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Sample records for undesirable pharmacokinetics poor

  1. Population pharmacokinetic modeling of glibenclamide in poorly controlled South African type 2 diabetic subjects

    Directory of Open Access Journals (Sweden)

    Rambiritch V

    2016-07-01

    Full Text Available Virendra Rambiritch,1 Poobalan Naidoo,2 Breminand Maharaj,1 Goonaseelan Pillai3 1University of KwaZulu-Natal, Durban, 2Department of Internal Medicine, RK Khan Regional Hospital, Chatsworth, South Africa; 3Novartis Pharma AG, Basel, Switzerland Aim: The aim of this study was to describe the pharmacokinetics (PK of glibenclamide in poorly controlled South African type 2 diabetic subjects using noncompartmental and model-based methods. Methods: A total of 24 subjects with type 2 diabetes were administered increasing doses (0 mg/d, 2.5 mg/d, 5 mg/d, 10 mg/d, and 20 mg/d of glibenclamide daily at 2-week intervals. Plasma glibenclamide, glucose, and insulin determinations were performed. Blood sampling times were 0 minute, 30 minutes, 60 minutes, 90 minutes, and 120 minutes (post breakfast sampling and 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, and 420 minutes (post lunch sampling on days 14, 28, 42, 56, and 70 for doses of 0 mg, 2.5 mg, 5.0 mg, 10 mg, and 20 mg, respectively. Blood sampling was performed after the steady state was reached.  A total of 24 individuals in the data set contributed to a total of 841 observation records. The PK was analyzed using noncompartmental analysis methods, which were implemented in WinNonLin®, and population PK analysis using NONMEM®. Glibenclamide concentration data were log transformed prior to fitting. Results: A two-compartmental disposition model was selected after evaluating one-, two-, and three-compartmental models to describe the time course of glibenclamide plasma concentration data. The one-compartment model adequately described the data; however, the two-compartment model provided a better fit. The three-compartment model failed to achieve successful convergence. A more complex model, to account for enterohepatic recirculation that was observed in the data, was unsuccessful. Conclusion: In South African diabetic subjects, glibenclamide demonstrates linear PK and was best

  2. Filtering Undesirable Flows in Networks

    NARCIS (Netherlands)

    Polevoy, G.; Trajanovski, S.; Grosso, P.; de Laat, C.; Gao, X.; Du, H.; Han, M.

    2017-01-01

    We study the problem of fully mitigating the effects of denial of service by filtering the minimum necessary set of the undesirable flows. First, we model this problem and then we concentrate on a subproblem where every good flow has a bottleneck. We prove that unless P=NP, this subproblem is

  3. A poor metabolizer of both CYP2C19 and CYP2D6 identified by mechanistic pharmacokinetic simulation in a fatal drug poisoning case involving venlafaxine

    DEFF Research Database (Denmark)

    Jornil, J; Nielsen, T S; Rosendal, I

    2013-01-01

    Abstract We present a fatal drug poisoning case involving venlafaxine (VEN). The deceased took his medication regularly (including 150 mg VEN twice daily), and nothing in the case or autopsy findings pointed towards suicide. The toxicological assessment concluded that the cause of death was most...... combined with genotyping were considered very useful in this fatal drug poisoning case. Keywords CYP2D6; CYP2C19; Venlafaxine; Poor metabolizer; Drug poisoning; Mechanistic pharmacokinetic simulation --------------------------------------------------------------------------------...

  4. Interventional radiology and undesirable effects

    International Nuclear Information System (INIS)

    Benderitter, M.

    2009-01-01

    As some procedures of interventional radiology are complex and long, doses received by patients can be high and cause undesired effects, notably on the skin or in underlying tissues (particularly in the brain as far as interventional neuroradiology is concerned and in lungs in the case of interventional cardiology). The author briefly discusses some deterministic effects in interventional radiology (influence of dose level, delay of appearance of effects, number of accidents). He briefly comments the diagnosis and treatment of severe radiological burns

  5. Endovascular rescue method for undesirably stretched coil.

    Science.gov (United States)

    Cho, Jae Hoon

    2014-10-01

    Undesirable detachment or stretching of coils within the parent artery during aneurysm embolization can be related with thrombus formation, which can be caused occlusion of parent artery or embolic event(s). To escape from this situation, several rescue methods have been reported. A case with undesirably stretched coil in which another rescue method was used, is presented. When the stretched coil is still located in the coil delivery microcatheter, the stretched coil can be removed safely using a snare and a handmade monorail microcatheter. After a snare is lodged in the handmade monorail microcatheter, the snare is introduced over the coil delivery micorcatheter and located in the distal part of the stretched coil. After then, the handmade monorail microcatheter captures the stretched coil and the snare as one unit. This technique using a handmade monorail microcatheter and a snare can be a good rescue modality for the undesirably stretched coil, still remained within the coil delivery microcatheter.

  6. Risk sectors for undesirable behaviour and mobbing

    NARCIS (Netherlands)

    Hubert, A.B.; Veldhoven, M.J.P.M. van

    2001-01-01

    The aim of this short note was to get an impression of risk sectors for the prevalence of undesirable behaviour and mobbing in The Netherlands. Data were collected from 1995 to 1999 with the Questionnaire on The Assessment and Experience of Work (Vragenlijst Beleving en Beoordeling van de Arbeid;

  7. The undesirable effects of neuromuscular blocking drugs

    DEFF Research Database (Denmark)

    Claudius, C; Garvey, L H; Viby-Mogensen, J

    2009-01-01

    Neuromuscular blocking drugs are designed to bind to the nicotinic receptor at the neuromuscular junction. However, they also interact with other acetylcholine receptors in the body. Binding to these receptors causes adverse effects that vary with the specificity for the cholinergic receptor...... in question. Moreover, all neuromuscular blocking drugs may cause hypersensitivity reactions. Often the symptoms are mild and self-limiting but massive histamine release can cause systematic reactions with circulatory and respiratory symptoms and signs. At the end of anaesthesia, no residual effect...... of a neuromuscular blocking drug should be present. However, the huge variability in response to neuromuscular blocking drugs makes it impossible to predict which patient will suffer postoperative residual curarization. This article discusses the undesirable effects of the currently available neuromuscular blocking...

  8. Undesirable compounds in oils and fats: analysis and regulation

    Directory of Open Access Journals (Sweden)

    Lacoste Florence

    2003-03-01

    Full Text Available The aim of this paper is to present, for some undesirable compounds representative of the major origins, a comparison between the efficiency of the analytical methods used (sensitivity, precision and existing regulations. An idea of the different origins of the presence of undesirable compounds in oils and fats is given. Then a focus is done on guidelines on contaminant analysis provided by European directives or Codex Alimentarius. The reliability of some existing test methods compared to regulations is also examined: lead, hexane, polycyclic aromatic hydrocarbons, and pesticide residues.

  9. A safety control device for detecting undesirable conditions

    Energy Technology Data Exchange (ETDEWEB)

    1974-09-26

    The invention relates to safety control devices. It deals with a device adapted to transmit a warning signal and to the detection of an undesirable condition in an associated apparatus, said device comprising switching means comprising transistors mounted in a reaction path, feeding means for opening the switching means whenever an undesirable condition has been detected by sensors, whereby an oscillator is caused to stop oscillating, and an outlet device controlled by the oscillator stoppage. This can be applied to the supervision of nuclear reactor.

  10. Free-Will and the Undesirability of Moral Education

    Science.gov (United States)

    Gordon, David

    1975-01-01

    This paper makes two arguments: (1) that education does not imply determinism; and (2) that if one takes the libertarian position with regard to the free-will/determinism issue, one is forced to the conclusion that moral education is undesirable. (RC)

  11. A two stage data envelopment analysis model with undesirable output

    Science.gov (United States)

    Shariff Adli Aminuddin, Adam; Izzati Jaini, Nur; Mat Kasim, Maznah; Nawawi, Mohd Kamal Mohd

    2017-09-01

    The dependent relationship among the decision making units (DMU) is usually assumed to be non-existent in the development of Data Envelopment Analysis (DEA) model. The dependency can be represented by the multi-stage DEA model, where the outputs from the precedent stage will be the inputs for the latter stage. The multi-stage DEA model evaluate both the efficiency score for each stages and the overall efficiency of the whole process. The existing multi stage DEA models do not focus on the integration with the undesirable output, in which the higher input will generate lower output unlike the normal desirable output. This research attempts to address the inclusion of such undesirable output and investigate the theoretical implication and potential application towards the development of multi-stage DEA model.

  12. A Case of Undesired Bleb Developed After Penetrating Injury

    Directory of Open Access Journals (Sweden)

    Cem Ozgonul

    2014-03-01

    Full Text Available Eighty-year-old male patient was admitted to our policlinic with stinging, burning and itching in both eyes. Ophthalmological examination revealed avascular undesired bleb that releated with anterior chamber at 2-3 hour quadrant nasal limbus with the surrounding corneal and conjunctival epithelium was vascularized and the dimension was 3x3x3 mm. Towards these findings, we questioned the patient again and we found that, 40 years ago, a broken part of the shaving razor had injured his eye. After penetrating injury of the eye, because of the sutured wound leakage, undesired bleb formations can be seen. We suggest that kind of patient shold be followed up to prevent late complications of penetrating injury.

  13. Worry and perceived threat of proximal and distal undesirable outcomes.

    Science.gov (United States)

    Bredemeier, Keith; Berenbaum, Howard; Spielberg, Jeffrey M

    2012-04-01

    Individuals who are prone to worry tend to overestimate the likelihoods and costs of future undesirable outcomes. However, it is unclear whether these relations vary as a function of the timeframe of the event in question. In the present study, 342 undergraduate students completed a self-report measure of worry and rated the perceived probabilities and costs of 40 undesirable outcomes. Specifically, each participant estimated the probability that each of these outcomes would occur within three different timeframes: the next month, the next year, and the next 10 years. We found that the strength of the association between worry and probability estimates was strongest for the most proximal timeframe. Probability estimates were more strongly associated with worry for participants with elevated cost estimates, and this interactive effect was strongest for the most distal timeframe. Implications of these findings for understanding the etiology and treatment of excessive worry are discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Cycles of undesirable substances in the food chain

    International Nuclear Information System (INIS)

    2012-01-01

    The working group ''Carry over of undesirable substances in animal feed'' at the Federal Ministry of Food, Agriculture and Forestry (BMELV) in cooperation with the Institute of Animal Nutrition of the Friedrich-Loeffler-Institute (FLI) performed on 27 and 28 October 2011 in Braunschweig a workshop on ''cycles of undesirable substances in Food Chain ''. The aim of the workshop was to present the latest findings of research and Carry over Recommendations of the Carry over - Working Group on undesirable substances in feed and production processes of the feed industry, to evaluate and discuss about this with representatives from science, business and management and to work out the further research and action need. The focus of the considerations were the pathways, the carry over and the Exposure to dioxins and other halogenated hydrocarbons, the effects of Mycotoxins in feed and starting points for preventive measures, the soil contamination and the exposure of humans and animals by cadmium and case studies on Nitrite in feed, antibiotics in plants and residues of pesticides and radionuclides in feed. Furthermore the risks associated with specified manufacturing processes of feed are considered, especially the used materials that come into contact with animal feed, and the risks from nanotechnology. [de

  15. Role of Fault Attributions and Other Factors in Adults' Attitudes Toward Hypothetical Children With an Undesirable Characteristic.

    Science.gov (United States)

    Wadian, Taylor W; Sonnentag, Tammy L; Jones, Tucker L; Barnett, Mark A

    2018-01-01

    A total of 184 adults read descriptions of six hypothetical children with various undesirable characteristics (i.e., being extremely overweight, extremely aggressive, extremely shy, a poor student, a poor athlete, displaying symptoms of attention deficit hyperactivity disorder). Following each description, the participants were asked to rate how much they disagree or agree that the child, the child's parents, and the child's biological condition (i.e., "something wrong inside the child's body or brain") are at fault for the onset and the perpetuation of the undesirable characteristic. In addition, the participants were asked to rate their attitude toward each child using a 100-point "feeling thermometer." Analyses of the participants' various fault attribution ratings revealed that they tended to agree more strongly that a child's parents and his/her biological condition are at fault for the onset and the perpetuation of the child's undesirable characteristic than is the child him/herself. Despite the participants' reluctance to blame a hypothetical child for his/her undesirable characteristic, regression analyses revealed that, in general, the more they blamed the child for the onset of his/her undesirable characteristic, the more negative their attitude was toward the child. However, the participants' ratings of the extent to which the child's parents or biological condition are at fault for the onset and the perpetuation of the child's undesirable characteristic were not found to be associated with their attitude toward any of the children. Similarities and differences between the present findings and those reported in prior studies involving younger individuals are addressed.

  16. Undesirable Effects of Media on Children: Why Limitation is Necessary?

    Science.gov (United States)

    Karaagac, Aysu Turkmen

    2015-06-01

    Pervasive media environment is a social problem shared by most of the countries around the world. Several studies have been performed to highlight the undesired effects of media on children. Some of these studies have focused on the time spent by children watching television, playing with computers or using mobile media devices while some others have tried to explain the associations between the obesity, postural abnormalities or psychological problems of children, and their media use. This article discusses the recent approaches to curb influence of media on children, and the importance of family media literacy education programs with particular relevance to developing countries.

  17. Adjustable liquid aperture to eliminate undesirable light in holographic projection.

    Science.gov (United States)

    Wang, Di; Liu, Chao; Li, Lei; Zhou, Xin; Wang, Qiong-Hua

    2016-02-08

    In this paper, we propose an adjustable liquid aperture to eliminate the undesirable light in a holographic projection. The aperture is based on hydrodynamic actuation. A chamber is formed with a cylindrical tube. A black droplet is filled in the sidewall of the cylinder tube and the outside space is the transparent oil which is immiscible with the black droplet. An ultrathin glass sheet is attached on the bottom substrate of the device and a black shading film is secured to the central area of the glass sheet. By changing the volume of the black droplet, the black droplet will move to the middle or sidewall due to hydrodynamic actuation, so the device can be used as an adjustable aperture. A divergent spherical wave and a solid lens are used to separate the focus planes of the reconstructed image and diffraction beams induced by the liquid crystal on silicon in the holographic projection. Then the aperture is used to eliminate the diffraction beams by adjusting the size of the liquid aperture and the holographic projection does not have undesirable light.

  18. Undesirable substances in vegetable oils: anything to declare?

    Directory of Open Access Journals (Sweden)

    Lacoste Florence

    2014-01-01

    Full Text Available The presence of undesirable compounds in vegetable and animal oils and fats may have many different origins. Although the potential toxicity of most of these undesirable compounds is real, poisoning risks are rather limited due to the efficient elimination during oil-refining steps, careful conditioning, choice of efficient packaging and industrial quality control management. However the research of contaminants is part of multiple controls conducted by fat and oil industry to verify the conformity of products placed on the market in relation to regulations such as the European commission regulation EC No. 1881/2006 setting maximum levels for some contaminants in food as lead, some mycotoxins, dioxins, polychlorobiphenyls, benzo[a]pyrene. In the absence of regulation, the detection of contaminants must be addressed in partnership with authorities according to the toxicity of molecules. The controls are not confined to environmental contaminants. They also include compounds that can be formed during the production process of vegetable oils such as esters of 3-monochloropropanediol. This article focuses more particularly on heavy metals, polycyclic aromatic hydrocarbons, mineral oils, phthalates and 3-MCPD or glycidyl esters. Aspects such as methods for analysis, limits fixed by EC regulation and occurrence in vegetable oils are discussed.

  19. [Undesired treatment effects in behavior group therapy: Frequency and spectrum].

    Science.gov (United States)

    Linden, M; Walter, M; Fritz, K; Muschalla, B

    2015-11-01

    Psychotherapy not only has positive but also negative effects, which is especially true for group psychotherapy due to psychodynamic and interactional processes. Using the UE-G questionnaire 71 patients who participated in cognitive behavioral group psychotherapy reported on negative experiences in the context of the group therapy. The answers were then validated in a qualitative interview. Of the patients 98.6% reported about at least one negative experience and 43.7% about severe or extremely severe negative experiences. Most prominent was the induction of hopelessness and demoralization by what patients saw and heard from other patients in the group. Burdensome and therefore undesired treatment effects are regularly seen in group psychotherapy, because of treatment or patient related factors. In any case they must be taken into account during treatment, in the training of group psychotherapists and in quality control.

  20. Pig herd monitoring and undesirable tripping and stepping prevention

    DEFF Research Database (Denmark)

    Gronskyte, Ruta; Clemmensen, Line Katrine Harder; Hviid, Marchen Sonja

    2015-01-01

    Humane handling and slaughter of livestock are of major concern in modern societies. Monitoring animal wellbeing in slaughterhouses is critical in preventing unnecessary stress and physical damage to livestock, which can also affect the meat quality. The goal of this study is to monitor pig herds...... at the slaughterhouse and identify undesirable events such as pigs tripping or stepping on each other. In this paper, we monitor pig behavior in color videos recorded during unloading from transportation trucks. We monitor the movement of a pig herd where the pigs enter and leave a surveyed area. The method is based...... on optical flow, which is not well explored for monitoring all types of animals, but is the method of choice for human crowd monitoring. We recommend using modified angular histograms to summarize the optical flow vectors. We show that the classification rate based on support vector machines is 93% of all...

  1. Cosmetics Europe Guidelines on the Management of Undesirable Effects and Reporting of Serious Undesirable Effects from Cosmetics in the European Union

    Directory of Open Access Journals (Sweden)

    Gerald Renner

    2017-01-01

    Full Text Available The European Union (EU Cosmetics Regulation (EC No. 1223/2009 requires companies to collect and assess reports of adverse health effects from the cosmetic products (undesirable effects they market. Furthermore, undesirable effects that are considered as serious need to be reported to the national competent authorities. Cosmetics Europe, representing the European cosmetics industry, has developed these guidelines to promote a consistent practical approach for the management of undesirable effects and the notification of serious undesirable effects. Following these guidelines allows companies concerned to demonstrate due diligence and compliance with the legal requirements.

  2. Environmentally Clean Mitigation of Undesirable Plant Life Using Lasers

    Energy Technology Data Exchange (ETDEWEB)

    Rubenchik, A M; McGrann, T J; Yamamoto, R M; Parker, J M

    2009-07-01

    This concept comprises a method for environmentally clean destruction of undesirable plant life using visible or infrared radiation. We believe that during the blossom stage, plant life is very sensitive to electromagnetic radiation, with an enhanced sensitivity to specific spectral ranges. Small doses of irradiation can arrest further plant growth, cause flower destruction or promote plant death. Surrounding plants, which are not in the blossoming stage, should not be affected. Our proposed mechanism to initiate this effect is radiation produced by a laser. Tender parts of the blossom possess enhanced absorptivity in some spectral ranges. This absorption can increase the local tissue temperature by several degrees, which is sufficient to induce bio-tissue damage. In some instances, the radiation may actually stimulate plant growth, as an alternative for use in increased crop production. This would be dependent on factors such as plant type, the wavelength of the laser radiation being used and the amount of the radiation dose. Practical, economically viable realization of this concept is possible today with the advent of high efficiency, compact and powerful laser diodes. The laser diodes provide an efficient, environmentally clean source of radiation at a variety of power levels and radiation wavelengths. Figure 1 shows the overall concept, with the laser diodes mounted on a movable platform, traversing and directing the laser radiation over a field of opium poppies.

  3. Nanosuspension Technology for Solubilizing Poorly Soluble Drugs

    OpenAIRE

    Deoli Mukesh

    2012-01-01

    Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. It is estimated that around 40% of drugs in the pipeline cannot be delivered through the preferred route or in some cases, at all owing to poor water solubility. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor1 EL). To date, nanoscale systems f...

  4. Undesired Behaviors Faced in Classroom by Physics Teachers in High Schools

    Science.gov (United States)

    Bayar, Adem; Kerns, James H.

    2015-01-01

    The aim of this study is to define undesired behaviors in the classroom, to better understand the reasons of these undesired behaviors, and to offer strategies to overcome these behaviors. The researchers have used a qualitative research approach in this study. For this aim, the researchers have purposefully selected 12 physics teachers who work…

  5. Enhanced DEA model with undesirable output and interval data for rice growing farmers performance assessment

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Sahubar Ali Mohd. Nadhar, E-mail: sahubar@uum.edu.my; Ramli, Razamin, E-mail: razamin@uum.edu.my; Baten, M. D. Azizul, E-mail: baten-math@yahoo.com [School of Quantitative Sciences, UUM College of Arts and Sciences, Universiti Utara Malaysia, 06010 Sintok, Kedah (Malaysia)

    2015-12-11

    Agricultural production process typically produces two types of outputs which are economic desirable as well as environmentally undesirable outputs (such as greenhouse gas emission, nitrate leaching, effects to human and organisms and water pollution). In efficiency analysis, this undesirable outputs cannot be ignored and need to be included in order to obtain the actual estimation of firms efficiency. Additionally, climatic factors as well as data uncertainty can significantly affect the efficiency analysis. There are a number of approaches that has been proposed in DEA literature to account for undesirable outputs. Many researchers has pointed that directional distance function (DDF) approach is the best as it allows for simultaneous increase in desirable outputs and reduction of undesirable outputs. Additionally, it has been found that interval data approach is the most suitable to account for data uncertainty as it is much simpler to model and need less information regarding its distribution and membership function. In this paper, an enhanced DEA model based on DDF approach that considers undesirable outputs as well as climatic factors and interval data is proposed. This model will be used to determine the efficiency of rice farmers who produces undesirable outputs and operates under uncertainty. It is hoped that the proposed model will provide a better estimate of rice farmers’ efficiency.

  6. Enhanced DEA model with undesirable output and interval data for rice growing farmers performance assessment

    International Nuclear Information System (INIS)

    Khan, Sahubar Ali Mohd. Nadhar; Ramli, Razamin; Baten, M. D. Azizul

    2015-01-01

    Agricultural production process typically produces two types of outputs which are economic desirable as well as environmentally undesirable outputs (such as greenhouse gas emission, nitrate leaching, effects to human and organisms and water pollution). In efficiency analysis, this undesirable outputs cannot be ignored and need to be included in order to obtain the actual estimation of firms efficiency. Additionally, climatic factors as well as data uncertainty can significantly affect the efficiency analysis. There are a number of approaches that has been proposed in DEA literature to account for undesirable outputs. Many researchers has pointed that directional distance function (DDF) approach is the best as it allows for simultaneous increase in desirable outputs and reduction of undesirable outputs. Additionally, it has been found that interval data approach is the most suitable to account for data uncertainty as it is much simpler to model and need less information regarding its distribution and membership function. In this paper, an enhanced DEA model based on DDF approach that considers undesirable outputs as well as climatic factors and interval data is proposed. This model will be used to determine the efficiency of rice farmers who produces undesirable outputs and operates under uncertainty. It is hoped that the proposed model will provide a better estimate of rice farmers’ efficiency

  7. Enhanced DEA model with undesirable output and interval data for rice growing farmers performance assessment

    Science.gov (United States)

    Khan, Sahubar Ali Mohd. Nadhar; Ramli, Razamin; Baten, M. D. Azizul

    2015-12-01

    Agricultural production process typically produces two types of outputs which are economic desirable as well as environmentally undesirable outputs (such as greenhouse gas emission, nitrate leaching, effects to human and organisms and water pollution). In efficiency analysis, this undesirable outputs cannot be ignored and need to be included in order to obtain the actual estimation of firms efficiency. Additionally, climatic factors as well as data uncertainty can significantly affect the efficiency analysis. There are a number of approaches that has been proposed in DEA literature to account for undesirable outputs. Many researchers has pointed that directional distance function (DDF) approach is the best as it allows for simultaneous increase in desirable outputs and reduction of undesirable outputs. Additionally, it has been found that interval data approach is the most suitable to account for data uncertainty as it is much simpler to model and need less information regarding its distribution and membership function. In this paper, an enhanced DEA model based on DDF approach that considers undesirable outputs as well as climatic factors and interval data is proposed. This model will be used to determine the efficiency of rice farmers who produces undesirable outputs and operates under uncertainty. It is hoped that the proposed model will provide a better estimate of rice farmers' efficiency.

  8. Rapid detection of undesired cosmetic ingredients by matrix-assisted laser desorption ionization time-of-flight mass spectrometry.

    Science.gov (United States)

    Ouyang, Jie; An, Dongli; Chen, Tengteng; Lin, Zhiwei

    2017-10-01

    In recent years, cosmetic industry profits soared due to the widespread use of cosmetics, which resulted in illicit manufacturers and products of poor quality. Therefore, the rapid and accurate detection of the composition of cosmetics has become crucial. At present, numerous methods, such as gas chromatography and liquid chromatography-mass spectrometry, were available for the analysis of cosmetic ingredients. However, these methods present several limitations, such as failure to perform comprehensive and rapid analysis of the samples. Compared with other techniques, matrix-assisted laser desorption ionization time-of-flight mass spectrometry offered the advantages of wide detection range, fast speed and high accuracy. In this article, we briefly summarized how to select a suitable matrix and adjust the appropriate laser energy. We also discussed the rapid identification of undesired ingredients, focusing on antibiotics and hormones in cosmetics.

  9. Pharmacokinetics: curiosity or cure

    International Nuclear Information System (INIS)

    Notari, R.E.

    1979-01-01

    What is the fate of a drug from the time of its introduction into the body to the end of its duration. Pharmacokinetic studies are often designed to provide an answer to this question. But this question may be asked of any drug and research that is limited to answering it will remain empirical. Pharmacokinetic studies can provide answers to many other drug-related questions. In doing so pharmacokinetic research has the potential of improving drug therapy as well as the design and evaluation of drugs. While significant contributions can be cited, the future of pharmacokinetics depends upon its increased impact on clinical practice and drug design. How can a molecule be tailored for site specificity. Can chemical modification selectively alter absorption, distribution, metabolism, binding or excretion. In what new ways can pharmacokinetic information increase the predictability of drug therapy. Such questions, to which pharmacokinetics should provide answers, are numerous and easily identified. But the definitive studies are difficult both to create and conduct. Whether or not pharmacokinetics can achieve its full potential will depend upon the extent to which it can provide answers to these currently unanswered questions

  10. Lisdexamfetamine: A pharmacokinetic review.

    Science.gov (United States)

    Comiran, Eloisa; Kessler, Félix Henrique; Fröehlich, Pedro Eduardo; Limberger, Renata Pereira

    2016-06-30

    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Energy efficiency of selected OECD countries: A slacks based model with undesirable outputs

    International Nuclear Information System (INIS)

    Apergis, Nicholas; Aye, Goodness C.; Barros, Carlos Pestana; Gupta, Rangan; Wanke, Peter

    2015-01-01

    This paper presents an efficiency assessment of selected OECD countries using a Slacks Based Model with undesirable or bad outputs (SBM-Undesirable). In this research, SBM-Undesirable is used first in a two-stage approach to assess the relative efficiency of OECD countries using the most frequent indicators adopted by the literature on energy efficiency. Besides, in the second stage, GLMM–MCMC methods are combined with SBM-Undesirable results as part of an attempt to produce a model for energy performance with effective predictive ability. The results reveal different impacts of contextual variables, such as economic blocks and capital–labor ratio, on energy efficiency levels. - Highlights: • We analyze the energy efficiency of selected OECD countries. • SBM-Undesirable and MCMC–GLMM are combined for this purpose. • Find that efficiency levels are high but declining over time. • Analysis with contextual variables shows varying efficiency levels across groups. • Capital-intensive countries are more energy efficient than labor-intensive countries.

  12. Desirable and undesirable future thoughts call for different scene construction processes.

    Science.gov (United States)

    de Vito, S; Neroni, M A; Gamboz, N; Della Sala, S; Brandimonte, M A

    2015-01-01

    Despite the growing interest in the ability of foreseeing (episodic future thinking), it is still unclear how healthy people construct possible future scenarios. We suggest that different future thoughts require different processes of scene construction. Thirty-five participants were asked to imagine desirable and less desirable future events. Imagining desirable events increased the ease of scene construction, the frequency of life scripts, the number of internal details, and the clarity of sensorial and spatial temporal information. The initial description of general personal knowledge lasted longer in undesirable than in desirable anticipations. Finally, participants were more prone to explicitly indicate autobiographical memory as the main source of their simulations of undesirable episodes, whereas they equally related the simulations of desirable events to autobiographical events or semantic knowledge. These findings show that desirable and undesirable scenarios call for different mechanisms of scene construction. The present study emphasizes that future thinking cannot be considered as a monolithic entity.

  13. Ranking of bank branches with undesirable and fuzzy data: A DEA-based approach

    Directory of Open Access Journals (Sweden)

    Sohrab Kordrostami

    2016-07-01

    Full Text Available Banks are one of the most important financial sectors in order to the economic development of each country. Certainly, efficiency scores and ranks of banks are significant and effective aspects towards future planning. Sometimes the performance of banks must be measured in the presence of undesirable and vague factors. For these reasons in the current paper a procedure based on data envelopment analysis (DEA is introduced for evaluating the efficiency and complete ranking of decision making units (DMUs where undesirable and fuzzy measures exist. To illustrate, in the presence of undesirable and fuzzy measures, DMUs are evaluated by using a fuzzy expected value approach and DMUs with similar efficiency scores are ranked by using constraints and the Maximal Balance Index based on the optimal shadow prices. Afterwards, the efficiency scores of 25 branches of an Iranian commercial bank are evaluated using the proposed method. Also, a complete ranking of bank branches is presented to discriminate branches.

  14. Pharmacokinetics of Snake Venom

    OpenAIRE

    Suchaya Sanhajariya; Stephen B. Duffull; Geoffrey K. Isbister

    2018-01-01

    Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present) and Medline (1946–present). For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, ...

  15. Risk management of undesirable substances in feed following updated risk assessments

    International Nuclear Information System (INIS)

    Verstraete, Frans

    2013-01-01

    Directive 2002/32/EC of 7 May 2002 of the European Parliament and of the Council on undesirable substances in animal feed is the framework for the EU action on undesirable substances in feed. This framework Directive provides: ⁎that products intended for animal feed may enter for use in the Union from third countries, be put into circulation and/or used in the Union only if they are sound, genuine and of merchantable quality and therefore when correctly used do not represent any danger to human health, animal health or to the environment or could adversely affect livestock production. ⁎that in order to protect animal and public health and the environment, maximum levels for specific undesirable substances shall be established where necessary. ⁎for mandatory consultation of a scientific body (EFSA) for all provisions which may have an effect upon public health or animal health or on the environment. ⁎that products intended for animal feed containing levels of an undesirable substance that exceed the established maximum level may not be mixed for dilution purposes with the same, or other, products intended for animal feed and may not be used for the production of compound feed. Based on the provisions and principles laid down in this framework Directive, maximum levels for a whole range of undesirable substances have been established at EU level. During the discussions in view of the adoption of Directive 2002/32/EC, the European Commission made the commitment to review all existing provisions on undesirable substances on the basis of updated scientific risk assessments. Following requests of the European Commission, the Panel on Contaminants in the Food Chain (CONTAM) from the European Food Safety Authority (EFSA) has completed a series of 30 risk assessments undertaken over the last 5 years on undesirable substances in animal feed reviewing the possible risks for animal and human health due to the presence of these substances in animal feed. EU legislation

  16. Risk management of undesirable substances in feed following updated risk assessments

    Energy Technology Data Exchange (ETDEWEB)

    Verstraete, Frans, E-mail: Frans.Verstraete@ec.europa.eu

    2013-08-01

    Directive 2002/32/EC of 7 May 2002 of the European Parliament and of the Council on undesirable substances in animal feed is the framework for the EU action on undesirable substances in feed. This framework Directive provides: ⁎that products intended for animal feed may enter for use in the Union from third countries, be put into circulation and/or used in the Union only if they are sound, genuine and of merchantable quality and therefore when correctly used do not represent any danger to human health, animal health or to the environment or could adversely affect livestock production. ⁎that in order to protect animal and public health and the environment, maximum levels for specific undesirable substances shall be established where necessary. ⁎for mandatory consultation of a scientific body (EFSA) for all provisions which may have an effect upon public health or animal health or on the environment. ⁎that products intended for animal feed containing levels of an undesirable substance that exceed the established maximum level may not be mixed for dilution purposes with the same, or other, products intended for animal feed and may not be used for the production of compound feed. Based on the provisions and principles laid down in this framework Directive, maximum levels for a whole range of undesirable substances have been established at EU level. During the discussions in view of the adoption of Directive 2002/32/EC, the European Commission made the commitment to review all existing provisions on undesirable substances on the basis of updated scientific risk assessments. Following requests of the European Commission, the Panel on Contaminants in the Food Chain (CONTAM) from the European Food Safety Authority (EFSA) has completed a series of 30 risk assessments undertaken over the last 5 years on undesirable substances in animal feed reviewing the possible risks for animal and human health due to the presence of these substances in animal feed. EU legislation

  17. Testosterone for Poor Ovarian Responders

    DEFF Research Database (Denmark)

    Polyzos, Nikolaos P; Davis, Susan R; Drakopoulos, Panagiotis

    2016-01-01

    Testosterone, an androgen that directly binds to the androgen receptor, has been shown in previous small randomized controlled trials to increase the reproductive outcomes of poor ovarian responders. In most of these studies, transdermal testosterone in relatively high doses was administered before...... ovarian stimulation with a duration varying from 5 to 21 days. Nevertheless, the key question to be asked is whether, based on ovarian physiology and testosterone pharmacokinetics, a short course of testosterone administration of more than 10 mg could be expected to have any beneficial effect...... stages. In addition, extreme testosterone excess is not only likely to induce adverse events but has also the potential to be ineffective and even detrimental. Thus, evidence from clinical studies is not enough to either "reopen" or "close" the "androgen chapter" in poor responders, mainly because...

  18. Array diagnostics, spatial resolution, and filtering of undesired radiation with the 3D reconstruction algorithm

    DEFF Research Database (Denmark)

    Cappellin, C.; Pivnenko, Sergey; Jørgensen, E.

    2013-01-01

    This paper focuses on three important features of the 3D reconstruction algorithm of DIATOOL: the identification of array elements improper functioning and failure, the obtainable spatial resolution of the reconstructed fields and currents, and the filtering of undesired radiation and scattering...

  19. Relationships between College Students' Credit Card Debt, Undesirable Academic Behaviors and Cognitions, and Academic Performance

    Science.gov (United States)

    Hogan, Eileen A.; Bryant, Sarah K.; Overymyer-Day, Leslie E.

    2013-01-01

    The acquisition of credit card debt by college students has long been a topic of concern. This study explores relationships among debt, undesirable academic behaviors and cognitions, and academic performance, through surveys of 338 students in a public university, replicating two past measures of credit card debt and creating new measures of…

  20. A survey on the presence of undesirable botanical substances in feed in the European Union

    NARCIS (Netherlands)

    Raamsdonk, van L.W.D.; Vancutsem, J.; Jorgensen, J.S.

    2009-01-01

    Directive 2002/32/EC of the European Parliament and of the Council of 7 May 2002 on undesirable substances in animal feed lists a range of substances from botanical origin (weed seeds) and additionally some chemical compounds directly originating from specific weeds. In order to examine the actual

  1. School Social Workers' Perceived Efficacy at Tasks Related to Curbing Suspension and Undesirable Behaviors

    Science.gov (United States)

    Teasley, Martell L.; Miller, Christina R.

    2011-01-01

    This study explores school social workers' perceptions of their ability to successfully engage in practice tasks that reduce the likelihood of school suspension and undesirable behaviors among racial and ethnic groups within diverse geographical locations (urban, suburban, and rural). Using survey research methods with a convenience sample, 201…

  2. UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

    Science.gov (United States)

    Understanding the pharmacokinetics of a chemical¯its absorption, distribution, metabolism, and excretion in humans and laboratory animals ¯ is critical to the assessment of its human health risks. For trichloroethylene (TCE), numerous physiologically-based pharmacokinetic (PBPK)...

  3. Rice growing farmers efficiency measurement using a slack based interval DEA model with undesirable outputs

    Science.gov (United States)

    Khan, Sahubar Ali Mohd. Nadhar; Ramli, Razamin; Baten, M. D. Azizul

    2017-11-01

    In recent years eco-efficiency which considers the effect of production process on environment in determining the efficiency of firms have gained traction and a lot of attention. Rice farming is one of such production processes which typically produces two types of outputs which are economic desirable as well as environmentally undesirable. In efficiency analysis, these undesirable outputs cannot be ignored and need to be included in the model to obtain the actual estimation of firm's efficiency. There are numerous approaches that have been used in data envelopment analysis (DEA) literature to account for undesirable outputs of which directional distance function (DDF) approach is the most widely used as it allows for simultaneous increase in desirable outputs and reduction of undesirable outputs. Additionally, slack based DDF DEA approaches considers the output shortfalls and input excess in determining efficiency. In situations when data uncertainty is present, the deterministic DEA model is not suitable to be used as the effects of uncertain data will not be considered. In this case, it has been found that interval data approach is suitable to account for data uncertainty as it is much simpler to model and need less information regarding the underlying data distribution and membership function. The proposed model uses an enhanced DEA model which is based on DDF approach and incorporates slack based measure to determine efficiency in the presence of undesirable factors and data uncertainty. Interval data approach was used to estimate the values of inputs, undesirable outputs and desirable outputs. Two separate slack based interval DEA models were constructed for optimistic and pessimistic scenarios. The developed model was used to determine rice farmers efficiency from Kepala Batas, Kedah. The obtained results were later compared to the results obtained using a deterministic DDF DEA model. The study found that 15 out of 30 farmers are efficient in all cases. It

  4. Clinical pharmacokinetics of melatonin

    DEFF Research Database (Denmark)

    Harpsøe, Nathja Groth; Andersen, Lars Peter Holst; Gögenur, Ismail

    2015-01-01

    was performed in PubMed and Embase databases. The pharmacokinetic variables included maximal plasma/serum concentration (Cmax), time to maximal plasma/serum concentration (Tmax), elimination half-life (T1/2), area-under-the-curve plasma/serum concentrations (AUC), clearance (Cl), volume of distribution (VD......) and 1602 L (4 mg, oral). Bioavailability of oral melatonin ranged from 9 to 33%. Pharmacokinetics was affected by age, caffeine, smoking, oral contraceptives, feeding status, and fluvoxamine. Critically ill patients displayed accelerated absorption and compromised elimination. CONCLUSIONS: Despite...

  5. Experimental investigation of undesired stable equilibria in pumpkin shape super-pressure balloon designs

    Science.gov (United States)

    Schur, W. W.

    2004-01-01

    Excess in skin material of a pneumatic envelope beyond what is required for minimum enclosure of a gas bubble is a necessary but by no means sufficient condition for the existence of multiple equilibrium configurations for that pneumatic envelope. The very design of structurally efficient super-pressure balloons of the pumpkin shape type requires such excess. Undesired stable equilibria in pumpkin shape balloons have been observed on experimental pumpkin shape balloons. These configurations contain regions with stress levels far higher than those predicted for the cyclically symmetric design configuration under maximum pressurization. Successful designs of pumpkin shape super-pressure balloons do not allow such undesired stable equilibria under full pressurization. This work documents efforts made so far and describes efforts still underway by the National Aeronautics and Space Administration's Balloon Program Office to arrive on guidance on the design of pumpkin shape super-pressure balloons that guarantee full and proper deployment.

  6. Data Envelopment Analysis with Fixed Inputs, Undesirable Outputs and Negative Data

    Directory of Open Access Journals (Sweden)

    F. Seyed Esmaeili

    2017-03-01

    Full Text Available In Data Envelopment Analysis (DEA, different models have been measured to evaluate the performance of decision making units with multiple inputs and outputs. Revised model of Slack-based measures known as MBSM of collective models family has been introduced by Sharp et al. Slack-based measure has been introduced by Ton. In this study, a model is proposed that is able to estimate the efficiency when a number of outputs of decision making units are undesirable, inputs are fixed and some of outputs and inputs are negative. So that, level of undesirable output is reduced at the constant level of inputs in the evaluation unit and by conserving the efficiency.

  7. Pharmacokinetics of Alternative Administration Routes of Melatonin

    DEFF Research Database (Denmark)

    Zetner, D.; Andersen, L. P.H.; Rosenberg, J.

    2016-01-01

    Background: Melatonin is traditionally administered orally but has a poor and variable bioavailability. This study aims to present an overview of studies investigating the pharmacokinetics of alternative administration routes of melatonin. Methods: A systematic literature search was performed...... and included experimental or clinical studies, investigating pharmacokinetics of alternative administration routes of melatonin in vivo. Alternative administration routes were defined as all administration routes except oral and intravenous. Results: 10 studies were included in the review. Intranasal....... Subcutaneous injection of melatonin displayed a rapid absorption rate compared to oral administration. Conclusion: Intranasal administration of melatonin has a large potential, and more research in humans is warranted. Transdermal application of melatonin has a possible use in a local application, due to slow...

  8. Undesirable Behaviors Elementary School Classroom Teachers Encounter in the Classroom and Their Reasons

    OpenAIRE

    E.G. Balcik; S. Gulec

    2011-01-01

    The present study aims to determine how often elementary school teachers encounter undesirable behaviors in the classroom and what their thoughts regarding possible reasons of these behaviors are. The teachers’ opininon about the prevalence of these behaviors and their possible reasons were evaluated according to gender, marital status, level of class being taught, size of class being taught and it was tried to be determined if there were significant differences between variables. The measure...

  9. DEREGULATION, FINANCIAL CRISIS, AND BANK EFFICIENCY IN TAIWAN: AN ESTIMATION OF UNDESIRABLE OUTPUTS

    OpenAIRE

    Liao, Chang-Sheng

    2018-01-01

    Purpose- This study investigates the undesirable impacts of outputson bank efficiency and contributes to the literature by assessing howregulation policies and other events impact bank efficiency in Taiwan inregards to deregulation, financial crisis, and financial reform from 1993 to2011. Methodology- In order to effectively deal with both undesirableand desirable outputs, this study follows Seiford and Zhu (2002), who recommendusing the standard data envelopment analysis model to measure per...

  10. Development of Data Envelopment Analysis for the Performance Evaluation of Green Supply Chain with Undesirable Outputs

    Directory of Open Access Journals (Sweden)

    Alireza Alinezhad

    2016-08-01

    Full Text Available A fundamental problem is the use of DEA in multistep or multilevel processes such as supply chain, lack of attention to processes’ internal communications in a way that the recent studies on DEA in the context of serial processes have focused on closed systems that the outputs of one level become the inputs of the next level and none of the inputs enter the mediator process. The present study aimed to examine the general dimensions of an open multilevel process. Here, some of the data such as inputs and outputs are supposed to leave the system while other outputs turn into the inputs of the next level. The new inputs can enter the next level as well. We expand this mode for network structures. The overall performance of such a structure is considered as a weighted average of sectors’ performance or distinct steps. Therefore, this suggested model in this study, not only provides the possibility to evaluate the performance of the entire network, but creates the performance analysis for each of the sub-processes. On the other hand, considering the data with undesirable structure leads to more correct performance estimation. In the real world, all productive processes do not comprise desirable factors. Therefore, presenting a structure that is capable of taking into account the undesirable structure is of crucial importance. In this study, a new model in the DEA by network structure is offered that can analyze the performance considering undesirable factors.

  11. Albendazole nanocrystals with improved pharmacokinetic performance in mice.

    Science.gov (United States)

    Paredes, Alejandro J; Bruni, Sergio Sánchez; Allemandi, Daniel; Lanusse, Carlos; Palma, Santiago D

    2018-02-01

    Albendazole (ABZ) is a broad-spectrum antiparasitic agent with poor aqueous solubility, which leads to poor/erratic bioavailability and therapeutic failures. Here, we aimed to produce a novel formulation of ABZ nanocrystals (ABZNC) and assess its pharmacokinetic performance in mice. Results/methodology: ABZNC were prepared by high-pressure homogenization and spray-drying processes. Redispersion capacity and solid yield were measured in order to obtain an optimized product. The final particle size was 415.69±7.40 nm and the solid yield was 72.32%. The pharmacokinetic parameters obtained in a mice model for ABZNC were enhanced (p < 0.05) with respect to the control formulation. ABZNC with improved pharmacokinetic behavior were produced by a simple, inexpensive and potentially scalable methodology.

  12. Pharmacokinetics of Melatonin

    DEFF Research Database (Denmark)

    Andersen, Lars Peter Holst; Gögenur, Ismail; Rosenberg, Jacob

    2016-01-01

    Despite widespread clinical application of melatonin, several unanswered questions remain regarding the pharmacokinetics of this drug. This lack of knowledge may contribute to the inconsistency of results in previous clinical studies. Currently, a t max value of 30-45 min and a t ½elimination of ...

  13. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance ≥ 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic...

  14. Pharmacokinetic evaluation of pemetrexed

    DEFF Research Database (Denmark)

    Sørensen, Jens Benn

    2011-01-01

    correlates with renal function and it may be safely used with vitamin supplementation in patients with creatinine clearance = 45 ml/min. The pharmacokinetics of pemetrexed is also largely unchanged in third-space fluids and can be feasibly and safely administered in combination with several other cytotoxic...

  15. 32 CFR 887.7 - Persons separated under other than honorable conditions (undesirable or bad conduct) or...

    Science.gov (United States)

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Persons separated under other than honorable conditions (undesirable or bad conduct) or dishonorable discharge. 887.7 Section 887.7 National Defense... honorable conditions (undesirable or bad conduct) or dishonorable discharge. Those persons whose character...

  16. A survey on the presence of undesirable botanical substances in feed in the European Union

    Directory of Open Access Journals (Sweden)

    van Raamsdonk LWD.

    2009-01-01

    Full Text Available Directive 2002/32/EC of the European Parliament and of the Council of 7 May 2002 on undesirable substances in animal feed lists a range of substances from botanical origin (weed seeds and additionally some chemical compounds directly originating from specific weeds. In order to examine the actual status of enforcement and of the present occurrence of these botanical substances, a survey was carried out. A questionnaire was sent to 103 laboratories, including official control labs from all member states of the European Union. The results, indicating the frequency of occurrence as far as reported, are compared to the publications of the EU Rapid Alert System for Food and Feed (RASFF. A total of 44 questionnaires was returned (42.7% from 22 member states. Ten member states predominantly from north-western Europe appeared to have an active monitoring of botanical undesirable substances. The questionnaire results did not indicate that the other member states enforce this part of Directive 2002/32/EC. Reports on the frequency of occurrence include: a few to 25-50% of the samples contain traces of ergot (8 member states, a few to 24% contain at least some traces of thorn apple (6 member states, zero to 17% contain some castor oil plant seeds (3 member states, zero to a few samples contain Crotalaria seeds (3 member states, and zero to 6% contain traces of Sareptian mustard (4 member states. One member state conducted extra surveillance since several cases of animal intoxications have been reported. In some cases a coincidence with undesirable botanical substances was found.

  17. Undesirable Behaviors Elementary School Classroom Teachers Encounter in the Classroom and Their Reasons

    Directory of Open Access Journals (Sweden)

    E.G. Balcik

    2011-12-01

    Full Text Available The present study aims to determine how often elementary school teachers encounter undesirable behaviors in the classroom and what their thoughts regarding possible reasons of these behaviors are. The teachers’ opininon about the prevalence of these behaviors and their possible reasons were evaluated according to gender, marital status, level of class being taught, size of class being taught and it was tried to be determined if there were significant differences between variables. The measurement tool was applied to a total of 54 teachers at 5 schools in Gölcük district of the Kocaeli province. The data collection tool is composed of three sections. The first section is for establishing teachers’ personal information. In this study, as a data collection tool, a questionnaire was used. When preparing questions for the questionnaire, following the examination of resources available, the questionnaire prepared by Aksoy (1999 and used in the thesis study entitled “Classroom Management and Student Discipline in Elementary Schools of Ankara” and also used in the thesis study by Boyraz (2007 entitled “Discipline Problems that Candidate Teachers Servicing at Elementary Schools Encounter in the Classroom” was employed. Although the validity and reliability of the questionnaire was tested by Aksoy (1999 and Boyraz (2007, the reliability study for the questionnaire was retested and found to be 0,9. The questionnaire include 42 items. 19 of them are related to the reasons of undesirable behaviors observed in the classroom and 23 of them are related to undesirable behaviors observed in the classroom.

  18. Productivity Growth-Accounting for Undesirable Outputs and Its Influencing Factors: The Case of China

    Directory of Open Access Journals (Sweden)

    Junfeng Zhang

    2016-11-01

    Full Text Available Presently, China’s social development is facing the dilemma of supporting economic growth and reducing emissions. Therefore, it is crucial to analyse productivity growth and examine its relationship with influencing factors in China. This study evaluated the total factor productivity (TFP growth of 30 provinces in China by adopting the Malmquist-Luenberger (ML productivity index and incorporating undesirable outputs from 2011–2014. Then, a Tobit regression model was employed to explore the factors that influence China’s TFP growth. The results show that the average annual growth of the Malmquist-Luenberger productivity index was lower than that of the traditional Malmquist (M productivity index growth during the research period. The findings reveal several key conclusions: First, the true TFP growth in China will be overestimated if undesirable outputs are ignored. Second, technical changes are the main contributor to TFP growth. Third, there are huge regional disparities of productivity growth in China. Fourth, coal intensity, environmental regulations, and industrial structure have significantly negative effects on productivity growth, while real per capita gross domestic product (GDP and foreign direct investment (FDI have strongly positive effects on productivity growth.

  19. Microdosing of a Carbon-14 Labeled Protein in Healthy Volunteers Accurately Predicts Its Pharmacokinetics at Therapeutic Dosages

    NARCIS (Netherlands)

    Vlaming, M.L.; Duijn, E. van; Dillingh, M.R.; Brands, R.; Windhorst, A.D.; Hendrikse, N.H.; Bosgra, S.; Burggraaf, J.; Koning, M.C. de; Fidder, A.; Mocking, J.A.; Sandman, H.; Ligt, R.A. de; Fabriek, B.O.; Pasman, W.J.; Seinen, W.; Alves, T.; Carrondo, M.; Peixoto, C.; Peeters, P.A.; Vaes, W.H.

    2015-01-01

    Preclinical development of new biological entities (NBEs), such as human protein therapeutics, requires considerable expenditure of time and costs. Poor prediction of pharmacokinetics in humans further reduces net efficiency. In this study, we show for the first time that pharmacokinetic data of

  20. Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability.

    Science.gov (United States)

    Brown, Jacob T; Bishop, Jeffrey R

    2015-01-01

    Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder and is predominantly metabolized by the CYP2D6 enzyme. Differences in pharmacokinetic parameters as well as clinical treatment outcomes across CYP2D6 genotype groups have resulted in dosing recommendations within the product label, but clinical studies supporting the use of genotype guided dosing are currently lacking. Furthermore, pharmacokinetic and clinical studies have primarily focused on extensive as compared with poor metabolizers, with little information known about other metabolizer categories as well as genes involved in the pharmacodynamics of atomoxetine. This review describes the pharmacogenetic associations with atomoxetine pharmacokinetics, treatment response and tolerability with considerations for the clinical utility of this information.

  1. Cycles of undesirable substances in the food chain; Kreislaeufe unerwuenschter Stoffe in der Lebensmittelkette

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2012-12-15

    The working group ''Carry over of undesirable substances in animal feed'' at the Federal Ministry of Food, Agriculture and Forestry (BMELV) in cooperation with the Institute of Animal Nutrition of the Friedrich-Loeffler-Institute (FLI) performed on 27 and 28 October 2011 in Braunschweig a workshop on ''cycles of undesirable substances in Food Chain ''. The aim of the workshop was to present the latest findings of research and Carry over Recommendations of the Carry over - Working Group on undesirable substances in feed and production processes of the feed industry, to evaluate and discuss about this with representatives from science, business and management and to work out the further research and action need. The focus of the considerations were the pathways, the carry over and the Exposure to dioxins and other halogenated hydrocarbons, the effects of Mycotoxins in feed and starting points for preventive measures, the soil contamination and the exposure of humans and animals by cadmium and case studies on Nitrite in feed, antibiotics in plants and residues of pesticides and radionuclides in feed. Furthermore the risks associated with specified manufacturing processes of feed are considered, especially the used materials that come into contact with animal feed, and the risks from nanotechnology. [German] Die Arbeitsgruppe ''Carry over unerwuenschter Stoffe in Futtermitteln'' beim Bundesministerium fuer Ernaehrung, Landwirtschaft und Forsten (BMELV) hat in Zusammenarbeit mit dem Institut fuer Tierernaehrung des Friedrich-Loeffler-Instituts (FLI) am 27. und 28. Oktober 2011 in Braunschweig einen Workshop zum Thema ''Kreislaeufe unerwuenschter Stoffe in der Lebensmittelkette'' durchgefuehrt. Ziel des Workshops war es, die aktuellen Erkenntnisse der Carry over Forschung und die Empfehlungen der Carry over - Arbeitsgruppe zu unerwuenschten Stoffen in Futtermitteln und Produktionsverfahren in

  2. Clinical Pharmacokinetics of Paclitaxel Monotherapy

    DEFF Research Database (Denmark)

    Stage, Tore B; Bergmann, Troels K; Kroetz, Deanna L

    2018-01-01

    Paclitaxel is an anticancer agent efficacious in the treatment of ovarian, breast, and lung cancer. Due to a strong link between the pharmacokinetics and therapeutic efficacy of paclitaxel, we reviewed the literature on paclitaxel pharmacokinetics. Systematic data mining was performed to extract ...

  3. Operation condition for continuous anti-solvent crystallization of CBZ-SAC cocrystal considering deposition risk of undesired crystals

    Science.gov (United States)

    Nishimaru, Momoko; Nakasa, Miku; Kudo, Shoji; Takiyama, Hiroshi

    2017-07-01

    Crystallization operation of cocrystal production has deposition risk of undesired crystals. Simultaneously, continuous manufacturing processes are focused on. In this study, conditions for continuous cocrystallization considering risk reduction of undesired crystals deposition were investigated on the view point of thermodynamics and kinetics. The anti-solvent cocrystallization was carried out in four-component system of carbamazepine, saccharin, methanol and water. From the preliminary batch experiment, the relationships among undesired crystal deposition, solution composition decided by mixing ratio of solutions, and residence time for the crystals were considered, and then the conditions of continuous experiment were decided. Under these conditions, the continuous experiment was carried out. The XRD patterns of obtained crystals in the continuous experiment showed that desired cocrystals were obtained without undesired crystals. This experimental result was evaluated by using multi-component phase diagrams from the view point of the operation point's movement. From the evaluation, it was found that there is a certain operation condition which the operation point is fixed with time in the specific domain without the deposition risk of undesired single component crystals. It means the possibility of continuous production of cocrystals without deposition risk of undesired crystals was confirmed by using multi-component phase diagrams.

  4. Pharmacokinetics of Snake Venom

    Directory of Open Access Journals (Sweden)

    Suchaya Sanhajariya

    2018-02-01

    Full Text Available Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present and Medline (1946–present. For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, the disposition of snake venom was described by a two-compartment model consisting of a rapid distribution phase and a slow elimination phase, with half-lives of 5 to 48 min and 0.8 to 28 h, respectively, following rapid intravenous injection of the venoms or toxins. When the venoms or toxins were administered intramuscularly or subcutaneously, an initial absorption phase and slow elimination phase were observed. The bioavailability of venoms or toxins ranged from 4 to 81.5% following intramuscular administration and 60% following subcutaneous administration. The volume of distribution and the clearance varied between snake species. For humans, 24 out of 666 initially identified publications contained sufficient information and timed venom concentrations in the absence of antivenom therapy for data extraction. The data were extracted and modelled in NONMEM. A one-compartment model provided the best fit, with an elimination half-life of 9.71 ± 1.29 h. It is intended that the quantitative information provided in this review will provide a useful basis for future studies that address the pharmacokinetics of snakebite in humans.

  5. The application of game theory and cognitive economy to analyze the problem of undesired location

    International Nuclear Information System (INIS)

    Villani, S.

    2008-01-01

    The analysts of the processes of public bodies decision - taking have long been discussing on the establishment of proper strategies to manage environmental conflicts - above all the so-called problems of undesired location of public works and facilities - efficiently (i.e. on a short-period basis so as to grant decision and agreement stability) and fairly (the parties' satisfaction is itself a further guarantee of decision and agreement stability). Each strategy, anyway, is still in progress, like a universe to create and explore. Therefore, in this paper, we will focus on the analysis of the problem and provide as well some theoretical proposals to arrange a new interpreting model of public bodies decision-taking processes based on the achievements of two new subject-matters: evolutionary game theory and cognitive economy. Both sciences share their investigation field with law and economic science. [it

  6. Method of eliminating undesirable gaseous products resulting in underground uranium ore leaching

    International Nuclear Information System (INIS)

    Krizek, J.; Dedic, K.; Johann, J.; Haas, F.; Sokola, K.

    1980-01-01

    The method described is characteristic of the fact that gases being formed or dissolved are oxidized using a combined oxidation-reduction system consisting of airborne oxygen, oxygen carriers and a strong irreversible oxidant. The oxygen carrier system consists of a mixture of Fe 2+ and Fe 3+ cations or of Cu + and Cu 2+ cations introduced in solutions in form of iron salts at a concentration of 0.0001 to 0.003 M, or copper salts maximally of 0.0003 M. The irreversible oxidant shows a standard redox potential of at least +1.0 V. In addition to undesirable product elimination, the method allows increasing the leaching process yield. (J.B.)

  7. BETWEEN THE RIGHT AND THE COMMON. HOW GROUPS REACT TO SOCIALLY UNDESIRABLE BEHAVIOUR

    Directory of Open Access Journals (Sweden)

    Komendant-Brodowska Agata

    2017-06-01

    Full Text Available The aim of the paper is to analyse the relationship between group characteristics and the scope of reaction of the group to socially undesirable behaviour. Sometimes small groups or communities fail to react to undesirable or violent behaviour and their apathy can have devastating consequences. Such a situation can occur among co-workers witnessing workplace mobbing, or neighbours who do not react to a suspicion of domestic violence. Reasons for their inaction are diverse and can include fear, doubts concerning the necessity of such a reaction, and also conformity. In the paper I examine a seemingly favourable situation: I assume that reaction is costless and all the members of the group would like to react (internalised norm, but they also want to conform. In order to analyse the factors that can influence the scope of group reaction, a structurally embedded sequential coordination game was played for different initial conditions. Computer simulations were conducted for networks of a specific type (Erd¨os-R´enyi random graph. The main aim of the analysis was to identify non-structural and structural features of the group that can impede or even block the intervention of the group. There is a positive relationship between the scope of group reaction and the strength of the internalized norm, whereas the level of conformity affects the chances of group intervention in a negative way. Heterogeneity of the group is an important factor - the scope of reaction is higher when members of the group have different levels of norm internalisation and conformity. There is a non-linear relationship between network density and the scope of reaction. Both low and high density can make it harder for people to act.

  8. Removing undesirable color and boosting biological activity in red beet extracts using gamma irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung Sik; Lee, Eun Mi; Hong, Sung Hyun; Bai, Hyoung Woo; Chung, Byung Yeoup [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Lee, In Chul [Youngdong University, Youngdong (Korea, Republic of)

    2011-10-15

    Red beet (Beta vulgaris L.) is a traditional and popular vegetable distributed in many part of the world and has been used as a natural colorant in many dairy products, beverages, candies and cattle products. Red beet roots contain two groups of betalain pigments, redviolet betacyanins and yellow betaxanthins. Betalains possess several biological activities such as antioxidant, anti-inflammatory, hepatoprotective, and anticancer properities. Recent trend of using natural products in industries tends toward multifunctional, high quality, and highpriced value foods and cosmetics. To meet the needs of consumers, cosmetics, medicine, and foods should contain the proper amount of natural products. Although the color removal processes such as filtration and absorption by clay are still useful, these procedures are difficult, time-consuming and costly. To overcome this problem, the radiation technology has emerged as a new way. Radiation technology has been applied to the decomposition and decoloration of pigment and is an efficient technique for inactivating pathogens, removing undesirable color in biomaterial extracts and improving or maintaining biological activities. Gamma-irradiation and electron beamirradiation techniques in previous reports were applied in order to remove any undesirable color and to improve or maintain biological activities of various extracts such as green tea leaves, licorice root, and S. chinensis fruits. Latorre et al. reported that betacyanin concentration decreased with the irradiation dose and significantly, in 35%, after 2.0 kGy of gamma-ray, whereas betaxathin concentration increased (about 11%-ratio with respect to control) after 1 kGy but decreased (about 19%) after 2 kGy. However, they did not try to analysis for completed removal of red beet pigments. Therefore, it is necessary to find the optimum irradiation dose for entirely removing red pigments in red beet. The aim of this work was to address the effects of the color removal and

  9. Qualitative screening of undesirable compounds from feeds to fish by liquid chromatography coupled to mass spectrometry.

    Science.gov (United States)

    Nácher-Mestre, Jaime; Ibáñez, María; Serrano, Roque; Pérez-Sánchez, Jaume; Hernández, Félix

    2013-03-06

    This paper describes the development, validation, and application of a rapid screening method for the detection and identification of undesirable organic compounds in aquaculture products. A generic sample treatment was applied without any purification or preconcentration step. After extraction of the samples with acetonitrile/water 80:20 (0.1% formic acid), the extracts were centrifuged and directly injected in the LC-HRMS system, consisting of ultra-high performance liquid chromatography coupled to hybrid quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS). A qualitative validation was carried out for over 70 representative compounds, including antibiotics, pesticides, and mycotoxins, in fish feed and fish fillets spiked at 20 and 100 μg/kg. At the highest level, the great majority of compounds were detected (using the most abundant ion, typically the protonated molecule) and unequivocally identified (on the basis of the presence of two accurate-mass measured ions). At the 20 μg/kg level, many contaminants could already be detected, although identification using two ions was not fully reached for some of them, mainly in fish feed due to the complexity of this matrix. Subsequent application of this screening methodology to aquaculture samples made it possible to find several compounds from the target list, such as the antibiotic ciprofloxacin, the insecticide pirimiphos-methyl, and the mycotoxins fumonisin B2 and zearalenone. A retrospective analysis of accurate-mass full-spectrum acquisition data provided by QTOF MS was also made, without either reprocessing or injecting the samples. This allowed the detection and tentative identification of other organic undesirables different from those included in the validated list.

  10. Removing undesirable color and boosting biological activity in red beet extracts using gamma irradiation

    International Nuclear Information System (INIS)

    Lee, Seung Sik; Lee, Eun Mi; Hong, Sung Hyun; Bai, Hyoung Woo; Chung, Byung Yeoup; Lee, In Chul

    2011-01-01

    Red beet (Beta vulgaris L.) is a traditional and popular vegetable distributed in many part of the world and has been used as a natural colorant in many dairy products, beverages, candies and cattle products. Red beet roots contain two groups of betalain pigments, redviolet betacyanins and yellow betaxanthins. Betalains possess several biological activities such as antioxidant, anti-inflammatory, hepatoprotective, and anticancer properities. Recent trend of using natural products in industries tends toward multifunctional, high quality, and highpriced value foods and cosmetics. To meet the needs of consumers, cosmetics, medicine, and foods should contain the proper amount of natural products. Although the color removal processes such as filtration and absorption by clay are still useful, these procedures are difficult, time-consuming and costly. To overcome this problem, the radiation technology has emerged as a new way. Radiation technology has been applied to the decomposition and decoloration of pigment and is an efficient technique for inactivating pathogens, removing undesirable color in biomaterial extracts and improving or maintaining biological activities. Gamma-irradiation and electron beamirradiation techniques in previous reports were applied in order to remove any undesirable color and to improve or maintain biological activities of various extracts such as green tea leaves, licorice root, and S. chinensis fruits. Latorre et al. reported that betacyanin concentration decreased with the irradiation dose and significantly, in 35%, after 2.0 kGy of gamma-ray, whereas betaxathin concentration increased (about 11%-ratio with respect to control) after 1 kGy but decreased (about 19%) after 2 kGy. However, they did not try to analysis for completed removal of red beet pigments. Therefore, it is necessary to find the optimum irradiation dose for entirely removing red pigments in red beet. The aim of this work was to address the effects of the color removal and

  11. Undesired small RNAs originate from an artificial microRNA precursor in transgenic petunia (Petunia hybrida.

    Directory of Open Access Journals (Sweden)

    Yulong Guo

    Full Text Available Although artificial microRNA (amiRNA technology has been used frequently in gene silencing in plants, little research has been devoted to investigating the accuracy of amiRNA precursor processing. In this work, amiRNAchs1 (amiRchs1, based on the Arabidopsis miR319a precursor, was expressed in order to suppress the expression of CHS genes in petunia. The transgenic plants showed the CHS gene-silencing phenotype. A modified 5' RACE technique was used to map small-RNA-directed cleavage sites and to detect processing intermediates of the amiRchs1 precursor. The results showed that the target CHS mRNAs were cut at the expected sites and that the amiRchs1 precursor was processed from loop to base. The accumulation of small RNAs in amiRchs1 transgenic petunia petals was analyzed using the deep-sequencing technique. The results showed that, alongside the accumulation of the desired artificial microRNAs, additional small RNAs that originated from other regions of the amiRNA precursor were also accumulated at high frequency. Some of these had previously been found to be accumulated at low frequency in the products of ath-miR319a precursor processing and some of them were accompanied by 3'-tailing variant. Potential targets of the undesired small RNAs were discovered in petunia and other Solanaceae plants. The findings draw attention to the potential occurrence of undesired target silencing induced by such additional small RNAs when amiRNA technology is used. No appreciable production of secondary small RNAs occurred, despite the fact that amiRchs1 was designed to have perfect complementarity to its CHS-J target. This confirmed that perfect pairing between an amiRNA and its targets is not the trigger for secondary small RNA production. In conjunction with the observation that amiRNAs with perfect complementarity to their target genes show high efficiency and specificity in gene silencing, this finding has an important bearing on future applications of ami

  12. Undesired small RNAs originate from an artificial microRNA precursor in transgenic petunia (Petunia hybrida).

    Science.gov (United States)

    Guo, Yulong; Han, Yao; Ma, Jing; Wang, Huiping; Sang, Xianchun; Li, Mingyang

    2014-01-01

    Although artificial microRNA (amiRNA) technology has been used frequently in gene silencing in plants, little research has been devoted to investigating the accuracy of amiRNA precursor processing. In this work, amiRNAchs1 (amiRchs1), based on the Arabidopsis miR319a precursor, was expressed in order to suppress the expression of CHS genes in petunia. The transgenic plants showed the CHS gene-silencing phenotype. A modified 5' RACE technique was used to map small-RNA-directed cleavage sites and to detect processing intermediates of the amiRchs1 precursor. The results showed that the target CHS mRNAs were cut at the expected sites and that the amiRchs1 precursor was processed from loop to base. The accumulation of small RNAs in amiRchs1 transgenic petunia petals was analyzed using the deep-sequencing technique. The results showed that, alongside the accumulation of the desired artificial microRNAs, additional small RNAs that originated from other regions of the amiRNA precursor were also accumulated at high frequency. Some of these had previously been found to be accumulated at low frequency in the products of ath-miR319a precursor processing and some of them were accompanied by 3'-tailing variant. Potential targets of the undesired small RNAs were discovered in petunia and other Solanaceae plants. The findings draw attention to the potential occurrence of undesired target silencing induced by such additional small RNAs when amiRNA technology is used. No appreciable production of secondary small RNAs occurred, despite the fact that amiRchs1 was designed to have perfect complementarity to its CHS-J target. This confirmed that perfect pairing between an amiRNA and its targets is not the trigger for secondary small RNA production. In conjunction with the observation that amiRNAs with perfect complementarity to their target genes show high efficiency and specificity in gene silencing, this finding has an important bearing on future applications of amiRNAs in gene

  13. Insulin aspart pharmacokinetics

    DEFF Research Database (Denmark)

    Rasmussen, Christian Hove; Roge, Rikke Meldgaard; Ma, Zhulin

    2014-01-01

    Background: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control postprandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between...... to investigate and quantify the properties of the subcutaneous depot. Data from Brange et al. (1990) are used to determine the effects of insulin chemistry in subcutis on the absorption rate. Intravenous (i.v.) bolus and infusion PK data for human insulin are used to understand and quantify the systemic...... distribution and elimination (Porksen et al., 1997; Sjostrand et al., 2002). PK and PD profiles for type 1 diabetics from Chen et al. (2005) are analyzed to demonstrate the effects of IAsp antibodies in terms of bound and unbound insulin. PK profiles from Thorisdottir et al. (2009) and Ma et al. (2012b...

