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Sample records for acceptable pharmacokinetic properties

  1. Moclobemide: evolution, pharmacodynamic, and pharmacokinetic properties.

    PubMed

    Bonnet, Udo

    2002-01-01

    The benzamide moclobemide is a reversible inhibitor of monoamine-oxidase-A (RIMA). It has been extensively evaluated in the treatment of a wide spectrum of depressive disorders and less extensively in anxiety disorders. While clinical aspects will be presented in a subsequent review, this article focuses primarily on moclobemide's evolution, pharmacodynamic and pharmacokinetic properties. In particular, the effects on neurotransmission and intracellular signal transduction, the neuroendocrine system, the tyramine pressure response and animal models of depression are surveyed. In addition, other CNS effects are reviewed with special respect to experimental serotonergic syndrome, anxiolytic and antinociceptive activity, sleep, cognition and driving performance, neuroprotection and seizures.

  2. Studies of the pharmacokinetic properties of nimorazole.

    PubMed Central

    Overgaard, J.; Overgaard, M.; Timothy, A. R.

    1983-01-01

    The pharmacokinetics of the hypoxic radio-sensitizer nimorazole were studied in 19 individuals after single oral doses of between 0.5-3.5 g. HPLC measurements showed, after a rapid absorption, a linear relationship between peak plasma concentration and given dose. Mean elimination half life was 3.1 h. A tendency to a dose-dependent variation in the apparent volume of distribution, total body clearance and elimination half life suggest non-linear pharmacokinetics of nimorazole. Tumour concentrations measured in 5 patients gave tumour/plasma ratios between 0.8-1.3. No toxicity was observed. The results indicate that nimorazole may have potential as a clinically useful hypoxic radiosensitizer. PMID:6871077

  3. Pharmacokinetic properties and in silico ADME modeling in drug discovery.

    PubMed

    Honório, Kathia M; Moda, Tiago L; Andricopulo, Adriano D

    2013-03-01

    The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME--absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry.

  4. 24 CFR 203.361 - Acceptance of property by Commissioner.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 2 2010-04-01 2010-04-01 false Acceptance of property by... AUTHORITIES SINGLE FAMILY MORTGAGE INSURANCE Contract Rights and Obligations Claim Procedure § 203.361 Acceptance of property by Commissioner. Upon receipt of notice of property transfer the Commissioner...

  5. 48 CFR 28.203-3 - Acceptance of real property.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Acceptance of real... Acceptance of real property. (a) Whenever a bond with a security interest in real property is submitted, the..., () performance bond, () or payment bond obligations as an individual surety on solicitation/contract...

  6. 10 CFR 603.550 - Acceptability of intellectual property.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Acceptability of intellectual property. 603.550 Section 603.550 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Pre-Award Business Evaluation Cost Sharing § 603.550 Acceptability of intellectual property....

  7. The ACCEPT 2.0 database of galaxy cluster properties

    NASA Astrophysics Data System (ADS)

    Baldi, Alessandro; Donahue, Megan; Voit, Gerard Mark; Ettori, Stefano; Mahdavi, Andisheh

    2014-08-01

    The current public ACCEPT database of cluster properties includes radial profiles of temperature, electron density, entropy, and cooling time. With the new ACCEPT2 project we are currently doubling the number of clusters in ACCEPT and expanding the current suite of properties to include uniformly measured profiles of gas mass and hydrostatic equilibrium mass along with signatures of dynamical relaxation (centroid shift, power ratios, surface brightness concentration, temperature ratios) and global quantities such as core-excised temperatures, X-ray luminosities, and metallicities. We are presenting the first results obtained on the relationship between cool cores and dynamical relaxation, the reliability of hydrostatic mass profiles, and the dependence of the gas mass fraction on halo mass, redshift, and the degree of relaxation.

  8. 42 CFR 35.65 - Acceptable personal property.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Acceptable personal property. 35.65 Section 35.65 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES MEDICAL CARE AND EXAMINATIONS HOSPITAL AND STATION MANAGEMENT Contributions for the Benefit of Patients § 35.65...

  9. Discovery of a Potent and Selective ROMK Inhibitor with Pharmacokinetic Properties Suitable for Preclinical Evaluation

    PubMed Central

    2015-01-01

    A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated. PMID:26191360

  10. Thermophysical properties of HCFC-124; An environmentally acceptable refrigerant

    SciTech Connect

    Shankland, I.R.; Basu, R.S.; Wilson, D.P. )

    1990-01-01

    Thermodynamic property data, including critical properties, vapor pressure, saturated liquid density, PVT properties, and ideal gas heat capacity, are presented for HCFC-1-24 (CF{sub 3}CHCIF), an environmentally acceptable substitute for R-12 and R-114 in certain refrigerating and air-conditioning applications. A standard Martin-Hou equation of state, developed from these data, is also presented. This equation of state can be used to generate thermodynamic tables and charts. The data and correlations presented here are expected to be of use to the industry in the development of HCFC-124 as a working fluid for refrigerating and air-conditioning applications.

  11. Efficacy, physical properties and pharmacokinetics of sterically-stabilized liposome-encapsulated hemoglobin.

    PubMed

    Zheng, S; Zheng, Y; Beissinger, R

    1994-01-01

    We recently reported that hemoglobin (Hb) encapsulated in liposomes (LEH) containing phosphatidyl-inositol (PI) was efficacious in rats. However, liposomes containing PI may temporarily compromise mononuclear phagocytic system (MPS) function. The objective of this study was then to determine whether a polyethylene oxide derivative of phosphatidyl ethanolamine (PEG-PE) would serve as an acceptable substitute for PI in our LEH formulation. In this study we compare the physical properties, pharmacokinetics and efficacy in life support obtained for Hb encapsulated with either PI or PEG-PE phospholipids. Both liposome compositions contained the same matrix lipids, egg derived phosphatidyl choline (PC) and cholesterol, were of similar size and contained the same amount of encapsulated Hb. The liposomes differed only in their phospholipid component, one containing 5 mol% PI and the other an equal amount of the sterically-stabilizing lipid PEG-PE. The physical characteristics of the PI and PEG-PE compositions were remarkably similar: only small amounts of Met-Hb were generated during processing and following 1 month frozen storage, oxygen affinity and cooperativity and steady shear viscosity values for 30% by volume suspensions (in isotonic/isooncotic saline containing albumin) were near the normal values expected for whole blood, incubation in plasma at 37 degrees C resulted in only small amounts of Hb release and shear had very little impact on Hb leakage. Circulation half-lives following 50% isovolemic exchange-transfusion in rats were also similar, about 15-20 hours for either formation. Animals survived following 97% isovolemic exchange-transfusion of both compositions, confirming the efficacy of each. PMID:7994371

  12. Toxicity, pharmacokinetics, and photodynamic properties of chlorin e6

    NASA Astrophysics Data System (ADS)

    Kostenich, Gennady; Zhuravkin, Ivan N.; Gurinovich, G. P.; Zhavrid, Edvard A.

    1993-03-01

    Toxicity, pharmacokinetics, and the tumor damage effect of chlorin e6 after light irradiation were studied. The results show that chlorin e6 LD50 value in C57Bl mice was 189 +/- 10 mg/kg, in non-inbred white rats it was 99 +/- 14 mg/kg 14 days after the agent iv injection. The concentration of chlorin e6 in blood, liver, kidney, spleen, and tumors (sarcoma M-1 and sarcoma 45) of the rats was determined by the fluorescence method 3, 6, 12, 18, 24, 48, and 72 hours after the agent iv injection at the dose of 10 mg/kg. For this purpose chlorin e6 was extracted from tissues by detergent triton X-100. The depth of necrosis spreading in tumor tissue was evaluated after chlorin e6 injection at the doses of 1 - 10 mg/kg and subsequent irradiation by a krypton laser with light energy density of 90 J/cm2, using the method of vital staining with Evans blue. It was found that depending on the agent dose and time interval between chlorin e6 injection and photoradiation, the depth of tumor necrosis varied from 4.0 to 16.6 mm in sarcoma M-1 and from 5.0 to 15.0 in sarcoma 45.

  13. Pharmacokinetic and pharmacodynamic properties of the new AEDs: A review article

    PubMed Central

    Pakdaman, Hossein; Harirchian, Mohammad Hossein; Omrani, Hossein-Ali Ghelichnia; Ghabaee, Mojdeh; Zamani, Babak; Bahrami, Parviz; Siroos, Bahaadin

    2013-01-01

    The new-AEDs, whose developments were motivated following the discovery of the valproate and its marketing in the U.S in 1978, have presented more therapeutic options. There are approximately twenty four FDA-approved antiepileptic drugs for use in patients with epilepsy, five of which were identified and have come on to the market between 2009 and 2012. The new-AEDs are of interest, not due to their efficacy, but rather owing to better tolerance, favorable pharmacokinetic profile, fewer interactions, and in some instances, lesser protein binding. No standard AED or those in developing have all properties of an ideal antiepileptic drug, thus to achieve desirable outcome, physicians should be aware of pharmacokinetics (PKs) and pharmacodynamics (PDs) of drugs. This review describes briefly the major features of the new AEDs. PMID:24250926

  14. Comparative Pharmacokinetic Properties and Antitumor Activity of the Marine HDACi Largazole and Largazole Peptide Isostere

    PubMed Central

    Pilon, John L.; Clausen, Dane J.; Hansen, Ryan J.; Lunghofer, Paul J.; Charles, Brad; Rose, Barbara J.; Thamm, Douglas H.; Gustafson, Daniel L.; Bradner, James E.; Williams, Robert M.

    2015-01-01

    Purpose Largazole is a potent class I selective HDACi natural product isolated from the marine cyanobacteria Symploca sp. The purpose of this study was to test synthetic analogs of Largazole to identify potential scaffold structural modifications that would improve the drug-like properties of this clinically relevant natural product. Methods The impact of Largazole scaffold replacements on in vitro growth inhibition, cell cycle arrest, induction of apoptosis, pharmacokinetic properties, and in vivo activity using a xenograft model were investigated. Results In vitro studies in colon, lung, and pancreatic cancer cell lines showed that pyridyl substituted Largazole analogs had low nanomolar/high-picomolar activity on cell proliferation, and induced apoptosis and cell cycle arrest at concentrations equivalent to or lower than the parent compound Largazole. Using IV bolus delivery at 5mg/kg, two compartmental pharmacokinetic modeling on the peptide isostere analog of Largazole indicated improved pharmacokinetics including AUC, CL, and Vss. In the A549 non-small cell lung carcinoma xenograft model using a dosage of 5 mg/kg administered intraperitoneally every other day, Largazole, Largazole thiol, and Largazole peptide isostere demonstrated tumor growth inhibition (TGI%) of 32, 44, and 66 percent respectively. Moreover, the decreased tumor growth rate for Largazole peptide isostere was statistically significant compared to control (p=0.002) and superior to Largazole (p=0.006). Surprisingly tumor growth inhibition in this system and treatment regimen was not observed with the potent pyridyl-based analogs. Conclusions Our results establish that replacing the depsipepitde linkage in Largazole with an amide may impart pharmacokinetic advantage and that alternative prodrug forms of largazole are feasible. PMID:25616967

  15. Tailoring the magnetic and pharmacokinetic properties of iron oxide magnetic particle imaging tracers

    PubMed Central

    Ferguson, Richard Mathew; Khandhar, Amit P; Arami, Hamed; Hua, Loc; Hovorka, Ondrej; Krishnan, Kannan M.

    2014-01-01

    Magnetic particle imaging (MPI) is an attractive new modality for imaging distributions of iron oxide nanoparticle tracers in vivo. With exceptional contrast, high sensitivity, and good spatial resolution, MPI shows promise for clinical imaging in angiography and oncology. Critically, MPI requires high-quality iron oxide nanoparticle tracers with tailored magnetic and surface properties to achieve its full potential. In this review, we discuss optimizing iron oxide nanoparticles’ physical, magnetic, and pharmacokinetic properties for MPI, highlighting results from our recent work in which we demonstrated tailored, biocompatible iron oxide nanoparticle tracers that provided two times better linear spatial resolution and five times better signal-to-noise ratio than Resovist. PMID:23787461

  16. A Phase 1 Randomized, Open Label, Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Three Formulations of Tenofovir 1% Gel (the CHARM-01 Study)

    PubMed Central

    Mcgowan, Ian; Cranston, Ross D.; Duffill, Kathryn; Siegel, Aaron; Engstrom, Jarret C.; Nikiforov, Alexyi; Jacobson, Cindy; Rehman, Khaja K.; Elliott, Julie; Khanukhova, Elena; Abebe, Kaleab; Mauck, Christine; Spiegel, Hans M. L.; Dezzutti, Charlene S.; Rohan, Lisa C.; Marzinke, Mark A.; Hiruy, Hiwot; Hendrix, Craig W.; Richardson-Harman, Nicola; Anton, Peter A.

    2015-01-01

    Objectives The CHARM-01 study characterized the safety, acceptability, pharmacokinetics (PK), and pharmacodynamics (PD) of three tenofovir (TFV) gels for rectal application. The vaginal formulation (VF) gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials and the RMP-02/MTN-006 Phase 1 rectal safety study. The reduced glycerin VF (RGVF) gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. A third rectal specific formulation (RF) gel was also evaluated in the CHARM-01 study. Methods Participants received 4 mL of the three TFV gels in a blinded, crossover design: seven daily doses of RGVF, seven daily doses of RF, and six daily doses of placebo followed by one dose of VF, in a randomized sequence. Safety, acceptability, compartmental PK, and explant PD were monitored throughout the trial. Results All three gels were found to be safe and acceptable. RF and RGVF PK were not significantly different. Median mucosal mononuclear cell (MMC) TFV-DP trended toward higher values for RF compared to RGVF (1136 and 320 fmol/106 cells respectively). Use of each gel in vivo was associated with significant inhibition of ex vivo colorectal tissue HIV infection. There was also a significant negative correlation between the tissue levels of TFV, tissue TFV-DP, MMC TFV-DP, rectal fluid TFV, and explant HIV-1 infection. Conclusions All three formulations were found to be safe and acceptable. However, the safety profile of the VF gel was only based on exposure to one dose whereas participants received seven doses of the RGVF and RF gels. There was a trend towards higher tissue MMC levels of TFV-DP associated with use of the RF gel. Use of all gels was associated with significant inhibition of ex vivo tissue HIV infection. Trial Registration ClinicalTrials.gov NCT01575405 PMID:25942472

  17. A novel approach to investigate the effect of methionine oxidation on pharmacokinetic properties of therapeutic antibodies

    PubMed Central

    Stracke, Jan; Emrich, Thomas; Rueger, Petra; Schlothauer, Tilman; Kling, Lothar; Knaupp, Alexander; Hertenberger, Hubert; Wolfert, Andreas; Spick, Christian; Lau, Wilma; Drabner, Georg; Reiff, Ulrike; Koll, Hans; Papadimitriou, Apollon

    2014-01-01

    Preserving the chemical and structural integrity of therapeutic antibodies during manufacturing and storage is a major challenge during pharmaceutical development. Oxidation of Fc methionines Met252 and Met428 is frequently observed, which leads to reduced affinity to FcRn and faster plasma clearance if present at high levels. Because oxidation occurs in both positions simultaneously, their individual contribution to the concomitant changes in pharmacokinetic properties has not been clearly established. A novel pH-gradient FcRn affinity chromatography method was applied to isolate three antibody oxidation variants from an oxidized IgG1 preparation based on their FcRn binding properties. Physico-chemical characterization revealed that the three oxidation variants differed predominantly in the number of oxMet252 per IgG (0, 1, or 2), but not significantly in the content of oxMet428. Corresponding to the increase in oxMet252 content, stepwise reduction of FcRn affinity in vitro, as well as faster clearance and shorter terminal half-life, in huFcRn-transgenic mice were observed. A single Met252 oxidation per antibody had no significant effect on pharmacokinetics (PK) compared with unmodified IgG. Importantly, only molecules with both heavy chains oxidized at Met252 exhibited significantly faster clearance. In contrast, Met428 oxidation had no apparent negative effect on PK and even led to somewhat improved FcRn binding and slower clearance. This minor effect, however, seemed to be abrogated by the dominant effect of Met252 oxidation. The novel approach of functional chromatographic separation of IgG oxidation variants followed by physico-chemical and biological characterization has yielded the first experimentally-backed explanation for the unaltered PK properties of antibody preparations containing relatively high Met252 and Met428 oxidation levels. PMID:25517308

  18. Discovery of a potent class I selective ketone histone deacetylase inhibitor with antitumor activity in vivo and optimized pharmacokinetic properties.

    PubMed

    Kinzel, Olaf; Llauger-Bufi, Laura; Pescatore, Giovanna; Rowley, Michael; Schultz-Fademrecht, Carsten; Monteagudo, Edith; Fonsi, Massimiliano; Gonzalez Paz, Odalys; Fiore, Fabrizio; Steinkühler, Christian; Jones, Philip

    2009-06-11

    The optimization of a potent, class I selective ketone HDAC inhibitor is shown. It possesses optimized pharmacokinetic properties in preclinical species, has a clean off-target profile, and is negative in a microbial mutagenicity (Ames) test. In a mouse xenograft model it shows efficacy comparable to that of vorinostat at a 10-fold reduced dose.

  19. 41 CFR 102-75.1155 - May an acceptable gift of property be converted to money?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... of property be converted to money? 102-75.1155 Section 102-75.1155 Public Contracts and Property...-75.1155 May an acceptable gift of property be converted to money? GSA can determine whether or not a gift of property can and should be converted to money. After conversion, GSA must deposit the...

  20. Insulin degludec's ultra-long pharmacokinetic properties observed in adults are retained in children and adolescents with type 1 diabetes.

    PubMed

    Biester, Torben; Blaesig, Sarah; Remus, Kerstin; Aschemeier, Bärbel; Kordonouri, Olga; Granhall, Charlotte; Søndergaard, Flemming; Kristensen, Niels Rode; Haahr, Hanne; Danne, Thomas

    2014-02-01

    Insulin degludec (IDeg) is a basal insulin with an ultra-long pharmacokinetic profile in adults that at steady-state produces remarkably flat and stable insulin levels; however, no studies have yet reported on the pharmacokinetic properties of IDeg in subjects younger than 18 years of age. This was a single-centre, randomised, single-dose, double-blind, two-period crossover trial conducted in children (6-11 years), adolescents (12-17 years), and adults (18-65 years) with type 1 diabetes. Subjects received a single subcutaneous dose of 0.4 U/kg IDeg or insulin glargine (IGlar), respectively, on two separate dosing visits, with pharmacokinetic blood sampling up to 72-h postdose. A total of 37 subjects (12 children, 13 adolescents, and 12 adults) completed the trial. Total exposure of IDeg after a single dose (AUCIDeg ,0-∞, SD ) was higher in children compared to adults [estimated ratio children/adults 1.48 (95% confidence interval, CI: 0.98; 2.24)] and in adolescents compared to adults [estimated ratio adolescents/adults 1.33 (95% CI: 1.08; 1.64)]; however, the difference was only statistically significant for the latter comparison. No statistically significant difference in maximum concentration of IDeg (Cmax, IDeg , SD ) was observed. Estimated ratios for Cmax, IDeg , SD were (children/adults) 1.20 (95% CI: 0.90; 1.60) and (adolescents/adults) 1.23 (95% CI: 1.00; 1.51). Simulated mean steady state pharmacokinetic profiles supported a flat and stable IDeg exposure across a 24-h dosing interval. IDeg was detectable in serum for at least 72 h (end of blood sampling period) in all subjects following single dose. In conclusion, the ultra-long pharmacokinetic properties of IDeg observed in adults are preserved in children and adolescents with type 1 diabetes.

  1. ADMET evaluation in drug discovery. 11. PharmacoKinetics Knowledge Base (PKKB): a comprehensive database of pharmacokinetic and toxic properties for drugs.

    PubMed

    Cao, Dongyue; Wang, Junmei; Zhou, Rui; Li, Youyong; Yu, Huidong; Hou, Tingjun

    2012-05-25

    Good and extensive experimental ADMET (absorption, distribution, metabolism, excretion, and toxicity) data is critical for developing reliable in silico ADMET models. Here we develop a PharmacoKinetics Knowledge Base (PKKB) to compile comprehensive information about ADMET properties into a single electronic repository. We incorporate more than 10 000 experimental ADMET measurements of 1685 drugs into the PKKB. The ADMET properties in the PKKB include octanol/water partition coefficient, solubility, dissociation constant, intestinal absorption, Caco-2 permeability, human bioavailability, plasma protein binding, blood-plasma partitioning ratio, volume of distribution, metabolism, half-life, excretion, urinary excretion, clearance, toxicity, half lethal dose in rat or mouse, etc. The PKKB provides the most extensive collection of freely available data for ADMET properties up to date. All these ADMET properties, as well as the pharmacological information and the calculated physiochemical properties are integrated into a web-based information system. Eleven separated data sets for octanol/water partition coefficient, solubility, blood-brain partitioning, intestinal absorption, Caco-2 permeability, human oral bioavailability, and P-glycoprotein inhibitors have been provided for free download and can be used directly for ADMET modeling. The PKKB is available online at http://cadd.suda.edu.cn/admet.

  2. 10 CFR 603.540 - Acceptability of fully depreciated real property or equipment.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 4 2010-01-01 2010-01-01 false Acceptability of fully depreciated real property or equipment. 603.540 Section 603.540 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY INVESTMENT AGREEMENTS Pre-Award Business Evaluation Cost Sharing § 603.540 Acceptability of fully...

  3. Further Evaluation of the Psychometric Properties of the Acceptance and Action Questionnaire-II

    ERIC Educational Resources Information Center

    Fledderus, Martine; Oude Voshaar, Martijn A. H.; ten Klooster, Peter M.; Bohlmeijer, Ernst T.

    2012-01-01

    The Acceptance and Action Questionnaire-II (AAQ-II) is a self-report measure designed to assess experiential avoidance as conceptualized in acceptance and commitment therapy (ACT). The current study is the first to evaluate the psychometric properties of the AAQ-II in a large sample of adults (N = 376) with mild to moderate levels of depression…

  4. 10 CFR 603.550 - Acceptability of intellectual property.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... property (e.g., copyrighted material, including software) as cost sharing because: (1) It is difficult to... the contribution. For example, a for-profit firm may offer the use of commercially available software... the software would not be a reasonable basis for valuing its use....

  5. 10 CFR 603.550 - Acceptability of intellectual property.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... property (e.g., copyrighted material, including software) as cost sharing because: (1) It is difficult to... the contribution. For example, a for-profit firm may offer the use of commercially available software... the software would not be a reasonable basis for valuing its use....

  6. 10 CFR 603.550 - Acceptability of intellectual property.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... property (e.g., copyrighted material, including software) as cost sharing because: (1) It is difficult to... the contribution. For example, a for-profit firm may offer the use of commercially available software... the software would not be a reasonable basis for valuing its use....

  7. A novel stearic acid-modified hirudin peptidomimetic with improved pharmacokinetic properties and anticoagulant activity.

    PubMed

    Liu, Zhuguo; Yu, Zheng; Huang, Yuanyuan; Zhang, Yan; Han, Guozhu; Li, Xian; Dong, Mingxin; Yu, Shuo; Wang, Yu; Hu, Jie; Guo, Huiqin; Cheng, Yuanguo; Lv, Li; Dai, Qiuyun

    2015-01-01

    A novel hirudin isoform 3 mimetic peptide, named peptide S2, has been prepared by introduction of a stearic acid modification. Peptide S2 exhibited superior inhibitory activity to hirulog-1 (Bivariludin) and showed significantly higher anticoagulant potency in vivo. Peptide S2 elevated the thrombin time, prothrombin time and activated partial thromboplastin time of rat and human plasma more efficiently than hirulog-1 and the unmodified form of peptide S2 (peptide 1). Furthermore, peptide S2 inhibited arterial thrombosis and inferior vena cava in rat model 8 h after administration, and was 10-fold more potent than hirulog-1 300 min after administration of 0.1 μmol/kg peptide. The enhanced antithrombotic activity could be attributed to its long half-life (T1/2 = 212.2 ± 58.4 min), which was 13.1 and 14.7-fold longer than those of hirulog-1 (T1/2 = 15.1 ± 1.3 min) and peptide 1 (T1/2 = 13.5 ± 2.6 min), respectively. Further enzymatic degradation and binding assay with human serum albumin (HSA) demonstrated that the longer duration time should be originated from the slowing of trypsin or thrombin-mediated degradation, as well as its binding to HSA. The improved pharmacokinetic properties observed for peptide S2 has made it a promising therapeutic agent for the treatment of thrombi-related diseases.

  8. Improvement of pyrazolo[3,4-d]pyrimidines pharmacokinetic properties: nanosystem approaches for drug delivery

    PubMed Central

    Vignaroli, Giulia; Calandro, Pierpaolo; Zamperini, Claudio; Coniglio, Federica; Iovenitti, Giulia; Tavanti, Matteo; Colecchia, David; Dreassi, Elena; Valoti, Massimo; Schenone, Silvia; Chiariello, Mario; Botta, Maurizio

    2016-01-01

    Pyrazolo[3,4-d]pyrimidines are a class of compounds with a good activity against several cancer cell lines. Despite the promising anticancer activity, these molecules showed a poor aqueous solubility. This issue could threat the future development of pyrazolo[3,4-d]pyrimidines as clinical drug candidates. With the aim of improving their solubility profile and consequently their pharmacokinetic properties, we have chosen four compounds (1–4) on the base of their anti-neuroblastoma activity and we have developed albumin nanoparticles and liposomes for the selected candidates. Albumin nanoparticles and liposomes were prepared and characterized regarding size and ζ-potential distribution, polidispersity index, entrapment efficiency and activity against SH-SY5Y human neuroblastoma cell line. The most promising nanosystem, namely LP-2, was chosen to perform further studies: confocal microscopy, stability and drug release in physiological conditions, and biodistribution. Altogether, the obtained data strongly indicate that the encapsulation of pyrazolo[3,4-d]pyrimidines in liposomes represent an effective method to overcome the poor water solubility. PMID:26898318

  9. Pharmacokinetic Properties of Artemether, Dihydroartemisinin, Lumefantrine, and Quinine in Pregnant Women with Uncomplicated Plasmodium falciparum Malaria in Uganda

    PubMed Central

    Kloprogge, Frank; Dhorda, Mehul; Jullien, Vincent; Nosten, Francois; White, Nicholas J.; Guerin, Philippe J.; Piola, Patrice

    2013-01-01

    Pregnancy alters the pharmacokinetic properties of many drugs used in the treatment of malaria, usually resulting in lower drug exposures. This increases the risks of treatment failure, adverse outcomes for the fetus, and the development of resistance. The pharmacokinetic properties of artemether and its principal metabolite dihydroartemisinin (n = 21), quinine (n = 21), and lumefantrine (n = 26) in pregnant Ugandan women were studied. Lumefantrine pharmacokinetics in a nonpregnant control group (n = 17) were also studied. Frequently sampled patient data were evaluated with noncompartmental analysis. No significant correlation was observed between estimated gestational age and artemether, dihydroartemisinin, lumefantrine, or quinine exposures. Artemether/dihydroartemisinin and quinine exposures were generally low in these pregnant women compared to values reported previously for nonpregnant patients. Median day 7 lumefantrine concentrations were 488 (range, 30.7 to 3,550) ng/ml in pregnant women compared to 720 (339 to 2,150) ng/ml in nonpregnant women (P = 0.128). There was no statistical difference in total lumefantrine exposure or maximum concentration. More studies with appropriate control groups in larger series are needed to characterize the degree to which pregnant women are underdosed with current antimalarial dosing regimens. PMID:23917320

  10. Pharmacokinetic properties of γ-hydroxybutyrate (GHB) in whole blood, serum, and urine.

    PubMed

    Brailsford, Alan D; Cowan, David A; Kicman, Andrew T

    2012-03-01

    Over the last 10-15 years, γ-hydroxybutyrate (GHB) and γ-butyrolactone have become increasingly popular "club drugs", but they have also gained attention as potential agents of drug-facilitated sexual assault (DFSA). Several studies have attempted to characterize GHB's pharmacokinetic properties in humans, and the aim of this paper is to build on this research with an emphasis on DFSA cases. A 25 mg/kg dose of GHB was given to 12 GHB-naïve volunteers (6 men and 6 women). Urine and blood samples (serum and whole blood) were collected and analyzed by gas chromatography-mass spectrometry following liquid-liquid extraction. The urinary T(max) was 1 h in 11 volunteers with a mean C(max) of 67.6 mg/L (32.6-161.3 mg/L). Urinary concentrations rapidly decreased to < 10 mg/L (interpretive limit) for 11 volunteers after just 4 h. Data derived from whole blood (mean C(max) = 48.0 mg/L, T(max) = 24.6 min) closely matched that from serum (mean C(max) = 59.4 mg/L, T(max) = 23.3 min), suggesting GHB is distributed into erythrocytes. All 12 volunteers had GHB concentrations of less than 5 mg/L in both whole blood and serum after 3 h. Results verify the rapid elimination of GHB and the limited retrospective power of a concentration-based approach to prove GHB administration in blood and urine and confirm that, in DFSA cases, samples should be collected as soon as possible.

