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;

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)

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.

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.

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.

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

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.

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...

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.

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.

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.

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.

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.

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

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

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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.

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

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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.

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.

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.

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

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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.

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.

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...

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.

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.

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

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

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.

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.

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.

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

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.

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...

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

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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.

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

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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

Personalized therapeutics for levofloxacin: a focus on pharmacokinetic concerns.

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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

Pharmacokinetics of procaterol in thoroughbred horses.

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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.

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

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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

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

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...

UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

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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)...

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

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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.

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

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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.

Computational Analysis of Pharmacokinetic Behavior of Ampicillin

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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.

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 ...

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

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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.

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...

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

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....

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

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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.

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

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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.

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

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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.

Pharmacokinetics of mitragynine in man

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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

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, ...

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

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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.

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

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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.

[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.

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

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.

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.

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...

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.

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.

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

[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.

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.

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.

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.

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.

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 %).

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.

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.

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.

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…

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...

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.

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...

[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

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.

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.

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.

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.

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 ...

[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.

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…

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.

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...

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.

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...

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.

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.

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

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

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.

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

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...

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

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.

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.

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

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.

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...

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.

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…

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

[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.

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....

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.

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.

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 ...

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.

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...

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.

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.

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.

[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.

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.

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,

[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.

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.

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.

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.

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.)

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.

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

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.

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.

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...

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.

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.

[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.

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.

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...

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.

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.

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.

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

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...

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...

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.

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.

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

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.

Pharmacokinetic study of gallocatechin-7-gallate from Pithecellobium clypearia Benth. in rats

Directory of Open Access Journals (Sweden)

Chao Li

2016-01-01

Full Text Available The pharmacokinetic profile of gallocatechin-7-gallate (J10688 was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD rats received 1, 3, and 10 mg/kg (i.v. of J10688 and plasma drug concentrations were determined by a high performance liquid chromatography-mass spectrometry (LC–MS method. The pharmacokinetic software Data Analysis System (Version 3.0 was used to calculate the pharmacokinetic parameters. For different i.v. doses of J10688, the mean peak plasma concentration (C0 values ranged from 11.26 to 50.82 mg/L, and mean area under the concentration-time curve (AUC0–t values ranged from 1.75 to 11.80 (mg·h/L. J10688 lacked dose-dependent pharmacokinetic properties within doses between 1 and 10 mg/kg, based on the power model. The method developed in this study was sensitive, precise, and stable. The pharmacokinetic properties of J10688 in SD rats were shown to have rapid distribution and clearance values. These pharmacokinetic results may contribute to an improved understanding of the pharmacological actions of J10688.

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...

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...

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...

Time-dependent pharmacokinetics of dexamethasone and its efficacy in human breast cancer xenograft mice: a semi-mechanism-based pharmacokinetic/pharmacodynamic model.

Science.gov (United States)

Li, Jian; Chen, Rong; Yao, Qing-Yu; Liu, Sheng-Jun; Tian, Xiu-Yun; Hao, Chun-Yi; Lu, Wei; Zhou, Tian-Yan

2018-03-01

Dexamethasone (DEX) is the substrate of CYP3A. However, the activity of CYP3A could be induced by DEX when DEX was persistently administered, resulting in auto-induction and time-dependent pharmacokinetics (pharmacokinetics with time-dependent clearance) of DEX. In this study we investigated the pharmacokinetic profiles of DEX after single or multiple doses in human breast cancer xenograft nude mice and established a semi-mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for characterizing the time-dependent PK of DEX as well as its anti-cancer effect. The mice were orally given a single or multiple doses (8 mg/kg) of DEX, and the plasma concentrations of DEX were assessed using LC-MS/MS. Tumor volumes were recorded daily. Based on the experimental data, a two-compartment model with first order absorption and time-dependent clearance was established, and the time-dependence of clearance was modeled by a sigmoid E max equation. Moreover, a semi-mechanism-based PK/PD model was developed, in which the auto-induction effect of DEX on its metabolizing enzyme CYP3A was integrated and drug potency was described using an E max equation. The PK/PD model was further used to predict the drug efficacy when the auto-induction effect was or was not considered, which further revealed the necessity of adding the auto-induction effect into the final PK/PD model. This study established a semi-mechanism-based PK/PD model for characterizing the time-dependent pharmacokinetics of DEX and its anti-cancer effect in breast cancer xenograft mice. The model may serve as a reference for DEX dose adjustments or optimization in future preclinical or clinical studies.

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

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

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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

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

Poly(n-butylcyanoacrylate nanoparticles for oral delivery of quercetin: preparation, characterization, and pharmacokinetics and biodistribution studies in Wistar rats

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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

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.

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...

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

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

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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 %.

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

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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.

"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.

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).

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

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

A comprehensive review of recent studies on pharmacokinetics of traditional Chinese medicines (2014-2017) and perspectives.

Science.gov (United States)

Shi, Peiying; Lin, Xinhua; Yao, Hong

2018-05-01

Traditional Chinese medicines (TCMs) have a long history for safely treating human diseases. Unlike western medicine, TCMs usually contain multiple components synergistically and holistically acting on the diseases. It remains a big challenge to represent rationally the in vivo process of multiple components of TCMs for understanding the relationship between administration and therapeutic effects. For years, efforts were always made to face the challenge, and the achievements were obvious. Here, we give an comprehensive overview of the recent investigation progress (from 2015 to 2017, except the part of 'integrated pharmacokinetics of TCMs' from 2014 to 2017 and the part of 'reverse pharmacokinetics in drug discovery from natural medicines' in 2014) on pharmacokinetics of TCMs, mainly referring to the following six aspects: (1) classical pharmacokinetic studies on TCMs; (2) absorbed components and metabolites identification of TCMs; (3) pharmacokinetic herb-drug interactions and herb-herb interactions with TCMs; (4) integrated pharmacokinetics of TCMs; (5) pharmacokinetic and pharmacodynamic combination studies to dissect the action mechanisms of TCMs; and (6) reverse pharmacokinetics in drug discovery from natural medicines. Finally, based on the insights from the recent progress and our latest efforts, we propose new perspectives on the integrated pharmacokinetics of TCMs.

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.

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.

The Brain and Propranolol Pharmacokinetics in the Elderly

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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.

Pharmacokinetics, Dose Proportionality, and Bioavailability of Bazedoxifene in Healthy Postmenopausal Women.

Science.gov (United States)

McKeand, William

2017-09-01

Bazedoxifene is a selective estrogen receptor modulator that has estrogen agonist effects on bone and lipid metabolism while having neutral or estrogen antagonist effects on the breast and endometrium. The present report describes findings from 3 Phase I clinical studies that evaluated the single-dose pharmacokinetics (study 1; n = 84), multiple-dose pharmacokinetics (study 2; n = 23), and absolute bioavailability (study 3; n = 18) of bazedoxifene. All 3 studies enrolled healthy postmenopausal women who were either naturally postmenopausal or had undergone bilateral oophorectomy at least 6 months before the start of the study. Study 1 showed that unconjugated and total (unconjugated and conjugated) bazedoxifene levels increased proportionally with ascending oral doses of bazedoxifene (through the dose range of 5-120 mg). Evaluation with or without food intake was conducted at the 10-mg dose, with no clinically relevant effect on pharmacokinetic parameters. Study 2 showed that bazedoxifene achieved steady state in 1 week and exhibited linear pharmacokinetics in doses of 5 to 40 mg with no unexpected accumulation over the dose range. In accordance with a linear pharmacokinetic profile, mean maximum plasma concentration values increased with increasing dose, with values of 1.6, 6.2, and 12.5 ng/mL for the 5-, 20-, and 40-mg doses, respectively. In study 3, tablet and capsule formulations of bazedoxifene formulations had an estimated oral bioavailability of ~6%. The clearance of bazedoxifene was 0.4 (0.1) L/h/kg based on intravenous administration. The oral formulations had comparable exposure profiles with respect to AUC and AUC0-t, and the 90% CIs for these values were within the bioequivalence limits of 80% to 125%. Bazedoxifene was safe and well tolerated in all 3 studies. These pharmacokinetic evaluations in healthy postmenopausal women found that bazedoxifene displayed linear pharmacokinetics with doses ranging from 5 to 40 mg, with no unexpected accumulation

Clinical Pharmacology and Pharmacokinetics of Levetiracetam

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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.

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 ...

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

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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.

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

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

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

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...

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....

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)-...

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

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.

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.

[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.

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.

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

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

Dose optimisation of antibiotics in children: application of pharmacokinetics/pharmacodynamics in paediatrics.

Science.gov (United States)

Downes, Kevin J; Hahn, Andrea; Wiles, Jason; Courter, Joshua D; Vinks, Alexander A

2014-03-01

The judicious use of antibiotics to combat infections in children relies upon appropriate selection of an agent, dose and duration to maximise efficacy and to minimise toxicity. Critical to dose optimisation is an understanding of the pharmacokinetics and pharmacodynamics of available drugs. Optimal dosing strategies may take advantage of pharmacokinetic/pharmacodynamic (PK/PD) principles so that antibiotic dosing can be individualised to assure effective bacterial killing in patients who have altered pharmacokinetics or who have infections with less susceptible or resistant organisms. This review will outline the fundamentals of antimicrobial pharmacokinetics/pharmacodynamics through discussion of antibacterial agents most often used in children. We aim to highlight the importance of dose optimisation in paediatrics and describe non-conventional dosing strategies that can take advantage of PK/PD principles at the bedside. Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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.

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.

Estimation of pharmacokinetic parameters from non-compartmental variables using Microsoft Excel.

Science.gov (United States)

Dansirikul, Chantaratsamon; Choi, Malcolm; Duffull, Stephen B

2005-06-01

This study was conducted to develop a method, termed 'back analysis (BA)', for converting non-compartmental variables to compartment model dependent pharmacokinetic parameters for both one- and two-compartment models. A Microsoft Excel spreadsheet was implemented with the use of Solver and visual basic functions. The performance of the BA method in estimating pharmacokinetic parameter values was evaluated by comparing the parameter values obtained to a standard modelling software program, NONMEM, using simulated data. The results show that the BA method was reasonably precise and provided low bias in estimating fixed and random effect parameters for both one- and two-compartment models. The pharmacokinetic parameters estimated from the BA method were similar to those of NONMEM estimation.

Association of CYP2B6, CYP3A5, and CYP2C19 genetic polymorphisms with sibutramine pharmacokinetics in healthy Korean subjects.

Science.gov (United States)

Kim, K A; Song, W K; Park, J Y

2009-11-01

We assessed the association of CYP2B6, CYP3A5, and CYP2C19 polymorphisms with sibutramine pharmacokinetics. Forty six healthy male subjects were enrolled, and their CYP2B6 (*4 and *6), CYP3A5 (*3), and CYP2C19 (*2, and *3) genotypes were analyzed. After a single 15-mg dose of sibutramine was administered, plasma concentrations of sibutramine and its metabolites, M1 and M2, were measured. CYP2B6 and CYP3A5 polymorphisms did not affect the pharmacokinetics of sibutramine and its metabolites. However, the CYP2C19 genotype substantially influenced plasma levels of sibutramine and its metabolites. The mean area under the curve (AUC) of sibutramine in CYP2C19 intermediate metabolizers (IMs; *1/*2 or *1/*3) and poor metabolizers (PMs; *2/*2, *2/*3)) was 18.5 and 252.2% higher, respectively, than the AUC in extensive metabolizers (EMs, *1/*1) (P sibutramine.

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

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

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

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)

Pharmacokinetics and Concentration-Effect Relationship of Oral LSD in Humans.

Science.gov (United States)

Dolder, Patrick C; Schmid, Yasmin; Haschke, Manuel; Rentsch, Katharina M; Liechti, Matthias E

2015-06-24

The pharmacokinetics of oral lysergic acid diethylamide are unknown despite its common recreational use and renewed interest in its use in psychiatric research and practice. We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of lysergic acid diethylamide and its main metabolite after administration of a single oral dose of lysergic acid diethylamide (200 μg) in 8 male and 8 female healthy subjects. Plasma lysergic acid diethylamide concentrations were quantifiable (>0.1 ng/mL) in all the subjects up to 12 hours after administration. Maximal concentrations of lysergic acid diethylamide (mean±SD: 4.5±1.4 ng/mL) were reached (median, range) 1.5 (0.5-4) hours after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6±0.9 hours up to 12 hours and slower elimination thereafter with a terminal half-life of 8.9±5.9 hours. One percent of the orally administered lysergic acid diethylamide was eliminated in urine as lysergic acid diethylamide, and 13% was eliminated as 2-oxo-3-hydroxy-lysergic acid diethylamide within 24 hours. No sex differences were observed in the pharmacokinetic profiles of lysergic acid diethylamide. The acute subjective and sympathomimetic responses to lysergic acid diethylamide lasted up to 12 hours and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance. These first data on the pharmacokinetics and concentration-effect relationship of oral lysergic acid diethylamide are relevant for further clinical studies and serve as a reference for the assessment of intoxication with lysergic acid diethylamide. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Pharmacokinetics and Biodistribution of the Illegal Food Colorant Rhodamine B in Rats.

Science.gov (United States)

Cheng, Yung-Yi; Tsai, Tung-Hu

2017-02-08

The International Agency for Research on Cancer (IARC) demonstrated rhodamine B as a potential carcinogen in 1978. Nevertheless, rhodamine B has been illegally used as a colorant in food in many countries. Few pharmacokinetic and toxicological investigations have been performed since the first pharmacokinetic study on rhodamine B in 1961. The aims of this study were to develop a simple and sensitive high-performance liquid chromatography method with fluorescence detection for the quantitative detection of rhodamine B in the plasma and organs of rats and to estimate its pharmacokinetics and biodistribution. The results demonstrated that the oral bioavailabilities of rhodamine B were 28.3 and 9.8% for the low-dose and high-dose exposures, respectively. Furthermore, rhodamine B was highly accumulated in the liver and, to a lesser extent, the kidney, but was undetectable in the brain. These results provide useful information for improving the pharmacokinetics and biodistribution of rhodamine B, supporting additional food safety evaluations.

Dynamic contrast-enhanced magnetic resonance imaging and pharmacokinetic models in prostate cancer

International Nuclear Information System (INIS)

Franiel, Tobias; Hamm, Bernd; Hricak, Hedvig

2011-01-01

Dynamic contrast-enhanced MRI enables noninvasive analysis of prostate vascularization as well as tumour angiogenesis and capillary permeability characteristics in prostate cancers. Pharmacokinetic models summarizing the complex information provided by signal intensity-time curves for a few quantitative pharmacokinetic parameters are increasingly being used in the routine clinical setting. This review consists of two parts. The first part discusses the advantages and disadvantages of the MR pulse sequences that can be used for performing DCE-MRI and also of the most widely used pharmacokinetic parameters and models and the parameters they describe. The second part outlines the range of current and potential future clinical applications of DCE-MRI and pharmacokinetic parametric maps in patients with prostate cancer, with reference to the current scientific literature on the topic. The potential clinical applications of DCE-MRI for prostate cancer include detection, localization, and staging, differentiation of recurrent cancer and estimation of the patient's prognosis, as well as monitoring of treatment response. (orig.)

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...

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

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

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

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

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.

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.

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.

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.

Pharmacokinetics of Repeated Melatonin Drug Administrations Prior to and After Surgery

DEFF Research Database (Denmark)

Harpsøe, Nathja Groth; Andersen, Lars Peter Kloster; Mielke, Louise Vennegaard

2016-01-01

BACKGROUND: Recent clinical studies have documented the analgesic, anti-inflammatory, antioxidative and anxiolytic effects of exogenous melatonin. The pharmacokinetic properties of melatonin have primarily been investigated in experimental studies. OBJECTIVE: The aim of this study was to estimate...... the pharmacokinetics of melatonin in patients undergoing surgery and general anesthesia. METHODS: The study was designed as a prospective, two-phase cohort study. Patients were candidates for subpectoral breast augmentation surgery, and surgical procedures were performed by a single surgeon. The perioperative...... treatment protocol was standardized between patients. During the study, each patient received two separate oral administrations of melatonin 10 mg. Melatonin was administered 60 min before surgery, and at 9:00 p.m. the evening after surgery. The pharmacokinetic variables absorption half-life (t ½ absorption...

Investigation of an alternative generic model for predicting pharmacokinetic changes during physiological stress.

Science.gov (United States)

Peng, Henry T; Edginton, Andrea N; Cheung, Bob

2013-10-01

Physiologically based pharmacokinetic models were developed using MATLAB Simulink® and PK-Sim®. We compared the capability and usefulness of these two models by simulating pharmacokinetic changes of midazolam under exercise and heat stress to verify the usefulness of MATLAB Simulink® as a generic PBPK modeling software. Although both models show good agreement with experimental data obtained under resting condition, their predictions of pharmacokinetics changes are less accurate in the stressful conditions. However, MATLAB Simulink® may be more flexible to include physiologically based processes such as oral absorption and simulate various stress parameters such as stress intensity, duration and timing of drug administration to improve model performance. Further work will be conducted to modify algorithms in our generic model developed using MATLAB Simulink® and to investigate pharmacokinetics under other physiological stress such as trauma. © The Author(s) 2013.

Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin.

Science.gov (United States)

Jolling, Koen; Perez Ruixo, Juan Jose; Hemeryck, Alex; Vermeulen, An; Greway, Tony

2005-04-01

The aim of this study was to develop a population pharmacokinetic model for interspecies allometric scaling of pegylated r-HuEPO (PEG-EPO) pharmacokinetics to man. A total of 927 serum concentrations from 193 rats, 6 rabbits, 34 monkeys, and 9 dogs obtained after a single dose of PEG-EPO, administered by the i.v. (dose range: 12.5-550 microg/kg) and s.c. (dose range: 12.5-500 microg/kg) routes, were pooled in this analysis. An open two-compartment model with first-order absorption and lag time (Tlag) and linear elimination from the central compartment was fitted to the data using the NONMEM V software. Body weight (WT) was used as a scaling factor and the effect of brain weight (BW), sex, and pregnancy status on the pharmacokinetic parameters was investigated. The final model was evaluated by means of a non-parametric bootstrap analysis and used to predict the PEG-EPO pharmacokinetic parameters in healthy male subjects. The systemic clearance (CL) in males was estimated to be 4.08WT1.030xBW-0.345 ml/h. In females, the CL was 90.7% of the CL in males. The volumes of the central (Vc) and the peripheral (Vp) compartment were characterized as 57.8WT0.959 ml, and 48.1WT1.150 ml, respectively. Intercompartmental flow was estimated at 2.32WT0.930 ml/h. Absorption rate constant (Ka) was estimated at 0.0538WT-0.149. The absolute s.c. bioavailability F was calculated at 52.5, 80.2, and 49.4% in rat, monkey, and dog, respectively. The interindividual variability in the population pharmacokinetic parameters was fairly low (parametric bootstrap confirmed the accuracy of the NONMEM estimates. The mean model predicted pharmacokinetic parameters in healthy male subjects of 70 kg were estimated at: CL: 26.2 ml/h; Vc: 3.6l; Q: 286 l/h; Vp: 6.9l, and Ka: 0.031 h-1. The population pharmacokinetic model developed was appropriate to describe the time course of PEG-EPO serum concentrations and their variability in different species. The model predicted pharmacokinetics of PEG-EPO in

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.

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

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

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

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.

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...

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....

In Silico Ocular Pharmacokinetic Modeling: Delivery of Topical FK962 to Retina.

Science.gov (United States)

Mori, Ayumi; Yabuta, Chiho; Kishimoto, Yayoi; Kozai, Seiko; Ohtori, Akira; Shearer, Thomas R; Azuma, Mitsuyoshi

2017-09-01

To establish the in silico ocular pharmacokinetic modeling for eye drops, and to simulate the dose regimen for FK962 in human choroid/retinal diseases. Pharmacokinetics for FK962 in vivo was performed by a single instillation of drops containing 0.1% 14 C-FK962 in rabbit eyes. Permeation of FK962 across the cornea, sclera, and choroid/retina was measured in vitro. Neurite elongation by FK962 was measured in cultured rat retinal ganglion cells. Parameters from the experimental data were used in an improved in silico model of ocular pharmacokinetics of FK962 in man. The mean concentration of FK962 in ocular tissues predicted by in silico modeling was consistent with in vivo results, validating the in silico model. FK962 rapidly penetrated into the anterior and posterior segments of the eye and then diffused into the vitreous body. The in silico pharmacokinetic modeling also predicted that a dose regimen of 0.0054% FK962 twice per day would produce biologically effective concentrations of FK962 in the choroid/retina, where FK962 facilitates rat neurite elongation. Our in silico model for ocular pharmacokinetics is useful (1) for predicting drug concentrations in specific ocular tissues after topical instillation, and (2) for suggesting the optimal dose regimens for eye drops. The pharmacodynamics for FK962 produced by this model may be useful for clinical trials against retinal neuropathy.

Effects of amoxicillin/clavulanic acid on the pharmacokinetics of valproic acid

Directory of Open Access Journals (Sweden)

Lee SY

2015-08-01

Full Text Available Soo-Yun Lee,1 Wooseong Huh,2 Jin Ah Jung,3 Hye Min Yoo,2 Jae-Wook Ko,1,2 Jung-Ryul Kim2,4 1Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 2Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, 3Department of Clinical Pharmacology, Inje University, Busan Paik Hospital, Busan, 4Department of Clinical Research and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea Abstract: Valproic acid (VPA is mainly metabolized via glucuronide, which is hydrolyzed by β-glucuronidase and undergoes enterohepatic circulation. Amoxicillin/clavulanic acid (AMC administration leads to decreased levels of β-glucuronidase-producing bacteria, suggesting that these antibiotics could interrupt enterohepatic circulation and thereby alter the pharmacokinetics of VPA. This study aimed to evaluate the effects of AMC on the pharmacokinetics of VPA. This was an open-label, two-treatment, one-sequence study in 16 healthy volunteers. Two treatments were evaluated; treatment VPA, in which a single dose of VPA 500 mg was administered, and treatment AMC + VPA, in which multiple doses of AMC 500/125 mg were administered three times daily for 7 days and then a single dose of VPA was administered. Blood samples were collected up to 48 hours. Pharmacokinetic parameters were calculated using noncompartmental methods. Fifteen subjects completed the study. Systemic exposures and peak concentrations of VPA were slightly lower with treatment AMC + VPA than with treatment VPA (AUClast, 851.0 h·mg/L vs 889.6 h·mg/L; Cmax, 52.1 mg/L vs 53.0 mg/L. There were no significant between-treatment effects on pharmacokinetics (95% confidence interval [CI] of AUClast and Cmax (95.7 [85.9–106.5] and 98.3 [91.6–105.6], respectively. Multiple doses of AMC had no significant effects on the pharmacokinetics of VPA; thus, no dose adjustment is necessary. Keywords: drug–drug interaction, pharmacokinetics

Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol.

Science.gov (United States)

Franken, L G; de Winter, B C M; van Esch, H J; van Zuylen, L; Baar, F P M; Tibboel, D; Mathôt, R A A; van Gelder, T; Koch, B C P

2016-06-01

A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended.

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

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

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.

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

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.

Pharmacokinetics and pharmacodynamics of rhubarb anthraquinones extract in normal and disease rats.

Science.gov (United States)

Li, Peijin; Lu, Qianfeng; Jiang, Wenjiao; Pei, Xue; Sun, Yilin; Hao, Haiping; Hao, Kun

2017-07-01

Anthraquinones extract from Rheum palmatum L. (rhubarb) including rhein, emodin, aloe-emodin, chrysophanol, physcion and sennoside A, has been widely used in China to treat various diseases. This study was designed to explore the pharmacokinetic and pharmacodynamic properties of rhubarb anthraquinones extract in diabetic nephropathy and acute liver injury rats. The diabetic nephropathy and acute liver injury rats were induced by intraperitoneal injection with streptozotocin (STZ) and carbon tetrachloride (CCL 4 ), respectively. The rats were treated with different doses of rhubarb anthraquinones extract (37.5, 75 and 150mg/kg) as administration groups. For pharmacokinetics, the drug concentrations of rhubarb anthraquinones consisting of rhein, emodin, aloe-emodin, chrysophanol, physcion and sennoside A were determined. For pharmacodynamics, the anti-diabetic nephropathy and hepatoprotective effects were assessed under different dosage regimens. The rhein, emodin, aloe-emodin, chrysophanol were considered as pharmacokinetic markers at three doses of rhubarb anthraquinones extract. In diabetic nephropathy rats, no obvious pharmacokinetic change of the four ingredients was observed compared with control rats. However, the plasma exposures of the four ingredients increased in acute liver injury rats compared with control rats. The serum creatinine (SCr), blood urea nitrogen (BUN) and urine protein (UP) values in diabetic nephropathy rats decreased compared with those in the model group, which suggested that rhubarb anthraquinones extract displayed certain therapeutic and preventive effects against the diabetic nephropathy. However, rhubarb anthraquinones extract cannot ameliorate the CCL 4 -induced liver injury under the three different dosage regimens. There was no significant pharmacokinetic difference after a single oral administration of rhubarb anthraquinones extract between control and diabetic nephropathy rats. However, apparent pharmacokinetic differences were

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...

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.

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.

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.

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.