  14. Field tests of an acephate baiting system designed for eradicating undesirable honey bees (Hymenoptera: Apidae).

    Science.gov (United States)

    Danka, R G; Williams, J L; Sugden, E A; Rivera, R

    1992-08-01

    Field evaluations were made of a baiting system designed for use by regulatory agencies in suppressing populations of undesirable feral honey bees, Apis mellifera L. (e.g., bees posing hazards [especially Africanized bees] and colonies infested with parasitic mites). Bees from feral or simulated feral (hived) colonies were lured with honey and Nasonov pheromone components to feeders dispensing sucrose-honey syrup. After 1-3 wk of passive training to feeders, colonies were treated during active foraging by replacing untreated syrup with syrup containing 500 ppm (mg/liter) acephate (Orthene 75 S). In four trials using hived colonies on Grant Terre Island, LA., 21 of 29 colonies foraged actively enough at baits to be treated, and 20 of the 22 treated were destroyed. In the lower Rio Grande Valley of Texas (two trials at each of two trials), treatments killed 11 of 16 colonies (6 of 10 hived; 50 of 6 feral). Overall results showed that all 11 colonies that collected greater than 25 mg acephate died, whereas 3 of 10 colonies receiving less than 25 mg survived. Delivering adequate doses required a minimum of approximately 100 bees per target colony simultaneously collecting treated syrup. The system destroyed target colonies located up to nearly 700 m away from baits. Major factors limiting efficacy were conditions inhibiting foraging at baits (e.g., competing natural nectar sources and temperatures and winds that restricted bee flight).

  15. The presence of undesirable mould species on the surface of dry sausages

    Directory of Open Access Journals (Sweden)

    Vesković-Moračanin Slavica M.

    2008-01-01

    Full Text Available Transition from manufacture to the industrial way of meat production and processing, as well as contemporary concept of food quality and safety, have led to the application of starter cultures. Their application leads towards the streamlining of the production process in the desired direction, quality improvement and its harmonization, and thereby to its standardization. Application of moulds in the meat industry is based on positive effects of their proteolytic and lipolytic egzoenzymes which, as a consequence, leads to the creation of characteristic sensory properties ('flavor' of fermented products. Penicillium nalgiovense is a typical representative of moulds used in the production of fermented sausages-salamis from our region. Samples of 'zimska salama' (dry sausage, produced with Penicillium nalgiovense, were evaluated as hygienically unacceptable. Their sensory properties changed due to contamination of this mould during the ripening process. Micological analysis discovered the presence of Penicillium aurantiogriseum, which is a frequent mould contaminant in the meat industry. At the same time, thin layer chromatography revealed no possibility of metabolic activity of this mould in the creation of mycotoxins. However, the presence of this mould on the surface of 'zimska salama' is considered as undesirable due to formation of 'off flavor' in products. Such product is considered as hygienically unacceptable and cannot be used for the human consumption.

  16. Tracking Progress in Improving Diagnosis: A Framework for Defining Undesirable Diagnostic Events.

    Science.gov (United States)

    Olson, Andrew P J; Graber, Mark L; Singh, Hardeep

    2018-01-29

    Diagnostic error is a prevalent, harmful, and costly phenomenon. Multiple national health care and governmental organizations have recently identified the need to improve diagnostic safety as a high priority. A major barrier, however, is the lack of standardized, reliable methods for measuring diagnostic safety. Given the absence of reliable and valid measures for diagnostic errors, we need methods to help establish some type of baseline diagnostic performance across health systems, as well as to enable researchers and health systems to determine the impact of interventions for improving the diagnostic process. Multiple approaches have been suggested but none widely adopted. We propose a new framework for identifying "undesirable diagnostic events" (UDEs) that health systems, professional organizations, and researchers could further define and develop to enable standardized measurement and reporting related to diagnostic safety. We propose an outline for UDEs that identifies both conditions prone to diagnostic error and the contexts of care in which these errors are likely to occur. Refinement and adoption of this framework across health systems can facilitate standardized measurement and reporting of diagnostic safety.

  17. On the undesired frequency chirping in photonic time-stretch systems

    Science.gov (United States)

    Xu, Yuxiao; Chi, Hao; Jin, Tao; Zheng, Shilie; Jin, Xiaofeng; Zhang, Xianmin

    2017-12-01

    The technique of photonic time stretch (PTS) has been intensively investigated in the past decade due to its potential in the acquisition of ultra-high speed signals. The frequency-related RF power fading in the PTS systems with double sideband (DSB) modulation has been well-known, which limits the maximum modulation frequency. Some solutions have been proposed to solve this problem. In this paper, we report another effect, i.e., undesired frequency chirping, which also relates to the performance degradation of PTS systems with DSB modulation, for the first time to our knowledge. Distinct from the nonlinearities caused by nonlinear modulation and square-law photodetection, which is common in radio frequency analog optical links, this frequency chirping originates from the addition of two beating signals with a relative delay after photodetection. A theoretical model for exactly describing the frequency chirping is presented, and is then verified by simulations. Discussion on the method to avoid the frequency chirping is also presented.

  18. Study on Operator Actions during the Occurrences of Undesirable Events in PUSPATI TRIGA Reactor

    International Nuclear Information System (INIS)

    Tom, P.P.; Nurul Husna Zainal Abidin; Lanyau, T.A.; Zaredah Hashim

    2016-01-01

    Due to the recent Fukushima accident, the potential risks at one and only nuclear research reactor in the country, which is the PUSPATI TRIGA Reactor (RTP), has increasingly gain concerns and an attempt on the development of Level 1 Probabilistic Safety Assessment (PSA) for this reactor has been commenced. The preliminary scope of the PSA is to analyse the risk of core degradation during normal daily operation due to the random component failure and human error. SPAR-H and THERP method is used for quantifying human error probability (HEP). However, the scopes of this study only cover the qualitative parts that use interview/questionnaire method. The objectives of the questionnaire are to identify the main action for RTP operators when any undesired incident occurs during full power operation that might be caused by random component failures. From the questionnaires that have been conducted, the respondents consisted of 4 licensed operators and 9 trainee operators. All licensed operators have experience of operating reactor for more than 15 years while the trainee operator have been operate the reactor with experience of less than 10 years. Generally, in the event of an abnormal condition involving the reactor, an operator whether a licensed operator or the trainee does not have to ask permission in advance from the top individuals to carry out scram. This is to prevent the situation becoming increasingly severe if the reactor is still operating. With complete training and knowledge derived from the management, an operator can act efficiently in any emergency case. (author)

  19. When carbon nanotubes encounter the immune system: desirable and undesirable effects.

    Science.gov (United States)

    Dumortier, Hélène

    2013-12-01

    The role of our immune system is to bring efficient protection against invasion by foreign elements, not only pathogens but also any material it may be in contact with. Nanoparticles may enter the body and encounter the immune system either intentionally (e.g. administration for biomedical application) or not (e.g. respiratory occupational exposure). Therefore, it is of fundamental importance to get a thorough knowledge of the way they interact with immune cells and all related consequences. Among nanomaterials, carbon nanotubes (CNTs) are of special interest because of their tremendous field of applications. Consequently, their increasing production, processing and eventual incorporation into new types of composites and/or into biological systems have raised fundamental issues regarding their potential impact on health. This review aims at giving an overview of the known desirable and undesirable effects of CNTs on the immune system, i.e. beneficial modulation of immune cells by CNTs engineered for biomedical applications versus toxicity, inflammation and unwanted immune reactions triggered by CNTs themselves. © 2013 Elsevier B.V. All rights reserved.

  20. Pharmacokinetics of Cannabinoids

    Directory of Open Access Journals (Sweden)

    Iain J McGilveray

    2005-01-01

    Full Text Available Delta-9-tetrahydrocannabinol (Δ-9-THC is the main psychoactive ingredient of cannabis (marijuana. The present review focuses on the pharmacokinetics of THC, but also includes known information for cannabinol and cannabidiol, as well as the synthetic marketed cannabinoids, dronabinol (synthetic THC and nabilone. The variability of THC in plant material (0.3% to 30% leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level of 152±86.3 ng/mL occured approximately 10 min after inhalation. Oral THC, on the other hand, is only 4% to 12% bioavailable and absorption is highly variable. THC is eliminated from plasma in a multiphasic manner, with low amounts detectable for over one week after dosing. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20% and 100% of parent, respectively. THC is widely distributed, particularly to fatty tissues, but less than 1% of an administered dose reaches the brain, while the spleen and body fat are long-term storage sites. The elimination of THC and its many metabolites (from all routes occurs via the feces and urine. Metabolites persist in the urine and feces for severalweeks. Nabilone is well absorbed and the pharmacokinetics, although variable, appear to be linear from oral doses of 1 mg to 4 mg (these doses show a plasma elimination half-life of approximately 2 h. As with THC, there is a high first-pass effect, and the feces to urine ratio of excretion is similar to other cannabinoids. Pharmacokineticpharmacodynamic modelling with plasma THC versus cardiac and psychotropic effects show that after equilibrium is reached, the intensity of effect is proportional to the plasma THC profile. Clinical trials have found that nabilone produces less tachycardia and less euphoria than THC for a similar antiemetic response.

  1. Pharmacokinetics of clomipramine during pregnancy

    NARCIS (Netherlands)

    Ter Horst, P G J; Proost, J H; Smit, J P; Vries, M T; de Jong-van den Berg, Lolkje; Wilffert, B

    2015-01-01

    Clomipramine is one of the drugs for depression during pregnancy; however, pharmacokinetic data of clomipramine and its active metabolite desmethylclomipramine in this vulnerable period are lacking. In this study, we describe clomipramine and desmethylclomipramine concentrations including their

  2. PHARMACOKINETIC RESEARCHES AND PRACTICAL MEDICINE

    Directory of Open Access Journals (Sweden)

    V. G. Belolipetskaya

    2015-12-01

    Full Text Available An article gives in a comprehensive manner the main idea of pharmacokinetics, as the science about rules of substances behavior in the internal environment of the organism, as well as of main parameters of pharmacokinetic researches. The article provides vivid and very  persuasive examples of high practical importance of this science both for creating new medical forms of drugs and for choosing the optimal of therapy regime.

  3. PHARMACOKINETIC RESEARCHES AND PRACTICAL MEDICINE

    Directory of Open Access Journals (Sweden)

    V. G. Belolipetskaya

    2005-01-01

    Full Text Available An article gives in a comprehensive manner the main idea of pharmacokinetics, as the science about rules of substances behavior in the internal environment of the organism, as well as of main parameters of pharmacokinetic researches. The article provides vivid and very  persuasive examples of high practical importance of this science both for creating new medical forms of drugs and for choosing the optimal of therapy regime.

  4. Pharmacokinetics of rilmenidine in healthy subjects

    International Nuclear Information System (INIS)

    Genissel, P.; Bromet, N.; Fourtillan, J.B.; Mignot, A.; Albin, H.

    1988-01-01

    Rilmenidine is a novel alpha 2-adrenoceptor agonist, used in the treatment of mild or moderate hypertension at the oral dose of 1 mg once or twice daily. The pharmacokinetic parameters were investigated after single or repeated administration in healthy subjects, using labeled and unlabeled compounds. Rilmenidine was rapidly and extensively absorbed, with an absolute bioavailability factor close to 1 and a maximal plasma concentration achieved within 2 hours. Rilmenidine was not subject to presystemic metabolism. Distribution was independent of the free fraction because rilmenidine was weakly bound to plasma proteins (less than 10%). The volume of distribution was approximately 5 l.kg-1 (315 liters). Elimination was rapid with a total body plasma clearance of approximately 450 ml.min-1 and an elimination half-life of approximately 8 hours. Renal excretion was the major elimination process (two-thirds of the total clearance). Metabolism was very poor, with a renal elimination of rilmenidine as the parent drug (urinary fraction of rilmenidine was about 65% and no metabolite plasma levels were detected). Linear pharmacokinetics were demonstrated for rilmenidine from 0.5 to 2 mg but, at 3 mg, a slight deviation from linearity was observed. In repeated administration, the linear disposition of rilmenidine with dose was confirmed

  5. Pharmacokinetics of procaterol in thoroughbred horses.

    Science.gov (United States)

    Kusano, K; Nomura, M; Toju, K; Ishikawa, Y; Minamijima, Y; Yamashita, S; Nagata, S

    2016-06-01

    Procaterol (PCR) is a beta-2-adrenergic bronchodilator widely used in Japanese racehorses for treating lower respiratory disease. The pharmacokinetics of PCR following single intravenous (0.5 μg/kg) and oral (2.0 μg/kg) administrations were investigated in six thoroughbred horses. Plasma and urine concentrations of PCR were measured using liquid chromatography-mass spectrometry. Plasma PCR concentration following intravenous administration showed a biphasic elimination pattern. The systemic clearance was 0.47 ± 0.16 L/h/kg, the steady-state volume of the distribution was 1.21 ± 0.23 L/kg, and the elimination half-life was 2.85 ± 1.35 h. Heart rate rapidly increased after intravenous administration and gradually decreased thereafter. A strong correlation between heart rate and plasma concentration of PCR was observed. Plasma concentrations of PCR after oral administration were not quantifiable in all horses. Urine concentrations of PCR following intravenous and oral administrations were quantified in all horses until 32 h after administration. Urine PCR concentrations were not significantly different on and after 24 h between intravenous and oral administrations. These results suggest that the bioavailability of orally administrated PCR in horses is very poor, and the drug was eliminated from the body slowly based on urinary concentrations. This report is the first study to demonstrate the pharmacokinetic character of PCR in thoroughbred horses. © 2015 John Wiley & Sons Ltd.

  6. Size exclusion chromatography of lignin: The mechanistic aspects and elimination of undesired secondary interactions.

    Science.gov (United States)

    Andrianova, Anastasia A; Yeudakimenka, Natallia A; Lilak, Samuel L; Kozliak, Evguenii I; Ugrinov, Angel; Sibi, Mukund P; Kubátová, Alena

    2018-01-26

    Characterization of lignin and its degradation products, more specifically determination of their molecular weight (MW) distribution, is essential for assessment and applications of these potentially renewable phenolics. Several representative gel filtration and gel permeation systems were evaluated in this work focusing on understanding of undesired secondary non-SEC interactions while utilizing four sets of commercially available polymeric standards as well as low-MW lignin model compounds including diarene standards synthesized in-house. The gel permeation column with a nonpolar highly cross-linked porous polystyrene/divinylbenzene-based stationary phase provided the most effective separation by MW for both low and high MW model compounds. Notably, the column with a higher pore and lower particle size provided a better resolution towards polymeric standards, even though the particle size effect was downplayed in the earlier SEC studies of lignin. For two other evaluated gel filtration and gel permeation columns, the separation was strongly affected by functionalities of the analytes and correlated with the compounds' pK a rather than MW. We showed that the separation on the stationary phases featuring polar hydroxyl groups led to specific column-analyte secondary interactions, perhaps based on their hydrogen bonding with lignin. Further, the SEC column evaluation yielded similar results with two sets of chemically different standards. This setup may be used as a general approach to selecting an applicable column for lignin SEC analysis. We confirmed the obtained results with a different independent method implementing a novel approach for lignin number-average MW (M n ) calculation based on laser desorption/ionization time-of-flight mass spectrometry (LDI-TOF-MS) data. The determined M n corroborated the SEC results. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Formation of undesired by-products in deNO{sub x} catalysis by hydrocarbons

    Energy Technology Data Exchange (ETDEWEB)

    Radtke, Frank; Koeppel, Rene A; Baiker, Alfons [Department of Chemical Engineering and Industrial Chemistry, Swiss Federal Institute of Technology, ETH-Zentrum, Zuerich (Switzerland)

    1995-11-20

    The catalytic performance of Cu/ZSM-5 and {gamma}-alumina in the selective catalytic reduction of nitrogen oxides by alkenes in excess oxygen and the formation of potentially harmful by-products such as hydrogen cyanide, cyanic acid, ammonia, nitrous oxide and carbon monoxide have been studied by means of FT-IR-gas phase analysis. Over Cu/ZSM-5 the reduction activity was strongly influenced by the type of hydrocarbon, while there was no significant difference when starting from NO or NO{sub 2}. In contrast, with {gamma}-alumina NO{sub 2} was reduced more efficiently than NO with both reductants. Water addition strongly suppressed the catalytic activity of {gamma}-alumina. Regarding the formation of undesired by-products, substantial amounts of carbon monoxide were observed in all experiments, independently of the feed composition. The type of catalyst, the use of either NO or NO{sub 2}, the alkene used as a reductant and water strongly influenced the formation of other by-products. With alumina ethene showed a lower tendency to form HCN as compared to propene and water addition further suppressed by-product formation. This contrasts the findings with Cu/ZSM-5, where HCN production was not significantly altered by the presence of water. On this catalyst HNCO was found additionally for dry feeds, whereas ammonia appeared in the presence of water in the same temperature range. Under special feed gas compositions further by-products, formaldehyde and hydrocarbons, were found over Cu/ZSM-5, whereas none of these compounds were observed over {gamma}-alumina

  8. The Emperor’s New Clothing: National Responses to “Undesirable and Unreturnable” Aliens under Asylum and Immigration Law

    NARCIS (Netherlands)

    Cantor, David James; van Wijk, J.; Singer, Sarah; Bolhuis, M.P.

    2017-01-01

    The “scandal” of foreign criminals whom our governments cannot send back to their own countries has become something of a tabloid obsession. Yet, while suspected or convicted of serious crimes or considered to pose a danger to society, such “undesirable and unreturnable” aliens equally often

  9. Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice (GCRP)

    DEFF Research Database (Denmark)

    Viby-Mogensen, J.; Østergaard, D.; Donati, F.

    2000-01-01

    Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design......Good Clinical Research Practice (GCRP), neuromuscular blocking agents, pharmacokinetics, pharmacokinetic/pharmacodynamic modeling, population pharmacokinetics, statistics, study design...

  10. Modelling delays in pharmacokinetics

    International Nuclear Information System (INIS)

    Farooqi, Z.H.; Lambrecht, R.M.

    1990-01-01

    Linear system analysis has come to form the backbone of pharmacokinetics. Natural systems usually involve time delays, thus models incorporating them would be an order closer approximation to the real world compared to those that do not. Delays may be modelled in several ways. The approach considered in this study is to have a discrete-time delay dependent rate with the delay respresenting the duration between the entry of a drug into a compartment and its release in some form (may be as a metabolite) from the compartment. Such a delay may be because of one or more of several physiological reasons, like, formation of a reservoir, slow metabolism, or receptor binding. The mathematical structure this gives rise to is a system of delay-differential equations. Examples are given of simple one and two compartment systems with drugs like bumetanide, carbamazepine, and quinolone-caffeine interaction. In these examples generally a good fit is obtained and the suggested models form a good approximation. 21 refs., 6 figs

  11. Clinical pharmacokinetics of phenobarbital in neonates

    NARCIS (Netherlands)

    Touw, D J; Graafland, O; Cranendonk, A; Vermeulen, R J; van Weissenbruch, M M

    2000-01-01

    Demographic and clinical pharmacokinetic data collected from term and preterm neonates who were treated with intravenous phenobarbital have been analysed to evaluate the role of patient characteristics in pharmacokinetic parameters. Significant relationships between total body weight (TBW) or body

  12. Inference in `poor` languages

    Energy Technology Data Exchange (ETDEWEB)

    Petrov, S.

    1996-10-01

    Languages with a solvable implication problem but without complete and consistent systems of inference rules (`poor` languages) are considered. The problem of existence of finite complete and consistent inference rule system for a ``poor`` language is stated independently of the language or rules syntax. Several properties of the problem arc proved. An application of results to the language of join dependencies is given.

  13. Ofloxacin pharmacokinetics in renal failure.

    OpenAIRE

    Fillastre, J P; Leroy, A; Humbert, G

    1987-01-01

    The pharmacokinetics of ofloxacin were investigated in 12 normal subjects and 21 uremic patients after the administration of a single oral 200-mg dose. An open three-compartment body model was used to calculate ofloxacin pharmacokinetic parameters. In healthy subjects, the peak plasma level averaged 2.24 +/- 0.90 micrograms/ml and was obtained at 0.83 +/- 0.31 h. The absorption rate constant was 4.22 +/- 1.64 h-1. The terminal half-life was 7.86 +/- 1.81 h. The apparent volume of distribution...

  14. PHARMACOKINETICS AND PHARMACOKINETIC DYNAMIC RELATIONSHIP OF ROCURONIUM BROMIDE IN HUMANS

    NARCIS (Netherlands)

    WIERDA, JMKH; PROOST, JH; SCHIERE, S; HOMMES, FDM

    The existing human pharmacokinetic studies have been reviewed and compared with data derived from animals. The earliest study confirms the similarity of rocuronium to vecuronium with respect to the variables derived from the plasma concentration decay curves and the proportion excreted renally.

  15. Nanonization strategies for poorly water-soluble drugs.

    Science.gov (United States)

    Chen, Huabing; Khemtong, Chalermchai; Yang, Xiangliang; Chang, Xueling; Gao, Jinming

    2011-04-01

    Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor(®) EL). In this review, several major nanonization techniques that seek to overcome these limitations for drug solubilization are presented. Strategies including drug nanocrystals, nanoemulsions and polymeric micelles are reviewed. Finally, perspectives on existing challenges and future opportunities are highlighted. Published by Elsevier Ltd.

  16. UNDESIRED REACTIONS AT THE UROGRAPHY IN THE CORRELATION OF THE IODIC AND THE NON-TODIC CONTRAST MEDIA

    Directory of Open Access Journals (Sweden)

    Rade R. Babić

    2000-07-01

    Full Text Available The paper analyzes the undesired reactions at 6053 urographies (IVU in thecorrelation of the iodic and the non-iodic contrast media (ICM.Depending on the allergological status the ICM (iodic or non-iodic is chosenfor the sake of carrying out an urographic examination as well as the necessarypremedication measures.The undesired reactions to the TCM are registered in 4,87% (1:20 TVU,namely in 5,6% (1:17 TVU to the iodic and in 2,39% (1:41 IVU to the non-iodicICM.At the intravenous application of the iodic ICM at the IVU the undesiredreactions are registered for2,4 times more often than at the application of the non-iodicICM.

  17. Exploiting the Poor

    DEFF Research Database (Denmark)

    Kamp Justesen, Mogens; Bjørnskov, Christian

    2014-01-01

    While extant research has focused on the causes and consequences of corruption at the macro-level, less effort has been devoted to understanding the micro-foundation of corruption. We argue that poor people are more likely to be victims of corrupt behavior by street-level bureaucrats as the poor...... often rely heavily on services provided by governments. We test this proposition using micro-level survey data from the Afrobaromenter. Multilevel regressions across 18 countries show that poor people are much more prone to experience having to pay bribes to government officials....

  18. Accounting for the Poor

    OpenAIRE

    Robert M. Townsend

    2013-01-01

    Economists and other social scientists have long tried to understand the nature of poverty and how poor people make decisions. For example, T.W. Schultz, a Nobel Laureate, former professor of economics at the University of Chicago, and former president of the American Economic Association, spent his career working in development and agricultural economics. In his 1980 Nobel Prize acceptance speech, Schultz suggests that there is some accounting for the behavior of the poor in agriculture. "Fa...

  19. Evaluation of pharmacokinetics underlies the collaborated usage of lamivudine and oxymatrine in beagle dogs

    Directory of Open Access Journals (Sweden)

    Zhenbao Li

    2016-10-01

    Full Text Available Combinational therapy of lamivudine and oxymatrine has been employed in the battle against hepatitis B virus in clinical setting. However, the pharmacokinetic behavior of the drug or active metabolism in intravenous/oral co-administration regime is poorly investigated. Herein, we evaluated the pharmacokinetic characteristic through a tailor-designed 3 way crossover-Latin square experiment in adult male beagle dogs. Six dogs were randomly treated by intravenous administration of lamivudine (2.5 mg/kg, oxymatrine (15 mg/kg and combinational dosage, named as intravenous regime. Meanwhile the other six dogs were orally administrated with lamivudine (2.5 mg/kg, oxymatrine (15 mg/kg and combinational dosage, named as oral regime. The pharmacokinetic feature in simultaneous oral treatment appeared to have no significant difference when compared with individual administration, even including matrine, the active metabolite of oxymatrine. In intravenous regime, the main pharmacokinetic parameters of simultaneous administration were nearly consistent with intravenous regime remedy. The collaborated application of lamivudine and oxymatrine contributed to non-distinctive pharmacokinetic fluctuations of beagle dogs in intravenous/oral regime, compared with individual employment, which established a vital base for the clinical co-administration against hepatitis B. Furthermore, the present study demonstrated that the determination of pharmacokinetics between combinational and individual therapy might assist in the development of drug compatibility in clinical therapy.

  20. Pharmacokinetics of mitragynine in man

    Directory of Open Access Journals (Sweden)

    Trakulsrichai S

    2015-04-01

    Full Text Available Satariya Trakulsrichai,1,2 Korbtham Sathirakul,3,4 Saranya Auparakkitanon,5 Jatupon Krongvorakul,5 Jetjamnong Sueajai,5 Nantida Noumjad,5 Chonlaphat Sukasem,5 Winai Wananukul2,6 1Department of Emergency Medicine, Faculty of Medicine Ramathibodi Hospital, 2Ramathibodi Poison Center, Faculty of Medicine Ramathibodi Hospital, 3Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 4Center for Drug Research Discovery and Development, Thammasat Univerisity, Prathumthani, Thailand; 5Department of Pathology, Faculty of Medicine Ramathibodi Hospital, 6Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand Background: Kratom, known botanically as Mitragyna speciosa (Korth., is an indigenous tree in Southeast Asia. Kratom is currently easily available worldwide via special shops and the Internet to use as a drug of abuse, opioid alternative, or pain killer. So far, the pharmacokinetics of this plant has been studied only in animals, and there is no such study in humans. The major abundant active alkaloid in Kratom, mitragynine, is one of the promising new chemical substances to be developed as a new drug. The aim of this study was to examine the pharmacokinetics of mitragynine and assess the linearity in pharmacokinetics in chronic users.Methods: Since Kratom is illegal in Thailand, studies in healthy subjects would be unethical. We therefore conducted a prospective study by enrolling ten chronic, regular, healthy users. We adjusted the steady state in each subject by giving a known amount of Kratom tea for 7 days before commencement of the experiment. We admitted and gave different oral doses to subjects to confirm linearity in pharmacokinetics. The mitragynine blood concentrations at 17 times points and the urine concentrations during the 24-hour period were collected and measured by liquid chromatography-tandem mass spectrometry method. Results: Ten male subjects completed

  1. 9. Poor medication

    African Journals Online (AJOL)

    Sitwala

    Majority (60%) of the patients were reviewed at least twice in the last 6 months at the time of the interview. 195 (83%) patients reported that drugs prescribed were not available at the hospital pharmacy, but 186 (79%) of. Factors Associated With Poor Medication Adherence. In Hypertensive Patients In Lusaka, Zambia. 1,4. 1.

  2. Are undesirable contact kinematics minimized after kinematically aligned total knee arthroplasty? An intersurgeon analysis of consecutive patients.

    Science.gov (United States)

    Howell, Stephen M; Hodapp, Esther E; Vernace, Joseph V; Hull, Maury L; Meade, Thomas D

    2013-10-01

    Tibiofemoral contact kinematics or knee implant motions have a direct influence on patient function and implant longevity and should be evaluated for any new alignment technique such as kinematically aligned total knee arthroplasty (TKA). Edge loading of the tibial liner and external rotation (reverse of normal) and adduction of the tibial component on the femoral component are undesirable contact kinematics that should be minimized. Accordingly, this study determined whether the overall prevalence of undesirable contact kinematics during standing, mid kneeling near 90 degrees and full kneeling with kinematically aligned TKA are minimal and not different between groups of consecutive patients treated by different surgeons. Three surgeons were asked to perform cemented, kinematically aligned TKA with patient-specific guides in a consecutive series of patients with their preferred cruciate-retaining (CR) implant. In vivo tibiofemoral contact positions were obtained using a 3- to 2-dimensional image registration technique in 69 subjects (Vanguard CR-TKA N = 22, and Triathlon CR-TKA N = 47). Anterior or posterior edge loading of the tibial liner was not observed. The overall prevalence of external rotation of the tibial component on the femoral component of 6 % was low and not different between surgeons (n.s.). The overall prevalence of adduction of the tibial component on the femoral component of 4 % was low and not different between surgeons (n.s.). Kinematically aligned TKA minimized the undesirable contact kinematics of edge loading of the tibial liner, and external rotation and adduction of the tibial component on the femoral component during standing and kneeling, which suggests an optimistic prognosis for durable long-term function. III.

  3. Heritability of metoprolol and torsemide pharmacokinetics

    DEFF Research Database (Denmark)

    Matthaei, Johannes; Brockmöller, Jürgen; Tzvetkov, Mladen

    2015-01-01

    Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9 and OATP1B1 has been extensively studied. However, it is still unknown how much of variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors....... of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated. This article is protected by copyright. All rights reserved....

  4. Population Pharmacokinetics of Intranasal Scopolamine

    Science.gov (United States)

    Wu, L.; Chow, D. S. L.; Putcha, L.

    2013-01-01

    Introduction: An intranasal gel dosage formulation of scopolamine (INSCOP) was developed for the treatment of Space Motion Sickness (SMS).The bioavailability and pharmacokinetics (PK) was evaluated using data collected in Phase II IND protocols. We reported earlier statistically significant gender differences in PK parameters of INSCOP at a dose level of 0.4 mg. To identify covariates that influence PK parameters of INSCOP, we examined population covariates of INSCOP PK model for 0.4 mg dose. Methods: Plasma scopolamine concentrations versus time data were collected from 20 normal healthy human subjects (11 male/9 female) after a 0.4 mg dose. Phoenix NLME was employed for PK analysis of these data using gender, body weight and age as covariates for model selection. Model selection was based on a likelihood ratio test on the difference of criteria (-2LL). Statistical significance for base model building and individual covariate analysis was set at P less than 0.05{delta(-2LL)=3.84}. Results: A one-compartment pharmacokinetic model with first-order elimination best described INSCOP concentration ]time profiles. Inclusion of gender, body weight and age as covariates individually significantly reduced -2LL by the cut-off value of 3.84(P less than 0.05) when tested against the base model. After the forward stepwise selection and backward elimination steps, gender was selected to add to the final model which had significant influence on absorption rate constant (ka) and the volume of distribution (V) of INSCOP. Conclusion: A population pharmacokinetic model for INSCOP has been identified and gender was a significant contributing covariate for the final model. The volume of distribution and Ka were significantly higher in males than in females which confirm gender-dependent pharmacokinetics of scopolamine after administration of a 0.4 mg dose.

  5. Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients

    NARCIS (Netherlands)

    Yu, Huixin; van Erp, Nielka; Bins, Sander; Mathijssen, Ron H J; Schellens, Jan H M; Beijnen, Jos H.; Steeghs, Neeltje; Huitema, Alwin D R

    Background and Objective: Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients. Methods: Pharmacokinetic data were available from 96

  6. Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients

    NARCIS (Netherlands)

    Yu, H.; Erp, N. van; Bins, S.; Mathijssen, R.H.; Schellens, J.H.; Beijnen, J.H.; Steeghs, N.; Huitema, A.D.

    2017-01-01

    BACKGROUND AND OBJECTIVE: Pazopanib is a multi-targeted anticancer tyrosine kinase inhibitor. This study was conducted to develop a population pharmacokinetic (popPK) model describing the complex pharmacokinetics of pazopanib in cancer patients. METHODS: Pharmacokinetic data were available from 96

  7. Pharmacokinetics of drugs in pregnancy.

    Science.gov (United States)

    Feghali, Maisa; Venkataramanan, Raman; Caritis, Steve

    2015-11-01

    Pregnancy is a complex state where changes in maternal physiology have evolved to favor the development and growth of the placenta and the fetus. These adaptations may affect preexisting disease or result in pregnancy-specific disorders. Similarly, variations in physiology may alter the pharmacokinetics or pharmacodynamics that determines drug dosing and effect. It follows that detailed pharmacologic information is required to adjust therapeutic treatment strategies during pregnancy. Understanding both pregnancy physiology and the gestation-specific pharmacology of different agents is necessary to achieve effective treatment and limit maternal and fetal risk. Unfortunately, most drug studies have excluded pregnant women based on often-mistaken concerns regarding fetal risk. Furthermore, over two-thirds of women receive prescription drugs while pregnant, with treatment and dosing strategies based on data from healthy male volunteers and non-pregnant women, and with little adjustment for the complex physiology of pregnancy and its unique disease states. This review will describe basic concepts in pharmacokinetics and their clinical relevance and highlight the variations in pregnancy that may impact the pharmacokinetic properties of medications. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Influence of diabetes on the pharmacokinetic behavior of natural polyphenols.

    Science.gov (United States)

    Xiao, Jianbo; Högger, Petra

    2014-01-01

    The development of food fortified with polyphenols and polyphenol-rich foods represents a novel approach to prevent or attenuate type 2 diabetes. It has been reported that type 2 diabetes may affect the pharmacokinetics of various drugs in several animal models. There is powerful evidence linking dietary polyphenols consumption with the risk factors defining type 2 diabetes, even if some opposite results occurred. This mini-review summarizes important advances on diabetes-associated changes in pharmacokinetics of natural polyphenols. The pharmacokinetic behavior between drugs and dietary polyphenols probably may be different due to (i) Ingested dose/amount per day. The dietary polyphenol intake per day is much higher than that of clinical drugs; (ii) Complexity of the components. Clinical drugs are well-characterized and typically small molecules. However, the polyphenols in diet are unimaginably complex; (iii) Interaction with food proteins. Although the effects of food proteins on the bioavailability of polyphenols are still not examined in much detail, direct binding interactions of polyphenols to proteins always occur; (iv) The most common polyphenols in the human diet have a low intrinsic activity and are poorly absorbed from the intestine, highly metabolized, or rapidly eliminated. Although there is very limited information available so far, it is proposed that type 2 diabetes influences the pharmacokinetic behavior of dietary polyphenols including: i) competition of glucose with polyphenols regarding binding to plasma proteins; ii) weakened non-covalent interaction affinities of plasma proteins for natural polyphenols due to protein glycation in type II diabetes; iii) the enhanced clearance of polyphenols in type 2 diabetes. An understanding of diabetes-associated changes in absorption, distribution, metabolism, elimination and bioactivities of natural polyphenols as well as the mechanism of the variability should lead to the improvement of the benefits of

  9. Patient acceptability and practical implications of pharmacokinetic studies in patients with advanced cancer.

    Science.gov (United States)

    Dobbs, N A; Twelves, C J; Ramirez, A J; Towlson, K E; Gregory, W M; Richards, M A

    1993-01-01

    We have studied the practical implications and acceptability to patients of pharmacokinetic studies in 34 women receiving anthracyclines for advanced breast cancer. The following parameters were recorded: age, ECOG performance status, psychological state (Rotterdam Symptom Checklist), cytotoxic drug and dose, number of venepunctures for treatment and sampling, and time when the sampling cannula was removed. Immediately after finishing pharmacokinetic sampling, patients completed a questionnaire which revealed that (i) all patients understood sampling was for research, (ii) 35% of patients experienced problems with sampling, (iii) benefits from participation were perceived by 56% of patients. Of 20 patients later questioned after completion of their treatment course, 40% recalled difficulties with blood sampling. Factors identifying in advance those patients who tolerate pharmacokinetic studies poorly were not identified but the number of venepunctures should be minimised. Patients may also perceive benefits from 'non-therapeutic' research.

  10. Savings for the Poor

    OpenAIRE

    Ignacio Mas

    2010-01-01

    This paper reviews the relevance of formal financial services – in particular, savings – to poor people, the economic factors that have hindered the mass-scale delivery of such services in developing countries, and the technology-based opportunities that exist today to make massive gains in financial inclusion. It also highlights the benefits to government from universal financial access, as well as the key policy enablers that would need to be put in place to allow the necessary innovati...

  11. Poorly Differentiated Thyroid Carcinoma.

    Science.gov (United States)

    Setia, Namrata; Barletta, Justine A

    2014-12-01

    Poorly differentiated thyroid carcinoma (PDTC) has been recognized for the past 30 years as an entity showing intermediate differentiation and clinical behavior between well-differentiated thyroid carcinomas (ie, papillary thyroid carcinoma and follicular thyroid carcinoma) and anaplastic thyroid carcinoma; however, there has been considerable controversy around the definition of PDTC. In this review, the evolution in the definition of PDTC, current diagnostic criteria, differential diagnoses, potentially helpful immunohistochemical studies, and molecular alterations are discussed with the aim of highlighting where the diagnosis of PDTC currently stands. Published by Elsevier Inc.

  12. Evaluation of input output efficiency of oil field considering undesirable output —A case study of sandstone reservoir in Xinjiang oilfield

    Science.gov (United States)

    Zhang, Shuying; Wu, Xuquan; Li, Deshan; Xu, Yadong; Song, Shulin

    2017-06-01

    Based on the input and output data of sandstone reservoir in Xinjiang oilfield, the SBM-Undesirable model is used to study the technical efficiency of each block. Results show that: the model of SBM-undesirable to evaluate its efficiency and to avoid defects caused by traditional DEA model radial angle, improve the accuracy of the efficiency evaluation. by analyzing the projection of the oil blocks, we find that each block is in the negative external effects of input redundancy and output deficiency benefit and undesirable output, and there are greater differences in the production efficiency of each block; the way to improve the input-output efficiency of oilfield is to optimize the allocation of resources, reduce the undesirable output and increase the expected output.

  13. Drug Transport and Pharmacokinetics for Chemical Engineers

    Science.gov (United States)

    Simon, Laurent; Kanneganti, Kumud; Kim, Kwang Seok

    2010-01-01

    Experiments in continuous-stirred vessels were proposed to introduce methods in pharmacokinetics and drug transport to chemical engineering students. The activities can be incorporated into the curriculum to illustrate fundamentals learned in the classroom. An appreciation for the role of pharmacokinetics in drug discovery will also be gained…

  14. Negative symbolic aspects in destination branding: exploring the role of the 'undesired self' on web-based vacation information search intentions among potential first-time visitors

    OpenAIRE

    Bosnjak, Michael

    2010-01-01

    Tourist destination choices depend, among other factors, on the match between the destination’s personality image and consumers’ self-concept, in line with self-image congruence theory. Motives also mediate this relationship, yet tourism research largely neglects the influence of avoidance motives. This study applies the product-based construct of undesired congruity, or consumers’ tendency to avoid undesired stereotypical images, to the context of web-based vacation destination information s...

  15. Personalized therapeutics for levofloxacin: a focus on pharmacokinetic concerns.

    Science.gov (United States)

    Gao, Chu-Han; Yu, Lu-Shan; Zeng, Su; Huang, Yu-Wen; Zhou, Quan

    2014-01-01

    Personalized medicine should be encouraged because patients are complex, and this complexity results from biological, medical (eg, demographics, genetics, polypharmacy, and multimorbidities), socioeconomic, and cultural factors. Levofloxacin (LVX) is a broad-spectrum fluoroquinolone antibiotic. Awareness of personalized therapeutics for LVX seems to be poor in clinical practice, and is reflected in prescribing patterns. Pharmacokinetic-pharmacodynamic studies have raised concerns about suboptimal patient outcomes with the use of LVX for some Gram-negative infections. Meanwhile, new findings in LVX therapeutics have only been sporadically reported in recent years. Therefore, an updated review on personalized LVX treatment with a focus on pharmacokinetic concerns is necessary. Relevant literature was identified by performing a PubMed search covering the period from January 1993 to December 2013. We included studies describing dosage adjustment and factors determining LVX pharmacokinetics, or pharmacokinetic-pharmacodynamic studies exploring how best to prevent the emergence of resistance to LVX. The full text of each included article was critically reviewed, and data interpretation was performed. In addition to limiting the use of fluoroquinolones, measures such as reducing the breakpoints for antimicrobial susceptibility testing, choice of high-dose short-course of once-daily LVX regimen, and tailoring LVX dose in special patient populations help to achieve the validated pharmacokinetic-pharmacodynamic target and combat the increasing LVX resistance. Obese individuals with normal renal function cleared LVX more efficiently than normal-weight individuals. Compared with the scenario in healthy subjects, standard 2-hour spacing of calcium formulations and oral LVX was insufficient to prevent a chelation interaction in cystic fibrosis patients. Inconsistent conclusions were derived from studies of the influence of sex on the pharmacokinetics of LVX, which might be

  16. Habitual plate-waste of 6- to 9-year-olds may not be associated with lower nutritional needs or taste acuity, but undesirable dietary factors.

    Science.gov (United States)

    Baik, Ji-Yoon; Lee, Hongmie

    2009-12-01

    Efforts to reduce plate-waste (PW) are limited to those by a dietitian who serves the entire school rather than a better characterization of individuals who are served. We tested the hypothesis that children reporting habitual PW would have different physical or dietary characteristics compared with children without PW. Participants were 407 children aged 6 to 9 years in elementary schools in Kyeonggi, Korea. Information on eating behavior and food preference was collected using a questionnaire administered by parents. Among them, 91 students participated further in anthropometry, step counting, taste acuity tests, and nutrition intake from school lunches. Participants were divided into tertiles according to total frequency of leaving PW from each meal on a typical day: no PW, moderate PW, and habitual PW. Children with habitual PW showed several undesirable characteristics: consuming less of various vegetables, eating only what they like, poor table manners, and frequent consumption of street foods and cookies/beverages/fast foods. Whereas height, weight, and obesity index as well as taste acuity and daily steps in the habitual PW group were not significantly different, intakes of potassium, niacin, and folate were significantly lower compared with the other groups. Therefore, habitual PW did not seem to result from having a lower energy requirement or different taste acuity, or result in observed slowed growth, but it could place children at a risk for insufficient nutritional intake, consequently impairing growth and general health. The results emphasize the parental role in shaping children's diet and provide information for developing strategies to reduce PW of individual children.

  17. Pharmacokinetics of Chinese medicines: strategies and perspectives.

    Science.gov (United States)

    Yan, Ru; Yang, Ying; Chen, Yijia

    2018-01-01

    pharmacokinetic modeling to offer a comprehensive understanding of the PK-PD relationship of CMs. Moreover, validated clinical benefits of CMs and poor translational potential of animal PK data urge more research efforts in human PK study.

  18. Diamagnetic composite material structure for reducing undesired electromagnetic interference and eddy currents in dielectric wall accelerators and other devices

    Science.gov (United States)

    Caporaso, George J.; Poole, Brian R.; Hawkins, Steven A.

    2015-06-30

    The devices, systems and techniques disclosed here can be used to reduce undesired effects by magnetic field induced eddy currents based on a diamagnetic composite material structure including diamagnetic composite sheets that are separated from one another to provide a high impedance composite material structure. In some implementations, each diamagnetic composite sheet includes patterned conductor layers are separated by a dielectric material and each patterned conductor layer includes voids and conductor areas. The voids in the patterned conductor layers of each diamagnetic composite sheet are arranged to be displaced in position from one patterned conductor layer to an adjacent patterned conductor layer while conductor areas of the patterned conductor layers collectively form a contiguous conductor structure in each diamagnetic composite sheet to prevent penetration by a magnetic field.

  19. Nanofluids and chemical highly retentive hydrogels for controlled and selective removal of overpaintings and undesired graffiti from street art.

    Science.gov (United States)

    Giorgi, Rodorico; Baglioni, Michele; Baglioni, Piero

    2017-06-01

    One of the main problems connected to the conservation of street art is the selective removal of overlying undesired graffiti, i.e., drawings and tags. Unfortunately, selective and controlled removal of graffiti and overpaintings from street art is almost unachievable using traditional methodologies. Recently, the use of nanofluids confined in highly retentive pHEMA/PVP semi-interpenetrated polymer networks was proposed. Here, we report on the selective removal of acrylic overpaintings from a layer of acrylic paint on mortar mockups in laboratory tests. The results of the cleaning tests were characterized by visual and photographic observation, optical microscopy, and FT-IR microreflectance investigation. It was shown that this methodology represents a major advancement with respect to the use of nonconfined neat solvents.

  20. [Poor insight and psychosis].

    Science.gov (United States)

    Giotakos, O

    2017-01-01

    A variety of phenomena might be considered as reflecting impaired insight in psychosis, like failure to recognize signs, symptoms or disease, failure to derive appropriate cognitive representations, despite recognition of the disease, and misattribution of the source or cause of the disease. The unawareness of tardive dyskinesia symptoms in schizophrenic patients points that self-awareness deficits in schizophrenia may be domain specific. Poor insight is an independent phenomenological and a prevalent feature in psychotic disorders in general, and in schizophrenia in particular, but we don't know yet if delusions in schizophrenia are the result of an entirely normal attempt to account for abnormal perceptual experiences or a product of abnormal experience but of normal reasoning. The theoretical approaches regarding impaired insight include the disturbed perceptual input, the impaired linkage between thought and emotion and the breakdown of the process of self-monitoring and error checking. The inability to distinguish between internally and externally generated mental events has been described by the metarepresentation theory. This theory includes the awareness of ones' goals, which leads to disorders of willed action, the awareness of intention, which leads to movement disorders, and the awareness of intentions of others, which leads to paranoid delusions. The theory of metarepresentation implies mainly output mechanisms, like the frontal cortex, while the input mechanism implies posterior brain systems, including the parietal lobe. There are many similarities between the disturbances of awareness seen in schizophrenia and those seen as a result of known neurological impairment. Neuropsychological models of impaired insight typically attribute the disturbance to any of a variety of core deficits in the processing of information. In this respect, lack of insight is on conceptual par with alogia, apraxia or aphasia in reflecting disturbed cognitive processing. In

  1. The 'poor man's laryngogram'

    International Nuclear Information System (INIS)

    Bartelt, D.

    1991-01-01

    This paper is reassessment of an old method improved by well-directed application of well-known maneuvers of laryngo-pharyngeal function. Although not as visually attractive as a dedicated laryngogram (now hardly ever requested), it does render similarly reliable diagnostic information, which, supported, as occasionally necessary, by conventional tomography, can even surpass that given by the older technique. Its main advantage lies in providing cheap, quick, noninvasive studies with minimal descomfort for the patient. Should further investigation be necessary, for analysis of deep extension, modern cross-sectional imaging methods (especially MR) far surpass even dedicated laryngography in diagnostic value and can be based adequately on 'poor mans's laryngography'. Ways in which this method may be optimised, especially those involving laryngopharyngeal function, are briefly presented - with emphasis on relevant practical aspects - as are normal and abnormal findings. (orig.) [de

  2. REMO poor man's reanalysis

    Science.gov (United States)

    Ries, H.; Moseley, C.; Haensler, A.

    2012-04-01

    Reanalyses depict the state of the atmosphere as a best fit in space and time of many atmospheric observations in a physically consistent way. By essentially solving the data assimilation problem in a very accurate manner, reanalysis results can be used as reference for model evaluation procedures and as forcing data sets for different model applications. However, the spatial resolution of the most common and accepted reanalysis data sets (e.g. JRA25, ERA-Interim) ranges from approximately 124 km to 80 km. This resolution is too coarse to simulate certain small scale processes often associated with extreme events. In addition, many models need higher resolved forcing data ( e.g. land-surface models, tools for identifying and assessing hydrological extremes). Therefore we downscaled the ERA-Interim reanalysis over the EURO-CORDEX-Domain for the time period 1989 to 2008 to a horizontal resolution of approximately 12 km. The downscaling is performed by nudging REMO-simulations to lower and lateral boundary conditions of the reanalysis, and by re-initializing the model every 24 hours ("REMO in forecast mode"). In this study the three following questions will be addressed: 1.) Does the REMO poor man's reanalysis meet the needs (accuracy, extreme value distribution) in validation and forcing? 2.) What lessons can be learned about the model used for downscaling? As REMO is used as a pure downscaling procedure, any systematic deviations from ERA-Interim result from poor process modelling but not from predictability limitations. 3.) How much small scale information generated by the downscaling model is lost with frequent initializations? A comparison to a simulation that is performed in climate mode will be presented.

  3. Pharmacokinetics and dosimetry, an introduction

    International Nuclear Information System (INIS)

    Notari, R.E.

    1981-01-01

    Classical pharmacokinetic techniques attempt to quantify the time course for drug in the body by assaying samples of blood or urine as a function of time. The mathematical descriptions that have emerged from this approach have proven extremely valuable to both drug research and drug therapy. Since the monitoring of patients' drug blood levels by obtaining a few small blood samples at key times is clinically practical, individualization of dosage regimens has become a reality. This has dramatically altered certain types of drug therapy. These improvements are limited to cases wherein biological response can be related to drug blood levels since the mathematics are capable only of describing the sampled fluids. Non-sampled fluids are considered as additional compartments or pools and described collectively using kinetic equations for mass balance. This limits progress in those areas of research which require assessment of the relationship of specific organ contents to that of the blood. The author suggests that radiopharmaceutical techniques which can provide the time course in specific organs might be coupled with classical pharmacokinetic approaches to provide insight not previously achieved

  4. A comprehensive physiologically based pharmacokinetic ...

    Science.gov (United States)

    Published physiologically based pharmacokinetic (PBPK) models from peer-reviewed articles are often well-parameterized, thoroughly-vetted, and can be utilized as excellent resources for the construction of models pertaining to related chemicals. Specifically, chemical-specific parameters and in vivo pharmacokinetic data used to calibrate these published models can act as valuable starting points for model development of new chemicals with similar molecular structures. A knowledgebase for published PBPK-related articles was compiled to support PBPK model construction for new chemicals based on their close analogues within the knowledgebase, and a web-based interface was developed to allow users to query those close analogues. A list of 689 unique chemicals and their corresponding 1751 articles was created after analysis of 2,245 PBPK-related articles. For each model, the PMID, chemical name, major metabolites, species, gender, life stages and tissue compartments were extracted from the published articles. PaDEL-Descriptor, a Chemistry Development Kit based software, was used to calculate molecular fingerprints. Tanimoto index was implemented in the user interface as measurement of structural similarity. The utility of the PBPK knowledgebase and web-based user interface was demonstrated using two case studies with ethylbenzene and gefitinib. Our PBPK knowledgebase is a novel tool for ranking chemicals based on similarities to other chemicals associated with existi

  5. Pharmacokinetics of metformin during pregnancy.

    Science.gov (United States)

    Eyal, Sara; Easterling, Thomas R; Carr, Darcy; Umans, Jason G; Miodovnik, Menachem; Hankins, Gary D V; Clark, Shannon M; Risler, Linda; Wang, Joanne; Kelly, Edward J; Shen, Danny D; Hebert, Mary F

    2010-05-01

    Our objective was to evaluate the pharmacokinetics of metformin during pregnancy. Serial blood and urine samples were collected over one steady-state dosing interval in women treated with metformin during early to late pregnancy (n = 35) and postpartum (n = 16). Maternal and umbilical cord blood samples were obtained at delivery from 12 women. Metformin concentrations were also determined in breast milk samples obtained over one dosing interval in 6 women. Metformin renal clearance increased significantly in mid (723 +/- 243 ml/min, P pregnancy (625 +/- 130 ml/min, P metformin net secretion clearance (480 +/- 190 ml/min, P pregnancy versus postpartum, respectively. Metformin concentrations at the time of delivery in umbilical cord plasma ranged between nondetectable (metformin through breast milk was 0.13 to 0.28 mg, and the relative infant dose was metformin pharmacokinetics are affected by pregnancy-related changes in renal filtration and net tubular transport and can be roughly estimated by the use of creatinine clearance. At the time of delivery, the fetus is exposed to metformin concentrations from negligible to as high as maternal concentrations. In contrast, infant exposure to metformin through the breast milk is low.

  6. Computational Analysis of Pharmacokinetic Behavior of Ampicillin

    Directory of Open Access Journals (Sweden)

    Mária Ďurišová

    2016-07-01

    Full Text Available orrespondence: Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, 841 04 Bratislava, Slovak Republic. Phone + 42-1254775928; Fax +421254775928; E-mail: maria.durisova@savba.sk 84 RESEARCH ARTICLE The objective of this study was to perform a computational analysis of the pharmacokinetic behavior of ampicillin, using data from the literature. A method based on the theory of dynamic systems was used for modeling purposes. The method used has been introduced to pharmacokinetics with the aim to contribute to the knowledge base in pharmacokinetics by including the modeling method which enables researchers to develop mathematical models of various pharmacokinetic processes in an identical way, using identical model structures. A few examples of a successful use of the modeling method considered here in pharmacokinetics can be found in full texts articles available free of charge at the website of the author, and in the example given in the this study. The modeling method employed in this study can be used to develop a mathematical model of the pharmacokinetic behavior of any drug, under the condition that the pharmacokinetic behavior of the drug under study can be at least partially approximated using linear models.

  7. Children's Perceptions of Hypothetical Peers With Undesirable Characteristics: Role of the Peers' Desire to Change, Source of Effort to Change, and Outcome.

    Science.gov (United States)

    Barnett, Mark A; Sonnentag, Tammy L; Wadian, Taylor W; Jones, Tucker L; Langley, Courtney A

    2015-01-01

    The present study, involving sixth- to eighth-grade students, is an extension of a prior investigation (Barnett, Livengood, Sonnentag, Barlett, & Witham, 2010) that examined children's perceptions of hypothetical peers with various undesirable characteristics. Results indicate that children's perceptions of hypothetical peers with an undesirable characteristic are influenced by the peers' desire to change, the source of effort to change, and the peers' success or failure in changing the characteristic. The children anticipated responding more favorably to peers who were successful in overcoming an undesirable characteristic than peers who were unsuccessful. Regardless of the peers' outcome, the children anticipated responding more favorably to peers who tried to change than peers who relied on the effort of adult authorities to motivate change. The children perceived successful peers as experiencing more positive affect than their unsuccessful counterparts, especially if the success was presented as a fulfillment of the peers' desire to change their undesirable characteristic. Finally, the children's ratings reflected the belief that, among peers who failed to change their undesirable characteristic, lacking the desire to change increases the relative likelihood that the characteristic will be permanent.

  8. Pharmacokinetics of thiamphenicol in dogs.

    Science.gov (United States)

    Castells, G; Intorre, L; Franquelo, C; Cristòfol, C; Pérez, B; Martí, G; Arboix, M

    1998-11-01

    To determine pharmacokinetic parameters of thiamphenicol (TAP) after IV and IM administration in dogs. 6 healthy 2- to 3-year-old male Beagles. IN a crossover design study, 3 dogs were given TAP IV, and 3 dogs were given TAP IM, each at a dosage of 40 mg/kg of body weight. Three weeks later, the same dogs were given a second dose by the opposite route. At preestablished times after TAP administration, blood samples were collected through a catheter placed in the cephalic vein, and TAP concentration was determined by use of a high-performance liquid chromatography. Results-Kinetics of TAP administered IV were fitted by a biexponential equation with a rapid first disposition phase followed by a slower disposition phase. Elimination half-life was short (1.7+/-0.3 hours), volume of distribution at steady state was 0.66+/-0.05 L/kg, and plasma clearance was 5.3+/-0.7 ml/min/kg. After IM administration, absorption was rapid. Peak plasma concentration (25.1+/-10.3 microg/ml) was reached about 45 minutes after drug administration. The apparent elimination half-life after IM administration (5.6+/-4.6 hours) was longer than that after IV administration probably because of the slow absorption rate from the muscle. Mean bioavailability after IM administration was 96+/-7%. The pharmacokinetic profile of TAP in dogs suggests that it may be therapeutically useful against susceptible microorganisms involved in the most common infections in dogs, such as tracheobronchitis, enterocolitis, mastitis, and urinary tract infections.

  9. [Pharmacokinetics of crocetin in rats].

    Science.gov (United States)

    Liu, Tong-zheng; Qian, Zhi-yu

    2002-05-01

    To develop an HPLC method for the determination of crocetin in rat plasma and study the pharmacokinetics in rats. Hypersil C18 column (5 microns, 4.6 mm x 200 mm) was used at column temperature 30 degrees C. The mobile phase consisted of methanol-water-acetic acid (75:24.5:0.5) at the flow rate of 1.0 mL.min-1. The UV detection wave length was 423 nm. The calibration curve was linear (gamma = 0.9996) in the range from 0.49 microgram.mL-1 to 7.87 micrograms.mL-1 for crocetin. The mean recovery was 105.2%. The lowest detectable concentration of crocetin was 0.14 microgram.mL-1 (S/N = 3). The RSDs of within-day and between-day were all less than 5%. The plasma crocetin was steady. The HPLC method of determination of crocetin in the plasma was established. After single dose of 50 mg.kg-1 ig in 10 rats, the main pharmacokinetic parameters were estimated as follows: T1/2 alpha (30 +/- 6) min, Tmax(65 +/- 16) min, Cmax(5.0 +/- 1.0) microgram.mL-1, AUC0-T(845 +/- 109) microgram.min.mL-1, Vd(5.0 +/- 0.8) L.kg-1. Crocetin was shown to be absorbed into the blood through the gastrointestinal tract. This method is quick, precise and reliable. Crocetin was shown to be quickly absorbed in rats.

  10. Individualized Hydrocodone Therapy Based on Phenotype, Pharmacogenetics, and Pharmacokinetic Dosing.

    Science.gov (United States)

    Linares, Oscar A; Fudin, Jeffrey; Daly, Annemarie L; Boston, Raymond C

    2015-12-01

    (1) To quantify hydrocodone (HC) and hydromorphone (HM) metabolite pharmacokinetics with pharmacogenetics in CYP2D6 ultra-rapid metabolizer (UM), extensive metabolizer (EM), and poor metabolizer (PM) metabolizer phenotypes. (2) To develop an HC phenotype-specific dosing strategy for HC that accounts for HM production using clinical pharmacokinetics integrated with pharmacogenetics for patient safety. In silico clinical trial simulation. Healthy white men and women without comorbidities or history of opioid, or any other drug or nutraceutical use, age 26.3±5.7 years (mean±SD; range, 19 to 36 y) and weight 71.9±16.8 kg (range, 50 to 108 kg). CYP2D6 phenotype-specific HC clinical pharmacokinetic parameter estimates and phenotype-specific percentages of HM formed from HC. PMs had lower indices of HC disposition compared with UMs and EMs. Clearance was reduced by nearly 60% and the t1/2 was increased by about 68% compared with EMs. The canonical order for HC clearance was UM>EM>PM. HC elimination mainly by the liver, represented by ke, was reduced about 70% in PM. However, HC's apparent Vd was not significantly different among UMs, EMs, and PM. The canonical order of predicted plasma HM concentrations was UM>EM>PM. For each of the CYP2D6 phenotypes, the mean predicted HM levels were within HM's therapeutic range, which indicates HC has significant phenotype-dependent pro-drug effects. Our results demonstrate that pharmacogenetics afford clinicians an opportunity to individualize HC dosing, while adding enhanced opportunity to account for its conversion to HM in the body.

  11. Glipizide Pharmacokinetics in Healthy and Diabetic Volunteers

    African Journals Online (AJOL)

    Erah

    Purpose: Disease state may contribute to alteration in drug pharmacokinetics. The purpose of .... dependency or drug abuse, known allergy to ... HPLC analysis of glipizide ... months when stored at 4 0C, protected from .... plasma and urine.

  12. Chiral Pesticide Pharmacokinetics: A Range of Values

    Science.gov (United States)

    Approximately 30% of pesticides are chiral and used as mixtures of two or more stereoisomers. In biological systems, these stereoisomers can exhibit significantly different pharmacokinetics (absorption, distribution, metabolism, and elimination). In spite of these differences, th...

  13. Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

    NARCIS (Netherlands)

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

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

  14. Potential conflict between TRIPS and GATT concerning parallel importation of drugs and possible solution to prevent undesirable market segmentation.

    Science.gov (United States)

    Lo, Chang-Fa

    2011-01-01

    From international perspective, parallel importation, especially with respect to drugs, has to do with the exhaustion principle in Article 6 of the TRIPS Agreement and the general exception in Article XX of the GATT 1994. Issues concerning the TRIPS Agreement have been constant topics of discussion. However, parallel importation in relation to the general rules of the GATT 1994 as well as to its exceptions provided in Article XX was not seriously discussed. In the view of the paper, there is a conflict between the provisions in these two agreements. The paper explains such conflict and tries to propose a method of interpretation to resolve the conflict between GATT Article XX and TRIPS Article 6 concerning parallel importation for the purpose of reducing the possible undesirable market segmentation in pharmaceutical sector. The method suggested in the paper is a proper application of good faith principle in the Vienna Convention to interpret GATT Article XX, so that there could be some flexibility for those prohibitions of parallel importation which have positive effect on international trade.

  15. "Should I or shouldn't I?" Imitation of undesired versus allowed actions from peer and adult models by 18- and 24-month-old toddlers.

    Science.gov (United States)

    Seehagen, Sabine; Schneider, Silvia; Miebach, Kristin; Frigge, Katharina; Zmyj, Norbert

    2017-11-01

    Imitation is a common way of acquiring novel behaviors in toddlers. However, little is known about toddlers' imitation of undesired actions. Here we investigated 18- and 24-month-olds' (N=110) imitation of undesired and allowed actions from televised peer and adult models. Permissiveness of the demonstrated actions was indicated by the experimenter's response to their execution (angry or neutral). Analyses revealed that toddlers' imitation scores were higher after demonstrations of allowed versus undesired actions, regardless of the age of the model. In agreement with prior research, these results suggest that third-party reactions to a model's actions can be a powerful cue for toddlers to engage in or refrain from imitation. In the context of the present study, third-party reactions were more influential on imitation than the model's age. Considering the relative influence of different social cues for imitation can help to gain a fuller understanding of early observational learning. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Pharmacokinetics of Botanical Drugs and Plant Extracts.

    Science.gov (United States)

    Dominguez More, Gina Paola; Cardenas, Paola Andrea; Costa, Geison M; Simoes, Claudia M O; Aragon, Diana Marcela

    2017-01-01

    Botanical drugs contain plant extracts, which are complex mixtures of compounds. As with conventional drugs, it is necessary to validate their efficacy and safety through preclinical and clinical studies. However, pharmacokinetic studies for active constituents or characteristic markers in botanical drugs are rare. The objective of this review was to investigate the global state of the art in pharmacokinetic studies of active ingredients present in plant extracts and botanical drugs. A review of pharmacokinetics studies of chemical constituents of plant extracts and botanical drugs was performed, with a total of 135 studies published between January 2004 and February 2015 available in recognized scientific databases. Botanical preparations were mainly found in the form of aqueous extracts of roots and rhizomes. The most widely studied species was Salvia miltiorrhiza Bunge, and the compound most frequently used as a pharmacokinetic marker was berberine. Most studies were performed using the Sprague Dawley rat model, and the preparations were mainly administered orally in a single dose. Quantification of plasma concentrations of pharmacokinetic markers was performed mainly by liquid-liquid extraction, followed by high performance liquid chromatography coupled to mass spectrometry detector. In conclusion, in recent years there has been an increasing interest among researchers worldwide in the study of pharmacokinetics of bioactive compounds in botanical drugs and plant extracts, especially those from the Traditional Chinese Medicine. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Application of Physiologically-Based Pharmacokinetic Modeling for the Prediction of Tofacitinib Exposure in Japanese.

    Science.gov (United States)

    Suzuki, Misaki; Tse, Susanna; Hirai, Midori; Kurebayashi, Yoichi

    2017-05-09

    Tofacitinib (3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3 -oxopropanenitrile) is an oral Janus kinase inhibitor that is approved in countries including Japan and the United States for the treatment of rheumatoid arthritis, and is being developed across the globe for the treatment of inflammatory diseases. In the present study, a physiologically-based pharmacokinetic model was applied to compare the pharmacokinetics of tofacitinib in Japanese and Caucasians to assess the potential impact of ethnicity on the dosing regimen in the two populations. Simulated plasma concentration profiles and pharmacokinetic parameters, i.e. maximum concentration and area under plasma concentration-time curve, in Japanese and Caucasian populations after single or multiple doses of 1 to 30 mg tofacitinib were in agreement with clinically observed data. The similarity in simulated exposure between Japanese and Caucasian populations supports the currently approved dosing regimen in Japan and the United States, where there is no recommendation for dose adjustment according to race. Simulated results for single (1 to 100 mg) or multiple doses (5 mg twice daily) of tofacitinib in extensive and poor metabolizers of CYP2C19, an enzyme which has been shown to contribute in part to tofacitinib elimination and is known to exhibit higher frequency in Japanese compared to Caucasians, were also in support of no recommendation for dose adjustment in CYP2C19 poor metabolizers. This study demonstrated a successful application of physiologically-based pharmacokinetic modeling in evaluating ethnic sensitivity in pharmacokinetics at early stages of development, presenting its potential value as an efficient and scientific method for optimal dose setting in the Japanese population.