  11. A novel stearic acid-modified hirudin peptidomimetic with improved pharmacokinetic properties and anticoagulant activity

    PubMed Central

    Liu, Zhuguo; Yu, Zheng; Huang, Yuanyuan; Zhang, Yan; Han, Guozhu; Li, Xian; Dong, Mingxin; Yu, Shuo; Wang, Yu; Hu, Jie; Guo, Huiqin; Cheng, Yuanguo; Lv, Li; Dai, Qiuyun

    2015-01-01

    A novel hirudin isoform 3 mimetic peptide, named peptide S2, has been prepared by introduction of a stearic acid modification. Peptide S2 exhibited superior inhibitory activity to hirulog-1 (Bivariludin) and showed significantly higher anticoagulant potency in vivo. Peptide S2 elevated the thrombin time, prothrombin time and activated partial thromboplastin time of rat and human plasma more efficiently than hirulog-1 and the unmodified form of peptide S2 (peptide 1). Furthermore, peptide S2 inhibited arterial thrombosis and inferior vena cava in rat model 8 h after administration, and was 10-fold more potent than hirulog-1 300 min after administration of 0.1 μmol/kg peptide. The enhanced antithrombotic activity could be attributed to its long half-life (T1/2 = 212.2 ± 58.4 min), which was 13.1 and 14.7-fold longer than those of hirulog-1 (T1/2 = 15.1 ± 1.3 min) and peptide 1 (T1/2 = 13.5 ± 2.6 min), respectively. Further enzymatic degradation and binding assay with human serum albumin (HSA) demonstrated that the longer duration time should be originated from the slowing of trypsin or thrombin–mediated degradation, as well as its binding to HSA. The improved pharmacokinetic properties observed for peptide S2 has made it a promising therapeutic agent for the treatment of thrombi-related diseases. PMID:26400022

  12. Semisynthetic bile acid FXR and TGR5 agonists: physicochemical properties, pharmacokinetics, and metabolism in the rat.

    PubMed

    Roda, Aldo; Pellicciari, Roberto; Gioiello, Antimo; Neri, Flavia; Camborata, Cecilia; Passeri, Daniela; De Franco, Francesca; Spinozzi, Silvia; Colliva, Carolina; Adorini, Luciano; Montagnani, Marco; Aldini, Rita

    2014-07-01

    We report on the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of semisynthetic bile acid analogs, including 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid (a selective farnesoid X receptor [FXR] receptor agonist), 6α-ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid (a specific Takeda G protein-coupled receptor 5 [TGR5] receptor agonist), and 6α-ethyl-3α,7α-dihydroxy-24-nor-5β-cholan-23-sulfate (a dual FXR/TGR5 agonist). We measured the main physicochemical properties of these molecules, including ionization constants, water solubility, lipophilicity, detergency, and protein binding. Biliary secretion and metabolism and plasma and hepatic concentrations were evaluated by high-pressure liquid chromatography-electrospray-mass spectrometry/mass spectrometry in bile fistula rat and compared with natural analogs chenodeoxycholic, cholic acid, and taurochenodexycholic acid and intestinal bacteria metabolism was evaluated in terms of 7α-dehydroxylase substrate-specificity in anaerobic human stool culture. The semisynthetic derivatives detergency, measured in terms of their critical micellar concentration, was quite similar to the natural analogs. They were slightly more lipophilic than the corresponding natural analogs, evaluated by their 1-octanol water partition coefficient (log P), because of the ethyl group in 6 position, which makes these molecules very stable toward bacterial 7-dehydroxylation. The hepatic metabolism and biliary secretion were different: 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid, as chenodeoxycholic acid, was efficiently conjugated with taurine in the liver and, only in this form, promptly and efficiently secreted in bile. 6α-Ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid was poorly conjugated with taurine because of the steric hindrance of the methyl at C23(S) position metabolized to the C23(R) isomer and partly conjugated with taurine. Conversely, 6

  13. Semisynthetic bile acid FXR and TGR5 agonists: physicochemical properties, pharmacokinetics, and metabolism in the rat.

    PubMed

    Roda, Aldo; Pellicciari, Roberto; Gioiello, Antimo; Neri, Flavia; Camborata, Cecilia; Passeri, Daniela; De Franco, Francesca; Spinozzi, Silvia; Colliva, Carolina; Adorini, Luciano; Montagnani, Marco; Aldini, Rita

    2014-07-01

    We report on the relationship between the structure-pharmacokinetics, metabolism, and therapeutic activity of semisynthetic bile acid analogs, including 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid (a selective farnesoid X receptor [FXR] receptor agonist), 6α-ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid (a specific Takeda G protein-coupled receptor 5 [TGR5] receptor agonist), and 6α-ethyl-3α,7α-dihydroxy-24-nor-5β-cholan-23-sulfate (a dual FXR/TGR5 agonist). We measured the main physicochemical properties of these molecules, including ionization constants, water solubility, lipophilicity, detergency, and protein binding. Biliary secretion and metabolism and plasma and hepatic concentrations were evaluated by high-pressure liquid chromatography-electrospray-mass spectrometry/mass spectrometry in bile fistula rat and compared with natural analogs chenodeoxycholic, cholic acid, and taurochenodexycholic acid and intestinal bacteria metabolism was evaluated in terms of 7α-dehydroxylase substrate-specificity in anaerobic human stool culture. The semisynthetic derivatives detergency, measured in terms of their critical micellar concentration, was quite similar to the natural analogs. They were slightly more lipophilic than the corresponding natural analogs, evaluated by their 1-octanol water partition coefficient (log P), because of the ethyl group in 6 position, which makes these molecules very stable toward bacterial 7-dehydroxylation. The hepatic metabolism and biliary secretion were different: 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid, as chenodeoxycholic acid, was efficiently conjugated with taurine in the liver and, only in this form, promptly and efficiently secreted in bile. 6α-Ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid was poorly conjugated with taurine because of the steric hindrance of the methyl at C23(S) position metabolized to the C23(R) isomer and partly conjugated with taurine. Conversely, 6

  14. 10 CFR 603.540 - Acceptability of fully depreciated real property or equipment.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 10 Energy 4 2011-01-01 2011-01-01 false Acceptability of fully depreciated real property or equipment. 603.540 Section 603.540 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY... time of the negotiations; (c) The effect of any increased maintenance charges or decreased...

  15. 10 CFR 603.540 - Acceptability of fully depreciated real property or equipment.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 10 Energy 4 2012-01-01 2012-01-01 false Acceptability of fully depreciated real property or equipment. 603.540 Section 603.540 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY... time of the negotiations; (c) The effect of any increased maintenance charges or decreased...

  16. 10 CFR 603.540 - Acceptability of fully depreciated real property or equipment.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 10 Energy 4 2013-01-01 2013-01-01 false Acceptability of fully depreciated real property or equipment. 603.540 Section 603.540 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY... time of the negotiations; (c) The effect of any increased maintenance charges or decreased...

  17. 10 CFR 603.540 - Acceptability of fully depreciated real property or equipment.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 10 Energy 4 2014-01-01 2014-01-01 false Acceptability of fully depreciated real property or equipment. 603.540 Section 603.540 Energy DEPARTMENT OF ENERGY (CONTINUED) ASSISTANCE REGULATIONS TECHNOLOGY... officer must consider: (a) The original cost of the asset; (b) Its estimated remaining useful life at...

  18. Lisdexamfetamine: A pharmacokinetic review.

    PubMed

    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. PMID:27125257

  19. Lisdexamfetamine: A pharmacokinetic review.

    PubMed

    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.

  20. Regression methods for developing QSAR and QSPR models to predict compounds of specific pharmacodynamic, pharmacokinetic and toxicological properties.

    PubMed

    Yap, C W; Li, H; Ji, Z L; Chen, Y Z

    2007-11-01

    Quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) models have been extensively used for predicting compounds of specific pharmacodynamic, pharmacokinetic, or toxicological property from structure-derived physicochemical and structural features. These models can be developed by using various regression methods including conventional approaches (multiple linear regression and partial least squares) and more recently explored genetic (genetic function approximation) and machine learning (k-nearest neighbour, neural networks, and support vector regression) approaches. This article describes the algorithms of these methods, evaluates their advantages and disadvantages, and discusses the application potential of the recently explored methods. Freely available online and commercial software for these regression methods and the areas of their applications are also presented. PMID:18045213

  1. Casein peptization, functional properties, and sensory acceptance of processed cheese spreads made with different emulsifying salts.

    PubMed

    Cunha, Clarissa R; Viotto, Walkiria H

    2010-01-01

    "Requeijão cremoso" is a traditional Brazilian processed cheese spread, showing ample acceptance on the national market. Emulsifying salts (ES) are an important factor influencing the characteristics of processed cheeses, but the literature presents conflicting results about their action on cheese functionality. Requeijão cremoso obtained from anhydrous ingredients allows the study of the influence of each type of ES on the cheese properties, since it can be treated as a model system where the variables are limited and well known. The objective of this study was to evaluate the effect of different types of ES (TSC-sodium citrate, SHMP-sodium hexametaphosphate, STPP-sodium tripolyphosphate, and TSPP-tetrasodium pyrophosphate) on the sensory and functional characteristics of requeijão cremoso-processed cheeses obtained from anhydrous ingredients. The physicochemical composition, degree of casein dissociation, fat particle size, melting index, color, texture profile, and sensory acceptance of the cheeses were determined. The functional behavior of processed cheeses was strongly influenced by the type of ES and its physicochemical properties including its ability to bind Ca, the casein dispersion during cooking, and the possible creation of cross-links with casein during cooling. The cheese made with SHMP was the one most differentiated from the others, presenting lower melting index, whiter color, and higher values for hardness, gumminess, and adhesiveness. The differences in texture had an impact on sensory acceptance: with the exception of the sample manufactured with sodium hexametaphosphate, all the samples presented good sensory acceptance.

  2. Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties

    SciTech Connect

    Liu Aiming; Xie Shuilin; Sun He; Gonzalez, Frank J.; Wei Xiaoxiong; Dai Renke

    2009-03-15

    Fibrate drugs are PPAR{alpha} agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reportedly associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPAR{alpha} agonist-induced hepatotoxicity, we studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 days). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16th dosage of P1 and 17th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey no. 2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This study revealed Cynomolgus monkey may be a good animal model for myotoxicity evaluation with sensitivity, reproducibility and similarities to humans. More interestingly, they exhibited a much higher incidence of myotoxicity than that of humans. Sustained high drug concentration plays an important role for the occurrence of myotoxicity. This may suggest an influence of drug transport and metabolism on myotoxicity.

  3. Pharmacokinetics and stability properties of catalase modified with water-soluble polysaccharides.

    PubMed

    Valdivia, Aymara; Pérez, Yunel; Gómez, Leissy; Ramírez, Hector L; Schacht, Etienne H; Villalonga, Reynaldo

    2006-07-01

    Bovine liver catalase (EC 1.11.1.6) was chemically modified with mannan, carboxymethylcellulose, and carboxymethylchitin. The enzyme retained about 48-97% of the initial specific activity after glycosidation with the polysaccharides. The prepared neoglycoenzyme was 1.9-5.7 fold more stable against the thermal inactivation processes at 55 degrees C, in comparison with the native counterpart. Also, the modified enzyme was more resistant to proteolytic degradation with trypsin. Pharmacokinetics studies revealed higher plasma half-life time for all the enzyme-polymer preparations, but better results were achieved for the enzyme modified with the anionic macromolecules. PMID:16838281

  4. 41 CFR 102-75.1290 - What happens if the landholding agency requesting the property does not promptly accept custody...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... landholding agency requesting the property does not promptly accept custody and accountability? 102-75.1290... not promptly accept custody and accountability? (a) The requesting agency must assume protection and... accountability for the property. (b) After notifying the requesting agency, GSA may, at its discretion,...

  5. 41 CFR 102-75.1290 - What happens if the landholding agency requesting the property does not promptly accept custody...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... landholding agency requesting the property does not promptly accept custody and accountability? 102-75.1290... not promptly accept custody and accountability? (a) The requesting agency must assume protection and... accountability for the property. (b) After notifying the requesting agency, GSA may, at its discretion,...

  6. 41 CFR 102-75.1290 - What happens if the landholding agency requesting the property does not promptly accept custody...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... landholding agency requesting the property does not promptly accept custody and accountability? 102-75.1290... not promptly accept custody and accountability? (a) The requesting agency must assume protection and... accountability for the property. (b) After notifying the requesting agency, GSA may, at its discretion,...

  7. 41 CFR 102-75.1290 - What happens if the landholding agency requesting the property does not promptly accept custody...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... landholding agency requesting the property does not promptly accept custody and accountability? 102-75.1290... not promptly accept custody and accountability? (a) The requesting agency must assume protection and... accountability for the property. (b) After notifying the requesting agency, GSA may, at its discretion,...

  8. 41 CFR 102-75.1290 - What happens if the landholding agency requesting the property does not promptly accept custody...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... landholding agency requesting the property does not promptly accept custody and accountability? 102-75.1290... not promptly accept custody and accountability? (a) The requesting agency must assume protection and... accountability for the property. (b) After notifying the requesting agency, GSA may, at its discretion,...

  9. PHARMACOKINETIC PROPERTIES OF A SINGLE ADMINISTRATION OF ORAL GABAPENTIN IN THE GREAT HORNED OWL (BUBO VIRGINIANUS).

    PubMed

    Yaw, Taylor J; Zaffarano, Bianca A; Gall, Andrew; Olds, June E; Wulf, Larry; Papastavros, Efthimia; Coetzee, Johann F

    2015-09-01

    Gabapentin (1-[aminomethyl] cyclohexane acetic acid) is a γ-aminobutyric acid analogue that has been shown to be efficacious for neuropathic pain control in humans. Plasma gabapentin concentrations >2 μg/ml are considered effective in treating epilepsy in humans and are suggested to provide analgesia for neuropathic pain. This study investigated the pharmacokinetics of a single oral dose of gabapentin suspension (11 mg/kg) in great horned owls ( Bubo virginianus ). Plasma gabapentin concentrations were determined in six healthy birds for 48 hr using high-performance liquid chromatography with mass spectrometric detection. Plasma gabapentin concentrations were estimated by noncompartmental pharmacokinetic analysis. The harmonic mean (±SD) maximum concentration (Cmax), time to maximum concentration (Tmax), and elimination half-life (tv2λZ) for gabapentin (11 mg/kg) were 6.17±0.83 μg/ml, 51.43±5.66 min, and 264.60±69.35 min, respectively. In this study, plasma gabapentin concentrations were maintained above 2 μg/ml for 528 min (8.8 hr), suggesting that gabapentin administered orally every 8 hr may be appropriate in great horned owls.

  10. A novel ibuprofen derivative with anti-lung cancer properties: synthesis, formulation, pharmacokinetic and efficacy studies.

    PubMed

    Cheng, Ka-Wing; Nie, Ting; Ouyang, Nengtai; Alston, Ninche; Wong, Chi C; Mattheolabakis, George; Papayannis, Ioannis; Huang, Liqun; Rigas, Basil

    2014-12-30

    Phospho-non-steroidal anti-inflammatory drugs (phospho-NSAIDs) are a novel class of NSAID derivatives with potent antitumor activity. However, phospho-NSAIDs have limited stability in vivo due to their rapid hydrolysis by carboxylesterases at their carboxylic ester link. Here, we synthesized phospho-ibuprofen amide (PIA), a metabolically stable analog of phospho-ibuprofen, formulated it in nanocarriers, and evaluated its pharmacokinetics and anticancer efficacy in pre-clinical models of human lung cancer. PIA was 10-fold more potent than ibuprofen in suppressing the growth of human non-small-cell lung cancer (NSCLC) cell lines, an effect mediated by favorably altering cytokinetics and inducing oxidative stress. Pharmacokinetic studies in rats revealed that liposome-encapsulated PIA exhibited remarkable resistance to hydrolysis by carboxylesterases, remaining largely intact in the systemic circulation, and demonstrated selective distribution to the lungs. The antitumor activity of liposomal PIA was evaluated in a metastatic model of human NSCLC in mice. Liposomal PIA strongly inhibited lung tumorigenesis (>95%) and was significantly (p<0.05) more efficacious than ibuprofen. We observed a significant induction of urinary 8-iso-prostaglandin F2αin vivo, which indicates that ROS stress probably plays an important role in mediating the antitumor efficacy of PIA. Our findings suggest that liposomal PIA is a potent agent in the treatment of lung cancer and merits further evaluation.

  11. PHARMACOKINETIC PROPERTIES OF A SINGLE ADMINISTRATION OF ORAL GABAPENTIN IN THE GREAT HORNED OWL (BUBO VIRGINIANUS).

    PubMed

    Yaw, Taylor J; Zaffarano, Bianca A; Gall, Andrew; Olds, June E; Wulf, Larry; Papastavros, Efthimia; Coetzee, Johann F

    2015-09-01

    Gabapentin (1-[aminomethyl] cyclohexane acetic acid) is a γ-aminobutyric acid analogue that has been shown to be efficacious for neuropathic pain control in humans. Plasma gabapentin concentrations >2 μg/ml are considered effective in treating epilepsy in humans and are suggested to provide analgesia for neuropathic pain. This study investigated the pharmacokinetics of a single oral dose of gabapentin suspension (11 mg/kg) in great horned owls ( Bubo virginianus ). Plasma gabapentin concentrations were determined in six healthy birds for 48 hr using high-performance liquid chromatography with mass spectrometric detection. Plasma gabapentin concentrations were estimated by noncompartmental pharmacokinetic analysis. The harmonic mean (±SD) maximum concentration (Cmax), time to maximum concentration (Tmax), and elimination half-life (tv2λZ) for gabapentin (11 mg/kg) were 6.17±0.83 μg/ml, 51.43±5.66 min, and 264.60±69.35 min, respectively. In this study, plasma gabapentin concentrations were maintained above 2 μg/ml for 528 min (8.8 hr), suggesting that gabapentin administered orally every 8 hr may be appropriate in great horned owls. PMID:26352959

  12. Pharmacokinetic properties of isorhamnetin, kaempferol and quercetin after oral gavage of total flavones of Hippophae rhamnoides L. in rats using a UPLC-MS method.

    PubMed

    Li, Guowen; Zeng, Xiaoli; Xie, Yan; Cai, Zhenzhen; Moore, Jeffrey C; Yuan, Xiurong; Cheng, Zhihong; Ji, Guang

    2012-01-01

    An ultra performance liquid chromatography-mass spectrometric (UPLC-MS) method was developed to investigate the pharmacokinetic properties of isorhamnetin, kaempferol and quercetin from a total flavone extract of Hippophae rhamnoides L. (TFH) after single dose oral administration. Rat plasma samples were pretreated using liquid-liquid extraction, and chromatographic separation was performed on a C(18) column using a linear gradient of methanol and formic acid (0.1%). The pharmacokinetic parameters of isorhamnetin, kaempferol and quercetin from TFH in rats were quantitatively determined by UPLC with photodiode array detection (PDA). The qualitative detection of the three flavones was accomplished by selected ion monitoring in negative ion mode ESI-MS. Results of the pharmacokinetic study indicate that the three flavones in TFH were absorbed by passive diffusion in rats, and no "double-peak" phenomenon was observed in C-t curves of the three flavones from TFH except for quercetin. Results of this study indicate that the pharmacokinetic behaviors of isorhamnetin, kaempferol and quercetin when administered together in a complex herbal extract might be different than the individual behaviors of the same compounds administered in their pure forms. Results of this study also demonstrate that UPLC-MS is a rapid and practical method to determine the pharmacokinetic parameters of flavones present in an herbal extract. PMID:22056665

  13. Effect of flaxseed flour incorporation on the physical properties and consumer acceptability of cereal bars.

    PubMed

    Khouryieh, H; Aramouni, F

    2013-12-01

    Extensive research has revealed numerous nutritional and health benefits of flaxseed due primarily to its nutrients content. The objective of this study was to evaluate the effect of flaxseed flour addition on the physical and sensory characteristics of cereal bars. Four formulations of the flaxseed cereal bars were prepared by partially replacing oats with flaxseed flour added at levels of 0 (control), 6%, 12% and 18%. There were no significant differences (p > 0.05) in water activity, moisture and firmness values between the flaxseed bars and control. Flaxseed addition significantly (p < 0.05) decreased lightness and increased redness of the bars. There were no significant differences (p > 0.05) between the 12% flax cereal bars and the control with respect to sensory attributes and overall acceptability. The overall acceptability for both 12% flax bars and the control was in between 'like moderately' and 'like slightly' on the 9-point hedonic scale. The overall acceptability was most highly correlated with flavor acceptability for both control (r = 0.80) and 12% flax (r = 0.82) cereal bars. Flaxseed bars provided 12% dietary fiber of the daily recommended value. These results indicated that flaxseed flour incorporation up to 12% substantially enhanced the nutritional qualities of the cereal bars without affecting their sensory and quality properties.

  14. Effect of flaxseed flour incorporation on the physical properties and consumer acceptability of cereal bars.

    PubMed

    Khouryieh, H; Aramouni, F

    2013-12-01

    Extensive research has revealed numerous nutritional and health benefits of flaxseed due primarily to its nutrients content. The objective of this study was to evaluate the effect of flaxseed flour addition on the physical and sensory characteristics of cereal bars. Four formulations of the flaxseed cereal bars were prepared by partially replacing oats with flaxseed flour added at levels of 0 (control), 6%, 12% and 18%. There were no significant differences (p > 0.05) in water activity, moisture and firmness values between the flaxseed bars and control. Flaxseed addition significantly (p < 0.05) decreased lightness and increased redness of the bars. There were no significant differences (p > 0.05) between the 12% flax cereal bars and the control with respect to sensory attributes and overall acceptability. The overall acceptability for both 12% flax bars and the control was in between 'like moderately' and 'like slightly' on the 9-point hedonic scale. The overall acceptability was most highly correlated with flavor acceptability for both control (r = 0.80) and 12% flax (r = 0.82) cereal bars. Flaxseed bars provided 12% dietary fiber of the daily recommended value. These results indicated that flaxseed flour incorporation up to 12% substantially enhanced the nutritional qualities of the cereal bars without affecting their sensory and quality properties. PMID:23733813

  15. Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors.

    PubMed

    Brullo, Chiara; Massa, Matteo; Villa, Carla; Ricciarelli, Roberta; Rivera, Daniela; Pronzato, Maria Adelaide; Fedele, Ernesto; Barocelli, Elisabetta; Bertoni, Simona; Flammini, Lisa; Bruno, Olga

    2015-07-01

    A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity.

  16. Psychometric Properties of the Persian Version of the Social Anxiety - Acceptance and Action Questionnaire

    PubMed Central

    Soltani, Esmail; Bahrainian, Seyed Abdolmajid; Masjedi Arani, Abbas; Farhoudian, Ali; Gachkar, Latif

    2016-01-01

    Background Social anxiety disorder is often related to specific impairment or distress in different areas of life, including occupational, social and family settings. Objective The purpose of the present study was to examine the psychometric properties of the persian version of the social anxiety-acceptance and action questionnaire (SA-AAQ) in university students. Materials and Methods In this descriptive cross-sectional study, 324 students from Shahid Beheshti University of Medical Sciences participated via the cluster sampling method during year 2015. Factor analysis by the principle component analysis method, internal consistency analysis, and convergent and divergent validity were conducted to examine the validity of the SA-AAQ. To calculate the reliability of the SA-AAQ, Cronbach’s alpha and test-retest reliability were used. Results The results from factor analysis by principle component analysis method yielded three factors that were named acceptance, action and non-judging of experience. The three-factor solution explained 51.82% of the variance. Evidence for the internal consistency of SA-AAQ was obtained via calculating correlations between SA-AAQ and its subscales. Support for convergent and discriminant validity of the SA-AAQ via its correlations with the acceptance and action questionnaire - II, social interaction anxiety scale, cognitive fusion questionnaire, believability of anxious feelings and thoughts questionnaire, valued living questionnaire and WHOQOL- BREF was obtained. The reliability of the SA-AAQ via calculating Cronbach’s alpha and test-retest coefficients yielded values of 0.84 and 0.84, respectively. Conclusions The Iranian version of the SA-AAQ has acceptable levels of psychometric properties in university students. The SA-AAQ is a valid and reliable measure to be utilized in research investigations and therapeutic interventions. PMID:27803719

  17. Pharmacokinetic Properties and Human Use Characteristics of an FDA-Approved Intranasal Naloxone Product for the Treatment of Opioid Overdose.

    PubMed

    Krieter, Philip; Chiang, Nora; Gyaw, Shwe; Skolnick, Phil; Crystal, Roger; Keegan, Fintan; Aker, Julie; Beck, Melissa; Harris, Jennifer

    2016-10-01

    Parenteral naloxone has been approved to treat opiate overdose for over 4 decades. Intranasal naloxone, administered "off label" using improvised devices, has been widely used by both first responders and the lay public to treat overdose. However, these improvised devices require training for effective use, and the recommended volumes (2 to 4 mL) exceed those considered optimum for intranasal administration. The present study compared the pharmacokinetic properties of intranasal naloxone (2 to 8 mg) delivered in low volumes (0.1 to 0.2 mL) using an Aptar Unit-Dose device to an approved (0.4 mg) intramuscular dose. A parallel study assessed the ease of use of this device in a simulated overdose situation. All doses of intranasal naloxone resulted in plasma concentrations and areas under the curve greater than those observed following the intramuscular dose; the time to reach maximum plasma concentrations was not different following intranasal and intramuscular administration. Plasma concentrations of naloxone were dose proportional between 2 and 8 mg and independent of whether drug was administered to 1 or both nostrils. In a study using individuals representative of the general population, >90% were able to perform both critical tasks (inserting nozzle into a nostril and pressing plunger) needed to deliver a simulated dose of naloxone without prior training. Based on both pharmacokinetic and human use studies, a 4-mg dose delivered in a single device (0.1 mL) was selected as the final product. This product can be used by first responders and the lay public, providing an important and potentially life-saving intervention for victims of an opioid overdose. PMID:27145977

  18. Use of solubilizers in preclinical formulations: Effect of Cremophor EL on the pharmacokinetic properties on early discovery compounds.

    PubMed

    Liu, Bo; Gordon, William Perry; Richmond, Wendy; Groessl, Todd; Tuntland, Tove

    2016-05-25

    The aim of the present study was to determine whether Cremophor EL is a suitable surfactant that can be routinely applied to pharmacokinetic (PK) studies in early drug discovery without influencing the intrinsic PK characteristics of the new chemical entities (NCEs). Cremophor EL, a polyoxyl 35 castor oil, has been used as a solubilization aid for water-insoluble compounds in pre-clinical drug discovery. The effect of Cremophor EL on the PK properties of NCEs was examined in seven structurally diverse discovery compounds after intravenous administration. Significant effects of Cremophor EL on plasma volume of distribution (Vss) and plasma clearance (CL) were observed in compounds with moderate to high Vss or CL. The plasma Vss decreased more than 2-fold and the Vss binning category decreased by one unit (e.g. from moderate to low Vss) in 6 of 7 test compounds. Two to five-fold reduction of CL was observed with these 6 compounds. Effect on the terminal half-life (T1/2) was minimal. Using one of these 7 NCEs, concentration dependent effect of Cremophor EL in the vehicle was also determined. Higher percentage of Cremophor EL in vehicle resulted in progressively increased alterations on the plasma CL and Vss. Taken together, these findings indicated that Cremophor EL altered the intrinsic PK properties of these discovery compounds in a concentration dependent manner.

  19. Evaluation of pharmacokinetic properties and anaesthetic effects of propofol in a new perfluorohexyloctane (F6H8) emulsion in rats--A comparative study.

    PubMed

    Tsagogiorgas, Charalambos; Theisinger, Sonja; Heesch, Elisabeth; Krebs, Jörg; Holm, René; Beck, Grietje; Yard, Benito

    2015-01-01

    Propofol (2,6-diisopropylphenol) is a safe and widely used anaesthetic, but due to low water solubility and high lipophilicity a difficult compound to formulate. The solubility of propofol in the semifluorinated alkane perfluorohexyloctane (F6H8) is very high (>300 mg/ml). In the present work we investigate if a F6H8-based emulsion could be used as a new intravenous drug delivery system for propofol from a pharmacokinetic, pharmacodynamic and safety point of view. The pharmacokinetic parameters were evaluated after an intravenous bolus injection of either Disoprivan(®) or a F6H8-based propofol emulsion in Wistar rats. The onset and end of sedation after multiple dosings (5, 10 and 15 mg/kg bw) were examined. Clinical chemistry and histology were assessed. No significant difference was found for any of the pharmacokinetic parameters. No differences in the onset nor the end of sedation in the tested dosages could be detected. Histology scores revealed no differences. A slightly increased alanine aminotransferase (ALT) was measured after multiple application of the F6H8-propofol emulsion. In conclusion, the F6H8-propofol emulsion showed no significant different pharmacokinetics and sedation properties, compared to a commercial soy-based propofol emulsion. Further, no toxic effects could be detected on the F6H8 emulsion indicating it was a safe excipient in rats.