Preclinical pharmacokinetics, interspecies scaling, and pharmacokinetics of a Phase I clinical trial of TTAC-0001, a fully human monoclonal antibody against vascular endothelial growth factor 2

Directory of Open Access Journals (Sweden)

Lee WS

2018-03-01

Full Text Available Weon Sup Lee,1 Sang Ryeol Shim,1 Seon Young Lee,1 Jin San Yoo,1 Sung Kweon Cho2 1PharmAbcine, Inc., Daejeon, Republic of Korea; 2Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea Background: VEGF is a highly selective mitogen that serves as the central regulator of tumor angiogenesis by mediating endothelial proliferation, permeability, and survival. Tanibirumab (TTAC-0001 is a fully human IgG1 monoclonal antibody derived from a fully human naïve single-chain variable fragment (ScFv phage library that was developed to inhibit the effects of VEGF in the treatment of solid tumors, especially those of the brain. Methods: In the present study, we conducted intravenous pharmacokinetic studies of TTAC-0001 in mice, rats, and cynomolgus monkeys. At the doses studied (3 mg/kg, 10 mg/kg, 30 mg/kg, TTAC-0001 exhibited dose proportionality in mice and monkeys. At a dose of ~10 mg/kg, the clearance of TTAC-0001 from serum was 0.017 mL/h in mice, 0.35 mL/h in rats, and 2.19 mL/h in cynomolgus monkeys, and the terminal half-life ranged from 20–30 h among the three species. Pharmacokinetic data in mice, rats, and cynomolgus monkeys were used to predict the pharmacokinetics of TTAC-0001 in humans using allometric scaling. The predicted serum clearance of TTAC-0001 in humans was 102.45 mL/h and the terminal half-life was 27.52 h. Results: The maximum life span-corrected clearance value was 72.92 mL/h. The observed clearance in humans was more similar to the predicted scaled clearance. Conclusion: We investigated the pharmacokinetics of TTAC-0001 in mice, rats, and cynomolgus monkeys after intravenous administration. At the doses studied, TTAC-0001 exhibited dose proportionality in mice and monkeys. The scaled pharmacokinetics of TTAC-0001 reported here was useful for designing first-in-human studies. Allometric scaling in the therapeutic antibody is feasible. Keywords: VEGF2, tanibirumab, pharmacokinetics

Pharmacokinetics of labelled compounds with technetium-99m and samarium-153

International Nuclear Information System (INIS)

Borda O, L.B.; Torres L, M.N.

1997-01-01

The purpose of this investigation was to establish the different pharmacokinetics parameters of the main radiopharmaceuticals labeled with technetium-99m and samarium-153. These parameters could be subsequently used as reference to compare other products with the same use. Mathematical models and a computerized pharmacokinetic program were used to this purpose. A biodistribution study in quadruplicate and/or quintuplicate was conducted for each radiopharmaceutical, data was was obtained in injection dose percentages. The biodistribution study involved the injection of a predetermined dose of the radiopharmaceutical into animals (rats or mice), which were subsequently put away at different time intervals, removing the relevant organs. Activity in each organ was read by means of a well-type NaI scintillation counter, data obtained in activity counts was transformed into injection dose percentages. Based on these percentages, the mathematical model was constructed and the pharmacokinetic parameters were obtained using the computerized program Expo 2 v. 1, which is written in C language and works in windows. Analyzing the results obtained, we can conclude that the use of the Expo 2 v. 1 program for a bi compartmental analysis allowed us to obtain reliable pharmacokinetic parameters which describe what happens in the organism when the radiopharmaceutical passes from the central compartment to the peripheral one and vice versa

Effect of feeding on the pharmacokinetics of oral minocycline in healthy research dogs.

Science.gov (United States)

Hnot, Melanie L; Cole, Lynette K; Lorch, Gwendolen; Rajala-Schultz, Paivi J; Papich, Mark G

2015-12-01

The effect of food on minocycline oral absorption in dogs is unknown. The objective was to determine the pharmacokinetics of minocycline after administration of a single oral dose in fed and fasted dogs. Ten research hounds were administered oral minocycline (approximately 5 mg/kg) with and without food, in a crossover study, with a one-week wash-out between treatments. Blood samples were collected immediately prior to minocycline administration and over 24 h. Minocycline plasma drug concentrations were measured using high-performance liquid chromatography using ultraviolet detection and were analysed with compartmental modelling to determine primary pharmacokinetic parameters. Each dog was analysed independently, followed by calculation of means and variation of the dogs. The Wilcoxon signed-rank test [analysing secondary pharmacokinetic parameters - peak concentration (CMAX ), area under the concentration versus time curve (AUC)] was used to compare the two groups. A population pharmacokinetic modelling approach was performed using nonlinear mixed effects modelling of primary parameters for the population as fixed effects and the difference between subjects as a random effect. Covariate analysis was used to identify the source of variability in the population. No significant difference was found between treatments for AUC (P = 0.0645), although AUC was higher in fasted dogs. A significant difference was found for CMAX (P = 0.0059), with fasted dogs attaining a higher CMAX . The covariate of fed versus fasted accounted for a significant variation in the pharmacokinetics. Because feeding was a significant source of variation for the population's primary pharmacokinetic parameters and fasted dogs had higher minocycline concentrations, we recommend administering minocycline without food. © 2015 ESVD and ACVD.

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...

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.

Population pharmacokinetics of phenobarbital in infants with neonatal encephalopathy treated with therapeutic hypothermia.

Science.gov (United States)

Shellhaas, Renée A; Ng, Chee M; Dillon, Christina H; Barks, John D E; Bhatt-Mehta, Varsha

2013-02-01

Phenobarbital is the first-line treatment for neonatal seizures. Many neonates with hypoxic ischemic encephalopathy are treated with therapeutic hypothermia, and about 40% have clinical seizures. Little is known about the pharmacokinetics of phenobarbital in infants with hypoxic ischemic encephalopathy who undergo therapeutic hypothermia. The objective of this study was to determine the effect of therapeutic hypothermia on phenobarbital pharmacokinetics, taking into account maturational changes. Level 3 neonatal ICU. Infants with hypoxic ischemic encephalopathy and suspected seizures, all treated with phenobarbital. Some of these infants also received treatment with therapeutic hypothermia. None. A retrospective cohort study of 39 infants with hypoxic ischemic encephalopathy treated with phenobarbital (20 were treated with therapeutic hypothermia and 19 were not). Data on phenobarbital plasma concentrations were collected in 39 subjects with hypoxic ischemic encephalopathy with or without therapeutic hypothermia. Using nonlinear mixed-effects modeling, population pharmacokinetics of phenobarbital were developed with a total of 164 plasma concentrations. A one-compartment model best described the pharmacokinetics. The clearance of phenobarbital was linearly related to body weight and matured with increasing age with a maturation half-life of 22.1 days. Therapeutic hypothermia did not influence the pharmacokinetic parameters of phenobarbital. Therapeutic hypothermia does not influence the clearance of phenobarbital after accounting for weight and age. Standard phenobarbital dosing is appropriate for the initial treatment of seizures in neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia.

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.

Vascular input function correction of inflow enhancement for improved pharmacokinetic modeling of liver DCE-MRI.

Science.gov (United States)

Ning, Jia; Schubert, Tilman; Johnson, Kevin M; Roldán-Alzate, Alejandro; Chen, Huijun; Yuan, Chun; Reeder, Scott B

2018-06-01

To propose a simple method to correct vascular input function (VIF) due to inflow effects and to test whether the proposed method can provide more accurate VIFs for improved pharmacokinetic modeling. A spoiled gradient echo sequence-based inflow quantification and contrast agent concentration correction method was proposed. Simulations were conducted to illustrate improvement in the accuracy of VIF estimation and pharmacokinetic fitting. Animal studies with dynamic contrast-enhanced MR scans were conducted before, 1 week after, and 2 weeks after portal vein embolization (PVE) was performed in the left portal circulation of pigs. The proposed method was applied to correct the VIFs for model fitting. Pharmacokinetic parameters fitted using corrected and uncorrected VIFs were compared between different lobes and visits. Simulation results demonstrated that the proposed method can improve accuracy of VIF estimation and pharmacokinetic fitting. In animal study results, pharmacokinetic fitting using corrected VIFs demonstrated changes in perfusion consistent with changes expected after PVE, whereas the perfusion estimates derived by uncorrected VIFs showed no significant changes. The proposed correction method improves accuracy of VIFs and therefore provides more precise pharmacokinetic fitting. This method may be promising in improving the reliability of perfusion quantification. Magn Reson Med 79:3093-3102, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

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

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

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.

A quick review of carbamazepine pharmacokinetics in epilepsy from 1953 to 2012.

Science.gov (United States)

Tolou-Ghamari, Zahra; Zare, Mohammad; Habibabadi, Jafar Mehvari; Najafi, Mohammad Reza

2013-03-01

Carbamazepine has been used as AEDs since 1965, and is most effective against partial seizures. Two basic mechanisms of action have been proposed: 1) enhancement of sodium channel inactivation by reducing high-frequency repetitive firing of action potentials, 2) and action on synaptic transmission. The aim of this study was to provide a review of carbamazepine pharmacokinetics and its management guidelines in Iranian epileptic population. Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO), Web of Science were searched; 1600, 722 and 167 research and review articles relevant to the topics; carbamazepine pharmacokinetics, carbamazepine pharmacokinetics in epilepsy and review on carbamazepine pharmacokinetics in epilepsy were found, respectively. Carbamazepine is highly bound to plasma proteins. In patients the protein-bound fraction ranged from 75-80% of the total plasma concentration. Bioavailability ranges from 75-85%. The rate or extent of absorption was not be affected by food. It is completely metabolized and the main metabolite is carbamazepine-epoxide (CBZ-E). Carbamazepine induces its own metabolism, leading to increased clearance, shortened serum half-life, and progressive decrease in serum levels. Increases in daily dosage are necessary to maintain plasma concentration. Severe liver dysfunction may cause disordered pharmacokinetics. In cardiac failure, congestion of major vital organs, including kidneys, may result in abnormally slow absorption and metabolism. Carbamazepine shows variability due to its narrow therapeutic window. Therefore clinical management in a3n Iranian epileptic population should focus on results derived from therapeutic drug monitoring in order to reduce inter and intra- individual variability in plasma drug concentrations.

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-.

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...

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

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 ...

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

Population pharmacokinetics and dosing regimen design of milrinone in preterm infants

Science.gov (United States)

Paradisis, Mary; Jiang, Xuemin; McLachlan, Andrew J; Evans, Nick; Kluckow, Martin; Osborn, David

2007-01-01

Aims To define the pharmacokinetics of milrinone in very preterm infants and determine an optimal dose regimen to prevent low systemic blood flow in the first 12 h after birth. Methods A prospective open‐labelled, dose‐escalation pharmacokinetic study was undertaken in two stages. In stage one, infants received milrinone at 0.25 μg/kg/min (n = 8) and 0.5 μg/kg/min (n = 11) infused from 3 to 24 h of age. Infants contributed 4–5 blood samples for concentration–time data which were analysed using a population modelling approach. A simulation study was used to explore the optimal dosing regimen to achieve target milrinone concentrations (180–300 ng/ml). This milrinone regimen was evaluated in stage two (n = 10). Results Infants (n = 29) born before 29 weeks gestation were enrolled. Milrinone pharmacokinetics were described using a one‐compartment model with first‐order elimination rate, with a population mean clearance (CV%) of 35 ml/h (24%) and volume of distribution of 512 ml (21%) and estimated half‐life of 10 h. The 0.25 and 0.5 μg/kg/min dosage regimens did not achieve optimal milrinone concentration‐time profiles to prevent early low systemic blood flow. Simulation studies predicted a loading infusion (0.75 μg/kg/min for 3 h) followed by maintenance infusion (0.2 μg/kg/min until 18 h of age) would provide an optimal milrinone concentration profile. This was confirmed in stage two of the study. Conclusion Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology. PMID:16690639

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.

Population pharmacokinetics of dihydroartemisinin and piperaquine in pregnant and nonpregnant women with uncomplicated malaria.

Science.gov (United States)

Tarning, Joel; Rijken, Marcus J; McGready, Rose; Phyo, Aung Pyae; Hanpithakpong, Warunee; Day, Nicholas P J; White, Nicholas J; Nosten, François; Lindegardh, Niklas

2012-04-01

Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boarder were treated with a standard fixed oral 3-day treatment, and venous plasma concentrations of both drugs were measured frequently for pharmacokinetic evaluation. Population pharmacokinetics were evaluated with nonlinear mixed-effects modeling. The main pharmacokinetic finding was an unaltered total exposure to piperaquine but reduced exposure to dihydroartemisinin in pregnant compared to nonpregnant women with uncomplicated malaria. Piperaquine was best described by a three-compartment disposition model with a 45% higher elimination clearance and a 47% increase in relative bioavailability in pregnant women compared with nonpregnant women. The resulting net effect of pregnancy was an unaltered total exposure to piperaquine but a shorter terminal elimination half-life. Dihydroartemisinin was best described by a one-compartment disposition model with a 38% lower relative bioavailability in pregnant women than nonpregnant women. The resulting net effect of pregnancy was a decreased total exposure to dihydroartemisinin. The shorter terminal elimination half-life of piperaquine and lower exposure to dihydroartemisinin will shorten the posttreatment prophylactic effect and might affect cure rates. The clinical impact of these pharmacokinetic findings in pregnant women with uncomplicated malaria needs to be evaluated in larger series.

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.

Development of a physiologically based pharmacokinetic model for bisphenol A in pregnant mice

International Nuclear Information System (INIS)

Kawamoto, Yuko; Matsuyama, Wakoto; Wada, Masahiro; Hishikawa, Junko; Chan, Melissa Pui Ling; Nakayama, Aki; Morisawa, Shinsuke

2007-01-01

Bisphenol A (BPA) is a weakly estrogenic monomer used to produce polymers for food contact and other applications, so there is potential for oral exposure of humans to trace amounts via ingestion. To date, no physiologically based pharmacokinetic (PBPK) model has been located for BPA in pregnant mice with or without fetuses. An estimate by a mathematical model is essential since information on humans is difficult to obtain experimentally. The PBPK model was constructed based on the pharmacokinetic data of our experiment following single oral administration of BPA to pregnant mice. The risk assessment of bisphenol A (BPA) on the development of human offspring is an important issue. There have been limited data on the exposure level of human fetuses to BPA (e.g. BPA concentration in cord blood) and no information is available on the pharmacokinetics of BPA in humans with or without fetuses. In the present study, we developed a physiologically based pharmacokinetic (PBPK) model describing the pharmacokinetics of BPA in a pregnant mouse with the prospect of future extrapolation to humans. The PBPK model was constructed based on the pharmacokinetic data of an experiment we executed on pregnant mice following single oral administration of BPA. The model could describe the rapid transfer of BPA through the placenta to the fetus and the slow disappearance from fetuses. The simulated time courses after three-time repeated oral administrations of BPA by the constructed model fitted well with the experimental data, and the simulation for the 10 times lower dose was also consistent with the experiment. This suggested that the PBPK model for BPA in pregnant mice was successfully verified and is highly promising for extrapolation to humans who are expected to be exposed more chronically to lower doses

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

Pharmacokinetic evaluation of Shenfu Injection in beagle dogs after intravenous drip administration

Directory of Open Access Journals (Sweden)

Yuqiao Zhang

2016-10-01

Full Text Available Shenfu Injection (SFI is a well-defined Chinese herbal formulation that is obtained from red ginseng and processed aconite root. The main active constituents in SFI are ginsenosides and aconitum alkaloids. In this work, ginsenosides (ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rc and aconitum alkaloids (benzoylmesaconine and fuziline were used as the index components to explore the pharmacokinetic behavior of SFI. A selective and sensitive HPLC–MS/MS method was developed for the quantification of ginsenosides and aconitum alkaloids in dog plasma and was used to characterize the pharmacokinetics of the five index components after intravenous drip of three different dosages of SFI in beagle dogs. The pharmacokinetic properties of the index components were linear over the dose range of 2–8 mL/kg.

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.

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.

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.

Moxifloxacin pharmacokinetics and pleural fluid penetration in patients with pleural effusion.

Science.gov (United States)

Chatzika, Kalliopi; Manika, Katerina; Kontou, Paschalina; Pitsiou, Georgia; Papakosta, Despina; Zarogoulidis, Konstantinos; Kioumis, Ioannis

2014-01-01

The aim of this study was to evaluate the pharmacokinetics and penetration of moxifloxacin (MXF) in patients with various types of pleural effusion. Twelve patients with empyema/parapneumonic effusion (PPE) and 12 patients with malignant pleural effusion were enrolled in the study. A single-dose pharmacokinetic study was performed after intravenous administration of 400 mg MXF. Serial plasma (PL) and pleural fluid (PF) samples were collected during a 24-h time interval after drug administration. The MXF concentration in PL and PF was determined by high-performance liquid chromatography, and main pharmacokinetic parameters were estimated. Penetration of MXF in PF was determined by the ratio of the area under the concentration-time curve from time zero to 24 h (AUC24) in PF (AUC24PF) to the AUC24 in PL. No statistically significant differences in the pharmacokinetics in PL were observed between the two groups, despite the large interindividual variability in the volume of distribution, clearance, and elimination half-life. The maximum concentration in PF (CmaxPF) in patients with empyema/PPE was 2.23±1.31 mg/liter, and it was detected 7.50±2.39 h after the initiation of the infusion. In patients with malignant effusion, CmaxPF was 2.96±1.45 mg/liter, but it was observed significantly earlier, at 3.58±1.38 h (Ppleural effusion.

The effect of age on digoxin pharmacokinetics in Fischer-344 rats

International Nuclear Information System (INIS)

Evans, R.L.; Owens, S.M.; Ruch, S.; Kennedy, R.H.; Seifen, E.

1990-01-01

Digoxin protein binding and pharmacokinetics were studied in 4-, 14-, and 25-month-old male Fischer-344 rats to determine if there were age-dependent changes in digoxin disposition. Serum protein binding did not differ among age groups. The average percentage unbound digoxin for all animals was 61.3 ± 5.3% (means ± SD, n = 15). For pharmacokinetic studies, [ 3 H]digoxin and 1 mg/kg unlabeled digoxin were administered as an intravenous bolus dose to animals from each age group. The [ 3 H]digoxin terminal elimination half-life was 2.0, 2.3, and 2.5 hr, respectively. The steady-state volume of distribution in the three age groups was 1.51, 1.49, and 1.27 liters/kg, respectively. Total body clearance for the three age groups was 14.2, 12.1, and 7.5 ml/min/kg, respectively. Analysis of variance of these data followed by Duncan's multiple range test indicated a significant decrease in clearance in the aged rats (25-month-old, p less than 0.05). This age-dependent decrease in clearance suggested that digoxin pharmacokinetics could be a significant factor in age-related alterations in digoxin cardiotoxicity in the rat, as it is in humans, and that the Fischer-344 rat could be a useful model for studies of digoxin pharmacokinetic changes with age

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.

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.

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.

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...

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.

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.

The pharmacokinetics of L-tryptophan following its intravenous and oral administration.

OpenAIRE

Green, A R; Aronson, J K; Cowen, P J

1985-01-01

The pharmacokinetics of L-tryptophan (5 g and 7.5 g) have been studied after its intravenous administration to healthy subjects and the results compared with those obtained after oral administration (0.7 g-3.5 g). In order to do this, we have re-analysed previously published data relating to oral administration. The data obtained following the oral administration of L-tryptophan suggest that the total body clearance and apparent volume of distribution are saturable. The pharmacokinetics of tr...

Evaluation of pharmacokinetic model designs for subcutaneous infusion of insulin aspart

DEFF Research Database (Denmark)

Mansell, Erin J.; Schmidt, Signe; Docherty, Paul D.

2017-01-01

Effective mathematical modelling of continuous subcutaneous infusion pharmacokinetics should aid understanding and control in insulin therapy. Thorough analysis of candidate model performance is important for selecting the appropriate models. Eight candidate models for insulin pharmacokinetics...... included a range of modelled behaviours, parameters and complexity. The models were compared using clinical data from subjects with type 1 diabetes with continuous subcutaneous insulin infusion. Performance of the models was compared through several analyses: R2 for goodness of fit; the Akaike Information...

Research of pharmacokinetics of L-threonate calcium with 45Ca radiotrace

International Nuclear Information System (INIS)

Tong Jian; Niu Huisheng; Li Huaifen

2001-01-01

The pharmacokinetics of calcium in L-threonate calcium is studied by radiotrace method. The results show the relationship between drug-time curve, pharmacokinetics parameters and dosage are positive correlation, and calcium distributes in important tissues such as stomach, intestines, blood and bone. In 24 hours, about 40% calcium is drained in urine, 30% calcium is evacuated in feces, 10%-20% calcium deposit in blood or bone. The radiotrace method is a kind of special, sensitive, accurate method of testing calcium metabolism

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

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....

The Statistical Package for the Social Sciences (SPSS) as an adjunct to pharmacokinetic analysis.

Science.gov (United States)

Mather, L E; Austin, K L

1983-01-01

Computer techniques for numerical analysis are well known to pharmacokineticists. Powerful techniques for data file management have been developed by social scientists but have, in general, been ignored by pharmacokineticists because of their apparent lack of ability to interface with pharmacokinetic programs. Extensive use has been made of the Statistical Package for the Social Sciences (SPSS) for its data handling capabilities, but at the same time, techniques have been developed within SPSS to interface with pharmacokinetic programs of the users' choice and to carry out a variety of user-defined pharmacokinetic tasks within SPSS commands, apart from the expected variety of statistical tasks. Because it is based on a ubiquitous package, this methodology has all of the benefits of excellent documentation, interchangeability between different types and sizes of machines and true portability of techniques and data files. An example is given of the total management of a pharmacokinetic study previously reported in the literature by the authors.

Dose optimisation of antibiotics in children: application of pharmacokinetics/pharmacodynamics in paediatrics

OpenAIRE

Downes, Kevin J.; Hahn, Andrea; Wiles, Jason; Courter, Joshua D.; Vinks, Alexander A.

2013-01-01

The judicious use of antibiotics to combat infections in children relies upon appropriate selection of an agent, dose and duration to maximise efficacy and to minimise toxicity. Critical to dose optimisation is an understanding of the pharmacokinetics and pharmacodynamics of available drugs. Optimal dosing strategies may take advantage of pharmacokinetic/pharmacodynamic (PK/PD) principles so that antibiotic dosing can be individualised to assure effective bacterial killing in patients who hav...

[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.

Comparative Pharmacokinetics of Chlorpyrifos versus its Major Metabolites Following Oral Administration in the Rat

Energy Technology Data Exchange (ETDEWEB)

Busby-Hjerpe, Andrea L.; Campbell, James A.; Smith, Jordan N.; Lee, Sookwang; Poet, Torka S.; Barr, Dana; Timchalk, Charles

2010-01-31

Chlorpyrifos (CPF) is a commonly used diethylphosphorothionate organophosphorus (OP) insecticide. Diethylphosphate (DEP), diethylthiophosphate (DETP) and 3,5,6-trichloro-2-pyridinol (TCPy) are products of in vivo metabolism and environmental degradation of CPF and are routinely measured in urine as biomarkers of exposure. Hence, urinary biomonitoring of TCPy, DEP and DETP may be reflective of an individual’s contact with both the parent pesticide and exposure to these metabolites. In the current study, simultaneous dosing of 13C- or 2H- isotopically labeled CPF (13Clabeled CPF, 5 13C on the TCPy ring; or 2H-labeled CPF, diethyl-D10 (deuterium labeled) on the side chain) were exploited to directly compare the pharmacokinetics and metabolism of CPF with TCPy, and DETP. Individual metabolites were co-administered (oral gavage) with the parent compound at equal molar doses (14 μmol/kg; ~5mg/kg CPF). The key objective in the current study was to quantitatively evaluate the pharmacokinetics of the individual metabolites relative to their formation following a dose of CPF. Major differences in the pharmacokinetics between CPF and metabolites doses were observed within the first 3 h of exposure, due to the required metabolism of CPF to initially form TCPy and DETP. Nonetheless, once a substantial amount of CPF has been metabolized (≥ 3 h post-dosing) pharmacokinetics for both treatment groups and metabolites were very comparable. Urinary excretion rates for orally administered TCPy and DETP relative to 13C-CPF or 2H-CPF derived 13C-TCPy and 2H-DETP were consistent with blood pharmacokinetics, and the urinary clearance of metabolite dosed groups were comparable with the results for the 13C- and 2H-CPF groups. Since the pharmacokinetics of the individual metabolites were not modified by co-exposure to 3 CPF; it suggests that environmental exposure to low dose mixtures of pesticides and metabolites will not impact the pharmacokinetics of either.

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.

Effect of co-medication on the pharmacokinetic parameters of phenobarbital in asphyxiated newborns.

Science.gov (United States)

Šíma, M; Pokorná, P; Hronová, K; Slanař, O

2015-01-01

Phenobarbital is an anticonvulsive drug widely used in newborns with hypoxic-ischemic encephalopathy. The objective of our study was to describe possible effect of frequently co-administered medications (dopamine, dobutamine, norepinephrine, furosemide, phenytoin, and analgesics) on the phenobarbital pharmacokinetics in full term newborns with hypoxic-ischemic encephalopathy. Phenobarbital pharmacokinetic parameters (standardized intravenous loading dose was 10-20 mg/kg, maintenance dose 2-6 mg/kg/day) were computed using non-compartmental analysis. Co-medication was evaluated throughout the whole treatment period up to 5 days. Volume of distribution, clearance, and half-life median values (95 % CI) for phenobarbital in the whole study population (n=37) were 0.48 (0.41-0.56) l/kg, 0.0034 (0.0028-0.0040) l/h/kg, and 93.7 (88.1-99.2) h, respectively. Phenobarbital pharmacokinetic parameters were not significantly affected by vasoactive drugs (dopamine, dobutamine, and norepinephrine), furosemide, phenytoin, or analgesics. Furthermore, no dose-dependent alteration of phenobarbital pharmacokinetic parameters was noted for vasoactive medication at doses equivalent to cumulative vasoactive-inotropic score (area under the curve in a plot of vasoactive-inotropic score against time) 143.2-8473.6, furosemide at cumulative doses of 0.2-42.9 mg/kg, or phenytoin at cumulative doses of 10.3-46.2 mg/kg. Phenobarbital pharmacokinetics was not affected by investigated co-administered drugs used in newborns with hypoxic-ischemic encephalopathy in real clinical settings.

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

One should avoid retro-orbital pharmacokinetic sample collections for intranasal dosing in rats: Illustration of spurious pharmacokinetics generated for anti-migraine drugs zolmitriptan and eletriptan.