  18. The effect of respiratory disorders on clinical pharmacokinetic variables.

    Science.gov (United States)

    Taburet, A M; Tollier, C; Richard, C

    1990-12-01

    Respiratory disorders induce several pathophysiological changes involving gas exchange and acid-base balance, regional haemodynamics, and alterations of the alveolocapillary membrane. The consequences for the absorption, distribution and elimination of drugs are evaluated. Drug absorption after inhalation is not significantly impaired in patients. With drugs administered by this route, an average of 10% of the dose reaches the lungs. It is not completely clear whether changes in pulmonary endothelium in respiratory failure enhance lung absorption. The effects of changes in blood pH on plasma protein binding and volume of distribution are discussed, but relevant data are not available to explain the distribution changes observed in acutely ill patients. Lung diffusion of some antimicrobial agents is enhanced in patients with pulmonary infections. Decreased cardiac output and hepatic blood flow in patients under mechanical ventilation cause an increase in the plasma concentration of drugs with a high hepatic extraction ratio, such as lidocaine (lignocaine). On a theoretical basis, hypoxia should lead to decreased biotransformation of drugs with a low hepatic extraction ratio, but in vivo data with phenazone (antipyrine) or theophylline are conflicting. The effects of disease on the lung clearance of drugs are discussed but clinically relevant data are lacking. The pharmacokinetics of drugs in patients with asthma or chronic obstructive pulmonary disease are reviewed. Stable asthma and chronic obstructive pulmonary disease do not appear to affect the disposition of theophylline or beta 2-agonists such as salbutamol (albuterol) or terbutaline. Important variations in theophylline pharmacokinetics have been reported in critically ill patients, the causes of which are more likely to be linked to the poor condition of the patients than to a direct effect of hypoxia or hypercapnia. Little is known regarding the pharmacokinetics of cromoglycate, ipratropium, corticoids or

  19. Pharmacokinetics of paroxetine, a selective serotonin reuptake inhibitor, in Grey parrots (Psittacus erithacus erithacus): influence of pharmaceutical formulation and length of dosing.

    Science.gov (United States)

    van Zeeland, Y R A; Schoemaker, N J; Haritova, A; Smit, J W; van Maarseveen, E M; Lumeij, J T; Fink-Gremmels, J

    2013-02-01

    Paroxetine, a selective serotonin reuptake inhibitor, may be beneficial in the treatment of behavioural disorders in pet birds. The lack of pharmacokinetic data and clinical trials currently limits the use of this drug in clinical avian practice. This paper evaluates the pharmacokinetic properties and potential side effects of single and repeated dosing of paroxetine in Grey parrots (Psittacus erithacus erithacus). Paroxetine pharmacokinetics were studied after single i.v. and single oral dosing, and after repeated oral administration during 1 month. Plasma paroxetine concentrations were determined by liquid chromatography-tandem mass spectrometry. No undesirable side effects were observed during the study. Pharmacokinetic analysis revealed a quick distribution and rapid elimination after i.v. administration. Oral administration of paroxetine HCl dissolved in water resulted in a relatively slow absorption (T(max)=5.9±2.6 h) and a low bioavailability (31±15%). Repeated administration resulted in higher rate of absorption, most likely due to a saturation of the cytochrome P450-mediated first-pass metabolism. This study shows that oral administration of paroxetine HCl (4 mg/kg twice daily) in parrots results in plasma concentrations within the therapeutic range recommended for the treatment of depressions in humans. Further studies are needed to demonstrate the clinical efficacy of this dosage regimen in parrots with behavioural disorders. © 2012 Blackwell Publishing Ltd.

  20. Personalized therapeutics for levofloxacin: a focus on pharmacokinetic concerns

    Directory of Open Access Journals (Sweden)

    Gao CH

    2014-03-01

    Full Text Available Chu-Han Gao,1 Lu-Shan Yu,2 Su Zeng,2 Yu-Wen Huang,1 Quan Zhou11Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, 2Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of ChinaBackground: Personalized medicine should be encouraged because patients are complex, and this complexity results from biological, medical (eg, demographics, genetics, polypharmacy, and multimorbidities, socioeconomic, and cultural factors. Levofloxacin (LVX is a broad-spectrum fluoroquinolone antibiotic. Awareness of personalized therapeutics for LVX seems to be poor in clinical practice, and is reflected in prescribing patterns. Pharmacokinetic–pharmacodynamic studies have raised concerns about suboptimal patient outcomes with the use of LVX for some Gram-negative infections. Meanwhile, new findings in LVX therapeutics have only been sporadically reported in recent years. Therefore, an updated review on personalized LVX treatment with a focus on pharmacokinetic concerns is necessary.Methods: Relevant literature was identified by performing a PubMed search covering the period from January 1993 to December 2013. We included studies describing dosage adjustment and factors determining LVX pharmacokinetics, or pharmacokinetic–pharmacodynamic studies exploring how best to prevent the emergence of resistance to LVX. The full text of each included article was critically reviewed, and data interpretation was performed.Results: In addition to limiting the use of fluoroquinolones, measures such as reducing the breakpoints for antimicrobial susceptibility testing, choice of high-dose short-course of once-daily LVX regimen, and tailoring LVX dose in special patient populations help to achieve the validated pharmacokinetic–pharmacodynamic target and combat the increasing LVX resistance. Obese individuals with normal renal function cleared LVX

  1. Enhancement of curcumin oral absorption and pharmacokinetics of curcuminoids and curcumin metabolites in mice

    Science.gov (United States)

    Zhongfa, Liu; Chiu, Ming; Wang, Jiang; Chen, Wei; Yen, Winston; Fan-Havard, Patty; Yee, Lisa D.; Chan, Kenneth K.

    2012-01-01

    Purpose Curcumin has shown a variety of biological activity for various human diseases including cancer in preclinical setting. Its poor oral bioavailability poses significant pharmacological barriers to its clinical application. Here, we established a practical nano-emulsion curcumin (NEC) containing up to 20% curcumin (w/w) and conducted the pharmacokinetics of curcuminoids and curcumin metabolites in mice. Methods This high loading NEC was formulated based on the high solubility of curcumin in polyethylene glycols (PEGs) and the synergistic enhancement of curcumin absorption by PEGs and Cremophor EL. The pharmacokinetics of curcuminoids and curcumin metabolites was characterized in mice using a LC–MS/MS method, and the pharmacokinetic parameters were determined using WinNonlin computer software. Results A tenfold increase in the AUC0→24h and more than 40-fold increase in the Cmax in mice were observed after an oral dose of NEC compared with suspension curcumin in 1% methylcellulose. The plasma pharmacokinetics of its two natural congeners, demethoxycurcumin and bisdemethoxycurcumin, and three metabolites, tetrahydrocurcumin (THC), curcumin-O-glucuronide, and curcumin-O-sulfate, was characterized for the first time in mice after an oral dose of NEC. Conclusion This oral absorption enhanced NEC may provide a practical formulation to conduct the correlative study of the PK of curcuminoids and their pharmacodynamics, e.g., hypomethylation activity in vivo. PMID:21968952

  2. Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition.

    Science.gov (United States)

    Yu, Guo; Li, Guo-Fu; Markowitz, John S

    2016-05-01

    Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children (≥6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8-10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed.

  3. Differing disintegration and dissolution rates, pharmacokinetic profiles and gastrointestinal tolerability of over the counter ibuprofen formulations.

    Science.gov (United States)

    Bjarnason, Ingvar; Sancak, Ozgur; Crossley, Anne; Penrose, Andrew; Lanas, Angel

    2018-02-01

    Formulations of over the counter (OTC) NSAIDs differ substantially, but information is lacking on whether this alters their gastrointestinal profiles. To assess disintegration and dissolution rates and pharmacokinetics of four preparations of OTC ibuprofen and relate these with spontaneously reported gastrointestinal adverse events. Disintegration and dissolution rates of ibuprofen tablets as (a) acid, (b) sodium salt, (c) lysine salt, and (d) as a liquid gelatine capsule were assessed. Pharmacokinetic data gastrointestinal and spontaneously reported adverse events arising from global sales were obtained from files from Reckitt Benckiser. Disintegration at low pH was progressively shorter for the preparations from a-to-d with formation of correspondingly smaller ibuprofen crystals, while dissolution was consistently poor. Dissolution at a neutral pH was least rapid for the liquid gelatine capsule. Pharmacokinetic data showed a shorter t max and a higher C max for preparations b-d as compared with ibuprofen acid. Spontaneously reported abdominal symptoms were rare with the liquid gelatine preparation. The formulations of OTC ibuprofen differ in their disintegration and dissolution properties, pharmacokinetic profiles and apparent gastrointestinal tolerability. Spontaneously reported abdominal symptoms were five times lower with the liquid gelatine capsule as compared with ibuprofen acid despite a 30% increase in C max . © 2017 Royal Pharmaceutical Society.

  4. Pharmacokinetics of hederacoside C, an active ingredient in AG NPP709, in rats.

    Science.gov (United States)

    Kim, Ju Myung; Yoon, Ji Na; Jung, Ji Won; Choi, Hye Duck; Shin, Young June; Han, Chang Kyun; Lee, Hye Suk; Kang, Hee Eun

    2013-11-01

    1. Hederacoside C (HDC) is one of the active ingredients in Hedera helix leaf extract (Ivy Ex.) and AG NPP709, a new botanical drug to treat acute respiratory infection and chronic inflammatory bronchitis. However, information regarding its pharmacokinetic properties remains limited. 2. Here, we report the pharmacokinetics of HDC in rats after intravenous administration of HDC (3, 12.5, and 25 mg/kg) and after oral administration of HDC, Ivy Ex., and AG NPP709 (equivalent to 12.5, 25, and 50 mg/kg HDC). 3. Linear pharmacokinetics of HDC were identified upon its intravenous administration at doses of 3-25 mg/kg. Intravenous administration of HDC results in relatively slow clearance (1.46-2.08 mL/min/kg) and a small volume of distribution at steady state (138-222 mL/kg), while oral administration results in a low absolute oral bioavailability (F) of 0.118-0.250%. The extremely low F of HDC may be due to poor absorption of HDC from the gastrointestinal (GI) tract and/or its decomposition therein. 4. The oral pharmacokinetics of HDC did not differ significantly among pure HDC, Ivy Ex., and AG NPP709.

  5. The pharmacokinetic behaviour of hypoxoside taken orally by ...

    African Journals Online (AJOL)

    measured with a high-performance liquid chromatography . method. For the ... the South African Medicines Control Council to conduct a phase I pharmacokinetic and ... The significance of various factors that influence the pharmacokinetic ...

  6. A comparative analysis of China’s regional energy and emission performance: Which is the better way to deal with undesirable outputs?

    International Nuclear Information System (INIS)

    Wang Ke; Wei Yiming; Zhang Xian

    2012-01-01

    Measuring and improving the energy performance with considering emission constraints is an important issue for China’s energy conservation, pollutant emissions reduction and environment protection. This study utilizes several data envelopment analysis (DEA) based models to evaluate the total-factor energy and emission performance of China’s 30 regions within a joint production framework of considering desirable and undesirable outputs as well as separated energy and non-energy inputs. DEA window analysis is applied in this study to deal with cross-sectional and time-varying data, so as to measure the performance during the period of 2000–2009. Two treatments for undesirable outputs are combined with DEA models and the associated indicators for simplex energy performance and unified energy and emission performance measurement are proposed and compared. The evaluation results indicate that the treatment of undesirable outputs transformation is more appropriate for China’s regional energy and emission performance evaluation because it has stronger discriminating power and can provide more reasonable evaluation results that characterize China’s regions. The empirical result shows that east China has the highest and the most balanced energy and emission performance. The energy and emission performance of China remained stable during 2000–2003, decreased slightly during 2004–2006, and has continuously increased since 2007. - Highlights: ► We evaluate China’s regional energy and emission performance using DEA based models. ► We compare two undesirable outputs treatments according to the evaluation results. ► To treat undesirable outputs as inputs has weaker discriminating power in evaluation. ► Simplex energy performance, without environmental factors, is a biased evaluation. ► China’s energy and emission performance is approximately stable during study period.

  7. The Influence of CYP2D6 Phenotype on the Pharmacokinetic Profile of Atomoxetine in Caucasian Healthy Subjects

    Directory of Open Access Journals (Sweden)

    Todor Ioana

    2017-06-01

    Full Text Available Objective: To analyze a potential phenotypic variation within the studied group based on the pharmacokinetic profile of atomoxetine and its active metabolite, and to further investigate the impact of CYP2D6 phenotype on atomoxetine pharmacokinetics. Methods: The study was conducted as an open-label, non-randomized clinical trial which included 43 Caucasian healthy volunteers. Each subject received a single oral dose of atomoxetine 25 mg. Subsequently, atomoxetine and 4-hydroxyatomoxetine-O-glucuronide (glucuronidated active metabolite plasma concentrations were determined and a noncompartmental method was used to calculate the pharmacokinetic parameters of both compounds. Further on, the CYP2D6 metabolic phenotype was assessed using the area under the curve (AUC metabolic ratio (atomoxetine/ 4-hydroxyatomoxetine-O-glucuronide and specific statistical tests (Lilliefors (Kolgomorov-Smirnov and Anderson-Darling test. The phenotypic differences in atomoxetine disposition were identified based on the pharmacokinetic profile of the parent drug and its metabolite. Results: The statistical analysis revealed that the AUC metabolic ratio data set did not follow a normal distribution. As a result, two different phenotypes were identified, respectively the poor metabolizer (PM group which included 3 individuals and the extensive metabolizer (EM group which comprised the remaining 40 subjects. Also, it was demonstrated that the metabolic phenotype significantly influenced atomoxetine pharmacokinetics, as PMs presented a 4.5-fold higher exposure to the parent drug and a 3.2-fold lower exposure to its metabolite in comparison to EMs. Conclusions: The pharmacokinetic and statistical analysis emphasized the existence of 2 metabolic phenotypes: EMs and PMs. Furthermore, it was proved that the interphenotype variability had a marked influence on atomoxetine pharmacokinetic profile.

  8. Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles

    Science.gov (United States)

    Kang, Homan; Mintri, Shrutika; Menon, Archita Venugopal; Lee, Hea Yeon; Choi, Hak Soo; Kim, Jonghan

    2015-11-01

    Nanoparticles (NPs) are considered a promising tool in both diagnosis and therapeutics. Theranostic NPs possess the combined properties of targeted imaging and drug delivery within a single entity. While the categorization of theranostic NPs is based on their structure and composition, the pharmacokinetics of NPs are significantly influenced by the physicochemical properties of theranostic NPs as well as the routes of administration. Consequently, altered pharmacokinetics modify the pharmacodynamic efficacy and toxicity of NPs. Although theranostic NPs hold great promise in nanomedicine and biomedical applications, a lack of understanding persists on the mechanisms of the biodistribution and adverse effects of NPs. To better understand the diagnostic and therapeutic functions of NPs, this review discusses the factors that influence the pharmacokinetics, pharmacodynamics and toxicology of theranostic NPs, along with several strategies for developing novel diagnostic and therapeutic modalities.

  9. An interactive program for pharmacokinetic modeling.

    Science.gov (United States)

    Lu, D R; Mao, F

    1993-05-01

    A computer program, PharmK, was developed for pharmacokinetic modeling of experimental data. The program was written in C computer language based on the high-level user-interface Macintosh operating system. The intention was to provide a user-friendly tool for users of Macintosh computers. An interactive algorithm based on the exponential stripping method is used for the initial parameter estimation. Nonlinear pharmacokinetic model fitting is based on the maximum likelihood estimation method and is performed by the Levenberg-Marquardt method based on chi 2 criterion. Several methods are available to aid the evaluation of the fitting results. Pharmacokinetic data sets have been examined with the PharmK program, and the results are comparable with those obtained with other programs that are currently available for IBM PC-compatible and other types of computers.

  10. Clinical pharmacokinetics of 5-methyltetrahydrohomofolate

    International Nuclear Information System (INIS)

    Loo, T.L.; Jiushi, L.; Lu, K.; Savaraj, N.

    1983-01-01

    DL-N5-Methyltetrahydrohomofolate (MTHHF; NSC-139490; N- [(4-[(2-(2-amino-3,4,5,6,7,8-hexahydro-4-oxo-5-methyl-6- pteridinyl)ethyl) amino) benzoyl)] -L-glutamate), a new folate antagonist of relatively low toxicity, is active against experimental tumor systems resistant to methotrexate and consequently now in clinical trial. We investigated its clinical pharmacokinetics in six patients; four of them received by rapid i.v. infusion tracer doses of [N5-methyl- 14 C]MTHHF ranging from 13 to 16 mg/sq m, and 2 received 150 mg/sq m; the total radioactivity dose was 100 to 200 mu Ci/patient. MTHHF was assayed by radiochemical and chromatographic techniques. The elimination of MTHHF from the plasma followed a triexponential pattern, with a harmonic mean initial half-life of 20.1 min, an intermediary half-life of 4.5 hr, and a terminal half-life of 74.6 hr. The apparent volume of distribution was 1.6 liters/kg, suggesting rapid and extensive tissue binding. This, together with the low total clearance of 0.2 ml/kg/min, contributed to the long half-life of this agent. Although 68% of the administered dose was excreted in the urine on the first day, only an additional 1% was excreted on the ensuing 3 days. In the two patients who received the higher dose, very little MTHHF was found in the cerebrospinal fluid. In concentrations ranging from 25 to 500 micrograms/ml, the drug was about 50% bound to plasma protein. MTHHF was not metabolized in humans as also reported in animals. These results suggest that MTHHF is excreted in the bile to certain extent. Moreover, since it tends to localize and persist in the body, to forestall cumulative toxicity, frequent administration of this agent should be undertaken only with caution

  11. Curcumin as a clinically-promising anti-cancer agent: pharmacokinetics and drug interactions.

    Science.gov (United States)

    Adiwidjaja, Jeffry; McLachlan, Andrew J; Boddy, Alan V

    2017-09-01

    Curcumin has been extensively studied for its anti-cancer properties. While a diverse array of in vitro and preclinical research support the prospect of curcumin use as an anti-cancer therapeutic, most human studies have failed to meet the intended clinical expectation. Poor systemic availability of orally-administered curcumin may account for this disparity. Areas covered: This descriptive review aims to concisely summarise available clinical studies investigating curcumin pharmacokinetics when administered in different formulations. A critical analysis of pharmacokinetic- and pharmacodynamic-based interactions of curcumin with concomitantly administered drugs is also provided. Expert opinion: The encouraging clinical results of curcumin administration are currently limited to people with colorectal cancer, given that sufficient curcumin concentrations persist in colonic mucosa. Higher parent curcumin systemic exposure, which can be achieved by several newer formulations, has important implications for optimal treatment of cancers other than those in gastrointestinal tract. Curcumin-drug pharmacokinetic interactions are also almost exclusively in the enterocytes, owing to extensive first pass metabolism and poor curcumin bioavailability. Greater scope of these interactions, i.e. modulation of the systemic elimination of co-administered drugs, may be expected from more-bioavailable curcumin formulations. Further studies are still warranted, especially with newer formulations to support the inclusion of curcumin in cancer therapy regimens.

  12. Pharmacokinetics of thiamine derivatives especially of benfotiamine.

    Science.gov (United States)

    Loew, D

    1996-02-01

    Pharmacokinetic data of orally administered lipid-soluble thiamine analogues like benfotiamine are reviewed and assessed. It is quite clear that benfotiamine is absorbed much more better than water-soluble thiamine salts: maximum plasma levels of thiamine are about 5 times higher after benfotiamine, the bioavailability is at maximum about 3.6 times as high as that of thiamine hydrochloride and better than other lipophilic thiamine derivates. The physiological activity (alphaETK) increased only after benfotiamine was given. Due to its excellent pharmacokinetic profile benfotiamine should be preferred in treatment of relevant indications.

  13. Isolation, characterization, and in rats plasma pharmacokinetic study of a new triterpenoid saponin from Dianthus superbus.

    Science.gov (United States)

    Ren, Yina; Xu, Xiaobao; Zhang, Qianlan; Lu, Yongzhuang; Li, Ximin; Zhang, Lin; Tian, Jingkui

    2017-02-01

    One new oleanolic acid triterpenoid saponin, 3-O-β-D-glucopyranosyl olean-11, 13(18)-diene-23,28-dioic acid, (hereafter referred to as DS-1) was isolated from the traditional Chinese medicinal plant Dianthus superbus (D. superbus). DS-1 plays an important role in the bioactivity of D. superbus. Thus, a sensitive, reliable and accurate reversed-phased liquid chromatography with tandem mass spectrometry (LC-MS/MS) in negative ion mode was developed and validated for the quantification and pharmacokinetic study of DS-1 in rats plasma. The pharmacokinetic profile showed that DS-1 was rapidly absorbed and eliminated in plasma, indicating that significant accumulation of the compound in biological specimen is unlikely. In addition, poor absorption into systemic circulation was observed after oral administration of DS-1, resulting in low absolute bioavailability (0.92 %).

  14. Pharmacokinetics and pharmacokinetic variability of heroin and its metabolites: review of the literature

    NARCIS (Netherlands)

    Rook, Elisabeth J.; Huitema, Alwin D. R.; van den Brink, Wim; van Ree, Jan M.; Beijnen, Jos H.

    2006-01-01

    This article reviews the pharmacokinetics of heroin after intravenous, oral, intranasal, intramuscular and rectal application and after inhalation in humans, with a special focus on heroin maintenance therapy in heroin dependent patients. In heroin maintenance therapy high doses pharmaceutically

  15. Are the energy poor also income poor? Evidence from India

    International Nuclear Information System (INIS)

    Khandker, Shahidur R.; Barnes, Douglas F.; Samad, Hussain A.

    2012-01-01

    The energy poverty line is defined as the threshold point at which energy consumption begins to rise with increases in household income. This approach is applied to cross-sectional data from a comprehensive 2005 household survey representative of both urban and rural India. The objective is to determine if the energy poor are also income poor and whether and how energy policies help reduce energy poverty, independent of income. The findings suggest that in rural areas some 57% of households are energy poor, versus 22% that are income poor. But in urban areas the energy poverty rate is 28% compared to 20% that are income poor. That is, energy policies are expected to play some roles in mitigating energy poverty. We find that reducing energy poverty requires not only support for rural electrification, but also more use of modern cooking fuels such as LPG. While income growth matters, a combination of energy related programs can play an independent and substantial role in reducing energy poverty. - Highlights: ► This paper applies a new approach to measuring energy poverty to rural and urban India. ► It also compares and contrasts income poverty with energy poverty in the context of India. ► Findings suggest that income poverty tracks energy poverty in urban India, but not in rural India. ► Income growth is very important in reducing energy poverty. ► In addition, access to and reliability of modern sources (electricity, LPG) are also helpful.

  16. Clinical Pharmacokinetics and Pharmacodynamics of Albiglutide

    DEFF Research Database (Denmark)

    Brønden, Andreas; Knop, Filip K; Christensen, Mikkel B

    2017-01-01

    Albiglutide is a long-acting, glucagon-like peptide-1 receptor agonist for subcutaneous administration with a recommended dose of 30-50 mg once weekly. The aim of this article is to outline the pharmacokinetic and pharmacodynamic properties of albiglutide including the clinical efficacy and safet...

  17. Glipizide Pharmacokinetics in Healthy and Diabetic Volunteers

    African Journals Online (AJOL)

    Erah

    Purpose: Disease state may contribute to alteration in drug pharmacokinetics. The purpose of this study was to determine the effect of non-insulin dependent diabetes mellitus (NIDDM) on the ... assayed using a sensitive and validated reverse phase high performance liquid ..... factors may contribute to these variations. [17].

  18. Pharmacological activities and pharmacokinetic study of hyperoside ...

    African Journals Online (AJOL)

    Studies on its pharmacokinetic (PK) properties revealed that it is a stable compound ... attention in drug discovery and food supplement research ... neurotrophic factor (BDNF) and cAMP response element ... antidepressant effect of hyperoside is mediated through .... Saposhnikovia divaricata by high performance counter-.

  19. The role of pharmacokinetics in risk assessment

    International Nuclear Information System (INIS)

    Reitz, R.H.; Fox, T.R.; Watanabe, P.G.

    1986-01-01

    Pharmacokinetics can aid in the formulation of risk estimations by selection of doses for toxicity studies, by distinguishing between ''internal dose or toxifor concentration'' and ''applied dose,'' by providing a physiological basis for extrapolating between species, and by helping us to visualize the toxicological consequences of processes which we cannot quantify. 10 refs., 6 figs., 2 tabs

  20. Human pharmacokinetics of proguanil and its metabolites

    DEFF Research Database (Denmark)

    Bygbjerg, Ib Christian; Ravn, P; Rønn, A

    1987-01-01

    The pharmacokinetics of proguanil and its metabolites cycloguanil and p-chlorophenylbiguanide were studied in five healthy volunteers taking 200 mg orally for 14 days. A highly sensitive and specific high-performance liquid chromatographic assay was applied, clearly identifying all three compounds...

  1. Circadian variation in the pharmacokinetics of verapamil

    DEFF Research Database (Denmark)

    Jespersen, C M; Frederiksen, M; Hansen, J F

    1989-01-01

    greater bioavailability (AUC) and a prolonged time to peak concentration was found. During the night (24.00 h-06.00 h) the half-life of verapamil was significantly longer than during the day (16.00 h-22.00 h). These differences in pharmacokinetics may be due to reduced hepatic blood flow at night...

  2. [Impact of ECMO on drugs pharmacokinetics].

    Science.gov (United States)

    Hasni, Nesrine; Lemaitre, Florian; Fernandez, Christine; Combes, Alain; Farinotti, Robert

    2011-01-01

    Extracorporeal membrane oxygenation (ECMO) is a life support system used in the treatment of patients of all ages with severe respiratory or cardiorespiratory failure. Despite the intensive use of drugs in the treatment of patients on ECMO, few studies have been conducted to determine the impact of this device on the pharmacokinetics of drugs. Publications in this field have shown pharmacokinetics changes resulting in an increase in volume of distribution of drugs and/or decreased clearance with consequent increase of their half-life. Reduced plasma concentrations of some drugs due to their adsorption on the different components of the circuit further complicates the determination of pharmacokinetic parameters of patients treated by ECMO. The literature published up to now on the pharmacokinetic changes associated with ECMO provide preliminary support for dosage adjustment. However, more research is needed to identify dosage strategies for this patient population. © 2011 Société Française de Pharmacologie et de Thérapeutique.

  3. Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with Down syndrome and acute lymphoblastic leukemia

    NARCIS (Netherlands)

    Buitenkamp, Trudy D.; Mathôt, Ron A. A.; de Haas, Valerie; Pieters, Rob; Zwaan, C. Michel

    2010-01-01

    Children with Down syndrome have an increased risk of developing acute lymphoblastic leukemia and a poor tolerance of methotrexate. This latter problem is assumed to be caused by a higher cellular sensitivity of tissues in children with Down syndrome. However, whether differences in pharmacokinetics

  4. Investigation on Strengthening Approaches Adopted for Poorly Detailed RC Corbels

    Directory of Open Access Journals (Sweden)

    Ram Chandra Neupane

    2017-05-01

    Full Text Available Poor detailing of the position of bearing pad over reinforced concrete (RC corbel may lead to premature failure, which is undesired and structurally vulnerable. An appropriate retrofitting solution is necessary to ensure the functionality of such RC corbels. Considering the growing popularity of external carbon fiber-reinforced polymer (CFRP in retrofitting, this research examines the effectiveness of an externally wrapped unidirectional CFRP sheet and compares its performance against traditional retrofitting methods. Moreover, it is intended to fulfill the lack of extensive research on external CFRP application for corbel strengthening. A total of eight medium-scale corbel specimens were tested on vertical load. Observed premature failure due to placing the bearing pad near the edge of corbel was verified and the effectiveness of the proposed structural strengthening solutions was studied. Experimental results show that although the loading capacity of the damaged corbel due to the poor detailing of bearing pad position could not be fully recovered, the external CFRP wrapping method demonstrated superior performance over RC jacketing and was able to prevent localized failure. Further study based on non-linear 3D finite element analysis (FEA was carried out to identify the governing parameters of each retrofitting solution. Numerical studies suggested important parameters of various retrofitting alternatives for higher capacity assurance.

  5. Use of nanotechnology for improved pharmacokinetics and activity of immunogenic cell death inducers used in cancer chemotherapy.

    Science.gov (United States)

    Janicka, Martyna; Gubernator, Jerzy

    2017-09-01

    Immunogenic cell death inducers (ICD inducers) are a diverse group of therapeutic molecules capable of eliciting an adaptive immune response against the antigens present on the surface of dying cancer cells. Most of these molecules suffer from low bioavailability, high toxicity and poor pharmacokinetics which limit their application. It is believed that nanotechnology, in particular nano-sized nanocarriers, can address most of the issues that limit the use of ICD inducers. Area covered: The mechanism of action of ICD inducers and their limitations is discussed. In addition, we cover the novel possibilities arising from the use of nanotechnology to improve delivery of ICD inducers to the target tissue as well as the restrictions of modern nanotechnology. Expert opinion: At present, nanocarrier formulations suffer from low bioavailability, poor pharmacokinetics and stability issues. Nonetheless, there is a tremendous future for combinatorial immune-pharmacological treatments of human tumors based on nanocarrier delivery of ICD inducers.

  6. Efficient CRISPR-Cas9-mediated generation of knockin human pluripotent stem cells lacking undesired mutations at the targeted locus.

    Science.gov (United States)

    Merkle, Florian T; Neuhausser, Werner M; Santos, David; Valen, Eivind; Gagnon, James A; Maas, Kristi; Sandoe, Jackson; Schier, Alexander F; Eggan, Kevin

    2015-05-12

    The CRISPR-Cas9 system has the potential to revolutionize genome editing in human pluripotent stem cells (hPSCs), but its advantages and pitfalls are still poorly understood. We systematically tested the ability of CRISPR-Cas9 to mediate reporter gene knockin at 16 distinct genomic sites in hPSCs. We observed efficient gene targeting but found that targeted clones carried an unexpectedly high frequency of insertion and deletion (indel) mutations at both alleles of the targeted gene. These indels were induced by Cas9 nuclease, as well as Cas9-D10A single or dual nickases, and often disrupted gene function. To overcome this problem, we designed strategies to physically destroy or separate CRISPR target sites at the targeted allele and developed a bioinformatic pipeline to identify and eliminate clones harboring deleterious indels at the other allele. This two-pronged approach enables the reliable generation of knockin hPSC reporter cell lines free of unwanted mutations at the targeted locus. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  7. A Review on Pharmacokinetic Modeling and the Effects of Environmental Stressors on Pharmacokinetics for Operational Medicine: Operational Pharmacokinetics

    Science.gov (United States)

    2009-09-01

    Manning et al. 1986), which may cause physiological changes. For example, emotional distress may lead to elevated heart rate, blood pressure and...related changes in renal functions were reported during a Stroop word color conflict test (Fauvel, Hadj-Aissa et al. 1991). Emotional stressors could...M. Skee, et al. (2001). "Pharmacokinetics of norelgestromin and ethinyl estradiol delivered by a contraceptive patch (Ortho Evra (TM)/Evra (TM

  8. Population pharmacokinetics of proguanil in patients with acute P. falciparum malaria after combined therapy with atovaquone.

    Science.gov (United States)

    Hussein, Z; Eaves, C J; Hutchinson, D B; Canfield, C J

    1996-11-01

    1. The pharmacokinetics of proguanil were evaluated in patients with acute P. falciparum malaria receiving concomitantly proguanil hydrochloride and atovaquone. The population consisted of 203 Blacks, 112 Orientals and 55 Malays; 274 males and 96 females. Of the 370 patients, 114 and 256 patients were classified as 'poor' and 'extensive' metabolizers of proguanil, respectively. Body weight and age ranged between 11-110 kg and 3-65 years, respectively. 2. A one compartment model with first-order absorption and elimination was fitted to proguanil plasma concentration-time profiles, using non-linear mixed effect modelling (NONMEM). 3. Oral clearance (CLo) showed a 0.785 power relationship with body weight and was 13% higher in Orientals than Blacks and Malays and 17% lower in 'poor' than 'extensive' metabolizers. According to the mean weight of each population, the final population estimates of CLo in Blacks, Orientals and Malays who are 'extensive' metabolizers were 54.0, 61.5 and 64.3 l h-1, respectively. Age, gender and dose had no significant effects on CLo. 4. Apparent volume of distribution (V/F) showed a 0.88 power relationship with body weight. The final population estimates were 562 and 1629 l in children ( 15 years, respectively, who had a mean body weight of 22.6 and 54.8 kg, respectively. The effect of other covariates on V/F was not examined. 5. The final magnitudes of interpatient variability in CLo and V/F were relatively low at 22.5 and 17.0%, respectively. 6. Population pharmacokinetic parameter estimates in Black, Oriental and Malay patients with acute P. falciparum malaria are in good agreement with results of pharmacokinetic studies in healthy Caucasian volunteers. In view of the 30-50% residual variability in proguanil plasma concentrations, the slight effects of Orientals and 'poor' metabolizers on CLo are unlikely to be clinically significant. Hence, dose recommendation will be solely based on body weight.

  9. Pharmacokinetic profile of phytoconstituent(s isolated from medicinal plants—A comprehensive review

    Directory of Open Access Journals (Sweden)

    Piyush Mehta

    2015-10-01

    Full Text Available Herbal medicine, the backbone of traditional medicine, has played an important role in human health and welfare for a long period. Traditional therapeutic approaches of regional significance are found in Africa, South and Central America, China, India, Tibet, Indonesia, and the Pacific Islands. The considerable scientific significance and commercial potential of traditional medicines have resulted in increased international attention and global market demands for herbal medicines, especially Chinese herbal medicines. Herbal medicines currently are the primary form of health care for the poor in the developing countries, and also are widely used as a supplement or substitute for conventional drugs in developed countries. These traditional medicines have a pivotal role in the treatment of various ailments and more than 50% of drugs used in Western pharmacopoeia are isolated from herbs or derived from modifications of chemicals found in plants. Herbal medicines usually contain a complex mixture of various bioactive molecules, which make its standardization complicated, and there is little information about all compounds responsible for pharmacological activity. Several research papers have been published that claim pharmacological activity of herbal medicines but few are discussing the role of the exact phytoconstituent. Understanding the pharmacokinetic profile of such phytoconstituents is essential. Although there are research papers that deal with pharmacokinetic properties of phytoconstituents, there are a number of phytoconstituents yet to be explored for their kinetic properties. This article reviews the pharmacokinetic profile of 50 different therapeutically effective traditional medicinal plants from the year 2003 onward.

  10. Pharmacokinetics of dietary kaempferol and its metabolite 4-hydroxyphenylacetic acid in rats.

    Science.gov (United States)

    Zabela, Volha; Sampath, Chethan; Oufir, Mouhssin; Moradi-Afrapoli, Fahimeh; Butterweck, Veronika; Hamburger, Matthias

    2016-12-01

    Kaempferol is a major flavonoid in the human diet and in medicinal plants. The compound exerts anxiolytic activity when administered orally in mice, while no behavioural changes were observed upon intraperitoneal administration, or upon oral administration in gut sterilized animals. 4-Hydroxyphenylacetic acid (4-HPAA), which possesses anxiolytic effects when administered intraperitoneally, is a major intestinal metabolite of kaempferol. Pharmacokinetic properties of the compounds are currently not clear. UHPLC-MS/MS methods were validated to support pharmacokinetic studies of kaempferol and 4-HPAA in rats. Non-compartmental and compartmental analyses were performed. After intravenous administration, kaempferol followed a one-compartment model, with a rapid clearance (4.40-6.44l/h/kg) and an extremely short half-life of 2.93-3.79min. After oral gavage it was not possible to obtain full plasma concentration-time profiles of kaempferol. Pharmacokinetics of 4-HPAA was characterized by a two-compartment model, consisting of a quick distribution phase (half-life 3.04-6.20min) followed by a fast elimination phase (half-life 19.3-21.1min). Plasma exposure of kaempferol is limited by poor oral bioavailability and extensive metabolism. Both compounds are rapidly eliminated, so that effective concentrations at the site of action do not appear to be reached. At present, it is not clear how the anxiolytic-like effects reported for the compounds can be explained. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Comparison of Dapivirine Vaginal Gel and Film Formulation Pharmacokinetics and Pharmacodynamics (FAME 02B).

    Science.gov (United States)

    Robinson, Jennifer A; Marzinke, Mark A; Bakshi, Rahul P; Fuchs, Edward J; Radebaugh, Christine L; Aung, Wutyi; Spiegel, Hans M L; Coleman, Jenell S; Rohan, Lisa C; Hendrix, Craig W

    2017-04-01

    While preexposure prophylaxis with oral tenofovir/emtricitabine reduces HIV acquisition rates, poor adherence to and acceptability of vaginal gels and the potential for evolving drug resistance have led to development of vaginal film formulations and other antiretroviral drugs, respectively, including the non-nucleoside reverse transcriptase inhibitor dapivirine. In this two-arm crossover study of a novel fast-dissolving dapivirine film and a previously studied semisolid dapivirine gel, 10 healthy women received a single 1.25 mg vaginal dose of each study product; one withdrew after the first dose. Clinical, pharmacokinetic, and antiviral pharmacodynamic assessments (ex vivo HIV-BaL challenge of tissue explants) were performed over 168 h postdose. Six of ten participants experienced mild to moderate adverse effects, similar between products, with no severe adverse events or adverse events attributed to study products. There were no statistically significant differences in plasma, cervicovaginal fluid (CVF), or cervical tissue dapivirine concentrations between the gel and film (all p > .05). CVF dapivirine concentrations were 1.5 and 6 log 10 greater than tissue and plasma concentrations, respectively (p dapivirine film and gel performed similarly in terms of tolerability, pharmacokinetics, and antiviral effect. Dapivirine film may provide an alternative to pharmacokinetically comparable dapivirine gel formulations. Effectiveness remains to be tested.

  12. Sirolimus formulation with improved pharmacokinetic properties produced by a continuous flow method.

    Science.gov (United States)

    Solymosi, Tamás; Angi, Réka; Basa-Dénes, Orsolya; Ránky, Soma; Ötvös, Zsolt; Glavinas, Hristos; Filipcsei, Genovéva; Heltovics, Gábor

    2015-08-01

    The oral bioavailability of Sirolimus is limited by poor dissolution of the compound in the gastrointestinal tract resulting in a low bioavailability and large inter-individual differences in blood levels. Several different formulation approaches were applied to overcome these disadvantageous pharmacokinetic properties including the marketed oral solution and a tablet form containing wet milled nanocrystals. These approaches deliver improved pharmacokinetics, yet, they share the characteristics of complex production method and composition. We have developed a nanostructured Sirolimus formulation prepared by the controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. We have shown that contrary to the batch production the process could be easily intensified and scaled up; apparently the uniformity of the precipitation is heavily dependent on the production parameters, most likely the mixing of the solvent and antisolvent. We compared the physicochemical and pharmacokinetic properties of the nanostructured formula with the marketed nanoformula. We found that our method produces particles in the size range of less than 100nm. The solid form redispersed instantaneously in water and in biorelevant media. Both the solid form and the redispersed colloid solution showed excellent stability even in accelerated test conditions. The oral administration of the nanostructured formula resulted in faster absorption, higher exposure and higher trough concentrations when compared to the marked form. These advantageous properties could allow the development of solid oral Sirolimus formulae with lower strength and gel based topical delivery systems. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. PHARMACOKINETICS OF PIROXICAM IN CRANES (FAMILY GRUIDAE).

    Science.gov (United States)

    Keiper, Naomi L; Cox, Sherry K; Doss, Grayson A; Elsmo, Betsy; Franzen-Klein, Dana; Hartup, Barry K

    2017-09-01

    To investigate the pharmacokinetics of the nonsteroidal anti-inflammatory drug (NSAID) piroxicam in cranes, three brolgas (Antigone rubicunda) were administered piroxicam as a single oral dose at 0.5 mg/kg and 1.0 mg/kg during separate trials. Serial blood samples were collected for quantification of piroxicam in plasma. Piroxicam was readily absorbed at both dosages, and no adverse effects were observed. Plasma concentrations peaked at 3.67 hr with a concentration of 4.00 μg/ml for the lower dosage, and at 0.83 hr at 8.77 μg/ml for the higher dosage. Piroxicam may exhibit linear kinetics and dose proportionality in brolgas, but will require further study. Mean peak plasma concentrations in brolgas were comparable to concentrations demonstrated to be analgesic in humans. To the authors' knowledge, this study represents the first pharmacokinetic investigation of piroxicam in an avian species.

  14. Tubocurarine and pancuronium: a pharmacokinetic view.

    Science.gov (United States)

    Shanks, C A; Somogyi, A A; Ramzan, M I; Triggs, E J

    1980-02-01

    This review is an attempt to bring together the pharmacokinetic data on d-tubocurarine and pancuronium with clinical observations on relaxant dosage and effect. The modelling techniques used here represent an oversimplification of the relationships between relaxant plasma concentration and response as they do not predict either the time of onset of paralysis or its peak intensity. However, they do enable calculation of a bolus dose of relaxant required to achieve a particular intensity of paralysis for the average patient once pseudo-distribution equilibrium has been achieved. This has been further extended to predict the cumulation of the relaxants with subsequent dosage in average patients. Suggested regimens incorporating bolus and infusion doses of the relaxants to achieve continuous neuromuscular blockade have been calculated also. Averaged pharmacokinetic parameters derived from patients with renal or hepatic dysfunction have been used to predict the likely duration and intensities of paralysis for the relaxants.

  15. Clinical Pharmacology and Pharmacokinetics of Levetiracetam

    Directory of Open Access Journals (Sweden)

    Chanin Clark Wright

    2013-12-01

    Full Text Available Status epilepticus and acute repetitive seizures still pose a management challenge despite the recent advances in the field of epilepsy. Parenteral formulations of old anticonvulsants are still a cornerstone in acute seizure management and are approved by the FDA. Intravenous levetiracetam, a second generation anticonvulsant, is approved by the FDA as an adjunctive treatment in patients 16 years or older when oral administration is not available. Data have shown that it has a unique mechanism of action, linear pharmacokinetics and no known drug interactions with other anticonvulsants. In this paper, we will review the current literature about the pharmacology and pharmacokinetics of intravenous levetiracetam and the safety profile of this new anticonvulsant in acute seizure management of both adults and children.

  16. [Feasibility, in general practice, to give to the patients clear, loyal and appropriate information about the undesirable side effects of the medicines prescribed. EICLAT study].

    Science.gov (United States)

    Arnould, Pascale; Raineri, François; Hebbrecht, Gilles; Duhot, Didier

    2011-12-01

    Drug prescription in general practice is present in 78 to 83% of consultations; practitioners must give to their patient clear loyal and appropriate information about the undesirable side effects of the medicines prescribed. The object of the EICLAT study was to give some light on the feasibility to respect this obligation. To that effect the study evaluates, for a normal prescription activity, the average number of potential undesirable side effects (USE) in relation with the number of lines of different medicines prescribed in each doctor's prescription. A total of 8,382 doctor's prescriptions, generating 34,427 lines of prescriptions given by 175 general practitioners, were analysed. Amongst these prescriptions, 11% included only one line, 55% from 2 to 4 lines and 34% 5 lines or more. The average doctor's prescription was of 4 lines of medicines generating 407 potential USE, of which 194 were different (the same undesirable effect may be present twice or more in the same doctor's prescription), and 293 frequent or serious potential USE, of which 166 were different. The patent medicines with a major or important added medical value (AMV), present in 7,840 doctor's prescriptions for a total of 24,127 lines exposed the patient, in the average, to 151 frequent or serious USE different. The patent medicines with an insufficient AMV, present in 2,292 prescriptions for a total of 3,887 lines, exposed the patient to 37 frequent and/or serious potential USE. Supposing that the information provided by the legal authority is sufficiently adequate, precise and exhaustive, the volume of information that must be given to the patient is not compatible with the present conditions of exercise of the profession.

  17. The pharmacokinetics of the interstitial space in humans

    OpenAIRE

    Levitt, David G

    2003-01-01

    Background The pharmacokinetics of extracellular solutes is determined by the blood-tissue exchange kinetics and the volume of distribution in the interstitial space in the different organs. This information can be used to develop a general physiologically based pharmacokinetic (PBPK) model applicable to most extracellular solutes. Methods The human pharmacokinetic literature was surveyed to tabulate the steady state and equilibrium volume of distribution of the solutes mannitol, EDTA, morphi...

  18. Preparation and ocular pharmacokinetics of ganciclovir liposomes

    OpenAIRE

    Shen, Yan; Tu, Jiasheng

    2007-01-01

    Ophthalmic liposomes of ganciclovir (GCV) were prepared by the reverse phase evaporation method, and their ocular pharmacokinetics in albino rabbits were compared with those obtained after dosing with GCV solution. The in vitro transcorneal permeability of GCV liposomes was found to be 3.9-fold higher than that of the solution. After in vivo instillation in albino rabbits, no difference was found in the precorneal elimination rate of GCV from liposome vs solution dosing. The aqueous humor con...

  19. Perioperative pharmacokinetics of methadone in adolescents.

    Science.gov (United States)

    Sharma, Anshuman; Tallchief, Danielle; Blood, Jane; Kim, Thomas; London, Amy; Kharasch, Evan D

    2011-12-01

    Methadone is frequently administered to adults experiencing anesthesia and receiving pain treatment. Methadone pharmacokinetics in adults are well characterized, including the perioperative period. Methadone is also used in children. There is, however, no information on methadone pharmacokinetics in children of any age. The purpose of this investigation was to determine the pharmacokinetics of intravenous methadone in children undergoing surgery. Perioperative opioid-sparing effects were also assessed. Eligible subjects were children 5-18 yr undergoing general anesthesia and surgery, with an anticipated postoperative inpatient stay exceeding 3 days. Three groups of 10 to 11 patients each received intravenous methadone hydrochloride after anesthetic induction in ascending dose groups of 0.1, 0.2, and 0.3 mg/kg (up to 20 mg). Anesthetic care was not otherwise changed. Venous blood was obtained for 4 days, for stereoselective determination of methadone and metabolites. Pain assessments were made each morning. Daily and total opioid consumption was determined. Perioperative opioid consumption and pain was determined in a second cohort, which was matched to age, sex, race, ethnicity, surgical procedure, and length of stay, but not receiving methadone. The final methadone study cohort was 31 adolescents (14 ± 2 yr, range 10-18) undergoing major spine surgery for a diagnosis of scoliosis. Methadone pharmacokinetics were linear over the dose range 0.1-0.3 mg/kg. Disposition was stereoselective. Methadone administration did not dose-dependently affect postoperative pain scores, and did not dose-dependently decrease daily or total postoperative opioid consumption in spinal fusion patients. Methadone enantiomer disposition in adolescents undergoing surgery was similar to that in healthy adults.

  20. Commercial Bank Efficiency Evaluation in Consideration of the Undesirable Output and Its Link with Stakeholders Relationship: An Application of China’s Commercial Banks

    Directory of Open Access Journals (Sweden)

    Jianyue Ji

    2014-01-01

    Full Text Available Based on the modern contract theory, expectancy theory, and stakeholder theory, this paper analyzes how stakeholders relationship influences the efficiency of commercial banks and finds that the efficiency is a function of stakeholders relationship. A DEA model with Seiford's linear transformation function is developed to evaluate the efficiency in consideration of the undesirable output. The panel Tobit model is established to conduct empirical research with data of 14 Chinese commercial banks from 2004 to 2012. The study finds that except for business customer relation, stakeholder relationship is the key variable that influences comprehensive efficiency of commercial banks.

  1. Pharmacokinetics of linezolid in critically ill patients.

    Science.gov (United States)

    Sazdanovic, Predrag; Jankovic, Slobodan M; Kostic, Marina; Dimitrijevic, Aleksandra; Stefanovic, Srdjan

    2016-06-01

    Linezolid is an oxazolidinone antibiotic active against Gram-positive bacteria, and is most commonly used to treat life-threatening infections in critically ill patients. The pharmacokinetics of linezolid are profoundly altered in critically ill patients, partly due to decreased function of vital organs, and partly because life-sustaining drugs and devices may change the extent of its excretion. This article is summarizes key changes in the pharmacokinetics of linezolid in critically ill patients. The changes summarized are clinically relevant and may serve as rationale for dosing recommendations in this particular population. While absorption and penetration of linezolid to tissues are not significantly changed in critically ill patients, protein binding of linezolid is decreased, volume of distribution increased, and metabolism may be inhibited leading to non-linear kinetics of elimination; these changes are responsible for high inter-individual variability of linezolid plasma concentrations, which requires therapeutic plasma monitoring and choice of continuous venous infusion as the administration method. Acute renal or liver failure decrease clearance of linezolid, but renal replacement therapy is capable of restoring clearance back to normal, obviating the need for dosage adjustment. More population pharmacokinetic studies are necessary which will identify and quantify the influence of various factors on clearance and plasma concentrations of linezolid in critically ill patients.

  2. Enantioselective pharmacokinetics of sibutramine in rat.

    Science.gov (United States)

    Noh, Keumhan; Bae, Kyoungjin; Min, Bokyoung; Kim, Eunyoung; Kwon, Kwang-il; Jeong, Taecheon; Kang, Wonku

    2010-02-01

    Racemic sibutramine is widely used to treat obesity owing to its inhibition of serotonin and noradrenaline reuptake in synapses. Although the enantioselective effects of sibutramine and its two active desmethyl-metabolites, monodesmethylsibutramine (MDS) and didesmethylsibutramine (DDS), on anorexia and energy expenditure have been elucidated, the enantioselective pharmacokinetics of sibutramine are still unclear. Therefore, we aimed to characterize the enantioselective pharmacokinetics of sibutramine and its metabolites in plasma and urine following an intravenous and a single oral administration of sibutramine in rats. The absolute bioavailability of sibutramine was only about 7%. The pharmacologically less effective S-isomer of DDS was predominant in the plasma: the C ( max ) and the AUC ( inf ) were 28 and 30 times higher than those of the R-isomer, respectively (psibutramine metabolites MDS and DDS were present at lower concentrations, owing to their rapid biotransformation to hydroxylated and/or carbamoylglucuronized forms and their faster excretion in the urine. The present study is the first to elucidate the enantioselective pharmacokinetics of sibutramine in rats.

  3. Pegylated interferon fractal pharmacokinetics: individualized dosing for hepatitis C virus infection.

    Science.gov (United States)

    Jain, Mamta K; Pasipanodya, Jotam G; Alder, Lara; Lee, William M; Gumbo, Tawanda

    2013-03-01

    Despite recent advances in hepatitis C virus (HCV) therapeutics, the combination of pegylated interferon and ribavirin (PEGIFN/RBV) remains the cornerstone of treatment. Optimization and individualization of PEGIFN dosing could improve outcomes. Week one PEGIFN serum concentrations in 42 HCV genotype 1-infected patients treated with conventional PEGIFN/RBV were analyzed using multicompartmental pharmacokinetic models. For each patient, pharmacokinetic parameter estimates, weight, age, interleukin-28B (IL-28B) single-nucleotide polymorphism, CD4 count, baseline HCV RNA, gender, race, and HIV status were examined using classification and regression tree analysis to identify factors predictive of sustained viral response (SVR). Survival analysis was performed to compare the time to undetectable viral load in patients with and without the highest scoring predictor. PEGIFN concentrations varied at least 87-fold. Pharmacokinetics were best described by a two-compartment model with an 8.4-h absorption lag. Patient weight correlated with PEGIFN systemic clearance based on fractal geometry relationships. SVR was achieved in 36% of patients; a PEGIFN cumulative 1-week area under the curve (AUC) of ≤0.79 mg · h/liter scored highest in predicting poor response, followed by a weight of ≥93.7 kg. Patients with a PEGIFN AUC of >0.79 mg · h/liter achieved undetectable viral load more rapidly than those with a lower AUC (hazard ratio, 1.63; 95% confidence interval, 1.21 to 2.04). PEGIFN exhibits wide pharmacokinetic variability, mainly driven by patient weight, so that the standard dose may not reach levels needed to achieve SVR. Optimizing dose to patient weight and PEGIFN AUC in the first week offers a solution to improve SVR and to potentially shorten duration of therapy.

  4. Formulation and In-vivo Pharmacokinetic Consideration of Intranasal Microemulsion and Mucoadhesive Microemulsion of Rivastigmine for Brain Targeting.

    Science.gov (United States)

    Shah, Brijesh; Khunt, Dignesh; Misra, Manju; Padh, Harish

    2018-01-02

    Presence of tight junctions in blood brain barrier (BBB) pose a major hurdle for delivery of drug and severely affects adequate therapeutic concentration to reach the brain. In present work, we have selected Rivastigmine hydrogen tartrate (RHT), a reversible cholinesterase inhibitor, which exhibits extensive first-pass metabolism, resulting in limited absolute bioavailability (36%). RHT shows extremely low aqueous solubility and poor penetration, resulting in inadequate concentration reaching the brain, thus necessitating frequent oral dosing. To overcome these problems of RHT, microemulsion (ME) and mucoadhesive microemulsion (MME) of RHT were formulated for brain targeting via intranasal delivery route and compared on the basis of in vivo pharmacokinetics. ME and MME formulations containing RHT were developed by water titration method. Characterization of ME and MME was done for various physicochemical parameters, nasal spray pattern, and in vivo pharmacokinetics quantitatively and qualitatively (gamma scintigraphy studies). The developed ME and MME were transparent having globule size approximately in the range of 53-55 nm. Pharmacokinetic studies showed higher values for C max and DTP for intranasal RHT: CH-ME over RHT-ME, thus indicating the effect of chitosan in modulating tight junctions, thereby enhanced paracellular transport of RHT. Gamma scintigraphy and in vivo pharmacokinetic study suggested enhanced RHT concentration, upon intranasal administration of RHT:CH-ME, compare with other groups administered formulations intranasally. These findings suggested the potential of non-invasive intranasal route for brain delivery, especially for therapeutics, facing challenges in oral administration.

  5. In vitro and in vivo studies of pharmacokinetics and antitumor efficacy of D07001-F4, an oral gemcitabine formulation.

    Science.gov (United States)

    Hao, Wei-Hua; Wang, Jong-Jing; Hsueh, Shu-Ping; Hsu, Pei-Jing; Chang, Li-Chien; Hsu, Chang-Shan; Hsu, Kuang-Yang

    2013-02-01

    The chemotherapy agent gemcitabine is currently administered intravenously because the drug has poor oral bioavailability. In order to assess the pharmacokinetics and antitumor activity of D07001-F4, a new self-microemulsifying oral drug delivery system preparation of gemcitabine, this study was performed to compare the effect of D07001-F4 with administered gemcitabine in vitro and in vivo. D07001-F4 pharmacokinetics was examined by evaluation of in vitro deamination of D07001-F4 and gemcitabine hydrochloride by recombinant human cytidine deaminase (rhCDA) and in vivo evaluation of D07001-F4 pharmacokinetics in mice. Antitumor activity was evaluated by comparing the effect of D07001-F4 and gemcitabine hydrochloride in inhibiting growth in nine cancer cell lines and by examining the effect of D07001-F4 and gemcitabine in two xenograft tumor models in mice. In vitro deamination of D07001-F4 by rhCDA was 3.3-fold slower than deamination of gemcitabine hydrochloride. Growth inhibition by D07001-F4 of 7 of the 8 cancer cell lines was increased compared with that seen with gemcitabine hydrochloride, and D07001-F4 inhibited the growth of pancreatic and colon cancer xenografts. In vivo pharmacokinetics showed the oral bioavailability of D07001-F4 to be 34%. D07001-F4 was effective against several cancer types, was metabolized more slowly than gemcitabine hydrochloride, and exhibited enhanced oral bioavailability.

  6. Energy poor or fuel poor: What are the differences?

    International Nuclear Information System (INIS)

    Li, Kang; Lloyd, Bob; Liang, Xiao-Jie; Wei, Yi-Ming

    2014-01-01

    Energy poverty and fuel poverty are descriptors of problems of households' energy consumption, they are both distinct problems and have been addressed by many researchers, organizations and governments. Cross use of the terms of energy poverty and fuel poverty in published papers is common. As an accurate descriptor is the presupposition of research and policy development, especially for those who just started to pay attention to this issue, this paper compares the definitions, research priorities, status quo, and problems of these two concepts, and summarizes the relationship between them. The paper suggests that only when the research targets are households who are living in a cold climate and have difficulty in getting access to electricity or modern cooking facilities, and in supplying indoor heating with appropriate cost, the concepts of energy poverty and fuel poverty have the chance to be broadened and mutually integrated. - Highlights: • Address energy poverty and fuel poverty simultaneously. • Compare energy poverty and fuel poverty from 4 perspectives. • Summarize the relationship between energy poverty and fuel poverty. • Divide energy poor and fuel poor into three categories

  7. Pharmacokinetic properties of 2nd-generation fibroblast growth factor-1 mutants for therapeutic application.

    Directory of Open Access Journals (Sweden)

    Xue Xia

    Full Text Available Fibroblast growth factor-1 (FGF-1 is an angiogenic factor with therapeutic potential for the treatment of ischemic disease. FGF-1 has low intrinsic thermostability and is characteristically formulated with heparin as a stabilizing agent. Heparin, however, adds a number of undesirable properties that negatively impact safety and cost. Mutations that increase the thermostability of FGF-1 may obviate the need for heparin in formulation and may prove to be useful "2nd-generation" forms for therapeutic use. We report a pharmacokinetic (PK study in rabbits of human FGF-1 in the presence and absence of heparin, as well as three mutant forms having differential effects upon thermostability, buried reactive thiols, and heparin affinity. The results support the hypothesis that heparan sulfate proteoglycan (HSPG in the vasculature of liver, kidney and spleen serves as the principle peripheral compartment in the distribution kinetics. The addition of heparin to FGF-1 is shown to increase endocrine-like properties of distribution. Mutant forms of FGF-1 that enhance thermostability or eliminate buried reactive thiols demonstrate a shorter distribution half-life, a longer elimination half-life, and a longer mean residence time (MRT in comparison to wild-type FGF-1. The results show how such mutations can produce useful 2nd-generation forms with tailored PK profiles for specific therapeutic application.

  8. [Clinical and pharmacokinetics evaluation of flomoxef in pediatrics].

    Science.gov (United States)

    Higashino, H; Kobayashi, T; Shuto, K; Matsui, T; Hasui, M; Nogi, S; Adachi, Y; Kobayashi, Y; Araki, A; Sonoda, N

    1987-08-01

    Flomoxef (FMOX, 6315-S), a new parenteral oxacephem antibiotic was investigated for its clinical efficacy and pharmacokinetics. The results obtained are summarized below. 1. Twenty-eight patients were treated with 39-152 mg/kg per day of FMOX by intravenous administration. Diagnosis of patients were pneumonia in 15 patients, acute upper respiratory tract infection in 5, acute enterocolitis in 3, urinary tract infection in 2 and cholangitis, suppurative lymphadenitis and suspicious sepsis in 1 patient each. Clinical effect was excellent in 7 cases, good in 8, fair in 5, poor in 2 and 6 cases were excluded because therapy periods were too short and other antibiotics were used together. Efficacy rate was 68% and the rate of bacterial disappearance was 83%. 2. Rash was found in 5 cases and thrombocytosis was found in 1 out of 28 cases. However, no severe adverse reaction was encountered. 3. The peak serum level of FMOX was 51.0 micrograms/ml after 20 mg/kg of drip infusion for 30 minutes and the half-life was 17.2 minutes in alpha-phase and 58.2 minutes in beta-phase.

  9. 1,3-disubstituted ureas functionalized with ether groups are potent inhibitors of the soluble epoxide hydrolase with improved pharmacokinetic properties.

    Science.gov (United States)

    Kim, In-Hae; Tsai, Hsing-Ju; Nishi, Kosuke; Kasagami, Takeo; Morisseau, Christophe; Hammock, Bruce D

    2007-10-18

    Soluble epoxide hydrolase (sEH) is a therapeutic target for treating hypertension and inflammation. 1,3-Disubstituted ureas functionalized with an ether group are potent sEH inhibitors. However, their relatively low metabolic stability leads to poor pharmacokinetic properties. To improve their bioavailability, we investigated the effect of incorporating various polar groups on the ether function on the inhibition potencies, physical properties, in vitro metabolic stability, and pharmacokinetic properties. The structure-activity relationship studies showed that a hydrophobic linker between the urea group and the ether function is necessary to keep their potency. In addition, urea-ether inhibitors having a polar group such as diethylene glycol or morpholine significantly improved their physical properties and metabolic stability without any loss of inhibitory potency. Furthermore, improved pharmacokinetic properties in murine and canine models were obtained with the resulting inhibitors. These findings will facilitate the usage of sEH inhibitors in animal models of hypertension and inflammation.

  10. Poorly studied phenomena in geoelectrics

    Directory of Open Access Journals (Sweden)

    В. С. Могилатов

    2016-12-01

    Full Text Available Undoubtedly, modern geoelectric technologies emerge in the result of the development of traditional approaches and techniques. However of more interest is the appearance of completely new technologies based on new effects and new models of interaction of geological medium and electromagnetic field. The author does not commit to indicate principally new directions, but only wants to discuss some poorly known facts from the theory and practice of geoelectrics. The outcome of this study could be considered attracting the attention of experts to non-traditional signals in geoelectrics. The reviewed phenomena of interest, not fully implemented in practice in the author’s opinion, are field split into two polarizations: transverse electric (the ТЕ-field and transverse magnetic (the ТМ-field, then some poorly known properties of ТМ-field, the role of bias currents, the anisotropy of horizontal resistances, the role of geomagnetic field in geoelectric sounding, the unique resolution of CSEM (Controlled Source Electro-Magnetic techniques at sea.

  11. Clinical studies with oral lipid based formulations of poorly soluble compounds

    DEFF Research Database (Denmark)

    Fatouros, Dimitrios; Karpf, Ditte M; Nielsen, Flemming S

    2007-01-01

    . Several drug products intended for oral administration have been marketed utilizing lipid and surfactant based formulations. Sandimmune((R)) and Sandimmune Neoral((R)) (cyclosporin A, Novartis), Norvir((R)) (ritonavir), and Fortovase((R)) (saquinavir) have been formulated in self-emulsifying drug delivery...... systems (SEDDS). This review summarizes published pharmacokinetic studies of orally administered lipid based formulations of poorly aqueous soluble drugs in human subjects. Special attention has been paid to the physicochemical characteristics of the formulations, when available and the impact...

  12. Prediction of human CNS pharmacokinetics using a physiologically-based pharmacokinetic modeling approach

    NARCIS (Netherlands)

    Yamamoto, Yumi; Valitalo, Pyry A.; Wong, Yin Cheong; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Beukers, Margot W.; Kokki, Hannu; Kokki, Merja; Danhof, Meindert; van Hasselt, Johan G. C.; de Lange, Elizabeth C. M.

    2018-01-01

    Knowledge of drug concentration-time profiles at the central nervous system (CNS) target-site is critically important for rational development of CNS targeted drugs. Our aim was to translate a recently published comprehensive CNS physiologically-based pharmacokinetic (PBPK) model from rat to human,

  13. Population pharmacokinetics and relationship between demographic and clinical variables and pharmacokinetics of gentamicin in neonates

    NARCIS (Netherlands)

    Stolk, L M L; Degraeuwe, P L J; Nieman, F H M; de Wolf, M C; de Boer, A|info:eu-repo/dai/nl/075097346

    Population pharmacokinetic parameter estimates were calculated from 725 routine plasma gentamicin concentrations obtained in 177 neonates of 24 to 42 weeks' gestational age in their first week of life. Kel increases and V/W decreases with increasing gestational age. Almost identical results were

  14. Pharmacokinetic studies of active triterpenoid saponins and the total secondary saponin from Anemone raddeana Regel.

    Science.gov (United States)

    Zhang, Dandan; Lei, Tianli; Lv, Chongning; Zhao, Huimin; Xu, Haiyan; Lu, Jincai

    2017-02-15

    The rhizome of Anemone raddeana Regel, a Traditional Chinese Medicine (TCM) which has a robust history treating rheumatism and neuralgia. The total secondary saponin (TSS) from it has demonstrated antitumor activity. In this study, a rapid and validated LC-MS/MS method was developed to simultaneously determine the active compounds (Hederacolchiside A1 and Eleutheroside K). Analytes were separated on a reverse-phase C18 column with acetonitrile-water (5mmol/L ammonium acetate) as the mobile phase. This assay showed acceptable linearity (r>0.99) over the concentration range 5-1000 nmol/L for two analytes. The intra- and inter-day precision was within 8.06% and accuracy was ranged from -3.16% to 3.34% for two analytes. The mean extraction recoveries of analytes and IS from rat plasma were all more than 76.0%. Under the developed analytical conditions, the obtained values of main pharmacokinetic parameters (C max and AUC 0-t ) indicated that the pure compounds were more efficient than the TSS extract in Hederacolchiside A1 and Eleutheroside K absorption. In addition, pharmacokinetic studies of two individual compounds demonstrated their poor oral absorption in rat ( a F%, 0.019-1.521). In the study of absorption and transportation of Hederacolchiside A1 and Eleutheroside K in Caco-2 cell monolayer model, the uptake permeability was in 10 -6 cm/sec range suggesting poor absorption, which confirmed the previous pharmacokinetic profiles in vivo. Interestingly, the uptake ratio of them declined significantly when treated with phloridzin (SGLT1 inhibitor). It indicated that the absorption of Hederacolchiside A1 in intestine was mainly through positive transport and SGLT1 might participate in its active absorption. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Pharmacokinetic profile of dextromethorphan hydrobromide in a syrup formulation in children and adolescents.

    Science.gov (United States)

    Guenin, Eric; Armogida, Marianna; Riff, Dennis

    2014-09-01

    Dextromethorphan hydrobromide (DM) is a widely used antitussive. This study determined, for the first time, the basic pharmacokinetic profile of DM and its active metabolite, dextrorphan (DP) in children and adolescents. Thirty-eight male and female subjects at risk for developing an upper respiratory tract infection (URTI), or symptomatic with cough due to URTI, were enrolled in this single-dose, open-label study: ages 2-5 years (Group A, n = 8), 6-11 years (Group B, n = 17), 12-17 years (Group C, n = 13). Subjects were genotyped for cytochrome P450 (CYP) 2D6 polymorphisms and characterized as poor (PM) or non-poor metabolizers (non-PM). Groups A and B were dosed using an age-weight dosing schedule (DM range 7.5-24.75 mg); a 30-mg dose was used for Group C. Average exposures to total DP increased as age group increased, and average exposure to DM was highest in the adolescent group. One subject in that group was a PM. The terminal half-life (t ½) values were longer in the adolescent group due in part to the single PM subject. No relationship between body weight and pharmacokinetic parameters was noted. This is the first evaluation of the pharmacokinetic characteristics of DM in children and adolescents. A single dose of DM in this population was safe, and well tolerated at all doses tested. The data are used to model and compare pediatric DM exposures with those of adults.

  16. Dermal pharmacokinetics of microemulsion formulations determined by in vivo microdialysis

    DEFF Research Database (Denmark)

    Kreilgaard, Mads

    2001-01-01

    To investigate the potential of improving dermal drug delivery of hydrophilic and lipophilic substances by formulation in microemulsion vehicles and to establish a reliable pharmacokinetic model to analyze cutaneous microdialysis data.......To investigate the potential of improving dermal drug delivery of hydrophilic and lipophilic substances by formulation in microemulsion vehicles and to establish a reliable pharmacokinetic model to analyze cutaneous microdialysis data....

  17. Pharmacokinetics of first-line tuberculosis drugs in tanzanian patients

    NARCIS (Netherlands)

    Tostmann, A.; Mtabho, C.M.; Semvua, H.H.; Boogaard, J. van den; Kibiki, G.S.; Boeree, M.J.; Aarnoutse, R.E.

    2013-01-01

    East Africa has a high tuberculosis (TB) incidence and mortality, yet there are very limited data on exposure to TB drugs in patients from this region. We therefore determined the pharmacokinetic characteristics of first-line TB drugs in Tanzanian patients using intensive pharmacokinetic sampling.