  20. Thymoquinone-loaded nanostructured lipid carriers: preparation, gastroprotection, in vitro toxicity, and pharmacokinetic properties after extravascular administration

    PubMed Central

    Abdelwahab, Siddig Ibrahim; Sheikh, Bassem Yousef; Taha, Manal Mohamed Elhassan; How, Chee Wun; Abdullah, Rasedee; Yagoub, Umar; El-Sunousi, Rashad; Eid, Eltayeb EM

    2013-01-01

    Background Nanostructured lipid carriers (NLCs), composed of solid and liquid lipids, and surfactants are potentially good colloidal drug carriers. Thymoquinone is the main bioactive compound of Nigella sativa. In this study, the preparation, gastroprotective effects, and pharmacokinetic (PK) properties of thymoquinone (TQ)-loaded NLCs (TQNLCs) were evaluated. Method TQNLCs were prepared using hydrogenated palm oil (Softisan® 154), olive oil, and phosphatidylcholine for the lipid phase and sorbitol, polysorbate 80, thimerosal, and double distilled water for the liquid lipid material. A morphological assessment of TQNLCs was performed using various methods. Analysis of the ulcer index, hydrogen concentration, mucus content, and biochemical and histochemical studies confirmed that the loading of TQ into the NLCs significantly improved the gastroprotective activity of this natural compound against the formation of ethanol-induced ulcers. The safety of TQNLC was tested on WRL68 liver normal cells with cisplatin as a positive control. Results The average diameter of the TQNLCs was 75 ± 2.4 nm. The particles had negative zeta potential values of −31 ± 0.1 mV and a single melting peak of 55.85°C. Immunohistochemical methods revealed that TQNLCs inhibited the formation of ethanol-induced ulcers through the modulation of heat shock protein-70 (Hsp70). Acute hepatotoxic effects of the TQNLCs were not observed in rats or normal human liver cells (WRL-68). After validation, PK studies in rabbits showed that the PK properties of TQ were improved and indicated that the drug behaves linearly. The Tmax, Cmax, and elimination half-life of TQ were found to be 3.96 ± 0.19 hours, 4811.33 ± 55.52 ng/mL, and 4.4933 ± 0.015 hours, respectively, indicating that TQ is suitable for extravascular administration. Conclusion NLCs could be a promising vehicle for the oral delivery of TQ and improve its gastroprotective properties. PMID:23818776

  1. An Updated Review on Drug-Induced Cholestasis: Mechanisms and Investigation of Physicochemical Properties and Pharmacokinetic Parameters

    PubMed Central

    YANG, KYUNGHEE; KÖCK, KATHLEEN; SEDYKH, ALEXANDER; TROPSHA, ALEXANDER; BROUWER, KIM L.R.

    2014-01-01

    Drug-induced cholestasis is an important form of acquired liver disease and is associated with significant morbidity and mortality. Bile acids are key signaling molecules, but they can exert toxic responses when they accumulate in hepatocytes. This review focuses on the physiological mechanisms of drug-induced cholestasis associated with altered bile acid homeostasis due to direct (e.g. bile acid transporter inhibition) or indirect (e.g. activation of nuclear receptors, altered function/expression of bile acid transporters) processes. Mechanistic information about the effects of a drug on bile acid homeostasis is important when evaluating the cholestatic potential of a compound, but experimental data often are not available. The relationship between physicochemical properties, pharmacokinetic parameters, and inhibition of the bile salt export pump (BSEP) among seventy-seven cholestatic drugs with different pathophysiological mechanisms of cholestasis (i.e. impaired formation of bile vs. physical obstruction of bile flow) was investigated. The utility of in silico models to obtain mechanistic information about the impact of compounds on bile acid homeostasis to aid in predicting the cholestatic potential of drugs is highlighted. PMID:23653385

  2. Characterization of in Vitro Pharmacokinetic Properties of Hoodigogenin A from Hoodia gordonii

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study was aimed to determine ADME properties of Hoodigogenin A, which is aglycone of oxypregnane steroidal glycoside P57AS3 (P57) isolated from Hoodia gordonii. A series of in vitro assays were used to predict its gastric, intestinal and metabolic stability, intestinal and blood brain barrier (...

  3. Pharmacokinetics & Neurophysiology

    ERIC Educational Resources Information Center

    Davis, Andrew S.; Salpekar, Jay A.

    2009-01-01

    Medications administered in clinical practice obtain their therapeutic effect only to the extent that the drug is present in the appropriate concentration at the desired site. To achieve this goal, the prescribing clinician must be aware of how a drug may interact with the physiology of the patient. Pharmacokinetics is the study of this process…

  4. Charge Variants of an Avastin Biosimilar Isolation, Characterization, In Vitro Properties and Pharmacokinetics in Rat

    PubMed Central

    Liu, Wan-Hui; Tao, Wen-Jie; Liu, Li-Li; Shen, Zhen-Duo

    2016-01-01

    The similarity between a proposed biosimilar product and the reference product can be affected by many factors. This study is designed to examine whether any subtle difference in the distribution of the charge variants of an Avastin biosimilar can affect its in vitro potency and in vivo PK. Here, the acidic, basic and main peak fractions of a biosimilar product were isolated using high-performance cation-exchange chromatography and were subjected to various studies to compare their in vitro properties and in vivo PK profile. A serial of analytical methods, including size exclusion chromatography (SEC), imaged capillary isoelectric focusing (icIEF) capillary zone electrophoresis (CZE) and cation-exchange chromatography (CEX-HPLC) were also used to characterize the isolated charge variants. The kinetics constant was measured using a Biacore X100 system. The study indicates the biosimilar product has a high similarity with avastin in physicochemical properties. The potency in vitro and PK profile in rat of charge variants and biosimilar product are consistent with avastin. PMID:26987122

  5. Cardioprotective effects and pharmacokinetic properties of a controlled release formulation of a novel hydrogen sulfide donor in rats with acute myocardial infarction

    PubMed Central

    Tran, Ba Hieu; Huang, Chengrong; Zhang, Qiuyan; Liu, Xu; Lin, Shizhou; Liu, Hongrui; Wang, Shujun; Zhu, Yi Zhun

    2015-01-01

    We previously reported that S-propargyl-cysteine (SPRC) exerts cardioprotective effects by elevating H2S levels via the CSE/H2S pathway. In the present study, we investigated the cardioprotective effects and pharmacokinetic properties of a controlled release formulation of SPRC (CR-SPRC) in an in vivo rat model of myocardial infarction (MI). Rats were randomly assigned to seven groups that were pre-treated with CR-SPRC daily for 7 days prior to ligation of the left anterior descending coronary artery to induce MI. Cardiac function and infarct size were determined after MI, and we examined the activity of antioxidant enzymes, expression of anti-inflammation proteins and hydrogen sulfide levels. Mixed-mode, reversed-phase and cation-exchange HPLC–MS/MS were used to compare the pharmacokinetic properties of CR-SPRC and SPRC. CR-SPRC significantly reduced infarct size and creatine kinase (CK) and lactate dehydrogenase (LDH) leakage and it preserved cardiac function during MI. CR-SPRC displayed antioxidant properties, preserving glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) levels whereas reducing malondialdehyde (MDA) levels. Moreover, CR-SPRC significantly reduced the protein levels of inflammatory biomarkers (phospho-NF-κB p65/NF-κB p65, TNF-α) and increased cystathionine-γ-lyase (CSE) and Iκ-Bα protein levels. CR-SPRC had better pharmacokinetic properties than SPRC, with a reduced concentration peak (Cmax), prolonged time to reach peak concentration (Tmax), prolonged mean residence time (MRTinf) and increased AUC0–t. CR-SPRC showed protective effects against MI via the CSE/H2S pathway and demonstrated better cardioprotective effects than SPRC by prolonging the release of endogenous H2S. PMID:26182378

  6. Nanodrugs: pharmacokinetics and safety

    PubMed Central

    Onoue, Satomi; Yamada, Shizuo; Chan, Hak-Kim

    2014-01-01

    To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity), and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges. PMID:24591825

  7. Stealth liposomes and long circulating nanoparticles: critical issues in pharmacokinetics, opsonization and protein-binding properties.

    PubMed

    Moghimi, S M; Szebeni, J

    2003-11-01

    This article critically examines and evaluates the likely mechanisms that contribute to prolonged circulation times of sterically protected nanoparticles and liposomes. It is generally assumed that the macrophage-resistant property of sterically protected particles is due to suppression in surface opsonization and protein adsorption. However, recent evidence shows that sterically stabilized particles are prone to opsonization particularly by the opsonic components of the complement system. We have evaluated these phenomena and discussed theories that reconcile complement activation and opsonization with prolonged circulation times. With respect to particle longevity, the physiological state of macrophages also plays a critical role. For example, stimulated or newly recruited macrophages can recognize and rapidly internalize sterically protected nanoparticles by opsonic-independent mechanisms. These concepts are also examined.

  8. Pharmacokinetic properties of single-dose primaquine in Papua New Guinean children: feasibility of abbreviated high-dose regimens for radical cure of vivax malaria.

    PubMed

    Moore, Brioni R; Salman, Sam; Benjamin, John; Page-Sharp, Madhu; Robinson, Leanne J; Waita, Elizabeth; Batty, Kevin T; Siba, Peter; Mueller, Ivo; Davis, Timothy M E; Betuela, Inoni

    2014-01-01

    Since conventional 14-day primaquine (PMQ) radical cure of vivax malaria is associated with poor compliance, and as total dose, not therapy duration, determines efficacy, a preliminary pharmacokinetic study of two doses (0.5 and 1.0 mg/kg of body weight) was conducted in 28 healthy glucose-6-phosphate dehydrogenase-normal Papua New Guinean children, aged 5 to 12 years, to facilitate development of abbreviated high-dose regimens. Dosing was with food and was directly observed, and venous blood samples were drawn during a 168-h postdose period. Detailed safety monitoring was performed for hepatorenal function and hemoglobin and methemoglobin concentrations. Plasma concentrations of PMQ and its metabolite carboxyprimaquine (CPMQ) were determined by liquid chromatography-mass spectrometry and analyzed using population pharmacokinetic methods. The derived models were used in simulations. Both single-dose regimens were well tolerated with no changes in safety parameters. The mean PMQ central volume of distribution and clearance relative to bioavailability (200 liters/70 kg and 24.6 liters/h/70 kg) were within published ranges for adults. The median predicted maximal concentrations (Cmax) for both PMQ and CPMQ after the last dose of a 1.0 mg/kg 7-day PMQ regimen were approximately double those at the end of 14 days of 0.5 mg/kg daily, while a regimen of 1.0 mg/kg twice daily resulted in a 2.38 and 3.33 times higher Cmax for PMQ and CPMQ, respectively. All predicted median Cmax concentrations were within ranges for adult high-dose studies that also showed acceptable safety and tolerability. The present pharmacokinetic data, the first for PMQ in children, show that further studies of abbreviated high-dose regimens are feasible in this age group. PMID:24189254

  9. Pharmacokinetic and Pharmacodynamic Properties of Anti-VEGF Drugs After Intravitreal Injection.

    PubMed

    Semeraro, Francesco; Morescalchi, Francesco; Duse, Sarah; Gambicorti, Elena; Cancarini, Anna; Costagliola, Ciro

    2015-01-01

    Subretinal neovascularization and pathologic ocular angiogenesis are common causes of progressive, irreversible impairment of central vision, and dramatically affect quality of life. Anti-vascular endothelial growth factor (anti-VEGF) therapy has improved the quality of life for many patients with age-related macular degeneration, diabetic retinopathy, and other ocular diseases involving neovascularization and edema. In these pathologies, the inhibition of intraocular VEGF is the only therapy that can preserve vision. Four anti-VEGF drugs are currently used to treat ocular neovascularization; pegaptanib, ranibizumab, and aflibercept have been approved for this condition, while bevacizumab can be used off-label. Anti-VEGF therapy is administered regularly for many months or years because its suspension or discontinuation may cause recurrence of neovascularization. On the other hand, VEGF is necessary for the survival of retinal and choroidal endothelial cells. Experimental studies in animal models have shown that local inhibition of VEGF causes thinning and atrophy of the choriocapillaris and degeneration of photoreceptors, primarily cones. These studies combined with clinical experience indicated that prolonged VEGF inhibition could impair retinal function. Moreover, anti-VEGF compounds can cross the blood-retina barrier, enter the systemic circulation, and inhibit serum VEGF. Since circulating VEGF protects blood vessel integrity, prolonged anti-VEGF treatment could induce thromboembolic adverse events from vascular causes such as heart attack and stroke, and even death. The ocular dosing regimen and systemic toxicity of anti-VEGF compounds are therefore central concerns. A better understanding of this topic requires knowledge of the metabolism, tissue distribution, and clearance of anti-VEGF compounds. This manuscript reviews the properties of anti-VEGF compounds following intravitreal administration. PMID:26424177

  10. Psychometric Properties of the Acceptance and Action Questionnaire-II for Chinese College Students and Elite Chinese Athletes

    ERIC Educational Resources Information Center

    Zhang, Chun-Qing; Chung, Pak-Kwong; Si, Gangyan; Liu, Jing Dong

    2014-01-01

    The purpose of the present study was to examine the psychometric properties of the Chinese version of the Acceptance and Action Questionnaire-II (AAQ-II) across two samples of Chinese college students (n = 183 and n = 366) and a sample of elite Chinese athletes (n = 330). Exploratory and confirmatory factor analyses supported the existence of a…

  11. Modeling Pharmacokinetics.

    PubMed

    Bois, Frederic Y; Brochot, Céline

    2016-01-01

    Pharmacokinetics is the study of the fate of xenobiotics in a living organism. Physiologically based pharmacokinetic (PBPK) models provide realistic descriptions of xenobiotics' absorption, distribution, metabolism, and excretion processes. They model the body as a set of homogeneous compartments representing organs, and their parameters refer to anatomical, physiological, biochemical, and physicochemical entities. They offer a quantitative mechanistic framework to understand and simulate the time-course of the concentration of a substance in various organs and body fluids. These models are well suited for performing extrapolations inherent to toxicology and pharmacology (e.g., between species or doses) and for integrating data obtained from various sources (e.g., in vitro or in vivo experiments, structure-activity models). In this chapter, we describe the practical development and basic use of a PBPK model from model building to model simulations, through implementation with an easily accessible free software. PMID:27311461

  12. 41 CFR 102-75.1140 - What is the policy governing the acceptance or rejection of a conditional gift of real property...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... governing the acceptance or rejection of a conditional gift of real property for a particular defense... governing the acceptance or rejection of a conditional gift of real property for a particular defense purpose? Any Federal agency receiving an offer of a conditional gift of real property for a...

  13. Bardoxolone methyl (CDDO-Me) as a therapeutic agent: an update on its pharmacokinetic and pharmacodynamic properties

    PubMed Central

    Wang, Yan-Yang; Yang, Yin-Xue; Zhe, Hong; He, Zhi-Xu; Zhou, Shu-Feng

    2014-01-01

    Triterpenoids have been used for medicinal purposes in many Asian countries because of their anti-inflammatory, antioxidant, antiproliferative, anticancer, and anticarcinogenic properties. Bardoxolone methyl, the C-28 methyl ester of 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) known as CDDO-Me or RTA 402, is one of the derivatives of synthetic triterpenoids. CDDO-Me has been used for the treatment of chronic kidney disease, cancer (including leukemia and solid tumors), and other diseases. In this review, we will update our knowledge of the clinical pharmacokinetics and pharmacodynamics of CDDO-Me, highlighting its clinical benefits and the underlying mechanisms involved. The role of the Kelch-like erythroid cell-derived protein with CNC homology-associated protein 1 (Keap1)/the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the therapeutic activities of CDDO-Me will be discussed. CDDO-Me contains α,β-unsaturated carbonyl groups on rings A and C that can generate reversible adducts with the thiol groups of Cys residues in target proteins such as Keap1 and IκB kinase. At low nanomolar concentrations, CDDO-Me protects the cells against oxidative stress via inhibition of reactive oxygen species generation, while CDDO-Me at low micromolar concentrations induces apoptosis by increasing reactive oxygen species and decreasinging intracellular glutathione levels. Through Keap1/Nrf2 and nuclear factor-κB pathways, this agent can modulate the activities of a number of important proteins that regulate inflammation, redox balance, cell proliferation and programmed cell death. In a Phase I trial in cancer patients, CDDO-Me was found to have a slow and saturable oral absorption, a relatively long terminal phase half-life (39 hours at 900 mg/day), nonlinearity (dose-dependent) at high doses (600–1,300 mg/day), and high interpatient variability. As a multifunctional agent, CDDO-Me has improved the renal function in patients with chronic kidney disease

  14. Pharmacological and pharmacokinetic properties of JNJ-40411813, a positive allosteric modulator of the mGlu2 receptor

    PubMed Central

    Lavreysen, Hilde; Ahnaou, Abdellah; Drinkenburg, Wilhelmus; Langlois, Xavier; Mackie, Claire; Pype, Stefan; Lütjens, Robert; Le Poul, Emmanuel; Trabanco, Andrés A; Nuñez, José María Cid

    2015-01-01

    Compounds modulating metabotropic glutamate type 2 (mGlu2) receptor activity may have therapeutic benefits in treating psychiatric disorders like schizophrenia and anxiety. The pharmacological and pharmacokinetic properties of a novel mGlu2 receptor-positive allosteric modulator (PAM), 1-butyl-3-chloro-4-(4-phenyl-1-piperidinyl)-2(1H)-pyridinone (JNJ-40411813/ADX71149) are described here. JNJ-40411813 acts as a PAM at the cloned mGlu2 receptor: EC50 = 147 ± 42 nmol/L in a [35S]GTPγS binding assay with human metabotropic glutamate type 2 (hmGlu2) CHO cells and EC50 = 64 ± 29 nmol/L in a Ca2+ mobilization assay with hmGlu2 Gα16 cotransfected HEK293 cells. [35S]GTPγS autoradiography on rat brain slices confirmed PAM activity of JNJ-40411813 on native mGlu2 receptor. JNJ-40411813 displaced [3H]JNJ-40068782 and [3H]JNJ-46281222 (mGlu2 receptor PAMs), while it failed to displace [3H]LY341495 (a competitive mGlu2/3 receptor antagonist). In rats, JNJ-40411813 showed ex vivo mGlu2 receptor occupancy using [3H]JNJ-46281222 with ED50 of 16 mg/kg (p.o.). PK-PD modeling using the same radioligand resulted in an EC50 of 1032 ng/mL. While JNJ-40411813 demonstrated moderate affinity for human 5HT2A receptor in vitro (Kb = 1.1 μmol/L), higher than expected 5HT2A occupancy was observed in vivo (in rats, ED50 = 17 mg/kg p.o.) due to a metabolite. JNJ-40411813 dose dependently suppressed REM sleep (LAD, 3 mg/kg p.o.), and promoted and consolidated deep sleep. In fed rats, JNJ-40411813 (10 mg/kg p.o.) was rapidly absorbed (Cmax 938 ng/mL at 0.5 h) with an absolute oral bioavailability of 31%. Collectively, our data show that JNJ-40411813 is an interesting candidate to explore the therapeutic potential of mGlu2 PAMs, in in vivo rodents experiments as well as in clinical studies. PMID:25692015

  15. Pharmacokinetic properties of lansoprazole (30-mg enteric-coated capsules) and its metabolites: A single-dose, open-label study in healthy Chinese male subjects

    PubMed Central

    Song, Min; Gao, Xuan; Hang, Tai-Jun; Wen, Ai-Dong

    2009-01-01

    Background: Lansoprazole, a benzimidazole derivative, is indicated for the treatment of various peptic diseases. It is metabolized mainly in the liver, and its primary active metabolites present in plasma are 5′-hydroxy lansoprazole and lansoprazole sulfone. Few data are available on the pharmacokinetic properties of lansoprazole, 5′-hydroxy lansoprazole, and lansoprazole sulfone, which can be used to measure cytochrome P450 (CYP) 2C19 activity. Objectives: The aims of this study were to investigate the clinical plasma pharmacokinetic properties of lansoprazole and its metabolites in healthy Chinese male volunteers, and to assess the influences of CYP2C19 on the pharmacokinetics of lansoprazole. Methods: Healthy adult Chinese male volunteers were enrolled in this single-dose, open-label study. All patients received a single oral enteric capsule containing 30 mg of lansoprazole after a 12-hour overnight fast. Serial blood samples were collected immediately before (0 hour) and at 20, 40, 60, 90, 120, and 150 minutes and 3, 4, 6, 8, 10, 12, 15, and 24 hours after study drug administration. The plasma concentrations of lansoprazole, 5′-hydroxy lansoprazole, and lansoprazole sulfone were determined using a validated internal standard high-performance liquid chromatography—tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic properties (including Cmax, Tmax, elimination t½ [t½z], mean residence time [MRT], AUC0–24, AUC0−∞, apparent oral clearance [CLz/F], and apparent volume of distribution [Vz/F]) were determined using the noncompartmental method. Results: Twenty volunteers (mean [SD] age, 34.9 [2.9] years; weight, 64.6 [2.2] kg; height, 171.3 [3.3] cm) were enrolled in and completed the study. The mean (SD) pharmacokinetic properties of lansoprazole were as follows: Cmax, 1047 (344) ng/mL; Tmax, 2.0 (0.7) hours; t½z, 2.24 (1.43) hours; MRT, 3.62 (0.87) hours; AUC0−24, 3388 (1484) ng/mL/h; AUC0-∞, 3496 (1693) ng/mL/h; CLz/F, 9.96 (3.74) L

  16. Pharmacokinetics of Cannabis in Cancer Cachexia-Anorexia Syndrome.

    PubMed

    Reuter, Stephanie E; Martin, Jennifer H

    2016-07-01

    Anorexia can affect up to 90 % of people with advanced cancer. It is a complex symptom associated with changes in taste, lack of hunger at mealtimes and lack of food enjoyment. Associated weight loss is part of the physical decline that occurs as cancer worsens. Weight loss can also occur from cachexia, the increased metabolism of energy due to raised inflammatory cytokines, liver metastases and other factors seen in several advanced cancers. Independent of anorexia, although frequently associated (where it is referred to as the cachexia-anorexia syndrome), it accounts for a significant amount of morbidity and deaths in people with cancer. In particular, quality of life for the patient and the family is significantly affected with this syndrome as it causes anxiety and distress. Therefore, it is important that research into therapies is undertaken, particularly focusing on an understanding of the pharmacokinetic properties of compounds in this cachexic population. Cannabinoids are one such group of therapies that have received a large amount of media focus recently. However, there appears to be a lack on rigorous pharmacokinetic data of these complex and varied compounds in the cachexic population. Similarly, there is a lack of pharmacokinetic data in any population group for the non- tetrahydrocannabinol (THC) and cannabidiol (CBD) cannabinoids (often due to the lack of analytical standards for quantification). This review will thus examine the pharmacokinetics of major cannabinoids i.e. THC and CBD in a cancer population. Overall, based on the current literature, evidence for the use of cannabinoids for the treatment of cancer-related cachexia-anorexia syndrome remains equivocal. A high-quality, rigorous, phase I/II study to elicit pharmacokinetic dose-concentration and concentration-response data, with a clinically acceptable mode of delivery to reduce intrapatient variability and enable more consistent bioavailability is needed in this population.

  17. Pharmacokinetics of Cannabis in Cancer Cachexia-Anorexia Syndrome.

    PubMed

    Reuter, Stephanie E; Martin, Jennifer H

    2016-07-01

    Anorexia can affect up to 90 % of people with advanced cancer. It is a complex symptom associated with changes in taste, lack of hunger at mealtimes and lack of food enjoyment. Associated weight loss is part of the physical decline that occurs as cancer worsens. Weight loss can also occur from cachexia, the increased metabolism of energy due to raised inflammatory cytokines, liver metastases and other factors seen in several advanced cancers. Independent of anorexia, although frequently associated (where it is referred to as the cachexia-anorexia syndrome), it accounts for a significant amount of morbidity and deaths in people with cancer. In particular, quality of life for the patient and the family is significantly affected with this syndrome as it causes anxiety and distress. Therefore, it is important that research into therapies is undertaken, particularly focusing on an understanding of the pharmacokinetic properties of compounds in this cachexic population. Cannabinoids are one such group of therapies that have received a large amount of media focus recently. However, there appears to be a lack on rigorous pharmacokinetic data of these complex and varied compounds in the cachexic population. Similarly, there is a lack of pharmacokinetic data in any population group for the non- tetrahydrocannabinol (THC) and cannabidiol (CBD) cannabinoids (often due to the lack of analytical standards for quantification). This review will thus examine the pharmacokinetics of major cannabinoids i.e. THC and CBD in a cancer population. Overall, based on the current literature, evidence for the use of cannabinoids for the treatment of cancer-related cachexia-anorexia syndrome remains equivocal. A high-quality, rigorous, phase I/II study to elicit pharmacokinetic dose-concentration and concentration-response data, with a clinically acceptable mode of delivery to reduce intrapatient variability and enable more consistent bioavailability is needed in this population. PMID

  18. 76 FR 35213 - AJT Mining Properties, Inc.; Notice of Preliminary Permit Application Accepted for Filing and...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-16

    ... Energy Regulatory Commission AJT Mining Properties, Inc.; Notice of Preliminary Permit Application..., 2011, AJT Mining Properties, Inc., filed an application for a preliminary permit, pursuant to section 4...: Mr. Scott Willis, AJT Mining Properties, Inc., 5601 Tonsgard Court, Juneau, Alaska 99801; phone:...

  19. Safety, pharmacokinetic and pharmacodynamic properties of TV-1106, a long-acting GH treatment for GH deficiency

    PubMed Central

    Cohen-Barak, Orit; Sakov, Anat; Rasamoelisolo, Michele; Bassan, Merav; Brown, Kurt; Mendzelevski, Boaz; Spiegelstein, Ofer

    2015-01-01

    Background TV-1106 (Teva Pharmaceuticals) is a genetically fused recombinant protein of human GH (hGH) and human serum albumin, in development for treatment of GH deficiency (GHD). TV-1106 is expected to have an extended duration of action compared to daily GH treatment and may enable a reduction in the frequency of injections and improve compliance and quality of life for adults and children requiring GHD therapy. Objective To assess the safety, local tolerability, pharmacokinetics and pharmacodynamics of TV-1106 following single s.c. injections in healthy male volunteers. Methods Subjects (n=56) were assigned to one of seven ascending dose groups (3–100 mg) and received either a single dose of TV-1106 (n=6) or placebo (n=2) by s.c. injection. Results Eighteen subjects reported 43 adverse effects (AEs), which were mild to moderate; no serious AEs (SAEs) occurred. In 50, 70 and 100 mg groups there were mild to moderate increases in heart rate and systolic blood pressure that significantly correlated with higher levels of IGF1. TV-1106 showed pharmacokinetic characteristics of a long-acting hGH as demonstrated by a terminal elimination half-life of 23–35 h, delayed time of peak concentration, and systemic levels seen up to 7 days after dosing. IGF1 levels increased in a dose-dependent manner, before reaching a plateau, with levels above baseline extending beyond 7 days post dose. Conclusion Single administration of TV-1106 up to 100 mg was safe in healthy volunteers. Pharmacokinetics and pharmacodynamics support once-weekly administration in patients with GHD. PMID:26286586

  20. Ebola Virus Infection: Review of the Pharmacokinetic and Pharmacodynamic Properties of Drugs Considered for Testing in Human Efficacy Trials.

    PubMed

    Madelain, Vincent; Nguyen, Thi Huyen Tram; Olivo, Anaelle; de Lamballerie, Xavier; Guedj, Jérémie; Taburet, Anne-Marie; Mentré, France

    2016-08-01

    The 2014-2015 outbreak of Ebola virus disease is the largest epidemic to date in terms of the number of cases, deaths, and affected areas. In October 2015, no antiviral agents had proven antiviral efficacy in patients. However, in September 2014, the World Health Organization inventoried and has since regularly updated a list of potential drug candidates with demonstrated antiviral efficacy in in vitro or animal models. This includes agents belonging to various therapeutic classes, namely direct antiviral agents (favipiravir and BCX4430), a combination of antibodies (ZMapp), type I interferons, RNA interference-based drugs (TKM-Ebola and AVI-7537), and anticoagulant drugs (rNAPc2). Here, we review the pharmacokinetic and pharmacodynamic information presently available for these drugs, using data obtained in healthy volunteers for pharmacokinetics and data obtained in human clinical trials or animal models for pharmacodynamics. Future studies evaluating these drugs in clinical trials are critical to confirm their efficacy in humans, propose appropriate doses, and evaluate the possibility of treatment combinations.

  1. Effect of addition of thermally modified cowpea protein on sensory acceptability and textural properties of wheat bread and sponge cake.