Science.gov (United States)

Patel, Harilal; Patel, Prakash; Modi, Nirav; Shah, Shaival; Ghoghari, Ashok; Variya, Bhavesh; Laddha, Ritu; Baradia, Dipesh; Dobaria, Nitin; Mehta, Pavak; Srinivas, Nuggehally R

2017-08-30

Because of the avoidance of first pass metabolic effects due to direct and rapid absorption with improved permeability, intranasal route represents a good alternative for extravascular drug administration. The aim of the study was to investigate the intranasal pharmacokinetics of two anti-migraine drugs (zolmitriptan and eletriptan), using retro-orbital sinus and jugular vein sites sampling. In a parallel study design, healthy male Sprague-Dawley (SD) rats aged between 8 and 12weeks were divided into groups (n=4 or 5/group). The animals of individual groups were dosed intranasal (~1.0mg/kg) and oral doses of 2.1mg/kg of either zolmitriptan or eletriptan. Serial blood sampling was performed from jugular vein or retro-orbital site and plasma samples were analyzed for drug concentrations using LC-MS/MS assay. Standard pharmacokinetics parameters such as T max , C max , AUC last , AUC 0-inf and T 1/2 were calculated and statistics of derived parameters was performed using unpaired t-test. After intranasal dosing, the mean pharmacokinetic parameters C max and AUC inf of zolmitriptan/eletriptan showed about 17-fold and 3-5-fold higher values for retro-orbital sampling as compared to the jugular vein sampling site. Whereas after oral administration such parameters derived for both drugs were largely comparable between the two sampling sites and statistically non-significant. In conclusion, the assessment of plasma levels after intranasal administration with retro-orbital sampling would result in spurious and misleading pharmacokinetics. Copyright © 2017 Elsevier B.V. All rights reserved.

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].

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…

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.

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

A Mathematical Model of the Effect of Immunogenicity on Therapeutic Protein Pharmacokinetics

OpenAIRE

Chen, Xiaoying; Hickling, Timothy; Kraynov, Eugenia; Kuang, Bing; Parng, Chuenlei; Vicini, Paolo

2013-01-01

A mathematical pharmacokinetic/anti-drug-antibody (PK/ADA) model was constructed for quantitatively assessing immunogenicity for therapeutic proteins. The model is inspired by traditional pharmacokinetic/pharmacodynamic (PK/PD) models, and is based on the observed impact of ADA on protein drug clearance. The hypothesis for this work is that altered drug PK contains information about the extent and timing of ADA generation. By fitting drug PK profiles while accounting for ADA-mediated drug cle...

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 ...

Concurrent administration of anticancer chemotherapy drug and herbal medicine on the perspective of pharmacokinetics

Directory of Open Access Journals (Sweden)

Yung-Yi Cheng

2018-04-01

Full Text Available With an increasing number of cancer patients seeking an improved quality of life, complementary and alternative therapies are becoming more common ways to achieve such improvements. The potential risks of concurrent administration are serious and must be addressed. However, comprehensive evidence for the risks and benefits of combining anticancer drugs with traditional herbs is rare. Pharmacokinetic investigations are an efficient way to understand the influence of concomitant remedies. Therefore, this study aimed to collect the results of pharmacokinetic studies relating to the concurrent use of cancer chemotherapy and complementary and alternative therapies. According to the National Health Insurance (NHI database in Taiwan and several publications, the three most commonly prescribed formulations for cancer patients are Xiang-Sha-Liu-Jun-Zi-Tang, Jia-Wei-Xiao-Yao-San and Bu-Zhong-Yi-Qi-Tang. The three most commonly prescribed single herbs for cancer patients are Hedyotis diffusa, Scutellaria barbata, and Astragalus membranaceus. Few studies have discussed herb–drug interactions involving these herbs from a pharmacokinetics perspective. Here, we reviewed Jia-Wei-Xiao-Yao-San, Long-Dan-Xie-Gan-Tang, Curcuma longa and milk thistle to provide information based on pharmacokinetic evidence for healthcare professionals to use in educating patients about the risks of the concomitant use of various remedies. Keywords: Traditional Chinese medicine, Chemotherapy drug, Pharmacokinetics, Herb–drug interaction

[Pharmacokinetic study of six aconitine alkaloids in aconiti lateralis radix praeparata in beagle dogs].

Science.gov (United States)

Xiao, Ri-Ping; Lai, Xiao-Ping; Zhao, Yai; Yu, Liang-Wen; Zhu, Yue-Lan; Li, Geng

2014-02-01

To study the pharmacokinetics characteristics of six Aconitum alkaloids aconitine (AC), mesaconitine (MA), hypaconitine (HA), benzoylaconine (BAC), benzoylmesaconine (BMA) and benzoylhypaconine (BHA) in beagle dogs. An ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for simultaneous quantitation of six Aconitum alkaloids in beagle dog plasma after oral administration of Aconiti Lateralis Radix Praeparata decoction. UPLC/MS/MS system coupled with an electrospray ionization (ESI) source was performed in multiple-reaction monitoring (MRM) mode. Sample preparation was performed with solid-phase extraction(SPE) on a 3 mL HLB cartridge before the analysis. The separation was applied on a Waters C8 column (100 mm x 2.1 mm, 1.7 microm) and a gradient elution of methanol and 0.2% formic acid-water was used as mobile phase. The pharmacokinetic parameters were calculated by the results of the analysis through the DAS 2. 1 software (Drug and Statistics for Windows). The results showed that the fitting model for the six Aconitum alkaloids was the one-compartment model pharmacokinetics. The method is successfully used for the pharmacokinetic evaluation of the six Aconitum alkaloids in beagle dog plasma, it can help monitor the ADME/Tox process when taking Aconiti Lateralis Radix Praeparata by observing the pharmacokinetic process. The results provide a good reference for clinical treatment and safe application of Aconiti Lateralis Radix Praeparata.

Pharmacokinetics and pharmacodynamics of SCT800, a new recombinant FVIII, in hemophilia A mice

Science.gov (United States)

Gu, Ruo-lan; Liu, Liang; Xie, Liang-zhi; Gai, Wen-lin; Cao, Si-shuo; Meng, Zhi-yun; Gan, Hui; Wu, Zhuo-na; Li, Jian; Zheng, Ying; Zhu, Xiao-xia; Dou, Gui-fang

2016-01-01

Aim: SCT800 is a new third-generation recombinant FVIII agent that is undergoing promising preclinical study. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles of SCT800 in hemophilia A mice. Methods: After hemophilia A mice were intravenously injected with single dose of SCT800 (80, 180, and 280 IU/kg) or the commercially available product Xyntha (280 IU/kg), pharmacokinetics profiles were evaluated based on measuring plasma FVIII: C. For pharmacodynamics study, dose-response curves of SCT800 and Xyntha (1–200 IU/kg) were constructed using a tail bleeding model monitoring both bleeding time and blood loss. Results: Pharmacokinetics profile analysis showed a dose independency of SCT800 ranging from 80 to 280 IU/kg and comparable pharmacokinetic profiles between SCT800 and Xyntha at the doses tested. Pharmacodynamics study revealed comparable ED50 values of SCT800 and Xyntha in the tail bleeding model: 14.78 and 15.81 IU/kg for bleeding time, respectively; 13.50 and 13.58 IU/kg for blood loss, respectively. Moreover, at the doses tested, the accompanying dose-related safety evaluation in the tail bleeding model showed lower hypercoagulable tendency and wider dosage range potential for SCT800 than Xyntha. Conclusion: In hemophilia A mice, SCT800 shows comparable pharmacokinetics and pharmacodynamics to Xyntha at the doses tested, and possibly with better safety properties. PMID:26806305

Population pharmacokinetics of tamsulosin hydrochloride in paediatric patients with neuropathic and non-neuropathic bladder

Science.gov (United States)

Tsuda, Yasuhiro; Tatami, Shinji; Yamamura, Norio; Tadayasu, Yusuke; Sarashina, Akiko; Liesenfeld, Karl-Heinz; Staab, Alexander; Schäfer, Hans-Günter; Ieiri, Ichiro; Higuchi, Shun

2010-01-01

AIMS The main objective of this study was to characterize the population pharmacokinetics of tamsulosin hydrochloride (HCl) in paediatric patients with neuropathic and non-neuropathic bladder. A secondary objective was to compare the pharmacokinetics in paediatric patients and adults. METHODS Tamsulosin HCl plasma concentrations in 1082 plasma samples from 189 paediatric patients (age range 2–16 years) were analyzed with NONMEM, applying a one compartment model with first-order absorption. Based on the principles of allometry, body weight was incorporated in the base model, along with fixed allometric exponents. Covariate analysis was performed by means of a stepwise forward inclusion and backward elimination procedure. Simulations based on the final model were used to compare the pharmacokinetics with those in adults. RESULTS Beside the priori-implemented body weight, only α1-acid glycoprotein had an effect on both apparent clearance and apparent volume of distribution. No other investigated covariates, including gender, age, race, patient population and concomitant therapy with anti-cholinergics, significantly affected the pharmacokinetics of tamsulosin HCl (P tamsulosin HCl in paediatric patients was established and it described the data well. There was no major difference in the pharmacokinetics of tamsulosin HCl between paediatric patients (age range 2–16 years) and adults when the effect of body weight was taken into consideration. PMID:20642551

Population pharmacokinetics and pharmacodynamics of linezolid-induced thrombocytopenia in hospitalized patients.

Science.gov (United States)

Tsuji, Yasuhiro; Holford, Nicholas H G; Kasai, Hidefumi; Ogami, Chika; Heo, Young-A; Higashi, Yoshitsugu; Mizoguchi, Akiko; To, Hideto; Yamamoto, Yoshihiro

2017-08-01

Thrombocytopenia is among the most important adverse effects of linezolid treatment. Linezolid-induced thrombocytopenia incidence varies considerably but has been associated with impaired renal function. We investigated the pharmacodynamic mechanism (myelosuppression or enhanced platelet destruction) and the role of impaired renal function (RF) in the development of thrombocytopenia. The pharmacokinetics of linezolid were described with a two-compartment distribution model with first-order absorption and elimination. RF was calculated using the expected creatinine clearance. The decrease platelets by linezolid exposure was assumed to occur by one of two mechanisms: inhibition of the formation of platelets (PDI) or stimulation of the elimination (PDS) of platelets. About 50% of elimination was found to be explained by renal clearance (normal RF). The population mean estimated plasma protein binding of linezolid was 18% [95% confidence interval (CI) 16%, 20%] and was independent of the observed concentrations. The estimated mixture model fraction of patients with a platelet count decreased due to PDI was 0.97 (95% CI 0.87, 1.00), so the fraction due to PDS was 0.03. RF had no influence on linezolid pharmacodynamics. We have described the influence of weight, renal function, age and plasma protein binding on the pharmacokinetics of linezolid. This combined pharmacokinetic, pharmacodynamic and turnover model identified that the most common mechanism of thrombocytopenia associated with linezolid is PDI. Impaired RF increases thrombocytopenia by a pharmacokinetic mechanism. The linezolid dose should be reduced in RF. © 2017 The British Pharmacological Society.

The Pharmacokinetics of Second-Generation Long-Acting Injectable Antipsychotics: Limitations of Monograph Values.

Science.gov (United States)

Lee, Lik Hang N; Choi, Charles; Collier, Abby C; Barr, Alasdair M; Honer, William G; Procyshyn, Ric M

2015-12-01

Product monographs (also known by terms such as Summary of Product Characteristics and Highlights of Prescribing Information, depending on the jurisdiction) provide essential information to ensure the safe and effective use of a drug. Medical practitioners often rely on these monographs for guidance on matters related to pharmacokinetics as well as indications, contraindications, clinical pharmacology, and adverse reactions. The clinical and scientific information found within these documents, forming the basis for decision making, are presumed to be derived from well-designed studies. The objective of this review is to examine the source and validity of the pharmacokinetic data used in establishing the half-lives and times to steady-state reported in the product monographs of second-generation long-acting injectable antipsychotics. Thus, we have critically evaluated the clinical trials from which the pharmacokinetic parameters listed in the product monographs were determined. In many cases, the pharmacokinetic information presented in product monographs is of limited use to clinicians wishing to optimize the effectiveness and tolerability of second-generation long-acting injectable antipsychotics. Under such circumstances, off-label prescribing practices may actually produce better clinical outcomes than if decisions were made based on the product monographs alone.

Do nitrates differ?

Science.gov (United States)

Fung, H.-L.

1992-01-01

1 The organic nitrates all share a common biochemical and physiological mechanism of action. 2 The organic nitrates differ substantially in their pharmacologic potency and pharmacokinetics. In vitro potency differences appear larger than the corresponding in vivo activities. 3 The duration of action of organic nitrates, after a single immediate-release dose, is governed by the pharmacokinetics of the drug. However, the duration of action of available sustained-release preparations, whatever the nitrate or formulation, is limited to about 12 h, due to the development of pharmacologic tolerance. 4 Nitrates do not appear to differ in their production of undesirable effects. PMID:1633079

Pharmacokinetics and pharmacodynamics study of rhein treating renal fibrosis based on metabonomics approach.

Science.gov (United States)

Sun, Hao; Luo, Guangwen; Xiang, Zheng; Cai, Xiaojun; Chen, Dahui

2016-12-01

The selection of effect indicators in the pharmacokinetic/ pharmacodynamic study of complex diseases to describe the relationship between plasma concentration and effect indicators is difficult. Three effect indicators of renal fibrosis were successfully determined. The relationship between pharmacokinetics and pharmacodynamics of rhein in rhubarb was elucidated. The study was a metabolomics analysis of rat plasma and pharmacokinetics/ pharmacodynamics of rhein. A sensitive and simple ultra performance liquid chromatography-tandem triple quadrupole mass spectrometry (UPLC-MS/MS) method was applied to determine the rhein plasma concentration in the rat model of renal fibrosis and rat sham-operated group after the administration of rhubarb decoction. Then, the ultra performance liquid chromatography-Micromass quadrupole-time of flight mass spectrometry (UPLC-QTOF/MS) metabolomics method was used to screen biomarkers of renal fibrosis in rat plasma. Furthermore, the relationship between the plasma concentration of rhein and the concentration of three biomarkers directly related to renal fibrosis were analyzed. The three screened biomarkers could represent the effect of rhein treatment on renal fibrosis. Increasing the plasma concentration of rhein tended to restore the concentration of the three biomarkers in the model group compared with that in the sham-operated group. Evident differences in the area under the plasma concentration-time curve (AUC) of rhein were also observed under different pathological states. The results provide valuable information for the clinical application of rhubarb. Rhein intervention could recover the physiological balance in living organisms from the pharmacokinetic/pharmacodynamic levels. New information on the pharmacokinetic/pharmacodynamic study of complex diseases is provided. Copyright © 2016 Elsevier GmbH. All rights reserved.

Human plasma concentrations of tolbutamide and acetaminophen extrapolated from in vivo animal pharmacokinetics using in vitro human hepatic clearances and simple physiologically based pharmacokinetic modeling for radio-labeled microdose clinical studies

International Nuclear Information System (INIS)

Yamazaki, Hiroshi; Kunikane, Eriko; Nishiyama, Sayako; Murayama, Norie; Shimizu, Makiko; Sugiyama, Yuichi; Chiba, Koji; Ikeda, Toshihiko

2015-01-01

The aim of the current study was to extrapolate the pharmacokinetics of drug substances orally administered in humans from rat pharmacokinetic data using tolbutamide and acetaminophen as model compounds. Adjusted animal biomonitoring equivalents from rat studies based on reported plasma concentrations were scaled to human biomonitoring equivalents using known species allometric scaling factors. In this extrapolation, in vitro metabolic clearance data were obtained using liver preparations. Rates of tolbutamide elimination were roughly similar in rat and human liver microsome experiments, but acetaminophen elimination by rat liver microsomes and cytosolic preparations showed a tendency to be faster than those in humans. Using a simple physiologically based pharmacokinetic (PBPK) model, estimated human plasma concentrations of tolbutamide and acetaminophen were consistent with reported concentrations. Tolbutamide cleared in a roughly similar manner in humans and rats, but medical-dose levels of acetaminophen cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in rats. The data presented here illustrate how pharmacokinetic data in combination with a simple PBPK model can be used to assist evaluations of the pharmacological/toxicological potential of new drug substances and for estimating human radiation exposures from radio-labeled drugs when planning human studies. (author)

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.

Pharmacokinetic and pharmacogenomic profiles of telmisartan after the oral microdose and therapeutic dose.

Science.gov (United States)

Ieiri, Ichiro; Nishimura, Chisa; Maeda, Kazuya; Sasaki, Tomohiro; Kimura, Miyuki; Chiyoda, Takeshi; Hirota, Tekeshi; Irie, Shin; Shimizu, Hitoshi; Noguchi, Takanori; Yoshida, Kenji; Sugiyama, Yuichi

2011-08-01

In this study, we evaluated (a) the contribution of SLCO1B3 and UGT1A polymorphisms to the pharmacokinetics of telmisartan in two forms, a microdose (MD) and a therapeutic dose (TD); (b) linkage disequilibrium (LD) between UGT1A1 and UGT1A3; and (c) linearity in the pharmacokinetics of telmisartan between the two forms. Telmisartan was orally administered at MD condition (100 μg), and then at TD condition (80 mg) to 33 healthy volunteers whose genotypes were prescreened by DMET Plus. Plasma concentrations of telmisartan and its glucuronide were measured by LC-MS/MS, and population pharmacokinetic analysis was performed. No obvious effect of SLCO1B3 polymorphisms (334T>G, 699G>A, and rs11045585) on the pharmacokinetics of telmisartan was observed. The strong LD between UGT1A1*6 and UGT1A3*4a, and between UGT1A1*28 and UGT1A3*2a were observed. After both MD and TD administration, the mean area under the curve0-24 (±standard deviation) of telmisartan was significantly lower and higher in individuals with the UGT1A3*2a (TD, 1701±970 ng hr/ml; MD, 978±537 pg hr/ml) and *4a variants (TD, 5340±1168; MD, 3145±1093), respectively, compared with those in individuals with UGT1A3*1/*1 (TD, 2969±1456; MD, 1669±726). These results were quantitatively confirmed by population pharmacokinetic analysis. Nonlinearity of the dose-exposure relationship was observed between the MD and TD. The haplotypes of UGT1A3 significantly influenced pharmacokinetics of telmisartan and a strong LD between UGT1A1 genotype and UGT1A3 haplotype was observed. These findings are potentially of pharmacological and toxicological importance to the development and clinical use of drugs.

The influence of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite.

Science.gov (United States)

Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Chira, Ruxandra; Briciu, Corina

2015-01-01

To evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers. 22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20-40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period. Paroxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively. Multiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide.

Pharmacokinetics and Pharmacodynamics of Lisdexamfetamine Compared with D-Amphetamine in Healthy Subjects

Directory of Open Access Journals (Sweden)

Patrick C. Dolder

2017-09-01

Full Text Available Rationale: Lisdexamfetamine is a prodrug of D-amphetamine used for the treatment of attention-deficit/hyperactivity disorder (ADHD. Lisdexamfetamine is thought to have a prolonged pharmacokinetic profile compared with oral D-amphetamine, possibly associated with lower drug liking and a lower risk of oral misuse. However, differences in the pharmacokinetics and pharmacodynamics of lisdexamfetamine and D-amphetamine have not been directly compared.Methods: Equimolar doses of D-amphetamine (40 mg and lisdexamfetamine (100 mg, and placebo were administered in 24 healthy subjects in a randomized, double-blind, placebo-controlled, cross-over study. Plasma concentrations of amphetamine, subjective effects, and vital signs were repeatedly assessed. The pharmacokinetic parameters were determined using compartmental modeling.Results: The increase in plasma concentrations of amphetamine had a 0.6 ± 0.6 h (mean ± SD longer lag time and reached peak levels 1.1 ± 1.5 h later after lisdexamfetamine administration compared with D-amphetamine administration, but no differences in maximal concentrations or total exposure (AUC were found between the two treatments. Consistent with the pharmacokinetics, the subjective and cardiovascular stimulant effects of lisdexamfetamine also occurred later compared with D-amphetamine. However, no differences in peak ratings of potentially abuse-related subjective drug effects (e.g., drug liking, drug high, stimulation, happy, well-being, and self-confidence were observed after lisdexamfetamine administration compared with D-amphetamine administration. Lisdexamfetamine and D-amphetamine also produced similar peak increases in mean arterial blood pressure, heart rate, body temperature, pupil size, and adverse effects.Conclusion: The pharmacokinetics and pharmacodynamics of lisdexamfetamine are similar to D-amphetamine administered 1h later. Lisdexamfetamine is likely associated with a similar risk of oral abuse as D

Cardiopulmonary bypass alters the pharmacokinetics of propranolol in patients undergoing cardiac surgery

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M.J.C. Carmona

2005-05-01

Full Text Available The pharmacokinetics of propranolol may be altered by hypothermic cardiopulmonary bypass (CPB, resulting in unpredictable postoperative hemodynamic responses to usual doses. The objective of the present study was to investigate the pharmacokinetics of propranolol in patients undergoing coronary artery bypass grafting (CABG by CPB under moderate hypothermia. We evaluated 11 patients, 4 women and 7 men (mean age 57 ± 8 years, mean weight 75.4 ± 11.9 kg and mean body surface area 1.83 ± 0.19 m², receiving propranolol before surgery (80-240 mg a day and postoperatively (10 mg a day. Plasma propranolol levels were measured before and after CPB by high-performance liquid chromatography. Pharmacokinetic Solutions 2.0 software was used to estimate the pharmacokinetic parameters after administration of the drug pre- and postoperatively. There was an increase of biological half-life from 4.5 (95% CI = 3.9-6.9 to 10.6 h (95% CI = 8.2-14.7; P < 0.01 and an increase in volume of distribution from 4.9 (95% CI = 3.2-14.3 to 8.3 l/kg (95% CI = 6.5-32.1; P < 0.05, while total clearance remained unchanged 9.2 (95% CI = 7.7-24.6 vs 10.7 ml min-1 kg-1 (95% CI = 7.7-26.6; NS after surgery. In conclusion, increases in drug distribution could be explained in part by hemodilution during CPB. On the other hand, the increase of biological half-life can be attributed to changes in hepatic metabolism induced by CPB under moderate hypothermia. These alterations in the pharmacokinetics of propranolol after CABG with hypothermic CPB might induce a greater myocardial depression in response to propranolol than would be expected with an equivalent dose during the postoperative period.

Pharmacokinetic drug-drug interaction and their implication in clinical management.

Science.gov (United States)

Palleria, Caterina; Di Paolo, Antonello; Giofrè, Chiara; Caglioti, Chiara; Leuzzi, Giacomo; Siniscalchi, Antonio; De Sarro, Giovambattista; Gallelli, Luca

2013-07-01

Drug-drug interactions (DDIs) are one of the commonest causes of medication error in developed countries, particularly in the elderly due to poly-therapy, with a prevalence of 20-40%. In particular, poly-therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic. In this review, using Medline, PubMed, Embase, Cochrane library and Reference lists we searched articles published until June 30 2012, and we described the mechanism of pharmacokinetic DDIs focusing the interest on their clinical implications.

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

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

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.

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

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

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...

Determination and pharmacokinetic study of catechin in rat plasma by HPLC

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Li Xie

2011-11-01

Full Text Available A high performance liquid chromatographic method was developed and validated for the quantitative determination of catechin in rat plasma and its pharmacokinetic study after intragastric administration of Catechu and Xiongdanjiangre Wan into SD rats. Plasma samples were prepared by protein precipitation using methanol–5% aqueous zinc sulfate (70:30, v/v as precipitant. Chromatographic separation was achieved on Hypersil C18 column (250 mm×4.6 mm, 10 μm with acetonitrile–water–triethylamine (6:94:0.3, v/v/v, pH 4.0±0.1, adjusted with phosphoric acid as mobile phase, followed by a UV detection at 207 nm. Good linearity was obtained over the range of 0.143–7.15 mg/L of catechin, with correlation coefficient of 0.9992. The method was simple, sensitive, accurate and reproducible and has been successfully applied to the pharmacokinetic study of catechin in rat plasma. Keywords: HPLC, Determination, Pharmacokinetic, Catechin, Rat, Plasma

CARVEDILOL POPULATION PHARMACOKINETIC ANALYSIS – APPLIED VALIDATION PROCEDURE

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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

Population pharmacokinetics of buprenorphine following a two-stage intravenous infusion in healthy volunteers

DEFF Research Database (Denmark)

Jensen, Mette Lykke; Foster, David J.R.; Upton, Richard N.

2007-01-01

The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only.......The aim of this investigation was to characterize the pharmacokinetics of buprenorphine following administration of an intravenous (i.v.) infusion. To date, the population kinetics of buprenorphine has been described for bolus administration only....

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.

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 ...

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.

Cannabinoid Disposition After Human Intraperitoneal Use: An Insight Into Intraperitoneal Pharmacokinetic Properties in Metastatic Cancer.

Science.gov (United States)

Lucas, Catherine J; Galettis, Peter; Song, Shuzhen; Solowij, Nadia; Reuter, Stephanie E; Schneider, Jennifer; Martin, Jennifer H

2018-01-06

Medicinal cannabis is prescribed under the provision of a controlled drug in the Australian Poisons Standard. However, multiple laws must be navigated in order for patients to obtain access and imported products can be expensive. Dose-response information for both efficacy and toxicity pertaining to medicinal cannabis is lacking. The pharmacokinetic properties of cannabis administered by traditional routes has been described but to date, there is no literature on the pharmacokinetic properties of an intraperitoneal cannabinoid emulsion. A cachectic 56-year-old female with stage IV ovarian cancer and peritoneal metastases presented to hospital with fevers, abdominal distension and severe pain, vomiting, anorexia, dehydration and confusion. The patient reported receiving an intraperitoneal injection, purported to contain 12 g of mixed cannabinoid (administered by a deregistered medical practitioner) two days prior to presentation. Additionally, cannabis oil oral capsules were administered in the hours prior to hospital admission. THC concentrations were consistent with the clinical state but not with the known pharmacokinetic properties of cannabis nor of intraperitoneal absorption. THC concentrations at the time of presentation were predicted to be ~60 ng/mL. Evidence suggests that blood THC concentrations >5 ng/mL are associated with substantial cognitive and psychomotor impairment. The predicted time for concentrations to drop <5 ng/mL was 49 days after administration. The unusual pharmacokinetic properties of the case suggest that there is a large amount unknown about cannabis pharmacokinetic properties. The pharmacokinetic properties of a large amount of a lipid soluble compound given intraperitoneally gave insights into the absorption and distribution of cannabinoids, particularly in the setting of metastatic malignancy. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

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.