  18. [Pharmacokinetics of digoxin in hyperthyroidism. Effect of methimazole].

    Science.gov (United States)

    Izbicka, Maria; Gasińska, Teresa; Dec, Renata

    2010-01-01

    Cardiovascular abnormalities may be the only manifestations of overt hyperthyroidism. In patients with heart failure and atrial fibrillation digoxin can be beneficial in controlling the symptoms and signs, but hyperthyroid patients show an impaired response or even resistance to digoxin treatment. The aim of the study is to establish: 1. Are there any differences in the pharmacokinetics of a single oral dose of digoxin between hypertyroid and euthyroid patients? 2. Does simultaneous administration of digoxin and methimazole affect the pharmacokinetics of a single oral dose of dogoxin? 3. Does methimazole-induced euthyroidism change the pharmacokinetics of a single oral dose of digoxin? The subject of the study were 28 patients with hyperthyroidism and 15 healthy persons. We evaluated the pharmacokinetics of a single oral dose of digoxin. Moreover we evaluated pharmacokinetics of a single dose of digoxin after simultaneous administration of digoxin and methimazole in 12 patients and 12 methimazole treated patients werere-assessed once they had become euthyroid. Hyperthyroid patients showed significantly lower serum digoxin concentrations, shorter T1/2 beta and a significantly smaller area under the concentration curve (AUC) that the control group. Administration of methimazole did not affect digoxin pharmacokinetics. In hyperthyroid patients: 1. the pharmacokinetics of a single oral dose of digoxin does differ from that observed in healthy subjects. 2.methimazole do not alter digoxin pharmacokinetics.

  19. Acetaminophen developmental pharmacokinetics in premature neonates and infants

    DEFF Research Database (Denmark)

    Anderson, Brian J; van Lingen, Richard A; Hansen, Tom G

    2002-01-01

    The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens.......The aim of this study was to describe acetaminophen developmental pharmacokinetics in premature neonates through infancy to suggest age-appropriate dosing regimens....

  20. An Allometric Model of Remifentanil Pharmacokinetics and Pharmacodynamics

    NARCIS (Netherlands)

    Eleveld, Douglas J.; Proost, Johannes H.; Vereecke, Hugo; Absalom, Anthony R.; Olofsen, Erik; Vuyk, Jaap; Struys, Michel M. R. F.

    Background: Pharmacokinetic and pharmacodynamic models are used to predict and explore drug infusion schemes and their resulting concentration profiles for clinical application. Our aim was to develop a pharmacokinetic-pharmacodynamic model for remifentanil that is accurate in patients with a wide

  1. 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...

  2. Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants, a population pharmacokinetic modelling approach.

    Science.gov (United States)

    Marsot, Amélie; Brevaut-Malaty, Véronique; Vialet, Renaud; Boulamery, Audrey; Bruguerolle, Bernard; Simon, Nicolas

    2014-08-01

    Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7-10 kg; patient's postnatal age: 0-206 days; GA: 27-42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1-10.6 mg/kg) per day was administered by 30-min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model software). Data were modelled with an allometric pharmacokinetic model, using three-fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (Vd ) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, Vd , F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration. © 2013 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

  3. Investigating pulmonary and systemic pharmacokinetics of inhaled olodaterol in healthy volunteers using a population pharmacokinetic approach.

    Science.gov (United States)

    Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kunz, Christina; Formella, Stephan; Kloft, Charlotte

    2016-03-01

    Olodaterol, a novel β2-adrenergic receptor agonist, is a long-acting, once-daily inhaled bronchodilator approved for the treatment of chronic obstructive pulmonary disease. The aim of the present study was to describe the plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers by population pharmacokinetic modelling and thereby to infer its pulmonary fate. Plasma and urine data after intravenous administration (0.5-25 μg) and oral inhalation (2.5-70 μg via the Respimat® inhaler) were available from a total of 148 healthy volunteers (single and multiple dosing). A stepwise model building approach was applied, using population pharmacokinetic modelling. Systemic disposition parameters were fixed to estimates obtained from intravenous data when modelling data after inhalation. A pharmacokinetic model, including three depot compartments with associated parallel first-order absorption processes (pulmonary model) on top of a four-compartment body model (systemic disposition model), was found to describe the data the best. The dose reaching the lung (pulmonary bioavailable fraction) was estimated to be 49.4% [95% confidence interval (CI) 46.1, 52.7%] of the dose released from the device. A large proportion of the pulmonary bioavailable fraction [70.1% (95% CI 66.8, 73.3%)] was absorbed with a half-life of 21.8 h (95% CI 19.7, 24.4 h). The plasma and urine pharmacokinetics of olodaterol after intravenous administration and oral inhalation in healthy volunteers were adequately described. The key finding was that a high proportion of the pulmonary bioavailable fraction had an extended pulmonary residence time. This finding was not expected based on the physicochemical properties of olodaterol. © 2015 The British Pharmacological Society.

  4. [Research progress on current pharmacokinetic evaluation of Chinese herbal medicines].

    Science.gov (United States)

    Li, Guofu; Zhao, Haoru; Yang, Jin

    2011-03-01

    In order to prove safety and efficacy, herbal medicines must undergo the rigorous scientific researches such as pharmacokinetic and bioavailability, before they are put on the market in the foreign countries. Botanical Drug Products promulgated by the US FDA could guide industry sponsors to develop herbal drugs, which was also an important reference for investigating Chinese herbal medicines. This paper reviews and discusses novel approaches for how to assess systemic exposure and pharmacokinetic of Chinese herbal medicines, which were in line with FDA guidance. This mainly focus on identifying pharmacokinetic markers of botanical products, integral pharmacokinetic study of multiple components, Biopharmaceutics drug disposition classification system, and population pharmacokinetic-pharmacodynamic study in herb-drug interaction.

  5. [Advances on pharmacokinetics of traditional Chinese medicine under disease states].

    Science.gov (United States)

    Gong, Zi-peng; Chen, Ying; Zhang, Rui-jie; Yang, Qing; Zhu, Xiao-xin

    2015-01-01

    In recent years, more and more research shows that the pharmacokinetic parameter of traditional Chinese medicine can be affected by the disease states. It's possible that drug metabolic enzymes, transporters, cell membrane permeability and the change of microbes group could be interfered with physiological and pathological changes, which enables the pharmacokinetics of traditional Chinese medicine in the body to be altered, including the process of absorption, distribution, metabolism and excretion, and then the pharmacokinetic parameters of traditional chinese medicine are altered. It's found that investigating the pharmacokinetic of traditional Chinese medicine in the pathological state is more useful than that of in normal state because the great part of traditional Chinese medicine is mainly used to treat disease. This article reflects the latest research on the pharmacokinetic of traditional Chinese medicine in the disease state such as diabete, cerebral ischemia, liver injury, inflammatory disease, nervous system disorders and fever in order to provide certain reference for clinicians designing reasonable administration dose.

  6. Pharmacokinetics of oral terbinafine in adult horses.

    Science.gov (United States)

    Younkin, T J; Davis, E G; Kukanich, B

    2017-08-01

    The primary study objective was to compare the pharmacokinetics of p.o. terbinafine alone to p.o. terbinafine administered with p.o. cimetidine in healthy adult horses. The second objective was to assess the pharmacokinetics of terbinafine when administered per rectum in two different suspensions at 30 mg/kg to adult horses. Six healthy adult horses were included in this crossover study. Plasma terbinafine concentrations were quantified with liquid chromatography and mass spectrometry. The half-life (geometric mean) was 8.38 and 10.76 h, for p.o. alone and p.o. with cimetidine, respectively. The mean maximum plasma concentrations were 0.291 μg/mL at 1.54 h and 0.418 μg/mL at 1.28 h for p.o. alone and p.o. with cimetidine, respectively. Terbinafine with cimetidine had an average C MAX 44% higher and the relative F was 153% compared p.o. terbinafine alone, but was not statistically different (P > 0.05). Terbinafine was infrequently detected when administered per rectum in two different suspensions (water or olive oil). Minor adverse effects included oral irritation, fever, and colic. All resolved spontaneously. More pharmacokinetic studies are indicated assessing drug-drug interactions and using multiple dosing intervals to improve our knowledge of effective oral dosing, the potential for drug accumulation, and systemic adverse effect of terbinafine in horses. © 2016 John Wiley & Sons Ltd.

  7. Solid lipid nanoparticles as oral delivery systems of phenolic compounds: Overcoming pharmacokinetic limitations for nutraceutical applications.

    Science.gov (United States)

    Nunes, Sara; Madureira, Ana Raquel; Campos, Débora; Sarmento, Bruno; Gomes, Ana Maria; Pintado, Manuela; Reis, Flávio

    2017-06-13

    Drug delivery systems, accompanied by nanoparticle technology, have recently emerged as prominent solutions to improve the pharmacokinetic properties, namely bioavailability, of therapeutic and nutraceutical agents. Solid lipid nanoparticles (SLNs) have received much attention from researchers due to their potential to protect or improve drug properties. SLNs have been reported to be an alternative system to traditional carriers, such as emulsions, liposomes, and polymeric nanoparticles. Phenolic compounds are widespread in plant-derived foodstuffs and therefore abundant in our diet. Over the last decades, phenolic compounds have received considerable attention due to several health promoting properties, mostly related to their antioxidant activity, which can have important implications for health. However, most of these compounds have been associated with poor bioavailability being poorly absorbed, rapidly metabolized and eliminated, which compromises its biological and pharmacological benefits. This paper provides a systematic review of the use of SLNs as oral delivery systems of phenolic compounds, in order to overcome pharmacokinetic limitations of these compounds and improved nutraceutical potential. In vitro studies, as well as works describing topical and oral treatments will be revisited and discussed. The classification, synthesis, and clinical application of these nanomaterials will be also considered in this review article.

  8. Serving the world's poor, profitably.

    Science.gov (United States)

    Prahalad, C K; Hammond, Allen

    2002-09-01

    By stimulating commerce and development at the bottom of the economic pyramid, multi-nationals could radically improve the lives of billions of people and help create a more stable, less dangerous world. Achieving this goal does not require MNCs to spearhead global social-development initiatives for charitable purposes. They need only act in their own self-interest. How? The authors lay out the business case for entering the world's poorest markets. Fully 65% of the world's population earns less than $2,000 per year--that's 4 billion people. But despite the vastness of this market, it remains largely untapped. The reluctance to invest is easy to understand, but it is, by and large, based on outdated assumptions of the developing world. While individual incomes may be low, the aggregate buying power of poor communities is actually quite large, representing a substantial market in many countries for what some might consider luxury goods like satellite television and phone services. Prices, and margins, are often much higher in poor neighborhoods than in their middle-class counterparts. And new technologies are already steadily reducing the effects of corruption, illiteracy, inadequate infrastructure, and other such barriers. Because these markets are in the earliest stages of economic development, revenue growth for multi-nationals entering them can be extremely rapid. MNCs can also lower costs, not only through low-cost labor but by transferring operating efficiencies and innovations developed to serve their existing operations. Certainly, succeeding in such markets requires MNCs to think creatively. The biggest change, though, has to come from executives: Unless business leaders confront their own preconceptions--particularly about the value of high-volume, low-margin businesses--companies are unlikely to master the challenges or reap the rewards of these developing markets.

  9. Low heritability in pharmacokinetics of talinolol

    DEFF Research Database (Denmark)

    Matthaei, Johannes; Tzvetkov, Mladen V; Gal, Valerie

    2016-01-01

    BACKGROUND: Efflux transporters like MDR1 and MRP2 may modulate the pharmacokinetics of about 50 % of all drugs. It is currently unknown how much of the variation in the activities of important drug membrane transporters like MDR1 or MRP2 is determined by genetic or by environmental factors...... of talinolol was predefined as the primary parameter. Heritability was analyzed by structural equation modeling and by within- and between-subject variance and talinolol clearance was correlated with polymorphisms in MDR1, MRP2, BCRP, MDR5, OATP1B1, and OCT1. RESULTS: Talinolol clearance varied approximately...

  10. Human physiologically based pharmacokinetic model for propofol

    Directory of Open Access Journals (Sweden)

    Schnider Thomas W

    2005-04-01

    Full Text Available Abstract Background Propofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK model for propofol. Methods PKQuest, a freely distributed software routine http://www.pkquest.com, was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1 the value of the propofol oil/water partition coefficient; 2 the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion. Results The PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters. The average weighted residual error (WRE of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model. Conclusion A PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a

  11. Cocrystals and alloys of nitazoxanide: enhanced pharmacokinetics.

    Science.gov (United States)

    Suresh, Kuthuru; Mannava, M K Chaitanya; Nangia, Ashwini

    2016-03-18

    Two isomorphous cocrystals of nitazoxanide (NTZ) with p-aminosalicylic acid (PASA) and p-aminobenzoic acid (PABA) as well as their alloys were prepared by slurry and grinding techniques. The cocrystals exhibit faster dissolution rates and higher pharmacokinetic properties compared to the reference drug, and surprisingly the cocrystal alloy NTZ-PABA : NTZ-PASA (0.75 : 0.25) exhibited 4 fold higher bioavailability of NTZ in Sprague Dawley rats. This study opens the opportunity for cocrystal alloys as improved medicines.

  12. Clinical pharmacokinetics of nisoldipine coat-core.

    Science.gov (United States)

    Heinig, R

    1998-09-01

    Nisoldipine, a calcium antagonist of the dihydropyridine type, is the active ingredient of the controlled release nisoldipine coat-core (CC) formulation. In humans, the absorption from nisoldipine CC occurs across the entire gastrointestinal tract with an increase in bioavailability in the colon because of the lower concentrations of metabolising enzymes in the distal gut wall. Although nisoldipine is almost completely absorbed, its absolute bioavailability from the CC tablet is only 5.5%, as a result of significant first-pass metabolism in the gut and liver. Nisoldipine is a high-clearance drug with substantial interindividual and relatively lower intraindividual variability in pharmacokinetics, dependent on liver blood flow. Nisoldipine is highly (> 99%) protein bound. Its elimination is almost exclusively via the metabolic route and renal excretion of metabolites dominates over excretion in the faeces. Although nisoldipine is administered as a racemic mixture, its plasma concentrations are almost entirely caused by the eutomer as a result of highly stereoselective intrinsic clearance. Nisoldipine CC demonstrates linear pharmacokinetics in the therapeutic dose range and its steady-state pharmacokinetics are predictable from single dose data. Steady-state is reached with the second dose when the drug is given once daily and the peak-trough fluctuations in plasma concentration is minimal. Plasma-concentrations of nisoldipine increase with age. Careful dose titration according to individual clinical response is recommended in the elderly. Nisoldipine CC should not be used in patients with liver cirrhosis, though dosage adjustments in patients with renal impairment are not necessary. Inter-ethnic differences in its pharmacokinetics are not evident. Owing to inhibition of metabolising enzymes, a small dosage adjustment decrement for nisoldipine CC may be required when it is given in combination with cimetidine. Concomitant ingestion of nisoldipine with grapefruit

  13. Pharmacokinetic comparison of seven 8-methoxypsoralen brands

    DEFF Research Database (Denmark)

    Menne, T; Andersen, Klaus Ejner; Larsen, E

    1981-01-01

    The pharmacokinetics of seven 8-MOP brands were evaluated in 7 volunteers using an incomplete bloc design. After a single oral dose the 8-MOP plasma level was followed for 3 hours. The plasma concentration was measured with a gas chromatographic - mass spectrometric method, using an isotopic...... dilution technique. The different brands could be divided into three groups. Two gave a high maximum concentration, four a medium, and one a low concentration. The large interbrand variation observed in this study can explain the variations in the results of the treatment and the differing numbers...

  14. Analysis of regional total factor energy efficiency in China under environmental constraints: based on undesirable-minds and DEA window model

    Science.gov (United States)

    Zhang, Shuying; Li, Deshan; Li, Shuangqiang; Jiang, Hanyu; Shen, Yuqing

    2017-06-01

    With China’s entrance into the new economy, the improvement of energy efficiency has become an important indicator to measure the quality of ecological civilization construction and economic development. According to the panel data of Chinese regions in 1996-2014, the nearest distance to the efficient frontier of Undesirable-MinDS Xeon model and DEA window model have been used to calculate the total factor energy efficiency of China’s regions. Study found that: Under environmental constraints, China’s total factor energy efficiency has increased after the first drop in the overall 1996-2014, and then increases again. And the difference between the regions is very large, showing a characteristic of “the east is the highest, the west is lower, and lowest is in the central” finally, this paper puts forward relevant policy suggestions.

  15. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    International Nuclear Information System (INIS)

    Fowler, J.S.; Volkow, N.D.; Wolf, A.P.

    1992-01-01

    Additionally, the use of PET to examine drug pharmacokinetics and pharmacadynamics and the relationship of these properties to the behavioral, therapeutic and toxic properties of drugs and substances of abuse is emerging as a powerful new scientific tool. The pharmacokinetic properties of a drug, which comprises all of the biological processes which determine the fraction of the drug available, can be measured using the labeled drug itself. For example, the labeled drug can be used to measure the absolute uptake, regional distribution and kinetics of a drug at its site of action in the body. Additionally the labeled drug and whole body its labeled metabolites and thus provide information an potential toxic effects as well as tissue half lives. On the other hand, different labeled tracers can be used to assess drug pharmacodynamics which include the biological Processes involved in the drug's effects. For example, with appropriate radiotracers, the effects of a drug on metabolism, neurotransmitter activity, blood flew, enzyme activity or other processes can be probed

  16. Clinical Population Pharmacokinetics and Toxicodynamics of Linezolid

    Science.gov (United States)

    Boak, Lauren M.; Rayner, Craig R.; Grayson, M. Lindsay; Paterson, David L.; Spelman, Denis; Khumra, Sharmila; Capitano, Blair; Forrest, Alan; Li, Jian

    2014-01-01

    Thrombocytopenia is a common side effect of linezolid, an oxazolidinone antibiotic often used to treat multidrug-resistant Gram-positive bacterial infections. Various risk factors have been suggested, including linezolid dose and duration of therapy, baseline platelet counts, and renal dysfunction; still, the mechanisms behind this potentially treatment-limiting toxicity are largely unknown. A clinical study was conducted to investigate the relationship between linezolid pharmacokinetics and toxicodynamics and inform strategies to prevent and manage linezolid-associated toxicity. Forty-one patients received 42 separate treatment courses of linezolid (600 mg every 12 h). A new mechanism-based, population pharmacokinetic/toxicodynamic model was developed to describe the time course of plasma linezolid concentrations and platelets. A linezolid concentration of 8.06 mg/liter (101% between-patient variability) inhibited the synthesis of platelet precursor cells by 50%. Simulations predicted treatment durations of 5 and 7 days to carry a substantially lower risk than 10- to 28-day therapy for platelet nadirs of linezolid therapy and large between-patient variability, close monitoring of patients for development of toxicity is important. Dose individualization based on plasma linezolid concentration profiles and platelet counts should be considered to minimize linezolid-associated thrombocytopenia. Overall, oxazolidinone therapy over 5 to 7 days even at relatively high doses was predicted to be as safe as 10-day therapy of 600 mg linezolid every 12 h. PMID:24514086

  17. Preparation and ocular pharmacokinetics of ganciclovir liposomes.

    Science.gov (United States)

    Shen, Yan; Tu, Jiasheng

    2007-12-07

    Ophthalmic liposomes of ganciclovir (GCV) were prepared by the reverse phase evaporation method, and their ocular pharmacokinetics in albino rabbits were compared with those obtained after dosing with GCV solution. The in vitro transcorneal permeability of GCV liposomes was found to be 3.9-fold higher than that of the solution. After in vivo instillation in albino rabbits, no difference was found in the precorneal elimination rate of GCV from liposome vs solution dosing. The aqueous humor concentration-time profiles of both liposomes and solution were well described by 2-compartmental pharmacokinetics with first-order absorption. The area under the curve of the aqueous humor concentration-time profiles of GCV liposomes was found to be 1.7-fold higher than that of GCV solution. Ocular tissue distribution of GCV from liposomes was 2 to 10 times higher in the sclera, cornea, iris, lens, and vitreous humor when compared with those observed after solution dosing. These results suggested that liposomes may hold some promise in ocular GCV delivery.

  18. Physiologic and Pharmacokinetic Changes in Pregnancy

    Directory of Open Access Journals (Sweden)

    Maged eCostantine

    2014-04-01

    Full Text Available Physiologic changes in pregnancy induce profound alterations to the pharmacokinetic properties of many medications. These changes affect distribution, absorption, metabolism, and excretion of drugs, and thus may impact their pharmacodynamic properties during pregnancy. Pregnant women undergo several adaptations in many organ systems. Some adaptations are secondary to hormonal changes in pregnancy, while others occur to support the gravid woman and her developing fetus. Some of the changes in maternal physiology during pregnancy include, for example, increased maternal fat and total body water, decreased plasma protein concentrations, especially albumin, increased maternal blood volume, cardiac output and blood flow to the kidneys and uteroplacental unit, and decreased blood pressure. The maternal blood volume expansion occurs at a larger proportion than the increase in red blood cell mass, which results in physiologic anemia and hemodilution. Other physiologic changes include increased tidal volume, partially compensated respiratory alkalosis, delayed gastric emptying and gastrointestinal motility, and altered activity of hepatic drug metabolizing enzymes. Understating these changes and their profound impact on the pharmacokinetic properties of drugs in pregnancy is essential to optimize maternal and fetal health.

  19. Undesirable behavior in forest campgrounds

    Science.gov (United States)

    Roger N. Clark

    1971-01-01

    A 3-year study indicates that nuisance behaviors, law violations, vandalism, and littering in forest campgrounds are more extensive than is generally believed. All campers share responsibility for the problems. Violations occur because of ignorance of, lack of understanding, or a willingness to disregard rules. Control measures are discussed, including an incentive...

  20. Pro Poor Growth in Cameroon

    Directory of Open Access Journals (Sweden)

    Samuel Fambon

    2017-06-01

    Full Text Available The purpose of this paper is to analyze the relationship between economic growth, poverty and income distribution in Cameroon, using both the data derived from three Cameroonian household surveys and the Poverty Equivalent Growth Rate (PEGR methodology developed by Kakwani et al. (2004, The study found that economic growth in Cameroon was pro poor over the period 1996–2007, which suggests that instead of increasing the economic growth rate alone, the poverty equivalent growth rate should also be maximized to achieve the poverty reduction objective, meaning that on the one hand, the growth rate should be boosted, and on the other, the distribution of income should also be concurrently improved. A decomposition of changes in poverty using the Kakwani (1997 approach reveal that the growth component dominates the redistribution component in the reduction of poverty. This suggests that the fall in absolute poverty over the survey period may be attributed to an increase in average household income, and not to the redistributive policies of the government.

  1. [Discussion about traditional Chinese medicine pharmacokinetics study based on first botanical drug approved by FDA].

    Science.gov (United States)

    Huang, Fanghua

    2010-04-01

    Pharmacokinetics study is one of main components of pharmaceuticals development. Food and Drug Administration (FDA) approved Veregen as the first botanical drug in 2006. This article introduced FDA's requirement on pharmacokinetics study of botanical drug and pharmacokinetics studies of Veregen, summarized current requirement and status quo of pharmacokinetics study on traditional Chinese medicine (TCM) and natural medicine in China, and discussed about pharmacokinetics study strategy for TCM and natural medicine.

  2. Population Pharmacokinetics of Tracers: A New Tool for Medical Imaging?

    Science.gov (United States)

    Gandia, Peggy; Jaudet, Cyril; Chatelut, Etienne; Concordet, Didier

    2017-02-01

    Positron emission tomography-computed tomography is a medical imaging method measuring the activity of a radiotracer chosen to accumulate in cancer cells. A recent trend of medical imaging analysis is to account for the radiotracer's pharmacokinetic properties at a voxel (three-dimensional-pixel) level to separate the different tissues. These analyses are closely linked to population pharmacokinetic-pharmacodynamic modelling. Kineticists possess the cultural background to improve medical imaging analysis. This article stresses the common points with population pharmacokinetics and highlights the methodological locks that need to be lifted.

  3. Reduction of undesired lateral forces acting on the flapper of a flapper–nozzle pilot valve by using an innovative flapper shape

    International Nuclear Information System (INIS)

    Zhang, Shengzhuo; Aung, Nay Zar; Li, Songjing

    2015-01-01

    Highlights: • The simulated flow rate and main flow force show a good agreement with experiments. • The innovative flapper has little influence on the flow-pressure characteristics. • The innovative flapper can greatly reduce the Y direction force on the upper part. • The innovative flapper reduces both the X and Z direction forces on the lower part. - Abstract: The stability and dynamic performance of a flapper–nozzle pilot valve significantly depend on the flow forces acting on the flapper. Due to the shape of the flapper and flow structure in the flapper–nozzle pilot valve there are undesired lateral forces acting on the flapper, which are very potential to interfere with the stability of the flapper. Aiming to reduce these undesired lateral forces, an innovative flapper shape is proposed and a comparative study of flow forces acting on the two different flapper shapes is conducted. A simple rectangle shape is selected as the innovative flapper shape. The flow forces acting on the traditional flapper shape and innovative flapper shape are evaluated by means of CFD (Computational Fluid Dynamics) simulations and verified with the results from the semi-experimental approach. The evaluation of the flow forces is performed for each flapper shape with two different flapper–nozzle clearances of 0.10 mm and 0.05 mm under seven different flow conditions with the variation of inlet pressures from 1 MPa to 7 MPa. A good agreement between CFD results and semi-experimental results shows that the proposed innovative flapper shape has no effect on flow control characteristics since it is giving approximately the same flow rate and main flow force as the traditional flapper shape at every flow condition. Meanwhile the innovative flapper shape effectively reduces the undesired lateral forces acting on the flapper by altering the flow structure and reducing the strength of the jet flow and cavitation occurred in the flow field of flapper–nozzle pilot valve. At the

  4. Pro-poor growth and gender inequality

    OpenAIRE

    Klasen, Stephan

    2006-01-01

    This paper examines to what extent gender gaps in education, health, employment, productive assets and inputs can affect pro poor growth (in the sense of increasing monetary incomes of the poor). After discussing serious methodological problems with examining gender issues in the context of an income-based pro-poor growth framework, the paper considers theory and evidence on the impact of gender inequality on pro poor growth. While there is a considerable literature suggesting negative impact...

  5. Pharmacokinetics of vinyl chloride in the rat

    International Nuclear Information System (INIS)

    Bolt, H.M.; Laib, R.J.; Kappus, H.; Buchter, A.

    1977-01-01

    When rats are exposed to [ 14 C]vinyl chloride in a closed system, the vinyl chloride present in the atmosphere equilibrates with the animals' organism within 15 min. The course of equilibration could be determined using rats which had been given 6-nitro-1,2,3-benzothiadiazole. This compound completely blocks metabolism of vinyl chloride. The enzymes responsible for metabolism of vinyl chloride are saturated at an atmospheric concentration of vinyl chloride of 250 ppm. Pharmacokinetic analysis shows that no significant cumulation of vinyl chloride or its major metabolites is to be expected on repeated administration of vinyl chlorides. This may be consistent with the theory that a reactive, shortly living metabolite which occurs in low concentration only, may be responsible for the toxic effects of vinyl chloride

  6. Minocycline pharmacokinetics and pharmacodynamics in dogs

    DEFF Research Database (Denmark)

    Maaland, Marit Gaastra; Guardabassi, Luca; Papich, Mark G.

    2014-01-01

    BACKGROUND: Although minocycline is not licensed for use in dogs, this tetracycline has therapeutic potential against meticillin-resistant Staphylococcus pseudintermedius. HYPOTHESIS/OBJECTIVES: The aim of this study was to establish rational dosage recommendations for minocycline use in dogs....... Specific objectives were to generate and analyse minocycline pharmacokinetic (PK) data on plasma and interstitial fluid (ISF) concentrations, plasma protein binding and pharmacodynamic (PD) data on antimicrobial activity against S. pseudintermedius. ANIMALS: Six healthy dogs from a research colony were...... used in this study. METHODS: Dogs were administered 5 mg/kg intravenously and 10 mg/kg orally (p.o.) of minocycline hydrochloride in separate crossover experiments. In vivo drug concentrations in plasma and in ISF collected by ultrafiltration were measured by high-performance liquid chromatography...

  7. Pharmacokinetics of topically applied sparfloxacin in rabbits

    Directory of Open Access Journals (Sweden)

    Satia Milan

    2005-01-01

    Full Text Available PURPOSE: Fluoroquinolones are antimicrobial agents that have a broad spectrum of activity and are widely used against many of the ocular pathogens, responsible for conjunctivitis, blepharitis, corneal ulcers etc. The aim of our study was to evaluate the ocular pharmacokinetics of sparfloxacin (0.3% w/v in the aqueous humour of rabbits. MATERIALS AND METHODS: Pharmacokinetics of topically administered sparfloxacin were determined after a single application of 50 µl topically. The aqueous humour samples were collected at 0, 0.25, 0.5, 1, 2, 3, 4, 5 or 6 hours after instillation. High Performance Thin Layer Chromatographic method was used to analyse the drug concentration in the aqueous humour samples. RESULTS: Fifteen minutes after the instillation of 50 µl of sparfloxacin 0.3% solution, the mean concentration in aqueous humour was found to be 1.4 µg/ml, which reaches the peak level of 3.7 µg/ml after 1.3 hours. At 6 hours, the sparfloxacin aqueous levels were 0.562 µg/ml. The clinical efficacy was predicted based on the Maximum Concentration (Cmax: Minimum Inhibitory Concentration (MIC and Area Under the Concentration-time curve (AUC:MIC ratios. CONCLUSION: The sparfloxacin levels in aqueous humour of rabbits are sufficiently high up to the 6 hours after instillation in the conjunctival sac to provide bactericidal effect against most of the ocular pathogens. Both Cmax:MIC and AUC:MIC ratios are high enough to provide bactericidal effect against most of the ocular pathogens. Sparfloxacin (0.3% ophthalmic preparation has excellent penetration through cornea.

  8. Pharmacokinetics of terbutaline in chronic kidney disease.

    Science.gov (United States)

    Bastiansen, Anders; Eggert, Sarah; Pedersen, Erland

    2013-11-01

    In healthy individuals upwards of 90 % of an injected dose of terbutaline is excreted in the urine. The purpose of this study is to determine the pharmacokinetic properties of terbutaline in patients with severe renal impairment as defined by a glomerular filtration rate (GFR) below 30 mL/min. Ten patients were included in the study. GFR was measured with Cr-EDTA clearance. They were given an intravenous injection of 0.500 mg of terbutaline. Blood samples were collected at intervals for 60 h and urine samples were collected for 96 h. The concentration of terbutaline in the blood and in the urine was used to calculate pharmacokinetic parameters. In patients with normal renal function the total clearance of terbutaline is 2.23-3 mL/min/kg. In our population the total clearance of terbutaline was found to be 1.72 (SD: 0.49) mL/min/kg of which approximately 15 % (0.25 mL/min/kg) was renal clearance. We calculated a distribution volume at steady state of 0.74 (SD: 0.22) L/kg with a terminal half-life of 7.93 (SD: 4.06) hours. The mean residence time (MRT) was 8.35 (SD: 4.93) hours. In healthy individuals the excretion of terbutaline is foremost renal but this study shows that severe renal impairment does not lower the total clearance of terbutaline to a degree that might be expected from the Cr-EDTA clearance. However, more research is needed to determine if dosage adjustment is warranted in patients with CKD.

  9. A systems approach for tumor pharmacokinetics.

    Directory of Open Access Journals (Sweden)

    Greg Michael Thurber

    Full Text Available Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design.

  10. Pharmacokinetics and efficacy of intraocular flurbiprofen.

    Science.gov (United States)

    Blazaki, S; Tsika, C; Tzatzarakis, M; Naoumidi, E; Tsatsakis, A; Tsatsanis, C; Tsilimbaris, Miltiadis K

    2017-12-01

    Intravitreal delivery of non-steroidal anti-inflammatory drugs could be an effective way to treat macular edema caused by posterior segment inflammation. In this study, we evaluated the intravitreal bioavailability and anti-inflammatory efficacy of flurbiprofen in rabbit eyes. For pharmacokinetics, 0.1 ml of 7.66 mg/ml flurbiprofen solution was injected intravitreally and vitreous drug levels were analyzed at specific time points using LC-MS technique. For efficacy, 100 ng lipopolysaccharide of E.coli was injected intravitreally in rabbits to induce inflammation. The animals were separated in three groups and received intraocular flurbiprofen, dexamethasone and PBS to serve as control. Complete ocular examination and total cell count in aqueous fluid were determined to evaluate the extent of inflammation. Eyes were then enucleated for histopathology analysis. The efficacy in the uveitis model was determined by clinical signs of inflammation, total leukocyte count and histology findings. No adverse events were observed during pharmacokinetic assessment. No signs of inflammation, hemorrhage or retina detachment were detected. The recovery of flurbiprofen from vitreous samples was 92.6%. The half-life of flurbiprofen was estimated to be 1.92 h with an elimination constant rate (K) of 0.36. Treatment with intraocular injections of flurbiprofen and dexamethasone significantly reduced total leukocyte count in a manner comparable to dexamethasone [reduction of 96.84% (p flurbiprofen injection compared to control eyes. Flurbiprofen is effective in suppressing inflammation in this experimental uveitis model. In our experimental setting, intravitreal flurbiprofen seem to have a therapeutic result comparable to dexamethasone. However, the half-life of the drug remains short, necessitating further research to prolong its presence in the vitreous cavity.

  11. [Pharmacokinetics of salazosulfapyridine in a hemodialysis patient].

    Science.gov (United States)

    Akiyama, Yuji; Fujimaki, Toshihisa; Sakurai, Yusei

    2003-06-01

    The patient was a 62-year-old female. Total gastrectomy was performed due to gastric ulcer in 1969. She was diagnosed as rheumatoid arthritis (RA) in 1985 and was developed to amyloidosis in 1991. She was started on hemodialysis (HD) for chronic renal failure in 1996. In 1998, her arthralgia was aggravated, and 100 mg/day of bucillamine was administered on the day of HD. Her arthralgia persisted, and switching to salazosulfapyridine (SASP) was considered. As there were no standards and no reports for the use of SASP in HD patients, we examined the pharmacokinetics of SASP and its metabolites, and compared our patient with the results of phase one study in normal subjects in Japan. In this case, the blood concentration of SASP was similar to that in healthy controls after single administration of 500 mg of SASP on the day of non-HD, while the concentration of sulfapyridine (SP) was higher than that in healthy donors. However, the blood concentrations of SASP, SP, and N4-acetyl-SP (AcSP) at 24 hours after administration were similar to those obtained in healthy men. SASP was not dialyzed, while about half of SP and AcSP, were dialyzed. In a five-day consecutive administration study also, the blood concentrations of these compounds on Day 5 were similar to those of phase one study, suggesting no accumulation. No adverse drug reaction was observed. As this case had the past history of total gastrectomy and amyloidosis, it is possible that this result is influenced by the factors. Therefore it is necessary to examine pharmacokinetics of SASP and its metabolites beforehand when administering this agent to other HD/RA patients.

  12. Cefazolin pharmacokinetics in cats under surgical conditions.

    Science.gov (United States)

    Albarellos, Gabriela A; Montoya, Laura; Passini, Sabrina M; Lupi, Martín P; Lorenzini, Paula M; Landoni, María F

    2017-10-01

    Objectives The aim of this study was to determine the plasma pharmacokinetic profile, tissue concentrations and urine elimination of cefazolin in cats under surgical conditions after a single intravenous dose of 20 mg/kg. Methods Intravenous cefazolin (20 mg/kg) was administered to nine young mixed-breed cats 30 mins before they underwent surgical procedures (ovariectomy or orchiectomy). After antibiotic administration, samples from blood, some tissues and urine were taken. Cefazolin concentrations were determined in all biological matrices and pharmacokinetic parameters were estimated. Results Initial plasma concentrations were high (C p(0) , 134.80 ± 40.54 µg/ml), with fast and moderately wide distribution (distribution half-life [t ½(d) ] 0.16 ± 0.15 h; volume of distribution at steady state [V (d[ss]) ] 0.29 ± 0.10 l/kg) and rapid elimination (body clearance [Cl B ], 0.21 ± 0.06 l/h/kg; elimination half-life [t ½ ], 1.18 ± 0.27 h; mean residence time 1.42 ± 0.36 h). Thirty to 60 mins after intravenous administration, cefazolin tissue concentrations ranged from 9.24 µg/ml (subcutaneous tissue) to 26.44 µg/ml (ovary). The tissue/plasma concentration ratio ranged from 0.18 (muscle) to 0.58 (ovary). Cefazolin urine concentrations were high with 84.2% of the administered dose being eliminated in the first 6 h postadministration. Conclusions and relevance Cefazolin plasma concentrations remained above a minimum inhibitory concentration of ⩽2 µg/ml up to 4 h in all the studied cats. This suggests that a single intravenous dose of 20 mg/kg cefazolin would be adequate for perioperative prophylactic use in cats.

  13. Population pharmacokinetic modelling of the enterohepatic recirculation of diclofenac and rofecoxib in rats

    Science.gov (United States)

    Huntjens, D R H; Strougo, A; Chain, A; Metcalf, A; Summerfield, S; Spalding, D J M; Danhof, M; Della Pasqua, O

    2008-01-01

    Background and purpose: Enterohepatic recirculation (EHC) is a common pharmacokinetic phenomenon that has been poorly modelled in animals. The presence of EHC leads to the appearance of multiple peaks in the concentration-time profile and increased exposure, which may have implications for drug effect and extrapolation across species. The aim of this investigation was to develop a population pharmacokinetic model for diclofenac and rofecoxib that describes EHC and to assess its consequence for the pharmacodynamics of both drugs. Experimental approach: The pharmacokinetics of diclofenac and rofecoxib was characterized in male rats following intravenous, intraperitoneal and oral administration. Blood samples were collected at pre-defined time points after dosing to determine plasma concentrations over time. A parametric approach using nonlinear mixed effects modelling was applied to describe EHC, whilst simulations were used to evaluate its impact on PGE2 inhibition. Key results: For diclofenac, EHC was described by a compartmental model with periodic transfer rate and metabolite formation rate. For rofecoxib, EHC modelling required a conversion compartment with first-order recycling rate and lag time. Based on model predictions, EHC causes an increase of 95% in the systemic exposure to diclofenac and of 15% in the exposure to rofecoxib. In addition, EHC prolongs the inhibition of PGE2 and increases the duration of the anti-inflammatory effect (24 h for rofecoxib 10 mg kg−1) without affecting maximum inhibition. Conclusions and implications: Our findings show the relevance of exploring EHC in a quantitative manner to accurately interpret pharmacodynamic findings in vivo, in particular when scaling across species. PMID:18193075

  14. Distribution and pharmacokinetic analysis of angiostatin radioiodine labeled with high stability

    International Nuclear Information System (INIS)

    Song, Sung Hee; Jung, Kyung-Ho; Paik, Jin-Young; Koh, Bong-Ho; Bae, Joon-Sang; Choe, Yearn Seong; Lee, Kyung-Han; Kim, Byung-Tae

    2005-01-01

    Objective: Radiotracers of anticancer agents provide important information on its in vivo handling. Angiostatin (AST) is a promising anticancer drug with potent antiangiogenic effects, but reported AST radiotracers suffer from poor in vivo stability. In this study, we synthesized an AST probe radioiodinated via the Bolton-Hunter reagent ( 125 I-BH-AST) and investigated its stability and biokinetics in mice. Methods: 125 I-BH-AST and conventional direct radioiodinated 125 I-AST were evaluated for human endothelial cell binding characteristics. In vivo stability of the radiotracers was compared by biodistribution studies in normal ICR mice. Angiostatin pharmacokinetics was analyzed by serial blood sampling after intravenous injection of 125 I-BH-AST with varying AST concentrations in mice. Results: Both 125 I-AST and 125 I-BH-AST retained selective endothelial binding as demonstrated by dose-dependent inhibition by nonradiolabeled AST. 125 I-BH-AST was substantially more stable in mice than 125 I-AST, with 28- and 7-fold lower 24-h thyroid and blood activities, respectively (15.5±1.5 vs. 430.9±32.2 and 0.1±0.0 vs. 0.8±0.0 %ID/g; both P 125 I-BH-AST, we found that 24-h AST accumulation was highest in the kidneys, followed by the liver and lungs. Kinetic analysis of 125 I-BH-AST revealed AST to have linear pharmacokinetics with a T 1/2 of 5.8±2.6 h, volume of distribution (V d ) of 6.8±1.3 ml and clearance of 0.8±0.1 ml/h. Conclusion: Radioiodine-labeled AST prepared by the BH method provides a radioprobe with superior stability and improved in vivo biokinetics that is useful for distribution and pharmacokinetic studies

  15. Preparation of finasteride capsules-loaded drug nanoparticles: formulation, optimization, in vitro, and pharmacokinetic evaluation

    Directory of Open Access Journals (Sweden)

    Ahmed TA

    2016-02-01

    technique in enhancing stability, solubility, and in vitro dissolution of poorly water-soluble drugs with possible impact on the drug bioavailability. Keywords: finasteride, nanoparticles, solvent evaporation, optimization, crystal growth, pharmacokinetic

  16. Metabolism, oral bioavailability and pharmacokinetics of chemopreventive kaempferol in rats

    Science.gov (United States)

    Barve, Avantika; Chen, Chi; Hebbar, Vidya; Desiderio, Joseph; Saw, Constance Lay-Lay; Kong, Ah-Ng

    2012-01-01

    The purpose of this study was to compare the hepatic and small intestinal metabolism, and examine bioavailability and gastro-intestinal first-pass effects of Kaempferol in the rats. Liver and small intestinal microsomes fortified with either NADPH or UDPGA were incubated with varying concentrations of Kaempferol for upto 120 minutes. Based on the values of the kinetic constants (Km and Vmax), the propensity for UDPGA-dependent conjugation as compared to NADPH-dependent oxidative metabolism was higher for both hepatic and small intestinal microsomes. Male Sprague-Dawley rats were administered Kaempferol intravenously (IV) (10, 25 mg/kg) or orally (100, 250 mg/kg). Gastro-intestinal first pass effects were observed by collecting portal blood after oral administration of 100 mg/kg Kaempferol. Pharmacokinetic parameters were obtained by Noncompartmental analysis using WinNonlin. After IV administration, the plasma concentration-time profiles for 10 and 25 mg/kg were consistent with high clearance (~ 3 L/hr/kg) and large volumes of distribution (8-12 L/kg). The disposition was characterized by a terminal half-life value of 3-4 hours. After oral administration the plasma concentration-time profiles demonstrated fairly rapid absorption (tmax ~ 1-2 hours). The area under the curve (AUC) values after IV and oral doses increased proportional to the dose. The bioavailability (F) was poor at ~ 2%. Analysis of portal plasma after oral administration revealed low to moderate absorption. Taken together, the low F of Kaempferol is attributed in part to extensive first-pass metabolism by glucuronidation and other metabolic pathways in the gut and in the liver. PMID:19722166

  17. Effect of Smoking on Pharmacokinetics of Clopidogrel, an ...

    African Journals Online (AJOL)

    ... in patients undergoing PCI. Keywords: Antiplatelet, Clopidogrel, Pharmacokinetics, Smoking, Cigarette ..... regimen of choice to prevent thrombotic complications. [2,16]. ... either the parent drug [19] or the carboxylic acid metabolite as an ...

  18. Pharmacokinetics of Rhodamine 110 and Its Organ Distribution in Rats.

    Science.gov (United States)

    Jiang, Shiau-Han; Cheng, Yung-Yi; Huo, Teh-Ia; Tsai, Tung-Hu

    2017-09-06

    Rhodamine dyes have been banned as food additives due to their potential tumorigenicity. Rhodamine 110 is illegal as a food additive, although its pharmacokinetics have not been characterized, and no accurate bioanalytical methods are available to quantify rhodamine 110. The aim of this study was to develop and validate a fast, stable, and sensitive method to quantify rhodamine 110 using high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) to assess its pharmacokinetics and organ distribution in awake rats. Rhodamine 110 exhibited linear pharmacokinetics and slow elimination after oral administration. Furthermore, its oral bioavailability was approximately 34-35%. The distribution in the liver and kidney suggests that these organs are primarily responsible for rhodamine 110 metabolism and elimination. Our investigation describes the pharmacokinetics and a quantification method for rhodamine 110, improving our understanding of the food safety of rhodamine dyes.

  19. A Comparative Study of the Pharmacokinetics of Conventional and ...

    African Journals Online (AJOL)

    Erah

    Purpose: To examine the pharmacokinetics of a formulated aceclofenac sustained release ... over 24 h and analyzed by high performance liquid chromatography (HPLC). .... The response factor .... slower drug disposition and prolonged effect.

  20. Pharmacokinetically guided dosing of (high-dose) chemotherapeutic agents

    NARCIS (Netherlands)

    Attema-de Jonge, M.E. (Milly Ellen)

    2004-01-01

    Due to variation in drug distribution, metabolism and elimination processes between patients, systemic exposure to chemotherapeutic agents may be highly variable from patient to patient after administration of similar doses. This pharmacokinetic variability may explain in part the large variability

  1. Analysis of the Environmental Efficiency of the Chinese Transportation Sector Using an Undesirable Output Slacks-Based Measure Data Envelopment Analysis Model

    Directory of Open Access Journals (Sweden)

    Xiaowei Song

    2015-07-01

    Full Text Available Many countries are attempting to reduce energy consumption and CO2 emissions while increasing the productivity and efficiency of their industries. An undesirable-output-oriented data envelopment analysis (DEA model with slacks-based measure (SBM was used to evaluate the changes in the environmental efficiency of the transportation sector in 30 Chinese provinces (municipalities and autonomous regions between 2003 and 2012. The potential for decreasing CO2 emissions and energy saving was also assessed. Transportation was found to be inefficient in most of the provinces and the average environmental efficiency was low (0.45. The overall average efficiency reached a maximum in 2005 and continually decreased until a minimum was reached in 2009; since then, it has increased. In general, transportation is more efficient in eastern than in central or western China. A sensitivity analysis was also carried out on the input and output indicators. Based on these findings, some policies are proposed to improve the environmental efficiency of the transportation sector in China.

  2. Absorption and pharmacokinetics of grapefruit flavanones in beagles

    OpenAIRE

    Mata Bilbao, María de Lourdes; Andrés Lacueva, Ma. Cristina; Roura Carvajal, Elena; Jáuregui Pallarés, Olga; Escribano Ferrer, Elvira; Torre, Celina; Lamuela Raventós, Rosa Ma.

    2007-01-01

    The present study evaluated the pharmacokinetics of three different grapefruit flavanone forms in dog plasma and demonstrated their absorption after an oral intake of a grapefruit extract; pharmacokinetic parameters of these forms were also determined. Ten healthy beagles were administered 70 mg citrus flavonoids as a grapefruit extract contained in capsules, while two additional dogs were used as controls and given an excipient. The grapefruit flavanone naringin, along with its metabolites n...

  3. 1,3-Disubstituted Ureas Functionalized with Ether Groups are Potent Inhibitors of the Soluble Epoxide Hydrolase with Improved Pharmacokinetic Properties

    OpenAIRE

    Kim, In-Hae; Tsai, Hsing-Ju; Nishi, Kosuke; Kasagami, Takeo; Morisseau, Christophe; Hammock, Bruce D.

    2007-01-01

    Soluble epoxide hydrolase (sEH) is a therapeutic target for treating hypertension and inflammation. 1,3-Disubstituted ureas functionalized with an ether group are potent sEH inhibitors. However, their relatively low metabolic stability leads to poor pharmacokinetic properties. To improve their bioavailability, we investigated the effect of incorporating various polar groups on the ether function on the inhibition potencies, physical properties, in vitro metabolic stability, and pharmacokineti...

  4. What characterizes persons with poor mental health?

    DEFF Research Database (Denmark)

    Christensen, Anne Illemann; Davidsen, Michael; Kjøller, Mette

    2014-01-01

    analysed by means of logistic regression models. Results: Men and women with poor mental health are characterized by being single, having a long-term illness, not being able to rely on help from others in case of illness and by feeling that family and friends demand too much of them. Men with poor mental...... health were further characterized by being a heavy smoker, and having a BMI below 25. Women with poor mental health were further characterized by being 16-44 years old and sedentary in leisure time. CONCLUSIONS THE PREVALENCE OF POOR MENTAL HEALTH IS HIGHER AMONG WOMEN THAN MEN, AND DIFFERENT FACTORS...... CHARACTERIZE MEN AND WOMEN WITH POOR MENTAL HEALTH THE PRESENT FINDINGS SUPPORT THE NOTION THAT BOTH SOCIO-DEMOGRAPHICS AND LIFESTYLE FACTORS ARE INDEPENDENTLY RELATED WITH POOR MENTAL HEALTH WE SUGGEST TAKING INTO ACCOUNT ALL THESE AREAS OF LIFE WHEN PLANNING ACTIVITIES TO PREVENT POOR MENTAL HEALTH AND WHEN...

  5. Effect of casopitant, a novel NK-1 antagonist, on the pharmacokinetics of dolasetron and granisetron.

    Science.gov (United States)

    Adams, Laurel M; Johnson, Brendan; Zhang, Ke; Yue, Lin; Kirby, Lyndon C; Lebowitz, Peter; Stoltz, Randall

    2009-09-01

    The objective of this study was to characterize the impact of casopitant, a novel neurokinin-1 receptor antagonist under investigation for the prevention of postoperative and chemotherapy-induced nausea and vomiting, on the pharmacokinetics of the commonly prescribed 5-hydroxytryptamine receptor 3 receptor antagonists, dolasetron or granisetron. In a phase I, open-label, two-part, two-period, single-sequence study, two cohorts of healthy subjects received either oral dolasetron (100 mg once daily for 3 days) or oral granisetron (2 mg once daily for 3 days) alone (period 1) and combined with oral casopitant, 150 mg day 1, 50 mg days 2 and 3 (period 2). Pharmacokinetics of hydrodolasetron and granisetron were assessed on days 1 and 3 of each period. Log-transformed area under the curve (AUC) and Cmax were statistically analyzed by performing an analysis of variance. Eighteen subjects were enrolled in the dolasetron cohort; nine subjects were CYP2D6 extensive metabolizers (EMs) and nine subjects were CYP2D6 poor metabolizers. Nineteen subjects were enrolled in the granisetron cohort. The largest changes in hydrodolasetron exposure after coadministration with casopitant were seen in CYP2D6 EMs, with a 24% increase in hydrodolasetron AUC on day 1 and 30% increase in Cmax on days 1 and 3. All other changes in hydrodolasetron exposure were granisetron exposure was not altered to any relevant extent (granisetron was well tolerated.

  6. Preparation and characterization of simvastatin/DMβCD complex and its pharmacokinetics in rats

    Directory of Open Access Journals (Sweden)

    Gu Fugen

    2018-06-01

    Full Text Available Simvastatin is poorly bioavailable because it is practically insoluble in water and shows dissolution rate-limited absorption. Solubilizing effects of several β-cyclodextrin (βCD derivatives such as HPβCD, SBEβCD and DMβCD on simvastatin in aqueous solution were investigated using the phase solubility technique. The solubility diagram of simvastatin with each βCD derivative could be classified as AL-type, indicating soluble complex formation of 1:1 stoichiometry. Among the above βCD derivatives DMβCD was found to be the ideal complexing agent for improving drug solubility. The simvastatin complex with DMβCD was prepared using the co-evaporation method and was then characterized by differential scanning calorimetry (DSC, Fourier-transform infrared spectroscopy (FT-IR and in vitro dissolution. Dissolution and pharmacokinetic studies indicated that the simvastatin/DMβCD complex exhibited an increased dissolution rate, rapid absorption, and improved bioavailability in rats compared to free drug. Maximum plasma concentration (cmax and the time to reach it (tmax were 21.86 μg mL−1 and 1.4 h for the drug complex, 8.25 μg mL−1 and 3.0 h for free drug, respectively. Main pharmacokinetic parameters such as tmax, cmax were significantly different (p < 0.01 between the simvastatin complex and free drug. Bioavailability of the simvastatin complex relative to free drug was up to 167.0 %.

  7. Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy.

    Science.gov (United States)

    Pasipanodya, Jotam G; Srivastava, Shashikant; Gumbo, Tawanda

    2012-07-01

    Using hollow-fiber tuberculosis studies, we recently demonstrated that nonadherence is not a significant factor for ADR and that therapy failure only occurs after a large proportion of doses are missed. Computer-aided clinical trial simulations have suggested that isoniazid and rifampin pharmacokinetic variability best explained poor outcomes. We were interested in determining whether isoniazid pharmacokinetic variability was associated with either microbiological failure or ADR in the clinic. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Prospective, randomized, controlled clinical trials that reported isoniazid acetylation status and microbiological outcomes were selected. The main effects examined were microbiological sputum conversion, ADR, and relapse. Effect size was expressed as pooled risk ratios (RRs) comparing rapid with slow acetylators. Thirteen randomized studies with 1631 rapid acetylators and 1751 slow acetylators met inclusion and exclusion criteria. Rapid acetylators were more likely than slow acetylators to have microbiological failure (RR, 2.0; 95% confidence interval [CI], 1.5-2.7), ADR (RR, 2.0; CI, 1.1-3.4), and relapse (RR, 1.3; CI, .9-2.0). Higher failure rates were encountered even in drug regimens comprising >3 antibiotics. No publication bias or small-study effects were observed for the outcomes evaluated. Pharmacokinetic variability to a single drug in the regimen is significantly associated with failure of therapy and ADR in patients. This suggests that individualized dosing for tuberculosis may be more effective than standardized dosing, which is prescribed in directly observed therapy programs.

  8. Pharmacokinetics of dextromethorphan and its metabolites in horses following a single oral administration.

    Science.gov (United States)

    Corado, Carley R; McKemie, Daniel S; Knych, Heather K

    2017-06-01

    Dextromethorphan is an N-methyl-D-aspartate (NMDA) non-competitive antagonist commonly used in human medicine as an antitussive. Dextromethorphan is metabolized in humans by cytochrome P450 2D6 into dextrorphan, which is reported to be more potent than the parent compound. The goal of this study is to describe the metabolism of and determine the pharmacokinetics of dextromethorphan and its major metabolites following oral administration to horses. A total of 23 horses received a single oral dose of 2 mg/kg. Blood samples were collected at time 0 and at various times up to 96 h post drug administration. Urine samples were collected from 12 horses up to 120 h post administration. Plasma and urine samples were analyzed using liquid chromatography-mass spectrometry, and the resulting data analyzed using non-compartmental analysis. The C max , T max , and the t 1/2 of dextromethorphan were 519.4 ng/mL, 0.55 h, and 12.4 h respectively. The area under the curve of dextromethorphan, free dextrorphan, and conjugated dextrorphan were 563.8, 2.19, and 6,691 h*ng/mL respectively. In addition to free and glucuronidated dextrorphan, several additional glucuronide metabolites were identified in plasma, including hydroxyl-desmethyl dextrorphan, desmethyl dextrorphan, and three forms of hydroxylated dextrorphan. Dextromethorphan was found to be eliminated from the urine predominately as the O-demethylated metabolite, dextrorphan. Several additional metabolites including several novel hydroxy-dextrorphan metabolites were also detected in the urine in both free and glucuronidated forms. No significant undesirable behavioural effects were noted throughout the duration of the study. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  9. DETERMINATION OF TAMSULOSIN HYDROCHLORIDE RELEASE PHARMACOKINETICS IN PROSTATE GLAND BY A RADIOTRACER METHOD

    Directory of Open Access Journals (Sweden)

    V. I. Grytsenko

    2013-10-01

    Full Text Available Introduction: recently in Ukraine prostate diseases have taken one of the leading places among male urological pathologies. Prostate gland hyperplasia is one of the most common ones. Causes of hyperplasia have not been reliably established so far, however, it has been proved that the poor state of androgen production in men is an integral condition for the development of benign prostatic hyperplasia. One of the urgent tasks of modern pharmaceutical science is to create new high-performance drugs in such dosage forms that provide optimal therapeutic effect with minimal adverse complications. Among a large number of drugs for the treatment of prostate diseases a prominent place is occupied by alpha-adrenoblockers – drugs of the first-line treatments that affect the α1А-adrenergic receptors, reduce or completely eliminate the muscle tone of the prostatic urethra and bladder neck. Tamsulosin hydrochloride is a selective and competitive blocker of postsynaptic α1А-adrenergic receptors. The selectivity of tamsulosin to α1А-adrenergic receptors, which are located in the bladder, is 20 times greater than its ability to interact with α1В-adrenoceptors that are located in vascular smooth muscles. Objective: to study the pharmacokinetics of tamsulosin hydrochloride release into prostate gland after oral and rectal administration by a radioactive-tracer technique. Materials and methods of research: tamsulosin hydrochloride substance and suppositories with this substance labeled by 14С with a specific activity of 3.7× 107Bq/mg. Pharmacokinetic studies of tamsulosin hydrochloride in the prostate were performed after oral and rectal administration. The experiments were carried out on white mature male rats of Wistar line weighing 210 ± 10 g. Pharmacokinetic studies were performed using a radioactive-tracer technique (tracers after oral and rectal administration of tamsulosin. Results and their discussion: after rectal administration the release of

  10. Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria

    Directory of Open Access Journals (Sweden)

    Bose Carl

    2011-05-01

    Full Text Available Abstract Background The World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS, are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA, were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC. Methods Data were obtained from 26 pregnant women in the second (22 - 26 weeks or the third (32 - 36 weeks trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC-MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling. Results A simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F and volume of distribution (V/F estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L for AS V/F, 895 L/h (788-1045 L/h for AS CL/F, 91.4 L (78.5-109 L for DHA V/F, and 64.0 L/h (55.1-75.2 L/h for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7 - 72.3%. Conclusions In this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that

  11. Potential pharmacokinetic effect of rifampicin on enrofloxacin in broilers: Roles of P-glycoprotein and BCRP induction by rifampicin.

    Science.gov (United States)

    Guo, Mengjie; Dai, Xiaohua; Hu, Dongmin; Zhang, Yu; Sun, Yong; Ren, Weilong; Wang, Liping

    2016-09-01

    P-glycoprotein ( P-GP: , encoding gene Abcb1) and Breast Cancer Resistance Protein ( BCRP: , encoding gene Abcg2) are transport proteins that play a major role in modulating the bioavailability of oral drugs in humans and rodents. It has been shown that rifampicin is the typical inducer of P-gp in rodents by activating the nuclear receptor. However, its effect on Abcb1, Abcg2, CYP3A, and chicken xenobiotic-sensing orphan nuclear receptor ( CXR: ) mRNA expression in broilers is poorly understood. This study explored the effect of rifampicin on mRNA expression of Abcb1, Abcg2, CYP3A37, CXR as well as its effect on the pharmacokinetics of enrofloxacin in broilers. The mRNA levels of Abcb1, Abcg2, CYP3A37, and CXR were significantly increased in the liver (except Abcg2), kidney, jejunum, and ileum (P 0.05) after treated with rifampicin. Further analysis revealed that the variation tendencies of Abcb1, Abcg2, and CYP3A37 expression levels were significantly correlated with CXR mRNA expression levels in liver, kidney, jejunum, and ileum. Coadministration of rifampicin significantly changed the pharmacokinetic behavior of enrofloxacin orally administered by showing clearly lower AUC0-∞, AUC0-t, and Cmax as well as longer Tmax. The bioavailability of orally administered enrofloxacin was decreased from 72.5% to 24.8% by rifampicin. However, rifampicin did not significantly change the pharmacokinetics of enrofloxacin following intravenous administration. Our study shows that rifampicin up-regulated the small intestinal level of P-gp and BCRP and suggests that P-gp and BCRP are key factors that affected pharmacokinetic behavior of orally administered enrofloxacin by limiting its absorption from the intestine in broilers. © 2016 Poultry Science Association Inc.

  12. A critical assessment for the value of markers to gate-out undesired events in HLA-peptide multimer staining protocols

    Directory of Open Access Journals (Sweden)

    Odunsi Kunle

    2011-07-01

    Full Text Available Abstract Background The introduction of antibody markers to identify undesired cell populations in flow-cytometry based assays, so called DUMP channel markers, has become a practice in an increasing number of labs performing HLA-peptide multimer assays. However, the impact of the introduction of a DUMP channel in multimer assays has so far not been systematically investigated across a broad variety of protocols. Methods The Cancer Research Institute's Cancer Immunotherapy Consortium (CRI-CIC conducted a multimer proficiency panel with a specific focus on the impact of DUMP channel use. The panel design allowed individual laboratories to use their own protocol for thawing, staining, gating, and data analysis. Each experiment was performed twice and in parallel, with and without the application of a dump channel strategy. Results The introduction of a DUMP channel is an effective measure to reduce the amount of non-specific MULTIMER binding to T cells. Beneficial effects for the use of a DUMP channel were observed across a wide range of individual laboratories and for all tested donor-antigen combinations. In 48% of experiments we observed a reduction of the background MULTIMER-binding. In this subgroup of experiments the median background reduction observed after introduction of a DUMP channel was 0.053%. Conclusions We conclude that appropriate use of a DUMP channel can significantly reduce background staining across a large fraction of protocols and improve the ability to accurately detect and quantify the frequency of antigen-specific T cells by multimer reagents. Thus, use of a DUMP channel may become crucial for detecting low frequency antigen-specific immune responses. Further recommendations on assay performance and data presentation guidelines for publication of MULTIMER experimental data are provided.

  13. Population pharmacokinetics of olprinone in healthy male volunteers

    Directory of Open Access Journals (Sweden)

    Kunisawa T

    2014-03-01

    Full Text Available Takayuki Kunisawa,1 Hidefumi Kasai,2 Makoto Suda,2 Manabu Yoshimura,3 Ami Sugawara,3 Yuki Izumi,3 Takafumi Iida,3 Atsushi Kurosawa,3 Hiroshi Iwasaki3 1Surgical Operation Department, Asahikawa Medical University Hospital, Hokkaido, Japan; 2Clinical Study Management Division, Bell Medical Solutions Inc, Tokyo, Japan; 3Department of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Hokkaido, Japan Background: Olprinone decreases the cardiac preload and/or afterload because of its vasodilatory effect and increases myocardial contractility by inhibiting phosphodiesterase III. Purpose: The objective of this study was to characterize the population pharmacokinetics of olprinone after a single continuous infusion in healthy male volunteers. Methods: We used 500 plasma concentration data points collected from nine healthy male volunteers for the study. The population pharmacokinetic analysis was performed using the nonlinear mixed effect model (NONMEM® software. Results: The time course of plasma concentration of olprinone was best described using a two-compartment model. The final pharmacokinetic parameters were total clearance (7.37 mL/minute/kg, distribution volume of the central compartment (134 mL/kg, intercompartmental clearance (7.75 mL/minute/kg, and distribution volume of the peripheral compartment (275 mL/kg. The interindividual variability in the total clearance was 12.4%, and the residual error variability (exponential and additive were 22.2% and 0.129 (standard deviation. The final pharmacokinetic model was assessed using a bootstrap method and visual predictive check. Conclusion: We developed a population pharmacokinetic model of olprinone in healthy male adults. The bootstrap method and visual predictive check showed that this model was appropriate. Our results might be used to develop the population pharmacokinetic model in patients. Keywords: phosphodiesterase III inhibitor, men, pharmacokinetic model

  14. Inflight Pharmacokinetic and Pharmacodynamic Responses to Medications Commonly Used in Spaceflight

    Science.gov (United States)

    Wotring, V. E.; Derendorf, H.; Kast, J.; Barger, L.; Basner, M.

    2016-01-01

    Researchers do not know if medications act the same in the spaceflight environment as they do on Earth. Aspects of the spaceflight environment (low gravity, radiation exposure, closed environment, stress) have been shown to alter human physiology. Some of these physiological changes could be expected to alter either pharmacokinetics (PK, how the body absorbs, distributes, metabolizes and excretes administered medications) or pharmacodynamics (PD, receptors or signaling systems that are the targets of medication action). Anecdotal data has suggested that, at least for certain medications or indications, inflight medication efficacy is poor. In order to prepare for exploration missions where speedy evacuation to Earth may not be a possibility, the likelihood of unexpected medication action must be determined.

  15. Use of Physiologically Based Pharmacokinetic (PBPK) Models ...

    Science.gov (United States)

    EPA announced the availability of the final report, Use of Physiologically Based Pharmacokinetic (PBPK) Models to Quantify the Impact of Human Age and Interindividual Differences in Physiology and Biochemistry Pertinent to Risk Final Report for Cooperative Agreement. This report describes and demonstrates techniques necessary to extrapolate and incorporate in vitro derived metabolic rate constants in PBPK models. It also includes two case study examples designed to demonstrate the applicability of such data for health risk assessment and addresses the quantification, extrapolation and interpretation of advanced biochemical information on human interindividual variability of chemical metabolism for risk assessment application. It comprises five chapters; topics and results covered in the first four chapters have been published in the peer reviewed scientific literature. Topics covered include: Data Quality ObjectivesExperimental FrameworkRequired DataTwo example case studies that develop and incorporate in vitro metabolic rate constants in PBPK models designed to quantify human interindividual variability to better direct the choice of uncertainty factors for health risk assessment. This report is intended to serve as a reference document for risk assors to use when quantifying, extrapolating, and interpretating advanced biochemical information about human interindividual variability of chemical metabolism.

  16. Nicotinamide pharmacokinetics in humans and mice

    International Nuclear Information System (INIS)

    Horsman, M.R.; Hoyer, M.; Overgaard, J.; Honess, D.J.; Dennis, A.F.

    1993-01-01

    Healthy human volunteers orally ingested escalating doses of up to 6 g nicotinamide in capsule form on an empty stomach. Some side-effects were seen although these were mild and transient. HPLC analysis of blood samples showed peak plasma levels, typically within 45 min after ingestion, which were linearly dependent on dose ingested. The elimination half-life and AUC were also found to increase with drug dose, although these increases were non-linear. Pharmacokinetic studies were also performed to female CDF1 mice with C3H mammary carcinomas grown in the right rear foot. Analysis of blood and tumour samples taken from mice injected i.p. with nicotinamide doses between 100-1000 mg/kg showed similar characteristics as the human data, although the elimination half-lives were not dose-dependent. The average peak plasma concentration of 160 μg/ml measured in humans after taking 6 g of nicotinamide was equivalent to that seen in mice after injecting 171 mg/kg. Using a regrowth delay assay the enhancement of radiation damage by nicotinamide in this mouse tumour was found to be independent of drug dose from 100-1000 mg/kg, resulting in a constant 1.3-fold increase in radiation response. Doses of nicotinamide that can be tolerated clinically should therefore produce adequate enhancements of radiation damage in human tumours. (author)

  17. Gentamicin pharmacokinetics in the chicken inner ear.

    Science.gov (United States)

    Bunting, Eric C; Park, Debra L; Durham, Dianne; Girod, Douglas A

    2004-06-01

    Avians have the unique ability to regenerate cochlear hair cells that are lost due to ototoxins or excessive noise. Many methodological techniques are available to damage the hair cells for subsequent scientific study. A recent method utilizes topical application of an ototoxic drug to the round window membrane. The current study examines the pharmacokinetics of gentamicin in the inner ear of chickens following topical application to the round window membrane or a single systemic high dose given intraperitoneally. Chickens were given gentamicin topically or systemically and survived for 1, 4, 12, 24, or 120 h (controls at 4 and 120 h). Serum and perilymph samples were obtained prior to sacrifice and measured for gentamicin levels. Results revealed higher levels of gentamicin in the perilymph of topically treated chickens than systemically treated chickens, with significant amounts of gentamicin still present in both at the latest survival time of 5 days. As expected, systemically treated chickens had much higher levels of gentamicin in the serum than topically treated chickens. Advantages and disadvantages to each method of drug administration are discussed.