    PubMed

    Campbell, Lydia; Euston, Stephen R; Ahmed, Mohamed A

    2016-03-01

    This paper investigates the sensory acceptability and textural properties of leavened wheat bread and sponge cake fortified with cow protein isolates that had been denatured and glycated by thermal treatment. Defatted cowpea flour was prepared from cow pea beans and the protein isolate was prepared (CPI) and thermally denatured (DCPI). To prepare glycated cowpea protein isolate (GCPI) the cowpea flour slurry was heat treated before isolation of the protein. CPI was more susceptible to thermal denaturation than GCPI as determined by turbidity and sulphydryl groups resulting in greater loss of solubility. This is attributed to the higher glycation degree and higher carbohydrate content of GCPI as demonstrated by glycoprotein staining of SDS PAGE gels. Water absorption of bread dough was significantly enhanced by DCPI and to a larger extent GCPI compared to the control, resulting in softer texture. CPI resulted in significantly increased crumb hardness in baked bread than the control whereas DCPI or GCPI resulted in significantly softer crumb. Bread fortified with 4% DCPI or GCPI was similar to control as regards sensory and textural properties whereas 4% CPI was significantly different, limiting its inclusion level to 2%. There was a trend for higher sensory acceptability scores for GCPI containing bread compared DCPI. Whole egg was replaced by 20% by GCPI (3.5%) in sponge cake without affecting the sensory acceptability, whereas CPI and DCPI supplemented cakes were significantly different than the control. PMID:26471676

  2. Effect of addition of thermally modified cowpea protein on sensory acceptability and textural properties of wheat bread and sponge cake.

    PubMed

    Campbell, Lydia; Euston, Stephen R; Ahmed, Mohamed A

    2016-03-01

    This paper investigates the sensory acceptability and textural properties of leavened wheat bread and sponge cake fortified with cow protein isolates that had been denatured and glycated by thermal treatment. Defatted cowpea flour was prepared from cow pea beans and the protein isolate was prepared (CPI) and thermally denatured (DCPI). To prepare glycated cowpea protein isolate (GCPI) the cowpea flour slurry was heat treated before isolation of the protein. CPI was more susceptible to thermal denaturation than GCPI as determined by turbidity and sulphydryl groups resulting in greater loss of solubility. This is attributed to the higher glycation degree and higher carbohydrate content of GCPI as demonstrated by glycoprotein staining of SDS PAGE gels. Water absorption of bread dough was significantly enhanced by DCPI and to a larger extent GCPI compared to the control, resulting in softer texture. CPI resulted in significantly increased crumb hardness in baked bread than the control whereas DCPI or GCPI resulted in significantly softer crumb. Bread fortified with 4% DCPI or GCPI was similar to control as regards sensory and textural properties whereas 4% CPI was significantly different, limiting its inclusion level to 2%. There was a trend for higher sensory acceptability scores for GCPI containing bread compared DCPI. Whole egg was replaced by 20% by GCPI (3.5%) in sponge cake without affecting the sensory acceptability, whereas CPI and DCPI supplemented cakes were significantly different than the control.

  3. The Coding Properties of Lysine-accepting Transfer Ribonucleic Acids from Black-eyed Peas 1

    PubMed Central

    Hague, Donald R.; Kofoid, Eric C.

    1971-01-01

    Lysine-accepting transfer RNA from ungerminated and germinated embryo axes of black-eyed peas (Vigna sinensis L. Savi) was fractionated on benzoylated diethylaminoethyl cellulose and reverse phase Freon columns. Cochromatography indicated the presence of two similar lysyl transfer RNA fractions in each tissue. Ribosome binding studies revealed that the larger of the two fractions in each case is specific for the AAG codon, while the smaller one recognizes AAA and AAG. Possible implications of this difference in quantities of isoacceptors in translation of genetic information are discussed. PMID:16657787

  4. The Coding Properties of Lysine-accepting Transfer Ribonucleic Acids from Black-eyed Peas.

    PubMed

    Hague, D R; Kofoid, E C

    1971-09-01

    Lysine-accepting transfer RNA from ungerminated and germinated embryo axes of black-eyed peas (Vigna sinensis L. Savi) was fractionated on benzoylated diethylaminoethyl cellulose and reverse phase Freon columns. Cochromatography indicated the presence of two similar lysyl transfer RNA fractions in each tissue. Ribosome binding studies revealed that the larger of the two fractions in each case is specific for the AAG codon, while the smaller one recognizes AAA and AAG. Possible implications of this difference in quantities of isoacceptors in translation of genetic information are discussed.

  5. Pharmacokinetics of Sparfloxacin in the Serum and Vitreous Humor of Rabbits: Physicochemical Properties That Regulate Penetration of Quinolone Antimicrobials

    PubMed Central

    Liu, Weiguo; Liu, Qing Feng; Perkins, Ruth; Drusano, George; Louie, Arnold; Madu, Assumpta; Mian, Umar; Mayers, Martin; Miller, Michael H.

    1998-01-01

    We have used a recently described animal model to characterize the ocular pharmacokinetics of sparfloxacin in vitreous humor of uninfected albino rabbits following systemic administration and direct intraocular injection. The relationships of lipophilicity, protein binding, and molecular weight to the penetration and elimination of sparfloxacin were compared to those of ciprofloxacin, fleroxacin, and ofloxacin. To determine whether elimination was active, elimination rates following direct injection with and without probenecid or heat-killed bacteria were compared. Sparfloxacin concentrations were measured in the serum and vitreous humor by a biological assay. Protein binding and lipophilicity were determined, respectively, by ultrafiltration and oil-water partitioning. Pharmacokinetic parameters were characterized with RSTRIP, an iterative, nonlinear, weighted, least-squares-regression program. The relationship between each independent variable and mean quinolone concentration or elimination rate in the vitreous humor was determined by multiple linear regression. The mean concentration of sparfloxacin in the vitreous humor was 59.4% ± 12.2% of that in serum. Penetration of sparfloxacin, ciprofloxacin, fleroxacin, and ofloxacin into, and elimination from, the vitreous humor correlated with lipophilicity (r2 > 0.999). The linear-regression equation describing this relationship was not improved by including the inverse of the square root of the molecular weight and/or the degree of protein binding. Elimination rates for each quinolone were decreased by the intraocular administration of probenecid. Heat-killed Staphylococcus epidermidis decreased the rate of elimination of fleroxacin. Penetration of sparfloxacin into the noninflamed vitreous humor was greater than that of any quinolone previously examined. There was an excellent correlation between lipophilicity and vitreous entry or elimination for sparfloxacin as well as ciprofloxacin, fleroxacin, and ofloxacin

  6. Physical properties and sixth graders' acceptance of an extruded ready-to-eat sweetpotato breakfast cereal

    NASA Technical Reports Server (NTRS)

    Dansby, M. Y.; Bovell-Benjamin, A. C.

    2003-01-01

    Extruded ready-to-eat breakfast cereals (RTEBCs) were made from varying levels of sweetpotato flour (SPF), whole-wheat bran (WWB), and extrusion cooking. Moisture, protein, and ash contents were lower in the 100% SPF than the 100% WWB. Carbohydrate, beta-carotene, and ascorbic acid contents were higher in the 100% SPF. Fat, thiamin, riboflavin contents, bulk densities, and the water absorption index were similar for the cereals. However, the expansion ratio was highest in the 100% SPF cereal. The 100% WWB had the lightest color and most fibrous morphology. Extruded RTEBC containing 100% SPF and 75%/25% SPF/WWB were well-liked and acceptable to sixth graders attending an elementary school in Auburn, Alabama, but the 100% WWB was unacceptable.

  7. Quantitative Property-Property Relationship for Screening-Level Prediction of Intrinsic Clearance of Volatile Organic Chemicals in Rats and Its Integration within PBPK Models to Predict Inhalation Pharmacokinetics in Humans

    PubMed Central

    Peyret, Thomas; Krishnan, Kannan

    2012-01-01

    The objectives of this study were (i) to develop a screening-level Quantitative property-property relationship (QPPR) for intrinsic clearance (CLint) obtained from in vivo animal studies and (ii) to incorporate it with human physiology in a PBPK model for predicting the inhalation pharmacokinetics of VOCs. CLint, calculated as the ratio of the in vivo Vmax (μmol/h/kg bw rat) to the Km (μM), was obtained for 26 VOCs from the literature. The QPPR model resulting from stepwise linear regression analysis passed the validation step (R2 = 0.8; leave-one-out cross-validation Q2 = 0.75) for CLint normalized to the phospholipid (PL) affinity of the VOCs. The QPPR facilitated the calculation of CLint (L PL/h/kg bw rat) from the input data on log Pow, log blood: water PC and ionization potential. The predictions of the QPPR as lower and upper bounds of the 95% mean confidence intervals (LMCI and UMCI, resp.) were then integrated within a human PBPK model. The ratio of the maximum (using LMCI for CLint) to minimum (using UMCI for CLint) AUC predicted by the QPPR-PBPK model was 1.36 ± 0.4 and ranged from 1.06 (1,1-dichloroethylene) to 2.8 (isoprene). Overall, the integrated QPPR-PBPK modeling method developed in this study is a pragmatic way of characterizing the impact of the lack of knowledge of CLint in predicting human pharmacokinetics of VOCs, as well as the impact of prediction uncertainty of CLint on human pharmacokinetics of VOCs. PMID:22685458

  8. 49 CFR 1544.201 - Acceptance and screening of individuals and accessible property.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ..., incendiary, or deadly or dangerous weapon. Each aircraft operator must use the measures in its security program to prevent or deter the carriage of any weapon, explosive, or incendiary on or about each... which it is responsible, and all accessible property under that individual's control, are inspected...

  9. Effect of dietary fiber on properties and acceptance of meat products: a review.

    PubMed

    Talukder, Suman

    2015-01-01

    Meat is an important source of all essential nutritional components of our daily diet as it content most of the essential amino acids, fatty acids, vitamins, and minerals which are lack in plant based food, but it is devoid of dietary fiber, which is very essential component for normal physiological/biochemical process. During meat products processing, its functional values can be improved by supplementation of dietary fiber rich vegetative substances like cereal and pulse flour, vegetable and fruits pulp, etc. by this process, a significant proportion of required daily allowance of dietary fiber can be fulfilled for the frequent meat consumers. The consumption of meat products fortified with of dietary fiber can lead to the prevention of diseases like coronary heart disease, diabetes, irritable bowel disease, obesity, etc. On the other hand, the dietary fiber can effectively be incorporated in the processed meat products as binders, extender, and filler, they can significantly replace the unhealthy fat components from the products; increase acceptability by improving nutritional components, pH, water-holding capacity, emulsion stability, shear press value, sensory characters, etc. of finished products. Addition of dietary fiber in the meat products can increase the cooking yield therefore the economic gain as well.

  10. Consumer acceptability and sensory profile of cooked broccoli with mustard seeds added to improve chemoprotective properties.

    PubMed

    Ghawi, Sameer Khalil; Shen, Yuchi; Niranjan, Keshavan; Methven, Lisa

    2014-09-01

    Broccoli, a rich source of glucosinolates, is a commonly consumed vegetable of the Brassica family. Hydrolysis products of glucosinolates, isothiocyanates, have been associated with health benefits and contribute to the flavor of Brassica. However, boiling broccoli causes the myrosinase enzyme needed for hydrolysis to denature. In order to ensure hydrolysis, broccoli must either be mildly cooked or active sources of myrosinase, such as mustard seed powder, can be added postcooking. In this study, samples of broccoli were prepared in 6 different ways; standard boiling, standard boiling followed by the addition of mustard seeds, sous vide cooking at low temperature (70 °C) and sous vide cooking at higher temperature (100 °C) and sous vide cooking at higher temperature followed by the addition of mustard seeds at 2 different concentrations. The majority of consumers disliked the mildly cooked broccoli samples (70 °C, 12 min, sous vide) which had a hard and stringy texture. The highest mean consumer liking was for standard boiled samples (100 °C, 7 min). Addition of 1% mustard seed powder developed sensory attributes, such as pungency, burning sensation, mustard odor, and flavor. One cluster of consumers (32%) found mustard seeds to be a good complement to cooked broccoli; however, the majority disliked the mustard-derived sensory attributes. Where the mustard seeds were partially processed, doubling the addition to 2% led to only the same level of mustard and pungent flavors as 1% unprocessed seeds, and mean consumer liking remained unaltered. This suggests that optimization of the addition level of partially processed mustard seeds may be a route to enhance bioactivity of cooked broccoli without compromising consumer acceptability. PMID:25156799

  11. Consumer acceptability and sensory profile of cooked broccoli with mustard seeds added to improve chemoprotective properties.

    PubMed

    Ghawi, Sameer Khalil; Shen, Yuchi; Niranjan, Keshavan; Methven, Lisa

    2014-09-01

    Broccoli, a rich source of glucosinolates, is a commonly consumed vegetable of the Brassica family. Hydrolysis products of glucosinolates, isothiocyanates, have been associated with health benefits and contribute to the flavor of Brassica. However, boiling broccoli causes the myrosinase enzyme needed for hydrolysis to denature. In order to ensure hydrolysis, broccoli must either be mildly cooked or active sources of myrosinase, such as mustard seed powder, can be added postcooking. In this study, samples of broccoli were prepared in 6 different ways; standard boiling, standard boiling followed by the addition of mustard seeds, sous vide cooking at low temperature (70 °C) and sous vide cooking at higher temperature (100 °C) and sous vide cooking at higher temperature followed by the addition of mustard seeds at 2 different concentrations. The majority of consumers disliked the mildly cooked broccoli samples (70 °C, 12 min, sous vide) which had a hard and stringy texture. The highest mean consumer liking was for standard boiled samples (100 °C, 7 min). Addition of 1% mustard seed powder developed sensory attributes, such as pungency, burning sensation, mustard odor, and flavor. One cluster of consumers (32%) found mustard seeds to be a good complement to cooked broccoli; however, the majority disliked the mustard-derived sensory attributes. Where the mustard seeds were partially processed, doubling the addition to 2% led to only the same level of mustard and pungent flavors as 1% unprocessed seeds, and mean consumer liking remained unaltered. This suggests that optimization of the addition level of partially processed mustard seeds may be a route to enhance bioactivity of cooked broccoli without compromising consumer acceptability.

  12. Influence of oak maturation regimen on composition, sensory properties, quality, and consumer acceptability of cabernet sauvignon wines.

    PubMed

    Crump, Anna M; Johnson, Trent E; Wilkinson, Kerry L; Bastian, Susan E P

    2015-02-11

    Oak barrels have long been the preferred method for oak maturation of wine, but barrels contribute significantly to production costs, so alternate oak maturation regimens have been introduced, particularly for wines at lower price points. To date, few studies have investigated consumers' acceptance of wines made using non-traditional oak treatments. In this study, two Cabernet Sauvignon wines were aged using traditional (i.e., barrel) and/or alternative (i.e., stainless steel or plastic tanks and vats, with oak wood added) maturation regimens. Chemical and sensory analyses were subsequently performed to determine the influence on wine composition and sensory properties, that is, the presence of key oak-derived volatile compounds and perceptible oak aromas and flavor. The quality of a subset of wines was rated by a panel of 10 wine experts using a 20-point scoring system, with all wines considered technically sound. Consumer acceptance of wines was also determined. Hedonic ratings ranged from 5.7 to 5.9 (on a 9-point scale), indicating there was no significant difference in consumers' overall liking of each wine. However, segmentation based on individual liking scores identified three distinct clusters comprising consumers with considerably different wine preferences. These results justify wine producers' use of alternative oak maturation regimens to achieve wine styles that appeal to different segments of their target market.

  13. Design, synthesis, and biological evaluation of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl derivatives as new irreversible epidermal growth factor receptor inhibitors with improved pharmacokinetic properties.

    PubMed

    Xu, Shilin; Xu, Tianfeng; Zhang, Lianwen; Zhang, Zhang; Luo, Jinfeng; Liu, Yingxue; Lu, Xiaoyun; Tu, Zhengchao; Ren, Xiaomei; Ding, Ke

    2013-11-14

    Structural optimization of a series of 2-oxo-3,4-dihydropyrimido[4,5-d]pyrimidinyl compounds, potential new irreversible EGFR inhibitors, was performed to improve pharmacokinetic properties of the compounds. This led to compound 2v with improved aqueous solubility and good pharmacokinetic properties which at the nanomolar level potently inhibits gefitinib-resistant EGFR(L858R/T790M) kinase and displays strong antiproliferative activity against H1975 nonsmall cell lung cancer cells. The new inhibitor also shows promising antitumor efficacy in a murine EGFR(L858R/T790M)-driven H1975 xenograft model without effect on body weight. These studies provide new lead compounds for further development of drugs for treatment of gefitinib-resistant nonsmall cell lung cancer patients.

  14. Quantitative and qualitative variation of fat in model vanilla custard desserts: effects on sensory properties and consumer acceptance.

    PubMed

    Tomaschunas, Maja; Köhn, Ehrhard; Bennwitz, Petra; Hinrichs, Jörg; Busch-Stockfisch, Mechthild

    2013-06-01

    The effects of variation in fat content (0.1% to 15.8%) and type of fat, using different types of milk, dairy cream, or vegetable fat cream, on sensory characteristics and consumer acceptance of starch-based vanilla model custards were studied. Descriptive analysis with trained panelists and consumer testing with untrained assessors were applied. Descriptive data were related to hedonic data using principal component analysis to determine drivers of liking and disliking. Results demonstrated an increasing effect of fat concerning visual and oral thickness, creamy flavor, and fat-related texture properties, as well as a decreasing effect concerning yellow color and surface shine. A lack of fat caused moderate intensities in pudding-like flavor attributes and an intensive jelly texture. Adding a vegetable fat cream led to lower intensities in attributes yellow color, cooked flavor, thick, and jelly texture, whereas intensities in vegetable fat flavor and fat-related texture properties increased. All consumers favored custards with medium fat contents, being high in pudding-like and vegetable fat flavor as well as in fat-related texture attributes. Nonfat custards were rejected due to jelly texture and moderate intensities in pudding-flavor attributes. High-fat samples were liked by some consumers, but their high intensities in thickness, white color, and creamy flavor also drove disliking for others.

  15. In silico optimization of pharmacokinetic properties and receptor binding affinity simultaneously: a 'parallel progression approach to drug design' applied to β-blockers.

    PubMed

    Advani, Poonam; Joseph, Blessy; Ambre, Premlata; Pissurlenkar, Raghuvir; Khedkar, Vijay; Iyer, Krishna; Gabhe, Satish; Iyer, Radhakrishnan P; Coutinho, Evans

    2016-01-01

    The present work exploits the potential of in silico approaches for minimizing attrition of leads in the later stages of drug development. We propose a theoretical approach, wherein 'parallel' information is generated to simultaneously optimize the pharmacokinetics (PK) and pharmacodynamics (PD) of lead candidates. β-blockers, though in use for many years, have suboptimal PKs; hence are an ideal test series for the 'parallel progression approach'. This approach utilizes molecular modeling tools viz. hologram quantitative structure activity relationships, homology modeling, docking, predictive metabolism, and toxicity models. Validated models have been developed for PK parameters such as volume of distribution (log Vd) and clearance (log Cl), which together influence the half-life (t1/2) of a drug. Simultaneously, models for PD in terms of inhibition constant pKi have been developed. Thus, PK and PD properties of β-blockers were concurrently analyzed and after iterative cycling, modifications were proposed that lead to compounds with optimized PK and PD. We report some of the resultant re-engineered β-blockers with improved half-lives and pKi values comparable with marketed β-blockers. These were further analyzed by the docking studies to evaluate their binding poses. Finally, metabolic and toxicological assessment of these molecules was done through in silico methods. The strategy proposed herein has potential universal applicability, and can be used in any drug discovery scenario; provided that the data used is consistent in terms of experimental conditions, endpoints, and methods employed. Thus the 'parallel progression approach' helps to simultaneously fine-tune various properties of the drug and would be an invaluable tool during the drug development process.

  16. Glycoluril–tetrathiafulvalene molecular clips: on the influence of electronic and spatial properties for binding neutral accepting guests

    PubMed Central

    Cotelle, Yoann; Hardouin-Lerouge, Marie; Legoupy, Stéphanie; Alévêque, Olivier

    2015-01-01

    Summary Glycoluril-based molecular clips incorporating tetrathiafulvalene (TTF) sidewalls have been synthesized through different strategies with the aim of investigating the effect of electrochemical and spatial properties for binding neutral accepting guests. We have in particular focused our study on the spacer extension in order to tune the intramolecular TTF···TTF distance within the clip and, consequently, the redox behavior of the receptor. Carried out at different concentrations in solution, electrochemical and spectroelectrochemical experiments provide evidence of mixed-valence and/or π-dimer intermolecular interactions between TTF units from two closed clips. The stepwise oxidation of each molecular clip involves an electrochemical mechanism with three one-electron processes and two charge-coupled chemical reactions, a scheme which is supported by electrochemical simulations. The fine-tunable π-donating ability of the TTF units and the cavity size allow to control binding interaction towards a strong electron acceptor such as tetrafluorotetracyanoquinodimethane (F4-TCNQ) or a weaker electron acceptor such as 1,3-dinitrobenzene (m-DNB). PMID:26199657

  17. Potentially acceptable substitutes for the chlorofluorocarbons: properties and performance features of HFC-134a, HCFC-123, and HCFC-141b

    NASA Astrophysics Data System (ADS)

    Sukornick, B.

    1989-05-01

    Potentially acceptable substitutes are known for CFC-11 and CFC-12-the most important Chlorofluorocarbons. HFC-134a could replace CFC-12 in airconditioning and refrigeration and both HCFC-123 and HCFC-141b show promise as CFC-11 substitutes. The replacement molecules all have significantly reduced greenhouse and ozone depletion potentials compared to their fully halogenated counterparts. HCFC-123 is theoretically a less efficient blowing agent than CFC-11, but 141b is more efficient. Results from experimental foaming tests confirm these relationships and show that initial insulating values are slightly lower for 141b and 123 than 11. Both substitutes are nonflammable liquids. Based on its physical properties, HFC-134a is an excellent replacement candidate for CFC-12. In addition, it is more thermally stable than CFC-12. A new family of HFC-134a compatible lubricant oils will be required. The estimated coefficient of performance (COP) of 134a is 96 98% that of CFC-12. Subacute toxicity tests show HFC-134a to have a low order of toxicity. HCFC-123 reveals no serious side effects at a concentration of 0.1% in subchronic tests and the inhalation toxicity of 141b is lower than that of CFC-11 based on a 6-h exposure. Chronic tests on all the new candidates will have to be completed for large-scale commercial use. Allied-Signal is conducting process development at a highly accelerated pace, and we plan to begin commercialization of substitutes within 5 years.

  18. Potentially acceptable substitutes for the chlorofluorocarbons: Properties and performance features of HFC-134a, HCFC-123, and HCFC-141b

    SciTech Connect

    Sukornick, B. )

    1989-05-01

    Potentially acceptable substitutes are known for CFC-11 and CFC-12 - the most important chlorofluorocarbons. HFC-134a could replace CFC-12 in air-conditioning and refrigeration and both HCFC-123 and HCFC-141b show promise as CFC-11 substitutes. The replacement molecules all have significantly reduced greenhouse and ozone depletion potentials compared to their fully halogenated counterparts. HCFC-123 is theoretically a less efficient blowing agent than CFC-11, but 141b is more efficient. Results from experimental foaming tests confirm these relationships and show that initial insulating values are slightly lower for 141 b and 123 than 11. Both substitutes are nonflammable liquids. Based on its physical properties, HFC-134a is an excellent replacement candidate for CFC-12. In addition, it is more thermally stable than CFC-12. A new family of HFC-134a compatible lubricant oils will be required. The estimated coefficient of performance (COP) of 134a is 96-98% that of CFC-12. Subacute toxicity tests show HFC-134a to have a low order of toxicity. HCFC-123 reveals no serious side effects at a concentration of 0.1% in subchronic tests and the inhalation toxicity of 141b is lower than that of CFC-11 based on a 6-h exposure. Chronic tests on all the new candidates will have to be completed for large-scale commercial use. Allied-Signal is conducting process development at a highly accelerated pace, and they plan to begin commercialization of substitutes within 5 years.

  19. Clinical pharmacokinetics and metabolism of bevantolol.

    PubMed

    Latts, J R

    1986-03-01

    Bevantolol (the hydrochloride salt) has pharmacokinetic properties that are clinically advantageous. Bevantolol is well absorbed orally (greater than 70%); and the systemic bioavailability is 60%. Peak plasma concentrations are achieved 1 to 2 hours following an oral dose. Elimination is first-order with an average elimination half-life of 1.5 hours. Bevantolol exhibits linear pharmacokinetics within the therapeutic range (100 to 400 mg) with no change in half-life with chronic dosing. These properties result in predictable plasma levels and predictable drug response.

  20. Paediatric pharmacokinetics: key considerations

    PubMed Central

    Batchelor, Hannah Katharine; Marriott, John Francis

    2015-01-01

    A number of anatomical and physiological factors determine the pharmacokinetic profile of a drug. Differences in physiology in paediatric populations compared with adults can influence the concentration of drug within the plasma or tissue. Healthcare professionals need to be aware of anatomical and physiological changes that affect pharmacokinetic profiles of drugs to understand consequences of dose adjustments in infants and children. Pharmacokinetic clinical trials in children are complicated owing to the limitations on blood sample volumes and perception of pain in children resulting from blood sampling. There are alternative sampling techniques that can minimize the invasive nature of such trials. Population based models can also limit the sampling required from each individual by increasing the overall sample size to generate robust pharmacokinetic data. This review details key considerations in the design and development of paediatric pharmacokinetic clinical trials. PMID:25855821

  1. The effect of food on the pharmacokinetic properties and bioequivalence of two formulations of pitavastatin calcium in healthy Chinese male subjects.

    PubMed

    Shang, Dewei; Deng, Shuhua; Yao, Zhenhong; Wang, Zhanzhang; Ni, Xiaojia; Zhang, Ming; Hu, Jinqing; Lu, Haoyang; Zhu, Xiuqing; Huang, Wencan; Qiu, Chang; Wen, Yuguan

    2016-01-01

    1. Pitavastatin is an effective treatment for primary hyperlipidemia and mixed dyslipidemia. The aim of the present study was to investigate the effect of food on the pharmacokinetic properties and bioequivalence of the original, branded, formulation of pitavastatin calcium and a new generic formulation in healthy Chinese male subjects under fasting and fed conditions. 2. Under fasting and fed conditions, 90% CIs of the geometric mean of generic/branded AUC0-48 h ratios were 92.2-102.4%, 93.1-104.5%, the ratios of ln(AUC0-∞) were 92.6-103.7%, 93.2-103.5%, and ln(Cmax) ratios were 90.7-110.3%, 84.7-100.8%, respectively. The generic and branded formulations were bioequivalent in terms of rate and extent of absorption under both the conditions. The average values of AUC0-48 h, AUC0-∞ and Cmax decreased noticeably following a high-fat breakfast. Values for AUC0-48 h were 87.69% and 83.7%, values for AUC0-∞ were 87.5% and 84.6%, and values for Cmax were 45.0% and 50.4% in subjects given the generic and branded preparations, respectively. The absorption of pitavastatin calcium tablets was delayed following a high-fat meal, with Tmax increasing by up to 2.43-fold. 3. Both formulations were generally well tolerated, with no serious adverse reactions reported. The newly developed generic formulation may provide a reliable alternative to the branded tablets for patients with primary hyperlipidemia or mixed dyslipidemia.

  2. Bevantolol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and angina pectoris.

    PubMed

    Frishman, W H; Goldberg, R J; Benfield, P

    1988-01-01

    Bevantolol is a new beta-adrenoceptor antagonist which possesses a relatively high degree of selectivity for beta 1-adrenoceptors. It is devoid of intrinsic sympathomimetic activity and possesses only weak local anaesthetic properties. Interestingly, bevantolol has been shown to cause a lowering effect on peripheral vascular resistance. Available clinical data indicate that bevantolol, given once or twice daily, is an effective agent in the management of mild to moderate hypertension and stable angina pectoris. In hypertension bevantolol has been shown to be of comparable therapeutic efficacy to both atenolol and propranolol, while in patients with angina pectoris the drug compared favourably with atenolol. During short and long term administration bevantolol has been well tolerated and few patients have withdrawn from treatment because of adverse effects. However, although the properties of bevantolol may offer theoretical advantages in some patients, only a few comparative studies have been reported, and thus it is presently unclear what advantages bevantolol may offer over existing treatments for hypertension or angina pectoris.

  3. Physicochemical and Pharmacokinetic Characterization of Amorphous Solid Dispersion of Meloxicam with Enhanced Dissolution Property and Storage Stability.

    PubMed

    Ochi, Masanori; Kimura, Keisuke; Kanda, Atsushi; Kawachi, Takaki; Matsuda, Akitoshi; Yuminoki, Kayo; Hashimoto, Naofumi

    2016-08-01

    The aim of the present study was to develop amorphous solid dispersion (ASD) of meloxicam (MEL) for providing rapid onset of action. ASDs of MEL with polyvinylpyrrolidone (PVP) K-30 (MEL/PVP), HPC-SSL (MEL/HPC), and Eudragit EPO (MEL/EPO) were prepared. The physicochemical properties were characterized by focusing on morphology, crystallinity, dissolution properties, stability, and the interaction of MEL with coexisting polymers. MEL/EPO was physicochemically stable after storage at 40°C/75% RH for 30 days. In contrast, recrystallization of MEL was observed in MEL/PVP and MEL/HPC at 40°C/50% RH for 30 days. Infrared spectroscopic studies and (1)H NMR analyses of MEL/EPO revealed that Eudragit EPO interacted with MEL and reduced intermolecular binding between MEL molecules. Intermolecular interaction of drug molecules is necessary for the formation of crystalline. Thus, the interaction of MEL with Eudragit EPO and interruption of the formation of supramolecular interaction between MEL molecules might lead to the inhibition of crystal growth of MEL. Of all the MEL solid dispersions prepared, MEL/EPO showed the largest improvement in dissolution behavior. Oral administration of MEL/EPO to rats showed rapid and enhanced MEL exposure with a 2.4-fold increase in bioavailability compared with crystalline MEL. Based on these findings, MEL/EPO was physicochemically stable and provided a rapid onset of action and enhanced bioavailability after oral administration. PMID:27435198

  4. Pharmacokinetics of drugs in pregnancy.

    PubMed

    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.

