift to the pelvic dead space was 137% when AUC's were used as the basis of the comparison. 5. Clinically, FMOX was excellently effective against adnexitis caused by Peptostreptococcus asaccharolyticus

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

Science.gov (United States)

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.

Total mercury concentration in common fish species of Lake Victoria ...

African Journals Online (AJOL)

Total mercury (THg) concentration was analysed in muscles of common fish species of Lake Victoria in the eastern and southern parts of the lake using cold vapour Atomic Absorption Spectrophotometric technique. Mercury concentration in all fish species was generally lower than the WHO maximum allowable ...

Species differences in drug glucuronidation: Humanized UDP-glucuronosyltransferase 1 mice and their application for predicting drug glucuronidation and drug-induced toxicity in humans.

Science.gov (United States)

Fujiwara, Ryoichi; Yoda, Emiko; Tukey, Robert H

2018-02-01

More than 20% of clinically used drugs are glucuronidated by a microsomal enzyme UDP-glucuronosyltransferase (UGT). Inhibition or induction of UGT can result in an increase or decrease in blood drug concentration. To avoid drug-drug interactions and adverse drug reactions in individuals, therefore, it is important to understand whether UGTs are involved in metabolism of drugs and drug candidates. While most of glucuronides are inactive metabolites, acyl-glucuronides that are formed from compounds with a carboxylic acid group can be highly toxic. Animals such as mice and rats are widely used to predict drug metabolism and drug-induced toxicity in humans. However, there are marked species differences in the expression and function of drug-metabolizing enzymes including UGTs. To overcome the species differences, mice in which certain drug-metabolizing enzymes are humanized have been recently developed. Humanized UGT1 (hUGT1) mice were created in 2010 by crossing Ugt1-null mice with human UGT1 transgenic mice in a C57BL/6 background. hUGT1 mice can be promising tools to predict human drug glucuronidation and acyl-glucuronide-associated toxicity. In this review article, studies of drug metabolism and toxicity in the hUGT1 mice are summarized. We further discuss research and strategic directions to advance the understanding of drug glucuronidation in humans. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Experimental characterization of a concentrating photovoltaic system varying the light concentration

International Nuclear Information System (INIS)

Renno, C.; Petito, F.; Landi, G.; Neitzert, H.C.

2017-01-01

Highlights: • Experimental characterization of a concentrating photovoltaic system. • Analysis of the point-focus concentrating system performances. • Photovoltaic system parameters as function of the concentration factor. - Abstract: The concentrating photovoltaic system represents one of the most promising solar technologies because it allows a more efficient energy conversion. When a CPV system is designed, the main parameter which has to be considered is the concentration factor that affects both the system energy performances and its configuration. An experimental characterization of a CPV system previously realized at the University of Salerno, is presented in this paper considering several aspects related to the optical configuration, the concentration factor and the solar cell used. In particular, the parameters of an Indium Gallium Phosphide/Gallium Arsenide/Germanium triple-junction solar cell are investigated as function of the concentration factor determined by means of an experimental procedure that uses different optical configurations. The maximum concentration factor reached by the CPV system is 310 suns. The cell parameters dependence on the concentration is reported together with an electroluminescence analysis of the Indium Gallium Phosphide/Gallium Arsenide/Germanium cell. A monitoring of the electrical power provided by the system during its working is also presented corresponding to different direct irradiance values. A mean power of 2.95 W with an average efficiency of 32.8% is obtained referring to a mean irradiance of 930 W/m"2; lower values are obtained when the irradiance is highly fluctuating. The concentrating photovoltaic system electric energy output is estimated considering different concentration levels; the maximal obtained value is 23.5 W h on a sunny day at 310×. Finally, the temperature of the triple-junction solar cell is evaluated for different months in order to evaluate the potential annual thermal energy production

Tangential Flow Ultrafiltration Allows Purification and Concentration of Lauric Acid-/Albumin-Coated Particles for Improved Magnetic Treatment.

Science.gov (United States)

Zaloga, Jan; Stapf, Marcus; Nowak, Johannes; Pöttler, Marina; Friedrich, Ralf P; Tietze, Rainer; Lyer, Stefan; Lee, Geoffrey; Odenbach, Stefan; Hilger, Ingrid; Alexiou, Christoph