  18. Virtual pharmacokinetic model of human eye.

    Science.gov (United States)

    Kotha, Sreevani; Murtomäki, Lasse

    2014-07-01

    A virtual pharmacokinetic 3D model of the human eye is built using Comsol Multiphysics® software, which is based on the Finite Element Method (FEM). The model considers drug release from a polymer patch placed on sclera. The model concentrates on the posterior part of the eye, retina being the target tissue, and comprises the choroidal blood flow, partitioning of the drug between different tissues and active transport at the retina pigment epithelium (RPE)-choroid boundary. Although most straightforward, in order to check the mass balance, no protein binding or metabolism is yet included. It appeared that the most important issue in obtaining reliable simulation results is the finite element mesh, while time stepping has hardly any significance. Simulations were extended to 100,000 s. The concentration of a drug is shown as a function of time at various points of retina, as well as its average value, varying several parameters in the model. This work demonstrates how anybody with basic knowledge of calculus is able to build physically meaningful models of quite complex biological systems. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Pharmacokinetics and toxicology of continuously infused nitroimidazoles

    International Nuclear Information System (INIS)

    Eifel, P.J.; Brown, J.M.

    1984-01-01

    The pharmacokinetics and toxicology of misonidazole (MISO) and SR-2508 given by continuous intraperitoneal infusion were studied in female C 3 H mice. The survival (time to death) of animals receiving continuous infusions of SR-2508 and MISO was compared and related to plasma concentration, rate of infusion and total amount of drug delivered. Brain and plasma concentrations were determined by HPLC. For SR-2508, plasma concentration was directly proportional to the infusion rate. However, as the infusion rate of MISO was doubled, the plasma concentration of MISO increased approximately 6-fold, reflecting a substantial increase in the apparent half-life. The brain/plasma concentration ratio in animals infused for up to 6 days with SR-2508 remained constant, at approximately 0.09. At plasma concentrations of 0.08-1.5 mM, animals receiving SR-2508 survived approximately 3 times as long as animals exposed to a comparable plasma concentration of MISO. Even at the lowest infusion rates employed in this study, the survival of mice receiving SR-2508 was much shorter than would have been predicted if the toxicity of these two drugs were solely related to the integral brain exposure. The low brain/plasma concentration ratio of SR-2508 was maintained throughout long continuous exposures

  20. Physiologically Based Pharmacokinetic Modeling of Therapeutic Proteins.

    Science.gov (United States)

    Wong, Harvey; Chow, Timothy W

    2017-09-01

    Biologics or therapeutic proteins are becoming increasingly important as treatments for disease. The most common class of biologics are monoclonal antibodies (mAbs). Recently, there has been an increase in the use of physiologically based pharmacokinetic (PBPK) modeling in the pharmaceutical industry in drug development. We review PBPK models for therapeutic proteins with an emphasis on mAbs. Due to their size and similarity to endogenous antibodies, there are distinct differences between PBPK models for small molecules and mAbs. The high-level organization of a typical mAb PBPK model consists of a whole-body PBPK model with organ compartments interconnected by both blood and lymph flows. The whole-body PBPK model is coupled with tissue-level submodels used to describe key mechanisms governing mAb disposition including tissue efflux via the lymphatic system, elimination by catabolism, protection from catabolism binding to the neonatal Fc (FcRn) receptor, and nonlinear binding to specific pharmacological targets of interest. The use of PBPK modeling in the development of therapeutic proteins is still in its infancy. Further application of PBPK modeling for therapeutic proteins will help to define its developing role in drug discovery and development. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  1. Pharmacokinetics and pharmacotherapy of thionamides in pregnancy.

    Science.gov (United States)

    Clark, Shannon M; Saade, George R; Snodgrass, Wayne R; Hankins, Gary D V

    2006-08-01

    Hyperthyroidism occurs in approximately 1 in every 1000 to 2000 pregnancies. Although the signs and symptoms of the disease are similar in the pregnant and nonpregnant patient, the complications of hyperthyroidism can have even more profound consequences for the mother and fetus during gestation. These include maternal heart failure, preeclampsia, miscarriage, and preterm labor; as well as fetal loss and low birth weight. Furthermore, thyroid function and laboratory testing for hyperthyroidism are altered in pregnancy. The gestational increase in thyroid size, increased thyroid-binding globulin levels, increased serum total T4 and total T3 levels, and decreased thyroid stimulating hormone levels often confuses the evaluation of the thyroid status in pregnancy. Worldwide, the thionamides-propylthiouracil, methimazole, and carbimazole-have been used in pregnancy for the treatment of hyperthyroidism. However, propylthiouracil has been the drug of choice in the United States because it is believed to have less potential to induce fetal/neonatal hypothyrodism, to cross the placenta and into breast milk to a lesser degree, and to be less teratogenic than methimazole or carbimazole. None of the above have been substantiated in more recent studies. The pharmacokinetics of the thionamides in the pregnant and nonpregnant states, as well as the pharmacotherapeutic recommendation for hyperthyroidism will be reviewed.

  2. [Pharmacokinetic interactions of telaprevir with other drugs].

    Science.gov (United States)

    Berenguer Berenguer, Juan; González-García, Juan

    2013-07-01

    Telaprevir is a new direct-acting antiviral drug for the treatment of hepatitis C virus (HCV) infection and is both a substrate and an inhibitor of cytochrome P450 (CYP450) isoenzymes. With the introduction of this new drug, assessment of drug-drug interactions has become a key factor in the evaluation of patients under treatment for HCV infection. During the treatment of this infection, many patients require other drugs to mitigate the adverse effects of anti-HCV drugs and to control other comorbidities. Moreover, most patients coinfected with HIV and HCV require antiretroviral therapy during treatment for HCV. Physicians should therefore be familiar with the pharmacokinetic properties of direct-acting antivirals for HCV treatment and their potential drug-drug interactions. The present article reviews the available information to date on the interactions of telaprevir with other drugs and provides recommendations for daily clinical practice. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  3. Insulin analogs with improved pharmacokinetic profiles.

    Science.gov (United States)

    Brange; Vølund

    1999-02-01

    The aim of insulin replacement therapy is to normalize blood glucose in order to reduce the complications of diabetes. The pharmacokinetics of the traditional insulin preparations, however, do not match the profiles of physiological insulin secretion. The introduction of the rDNA technology 20 years ago opened new ways to create insulin analogs with altered properties. Fast-acting analogs are based on the idea that an insulin with less tendency to self-association than human insulin would be more readily absorbed into the systemic circulation. Protracted-acting analogs have been created to mimic the slow, steady rate of insulin secretion in the fasting state. The present paper provides a historical review of the efforts to change the physicochemical and pharmacological properties of insulin in order to improve insulin therapy. The available clinical studies of the new insulins are surveyed and show, together with modeling results, that new strategies for optimal basal-bolus treatment are required for utilization of the new fast-acting analogs.

  4. The Undesirable Behaviors of Students in Academic Classrooms, and the Discipline Strategies Used by Faculty Members to Control Such Behaviors from the Perspective of the College of Education Students in King Saud University

    Science.gov (United States)

    Al Qahtani, Norah Saad Sultan

    2016-01-01

    This study aimed to identify the undesirable students' behaviors in academic classrooms, and the disciplinary, preventive and therapeutic strategies that will be used by faculty members to control those behaviors from the perspective of the College of Education's students in King Saud University. The results of the study has shown that the…

  5. Pharmacokinetics and pharmacodynamics of mivacurium in young adult and elderly patients

    DEFF Research Database (Denmark)

    Østergaard, Doris; Viby-Mogensen, Jørgen; Pedersen, N.A.

    2002-01-01

    age factors; butyrylcholinesterase; cholinesterase; dose-response curves; enzymes; metabolites; mivacurium; neuromuscular relaxants; pharmacodynamics; pharmacokinetics; pharmacology; pseudocholinesterase; stereoisomers......age factors; butyrylcholinesterase; cholinesterase; dose-response curves; enzymes; metabolites; mivacurium; neuromuscular relaxants; pharmacodynamics; pharmacokinetics; pharmacology; pseudocholinesterase; stereoisomers...

  6. Impact of pharmaceutical cocrystals: the effects on drug pharmacokinetics.

    Science.gov (United States)

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

    2014-09-01

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

  7. Pharmacokinetics of BMEDA after Intravenous Administration in Beagle Dogs

    Directory of Open Access Journals (Sweden)

    Chih-Hsien Chang

    2014-01-01

    Full Text Available The pharmacokinetics of N,N-bis(2-mercapatoethly-N',N'-diethylenediamine (BMEDA, a molecule that can form a chelate with rhenium-188 (188Re to produce the 188Re-BMEDA-liposomes, was studied. In this work, beagles received a single injection of BMEDA, at doses of 1, 2, or 5 mg/kg; the concentration of BMEDA in the beagles’ plasma was then analyzed and determined by liquid chromatography-mass spectrometry/mass spectrometry. Based on the pharmacokinetic parameters of BMEDA, we found that male and female animals shared similar patterns indicating that the pharmacokinetics of BMEDA is independent of gender differences. In addition, the pharmacokinetics of BMEDA was seen to be non-linear because the increase of mean AUC0–t and AUC0–∞ values tend to be greater than dose proportional while the mean Vss and CL values of BMEDA appeared to be dose dependent. The information on the pharmacokinetics of BMEDA generated from this study will serve as a basis to design appropriate pharmacology and toxicology studies for future human use.

  8. Drugs in space: Pharmacokinetics and pharmacodynamics in astronauts.

    Science.gov (United States)

    Kast, Johannes; Yu, Yichao; Seubert, Christoph N; Wotring, Virginia E; Derendorf, Hartmut

    2017-11-15

    Space agencies are working intensely to push the current boundaries of human spaceflight by sending astronauts deeper into space than ever before, including missions to Mars and asteroids. Spaceflight alters human physiology due to fluid shifts, muscle and bone loss, immune system dysregulation, and changes in the gastrointestinal tract and metabolic enzymes. These alterations may change the pharmacokinetics and/or pharmacodynamics of medications used by astronauts and subsequently might impact drug efficacy and safety. Most commonly, medications are administered during space missions to treat sleep disturbances, allergies, space motion sickness, pain, and sinus congestion. These medications are administered under the assumption that they act in a similar way as on Earth, an assumption that has not been investigated systematically yet. Few inflight pharmacokinetic data have been published, and pharmacodynamic and pharmacokinetic/pharmacodynamic studies during spaceflight are also lacking. Therefore, bed-rest models are often used to simulate physiological changes observed during microgravity. In addition to pharmacokinetic/pharmacodynamic changes, decreased drug and formulation stability in space could also influence efficacy and safety of medications. These alterations along with physiological changes and their resulting pharmacokinetic and pharmacodynamic effects must to be considered to determine their ultimate impact on medication efficacy and safety during spaceflight. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Computational opioid prescribing: a novel application of clinical pharmacokinetics.

    Science.gov (United States)

    Linares, Oscar A; Linares, Annemarie L

    2011-01-01

    We implemented a pharmacokinetics-based mathematical modeling technique using algebra to assist prescribers with point-of-care opioid dosing. We call this technique computational opioid prescribing (COP). Because population pharmacokinetic parameter values are needed to estimate drug dosing regimen designs for individual patients using COP, and those values are not readily available to prescribers because they exist scattered in the vast pharmacology literature, we estimated the population pharmacokinetic parameter values for 12 commonly prescribed opioids from various sources using the bootstrap resampling technique. Our results show that opioid dosing regimen design, evaluation, and modification is feasible using COP. We conclude that COP is a new technique for the quantitative assessment of opioid dosing regimen design evaluation and adjustment, which may help prescribers to manage acute and chronic pain at the point-of-care. Potential benefits include opioid dose optimization and minimization of adverse opioid drug events, leading to potential improvement in patient treatment outcomes and safety.

  10. Modeling in biopharmaceutics, pharmacokinetics and pharmacodynamics homogeneous and heterogeneous approaches

    CERN Document Server

    Macheras, Panos

    2016-01-01

    The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this new second edition book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with epirical, compartmental, and stochastic pharmacokinetic models, with two new chapters, one on fractional pharmacokinetics and one on bioequivalence; and the fourth mainly with classical and nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. This second edition has new information on reaction limited models of dissolution, non binary biopharmaceutic classification system, time varying models, and interf...

  11. Pharmacokinetics of oral and intravenous melatonin in healthy volunteers

    DEFF Research Database (Denmark)

    Andersen, Lars Peter Holst; Werner, Mads Utke; Rosenkilde, Mette Marie

    2016-01-01

    BACKGROUND: The aim was to investigate the pharmacokinetics of oral and iv melatonin in healthy volunteers. METHODS: The study was performed as a cohort crossover study. The volunteers received either 10 mg oral melatonin or 10 mg intravenous melatonin on two separate study days. Blood samples were...... collected at different time points following oral administration and short iv infusion, respectively. Plasma melatonin concentrations were determined by RIA technique. Pharmacokinetic analyses were performed by "the method of residuals" and compartmental analysis. The pharmacokinetic variables: k a, t 1....../2 absorption, t max, C max, t 1/2 elimination, AUC 0-∞, and bioavailability were determined for oral melatonin. C max, t 1/2 elimination, V d, CL and AUC 0-∞ were determined for intravenous melatonin. RESULTS: Twelve male volunteers completed the study. Baseline melatonin plasma levels did not differ...

  12. Pharmacokinetics of high-dose intravenous melatonin in humans

    DEFF Research Database (Denmark)

    Andersen, Lars P H; Werner, Mads U; Rosenkilde, Mette Marie

    2016-01-01

    This crossover study investigated the pharmacokinetics and adverse effects of high-dose intravenous melatonin. Volunteers participated in 3 identical study sessions, receiving an intravenous bolus of 10 mg melatonin, 100 mg melatonin, and placebo. Blood samples were collected at baseline and 0, 60......, 120, 180, 240, 300, 360, and 420 minutes after the bolus. Quantitative determination of plasma melatonin concentrations was performed using a radioimmunoassay technique. Pharmacokinetic parameters were estimated by a compartmental pharmacokinetic analysis. Adverse effects included assessments...... of sedation and registration of other symptoms. Sedation, evaluated as simple reaction times, was measured at baseline and 120, 180, 300, and 420 minutes after the bolus. Twelve male volunteers completed the study. Median (IQR) Cmax after the bolus injections of 10 mg and 100 mg of melatonin were 221...

  13. Special aspects of pharmacokinetics of inhalation anesthesia.

    Science.gov (United States)

    Hendrickx, J F A; De Wolf, A

    2008-01-01

    Recent interest in the use of low-flow or closed circuit anesthesia has rekindled interest in the pharmacokinetics of inhaled anesthetics. The kinetic properties of inhaled anesthetics are most often modeled by physiologic models because of the abundant information that is available on tissue solubilities and organ perfusion. These models are intuitively attractive because they can be easily understood in terms of the underlying anatomy and physiology. The use of classical compartment modeling, on the other hand, allows modeling of data that are routinely available to the anesthesiologist, and eliminates the need to account for every possible confounding factor at each step of the partial pressure cascade of potent inhaled agents. Concepts used to describe IV kinetics can readily be applied to inhaled agents (e.g., context-sensitive half-time and effect site concentrations). The interpretation of the F(A)/F(I) vs time curve is expanded by reintroducing the concept of the general anesthetic equation-the focus is shifted from "how F(A) approaches F(I)" to "what combination of delivered concentration and fresh gas flow (FGF) can be used to attain the desired F(A)." When the desired F(A) is maintained with a FGF that is lower than minute ventilation, rebreathing causes a discrepancy between the concentration delivered by the anesthesia machine (=selected by the anesthesiologist on the vaporizer, F(D)) and that inspired by the patient. This F(D)-F(I) discrepancy may be perceived as "lack of control" and has been the rationale to use a high FGF to ensure the delivered matched the inspired concentration. Also, with low FGF there is larger variability in F(D) because of interpatient variability in uptake. The F(D)-F(I) discrepancy increases with lower FGF because of more rebreathing, and as a consequence the uptake pattern seems to be more reflected in the F(D) required to keep F(A) constant. The clinical implication for the anesthesiologist is that with high FGF few F

  14. Pharmacokinetics of heparin and related polysaccharides

    International Nuclear Information System (INIS)

    Boneu, B.; Dol, F.; Caranobe, C.; Sie, P.; Houin, G.

    1989-01-01

    The pharmacodynamic profile of standard heparin (SH), a low molecular weight derivative (CY 216) and of dermatan sulfate (DS), a new potential antithrombotic drug, was investigated in the rabbit over a large range of doses. After bolus i.v. injection of low doses, the biological activity of SH disappeared exponentially; however, its half-life was prolonged when the dose injected increased, and over 158 micrograms/kg (100 anti-factor Xa U/kg) the biological activity disappeared as a concave-convex curve. CY 216 disappeared more slowly than SH at low doses but faster than SH at higher doses. More than 90% of the DS biological activity present 1 minute after the i.v. injection disappeared exponentially without dose-dependent effects. Increasing doses of the three drugs were then delivered for 5 h under continuous infusions. Below 500 micrograms/kg/h the DS and CY 216 plateau concentrations were higher than that of SH while above this dose the SH concentration was higher than that of DS and CY 216. These observations may be explained by the results of pharmacokinetics experiments where 125 I-labeled compounds were delivered by bolus i.v. injection in association with increasing doses of their unlabeled counterparts. For SH there was a 10-fold difference between the half-life of the lower dose (32 micrograms/kg or 5 anti-factor Xa U/kg) and that of the higher dose (3200 micrograms/kg); it was demonstrated that the half-life of SH continuously shortened as its plasma concentration decreased. In contrast the CY 216 and DS half-lives were very close, independent of the dose delivered, and therefore longer than that of SH at low doses and shorter than that of SH at higher doses

  15. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs

    Directory of Open Access Journals (Sweden)

    Varaporn Buraphacheep Junyaprasert

    2015-02-01

    Full Text Available Nanocrystals, a carrier-free colloidal delivery system in nano-sized range, is an interesting approach for poorly soluble drugs. Nanocrystals provide special features including enhancement of saturation solubility, dissolution velocity and adhesiveness to surface/cell membranes. Several strategies are applied for nanocrystals production including precipitation, milling, high pressure homogenization and combination methods such as NanoEdge™, SmartCrystal and Precipitation-lyophilization-homogenization (PLH technology. For oral administration, many publications reported useful advantages of nanocrystals to improve in vivo performances i.e. pharmacokinetics, pharmacodynamics, safety and targeted delivery which were discussed in this review. Additionally, transformation of nanocrystals to final formulations and future trends of nanocrystals were also described.

  16. Pharmacokinetics and Metabolism of (R,R)-Methoxyfenoterol in Rat

    OpenAIRE

    Siluk, Danuta; Mager, Donald E.; Kim, Hee Seung; Wang, Yan; Furimsky, Anna M.; Ta, Amy; Iyer, Lalitha V.; Green, Carol E.; Wainer, Irving W.

    2010-01-01

    (R,R)-Fenoterol (Fen), a β2-adrenoceptor agonist, is under clinical investigation in the treatment of congestive heart disease. The pharmacokinetics and metabolism of the 4-methoxyphenyl derivative of (R,R)-Fen, (R,R)-MFen, have been determined following intravenous and oral administration to the rat and compared with corresponding results obtained with (R,R)-Fen. Results of the study suggest that (R,R)-MFen can offer pharmacokinetic and metabolic advantages in comparison to an earlier (R,R)-...

  17. Dosing antibiotics in neonates: review of the pharmacokinetic data.

    Science.gov (United States)

    Rivera-Chaparro, Nazario D; Cohen-Wolkowiez, Michael; Greenberg, Rachel G

    2017-09-01

    Antibiotics are often used in neonates despite the absence of relevant dosing information in drug labels. For neonatal dosing, clinicians must extrapolate data from studies for adults and older children, who have strikingly different physiologies. As a result, dosing extrapolation can lead to increased toxicity or efficacy failures in neonates. Driven by these differences and recent legislation mandating the study of drugs in children and neonates, an increasing number of pharmacokinetic studies of antibiotics are being performed in neonates. These studies have led to new dosing recommendations with particular consideration for neonate body size and maturation. Herein, we highlight the available pharmacokinetic data for commonly used systemic antibiotics in neonates.

  18. Mongo Beti's The Poor Christ of Bomba

    African Journals Online (AJOL)

    2016-03-28

    Mar 28, 2016 ... discovered the Harlem Renaissance Movement or New Negro Movement ... Beti picks up as a subject for his satire in The Poor Christ of Bomba. ..... slave driver, and the indigenous man into an instrument of production” (6).

  19. A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling.

    Science.gov (United States)

    Li, Jin; Chai, Hongyu; Li, Yang; Chai, Xuyu; Zhao, Yan; Zhao, Yunfan; Tao, Tao; Xiang, Xiaoqiang

    2016-01-01

    Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients' compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box-Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box-Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry® film to produce pulsatile tablet of

  20. Where are the poor in International Economics?

    OpenAIRE

    Luis Carvalho; Aurora A.C. Teixeira

    2011-01-01

    Despite the fact that a very significant proportion of the human population is living with financial difficulties and other constraints typical of poverty, scientific studies in the areas of Economics and especially in International Economics that address the issue of poverty and of poor countries are very few. Using bibliometric techniques, we measured the attention paid by authors from the field of International Economics to poverty and poor countries. To this end, we sorted and analyzed al...

  1. Hydrogen-Poor Core-Collapse Supernovae

    Science.gov (United States)

    Pian, Elena; Mazzali, Paolo A.

    Hydrogen-poor core-collapse supernovae (SNe) signal the explosive death of stars more massive than the progenitors of hydrogen-rich core-collapse supernovae, i.e., approximately in the range 15-50 M⊙ in main sequence. Since hydrogen-poor core-collapse supernovae include those that accompany gamma-ray bursts (GRBs), which were all rigorously identified with type Ic supernovae, their explosion energies cover almost two decades. The light curves and spectra are consequently very heterogeneous and often bear the signature of an asymmetric, i.e., aspherical, explosion. Asphericity is best traced by early-time (within days of the explosion) optical spectropolarimetry and by late-epoch (more than ˜ 100 days after explosion) low-resolution spectroscopy. While the relationship between hydrogen-poor core-collapse supernovae to hydrogen-poor super-luminous supernovae is not understood, a known case of association between an ultra-long gamma-ray burst and a very luminous hydrogen-poor supernova may help unraveling the connection. This is tantalizingly pointing to a magnetar powering source for both phenomena, although this scenario is still highly speculative. Host galaxies of hydrogen-poor supernovae are always star forming; in those of completely stripped supernovae and gamma-ray burst supernovae, the spatial distribution of the explosions follows the blue/ultraviolet light, with a correlation that is more than linear.

  2. [Diagnostic value of quantitative pharmacokinetic parameters and relative quantitative pharmacokinetic parameters in breast lesions with dynamic contrast-enhanced MRI].

    Science.gov (United States)

    Sun, T T; Liu, W H; Zhang, Y Q; Li, L H; Wang, R; Ye, Y Y

    2017-08-01

    Objective: To explore the differential between the value of dynamic contrast-enhanced MRI quantitative pharmacokinetic parameters and relative pharmacokinetic quantitative parameters in breast lesions. Methods: Retrospective analysis of 255 patients(262 breast lesions) who was obtained by clinical palpation , ultrasound or full-field digital mammography , and then all lessions were pathologically confirmed in Zhongda Hospital, Southeast University from May 2012 to May 2016. A 3.0 T MRI scanner was used to obtain the quantitative MR pharmacokinetic parameters: volume transfer constant (K(trans)), exchange rate constant (k(ep))and extravascular extracellular volume fraction (V(e)). And measured the quantitative pharmacokinetic parameters of normal glands tissues which on the same side of the same level of the lesions; and then calculated the value of relative pharmacokinetic parameters: rK(rans)、rk(ep) and rV(e).To explore the diagnostic value of two pharmacokinetic parameters in differential diagnosis of benign and malignant breast lesions using receiver operating curves and model of logistic regression. Results: (1)There were significant differences between benign lesions and malignant lesions in K(trans) and k(ep) ( t =15.489, 15.022, respectively, P 0.05). The areas under the ROC curve(AUC)of K(trans), k(ep) and V(e) between malignant and benign lesions were 0.933, 0.948 and 0.387, the sensitivity of K(trans), k(ep) and V(e) were 77.1%, 85.0%, 51.0% , and the specificity of K(trans), k(ep) and V(e) were 96.3%, 93.6%, 60.8% for the differential diagnosis of breast lesions if taken the maximum Youden's index as cut-off. (2)There were significant differences between benign lesions and malignant lesions in rK(trans), rk(ep) and rV(e) ( t =14.177, 11.726, 2.477, respectively, P quantitative pharmacokinetic parameters and the prediction probability of relative quantitative pharmacokinetic parameters( Z =0.867, P =0.195). Conclusion: There was no significant

  3. Pharmacokinetics of dietary cancer chemopreventive compound dibenzoylmethane in rats and the impact of nanoemulsion and genetic knockout of Nrf2 on its disposition.

    Science.gov (United States)

    Lin, Wen; Hong, Jin-Liern; Shen, Guoxiang; Wu, Rachel T; Wang, Yuwen; Huang, Mou-Tuan; Newmark, Harold L; Huang, Qingrong; Khor, Tin Oo; Heimbach, Tycho; Kong, Ah-Ng

    2011-03-01

    The pharmacokinetic disposition of a dietary cancer chemopreventive compound dibenzoylmethane (DBM) was studied in male Sprague-Dawley rats after intravenous (i.v.) and oral (p.o.) administrations. Following a single i.v. bolus dose, the mean plasma clearance (CL) of DBM was low compared with the hepatic blood flow. DBM displayed a high volume of distribution (Vss). The elimination terminal t1/2 was long. The mean CL, Vss and AUC0-∞/dose were similar between the i.v. 10 and 10 mg/kg doses. After single oral doses (10, 50 and 250 mg/kg), the absolute oral bioavailability (F*) of DBM was 7.4%-13.6%. The increase in AUC was not proportional to the oral doses, suggesting non-linearity. In silico prediction of oral absorption also demonstrated low DBM absorption in vivo. An oil-in-water nanoemulsion containing DBM was formulated to potentially overcome the low F* due to poor water solubility of DBM, with enhanced oral absorption. Finally, to examine the role of Nrf2 on the pharmacokinetics of DBM, since DBM activates the Nrf2-dependent detoxification pathways, Nrf2 wild-type (+/+) mice and Nrf2 knockout (-/-) mice were utilized. There was an increased systemic plasma exposure of DBM in Nrf2 (-/-) mice, suggesting that the Nrf2 genotype could also play a role in the pharmacokinetic disposition of DBM. Taken together, the results show that DBM has low oral bioavailability which could be due in part to poor water solubility and this could be overcome by a nanotechnology-based drug delivery system and furthermore the Nrf2 genotype could also play a role in the pharmacokinetics of DBM. Copyright © 2010 John Wiley & Sons, Ltd.

  4. 'Undesirable inhabitant of the union ... supplying liquor to natives': D. F. Malan and the deportation of South Africa's British and Irish lumpen proletarians 1924-1933

    Directory of Open Access Journals (Sweden)

    Jonathan Hyslop

    Full Text Available Between 1924 and 1933 scores of British and Irish immigrants were deported from South Africa for crimes that were mainly of a petty character. Prominent in their records was the offence of supplying alcohol to black people, which had been criminalised under the country's racial forms of prohibition. These deportations took place under the direction of the minister of the Interior, D. F. Malan, later notorious as the initiator of the apartheid policy. The article contends that the process of deportation is revealing of both the social trajectory of some metropolitan migrants to the Empire and of the character of the South African state. While turn-of-the-century British immigrants to southern Africa are generally thought of as upwardly socially mobile, a minority took a downward path. As 'poor whites' they constituted a threat to racial boundaries. Malan, concerned to police these boundaries, sought to remove them from society. But he was constrained by his political alliance with the British immigrant labour movement and in the end was selective in his strategy, deporting the most marginalised or lumpen proletarian, while allowing those who could claim some shreds of respectability to remain. The organisational and bureaucratic processes of deportation are traced in detail. The article endorses Robert Bickers' view that imperial history has given too little attention to poor and working class British immigrants in the Empire.

  5. Pharmacokinetic interaction between scutellarin and valsartan in rats.

    Science.gov (United States)

    Cui, Ming-Yu; Tian, Chong-Chong; Ju, Ai-Xia; Zhang, Chun-Ting; Li, Qiu-Hong

    2013-04-01

    Scutellarin is the main effective constituent of breviscapine, a flavonoid mixture isolated from the dried whole plant of Erigeron breviscapus (Vant.) Hand-Mazz, and valsartan is used as an antihypertensive drug. These two drugs have already been clinically used together to treat diabetic nephropathy (DN) in China, and the combined medications showed some enhanced protection against DN. The aim of this study is to investigate the potential pharmacokinetic interaction between scutellarin and valsartan in rats. Breviscapine injection (20 mg x kg(-1), i.v.) and valsartan (15 mg x kg-, i.g.), either alone or together were given to 18 male Sprague-Dawley rats. Concentrations of scutellarin and valsartan were quantified by HPLC, and pharmacokinetic parameters were calculated by non-compartmental methods. We found that the pharmacokinetic parameters of scutellarin altered significantly after co-administration of oral valsartan. The plasma clearance (CL(p)) and the bile clearance (CL(b)) of scutellarin were reduced significantly in the presence of valsartan. After oral administration of valsartan with or without intravenous scutellarin, however, the pharmacokinetic parameters of valsartan were comparable. In conclusion, our data suggests that the concurrent use of valsartan reduces the biliary excretion of scutellarin, and this may be due to the inhibitory effect of valsartan on the biliary excretion of scutellarin mediated by Mrp2 (Multidrug resistance-associated protein 2).

  6. Radioreceptor assay analysis of tamsulosin and terazosin pharmacokinetics

    NARCIS (Netherlands)

    Taguchi, K.; Schäfers, R. F.; Michel, M. C.

    1998-01-01

    AIMS: A radioreceptor assay has been developed for alpha1-adrenoceptor subtypes and applied to a pharmacokinetic analysis of tamsulosin and terazosin. METHODS: Young, male, healthy volunteers received 0.4 mg tamsulosin (as Omnic modified release capsules) or 5 mg terazosin (as Flotrin tablets) in a

  7. Pharmacokinetic Interaction between Magnolol and Piperine in Rats ...

    African Journals Online (AJOL)

    Purpose: To investigate the pharmacokinetic mechanism of interaction between magnolol and piperine when co-administered to rats. Methods: The rats were divided into five groups as follows: magnolol group (625 mg/kg); low dose of piperine group (20 mg/kg); high dose of piperine group (40 mg/kg); low dose of piperine ...

  8. Formulation and Pharmacokinetic Evaluation of Controlled-Release ...

    African Journals Online (AJOL)

    A coating layer was then applied with a mixture of HPMC, ethylcellulose, shellac, and HPMC phthalate. The effect of several formulation variables on in vitro drug release was studied; furthermore, the drug release kinetics of the optimized formulation was evaluated. The in vivo pharmacokinetics of the optimized formulation ...

  9. Pediatric Pharmacokinetic Data: Implications for Environmental Risk Assessment for Children

    Science.gov (United States)

    Pharmacology and toxicology share a common interest in pharmacokinetic data, especially as it is available in pediatric populations. These data have been critical to the clinical pharmacologist for many years in designing age-specific dosing regimens. Now they are being used incr...

  10. Pharmacokinetics of aerosolized tobramycin in adult patients with cystic fibrosis

    NARCIS (Netherlands)

    Touw, D J; Jacobs, F A; Brimicombe, R W; Heijerman, H G; Bakker, W; Briemer, D D

    This study was performed to determine the clinical pharmacokinetics of tobramycin in six patients with cystic fibrosis (CF) after inhalation of 600 mg. Tobramycin was administered with an ultrasonic nebulizer (WISTO SENIOR). Blood and urine were sampled until 24 h after inhalation. Maximum

  11. Pharmacokinetics of ifosfamide and some metabolites in children

    NARCIS (Netherlands)

    Kaijser, G. P.; de Kraker, J.; Bult, A.; Underberg, W. J.; Beijnen, J. H.

    1998-01-01

    The pharmacokinetics of ifosfamide and some metabolites in children was investigated. The patients received various doses of ifosfamide, mostly by continuous infusion, over several days. The penetration of ifosfamide and its metabolites into the cerebrospinal fluid was also studied in four cases.

  12. Pharmacokinetic-pharmacodynamic guided trial design in oncology

    NARCIS (Netherlands)

    van Kesteren, Ch; Mathôt, R. A. A.; Beijnen, J. H.; Schellens, J. H. M.

    2003-01-01

    The application of pharmacokinetic (PK) and pharmacodynamic (PD) modeling in drug development has emerged during the past decades and it is has been suggested that the investigation of PK-PD relationships during drug development may facilitate and optimize the design of subsequent clinical

  13. A comparison of the pharmacokinetics of Aspen Ceftriaxone and ...

    African Journals Online (AJOL)

    Intravenous ceftriaxone, of which Rocephin (ROC) is the originator brand, is recommended as first-line therapy in South Africa. Despite concerns regarding therapeutic equivalence with generic agents, this is the first study that has been conducted comparing clinical pharmacokinetics (PK) of a generic ceftriaxone ...

  14. Plasma and cerebrospinal fluid pharmacokinetics of flurbiprofen in children

    Science.gov (United States)

    Kumpulainen, Elina; Välitalo, Pyry; Kokki, Merja; Lehtonen, Marko; Hooker, Andrew; Ranta, Veli-Pekka; Kokki, Hannu

    2010-01-01

    AIMS This study was designed to characterize paediatric pharmacokinetics and central nervous system exposure of flurbiprofen. METHODS The pharmacokinetics of flurbiprofen were studied in 64 healthy children aged 3 months to 13 years, undergoing surgery with spinal anaesthesia. Children were administered preoperatively a single dose of flurbiprofen intravenously as prodrug (n = 27) or by mouth as syrup (n = 37). A single cerebrospinal fluid (CSF) sample (n = 60) was collected at the induction of anaesthesia, and plasma samples (n = 304) before, during and after the operation (up to 20 h after administration). A population pharmacokinetic model was built using the NONMEM software package. RESULTS Flurbiprofen concentrations in plasma were well described by a three compartment model. The apparent bioavailability of oral flurbiprofen syrup was 81%. The estimated clearance (CL) was 0.96 l h−1 70 kg−1. Age did not affect the clearance after weight had been included as a covariate. The estimated volume of distribution at steady state (Vss) was 8.1 l 70 kg−1. Flurbiprofen permeated into the CSF, reaching concentrations that were seven-fold higher compared with unbound plasma concentrations. CONCLUSIONS Flurbiprofen pharmacokinetics can be described using only weight as a covariate in children above 6 months, while more research is needed in neonates and in younger infants. PMID:20840447

  15. Pharmacokinetics of antiretroviral drugs in infancy | McIlleron ...

    African Journals Online (AJOL)

    Dosing in infancy is complicated by inadequate characterisation of pharmacokinetics, unpredictable drug concentrations and a lack of suitable dosage forms. Additional challenges are presented by the concomitant administration of interacting drugs (e.g. rifampicin in antituberculosis treatment) and disease conditions that ...

  16. Validation of Individual Non-Linear Predictive Pharmacokinetic ...

    African Journals Online (AJOL)

    3Department of Veterinary Medicine, Faculty of Agriculture, University of Novi Sad, Novi Sad, Republic of Serbia ... Purpose: To evaluate the predictive performance of phenytoin multiple dosing non-linear pharmacokinetic ... status epilepticus affects an estimated 152,000 ..... causal factors, i.e., infection, inflammation, tissue.

  17. A comparison of the pharmacokinetics of Aspen Ceftriaxone and ...

    African Journals Online (AJOL)

    Medicines Control Council (MCC) requires proof of equivalence ... clinical pharmacokinetics (PK) of a generic ceftriaxone formulation with the originator. .... on performance of the quality control samples). ... Endogenous components of plasma had an insignificant effect .... Clinical features and prognostic factors in adults with.

  18. Formulation and Pharmacokinetic Evaluation of Controlled-Release ...

    African Journals Online (AJOL)

    The effect of several formulation variables on in ... The in vivo pharmacokinetics of the optimized formulation was compared ... Results: The core tablets exhibited extended release consisting of drug release from the embedded ... important factor in medical treatment with respect ... The solvents for high-performance liquid.

  19. 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.

  20. Evaluation of Pharmacokinetic Assumptions Using a 443 Chemical Library (IVIVE)

    Science.gov (United States)

    With the increasing availability of high-throughput and in vitro data for untested chemicals, there is a need for pharmacokinetic (PK) models for in vitro to in vivo extrapolation (IVIVE). Though some PBPK models have been created for individual compounds us...

  1. Evaluation of Pharmacokinetic Assumptions Using a 443 Chemical Library (SOT)

    Science.gov (United States)

    With the increasing availability of high-throughput and in vitro data for untested chemicals, there is a need for pharmacokinetic (PK) models for in vitro to in vivo extrapolation (IVIVE). Though some PBPK models have been created for individual compounds using in vivo data, we ...

  2. Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus

    NARCIS (Netherlands)

    Van Overmeire, B; Touw, D; Schepens, P J; Kearns, G L; van den Anker, J N

    2001-01-01

    OBJECTIVE: Our objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth. METHODS: Ibuprofen was administered on days 3, 4, and 5 by a 15-minute intravenous infusion of 10, 5, and 5 mg/kg, respectively, with the aim of

  3. Whole body [O-15]water pharmacokinetics measured in blood

    NARCIS (Netherlands)

    Maguire, RP; Spyrou, NM; Leenders, KL

    A simple pharmacokinetic model to explain the time course of [0-15]water in human whole blood after bolus injection is described. The model has been derived from measurements in twelve healthy volunteers who were measured repeatedly, resulting in 67 datasets, made in the context of PET blood flow

  4. PHARMACOKINETIC-PHARMACODYNAMIC DRUG-INTERACTIONS WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS

    NARCIS (Netherlands)

    BROUWERS, JRBJ; DESMET, PAGM

    1994-01-01

    The nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly prescribed, especially in the elderly population. In many countries more than 10 different NSAIDs are available. As the older pyrazole compounds like phenylbutazone, oxyphenbutazone and azapropazone are most prone to pharmacokinetic

  5. In vitro metabolism and pharmacokinetic studies on methylone

    DEFF Research Database (Denmark)

    Pedersen, Anders Just; Petersen, Trine Hedebrink; Linnet, Kristian

    2013-01-01

    Abuse of the stimulant designer drug methylone (methylenedioxymethcathinone) has been documented in most parts of the world. As with many of the new designer drugs that continuously appear in the illicit drug market, little is known about the pharmacokinetics of methylone. Using in vitro studies...

  6. Pharmacodynamics and pharmacokinetics of rocuronium in intensive care patients

    NARCIS (Netherlands)

    Sparr, H.J; Wierda, J.MKH; Proost, Johannes H.; Keller, C; Khuenl-Brady, K.S

    We have studied dose requirements, recovery times and pharmacokinetics of rocuronium in 32 intensive care patients. After an initial dose of 50 mg, rocuronium was administered as maintenance doses of 25 mg whenever two responses to train-of-four (TOF) stimulation reappeared (bolus group; n=27) or by

  7. 40 CFR 795.231 - Pharmacokinetics of isopropanal.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 31 2010-07-01 2010-07-01 true Pharmacokinetics of isopropanal. 795.231 Section 795.231 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC... radioactivity in blood and in various tissues, including bone, brain, fat, gastrointestinal tract, gonads, heart...

  8. Effect of Dehydration on the Pharmacokinetics of Mefenamic Acid

    OpenAIRE

    QAMAR, Shadab

    2014-01-01

    The pharmacokinetic properties and bioavailability of mefenamic acid was studied in normal and dehydrated rabbits. High perfomance liquid chromatography (HPLC) was used for the assay of mefenamic acid in plasma samples. The mean plasma concentration and area under the plasma concentration-time curve decreased but the volume of distribution and total body clearance increased significantly (P

  9. Grey-Box Modelling of Pharmacokinetic /Pharmacodynamic Systems

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Jacobsen, Judith L.; Pedersen, Oluf

    2004-01-01

    Grey-box pharmacokinetic/pharmacodynamic (PK/PD) modelling is presented as a promising way of modelling PK/PD systems. The concept behind grey-box modelling is based on combining physiological knowledge along with information from data in the estimation of model parameters. Grey-box modelling...

  10. Comparative Pharmacokinetics of Perfluorononanoic acid in Rats and Mice*.

    Science.gov (United States)

    Perfluorononanoic acid (PFNA), a member of the perfluoroalkyl acids (PFAAs) is found at low concentrations in the environment, but is also detectable in humans and wildlife. Previous studies have examined the pharmacokinetics (PK) of lower carbon-chain PFAAs, such as perfluorobut...

  11. First reports of clinical pharmacokinetics in Nigeria | Michael ...

    African Journals Online (AJOL)

    It is the basis of therapeutic drug monitoring with the ultimate goal of keeping drugs safe. This branch of pharmacology has become the most relevant to the sub-specialty of clinical pharmacology. First reports of Clinical Pharmacokinetics in Nigeria can be credited to two gifted Nigerians, Prof Ayodele O. Iyun and Prof Lateef ...

  12. Two-Compartment Pharmacokinetic Models for Chemical Engineers

    Science.gov (United States)

    Kanneganti, Kumud; Simon, Laurent

    2011-01-01

    The transport of potassium permanganate between two continuous-stirred vessels was investigated to help chemical and biomedical engineering students understand two-compartment pharmacokinetic models. Concepts of modeling, mass balance, parameter estimation and Laplace transform were applied to the two-unit process. A good agreement was achieved…

  13. Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide in Healthy Subjects.

    Science.gov (United States)

    Dolder, Patrick C; Schmid, Yasmin; Steuer, Andrea E; Kraemer, Thomas; Rentsch, Katharina M; Hammann, Felix; Liechti, Matthias E

    2017-10-01

    Lysergic acid diethylamide (LSD) is used recreationally and in clinical research. The aim of the present study was to characterize the pharmacokinetics and exposure-response relationship of oral LSD. We analyzed pharmacokinetic data from two published placebo-controlled, double-blind, cross-over studies using oral administration of LSD 100 and 200 µg in 24 and 16 subjects, respectively. The pharmacokinetics of the 100-µg dose is shown for the first time and data for the 200-µg dose were reanalyzed and included. Plasma concentrations of LSD, subjective effects, and vital signs were repeatedly assessed. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Geometric mean (95% confidence interval) maximum plasma concentration values of 1.3 (1.2-1.9) and 3.1 (2.6-4.0) ng/mL were reached 1.4 and 1.5 h after administration of 100 and 200 µg LSD, respectively. The plasma half-life was 2.6 h (2.2-3.4 h). The subjective effects lasted (mean ± standard deviation) 8.2 ± 2.1 and 11.6 ± 1.7 h for the 100- and 200-µg LSD doses, respectively. Subjective peak effects were reached 2.8 and 2.5 h after administration of LSD 100 and 200 µg, respectively. A close relationship was observed between the LSD concentration and subjective response within subjects, with moderate counterclockwise hysteresis. Half-maximal effective concentration values were in the range of 1 ng/mL. No correlations were found between plasma LSD concentrations and the effects of LSD across subjects at or near maximum plasma concentration and within dose groups. The present pharmacokinetic data are important for the evaluation of clinical study findings (e.g., functional magnetic resonance imaging studies) and the interpretation of LSD intoxication. Oral LSD presented dose-proportional pharmacokinetics and first-order elimination up to 12 h. The effects of LSD were related

  14. Gut Microbiota-Regulated Pharmacokinetics of Berberine and Active Metabolites in Beagle Dogs After Oral Administration.

    Science.gov (United States)

    Feng, Ru; Zhao, Zhen-Xiong; Ma, Shu-Rong; Guo, Fang; Wang, Yan; Jiang, Jian-Dong

    2018-01-01

    describe gut microbiota-regulated pharmacokinetics in beagle dogs after oral administration of BBR, which is beneficial for discovery of drugs with poor absorption but good therapeutic efficacy.

  15. Pharmacokinetics of rifampin in Peruvian tuberculosis patients with and without comorbid diabetes or HIV.

    Science.gov (United States)

    Requena-Méndez, Ana; Davies, Geraint; Ardrey, Alison; Jave, Oswaldo; López-Romero, Sonia L; Ward, Stephen A; Moore, David A J

    2012-05-01

    For drug-compliant patients, poor responses to tuberculosis (TB) treatment might be attributable to subtherapeutic drug concentrations. An impaired absorption of rifampin was previously reported for patients with diabetes mellitus (DM) or HIV. The objectives of this study were to determine whether TB drug pharmacokinetics differed in Peruvian TB patients with DM or HIV. In this cross-sectional study, TB patients, recruited from health centers in Lima, Peru, had blood samples taken at 2 and 6 h after directly observed TB drug ingestion, to determine plasma concentrations of rifampin. Of 105 patients, 50 had TB without a comorbidity, 26 had coexistent DM, and 29 had coexistent HIV. Unexpectedly, the overall median 2- and 6-h levels of rifampin were 1.6 and 3.2 mg/liter, respectively, and the time to the peak concentration was 6 h (slow absorber) instead of 2 h (fast absorber) for 61 patients (62.2%). The geometric mean peak concentration of drug in serum (C(max)) was significantly higher in fast absorbers than in slow absorbers (5.0 versus 3.8 mg/liter; P = 0.05). The rifampin C(max) was significantly lower in male patients than in female patients (3.3 versus 6.3 mg/liter; P < 0.001). Neither slow nor fast absorbers with comorbidities (DM or HIV) had significantly different C(max) results compared to those of TB patients without comorbidities. An analysis of variance regression analysis showed that female gender (P < 0.001) and the time to maximum concentration of drug in serum (T(max)) at 2 h (P = 0.012) were independently correlated with increased exposure to rifampin. Most of this Peruvian study population exhibited rifampin pharmacokinetics different from those conventionally reported, with delayed absorption and low plasma concentrations, independent of the presence of an HIV or DM comorbidity.

  16. Gap analysis of pharmacokinetics and pharmacodynamics in burn patients: a review.

    Science.gov (United States)

    Steele, Amanda N; Grimsrud, Kristin N; Sen, Soman; Palmieri, Tina L; Greenhalgh, David G; Tran, Nam K

    2015-01-01

    Severe burn injury results in a multifaceted physiological response that significantly alters drug pharmacokinetics and pharmacodynamics (PK/PD). This response includes hypovolemia, increased vascular permeability, increased interstitial hydrostatic pressure, vasodilation, and hypermetabolism. These physiologic alterations impact drug distribution and excretion-thus varying the drug therapeutic effect on the body or microorganism. To this end, in order to optimize critical care for the burn population it is essential to understand how burn injury alters PK/PD parameters. The purpose of this article is to describe the relationship between burn injury and drug PK/PD. We conducted a literature review via PubMed and Google to identify burn-related PK/PD studies. Search parameters included "pharmacokinetics," "pharmacodynamics," and "burns." Based on our search parameters, we located 38 articles that studied PK/PD parameters specifically in burns. Twenty-seven articles investigated PK/PD of antibiotics, 10 assessed analgesics and sedatives, and one article researched an antacid. Out of the 37 articles, there were 19 different software programs used and eight different control groups. The mechanisms behind alterations in PK/PD in burns remain poorly understood. Dosing techniques must be adapted based on burn injury-related changes in PK/PD parameters in order to ensure drug efficacy. Although several PK/PD studies have been undertaken in the burn population, there is wide variation in the analytical techniques, software, and study sample sizes used. In order to refine dosing techniques in burns and consequently improve patient outcomes, there must be harmonization among PK/PD analyses.

  17. Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt.

    Science.gov (United States)

    Sanphui, Palash; Tothadi, Srinu; Ganguly, Somnath; Desiraju, Gautam R

    2013-12-02

    Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H···O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug.

  18. Pharmacokinetics of oxytetracycline in broiler chickens following different routes of administration.

    Science.gov (United States)

    Ziółkowski, Hubert; Grabowski, Tomasz; Jasiecka, Agnieszka; Zuśka-Prot, Monika; Barski, Dariusz; Jaroszewski, Jerzy J

    2016-02-01

    The aim of this study was to determine the pharmacokinetics of oxytetracycline (OTC) in broiler chickens following intravenous (IV), intramuscular (IM), subcutaneous (SC) and oral (PO) administrations at a dose of 15 mg/kg bodyweight. Plasma concentrations of OTC were determined using liquid chromatography-tandem mass spectrometry and non-compartmental pharmacokinetic analysis was then conducted. The absorption half-life time was 1.23 ± 0.36 h, 1.19 ± 0.52 h, and 0.49 ± 0.38 h after IM, SC and PO administration, respectively. The elimination half-life time was 27.41 ± 6.06 h, 10.23 ± 4.20 h, 7.83 ± 0.56 h, and 14.86 ± 9.23 h, and the mean residence time was 9.67 ± 1.7 h, 11.45 ± 1.76 h, 11.38 ± 0.59 h, and 10.37 ± 3.91 h after IV, IM, SC and PO administration, respectively. Bioavailability was 76.88 ± 12.90%, 92.20 ± 10.53% and 12.13 ± 4.56% after IM, SC and PO administration, respectively, which indicated that OTC is poorly absorbed from the gastrointestinal tract in broiler chickens. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Cistanches Herba: An overview of its chemistry, pharmacology, and pharmacokinetics property.

    Science.gov (United States)

    Fu, Zhifei; Fan, Xiang; Wang, Xiaoying; Gao, Xiumei

    2018-06-12

    Cistanches Herba is an Orobanchaceae parasitic plant. As a commonly used Traditional Chinese Medicine (TCM), its traditional functions include treating kidney deficiency, impotence, female infertility and senile constipation. Chemical analysis of Cistanches Herba revealed that phenylethanoid glycosides, iridoids, lignans, oligosaccharides, and polysaccharides were the main constituents. Pharmacological studies demonstrated that Cistanches Herba exhibited neuroprotective, immunomodulatory, hormonal balancing, anti-fatigue, anti-inflammatory, hepatoprotection, anti-oxidative, anti-bacterial, anti-viral, and anti-tumor effects, etc. The aim of this review is to provide updated, comprehensive and categorized information on the phytochemistry, pharmacological research and pharmacokinetics studies of the major constituents of Cistanches Herba. The literature search was conducted by systematic searching multiple electronic databases including SciFinder, ISI Web of Science, PubMed, Google Scholar and CNKI. Information was also collected from journals, local magazines, books, monographs. To date, more than 100 compounds have been isolated from this genus, include phenylethanoid glycosides, carbohydrates, lignans, iridoids, etc. The crude extracts and isolated compounds have exhibited a wide range of in vitro and in vivo pharmacologic effects, such as neuroprotective, immunomodulatory, anti-inflammatory, hepatoprotection, anti-oxidative, anti-bacterial, and anti-tumor effects. The phenylethanoid glycosides, echinacoside and acteoside have attracted the most attention for their significantly neuropharmacology effects. Pharmacokinetic studies of echinacoside and acteoside also have also been summarized. Phenylethanoid glycosides have demonstrated wide pharmacological actions and have great clinical value if challenges such as poor bioavailability, fast and extensive metabolism are addressed. Apart from phenylethanoid glycosides, other constituents of Cistanches Herba, their

  20. Characterization, pharmacokinetics, and hypoglycemic effect of berberine loaded solid lipid nanoparticles

    Directory of Open Access Journals (Sweden)

    Xue M

    2013-12-01

    Full Text Available Mei Xue, Ming-xing Yang, Wei Zhang, Xiu-min Li, De-hong Gao, Zhi-min Ou, Zhi-peng Li, Su-huan Liu, Xue-jun Li, Shu-yu Yang Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, People’s Republic of China Abstract: The high aqueous solubility, poor permeability, and absorption of berberine (BBR result in its low plasma level after oral administration, which greatly limits its clinical application. BBR solid lipid nanoparticles (SLNs were prepared to achieve improved bioavailability and prolonged effect. Developed SLNs showed homogeneous spherical shapes, small size (76.8 nm, zeta potential (7.87 mV, encapsulation efficiency (58%, and drug loading (4.2%. The power of X-ray diffraction combined with 1H nuclear magnetic resonance spectroscopy was employed to analyze chemical functional groups and the microstructure of BBR-SLNs, and indicated that the drug was wrapped in a lipid carrier. Single dose (50 mg/kg oral pharmacokinetic studies in rats showed significant improvement (P<0.05 in the peak plasma concentration, area under the curve, and variance of mean residence time of BBR-SLNs when compared to BBR alone (P<0.05, suggesting improved bioavailability. Furthermore, oral administration of both BBR and BBR-SLNs significantly suppressed body weight gain, fasting blood glucose levels, and homeostasis assessment of insulin resistance, and ameliorated impaired glucose tolerance and insulin tolerance in db/db diabetic mice. BBR-SLNs at high dose (100 mg/kg showed more potent effects when compared to an equivalent dose of BBR. Morphologic analysis demonstrated that BBR-SLNs potentially promoted islet function and protected the islet from regeneration. In conclusion, our study demonstrates that by entrapping BBR into SLNs the absorption of BBR and its anti-diabetic action were effectively enhanced. Keywords: berberine, solid lipid nanoparticles, pharmacokinetic, hypoglycemic effect

  1. Compartmental analysis, imaging techniques and population pharmacokinetic. Experiences at CENTIS

    International Nuclear Information System (INIS)

    Hernández, Ignacio; León, Mariela; Leyva, Rene; Castro, Yusniel; Ayra, Fernando E.

    2016-01-01

    Introduction: In pharmacokinetic evaluation small rodents are used in a large extend. Traditional pharmacokinetic evaluations by the two steps approach can be replaced by the sparse data design which may also represent a complicated situation to evaluate satisfactorily from the statistical point of view. In this presentation different situations of sparse data sampling are analyzed based on practical consideration. Non linear mixed effect model was selected in order to estimate pharmacokinetic parameters in simulated data from real experimental results using blood sampling and imaging procedures. Materials and methods: Different scenarios representing several experimental designs of incomplete individual profiles were evaluated. Data sets were simulated based on real data from previous experiments. In all cases three to five blood samples were considered per time point. A combination of compartmental analysis with tumor uptake obtained by gammagraphy of radiolabeled drugs is also evaluated.All pharmacokinetic profiles were analyzed by means of MONOLIX software version 4.2.3. Results: All sampling schedules yield the same results when computed using the MONOLIX software and the SAEM algorithm. Population and individual pharmacokinetic parameters were accurately estimated with three or five determination per sampling point. According with the used methodology and software tool, it can be an expected result, but demonstrating the method performance in such situations, allow us to select a more flexible design using a very small number of animals in preclinical research. The combination with imaging procedures also allows us to construct a completely structured compartmental analysis. Results of real experiments are presented demonstrating the versatility of used methodology in different evaluations. The same sampling approach can be considered in phase I or II clinical trials. (author)

  2. The poorly explored impact of uncontrolled asthma

    DEFF Research Database (Denmark)

    O'Byrne, Paul M; Pedersen, Søren; Schatz, Michael

    2013-01-01

    The goal of asthma management is to achieve disease control; however, despite the availability of effective and safe medications, for many patients asthma remains uncontrolled. One reason for this is the fear of long-term side effects from the regular use of inhaled corticosteroids (ICSs). Adverse...... effects of poorly controlled asthma (for example, obesity, pneumonia, and risks to the fetus) can be perceived as side effects of ICSs. Poorly controlled asthma adversely affects children's cardiovascular fitness, while children with well-controlled asthma perform at the same level as their peers....... Children with uncontrolled asthma also have a higher frequency of obesity than children with controlled asthma. Stress can affect asthma control, and children with poorly controlled asthma are more likely to have learning disabilities compared with those with good control. In adults, focused attention...

  3. Poor housing quality: Prevalence and health effects.

    Science.gov (United States)

    Baker, Emma; Lester, Laurence H; Bentley, Rebecca; Beer, Andrew

    2016-01-01

    Housing is a central component of productive, healthy, and meaningful lives, and a principle social determinant of health and well-being. Surprisingly, though, evidence on the ways that housing influences health in Australia is poorly developed. This stems largely from the fact that the majority of the population are accommodated in good quality housing. The dominance of a "good housing paradigm" means that households living in poor quality and unhealthy housing are doubly disadvantaged-by the quality of their housing and because policy makers in Australia do not acknowledge the health effects of housing. In this article, we examine the relationship between health outcomes and quality of housing. We base our analysis on data from the Household Income and Labour Dynamics in Australia (HILDA) survey, a panel dataset that is representative across Australia. We find a sizeable, policy-important, and to date under-acknowledged cohort of Australians whose health is influenced by poor-condition dwellings.

  4. Is American business working for the poor?

    Science.gov (United States)

    Bane, M J; Ellwood, D T

    1991-01-01

    At first glance, poverty seems to have little to do with business. When most people--managers included--think about poverty, they assume that people are poor because they are isolated from the mainstream economy, not productive participants in it. But according to Harvard University professors Mary Jo Bane and David Ellwood, this is a misleading image of the true face of poverty in the United States today. Most poor adults--and a full 90% of poor children--live in families where work is the norm, not the exception. Poor people often work or want to work. But at the low-wage end of the American economy, having a job is no guarantee of avoiding poverty. Poverty is a business issue, then, because the American poor are part of the American work force. And this poses a problem for managers. In a more competitive and fast-changing economic environment, the performance of companies increasingly depends on the capabilities of their employees. In response to this human-resource challenge, more and more managers are embracing the language of "empowerment". And yet how can low-wage employees believe empowerment when their experience of work is, quite literally, impoverishment? It is unlikely that American companies can create the work force of the future with the poverty policies of the past. Fortunately, there are some simple policy mechanisms that can assist the working poor without putting an undue burden on business. Enacting them, however, requires managers to see poverty policy as one part of a national human-resource strategy that links the strategic concerns of companies to a broad social agenda.

  5. Pharmacokinetics and pharmacokinetic-dynamic relationship between rapacuronium (Org 9487) and its 3-desacetyl metabolite (Org 9488)

    NARCIS (Netherlands)

    Schiere, S; Proost, Hans; Schuringa, M; Wierda, J.MKH

    Rapacuronium (Org 9487) is a rapid-onset and short- to intermediate-acting muscle relaxant. Its 3-desacetyl metabolite, Org 9488, also exerts neuromuscular-blocking activity that. may became apparent after prolonged maintenance of relaxation with rapacuronium. In this study, the pharmacokinetic

  6. [Study on differences between pharmacokinetics and chromatopharmacodynamics for Chinese materia medica formulae].

    Science.gov (United States)

    He, Fuyuan; Deng, Kaiwen; Zou, Huan; Qiu, Yun; Chen, Feng; Zhou, Honghao

    2011-01-01

    To study on the differences between chromatopharmacokinetics (pharmacokinetics with fingerprint chromatography) and chromatopharmacodynamics (pharmacodynamics with fingerprint chromatography) of Chinese materia medica formulae to answer the question whether the pharmacokinetic parameters of multiple composites can be utilized to guide the medication of multiple composites. On the base of established four chromatopharmacology (pharmacology with chromatographic fingerprint), the pharmacokinetics, and pharmacodynamics were analyzed comparably on their mathematical model and parameter definition. On the basis of quantitative pharmacology, the function expressions and total statistical parameters, such as total zero moment, total first moment, total second moment of the pharmacokinetics, and pharmacodynamics were analyzed to the common expressions and elucidated results for single and multiple components in Chinese materia medica formulae. Total quantitative pharmacokinetic, i.e., chromatopharmacokinetic parameter were decided by each component pharmacokinetic parameters, whereas the total quantitative pharmacodynamic, i.e., chromatopharmacodynamic parameter were decided by both of pharmacokinetic and pharmacodynamic parameters of each components. The pharmacokinetic parameters were corresponded to pharmacodynamic parameters with an existing stable effective coefficient when the constitutive ratio of each composite was a constant. The effects of Chinese materia medica were all controlled by pharmacokinetic and pharmacodynamic coefficient. It is a special case that the pharmacokinetic parameter could independently guide the clinical medication for single component whereas the chromatopharmacokinetic parameters are not applied to the multiple drug combination system, and not be used to solve problems of chromatopharmacokinetic of Chinese materia medica formulae.

  7. Who speaks for the poor (question mark)

    International Nuclear Information System (INIS)

    Wyatt, Alan

    1981-01-01

    Nuclear energy benefits the poor, because it alleviates a shortage of petroleum. Less-developed countries suffer directly from a shortage of petroleum; also petroleum is necessary to raise food in the developed countries for export to the less-developed countries. (L.L.)

  8. Text comprehension strategy instruction with poor readers

    NARCIS (Netherlands)

    Van den Bos, K.P.; Aarnoudse, C.C.; Brand-Gruwel, S.

    1998-01-01

    The goal of this study was to investigate the effects of teaching text comprehension strategies to children with decoding and reading comprehension problems and with a poor or normal listening ability. Two experiments are reported. Four text comprehension strategies, viz., question generation,

  9. University Students with Poor Reading Comprehension

    Science.gov (United States)

    Georgiou, George K.; Das, J. P.

    2015-01-01

    The present study aimed to examine the nature of the working memory and general cognitive ability deficits experienced by university students with a specific reading comprehension deficit. A total of 32 university students with poor reading comprehension but average word-reading skills and 60 age-word-matched controls with no comprehension…

  10. Adult Literacy and the Poor Farming People.

    Science.gov (United States)

    Mathur, J. C.

    1978-01-01

    In discussing Rafe-uz-Zaman's essay on adult literacy and national development (see v9, n1 of this journal), the author cites examples to support his thesis that mass literacy campaigns in predominately agricultural countries can be successful only if there is simultaneous undertaking of economic development programs focused on the rural poor. (MF)

  11. Planning Behaviour in Good and Poor Readers

    Science.gov (United States)

    Mahapatra, Shamita

    2016-01-01

    A group of 50 good readers and a group of 50 poor readers of Grade 5 matched for age and intelligence and selected on the basis of their proficiency in reading comprehension were tested for their competence in word reading and the process of planning at three different levels, namely, perceptual, memory and conceptual in order to study the…

  12. Getting to Know L2 Poor Comprehenders

    Science.gov (United States)

    Zoghi, Masoud; Mustapha, Ramlee; Maasum, Tengku Nor Rizan BT Tengku Mohamad

    2011-01-01

    Among the plethora of studies conducted thus far to explore the factors affecting EFL reading effectiveness, scant attention seems to be paid to the why of poor reading comprehension of most EFL learners. In this regard, the present article capitalized on qualitative research on a small scale, for the purpose of addressing the not-so-often debated…

  13. Dealing with living in poor neighbourhoods

    NARCIS (Netherlands)

    Kleinhans, R.; Van der Land, M.; Doff, W.

    2010-01-01

    In this prologue to the special issue, the guest editors place the contributions in the context of current debates on living in concentrated poverty neighbourhoods. These debates concern two broad categories of residents: poor households that are assisted to move from concentrations of poverty to

  14. Correcting Poor Posture without Awareness or Willpower

    Science.gov (United States)

    Wernik, Uri

    2012-01-01

    In this article, a new technique for correcting poor posture is presented. Rather than intentionally increasing awareness or mobilizing willpower to correct posture, this approach offers a game using randomly drawn cards with easy daily assignments. A case using the technique is presented to emphasize the subjective experience of living with poor…

  15. Poor migrants in Bandung: settlement and employment

    NARCIS (Netherlands)

    Bruinessen, M.M. van

    1989-01-01

    Sukapakir is the real but appropriate name of a poor urban kampung in southwestern Bandung. It is one of the most densely populated neighbourhoods of the town now, although some forty years ago it was still a largely rural district. On the fringes of Sukapakir, one finds even today a few sawah

  16. Preliminary physiologically based pharmacokinetic models for benzo[a]pyrene and dibenzo[def,p]chrysene in rodents

    International Nuclear Information System (INIS)

    Crowell, Susan Ritger; Amin, Shantu G.; Anderson, Kim A.; Krishnegowda, Gowdahalli; Sharma, Arun K.; Soelberg, Jolen J.; Williams, David E.; Corley, Richard A.

    2011-01-01

    Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated as byproducts of natural and anthropogenic combustion processes. Despite significant public health concern, physiologically based pharmacokinetic (PBPK) modeling efforts for PAHs have so far been limited to naphthalene, plus simpler PK models for pyrene, nitropyrene, and benzo[a]pyrene (B[a]P). The dearth of published models is due in part to the high lipophilicity, low volatility, and myriad metabolic pathways for PAHs, all of which present analytical and experimental challenges. Our research efforts have focused upon experimental approaches and initial development of PBPK models for the prototypic PAH, B[a]P, and the more potent, albeit less studied transplacental carcinogen, dibenzo[def,p]chrysene (DBC). For both compounds, model compartments included arterial and venous blood, flow limited lung, liver, richly perfused and poorly perfused tissues, diffusion limited fat, and a two compartment theoretical gut (for oral exposures). Hepatic and pulmonary metabolism was described for both compounds, as were fractional binding in blood and fecal clearance. Partition coefficients for parent PAH along with their diol and tetraol metabolites were estimated using published algorithms and verified experimentally for the hydroxylated metabolites. The preliminary PBPK models were able to describe many, but not all, of the available data sets, comprising multiple routes of exposure (oral, intravenous) and nominal doses spanning several orders of magnitude. Supported by Award Number P42 ES016465 from the National Institute of Environmental Health Sciences. -- Highlights: ► We present PBPK models for benzo[a]pyrene (B[a]P) and dibenzo[def,p]chrysene (DBC). ► B[a]P model accurately predicts data from multiple sources over a wide dose range. ► DBC model was based on the B[a]P model as less chemical specific data is available. ► DBC model accurately predicted preliminary

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

    Science.gov (United States)

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

    2008-01-01

    To develop pharmacokinetics models to describe the disposition of small lipophilic molecules in the cornea and retina after periocular (subconjunctival or posterior subconjunctival) administration. Compartmental pharmacokinetics analysis was performed on the corneal and retinal data obtained after periocular administration of 3 mg of celecoxib (a selective COX-2 inhibitor) to Brown Norway (BN) rats. Berkeley Madonna, a differential and difference equation-based modeling software, was used for the pharmacokinetics modeling. The data were fit to different compartment models with first-order input and disposition, and the best fit was selected on the basis of coefficient of regression and Akaike information criteria (AIC). The models were validated by using the celecoxib data from a prior study in Sprague-Dawley (SD) rats. The corneal model was also fit to the corneal data for prednisolone at a dose of 2.61 mg in albino rabbits, and the model was validated at two other doses of prednisolone (0.261 and 26.1 mg) in these rabbits. Model simulations were performed with the finalized model to understand the effect of formulation on corneal and retinal pharmacokinetics after periocular administration. Celecoxib kinetics in the BN rat cornea can be described by a two-compartment (periocular space and cornea, with a dissolution step for periocular formulation) model, with parallel elimination from the cornea and the periocular space. The inclusion of a distribution compartment or a dissolution step for celecoxib suspension did not lead to an overall improvement in the corneal data fit compared with the two-compartment model. The more important parameter for enhanced fit and explaining the apparent lack of an increase phase in the corneal levels is the inclusion of the initial leak-back of the dose from the periocular space into the precorneal area. The predicted celecoxib concentrations from this model also showed very good correlation (r = 0.99) with the observed values in

  18. Parenting Efficacy and the Early School Adjustment of Poor and Near-Poor Black Children

    Science.gov (United States)

    Jackson, Aurora P.; Choi, Jeong-Kyun; Bentler, Peter M.