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.

Comparative Pharmacokinetics Study of Icariin and Icariside II in Rats

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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.

[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.

PHARMACOKINETICS OF DICLOFENAC SODIUM AND PAPAVERINE HYDROCHLORIDE AFTER ORAL ADMINISTRATION OF TABLETS TO RABBITS.

Science.gov (United States)

Kasperek, Regina; Zimmer, Łukasz; Jawień, Wojciech; Poleszak, Ewa

2015-01-01

Non-compartmental pharmacokinetic analysis of diclofenac sodium (DIC) and papaverine hydrochloride (PAP) after oral administration of composed tablets to rabbits was developed. HPLC method for determination of DIC and PAP in rabbit plasma was developed and validated. Chromatographic separation of DIC, PAP and the IS was achieved on a Zorbax SB C18 5-µm column (150 mm x 4.6 mm) using methanol-water (55:45, v/v) as mobile phase at a flow rate of 0.8 mL/min. Pharmacokinetic analysis showed that oral administration of a tablet composed of DIC and PAP do not change the pharmacokinetic parameters such as MRT, MAT, Cl and bioavailability of the active substances compared with single administration of DIC and PAP after single dose.

Pharmacokinetics of drugs in cachectic patients: a systematic review.

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Katja Trobec

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

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...

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

Pharmacokinetic drug-drug interaction and their implication in clinical management

Directory of Open Access Journals (Sweden)

Palleria Caterina

2013-01-01

Full Text Available Drug-drug interactions (DDIs are one of the commonest causes of medication error in developed countries, particularly in the elderly due to poly-therapy, with a prevalence of 20-40%. In particular, poly-therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic. In this review, using Medline, PubMed, Embase, Cochrane library and Reference lists we searched articles published until June 30 2012, and we described the mechanism of pharmacokinetic DDIs focusing the interest on their clinical implications.

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

Influence of Differing Analgesic Formulations of Aspirin on Pharmacokinetic Parameters

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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.

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.

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.

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.

Dynamic Contrast-enhanced MR Imaging in Renal Cell Carcinoma: Reproducibility of Histogram Analysis on Pharmacokinetic Parameters

Science.gov (United States)

Wang, Hai-yi; Su, Zi-hua; Xu, Xiao; Sun, Zhi-peng; Duan, Fei-xue; Song, Yuan-yuan; Li, Lu; Wang, Ying-wei; Ma, Xin; Guo, Ai-tao; Ma, Lin; Ye, Hui-yi

2016-01-01

Pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) have been increasingly used to evaluate the permeability of tumor vessel. Histogram metrics are a recognized promising method of quantitative MR imaging that has been recently introduced in analysis of DCE-MRI pharmacokinetic parameters in oncology due to tumor heterogeneity. In this study, 21 patients with renal cell carcinoma (RCC) underwent paired DCE-MRI studies on a 3.0 T MR system. Extended Tofts model and population-based arterial input function were used to calculate kinetic parameters of RCC tumors. Mean value and histogram metrics (Mode, Skewness and Kurtosis) of each pharmacokinetic parameter were generated automatically using ImageJ software. Intra- and inter-observer reproducibility and scan–rescan reproducibility were evaluated using intra-class correlation coefficients (ICCs) and coefficient of variation (CoV). Our results demonstrated that the histogram method (Mode, Skewness and Kurtosis) was not superior to the conventional Mean value method in reproducibility evaluation on DCE-MRI pharmacokinetic parameters (K trans & Ve) in renal cell carcinoma, especially for Skewness and Kurtosis which showed lower intra-, inter-observer and scan-rescan reproducibility than Mean value. Our findings suggest that additional studies are necessary before wide incorporation of histogram metrics in quantitative analysis of DCE-MRI pharmacokinetic parameters. PMID:27380733

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

A clinical pharmacokinetic microdosing study of docetaxel with Japanese patients with cancer.

Science.gov (United States)

Fujita, Ken-ichi; Yoshino, Etsuko; Kawara, Kaori; Maeda, Kazuya; Kusuhara, Hiroyuki; Sugiyama, Yuichi; Yokoyama, Taro; Kaneta, Toshikado; Ishida, Hiroo; Sasaki, Yasutsuna

2015-10-01

Whether microdosing studies can be used to evaluate the human pharmacokinetics of new anticancer drugs remains unclear. The disposition of docetaxel in cancer patients is linear in terms of dose proportionality. We examined whether the pharmacokinetics of docetaxel in a clinically relevant therapeutic dose could be predicted from the pharmacokinetics of a microdose of docetaxel in Japanese patients with cancer. A microdose of docetaxel (100 μg/patient) was given by 5-min intravenous infusion on day 1, followed by a therapeutic dose of docetaxel (60-75 mg m(-2)), given by 1-h intravenous infusion on day 8. Plasma docetaxel was analyzed by liquid chromatography-tandem mass spectrometry. A two-compartment pharmacokinetic model was used to calculate the area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf). Nine patients received both a microdose and therapeutic dose of docetaxel. The AUC0-inf after microdosing was 3640 ± 1150 ng h L(-1), while that after therapeutic dosing adjusted to 100 mg/patient was 2230 ± 757 µg h L(-1). The ratio of docetaxel clearance in therapeutic dose to that in microdose was 1.8 (P = 0.0041). Plasma α1-acid glycoprotein concentrations negatively correlated with docetaxel clearance at therapeutic dose, whereas the trend was weak at microdose. Docetaxel clearance showed marginal nonlinearity between microdose and therapeutic dose, presumably because of saturation of plasma protein binding; however, the magnitude was within twofold, allowing practically acceptable extrapolation.

Docetaxel-loaded PLGA and PLGA-PEG nanoparticles for intravenous application: pharmacokinetics and biodistribution profile.

Science.gov (United States)

Rafiei, Pedram; Haddadi, Azita

2017-01-01

Docetaxel is a highly potent anticancer agent being used in a wide spectrum of cancer types. There are important matters of concern regarding the drug's pharmacokinetics related to the conventional formulation. Poly(lactide- co -glycolide) (PLGA) is a biocompatible/biodegradable polymer with variable physicochemical characteristics, and its application in human has been approved by the United States Food and Drug Administration. PLGA gives polymeric nanoparticles with unique drug delivery characteristics. The application of PLGA nanoparticles (NPs) as intravenous (IV) sustained-release delivery vehicles for docetaxel can favorably modify pharmacokinetics, biofate, and pharmacotherapy of the drug in cancer patients. Surface modification of PLGA NPs with poly(ethylene glycol) (PEG) can further enhance NPs' long-circulating properties. Herein, an optimized fabrication approach has been used for the preparation of PLGA and PLGA-PEG NPs loaded with docetaxel for IV application. Both types of NP formulations demonstrated in vitro characteristics that were considered suitable for IV administration (with long-circulating sustained-release purposes). NP formulations were IV administered to an animal model, and docetaxel's pharmacokinetic and biodistribution profiles were determined and compared between study groups. PLGA and PEGylated PLGA NPs were able to modify the pharmacokinetics and biodistribution of docetaxel. Accordingly, the mode of changes made to pharmacokinetics and biodistribution of docetaxel is attributed to the size and surface properties of NPs. NPs contributed to increased blood residence time of docetaxel fulfilling their role as long-circulating sustained-release drug delivery systems. Surface modification of NPs contributed to more pronounced docetaxel blood concentration, which confirms the role of PEG in conferring long-circulation properties to NPs.

Incorporating pharmacokinetic differences between children and adults in assessing children's risks to environmental toxicants

International Nuclear Information System (INIS)

Ginsberg, Gary; Hattis, Dale; Sonawane, Babasaheb

2004-01-01

Children's risks from environmental toxicant exposure can be affected by pharmacokinetic factors that affect the internal dose of parent chemical or active metabolite. There are numerous physiologic differences between neonates and adults that affect pharmacokinetics including size of lipid, and tissue compartments, organ blood flows, protein binding capacity, and immature function of renal and hepatic systems. These factors combine to decrease the clearance of many therapeutic drugs, which can also be expected to occur with environmental toxicants in neonates. The net effect may be greater or lesser internal dose of active toxicant depending upon how the agent is distributed, metabolized, and eliminated. Child/adult pharmacokinetic differences decrease with increasing postnatal age, but these factors should still be considered in any children's age group, birth through adolescence, for which there is toxicant exposure. Physiologically based pharmacokinetic (PBPK) models can simulate the absorption, distribution, metabolism, and excretion of xenobiotics in both children and adults, allowing for a direct comparison of internal dose and risk across age groups. This review provides special focus on the development of hepatic cytochrome P-450 enzymes (CYPs) in early life and how this information, along with many factors unique to children, can be applied to PBPK models for this receptor population. This review describes a case study involving the development of neonatal PBPK models for the CYP1A2 substrates caffeine and theophylline. These models were calibrated with pharmacokinetic data in neonates and used to help understand key metabolic differences between neonates and adults across these two drugs

Influence of covariate distribution on the predictive performance of pharmacokinetic models in paediatric research

Science.gov (United States)

Piana, Chiara; Danhof, Meindert; Della Pasqua, Oscar

2014-01-01

Aims The accuracy of model-based predictions often reported in paediatric research has not been thoroughly characterized. The aim of this exercise is therefore to evaluate the role of covariate distributions when a pharmacokinetic model is used for simulation purposes. Methods Plasma concentrations of a hypothetical drug were simulated in a paediatric population using a pharmacokinetic model in which body weight was correlated with clearance and volume of distribution. Two subgroups of children were then selected from the overall population according to a typical study design, in which pre-specified body weight ranges (10–15 kg and 30–40 kg) were used as inclusion criteria. The simulated data sets were then analyzed using non-linear mixed effects modelling. Model performance was assessed by comparing the accuracy of AUC predictions obtained for each subgroup, based on the model derived from the overall population and by extrapolation of the model parameters across subgroups. Results Our findings show that systemic exposure as well as pharmacokinetic parameters cannot be accurately predicted from the pharmacokinetic model obtained from a population with a different covariate range from the one explored during model building. Predictions were accurate only when a model was used for prediction in a subgroup of the initial population. Conclusions In contrast to current practice, the use of pharmacokinetic modelling in children should be limited to interpolations within the range of values observed during model building. Furthermore, the covariate point estimate must be kept in the model even when predictions refer to a subset different from the original population. PMID:24433411

Clinical pharmacokinetics and effects of vincristine sulfate in dogs with transmissible venereal tumor (TVT).

Science.gov (United States)

Hantrakul, Supannika; Klangkaew, Narumol; Kunakornsawat, Sunee; Tansatit, Tawewan; Poapolathep, Ammart; Kumagai, Susumu; Poapolathep, Saranya

2014-12-01

This study was conducted to evaluate the pharmacokinetic characteristics of vincristine and their correlation with its clinical effects in dogs with transmissible venereal tumor (TVT). Dogs with TVT were intravenously administered vincristine sulfate at a dose of 0.7 mg/m(2) of body surface area. Blood samples were collected starting from 5 min to 48 hr after drug administration. The plasma concentration of vincristine was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of vincristine were characterized using a two-compartmental pharmacokinetic model. The volume of distribution, distribution half-life, elimination half-life and plasma clearance were 0.660 ± 0.210 l/kg, 21.5 ± 6.90 min, 47.6 ± 14.2 min and 0.010 ± 0.001 l/min/kg, respectively. Tumor regression was determined at weekly interval by a physical examination and histopathological analysis. In our study, three to eight administrations of vincristine at a dose of 0.7 mg/m(2) were able to induce a complete tumor regression without any evidence of gross lesion of disease. Therefore, this investigation provides the pharmacokinetic characteristics of vincristine in dogs with TVT, which may be used as an integration tool to gain a better understanding of the disposition properties of the drug and the correlation of these properties with the drug's clinical effects. In addition, we validated the LC-MS/MS method and found that it is suitable for the pharmacokinetic study of vincristine in dog plasma.

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.

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

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.

[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.

Chiral Plasma Pharmacokinetics of 3,4-Methylenedioxymethamphetamine and its Phase I and II Metabolites following Controlled Administration to Humans.

OpenAIRE

Steuer Andrea E; Schmidhauser Corina; Schmid Yasmin; Rickli Anna; Liechti Matthias E; Kraemer Thomas

2015-01-01

Generally, pharmacokinetic studies on 3,4-methylenedioxymethamphetamine (MDMA) in blood have been performed after conjugate cleavage, without taking into account that phase II metabolites represent distinct chemical entities with their own effects and stereoselective pharmacokinetics. The aim of the present study was to stereoselectively investigate the pharmacokinetics of intact glucuronide and sulfate metabolites of MDMA in blood plasma after a controlled single MDMA dose. Plasma samples fr...

Non-linear mixed-effects pharmacokinetic/pharmacodynamic modelling in NLME using differential equations

DEFF Research Database (Denmark)

Tornøe, Christoffer Wenzel; Agersø, Henrik; Madsen, Henrik

2004-01-01

The standard software for non-linear mixed-effect analysis of pharmacokinetic/phar-macodynamic (PK/PD) data is NONMEM while the non-linear mixed-effects package NLME is an alternative as tong as the models are fairly simple. We present the nlmeODE package which combines the ordinary differential...... equation (ODE) solver package odesolve and the non-Linear mixed effects package NLME thereby enabling the analysis of complicated systems of ODEs by non-linear mixed-effects modelling. The pharmacokinetics of the anti-asthmatic drug theophylline is used to illustrate the applicability of the nlme...

Pharmacokinetic profile of nifedipine GITS in hypertensive patients with chronic renal impairment.

Science.gov (United States)

Schneider, R; Stolero, D; Griffel, L; Kobelt, R; Brendel, E; Iaina, A

1994-01-01

25 hypertensive patients with normal or impaired renal function underwent pharmacokinetic and safety studies after single and multiple dose administration of nifedipine GITS (Gastro-Intestinal Therapeutic System) 60mg tablets. Complete pharmacokinetic data were obtained from 23 of these patients. Blood pressure and heart rate changes were compatible with the known properties of the drug. Impaired renal function did not affect the maximum plasma concentrations or bioavailability of nifedipine after single or multiple dose administration of nifedipine GITS, nor was there any evidence of excessive drug accumulation in the presence of renal impairment.

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.

Pharmacokinetic behavior of marbofloxacin in plasma from chickens at different seasons

Directory of Open Access Journals (Sweden)

Natalia Francisca Urzúa Pizarro1,

2017-10-01

Full Text Available The purpose of this study was to evaluate the differences in the disposition and plasma pharmacokinetic behavior of marbofloxacin (MAR in broiler chickens at different seasons. Chicken broilers (n = 345 were used, in lots of 5 individuals, divided into 6 groups depending on the way of administration, intravenous or oral (dose 2 mg/kg and the test period. Post-administration plasma samples were obtained at different times, intravenously (0.08 to 24 hours and orally (0.25 to 120 hours. A liquid-liquid extraction of MAR was performed by high-performance liquid chromatography (HPLC with a fluorescent detector. The plasma concentrations obtained at the different sampling times of each season, were analyzed with ANOVA and pharmacokinetic analysis was conducted with the PK Solution 2.0 software. The concentration of marbofloxacin in plasma was significantly lower in winter and summer than in spring, with MAR being detected in winter up to 72 hours post-application, coinciding with the differences in MAR pharmacokinetics parameters with increase in the average residence time (MRT is 9.4 hours in winter. Increased clearance MAR in summer (7.5 ml/min/kg coincides with MRT 6.3 hours. Finally, the oral bioavailability of MAR is lower in summer and winter (86 ± 1.7% and 78 ± 3.1% than in spring (94 ± 5.2 %. There are differences in the disposition and plasma pharmacokinetic behavior of MAR applied orally in broiler chickens, coinciding with the physiological changes in the thermoregulation of birds, considering its correct therapeutic management and contributing to provide safe food for human consumption.

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.

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

Pharmacokinetics and Safety of Amenamevir in Healthy Subjects: Analysis of Four Randomized Phase 1 Studies.

Science.gov (United States)

Kusawake, Tomohiro; Keirns, James J; Kowalski, Donna; den Adel, Martin; Groenendaal-van de Meent, Dorien; Takada, Akitsugu; Ohtsu, Yoshiaki; Katashima, Masataka

2017-12-01

Amenamevir (ASP2151) is a nonnucleoside antiherpesvirus compound available for the treatment of varicella-zoster virus infections. In this article we summarize the findings of four phase 1 studies in healthy participants. Four randomized phase 1 studies investigated the safety and pharmacokinetics of single and multiple doses of amenamevir, including the assessment of age group effect (nonelderly vs elderly), food effect, and the relative bioavailability of two formulations. Amenamevir was administered orally at various doses as a single dose (5-2400 mg) or daily (300 or 600 mg/day) for 7 days. Following single and multiple oral doses, amenamevir demonstrated a less than dose proportional increase in the pharmacokinetic parameters area under the plasma drug concentration versus time curve from time zero to infinity (AUC inf ) and C max . After single and multiple oral 300-mg doses of amenamevir, no apparent differences in pharmacokinetics were observed between nonelderly and elderly participants. In contrast, with the amenamevir 600-mg dose both the area under the plasma drug concentration versus time curve from time zero to 24 h and C max were slightly increased and renal clearance was decreased in elderly participants. The pharmacokinetics of amenamevir was affected by food, with AUC inf increased by about 90%. In the bioavailability study, AUC inf and C max were slightly lower following tablet versus capsule administration (decreased by 14 and 12%, respectively), with relative bioavailability of 86%. The different amenamevir doses and formulations were safe and well tolerated; no deaths or serious adverse events were reported. Amenamevir had less than dose proportional pharmacokinetic characteristics. Age may have an influence on amenamevir pharmacokinetics; however, the effect was considered minimal. The pharmacokinetics of amenamevir were affected by food, with AUC inf almost doubling when amenamevir was administered with food. The concentration versus

Pharmacokinetics of enrofloxacin and marbofloxacin in Japanese quails and common pheasants.

Science.gov (United States)

Lashev, L D; Dimitrova, D J; Milanova, A; Moutafchieva, R G

2015-04-01

The pharmacokinetics of enrofloxacin and marbofloxacin was studied in Japanese quails and common pheasants. Healthy mature birds from both species and both genders were treated intravenously and orally with enrofloxacin (10 mg/kg) and marbofloxacin (5 mg/kg). After intravenous administration enrofloxacin was extensively metabolised to ciprofloxacin. Metabolites of marbofloxacin were not detected. Values of volume of distribution were respectively 4.63 l/kg and 3.67 l/kg for enrofloxacin and 1.56 l/kg and 1.43 l/kg for marbofloxacin. In quails, total body clearance values were higher than those in pheasants and other avian species. After oral application enrofloxacin was rapidly absorbed in quails, more rapidly than marbofloxacin. Pheasants absorbed both antimicrobials at a lower rate. Higher bioavailability was observed for marbofloxacin (118%). Relatively low bioavailability was established in quails for enrofloxacin (26.4%), accompanied by extensive conversion to ciprofloxacin. Generally, quails absorbed and eliminated both fluoroquinolones more rapidly than pheasants; the latter showed pharmacokinetics similar to poultry. Because of favourable pharmacokinetic properties, marbofloxacin should be preferred for oral administration in Japanese quails and pheasants for treatment of infections caused by equally susceptible pathogens.

Steady-State Clozapine and Norclozapine Pharmacokinetics in Maori and European Patients.

Science.gov (United States)

Menkes, David B; Glue, Paul; Gale, Christopher; Lam, Frederic; Hung, Cheung-Tak; Hung, Noelyn

2018-01-01

Clozapine is the most effective drug for treatment-resistant schizophrenia, but its use is limited by toxicity. Because ethnicity has been reported to affect clozapine metabolism, we compared its steady state pharmacokinetics in New Zealand Maori and European patients. Clozapine and norclozapine steady state bioavailability was assessed over 24h under fasting and fed conditions in 12 Maori and 16 European patients treated for chronic psychotic illnesses with stable once-daily clozapine doses. Plasma clozapine and norclozapine concentrations were assessed using liquid chromatography with tandem mass spectrometry; pharmacokinetic parameters were calculated using standard non-compartmental methods, and compared using unpaired t-tests. Mean pharmacokinetic parameters (AUC, C max and C min ) for clozapine and norclozapine were virtually identical in Maori and European subjects, under both fed and fasted conditions. Clozapine bioavailability does not vary between Maori and European patients, and thus does not need to be considered in prescribing decisions. Additional studies are needed to identify if there are differences between Maori and European populations for drugs metabolized by other enzyme pathways. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

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

ADAM, a hands-on patient simulator for teaching principles of drug disposition and compartmental pharmacokinetics.

Science.gov (United States)

Zuna, Ines; Holt, Andrew

2017-11-01

To design, construct and validate a pharmacokinetics simulator that offers students hands-on opportunities to participate in the design, administration and analysis of oral and intravenous dosing regimens. The Alberta Drug Administration Modeller (ADAM) is a mechanical patient in which peristaltic circulation of water through a network of silicone tubing and glass bottles creates a representation of the outcomes of drug absorption, distribution, metabolism and elimination. Changing peristaltic pump rates and volumes in bottles allows values for pharmacokinetic constants to be varied, thereby simulating differences in drug properties and in patient physiologies and pathologies. Following administration of methylene blue dye by oral or intravenous routes, plasma and/or urine samples are collected and drug concentrations are determined spectrophotometrically. The effectiveness of the simulator in enhancing student competence and confidence was assessed in two undergraduate laboratory classes. The simulator effectively models one- and two-compartment drug behaviour in a mathematically-robust and realistic manner. Data allow calculation of numerous pharmacokinetic constants, by traditional graphing methods or with curve-fitting software. Students' competence in solving pharmacokinetic problems involving calculations and graphing improved significantly, while an increase in confidence and understanding was reported. The ADAM is relatively inexpensive and straightforward to construct, and offers a realistic, hands-on pharmacokinetics learning opportunity for students that effectively complements didactic lectures. © 2017 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Systemic and ocular pharmacokinetics of N-4-benzoylaminophenylsulfonylglycine (BAPSG), a novel aldose reductase inhibitor

OpenAIRE

Sunkara, Gangadhar; Ayalasomayajula, Surya P.; Rao, Cheruku S.; Vennerstrom, Jonathan L.; DeRuiter, Jack; Kompella, Uday B.

2004-01-01

To better develop N-[4-(benzoylamino)phenylsulfonyl]glycine (BAPSG), a potent and selective aldose reductase inhibitor capable of delaying the progression of ocular diabetic complications, the objective of this study was to assess its pharmacokinetics. The plasma pharmacokinetics of BASPG was assessed in male Sprague-Dawley rats following intravenous, intraperitoneal and oral routes of administration and its distribution to various tissues including those of the eye was studied following intr...

Population Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Malaria

OpenAIRE

Tarning, Joel; Rijken, Marcus J.; McGready, Rose; Phyo, Aung Pyae; Hanpithakpong, Warunee; Day, Nicholas P. J.; White, Nicholas J.; Nosten, François; Lindegardh, Niklas

2012-01-01

Pregnant women are particularly vulnerable to malaria. The pharmacokinetic properties of antimalarial drugs are often affected by pregnancy, resulting in lower drug concentrations and a consequently higher risk of treatment failure. The objective of this study was to evaluate the population pharmacokinetic properties of piperaquine and dihydroartemisinin in pregnant and nonpregnant women with uncomplicated malaria. Twenty-four pregnant and 24 matched nonpregnant women on the Thai-Myanmar boar...

A Physiologically Based Pharmacokinetic Model to Predict the Pharmacokinetics of Highly Protein-Bound Drugs and Impact of Errors in Plasma Protein Binding

Science.gov (United States)

Ye, Min; Nagar, Swati; Korzekwa, Ken

2015-01-01

Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data was often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding, and blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for terminal elimination half-life (t1/2, 100% of drugs), peak plasma concentration (Cmax, 100%), area under the plasma concentration-time curve (AUC0–t, 95.4%), clearance (CLh, 95.4%), mean retention time (MRT, 95.4%), and steady state volume (Vss, 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. PMID:26531057

Direct cell writing of 3D microorgan for in vitro pharmacokinetic model.

Science.gov (United States)

Chang, Robert; Nam, Jae; Sun, Wei

2008-06-01

A novel targeted application of tissue engineering is the development of an in vitro pharmacokinetic model for drug screening and toxicology. An in vitro pharmacokinetic model is needed to realistically and reliably predict in vivo human response to drug administrations and potential toxic exposures. This paper details the fabrication process development and adaptation of microfluidic devices for the creation of such a physiologically relevant pharmacokinetic model. First, an automated syringe-based, layered direct cell writing (DCW) bioprinting process creates a 3D microorgan that biomimics the cell's natural microenvironment with enhanced functionality. Next, soft lithographic micropatterning techniques are used to fabricate a microscale in vitro device to house the 3D microorgan. This paper demonstrates the feasibility of the DCW process for freeform biofabrication of 3D cell-encapsulated hydrogel-based tissue constructs with defined reproducible patterns, direct integration of 3D constructs onto a microfluidic device for continuous perfusion drug flow, and characterization of 3D tissue constructs with predictable cell viability/proliferation outcomes and enhanced functionality over traditional culture methods.

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...