  5. Pharmacokinetics, pharmacodynamics and toxicology of theranostic nanoparticles

    NASA Astrophysics Data System (ADS)

    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.

  6. Simulation of differential drug pharmacokinetics under heat and exercise stress using a physiologically based pharmacokinetic modeling approach.

    PubMed

    Sidhu, Pardeep; Peng, Henry T; Cheung, Bob; Edginton, Andrea

    2011-05-01

    Under extreme conditions of heat exposure and exercise stress, the human body undergoes major physiological changes. Perturbations in organ blood flows, gastrointestinal properties, and vascular physiology may impact the body's ability to absorb, distribute, and eliminate drugs. Clinical studies on the effect of these stressors on drug pharmacokinetics demonstrate that the likelihood of pharmacokinetic alteration is dependent on drug properties and the intensity of the stressor. The objectives of this study were to use literature data to quantify the correlation between exercise and heat exposure intensity to changing physiological parameters and further, to use this information for the parameterization of a whole-body, physiologically based pharmacokinetic model for the purposes of determining those drug properties most likely to demonstrate altered drug pharmacokinetics under stress. Cardiac output and most organ blood flows were correlated with heart rate using regression analysis. Other altered parameters included hematocrit and intravascular albumin concentration. Pharmacokinetic simulations of intravenous and oral administration of hypothetical drugs with either a low or high value of lipophilicity, unbound fraction in plasma, and unbound intrinsic hepatic clearance demonstrated that the area under the curve of those drugs with a high unbound intrinsic clearance was most affected (up to a 130% increase) following intravenous administration, whereas following oral administration, pharmacokinetic changes were smaller (<40% increase in area under the curve) for all hypothetical compounds. A midazolam physiologically based pharmacokinetic model was also used to demonstrate that simulated changes in pharmacokinetic parameters under exercise and heat stress were generally consistent with those reported in the literature.

  7. Redox properties of structural Fe in clay minerals. 1. Electrochemical quantification of electron-donating and -accepting capacities of smectites.

    PubMed

    Gorski, Christopher A; Aeschbacher, Michael; Soltermann, Daniela; Voegelin, Andreas; Baeyens, Bart; Marques Fernandes, Maria; Hofstetter, Thomas B; Sander, Michael

    2012-09-01

    Clay minerals often contain redox-active structural iron that participates in electron transfer reactions with environmental pollutants, bacteria, and biological nutrients. Measuring the redox properties of structural Fe in clay minerals using electrochemical approaches, however, has proven to be difficult due to a lack of reactivity between clay minerals and electrodes. Here, we overcome this limitation by using one-electron-transfer mediating compounds to facilitate electron transfer between structural Fe in clay minerals and a vitreous carbon working electrode in an electrochemical cell. Using this approach, the electron-accepting and -donating capacities (Q(EAC) and Q(EDC)) were quantified at applied potentials (E(H)) of -0.60 V and +0.61 V (vs SHE), respectively, for four natural Fe-bearing smectites (i.e., SWa-1, SWy-2, NAu-1, and NAu-2) having different total Fe contents (Fe(total) = 2.3 to 21.2 wt % Fe) and varied initial Fe(2+)/Fe(total) states. For every SWa-1 and SWy-2 sample, all the structural Fe was redox-active over the tested E(H) range, demonstrating reliable quantification of Fe content and redox state. Yet for NAu-1 and NAu-2, a significant fraction of the structural Fe was redox-inactive, which was attributed to Fe-rich smectites requiring more extreme E(H)-values to achieve complete Fe reduction and/or oxidation. The Q(EAC) and Q(EDC) values provided here can be used as benchmarks in future studies examining the extent of reduction and oxidation of Fe-bearing smectites.

  8. Tianeptine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression.

    PubMed

    Wilde, M I; Benfield, P

    1995-03-01

    Tianeptine is a novel antidepressant agent, both structurally (modified tricyclic) and in terms of its pharmacodynamic profile. Unlike other antidepressant agents, tianeptine stimulates the uptake of serotonin (5-hydroxytryptamine; 5-HT) in rat brain synaptosomes and rat and human platelets, increases 5-hydroxyindoleacetic acid (5-HIAA) levels in cerebral tissue and plasma, and reduces serotonergic-induced behaviour. Tianeptine reduces the hypothalamic-pituitary-adrenal response to stress, antagonises stress-induced behavioural deficits and prevents changes in cerebral morphology. The antidepressant efficacy of tianeptine, as shown in 2 trials of patients with major depression or depressed bipolar disorder with or without melancholia, is greater than that of placebo. In patients with major depression without melancholia or psychotic features, depressed bipolar disorder or dysthymic disorder, the antidepressant efficacy of short term (4 weeks to 3 months) tianeptine therapy appears to be similar to that of amitriptyline, imipramine and fluoxetine and may be superior to that of maprotiline in patients with coexisting depression and anxiety. However, submaximal dosages of amitriptyline and maprotiline were used in these studies. Preliminary evidence suggests that tianeptine may also be effective in patients with endogenous depression. Progressive therapeutic improvements have been observed with up to 1 year of tianeptine treatment, and long term therapy may reduce the rate of relapse or recurrence. Tianeptine is effective in the treatment of depression in elderly and post-alcohol-withdrawal patient subgroups. Tianeptine was more effective in reducing psychic anxiety than placebo in patients with major depression or depressed bipolar disorder with or without melancholia. The overall anxiolytic properties of tianeptine in patients with coexisting depression and anxiety appear to be similar to those of amitriptyline, imipramine and fluoxetine and may be superior to those

  9. Organophosphorus Insecticide Pharmacokinetics

    SciTech Connect

    Timchalk, Charles

    2010-01-01

    This chapter highlights a number of current and future applications of pharmacokinetics to assess organophosphate (OP) insecticide dosimetry, biological response and risk in humans exposed to these agents. Organophosphates represent a large family of pesticides where insecticidal as well as toxicological mode of action is associated with their ability to target and inhibit acetylcholinesterase (AChE). Pharmacokinetics entails the quantitative integration of physiological and metabolic processes associated with the absorption, distribution, metabolism and excretion (ADME) of drugs and xenobiotics. Pharmacokinetic studies provide important data on the amount of toxicant delivered to a target site as well as species-, age-, gender-specific and dose-dependent differences in biological response. These studies have been conducted with organophosphorus insecticides in multiple species, at various dose levels, and across different routes of exposure to understand their in vivo pharmacokinetics and how they contribute to the observed toxicological response. To access human exposure to organophosphorus insecticides, human pharmacokinetic studies have been conducted and used to develop biological monitoring strategies based on the quantitation of key metabolites in biological fluids. Pharmacokinetic studies with these insecticides are also useful to facilitate extrapolation of dosimetry and biological response from animals to humans and for the assessment of human health risk. In this regard, physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models are being utilized to assess risk and understand the toxicological implications of known or suspected exposures to various insecticides. In this chapter a number of examples are presented that illustrate the utility and limitation of pharmacokinetic studies to address human health concerns associated with organophosphorus insecticides.

  10. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling

    PubMed Central

    Moss, Darren Michael; Siccardi, Marco

    2014-01-01

    The delivery of therapeutic agents is characterized by numerous challenges including poor absorption, low penetration in target tissues and non-specific dissemination in organs, leading to toxicity or poor drug exposure. Several nanomedicine strategies have emerged as an advanced approach to enhance drug delivery and improve the treatment of several diseases. Numerous processes mediate the pharmacokinetics of nanoformulations, with the absorption, distribution, metabolism and elimination (ADME) being poorly understood and often differing substantially from traditional formulations. Understanding how nanoformulation composition and physicochemical properties influence drug distribution in the human body is of central importance when developing future treatment strategies. A helpful pharmacological tool to simulate the distribution of nanoformulations is represented by physiologically based pharmacokinetics (PBPK) modelling, which integrates system data describing a population of interest with drug/nanoparticle in vitro data through a mathematical description of ADME. The application of PBPK models for nanomedicine is in its infancy and characterized by several challenges. The integration of property–distribution relationships in PBPK models may benefit nanomedicine research, giving opportunities for innovative development of nanotechnologies. PBPK modelling has the potential to improve our understanding of the mechanisms underpinning nanoformulation disposition and allow for more rapid and accurate determination of their kinetics. This review provides an overview of the current knowledge of nanomedicine distribution and the use of PBPK modelling in the characterization of nanoformulations with optimal pharmacokinetics. Linked Articles This article is part of a themed section on Nanomedicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-17 PMID:24467481

  11. UNCERTAINTIES IN TRICHLOROETHYLENE PHARMACOKINETIC MODELS

    EPA Science Inventory

    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)...

  12. PHARMACOKINETICS AND METABOLISM OF A SELECTIVE ANDROGEN RECEPTOR MODULATOR IN RATS: IMPLICATION OF MOLECULAR PROPERTIES AND INTENSIVE METABOLIC PROFILE TO INVESTIGATE IDEAL PHARMACOKINETIC CHARACTERISTICS OF A PROPANAMIDE IN PRECLINICAL STUDY

    PubMed Central

    Wu, Di; Wu, Zengru; Yang, Jun; Nair, Vipin A.; Miller, Duane D.; Dalton, James T.

    2007-01-01

    S-1 [3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide] is one member of a series of potent selective androgen receptor modulators (SARMs) that are being explored and developed for androgen-dependent diseases. Recent studies showed that S-1 holds great promise as a novel therapeutic agent for benign hyperplasia [W. Gao, J. D. Kearbey, V. A. Nair, K. Chung, A. F. Parlow, D. D. Miller, and J. T. Dalton (2004) Endocrinology 145:5420–5428]. We examined the pharmacokinetics and metabolism of S-1 in rats as a component of our preclinical development of this compound and continued interest in structure-activation relationships for SARM action. Forty male Sprague-Dawley rats were randomly assigned to treatment groups and received either an i.v. or a p.o. dose of S-1 at a dose level of 0.1, 1, 10, or 30 mg/kg. S-1 demonstrated a low clearance (range, 3.6–5.2 ml/min/kg), a moderate volume of distribution (range, 1460–1560 ml/kg), and a terminal half-life ranging from 3.6 to 5.2 h after i.v. doses. The oral bioavailability of S-1 ranged from 55% to 60%. Forty phase I and phase II metabolites of S-1 were identified in the urine and feces of male Sprague-Dawley rats dosed at 50 mg/kg via the i.v. route. The two major urinary metabolites of S-1 were a carboxylic acid and a sulfate-conjugate of 4-nitro-3-trifluoromethylphenylamine. Phase I metabolites arising from A-ring nitro reduction to an aromatic amine and B-ring hydroxylation were also identified in the urinary and fecal samples of rats. Furthermore, a variety of phase II metabolites through sulfation, glucuronidation, and methylation were also found. These studies demonstrate that S-1 is rapidly absorbed, slowly cleared, moderately distributed, and extensively metabolized in rats. PMID:16381665

  13. Electron-Accepting π-Conjugated Molecules with Fluorine-Containing Dicyanovinylidene as Terminal Groups: Synthesis, Properties, and Semiconducting Characteristics.

    PubMed

    Ie, Yutaka; Uchida, Ayana; Kawaguchi, Nana; Nitani, Masashi; Tada, Hirokazu; Kakiuchi, Fumitoshi; Aso, Yoshio

    2016-09-01

    A series of electron-accepting π-conjugated molecules having fluorine-containing dicyanovinylidene as terminal groups has been synthesized for the application to electron-transporting semiconductors. This terminal group can be easily incorporated into π-conjugated frameworks. Electrochemical measurements indicated that these compounds showed low-lying lowest unoccupied molecular orbital energy levels, which could be fine-tuned by the combination of central unit. The thin films fabricated by solution process showed typical electron-transporting characteristics in field-effect transistors. PMID:27542071

  14. Pharmacokinetic evaluation of fosaprepitant dimeglumine

    PubMed Central

    Colon-Gonzalez, Francheska; Kraft, Walter K.

    2011-01-01

    Importance of the field Chemotherapy induced nausea and vomiting (CINV) is a common complication in the treatment of patients with cancer. The introduction of the first in class neurokinin-1 receptor antagonist aprepitant provided additive control on CINV in combination to existing antiemetics. Due to formulation issues, aprepitant is only available for oral administration. Fosaprepitant, a prodrug of aprepitant, was introduced to the market in 2008 as an intravenous bioequivalent to aprepitant. Areas covered in this review This review examines the chemical development of fosaprepitant, its pharmacokinetic properties, approved uses, and potential applications. What the reader will gain The reader will get up-to-date information on the pharmacology and clinical uses of fosaprepitant. Clinical studies have demonstrated pharmacokinetic bioequivalence of aprepitant 125-mg to fosaprepitant 115-mg, as well as comparable efficacy in prevention of acute and delayed emesis following the first day of chemotherapy regimens. Take home message Fosaprepitant is an IV pro-drug of aprepitant that offers a new alternative to patients with CINV. Currently, fosaprepitant can substitute oral aprepitant in the first day of a 3-day regimen. Current studies show that a single-day fosaprepitant regimen is also bioequivalent to the 3-day aprepitant regimen, this could significantly simplify the care for CINV patients in the future. PMID:20795794

  15. Pharmacokinetics interactions of monoclonal antibodies.

    PubMed

    Ferri, Nicola; Bellosta, Stefano; Baldessin, Ludovico; Boccia, Donatella; Racagni, Giorgi; Corsini, Alberto

    2016-09-01

    The clearance of therapeutic monoclonal antibodies (mAbs) typically does not involve cytochrome P450 (CYP450)-mediated metabolism or interaction with cell membrane transporters, therefore the pharmacokinetics interactions of mAbs and small molecule drugs are limited. However, a drug may affect the clearance of mAbs through the modulation of immune response (e.g., methotrexate reduces the clearance of infliximab, adalimumab, and golimumab, possibly due to methotrexate's inhibitory effect on the formation of antibodies against the mAbs). In addition, mAbs that are cytokine modulators may modify the metabolism of drugs through their effects on P450 enzymes expression. For example, cytokine modulators such as tocilizumab (anti-IL-6 receptor antibody) may reverse the "inhibitory" effect of IL-6 on CYP substrates, resulting in a "normalization" of CYP activities. Finally, a drug may alter the clearance of mAbs by either increasing or reducing the levels of expression of targets of mAbs on the cell surface. For instance, statins and fibrates induce PCSK9 expression and therefore increase cellular uptake and clearance of alirocumab and evolocumab, anti-PCSK9 antibodies. In the present review, we will provide an overview on the pharmacokinetics properties of mAbs as related to the most relevant examples of mAbs-small molecule drug interaction. PMID:27438459

  16. Pharmacokinetics interactions of monoclonal antibodies.

    PubMed

    Ferri, Nicola; Bellosta, Stefano; Baldessin, Ludovico; Boccia, Donatella; Racagni, Giorgi; Corsini, Alberto

    2016-09-01

    The clearance of therapeutic monoclonal antibodies (mAbs) typically does not involve cytochrome P450 (CYP450)-mediated metabolism or interaction with cell membrane transporters, therefore the pharmacokinetics interactions of mAbs and small molecule drugs are limited. However, a drug may affect the clearance of mAbs through the modulation of immune response (e.g., methotrexate reduces the clearance of infliximab, adalimumab, and golimumab, possibly due to methotrexate's inhibitory effect on the formation of antibodies against the mAbs). In addition, mAbs that are cytokine modulators may modify the metabolism of drugs through their effects on P450 enzymes expression. For example, cytokine modulators such as tocilizumab (anti-IL-6 receptor antibody) may reverse the "inhibitory" effect of IL-6 on CYP substrates, resulting in a "normalization" of CYP activities. Finally, a drug may alter the clearance of mAbs by either increasing or reducing the levels of expression of targets of mAbs on the cell surface. For instance, statins and fibrates induce PCSK9 expression and therefore increase cellular uptake and clearance of alirocumab and evolocumab, anti-PCSK9 antibodies. In the present review, we will provide an overview on the pharmacokinetics properties of mAbs as related to the most relevant examples of mAbs-small molecule drug interaction.

  17. Development of a Performance and Processing Property Acceptance Region for Cementitious Low-Level Waste Forms at Savannah River Site - 13174

    SciTech Connect

    Staub, Aaron V.; Reigel, Marissa M.

    2013-07-01

    The Saltstone Production and Disposal Facilities (SPF and SDF) at the Savannah River Site (SRS) have been treating decontaminated salt solution, a low-level aqueous waste stream (LLW) since facility commissioning in 1990. In 2012, the Saltstone Facilities implemented a new Performance Assessment (PA) that incorporates an alternate design for the disposal facility to ensure that the performance objectives of DOE Order 435.1 and the National Defense Authorization Act (NDAA) of Fiscal Year 2005 Section 3116 are met. The PA performs long term modeling of the waste form, disposal facility, and disposal site hydrogeology to determine the transport history of radionuclides disposed in the LLW. Saltstone has been successfully used to dispose of LLW in a grout waste form for 15 years. Numerous waste form property assumptions directly impact the fate and transport modeling performed in the PA. The extent of process variability and consequence on performance properties are critical to meeting the assumptions of the PA. The SPF has ensured performance property acceptability by way of implementing control strategies that ensure the process operates within the analyzed limits of variability, but efforts continue to improve the understanding of facility performance in relation to the PA analysis. A similar understanding of the impact of variability on processing parameters is important from the standpoint of the operability of the production facility. The fresh grout slurry properties (particularly slurry rheology and the rate of hydration and structure formation) of the waste form directly impact the pressure and flow rates that can be reliably processed. It is thus equally important to quantify the impact of variability on processing parameters to ensure that the design basis assumptions for the production facility are maintained. Savannah River Remediation (SRR) has been pursuing a process that will ultimately establish a property acceptance region (PAR) to incorporate

  18. Effect of variety and processing method on functional properties of traditional sweet potato flour ("elubo") and sensory acceptability of cooked paste ("amala").

    PubMed

    Fetuga, Ganiyat; Tomlins, Keith; Henshaw, Folake; Idowu, Michael

    2014-11-01

    "Amala" is a generic term in Nigeria, used to describe a thick paste prepared by stirring flour ("elubo") from yam, cassava or unripe plantain, in hot water, to form a smooth consistency. In order to overcome its high perishability and increase the utilization of sweet potato roots, three varieties of sweet potato roots were processed into flour using two methods. The interactive effect of variety and the processing method had a significant effect (P < 0.05) on all the functional properties of the flour except yellowness, setback viscosity, and peak time. Acceptable sweet potato "amala" with average sensory acceptability score of 7.5 were obtained from yellow-fleshed varieties irrespective of the processing method. Flour that produced acceptable "amala" were characterized by lower values of protein (2.20-3.94%), fiber (1.30-1.65%), total sugar (12.41-38.83 μg/mg), water absorption capacity (168-215 g/100 g), water solubility (8.29-14.65%), swelling power (0.52-0.82 g/g), and higher peak time (6.9-8.7 min).

  19. Effect of variety and processing method on functional properties of traditional sweet potato flour ("elubo") and sensory acceptability of cooked paste ("amala").

    PubMed

    Fetuga, Ganiyat; Tomlins, Keith; Henshaw, Folake; Idowu, Michael

    2014-11-01

    "Amala" is a generic term in Nigeria, used to describe a thick paste prepared by stirring flour ("elubo") from yam, cassava or unripe plantain, in hot water, to form a smooth consistency. In order to overcome its high perishability and increase the utilization of sweet potato roots, three varieties of sweet potato roots were processed into flour using two methods. The interactive effect of variety and the processing method had a significant effect (P < 0.05) on all the functional properties of the flour except yellowness, setback viscosity, and peak time. Acceptable sweet potato "amala" with average sensory acceptability score of 7.5 were obtained from yellow-fleshed varieties irrespective of the processing method. Flour that produced acceptable "amala" were characterized by lower values of protein (2.20-3.94%), fiber (1.30-1.65%), total sugar (12.41-38.83 μg/mg), water absorption capacity (168-215 g/100 g), water solubility (8.29-14.65%), swelling power (0.52-0.82 g/g), and higher peak time (6.9-8.7 min). PMID:25493186

  20. How do the Properties of Allan Hills 84001 Compare With Accepted Criteria for Evidence of Ancient Life?

    NASA Technical Reports Server (NTRS)

    Gibson, E. K., Jr.; McKay, D. S.; Thomas-Keprta, K.; Westall, F.; Romanek, C. A.

    1998-01-01

    Criteria for Past Life: To be confident that any sample contains evidence of past life or biogenic activity, one must determine beyond a shadow of a doubt that certain well-established features or biomarker signatures are present in the sample. In the case of martian samples, the criteria for past life have not been established because if life existed on the planet, we have no way of knowing its detailed characteristics. Lacking independent evidence about the nature of possible past life on Mars, the scientific community must use, for the time being, the criteria established for ancient samples from the Earth: (1) Do we know the geologic context of the sample? Is it compatible with past life? (2) Do we know the age of the sample and its stratigraphic location? Are they understood enough to relate possible life to geologic history? (3) Does the sample contain evidence of cellular morphology? (4) What structural remains of colonies or communities exist within the samples? (5) Is there any evidence of biominerals showing chemical or mineral disequilibria? (6) Is there any evidence of stable isotope patterns unique to biology? (7) Are there any organic biomarkers present? (8) Are the features indigenous to the sample? For acceptance of past life in a geologic sample, essentially all of these criteria must he met.

  1. Pharmacokinetic consequences of spaceflight

    NASA Technical Reports Server (NTRS)

    Putcha, L.; Cintron, N. M.

    1991-01-01

    Spaceflight induces a wide range of physiological and biochemical changes, including disruption of gastrointestinal (GI) function, fluid and electrolyte balance, circulatory dynamics, and organ blood flow, as well as hormonal and metabolic perturbations. Any of these changes can influence the pharmacokinetics and pharmacodynamics of in-flight medication. That spaceflight may alter bioavailability was proposed when drugs prescribed to alleviate space motion sickness (SMS) had little therapeutic effect. Characterization of the pharmacokinetic and/or pharmacodynamic behavior of operationally critical medications is crucial for their effective use in flight; as a first step, we sought to determine whether drugs administered in space actually reach the site of action at concentrations sufficient to elicit the therapeutic response.

  2. Pharmacokinetics and molecular detoxication.

    PubMed Central

    Cashman, J R; Perotti, B Y; Berkman, C E; Lin, J

    1996-01-01

    This paper presents a comprehensive overview of the pharmacokinetic parameters used from in vivo and in vitro studies that are important in order to understand the major conceptual approaches of toxicokinetics and the disposition of environmental chemicals. In vitro biochemical information concerning the detoxication of environmental chemicals is also presented. The discussion leads to a more complete appreciation for the use of in vitro measurements for in vivo correlations. The concept of interspecies scaling in the interpolation and extrapolation of fundamental biochemical metabolic processes is illustrated with a number of examples. Additional examples of in vitro-in vivo correlations are presented in the evaluation of the impact of chemical exposure to humans. Finally, several important metabolic detoxication enzymes are presented, including the mammalian microsomal cytochrome P450 and flavin-containing monooxygenases as well as carboxylesterases and glucuronosyltransferases, to provide insight into the processes of chemical detoxication in mammalian tissue and blood. Because interspecies scaling and the pharmacokinetics of chemical disposition have already shown their usefulness in understanding some examples of chemical disposition, our summary focuses on showing the usefulness of the pharmacokinetic equations and providing confidence in using the approach for in vitro-in vivo correlations. Ultimately, the presentation may provide the reader with a conceptual framework for future evaluation of the human health risks associated with environmental toxicants. PMID:8722108

  3. Image-driven pharmacokinetics: nanomedicine concentration across space and time.

    PubMed

    Brill, Dab A; MacKay, J Andrew

    2015-01-01

    Clinical pharmacokinetics (PK) primarily measures the concentration of drugs in the blood. For nanomedicines it may be more relevant to determine concentration within a target tissue. The emerging field of image-driven PK, which utilizes clinically accepted molecular imaging technology, empirically and noninvasively, measures concentration in multiple tissues. Image-driven PK represents the intersection of PK and biodistribution, combining to provide models of concentration across space and time. Image-driven PK can be used both as a research tool and in the clinic. This review explores the history of pharmacokinetics, technologies used in molecular imaging (especially positron emission tomography) and research using image-driven pharmacokinetic analysis. When standardized, image-driven PK may have significant implications in preclinical development as well as clinical optimization of targeted nanomedicines.

  4. Clinical pharmacokinetics of mirtazapine.

    PubMed

    Timmer, C J; Sitsen, J M; Delbressine, L P

    2000-06-01

    Mirtazapine is the first noradrenergic and specific serotonergic antidepressant ('NaSSA'). It is rapidly and well absorbed from the gastrointestinal tract after single and multiple oral administration, and peak plasma concentrations are reached within 2 hours. Mirtazapine binds to plasma proteins (85%) in a nonspecific and reversible way. The absolute bioavailability is approximately 50%, mainly because of gut wall and hepatic first-pass metabolism. Mirtazapine shows linear pharmacokinetics over a dose range of 15 to 80mg. The presence of food has a minor effect on the rate, but does not affect the extent, of absorption. The pharmacokinetics of mirtazapine are dependent on gender and age: females and the elderly show higher plasma concentrations than males and young adults. The elimination half-life of mirtazapine ranges from 20 to 40 hours, which is in agreement with the time to reach steady state (4 to 6 days). Total body clearance as determined from intravenous administration to young males amounts to 31 L/h. Liver and moderate renal impairment cause an approximately 30% decrease in oral mirtazapine clearance; severe renal impairment causes a 50% decrease in clearance. There were no clinically or statistically significant differences between poor (PM) and extensive (EM) metabolisers of debrisoquine [a cytochrome P450 (CYP) 2D6 substrate] with regard to the pharmacokinetics of the racemate. The pharmacokinetics of mirtazapine appears to be enantioselective, resulting in higher plasma concentrations and longer half-life of the (R)-(-)-enantiomer (18.0 +/-2.5h) compared with that of the (S)-(+)-enantiomer (9.9+/-3. lh). Genetic CYP2D6 polymorphism has different effects on the enantiomers. For the (R)-(-)-enantiomer there are no differences between EM and PM for any of the kinetic parameters; for (S)-(+)-mirtazapine the area under the concentration-time curve (AUC) is 79% larger in PM than in EM, and a corresponding longer half-life was found. Approximately 100% of

  5. Data sharing for pharmacokinetic studies.

    PubMed

    Anderson, Brian J; Merry, Alan F

    2009-10-01

    Pooling data from different pediatric studies can provide a single robust pharmacokinetic analysis that allows covariate analysis and hypothesis testing. Data sharing should be driven by the altruistic purpose of improving drug understanding to the clinical benefit of children. Electronic communications have rendered the sharing of data relatively easy, and data sharing within the wider scientific community has become commonplace. Data sharing allows verification of results, save costs and time, allows new interpretation of old data, and can fulfill teaching benefits. It may stimulate cooperative competition between researchers and allow individual researchers to concentrate on unique aspects of the scientific puzzle. However, there is occasionally a reluctance to share, in part because of fear of others stealing the hard work of a research group, which may not be recognized in subsequent publications that reuse data. Providing data may require additional effort for presentation in a suitable format. Data may be abused or used for purposes other than those for which they were collected. Propriety claims may limit access to industry-sponsored drug research. The question of who has ownership of data is contentious. Investigators often consider data they have collected to be their own property. Reputations and grants may be hinge on ownership of a data set. However, other team members, institutions, funding agencies, and the public also have a stake. The difficulties identified in the general scientific community also apply to data sharing for pediatric pharmacokinetic studies. There are few clearly established rules at present, and consideration of the issues hinges on ethical and philosophical arguments. The development of databases will depend on collaboration and cooperation and greater clarity and consensus over appropriate processes and procedures. PMID:19558615

  6. Effect of coadministered fat on the tolerability, safety, and pharmacokinetic properties of dihydroartemisinin-piperaquine in Papua New Guinean children with uncomplicated malaria.