    2009-01-01

    This short-term longitudinal study investigates whether maternal educational attainment, maternal employment status, and family income affect African American children's behavioral and cognitive functioning over time through their impacts on mothers' psychological functioning and parenting efficacy in a sample of 100 poor and near-poor single…

  19. Altering ethanol pharmacokinetics to treat alcohol use disorder: Can you teach an old dog new tricks?

    Science.gov (United States)

    Haass-Koffler, Carolina L; Akhlaghi, Fatemeh; Swift, Robert M; Leggio, Lorenzo

    2017-07-01

    Disulfiram was the first pharmacotherapy approved to treat alcohol use disorder in the 1950s. Disulfiram alters ethanol pharmacokinetics and causes uncomfortable reactions (e.g. headache, tachycardia, nausea, flushing and hypotension) when alcohol is consumed. Subsequently, a better understanding of the neurobiological pathways involved in alcohol use disorder led to the development of other medications (e.g. naltrexone and acamprosate). These neurobiological-based medications act on alcohol use disorder-related phenotypes including craving, stress, and/or withdrawal. The original approach to treat alcohol use disorder, by altering ethanol pharmacokinetics has been much less investigated. Recent research on ethanol pharmacokinetics has shed light on the mechanisms of action underlying alcohol use disorder and how some medications that alter ethanol pharmacokinetics may be helpful in treating alcohol use disorder. This review summarizes and discusses the complex pharmacokinetics of ethanol, and proposes that altering ethanol pharmacokinetics via novel pharmacological approaches may be a viable approach to treat alcohol use disorder.

  20. A Preliminary Pharmacokinetic Study of Betulin, the Main Pentacyclic Triterpene from Extract of Outer Bark of Birch (Betulae alba cortex

    Directory of Open Access Journals (Sweden)

    Melanie N. Laszczyk

    2008-12-01

    Full Text Available During the last two decades triterpenes have attracted attention because of their pharmacological potential. Triterpene extract (TE from outer bark of birch consisting mainly of betulin is able to form an oleogel which was successfully tested in the treatment of actinic keratosis. Some aspects of TE in vitro pharmacology are already known. Now we show preliminary pharmacokinetics of betulin and results of a subchronic toxicity study of TE in rats and dogs. Because of poor aqueous solubility of the TE-triterpenes (< 0.1 μg/mL respectively, for pharmacokinetic studies it was suspended in sesame oil (rats, i.p. and PEG 400 / 0.9 % NaCl (dogs, s.c.. I.p. administered, betulin, the main component of TE, shows time dependency over a period of 4 h and reaches a dose-independent serum level of 0.13 μg/mL. Dose dependency was observed with s.c. administration. At 300 mg/kg a maximum plasma concentration of 0.33 μg/mL betulin was detected after 28 daily applications. The subchronic toxicity study showed no toxicity of TE in rats (i.p. and dogs (s.c.. In conclusion, triterpene extract from birch bark is safe, its betulin is bioavailable and in addition to published triterpene biological activities TE provides high potential for further pharmaceutical and pharmacological research.

  1. Poor Semen Quality Predicts Increased Mortality

    DEFF Research Database (Denmark)

    Jensen, Tina Kold; Bostofte, Erik; Jacobsen, Rune

    Objective: Over recent decades a possible decrease in semen quality and an increase in the incidence of testicular cancer have been reported. In addition, men with poor semen quality have been reported to be at increased risk of developing testicular cancer whereas the risk of other cancers...... is not increased. The long-term survival of men with poor semen quality is, however, unknown. We therefore studied the associations between semen characteristics and subsequent mortality. Back to Top Material and Methods: The Copenhagen Sperm Analysis Laboratory is one of several public semen analysis laboratories...... in Denmark and examines semen samples mostly from men in the area of Copenhagen. Men are referred to the clinic by general practitioners and urologists, and the investigations are paid for through the public health system. A total of 34.442 men had a semen analysis done at the laboratory during 1963 to 1995...

  2. Lipid nanoparticles for the delivery of poorly water-soluble drugs.

    Science.gov (United States)

    Bunjes, Heike

    2010-11-01

    This review discusses important aspects of lipid nanoparticles such as colloidal lipid emulsions and, in particular, solid lipid nanoparticles as carrier systems for poorly water-soluble drugs, with a main focus on the parenteral and peroral use of these carriers. A short historical background of the development of colloidal lipid emulsions and solid lipid nanoparticles is provided and their similarities and differences are highlighted. With regard to drug incorporation, parameters such as the chemical nature of the particle matrix and the physicochemical nature of the drug, effects of drug partition and the role of the particle interface are discussed. Since, because of the crystalline nature of their lipid core, solid lipid nanoparticles display some additional important features compared to emulsions, their specificities are introduced in more detail. This mainly includes their solid state behaviour (crystallinity, polymorphism and thermal behaviour) and the consequences of their usually non-spherical particle shape. Since lipid nanoemulsions and -suspensions are also considered as potential means to alter the pharmacokinetics of incorporated drug substances, some underlying basic considerations, in particular concerning the drug-release behaviour of such lipid nanodispersions on dilution, are addressed as well. Colloidal lipid emulsions and solid lipid nanoparticles are interesting options for the delivery of poorly water-soluble drug substances. Their specific physicochemical properties need, however, to be carefully considered to provide a rational basis for their development into effective carrier systems for a given delivery task. © 2010 The Author. Journal compilation © 2010 Royal Pharmaceutical Society of Great Britain.

  3. Current stress and poor oral health

    OpenAIRE

    Vasiliou, A.; Shankardass, K.; Nisenbaum, R.; Qui?onez, C.

    2016-01-01

    Background Psychological stress appears to contribute to poor oral health systemically in combination with other chronic diseases. Few studies directly examine this relationship. Methods Data from a cross-sectional study of 2,412 participants between the ages of 25?64 years old living in the City of Toronto between 2009 and 2012 were used to examine the relationship between current stress and two self-rated oral health outcomes (general oral health and oral pain). Dental care utilization and ...

  4. Pharmacokinetics of inhaled anesthetics in green iguanas (Iguana iguana).

    Science.gov (United States)

    Brosnan, Robert J; Pypendop, Bruno H; Barter, Linda S; Hawkins, Michelle G

    2006-10-01

    To test the hypothesis that differences in anesthetic uptake and elimination in iguanas would counter the pharmacokinetic effects of blood:gas solubility and thus serve to minimize kinetic differences among inhaled agents. 6 green iguanas (Iguana iguana). Iguanas were anesthetized with isoflurane, sevoflurane, or desflurane in a Latin-square design. Intervals from initial administration of an anesthetic agent to specific induction events and from cessation of administration of an anesthetic agent to specific recovery events were recorded. End-expired gas concentrations were measured during anesthetic washout. Significant differences were not detected for any induction or recovery events for any inhalation agent in iguanas. Washout curves best fit a 2-compartment model, but slopes for both compartments did not differ significantly among the 3 anesthetics. Differences in blood:gas solubility for isoflurane, sevoflurane, and desflurane did not significantly influence differences in pharmacokinetics for the inhalation agents in iguanas.

  5. Effect of diclofenac on the pharmacokinetics of moxifloxacin in rats.

    Science.gov (United States)

    Chen, L; Guo, S; Xu, M; Wu, L-X; Zhang, J-H

    2014-07-01

    A sensitive and specific method was developed and validated for the determination of moxifloxacin in plasma using HPLC. The effect of diclofenac (12.5, 25, 50 mg/kg) on the pharmacokinetics of orally administered moxifloxacin (40 mg/kg) in rats was investigated. Pharmacokinetic parameters of moxifloxacin were determined in rats following oral administration to rats in the presence and absence of diclofenac. The coadministration of the 2 drugs resulted in 10~29.5% decrease of the AUC and a 24.7~34% decrease of t1/2 for moxifloxacin; Tmax for moxifloxacin was 1.41~1.9-fold higher than that after the administration of moxifloxacin alone; Cmax for moxifloxacin decreased by 20.5~49%, as compared to that after the administration of moxifloxacin alone. Consequently, moxifloxacin and diclofenac should be monitored closely for potential drug interactions. © Georg Thieme Verlag KG Stuttgart · New York.

  6. Nonstandard Finite Difference Method Applied to a Linear Pharmacokinetics Model

    Directory of Open Access Journals (Sweden)

    Oluwaseun Egbelowo

    2017-05-01

    Full Text Available We extend the nonstandard finite difference method of solution to the study of pharmacokinetic–pharmacodynamic models. Pharmacokinetic (PK models are commonly used to predict drug concentrations that drive controlled intravenous (I.V. transfers (or infusion and oral transfers while pharmacokinetic and pharmacodynamic (PD interaction models are used to provide predictions of drug concentrations affecting the response of these clinical drugs. We structure a nonstandard finite difference (NSFD scheme for the relevant system of equations which models this pharamcokinetic process. We compare the results obtained to standard methods. The scheme is dynamically consistent and reliable in replicating complex dynamic properties of the relevant continuous models for varying step sizes. This study provides assistance in understanding the long-term behavior of the drug in the system, and validation of the efficiency of the nonstandard finite difference scheme as the method of choice.

  7. Pharmacokinetics of trefoil peptides and their stability in gastrointestinal contents

    DEFF Research Database (Denmark)

    Kjellev, Stine; Vestergaard, Else Marie; Nexø, Ebba

    2007-01-01

    Trefoil factor family (TFF) peptides are considered promising for therapeutic use in gastrointestinal diseases, and there is a need to explore the fate of injected TFF and the stability of the peptides in the gastrointestinal tract. We studied the pharmacokinetics of intravenously (i.v.) administ......Trefoil factor family (TFF) peptides are considered promising for therapeutic use in gastrointestinal diseases, and there is a need to explore the fate of injected TFF and the stability of the peptides in the gastrointestinal tract. We studied the pharmacokinetics of intravenously (i.......v.) administered hTFF2 in mice and rats and of hTFF3 administered i.v., intramuscularly, intraperitoneally, and subcutaneously in mice, and estimated by ELISA the decay of the peptides added to rat and human gastrointestinal contents. We found that i.v. injected hTFF2 and hTFF3 were cleared from the circulation...

  8. Pharmacokinetics of drugs in cachectic patients: a systematic review.

    Directory of Open Access Journals (Sweden)

    Katja Trobec

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

  9. Pharmacokinetics of amikacin during hemodialysis and peritoneal dialysis

    DEFF Research Database (Denmark)

    Regeur, L; Colding, H; Jensen, H

    1977-01-01

    The pharmacokinetics of amikacin were examined in six bilaterally nephrectomized patients undergoing hemodialysis and in four patients with a minimal residual renal function undergoing peritoneal dialysis. The mean elimination half-life before the dialysis was 86.5 h in the anephric patients and 44...... renal function. During hemodialysis the half-life decreased to less than 10% (5.6 h) of the pretreatment value. The effectiveness of peritoneal dialysis was less as the half-life decreased to only about 30% (17.9 h) of the pretreatment value. During the dialyses a significant correlation between...... the half-life of amikacin and the decrease in blood urea and serum creatinine was demonstrated. The pharmacokinetic data were used to make dosage regimen recommendations for the treatment of patients undergoing intermittent hemodialysis or peritoneal dialysis....

  10. Modeling in biopharmaceutics, pharmacokinetics, and pharmacodynamics homogeneous and heterogeneous approaches

    CERN Document Server

    Macheras, Panos

    2006-01-01

    The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with empirical, compartmental, and stochastic pharmacokinetic models, and the fourth mainly with nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. Many examples are used to illustrate the intrinsic complexity of drug administration related phenomena in the human, justifying the use of advanced modeling methods. This timely and useful book will appeal to graduate students and researchers in pharmacology, pharmaceutical scienc...

  11. Stereotactic Radiosurgery for Poor Performance Status Patients

    Energy Technology Data Exchange (ETDEWEB)

    Kubicek, Gregory J., E-mail: kubicek-gregory@cooperhealth.edu [Department of Radiation Oncology, Cooper University Hospital, Camden, New Jersey (United States); Turtz, Alan [Department of Neurological Surgery, Cooper University Hospital, Camden, New Jersey (United States); Xue, Jinyu; Patel, Ashish; Richards, Gregory; LaCouture, Tamara [Department of Radiation Oncology, Cooper University Hospital, Camden, New Jersey (United States); Cappelli, Louis; Diestelkamp, Tim [Rowan Graduate School, Camden, New Jersey (United States); Saraiya, Piya [Department of Diagnostic Radiology, Cooper University Hospital, Camden, New Jersey (United States); Bexon, Anne [Department of Neurological Surgery, Cooper University Hospital, Camden, New Jersey (United States); Lerman, Nati [Department of Medical Oncology, Cooper University Hospital, Camden, New Jersey (United States); Goldman, Howard Warren [Department of Neurological Surgery, Cooper University Hospital, Camden, New Jersey (United States)

    2016-07-01

    Purpose: Patients with poor performance status (PS), usually defined as a Karnofsky Performance Status of 60 or less, were not eligible for randomized stereotactic radiosurgery (SRS) studies, and many guidelines suggest that whole-brain radiation therapy (WBRT) is the most appropriate treatment for poor PS patients. Methods and Materials: In this retrospective review of our SRS database, we identified 36 patients with PS of 60 or less treated with SRS for central nervous system (CNS) metastatic disease. PS, as defined by the Karnofsky Performance Status, was 60 (27 patients), 50 (8 patients), or 40 (1 patient). The median number of CNS lesions treated was 3. Results: Median overall survival (OS) was 7.2 months (range, 0.73-25.6 months). Fifteen patients (41%) were alive at 6 months, and 6 patients (16.6%) were alive at 1 year. There was no difference in OS in patients who underwent previous WBRT. There were no local failures or cases of radiation toxicity. Distant CNS failures were seen in 9 patients (25%). Conclusions: Our patients with poor PS had reasonable median OS and relatively low distant CNS failure rates. Patients in this patient population may be ideal candidates for SRS compared with WBRT given the low incidence of distant failure over their remaining lives and the favorable logistics of single-fraction treatment for these patients with debility and their caregivers.

  12. Pharmacokinetics of bevacizumab after topical and intravitreal administration in human eyes

    OpenAIRE

    Moisseiev, Elad; Waisbourd, Michael; Ben-Artsi, Elad; Levinger, Eliya; Barak, Adiel; Daniels, Tad; Csaky, Karl; Loewenstein, Anat; Barequet, Irina S.

    2013-01-01

    Background Topical bevacizumab is a potential treatment modality for corneal neovascularization, and several recent studies have demonstrated its efficacy. No previous study of the pharmacokinetics of topical bevacizumab has been performed in human eyes. The purpose of this study is to investigate the pharmacokinetics of topical administration of bevacizumab in human eyes, and also to compare the pharmacokinetics of intravitreal bevacizumab injections with previously reported data. Methods Tw...

  13. Pharmacokinetic and pharmacodynamic drug interactions with ethanol (alcohol).

    Science.gov (United States)

    Chan, Lingtak-Neander; Anderson, Gail D

    2014-12-01

    Ethanol (alcohol) is one of the most widely used legal drugs in the world. Ethanol is metabolized by alcohol dehydrogenase (ADH) and the cytochrome P450 (CYP) 2E1 drug-metabolizing enzyme that is also responsible for the biotransformation of xenobiotics and fatty acids. Drugs that inhibit ADH or CYP2E1 are the most likely theoretical compounds that would lead to a clinically significant pharmacokinetic interaction with ethanol, which include only a limited number of drugs. Acute ethanol primarily alters the pharmacokinetics of other drugs by changing the rate and extent of absorption, with more limited effects on clearance. Both acute and chronic ethanol use can cause transient changes to many physiologic responses in different organ systems such as hypotension and impairment of motor and cognitive functions, resulting in both pharmacokinetic and pharmacodynamic interactions. Evaluating drug interactions with long-term use of ethanol is uniquely challenging. Specifically, it is difficult to distinguish between the effects of long-term ethanol use on liver pathology and chronic malnutrition. Ethanol-induced liver disease results in decreased activity of hepatic metabolic enzymes and changes in protein binding. Clinical studies that include patients with chronic alcohol use may be evaluating the effects of mild cirrhosis on liver metabolism, and not just ethanol itself. The definition of chronic alcohol use is very inconsistent, which greatly affects the quality of the data and clinical application of the results. Our study of the literature has shown that a significantly higher volume of clinical studies have focused on the pharmacokinetic interactions of ethanol and other drugs. The data on pharmacodynamic interactions are more limited and future research addressing pharmacodynamic interactions with ethanol, especially regarding the non-central nervous system effects, is much needed.

  14. Transplacental pharmacokinetics of diclofenac in perfused human placenta.

    Science.gov (United States)

    Shintaku, Kyohei; Hori, Satoko; Tsujimoto, Masayuki; Nagata, Hideaki; Satoh, Shoji; Tsukimori, Kiyomi; Nakano, Hitoo; Fujii, Tomoyuki; Taketani, Yuji; Ohtani, Hisakazu; Sawada, Yasufumi

    2009-05-01

    The aims of this study were to evaluate the transplacental transfer properties of diclofenac and to determine the effect of L-lactic acid on the transplacental transfer of diclofenac. The maternal and fetal vessels of human placenta were perfused in a single-pass mode with a solution containing diclofenac and antipyrine. The transplacental pharmacokinetic model was fitted to the time profiles of the drug concentrations in the effluent and placenta to obtain transplacental pharmacokinetic parameters. In addition, chloride ion in the perfusate was partially replaced with L-lactic acid to see the change in the transplacental transfer properties of diclofenac. The TPT(ss) value (ratio of the rate of amount transferred across the placenta to that infused in the steady state) of diclofenac was 2.22%, which was approximately one-third that of antipyrine and was significantly reduced in the presence of L-lactic acid. The transplacental pharmacokinetic model could adequately explain the transplacental transfer of diclofenac with influx clearances from maternal and fetal perfusates to placental tissue of 0.276 and 0.0345 ml/min/g cotyledon and efflux rate constants from placental tissue to maternal and fetal perfusates of 0.406 and 0.0337 min(-1), respectively. By taking into account protein binding, the placental tissue/plasma concentration ratio in humans for diclofenac was estimated to be 0.108 ml/g of cotyledon and was smaller than that of antipyrine. In conclusion, human placental perfusion and transplacental pharmacokinetic modeling allowed us to determine the transplacental transfer properties of diclofenac quantitatively. Diclofenac may share transplacental transfer system(s) with L-lactic acid.

  15. Organic anion transporting polypeptide 1B transporters modulate hydroxyurea pharmacokinetics

    OpenAIRE

    Walker, Aisha L.; Lancaster, Cynthia S.; Finkelstein, David; Ware, Russell E.; Sparreboom, Alex

    2013-01-01

    Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assess...

  16. Population Pharmacokinetics of Fentanyl in the Critically Ill

    Science.gov (United States)

    Choi, Leena; Ferrell, Benjamin A; Vasilevskis, Eduard E; Pandharipande, Pratik P; Heltsley, Rebecca; Ely, E Wesley; Stein, C Michael; Girard, Timothy D

    2016-01-01

    Objective To characterize fentanyl population pharmacokinetics in patients with critical illness and identify patient characteristics associated with altered fentanyl concentrations. Design Prospective cohort study. Setting Medical and surgical ICUs in a large tertiary care hospital in the United States. Patients Patients with acute respiratory failure and/or shock who received fentanyl during the first five days of their ICU stay. Measurements and Main Results We collected clinical and hourly drug administration data and measured fentanyl concentrations in plasma collected once daily for up to five days after enrollment. Among 337 patients, the mean duration of infusion was 58 hours at a median rate of 100 µg/hr. Using a nonlinear mixed-effects model implemented by NONMEM, we found fentanyl pharmacokinetics were best described by a two-compartment model in which weight, severe liver disease, and congestive heart failure most affected fentanyl concentrations. For a patient population with a mean weight of 92 kg and no history of severe liver disease or congestive heart failure, the final model, which performed well in repeated 10-fold cross-validation, estimated total clearance (CL), intercompartmental clearance (Q), and volumes of distribution for the central (V1) and peripheral compartments (V2) to be 35 (95% confidence interval: 32 to 39) L/hr, 55 (42 to 68) L/hr, 203 (140 to 266) L, and 523 (428 to 618) L, respectively. Severity of illness was marginally associated with fentanyl pharmacokinetics but did not improve the model fit after liver and heart disease were included. Conclusions In this study, fentanyl pharmacokinetics during critical illness were strongly influenced by severe liver disease, congestive heart failure, and weight, factors that should be considered when dosing fentanyl in the ICU. Future studies are needed to determine if data-driven fentanyl dosing algorithms can improve outcomes for ICU patients. PMID:26491862

  17. Pharmacokinetic modeling of therapies for systemic lupus erythematosus

    OpenAIRE

    Yang, Xiaoyan; Sherwin, Catherine MT; Yu, Tian; Yellepeddi, Venkata K; Brunner, Hermine I; Vinks, Alexander A

    2015-01-01

    With the increasing use of different types of therapies in treating autoimmune diseases such as systemic lupus erythematosus (SLE), there is a need to utilize pharmacokinetic (PK) strategies to optimize the clinical outcome of these treatments. Various PK analysis approaches, including population PK modeling and physiologically based PK modeling, have been used to evaluate drug PK characteristics and population variability or to predict drug PK profiles in a mechanistic manner. This review ou...

  18. Pharmacokinetics of Caffeic Acid from Methanol Seed Extract of ...

    African Journals Online (AJOL)

    Purpose: To describe caffeic acid-based pharmacokinetics of methanol extract of seed of Syzygium cumini L. in rats. Methods: A dose of the extract (500 mg, equivalent to 37.135 mg caffeic acid) was administered orally to 6 male Wister rats, weighing 200 ± 10 g. Blood samples (0.5 mL), collected from the tail vein at 0, 15, ...

  19. [A study of population pharmacokinetics of linezolid in Chinese].

    Science.gov (United States)

    Zhang, L; Bai, N; Liu, Y N; Wang, R

    2016-12-12

    Objective: To study the population pharmacokinetic (PPK) profiles of linezolid in Chinese healthy volunteers and infected patients. Methods: Linezolid 600 mg was administered to 31 Chinese healthy volunteers with a single dose and to 57 infected patients every 12 h for at least 5 doses. High performance liquid chromatography was applied to determine the plasma concentration of linezolid. Nonlinear mixed-effects modeling method was applied to analyze the PPK profiles. Results: For healthy volunteers with single dose of linezolid, 2-compartment with linear elimination model was the most appropriate structural pharmacokinetic model. The population typical value of apparent volume of central compartment was 26.99 L, volume of peripheral compartment was 22.22 L, apparent clearance of central compartment was 7.99 L/h, and clearance of peripheral compartment was 101.28 L/h. For each 1 kg deviation of weight from the mean value, 0.62 L of volume of peripheral compartment was correlated. For Chinese infected patients with multiple doses of linezolid, 1-compartment with linear elimination model was the most appropriate structural pharmacokinetic model. The population typical value of apparent volume was 38.85 L, and apparent clearance was 4.70 L/h. For each 1 kg deviation of weight from the mean value, 0.79 L of volume, as well as 0.04 L/h of clearance were correlated. For each 1 year deviation of age from the mean value, -0.045 L/h of clearance was correlated. Conclusions: The pharmacokinetic profiles of linezolid in Chinese simulate a 2-compartment with linear elimination model when single dose is administrated, and the weight is linearly positive-correlated to volume. While a 1-compartment with linear elimination model is appropriate when multiple doses are administrated, and the weight is linearly positive-correlated to volume and clearance, but the age is linearly negative-correlated to clearance.

  20. Dose- and time-dependent pharmacokinetics of apigenin trimethyl ether.

    Science.gov (United States)

    Elhennawy, Mai Gamal; Lin, Hai-Shu

    2018-06-15

    Apigenin trimethyl ether (5,7,4'-trimethoxyflavone, ATE), one of the key polymethoxyflavones present in black ginger (rhizome of Kaempferia parviflora) possesses various health-promoting activities. To optimize its medicinal application, the pharmacokinetics of ATE was assessed in Sprague-Dawley rats with emphases to identify the impacts from dose and repeated dosing on its major pharmacokinetic parameters. Plasma ATE levels were monitored by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Upon single intravenous administration (2 mg/kg), plasma levels of ATE declined through an apparent first-order process while dose-escalation to 4 and 8 mg/kg led to its non-linear disposition, which could be described by the Michaelis-Menten model. Similarly, dose-dependent oral pharmacokinetics was confirmed and when the dose was escalated from 5 to 15 and 45 mg/kg, much longer mean residence time (MRT 0→last ), higher dose-normalized maximal plasma concentration (C max /Dose) and exposure (AUC/Dose) were observed at 15 and/or 45 mg/kg. One-week daily oral administration of ATE at 15 mg/kg caused its accelerated elimination and the plasma exposure (AUC) after intravenous (2 mg/kg) and oral administration (15 mg/kg) dropped ~40 and 60%, respectively. As ATE displayed both dose- and time-dependent pharmacokinetics, caution is needed in the medicinal applications of ATE and/or black ginger. Copyright © 2018 Elsevier B.V. All rights reserved.

  1. Pharmacokinetics of pirfenidone after topical administration in rabbit eye

    OpenAIRE

    Sun, Guoying; Lin, Xianchai; Zhong, Hua; Yang, Yangfan; Qiu, Xuan; Ye, Chengtian; Wu, Kaili; Yu, Minbin

    2011-01-01

    Purpose Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) is a new, broad-spectrum agent that has an inhibition effect on the proliferation, migration, and collagen contraction of human Tenon’s fibroblasts, and thus modulating the wound healing process of glaucoma filtering surgical site. This study investigated the pharmacokinetics of topically administered pirfenidone (0.5%) in rabbit eyes. Methods Pirfenidone solution (50 μl) was instilled into the rabbit’s conjunctival sac. The rabbits were...

  2. Pharmacokinetics of a 5-fluorouracil liposomal delivery system.

    OpenAIRE

    Simmons, S T; Sherwood, M B; Nichols, D A; Penne, R B; Sery, T; Spaeth, G L

    1988-01-01

    A liposomal delivery system was developed in an attempt to prolong ocular levels of 5-fluorouracil for glaucoma filtering surgery. The pharmacokinetics of the 5-fluorouracil liposomal delivery system were studied in normal pigmented rabbits with 5-fluorouracil labelled with carbon-14 (C-14). 14C 5-fluorouracil was incorporated into the liposomes at a concentration of 10 g/l and injected subconjunctivally in doses of 5 and 10 mg. Concentrations of 5-fluorouracil were assayed at 10 time interva...

  3. Comparative Pharmacokinetics Study of Icariin and Icariside II in Rats

    Directory of Open Access Journals (Sweden)

    Tao Cheng

    2015-12-01

    Full Text Available To explore the pharmacokinetic properties of icariin (ICA and icariside II (ICA II following intragastric and intravenous administration in rats, a rapid and sensitive method by using ultra-performance liquid chromatography–tandem mass spectroscopy (UPLC-MS/MS was developed and validated for the simultaneous quantification of ICA and ICA II in rat plasma. The quantification was performed by using multiple reaction monitoring of the transitions m/z 677.1/531.1 for ICA, 515.1/369.1 for ICA II and 463.1/301.1 for diosmetin-7-O-β-d-glucopyranoside (IS. The assay showed linearity over the concentration range of 1.03–1032 ng/mL, with correlation coefficients of 0.9983 and 0.9977. Intra- and inter-day precision and accuracy were within 15%. The lower limit of quantification for both ICA and ICA II was 1.03 ng/mL, respectively. The recovery of ICA and ICA II was more than 86.2%. The LC-MS/MS method has been successfully used in the pharmacokinetic studies of ICA and ICA II in rats. The results indicated that 91.2% of ICA was transformed into ICA II after oral administration by rats, whereas only 0.4% of ICA was transformed into ICA II after intravenous administration. A comparison of the pharmacokinetics of ICA and ICA II after oral administration revealed that the Cmax and AUC0–t of ICA II were 3.8 and 13.0 times higher, respectively, than those of ICA. However, after intravenous administration, the Cmax and AUC0–t of ICA II were about only 12.1% and 4.2% of those of ICA. These results suggest that ICA and ICA II have distinct pharmacokinetic properties, and the insights obtained facilitate future pharmacological action studies.

  4. Tranexamic Acid Mechanisms and Pharmacokinetics In Traumatic Injury

    Science.gov (United States)

    2017-10-01

    0704-0188 Public reporting burden for this collection of information is estimated to average 1 hour per response , including the time for reviewing... immunology , PK, and data analyses are currently under way. 15. SUBJECT TERMS Trauma, hemorrhage, transfusion, fibrinolysis, immune suppression...pharmacokinetics, outcomes, adverse events. 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON

  5. [Pharmacokinetic of four alkaloids of Yanshu injection in Beagel dogs].

    Science.gov (United States)

    Liu, Jiping; Xue, Mei; Huang, Xin; Wang, Shu; Jiang, Zhenzhou; Zhang, Luyong

    2012-06-01

    For studying the pharmacokinetic of Yanshu injections in Beagel dogs, a sensitive and reproducible LC-MS method for quantitative determination of matrine, oxymatrine, sophocarpine and oxysophocarpine in dog's plasma were developed and validated using monocrotaline as an internal standard after iv of Yanshu injections (Sophorae Flavescentis Radix and Heterosmilacis Japonicae Rhizoma). The separation of plasma samples was performed on a CN column by isocratic elution with methanol-10 mmol x L(-1) NH4Ac-0.02% HCOOH-H2O 90:10 as the mobile phase. The plasma concentration of four kinds of alkaloids were calculated in dog plasta by detection of healthy dogs given Yanshu injection fluid after in twelve hours of plasma samples, All data of concentration-time of four kinds of alkaloids were treated with pharmacokinetics program DAS 2. 0. MT, OMT, SP and OSP have a good linear relationship in 0.01-16.0, 0.02-60.0, 0.01-4.0, 0.02-16.0 mg x L(-1), respectively. The average recoveries were more than 90% and the RSD of precision and stability of the test were less than 6.4% iv 1.2 g x kg(-1) Yanshu injection, four kinds of alkaloids in rats meet the two-compartment open pharmacokinetic model, Cmax and the concentration of the original liquid in the proportion of the basic line, the AUC(0-infinity) of matrine and oxymatrine, sophocarpine and oxysophocarpine compared to the original both in the proportion of liquid increases, the MRT(0-infinity) and t(1/2z) of matrine and sophocarpine were less than oxymatrine and oxysophocarpine; four kinds of alkaloids apparent volume of distribution matrine > oxymatrine, sophocarpine > oxysophocarpine. A method with high recovery rate and good stabilitywas established to determine the blood concentration of MT, OMT, SP, OSP in Yanshu injection and applied in its pharmacokinetics successfully.

  6. Bioavailability and Pharmacokinetics of Oral Cocaine in Humans.

    Science.gov (United States)

    Coe, Marion A; Jufer Phipps, Rebecca A; Cone, Edward J; Walsh, Sharon L

    2018-06-01

    The pharmacokinetic profile of oral cocaine has not been fully characterized and prospective data on oral bioavailability are limited. A within-subject study was performed to characterize the bioavailability and pharmacokinetics of oral cocaine. Fourteen healthy inpatient participants (six males) with current histories of cocaine use were administered two oral doses (100 and 200 mg) and one intravenous (IV) dose (40 mg) of cocaine during three separate dosing sessions. Plasma samples were collected for up to 24 h after dosing and analyzed for cocaine and metabolites by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis, and a two-factor model was used to assess for dose and sex differences. The mean ± SEM oral cocaine bioavailability was 0.32 ± 0.04 after 100 and 0.45 ± 0.06 after 200 mg oral cocaine. Volume of distribution (Vd) and clearance (CL) were both greatest after 100 mg oral (Vd = 4.2 L/kg; CL = 116.2 mL/[min kg]) compared to 200 mg oral (Vd = 2.9 L/kg; CL = 87.5 mL/[min kg]) and 40 mg IV (Vd = 1.3 L/kg; CL = 32.7 mL/[min kg]). Oral cocaine area-under-thecurve (AUC) and peak concentration increased in a dose-related manner. AUC metabolite-to-parent ratios of benzoylecgonine and ecgonine methyl ester were significantly higher after oral compared to IV administration and highest after the lower oral dose. In addition, minor metabolites were detected in higher concentrations after oral compared to IV cocaine. Oral cocaine produced a pharmacokinetic profile different from IV cocaine, which appears as a rightward and downward shift in the concentration-time profile. Cocaine bioavailability values were similar to previous estimates. Oral cocaine also produced a unique metabolic profile, with greater concentrations of major and minor metabolites.

  7. Nanomedicine for improved efficacy of tuberculosis drugs – Pharmacokinetic importance

    CSIR Research Space (South Africa)

    Hayeshi, R

    2012-10-01

    Full Text Available Efficacy of Tuberculosis Drugs ? Pharmacokinetic importance Emerging Researcher Symposium Dr. Rose Hayeshi 10 October 2012 Outline ? Challenges in TB treatment ? Nanomedicine as proposed solution ? Results ? Conclusions ? CSIR 2012 Slide 2... ? 1 x 106 cfu/lung 3 x 103 cfu/spleen Effects of the Nanodrug on Mycobacaterium tuberculosis replication ? Nanodrug once a week vs conventional drug daily ? Treatment with nanoencapsulated TB drugs once a week, comparable to daily treatment...

  8. Pharmacokinetics of lysine clonixinate in children in postoperative care.

    Science.gov (United States)

    González-Martin, G; Cattan, C; Zuñiga, S

    1996-09-01

    The pharmacokinetics of 2 doses of intravenous lysine clonixinate (4 and 6 mg x kg-1) were studied in 10 children (age 4-10 years) under postoperative care. A single dose of the drug was injected in a forearm vein. Blood samples were collected at regular intervals for 3 hours. Serum clonixin concentrations (expressed as clonixin) were analyzed using a high pressure liquid chromatography method. Pharmacokinetic values were estimated by a nonlinear computer program. The distribution volume was similar in both groups of children (1.288 +/- 0.829 1 and 1. 139 +/- 0.667 1, respectively). There were no differences between the values of total plasma clearance and the administered doses (0.026 +/- 0.017 ml x min-1 and 0.017 +/- 0.008 ml x min-1, t = 1.07, p = 0.76). The elimination half-life was longer in children who received 6 mg x kg-1 (44.26 +/- 6.34 min vs 38.63 +/- 10.93 min) but this difference was not statistically significant (t = 0.99, p < 0.34). The pharmacokinetic parameters calculated in these children were different from those found by other authors in adults and experimental animals.

  9. Availability, Pharmaceutics, Security, Pharmacokinetics, and Pharmacological Activities of Patchouli Alcohol.

    Science.gov (United States)

    Hu, Guanying; Peng, Cheng; Xie, Xiaofang; Zhang, Sanyin; Cao, Xiaoyu

    2017-01-01

    Patchouli alcohol (PA), a tricyclic sesquiterpene, is one of the critical bioactive ingredients and is mainly isolated from aerial part of Pogostemon cablin (known as guanghuoxiang in China) belonging to Labiatae. So far, PA has been widely applied in perfume industries. This review was written with the use of reliable information published between 1974 and 2016 from libraries and electronic researches including NCKI, PubMed, Reaxys, ACS, ScienceDirect, Springer, and Wiley-Blackwell, aiming at presenting comprehensive outline of security, pharmacokinetics, and bioactivities of PA and at further providing a potential guide in exploring the PA and its use in various medical fields. We found that PA maybe was a low toxic drug that was acquired numerously through vegetable oil isolation and chemical synthesis and its stability and low water dissolution were improved in pharmaceutics. It also possessed specific pharmacokinetic characteristics, such as two-compartment open model, first-order kinetic elimination, and certain biometabolism and biotransformation process, and was shown to have multiple biological activities, that is, immunomodulatory, anti-inflammatory, antioxidative, antitumor, antimicrobial, insecticidal, antiatherogenic, antiemetic, whitening, and sedative activity. However, the systematic evaluations of preparation, pharmaceutics, toxicology, pharmacokinetics, and bioactivities underlying molecular mechanisms of action also required further investigation prior to practices of PA in clinic.

  10. Effect of the menstrual cycle in ethanol pharmacokinetics.

    Science.gov (United States)

    Haddad, L; Milke, P; Zapata, L; de la Fuente, J R; Vargas-Vorácková, F; Lorenzana-Jiménez, M; Corte, G; Tamayo, J; Kaplan, M; Márquez, M; Kershenobich, D

    1998-01-01

    Differences in ethanol pharmacokinetics within the menstrual cycle have previously been reported and attributed to variations in body composition, hormonal influences and gastric emptying. To establish the role of the menstrual cycle in ethanol pharmacokinetics associated with changes in body composition, ethanol blood concentrations were measured in nine healthy women during the midfollicular (P1, days 8-10) and midluteal (P2, days 22-24) phases of the menstrual cycle after a postprandial oral ethanol dose (0.3 g kg(-1)). Total body water was assessed by dual-energy x-ray densitometry (DEXA) on both occasions. Median total body water did not vary during either phase of the menstrual cycle (P1 = 54.54%, P2 = 54.66%; P = 0.9296). Median area under the ethanol concentration-time curve (AUC) was lower during P1 (215.33 mg.h dl(-1)) than during P2 (231.33 mg.h dl(-1))(P = 0.8253). No significant differences were found on ethanol pharmacokinetics in either phase of the menstrual cycle.

  11. Influence of Differing Analgesic Formulations of Aspirin on Pharmacokinetic Parameters

    Directory of Open Access Journals (Sweden)

    Kunal Kanani

    2015-08-01

    Full Text Available Aspirin has been used therapeutically for over 100 years. As the originator and an important marketer of aspirin-containing products, Bayer’s clinical trial database contains numerous reports of the pharmacokinetics of various aspirin formulations. These include evaluations of plain tablets, effervescent tablets, granules, chewable tablets, and fast-release tablets. This publication seeks to expand upon the available pharmacokinetic information concerning aspirin formulations. In the pre-systemic circulation, acetylsalicylic acid (ASA is rapidly converted into its main active metabolite, salicylic acid (SA. Therefore, both substances are measured in plasma and reported in the results. The 500 mg strength of each formulation was chosen for analysis as this is the most commonly used for analgesia. A total of 22 studies were included in the analysis. All formulations of 500 mg aspirin result in comparable plasma exposure to ASA and SA as evidenced by AUC. Tablets and dry granules provide a consistently lower Cmax compared to effervescent, granules in suspension and fast release tablets. Effervescent tablets, fast release tablets, and granules in suspension provide a consistently lower median Tmax compared to dry granules and tablets for both ASA and SA. This report reinforces the importance of formulation differences and their impact on pharmacokinetic parameters.

  12. Effects of pathological conditions on ocular pharmacokinetics of antimicrobial drugs.

    Science.gov (United States)

    Ueda, Kayoko; Ohtori, Akira; Tojo, Kakuji

    2010-10-01

    A diffusion model of ocular pharmacokinetics was used to estimate the effects of pathological conditions on ocular pharmacokinetics. In vivo rabbit data after topical instillation of ciprofloxacin and ofloxacin were compared with the simulated concentrations in the aqueous and vitreous humors. The barrier capacity of the surrounding membranes such as the retina/choroid/sclera (RCS) membrane and the cornea was characterized by dimensionless Sherwood number derived by the pseudo-steady state approach (PSSA). We assumed the barrier capacity decreased by inflammation; when the barrier capacity of the RCS membrane and the cornea was assumed to be one-tenth for the RCS membrane and a half for the cornea respectively, the in vivo data agreed with the simulated profile without contradiction. The drug concentration gradient simulated in the vitreous body near the RCS membrane was more significant in the inflamed eyes than in the normal eyes, suggesting that the elimination of the drugs from the RCS membrane was enhanced by inflammation. The present diffusion model can better describe the ocular pharmacokinetics in both normal and diseased conditions.

  13. The Brain and Propranolol Pharmacokinetics in the Elderly

    Directory of Open Access Journals (Sweden)

    Andy R. Eugene

    2015-09-01

    Full Text Available Propranolol, a non-selective β-blocker, has been found to have a tremendous array of indications. Recent evidence has suggested that propranolol may be effective in patients suffering from post-traumatic stress disorder by suppressing activity in the amygdala and thereby inhibiting emotional memory formation. Dosage requirements have been well established in the pediatric and adult population, however, there has been no definitive geriatric dose recommended in the package inserts made available to the public. The aim of this paper is to use pharmacokinetic simulations in order to establish a pharmacokinetic profile dosage equivalent for the elderly as has been found in young patients. After completing the Monte-Carlo simulations for the elderly and young patients, a single 10mg dose in the elderly has shown comparable pharmacokinetic profiles as found in young patients administered a 40mg single dose.

  14. Preparation and In Vivo Pharmacokinetics of the Tongshu Suppository

    Directory of Open Access Journals (Sweden)

    Guoqiang Liu

    2016-01-01

    Full Text Available Astragalus polysaccharide (APS (used for intestinal protection was added to formulate the Tongshu suppository to improve the pharmacokinetics of Aceclofenac, which were assessed in New Zealand rabbits using an orthogonal experimental design. The single-agent Aceclofenac was taken as the control formulation. The concentration-time and drug release curves were drawn, and Tmax (min, Cmax (μg·mL−1, AUC0→∞, and MRT were compared using a pharmacokinetic systems program. The formulated Tongshu suppository had moderate hardness, a smooth surface with uniform color, and theoretical drug-loading rate of 8%. Its release rate was in accordance with the drug preparation requirements. The concentration-time curves and drug release curves revealed that the maximum concentrations (Cmax were 4.18±1.03 μg·mL−1 and 3.34±0.41 μg·mL−1 for the Tongshu and Aceclofenac suppositories, respectively, showing statistically insignificant difference, while the peak times were 34.87±4.69 min and 34.76±6.34 min, respectively, also showing statistically insignificant difference. Compared with the Aceclofenac suppository, the relative bioavailability of the Tongshu suppository was 104.4%, and the difference between them was statistically insignificant. In this experiment, the Tongshu suppository was prepared using the hot-melt method. In vivo pharmacokinetic studies confirmed it had higher bioavailability than the Aceclofenac suppository.

  15. Preparation and In Vivo Pharmacokinetics of the Tongshu Suppository

    Science.gov (United States)

    Dong, Leilei; Lu, Kuan; Liu, Sisi; Zheng, Yingying

    2016-01-01

    Astragalus polysaccharide (APS) (used for intestinal protection) was added to formulate the Tongshu suppository to improve the pharmacokinetics of Aceclofenac, which were assessed in New Zealand rabbits using an orthogonal experimental design. The single-agent Aceclofenac was taken as the control formulation. The concentration-time and drug release curves were drawn, and T max (min), C max (μg·mL−1), AUC0→∞, and MRT were compared using a pharmacokinetic systems program. The formulated Tongshu suppository had moderate hardness, a smooth surface with uniform color, and theoretical drug-loading rate of 8%. Its release rate was in accordance with the drug preparation requirements. The concentration-time curves and drug release curves revealed that the maximum concentrations (C max) were 4.18 ± 1.03 μg·mL−1 and 3.34 ± 0.41 μg·mL−1 for the Tongshu and Aceclofenac suppositories, respectively, showing statistically insignificant difference, while the peak times were 34.87 ± 4.69 min and 34.76 ± 6.34 min, respectively, also showing statistically insignificant difference. Compared with the Aceclofenac suppository, the relative bioavailability of the Tongshu suppository was 104.4%, and the difference between them was statistically insignificant. In this experiment, the Tongshu suppository was prepared using the hot-melt method. In vivo pharmacokinetic studies confirmed it had higher bioavailability than the Aceclofenac suppository. PMID:27610366

  16. Availability, Pharmaceutics, Security, Pharmacokinetics, and Pharmacological Activities of Patchouli Alcohol

    Directory of Open Access Journals (Sweden)

    Guanying Hu

    2017-01-01

    Full Text Available Patchouli alcohol (PA, a tricyclic sesquiterpene, is one of the critical bioactive ingredients and is mainly isolated from aerial part of Pogostemon cablin (known as guanghuoxiang in China belonging to Labiatae. So far, PA has been widely applied in perfume industries. This review was written with the use of reliable information published between 1974 and 2016 from libraries and electronic researches including NCKI, PubMed, Reaxys, ACS, ScienceDirect, Springer, and Wiley-Blackwell, aiming at presenting comprehensive outline of security, pharmacokinetics, and bioactivities of PA and at further providing a potential guide in exploring the PA and its use in various medical fields. We found that PA maybe was a low toxic drug that was acquired numerously through vegetable oil isolation and chemical synthesis and its stability and low water dissolution were improved in pharmaceutics. It also possessed specific pharmacokinetic characteristics, such as two-compartment open model, first-order kinetic elimination, and certain biometabolism and biotransformation process, and was shown to have multiple biological activities, that is, immunomodulatory, anti-inflammatory, antioxidative, antitumor, antimicrobial, insecticidal, antiatherogenic, antiemetic, whitening, and sedative activity. However, the systematic evaluations of preparation, pharmaceutics, toxicology, pharmacokinetics, and bioactivities underlying molecular mechanisms of action also required further investigation prior to practices of PA in clinic.

  17. A decade of experience with a clinical pharmacokinetics service.

    Science.gov (United States)

    Ambrose, P J; Smith, W E; Palarea, E R

    1988-09-01

    The development, operation, and functions of the pharmacokinetics service at Memorial Medical Center of Long Beach (MMCLB) are described, and the data used to determine the quality and cost-effectiveness of the service are presented. Current functions of the pharmacokinetics service at MMCLB include making brief written comments about the interpretations of serum drug concentrations (SDCs) and oral recommendations to physicians on dosage adjustment; provision of written consultations with dosage recommendations; provision of drug information, education, and research; and development of drug dosing guidelines for the pharmacy and medical staff. During the 10-year existence of this service, costs have been justified on the basis of not only revenue generated by the service (in the form of "drug concentration scheduling" and "drug concentration evaluation" fees charged to patients) but also by cost savings resulting from the prevention of inappropriate, misleading, and potentially dangerous SDCs. An audit conducted in 1986 showed that the policy of having pharmacists schedule the sampling times for SDCs saves about $500,000 annually. Quality assurance has been documented by auditing compliance with and therapeutic effectiveness of dosing guidelines and by working with laboratory personnel to identify and prevent spurious SDC results and assay errors. The methods used by the pharmacokinetics service at MMCLB to document the benefits of the service have been vital in proving both its cost-effectiveness and its positive effect on patient care.

  18. Effect of gemfibrozil and fenofibrate on the pharmacokinetics of atorvastatin.

    Science.gov (United States)

    Whitfield, Lloyd R; Porcari, Anthony R; Alvey, Christine; Abel, Robert; Bullen, William; Hartman, Daniel

    2011-03-01

    Coadministration of statins and fibrates is beneficial in some patients by allowing simultaneous reduction of triglycerides and low-density lipoprotein cholesterol alongside elevation of high-density lipoprotein cholesterol. However, the potential for drug interactions must be taken into consideration. Gemfibrozil increases systemic exposure to various different statins, whereas similar effects are not observed with fenofibrate, suggesting it may be a more appropriate choice for coadministration with statins. Gemfibrozil is reported to cause a moderate increase in the area under the curve (AUC) of atorvastatin, but the effect of fenofibrate on atorvastatin pharmacokinetics has not been described. This study compared the effects of multiple-dose administration of gemfibrozil and fenofibrate on the single-dose pharmacokinetics of atorvastatin. Gemfibrozil coadministration led to significant increases in the AUC of atorvastatin, 2-hydroxyatorvastatin, 2-hydroxyatorvastatin lactone, and 4-hydroxyatorvastatin lactone. In contrast, fenofibrate administration did not lead to clinically meaningful changes in the AUC for atorvastatin, atorvastatin lactone, 2-hydroxyatorvastatin, or 2-hydroxyatorvastatin lactone. The absence of a significant pharmacokinetic interaction between fenofibrate and atorvastatin is consistent with recent results showing no difference in safety profile between atorvastatin as monotherapy or in combination with fenofibric acid. Together, these data suggest that atorvastatin-fenofibrate combination therapy is unlikely to pose a risk to patients.

  19. Effect of gemfibrozil on the pharmacokinetics of mitiglinide in rats.

    Science.gov (United States)

    Jin, L; Cao, Q

    2012-01-01

    A sensitive and specific method was developed and validated for the determination of mitiglinide in plasma using LC-MS/MS. The effect of gemfibrozil on the pharmacokinetics of orally administered mitiglinide in rats was investigated. The validated method in positive electrospray ionization mode using MRM and fully validated according to commonly accepted criteria. The desired sensitivity of mitiglinide was achieved with an LOQ of 0.5 ng/mL and the short run time was suitable for analysis of the large batches of samples. The method was successfully used to analyze rats plasma samples for application in pharmacokinetic studies. Pharmacokinetic parameters of mitiglinide were determined in rats following oral (0.25, 0.5, 1 mg/kg) administration to rats in the presence and absence of gemfibrozil (1 mg/kg). Compared to those animals in an oral control group (given mitiglinide alone), the area under the plasma concentration-time curve (AUC) of mitiglinide were increased significantly by 2.8, 3.5, 4.1-fold (0.25, 0.5, 1 mg/kg) by gemfibrozil, respectively. Consequently, the bioavailability of mitiglinide in the presence of gemfibrozil was significantly enhanced compared to that in oral control group (only mitiglinide). Gemfibrozil significantly enhanced the oral bioavailability of mitiglinide, suggesting that concurrent use of gemfibrozil and mitiglinide should be monitored closely for potential drug interactions. © Georg Thieme Verlag KG Stuttgart · New York.

  20. Requirements for pharmacokinetic evaluation of antibiotics in phase I studies.

    Science.gov (United States)

    Bergan, T

    1986-01-01

    Initial pharmacokinetic studies usually include healthy volunteers to minimize variation generated by diseases. Ethical aspects of initial studies are paramount. The guidelines of the Helsinki Declaration should be followed or even extended. Thorough toxicologic screening in animals is a prerequisite. The use of radioisotopes for pharmacokinetic studies should be limited. The basic design of studies includes cross-over administration of intravenous and oral doses of several sizes. Bioavailability, total area under the serum concentration curve, serum half-life, amount eliminated in urine as active drug, and metabolism are the most important data. The fate of the parent compound and of its possible metabolites in both healthy persons and ill individuals (including those with renal or hepatic dysfunction) should be monitored. Diet may have consequences with regard to recommended dosage schedules. When possible, tissue penetration of antibiotics should be assessed, preferably through the analysis of peripheral human lymph and of suction-blister and peritoneal fluids. Theoretical dosage schedules based on pharmacokinetic assessments in healthy persons should be tested in patients with infectious disease, particularly in those with reduced renal and/or hepatic function.

  1. HPLC assay for ethiofos in plasma: Application to pharmacokinetics in the beagle dog

    International Nuclear Information System (INIS)

    Swynnerton, N.F.; Mangold, D.J.; Ludden, T.M.

    1985-01-01

    An HPLC assay for ethiofos [S-2-(3-amino-propylamino)ethyl phosphorothioate, WR 2727] in plasma is presented. Its application to the development of pharmacokinetic parameters following IV administration of the drug to beagle dogs is demonstrated and preliminary pharmacokinetics of four dosings will be presented. Following a dose of 150 mg kg -1 , the plasma concentration versus time profile was best described by a two-compartment pharmacokinetics model. Mean pharmacokinetic parameters were: terminal elimination half-life = 16.0 minutes, volume of central compartment = 129 mL kg -1 , and clearance = 11.0 mL min -1 kg -1

  2. Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects.

    Science.gov (United States)

    de Haas, S L; Schoemaker, R C; van Gerven, J M A; Hoever, P; Cohen, A F; Dingemanse, J

    2010-11-01

    Zolpidem is one of the most frequently prescribed hypnotics, as it is a very short-acting compound with relatively few side effects. Zolpidem's short duration of action is partly related to its short elimination half-life, but the associations between plasma levels and pharmacodynamic (PD) effects are not precisely known. In this study, the concentration-effect relationships for zolpidem were modelled. Zolpidem (10 mg) was administered in a double-blind, randomised, placebo-controlled trial to determine PD and pharmacokinetics (PK) in 14 healthy volunteers. Zolpidem was absorbed and eliminated quickly, with a median T(max) of 0.78 h (range: 0.33-2.50) and t(1/2) of 2.2 h. Zolpidem reduced saccadic peak velocity (SPV), adaptive tracking performance, electroencephalogram (EEG) alpha power and visual analogue scale (VAS) alertness score and increased body sway, EEG beta power and VAS 'feeling high'. Short- and long-term memory was not affected. Central nervous system effects normalised more rapidly than the decrease of plasma concentrations. For most effects, zolpidem's short duration of action could be adequately described by both a sigmoid E(max) model and a transit tolerance model. For SPV and EEG alpha power, the tolerance model seemed less suitable. These PK/PD models have different implications for the mechanism underlying zolpidem's short duration of action. A sigmoid E(max) model (which is based on ligand binding theory) would imply a threshold value for the drug's effective concentrations. A transit tolerance model (in which a hypothetical factor builds up with time that antagonises the effects of the parent compound) is compatible with a rapid reversible desensitisation of GABAergic subunits.

  3. Clinical pharmacokinetics of aminoglycosides in the neonate: a review.

    Science.gov (United States)

    Pacifici, Gian Maria

    2009-04-01

    Sepsis is common in neonates and is a major cause of morbidity and mortality. Sixty percent of preterm neonates receive at least one antibiotic, and 43% of the antibiotics administered to these neonates are aminoglycosides. The clearance (Cl), serum half-life (t(1/2)), and volume of distribution (Vd) of aminoglycosides change during the neonatal life, and the pharmacokinetics of aminoglycosides need to be studied in neonates in order to optimise therapy with these drugs. The aim of this work is to review the published data on the pharmacokinetics of aminoglycosides in order to provide a critical analysis of the literature that can be a useful tool in the hands of physicians. The bibliographic search was performed electronically using PubMed, as the search engine, through July 11th, 2008. Firstly, a Medline search was performed with the keywords "pharmacokinetics of aminoglycosides in neonates" with the limit of "human". Other Medline searches were performed with the keywords "pharmacokinetics of ... in neonates" followed by the name of the aminoglycosides: amikacin, gentamicin, netilmicin and tobramycin. In addition, the book Neofax: A Manual of Drugs Used in Neonatal Care by Young and Mangum (Thomson Healthcare, 2007) was consulted. The aminoglycosides are mainly eliminated by the kidney, and their elimination rates are reduced at birth. As a consequence Cl is reduced and t(1/2) is prolonged in the neonate as compared to more mature infants. The high body-water content of the neonate results in a large Vd of aminoglycosides as these drugs are fairly water soluble. Postnatal development is an important factor in the maturation of the neonate, and as postnatal age proceeds, Cl of aminoglycosides increases. The maturation of the kidney governs the pharmacokinetics of aminoglycosides in the infant. Cl and t(1/2) are influenced by development, and this must be taken into consideration when planning a dosage regimen with aminoglycosides in the neonate. Aminoglycosides

  4. Disposition pathways and pharmacokinetics of herbal medicines in humans.

    Science.gov (United States)

    He, S-M; Li, C G; Liu, J-P; Chan, E; Duan, W; Zhou, S-F

    2010-01-01

    Pharmacokinetic studies have become an integral part of modern drug development, but these studies are not regulatory needs for herbal remedies. This paper updates our current knowledge on the disposition pathways and pharmacokinetic properties of commonly used herbal medicines in humans. To retrieve relevant data, the authors have searched through computer-based literatures by full text search in Medline (via Pubmed), ScienceDirect, Current Contents Connect (ISI), Cochrance Library, CINAHL (EBSCO), CrossRef Search and Embase (all from inception to May 2010). Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are determining factors for the in vivo bioavailability, disposition and distribution of herbal remedies. There are increasing pharmacokinetic studies of herbal remedies, but these studies are mainly focused on a small number of herbal remedies including St John's wort, milk thistle, sculcap, curcumin, echinacea, ginseng, ginkgo, and ginger. The pharmacokinetic data of a small number of purified herbal ingredients, including anthocyanins, berberine, catechins, curcumin, lutein and quercetin, are available. For the majority of herbal remedies used in folk medicines, data on their disposition and biological fate in humans are lacking or in paucity. For a herbal medicine, the pharmacological effect is achieved when the bioactive agents or the metabolites reach and sustain proper levels at their sites of action. Both the dose levels and fates of active components in the body govern their target-site concentrations after administration of an herbal remedy. In this regard, a safe and optimal use of herbal medicines requires a

  5. Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults.

    Science.gov (United States)

    Brown, Randall T; Nicholas, Christopher R; Cozzi, Nicholas V; Gassman, Michele C; Cooper, Karen M; Muller, Daniel; Thomas, Chantelle D; Hetzel, Scott J; Henriquez, Kelsey M; Ribaudo, Alexandra S; Hutson, Paul R

    2017-12-01

    Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults. Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods. No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied. The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose. NCT02163707.

  6. Pharmacokinetic Study of Piracetam in Focal Cerebral Ischemic Rats.

    Science.gov (United States)

    Paliwal, Pankaj; Dash, Debabrata; Krishnamurthy, Sairam

    2018-04-01

    Cerebral ischemia affects hepatic enzymes and brain permeability extensively. Piracetam was investigated up to phase III of clinical trials and there is lack of data on brain penetration in cerebral ischemic condition. Thus, knowledge of the pharmacokinetics and brain penetration of piracetam during ischemic condition would aid to improve pharmacotherapeutics in ischemic stroke. Focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h in male Wistar rats followed by reperfusion. After 24 h of middle cerebral artery occlusion or 22 h of reperfusion, piracetam was administered for pharmacokinetic, brain penetration, and pharmacological experiments. In pharmacokinetic study, blood samples were collected at different time points after 200-mg/kg (oral) and 75-mg/kg (intravenous) administration of piracetam through right external jugular vein cannulation. In brain penetration study, the cerebrospinal fluid, systemic blood, portal blood, and brain samples were collected at pre-designated time points after 200-mg/kg oral administration of piracetam. In a separate experiment, the pharmacological effect of the single oral dose of piracetam in middle cerebral artery occlusion was assessed at a dose of 200 mg/kg. All the pharmacokinetic parameters of piracetam including area under curve (AUC 0-24 ), maximum plasma concentration (C max ), time to reach the maximum plasma concentration (t max ), elimination half-life (t 1/2 ), volume of distribution (V z ), total body clearance, mean residence time, and bioavailability were found to be similar in ischemic stroke condition except for brain penetration. Piracetam exposure (AUC 0-2 ) in brain and CSF were found to be 2.4- and 3.1-fold higher, respectively, in ischemic stroke compared to control rats. Piracetam significantly reduced infarct volume by 35.77% caused by middle cerebral artery occlusion. There was no change in the pharmacokinetic parameters of piracetam in the ischemic stroke model except for

  7. Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients.

    Science.gov (United States)

    Sime, Fekade B; Stuart, Janine; Butler, Jenie; Starr, Therese; Wallis, Steven C; Pandey, Saurabh; Lipman, Jeffrey; Roberts, Jason A

    2018-06-01

    To date, there is no information on the intravenous (i.v.) posaconazole pharmacokinetics for intensive care unit (ICU) patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of i.v. posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if they were aged ≥18 years, central venous access was available, they were not pregnant, and they had not received prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 min. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by noncompartmental methods. Eight patients (7 male) were enrolled with the following characteristics: median age, 46 years (interquartile range [IQR], 40 to 51 years); median weight, 68 kg (IQR, 65 to 82 kg); and median albumin concentration, 20 g/liter (IQR, 18 to 24 g/liter). Median (IQR) pharmacokinetic parameter estimates were as follows: observed maximum concentration during sampling period ( C max ), 1,702 ng/ml (1,352 to 2,141 ng/ml); area under the concentration-time curve from zero to infinity (AUC 0-∞ ), 17,932 ng · h/ml (13,823 to 27,905 ng · h/ml); clearance (CL), 16.8 liters/h (11.1 to 21.7 liters/h); and volume of distribution ( V ), 529.1 liters (352.2 to 720.6 liters). The V and CL were greater than 2-fold and the AUC 0-∞ was 39% of the values reported for heathy volunteers. The AUC 0-∞ was only 52% of the steady-state AUC 0-24 reported for hematology patients. The median of estimated average steady-state concentrations was 747 ng/ml (IQR, 576 to 1,163 ng/ml), which is within but close to the lower end of the previously recommended therapeutic range of 500 to 2,500 ng/ml. In conclusion, we observed different pharmacokinetics of i.v. posaconazole in

  8. A 'Scottish Poor Law of Lunacy'? Poor Law, Lunacy Law and Scotland's parochial asylums.

    Science.gov (United States)

    Farquharson, Lauren

    2017-03-01

    Scotland's parochial asylums are unfamiliar institutional spaces. Representing the concrete manifestation of the collision between two spheres of legislation, the Poor Law and the Lunacy Law, six such asylums were constructed in the latter half of the nineteenth century. These sites expressed the enduring mandate of the Scottish Poor Law 1845 over the domain of 'madness'. They were institutions whose very existence was fashioned at the directive of the local arm of the Poor Law, the parochial board, and they constituted a continuing 'Scottish Poor Law of Lunacy'. Their origins and operation significantly subverted the intentions and objectives of the Lunacy Act 1857, the aim of which had been to institute a public district asylum network with nationwide coverage.

  9. PLGA-soya lecithin based micelles for enhanced delivery of methotrexate: Cellular uptake, cytotoxic and pharmacokinetic evidences.

    Science.gov (United States)

    Singh, Anupama; Thotakura, Nagarani; Kumar, Rajendra; Singh, Bhupinder; Sharma, Gajanand; Katare, Om Prakash; Raza, Kaisar

    2017-02-01

    Biocompatible and biodegradable polymers like PLGA have revolutionized the drug delivery approaches. However, poor drug loading and substantially high lipophilicity, pave a path for further tailing of this promising agent. In this regard, PLGA was feathered with biocompatible phospholipid and polymeric micelles were developed for delivery of Methotrexate (MTX) to cancer cells. The nanocarriers (114.6nm±5.5nm) enhanced the cytotoxicity of MTX by 2.13 folds on MDA-MB-231 cells. Confocal laser scanning microscopy confirmed the increased intracellular delivery. The carrier decreased the protein binding potential and enhanced the bioavailable fraction of MTX. Pharmacokinetic studies vouched substantial enhancement in AUC and bioresidence time, promising an ideal carrier to effectively deliver the drug to the site of action. The developed nanocarriers offer potential to deliver the drug in the interiors of cancer cells in an effective manner for improved therapeutic action. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Current stress and poor oral health.

    Science.gov (United States)

    Vasiliou, A; Shankardass, K; Nisenbaum, R; Quiñonez, C

    2016-09-02

    Psychological stress appears to contribute to poor oral health systemically in combination with other chronic diseases. Few studies directly examine this relationship. Data from a cross-sectional study of 2,412 participants between the ages of 25-64 years old living in the City of Toronto between 2009 and 2012 were used to examine the relationship between current stress and two self-rated oral health outcomes (general oral health and oral pain). Dental care utilization and access to dental insurance were examined as effect modifiers. A positive relationship between current stress and poor oral health was observed for both outcomes (oral pain coefficient 0.32, 95 % CI 0.26-0.38; general oral health coefficient 0.28, 95 % CI 0.19-0.36). Effects on oral pain were stronger for the uninsured, while effects on general oral health were stronger with decreasing socioeconomic position. Our findings suggest that individuals with greater perceived stress also report poorer oral health, and that this relationship is modified by dental insurance and socioeconomic position. These findings warrant a greater focus on the role of psychological stress in the development of oral disease, including how perceived stress contributes to health inequities in self-reported oral health status. Patients experiencing stressful lives may differentially require closer monitoring and more vigilant maintenance of their oral health, above and beyond that which is needed to achieve a state of health in the oral environment of less stressed individuals. There may be health promoting effects of addressing psychosocial concerns related to dental care - particularly for the poor and uninsured.

  11. EXTREMELY METAL-POOR GALAXIES: THE ENVIRONMENT

    Energy Technology Data Exchange (ETDEWEB)

    Filho, M. E. [Universidad de Las Palmas de Gran Canaria–Universidad de La Laguna, CIE Canarias: Tri-Continental Atlantic Campus, Canary Islands (Spain); Almeida, J. Sánchez; Muñoz-Tuñón, C. [Instituto Astrofísica de Canarias, E-38200 La Laguna, Tenerife (Spain); Nuza, S. E.; Kitaura, F.; Heß, S., E-mail: mfilho@astro.up.pt [Leibniz-Institut für Astrophysik Potsdam (AIP), An der Sternwarte 16, D-14482 Potsdam (Germany)

    2015-04-01

    We have analyzed bibliographical observational data and theoretical predictions, in order to probe the environment in which extremely metal-poor dwarf galaxies (XMPs) reside. We have assessed the H i component and its relation to the optical galaxy, the cosmic web type (voids, sheets, filaments and knots), the overdensity parameter and analyzed the nearest galaxy neighbors. The aim is to understand the role of interactions and cosmological accretion flows in the XMP observational properties, particularly the triggering and feeding of the star formation. We find that XMPs behave similarly to Blue Compact Dwarfs; they preferably populate low-density environments in the local universe: ∼60% occupy underdense regions, and ∼75% reside in voids and sheets. This is more extreme than the distribution of irregular galaxies, and in contrast to those regions preferred by elliptical galaxies (knots and filaments). We further find results consistent with previous observations; while the environment does determine the fraction of a certain galaxy type, it does not determine the overall observational properties. With the exception of five documented cases (four sources with companions and one recent merger), XMPs do not generally show signatures of major mergers and interactions; we find only one XMP with a companion galaxy within a distance of 100 kpc, and the H i gas in XMPs is typically well-behaved, demonstrating asymmetries mostly in the outskirts. We conclude that metal-poor accretion flows may be driving the XMP evolution. Such cosmological accretion could explain all the major XMP observational properties: isolation, lack of interaction/merger signatures, asymmetric optical morphology, large amounts of unsettled, metal-poor H i gas, metallicity inhomogeneities, and large specific star formation.