Pharmacokinetic-pharmacodynamic modeling of diclofenac in normal and Freund's complete adjuvant-induced arthritic rats

Science.gov (United States)

Zhang, Jing; Li, Pei; Guo, Hai-fang; Liu, Li; Liu, Xiao-dong

2012-01-01

Aim: To characterize pharmacokinetic-pharmacodynamic modeling of diclofenac in Freund's complete adjuvant (FCA)-induced arthritic rats using prostaglandin E2 (PGE2) as a biomarker. Methods: The pharmacokinetics of diclofenac was investigated using 20-day-old arthritic rats. PGE2 level in the rats was measured using an enzyme immunoassay. A pharmacokinetic-pharmacodynamic (PK-PD) model was developed to illustrate the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production. The inhibition of diclofenac on lipopolysaccharide (LPS)-induced PGE2 production in blood cells was investigated in vitro. Results: Similar pharmacokinetic behavior of diclofenac was found both in normal and FCA-induced arthritic rats. Diclofenac significantly decreased the plasma levels of PGE2 in both normal and arthritic rats. The inhibitory effect on PGE2 levels in the plasma was in proportion to the plasma concentration of diclofenac. No delay in the onset of inhibition was observed, suggesting that the effect compartment was located in the central compartment. An inhibitory effect sigmoid Imax model was selected to characterize the relationship between the plasma concentration of diclofenac and the inhibition of PGE2 production in vivo. The Imax model was also used to illustrate the inhibition of diclofenac on LPS-induced PGE2 production in blood cells in vitro. Conclusion: Arthritis induced by FCA does not alter the pharmacokinetic behaviors of diclofenac in rats, but the pharmacodynamics of diclofenac is slightly affected. A PK-PD model characterizing an inhibitory effect sigmoid Imax can be used to fit the relationship between the plasma PGE2 and diclofenac levels in both normal rats and FCA-induced arthritic rats. PMID:22842736

The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides.

Science.gov (United States)

Holt, Jonathon D S; Cameron, David; Dias, Nicola; Holding, Jeremy; Muntendam, Alex; Oostebring, Freddy; Dreier, Peter; Rohan, Lisa; Nuttall, Jeremy

2015-07-01

When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo.

Science.gov (United States)

Thurber, Greg M; Yang, Katy S; Reiner, Thomas; Kohler, Rainer H; Sorger, Peter; Mitchison, Tim; Weissleder, Ralph

2013-01-01

Pharmacokinetic analysis at the organ level provides insight into how drugs distribute throughout the body, but cannot explain how drugs work at the cellular level. Here we demonstrate in vivo single-cell pharmacokinetic imaging of PARP-1 inhibitors and model drug behaviour under varying conditions. We visualize intracellular kinetics of the PARP-1 inhibitor distribution in real time, showing that PARP-1 inhibitors reach their cellular target compartment, the nucleus, within minutes in vivo both in cancer and normal cells in various cancer models. We also use these data to validate predictive finite element modelling. Our theoretical and experimental data indicate that tumour cells are exposed to sufficiently high PARP-1 inhibitor concentrations in vivo and suggest that drug inefficiency is likely related to proteomic heterogeneity or insensitivity of cancer cells to DNA-repair inhibition. This suggests that single-cell pharmacokinetic imaging and derived modelling improve our understanding of drug action at single-cell resolution in vivo.

Effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel in rats.

Science.gov (United States)

Chen, Xinmeng; Jin, Jing; Chen, Yaobin; Peng, Lingling; Zhong, Guoping; Li, Jiali; Bi, Huichang; Cai, Yefeng; Huang, Min

2015-01-01

Erigeron breviscapus (Vant.) Hand-Mazz, a traditional Chinese medicine, is often co-prescribed with clopidogrel for the treatment of ischemic vascular diseases. Scutellarin is the representative bioactive flavonoid isolated from this herb. The aim of this study was to explore the effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel. The in vitro studies using rat liver microsomes showed that scutellarin significantly inhibited the metabolism of clopidogrel. The IC50 value was 2.1 µM. Ten male rats were employed to investigate the effect of scutellarin on the pharmacokinetics of clopidogrel in vivo. After pretreatment with scutellarin, there were significant increases in the AUC0-∞ (from 0.9 ± 0.4 to 1.7 ± 0.6 ng/ml h; p <0.05) and Cmax (from 0.4 ± 0.1 to 0.9 ± 0.1 ng/ml; p <0.05) of clopidogrel. The pharmacokinetic data for clopidogrel active metabolite showed significant decreases in AUC0-∞ (18.2 ± 5.6 to 11.4 ± 3.7 ng/ml h; p <0.05) and Cmax (from 8.2 ± 1.2 to 4.3 ± 0.3 ng/ml; p <0.05) after pretreatment with scutellarin. Collectively, the metabolism and pharmacokinetics of clopidogrel were significantly affected by scutellarin. This study indicated that potential herb-drug interaction between scutellarin and clopidogrel should be taken into consideration in clinical use. Copyright © 2014 John Wiley & Sons, Ltd.

Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine.

Science.gov (United States)

Zandvliet, Anthe S; Huitema, Alwin D R; de Jonge, Milly E; den Hoed, Rob; Sparidans, Rolf W; Hendriks, Vincent M; van den Brink, Wim; van Ree, Jan M; Beijnen, Jos H

2005-01-01

The stimulant effect of caffeine, as an additive in diacetylmorphine preparations for study purposes, may interfere with the pharmacodynamic effects of diacetylmorphine. In order to obtain insight into the pharmacology of caffeine after inhalation in heroin users, the pharmacokinetics of caffeine and its dimethylxanthine metabolites were studied. The objectives were to establish the population pharmacokinetics under these exceptional circumstances and to compare the results to published data regarding intravenous and oral administration in healthy volunteers. Diacetylmorphine preparations containing 100 mg of caffeine were used by 10 persons by inhalation. Plasma concentrations of caffeine, theobromine, paraxanthine and theophylline were measured by high performance liquid chromatography. Non-linear mixed effects modelling was used to estimate population pharmacokinetic parameters. The model was evaluated by the jack-knife procedure. Caffeine was rapidly and effectively absorbed after inhalation. Population pharmacokinetics of caffeine and its dimethylxanthine metabolites could adequately and simultaneously be described by a linear multi-compartment model. The volume of distribution for the central compartment was estimated to be 45.7 l and the apparent elimination rate constant of caffeine at 8 hr after inhalation was 0.150 hr(-1) for a typical individual. The bioavailability was approximately 60%. The presented model adequately describes the population pharmacokinetics of caffeine and its dimethylxanthine metabolites after inhalation of the caffeine sublimate of a 100 mg tablet. Validation proved the stability of the model. Pharmacokinetics of caffeine after inhalation and intravenous administration are to a large extent similar. The bioavailability of inhaled caffeine is approximately 60% in experienced smokers.

Pharmacokinetic drug interactions of antimicrobial drugs : a systematic review on oxazolidinones, rifamycines, macrolides, fluoroquinolones, and Beta-lactams

NARCIS (Netherlands)

Bolhuis, Mathieu S; Panday, Prashant N; Pranger, Arianna D; Kosterink, Jos G W; Alffenaar, Jan-Willem C

2011-01-01

Like any other drug, antimicrobial drugs are prone to pharmacokinetic drug interactions. These drug interactions are a major concern in clinical practice as they may have an effect on efficacy and toxicity. This article provides an overview of all published pharmacokinetic studies on drug

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 ...

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.

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.

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.

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.

Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats

International Nuclear Information System (INIS)

Milesi-Halle, Alessandra; Hendrickson, Howard P.; Laurenzana, Elizabeth M.; Gentry, W. Brooks; Owens, S. Michael

2005-01-01

These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague-Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague-Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration-time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, and percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats

Alterations in Pharmacokinetics of Gemcitabine and Erlotinib by Concurrent Administration of Hyangsayukgunja-Tang, a Gastroprotective Herbal Medicine.

Science.gov (United States)

Kim, Tae Hwan; Shin, Soyoung; Kim, Sarah; Bulitta, Jürgen B; Weon, Kwon-Yeon; Joo, Sang Hoon; Ma, Eunsook; Yoo, Sun Dong; Park, Gi-Young; Kwon, Dong Rak; Jeong, Seok Won; Lee, Da Young; Shin, Beom Soo

2017-09-10

Gemcitabine and erlotinib are the chemotherapeutic agents used in the treatment of various cancers and their combination is being accepted as a first-line treatment of advanced pancreatic cancer. Hyangsayukgunja-tang (HYT) is a traditional oriental medicine used in various digestive disorders and potentially helpful to treat gastrointestinal adverse effects related to chemotherapy. The present study was aimed to evaluate the effect of HYT on the pharmacokinetics of gemcitabine and erlotinib given simultaneously in rats. Rats were pretreated with HYT at an oral dose of 1200 mg/kg/day once daily for a single day or 14 consecutive days. Immediately after pretreatment with HYT, gemcitabine and erlotinib were administered by intravenous injection (10 mg/kg) and oral administration (20 mg/kg), respectively. The effects of HYT on pharmacokinetics of the two drugs were estimated by non-compartmental analysis and pharmacokinetic modeling. The pharmacokinetics of gemcitabine and erlotinib were not altered by single dose HYT pretreatment. However, the plasma levels of OSI-420 and OSI-413, active metabolites of erlotinib, were significantly decreased in the multiple dose HYT pretreatment group. The pharmacokinetic model estimated increased systemic clearances of OSI-420 and OSI-413 by multiple doses of HYT. These data suggest that HYT may affect the elimination of OSI-420 and OSI-413.

The pharmacokinetics of morphine and lidocaine in nine severe trauma patients.

Science.gov (United States)

Berkenstadt, H; Mayan, H; Segal, E; Rotenberg, M; Almog, S; Perel, A; Ezra, D

1999-12-01

To study the pharmacokinetic parameters of morphine and lidocaine after a single intravenous (i.v.) bolus in severe trauma patients. Clinical case study. Department of Anesthesiology and Intensive Care of a university hospital. Nine patients, ages 24 to 91 years (mean 54.4 yrs), admitted to the hospital with severe trauma (Injury Severity Score > 20) were included in the study. After initial evaluation and stabilization, a single i.v. dose of morphine 0.025 mg/kg and lidocaine 1.5 mg/kg was given separately, and blood samples were drawn for each drug serum concentration. Morphine pharmacokinetics was studied in eight patients, lidocaine pharmacokinetics in seven patients, and both drugs were studied in six patients. Morphine clearance 2.5 to 10 ml/kg/min (6 +/- 2.6, mean +/- SD) and volume of distribution 0.28 to 3.30 L/kg (1.4 +/- 1.0) were found to be lower than values described previously for healthy volunteers (33.5 +/- 9 ml/kg/min and 5.16 +/- 1.40 L/kg, respectively), and are similar to those described in trauma patients (5 +/- 2.9 ml/kg/min and 0.9 +/- 0.2 L/kg, respectively). In contrast, lidocaine clearance 4.5 to 9.4 ml/kg/min (6.7 +/- 1.7) and volume of distribution 0.39 to 1.20 L/kg (0.72 +/- 0.28) were similar to the value described in healthy volunteers (10 ml/kg/min and 1.32 L/kg, respectively). Changes in pharmacokinetics of drugs eliminated by the liver may occur in patients with severe trauma. The preserved lidocaine clearance indicates an almost normal hepatic blood flow and suggests that other mechanisms may be involved in the lower morphine clearance. The findings may have applications for the treatment of severe trauma patients and suggest that drug monitoring might be needed in some instances so as to avoid toxicity.

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.

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

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.

Integrated pharmacokinetics of major bioactive components in MCAO rats after oral administration of Huang-Lian-Jie-Du-Tang.

Science.gov (United States)

Zhu, Huaxu; Qian, Zhilei; Li, Huan; Guo, Liwei; Pan, Linmei; Zhang, Qichun; Tang, Yuping

2012-05-07

Huang-Lian-Jie-Du-Tang (HLJDT, or Oren-gedoku-to in Japanese), an important multi-herb remedy in China and other Asia countries, has been used clinically to treat cerebral ischemia for decades. According to the previous studies we have reported, an HPLC method was developed and validated for determination of berberine, palmatine, baicalin, baicalein and geniposide simultaneously in MCAO rat plasma after administration of HLJDT aqueous extract. A classified integral pharmacokinetic method was put forward after having compared the integrated concentration-time profile with that of single component. An AUC based weighting approach was used for integrated principle. The results indicated the classified integral pharmacokinetic profile of index components from HLJDT could reveal the pharmacokinetic behavior of original components, and was corresponding to the holistic pharmacological effects of anti-ischemia with HLJDT. This study was aimed to explore an approach that could be applied to integrate the pharmacokinetic behavior of different components derived from HLJDT. The integrated pharmacokinetic results also provided more information for further understanding of the clinical cerebrovascular disease in use of HLJDT. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

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.

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.

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 ...

[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.

Pharmacokinetics of fexofenadine: evaluation of a microdose and assessment of absolute oral bioavailability.

Science.gov (United States)

Lappin, Graham; Shishikura, Yoko; Jochemsen, Roeline; Weaver, Richard John; Gesson, Charlotte; Houston, Brian; Oosterhuis, Berend; Bjerrum, Ole J; Rowland, Malcolm; Garner, Colin

2010-05-12

A human pharmacokinetic study was performed to assess the ability of a microdose to predict the pharmacokinetics of a therapeutic dose of fexofenadine and to determine its absolute oral bioavailability. Fexofenadine was chosen to represent an unmetabolized transporter substrate (P-gP and OATP). Fexofenadine was administered to 6 healthy male volunteers in a three way cross-over design. A microdose (100microg) of (14)C-drug was administered orally (period 1) and intravenously by 30min infusion (period 2). In period 3 an intravenous tracer dose (100microg) of (14)C-drug was administered simultaneously with an oral unlabelled therapeutic dose (120mg). Plasma was collected from all 3 periods and analysed for both total (14)C content and parent drug by accelerator mass spectrometry (AMS). For period 3, plasma samples were also analysed using HPLC-fluorescence to determine total drug concentration. Urine was collected and analysed for total (14)C. Good concordance between the microdose and therapeutic dose pharmacokinetics was observed. Microdose: CL 13L/h, CL(R) 4.1L/h, V(ss) 54L, t(1/2) 16h; therapeutic dose: CL 16L/h, CL(R) 6.2L/h, V(ss) 64L, t(1/2) 12h. The absolute oral bioavailability of fexofenadine was 0.35 (microdose 0.41, therapeutic dose 0.30). Despite a 1200-fold difference in dose of fexofenadine, the microdose predicted well the pharmacokinetic parameters following a therapeutic dose for this transporter dependent compound.

Evaluation of the Potential Pharmacokinetic Interaction between Atomoxetine and Fluvoxamine in Healthy Volunteers.

Science.gov (United States)

Todor, Ioana; Popa, Adina; Neag, Maria; Muntean, Dana; Bocsan, Corina; Buzoianu, Anca; Vlase, Laurian; Gheldiu, Ana-Maria; Briciu, Corina

2017-01-01

Attention deficit hyperactivity disorder (ADHD) is frequently associated with other psychiatric pathologies. Therefore, the present study investigated a possible pharmacokinetic interaction between atomoxetine (ATX), a treatment option for ADHD, and an antidepressant, namely, fluvoxamine (FVX). Designed as an open-label, non-randomized clinical trial, the study included 2 periods. In period 1 (reference), each subject received ATX 25 mg (single-dose), whereas in period 2 (test), all subjects were given a combination of ATX 25 mg + FVX 100 mg, following a 6-day pretreatment regimen with the enzymatic inhibitor. Non-compartmental methods were employed to determine the pharmacokinetic parameters of ATX and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide. The results revealed significant differences between the study periods for Cmax, AUC0-t and AUC0-∞ values corresponding to ATX and its metabolite. Small, but statistically significant increases in AUC values were reported for both parent drug (1,583.05 ± 1,040.29 vs. 2,111.55 ± 1,411.59 ng*h/ml) and 4-hydroxyatomoxetine-O-glucuronide (5,754.71 ± 1,235.5 vs. 6,293.17 ± 1,219.34 ng*h/ml) after combined treatment of ATX and the enzymatic inhibitor. FVX had a modest effect on the pharmacokinetics of ATX and 4-hydroxyatomoxetine-O-glucuronide. The presence or absence of any clinical consequences associated with this pharmacokinetic drug-drug interaction needs to be established in future studies. © 2016 S. Karger AG, Basel.

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 ...

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.

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

A Combined Pharmacokinetic and Radiologic Assessment of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Predicts Response to Chemoradiation in Locally Advanced Cervical Cancer

International Nuclear Information System (INIS)

Semple, Scott; Harry, Vanessa N. MRCOG.; Parkin, David E.; Gilbert, Fiona J.

2009-01-01

Purpose: To investigate the combination of pharmacokinetic and radiologic assessment of dynamic contrast-enhanced magnetic resonance imaging (MRI) as an early response indicator in women receiving chemoradiation for advanced cervical cancer. Methods and Materials: Twenty women with locally advanced cervical cancer were included in a prospective cohort study. Dynamic contrast-enhanced MRI was carried out before chemoradiation, after 2 weeks of therapy, and at the conclusion of therapy using a 1.5-T MRI scanner. Radiologic assessment of uptake parameters was obtained from resultant intensity curves. Pharmacokinetic analysis using a multicompartment model was also performed. General linear modeling was used to combine radiologic and pharmacokinetic parameters and correlated with eventual response as determined by change in MRI tumor size and conventional clinical response. A subgroup of 11 women underwent repeat pretherapy MRI to test pharmacokinetic reproducibility. Results: Pretherapy radiologic parameters and pharmacokinetic K trans correlated with response (p < 0.01). General linear modeling demonstrated that a combination of radiologic and pharmacokinetic assessments before therapy was able to predict more than 88% of variance of response. Reproducibility of pharmacokinetic modeling was confirmed. Conclusions: A combination of radiologic assessment with pharmacokinetic modeling applied to dynamic MRI before the start of chemoradiation improves the predictive power of either by more than 20%. The potential improvements in therapy response prediction using this type of combined analysis of dynamic contrast-enhanced MRI may aid in the development of more individualized, effective therapy regimens for this patient group.

Biosynthesis, natural sources, dietary intake, pharmacokinetic properties, and biological activities of hydroxycinnamic acids.

Science.gov (United States)

El-Seedi, Hesham R; El-Said, Asmaa M A; Khalifa, Shaden A M; Göransson, Ulf; Bohlin, Lars; Borg-Karlson, Anna-Karin; Verpoorte, Rob

2012-11-07

Hydroxycinnamic acids are the most widely distributed phenolic acids in plants. Broadly speaking, they can be defined as compounds derived from cinnamic acid. They are present at high concentrations in many food products, including fruits, vegetables, tea, cocoa, and wine. A diet rich in hydroxycinnamic acids is thought to be associated with beneficial health effects such as a reduced risk of cardiovascular disease. The impact of hydroxycinnamic acids on health depends on their intake and pharmacokinetic properties. This review discusses their chemistry, biosynthesis, natural sources, dietary intake, and pharmacokinetic properties.

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.

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.

Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients.

Science.gov (United States)

Sassen, Sebastiaan D T; Mathôt, Ron A A; Pieters, Rob; Kloos, Robin Q H; de Haas, Valérie; Kaspers, Gertjan J L; van den Bos, Cor; Tissing, Wim J E; Te Loo, Maroeska; Bierings, Marc B; Kollen, Wouter J W; Zwaan, Christian M; van der Sluis, Inge M

2017-03-01

Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m 2 three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM ® A 2-compartment linear model with allometric scaling best described the data. Inter-individual and inter-occasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher ( P <0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m 2 might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards. (Registered at NTR 3379 Dutch Trial Register; www.trialregister.nl). Copyright© Ferrata Storti Foundation.

Medicinal cannabis does not influence the clinical pharmacokinetics of irinotecan and docetaxel.

Science.gov (United States)

Engels, Frederike K; de Jong, Floris A; Sparreboom, Alex; Mathot, Ron A A; Loos, Walter J; Kitzen, Jos J E M; de Bruijn, Peter; Verweij, Jaap; Mathijssen, Ron H J

2007-03-01

To date, data regarding the potential of cannabinoids to modulate cytochrome P450 isozyme 3A (CYP3A) activity are contradictory. Recently, a standardized medicinal cannabis product was introduced in The Netherlands. We anticipated an increased use of medicinal cannabis concurrent with anticancer drugs, and undertook a drug-interaction study to evaluate the effect of concomitant medicinal cannabis on the pharmacokinetics of irinotecan and docetaxel, both subject to CYP3A-mediated biotransformation. Twenty-four cancer patients were treated with i.v. irinotecan (600 mg, n = 12) or docetaxel (180 mg, n = 12), followed 3 weeks later by the same drugs concomitant with medicinal cannabis (200 ml herbal tea, 1 g/l) for 15 consecutive days, starting 12 days before the second treatment. Blood samples were obtained up to 55 hours after dosing and analyzed for irinotecan and its metabolites (SN-38, SN-38G), respectively, or docetaxel. Pharmacokinetic analyses were performed during both treatments. Results are reported as the mean ratio (95% confidence interval [CI]) of the observed pharmacokinetic parameters with and without concomitant medicinal cannabis. Medicinal cannabis administration did not significantly influence exposure to and clearance of irinotecan (1.04; CI, 0.96-1.11 and 0.97; CI, 0.90-1.05, respectively) or docetaxel (1.11; CI, 0.94-1.28 and 0.95; CI, 0.82-1.08, respectively). Coadministration of medicinal cannabis, as herbal tea, in cancer patients treated with irinotecan or docetaxel does not significantly influence the plasma pharmacokinetics of these drugs. The evaluated variety of medicinal cannabis can be administered concomitantly with both anticancer agents without dose adjustments.

Pharmacokinetic variability of long-acting stimulants in the treatment of children and adults with attention-deficit hyperactivity disorder.

Science.gov (United States)

Ermer, James C; Adeyi, Ben A; Pucci, Michael L

2010-12-01

Methylphenidate- and amfetamine-based stimulants are first-line pharmacotherapies for attention-deficit hyperactivity disorder, a common neurobehavioural disorder in children and adults. A number of long-acting stimulant formulations have been developed with the aim of providing once-daily dosing, employing various means to extend duration of action, including a transdermal delivery system, an osmotic-release oral system, capsules with a mixture of immediate- and delayed-release beads, and prodrug technology. Coefficients of variance of pharmacokinetic measures can estimate the levels of pharmacokinetic variability based on the measurable variance between different individuals receiving the same dose of stimulant (interindividual variability) and within the same individual over multiple administrations (intraindividual variability). Differences in formulation clearly impact pharmacokinetic profiles. Many medications exhibit wide interindividual variability in clinical response. Stimulants with low levels of inter- and intraindividual variability may be better suited to provide consistent levels of medication to patients. The pharmacokinetic profile of stimulants using pH-dependent bead technology can vary depending on food consumption or concomitant administration of medications that alter gastric pH. While delivery of methylphenidate with the transdermal delivery system would be unaffected by gastrointestinal factors, intersubject variability is nonetheless substantial. Unlike the beaded formulations and, to some extent (when considering total exposure) the osmotic-release formulation, systemic exposure to amfetamine with the prodrug stimulant lisdexamfetamine dimesylate appears largely unaffected by such factors, likely owing to its dependence on systemic enzymatic cleavage of the precursor molecule, which occurs primarily in the blood involving red blood cells. The high capacity but as yet unidentified enzymatic system for conversion of lisdexamfetamine

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.

Pharmacokinetic parameters derived from dynamic contrast enhanced MRI of cervical cancers predict chemoradiotherapy outcome

International Nuclear Information System (INIS)

Andersen, Erlend K.F.; Hole, Knut Håkon; Lund, Kjersti V.; Sundfør, Kolbein; Kristensen, Gunnar B.; Lyng, Heidi; Malinen, Eirik

2013-01-01

Purpose: To assess the prognostic value of pharmacokinetic parameters derived from pre-chemoradiotherapy dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) of cervical cancer patients. Materials and methods: Seventy-eight patients with locally advanced cervical cancer underwent DCE-MRI with Gd-DTPA before chemoradiotherapy. The pharmacokinetic Brix and Tofts models were fitted to contrast enhancement curves in all tumor voxels, providing histograms of several pharmacokinetic parameters (Brix: A Brix , k ep , k el , Tofts: K trans , ν e ). A percentile screening approach including log-rank survival tests was undertaken to identify the clinically most relevant part of the intratumoral parameter distribution. Clinical endpoints were progression-free survival (PFS) and locoregional control (LRC). Multivariate analysis including FIGO stage and tumor volume was used to assess the prognostic significance of the imaging parameters. Results: A Brix , k el , and K trans were significantly (P e was significantly positively correlated with PFS only. k ep showed no association with any endpoint. A Brix was positively correlated with K trans and ν e , and showed the strongest association with endpoint in the log-rank testing. k el and K trans were independent prognostic factors in multivariate analysis with LRC as endpoint. Conclusions: Parameters estimated by pharmacokinetic analysis of DCE-MR images obtained prior to chemoradiotherapy may be used for identifying patients at risk of treatment failure

[Research progress of pharmacokinetics and pharmacodynamics of total glucosides of peony in hepatoprotective effects].

Science.gov (United States)

Zuo, Zhi-Yan; Zhan, Shu-Yu; Huang, Xuan; Ding, Bao-Yue; Liu, Yu-Qian; Ruan, Yu-Er; Jiang, Ning-Hua

2017-10-01

Total glucosides of peony (TGP), containing the effective components of paeoniflorin (Pae), albiflorin (Alb) and so on, are effective parts of Radix Paeoniae Alba. And it possesses extensive pharmacological actions, one of which is hepatoprotective effect. In recent years, abundant of pharmacokinetics and pharmacodynamics research of TGP in hepatoprotective effects have been performed. However, the relative medicine of TGP in hepatoprotective effect has not been developed for clinical application. In order to provide reference for the development and rational clinical application of TGP, the research progresses of pharmacokinetics and pharmacodynamics of TGP in hepatoprotective effect were summarized in this paper. Pharmacokinetics research has clarified the process of absorption, distribution, metabolism and excretion of TGP in vivo, and liver injury disease can significantly influence its metabolic processes. Pharmacodynamics studies suggested that TGP can protect against acute liver injury, non-alcoholic fatty liver diseases (NAFLD), chronic liver fibrosis and liver cancer. However, the action mechanism and in vivo process about hepatoprotective effects of TGP have not been clearly revealed. How liver injury influences the metabolism of TGP and its integrated regulation through multiple targets need to be further studied. The combined pharmacokinetics and pharmacodynamics studies should be performed in favour of medicine development and clinical application of TGP in hepatoprotective effects. Copyright© by the Chinese Pharmaceutical Association.