    PubMed

    Moore, B R; Benjamin, J M; Salman, S; Griffin, S; Ginny, E; Page-Sharp, M; Robinson, L J; Siba, P; Batty, K T; Mueller, I; Davis, T M E

    2014-10-01

    Coadministration of dihydroartemisinin-piperaquine (DHA-PQ) with fat may improve bioavailability and antimalarial efficacy, but it might also increase toxicity. There have been no studies of these potential effects in the pediatric age group. The tolerability, safety, efficacy, and pharmacokinetics of DHA-PQ administered with or without 8.5 g fat were investigated in 30 Papua New Guinean children aged 5 to 10 years diagnosed with uncomplicated falciparum malaria. Three daily 2.5:11.5-mg-base/kg doses were given with water (n = 14, group A) or milk (n = 16, group B), with regular clinical/laboratory assessment and blood sampling over 42 days. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and DHA was assayed using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models for PQ and DHA were developed using a population-based approach. DHA-PQ was generally well tolerated, and initial fever and parasite clearance were prompt. There were no differences in the areas under the concentration-time curve (AUC0-∞) for PQ (median, 41,906 versus 36,752 μg · h/liter in groups A and B, respectively; P = 0.24) or DHA (4,047 versus 4,190 μg · h/liter; P = 0.67). There were also no significant between-group differences in prolongation of the corrected electrocardiographic QT interval (QTc) initially during follow-up, but the QTc tended to be higher in group B children at 24 h (mean ± standard deviation [SD], 15 ± 10 versus 6 ± 15 ms(0.5) in group A, P = 0.067) and 168 h (10 ± 18 versus 1 ± 23 ms(0.5), P = 0.24) when plasma PQ concentrations were relatively low. A small amount of fat does not change the bioavailability of DHA-PQ in children, but a delayed persistent effect on ventricular repolarization cannot be excluded.

  7. Effect of coadministered fat on the tolerability, safety, and pharmacokinetic properties of dihydroartemisinin-piperaquine in Papua New Guinean children with uncomplicated malaria.

    PubMed

    Moore, B R; Benjamin, J M; Salman, S; Griffin, S; Ginny, E; Page-Sharp, M; Robinson, L J; Siba, P; Batty, K T; Mueller, I; Davis, T M E

    2014-10-01

    Coadministration of dihydroartemisinin-piperaquine (DHA-PQ) with fat may improve bioavailability and antimalarial efficacy, but it might also increase toxicity. There have been no studies of these potential effects in the pediatric age group. The tolerability, safety, efficacy, and pharmacokinetics of DHA-PQ administered with or without 8.5 g fat were investigated in 30 Papua New Guinean children aged 5 to 10 years diagnosed with uncomplicated falciparum malaria. Three daily 2.5:11.5-mg-base/kg doses were given with water (n = 14, group A) or milk (n = 16, group B), with regular clinical/laboratory assessment and blood sampling over 42 days. Plasma PQ was assayed by high-performance liquid chromatography with UV detection, and DHA was assayed using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models for PQ and DHA were developed using a population-based approach. DHA-PQ was generally well tolerated, and initial fever and parasite clearance were prompt. There were no differences in the areas under the concentration-time curve (AUC0-∞) for PQ (median, 41,906 versus 36,752 μg · h/liter in groups A and B, respectively; P = 0.24) or DHA (4,047 versus 4,190 μg · h/liter; P = 0.67). There were also no significant between-group differences in prolongation of the corrected electrocardiographic QT interval (QTc) initially during follow-up, but the QTc tended to be higher in group B children at 24 h (mean ± standard deviation [SD], 15 ± 10 versus 6 ± 15 ms(0.5) in group A, P = 0.067) and 168 h (10 ± 18 versus 1 ± 23 ms(0.5), P = 0.24) when plasma PQ concentrations were relatively low. A small amount of fat does not change the bioavailability of DHA-PQ in children, but a delayed persistent effect on ventricular repolarization cannot be excluded. PMID:25049242

  8. Pharmacokinetics of oral rufinamide in dogs.

    PubMed

    Wright, H M; Chen, A V; Martinez, S E; Davies, N M

    2012-12-01

    The objective of this study was to determine the pharmacokinetic properties and short-term adverse effect profile of single-dose oral rufinamide in healthy dogs. Six healthy adult dogs were included in the study. The pharmacokinetics of rufinamide were calculated following administration of a single mean oral dose of 20.0 mg/kg (range 18.6-20.8 mg/kg). Plasma rufinamide concentrations were determined using high-performance liquid chromatography, and pharmacokinetic data were analyzed using commercial software. No adverse effects were observed. The mean terminal half-life was 9.86 ± 4.77 h. The mean maximum plasma concentration was 19.6 ± 5.8 μg/mL, and the mean time to maximum plasma concentration was 9.33 ± 4.68 h. Mean clearance was 1.45 ± 0.70 L/h. The area under the curve (to infinity) was 411 ± 176 μg · h/mL. Results of this study suggest that rufinamide given orally at 20 mg/kg every 12 h in healthy dogs should result in a plasma concentration and half-life sufficient to achieve the therapeutic level extrapolated from humans without short-term adverse effects. Further investigation into the efficacy and long-term safety of rufinamide in the treatment of canine epilepsy is warranted. PMID:22132708

  9. Pharmacokinetics of ketoprofen syrup in small children.

    PubMed

    Kokki, H; Le Liboux, A; Jekunen, A; Montay, G; Heikkinen, M

    2000-04-01

    Ketoprofen is a nonsteroidal anti-inflammatory drug with analgesic, anti-inflammatory, and antipyretic properties. Its pharmacokinetics has not been determined in small children. The objective here was to determine the pharmacokinetics of ketoprofen syrup, 0.5 mg/kg, in two groups of 10 children. Group 1 was from ages 6 months up to 2 years (7/10 younger than 1 year), and Group 2 was from ages 2 to 7 years. Venous blood samples were collected before drug administration and 0.5, 1, 2, 4, 6, 8, and 12 hours after. A validated HPLC method was used to determine plasma levels of ketoprofen. The lower limit of quantification was 0.02 microgram/ml of plasma. Ketoprofen syrup was absorbed rapidly, the plasma level reaching its maximum at 0.5 hours, with C0.5 hours = 3 micrograms/ml. The pharmacokinetics was similar between the two groups of children. The elimination half-life, 2.0 hours in Group 1 or 1.9 hours in Group 2, was similar to that reported in adults. PMID:10761162

  10. Cyclophosphamide pharmacokinetics in children.

    PubMed

    Yule, S M; Boddy, A V; Cole, M; Price, L; Wyllie, R; Tasso, M J; Pearson, A D; Idle, J R

    1996-01-01

    1. Cyclophosphamide pharmacokinetics were measured in 38 children with cancer. 2. A high degree of inter-patient variation was seen in all pharmacokinetic parameters. Cyclophosphamide half-life varied between 1.1 and 16.8 h, clearance varied between 1.2 and 10.61 h-1 m-2 and volume of distribution varied between 0.26 and 1.48 1 kg-1. 3. The half-life of cyclophosphamide was prolonged at high dose levels (P = 0.008). 4. Children who had received prior treatment with dexamethasone showed a mean increase in clearance of 2.51 h-1 m-2 (P = 0.001) presumably as a result of CYP450 enzyme induction. 5. Treatment with allopurinol or chlorpromazine was associated with a significant increase in cyclophosphamide half-life (P < 0.001 in both cases). 6. Dose and concurrent treatment may influence cyclophosphamide metabolism in vivo and thus potentially alter the drugs therapeutic effect.

  11. Effect of small-molecule modification on single-cell pharmacokinetics of PARP inhibitors.

    PubMed

    Thurber, Greg M; Reiner, Thomas; Yang, Katherine S; Kohler, Rainer H; Weissleder, Ralph

    2014-04-01

    The heterogeneous delivery of drugs in tumors is an established process contributing to variability in treatment outcome. Despite the general acceptance of variable delivery, the study of the underlying causes is challenging, given the complex tumor microenvironment including intra- and intertumor heterogeneity. The difficulty in studying this distribution is even more significant for small-molecule drugs where radiolabeled compounds or mass spectrometry detection lack the spatial and temporal resolution required to quantify the kinetics of drug distribution in vivo. In this work, we take advantage of the synthesis of fluorescent drug conjugates that retain their target binding but are designed with different physiochemical and thus pharmacokinetic properties. Using these probes, we followed the drug distribution in cell culture and tumor xenografts with temporal resolution of seconds and subcellular spatial resolution. These measurements, including in vivo permeability of small-molecule drugs, can be used directly in predictive pharmacokinetic models for the design of therapeutics and companion imaging agents as demonstrated by a finite element model. PMID:24552776

  12. Effect of Small Molecule Modification on Single Cell Pharmacokinetics of PARP Inhibitors

    PubMed Central

    Thurber, Greg M.; Reiner, Thomas; Yang, Katherine S; Kohler, Rainer; Weissleder, Ralph

    2014-01-01

    The heterogeneous delivery of drugs in tumors is an established process contributing to variability in treatment outcome. Despite the general acceptance of variable delivery, the study of the underlying causes is challenging given the complex tumor microenvironment including intra- and inter-tumor heterogeneity. The difficulty in studying this distribution is even more significant for small molecule drugs where radiolabeled compounds or mass spectrometry detection lack the spatial and temporal resolution required to quantify the kinetics of drug distribution in vivo. In this work, we take advantage of the synthesis of fluorescent drug conjugates that retain their target binding but are designed with different physiochemical and thus pharmacokinetic properties. Using these probes, we followed the drug distribution in cell culture and tumor xenografts with temporal resolution of seconds and subcellular spatial resolution. These measurements, including in vivo permeability of small molecule drugs, can be used directly in predictive pharmacokinetic models for the design of therapeutics and companion imaging agents as demonstrated by a finite element model. PMID:24552776

  13. Formulation, pharmacokinetics and pharmacodynamics of topical microbicides.

    PubMed

    Adams, Jessica L; Kashuba, Angela D M

    2012-08-01

    The development of safe topical microbicides that effectively prevent human immunodeficiency virus (HIV) infection is a major goal in curbing the human immunodeficiency virus pandemic. A number of past failures resulting from mucosal toxicity or lack of efficacy have informed the field. Products that caused toxicity to the female genital tract mucosa, and thereby increased the likelihood of HIV acquisition, included nonoxynol 9, cellulose sulfate, and C31 G vaginal gel Savvy. Topical products that were ineffective in preventing HIV infection include BufferGel, Carraguard, and PRO 2000. Antiretroviral drugs such as tenofovir and dapivirine formulated into microbicide products have shown promise, but there is much to learn about ideal product formulation and acceptability, and drug distribution and disposition (pharmacokinetics). Current formulations for water-soluble molecules include vaginally or rectally applied gels, vaginal rings, films and tablets. Dosing strategies (e.g. coitally dependent or independent) will be based on the pharmacokinetics of the active ingredient and the tolerance for less than perfect adherence. PMID:22306523

  14. Pharmacokinetics of cefixime

    SciTech Connect

    Tonelli, A.P.

    1987-01-01

    The serum protein binding of cefixime, was concentration-dependent. Below 30 mcg/mL, free-fractions (fu) of cefixime in dog serum were approximately 8%. As cefixime concentrations increased, concomitant increases in free-fraction were observed. At 328 mcg/mL almost half of the cefixime in serum was not bound. To examine the effect of this concentration-dependent binding on cefixime's pharmacokinetics, four dogs were administered 50 mg/kg of the carbon 14-labeled drug by the oral and intravenous routes. The absolute bioavailability of cefixime was 48.0 +/- 17% (mean +/- SD). Absorption of radioactivity was 51.9 +/- 18%. Cefixime's elimination was a function of its free-fraction in serum and reabsorption of filtered drug by the kidney.

  15. Pharmacokinetics of marbofloxacin in horses.

    PubMed

    Bousquet-Melou, A; Bernard, S; Schneider, M; Toutain, P L

    2002-07-01

    Marbofloxacin is a fluoroquinolone antibiotic expected to be effective in the treatment of infections involving gram-negative and some gram-positive bacteria in horses. In order to design a rational dosage regimen for the substance in horses, the pharmacokinetic properties of marbofloxacin were investigated in 6 horses after i.v., subcutaneous and oral administration of a single dose of 2 mg/kg bwt and the minimal inhibitory concentrations (MIC) assessed for bacteria isolated from equine infectious pathologies. The clearance of marbofloxacin was mean +/- s.d. 0.25 +/- 0.05 l/kg/h and the terminal half-life 756 +/- 1.99 h. The marbofloxacin absolute bioavailabilities after subcutaneous and oral administration were 98 +/- 11% and 62 +/- 8%, respectively. The MIC required to inhibit 90% of isolates (MIC90) was 0.027 microg/ml for enterobacteriaceae and 0.21 microg/ml for Staphylococcus aureus. The values of surrogate markers of antimicrobial efficacy (AUIC, Cmax/MIC ratio, time above MIC90) were calculated and the marbofloxacin concentration profiles simulated for repeated administrations. These data were used to determine rational dosage regimens for target bacteria. Considering the breakpoint values of efficacy indices for fluoroquinolones, a marbofloxacin dosage regimen of 2 mg/kg bwt/24 h by i.v., subcutaneous or oral routes was more appropriate for enterobacteriaceae than for S. aureus.

  16. Pharmacokinetic interactions with thiazolidinediones.

    PubMed

    Scheen, André J

    2007-01-01

    Type 2 diabetes mellitus is a complex disease combining defects in insulin secretion and insulin action. New compounds called thiazolidinediones or glitazones have been developed for reducing insulin resistance. After the withdrawal of troglitazone because of liver toxicity, two compounds are currently used in clinical practice, rosiglitazone and pioglitazone. These compounds are generally used in combination with other pharmacological agents. Because they are metabolised via cytochrome P450 (CYP), glitazones are exposed to numerous pharmacokinetic interactions. CYP2C8 and CYP3A4 are the main isoenzymes catalysing biotransformation of pioglitazone (as with troglitazone), whereas rosiglitazone is metabolised by CYP2C9 and CYP2C8. For both rosiglitazone and pioglitazone, the most relevant interactions have been described in healthy volunteers with rifampicin (rifampin), which results in a significant decrease of area under the plasma concentration-time curve [AUC] (54-65% for rosiglitazone, p<0.001; 54% for pioglitazone, p<0.001), and with gemfibrozil, which results in a significant increase of AUC (130% for rosiglitazone, p<0.001; 220-240% for pioglitazone, p<0.001). The relevance of such drug-drug interactions in patients with type 2 diabetes remains to be evaluated. However, in the absence of clinical data, it is prudent to reduce the dosage of each glitazone by half in patients treated with gemfibrozil. Conversely, rosiglitazone and pioglitazone do not seem to significantly affect the pharmacokinetics of other compounds. Although some food components have also been shown to potentially interfere with drugs metabolised with the CYP system, no published study deals specifically with these possible CYP-mediated food-drug interactions with glitazones.

  17. Steady-State Pharmacokinetics of Bupropion SR in Juvenile Patients

    ERIC Educational Resources Information Center

    Daviss, W. Burleson; Perel, James M.; Rudolph, George R.; Axelson, David A.; Gilchrist, Richard; Nuss, Sharon; Birmaher, Boris; Brent, David A.

    2005-01-01

    Objective: To examine the steady-state pharmacokinetic properties of bupropion sustained release (SR) and their potential developmental differences in youths. Method: Eleven boys and eight girls aged 11 to 17 years old were prescribed bupropion SR monotherapy for attention-deficit/hyperactivity disorder (n = 16) and/or depressive disorders (n =…

  18. SUBCELLULAR PHARMACOKINETICS AND ITS POTENTIAL FOR LIBRARY FOCUSING (R826652)

    EPA Science Inventory

    Abstract

    Subcellular pharmacokinetics (SP) optimizes biology-related factors in the design of libraries for high throughput screening by defining comparatively narrow ranges of properties (lipophilicity, amphiphilicity, acidity, reactivity, 3D-structural features) of t...

  19. Comparative pharmacokinetics of perfluorononanoic acid in rat and mouse

    EPA Science Inventory

    Perfluorononanoic acid (PFNA) is a fluorinated organic chemical found at low levels in the environment, but is detectable in humans and wildlife. The present study compared the pharmacokinetic properties of PFNA in two laboratory rodent species. Male and female Sprague-Dawley rat...

  20. Comparative Pharmacokinetics of Perfluorononanoic acid in Rats and Mice

    EPA Science Inventory

    Perfluorononanoic acid (PFNA) is a fluorinated organic chemical found at low levels in the environment, but is detectable in humans and wildlife. This study compared the pharmacokinetic properties of PFNA in two laboratory rodent species. Male and female Sprague-Dawley rats (n ...

  1. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    SciTech Connect

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

    1992-12-31

    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.

  2. Drug pharmacokinetics and pharmacodynamics: Technological considerations

    SciTech Connect

    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.

  3. Physiologic and pharmacokinetic changes in pregnancy.

    PubMed

    Costantine, Maged M

    2014-01-01

    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. PMID:24772083

  4. Pharmacokinetics and pharmacogenomics in gastric cancer chemotherapy.

    PubMed

    Nishiyama, Masahiko; Eguchi, Hidetaka

    2009-05-20

    Despite extensive efforts, treatment of gastric cancer by chemotherapy, the globally accepted standard, is yet undetermined, and uncertainty remains regarding the optimal regimen. Recent introduction of active "new generation agents" offers hope for improving patient outcomes. Current chemotherapeutic trials provided several regimens that may become a possible standard treatment, including docetaxel/cisplatin/5-FU (TCF) and cisplatin/S-1 for advanced and metastatic cancer and S-1 monotherapy in the adjuvant setting. Along with the development of novel active regimens, individual optimization of cancer chemotherapy has been attempted in order to reduce toxicity and enhance tumor response. Unlike the rare and limited contribution of pharmacokinetic studies, pharmacogenomic studies are increasing the potential to realize the therapeutics against gastric cancer. Despite the limited data, pharmacogenomics in gastric cancer have provided a number of putative biomarkers for the prediction of tumor response to chemotherapies and of toxicity.

  5. Physiologically-based pharmacokinetic models: approaches for enabling personalized medicine.

    PubMed

    Hartmanshenn, Clara; Scherholz, Megerle; Androulakis, Ioannis P

    2016-10-01

    Personalized medicine strives to deliver the 'right drug at the right dose' by considering inter-person variability, one of the causes for therapeutic failure in specialized populations of patients. Physiologically-based pharmacokinetic (PBPK) modeling is a key tool in the advancement of personalized medicine to evaluate complex clinical scenarios, making use of physiological information as well as physicochemical data to simulate various physiological states to predict the distribution of pharmacokinetic responses. The increased dependency on PBPK models to address regulatory questions is aligned with the ability of PBPK models to minimize ethical and technical difficulties associated with pharmacokinetic and toxicology experiments for special patient populations. Subpopulation modeling can be achieved through an iterative and integrative approach using an adopt, adapt, develop, assess, amend, and deliver methodology. PBPK modeling has two valuable applications in personalized medicine: (1) determining the importance of certain subpopulations within a distribution of pharmacokinetic responses for a given drug formulation and (2) establishing the formulation design space needed to attain a targeted drug plasma concentration profile. This review article focuses on model development for physiological differences associated with sex (male vs. female), age (pediatric vs. young adults vs. elderly), disease state (healthy vs. unhealthy), and temporal variation (influence of biological rhythms), connecting them to drug product formulation development within the quality by design framework. Although PBPK modeling has come a long way, there is still a lengthy road before it can be fully accepted by pharmacologists, clinicians, and the broader industry. PMID:27647273

  6. Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data.

    PubMed

    Del Amo, Eva M; Urtti, Arto

    2015-08-01

    Intravitreal administration is the method of choice in drug delivery to the retina and/or choroid. Rabbit is the most commonly used animal species in intravitreal pharmacokinetics, but it has been criticized as being a poor model of human eye. The critique is based on some anatomical differences, properties of the vitreous humor, and observed differences in drug concentrations in the anterior chamber after intravitreal injections. We have systematically analyzed all published information on intravitreal pharmacokinetics in the rabbit and human eye. The analysis revealed major problems in the design of the pharmacokinetic studies. In this review we provide advice for study design. Overall, the pharmacokinetic parameters (clearance, volume of distribution, half-life) in the human and rabbit eye have good correlation and comparable absolute values. Therefore, reliable rabbit-to-man translation of intravitreal pharmacokinetics should be feasible. The relevant anatomical and physiological parameters in rabbit and man show only small differences. Furthermore, the claimed discrepancy between drug concentrations in the human and rabbit aqueous humor is not supported by the data analysis. Based on the available and properly conducted pharmacokinetic studies, the differences in the vitreous structure in rabbits and human patients do not lead to significant pharmacokinetic differences. This review is the first step towards inter-species translation of intravitreal pharmacokinetics. More information is still needed to dissect the roles of drug delivery systems, disease states, age and ocular manipulation on the intravitreal pharmacokinetics in rabbit and man. Anyway, the published data and the derived pharmacokinetic parameters indicate that the rabbit is a useful animal model in intravitreal pharmacokinetics.

  7. Discovery of substituted lactams as novel dual orexin receptor antagonists. Synthesis, preliminary structure-activity relationship studies and efforts towards improved metabolic stability and pharmacokinetic properties. Part 1.

    PubMed

    Sifferlen, Thierry; Boller, Amandine; Chardonneau, Audrey; Cottreel, Emmanuelle; Hoecker, Johannes; Aissaoui, Hamed; Williams, Jodi T; Brotschi, Christine; Heidmann, Bibia; Siegrist, Romain; Gatfield, John; Treiber, Alexander; Brisbare-Roch, Catherine; Jenck, Francois; Boss, Christoph

    2014-02-15

    Starting from a thiazolidin-4-one HTS hit, a novel series of substituted lactams was identified and developed as dual orexin receptor antagonists. In this Letter, we describe our initial efforts towards the improvement of potency and metabolic stability. These investigations delivered optimized lead compounds with CNS drug-like properties suitable for further optimization. PMID:24447850

  8. The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol

    PubMed Central

    2010-01-01

    Background Ibuprofen and paracetamol differ in their mode of action and related therapeutic effects, suggesting that combined administration may offer improved analgesia. Reported here are the results of two studies on the pharmacokinetic properties of a novel ibuprofen (200 mg) and paracetamol (500 mg) fixed-dose combination tablet. Methods Both studies were open-label, randomised studies in healthy volunteers: Study 1 was a four-way crossover, single-dose study; Study 2 was a two-way cross-over, repeat-dose study. Results Pharmacokinetic parameters for ibuprofen and paracetamol were similar for the combination and monotherapy tablets (values falling within the 80% to 125% acceptable bioequivalence range) except for the rate of absorption of paracetamol from the combination (tmax), which was significantly faster compared with monotherapy (median difference 10 minutes; p < 0.05). Mean plasma concentrations of both drugs were higher, earlier, following administration of the combination tablet compared with monotherapy. Mean plasma levels at 10 and 20 minutes were 6.64 μg.mL-1 and 16.81 μg.mL-1, respectively, for ibuprofen from the combination, compared with 0.58 μg.mL-1 and 9.00 μg.mL-1, respectively, for monotherapy. For paracetamol, mean plasma levels at 10 and 20 minutes were 5.43 μg.mL-1 and 14.54 μg.mL-1, respectively, for the combination compared with 0.33 μg.mL-1 and 9.19 μg.mL-1, respectively, for monotherapy. The rate of absorption of both ibuprofen and paracetamol was significantly delayed when the combination tablet was administered in the fed versus fasted state; median delay was 25 minutes for ibuprofen (p > 0.05) and 55 minutes for paracetamol (p < 0.001). The pharmacokinetic parameters were comparable irrespective of whether the combination tablet was given twice or three times daily; systemic exposure was, however, approximately 1.4 times greater for both drugs when given three times daily. Conclusions Administration of ibuprofen and

  9. Pharmacokinetics and Pharmacodynamics in Space

    NASA Technical Reports Server (NTRS)

    Putcha, Lakshmi; Cintron, Nitza M.

    1990-01-01

    The Pharmacokinetics and Pharmacodynamics Panel met on 29-30 Aug. 1988 at the Lunar and Planetary Institute in Houston, Texas to discuss pharmacokinetic and pharmacodynamic implications of space flight and make recommendations for operational and research strategies. Based on the knowledge available on the physiological changes that occur during space flight, the dependence of pharmacokinetics on physiological factors, and the therapeutic requirements for future space missions, the panel made several recommendations for research. It was suggested that using medications available with a large (wide) therapeutic window will avoid unforeseen therapeutic consequences during flight. The sequence for conducting research was outlined as follows: (1) identify ground-based simulation models (e.g., antiorthostatic bed rest) for conducting pharmacokinetic and pharmacodynamic research; (2) estimate parametric changes in these models using pharmacologic agents that have different pharmacokinetic characteristics and a narrow therapeutic index; (3) verify these findings during flight; and (4) develop and identify appropriate and effective drug delivery systems, dosage forms, and regimens. The panel recommended gaining a thorough understanding of the pharmacokinetic deviations of medications that have a narrow therapeutic index (e.g. cardiovascular drugs and sedative hypnotics) in order to ensure safe and effective treatment during flight with these agents. It was also suggested that basic information on physiological factors such as organ blood flow, protein composition and binding, tissue distribution, and metabolism by hepatic enzymes must be accumulated by conducting ground-based animal and human studies using models of weightlessness. This information will be useful to construct and identify physiologically based pharmacokinetic models that can provide valuable information on the pharmacodynamic consequences of space flight and aid in identifying appropriate therapeutic

  10. 48 CFR 245.606-3 - Acceptance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Acceptance. 245.606-3..., DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT GOVERNMENT PROPERTY Reporting, Redistribution, and Disposal of Contractor Inventory 245.606-3 Acceptance. (a) If the schedules are acceptable, the plant clearance...

  11. Applied Pharmacokinetics: Course Description and Retrospective Evaluation.

    ERIC Educational Resources Information Center

    Beck, Diane E.

    1984-01-01

    An applied course designed to allow students to formulate pharmacokinetic recommendations individually for actual patient data and compare their recommendations to those of a pharmacokinetic consulting service is described and evaluated, and an objective student evaluation method is outlined. (MSE)

  12. Intratumoral Pharmacokinetics: Challenges to Nanobiomaterials.

    PubMed

    Al-Abd, Ahmed M; Al-Abbasi, Fahad A; Torchilin, Vladimir P

    2015-01-01

    Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. Solid tumor tissue is characterized by high density of vascular bed however; the vast majority of these blood vessels are not functioning. The vast majority of solid tumors can be described as poorly perfused with blood; and anticancer agents need to penetrate/distribute avascularly within solid tumor micro-milieu. Classic pharmacokinetic parameters correlate drug status within central compartment (blood) to all perfused body tissues according to their degree of perfusion. Yet, these classic pharmacokinetic parameters cannot fully elucidate the intratumoral drug penetration/distribution status of anticancer drugs due to the great discrepancies in perfusion between normal and solid tumor tissues. Herein, we will discuss the recently proposed pharmacokinetic parameters that might accurately portray the distribution of anticancer agents within solid tumor micro-milieu. In addition, we will present the new challenges attributed to these new pharmacokinetic parameters towards designing nanobiomaterial drug delivery system. PMID:26027565

  13. The design and synthesis of a potent glucagon receptor antagonist with favorable physicochemical and pharmacokinetic properties as a candidate for the treatment of type 2 diabetes mellitus.

    PubMed

    Guzman-Perez, Angel; Pfefferkorn, Jeffrey A; Lee, Esther C Y; Stevens, Benjamin D; Aspnes, Gary E; Bian, Jianwei; Didiuk, Mary T; Filipski, Kevin J; Moore, Dianna; Perreault, Christian; Sammons, Matthew F; Tu, Meihua; Brown, Janice; Atkinson, Karen; Litchfield, John; Tan, Beijing; Samas, Brian; Zavadoski, William J; Salatto, Christopher T; Treadway, Judith

    2013-05-15

    A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation.