  12. Justice, Work, and the Ghetto Poor

    OpenAIRE

    Shelby, Tommie

    2012-01-01

    In view of the explanatory significance of joblessness, some social scientists, policymakers,and commentators have advocated strong measures to ensure that the ghetto poor work, includingmandating work as a condition of receiving welfare benefits. Indeed, across the ideological po-litical spectrum, work is often seen as a moral or civic duty and as a necessary basis for personaldignity. And this normative stance is now instantiated in federal and state law, from the tax schemeto public benefits....

  13. Bureaucracy and Pro-poor Change

    OpenAIRE

    Ali Cheema; Asad Sayeed

    2006-01-01

    Based on the premise that a functioning state is a necessary pre-requisite for pro-poor change, it is critical to investigate the role of the bureaucracy as a key catalyst in this process. Weber (1968) ascribes bureaucracies to be anchors of the modern nation state as their conduct is based on rational-legal norms. Bureaucracies, according to this ideal type, temper the populist urges of politicians who wish to execute policy unencumbered by rules and procedures. State success or failure in m...

  14. Access to energy for the poor

    International Nuclear Information System (INIS)

    Huntjens, E.; Van Bussel, F.; Raats, M.

    2005-01-01

    Paper dealing with the topic E nergy consumption and economic development (in developed / wealthy and undeveloped / poor regions; energy price, social influence and energy efficiency. 'Brothers and sisters, I want to tell you this. The greatest thing on earth is to have the love of God in your heart, and the next greatest thing is to have electricity in your house.' In the early 1940s a farmer, who had just been connected to the electric grid, gave witness in a rural church in the United States of America(author)

  15. Association of diarrhoea, poor hygiene and poor social conditions in childhood with blood pressure in adulthood.

    Science.gov (United States)

    Kauhanen, L; Lynch, J W; Lakka, H-M; Kauhanen, J; Smith, G D

    2010-05-01

    Previous research has suggested that dehydration in infancy may lead to high blood pressure in later life because of sodium retention. The purpose of this study was to examine the effect of poor hygiene of the child, poor social and poor housing conditions at home and diarrhoea in childhood as proxies for dehydration on high blood pressure in later life. Data were from a subset of participants in the Kuopio Ischaemic Heart Disease Risk Factor Study, a population-based cohort study in eastern Finland. Information on childhood factors was collected from school health records (n=952), from the 1930s to the 1950s. Adult data were obtained from baseline examinations of the Kuopio Ischaemic Heart Disease Risk Factor Study cohort (n=2682) in 1984-1989. Men who had poor hygiene in childhood had on average 4.07 mm Hg (95% CI 0.53 to 7.61) higher systolic blood pressure than men who had good or satisfactory hygiene in childhood in the age-adjusted analysis. Reports of diarrhoea were not associated with adult blood pressure. The authors' findings suggest that poor hygiene and living in poor social conditions in childhood are associated with higher systolic blood pressure in adulthood. Reported childhood diarrhoea did not explain the link between hygiene and high blood pressure in adulthood.

  16. Education of quality to the poor

    Directory of Open Access Journals (Sweden)

    H.M. van der Merwe

    2011-09-01

    Full Text Available Quality education often eludes South African learners from poverty- stricken environments. There are, however, some notable exceptions. This article looks at how quality education based on social capital is provided to the poor. The author reports on a qualitative investigation based on both focus group and individual interviews conducted at a resource-poor KwaZulu- Natal school serving learners from Grade R to 9. The findings show that quality education at the research site relates to the moral agency of the school principal and teaching staff. Through their ethics of being and doing, the school principal and teaching staff ensure that sufficient resources, sound home-school relations, and a high premium on moral values result in a receptive learner corps. This environment encourages these learners to act with diligence, honesty, politeness, respect and service to the community. The findings contribute to research that maintains that quality education is indicative of the school principal and teachers‟ ethics of being and of doing.

  17. Alleviating energy poverty for the world's poor

    International Nuclear Information System (INIS)

    Sagar, Ambuj D.

    2005-01-01

    Improving energy services for poor households in developing countries remains one of the most pressing challenges facing the development community. The dependence of these households on traditional forms of energy leads to significant health impacts as well as other major disbenefits, yet there has been little progress in meeting this challenge. This viewpoint argues for an 'energy-poverty alleviation' fund to help provide modern energy services to these households. It also proposes an approach through which to create such a fund, namely by introducing an incremental levy on petroleum. Notably, this scheme does not need a global agreement since a levy could be introduced by major oil-exporting countries. The implementation of this mechanism would result in a climate-friendly outcome (even before taking into account the elimination of products of incomplete combustion resulting from the traditional household use of biomass-based fuels) while providing immense socio-economic benefits to the world's poor. Such an approach would allow significant progress on the sustainable development front while reducing global greenhouse gas emissions, and therefore is very much consistent with the United Nations Framework Convention on Climate Change

  18. Crisis and Communication among Rural Poor People

    Directory of Open Access Journals (Sweden)

    Agus Ganjar Runtiko

    2015-07-01

    Full Text Available The effect of the crisis is often multiple on people in rural poverty that secluded and away from the reach of government. Main factor cannot be ignored in crisis is communication. Prolonged crisis will occur when the channels of communication in society clogged. This study establishes three specific targets: (1 To obtain a comprehensive overview of the rural poor people’s knowledge about the crisis and the potential impact, (2 To discover crisis problems faced by the rural people poor, (3 To enlist communication problems in a crisis situation. This study used a qualitative method with a case study approach. Research data collect by conducting FGD of 40 informants selected based on purposive sampling, furthermore eight people were interviewed in depth, plus other supporting informant. The results of the research show people on those two locations have understood the crisis based on their experience of dealing with it. They believe the economic crisis as the first aspect that must be resolved. The completion of crisis should consider indigenous wisdom to avoid a new crisis.

  19. Poly(n-butylcyanoacrylate nanoparticles for oral delivery of quercetin: preparation, characterization, and pharmacokinetics and biodistribution studies in Wistar rats

    Directory of Open Access Journals (Sweden)

    Bagad M

    2015-06-01

    Full Text Available Mayur Bagad, Zaved Ahmed KhanMedical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore Tamil Nadu, IndiaBackground: Quercetin (QT is a potential bioflavonol and antioxidant with poor bioavailability and very low distribution in the brain. A new oral delivery system comprising of poly(n-butylcyanoacrylate nanoparticles (PBCA NPs was introduced to improve the oral bioavailability of QT and to increase its distribution in the brain. Physicochemical characteristics, in vitro release, stability in simulated gastric fluid and intestinal fluids, and pharmacokinetics and biodistribution studies of QT-PBCA NPs coated with polysorbate-80 (P-80 were investigated.Objective: This study aimed to investigate the physicochemical characteristics, in vitro release, stability in simulated gastric fluid and intestinal fluids, and pharmacokinetics and biodistribution studies of QT-PBCA NPs coated with polysorbate-80 (P-80.Results: The results showed that QT-PBCA NPs and QT-PBCA NPs coated with P-80 (QT-PBCA+P-80 had mean particle sizes of 161.1±0.44 nm and 166.6±0.33 nm respectively, and appeared spherical in shape under transmission electron microscopy. The mean entrapment efficiency was 79.86%±0.45% for QT-PBCA NPs and 74.58%±1.44% for QT-PBCA+P-80. The in vitro release of QT-PBCA NPs and QT-PBCA+P-80 showed an initial burst release followed by a sustained release when compared to free QT. The relative bioavailability of QT-PBCA NPs and QT-PBCA+P-80 enhanced QT bioavailability by 2.38- and 4.93-fold respectively, when compared to free QT. The biodistribution study in rats showed that a higher concentration of QT was detected in the brain after the NPs were coated with P-80.Conclusion: This study indicates that PBCA NPs coated with P-80 can be potential drug carriers for poorly water-soluble drugs. These NPs were observed to improve the drugs’ oral bioavailability and enhance their transport to the brain

  20. Soya phospholipid complex of mangiferin enhances its hepatoprotectivity by improving its bioavailability and pharmacokinetics.

    Science.gov (United States)

    Bhattacharyya, Sauvik; Ahmmed, Sk Milan; Saha, Bishnu Pada; Mukherjee, Pulok K

    2014-05-01

    Mangiferin is a xanthonoid present in Mangifera indica. It has been reported for a variety of pharmacological activities, including hepatoprotection. However, the major disadvantage of mangiferin is its reduced biological activity due to poor absorption, low bioavailability and rapid elimination from the body after administration. The aim of this study was to prepare a phospholipid complex of mangiferin to overcome these limitations and to investigate the impact of the complex on hepatoprotective activity and bioavailability. The results showed that the complex has an enhanced hepatoprotective and in vivo antioxidant activity as compared to pure mangiferin at the same dose level (30 and 60 mg kg⁻¹). The complex restored the levels of serum hepatic marker enzymes and liver antioxidant enzymes with respect to carbon tetrachloride-treated animals. The complex also increased the bioavailability of mangiferin in rat serum by 9.75-fold compared to pure mangiferin at the same dose level and enhanced the elimination half-life (t(1/2 el)) from 1.71 ± 0.12 h⁻¹ to 3.52 ± 0.27 h⁻¹. The results suggested that the complexation of mangiferin with soya phospholipid enhanced the hepatoprotection and in vivo antioxidant activity, which may be due to the improved bioavailability and pharmacokinetics of mangiferin in rat serum. © 2013 Society of Chemical Industry.

  1. Multichannel imaging to quantify four classes of pharmacokinetic distribution in tumors.

    Science.gov (United States)

    Bhatnagar, Sumit; Deschenes, Emily; Liao, Jianshan; Cilliers, Cornelius; Thurber, Greg M

    2014-10-01

    Low and heterogeneous delivery of drugs and imaging agents to tumors results in decreased efficacy and poor imaging results. Systemic delivery involves a complex interplay of drug properties and physiological factors, and heterogeneity in the tumor microenvironment makes predicting and overcoming these limitations exceptionally difficult. Theoretical models have indicated that there are four different classes of pharmacokinetic behavior in tissue, depending on the fundamental steps in distribution. In order to study these limiting behaviors, we used multichannel fluorescence microscopy and stitching of high-resolution images to examine the distribution of four agents in the same tumor microenvironment. A validated generic partial differential equation model with a graphical user interface was used to select fluorescent agents exhibiting these four classes of behavior, and the imaging results agreed with predictions. BODIPY-FL exhibited higher concentrations in tissue with high blood flow, cetuximab gave perivascular distribution limited by permeability, high plasma protein and target binding resulted in diffusion-limited distribution for Hoechst 33342, and Integrisense 680 was limited by the number of binding sites in the tissue. Together, the probes and simulations can be used to investigate distribution in other tumor models, predict tumor drug distribution profiles, and design and interpret in vivo experiments. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

  2. Mucuna pruriens for Parkinson's disease: Low-cost preparation method, laboratory measures and pharmacokinetics profile.

    Science.gov (United States)

    Cassani, Erica; Cilia, Roberto; Laguna, Janeth; Barichella, Michela; Contin, Manuela; Cereda, Emanuele; Isaias, Ioannis U; Sparvoli, Francesca; Akpalu, Albert; Budu, Kwabena Ofosu; Scarpa, Maria Teresa; Pezzoli, Gianni

    2016-06-15

    Parkinson's disease (PD) is a progressive neurological condition. Levodopa (LD) is the gold standard therapy for PD patients. Most PD patients in low-income areas cannot afford long-term daily Levodopa therapy. The aim of our study was to investigate if Mucuna pruriens (MP), a legume with high LD content that grows in tropical regions worldwide, might be potential alternative for poor PD patients. We analyzed 25 samples of MP from Africa, Latin America and Asia. We measured the content in LD in various MP preparations (dried, roasted, boiled). LD pharmacokinetics and motor response were recorded in four PD patients, comparing MP vs. LD+Dopa-Decarboxylase Inhibitor (DDCI) formulations. Median LD concentration in dried MP seeds was 5.29%; similar results were obtained in roasted powder samples (5.3%), while boiling reduced LD content up to 70%. Compared to LD+DDCI, MP extract at similar LD dose provided less clinical benefit, with a 3.5-fold lower median AUC. Considering the lack of a DDCI, MP therapy may provide clinical benefit only when content of LD is at least 3.5-fold the standard LD+DDCI. If long-term MP proves to be safe and effective in controlled clinical trials, it may be a sustainable alternative therapy for PD in low-income countries. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  3. Pharmacokinetic drug evaluation of pazopanib for the treatment of uterine leiomyosarcomas.

    Science.gov (United States)

    Ferrero, Simone; Leone Roberti Maggiore, Umberto; Aiello, Nicoletta; Barra, Fabio; Ditto, Antonino; Bogani, Giorgio; Raspagliesi, Francesco; Lorusso, Domenica

    2017-08-01

    Uterine leiomyosarcomas (ULMS) represent 1.3% of all uterine malignant tumors. Surgery is the curative treatment for patients with early stage disease. In case of advanced, persistent or recurrent tumor, chemotherapy represents the standard of care, but these patients have a poor prognosis. As the results with available therapies are far from being satisfactory, research is focusing on identification of new compounds. In 2012 the Food and Drug Administration (FDA) licensed pazopanib for the treatment of advanced soft-tissue sarcomas failing previous chemotherapy. Areas covered: The aim of this article is to review the literature on the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of the tyrosine kinase inhibitor (TKI), pazopanib in the treatment of ULMS. Expert opinion: The discovery of some relevant signalling pathways in LMS cells led to the development of new targeted drugs with promising results in the management of these tumors. Pazopanib is a multi-target second-generation TKI with activity against growth factors involved in angiogenesis. It has shown promising results both in terms of efficacy and safety, as shown in the EORTC 62043 Study and the PALETTE trial. Further studies are awaited to evaluate its efficacy in uterine leiomyosarcomas.

  4. Pharmacokinetics and enhanced bioavailability of candidate cancer preventative agent, SR13668 in dogs and monkeys.

    Science.gov (United States)

    Kapetanovic, Izet M; Muzzio, Miguel; Hu, Shu-Chieh; Crowell, James A; Rajewski, Roger A; Haslam, John L; Jong, Ling; McCormick, David L

    2010-05-01

    SR13668 (2,10-dicarbethoxy-6-methoxy-5,7-dihydro-indolo-(2,3-b)carbazole), is a new candidate cancer chemopreventive agent under development. It was designed using computational modeling based on a naturally occurring indole-3-carbinol and its in vivo condensation products. It showed promising anti-cancer activity and its preclinical toxicology profile (genotoxicity battery and subchronic rat and dog studies) was unremarkable. However, it exhibited a very poor oral bioavailability (Solutol, were tested in dogs and monkeys. Levels of SR13668 were measured in plasma and blood using a high-performance liquid chromatograph-tandem mass spectrometer system. Non-compartmental analysis was used to derive pharmacokinetic parameters including the bioavailability. The Solutol formulation yielded better bioavailability reaching a maximum of about 14.6 and 7.3% in dogs and monkeys, respectively, following nominal oral dose of ca. 90 mg SR13668/m(2). Blood levels of SR13668 were consistently about threefold higher than those in plasma in both species. SR13668 did not cause untoward hematology, clinical chemistry, or coagulation effects in dogs or monkeys with the exception of a modest, reversible increase in liver function enzymes in monkeys. The lipid-based surfactant/emulsifiers, especially Solutol, markedly enhanced the oral bioavailability of SR13668 over that previously seen in preclinical studies. These formulations are being evaluated in a Phase 0 clinical study prior to further clinical development of this drug.

  5. Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues.

    Science.gov (United States)

    Fransson, Rebecca; Nordvall, Gunnar; Bylund, Johan; Carlsson-Jonsson, Anna; Kratz, Jadel M; Svensson, Richard; Artursson, Per; Hallberg, Mathias; Sandström, Anja

    2014-12-11

    The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.

  6. Bioavailability of Echinacea Constituents: Caco-2 Monolayers and Pharmacokinetics of the Alkylamides and Caffeic Acid Conjugates

    Directory of Open Access Journals (Sweden)

    R. Lehmann

    2005-10-01

    Full Text Available Many studies have been done over the years to assess the effectiveness of Echinacea as an immunomodulator. We have assessed the potential bioavailability of alkyl- amides and caffeic acid conjugates using Caco-2 monolayers and compared it to their actual bioavailability in a Phase I clinical trial. The caffeic acid conjugates permeated poorly through the Caco-2 monolayers. Alkylamides were found to diffuse rapidly through Caco-2 monolayers. Differences in diffusion rates for each alkylamide correlated to structural variations, with saturation and N-terminal methylation contributing to decreases in diffusion rates. Alkylamide diffusion is not affected by the presence of other constituents and the results for a synthetic alkylamide were in line with those for alkylamides found in an ethanolic Echinacea preparation. We examined plasma from healthy volunteers for 12 hours after ingestion of Echinacea tablets manufactured from an ethanolic liquid extract. Caffeic acid conjugates could not be identified in any plasma sample at any time after tablet ingestion. Alkylamides were detected in plasma 20 minutes after tablet ingestion and for each alkylamide, pharmacokinetic profiles were devised. The data are consistent with the dosing regimen of one tablet three times daily and supports their usage as the primary markers for quality Echinacea preparations.

  7. How poor are women in rural India?

    Science.gov (United States)

    Rajuladevi, A K

    1992-07-01

    The assessment of poor women in India as dependent and exploited regardless of poverty focused strategies is reflected in this review of relevant literature. The scholarly approaches to the problems of poor women involve redirection and expansion of resources to women (increase bank credit) through policy and institutional changes, and involve improving women's welfare through changes in class and gender hierarchies; both pertain to restructuring power groups. A little ascribed to belief is that the organization of women's numbers will empower women; the constraints are stated. There is also some argument over whether to design women-specific programs or integrate women into existing programs; some examples are given of successes and difficulties. The regionalization of poverty in eastern and central India is discussed. The growth of the poor has been among the landless, wage-dependent households. 9.6% of households (7.5 million) are headed by women. Women work fewer hours and at lower wage scales and have fewer employment opportunities. Lower earnings are coupled with differentials in demand for female and male labor in agriculture and a crowded labor market. There is a concentration of women in less visible, nonmonetary subsistence production and domestic work. Women are undercounted in employment studies. Women predominate in agricultural activity. Women's status is influenced by economic status, caste, and ethnic background. Domestic work increases status for women and households. The poorer households have greater labor force participation, particularly as wage laborers rather than unpaid family workers. Regional factors affecting rural household strategies are factors affecting the economy (topography, rainfall, climate) and the degree of development, plus sociocultural variables (kinship and religious beliefs which affect the social domain of women), and the degree of dependence on hired vs. family labor. There are sharp contrasts in the value and survival

  8. Detonation velocity in poorly mixed gas mixtures

    Science.gov (United States)

    Prokhorov, E. S.

    2017-10-01

    The technique for computation of the average velocity of plane detonation wave front in poorly mixed mixture of gaseous hydrocarbon fuel and oxygen is proposed. Here it is assumed that along the direction of detonation propagation the chemical composition of the mixture has periodic fluctuations caused, for example, by layered stratification of gas charge. The technique is based on the analysis of functional dependence of ideal (Chapman-Jouget) detonation velocity on mole fraction (with respect to molar concentration) of the fuel. It is shown that the average velocity of detonation can be significantly (by more than 10%) less than the velocity of ideal detonation. The dependence that permits to estimate the degree of mixing of gas mixture basing on the measurements of average detonation velocity is established.

  9. The Nordic version of working poor

    DEFF Research Database (Denmark)

    Ilsøe, Anna

    The development of service economies in the Western world has led to a debate on the quality of new service jobs as many are low-wage jobs with poor working conditions and career opportunities (Westergaard-Nielsen 2008; Gautié & Schmitt 2009; Kalleberg 2011). Empirical and theoretical work has...... from the European Labour Force Survey it is examined how low wage service work has developed in the private sector in the three countries since 2000 and which segments that can be identified. Data is drawn from the last quarter of 2000 (before the economic boom), 2007 (before the financial crisis....../restaurants, as the majority of low-wage private service workers in Denmark, Norway and Sweden work in these sectors (Bosch & Lehndorff 2005). We compare developments in the three countries to identify similar and different segments that have emerged over the past 15 years. Finally, the paper discusses findings in relation...

  10. Elucidating the in vivo fate of nanocrystals using a physiologically based pharmacokinetic model: a case study with the anticancer agent SNX-2112

    Directory of Open Access Journals (Sweden)

    Dong D

    2015-03-01

    Full Text Available Dong Dong,1* Xiao Wang,1* Huailing Wang,1 Xingwang Zhang,2 Yifei Wang,1 Baojian Wu2 1Guangzhou Jinan Biomedicine Research and Development Center, 2Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, People’s Republic of China *These authors contributed equally to this work Introduction: SNX-2112 is a promising anticancer agent but has poor solubility in both water and oil. In the study reported here, we aimed to develop a nanocrystal formulation for SNX-2112 and to determine the pharmacokinetic behaviors of the prepared nanocrystals. Methods: Nanocrystals of SNX-2112 were prepared using the wet-media milling technique and characterized by particle size, differential scanning calorimetry, drug release, etc. Physiologically based pharmacokinetic (PBPK modeling was undertaken to evaluate the drug’s disposition in rats following administration of drug cosolvent or nanocrystals. Results: The optimized SNX-2112 nanocrystals (with poloxamer 188 as the stabilizer were 203 nm in size with a zeta potential of -11.6 mV. In addition, the nanocrystals showed a comparable release profile to the control (drug cosolvent. Further, the rat PBPK model incorporating the parameters of particulate uptake (into the liver and spleen and of in vivo drug release was well fitted to the experimental data following administration of the drug nanocrystals. The results reveal that the nanocrystals rapidly released drug molecules in vivo, accounting for their cosolvent-like pharmacokinetic behaviors. Due to particulate uptake, drug accumulation in the liver and spleen was significant at the initial time points (within 1 hour. Conclusion: The nanocrystals should be a good choice for the systemic delivery of the poorly soluble drug SNX-2112. Also, our study contributes to an improved understanding of the in vivo fate of nanocrystals. Keywords: intravenous delivery, PBPK, tissue distribution, poloxamer 188

  11. Steady-state pharmacokinetics of pravastatin in children with familial hypercholesterolaemia

    NARCIS (Netherlands)

    Wiersma, Heleen E.; Wiegman, Albert; Koopmans, Richard P.; Bakker, Henk D.; Kastelein, John J. P.; van Boxtel, Chris J.

    2004-01-01

    Objective: To determine pharmacokinetic data for pravastatin in children, since current data are insufficient in this age group. Subjects and methods: A 2-week, multiple-dose, steady-state pharmacokinetic study was carried out with pravastatin 20mg daily in 24 children with familial

  12. Influence of Bariatric Surgery on the Use and Pharmacokinetics of Some Major Drug Classes

    NARCIS (Netherlands)

    Yska, Jan Peter; van der Linde, Susanne; Tapper, Veronique V.; Apers, Jan A.; Emous, Marloes; Totte, Erik R.; Wilffert, Bob; van Roon, Eric N.

    The purpose of this review is to evaluate the influence of bariatric surgery on the use and pharmacokinetics of some frequently used drugs. A PubMed literature search was conducted. Literature was included on influence of bariatric surgery on pharmacoepidemiology and pharmacokinetics. Drug classes

  13. Plasma paracetamol concentrations and pharmacokinetics following rectal administration in neonates and young infants

    DEFF Research Database (Denmark)

    Hansen, Tom Giedsing; O'Brien, K; Morton, N S

    1999-01-01

    Despite widespread use in children pharmacokinetic data about paracetamol are relatively scarce, not the least in the youngest age groups. This study aimed to describe plasma paracetamol concentrations and pharmacokinetics of a single rectal paracetamol dose in neonates and young infants....

  14. The effect of Yoyo bitters on the pharmacokinetics of single oral ...

    African Journals Online (AJOL)

    Blood samples were collected and analyzed for paracetamol using spectrophotometric method. The values obtained for the pharmacokinetics parameters when paracetamol was administered alone falls within previously reported values. Yoyo bitters did not statistically (P>0.05) affect the pharmacokinetics of paracetamol ...

  15. Sensorimotor Mismapping in Poor-pitch Singing.

    Science.gov (United States)

    He, Hao; Zhang, Wei-Dong

    2017-09-01

    This study proposes that there are two types of sensorimotor mismapping in poor-pitch singing: erroneous mapping and no mapping. We created operational definitions for the two types of mismapping based on the precision of pitch-matching and predicted that in the two types of mismapping, phonation differs in terms of accuracy and the dependence on the articulation consistency between the target and the intended vocal action. The study aimed to test this hypothesis by examining the reliability and criterion-related validity of the operational definitions. A within-subject design was used in this study. Thirty-two participants identified as poor-pitch singers were instructed to vocally imitate pure tones and to imitate their own vocal recordings with the same articulation as self-targets and with different articulation from self-targets. Definitions of the types of mismapping were demonstrated to be reliable with the split-half approach and to have good criterion-related validity with findings that pitch-matching with no mapping was less accurate and more dependent on the articulation consistency between the target and the intended vocal action than pitch-matching with erroneous mapping was. Furthermore, the precision of pitch-matching was positively associated with its accuracy and its dependence on articulation consistency when mismapping was analyzed on a continuum. Additionally, the data indicated that the self-imitation advantage was a function of articulation consistency. Types of sensorimotor mismapping lead to pitch-matching that differs in accuracy and its dependence on the articulation consistency between the target and the intended vocal action. Additionally, articulation consistency produces the self-advantage. Copyright © 2017 The Voice Foundation. Published by Elsevier Inc. All rights reserved.

  16. Management of poor quality irrigation water

    International Nuclear Information System (INIS)

    Change, M.H.; Leghari, A.M.; Sipio, Q.A.

    2000-01-01

    The effect of poor quality drainage effluent on moderately saline sodic, medium textured soil at different growth stages of wheat and cotton is reported. The irrigation treatments were: I) All canal irrigations, II) one irrigation of 75 mm with saline drainage effluent (EC = 3 dS m1) after four weeks sowing of the crop, III) one irrigation of 75 mm with saline drainage effluent after seven weeks sowing of the crop, and IV) one irrigation of 75 mm with saline drainage effluent after ten weeks sowing of the crop. The treatments receiving saline water gave significant decrease in crop yields as compared to canal irrigation treatment. The higher yield of wheat and seed cotton was recorded T1 followed by T2, T3 and T4. The trend of produce was T1< T2< T3< T4 respectively. Electrical conductivity of the soil (Ece) in T1 was decreased and in other three treatments was increased, whereas, pH decreased in T1 and T2. The SAR of soil decreased in all the treatments as compared with initial values. Treatment receiving an irrigation with saline water after four weeks of sowing (T2) was better in reducing soil salinity as compared to treatments receiving such water after 7 or 10 weeks os sowing. Poor quality water (EC = 3 d Sm/sup -1/) can be managed for irrigation after four weeks of swing of crops provided certain soil and water management practices like good seed bed preparation and proper drainage measures are adopted. (author)

  17. "Managing" the poor: neoliberalism, Medicaid HMOs and the triumph of consumerism among the poor.

    Science.gov (United States)

    Maskovsky, J

    2000-10-01

    In order to explore the contradictions of neoliberal health policy, this article examines Medicaid managed care in Philadelphia. At the federal and state levels, government is increasingly promoting private-sector market-based strategies over policies formerly associated with the welfare state, arguing that the former are the most effective means of achieving economic growth and guaranteeing social welfare. A prime example of this shift, Medicaid managed care is a policy by which states contract with private-sector health maintenance organizations to provide health coverage to the poor. Drawing on ethnographic and historical data, this paper shows how Pennsylvania's Medicaid managed care program has created access barriers for poor Philadelphians. It also illustrates how ideologies that justify this policy shift serve to mask its detrimental effects on the poor. By contrasting the state's consumerist model with one group's protest efforts, this article calls into question the neoliberal ideology that undergirds health and welfare "reform."

  18. Poor mental health status and aggression are associated with poor driving behavior among male traffic offenders

    Directory of Open Access Journals (Sweden)

    Abdoli N

    2015-08-01

    Full Text Available Nasrin Abdoli,1,2 Vahid Farnia,3 Ali Delavar,4 Alirez Esmaeili,5 Fariborz Dortaj,4 Noorali Farrokhi,4 Majid Karami,6 Jalal Shakeri,3 Edith Holsboer-Trachsler,7 Serge Brand7,8 1International University of Imam Reza, Mashhad, 2Kermanshah University of Medical Sciences, Kermanshah, 3Substance Abuse Prevention Research Center, Psychiatry Department, Kermanshah University of Medical Sciences, Kermanshah, 4Allameh Tabataba’i University, Tehran, 5Police University, Tehran, 6Baharestan Research Center, Kermanshah Transportation Terminal, Kermanshah, Iran, 7Center for Affective, Stress and Sleep Disorders, Psychiatric Clinics of the University of Basel, Basel, 8Department of Sport and Health Science, Sport Science Section, University of Basel, Basel, Switzerland Background: In Iran, traffic accidents and deaths from traffic accidents are among the highest in the world, and generally driver behavior rather than either technical failures or environmental conditions are responsible for traffic accidents. In the present study, we explored the extent to which aggressive traits, health status, and sociodemographic variables explain driving behavior among Iranian male traffic offenders. Method: A total of 443 male driving offenders (mean age: M =31.40 years, standard deviation =9.56 from Kermanshah (Iran took part in the study. Participants completed a questionnaire booklet covering sociodemographic variables, traits of aggression, health status, and driving behavior. Results: Poor health status, such as symptoms of depression, anxiety, insomnia, and social dysfunction, and also higher levels of trait aggression explained poor driving behavior. Multiple regressions indicated that poor health status, but not aggression, independently predicted poor driving behavior. Conclusion: Results suggest that health status concerns are associated with poor driving behavior. Prevention and intervention might therefore focus on drivers reporting poor mental health status

  19. Analytical Techniques and Pharmacokinetics of Gastrodia elata Blume and Its Constituents.

    Science.gov (United States)

    Wu, Jinyi; Wu, Bingchu; Tang, Chunlan; Zhao, Jinshun

    2017-07-08

    Gastrodia elata Blume ( G. elata ), commonly called Tianma in Chinese, is an important and notable traditional Chinese medicine (TCM), which has been used in China as an anticonvulsant, analgesic, sedative, anti-asthma, anti-immune drug since ancient times. The aim of this review is to provide an overview of the abundant efforts of scientists in developing analytical techniques and performing pharmacokinetic studies of G. elata and its constituents, including sample pretreatment methods, analytical techniques, absorption, distribution, metabolism, excretion (ADME) and influence factors to its pharmacokinetics. Based on the reported pharmacokinetic property data of G. elata and its constituents, it is hoped that more studies will focus on the development of rapid and sensitive analytical techniques, discovering new therapeutic uses and understanding the specific in vivo mechanisms of action of G. elata and its constituents from the pharmacokinetic viewpoint in the near future. The present review discusses analytical techniques and pharmacokinetics of G. elata and its constituents reported from 1985 onwards.

  20. Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers.

    Science.gov (United States)

    Jonkman, Kelly; Duma, Andreas; Olofsen, Erik; Henthorn, Thomas; van Velzen, Monique; Mooren, René; Siebers, Liesbeth; van den Beukel, Jojanneke; Aarts, Leon; Niesters, Marieke; Dahan, Albert

    2017-10-01

    Esketamine is traditionally administered via intravenous or intramuscular routes. In this study we developed a pharmacokinetic model of inhalation of nebulized esketamine with special emphasis on pulmonary absorption and bioavailability. Three increasing doses of inhaled esketamine (dose escalation from 25 to 100 mg) were applied followed by a single intravenous dose (20 mg) in 19 healthy volunteers using a nebulizer system and arterial concentrations of esketamine and esnorketamine were obtained. A multicompartmental pharmacokinetic model was developed using population nonlinear mixed-effects analyses. The pharmacokinetic model consisted of three esketamine, two esnorketamine disposition and three metabolism compartments. The inhalation data were best described by adding two absorption pathways, an immediate and a slower pathway, with rate constant 0.05 ± 0.01 min (median ± SE of the estimate). The amount of esketamine inhaled was reduced due to dose-independent and dose-dependent reduced bioavailability. The former was 70% ± 5%, and the latter was described by a sigmoid EMAX model characterized by the plasma concentration at which absorption was impaired by 50% (406 ± 46 ng/ml). Over the concentration range tested, up to 50% of inhaled esketamine is lost due to the reduced dose-independent and dose-dependent bioavailability. We successfully modeled the inhalation of nebulized esketamine in healthy volunteers. Nebulized esketamine is inhaled with a substantial reduction in bioavailability. Although the reduction in dose-independent bioavailability is best explained by retention of drug and particle exhalation, the reduction in dose-dependent bioavailability is probably due to sedation-related loss of drug into the air.

  1. Population pharmacokinetics of adefovir dipivoxil tablets in healthy Chinese volunteers.

    Science.gov (United States)

    Huang, Jihan; Zhang, Yaping; Huang, Xiaohui; Li, Lujin; Li, Yunfei; Wang, Kun; Yang, Juan; He, Yingchun; Lv, Yinghua; Zheng, Qingshan

    2014-01-01

    To develop a population pharmacokinetic model of adefovir dipivoxil in healthy volunteers and evaluate the effect of individual factors on the pharmacokinetics of adefovir dipivoxil. Plasma concentration data collected from 32 healthy Chinese subjects in a Phase I clinical study was pooled. Subjects received a single oral dose of 10 mg, 20 mg, or 30 mg adefovir dipivoxil, or multiple doses of 10 mg once a day for 9 days. Plasma concentrations of adefovir dipivoxil were measured using a validated liquid chromatography-mass spectrometric method. A nonlinear mixed-effect model was used to analyze the plasma concentration data of adefovir dipivoxil in healthy volunteers and to calculate the relevant parameters as well as inter- and intra-individual variability. The time course of adefovir dipivoxil concentration is best described by a first-order absorption and first-order elimination two-compartment model with lag time. The final estimate of total body clearance (CL) is 56.9 L/h and 78.7 L/h for single and multiple dosing regimen, respectively; the volume distribution of the central compartment (V2) is 106 L; inter-compartmental clearance (Q) is 220 L/h; volume distribution of the peripheral compartment (V3) is 498 L and 800 L for single and multiple dosing regimen, respectively; absorption rate is 0.509 h-1; and lag time is 0.315 hours. The inter-individual variabilities of CL and V2 were 22.4% and 58.9%, respectively. The proportional error of residual variability is 14.1% and the additive error is 0.30 ng/L. The final pharmacokinetic model was evaluated using a bootstrap method. A nonlinear mixed effect model for oral adefovir dipivoxil formulations was developed in healthy Chinese subjects. A multiple dosing regimen may significantly increase the body clearance and volume distribution of the peripheral compartment compared to a single dosing regimen. *These authors contribute equally to this work.

  2. The Influence of Normalization Weight in Population Pharmacokinetic Covariate Models.

    Science.gov (United States)

    Goulooze, Sebastiaan C; Völler, Swantje; Välitalo, Pyry A J; Calvier, Elisa A M; Aarons, Leon; Krekels, Elke H J; Knibbe, Catherijne A J

    2018-03-23

    In covariate (sub)models of population pharmacokinetic models, most covariates are normalized to the median value; however, for body weight, normalization to 70 kg or 1 kg is often applied. In this article, we illustrate the impact of normalization weight on the precision of population clearance (CL pop ) parameter estimates. The influence of normalization weight (70, 1 kg or median weight) on the precision of the CL pop estimate, expressed as relative standard error (RSE), was illustrated using data from a pharmacokinetic study in neonates with a median weight of 2.7 kg. In addition, a simulation study was performed to show the impact of normalization to 70 kg in pharmacokinetic studies with paediatric or obese patients. The RSE of the CL pop parameter estimate in the neonatal dataset was lowest with normalization to median weight (8.1%), compared with normalization to 1 kg (10.5%) or 70 kg (48.8%). Typical clearance (CL) predictions were independent of the normalization weight used. Simulations showed that the increase in RSE of the CL pop estimate with 70 kg normalization was highest in studies with a narrow weight range and a geometric mean weight away from 70 kg. When, instead of normalizing with median weight, a weight outside the observed range is used, the RSE of the CL pop estimate will be inflated, and should therefore not be used for model selection. Instead, established mathematical principles can be used to calculate the RSE of the typical CL (CL TV ) at a relevant weight to evaluate the precision of CL predictions.

  3. Pharmacokinetics of combined treatment with praziquantel and albendazole in neurocysticercosis

    Science.gov (United States)

    Garcia, Hector H; Lescano, Andres G; Lanchote, Vera L; Pretell, E Javier; Gonzales, Isidro; Bustos, Javier A; Takayanagui, Osvaldo M; Bonato, Pierina S; Horton, John; Saavedra, Herbert; Gonzalez, Armando E; Gilman, Robert H

    2011-01-01

    AIMS Neurocysticercosis is the most common cause of acquired epilepsy in the world. Antiparasitic treatment of viable brain cysts is of clinical benefit, but current antiparasitic regimes provide incomplete parasiticidal efficacy. Combined use of two antiparasitic drugs may improve clearance of brain parasites. Albendazole (ABZ) has been used together with praziquantel (PZQ) before for geohelminths, echinococcosis and cysticercosis, but their combined use is not yet formally recommended and only scarce, discrepant data exist on their pharmacokinetics when given together. We assessed the pharmacokinetics of their combined use for the treatment of neurocysticercosis. METHODS A randomized, double-blind, placebo-controlled phase II evaluation of the pharmacokinetics of ABZ and PZQ in 32 patients with neurocysticercosis was carried out. Patients received their usual concomitant medications including an antiepileptic drug, dexamethasone, and ranitidine. Randomization was stratified by antiepileptic drug (phenytoin or carbamazepine). Subjects had sequential blood samples taken after the first dose of antiparasitic drugs and again after 9 days of treatment, and were followed for 3 months after dosing. RESULTS Twenty-one men and 11 women, aged 16 to 55 (mean age 28) years were included. Albendazole sulfoxide concentrations were increased in the combination group compared with the ABZ alone group, both in patients taking phenytoin and patients taking carbamazepine. PZQ concentrations were also increased by the end of therapy. There were no significant side effects in this study group. CONCLUSIONS Combined ABZ + PZQ is associated with increased albendazole sulfoxide plasma concentrations. These increased concentrations could independently contribute to increased cysticidal efficacy by themselves or in addition to a possible synergistic effect. PMID:21332573

  4. Population pharmacokinetics of artesunate and amodiaquine in African children

    Directory of Open Access Journals (Sweden)

    Ouedraogo Alphonse

    2009-08-01

    Full Text Available Abstract Background Pharmacokinetic (PK data on amodiaquine (AQ and artesunate (AS are limited in children, an important risk group for malaria. The aim of this study was to evaluate the PK properties of a newly developed and registered fixed dose combination (FDC of artesunate and amodiaquine. Methods A prospective population pharmacokinetic study of AS and AQ was conducted in children aged six months to five years. Participants were randomized to receive the new artesunate and amodiaquine FDC or the same drugs given in separate tablets. Children were divided into two groups of 70 (35 in each treatment arm to evaluate the pharmacokinetic properties of AS and AQ, respectively. Population pharmacokinetic models for dihydroartemisinin (DHA and desethylamodiaquine (DeAq, the principal pharmacologically active metabolites of AS and AQ, respectively, and total artemisinin anti-malarial activity, defined as the sum of the molar equivalent plasma concentrations of DHA and artesunate, were constructed using the non-linear mixed effects approach. Relative bioavailability between products was compared by estimating the ratios (and 95% CI between the areas under the plasma concentration-time curves (AUC. Results The two regimens had similar PK properties in young children with acute malaria. The ratio of loose formulation to fixed co-formulation AUCs, was estimated as 1.043 (95% CI: 0.956 to 1.138 for DeAq. For DHA and total anti-malarial activity AUCs were estimated to be the same. Artesunate was rapidly absorbed, hydrolysed to DHA, and eliminated. Plasma concentrations were significantly higher following the first dose, when patients were acutely ill, than after subsequent doses when patients were usually afebrile and clinically improved. Amodiaquine was converted rapidly to DeAq, which was then eliminated with an estimated median (range elimination half-life of 9 (7 to 12 days. Efficacy was similar in the two treatments groups, with cure rates of 0

  5. [Pharmacokinetic studies of flomoxef in the neonatal field].

    Science.gov (United States)

    Kimura, K; Miyano, T; Shimomura, H

    1991-11-01

    Flomoxef (FMOX), a new broad spectrum oxacephem antibiotic, was studied in the neonatal field and the pharmacokinetic results obtained are summarized below. 1. Serum concentrations of FMOX after dosages of 20 mg/kg via 1 hour drip infusion were 21.8 +/- 7.59 micrograms/ml, 15.4 +/- 4.35 micrograms/ml, 4.3 +/- 2.88 micrograms/ml at 1, 2 and 5 hours after administration, respectively, and T 2/1 (beta)'s averaged 2.08 +/- 1.01 hours. 2. Urinary excretion rates were 53.38 +/- 16.94% in the first 7 hours after administration.

  6. Triprotic acid-base microequilibria and pharmacokinetic sequelae of cetirizine.

    Science.gov (United States)

    Marosi, Attila; Kovács, Zsuzsanna; Béni, Szabolcs; Kökösi, József; Noszál, Béla

    2009-06-28

    (1)H NMR-pH titrations of cetirizine, the widely used antihistamine and four related compounds were carried out and the related 11 macroscopic protonation constants were determined. The interactivity parameter between the two piperazine amine groups was obtained from two symmetric piperazine derivatives. Combining these two types of datasets, all the 12 microconstants and derived tautomeric constants of cetirizine were calculated. Upon this basis, the conflicting literature data of cetirizine microspeciation were clarified, and the pharmacokinetic absorption-distribution properties could be interpreted. The pH-dependent distribution of the microspecies is provided.

  7. A pharmacokinetic study of diclofenac sodium in rats.

    Science.gov (United States)

    Yuan, Jing; Ma, He; Cen, Nannan; Zhou, Ai; Tao, Hengxun

    2017-08-01

    The aim of the present study was to examine the pharmacokinetics of a single intravenous injection (i.v.) and oral administration (p.o.) of diclofenac sodium (DIC) in Sprague-Dawley (SD) rats. Twelve male SD rats were divided into 2 groups (n=6 per group); one group was injected intravenously with 2 mg/kg DIC, whereas the other group was lavaged with 2 mg/kg DIC. Blood samples were collected prior to DIC delivery (0 h) and 0.033, 0.083, 0.167, 0.25, 0.5, 1, 2, 4, 6, and 8 h post-administration. Blood plasma samples were analyzed using liquid chromatography-mass spectrometry (LC-MS/MS) following pretreatment to induce protein precipitation. Pharmacokinetics software was applied to calculate relevant pharmacokinetic parameters using a non-compartmental model. Following i.v. administration of DIC, the terminal elimination rate constant (λ z ), apparent terminal elimination half-life (t ½ ), area under the concentration-time curve from time 0 extrapolated to infinity (AUC0 -∞ ), clearance (CL), apparent volume of distribution (V z ), mean residence time (MRT), and apparent volume of distribution at steady state (V ss ) were 0.57±0.05 l/h, 1.22±0.11 h, 3356±238 h × ng/ml, 0.60±0.04 l/h, 1.05±0.10 l, 1.05±0.07 h and 0.63±0.07 l, respectively. Following p.o. administration of DIC, the λ z , t ½ , C max , t max , AUC 0-∞ , CL, V z , MRT were: 0.63±0.12 l/h, 1.12±0.18 h, 1272±112 ng/ml, 0.19±0.04 h, 2501±303 h × ng/ml, 0.81±0.10 l/h, 1.29±0.12 l, and 2.70±0.18 h, respectively. The pharmacokinetic parameters of i.v. and p.o. DIC in rats show that the drug is rapidly absorbed, distributed, and eliminated.

  8. 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

  9. Pharmacokinetic of antimony in mice with cutaneous Leishmaniasis

    International Nuclear Information System (INIS)

    Borborema, Samanta E.T.; Nascimento, Nanci do; Osso Junior, Joao A.

    2007-01-01

    Cutaneous Leishmaniasis (CL) remains a major world health problem, with about 1.5 million new cases each year. Caused by protozoa Leishmania, in South America, this infection can vary from a chronic skin ulcer, to an erosive mucosal disease and severe facial disfigurement. Pentavalent antimony (Sb +5 ) as sodium stibogluconate (Pentostam) or meglumine antimoniate (Glucantime) are main drugs for treating most forms of human leishmaniasis. For six decades, despite the recent developments, the effective therapy to cutaneous leishmaniasis has been based on long parenteral courses of such drugs, even though these are fairly costly, toxic and inconvenient to use, without adequate knowledge on their pharmacokinetics or mechanism of action. Pharmacokinetics studies could be based on bioactive traceable drugs, usually with radioactive isotopes, but antimony radioisotopes are unavailable commercially. Neutron irradiation is a powerful tool in the analysis of mineral content of samples, for antimony, there are at least two main isotopes that could be formed after neutron irradiation in nuclear reactor. The aim of the present study was to construct antimony salts with those radioisotopes to obtain tracers to compare the pharmacokinetic and the tissue distribution of neutron irradiated meglumine antimoniate in healthy and cutaneous leishmaniasis experimentally infected mice. Meglumine antimoniate, (Glucantime, Aventis, S.P, Brazil), was neutron irradiated inside the IEA-R1 nuclear reactor (IPEN/CNEN-SP), producing two radioisotopes 122 Sb and 124 Sb. Its biodistribution was verified in BALB/c mice experimentally infected with Leishmania (Leishmania) Amazonensis, which received a single intraperitoneal dose of the drug. At different times after injection, the tissues and blood were excised and activity measured in a NaI (Tl) scintillation counter. Compared with the healthy mice, experimentally infected mice had significantly lower maximum concentration of antimony and high

  10. Pharmacokinetics and Metabolism of 4R-Cembranoid

    OpenAIRE

    V?lez-Carrasco, Wanda; Green, Carol E.; Catz, Paul; Furimsky, Anna; O?Loughlin, Kathleen; Eterovi?, Vesna A.; Ferchmin, P. A.

    2015-01-01

    4R-cembranoid (4R) is a natural cyclic diterpenoid found in tobacco leaves that displays neuroprotective activity. 4R protects against NMDA, paraoxon (POX), and diisopropylfluorophosphate (DFP) damage in rat hippocampal slices and against DFP in rats in vivo. The purpose of this study was to examine the metabolism and pharmacokinetics of 4R as part of its preclinical development as a neuroprotective drug. 10 µM 4R was found to be very stable in plasma for up to 1 hr incubation. 4R metabolism ...

  11. Pharmacokinetic of antimony in mice with cutaneous Leishmaniasis

    Energy Technology Data Exchange (ETDEWEB)

    Borborema, Samanta E.T.; Nascimento, Nanci do [Instituto de Pesquisas Energeticas e Nucleares IPEN/CNEN-SP, Sao Paulo, SP (Brazil). Lab. de Biologia Molecular]. E-mails: samanta@usp.br; nnascime@ipen.br; Andrade Junior, Heitor F. de [Instituto de Pesquisas Energeticas e Nucleares IPEN/CNEN-SP, Sao Paulo, SP (Brazil). Lab. de Biologia Molecular; Instituto de Medicina Tropical de Sao Paulo, Sao Paulo, SP (Brazil); E-mail: hfandrad@usp.br; Osso Junior, Joao A. [Instituto de Pesquisas Energeticas e Nucleares IPEN/CNEN-SP, Sao Paulo, SP (Brazil). Centro de Radiofarmacia]. E-mail: jaosso@ipen.br

    2007-07-01

    Cutaneous Leishmaniasis (CL) remains a major world health problem, with about 1.5 million new cases each year. Caused by protozoa Leishmania, in South America, this infection can vary from a chronic skin ulcer, to an erosive mucosal disease and severe facial disfigurement. Pentavalent antimony (Sb{sup +5}) as sodium stibogluconate (Pentostam) or meglumine antimoniate (Glucantime) are main drugs for treating most forms of human leishmaniasis. For six decades, despite the recent developments, the effective therapy to cutaneous leishmaniasis has been based on long parenteral courses of such drugs, even though these are fairly costly, toxic and inconvenient to use, without adequate knowledge on their pharmacokinetics or mechanism of action. Pharmacokinetics studies could be based on bioactive traceable drugs, usually with radioactive isotopes, but antimony radioisotopes are unavailable commercially. Neutron irradiation is a powerful tool in the analysis of mineral content of samples, for antimony, there are at least two main isotopes that could be formed after neutron irradiation in nuclear reactor. The aim of the present study was to construct antimony salts with those radioisotopes to obtain tracers to compare the pharmacokinetic and the tissue distribution of neutron irradiated meglumine antimoniate in healthy and cutaneous leishmaniasis experimentally infected mice. Meglumine antimoniate, (Glucantime, Aventis, S.P, Brazil), was neutron irradiated inside the IEA-R1 nuclear reactor (IPEN/CNEN-SP), producing two radioisotopes {sup 122}Sb and {sup 124}Sb. Its biodistribution was verified in BALB/c mice experimentally infected with Leishmania (Leishmania) Amazonensis, which received a single intraperitoneal dose of the drug. At different times after injection, the tissues and blood were excised and activity measured in a NaI (Tl) scintillation counter. Compared with the healthy mice, experimentally infected mice had significantly lower maximum concentration of antimony

  12. ABT-773: pharmacokinetics and interactions with ranitidine and sucralfate.

    Science.gov (United States)

    Pletz, M W; Preechachatchaval, V; Bulitta, J; Allewelt, M; Burkhardt, O; Lode, H

    2003-03-01

    We assessed the pharmacokinetics and interaction of ABT-773 in 12 volunteers receiving ABT-773 alone or concomitantly with ranitidine or sucralfate. Data for 150 mg of ABT-773 were as follows: the maximum concentration of the drug in plasma (C(max)) was 318 ng/ml, its half-life was 5.66 h, and its area under the plasma concentration-time curve from 0 h to infinity (AUC(0- infinity )) was 1,662 ng. h/ml. Coadministration of ranitidine, reduced the C(max) (-25.7%) and AUC(0- infinity ) (-15.8%) significantly. Sucralfate had no impact on the bioavailability of ABT-773.

  13. A review on dronedarone: Pharmacological, pharmacodynamic and pharmacokinetic profile

    Directory of Open Access Journals (Sweden)

    Farah Iram

    2016-03-01

    Full Text Available Dronedarone, a benzofuran containing chemical compound, is a derivative of amiodarone which is classified as a Class III antiarrhythmic agent. It is prescribed to the cardiovascular patients who have paroxysmal or persistent atrial fibrillation to lower the chances of hospitalization. Amiodarone, sotalol, procainamide dofetilide, quinidine, ibutilide, flecainide, and propafenone are the other useful medicinal products used to treat atrial fibrillation or cardiac arrhythmia. Dronedarone was approved for clinical use in atrial fibrillation by the Food and Drug Administration in 2009. The generic name for dronedarone is Multaq (Sanofi Aventis. This article briefly highlights the important pharmacological, pharmacodynamic and pharmacokinetic properties of dronedarone.

  14. Formulation and pharmacokinetics of diclofenac lipid nanoemulsions for parenteral application.

    Science.gov (United States)

    Ramreddy, Srividya; Kandadi, Prabhakar; Veerabrahma, Kishan

    2012-01-01

    The objective of the present study was to formulate and determine the pharmacokinetics of stable o/w parenteral lipid nanoemulsions (LNEs) of diclofenac acid used to treat arthritic conditions. The LNEs of diclofenac acid with a mean size ranging from 200 to 240 nm and a zeta potential of -29.4 ± 1.04 mV (negatively charged LNEs) and 62.1 ± 3.5 (positively charged LNEs) emulsions were prepared by hot homogenization and ultrasonication process. The influence of formulation variables, such as the change in proportion of cholesterol, was studied, and optimized formulations were developed. The optimized formulations were relatively stable during centrifugal stress, dilution stress, and storage. The drug content and entrapment efficiency were determined using high-performance liquid chromatography. The in vitro drug release was carried out in phosphate-buffered saline pH 7.4 and cumulative amount of drug released was estimated using a UV-visible spectro-photometer. During in vivo pharmacokinetic studies in male Wistar rats, diclofenac serum concentration from LNEs was higher than that of Voveran injection and was detectable up to 12 h. Diclofenac in LNEs showed improved pharmacokinetic profile with increase in area under the curve, elimination half-life and mean residence time in comparison to Voveran. Our aim was to prepare and determine the pharmacokinetics of injectable lipid nanoemulsions of diclofenac acid for treating arthritic conditions by reducing the frequency of dosing and pain at site of injection. The nanoemulsions of diclofenac acid were prepared by homogenization and ultrasonication process. The sizes and charges of oil globules were determined. The effect of cholesterol on stability of emulsion was studied, and an optimized preparation was developed. The optimized formulations were stable during centrifugation, dilution, and storage. The total amount of drug in emulsion and percentage amount of drug present in emulsion globules were determined using

  15. CARVEDILOL POPULATION PHARMACOKINETIC ANALYSIS – APPLIED VALIDATION PROCEDURE

    Directory of Open Access Journals (Sweden)

    Aleksandra Catić-Đorđević

    2013-09-01

    Full Text Available Carvedilol is a nonselective beta blocker/alpha-1 blocker, which is used for treatment of essential hypertension, chronic stable angina, unstable angina and ischemic left ventricular dysfunction. The aim of this study was to describe carvedilol population pharmacokinetic (PK analysis as well as the validation of analytical procedure, which is an important step regarding this approach. In contemporary clinical practice, population PK analysis is often more important than standard PK approach in setting a mathematical model that describes the PK parameters. Also, it includes the variables that have particular importance in the drugs pharmacokinetics such as sex, body mass, dosage, pharmaceutical form, pathophysiological state, disease associated with the organism or the presence of a specific polymorphism in the isoenzyme important for biotransformation of the drug. One of the most frequently used approach in population PK analysis is the Nonlinear Modeling of Mixed Effects - NONMEM modeling. Analytical methods used in the data collection period is of great importance for the implementation of a population PK analysis of carvedilol in order to obtain reliable data that can be useful in clinical practice. High performance liquid chromatography (HPLC analysis of carvedilol is used to confirm the identity of a drug and provide quantitative results and also to monitor the efficacy of the therapy. Analytical procedures used in other studies could not be fully implemented in our research as it was necessary to perform certain modification and validation of the method with the aim of using the obtained results for the purpose of a population pharmacokinetic analysis. Validation process is a logical terminal phase of analytical procedure development that provides applicability of the procedure itself. The goal of validation is to ensure consistency of the method and accuracy of results or to confirm the selection of analytical method for a given sample

  16. Synthesis and pharmacokinetics of thiacoccide labeled with tritium

    International Nuclear Information System (INIS)

    Shestakov, A.D.; Kaminskii, Yu.L.; Nurova, I.M.; Nikitina, V.N.; Zaionts, V.I.; Maksimova, O.V.; Mikhailov, G.A.

    1986-01-01

    To obtain information on the pharmacokinetics of thiacoccide, the authors effect the synthesis of an analog of thiacoccide, viz., the hydrochloride of 2-methyl-N-(2'-n-propyl-4'-aminopyrimid-5'-ylmethyl)pyridinium chloride (I) labeled with tritium. The simplest way to introduce a tritium label into (I) is by isotopic exchange of hydrogen of (I) with H 3 HO. Typical material obtained from isotopic exchange with water labeled with tritium is shown. The dynamics of 3 H distribution in the organism of the chick and the rate of its elimination on single administration of thiacoccide containing isotope in both the methyl group and in the pyridine ring are shown

  17. Pharmacokinetics and biodistribution of radiolabeled avidin, streptavidin and biotin

    International Nuclear Information System (INIS)

    Rosebrough, S.F.

    1993-01-01

    The extraordinarily high affinity of avidin and streptavidin for biotin may be exploited in a two-step approach for delivering radiolabeled biotin derivatives suitable for imaging and therapy to target-bound streptavidin or avidin conjugated monoclonal antibodies (MAbs). The in vivo pharmacokinetics and biodistribution of radiolabeled avidin, streptavidin (SA) and DTPA-biocytinamide (DTPA-biotin) were studied in the rabbit and dog. SA circulated in the blood similar to other 60 kDa proteins, avidin cleared immediately and DTPA-biotin exhibited plasma clearance by glomerular filtration. (author)

  18. Pharmacokinetic/pharmacodynamic modeling for the determination of a cimicoxib dosing regimen in the dog.

    Science.gov (United States)

    Jeunesse, Elisabeth C; Schneider, Marc; Woehrle, Frederique; Faucher, Mathieu; Lefebvre, Herve P; Toutain, Pierre-Louis

    2013-12-11

    Cimicoxib is a new coxib anti-inflammatory drug for use in the dog. To determine a preclinical dosage regimen for cimicoxib in dog, a reversible model of kaolin-induced paw inflammation was used. Dosage regimens were established using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach (indirect response model). Analgesic, anti-inflammatory and antipyretic endpoints investigated with the inflammation model established the efficacy of cimicoxib at a dose of 2 mg/kg administered orally (single dose) in 12 beagle dogs.For both the oral and IV route of administration two groups of dogs to be identified namely Poor Metabolizers (PM) and Extensive Metabolizers (EM).The terminal half-life after oral administration was 8.0 ± 0.6 h for the PM and 4.6 ± 2.6 h for the EM groups, with the corresponding values after the IV route being 5.6 ± 1.7 h and 2.7 ± 0.9 h (mean ± SD).The main pharmacodynamic parameters (potency, efficacy, and sensitivity) were estimated for four endpoints (body temperature, creeping speed, ground vertical reaction force and clinical lameness score). The plasma concentration corresponding to half the maximum of the indirect effect were 239 μg/L for creeping speed, 284 μg/L for the lameness score, 161 μg/L for the ground reaction vertical force and 193 μg/L for the body temperature.To document possible polymorphism of the cimicoxib disposition in the target dog population, cimicoxib was administered by the intravenous route to 40 dogs (four different sized breeds). The cimicoxib half-lives in these 40 dogs were of same order of the magnitude as those of the EM beagle dogs. Thus pharmacokinetic and pharmacodynamic parameters obtained from the EM beagle dogs were selected to simulate the dose-effect relationship of cimicoxib after an oral administration allowing a dosage regimen to be selected for confirmation by a clinical trial. Cimicoxib was an efficacious anti-inflammatory, antipyretic and analgesic drug and a dosage regimen of 2 mg

  19. Pharmacokinetics and clinical effect of phenobarbital in children with severe falciparum malaria and convulsions

    Science.gov (United States)

    Kokwaro, Gilbert O; Ogutu, Bernhards R; Muchohi, Simon N; Otieno, Godfrey O; Newton, Charles R J C

    2003-01-01

    Aims Phenobarbital is commonly used to treat status epilepticus in resource-poor countries. Although a dose of 20 mg kg−1 is recommended, this dose, administered intramuscularly (i.m.) for prophylaxis, is associated with an increase in mortality in children with cerebral malaria. We evaluated a 15-mg kg−1 intravenous (i.v.) dose of phenobarbital to determine its pharmacokinetics and clinical effects in children with severe falciparum malaria and status epilepticus. Methods Twelve children (M/F: 11/1), aged 7–62 months, received a loading dose of phenobarbital (15 mg kg−1) as an i.v. infusion over 20 min and maintenance dose of 5 mg kg−1 at 24 and 48 h later. The duration of convulsions and their recurrence were recorded. Vital signs were monitored. Plasma and cerebrospinal fluid (CSF) phenobarbital concentrations were measured with an Abbott TDx FLx® fluorescence polarisation immunoassay analyser (Abbott Laboratories, Diagnostic Division, Abbott Park, IL, USA). Simulations were performed to predict the optimum dosage regimen that would maintain plasma phenobarbital concentrations between 15 and 20 mg l−1 for 72 h. Results All the children achieved plasma concentrations above 15 mg l−1 by the end of the infusion. Mean (95% confidence interval or median and range for Cmax) pharmacokinetic parameters were: area under curve [AUC (0, ∞) ]: 4259 (3169, 5448) mg l−1.h, t½: 82.9 (62, 103) h, CL: 5.8 (4.4, 7.3) ml kg−1 h−1, Vss: 0.8 (0.7, 0.9) l kg −1, CSF: plasma phenobarbital concentration ratio: 0.7 (0.5, 0.8; n = 6) and Cmax: 19.9 (17.9–27.9) mg l−1. Eight of the children had their convulsions controlled and none of them had recurrence of convulsions. Simulations suggested that a loading dose of 15 mg kg−1 followed by two maintenance doses of 2.5 mg kg−1 at 24 h and 48 h would maintain plasma phenobarbital concentrations between 16.4 and 20 mg l−1 for 72 h. Conclusions Phenobarbital, given as an i.v. loading dose, 15 mg kg−1

  20. A novel engineered VEGF blocker with an excellent pharmacokinetic profile and robust anti-tumor activity

    International Nuclear Information System (INIS)

    Liu, Lily; Yu, Haijia; Huang, Xin; Tan, Hongzhi; Li, Song; Luo, Yan; Zhang, Li; Jiang, Sumei; Jia, Huifeng; Xiong, Yao; Zhang, Ruliang; Huang, Yi; Chu, Charles C; Tian, Wenzhi

    2015-01-01

    Relatively poor penetration and retention in tumor tissue has been documented for large molecule drugs including therapeutic antibodies and recombinant immunoglobulin constant region (Fc)-fusion proteins due to their large size, positive charge, and strong target binding affinity. Therefore, when designing a large molecular drug candidate, smaller size, neutral charge, and optimal affinity should be considered. We engineered a recombinant protein by molecular engineering the second domain of VEGFR1 and a few flanking residues fused with the Fc fragment of human IgG1, which we named HB-002.1. This recombinant protein was extensively characterized both in vitro and in vivo for its target-binding and target-blocking activities, pharmacokinetic profile, angiogenesis inhibition activity, and anti-tumor therapeutic efficacy. HB-002.1 has a molecular weight of ~80 kDa, isoelectric point of ~6.7, and an optimal target binding affinity of <1 nM. The pharmacokinetic profile was excellent with a half-life of 5 days, maximal concentration of 20.27 μg/ml, and area under the curve of 81.46 μg · days/ml. When tested in a transgenic zebrafish embryonic angiogenesis model, dramatic inhibition in angiogenesis was exhibited by a markedly reduced number of subintestinal vessels. When tested for anti-tumor efficacy, HB-002.1 was confirmed in two xenograft tumor models (A549 and Colo-205) to have a robust tumor killing activity, showing a percentage of inhibition over 90% at the dose of 20 mg/kg. Most promisingly, HB-002.1 showed a superior therapeutic efficacy compared to bevacizumab in the A549 xenograft model (tumor inhibition: 84.7% for HB-002.1 versus 67.6% for bevacizumab, P < 0.0001). HB-002.1 is a strong angiogenesis inhibitor that has the potential to be a novel promising drug for angiogenesis-related diseases such as tumor neoplasms and age-related macular degeneration

  1. Poor people and poor fields? : integrating legumes for smallholder soil fertility management in Chisepo, central Malawi

    NARCIS (Netherlands)

    Kamanga, B.

    2011-01-01

    Soil infertility undermines the agriculture-based livelihoods in Malawi, where it is blamed for poor crop yields and the creation of cycles of poverty. Although technologies and management strategies have been developed to reverse the decline in soil fertility, they are under-used by smallholder

  2. Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

    Science.gov (United States)

    Heuberger, Jules A A C; Guan, Zheng; Oyetayo, Olubukayo-Opeyemi; Klumpers, Linda; Morrison, Paul D; Beumer, Tim L; van Gerven, Joop M A; Cohen, Adam F; Freijer, Jan

    2015-02-01

    Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.

  3. Prediction of the Pharmacokinetics, Pharmacodynamics, and Efficacy of a Monoclonal Antibody, Using a Physiologically Based Pharmacokinetic FcRn Model

    Science.gov (United States)

    Chetty, Manoranjenni; Li, Linzhong; Rose, Rachel; Machavaram, Krishna; Jamei, Masoud; Rostami-Hodjegan, Amin; Gardner, Iain

    2015-01-01

    Although advantages of physiologically based pharmacokinetic models (PBPK) are now well established, PBPK models that are linked to pharmacodynamic (PD) models to predict pharmacokinetics (PK), PD, and efficacy of monoclonal antibodies (mAbs) in humans are uncommon. The aim of this study was to develop a PD model that could be linked to a physiologically based mechanistic FcRn model to predict PK, PD, and efficacy of efalizumab. The mechanistic FcRn model for mAbs with target-mediated drug disposition within the Simcyp population-based simulator was used to simulate the pharmacokinetic profiles for three different single doses and two multiple doses of efalizumab administered to virtual Caucasian healthy volunteers. The elimination of efalizumab was modeled with both a target-mediated component (specific) and catabolism in the endosome (non-specific). This model accounted for the binding between neonatal Fc receptor (FcRn) and efalizumab (protective against elimination) and for changes in CD11a target concentration. An integrated response model was then developed to predict the changes in mean Psoriasis Area and Severity Index (PASI) scores that were measured in a clinical study as an efficacy marker for efalizumab treatment. PASI scores were approximated as continuous and following a first-order asymptotic progression model. The reported steady state asymptote (Y ss) and baseline score [Y (0)] was applied and parameter estimation was used to determine the half-life of progression (Tp) of psoriasis. Results suggested that simulations using this model were able to recover the changes in PASI scores (indicating efficacy) observed during clinical studies. Simulations of both single dose and multiple doses of efalizumab concentration-time profiles as well as suppression of CD11a concentrations recovered clinical data reasonably well. It can be concluded that the developed PBPK FcRn model linked to a PD model adequately predicted PK, PD, and efficacy of efalizumab. PMID

  4. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.