Population Pharmacokinetics of Tenofovir in Human Immunodeficiency Virus-Infected Patients Taking Highly Active Antiretroviral Therapy

OpenAIRE

Jullien, Vincent; Tréluyer, Jean-Marc; Rey, Elisabeth; Jaffray, Patrick; Krivine, Anne; Moachon, Laurence; Lillo-Le Louet, Agnès; Lescoat, Anne; Dupin, Nicolas; Salmon, Dominique; Pons, Gérard; Urien, Saïk

2005-01-01

The influence of renal function on tenofovir pharmacokinetics was investigated in 193 human immunodeficiency virus (HIV)-infected patients by the use of a population approach performed with the nonlinear mixed effects modeling program NONMEM. Tenofovir pharmacokinetics was well described by a two-compartment open model in which the absorption and the distribution rate constants are equal. Typical population estimates of apparent central distribution volume (Vc/F), peripheral distribution volu...

A phase I trial of vorinostat and alvocidib in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2.

Science.gov (United States)

Holkova, Beata; Supko, Jeffrey G; Ames, Matthew M; Reid, Joel M; Shapiro, Geoffrey I; Perkins, Edward Brent; Ramakrishnan, Viswanathan; Tombes, Mary Beth; Honeycutt, Connie; McGovern, Renee M; Kmieciak, Maciej; Shrader, Ellen; Wellons, Martha D; Sankala, Heidi; Doyle, Austin; Wright, John; Roberts, John D; Grant, Steven

2013-04-01

This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination. Patients received vorinostat (200 mg orally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily × 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly × 2. The alvocidib dose was escalated using a standard 3+3 design. Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m(2) (30-minute loading infusion) followed by 20 mg/m(2) (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose-limiting toxicities (DLT) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved although 13 of 26 evaluable patients exhibited stable disease. Alvocidib seemed to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21(CIP1) induction and downregulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent. Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules. ©2013 AACR.

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

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.

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

The effect of food on the absorption and pharmacokinetics of rivaroxaban.

Science.gov (United States)

Stampfuss, Jan; Kubitza, Dagmar; Becka, Michael; Mueck, Wolfgang

2013-07-01

Doses of 10 mg, 15 mg, and 20 mg of rivaroxaban are approved for the treatment and prevention of thromboembolic disorders in adult patients. In six Phase I studies, the pharmacokinetics, safety, and tolerability of 2.5 mg, 5 mg, 10 mg, 15 mg, and 20 mg rivaroxaban were investigated in healthy male subjects, and the influence of food on these parameters was investigated for the 10 mg, 15 mg, and 20 mg tablet doses. In addition, an oral suspension containing 1 mg/ml rivaroxaban, which is under investigation for future use in the pediatric population, was investigated at doses of 10 mg and 20 mg. Rivaroxaban was obtained from Bayer Pharma AG, Wuppertal, Germany. Six independent, single-dose, cross-over studies were performed in healthy male subjects (between 13 and 24 subjects were enrolled in each study) to determine the pharmacokinetics, safety, and tolerability of rivaroxaban under fasting and fed conditions. Study 1 was an absolute bioavailability study that compared 5 mg and 20 mg tablet doses with a 1 mg intravenous solution. Studies 2 and 3 were confirmatory food-effect studies that assessed 10 mg and 20 mg tablet doses, respectively, under fed and fasting conditions. Study 4 was a formulation study that evaluated oral suspensions of 10 mg (fasting) and 20 mg (fasting and fed) rivaroxaban vs. a 10 mg tablet (fasted). Study 5 was a dose-proportionality study that assessed 2.5 mg, 5 mg, and 10 mg tablets under fasting conditions. Study 6 was a dose-proportionality study that assessed tablet doses of 10 mg, 15 mg, and 20 mg under fed conditions. Pharmacokinetic parameters, including the area under the plasma concentration-time curve after a single dose, the maximum drug concentration in plasma after a single dose, dose-adjusted values of area under the plasma concentration-time curve and maximum drug concentration in plasma after a single dose, half-life associated with the terminal slope, and time to maximum concentration in plasma after a single dose were

Pharmacokinetics of Stereoisomeric Dipeptide Prodrugs of Acyclovir Following Intravenous and Oral Administrations in Rats: A Study Involving In vivo Corneal Uptake of Acyclovir Following Oral Dosing

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Ravi S.Talluri

2009-10-01

Full Text Available Objective: To delineate the plasma pharmacokinetics and determine the corneal uptake of valine based stereoisomeric dipeptide prodrugs of acyclovir (ACV in rats. Methods: Male Sprague-Dawley rats were used for the study. Pharmacokinetics of ACV, L-valine-acyclovir (LACV, L-valine- D-valine-acyclovir (LDACV and D-valine-L-valine acyclovir (DLACV prodrugs were delineated. These compounds were administered intravenously as a bolus via jugular vein cannula and orally by gavage. Samples were purified by protein precipitation method and analyzed by LC-MS/MS. Pertinent pharmacokinetic parameters were obtained by using WinNonlin. Corneal uptake studies of LDACV and LACV were studied following oral administration. Results: Following i.v. administration, the area under the curve (AUC in µM*min of generated ACV was in the order of LACV › LDACV › DLACV indicating their rate of metabolism. The AUC values of total drug obtained in the systemic circulation after oral administration LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 µM*min, respectively. DLACV exhibited poor oral absorption. Cmax (µM and AUC of the intact prodrug obtained in the systemic circulation following oral administration of LDACV were almost 4–5 times higher than LACV. Moreover, concentrations achieved in the cornea after oral administration of LDACV were almost two times of LACV. Conclusions: LDACV increased both the oral bioavailability and subsequent in vivo corneal uptake of ACV. Hence, LDACV can be considered as the most promising drug candidate for delivery of ACV, in treatment of both genital herpes and ocular herpes keratitis after oral administration.

Pharmacokinetics of Stereoisomeric Dipeptide Prodrugs of Acyclovir Following Intravenous and Oral Administrations in Rats: A Study Involving In vivo Corneal Uptake of Acyclovir Following Oral Dosing

Science.gov (United States)

Talluri, Ravi S.; Gaudana, Ripal; Hariharan, Sudharshan; Mitra, Ashim K.

2009-01-01

Objective To delineate the plasma pharmacokinetics and determine the corneal uptake of valine based stereoisomeric dipeptide prodrugs of acyclovir (ACV) in rats. Methods Male Sprague-Dawley rats were used for the study. Pharmacokinetics of ACV, L-valine-acyclovir (LACV), L-valine-D-valine-acyclovir (LDACV) and D-valine-L-valine acyclovir (DLACV) prodrugs were delineated. These compounds were administered intravenously as a bolus via jugular vein cannula and orally by gavage. Samples were purified by protein precipitation method and analyzed by LC-MS/MS. Pertinent pharmacokinetic parameters were obtained by using WinNonlin. Corneal uptake studies of LDACV and LACV were studied following oral administration. Results Following i.v. administration, the area under the curve (AUC) in μM*min of generated ACV was in the order of LACV > LDACV > DLACV indicating their rate of metabolism. The AUC values of total drug obtained in the systemic circulation after oral administration LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 μM*min, respectively. DLACV exhibited poor oral absorption. Cmax (μM) and AUC of the intact prodrug obtained in the systemic circulation following oral administration of LDACV were almost 4–5 times higher than LACV. Moreover, concentrations achieved in the cornea after oral administration of LDACV were almost two times of LACV. Conclusions LDACV increased both the oral bioavailability and subsequent in vivo corneal uptake of ACV. Hence, LDACV can be considered as the most promising drug candidate for delivery of ACV, in treatment of both genital herpes and ocular herpes keratitis after oral administration. PMID:23861607

Pharmacokinetics of Stereoisomeric Dipeptide Prodrugs of Acyclovir following Intravenous and Oral Administrations in Rats: A study Involving in vivo corneal Uptake of Acyclovir following Oral Dosing

Directory of Open Access Journals (Sweden)

Ravi S. Talluri

2009-01-01

Full Text Available Objective To delineate the plasma pharmacokinetics and determine the corneal uptake of valine based stereoisomeric dipeptide prodrugs of acyclovir (ACV in rats. Methods Male Sprague-Dawley rats were used for the study. Pharmacokinetics of ACV, L-valine-acyclovir (LACV, L-valine-D-valine-acyclovir (LDACV and D-valine-L-valine acyclovir (DLACV prodrugs were delineated. These compounds were administered intravenously as a bolus via jugular vein cannula and orally by gavage. Samples were purified by protein precipitation method and analyzed by LC-MS/MS. Pertinent pharmacokinetic parameters were obtained by using WinNonlin. Corneal uptake studies of LDACV and LACV were studied following oral administration. Results Following i.v. administration, the area under the curve (AUC in μM*min of generated ACV was in the order of LACV > LDACV > DLACV indicating their rate of metabolism. The AUC values of total drug obtained in the systemic circulation after oral administration LACV and LDACV were 1077.93 ± 236.09 and 1141.76 ± 73.67 μM*min, respectively. DLACV exhibited poor oral absorption. C max (μM and AUC of the intact prodrug obtained in the systemic circulation following oral administration of LDACV were almost 4–5 times higher than LACV. Moreover, concentrations achieved in the cornea after oral administration of LDACV were almost two times of LACV. Conclusions LDACV increased both the oral bioavailability and subsequent in vivo corneal uptake of ACV Hence, LDACV can be considered as the most promising drug candidate for delivery of ACV, in treatment of both genital herpes and ocular herpes keratitis after oral administration.

Pharmacokinetics of Cefovecin in Cynomolgus Macaques (Macaca fascicularis), Olive Baboons (Papio anubis), and Rhesus Macaques (Macaca mulatto)

Energy Technology Data Exchange (ETDEWEB)

Raabe, Brigitte M.; Lovaglio, Jamie A.; Grover, GScott; Brown, Scott A.; Boucher, Joseph F.; Yuan, Yang; Civil, Jacqueline R.; Gillhouse, Kimberly A.; Stubbs, Makeida N.; Hoggatt, Amber F.; Halliday, Lisa C.; Fortman, Jeffrey D.

2011-05-01

Cefovecin sodium is a long-acting, third-generation, cephalosporin antibiotic approved for the treatment of skin infections in dogs and cats. The pharmacokinetic properties of cefovecin were evaluated in cynomolgus macaques (Macaca fascicularis), olive baboons (Papio anubis), and rhesus macaques (Macaca mulatto) by using a single-dose (8 mg/kg SC) dosing regimen. Plasma cefovecin concentrations were determined by using ultra-performance liquid chromatography with tandem mass spectrometry, and a noncompartmental model was used to determine pharmacokinetic parameters. The half-life of cefovecin was 4.95 {+-} 1.47 h in cynomolgus macaques, 9.17 {+-} 1.84 h in olive baboons, and 8.40 {+-} 2.53 h in rhesus macaques. These values are considerably lower than the half-lives previously published for dogs (133 h) and cats (166 h). The extended half-life of cefovecin in dogs and cats is speculated to be due to active reabsorption of drug in the kidney tubules because plasma clearance is well below the normal glomerular filtration rate. In nonhuman primates, renal clearance rates approximated plasma clearance rates, suggesting that active renal reabsorption of cefovecin does not occur in these species. The pharmacokinetic properties of cefovecin in nonhuman primates are vastly different from the pharmacokinetic properties in dogs and cats, precluding its use as a long-acting antibiotic in nonhuman primates. This study highlights the importance of performing pharmacokinetic studies prior to extralabel drug usage.

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.

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

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

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...

Metoprolol Dose Equivalence in Adult Men and Women Based on Gender Differences: Pharmacokinetic Modeling and Simulations

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Andy R. Eugene

2016-11-01

Full Text Available Recent meta-analyses and publications over the past 15 years have provided evidence showing there are considerable gender differences in the pharmacokinetics of metoprolol. Throughout this time, there have not been any research articles proposing a gender stratified dose-adjustment resulting in an equivalent total drug exposure. Metoprolol pharmacokinetic data was obtained from a previous publication. Data was modeled using nonlinear mixed effect modeling using the MONOLIX software package to quantify metoprolol concentration–time data. Gender-stratified dosing simulations were conducted to identify equivalent total drug exposure based on a 100 mg dose in adults. Based on the pharmacokinetic modeling and simulations, a 50 mg dose in adult women provides an approximately similar metoprolol drug exposure to a 100 mg dose in adult men.

A review of morphine and morphine-6-glucuronide's pharmacokinetic-pharmacodynamic relationships in experimental and clinical pain

DEFF Research Database (Denmark)

Sverrisdóttir, Eva; Lund, Trine Meldgaard; Olesen, Anne Estrup

2015-01-01

Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can...... a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates....... Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course...

[Integration of pharmacokinetics and pharmacodynamics based on the in vivo analysis of drug-receptor binding].

Science.gov (United States)

Yamada, Shizuo

2015-01-01

  As I was deeply interested in the effects of drugs on the human body, I chose pharmacology as the subject of special study when I became a 4th year student at Shizuoka College of Pharmacy. I studied abroad as a postdoctoral fellow for two years, from 1978, under the tutelage of Professor Henry I. Yamamura (pharmacology) in the College of Medicine at the University of Arizona, USA. He taught me a variety of valuable skills such as the radioreceptor binding assay, which represented the most advanced technology developed in the US at that time. After returning home, I engaged in clarifying receptor abnormalities in pathological conditions, as well as in drug action mechanisms, by making the best use of this radioreceptor binding assay. In 1989, following the founding of the University of Shizuoka, I was invited by Professor Ryohei Kimura to join the Department of Pharmacokinetics. This switch in discipline provided a good opportunity for me to broaden my perspectives in pharmaceutical sciences. I worked on evaluating drug-receptor binding in vivo as a combined index for pharmacokinetics and pharmacological effect manifestation, with the aim of bridging pharmacology and pharmacokinetics. In fact, by focusing on data from in vivo receptor binding, it became possible to clearly rationalize the important consideration of drug dose-concentration-action relationships, and to study quantitative and kinetic analyses of relationships among pharmacokinetics, receptor binding and pharmacological effects. Based on this concept, I was able to demonstrate the utility of dynamic analyses of drug-receptor binding in drug discovery, drug fostering, and the proper use of pharmacokinetics with regard to many drugs.

Nonstandard Finite Difference Method Applied to a Linear Pharmacokinetics Model

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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.

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...

Relationship between pharmacokinetics of 5-FU in plasma and in saliva, and toxicity of 5-fluorouracil/folinic acid

NARCIS (Netherlands)

Jansman, FGA; Coenen, JLLM; De Graaf, JC; Tobi, H; Sleijfer, DT; Brouwers, JRBJ

2002-01-01

Background: Dose adaptation based on pharmacokinetic parameters has been shown to decrease toxicity of some 5-fluorouracil(5-FU)-based continuous infusion regimens. Patients and Methods: In the present study the relationship between 5-FU pharmacokinetics in plasma and in saliva, and toxicity was

Pharmacokinetics in Morbid Obesity: Influence of Two Bariatric Surgery Techniques on Paracetamol and Caffeine Metabolism.

Science.gov (United States)

Goday Arno, Albert; Farré, Magí; Rodríguez-Morató, Jose; Ramon, Jose M; Pérez-Mañá, Clara; Papaseit, Esther; Civit, Ester; Langohr, Klaus; Lí Carbó, Marcel; Boix, David Benaiges; Nino, Olga Castañer; Le Roux, Juana Antonia Flores; Pera, Manuel; Grande, Luis; de la Torre, Rafael

2017-12-01

The purpose of the study was to study the impact of the two most common bariatric surgery techniques on paracetamol pharmacokinetics (a marker of gastric emptying) and caffeine metabolism (a marker of liver function). In the present prospective study, we studied 24 morbid obese patients before, at 4 weeks, and 6 months after having undergone sleeve gastrectomy (n = 10) or Roux-en-Y gastric bypass (n = 14). For comparative purposes, 28 healthy controls (14 normal weights and 14 overweights) were also included in the study. Paracetamol pharmacokinetics was altered in the obese participants leading to lower bioavailability. Bariatric surgery resulted in faster absorption and normalized pharmacokinetic parameters, prompting an increase in paracetamol bioavailability. No differences were found between surgical procedures. In the case of caffeine, the ratio paraxanthine/caffeine did not differ between morbid obese and healthy individuals. This ratio remained unmodified after surgery, indicating that the liver function (assessed by cytochrome P450 1A2 activity) was unaffected by obesity or bariatric surgery. Paracetamol pharmacokinetics and caffeine plasma levels are altered in severely obese patients. The two studied bariatric surgical techniques normalize paracetamol oral bioavailability without impairing the liver function (measured by cytochrome P450 1A2 activity).

Pharmacokinetics of Intraperitoneal Cefalothin and Cefazolin in Patients Being Treated for Peritoneal Dialysis-Associated Peritonitis.

Science.gov (United States)

Roberts, Darren M; Ranganathan, Dwarakanathan; Wallis, Steven C; Varghese, Julie M; Kark, Adrian; Lipman, Jeffrey; Roberts, Jason A

2016-01-01

♦ The standard treatment of peritoneal dialysis (PD)-associated peritonitis (PD-peritonitis) is intraperitoneal (IP) administration of antibiotics. Only limited data on the pharmacokinetics and appropriateness of contemporary dose recommendations of IP cefalothin and cefazolin exist. The aim of this study was to describe the pharmacokinetics of IP cefalothin and cefazolin in patients treated for PD-peritonitis. ♦ As per international guidelines, IP cefalothin or cefazolin 15 mg/kg once daily was dosed with gentamicin in a 6-hour dwell to patients with PD-peritonitis during routine care. Serial plasma and PD effluent samples were collected over the first 24 hours of therapy. Antibiotic concentrations were quantified using a validated chromatographic method with pharmacokinetic analysis performed using a non-compartmental approach. ♦ Nineteen patients were included (cefalothin n = 8, cefazolin n = 11). The median bioavailability for both antibiotics exceeded 92%, but other pharmacokinetic parameters varied markedly between antibiotics. Both antibiotics achieved high PD effluent concentrations throughout the antibiotic dwell. Cefazolin had a smaller volume of distribution compared with cefalothin (14 vs 40 L, p = 0.003). The median trough total plasma antibiotic concentration for cefazolin and cefalothin during the dwell differed (plasma 56 vs 13 mg/L, p Peritoneal Dialysis.

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

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

Effect of antibodies to calcitonin on the pharmacokinetics and the pharmacodynamics of the hormone.

Science.gov (United States)

Tagliaro, F; Dorizzi, R; Luisetto, G

1995-01-01

Calcitonin pharmacokinetics and pharmacodynamics were studied in two groups of patients with postmenopausal osteoporosis, who, treated for one year with intranasal Asu1.7-eel calcitonin (eCT), had (Ab+) and had not (Ab-) developed a specific immune response to the drug. The treatment consisted of daily intranasal administrations of eCT (80 IU/die) with 1 g supplemental calcium. Eight women who had developed specific antibodies and 5 who had not, were given 50 IU of CT i.m., in order to assess the pharmacokinetics and pharmacodynamics of the drug. The rise of serum levels of the hormone was significantly greater in Ab+ than in Ab- patients. At the end of the study, no significant differences in mineral bone loss between the two groups were found. In conclusion, the presence of antibodies to eCT does not represent a negative event in the therapy of osteoporosis, but significantly affects the pharmacokinetics of the drug.

Pharmacokinetic models relevant to toxicity and metabolism for uranium in humans and animals

International Nuclear Information System (INIS)

Wrenn, M.E.

1989-01-01

Models to predict short and long term accumulation of uranium in the human kidney are reviewed and summarised. These are generally first order linear compartmental models or pseudo-pharmacokinetic models such as the retention model of the ICRP. Pharmacokinetic models account not only for transfer from blood to organs, but also recirculation from the organ to blood. The most recent information on mammalian and human metabolism of uranium is used to establish a revised model. The model is applied to the short term accumulation of uranium in the human kidney after a single rapid dosage to the blood, such as that obtained by inhaling UF6 or its hydrolysis products. It is shown that the maximum accumulation in the kidney under these conditions is less than the fraction of the material distributed from the blood to kidney if a true pharmacokinetic model is used. The best coefficients applicable to man in the authors' view are summarised in model V. For a half-time of two days in the mammalian kidney, the maximum concentration in kidney is 75% of that predicted by a retention model such as that used by the ICRP following a single acute intake. We conclude that one must use true pharmacokinetic models, which incorporate recirculation from the organs to the blood, in order to realistically predict time dependent uptake in the kidneys and other organs. Information is presented showing that the half-time for urinary excretion of soluble uranium in man after inhalation of UF6 is about one quarter of a day. (author)

Once-daily dosing of saquinavir and low-dose ritonavir in HIV-1-infected individuals: a pharmacokinetic pilot study

NARCIS (Netherlands)

van Heeswijk, R. P.; Veldkamp, A. I.; Mulder, J. W.; Meenhorst, P. L.; Lange, J. M.; Beijnen, J. H.; Hoetelmans, R. M.

2000-01-01

To investigate the steady-state pharmacokinetics of a once-daily dosing regimen of saquinavir soft gelatin capsules in combination with a low dose of ritonavir in HIV-1-infected individuals. Open-label, multi-dose, pharmacokinetic pilot study. Seven HIV-1-infected individuals who were treated with

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...

Pemetrexed safety and pharmacokinetics in patients with third-space fluid

DEFF Research Database (Denmark)

Dickgreber, Nicolas J; Sørensen, Jens Benn; Paz-Ares, Luis G

2010-01-01

Pemetrexed is established as first-line treatment with cisplatin for malignant pleural mesothelioma and advanced nonsquamous non-small-cell lung cancer (NSCLC) and as single-agent second-line treatment for nonsquamous NSCLC. Because the structure and pharmacokinetics of pemetrexed are similar...

The pharmacokinetics and safety profile of oral ganciclovir in combination with trimethoprim in HIV- and CMV-seropositive patients

Science.gov (United States)

Jung, Donald; AbdelHameed, Magdy H; Hunter, John; Teitelbaum, Philip; Dorr, Albert; Griffy, Kay

1999-01-01

Aims We investigated the pharmacokinetics and safety profile of oral ganciclovir coadministered with trimethoprim in HIV-and CMV-seropositive patients. Methods In an open-label, randomized, 3-way crossover study, 12 adult males received oral ganciclovir 1000 mg every 8h, oral trimethoprim 200 mg once daily, or both drugs concomitantly in a sequence of three 7-day treatment periods. Pharmacokinetic parameters were determined and adverse events recorded for each treatment. Results The presence of trimethoprim significantly decreased CLr (12.9%, P = 0.0068) and increased t1/2 (18.1%, P = 0.0378) of ganciclovir. However, these changes are unlikely to be clinically meaningful. There were no statistically significant changes in trimethoprim pharmacokinetic parameters in the presence of ganciclovir, with the exception of a 12.7% increase in Cmin. Ganciclovir was well tolerated when administered alone or in combination with trimethoprim. Conclusions There was no clinically significant pharmacokinetic interaction between oral ganciclovir and trimethoprim when coadministered. PMID:10215748

Tranexamic Acid Mechanisms and Pharmacokinetics In Traumatic Injury

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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

Population pharmacokinetics of artesunate and amodiaquine in African children

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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

Effect of age on the pharmacokinetics of polymorphic nimodipine in rats after oral administration

DEFF Research Database (Denmark)

Liu, Wenli; Wang, Xiaona; Chen, Ruilian

2016-01-01

The previous investigation has proved that their existed pharmacokinetic difference between the different crystal forms of the polymorphic drugs after oral administration. However, no systemic investigations have been made on the change of this pharmacokinetic difference, resulted either from...... and 3.06 in 9-month-old rats. Since age difference could result in unparallelled change of the absorption and bioavailability of the polymorphic drugs, the results in this experiment are of value for further investigation of crystal form selection in clinical trials and rational clinical application...

Pharmacokinetic Studies of Chinese Medicinal Herbs Using an Automated Blood Sampling System and Liquid Chromatography-mass Spectrometry

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Yu-Tse Wu

2012-01-01

Full Text Available The safety of herbal products is one of the major concerns for the modernization of traditional Chinese medicine, and pharmacokinetic data of medicinal herbs guide us to design the rational use of the herbal formula. This article reviews the advantages of the automated blood sampling (ABS systems for pharmacokinetic studies. In addition, three commonly used sample preparative methods, protein precipitation, liquid-liquid extraction and solid-phase extraction, are introduced. Furthermore, the definition, causes and evaluation of matrix effects in liquid chromatography-mass spectrometry (LC/MS analysis are demonstrated. Finally, we present our previous works as practical examples of the application of ABS systems and LC/MS for the pharmacokinetic studies of Chinese medicinal herbs.

A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding.

Science.gov (United States)

Ye, Min; Nagar, Swati; Korzekwa, Ken

2016-04-01

Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

An Extrusion Spheronization Approach to Enable a High Drug Load Formulation of a Poorly Soluble Drug with a Low Melting Surfactant.