  14. Raltegravir Pharmacokinetics during Pregnancy

    PubMed Central

    Watts, D. Heather; Stek, Alice; Best, Brookie M.; Wang, Jiajia; Capparelli, Edmund V.; Cressey, Tim R.; Aweeka, Francesca; Lizak, Patty; Kreitchmann, Regis; Burchett, Sandra K.; Shapiro, David E.; Hawkins, Elizabeth; Smith, Elizabeth; Mirochnick, Mark

    2014-01-01

    Objective We evaluated the pharmacokinetics (pk) of raltegravir in HIV-infected women during pregnancy and postpartum. Methods IMPAACT 1026s is an on-going prospective study of antiretroviral pk during pregnancy (NCT00042289). Women receiving 400 mg raltegravir twice daily in combination antiretroviral therapy had intensive steady state 12-hour pk profiles performed during pregnancy and at 6–12 weeks postpartum. Targets were trough concentration above 0.035 µg/mL, the estimated tenth percentile in non-pregnant historical controls. Results Median raltegravir AUC was 6.6 µg*hr/mL for second trimester (n= 16), 5.4 µg*hr/mL for third trimester (n=41), and 11.6 µg*hr/mL postpartum (n= 38) (p=0.03 pp vs 2nd trimester, p=0.001 pp vs third trimester). Trough concentrations were above the target in 69%, 80%, and 79% of second trimester, third trimester and postpartum subjects respectively, with wide variability (<0.010–0.917 µg/mL), and no significant difference between third trimester and postpartum trough concentrations was detected. The median ratio of cord blood/maternal raltegravir concentrations was 1.5. HIV RNA levels were < 400 copies/mL in 92% of women at delivery. Adverse events included elevated liver transaminases in one woman and vomiting in one. All infants with known status are HIV-uninfected. Conclusions Median raltegravir AUC was reduced by approximately 50% during pregnancy; trough concentrations were frequently below target both during late pregnancy and postpartum. Raltegravir readily crossed the placenta. High rates of viral suppression at delivery and the lack of a clear relationship between raltegravir concentration and virologic effect in nonpregnant adults suggest that despite the decreased exposure during pregnancy, a higher dose is not necessary. PMID:25162818

  15. Pharmacokinetics of mitragynine in man

    PubMed Central

    Trakulsrichai, Satariya; Sathirakul, Korbtham; Auparakkitanon, Saranya; Krongvorakul, Jatupon; Sueajai, Jetjamnong; Noumjad, Nantida; Sukasem, Chonlaphat; Wananukul, Winai

    2015-01-01

    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 the study without adverse reactions. The median duration of abuse was 1.75 years. We analyzed one subject separately due to the abnormal behavior of blood concentration. From data of nine subjects, the pharmacokinetic parameters established were time to reach the maximum plasma concentration (0.83±0.35 hour), terminal half-life (23.24±16.07 hours), and the apparent volume of distribution (38.04±24.32 L/kg). The urine excretion of unchanged form was 0.14%. The pharmacokinetics were observed to be oral two-compartment model. Conclusion This was the first pharmacokinetic study in humans, which demonstrated linearity and was consistent with the oral two-compartment model with a terminal half

  16. Fasudil and SOD Packaged in Peptide-studded-liposomes: Properties, Pharmacokinetics and Ex-vivo Targeting to Isolated Perfused Rat Lungs

    PubMed Central

    Gupta, Nilesh; Al-Saikhan, Fahad I; Patel, Brijeshkumar; Rashid, Jahidur; Ahsan, Fakhrul

    2015-01-01

    The present study investigated the feasibility of encapsulating two drugs, fasudil and superoxide dismutase (SOD), into liposomes for targeted and inhalational delivery to the pulmonary vasculature to treat pulmonary arterial hypertension (PAH). Nanosized liposomes were prepared by a thin-film formation and extrusion method, and the drugs were encapsulated by a modified freeze-thaw technique. The peptide CARSKNKDC (CAR), a pulmonary-specific targeting sequence, was conjugated on the surface of liposomes. Formulations were optimized for various physicochemical properties, tested for their ex-vivo and in-vivo drug absorption after intratracheal administration, and evaluated for short-term safety in healthy rats. The homogenous nanosized liposomes contained both SOD (~55% entrapment) and fasudil (~40% entrapment), and were stable at 4°C and after nebulization. Liposomes released the drugs in a controlled-release fashion. Compared with plain liposomes, CAR-liposomes increased the uptake by pulmonary endothelial and smooth muscle cells by ~2-fold. CAR-liposomes extended the biological half-lives of SOD and fasudil by ~3-fold. Ex-vivo studies demonstrated that CAR-liposomes were better retained in the lungs than plain liposomes. Bronchoalveolar lavage studies indicated the safety of peptide-equipped liposomes as pulmonary delivery carriers. Overall, this study demonstrates that CAR-liposomes may be used as inhalational carriers for SOD plus fasudil-based combination therapy for PAH. PMID:25888802

  17. Fasudil and SOD packaged in peptide-studded-liposomes: Properties, pharmacokinetics and ex-vivo targeting to isolated perfused rat lungs.

    PubMed

    Gupta, Nilesh; Al-Saikhan, Fahad I; Patel, Brijeshkumar; Rashid, Jahidur; Ahsan, Fakhrul

    2015-07-01

    The present study investigated the feasibility of encapsulating two drugs, fasudil and superoxide dismutase (SOD), into liposomes for targeted and inhalational delivery to the pulmonary vasculature to treat pulmonary arterial hypertension (PAH). Nanosized liposomes were prepared by a thin-film formation and extrusion method, and the drugs were encapsulated by a modified freeze-thaw technique. The peptide CARSKNKDC (CAR), a pulmonary-specific targeting sequence, was conjugated on the surface of liposomes. Formulations were optimized for various physicochemical properties, tested for their ex-vivo and in-vivo drug absorption after intratracheal administration, and evaluated for short-term safety in healthy rats. The homogenous nanosized liposomes contained both SOD (~55% entrapment) and fasudil (~40% entrapment), and were stable at 4°C and after nebulization. Liposomes released the drugs in a controlled-release fashion. Compared with plain liposomes, CAR-liposomes increased the uptake by pulmonary endothelial and smooth muscle cells by ~2-fold. CAR-liposomes extended the biological half-lives of SOD and fasudil by ~3-fold. Ex-vivo studies demonstrated that CAR-liposomes were better retained in the lungs than plain liposomes. Bronchoalveolar lavage studies indicated the safety of peptide-equipped liposomes as pulmonary delivery carriers. Overall, this study demonstrates that CAR-liposomes may be used as inhalational carriers for SOD plus fasudil-based combination therapy for PAH. PMID:25888802

  18. UPLC-MS/MS determination of ephedrine, methylephedrine, amygdalin and glycyrrhizic acid in Beagle plasma and its application to a pharmacokinetic study after oral administration of Ma Huang Tang.

    PubMed

    Yan, Tianhua; Fu, Qiang; Wang, Jing; Ma, Shiping

    2015-02-01

    An ultra performance liquid chromatography-mass spectrometric (UPLC-MS) method was developed to investigate the pharmacokinetic properties of ephedrine, methylephedrine, amygdalin, and glycyrrhizic acid after oral gavage of Ma Huang Tang (MHT) in Beagles. Beagle plasma samples were pretreated using liquid-liquid extraction, and chromatographic separation was performed on a C18 column using a linear gradient of water-formic acid mixture (0.1%). The pharmacokinetic parameters of ephedrine, methylephedrine, amygdalin, and glycyrrhizic acid from MHT in Beagles were quantitatively determined by UPLC with tandem mass detector. The qualitative detection of the four compounds was accomplished by selected ion monitoring in negative/positive ion modes electrospray ionization-mass spectrometry (ESI-MS). Detection was based on multiple reaction monitoring with the precursor-to-product ion transitions m/z 166.096-116.983 (ephedrine), m/z 179.034-146.087 (methylephedrine), m/z 456.351-323.074 (amygdalin), and m/z 821.606-351.062 (glycyrrhizic acid). The selectivity, sensitivity, linearity, accuracy, precision, extraction recovery, ion suppression, and stability were within the acceptable ranges. The method described was successfully applied to reveal the pharmacokinetic properties of ephedrine, methylephedrine, amygdalin, and glycyrrhizic acid after oral gavage of MHT in Beagles.

  19. 41 CFR 105-8.170-10 - Acceptance of appeals.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Acceptance of appeals. 105-8.170-10 Section 105-8.170-10 Public Contracts and Property Management Federal Property Management... Acceptance of appeals. The Special Counsel shall accept and process any timely appeal. A party may appeal...

  20. Emodin: A Review of its Pharmacology, Toxicity and Pharmacokinetics.

    PubMed

    Dong, Xiaoxv; Fu, Jing; Yin, Xingbin; Cao, Sali; Li, Xuechun; Lin, Longfei; Ni, Jian

    2016-08-01

    Emodin is a natural anthraquinone derivative that occurs in many widely used Chinese medicinal herbs, such as Rheum palmatum, Polygonum cuspidatum and Polygonum multiflorum. Emodin has been used as a traditional Chinese medicine for over 2000 years and is still present in various herbal preparations. Emerging evidence indicates that emodin possesses a wide spectrum of pharmacological properties, including anticancer, hepatoprotective, antiinflammatory, antioxidant and antimicrobial activities. However, emodin could also lead to hepatotoxicity, kidney toxicity and reproductive toxicity, particularly in high doses and with long-term use. Pharmacokinetic studies have demonstrated that emodin has poor oral bioavailability in rats because of its extensive glucuronidation. This review aims to comprehensively summarize the pharmacology, toxicity and pharmacokinetics of emodin reported to date with an emphasis on its biological properties and mechanisms of action. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27188216

  1. Emodin: A Review of its Pharmacology, Toxicity and Pharmacokinetics.

    PubMed

    Dong, Xiaoxv; Fu, Jing; Yin, Xingbin; Cao, Sali; Li, Xuechun; Lin, Longfei; Ni, Jian

    2016-08-01

    Emodin is a natural anthraquinone derivative that occurs in many widely used Chinese medicinal herbs, such as Rheum palmatum, Polygonum cuspidatum and Polygonum multiflorum. Emodin has been used as a traditional Chinese medicine for over 2000 years and is still present in various herbal preparations. Emerging evidence indicates that emodin possesses a wide spectrum of pharmacological properties, including anticancer, hepatoprotective, antiinflammatory, antioxidant and antimicrobial activities. However, emodin could also lead to hepatotoxicity, kidney toxicity and reproductive toxicity, particularly in high doses and with long-term use. Pharmacokinetic studies have demonstrated that emodin has poor oral bioavailability in rats because of its extensive glucuronidation. This review aims to comprehensively summarize the pharmacology, toxicity and pharmacokinetics of emodin reported to date with an emphasis on its biological properties and mechanisms of action. Copyright © 2016 John Wiley & Sons, Ltd.

  2. Pharmacokinetics and pharmacodynamics of cannabinoids.

    PubMed

    Grotenhermen, Franjo

    2003-01-01

    Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marijuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial

  3. Development and characterization of pharmacokinetic parameters of fast-dissolving films containing levocetirizine.

    PubMed

    Choudhary, Dhagla R; Patel, Vishnu A; Chhalotiya, Usmangani K; Patel, Harsha V; Kundawala, Aliasgar J

    2012-09-01

    A fast-dissolving film containing levocetirizine, a non-sedative antihistamine drug, was developed using pullulan, xanthan gum, propylene glycol, and tween 80 as the base materials. The drug content of the prepared films was within an acceptable limit as prescribed by the USP. The film exhibited excellent stability for four months when stored at 40 °C and 75% humidity. In vitro dissolution studies suggested a rapid disintegration, in which most of levocetirizine (93.54 ± 3.9%) dissolved within 90 seconds after insertion into the medium. Subsequently, Sprague-Dawley rats were used to compare the pharmacokinetic properties of the film preparation administered to the oral cavity, to those with oral administration of the pure drug solution. The pharmacokinetic parameters were similar between the two groups in which AUC(0-t) (ng h/ml), AUC(0-∞) (ng h/ml) C(max) (ng/ml), T(max) (min), K(el) (h(-1)), and t(1/2) (h) of the reference were 452.033 ± 43.68, 465.78 ± 48.16, 237.16 ± 19.87, 30, 0.453 ± 0.051, and 1.536 ± 0.118, respectively, for the film formulation 447.233 ± 46.24, 458.22 ± 46.74, 233.32 ± 17.19, 30, 0.464 ± 0.060, and 1.496 ± 0.293, respectively. These results suggest that the present levocetirizine containing fast-dissolving film is likely to become one of the choices to treat different allergic conditions. PMID:23008821

  4. Predicting neonatal pharmacokinetics from prior data using population pharmacokinetic modeling.

    PubMed

    Wang, Jian; Edginton, Andrea N; Avant, Debbie; Burckart, Gilbert J

    2015-10-01

    Selection of the first dose for neonates in clinical trials is very challenging. The objective of this analysis was to assess if a population pharmacokinetic (PK) model developed with data from infants to adults is predictive of neonatal clearance and to evaluate what age range of prior PK data is needed for informative modeling to predict neonate exposure. Two sources of pharmacokinetic data from 8 drugs were used to develop population models: (1) data from all patients > 2 years of age, and (2) data from all nonneonatal patients aged > 28 days. The prediction error based on the models using data from subjects > 2 years of age showed bias toward overprediction, with median average fold error (AFE) for CL predicted/CLobserved greater than 1.5. The bias for predicting neonatal PK was improved when using all prior PK data including infants as opposed to an assessment without infant PK data, with the median AFE 0.91. As an increased number of pediatric trials are conducted in neonates under the Food and Drug Administration Safety and Innovation Act, dose selection should be based on the best estimates of neonatal pharmacokinetics and pharmacodynamics prior to conducting efficacy and safety studies in neonates. PMID:25907280

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

    PubMed

    Li, Chao; Song, Xiaowei; Song, Junke; Pang, Xiaocong; Wang, Zhe; Zhao, Ying; Lian, Wenwen; Liu, Ailin; Du, Guanhua

    2016-01-01

    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 (C 0) 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. PMID:26904400

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

    PubMed Central

    Li, Chao; Song, Xiaowei; Song, Junke; Pang, Xiaocong; Wang, Zhe; Zhao, Ying; Lian, Wenwen; Liu, Ailin; Du, Guanhua

    2015-01-01

    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. PMID:26904400

  7. Offer/Acceptance Ratio.

    ERIC Educational Resources Information Center

    Collins, Mimi

    1997-01-01

    Explores how human resource professionals, with above average offer/acceptance ratios, streamline their recruitment efforts. Profiles company strategies with internships, internal promotion, cooperative education programs, and how to get candidates to accept offers. Also discusses how to use the offer/acceptance ratio as a measure of program…

  8. CNS drug design: balancing physicochemical properties for optimal brain exposure.

    PubMed

    Rankovic, Zoran

    2015-03-26

    The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochemical properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most critical physicochemical and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chemistry strategies toward molecules with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.

  9. [Interspecies differences of noopept pharmacokinetics].

    PubMed

    Boĭko, S S; Korotkov, S A; Zherdev, V P; Gudasheva, T A; Ostrovskaia, R U; Voronina, T A

    2004-01-01

    Significant interspecific differences in the pharmacokinetics of noopept are manifested by a decrease in the drug elimination rate on the passage from rats to rabbits and humans. Very intensive metabolism of noopept was observed upon intravenous administration in rats. In these animals, presystemic elimination mechanisms lead to the formation of a specific metabolite representing a product of drug biotransformation hydroxylated at the phenyl ring. In rabbits, unchanged noopept circulates in the blood for a longer time upon both intravenous and peroral introduction, biotransformation proceeds at a much slower rate, and no metabolites analogous to that found in rats are detected. The noopept pharmacokinetics in humans differs from that in animals by still slower elimination and considerable individual variability. No drug metabolites are found in the human blood plasma, probably because of a relatively small dose and low concentration. PMID:15079908

  10. Pharmacokinetics and RC Circuit Concepts

    NASA Astrophysics Data System (ADS)

    Cock, Mieke De; Janssen, Paul

    2013-11-01

    Most introductory physics courses include a chapter on RC circuits in which the differential equations for the charging and discharging of a capacitor are derived. A number of papers in this journal describe lab experiments dealing with the measurement of different parameters in such RC circuits. In this contribution, we report on a lab experiment we developed for students majoring in pharmacy, using RC circuits to simulate a pharmacokinetic process.

  11. Population Pharmacokinetics of Intranasal Scopolamine

    NASA Technical Reports Server (NTRS)

    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.

  12. Aspartame pharmacokinetics - the effect of ageing.

    PubMed

    Puthrasingam, S; Heybroek, W M; Johnston, A; Maskrey, V; Swift, C G; Turner, P; Abrams, S M; Jackson, S H

    1996-05-01

    Aspartame is an intense sweetener which is increasingly used in the UK. It is registered at an acceptable daily intake (ADI) of 40 mg/kg, although there are no previous data relating to the metabolism of aspartame in older people. Twelve young and 12 elderly volunteers each received a single dose of approximately 40 mg/kg of aspartame. Baseline concentrations of phenylalanine (the main metabolite of aspartame) rose after ingestion with a significantly higher maximum concentration (Cmax) (81.3 vs. 63.3 micromol/1, p<0.01) and area under the plasma concentration-time curve extrapolated to infinity AUC 9(0-infinity)(518.7 vs. 353.5 micromol . h/l, p<0.01) in the elderly group. The higher concentrations reflected a significant fall in volume of distribution (V) from 2.03 to 1.59 1/kg (p <0.05) and clearance (CL) from 7.3 to 4.9 ml/min/kg (p <0.005) in the elderly group. The greater effect on CL than on V resulted in a small but non-significant rise in elimination half life (3.5 to 3.9 hours). The sizes of the differences were modest implying that there is no need on pharmacokinetic grounds for a change in the ADI for older people.

  13. Pharmacokinetic study of harmane and its 10 metabolites in rat after intravenous and oral administration by UPLC-ESI-MS/MS.

    PubMed

    Li, Shuping; Teng, Liang; Liu, Wei; Cheng, Xuemei; Jiang, Bo; Wang, Zhengtao; Wang, Chang-Hong

    2016-09-01

    Context The β-carboline alkaloid harmane is widely distributed in common foods, beverages and hallucinogenic plants. Harmane exerts potential in therapies for Alzheimer's and depression diseases. However, little information on its dynamic metabolic profiles and pharmacokinetics in vivo is currently available. Objective This study investigates the dynamic metabolic profiles and pharmacokinetic properties of harmane and its metabolites in rats in vivo. Materials and methods A highly selective, sensitive and rapid ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) method was developed and well-validated for simultaneous quantitative determination of harmane and its uncertain endogenous metabolite harmine, as well as for semiquantitative determination of 10 harmane metabolites in rats after intravenous injection and oral administration of harmane at 1.0 and 30.0 mg/kg, respectively. Results The calibration curves of harmane and harmine showed excellent linearity within the concentration range of 1-2000 ng/mL with acceptable accuracy, precision, selectivity, recovery, matrix effect and stability. Ten metabolites, including harmane but not harmine, were detected and identified after intravenous and oral administration of harmane. The absolute bioavailability of harmane following an oral dose was 19.41 ± 3.97%. According to the AUC0-t values of all the metabolites, the metabolic levels of phase II metabolites were higher than those of phase I metabolites, and the sulphation pathways were the dominant metabolic routes for harmane in both routes of administration. Discussion and conclusion The pharmacokinetic properties of harmane and its 10 metabolites in rats were determined. Sulphate conjugation was the predominant metabolic process of harmane in rats. PMID:26730489

  14. 41 CFR 105-8.170-6 - Acceptance of complaint.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 3 2010-07-01 2010-07-01 false Acceptance of complaint... Acceptance of complaint. (a) The Official shall accept a complete complaint that is filed in accordance with... the respondent of receipt and acceptance of the complaint. (b) If the Official receives a...

  15. Pharmacokinetic interactions of cimetidine 1987.

    PubMed

    Somogyi, A; Muirhead, M

    1987-05-01

    The number of studies on drug interactions with cimetidine has increased at a rapid rate over the past 5 years, with many of the interactions being solely pharmacokinetic in origin. Very few studies have investigated the clinical relevance of such pharmacokinetic interactions by measuring pharmacodynamic responses or clinical endpoints. Apart from pharmacokinetic studies, invariably conducted in young, healthy subjects, there have been a large number of in vitro and in vivo animal studies, case reports, clinical observations and general reviews on the subject, which is tending to develop an industry of its own accord. Nevertheless, where specific mechanisms have been considered, these have undoubtedly increased our knowledge on the way in which humans eliminate xenobiotics. There is now sufficient information to predict the likelihood of a pharmacokinetic drug-drug interaction with cimetidine and to make specific clinical recommendations. Pharmacokinetic drug interactions with cimetidine occur at the sites of gastrointestinal absorption and elimination including metabolism and excretion. Cimetidine has been found to reduce the plasma concentrations of ketoconazole, indomethacin and chlorpromazine by reducing their absorption. In the case of ketoconazole the interaction was clinically important. Cimetidine does not inhibit conjugation mechanisms including glucuronidation, sulphation and acetylation, or deacetylation or ethanol dehydrogenation. It binds to the haem portion of cytochrome P-450 and is thus an inhibitor of phase I drug metabolism (i.e. hydroxylation, dealkylation). Although generally recognised as a nonspecific inhibitor of this type of metabolism, cimetidine does demonstrate some degree of specificity. To date, theophylline 8-oxidation, tolbutamide hydroxylation, ibuprofen hydroxylation, misonidazole demethylation, carbamazepine epoxidation, mexiletine oxidation and steroid hydroxylation have not been shown to be inhibited by cimetidine in humans but

  16. 36 CFR 251.62 - Acceptance.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 251.62 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LAND USES Special Uses § 251.62 Acceptance. Except for an easement, a special use authorization shall become effective... extended by the authorized officer. Refusal of an applicant to sign and accept a special use...

  17. 36 CFR 251.62 - Acceptance.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 251.62 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LAND USES Special Uses § 251.62 Acceptance. Except for an easement, a special use authorization shall become effective... extended by the authorized officer. Refusal of an applicant to sign and accept a special use...

  18. 36 CFR 251.62 - Acceptance.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 251.62 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LAND USES Special Uses § 251.62 Acceptance. Except for an easement, a special use authorization shall become effective... extended by the authorized officer. Refusal of an applicant to sign and accept a special use...

  19. 36 CFR 251.62 - Acceptance.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 251.62 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LAND USES Special Uses § 251.62 Acceptance. Except for an easement, a special use authorization shall become effective... extended by the authorized officer. Refusal of an applicant to sign and accept a special use...

  20. 36 CFR 251.62 - Acceptance.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 251.62 Parks, Forests, and Public Property FOREST SERVICE, DEPARTMENT OF AGRICULTURE LAND USES Special Uses § 251.62 Acceptance. Except for an easement, a special use authorization shall become effective... extended by the authorized officer. Refusal of an applicant to sign and accept a special use...

  1. Pharmacokinetics and residues of enrofloxacin in chickens.

    PubMed

    Anadón, A; Martínez-Larrañaga, M R; Díaz, M J; Bringas, P; Martínez, M A; Fernàndez-Cruz, M L; Fernández, M C; Fernández, R

    1995-04-01

    The pharmacokinetic properties of enrofloxacin were determined in broiler chickens after single IV and orally administered doses of 10 mg/kg of body weight. After IV and oral administrations, the plasma concentration-time graph was characteristic of a two-compartment open model. The elimination half-life and the mean +/- SEM residence time of enrofloxacin for plasma were 10.29 +/- 0.45 and 9.65 +/- 0.48 hours, respectively, after IV administration and 14.23 +/- 0.46 and 15.30 +/- 0.53 hours, respectively, after oral administration. After single oral administration, enrofloxacin was absorbed slowly, with time to reach maximal plasma concentration of 1.64 +/- 0.04 hours. Maximal plasma concentration was 2.44 +/- 0.06 micrograms/ml. Oral bioavailability was found to be 64.0 +/- 0.2%. Statistically significant differences between the 2 routes of administration were found for the pharmacokinetic variables--half-lives of the distribution and elimination phase and apparent volume of distribution and volume of distribution at steady state. In chickens, enrofloxacin was extensively metabolized into ciprofloxacin. Residues of enrofloxacin and the major metabolite ciprofloxacin in fat, kidney, liver, lungs, muscles, and skin were measured in chickens that received an orally administered dose of 10 mg/kg once daily for 4 days. The results indicate that enrofloxacin and ciprofloxacin residues were cleared slowly. Mean muscle, liver, and kidney concentrations of the metabolite ciprofloxacin ranging between 0.020 and 0.075 micrograms/g persisted on day 12 in chickens after dosing. However, at the time of slaughter (12 days), enrofloxacin residues were only detected in liver and mean +/- SEM concentration was 0.025 +/- 0.003 micrograms/g.

  2. Pharmacokinetics, absorption and tissue distribution of tanshinone IIA solid dispersion.

    PubMed

    Hao, Haiping; Wang, Guangji; Cui, Nan; Li, Jing; Xie, Lin; Ding, Zuoqi

    2006-11-01

    This study was designed to elucidate the pharmacokinetics, absorption, tissue distribution and plasma protein binding properties of tanshinone IIA, a highly lipophilic compound isolated from Salvia miltiorrhiza. Tanshinone IIA was isolated using a previously well developed LC-MS/MS method. Its pharmacokinetic characteristics, absolute bioavailability, tissue distribution and plasma protein binding properties were determined. The membrane permeability was evaluated using Caco-2 cells in monolayer. The pharmacokinetic plasma profile of tanshinone IIA after a single intravenous dosing exhibited a triexponential pattern consisting of rapid distribution (t1/2 alpha, 0.024 h), slow redistribution (t1/2 beta, 0.34 h) and terminal elimination phase (t1/2 gamma, 7.5 h). Tanshinone IIA preferentially distributed into the reticuloendothelial system, especially into liver and lung, after either intravenous or oral doses. Tanshinone IIA (99.2 %) bound highly to plasma proteins, among which lipoprotein played an important role (77.5 %). Tanshinone IIA absorption was extremely poor with an absolute bioavailability below 3.5 %. Absorptive saturation was deduced from the fact that the AUC and Cmax increased less proportionally to dose and Tmax was significantly prolonged. The poor absorption of tanshinone IIA may be caused by its low aqueous solubility and limited membrane permeability. There were no significant differences of the apparent permeability coefficient for all tested concentrations and for the apical to basolateral and reverse direction transport, suggesting a passive transport mode and no involvement of an efflux protein. In conclusion, tanshinone IIA has a suitable pharmacokinetic behavior except for its poor absorption. A pharmaceutical strategy for promoting its absorption should be designed to develop tanshinone IIA as a new drug candidate. PMID:17024606

  3. An integrated pharmacokinetics ontology and corpus for text mining

    PubMed Central

    2013-01-01

    Background Drug pharmacokinetics parameters, drug interaction parameters, and pharmacogenetics data have been unevenly collected in different databases and published extensively in the literature. Without appropriate pharmacokinetics ontology and a well annotated pharmacokinetics corpus, it will be difficult to develop text mining tools for pharmacokinetics data collection from the literature and pharmacokinetics data integration from multiple databases. Description A comprehensive pharmacokinetics ontology was constructed. It can annotate all aspects of in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. It covers all drug metabolism and transportation enzymes. Using our pharmacokinetics ontology, a PK-corpus was constructed to present four classes of pharmacokinetics abstracts: in vivo pharmacokinetics studies, in vivo pharmacogenetic studies, in vivo drug interaction studies, and in vitro drug interaction studies. A novel hierarchical three level annotation scheme was proposed and implemented to tag key terms, drug interaction sentences, and drug interaction pairs. The utility of the pharmacokinetics ontology was demonstrated by annotating three pharmacokinetics studies; and the utility of the PK-corpus was demonstrated by a drug interaction extraction text mining analysis. Conclusions The pharmacokinetics ontology annotates both in vitro pharmacokinetics experiments and in vivo pharmacokinetics studies. The PK-corpus is a highly valuable resource for the text mining of pharmacokinetics parameters and drug interactions. PMID:23374886

  4. Population Pharmacokinetics of Abacavir in Pregnant Women

    PubMed Central

    Treluyer, Jean-Marc; Préta, Laure-Helene; Valade, Elodie; Pannier, Emmanuelle; Urien, Saik; Hirt, Déborah

    2014-01-01

    For the first time, a population approach was used to describe abacavir (ABC) pharmacokinetics in HIV-infected pregnant and nonpregnant women. A total of 266 samples from 150 women were obtained. No covariate effect (from age, body weight, pregnancy, or gestational age) on ABC pharmacokinetics was found. Thus, it seems unnecessary to adapt the ABC dosing regimen during pregnancy. PMID:25070097

  5. COMPUTATIONAL PHARMACOKINETICS DURING DEVELOPMENTAL WINDOWS OF SUSPECTIBILITY

    EPA Science Inventory

    ABSTRACT

    Computational modeling has an increasing role in analyses of biological effects including how the body handles chemicals (i.e. pharmacokinetics or toxicokinetics) and how the body responds to chemicals (i.e. pharmacodynamics or toxicodynamics). Pharmacokinetic mo...

  6. Drug Transport and Pharmacokinetics for Chemical Engineers

    ERIC Educational Resources Information Center

    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…

  7. The pharmacokinetics in mice and dogs of nitroimidazole radiosensitizers and chemosensitizers more lipophilic than misonidazole

    SciTech Connect

    White, R.; Workman, P.; Owen, L.

    1982-03-01

    The pharmacokinetic properties of nitroimidazole radiosensitizers and chemosensitizers more lipophilic than misonidazole (MISO) were examined. In dogs, 2 analogues showed comparable peak plasma concentrations with considerable shorter half-lives (t1/2) and reduced areas under curves (AUC). Benznidazole (R0 07-1051) had a much longer t1/2, a higher AUC, and somewhat higher peak concentrations. In mice tumor/plasma, brain/plasma, and tumor/brain ratios were generally similar to MISO, as was penetration of brain and peripheral nerve by benznidazole in dogs. Selection of lipophilic analogues with appropriate pharmacokinetic properties may facilitate accommodation of the potentially different requirements for improved radiosensitization or chemosensitization.

  8. Pharmacokinetics of oxfendazole in sheep.

    PubMed

    Marriner, S E; Bogan, J A

    1981-07-01

    Pharmacokinetics of oxfendazole and its sulfone metabolite were determined in 6 sheep. Oxfendazole achieved mean peak plasma concentrations of 0.76 micrograms/ml at 30 hours after oral administration of oxfendazole (10 mg/kg of body weight), and concentrations were detectable for up to 7 days after administration. Mean peak abomasal concentrations of 3.55 micrograms/ml occurred 20 hours after administration and were detectable up to 9 days after administration. Concentrations of sulfone in plasma and abomasal fluid were generally lower than were those of oxfendazole.

  9. Acceptability of BCG vaccination.

    PubMed

    Mande, R

    1977-01-01

    The acceptability of BCG vaccination varies a great deal according to the country and to the period when the vaccine is given. The incidence of complications has not always a direct influence on this acceptability, which depends, for a very large part, on the risk of tuberculosis in a given country at a given time.