    Science.gov (United States)

    Chen, Z R; Somogyi, A A; Reynolds, G; Bochner, F

    1991-04-01

    1. The pharmacokinetics, metabolism and partial clearances of codeine to morphine, norcodeine and codeine-6-glucuronide after single (30 mg) and chronic (30 mg 8 h for seven doses) administration of codeine were studied in eight subjects (seven extensive and one poor metaboliser of dextromethorphan). Codeine, codeine-6-glucuronide, morphine and norcodeine were measured by high performance liquid chromatographic assays. 2. After the single dose, the time to achieve maximum plasma codeine concentrations was 0.97 +/- 0.31 h (mean +/- s.d.) and for codeine-6-glucuronide it was 1.28 +/- 0.49 h. The plasma AUC of codeine-6-glucuronide was 15.8 +/- 4.5 times higher than that of codeine. The AUC of codeine in saliva was 3.4 +/- 1.1 times higher than that in plasma. The elimination half-life of codeine was 3.2 +/- 0.3 h and that of codeine-6-glucuronide was 3.2 +/- 0.9 h. 3. The renal clearance of codeine was 183 +/- 59 ml min-1 and was inversely correlated with urine pH (r = 0.81). These data suggest that codeine undergoes filtration at the glomerulus, tubular secretion and passive reabsorption. The renal clearance of codeine-6-glucuronide was 55 +/- 21 ml min-1, and was not correlated with urine pH. Its binding to human plasma was less than 10%. These data suggest that codeine-6-glucuronide undergoes filtration at the glomerulus and tubular reabsorption. This latter process is unlikely to be passive. 4. After chronic dosing, the pharmacokinetics of codeine and codeine-6-glucuronide were not significantly different from the single dose pharmacokinetics. 5. After the single dose, 86.1 +/- 11.4% of the dose was recovered in urine, of which 59.8 +/- 10.3% was codeine-6-glucuronide, 7.1 +/- 1.1% was total morphine, 6.9 +/- 2.1% was total norcodeine and 11.8 +/- 3.9% was unchanged codeine. These recoveries were not significantly different (P greater than 0.05) after chronic administration. 6. After the single dose, the partial clearance to morphine was 137 +/- 31 ml min-1 in

  5. Isolated microalbuminuria indicates a poor medical prognosis.

    Science.gov (United States)

    Scheven, Lieneke; Van der Velde, Marije; Lambers Heerspink, Hiddo J; De Jong, Paul E; Gansevoort, Ron T

    2013-07-01

    Microalbuminuria is often regarded as a sign of end-organ damage due to diabetes and/or hypertension, and as such to be associated with an increased risk for cardiovascular events. It has been questioned whether isolated microalbuminuria, that is microalbuminuria in the absence of a cardiovascular disease (CVD) history, hypertension and diabetes has clinical relevance. Included were 8356 subjects who participated in the first four screening rounds of the PREVEND study, a prospective, community-based, observational cohort study. Isolated microalbuminuria was defined as microalbuminuria (30-300 mg/24 h), in the absence of a CVD history, hypertension (blood pressuredefinition of isolated microalbuminuria, in which 2250 person-years of follow-up were available. In subjects with isolated microalbuminuria, the incidence rates of cardiovascular events and mortality, hypertension and diabetes were 15.3, 28.9 and 8.9 per 1000 person-year follow-up, respectively. Subjects with isolated microalbuminuria had an increased risk for cardiovascular events and mortality [crude HR 2.23 (1.63-3.07); Phypertension [OR 1.95 (1.47-2.59); Phypertension and/or diabetes. This increased risk remained significant after adjustment for age and gender. The relative risk held by isolated microalbuminuria was similar to the relative risk held by microalbuminuria in subjects that did have a CVD history, hypertension and/or diabetes. Isolated microalbuminuria indicates a poor prognosis and warrants medical attention.

  6. Poorly Understood Aspects of Striated Muscle Contraction

    Directory of Open Access Journals (Sweden)

    Alf Månsson

    2015-01-01

    Full Text Available Muscle contraction results from cyclic interactions between the contractile proteins myosin and actin, driven by the turnover of adenosine triphosphate (ATP. Despite intense studies, several molecular events in the contraction process are poorly understood, including the relationship between force-generation and phosphate-release in the ATP-turnover. Different aspects of the force-generating transition are reflected in the changes in tension development by muscle cells, myofibrils and single molecules upon changes in temperature, altered phosphate concentration, or length perturbations. It has been notoriously difficult to explain all these events within a given theoretical framework and to unequivocally correlate observed events with the atomic structures of the myosin motor. Other incompletely understood issues include the role of the two heads of myosin II and structural changes in the actin filaments as well as the importance of the three-dimensional order. We here review these issues in relation to controversies regarding basic physiological properties of striated muscle. We also briefly consider actomyosin mutation effects in cardiac and skeletal muscle function and the possibility to treat these defects by drugs.

  7. Relationship between craniomandibular disorders and poor posture.

    Science.gov (United States)

    Nicolakis, P; Nicolakis, M; Piehslinger, E; Ebenbichler, G; Vachuda, M; Kirtley, C; Fialka-Moser, V

    2000-04-01

    The purpose of this research was to show that a relationship between craniomandibular disorders (CMD) and postural abnormalities has been repeatedly postulated, but still remains unproven. This study was intended to test this hypothesis. Twenty-five CMD patients (mean age 28.2 years) were compared with 25 gender and age matched controls (mean age 28.3 years) in a controlled, investigator-blinded trial. Twelve postural and ten muscle function parameters were examined. Measurements were separated into three subgroups, consisting of those variables associated with the cervical region, the trunk in the frontal plane, and the trunk in the sagittal plane. Within these subgroups, there was significantly more dysfunction in the patients, compared to control subjects (Mann-Whitney U test p Postural and muscle function abnormalities appeared to be more common in the CMD group. Since there is evidence of the mutual influence of posture and the craniomandibular system, control of body posture in CMD patients is recommended, especially if they do not respond to splint therapy. Whether poor posture is the reason or the result of CMD cannot be distinguished by the data presented here.

  8. Poor, Old “Physical Education”

    Directory of Open Access Journals (Sweden)

    Earle F. Zeigler

    2014-01-01

    Full Text Available The field of physical activity (and related health education (“poor, old ‘PE’” needs to assert its "will to win" more vigorously then ever before. Scholarly and scientific investigation of the past 60 years since Sputnik was launched in 1957 has identified a wide variety of findings proving that a quality program can provide highly important benefits to the growing child and youth. Societal developments, including other curricular demands, have undoubtedly created uneasiness within the overall field of education. In North America the time and attention devoted to the relatively few involved in external highly competitive sport for the few has been a negative factor. At the same time intramural athletics for the large majority of children and youth has not been available to the extent it should be. There is now doubt as to the field’s ability to achieve high status within education. Therefore, we must pledge ourselves to make still greater efforts to become vibrant and stirring through absolute dedication and commitment in our professional endeavors. Ours is a high calling since we seek to improve the quality of life for all people on earth through the finest type of human motor performance in exercise, sport, and related expressive movement.

  9. Naringenin-loaded solid lipid nanoparticles: preparation, controlled delivery, cellular uptake, and pulmonary pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Ji P

    2016-03-01

    size of 98 nm, a polydispersity index of 0.258, a zeta potential of -31.4 mV, a total drug content of 9.76 mg, an EE of 79.11%, and a cumulative drug release of 80% in 48 hours with a sustained profile. In addition, 5% mannitol (w/v was screened as a cryoprotectant. Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction studies confirmed that the drug was encapsulated into SLNs in an amorphous form. The lyophilized powder was stable at both refrigeration (4°C and ambient temperature (25°C for 3 months, and the MTT assay demonstrated that the SLNs were nontoxic. The cellular uptake of fluorescein isothiocyanate-labeled SLNs in A549 cells was highly time dependent over a period of 3 hours, while the pharmacokinetic study in Sprague Dawley rats showed that the relative bioavailability of NRG-SLNs was 2.53-fold greater than that of NRG suspension after pulmonary administration. This study shows that SLNs offer a promising pulmonary delivery system to increase the bioavailability of the poorly water-soluble drug NRG.Keywords: naringenin, solid lipid nanoparticles, group contribution method, sustained profile, instillation technology, MTT, cellular uptake, pulmonary pharmacokinetics

  10. Pharmacokinetic study of mycophenolic acid in Iranian kidney transplant patients

    Directory of Open Access Journals (Sweden)

    Saeed Rezaee

    2013-02-01

    Full Text Available Background: The purpose of this study was to characterize the pharmacokinetic parameters of mycophenolic acid (MPA in Iranian kidney transplant patients. Methods: Plasma MPA concentration of mycophenolate mofetile (MMF 1 gram two times a day was measured in 21 Iranian kidney transplant recipients receiving treatment. Patients who entered the study had been transplanted for more than 3 months and their drug level was supposed to be at steady state. MMF concentration was measured with high-performance liquid chromatography (HPLC. Results: The plasma MPA concentration-time curve was characterized by an early sharp peak at about 1 hour postdose. The mean Area Under Curve (AUC, Cmax and Tmax were 47.0±18.3 µg.h/ml, 18.6±8.5 µg/ml and 1.0±0.5 hours respectively. Conclusion: The plasma MPA concentration-time curve pattern of Iranian patients was similar and consistent with previously reported profiles in other populations taking the same dose. Keywords: Mycophenolate mofetil, Mycophenolic acid, Pharmacokinetics, Area Under Curve, Kidney transplantation

  11. Human pharmacokinetics of iohexol. A new nonionic contrast medium

    International Nuclear Information System (INIS)

    Olsson, B.; Aulie, A.; Sveen, K.; Andrew, E.

    1983-01-01

    The pharmacokinetics of iohexol, a new nonionic, water-soluble contrast medium, have been determined after intravenous injection in 20 healthy volunteers, at four different dose levels (125-500 mg I/kg). The apparent volume of distribution was 0.27 1/kg, indicating distribution in the extracellular water. The biologic half-life was 121 minutes, comparable with that of other intravascular contrast media. Iohexol was excreted completely unmetabolized in the urine, with a 100% recovery 24 hours after injection. A comparison of iohexol and chromium-51 ( 51 Cr)-EDTA clearances indicates that iohexol is mainly excreted by glomerular filtration. The 51 Cr-EDTA clearance was the same when injected separately and concomitantly with iohexol, indicating that glomerular filtration rate is not affected by iohexol. No dose dependency was observed in the investigated parameters t1/2 alpha, t1/2 beta, Vd, ClT or ClR. Iohexol pharmacokinetics are in correspondence with previously reported data on intravascular contrast media

  12. Dose selection based on physiologically based pharmacokinetic (PBPK) approaches.

    Science.gov (United States)

    Jones, Hannah M; Mayawala, Kapil; Poulin, Patrick

    2013-04-01

    Physiologically based pharmacokinetic (PBPK) models are built using differential equations to describe the physiology/anatomy of different biological systems. Readily available in vitro and in vivo preclinical data can be incorporated into these models to not only estimate pharmacokinetic (PK) parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. They provide a mechanistic framework to understand and extrapolate PK and dose across in vitro and in vivo systems and across different species, populations and disease states. Using small molecule and large molecule examples from the literature and our own company, we have shown how PBPK techniques can be utilised for human PK and dose prediction. Such approaches have the potential to increase efficiency, reduce the need for animal studies, replace clinical trials and increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however some limitations need to be addressed to realise its application and utility more broadly.

  13. [Pharmacokinetic and clinical studies of flomoxef in the perinatal period].

    Science.gov (United States)

    Matsuda, S; Hirayama, H; Oh, K; Tamate, K; Sengoku, K; Ishikawa, M; Shimizu, T; Haga, H; Hasegawa, T; Takada, H

    1993-07-01

    Pharmacokinetic and clinical studies on flomoxef (FMOX) in the perinatal period were carried out and following results were obtained 1. The pharmacokinetic parameter T1/2's of FMOX in maternal serum, umbilical cord serum and amniotic fluid in mothers after single intravenous injection of 1 g (n = 46) and 2 g (n = 34) were 1.11, 9.24, 9.24 hours and 2.54, 12.49, 12.49 hours, respectively. Cmax's and Tmax's of umbilical cord serum and amniotic fluid were 12.71, 11.77 micrograms/ml and 0.57, 3.35 hours upon single dose of 1 g i.v., and 35.17, 12.37 micrograms/ml and 0.32, 3.42 hours upon single dose of 2 g i.v., respectively. 2. Clinical usefulness were evaluated in 93 cases including were various infections in pregnancy and puerperal period. In pregnancy cases, clinical efficacy rate was 95.5% (21/22), and 100% in puerperal period. Bacteriological response rate was 84.6% (eradicated: 29, decreased: 4, unchanged: 2, replaced: 4 and unknown: 8 cases). No severe side effects nor clinical laboratory test results were observed in any cases. From above basic and clinical results, we conclude that FMOX is a useful and safe agent for various infections in pregnancy and puerperal period.

  14. Doripenem pharmacokinetics in critically ill patients receiving continuous hemodiafiltration (CHDF).

    Science.gov (United States)

    Hidaka, Seigo; Goto, Koji; Hagiwara, Satoshi; Iwasaka, Hideo; Noguchi, Takayuki

    2010-01-01

    Objectives of the prospective, open-label study were to investigate pharmacokinetics of doripenem and determine appropriate doripenem regimens during continuous hemodiafiltration (CHDF) in critically ill patients with renal failure (creatinine clearance times during one dosing interval were measured in order to calculate pharmacokinetic parameters and clearance via hemodiafiltration. Mean half-life (+/-standard deviation) of doripenem was 7.9+/-3.7 hours. Total body clearance of doripenem was 58.0+/-12.7 ml/min, including clearance of 13.5+/-1.6 ml/min via CHDF. An IV dose of 250 mg of doripenem every 12 hours during CHDF provided adequate plasma concentrations for critically ill patients with renal failure, without resulting in accumulation upon steady-state. Thus, under the conditions tested, CHDF appeared to have little effect on doripenem clearance. Therefore, the blood level of doripenem can be satisfactorily controlled by adjustment of doripenem dose and dosing interval, in accordance with residual renal function in patients receiving CHDF.

  15. Pharmacokinetics and toxicology of therapeutic proteins: Advances and challenges

    Science.gov (United States)

    Vugmeyster, Yulia; Xu, Xin; Theil, Frank-Peter; Khawli, Leslie A; Leach, Michael W

    2012-01-01

    Significant progress has been made in understanding pharmacokinetics (PK), pharmacodynamics (PD), as well as toxicity profiles of therapeutic proteins in animals and humans, which have been in commercial development for more than three decades. However, in the PK arena, many fundamental questions remain to be resolved. Investigative and bioanalytical tools need to be established to improve the translation of PK data from animals to humans, and from in vitro assays to in vivo readouts, which would ultimately lead to a higher success rate in drug development. In toxicology, it is known, in general, what studies are needed to safely develop therapeutic proteins, and what studies do not provide relevant information. One of the major complicating factors in nonclinical and clinical programs for therapeutic proteins is the impact of immunogenicity. In this review, we will highlight the emerging science and technology, as well as the challenges around the pharmacokinetic- and safety-related issues in drug development of mAbs and other therapeutic proteins. PMID:22558487

  16. Enrofloxacin: pharmacokinetics and metabolism in domestic animal species.

    Science.gov (United States)

    López-Cadenas, Cristina; Sierra-Vega, Matilde; García-Vieitez, Juan J; Diez-Liébana, M José; Sahagún-Prieto, Ana; Fernández-Martínez, Nélida

    2013-12-01

    Enrofloxacin is a fluorquinolone exclusively developed for use in veterinary medicine (1980). The kinetics of enrofloxacin are characterized, in general terms, by high bioavailability in most species and rapid absorption after IM, SC or oral administration. However, several studies reported that enrofloxacin showed low bioavailability after oral administration in ruminants. This drug has a broad distribution in the organism, excellent tissue penetration and long serum half-life. Also, enrofloxacin is characterized by a low host toxicity, a broad antibacterial spectrum and high bactericidal activity against major pathogenic bacteria (both Gram-positive and Gram-negative), and intracellular organisms found in diseased animals. The kinetics vary according to the route of administration, formulation, animal species, age, body condition, and physiological status, all of which contribute to differences in drug efficacy. The pharmacokinetic properties of drugs are closely related to their pharmacological efficiency, so it is important to know their behavior in each species that is used. This article reviews the pharmacokinetics of enrofloxacin in several domestic animal species.

  17. Antibiotics: Pharmacokinetics, toxicity, resistance and multidrug efflux pumps.

    Science.gov (United States)

    Yılmaz, Çiğdem; Özcengiz, Gülay

    2017-06-01

    The discovery of penicillin followed by streptomycin, tetracycline, cephalosporins and other natural, semi-synthetic and synthetic antimicrobials completely revolutionized medicine by reducing human morbidity and mortality from most of the common infections. However, shortly after they were introduced to clinical practice, the development of resistance was emerged. The decreasing interest from antibiotic industry in spite of rapid global emergence of antibiotic resistance is a tough dilemma from the pointview of public health. The efficiency of antimicrobial treatment is determined by both pharmacokinetics and pharmacodynamics. In spite of their selective toxicity, antibiotics still cause severe, life-threatening adverse reactions in host body mostly due to defective drug metabolism or excessive dosing regimen. The present article aims at updating current knowledge on pharmacokinetics/pharmacodynamics concepts and models, toxicity of antibiotics as well as antibiotic resistance mechanisms, resistome analyses and search for novel antibiotic resistance determinants with special emphasis given to the-state-of-the-art regarding multidrug efflux pumps and their additional physiological functions in stress adaptation and virulence of bacteria. All these issues are highly linked to each other and not only important for most efficient and prolonged use of current antibiotics, but also for discovery and development of new antibiotics and novel inhibitors of antibiotic resistance determinants of pathogens. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2013-03-01

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

  19. Pharmacokinetic/Pharmacodinamics Integration of Sulfametazine in buffalo and cattle

    Directory of Open Access Journals (Sweden)

    M.I. San Andrés

    2010-02-01

    Full Text Available Sulfamethazine is a sulfonamide that presents a broad spectrum of activity, including Gram-positive and Gram-negative bacteria, Chlamydia spp. and some protozoa and it commonly used in ruminants. The aim of our work was to study the possible inter-species differences in the pharmacokinetic behavior and pharmacokinetic/ pharmacodynamic(PK/PD integration of sulfamethazine after intravenous administration in buffalo and bovine. A single intravenous dose of 60 mg/kg was administered to six bovine and five buffalo (3-4 month old and weighting 120±15kg. Plasma concentrations of sulfamethazine were determined by high performance liquid chromatography. Differences between bovine and buffalo calves were found in t½λ (buffaloes: t1/2λ =6.17±0.58h; bovine t1/2λ=7.46±1.05h, Cl (buffaloes: 45.31ml/h·kg; bovines 30.34ml/h·kg. As a consequence of the lower clearance in bovines, the AUC and t½λ values were higher in this species. Important differences between bovine and buffalo exist for microorganisms that have a MIC value<32μg/ml related to time over minimum inhibitory concentration and weighted AUC.

  20. Nitro-fatty acid pharmacokinetics in the adipose tissue compartment.

    Science.gov (United States)

    Fazzari, Marco; Khoo, Nicholas K H; Woodcock, Steven R; Jorkasky, Diane K; Li, Lihua; Schopfer, Francisco J; Freeman, Bruce A

    2017-02-01

    Electrophilic nitro-FAs (NO 2 -FAs) promote adaptive and anti-inflammatory cell signaling responses as a result of an electrophilic character that supports posttranslational protein modifications. A unique pharmacokinetic profile is expected for NO 2 -FAs because of an ability to undergo reversible reactions including Michael addition with cysteine-containing proteins and esterification into complex lipids. Herein, we report via quantitative whole-body autoradiography analysis of rats gavaged with radiolabeled 10-nitro-[ 14 C]oleic acid, preferential accumulation in adipose tissue over 2 weeks. To better define the metabolism and incorporation of NO 2 -FAs and their metabolites in adipose tissue lipids, adipocyte cultures were supplemented with 10-nitro-oleic acid (10-NO 2 -OA), nitro-stearic acid, nitro-conjugated linoleic acid, and nitro-linolenic acid. Then, quantitative HPLC-MS/MS analysis was performed on adipocyte neutral and polar lipid fractions, both before and after acid hydrolysis of esterified FAs. NO 2 -FAs preferentially incorporated in monoacyl- and diacylglycerides, while reduced metabolites were highly enriched in triacylglycerides. This differential distribution profile was confirmed in vivo in the adipose tissue of NO 2 -OA-treated mice. This pattern of NO 2 -FA deposition lends new insight into the unique pharmacokinetics and pharmacologic actions that could be expected for this chemically-reactive class of endogenous signaling mediators and synthetic drug candidates. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  1. Improved Antitumor Efficacy and Pharmacokinetics of Bufalin via PEGylated Liposomes

    Science.gov (United States)

    Yuan, Jiani; Zhou, Xuanxuan; Cao, Wei; Bi, Linlin; Zhang, Yifang; Yang, Qian; Wang, Siwang

    2017-11-01

    Bufalin was reported to show strong pharmacological effects including cardiotonic, antiviral, immune-regulation, and especially antitumor effects. The objective of this study was to determine the characterization, antitumor efficacy, and pharmacokinetics of bufalin-loaded PEGylated liposomes compared with bufalin entity, which were prepared by FDA-approved pharmaceutical excipients. Bufalin-loaded PEGylated liposomes and bufalin-loaded liposomes were prepared reproducibly with homogeneous particle size by the combination of thin film evaporation method and high-pressure homogenization method. Their mean particle sizes were 127.6 and 155.0 nm, mean zeta potentials were 2.24 and - 18.5 mV, and entrapment efficiencies were 76.31 and 78.40%, respectively. In vitro release profile revealed that the release of bufalin in bufalin-loaded PEGylated liposomes was slower than that in bufalin-loaded liposomes. The cytotoxicity of blank liposomes has been found within acceptable range, whereas bufalin-loaded PEGylated liposomes showed enhanced cytotoxicity to U251 cells compared with bufalin entity. In vivo pharmacokinetics indicated that bufalin-loaded PEGylated liposomes could extend or eliminate the half-life time of bufalin in plasma in rats. The results suggested that bufalin-loaded PEGylated liposomes improved the solubility and increased the drug concentration in plasma.

  2. Pharmacokinetics of oral terbinafine in horses and Greyhound dogs.

    Science.gov (United States)

    Williams, M M; Davis, E G; KuKanich, B

    2011-06-01

    The objective of the study was to assess the pharmacokinetics of terbinafine administered orally to horses and Greyhound dogs. A secondary objective was to assess terbinafine metabolites. Six healthy horses and six healthy Greyhound dogs were included in the pharmacokinetic data. The targeted dose of terbinafine was 20 and 30 mg/kg for horses and dogs, respectively. Blood was collected at predetermined intervals for the quantification of terbinafine concentrations with liquid chromatography and mass spectrometry. The half-life (geometric mean) was 8.1 and 8.6 h for horses and Greyhounds, respectively. The mean maximum plasma concentration was 0.31 and 4.01 μg/mL for horses and Greyhounds, respectively. The area under the curve (to infinity) was 1.793 h·μg/mL for horses and 17.253 h·μg/mL for Greyhounds. Adverse effects observed in one study horse included pawing at the ground, curling lips, head shaking, anxiety and circling, but these resolved spontaneously within 30 min of onset. No adverse effects were noted in the dogs. Ions consistent with carboxyterbinafine, n-desmethylterbinafine, hydroxyterbinafine and desmethylhydroxyterbinafine were identified in horse and Greyhound plasma after terbinafine administration. Further studies are needed assessing the safety and efficacy of terbinafine in horses and dogs. © 2010 Blackwell Publishing Ltd.

  3. The influence of stereoisomerism on the pharmacokinetics of Tc radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Hansen, L.; Taylor, A. [Atlanta, Emory Univ. School of Medicine, GA (United States). Dept. of Chemistry; Marzilli, L.G. [Atlanta, Emory Univ. School of Medicine, GA (United States). Dept. of Radiology

    1998-12-01

    The influence of stereoisomerism on the pharmacokinetics of Tc mono-oxo complexes is reviewed. Tc(V) mono-oxo complexes formed with N/S ligands have four donor groups from the ligands in an equatorial plane; the oxo ligand coordinates in an axial position. Stereoisomerism in Tc(V) mono-oxo complexes can be centered within the ligand (carbon atom in the chelate ring of ligating nitrogen of amine donors) or at the Tc. The metal center becomes chiral when an equatorial ligand has a head and a tail (i.e. the two ends of the ligand differ). All types of stereocenter can produce significantly different pharmacokinetic profiles for individual isomers. Thus, biological evaluation of separated stereoisomers is necessary to identify the optimal stereochemical configuration, particularly for radiopharmaceuticals targeted to receptor molecules with low specificity. Because of inter species variation, there is ultimately no substitute for human testing. Although it is possible that the increase in nonspecific binding of agents incorporating L- vs D-amino acids may more than offset any increased receptor binding, much more information is needed. Stereochemical factors can also lead to unpredictable differences in coordination geometry and thermodynamic preference of a single isomer; thus chemical characterization of stereo-isomers continues to be an important component of radiopharmaceutical development.

  4. Influence of oxytetracycline on carprofen pharmacodynamics and pharmacokinetics in calves.

    Science.gov (United States)

    Brentnall, C; Cheng, Z; McKellar, Q A; Lees, P

    2013-08-01

    A tissue cage model of inflammation in calves was used to determine the pharmacokinetic and pharmacodynamic properties of individual carprofen enantiomers, following the administration of the racemate. RS(±) carprofen was administered subcutaneously both alone and in combination with intramuscularly administered oxytetracycline in a four-period crossover study. Oxytetracycline did not influence the pharmacokinetics of R(-) and S(+) carprofen enantiomers, except for a lower maximum concentration (Cmax ) of S(+) carprofen in serum after co-administration with oxytetracycline. S(+) enantiomer means for area under the serum concentration-time curve (AUC0-96 h were 136.9 and 128.3 μg·h/mL and means for the terminal half-life (T(1/2) k10 ) were = 12.9 and 17.3 h for carprofen alone and in combination with oxytetracycline, respectively. S(+) carprofen AUC0-96 h in both carprofen treatments and T(1/2) k10 for carprofen alone were lower (P oxytetracycline in calves and indicate that no alteration to carprofen dosage is required when the drugs are co-administered. © 2012 John Wiley & Sons Ltd.

  5. Pharmacokinetics of paracetamol in chicks treated with metronidazole

    Directory of Open Access Journals (Sweden)

    S.M. Hussain

    2017-06-01

    Full Text Available Effect of metronidazole on the pharmacokinetics of paracetamol were examined in chicks. Chicks were dosed orally with metronidazole at 350 mg\\kg of body weight daily (10 -13 days of age. On the last day of metronidazole dosing, chicks injected intraperitoneally with paracetamol at of 50 mg\\kg of body weight. Paracetamol appeared in chick plasma at 52.00, 45.00, 40.75, 32.75, 23.25 µg \\ml after 0.25, 0.50, 0.75, 1, 2, 4 hours of injection respectively. A significantly decreased the concentration paracetamol at times of 0.25, 0.50, 0.75, 1, 4 hours post injection and appeared at concentrations of 36.62, 35.37, 25.62, 20.50, 11.00 µg\\ml. These was reflected by changes in the pharmacokinetics of paracetamol as show by the increase elimination rate constant (48% and decrease in the half-life (32 % and increase in volume distribution (29% and increase in clearance by (96% and decrease in the area under the plasma curve (33% and decrease in the area under moment curve 65% and lack mean residence time (33%. These results indicate that oral dosing of chicks with metronidazole for four consecutive days and this effect increase in the elemination rate of paracetamol and this effect must be considered when therapy with paracetamol when given during metronidazole therapy.

  6. PHARMACOKINETIC VARIATIONS OF OFLOXACIN IN NORMAL AND FEBRILE RABBITS

    Directory of Open Access Journals (Sweden)

    M. AHMAD, H. RAZA, G. MURTAZA AND N. AKHTAR

    2008-12-01

    Full Text Available The influence of experimentally Escherichia coli-induced fever (EEIF on the pharmacokinetics of ofloxacin was evaluated. Ofloxacin was administered @ 20 mg.kg-1 body weight intravenously to a group of eight healthy rabbits and compared these results to values in same eight rabbits with EEIF. Pharmacokinetic parameters of ofloxacin in normal and febrile rabbits were determined by using two compartment open kinetic model. Peak plasma level (Cmax and area under the plasma concentration-time curve (AUC0-α in normal and febrile rabbits did not differ (P>0.05. However, area under first moment of plasma concentration-time curve (AUMC0-α in febrile rabbits was significantly (P<0.05 higher than that in normal rabbits. Mean values for elimination rate constant (Ke, elimination half life (t1/2β and apparent volume of distribution (Vd were significantly (P<0.05 lower in febrile rabbits compared to normal rabbits, while mean residence time (MRT and total body clearance (Cl of ofloxacin did not show any significant difference in the normal and febrile rabbits. Clinical significance of the above results can be related to the changes in the volume of distribution and elimination half life that illustrates an altered steady state in febrile condition; hence, the need for an adjustment of dosage regimen in EEIF is required.

  7. Pharmacokinetics of linezolid during continuous hemodiafiltration: A case report.

    Science.gov (United States)

    Yamashina, Takuya; Tsuruyama, Moeko; Odawara, Miki; Tsuruta, Minako; Miyata, Hirochika; Kozono, Aki; Tsuji, Yasuhiro; Miyoshi, Takanori; Kawamata, Yosei; Hiraki, Yoichi

    2017-10-01

    The pharmacokinetics of linezolid clearance (CL LZD ) during continuous hemodiafiltration (CHDF) has not been comprehensively analyzed. Here, we examined CL LZD by CHDF in a patient with septic shock and disseminated intravascular coagulation due to methicillin-resistant Staphylococcus aureus. The extraction ratio of LZD by CHDF was 22.6%, and the protein-binding rate was 17.9% ± 7.7%. In addition, it was determined that the calculated total body clearance of LZD was 30.2 mL/min, plasma elimination half-life was 8.66 h, and the CL LZD by the dialyzer used for CHDF was 23.0 mL/min. From the obtained pharmacokinetics, the CL LZD of patients continuing CHDF was estimated to be approximately half of the reported CL LZD for healthy subjects. In addition, the LZD concentration of the sepsis patient who underwent CHDF remained higher than the minimum inhibitory concentration and was similar to the LZD concentrations reported in normal renal function patients. Although further studies are warranted, when LZD is administered to patients treated with CHDF, the present findings suggest that dose regulation is not required. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  8. Impact of Pregnancy on Zonisamide Pharmacokinetics in Rabbits

    Directory of Open Access Journals (Sweden)

    Kamal M. Matar

    2013-01-01

    Full Text Available Pregnancy is associated with various physiological changes which may lead to significant alterations in the pharmacokinetics of many drugs. The present study was aimed to investigate the potential effects of pregnancy on the pharmacokinetic profile of zonisamide (ZNM in the rabbit. Seven female rabbits were used in this study. The pregnant and nonpregnant rabbits received ZNM orally at a dose of 10 mg/kg and blood samples were collected from the animals just before receiving the drug and then serially for up to 24 h. The plasma samples were analyzed using tandem mass spectrometric method. Following a single oral dose of ZNM to the rabbits, the mean values of ZNM plasma concentrations at different times were consistently low in pregnant compared to nonpregnant rabbits. The mean values of ZNM’s Cmax and AUC0-∞ were significantly (P<0.05 decreased, whereas the CL/F exhibited substantial increase (P<0.05 in pregnant compared to nonpregnant rabbits. Tmax, t1/2abs, t1/2el, MRT, and Vd/F showed no significant differences between the two groups. The present study demonstrates that pregnancy decreased ZNM plasma concentrations in rabbits and that the decrease could be due to decreased extent of gastrointestinal absorption, induced hepatic metabolism, or enhanced renal elimination of the drug.

  9. BIOAVAILABILITY AND PHARMACOKINETICS OF NORFLOXACIN AFTER INTRAMUSCULAR ADMINISTRATION IN GOATS

    Directory of Open Access Journals (Sweden)

    WAJEEHA, F. H. KHAN AND I. JAVED

    2006-01-01

    Full Text Available Bioavailability and pharmacokinetics of two commercially available preparations of norfloxacin i.e. A (imported and B (locally prepared were determined in six healthy female goats after single intramuscular administration @ 5 mg/kg b.wt following crossover study design. The blood samples collected at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8 and 12 hours postmedication were also analysed for drug concentration by microbiological assay. Results revealed that preparation A showed higher (p<0.05 plasma drug levels than the preparation B at 1, 3, 6 and 8 hours after medication. Among bioavailability parameters AUC (g.h/ml and relative bioavailability (F% were higher for preparation A than the preparation B, while other parameters did not differ between the two preparations. Similarly, various pharmacokinetic parameters did not show any statistical difference between preparation A and B. The study revealed comparable elimination kinetics but different bioavailability of two commercial preparations of norfloxacin. It is concluded from the study that for optimal dosage regimen of drugs, the bioequivalence studies and kinetic behavior of the drugs are of paramount importance.

  10. Pharmacokinetics of cephalosporins in the neonate: a review

    Directory of Open Access Journals (Sweden)

    Gian Maria Pacifici

    2011-01-01

    Full Text Available The aim of this work was to review the published data on the pharmacokinetics of cephalosporins in neonates to provide a critical analysis of the literature as a useful tool for physicians. The bibliographic search was performed for articles published up to December 3, 2010, using PubMed. In addition, the book Neofax: A Manual of Drugs Used in Neonatal Care by Young and Mangum was consulted. The cephalosporins are mainly eliminated by the kidneys, and their elimination rates are reduced at birth. As a consequence, clearance is reduced and t1/2 is more prolonged in the neonate than in more mature infants. The neonate's substantial body water content creates a large volume of distribution (Vd of cephalosporins, as these drugs are fairly water soluble. Postnatal development is an important factor in the maturation of the neonate, and as postnatal age proceeds, the clearance of cephalosporins increases. The maturation of the kidney governs the pharmacokinetics of cephalosporins in the infant. Clearance and t1/2 are influenced by development, and this must be taken into consideration when planning a cephalosporin dosage regimen for the neonate.

  11. Metronidazole pharmacokinetics in patients with acute renal failure.

    Science.gov (United States)

    Somogyi, A A; Kong, C B; Gurr, F W; Sabto, J; Spicer, W J; McLean, A J

    1984-02-01

    The pharmacokinetics and metabolism of intravenous metronidazole were studied in six patients with acute renal failure. In two of the patients a single dose (500 mg) of metronidazole was administered, whereas in four patients the steady-state pharmacokinetics were studied after four days therapy of 500 mg twice daily. Plasma concentrations of metronidazole and its hydroxy and acetic acid metabolites were measured by a specific and sensitive HPLC method. The volume of distribution was 0.65 +/- 0.13 l/kg (mean +/- S.D.), elimination half-life was 9.9 +/- 2.5 h and total plasma clearance was 55.5 +/- 17.7 ml/min. Renal clearance was almost non-existent (1.4 +/- 1.4 ml/min), whereas non-renal clearance was 54.0 +/- 18.2 ml/min. Steady-state plasma concentrations of metronidazole were 15.3 +/- 3.8 mg/l, the hydroxy metabolite were 17.4 +/- 2.0 mg/l and the acetic acid metabolite were 1.2 +/- 0.8 mg/l. In the patients studied, a dosing regimen of 500 mg twice daily resulted in therapeutically adequate blood levels of metronidazole.

  12. Anphibole, an undesirable presence in cosmetic talc

    International Nuclear Information System (INIS)

    Amaral, M.A.M.

    1980-01-01

    A semi-quantitative X-ray diffractometric study, compared to CaO analysis, for the evaluation of the percentage of amphibole present in cosmetic talcs is presented. Scanning electron images show these needle-like minerals togheter with talc; these minerals can cause from simple allergies to serious health problems to the human being. (Author) [pt

  13. Undesired Plant-Derived Components in Food

    NARCIS (Netherlands)

    Dusemund, Birgit; Rietjens, Ivonne M.C.M.; Abraham, Klaus; Cartus, Alexander; Schrenk, Dieter

    2017-01-01

    Among the various chemical compounds, the class of natural plant-derived substances in the modern food chain is generating increasing concern. Adverse effects encountered may be various and pose risks of acute, subchronic, or chronic toxicity. The underlying mechanisms of toxicity may be

  14. Making law work for the poor

    Energy Technology Data Exchange (ETDEWEB)

    Cotula, Lorenzo

    2005-11-15

    To many, law – the systems of binding rules governing human relations – seems remote from the reality of daily struggle in poor and marginalised communities around the world. Yet, directly or indirectly, legal rules shape the way we behave in our everyday life, and contribute to organise social and economic relations (from commercial codes to EC 'freedom-of-movement' treaty provisions to welfare state legislation). Since the 1960s, development agencies have supported law reform processes in developing countries. Interest in law reform was recently revived by the recognition of the importance of institutional frameworks for social change ('New Institutional Economics'), and by the attention paid by several development agencies to concepts like good governance and the rule of law. Earlier emphasis on 'legal transplants' and naive assumptions about the way the law operates have given way to a better understanding of the complex nature of processes of legal and socio-economic change. Drawing on three examples, this paper explores the extent to which legal tools can contribute to improve the lives of poorer groups in both developing and developed countries; the conditions under which this is possible; and the constraints that such tools face in the pursuit of this aim. The paper aims to spark reflection and debate on these issues – not to come up with definitive answers. It is likely to be of interest for development lawyers, development practitioners working at a macro-planning level, and researchers. As for development practitioners, the paper sets out the case for taking law seriously as a tool for positive change. As for development lawyers, it argues that designing and implementing legal interventions that deliver that positive change is function not only of sound legal thinking, but also of a solid understanding of power relations and other social, cultural, political and economic factors that affect the way the law operates in

  15. Population pharmacokinetic model of transdermal nicotine delivered from a matrix-type patch.

    Science.gov (United States)

    Linakis, Matthew W; Rower, Joseph E; Roberts, Jessica K; Miller, Eleanor I; Wilkins, Diana G; Sherwin, Catherine M T

    2017-12-01

    Nicotine addiction is an issue faced by millions of individuals worldwide. As a result, nicotine replacement therapies, such as transdermal nicotine patches, have become widely distributed and used. While the pharmacokinetics of transdermal nicotine have been extensively described using noncompartmental methods, there are few data available describing the between-subject variability in transdermal nicotine pharmacokinetics. The aim of this investigation was to use population pharmacokinetic techniques to describe this variability, particularly as it pertains to the absorption of nicotine from the transdermal patch. A population pharmacokinetic parent-metabolite model was developed using plasma concentrations from 25 participants treated with transdermal nicotine. Covariates tested in this model included: body weight, body mass index, body surface area (calculated using the Mosteller equation) and sex. Nicotine pharmacokinetics were best described with a one-compartment model with absorption based on a Weibull distribution and first-order elimination and a single compartment for the major metabolite, cotinine. Body weight was a significant covariate on apparent volume of distribution of nicotine (exponential scaling factor 1.42). After the inclusion of body weight in the model, no other covariates were significant. This is the first population pharmacokinetic model to describe the absorption and disposition of transdermal nicotine and its metabolism to cotinine and the pharmacokinetic variability between individuals who were administered the patch. © 2017 The British Pharmacological Society.

  16. A Qualitative Review on the Pharmacokinetics of Antibiotics in Saliva: Implications on Clinical Pharmacokinetic Monitoring in Humans.

    Science.gov (United States)

    Kiang, Tony K L; Ensom, Mary H H

    2016-03-01

    We conducted a systematic search to describe the current state of knowledge regarding the utility of saliva for clinical pharmacokinetic monitoring (CPM) of antibiotics. Although the majority of identified studies lacked sufficient pharmacokinetic data needed to assign an appropriate suitability classification, most aminoglycosides, fluoroquinolones, macrolides, penicillins/cephalosporins, and tetracyclines are likely not suitable for CPM in saliva. No clear pattern of correlation was observed between physiochemical properties that favor drug distribution into saliva and the likelihood of the antibiotic being classified as suitable for CPM in saliva (and vice versa). Insufficient data were available to determine if pathophysiological conditions affected salivary distribution of antibiotics. Additional confirmatory data are required for drugs (especially in patients) that are deemed likely suitable for CPM in saliva because only a few studies were available and many focused only on healthy subjects. All studies identified had relatively small sample sizes and exhibited large variability. Very few studies reported salivary collection parameters (e.g., salivary flow, pH) that could potentially have some impact on drug distribution into saliva. The available data are heavily weighted on healthy subjects, and insufficient data were available to determine if pathophysiology had effects on saliva drug distribution. Some studies also lacked assay sensitivity for detecting antibiotics in saliva. Overall, this review can be useful to clinicians who desire an overview on the suitability of saliva for conducting CPM of specific antibiotics, or for researchers who wish to fill the identified knowledge gaps to move the science of salivary CPM further.

  17. Drug-like properties and the causes of poor solubility and poor permeability.

    Science.gov (United States)

    Lipinski, C A

    2000-01-01

    There are currently about 10000 drug-like compounds. These are sparsely, rather than uniformly, distributed through chemistry space. True diversity does not exist in experimental combinatorial chemistry screening libraries. Absorption, distribution, metabolism, and excretion (ADME) and chemical reactivity-related toxicity is low, while biological receptor activity is higher dimensional in chemistry space, and this is partly explainable by evolutionary pressures on ADME to deal with endobiotics and exobiotics. ADME is hard to predict for large data sets because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Currently, screening for biological receptor activity precedes or is concurrent with screening for properties related to "drugability." In the future, "drugability" screening may precede biological receptor activity screening. The level of permeability or solubility needed for oral absorption is related to potency. The relative importance of poor solubility and poor permeability towards the problem of poor oral absorption depends on the research approach used for lead generation. A "rational drug design" approach as exemplified by Merck advanced clinical candidates leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and, hence, poorer permeability. A high throughput screening (HTS)-based approach as exemplified by unpublished data on Pfizer (Groton, CT) early candidates leads to higher molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility.

  18. Effect of the CYP2C19 genotype on the pharmacokinetics of icotinib in healthy male volunteers.

    Science.gov (United States)

    Ruan, Can-Jun; Liu, Dong-Yang; Jiang, Ji; Hu, Pei

    2012-12-01

    Icotinib hydrochloride {4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline hydrochloride}, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), was designed for the treatment of non-small cell lung cancer (NSCLC). In the present study, we investigated the influence of the CYP2C19*2 and CYP2C19*3 alleles on the pharmacokinetics of icotinib in healthy Chinese volunteers. In a single-dose pharmacokinetic study, 12 healthy Chinese volunteers received an oral dose of 600 mg of icotinib. Plasma was sampled for up to 72 h post-dose, followed by quantification of icotinib by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS-MS). Five subjects genotyped as homozygous extensive metabolizers (CYP2C19*1/*1), 6 subjects genotyped as heterozygous extensive metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria. The mean icotinib AUC(0-∞) and C(max) (14.56 ±5.31 h mg/L and 2.32 ± 0.49 μg/mL) in homozygous EMs was 1.56 and 1.41-fold lower than that in heterozygous EMs (22.7 ± 6.11 and 3.28 ± 0.48, P = 0.046 and 0.047). The mean CL/F (44.18 ± 12.17 L/h) in homozygous EMs was 1.55-fold higher than that in heterozygous EMs (28.42 ± 9.23 L/h, P = 0.013). The data showed that the pharmacokinetics of icotinib differ significantly between homozygous EMs and heterozygous EMs in CYP2C19.

  19. Iron complexation to histone deacetylase inhibitors SAHA and LAQ824 in PEGylated liposomes can considerably improve pharmacokinetics in rats.

    Science.gov (United States)

    Wang, Yan; Tu, Sheng; Steffen, Dana; Xiong, May

    2014-01-01

    The formulation of histone deacetylase inhibitors (HDACi) is challenging due to poor water solubility and rapid elimination of drugs in vivo. This study investigated the effects of complexing iron (Fe3+) to the HDACi suberoylanilide hydroxamic acid (SAHA) and LAQ824 (LAQ) prior to their encapsulation into PEGylated liposomes, and investigated whether this technique could improve drug solubility, in vitro release and in vivo pharmacokinetic (PK) properties. METHODS. The reaction stoichiometry, binding constants and solubility were measured for Fe complexes of SAHA and LAQ. The complexes were passively encapsulated into PEGylated liposomes and characterized by size distribution, zeta-potential, encapsulation efficiency (EE), and in vitro drug release studies. PC-3 cells were used to verify the in vitro anticancer activity of the formulations. In vivo pharmacokinetic properties of liposomal LAQ-Fe (L-LAQ-Fe) was evaluated in rats. RESULTS. SAHA and LAQ form complexes with Fe at 1:1 stoichiometric ratio, with a binding constant on the order of 104 M-1. Fe complexation improved the aqueous solubility and the liposomal encapsulation efficiency of SAHA and LAQ (29-35% EE, final drug concentration > 1 mM). Liposomal encapsulated complexes (L-HDACi-Fe) exhibited sustained in vitro release properties compared to L-HDACi but cytotoxicity on PC-3 cells was comparable to free drugs. The PK of L-LAQ-Fe revealed 15-fold improvement in the plasma t1/2 (12.11 h)and 211-fold improvement in the AUC∞ (105.7 µg·h/ml) compared to free LAQ (0.79 h, 0.5 µg·h/ml). Similarly, the plasma t1/2 of Fe was determined to be 11.83 h in a separate experiment using radioactive Fe-59. The majority of Fe-59 activity was found in liver and spleen of rats and correlates with liposomal uptake by the mononuclear phagocyte system. CONCLUSIONS. We have demonstrated that encapsulation of Fe complexes of HDACi into PEGylated liposomes can improve overall drug aqueous solubility, in vitro release and in

  20. Luteolin-loaded solid lipid nanoparticles synthesis, characterization, & improvement of bioavailability, pharmacokinetics in vitro and vivo studies

    Science.gov (United States)

    Dang, Hao; Meng, Murtaza Hasan Weiwei; Zhao, Haiwei; Iqbal, Javed; Dai, Rongji; Deng, Yulin; Lv, Fang

    2014-04-01

    Luteolin (LU, 5,7,3',4'-tetrahydroxyflavone) most active compound in Chinese herbal flavones has been acting as a antimicrobial, anti-inflammatory, anti-cancer, and antimutagen. However, its poor bioavailability, hydrophobicity, and pharmacokinetics restrict clinical application. Here in this study, LU-loaded solid lipid nanoparticles have been prepared by hot-microemulsion ultrasonic technique to improve the bioavailability & pharmacokinetics of compound. LU-loaded solid lipid nanoparticle size was confirmed by particle size analyzer with range from 47 to 118 nm, having zepta potential -9.2 mV and polydisperse index 0.247, respectively. Round-shaped SLNPs were obtained by using transmission electron microscope, and encapsulation efficiency 74.80 % was calculated by using HPLC. Both in vitro and vivo studies, LC-MS/MS technique was used for quantification of Luteolin in rat. The T max value of drug with LU-SLNs after the administration was Ten times shorter than pure Luteolin suspension administration. C max value of drug after the administration of LU-SLNs was five times higher than obtained with native drug suspension. Luteolin with SLNs has increased the half-life approximately up to 2 h. Distribution and clearance of drug with SLNs were significantly decreased by 2.16-10.57 fold, respectively. In the end, the relative bioavailability of SLNs has improved about 4.89 compared to Luteolin with SLNs. From this study, it can be concluded that LU-SLNs have not only great potential for improving solubility but also increased the drug concentration in plasma. Furthermore, use of LC-MS/MS for quantification of LU-SLNs in rat plasma is reliable and of therapeutic usefulness, especially for neurodegenerative and cancerous disorders in humans.

  1. Pharmacokinetics of Levetiracetam in Healthy Hispaniolan Amazon Parrots ( Amazona ventralis ) After Oral Administration of a Single Dose.

    Science.gov (United States)

    Schnellbacher, Rodney; Beaufrère, Hugues; Vet, Dr Med; Arnold, Robert D; Tully, Thomas N; Mayer, Joerg; Divers, Stephen J

    2014-09-01

    Long-term anticonvulsive treatments have been poorly described in birds, and few pharmacokinetic studies have been performed, with mixed results. Levetiracetam, a new anticonvulsive drug, has shown good efficacy for monotherapy or adjunctive treatment of seizures in both human and veterinary medicine. To determine pharmacokinetics of levetiracetam in Hispaniolan Amazon parrots ( Amazona ventralis ), 20 healthy birds were randomly divided into 2 groups and administered either a 50 mg/kg (n = 10) or a 100 mg/kg (n = 10) oral dose of levetiracetam with no observable adverse effects. Blood samples were collected at baseline and at 12 time intervals (6 per group) for 16 hours. The concentration-time profiles resembled characteristic absorption, with maximum plasma concentrations of 61.0 μg/mL and 95.1 μg/mL at 60 minutes; terminal half-lives at 2.38 and 2.37 hours; volumes of distribution of 0.807 and 0.773 L/kg, with an area under the curve at 14 100 and 28 820 mg × min/L; and clearance rates of 3.65 and 3.60 mL/min per kg, respectively. Plasma concentrations were greater than 5.5 mg/L for up to 9.4 and 12 hours, suggesting an 8- and 12-hour oral dosing at 50 and 100 mg/kg, respectively, would be sufficient to maintain targeted values. Clinically, doses and frequencies may need escalation based on differences in species and individuals, and drug levels should be monitored.

  2. Pharmacokinetic modelling of intravenous tobramycin in adolescent and adult patients with cystic fibrosis using the nonparametric expectation maximization (NPEM) algorithm.

    Science.gov (United States)

    Touw, D J; Vinks, A A; Neef, C

    1997-06-01

    The availability of personal computer programs for individualizing drug dosage regimens has stimulated the interest in modelling population pharmacokinetics. Data from 82 adolescent and adult patients with cystic fibrosis (CF) who were treated with intravenous tobramycin because of an exacerbation of their pulmonary infection were analysed with a non-parametric expectation maximization (NPEM) algorithm. This algorithm estimates the entire discrete joint probability density of the pharmacokinetic parameters. It also provides traditional parametric statistics such as the means, standard deviation, median, covariances and correlations among the various parameters. It also provides graphic-2- and 3-dimensional representations of the marginal densities of the parameters investigated. Several models for intravenous tobramycin in adolescent and adult patients with CF were compared. Covariates were total body weight (for the volume of distribution) and creatinine clearance (for the total body clearance and elimination rate). Because of lack of data on patients with poor renal function, restricted models with non-renal clearance and the non-renal elimination rate constant fixed at literature values of 0.15 L/h and 0.01 h-1 were also included. In this population, intravenous tobramycin could be best described by median (+/-dispersion factor) volume of distribution per unit of total body weight of 0.28 +/- 0.05 L/kg, elimination rate constant of 0.25 +/- 0.10 h-1 and elimination rate constant per unit of creatinine clearance of 0.0008 +/- 0.0009 h-1/(ml/min/1.73 m2). Analysis of populations of increasing size showed that using a restricted model with a non-renal elimination rate constant fixed at 0.01 h-1, a model based on a population of only 10 to 20 patients, contained parameter values similar to those of the entire population and, using the full model, a larger population (at least 40 patients) was needed.

  3. PK/DB: database for pharmacokinetic properties and predictive in silico ADME models.

    Science.gov (United States)

    Moda, Tiago L; Torres, Leonardo G; Carrara, Alexandre E; Andricopulo, Adriano D

    2008-10-01

    The study of pharmacokinetic properties (PK) is of great importance in drug discovery and development. In the present work, PK/DB (a new freely available database for PK) was designed with the aim of creating robust databases for pharmacokinetic studies and in silico absorption, distribution, metabolism and excretion (ADME) prediction. Comprehensive, web-based and easy to access, PK/DB manages 1203 compounds which represent 2973 pharmacokinetic measurements, including five models for in silico ADME prediction (human intestinal absorption, human oral bioavailability, plasma protein binding, blood-brain barrier and water solubility). http://www.pkdb.ifsc.usp.br

  4. Towards overcoming poor readership and building reading culture ...

    African Journals Online (AJOL)

    Towards overcoming poor readership and building reading culture of in schools. ... of this paper is to find strategies that can overcome poor readership in schools. ... Keywords: English First Additional Language, Writing Skills, Spelling Errors, ...

  5. Causes and consequences of poor reading habit on primary school ...

    African Journals Online (AJOL)

    Causes and consequences of poor reading habit on primary school pupils in Enugu urban. ... Moreover, they noticed that poor reading habit negatively affect pupils' educational achievement. The researchers ... AJOL African Journals Online.

  6. Standard & Poor's kulupäid ei kummarda / Raivo Raigna

    Index Scriptorium Estoniae

    Raigna, Raivo

    2006-01-01

    Rahvusvaheline reitinguagentuur Standard & Poor's hoiatas, et ilma rahanduslike reformideta hakkab Eesti rahvastiku vananemine avaldama tugevat survet avaliku sektori rahandusele ja ühtlasi riigi reitingule. Standard & Poor'si nn. mustast stsenaariumist, pakutud lahendusest

  7. Contributing Factors to Poor Service Delivery by Administrative ...

    African Journals Online (AJOL)

    Poor service delivery by local government is crippling South African businesses .... main categories: one focuses on an employee's internal attributes (content ... admitted that their attitude to work was adversely affected by the poor quality.

  8. Information Lives of the Poor: Fighting poverty with technology ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    2016-05-05

    May 5, 2016 ... ... access to information and communication technologies (ICTs) in the ... the developing-country poor are using modern communication tools. ... Policy impacts ... A study on mobile phone use by the poor has resulted in the ...

  9. Influence of dosage form on the intravitreal pharmacokinetics of diclofenac.

    Science.gov (United States)

    Durairaj, Chandrasekar; Kim, Stephen J; Edelhauser, Henry F; Shah, Jaymin C; Kompella, Uday B

    2009-10-01

    To prepare a suspension form of diclofenac and compare the influence of the injected form (suspension versus solution) on the intravitreal pharmacokinetics of diclofenac in Dutch belted pigmented rabbits. Diclofenac acid was prepared and characterized in a suspension formulation. Rabbit eyes were injected with either diclofenac sodium solution (0.3 mg) or diclofenac acid suspension (10 mg) prepared in 0.1 mL balanced salt solution. Rabbits were killed at regular time intervals, the eyes enucleated, and drug content quantified in the vitreous humor and retina-choroid tissue by high-performance liquid chromatography. Pharmacokinetic models were developed for both the dosage forms, and simulations were performed for different doses. Diclofenac acid with an approximate 5-mum particle size exhibited 3.5-fold lower solubility in vitreous humor, when compared with its sodium salt. The estimated settling velocity of the suspension in the vitreous humor was 3 cm/h. After diclofenac sodium salt solution injection, drug levels declined rapidly with no drug levels detectable after 24 hours in the vitreous humor and 4 hours in the RC. Throughout the assessed time course, drug levels were higher in the vitreous. However, sustained, high drug levels were observed in both the vitreous humor and the retina-choroid even on day 21 after diclofenac acid suspension injection, with retina-choroid drug levels being higher beginning at 0.25 hour. The elimination half-life of diclofenac suspension was 24 and 18 days in vitreous and retina-choroid, respectively, compared to 2.9 and 0.9 hours observed with diclofenac sodium. The pharmacokinetic models developed indicated a slow-release distribution or depot compartment for the diclofenac acid suspension in the posterior segment. Simulations indicated the inability of a 10-mg dose of diclofenac sodium solution to sustain drug levels in the vitreous beyond 11 days. By choosing a less soluble form of a drug such as diclofenac acid, vitreous

  10. Pre-formulation characterization and pharmacokinetic evaluation of resveratrol

    Science.gov (United States)

    Robinson-Barnes, Keila Delores

    Resveratrol, a natural compound found in grapes has potential chemotherapy effects but very low oral bioavailability in humans. The objectives of this study are to quantitatively characterized and understand the physiochemical properties and the pharmacokinetic evaluation of resveratrol. Solubility of resveratrol was measured in 10 common solvents at 25°C using HPLC. The solution state pH stability of resveratrol was assessed in various USP buffers ranging from pH 2-10 for 24 hours at 37 °C. Human plasma protein binding was determined using ultracentrifugation technique. Stability of resveratrol in human and rat plasma was also assessed at 37°C. Aliquots of blank plasma were spiked with a standard drug concentration to yield final plasma concentration of 50 mug/mL. Samples were analyzed for resveratrol concentration up to 96 hours. A group (n=8) of jugular vein-cannulated adult male Sprague-Dawley rats were evaluated and received intravenous dose of 20 mg/kg resveratrol. Serial blood samples were collected up to 8 hours after the dose. Plasma concentrations of resveratrol were measured by an established LC-MS/MS method. Pharmacokinetic parameters were assessed using noncompartmental methods. Resveratrol is more soluble in alcohol and PEG-400, and stable in acidic pH. It binds highly to plasma proteins, and degrades slower in human then rat plasma. Resveratrol exhibits bioexponential disposition after intravenous administration and has a short elimination half-life. Resveratrol displays bioexponential disposition following intravenous administration. The estimated mean maximum concentration was 1045.5 ng/mL and rapidly dropped below 100 ng/mL within 30 minutes. The area under the concentration time curve (AUC) for resveratrol was 13888.7 min*ng/mL The mean terminal elimination half-life was 50.9 minutes. The mean total body clearance (Cl) and volume of distribution of trans-resveratrol were 1711.9mL/min/kg and 91087.8 mL/kg, respectively. Pre

  11. Pharmacokinetic characteristics and anticancer effects of 5-Fluorouracil loaded nanoparticles

    International Nuclear Information System (INIS)

    Li, Su; Wang, Anxun; Jiang, Wenqi; Guan, Zhongzhen

    2008-01-01

    It is expected that prolonged circulation of anticancer drugs will increase their anticancer activity while decreasing their toxic side effects. The purpose of this study was to prepare 5-fluorouracil (5-FU) loaded block copolymers, with poly(γ-benzyl-L-glutamate) (PBLG) as the hydrophobic block and poly(ethylene glycol) (PEG) as the hydrophilic block, and then examine the 5-FU release characteristics, pharmacokinetics, and anticancer effects of this novel compound. 5-FU loaded PEG-PBLG (5-FU/PEG-PBLG) nanoparticles were prepared by dialysis and then scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used to observe the shape and size of the nanoparticles, and ultraviolet spectrophotometry was used to evaluate the 5-FU in vitro release characteristics. The pharmacokinetic parameters of 5-FU/PEG-PBLG nanoparticles in rabbit plasma were determined by measuring the 5-FUby high-performance liquid chromatography (HPLC). To study in vivo effects, LoVo cells (human colon cancer cell line) or Tca8113 cells (human oral squamous cell carcinoma cell line) were implanted in BALB/c nude mice that were subsequently treated with 5-FU or 5-FU/PEG-PBLG nanospheres. 5-FU/PEG-PBLG nanoparticles had a core-shell spherical structure with a diameter of 200 nm and a shell thickness of 30 nm. The drug loading capacity was 27.1% and the drug encapsulation was 61.5%. Compared with 5-FU, 5-FU/PEG-PBLG nanoparticles had a longer elimination half-life (t 1/2 , 33.3 h vs. 5 min), lower peak concentration (C, 4563.5 μg/L vs. 17047.3 μg/L), and greater distribution volume (V D , 0.114 L vs. 0.069 L). Compared with a blank control, LoVo cell xenografts and Tca8113 cell xenografts treated with 5-FU or 5-FU/PEG-PBLG nanoparticles grew slower and had prolonged tumor doubling times. 5-FU/PEG-PBLG nanoparticles showed greater inhibition of tumor growth than 5-FU (p < 0.01). In the PEG-PBLG nanoparticle control group, there was no tumor inhibition (p > 0.05). In our

  12. Pharmacokinetic characteristics and anticancer effects of 5-Fluorouracil loaded nanoparticles

    Directory of Open Access Journals (Sweden)

    Jiang Wenqi

    2008-04-01

    Full Text Available Abstract Background It is expected that prolonged circulation of anticancer drugs will increase their anticancer activity while decreasing their toxic side effects. The purpose of this study was to prepare 5-fluorouracil (5-FU loaded block copolymers, with poly(γ-benzyl-L-glutamate (PBLG as the hydrophobic block and poly(ethylene glycol (PEG as the hydrophilic block, and then examine the 5-FU release characteristics, pharmacokinetics, and anticancer effects of this novel compound. Methods 5-FU loaded PEG-PBLG (5-FU/PEG-PBLG nanoparticles were prepared by dialysis and then scanning electron microscopy (SEM and transmission electron microscopy (TEM were used to observe the shape and size of the nanoparticles, and ultraviolet spectrophotometry was used to evaluate the 5-FU in vitro release characteristics. The pharmacokinetic parameters of 5-FU/PEG-PBLG nanoparticles in rabbit plasma were determined by measuring the 5-FUby high-performance liquid chromatography (HPLC. To study in vivo effects, LoVo cells (human colon cancer cell line or Tca8113 cells (human oral squamous cell carcinoma cell line were implanted in BALB/c nude mice that were subsequently treated with 5-FU or 5-FU/PEG-PBLG nanospheres. Results 5-FU/PEG-PBLG nanoparticles had a core-shell spherical structure with a diameter of 200 nm and a shell thickness of 30 nm. The drug loading capacity was 27.1% and the drug encapsulation was 61.5%. Compared with 5-FU, 5-FU/PEG-PBLG nanoparticles had a longer elimination half-life (t1/2, 33.3 h vs. 5 min, lower peak concentration (C, 4563.5 μg/L vs. 17047.3 μg/L, and greater distribution volume (VD, 0.114 L vs. 0.069 L. Compared with a blank control, LoVo cell xenografts and Tca8113 cell xenografts treated with 5-FU or 5-FU/PEG-PBLG nanoparticles grew slower and had prolonged tumor doubling times. 5-FU/PEG-PBLG nanoparticles showed greater inhibition of tumor growth than 5-FU (p 0.05. Conclusion In our model system, 5-FU/PEG-PBLG nanoparticles

  13. Advertising and the Poor. Journalism Monographs Number Seventy-Five.

    Science.gov (United States)

    Bowen, Lawrence

    This monograph examines the impact of media advertising on the poor. The first half of the report discusses research on the conceptual styles of the poor, mass communication among the poor, and advertising and the low-income consumer. The second half describes the methodology and results of a study of the advertising evaluation capacity and…

  14. Pharmacokinetics of Hyperthermic Intrathoracic Chemotherapy following Pleurectomy and Decortication

    Directory of Open Access Journals (Sweden)

    Paul H. Sugarbaker

    2012-01-01

    Full Text Available In patients with pseudomyxoma peritonei or peritoneal mesothelioma, direct extension of disease through the hemidiaphragm may result in an isolated progression of tumor within the pleural space. We monitored the intrapleural and plasma levels of mitomycin C and doxorubicin by HPLC assay in order to determine the pharmacokinetic behavior of this intracavitary use of chemotherapy. Our results showed a persistent high concentration of intrapleural drug as compared to plasma concentrations. The increased exposure for mitomycin C was 96, and the increased exposure for doxorubicin was 241. When the clearance of chemotherapy from the thoracic cavity was compared to clearance from the abdomen and pelvis, there was a considerably more rapid clearance from the abdomen as compared to the thorax. The pharmacologic study of intrapleural chemotherapy in these patients provides a strong pharmacologic rationale for regional chemotherapy in this group of patients.

  15. Market entry, power, pharmacokinetics: what makes a successful drug innovation?

    Science.gov (United States)

    Alt, Susanne; Helmstädter, Axel

    2018-02-01

    Depending on the timing of market entry, radical innovations can be distinguished from incremental innovations. Whereas a radical innovation typically is the first available derivative of a drug class, incremental innovations are launched later and show a certain benefit compared with the radical innovation. Here, we use historical market data relating to pharmacokinetic (PK), pharmacodynamic (PD), and other drug-related properties to investigate which derivatives within certain drug classes have been most successful on the market. Based on our investigations, we suggest naming the most successful drugs 'overtaking innovation', because they often exceed the market share of all the other derivatives. Seven drug classes showed that the overtaking innovation is never a radical innovation, but rather an early incremental innovation, with advantages in manageability and/or tolerance. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Developmental pharmacokinetics of gentamicin in preterm and term neonates

    DEFF Research Database (Denmark)

    Nielsen, Elisabet I; Sandström, Marie; Honoré, Per Hartvig

    2009-01-01

    0-45 days) were enrolled in the study. In total, 894 serum gentamicin samples were included in the analysis. The concentration-time profile was described using a three-compartment model. Gentamicin clearance increased with the GA and PNA (included in a nonlinear fashion). The GA was also identified...... in this patient population. METHODS: Data were collected in a prospective study performed in the Neonatal Intensive Care Unit at the University Children's Hospital, Uppsala, Sweden. Population pharmacokinetic modelling was performed using nonlinear mixed-effects modelling (NONMEM) software. Bodyweight...... was included as the primary covariate according to an allometric power model. Other evaluated covariates were age (postmenstrual age, gestational age [GA], postnatal age [PNA]), markers for renal function (serum creatinine, serum cystatin C) and concomitant medication with cefuroxime, vancomycin or indometacin...

  17. Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics.

    Science.gov (United States)

    Shah, Dhaval K

    2015-10-01

    Increasingly sophisticated protein engineering efforts have been undertaken lately to generate protein therapeutics with desired properties. This has resulted in the discovery of the next generation of protein therapeutics, which include: engineered antibodies, immunoconjugates, bi/multi-specific proteins, antibody mimetic novel scaffolds, and engineered ligands/receptors. These novel protein therapeutics possess unique physicochemical properties and act via a unique mechanism-of-action, which collectively makes their pharmacokinetics (PK) and pharmacodynamics (PD) different than other established biological molecules. Consequently, in order to support the discovery and development of these next generation molecules, it becomes important to understand the determinants controlling their PK/PD. This review discusses the determinants that a PK/PD scientist should consider during the design and development of next generation protein therapeutics. In addition, the role of systems PK/PD models in enabling rational development of the next generation protein therapeutics is emphasized.

  18. Pharmacokinetic aspects of the anti-epileptic drug substance vigabatrin

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  19. Pharmacokinetic, Pharmacogenetic, and Other Factors Influencing CNS Penetration of Antiretrovirals

    Directory of Open Access Journals (Sweden)

    Jacinta Nwamaka Nwogu

    2016-01-01

    Full Text Available Neurological complications associated with the human immunodeficiency virus (HIV are a matter of great concern. While antiretroviral (ARV drugs are the cornerstone of HIV treatment and typically produce neurological benefit, some ARV drugs have limited CNS penetration while others have been associated with neurotoxicity. CNS penetration is a function of several factors including sieving role of blood-brain and blood-CSF barriers and activity of innate drug transporters. Other factors are related to pharmacokinetics and pharmacogenetics of the specific ARV agent or mediated by drug interactions, local inflammation, and blood flow. In this review, we provide an overview of the various factors influencing CNS penetration of ARV drugs with an emphasis on those commonly used in sub-Saharan Africa. We also summarize some key associations between ARV drug penetration, CNS efficacy, and neurotoxicity.

  20. Pharmacokinetics of a 5-fluorouracil liposomal delivery system.

    Science.gov (United States)

    Simmons, S T; Sherwood, M B; Nichols, D A; Penne, R B; Sery, T; Spaeth, G L

    1988-01-01

    A liposomal delivery system was developed in an attempt to prolong ocular levels of 5-fluorouracil for glaucoma filtering surgery. The pharmacokinetics of the 5-fluorouracil liposomal delivery system were studied in normal pigmented rabbits with 5-fluorouracil labelled with carbon-14 (C-14). 14C 5-fluorouracil was incorporated into the liposomes at a concentration of 10 g/l and injected subconjunctivally in doses of 5 and 10 mg. Concentrations of 5-fluorouracil were assayed at 10 time intervals from 0.5 to 96 hours in cornea, sclera, and conjunctiva and at six time intervals from 0.5 to 12 hours in aqueous. Two peak concentrations were noted at approximately one and eight hours, with measurable levels present at 96 hours. This study demonstrates the ability of this liposomal delivery system to prolong levels of 5-fluorouracial in normal pigmented rabbits. PMID:3179257