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Tatavarti, Aditya; Kesisoglou, Filippos

2015-11-01

Vitamin E tocopherol polyethylene glycol succinate (TPGS) is a non-ionic surface active agent, known to enhance the bioavailability of lipophilic compounds via wettability, solubility, and in some cases permeability enhancement. MK-0536 is an anti-retroviral drug with poor wettability and solubility and a high dose. Based on pharmacokinetic studies in dogs and humans, use of vitamin E TPGS in oral solid formulations of MK-0536 provides desired PK characteristics. The use of vitamin E TPGS, however, in solid dosage forms is limited because of the processing challenges resulting from its waxy nature and low melting temperature (∼37°C). The current study, for the first time, demonstrates the use of an alternative low pressure extrusion and spheronization approach to enable high loadings of the poorly soluble, poorly compactable drug and relatively high levels of vitamin E TPGS. This approach not only aided in mitigating processing challenges arising from most high energy process steps such as milling, compression, and coating, but also enabled a higher drug load formulation that provided superior bioperformance relative to a conventional high shear wet granulated formulation. An encapsulated dosage form consisting of pellets prepared by extrusion spheronization with 75% (w/w) MK-0536 and 10% (w/w) vitamin E TPGS was developed. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Pharmacokinetics of dexmedetomidine administered to patients with end-stage renal failure and secondary hyperparathyroidism undergoing general anaesthesia.

Science.gov (United States)

Zhong, W; Zhang, Y; Zhang, M-Z; Huang, X-H; Li, Y; Li, R; Liu, Q-W

2018-06-01

The primary objective of this study was to compare the pharmacokinetics of dexmedetomidine in patients with end-stage renal failure and secondary hyperparathyroidism with those in normal individuals. Fifteen patients with end-stage renal failure and secondary hyperparathyroidism (Renal-failure Group) and 8 patients with normal renal and parathyroid gland function (Control Group) received intravenous 0.6 μg/kg dexmedetomidine for 10 minutes before anaesthesia induction. Arterial blood samples for plasma dexmedetomidine concentration analysis were drawn at regular intervals after the infusion was stopped. The pharmacokinetics were analysed using a nonlinear mixed-effect model with NONMEM software. The statistical significance of covariates was examined using the objective function (-2 log likelihood). In the forward inclusion and backward deletion, covariates (age, weight, sex, height, lean body mass [LBM], body surface area [BSA], body mass index [BMI], plasma albumin and grouping factor [renal failure or not]) were tested for significant effects on pharmacokinetic parameters. The validity of our population model was also evaluated using bootstrap simulations. The dexmedetomidine concentration-time curves fitted best with the principles of a two-compartmental pharmacokinetic model. No covariate of systemic clearance further improved the model. The final pharmacokinetic parameter values were as follows: V 1  = 60.6 L, V 2  = 222 L, Cl 1  = 0.825 L/min and Cl 2  = 4.48 L/min. There was no influence of age, weight, sex, height, LBM, BSA, BMI, plasma albumin and grouping factor (renal failure or not) on pharmacokinetic parameters. Although the plasma albumin concentrations (35.46 ± 4.13 vs 44.10 ± 1.12 mmol/L, respectively, P Renal-failure Group than in the Control Group (81.68 ± 18.08 vs 63.07 ± 13.45 μg/kg/min, respectively, P renal failure and hyperparathyroidism were similar to those in patients with normal renal function. Further

Clinical Pharmacokinetics of Penicillins, Cephalosporins and Aminoglycosides in the Neonate: A Review

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Gian Maria Pacifici

2010-08-01

Full Text Available Bacterial infections are common in the neonates and are a major cause of morbidity and mortality. Sixty percent of preterm infants admitted to neonatal intensive care units received at least one antibiotic during the first week of life. Penicillins, aminoglycosides and cephalosporins comprised 53, 43 and 16%, respectively. Kinetic parameters such as the half-life (t1/2, clearance (Cl, and volume of distribution (Vd change with development, so the kinetics of penicillins, cephalosporins and aminoglycosides need to be studied in order to optimise therapy with these drugs. The aim of this study is to review the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate in a single article in order to provide a critical analysis of the literature and thus provide a useful tool in the hands of physicians. The bibliographic search was performed electronically using PubMed, as the search engine, until February 2nd, 2010. Medline search terms were as follows: pharmacokinetics AND (penicillins OR cephalosporins OR aminoglycosides AND infant, newborn, limiting to humans. Penicillins, cephalosporins and aminoglycosides are fairly water soluble and are mainly eliminated by the kidneys. The maturation of the kidneys governs the pharmacokinetics of penicillins, cephalosporins and aminoglycosides in the neonate. The renal excretory function is reduced in preterms compared to term infants and Cl of these drugs is reduced in premature infants. Gestational and postnatal ages are important factors in the maturation of the neonate and, as these ages proceed, Cl of penicillins, cephalosporins and aminoglycosides increases. Cl and t1/2 are influenced by development and this must be taken into consideration when planning a dosage regimen with these drugs. More pharmacokinetic studies are required to ensure that the dose recommended for the treatment of sepsis in the neonate is evidence based.

Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues.

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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.

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

Excipient-drug pharmacokinetic interactions: Effect of disintegrants on efflux across excised pig intestinal tissues

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Werner Gerber

2018-04-01

Full Text Available Pharmaceutical excipients were designed originally to be pharmacologically inert. However, certain excipients were found to have altering effects on drug pharmacodynamics and/or pharmacokinetics. Pharmacokinetic interactions may be caused by modulation of efflux transporter proteins, intercellular tight junctions and/or metabolic enzyme amongst others. In this study, five disintegrants from different chemical classes were evaluated for P-glycoprotein (P-gp related inhibition and tight junction modulation effects. Bi-directional transport studies of the model compound, Rhodamine 123 (R123 were conducted in the absence (control group and presence (experimental groups of four concentrations of each selected disintegrant across excised pig jejunum tissue. The results showed that some of the selected disintegrants (e.g. Ac-di-sol® and Kollidon® CL-M increased R123 absorptive transport due to inhibition of P-gp related efflux, while another disintegrant (e.g. sodium alginate changed R123 transport due to inhibition of P-gp in conjunction with a transient opening of the tight junctions in a concentration dependent way. It may be concluded that the co-application of some disintegrants to the intestinal epithelium may lead to pharmacokinetic interactions with drugs that are susceptible to P-gp related efflux. However, the clinical significance of these in vitro permeation findings should be confirmed by means of in vivo studies. Keywords: Disintegrants, Excipient, Ex vivo, P-glycoprotein, Pharmacokinetic interactions, Rhodamine 123

A new approach to the compartmental analysis in pharmacokinetics: fractional time evolution of diclofenac.

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Popović, Jovan K; Atanacković, Milica T; Pilipović, Ana S; Rapaić, Milan R; Pilipović, Stevan; Atanacković, Teodor M

2010-04-01

This study presents a new two compartmental model and its application to the evaluation of diclofenac pharmacokinetics in a small number of healthy adults, during a bioequivalence trial. In the model the integer order derivatives are replaced by derivatives of real order often called fractional order derivatives. Physically that means that a history (memory) of a biological process, realized as a transfer from one compartment to another one with the mass balance conservation, is taken into account. This kind of investigations in pharmacokinetics is founded by Dokoumetzidis and Macheras through the one compartmental models while our contribution is the analysis of multi-dimensional compartmental models with the applications of the two compartmental model in evaluation of diclofenac pharmacokinetics. Two experiments were preformed with 12 healthy volunteers with two slow release 100 mg diclofenac tablet formulations. The agreement of the values predicted by the proposed model with the values obtained through experiments is shown to be good. Thus, pharmacokinetics of slow release diclofenac can be described well by a specific two compartmental model with fractional derivatives of the same order. Parameters in the model are determined by the least-squares method and the Particle Swarm Optimization (PSO) numerical procedure is used. The results show that the fractional order two compartmental model for diclofenac is superior in comparison to the classical two compartmental model. Actually this is true in general case since the classical one is a special case of the fractional one.

Raltegravir in HIV-1-Infected Pregnant Women: Pharmacokinetics, Safety, and Efficacy.

Science.gov (United States)

Blonk, Maren I; Colbers, Angela P H; Hidalgo-Tenorio, Carmen; Kabeya, Kabamba; Weizsäcker, Katharina; Haberl, Annette E; Moltó, José; Hawkins, David A; van der Ende, Marchina E; Gingelmaier, Andrea; Taylor, Graham P; Ivanovic, Jelena; Giaquinto, Carlo; Burger, David M

2015-09-01

The use of raltegravir in human immunodeficiency virus (HIV)-infected pregnant women is important in the prevention of mother-to-child HIV transmission, especially in circumstances when a rapid decline of HIV RNA load is warranted or when preferred antiretroviral agents cannot be used. Physiological changes during pregnancy can reduce antiretroviral drug exposure. We studied the effect of pregnancy on the pharmacokinetics of raltegravir and its safety and efficacy in HIV-infected pregnant women. An open-label, multicenter, phase 4 study in HIV-infected pregnant women receiving raltegravir 400 mg twice daily was performed (Pharmacokinetics of Newly Developed Antiretroviral Agents in HIV-Infected Pregnant Women Network). Steady-state pharmacokinetic profiles were obtained in the third trimester and postpartum along with cord and maternal delivery concentrations. Safety and virologic efficacy were evaluated. Twenty-two patients were included, of which 68% started raltegravir during pregnancy. Approaching delivery, 86% of the patients had an undetectable viral load (HIV-infected. Exposure to raltegravir was highly variable. Overall area under the plasma concentration-time curve (AUC) and plasma concentration at 12 hours after intake (C12h) plasma concentrations in the third trimester were on average 29% and 36% lower, respectively, compared with postpartum: Geometric mean ratios (90% confidence interval) were 0.71 (.53-.96) for AUC0-12h and 0.64 (.34-1.22) for C12h. The median ratio of raltegravir cord to maternal blood was 1.21 (interquartile range, 1.02-2.17; n = 9). Raltegravir was well tolerated during pregnancy. The pharmacokinetics of raltegravir showed extensive variability. The observed mean decrease in exposure to raltegravir during third trimester compared to postpartum is not considered to be of clinical importance. Raltegravir can be used in standard dosages in HIV-infected pregnant women. NCT00825929. © The Author 2015. Published by Oxford University

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

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...

Pharmacokinetic analysis of Gd-DTPA enhancement in dynamic MR of breast carcinoma

International Nuclear Information System (INIS)

Hess, T.; Knopp, M.V.; Hoffmann, U.; Brix, G.; Junkermann, H.; Zuna, I.; Fournier, D. von; Kaick, G. van

1994-01-01

Dynamic Gd-DTPA enhanced MR of the breast was performed in one single slice in 27 patients with suspicious nodular lesions. The results could be histologically verified in all cases. A rapid spin-echo sequence with a time resolution of 8.75 s was used for the dynamic examination. The signal changes were analysed using a pharmacokinetic model which allowed parametrization of the contrast enhancement and transformation of the data into colour coded parameter images. The parameters allowed reliable distinction of 9 benign from 18 malignant lesions (p 21 ''). One fibroadenoma could not be distinguished from the carcinomas. Lymph node metastases and the pharmacokinetic parameter amplitude correlated significantly (p<0.05). (orig.)

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.

Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study.

Science.gov (United States)

Wiebe, Sabrina; Schnell, David; Külzer, Raimund; Gansser, Dietmar; Weber, Anne; Wallenstein, Gudrun; Halabi, Atef; Conrad, Anja; Wind, Sven

2017-06-01

Afatinib is an oral irreversible ErbB-Family Blocker indicated for treatment of patients with EGFR mutation positive advanced non-small cell lung cancer. This trial assessed whether renal impairment influences the pharmacokinetics and safety of afatinib. This was an open-label, single-dose study. Pharmacokinetic parameters after afatinib 40 mg were investigated in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate 30-59 mL/min/1.73 m 2 and 15-29 mL/min/1.73 m 2 , respectively) and healthy matched controls (n = 14). Plasma and urine samples were collected before and up to 14 days after dosing for pharmacokinetic and plasma protein-binding assessment. Primary endpoints were area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUC last ) and maximum plasma concentration (C max ) between subjects with renal impairment and healthy matched controls. Pharmacokinetic profiles and plasma protein binding were similar in all groups. The extent of exposure, as indicated by AUC last and C max , was generally similar between the matched treatment groups, with the exception of the geometric mean ratio of AUC last for subjects with severe renal impairment, which showed a trend towards a higher value compared with matched healthy subjects (150.0 % [90 % CI 105.3-213.7]) Inter-individual variability was moderate (geometric mean coefficient of variation 28-39 % for moderate impairment, 34-42 % for severe impairment). Afatinib was well tolerated and urinary excretion was minimal. Moderate-to-severe renal impairment had a minor influence on the pharmacokinetics of afatinib that was within the observed inter-individual variability, suggesting that afatinib treatment can be considered in this patient population. Registered at ClinicalTrials.gov as NCT02096718.

Pharmacokinetics and clinical efficacy of phenobarbital in asphyxiated newborns treated with hypothermia: a thermopharmacological approach.

Science.gov (United States)

van den Broek, M P H; Groenendaal, F; Toet, M C; van Straaten, H L M; van Hasselt, J G C; Huitema, A D R; de Vries, L S; Egberts, A C G; Rademaker, C M A

2012-10-01

Therapeutic hypothermia can influence the pharmacokinetics and pharmacodynamics of drugs, the discipline which is called thermopharmacology. We studied the effect of therapeutic hypothermia on the pharmacokinetics of phenobarbital in asphyxiated neonates, and the clinical efficacy and the effect of phenobarbital on the continuous amplitude-integrated electroencephalography (aEEG) in a prospective study. Data were obtained from the prospective SHIVER study, performed in two of the ten Dutch level III neonatal intensive care units. Phenobarbital data were collected between 2008 and 2010. Newborns were eligible for inclusion if they had a gestational age of at least 36 weeks and presented with perinatal asphyxia and encephalopathy. According to protocol in both hospitals an intravenous (repeated) loading dose of phenobarbital 20 mg/kg divided in 1-2 doses was administered if seizures occurred or were suspected before or during the hypothermic phase. Phenobarbital plasma concentrations were measured in plasma using a fluorescence polarization immunoassay. aEEG was monitored continuously. A one-compartmental population pharmacokinetic/pharmacodynamic model was developed using a multi-level Markov transition model. No (clinically relevant) effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness was 66%. While we still advise an initial loading dose of 20 mg/kg, clinicians should not be reluctant to administer an additional dose of 10-20 mg/kg. An additional dose should be given before switching to a second-line anticonvulsant drug. Based on our pharmacokinetic/pharmacodynamic model, administration of phenobarbital under hypothermia seems to reduce the transition rate from a continuous normal voltage (CNV) to discontinuous normal voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to the additional neuroprotection of phenobarbital in infants with a CNV pattern.

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.

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...

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

Pharmacokinetics of linezolid in bone tissue investigated by in vivo microdialysis

DEFF Research Database (Denmark)

Stolle, L.B.; Plock, N.; Joukhadar, C.

2008-01-01

Pharmacokinetics of unbound anti-infectives in bone is difficult to characterize. The aim of this study was to assess the feasibility of the microdialysis technique to cancellous bone for single dose pharmacokinetic investigations of the anti-infective linezolid. Serial bone biopsies (left tibia......) and microdialysate samples (right tibia: 2 catheters) as well as plasma and bone marrow samples were obtained from 10 pigs. The concentrations of linezolid reached bacteriostatic levels in plasma, bone marrow, bone biopsies and microdialysates. With the use of microdialysis we here present the first results...... for unbound linezolid bone penetration. Unbound linezolid concentrations in bone obtained by microdialysis were lower than might have been expected from previous bone biopsy studies. To achieve effective concentrations (24 h) for susceptible organisms the chosen dose of linezolid might not be sufficient...

Pharmacokinetic and biopharmaceutic aspects of some psoralen derivatives used in dermatology

International Nuclear Information System (INIS)

Stolk, L.M.L.

1982-01-01

In the present thesis the pharmacokinetic and biopharmaceutic properties of some psoralen derivatives, that are used in photochemotherapy of dermatological diseases like vitiligo and psoriasis, are studied. Photochemotherapy is a combination of oral administration of one of the psoralen derivatives, 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) or 4, 5', 8-trimethylpsoralen (TMP), and irradiation with long wave ultraviolet light, U.V.-A (320-400 nm), two hours later. This treatment is commonly called PUVA (Psoralen-UV-A). The purpose of the investigation was to develop an 8-MOP dosage form with a fast and reproducible absorption. Various dosage forms of 8-MOP were administered to volunteers and patients and 8-MOP concentrations in body fluids determined. Also the pharmacokinetic properties of 5-MOP and TMP were investigated in a pilot study. (Auth.)

Population Pharmacokinetics of Morphine and Morphine-6-Glucuronide following Rectal Administration

DEFF Research Database (Denmark)

Brokjær, Anne; Kreilgaard, Mads; Olesen, Anne Estrup

2015-01-01

INTRODUCTION: To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: 1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), 2...... cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid...... chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. RESULTS: A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described...

Pharmacokinetics of Cefuroxime in Cortical and Cancellous Bone Obtained by Microdialysis - a Porcine Study

DEFF Research Database (Denmark)

Tøttrup, Mikkel; Forsingdal Hardlei, Tore; Bendtsen, Michael

2014-01-01

. As reference, free and total plasma concentrations were also measured. The animals received a bolus of 1500 mg cefuroxime over 30 min. No significant differences between key pharmacokinetic parameters for sealed and unsealed drill holes in cortical bone were found. The mean area under the concentration...... (MD) technique for measurement of cefuroxime in bone, and to obtain pharmacokinetic profiles for the same drug in porcine cortical and cancellous bone. Measurements were conducted in bone-wax sealed and unsealed drill holes in cortical bone, in drill holes in cancellous bone and in subcutaneous tissue...

Flucytosine Pharmacokinetics in a Critically Ill Patient Receiving Continuous Renal Replacement Therapy.

Science.gov (United States)

Kunka, Megan E; Cady, Elizabeth A; Woo, Heejung C; Thompson Bastin, Melissa L

2015-01-01

Purpose. A case report evaluating flucytosine dosing in a critically ill patient receiving continuous renal replacement therapy. Summary. This case report outlines an 81-year-old male who was receiving continuous venovenous hemofiltration (CVVH) for acute renal failure and was being treated with flucytosine for the treatment of disseminated Cryptococcus neoformans infection. Due to patient specific factors, flucytosine was empirically dose adjusted approximately 50% lower than intermittent hemodialysis (iHD) recommendations and approximately 33% lower than CRRT recommendations. Peak and trough levels were obtained, which were supratherapeutic, and pharmacokinetic parameters were calculated. The patient experienced thrombocytopenia, likely due to elevated flucytosine levels, and flucytosine was ultimately discontinued. Conclusion. Despite conservative flucytosine dosing for a patient receiving CVVH, peak and trough serum flucytosine levels were supratherapeutic (120 μg/mL at 2 hours and 81 μg/mL at 11.5 hours), which increased drug-related adverse effects. The results indicate that this conservative dosing regimen utilizing the patient's actual body weight was too aggressive. This case report provides insight into flucytosine dosing in CVVH, a topic that has not been investigated previously. Further pharmacokinetic studies of flucytosine dosing in critically ill patients receiving CVVH are needed in order to optimize pharmacokinetic and pharmacodynamic parameters while avoiding toxic flucytosine exposure.

Pharmacokinetic study of benfotiamine and the bioavailability assessment compared to thiamine hydrochloride.

Science.gov (United States)

Xie, Feifan; Cheng, Zeneng; Li, Sanwang; Liu, Xingling; Guo, Xin; Yu, Peng; Gu, Zhenkun

2014-06-01

Benfotiamine is a lipid-soluble thiamine precursor which can transform to thiamine in vivo and subsequently be metabolized to thiamine monophosphate (TMP) and thiamine diphosphate (TDP). This study investigated the pharmacokinetic profiles of thiamine and its phosphorylated metabolites after single- and multiple-dose administration of benfotiamine in healthy Chinese volunteers, and assessed the bioavailability of orally benfotiamine administration compared to thiamine hydrochloride. In addition, concentration of hippuric acid in urine which is produced in the transformation process of benfotiamine was determined. The results showed that thiamine and its phosphorylated metabolites exhibited different pharmacokinetic characteristics in plasma, blood and erythrocyte, and one-compartment model provided the best fit for pharmacokinetic profiles of thiamine. The transformation process of benfotiamine to thiamine produced large amount of hippuric acid. No accumulation of hippuric acid was observed after multiple-dose of benfotiamine. Compared to thiamine hydrochloride, the bioavailability of thiamine in plasma and TDP in erythrocyte after oral administration of benfotiamine were 1147.3 ± 490.3% and 195.8 ± 33.8%, respectively. The absorption rate and extent of benfotiamine systemic availability of thiamine were significantly increased indicating higher bioavailability of thiamine from oral dose of benfotiamine compared to oral dose of thiamine hydrochloride. © 2014, The American College of Clinical Pharmacology.

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.

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

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...

Clinical trial: single- and multiple-dose pharmacokinetics of polyethylene glycol (PEG-3350) in healthy young and elderly subjects.

Science.gov (United States)

Pelham, R W; Nix, L C; Chavira, R E; Cleveland, M Vb; Stetson, P

2008-07-01

The pharmacokinetics of polyethylene glycol 3350 (PEG-3350) have not been fully described because of lack of a sufficiently sensitive analytical method. To describe the pharmacokinetics of PEG-3350 in humans. A highly sensitive, high performance liquid chromatography with mass spectrometry (HPLC/MS/MS) method was developed for PEG-3350 in urine, plasma and faeces with quantification limits of 30 ng/mL, 100 ng/mL and 500 microg/g respectively. Noncompartmental pharmacokinetics methods were used and the effects of gender, age, renal status and dosing frequency were examined after the oral administration of 17 g to healthy volunteers. Peak PEG-3350 plasma concentrations occurred at 2-4 h and declined to nonquantifiable levels usually within 18 h after single and multiple doses, with a half-life of about 4-6 h. Steady state was reached within 5 days of dosing. Mean urinary excretion of the administered dose ranged from 0.19% to 0.25%. Age, gender or mild kidney impairment did not alter the pharmacokinetics of PEG-3350. Mean faecal excretion of the administered dose was 93% in young subjects. For the first time, a highly sensitive assay allowed comprehensive pharmacokinetics studies of PEG-3350 in humans. These studies confirmed that orally administered PEG-3350 is minimally absorbed, rapidly excreted and primarily eliminated via faeces.

Biodistribution and pharmacokinetic of 1E10 monoclonal antibody after subcutaneous administration in healthy mice

International Nuclear Information System (INIS)

León, M; Hernández, I; Aldana, L; Ayra, F; Castro, Y; Leyva, R; García, L; Casaco, A

2016-01-01

To evaluate biodistribution and pharmacokinetic of the 1E10, the molecule was radio labelled with 125I and incorporated into a cold antibody formulation. Isotopic labeling was carried out by means of standardized methods.Introduction:1E10 monoclonal antibody was developed at Centre of Molecular Immunology (CIM) as antitumoral drug with proved efficacy in experimental models. In the present investigation, biodistribution and pharmacokinetic studies were conducted with the help of radio isotopic labeling. Materials and methods: 1E10 was supplied by CIM and labeled with 125I by the iodogen method. To male Balb/c mice from CENPALAB a single subcutaneous administration of 1 mg/kg was performed in the supra scapular region and accommodated in metabolic cages during experiments. Blood samples were taken alternating five groups of three animals according with a sparse data design. Biodistribution was carried out by direct organ sampling and radioactive counting. Pharmacokinetic was performed by compartmental analysis. Urine and faces were collected at regular time intervals. Results: Observed pharmacokinetic behaviour is typical of an immunoglobulin in the assay system used, showing a slow clearance and a small volume of distribution. Biodistribution shows no preference for any sampled organs or tissues. Only a high relative uptake was observed in axillary and brachial lymph nodes close to administration site. (author)

Development of a paediatric population-based model of the pharmacokinetics of rivaroxaban.

Science.gov (United States)

Willmann, Stefan; Becker, Corina; Burghaus, Rolf; Coboeken, Katrin; Edginton, Andrea; Lippert, Jörg; Siegmund, Hans-Ulrich; Thelen, Kirstin; Mück, Wolfgang

2014-01-01

Venous thromboembolism has been increasingly recognised as a clinical problem in the paediatric population. Guideline recommendations for antithrombotic therapy in paediatric patients are based mainly on extrapolation from adult clinical trial data, owing to the limited number of clinical trials in paediatric populations. The oral, direct Factor Xa inhibitor rivaroxaban has been approved in adult patients for several thromboembolic disorders, and its well-defined pharmacokinetic and pharmacodynamic characteristics and efficacy and safety profiles in adults warrant further investigation of this agent in the paediatric population. The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for rivaroxaban doses of 10 and 20 mg in adults and to scale this model to the paediatric population (0-18 years) to inform the dosing regimen for a clinical study of rivaroxaban in paediatric patients. Experimental data sets from phase I studies supported the development and qualification of an adult PBPK model. This adult PBPK model was then scaled to the paediatric population by including anthropometric and physiological information, age-dependent clearance and age-dependent protein binding. The pharmacokinetic properties of rivaroxaban in virtual populations of children were simulated for two body weight-related dosing regimens equivalent to 10 and 20 mg once daily in adults. The quality of the model was judged by means of a visual predictive check. Subsequently, paediatric simulations of the area under the plasma concentration-time curve (AUC), maximum (peak) plasma drug concentration (C max) and concentration in plasma after 24 h (C 24h) were compared with the adult reference simulations. Simulations for AUC, C max and C 24h throughout the investigated age range largely overlapped with values obtained for the corresponding dose in the adult reference simulation for both body weight-related dosing regimens. However

Meta-Analysis of Clinical Studies Supports the Pharmacokinetic Variability Hypothesis for Acquired Drug Resistance and Failure of Antituberculosis Therapy

OpenAIRE

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

2012-01-01

Laboratory studies have questioned nonadherence as a cause of antituberculosis drug failure and propose that between-patient pharmacokinetic variability may be the cause. This meta-analysis provides clinical evidence that pharmacokinetic variability of isoniazid alone leads to worse microbiological failure, relapse, and acquired drug resistance.