2015-08-14

Superparamagnetic iron oxide nanoparticles (SPIONs) are frequently used for drug targeting, hyperthermia and other biomedical purposes. Recently, we have reported the synthesis of lauric acid-/albumin-coated iron oxide nanoparticles SEON(LA-BSA), which were synthesized using excess albumin. For optimization of magnetic treatment applications, SPION suspensions need to be purified of excess surfactant and concentrated. Conventional methods for the purification and concentration of such ferrofluids often involve high shear stress and low purification rates for macromolecules, like albumin. In this work, removal of albumin by low shear stress tangential ultrafiltration and its influence on SEON(LA-BSA) particles was studied. Hydrodynamic size, surface properties and, consequently, colloidal stability of the nanoparticles remained unchanged by filtration or concentration up to four-fold (v/v). Thereby, the saturation magnetization of the suspension can be increased from 446.5 A/m up to 1667.9 A/m. In vitro analysis revealed that cellular uptake of SEON(LA-BSA) changed only marginally. The specific absorption rate (SAR) was not greatly affected by concentration. In contrast, the maximum temperature Tmax in magnetic hyperthermia is greatly enhanced from 44.4 °C up to 64.9 °C by the concentration of the particles up to 16.9 mg/mL total iron. Taken together, tangential ultrafiltration is feasible for purifying and concentrating complex hybrid coated SPION suspensions without negatively influencing specific particle characteristics. This enhances their potential for magnetic treatment.

Cannabis use: a perspective in relation to the proposed UK drug-driving legislation.

Science.gov (United States)

Wolff, Kim; Johnston, Atholl

2014-01-01

With regard to THC (Δ(9)-tetrahydrocannabinol), the main psychoactive constituent identified in the plant Cannabis sativa L, several facts are indisputable. Cannabis remains the most commonly used drug in the UK among those who reported driving under the influence of illegal drugs in the previous 12 months. There is a significant dose-related decrement in driving performance following cannabis use; raised blood THC concentrations are significantly associated with increased traffic crash and death risk. When cannabis and alcohol are detected together, there is a greater risk to road safety than when either drug is used alone. Patterns of use are important when interpreting blood concentration data: Smoking infrequently a single cannabis cigarette leads to peak plasma THC concentrations (21-267 µg/L) causing acute intoxication. In habitual, daily users, plasma THC concentrations range from 1.0 to 11.0 µg/L and are maintained by sequestration of the drug from the tissues. These facts undoubtedly make setting thresholds for drug-driving legislation difficult but there is clearly a case for cannabis. Determining minimum blood THC concentrations at which a driver becomes sufficiently impaired to be unable to safely drive a vehicle is of particular concern given the increasing medicinal use of the drug. Internationally legislation for driving under the influence of drugs (DUID) is based on either a proof of impairment or a per se approach. For the latter this can be either zero-tolerance or based on concentration limits such as those used for alcohol. The different approaches are considered against current scientific evidence. Copyright © 2013 John Wiley & Sons, Ltd.

Examining the Spatial Distribution of Law Enforcement Encounters among People Who Inject Drugs after Implementation of Mexico’s Drug Policy Reform

OpenAIRE

Gaines, Tommi L.; Beletsky, Leo; Arredondo, Jaime; Werb, Daniel; Rangel, Gudelia; Vera, Alicia; Brouwer, Kimberly

2014-01-01

In 2009, Mexico decriminalized the possession of small amounts of illicit drugs for personal use in order to refocus law enforcement resources on drug dealers and traffickers. This study examines the spatial distribution of law enforcement encounters reported by people who inject drugs (PWID) in Tijuana, Mexico to identify concentrated areas of policing activity after implementation of the new drug policy. Mapping the physical location of law enforcement encounters provided by PWID (n = 461) ...

A development perspective on adolescent drug abuse.

Science.gov (United States)

Baumrind, D; Moselle, K A

1985-01-01

Adolescent drug use is placed in an historical and developmental perspective. Existing evidence concerning causes and consequences of adolescent drug use is inconclusive. In the absence of conclusive empirical evidence and cogent theories, we present a prima facie case against early adolescent drug use by defending six propositions which posit specific cognitive, conative, and affective negative consequences including impairment of attention and memory; developmental lag imposing categorical limitations on the level of maximum functioning available to the user in cognitive, moral and psychosocial domains; amotivational syndrome; consolidation of diffuse or negative identity; and social alienation and estrangement. We call for a program of research which could provide credible evidence to support or rebut these propositions, and thus address the factual claims underlying the sociomoral concerns of social policy planners.