Influence of high-dose ketoconazole on the pharmacokinetics of docetaxel

NARCIS (Netherlands)

Engels, Frederike K.; Mathot, Ron A. A.; Loos, Walter J.; van Schaik, Ron H. N.; Verweij, Jaap

2006-01-01

The pharmacokinetics (PK) of docetaxel are characterized by large inter-individual variability in systemic drug exposure (AUC) and drug clearance. The PK variability is thought to be largely related to differences in the catalytic function of CYP3A, involved in docetaxel metabolism and elimination.

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 ...

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

Phenobarbital in intensive care unit pediatric population: predictive performances of population pharmacokinetic model.

Science.gov (United States)

Marsot, Amélie; Michel, Fabrice; Chasseloup, Estelle; Paut, Olivier; Guilhaumou, Romain; Blin, Olivier

2017-10-01

An external evaluation of phenobarbital population pharmacokinetic model described by Marsot et al. was performed in pediatric intensive care unit. Model evaluation is an important issue for dose adjustment. This external evaluation should allow confirming the proposed dosage adaptation and extending these recommendations to the entire intensive care pediatric population. External evaluation of phenobarbital published population pharmacokinetic model of Marsot et al. was realized in a new retrospective dataset of 35 patients hospitalized in a pediatric intensive care unit. The published population pharmacokinetic model was implemented in nonmem 7.3. Predictive performance was assessed by quantifying bias and inaccuracy of model prediction. Normalized prediction distribution errors (NPDE) and visual predictive check (VPC) were also evaluated. A total of 35 infants were studied with a mean age of 33.5 weeks (range: 12 days-16 years) and a mean weight of 12.6 kg (range: 2.7-70.0 kg). The model predicted the observed phenobarbital concentrations with a reasonable bias and inaccuracy. The median prediction error was 3.03% (95% CI: -8.52 to 58.12%), and the median absolute prediction error was 26.20% (95% CI: 13.07-75.59%). No trends in NPDE and VPC were observed. The model previously proposed by Marsot et al. in neonates hospitalized in intensive care unit was externally validated for IV infusion administration. The model-based dosing regimen was extended in all pediatric intensive care unit to optimize treatment. Due to inter- and intravariability in pharmacokinetic model, this dosing regimen should be combined with therapeutic drug monitoring. © 2017 Société Française de Pharmacologie et de Thérapeutique.

Pharmacokinetic study of isatin in dog plasma by liquid chromatography tandem mass spectrometry.

Science.gov (United States)

Ren, A; Wang, Q; Fang, Z; Gao, M; Wang, H; Zhang, J; Xu, W; Yue, W; Yin, L; Liu, Z; Li, X; Ding, B

2015-12-01

A sensitive and selective method was developed and validated to study the pharmacokinetics of isatin. The blood samples were pretreated by protein precipitation method using methanol. Quetiapine was used as an internal standard. After pretreatment, the samples were assayed by LC/MS/MS method and the pharmacokinetic parameters were calculated by WinNonlin 5.2 using non-compartment model. The separation was performed on a Venusil XBP PH column (5 µm, 2.0×100 mm) with an isocratic mobile phase consisted of methanol-water (containing 50 mM ammonium formate) (65:35, v/v) at a flow rate of 0.3 mL/min. The Agilent G6410B triple quadrupole LC/MS system was operated under the multiple reactions monitoring mode (MRM) using the electrospray ionization technique in positive mode. The lower limits of quantification (LLOQ) of the analyte of the method was 10 ng/mL. The method was linear with correlation coefficient >0.995. The intraday and interday accuracy and precision of the assay were acceptable. This method has been applied successfully to a pharmacokinetic study involving the oral and intravenous administration of isatin to beagle dogs.

Clinical Pharmacokinetics of IPX066: Evaluation of Dose Proportionality and Effect of Food in Healthy Volunteers.

Science.gov (United States)

Yao, Hsuan-Ming; Hsu, Ann; Gupta, Suneel; Modi, Nishit B

2016-01-01

IPX066 is an oral, extended-release capsule formulation of carbidopa-levodopa (CD-LD) available in 4 strengths. The goals of this investigation were to assess the dose proportionality of IPX066 and to study the effects of a high-fat, high-calorie meal and of sprinkling the capsule contents on applesauce on the pharmacokinetics of IPX066 in healthy volunteers. Three open-label studies were conducted. In the first study, subjects received 1 capsule of each IPX066 strength (23.75-95, 36.25-145, 48.75-195, and 61.25-245 mg of CD-LD). In the second study, subjects received 1 and 2 capsules of IPX066 245-mg LD under fasting conditions. In the third study, subjects received 2 capsules of IPX066 245-mg LD under 3 conditions: fasting; following a high-fat, high-calorie breakfast; and with the capsule contents sprinkled on applesauce under fasting conditions. Peak plasma concentrations (Cmax) and systemic exposure (AUCt, AUCinf) for LD and CD increased dose-proportionally over the range of the IPX066 capsule strengths. Comparison of 1 and 2 IPX066 245-mg LD capsules showed dose-proportional pharmacokinetics for Cmax and AUCt. Sprinkling the capsule contents on applesauce did not affect the pharmacokinetics. A high-fat, high-calorie meal delayed the initial increase in LD concentration by approximately 1 to 2 hours, reduced Cmax by 21%, and increased AUCinf by 13% compared with the fasted state. IPX066 shows dose-proportional pharmacokinetics. Sprinkling the capsule contents on applesauce does not affect the pharmacokinetics; a high-fat, high-calorie meal delayed absorption by 1 to 2 hours, slightly reduced Cmax, and slightly increased extent of absorption.

Safety and Pharmacokinetic Profiles of Repeated-Dose Micafungin in Children and Adolescents Treated for Invasive Candidiasis

Science.gov (United States)

Benjamin, Daniel K.; Deville, Jaime G.; Azie, Nkechi; Kovanda, Laura; Roy, Mike; Wu, Chunzhang; Arrieta, Antonio

2013-01-01

Background Micafungin is an echinocandin with proven efficacy against a broad range of fungal infections, including those caused by Candida species. Objective To evaluate the safety and pharmacokinetics of once-daily 3 mg/kg and 4.5 mg/kg micafungin in children with proven, probable, or suspected invasive candidiasis. Methods Micafungin safety and pharmacokinetics were assessed in two Phase I, open-label, repeat-dose trials. In Study 2101, children aged 2–16 years were grouped by weight to receive 3 mg/kg (≥25 kg) or 4.5 mg/kg (<25 kg) intravenous micafungin for 10–14 days. In Study 2102, children aged 4 months to <2 years received 4.5 mg/kg micafungin. Study protocols were otherwise identical. Results Safety was analyzed in seventy-eight and nine children in Studies 2101 and 2102, respectively. Although adverse events were experienced by most children (2101: n = 62; 2102: n = 9), micafungin-related adverse events were less common (2101: n = 28; 2102: n = 1), and the number of patients discontinuing due to adverse events was low (2101: n = 4; 2102: n = 1). The most common micafungin-related adverse events were infusion-associated symptoms, pyrexia, and hypomagnesemia (Study 2101), and liver function abnormalities (Study 2102). The micafungin pharmacokinetic profile was similar to that seen in other studies conducted in children, but different than that observed in adults. Conclusions In this small cohort of children, once-daily doses of 3 mg/kg and 4.5 mg/kg micafungin were well tolerated. Pharmacokinetic data will be combined in a population pharmacokinetic analysis to support U.S. dosing recommendations in children. PMID:23958810

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

Pharmacokinetic Comparison of Inhaled Fixed Combination vs. the Free Combination of Beclomethasone and Formoterol pMDIs in Asthmatic Children

DEFF Research Database (Denmark)

Chawes, Bl; Piccinno, A; Kreiner-Møller, Eskil

2012-01-01

/mL) ratio Test/Reference 0.97 [0.85-1.10]. All pharmacokinetic and pharmacodynamic endpoints showed non-superiority in favour of the Test drug. One adverse event (vertigo) occurred but was not considered treatment-related. CONCLUSION: BDP and Formoterol pharmacokinetic and pharmacodynamic effects are non...

Biodegradable nanoparticles for improved kidney bioavailability of rhein: preparation, characterization, plasma, and kidney pharmacokinetics.

Science.gov (United States)

Wei, Yinghui; Luo, Xiaoting; Guan, Jiani; Ma, Jianping; Zhong, Yicong; Luo, Jingwen; Li, Fanzhu

2017-11-01

The aim of this work is to develop biodegradable nanoparticles for improved kidney bioavailability of rhein (RH). RH-loaded nanoparticles were prepared using an emulsification solvent evaporation method and fully characterized by several techniques. Kidney pharmacokinetics was assessed by implanting a microdialysis probe in rat's kidney cortex. Blood samples were simultaneously collected (via femoral artery) for assessing plasma pharmacokinetics. Optimized nanoparticles were small, with a mean particle size of 132.6 ± 5.95 nm, and homogeneously dispersed. The charge on the particles was nearly zero, the encapsulation efficiency was 62.71 ± 3.02%, and the drug loading was 1.56 ± 0.15%. In vitro release of RH from the nanoparticles showed an initial burst release followed by a sustained release. Plasma and kidney pharmacokinetics showed that encapsulation of RH into nanoparticles significantly increased its kidney bioavailability (AUC kidney /AUC plasma  = 0.586 ± 0.072), clearly indicating that nanoparticles are a promising strategy for kidney drug delivery.

Absolute quantification of pharmacokinetic distribution of RES colloids in individuals with normal liver function

International Nuclear Information System (INIS)

Herzog, H.; Spohr, G.; Notohamiprodjo, G.; Feinendegen, L.E.

1987-01-01

Estimates of the radiation dose resulting from liver-spleen scintigraphy 99 TCsup(m)-labelled colloids are based on pharmacokinetic data mainly determined in animals. The aim of this study was to check the pharmacokinetic data by direct, absolute in vivo quantification in man. Liver and spleen activities were directly measured using a double-energy window technique. Activities in other organs were quantified by conjugate whole-body scans. All measurement procedures were checked using the whole-body Alderson phantom. Pharmacokinetic data for sulphur colloid, tin colloid, human serum albumin (HSA) millimicrospheres, and phytate were obtained in 13 to 20 normal subjects for each type of colloid. Depending on the colloid type liver uptake was between 54 and 75% of the total administered dose (TAD) and spleen uptake was 3.5 to 21% TAD. Activity measured in blood, urine, lung and thyroid proved to be far from negligible. The results of this work suggest a correction of the animal-based data of colloid distribution and radiation dose on the basis of the direct measurement of absolute uptake in man. (author)

Genetic Variants in Transcription Factors Are Associated With the Pharmacokinetics and Pharmacodynamics of Metformin

Science.gov (United States)

Goswami, S; Yee, SW; Stocker, S; Mosley, JD; Kubo, M; Castro, R; Mefford, JA; Wen, C; Liang, X; Witte, J; Brett, C; Maeda, S; Simpson, MD; Hedderson, MM; Davis, RL; Roden, DM; Giacomini, KM; Savic, RM

2014-01-01

One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator–activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response. PMID:24853734

Development of a simple chromatographic method for the determination of piracetam in human plasma and its pharmacokinetic evaluation.

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Barkat, K; Ahmad, M; Minhas, M U; Malik, M Z; Sohail, M

2014-07-01

The objective of study was to develop an accurate and reproducible HPLC method for determination of piracetam in human plasma and to evaluate pharmacokinetic parameters of 800 mg piracetam. A simple, rapid, accurate, precise and sensitive high pressure liquid chromatography method has been developed and subsequently validated for determination of piracetam. This study represents the results of a randomized, single-dose and single-period in 18 healthy male volunteers to assess pharmacokinetic parameters of 800 mg piracetam tablets. Various pharmacokinetic parameters were determined from plasma for piracetam and found to be in good agreement with previous reported values. The data was analyzed by using Kinetica® version 4.4 according to non-compartment model of pharmacokinetic analysis and after comparison with previous studies, no significant differences were found in present study of tested product. The major pharmacokinetic parameters for piracetam were as follows: t1/2 was (4.40 ± 0.179) h; Tmax value was (2.33 ± 0.105) h; Cmax was (14.53 ± 0.282) µg/mL; the AUC(0-∞) was (59.19 ± 4.402) µg · h/mL. AUMC(0-∞) was (367.23 ± 38.96) µg. (h)(2)/mL; Ke was (0.16 ± 0.006) h; MRT was (5.80 ± 0.227) h; Vd was (96.36 ± 8.917 L). A rapid, accurate and precise high pressure liquid chromatography method was developed and validated before the study. It is concluded that this method is very useful for the analysis of pharmacokinetic parameters, in human plasma and assured the safety and efficacy of piracetam, can be effectively used in medical practice. © Georg Thieme Verlag KG Stuttgart · New York.

Effect of fluoxetine on the pharmacokinetics of lansoprazole: a two-treatment period study in healthy male subjects.

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Vlase, Laurian; Popa, Adina; Neag, Maria; Muntean, Dana; Leucuta, Sorin E

2011-10-01

Fluoxetine is an inhibitor of the main metabolizing enzymes of lansoprazole and could influence the pharmacokinetics of lansoprazole. The changes in lansoprazole pharmacokinetics could have clinical significance concerning the safety of the therapy. The aim of this study was to evaluate the pharmacokinetic interaction between fluoxetine and lansoprazole in healthy subjects. A dose of lansoprazole 30 mg, alone or in combination with fluoxetine 60 mg, was administered to 18 healthy male subjects in a two-treatment study design, separated by an 8-day period in which fluoxetine alone was administered as a single oral daily dose. Plasma concentrations of lansoprazole were determined during a 12-hour period following drug administration. Lansoprazole plasma concentrations were determined by a validated liquid chromatography-mass spectrometry method. The pharmacokinetic parameters of lansoprazole were calculated using non-compartmental analysis. In the two periods of treatment, the mean maximum plasma concentration (C(max)) values were 817 ng/mL (lansoprazole alone) and 1370 ng/mL (lansoprazole in combination with fluoxetine after pre-treatment with fluoxetine for 8 days) [p lansoprazole and suggest that the observed interaction may be clinically significant, although its clinical relevance has yet to be confirmed.

Plasma Pharmacokinetic and Heart Distribution Studies of Z-GP-EPI ...

African Journals Online (AJOL)

22, 44 µmol/kg) by intravenous injection and 70 mice (30 ... anticancer agents at the tumor site, where drug- converting ... at a temperature of 25 ± 2 °C and a relative humidity of 75 ± 5 ..... Jones G. Pharmacokinetics of vitamin D toxicity. Am J.

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

Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens.

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Alqahtani, Saeed A; Alsultan, Abdullah S; Alqattan, Hussain M; Eldemerdash, Ahmed; Albacker, Turki B

2018-04-23

The purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analysed using the Architect i4000SR Immunoassay Analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. One-hundred and sixty-eight blood samples were analysed from 28 patients. The pharmacokinetics of vancomycin was best described by a two-compartment model with between-subject variability in CL, V of the central compartment, and V of the peripheral compartment. CL and central compartment V of vancomycin were related to CL CR , body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC 0--24 /MIC > 400 for an MIC of 1 mg/L, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15 mg/kg and 20 mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 mg/kg and 30 mg/kg) of vancomycin. Copyright © 2018 American Society for Microbiology.

Pharmacokinetics study of bio-adhesive tablet of Panax notoginseng saponins

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Feng Hanzhou

2011-06-01

Full Text Available Abstract Panax notoginseng saponin (PNS is the main active gradient of Chinese traditional medicine Panax notoginseng. Although its prominent therapeutic efficacy has been demonstrated by various researchers, the broader application is restricted by the low bioavailability of PNS. This article aims to discuss PNS's plasma pharmacokinetics after oral administration of bio-adhesive tablet of PNS to beagle dogs and improve its bioavailability in comparison with normal tablet. The bio-adhesive tablet was prepared according to our previous patent, using chitosan as main excipient. A simple and sensitive LC-MS/MS combined with solid-phase extraction (SPE method for the analysis of PNS in dog's plasma was developed in our previous study, and was validated to apply in the pharmacokinetics study in this work. Three ingredients: Notoginsenoside R1 (R1, Ginsenoside Rg1 (Rg1 and Ginsenoside Rb1 (Rb1 (Figure 1, were chosen as indicators of PNS to analyze it in vivo. Statistically significant increase (P

Doripenem pharmacokinetics in critically ill patients receiving continuous hemodiafiltration (CHDF).

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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.

The Pharmacokinetics of Enrofloxacin in Adult African Clawed Frogs (Xenopus laevis)

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Howard, Antwain M; Papich, Mark G; Felt, Stephen A; Long, Charles T; McKeon, Gabriel P; Bond, Emmitt S; Torreilles, Stéphanie L; Luong, Richard H; Green, Sherril L

2010-01-01

Pharmacokinetics of enrofloxacin, a fluoroquinolone antibiotic, was determined in adult female Xenopus laevis after single-dose administration (10 mg/kg) by intramuscular or subcutaneous injection. Frogs were evaluated at various time points until 8 h after injection. Plasma was analyzed for antibiotic concentration levels by HPLC. We computed pharmacokinetic parameters by using noncompartmental analysis of the pooled concentrations (naive pooled samples). After intramuscular administration of enrofloxacin, the half-life was 5.32 h, concentration maximum was 10.85 µg/mL, distribution volume was 841.96 mL/kg, and area under the time–concentration curve was 57.59 µg×h/mL; after subcutaneous administration these parameters were 4.08 h, 9.76 µg/mL, 915.85 mL/kg, and 47.42 µg×h/mL, respectively. According to plasma pharmacokinetics, Xenopus seem to metabolize enrofloxacin in a manner similar to mammals: low levels of the enrofloxacin metabolite, ciprofloxacin, were detected in the frogs’ habitat water and plasma. At necropsy, there were no gross or histologic signs of toxicity after single-dose administration; toxicity was not evaluated for repeated dosing. The plasma concentrations reached levels considered effective against common aquatic pathogens and suggest that a single, once-daily dose would be a reasonable regimen to consider when treating sick frogs. The treatment of sick frogs should be based on specific microbiologic identification of the pathogen and on antibiotic susceptibility testing. PMID:21205443

Comparative Pharmacokinetics and Allometric Scaling of Carboplatin in Different Avian Species.

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Gunther Antonissen

Full Text Available The use of chemotherapeutics as a possible treatment strategy in avian oncology is steadily increasing over the last years. Despite this, literature reports regarding dosing strategies and pharmacokinetic behaviour of chemotherapeutics in avian species are lacking. The aim of the present study was to investigate the pharmacokinetics of carboplatin in a representative species of the order of Galliformes, Anseriformes, Columbiformes and Psittaciformes. Eight chickens, ducks and pigeons and twenty-eight parakeets were administered carboplatin intravenously (5 mg/kg body weight. A specific and sensitive liquid chromatography-tandem mass spectrometry method was developed and validated for quantification of the free carboplatin in plasma of the four birds species (limit of quantification: 20 ng/mL for chicken and duck, 50 ng/mL for pigeon and 100 ng/mL for parakeets. Non-compartmental pharmacokinetic analysis and allometric scaling demonstrated a significant correlation (R² = 0.9769 between body weight (BW and elimination half-life (T1/2el. T1/2el ranged from 0.41 h in parakeets (BW: 61 ± 8 g to 1.16 h chickens (BW: 1909 ± 619 g. T1/2el is a good parameter for dose optimization of carboplatin in other avian species, since also the previously reported T1/2el in cockatoos (average BW: 769 ± 68 g of 1.00 h corresponds to the results obtained in the present study.

Cocrystals and alloys of nitazoxanide: enhanced pharmacokinetics.

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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.

Population pharmacokinetics of oxaliplatin (85 mg/m(2)) in combination with 5-fluorouracil in patients with advanced colorectal cancer

NARCIS (Netherlands)

Kho, Y.H.; Jansman, F.G.A.; Prins, N.H.; Neef, C.; Brouwers, J.R.B.J.

Pharmacokinetic (PK) studies of oxaliplatin, using a dose regimen of 85mg/m(2) are lacking. A PK model may be used in future studies to investigate the relationship between pharmacokinetics and dose limiting toxicity. The purpose of this study was to construct a population PK model to describe

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...

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.

Mefloquine pharmacokinetics and mefloquine-artesunate effectiveness in Peruvian patients with uncomplicated Plasmodium falciparum malaria

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Quezada Wilmer

2009-04-01

Full Text Available Abstract Background Artemisinin-based combination therapy (ACT is recommended as a means of prolonging the effectiveness of first-line malaria treatment regimens. Different brands of mefloquine (MQ have been reported to be non-bioequivalent; this could result in sub-therapeutic levels of mefloquine with decreased efficacy. In 2002, mefloquine-artesunate (MQ-AS combination therapy was adopted as the first-line treatment for uncomplicated Plasmodium falciparum malaria in the Amazon region of Peru. Although MQ resistance has yet to be reported from the Peruvian Amazon, it has been reported from other countries in the Amazon Region. Therefore, continuous monitoring is warranted to ensure that the first-line therapy remains efficacious. This study examines the in vivo efficacy and pharmacokinetic parameters through Day 56 of three commercial formulations of MQ (Lariam®, Mephaquin®, and Mefloquina-AC® Farma given in combination with artesunate. Methods Thirty-nine non-pregnant adults with P. falciparum mono-infection were randomly assigned to receive artesunate in combination with either (1 Lariam, (2 Mephaquin, or (3 Mefloquina AC. Patients were assessed on Day 0 (with blood samples for pharmacokinetics at 0, 2, 4, and 8 hours, 1, 2, 3, 7, and then weekly until day 56. Clinical and parasitological outcomes were based on the standardized WHO protocol. Whole blood mefloquine concentrations were determined by high-performance liquid chromatography and pharmacokinetic parameters were determined using non-compartmental analysis of concentration versus time data. Results By day 3, all patients had cleared parasitaemia except for one patient in the AC Farma arm; this patient cleared by day 4. No recurrences of parasitaemia were seen in any of the 34 patients. All three MQ formulations had a terminal half-life of 14–15 days and time to maximum plasma concentration of 45–52 hours. The maximal concentration (Cmax and interquartile range was 2,820 ng

Pharmacokinetic bioequivalence studies of a fixed-dose combination of tamsulosin and dutasteride in healthy volunteers.

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Fossler, Michael J; Collins, David A; Thompson, Meg M; Nino, Antonio; Bianco, Joseph J; Chetty, Dushen

2014-05-01

The combination of dutasteride and tamsulosin may be more effective for the treatment of symptomatic benign prostatic hyperplasia than either treatment alone. We report the results of three pharmacokinetics and tolerability studies, which used a dutasteride/tamsulosin HCl (0.5 mg/0.2 mg) fixed-dose combination (FDC) capsules containing a small dutasteride soft gelatin capsule (smaller than commercial Avodart™) and modified-release tamsulosin pellets that have different amounts of enteric coating. These studies compared the test products to commercial Avodart™ (dutasteride 0.5 mg) and two different commercial tamsulosin HCl 0.2 mg products, Harnal™ Capsules or Harnal-D™ Tablets, which are reportedly bioequivalent to each other. All three studies were randomized single-dose studies in healthy male adults. Study 1 [N = 86 (NCT01254071)] was a two-period crossover study of a dutasteride/tamsulosin HCl FDC versus coadministered Avodart™ and Harnal-D™ Tablets. The pharmacokinetics of both dutasteride and tamsulosin were studied. Study 2 [N = 27 (NCT01471678)] was a four-period crossover study of dutasteride/tamsulosin HCl FDC formulations versus Avodart™ and Harnal™ Capsules or Harnal-D™ Tablets. Only the pharmacokinetics of tamsulosin were studied. Study 3 [N = 40 (NCT01495026)] was a two-period study of dutasteride/tamsulosin HCl FDC formulations versus coadministered Avodart™ and Harnal-D™ Tablets. In this study, only the pharmacokinetics of tamsulosin were studied. Study 2 assessed fed-state pharmacokinetics. Studies 1 and 3 assessed fed- and fasted-state pharmacokinetics. All dutasteride/tamsulosin HCl FDC formulations and coadministered treatments were well-tolerated. In Study 1, the FDC dutasteride was bioequivalent to Avodart™ coadministered with tamsulosin under fed and fasted conditions. In Study 1, the FDC tamsulosin had a slower release than commercial Harnal-D™ Tablets coadministered with dutasteride (fed and fasted

The Influence of Normalization Weight in Population Pharmacokinetic Covariate Models.

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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.

Dose Assessment of Cefquinome by Pharmacokinetic/Pharmacodynamic Modeling in Mouse Model of Staphylococcus aureus Mastitis

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Yang Yu

2016-10-01

Full Text Available This work aimed to characterize the mammary gland pharmacokinetics of cefquinome after an intramammary administration and integrate pharmacokinetic/pharmacodynamic model. The pharmacokinetic profiles of cefquinome in gland tissue were measured using high performance liquid chromatograph. Therapeutic regimens covered various dosages ranging from 25 to 800 μg/gland and multiple dosing intervals of 8, 12, and 24 h. The in vivo bacterial killing activity elevated when dosage increased or when dosing intervals were shortened. The best antibacterial effect was demonstrated by a mean 1.5 log10CFU/gland visible count reduction. On the other hand, the results showed that the percentage of time duration of drug concentration exceeding the MIC during a dose interval (%T > MIC was generally 100% because of the influence of drug distribution caused by the blood-milk barrier. Therefore, pharmacokinetic/pharmacodynamic parameter of the ratio of area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC was used to describe the efficacy of cefquinome instead of %T > MIC. When the magnitude of AUC0-24/MIC exceeding 16571.55 h•mL/g, considerable activity of about 1.5 log10CFU/g gland bacterial count reduction was observed in vivo. Based on the Monte Carlo simulation, the clinical recommended regimen of three infusions of 75 mg per quarter every 12 h can achieve a 76.67% cure rate in clinical treatment of bovine mastitis caused by Staphylococcus aureus infection.