Drug delivery system and breast cancer cells

Science.gov (United States)

Colone, Marisa; Kaliappan, Subramanian; Calcabrini, Annarica; Tortora, Mariarosaria; Cavalieri, Francesca; Stringaro, Annarita

2016-06-01

Recently, nanomedicine has received increasing attention for its ability to improve the efficacy of cancer therapeutics. Nanosized polymer therapeutic agents offer the advantage of prolonged circulation in the blood stream, targeting to specific sites, improved efficacy and reduced side effects. In this way, local, controlled delivery of the drug will be achieved with the advantage of a high concentration of drug release at the target site while keeping the systemic concentration of the drug low, thus reducing side effects due to bioaccumulation. Various drug delivery systems such as nanoparticles, liposomes, microparticles and implants have been demonstrated to significantly enhance the preventive/therapeutic efficacy of many drugs by increasing their bioavailability and targetability. As these carriers significantly increase the therapeutic effect of drugs, their administration would become less cost effective in the near future. The purpose of our research work is to develop a delivery system for breast cancer cells using a microvector of drugs. These results highlight the potential uses of these responsive platforms suited for biomedical and pharmaceutical applications. At the request of all authors of the paper an updated version was published on 12 July 2016. The manuscript was prepared and submitted without Dr. Francesca Cavalieri's contribution and her name was added without her consent. Her name has been removed in the updated and re-published article.

A Comparative Pharmacokinetics Study of the Anti-Parkinsonian Drug Pramipexole

Directory of Open Access Journals (Sweden)

Ratih S. I. Putri

2016-11-01

Full Text Available The present study aimed to compare pharmacokinetic parameters of two pramipexole 0.25 mg formulations in order to show bioequivalence. The study was conducted in a randomized, open-label, two-period, two-sequence, and crossover design, involving 23 healthy volunteers. One of the 0.25 mg formulations of pramipexole evaluated in the study was manufactured by PT Dexa Medica, Palembang, Indonesia, the other, used as the reference, by Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany. All eligible subjects were required to fast before each drug administration period, which was separated by a one-week washout period. Pramipexole concentrations in plasma were assayed using a validated ultra performance liquid chromatography with mass spectrometry (UPLC-MS/MS detector. The evaluated pharmacokinetic parameters included the area under the plasma concentration curve from time zero to the last observed measurable concentration (AUC0-t, the area under the plasma concentration curve extrapolated to infinite time (AUC0-∞, the maximum plasma concentration (Cmax, the time to reach Cmax (tmax, and the plasma concentration half-life (t1/2. To evaluate the bioequivalence of those two pramipexole formulations, 90% confidence intervals (CIs for geometric mean ratios of both formulations were calculated for AUC and Cmax parameters, while tmax and t1/2 differences were analyzed on the non-transformed data using Wilcoxon matched-pairs and a Student’s paired t-test, respectively. The 90% CIs for the geometric mean ratios of the two pramipexole formulations were 95.89% (90.73%–101.34%, 95.53% (89.75%–101.68%, and 92.11% (84.35%–100.58% for AUC0-t, AUC0-∞, and Cmax, respectively. There were no statistically significant differences for tmax and t1/2 between the two pramipexole formulations. It is concluded that two pramipexole formulations in this study were bioequivalent.

A Comparative Pharmacokinetics Study of the Anti-Parkinsonian Drug Pramipexole.

Science.gov (United States)

Putri, Ratih S I; Setiawati, Effi; Aziswan, Syifa A; Ong, Fenny; Tjandrawinata, Raymond R; Susanto, Liana W

2016-11-18

The present study aimed to compare pharmacokinetic parameters of two pramipexole 0.25 mg formulations in order to show bioequivalence. The study was conducted in a randomized, open-label, two-period, two-sequence, and crossover design, involving 23 healthy volunteers. One of the 0.25 mg formulations of pramipexole evaluated in the study was manufactured by PT Dexa Medica, Palembang, Indonesia, the other, used as the reference, by Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany. All eligible subjects were required to fast before each drug administration period, which was separated by a one-week washout period. Pramipexole concentrations in plasma were assayed using a validated ultra performance liquid chromatography with mass spectrometry (UPLC-MS/MS) detector. The evaluated pharmacokinetic parameters included the area under the plasma concentration curve from time zero to the last observed measurable concentration (AUC 0-t ), the area under the plasma concentration curve extrapolated to infinite time (AUC 0-∞ ), the maximum plasma concentration (C max ), the time to reach C max (t max ), and the plasma concentration half-life (t 1/2 ). To evaluate the bioequivalence of those two pramipexole formulations, 90% confidence intervals (CIs) for geometric mean ratios of both formulations were calculated for AUC and C max parameters, while t max and t 1/2 differences were analyzed on the non-transformed data using Wilcoxon matched-pairs and a Student's paired t -test, respectively. The 90% CIs for the geometric mean ratios of the two pramipexole formulations were 95.89% (90.73%-101.34%), 95.53% (89.75%-101.68%), and 92.11% (84.35%-100.58%) for AUC 0-t , AUC 0-∞ , and C max , respectively. There were no statistically significant differences for t max and t 1/2 between the two pramipexole formulations. It is concluded that two pramipexole formulations in this study were bioequivalent.

Tenofovir alafenamide (TAF) does not deplete mitochondrial DNA in human T-cell lines at intracellular concentrations exceeding clinically relevant drug exposures.