  10. ATLAS ACCEPTANCE TEST

    SciTech Connect

    Cochrane, J. C. , Jr.; Parker, J. V.; Hinckley, W. B.; Hosack, K. W.; Mills, D.; Parsons, W. M.; Scudder, D. W.; Stokes, J. L.; Tabaka, L. J.; Thompson, M. C.; Wysocki, Frederick Joseph; Campbell, T. N.; Lancaster, D. L.; Tom, C. Y.

    2001-01-01

    The acceptance test program for Atlas, a 23 MJ pulsed power facility for use in the Los Alamos High Energy Density Hydrodynamics program, has been completed. Completion of this program officially releases Atlas from the construction phase and readies it for experiments. Details of the acceptance test program results and of machine capabilities for experiments will be presented.

  11. Self-assembly properties of semiconducting donor-acceptor-donor bithienyl derivatives of tetrazine and thiadiazole-effect of the electron accepting central ring.

    PubMed

    Zapala, Joanna; Knor, Marek; Jaroch, Tomasz; Maranda-Niedbala, Agnieszka; Kurach, Ewa; Kotwica, Kamil; Nowakowski, Robert; Djurado, David; Pecaut, Jacques; Zagorska, Malgorzata; Pron, Adam

    2013-11-26

    Scanning tunneling microscopy was used to study the effect of the electron-accepting unit and the alkyl substituent's position on the type and extent of 2D supramolecular organization of penta-ring donor-acceptor-donor (DAD) semiconductors, consisting of either tetrazine or thiadiazole central acceptor ring symmetrically attached to two bithienyl groups. Microscopic observations of monomolecular layers on HOPG of four alkyl derivatives of the studied adsorbates indicate significant differences in their 2D organizations. Ordered monolayers of thiadiazole derivatives are relatively loose and, independent of the position of alkyl substituents, characterized by large intermolecular separation of acceptor units in the adjacent molecules located in the face-to-face configuration. The 2D supramolecular architecture in both derivatives of thiadiazole is very sensitive to the alkyl substituent's position. Significantly different behavior is observed for derivatives of tetrazine (which is a stronger electron acceptor). Stronger intermolecular DA interactions in these adsorbates generate an intermolecular shift in the monolayer, which is a dominant factor determining the 2D structural organization. As a consequence of this molecular arrangement, tetrazine groups (A segments) face thiophene rings (D segments) of the neighboring molecules. Monolayers of tetrazine derivatives are therefore much more densely packed and characterized by similar π-stacking of molecules independently of the position of alkyl substituents. Moreover, a comparative study of 3D supramolecular organization, deduced from the X-ray diffraction patterns, is also presented clearly confirming the polymorphism of the studied adsorbates.

  12. Pharmacology in space. Part 1. Influence of adaptive changes on pharmacokinetics

    NASA Technical Reports Server (NTRS)

    Lathers, C. M.; Charles, J. B.; Bungo, M. W.

    1989-01-01

    The topic of pharmacology in space, i.e. the administration of drugs during space flight and the subsequent pharmacokinetic handling of the pharmaceuticals, is a new field about which little is known. In a two-part series, Claire Lathers and colleagues highlight some of the current questions in this field. In this first article the physiological and biochemical changes associated with weightlessness in space are discussed. These changes induce adaptive alterations which may influence the pharmacokinetic properties of drugs. The cardiovascular system is of particular relevance here. Also discussed are the classes of pharmacological agent that are most likely to be used during space flight for medical problems and thus, by necessity, will become drugs to be examined in space to determine whether their pharmacokinetic and pharmacodynamic properties are altered. Therapy of the most common spaceflight ailment-motion sickness-will be considered next month in Part 2.

  13. Development of a computer-based instructional system in pharmacokinetics: efficacy in clinical pharmacology teaching for senior medical students.

    PubMed

    Feldman, R D; Schoenwald, R; Kane, J

    1989-02-01

    The teaching of pharmacokinetics is acknowledged to be a key aspect of the core curriculum in clinical pharmacology and therapeutics, but is also widely acknowledged to be a very difficult part of the curriculum to teach. In order to assess the potential efficacy of interactive computer instruction in clinical pharmacokinetics we have developed a prototype computer-based instructional package. The courseware contains a comprehensive learning system including tutorial, simulation, and problem solving components. To determine the efficacy of this approach we randomly assigned senior medical student volunteers enrolled in the fourth year clinical pharmacology and therapeutics course to receive conventional teaching in clinical pharmacokinetics and/or adjuctive teaching using the computer-based instructional system. There was a high degree of acceptance of the program and over the short term of the trial those students using the computer program scored significantly higher [35%, P less than 0.05] on the mid-term pharmacokinetics quiz. The data suggests that a computerized instructional system in pharmacokinetics may significantly improve the teaching of clinical pharmacokinetics to medical students. PMID:2654201

  14. Integration of pharmacokinetic and pharmacodynamic indices of marbofloxacin in turkeys.

    PubMed

    Haritova, Aneliya Milanova; Rusenova, Nikolina Velizarova; Parvanov, Parvan Rusenov; Lashev, Lubomir Dimitrov; Fink-Gremmels, Johanna

    2006-11-01

    Fluoroquinolones are extensively used in the treatment of systemic bacterial infections in poultry, including systemic Escherichia coli bacillosis, which is a common disease in turkey flocks. Marbofloxacin has been licensed for use in various mammalian species, but not as yet for turkeys, although its kinetic properties distinguish it from other fluoroquinolones. For example, the longer half-life of marbofloxacin in many animal species has been appreciated in veterinary practice. It is generally accepted that, for fluoroquinolones, the optimal dose should be estimated on the basis of the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the drug under consideration. Knowledge of these specific data for the target animal species allows the establishment of an integrated PK-PD model that is of high predictive value. In the present study, the antibacterial efficacy (PD indices) against a field isolate of Escherichia coli O78/K80 was investigated ex vivo following oral and intravenous administration of marbofloxacin to turkeys (breed BUT 9; six animals per group) at a dose of 2 mg/kg of body weight (BW). At the same time, the serum concentrations of marbofloxacin were measured at different time intervals by a standardized high-performance liquid chromatography method, allowing the calculation of the most relevant kinetic parameters (PK parameters). The in vitro serum inhibitory activity of marbofloxacin against the selected E. coli strain, O78/K80, was 0.5 mug/ml in the blood serum of turkeys, and the ratio of the maximum concentration of the drug in serum to the serum inhibitory activity was 1.34. The lowest ratio of the measured serum concentration multiplied by the incubation period of 24 h to the serum inhibitory activity required for bacterial elimination was lower than the ratio of the area under the serum concentration-time curve (AUC) to the serum inhibitory activity. These first results suggested that the recommended dose of 2 mg/kg BW of

  15. In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs

    PubMed Central

    Restrepo Valencia, Piedad

    2015-01-01

    Introduction: The in vitro-in vivo pharmacokinetic correlation models (IVIVC) are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC) obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance. PMID:26600625

  16. Divalproex-ER pharmacokinetics in older children and adolescents.

    PubMed

    Dutta, Sandeep; Zhang, Yiming; Conway, Jeannine M; Sallee, Floyd R; Biton, Victor; Reed, Michael D; Kearns, Gregory L

    2004-05-01

    Valproic acid pharmacokinetic profile and tolerability after administration of divalproex sodium extended-release tablets was characterized in older children and adolescents. In this multiple-dose, open-label, pharmacokinetic study, the patients were divided into two age groups, 8-11 years (older children; n = 15) and 12-17 years (adolescents; n = 14). Once-daily administration of divalproex sodium extended-release tablets (doses ranged from 250 to 1750 mg) in older children and adolescents produced relatively flat plasma valproic acid concentration-time profiles over the entire 24-hour dosing interval, similar to the pharmacokinetic performance of this formulation in adults. The mean (standard deviation) oral clearance values for unbound valproic acid were 94.3 (51.8) and 82.3 (28.2) mL/h/kg and for total valproic acid were 11.2 (3.77) and 9.06 (2.03) mL/h/kg in older children and adolescents, respectively. Two patients discontinued for administrative reasons, whereas one discontinued for an adverse event (flulike syndrome). Adverse events reported by three or more patients were flu syndrome (5 patients, 17.2%) and headache (3 patients, 10.3%). Reported adverse events were generally mild to moderate in severity and similar to those reported in previous divalproex studies. This study demonstrates that in older children and adolescents, once-daily administration of divalproex sodium extended-release tablets may potentially be used to sustain plasma valproic acid concentrations within the usually accepted therapeutic ranges for various indications. PMID:15165635

  17. Population pharmacokinetics of pyrazinamide in elephants.

    PubMed

    Zhu, M; Maslow, J N; Mikota, S K; Isaza, R; Dunker, F; Riddle, H; Peloquin, C A

    2005-10-01

    This study was undertaken to characterize the population pharmacokinetics (PK), therapeutic dose, and preferred route of administration for pyrazinamide (PZA) in elephants. Twenty-three African (Loxodonta africana) and Asian (Elephas maximus) elephants infected with or in contact with others culture positive for Mycobacterium tuberculosis were dosed under treatment conditions. PZA was dosed daily at 20-30 mg/kg via oral (fasting or nonfasting state) or rectal (enema or suppository) administration. Blood samples were collected 0-24 h postdose. Population PK was estimated using nonlinear mixed effect modeling. Drug absorption was rapid with T(max) at or before 2 h regardless of the method of drug administration. C(max) at a mean dose of 25.6 (+/-4.6) mg/kg was 19.6 (+/-9.5 microg/mL) for PZA given orally under fasting conditions. Under nonfasting conditions at a mean dose of 26.1 +/- 4.2 mg/kg, C(max) was 25% (4.87 +/- 4.89 microg/mL) and area under concentration curve (AUC) was 30% of the values observed under fasting conditions. Mean rectal dose of 32.6 +/- 15.2 mg/kg yielded C(max) of 12.3 +/- 6.3 microg/mL, but comparable AUC to PZA administered orally while fasting. Both oral and rectal administration of PZA appeared to be acceptable and oral dosing is preferred because of the higher C(max) and lower inter-subject variability. A starting dose of 30 mg/kg is recommended with drug monitoring between 1 and 2 h postdose. Higher doses may be required if the achieved C(max) values are below the recommended 20-50 microg/mL range. PMID:16207301

  18. Acceptance procedures: Microfilm printer

    NASA Technical Reports Server (NTRS)

    Lockwood, H. E.

    1973-01-01

    Acceptance tests were made for a special order automatic additive color microfilm printer. Tests include film capacity, film transport, resolution, illumination uniformity, exposure range checks, and color cuing considerations.

  19. Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study

    PubMed Central

    Bekker, Pirow; Dairaghi, Daniel; Seitz, Lisa; Leleti, Manmohan; Wang, Yu; Ertl, Linda; Baumgart, Trageen; Shugarts, Sarah; Lohr, Lisa; Dang, Ton; Miao, Shichang; Zeng, Yibin; Fan, Pingchen; Zhang, Penglie; Johnson, Daniel; Powers, Jay; Jaen, Juan; Charo, Israel; Schall, Thomas J.

    2016-01-01

    The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773. PMID:27768695

  20. Fluconazole Pharmacokinetics in Burn Patients

    PubMed Central

    Boucher, Bradley A.; King, Stephen R.; Wandschneider, Heidi L.; Hickerson, William L.; Hanes, Scott D.; Herring, Vanessa L.; Canada, Todd W.; Hess, Mary M.

    1998-01-01

    The pharmacokinetics of fluconazole in nine adult patients with severe (30 to 95% total body surface area) burns were studied. There was no significant difference in half-life (t1/2), clearance (CL), or volume of distribution (V) over time in five patients on days 3 and 8 of the study (P > 0.05). Combined parameter estimates (means ± standard deviations) for all nine patients for the two study periods were as follows: t1/2, 24.4 ± 5.8 h; CL, 0.36 ± 0.09 ml/min/kg; and V, 0.72 ± 0.12 liters/kg. These estimates of t1/2 and CL in burn patients were approximately 13% shorter and 30% more rapid, respectively, than the most extreme estimates reported for other populations. PMID:9559811

  1. Pharmacokinetics of sulfamethazine in buffaloes.

    PubMed

    Khan, F H; Nawaz, M; Anwar-Ul-Hassan, S

    1980-01-01

    Pharmacokinetic parameters which describe distribution and elimination of sulfamethazine were determined in buffaloes. Following intravenous administration of a single dose (100 mg/kg), disposition of the drug was described in terms of biexponential expression: Cp = Ae alpha t + Be-beta t. Based on total (free and bound) sulfonamide levels in the plasma, pseudo-distribution equilibrium was rapidly attained and the half-life value of 5.54 +/- 0.41 h (mean +/- S.D., n = 8) was recorded. Body clearance was 56 +/- 7 ml x kg-1 x h-1. Based on this study we suggest an intravenous dosage regimen consisting of 38.4 mg sulfamethazine/kg body-weight repeated at 12 h inrervals. With this dosage level the predicted plasma concentrations will oscillate between 125 and 25 micrograms/ml during the steady-state. The influence of febrile states and bacterial diseases on predicted levels remains to be verified experimentally. PMID:7436332

  2. Pattern Recognition in Pharmacokinetic Data Analysis.

    PubMed

    Gabrielsson, Johan; Meibohm, Bernd; Weiner, Daniel

    2016-01-01

    Pattern recognition is a key element in pharmacokinetic data analyses when first selecting a model to be regressed to data. We call this process going from data to insight and it is an important aspect of exploratory data analysis (EDA). But there are very few formal ways or strategies that scientists typically use when the experiment has been done and data collected. This report deals with identifying the properties of a kinetic model by dissecting the pattern that concentration-time data reveal. Pattern recognition is a pivotal activity when modeling kinetic data, because a rigorous strategy is essential for dissecting the determinants behind concentration-time courses. First, we extend a commonly used relationship for calculation of the number of potential model parameters by simultaneously utilizing all concentration-time courses. Then, a set of points to consider are proposed that specifically addresses exploratory data analyses, number of phases in the concentration-time course, baseline behavior, time delays, peak shifts with increasing doses, flip-flop phenomena, saturation, and other potential nonlinearities that an experienced eye catches in the data. Finally, we set up a series of equations related to the patterns. In other words, we look at what causes the shapes that make up the concentration-time course and propose a strategy to construct a model. By practicing pattern recognition, one can significantly improve the quality and timeliness of data analysis and model building. A consequence of this is a better understanding of the complete concentration-time profile.

  3. Triprotic acid-base microequilibria and pharmacokinetic sequelae of cetirizine.

    PubMed

    Marosi, Attila; Kovács, Zsuzsanna; Béni, Szabolcs; Kökösi, József; Noszál, Béla

    2009-06-28

    (1)H NMR-pH titrations of cetirizine, the widely used antihistamine and four related compounds were carried out and the related 11 macroscopic protonation constants were determined. The interactivity parameter between the two piperazine amine groups was obtained from two symmetric piperazine derivatives. Combining these two types of datasets, all the 12 microconstants and derived tautomeric constants of cetirizine were calculated. Upon this basis, the conflicting literature data of cetirizine microspeciation were clarified, and the pharmacokinetic absorption-distribution properties could be interpreted. The pH-dependent distribution of the microspecies is provided.

  4. Chiral Pesticide Pharmacokinetics: A Range of Values

    EPA Science Inventory

    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...

  5. Opioid pharmacokinetic drug-drug interactions.

    PubMed

    Overholser, Brian R; Foster, David R

    2011-09-01

    Pharmacokinetic drug-drug interactions (DDIs) involving opioid analgesics can be problematic. Opioids are widely used, have a narrow therapeutic index, and can be associated with severe toxicity. The purpose of this review is to describe pharmacokinetic DDIs associated with opioids frequently encountered in managed care settings (morphine, codeine, oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, tramadol, and methadone). An introduction to the pharmacokinetic basis of DDIs is provided, and potential DDIs associated with opioids are reviewed. Opioids metabolized by the drug metabolizing enzymes of the cytochrome P450 (CYP450) system (codeine, oxycodone, hydrocodone, fentanyl, tramadol, and methadone) are associated with numerous DDIs that can result in either a reduction in opioid effect or excess opioid effects. Conversely, opioids that are not metabolized by that system (morphine, oxymorphone, and hydromorphone) tend to be involved in fewer CYP450-associated pharmacokinetic DDIs.

  6. A PHARMACOKINETIC PROGRAM (PKFIT) FOR R

    EPA Science Inventory

    The purpose of this study was to create a nonlinear regression (including a genetic algorithm) program (R script) to deal with data fitting for pharmacokinetics (PK) in R environment using its available packages. We call this tool as PKfit.

  7. Effectiveness, Safety, and Pharmacokinetics of Quetiapine in Aggressive Children with Conduct Disorder

    ERIC Educational Resources Information Center

    Findling, Robert L.; Reed, Michael D.; O'Riordan, Mary Ann; Demeter, Christine A.; Stansbrey, Robert J.; McNamara, Nora K.

    2006-01-01

    Objective: To provide an initial description of the effectiveness and pharmacokinetics (PK) of quetiapine in aggressive children with conduct disorder (CD). Method: This 8-week, open-label outpatient trial, enrolled patients ages 6 to 12 years with CD. Outcome measures included the Rating of Aggression Against People and/or Property Scale…

  8. Pharmacokinetics and dosimetry of the anti-androgen vinclozolin after oral administration inthe rat

    EPA Science Inventory

    Vinclozolin (V) is a fungicide with antiandrogenic properties. To determine the pharmacokinetics and dosimetry of V, adult male rats were administered an oral dose of V (100 mg/kg) in corn oil and sacrificed over time after dosing. V and its metabolites were analyzed in serum and...

  9. Oritavancin Pharmacokinetics and Bone Penetration in Rabbits

    PubMed Central

    Ostiguy, Valerie; Cadieux, Cordelia; Malouin, Mireille; Belanger, Odette; Far, Adel Rafai; Parr, Thomas R.

    2015-01-01

    The pharmacokinetics and bone concentrations of oritavancin were investigated after a single intravenous dose was administered to rabbits. The pharmacokinetic profile of oritavancin in rabbits showed that it is rapidly distributed to bone tissues, with concentrations remaining stable for up to 168 h, the last measured time point. Based on these findings, further evaluation of oritavancin for the treatment of infections in bone tissues is warranted. PMID:26239977

  10. The Pharmacokinetics of Potassium in Humans Is Unusual.

    PubMed

    Hinderling, Peter H

    2016-10-01

    Potassium is critical for maintaining cellular tonicity, propagation of nerve impulses, contraction of cardiac, skeletal, and smooth muscles, and normal renal function. The focus of this review is on the pharmacokinetics of potassium, K(+) , after administration of liquid and solid formulations of potassium chloride, KCl, to healthy subjects. Potassium can be considered an endogenous and exogenous compound. The amounts of endogenous K(+) are kept constant by balancing intake and loss of exogenous K(+) . Food and ingestion of KCl-containing medicines are sources for exogenous K(+) . In the pharmacokinetic context exogenous K(+) from KCl-containing medicines, K(+) exo,dose , is of primary interest. The distinction between the different K(+) entities is critical for obtaining unbiased estimates of the kinetic parameters for K(+) exo,dose . A literature search using prespecified acceptance criteria was performed. Publications were selected that reported plasma and urine data of K(+) exo,dose directly or provided information allowing their determination. Additional criteria applied included that the studies used a randomized design and controlled for the important covariates. Most of the selected publications reported urinary excretion data. Only 2 publications also reported plasma concentrations. The excursions of the plasma concentrations of K(+) exo,dose were considered too small to be of use by most investigators. The aggregate results indicate that urinary recovery data have the potential for providing reliable estimates for bioavailability and bioequivalence of K(+) exo,dose with KCl-containing formulations. Absorption efficiency, peak rates, and corresponding times of K(+) exo,dose with liquid formulations are fairly consistent among studies. The mean absorption efficiency of K(+) exo,dose with solid and liquid formulations of KCl ranges between 70% and 90%. The absorption rate of liquid formulations is rapid, whereas the solid formulations show extended release

  11. Linear mixed-effect multivariate adaptive regression splines applied to nonlinear pharmacokinetics data.

    PubMed

    Gries, J M; Verotta, D

    2000-08-01

    In a frequently performed pharmacokinetics study, different subjects are given different doses of a drug. After each dose is given, drug concentrations are observed according to the same sampling design. The goal of the experiment is to obtain a representation for the pharmacokinetics of the drug, and to determine if drug concentrations observed at different times after a dose are linear in respect to dose. The goal of this paper is to obtain a representation for concentration as a function of time and dose, which (a) makes no assumptions on the underlying pharmacokinetics of the drug; (b) takes into account the repeated measure structure of the data; and (c) detects nonlinearities in respect to dose. To address (a) we use a multivariate adaptive regression splines representation (MARS), which we recast into a linear mixed-effects model, addressing (b). To detect nonlinearity we describe a general algorithm that obtains nested (mixed-effect) MARS representations. In the pharmacokinetics application, the algorithm obtains representations containing time, and time and dose, respectively, with the property that the bases functions of the first representation are a subset of the second. Standard statistical model selection criteria are used to select representations linear or nonlinear in respect to dose. The method can be applied to a variety of pharmacokinetics (and pharmacodynamic) preclinical and phase I-III trials. Examples of applications of the methodology to real and simulated data are reported.

  12. Comparative pharmacokinetics of liquid and lyophilized formulations of IV RhIG immune globulin.

    PubMed

    Sinclair, Chris J; Brooks, William; Genereux, Maurice Gilles

    2008-07-01

    To compare the pharmacokinetics, safety, and tolerability of the liquid and lyophilized formulations of Rh(0)(D) immune globulin intravenous (human) (IV RhIG) administered intramuscularly (IM) and intravenously (IV). In 2 randomized, parallel arm, blinded, phase I studies, 142 healthy adult volunteers received a single dose of either the liquid or lyophilized formulation administered IM (300 microg in Study 1; 15 microg/kg in Study 2) or IV (50 microg/kg in Study 1). Pharmacokinetics (area under the curve [AUC}, C(max), t(1/2), T(max)) and safety data were assessed over 84 days. The 2 formulations had comparable pharmacokinetics following both IM and IV administration. The ratios (90% confidence intervals) for AUC and C(max) treatment means were, for most assessments, within the predefined FDA acceptance range of 80%-125%, demonstrating the bioequivalence of the liquid and lyophilized formulations. Both formulations were equally well tolerated. Study results demonstrate comparable safety and pharmacokinetic profiles of the liquid and lyophilized formulations of IV RhIG. These findings suggest that the liquid formulation will be therapeutically equivalent to the lyophilized formulation but in a more convenient ready-to-use dosage form that may also reduce preparation errors.

  13. Nanoparticle Drug Loading as a Design Parameter to Improve Docetaxel Pharmacokinetics and Efficacy

    PubMed Central

    Chu, Kevin S.; Schorzman, Allison N.; Finniss, Mathew C.; Bowerman, Charles J.; Peng, Lei; Luft, J. Christopher; Madden, Andrew; Wang, Andrew Z.; Zamboni, William C.; DeSimone, Joseph M.

    2013-01-01

    Nanoparticle (NP) drug loading is one of the key defining characteristics of a NP formulation. However, the effect of NP drug loading on therapeutic efficacy and pharmacokinetics has not been thoroughly evaluated. Herein, we characterized the efficacy, toxicity and pharmacokinetic properties of NP docetaxel formulations that have differential drug loading but are otherwise identical. Particle Replication in Non-wetting Templates (PRINT®), a soft-lithography fabrication technique, was used to formulate NPs with identical size, shape and surface chemistry, but with variable docetaxel loading. The lower weight loading (9%-NP) of docetaxel was found to have a superior pharmacokinetic profile and enhanced efficacy in a murine cancer model when compared to that of a higher docetaxel loading (20%-NP). The 9%-NP docetaxel increased plasma and tumor docetaxel exposure and reduced liver, spleen and lung exposure when compared to that of 20%-NP docetaxel. PMID:23899444

  14. In vitro and in vivo pharmacokinetic characterizations of AMG 900, an orally bioavailable small molecule inhibitor of aurora kinases.

    PubMed

    Huang, Liyue; Be, Xuhai; Berry, Loren; Moore, Earl; Janosky, Brett; Wells, Mary; Pan, Wei-Jian; Zhao, Zhiyang; Lin, Min-Hwa Jasmine

    2011-05-01

    AMG 900 is a small molecule being developed as an orally administered, highly potent, and selective pan-aurora kinase inhibitor. The aim of the investigations was to characterize in vitro and in vivo pharmacokinetic (PK) properties of AMG 900 in preclinical species. AMG 900 was rapidly metabolized in liver microsomes and highly bound to plasma proteins in the species tested. It was a weak Pgp substrate with good passive permeability. AMG 900 exhibited a low-to-moderate clearance and a small volume of distribution. Its terminal elimination half-life ranged from 0.6 to 2.4 h. AMG 900 was well-absorbed in fasted animals with an oral bioavailability of 31% to 107%. Food intake had an effect on rate (rats) or extent (dogs) of AMG 900 oral absorption. The clearance and volume of distribution at steady state in humans were predicted to be 27.3 mL/h/kg and 93.9 mL/kg, respectively. AMG 900 exhibited acceptable PK properties in preclinical species and was predicted to have low clearance in humans. AMG 900 is currently in Phase I clinical testing as a treatment for solid tumours. Preliminary human PK results appear to be consistent with the predictions.

  15. Smaller hospitals accept advertising.

    PubMed

    Mackesy, R

    1988-07-01

    Administrators at small- and medium-sized hospitals gradually have accepted the role of marketing in their organizations, albeit at a much slower rate than larger institutions. This update of a 1983 survey tracks the increasing competitiveness, complexity and specialization of providing health care and of advertising a small hospital's services. PMID:10288550

  16. Students Accepted on Probation.

    ERIC Educational Resources Information Center

    Lorberbaum, Caroline S.

    This report is a justification of the Dalton Junior College admissions policy designed to help students who had had academic and/or social difficulties at other schools. These students were accepted on probation, their problems carefully analyzed, and much effort devoted to those with low academic potential. They received extensive academic and…

  17. Approaches to acceptable risk

    SciTech Connect

    Whipple, C.

    1997-04-30

    Several alternative approaches to address the question {open_quotes}How safe is safe enough?{close_quotes} are reviewed and an attempt is made to apply the reasoning behind these approaches to the issue of acceptability of radiation exposures received in space. The approaches to the issue of the acceptability of technological risk described here are primarily analytical, and are drawn from examples in the management of environmental health risks. These include risk-based approaches, in which specific quantitative risk targets determine the acceptability of an activity, and cost-benefit and decision analysis, which generally focus on the estimation and evaluation of risks, benefits and costs, in a framework that balances these factors against each other. These analytical methods tend by their quantitative nature to emphasize the magnitude of risks, costs and alternatives, and to downplay other factors, especially those that are not easily expressed in quantitative terms, that affect acceptance or rejection of risk. Such other factors include the issues of risk perceptions and how and by whom risk decisions are made.

  18. Why was Relativity Accepted?

    NASA Astrophysics Data System (ADS)

    Brush, S. G.

    Historians of science have published many studies of the reception of Einstein's special and general theories of relativity. Based on a review of these studies, and my own research on the role of the light-bending prediction in the reception of general relativity, I discuss the role of three kinds of reasons for accepting relativity (1) empirical predictions and explanations; (2) social-psychological factors; and (3) aesthetic-mathematical factors. According to the historical studies, acceptance was a three-stage process. First, a few leading scientists adopted the special theory for aesthetic-mathematical reasons. In the second stage, their enthusiastic advocacy persuaded other scientists to work on the theory and apply it to problems currently of interest in atomic physics. The special theory was accepted by many German physicists by 1910 and had begun to attract some interest in other countries. In the third stage, the confirmation of Einstein's light-bending prediction attracted much public attention and forced all physicists to take the general theory of relativity seriously. In addition to light-bending, the explanation of the advance of Mercury's perihelion was considered strong evidence by theoretical physicists. The American astronomers who conducted successful tests of general relativity became defenders of the theory. There is little evidence that relativity was `socially constructed' but its initial acceptance was facilitated by the prestige and resources of its advocates.

  19. Pharmacokinetics of pantoprazole in man.

    PubMed

    Huber, R; Hartmann, M; Bliesath, H; Lühmann, R; Steinijans, V W; Zech, K

    1996-05-01

    The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis, duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(0,inf.) is approximately 5 mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral administration. Pantoprazole is extensively metabolized in the liver, has a total serum clearance of 0.1 l/h/kg, a serum elimination half-life of about 1.1 h, and an apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose. The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The pharmacokinetics of pantoprazole are unaltered in patients with renal failure. In patients with severe liver cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The clearance of pantoprazole is only slightly affected by age, its half-life being approximately 1.25 h in the elderly. Concomitant intake of food had no influence on the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450 interaction with concomitantly administered drugs in any of the studies conducted to date. Lack of interaction was also demonstrated with a coadministered antacid. The absence of inductive effects on metabolism after chronic administration was first shown by using antipyrine as a probe for mixed functional oxidative cytochrome P450 enzymes. Absence of CYP1A2

  20. Pharmacokinetics of pantoprazole in man.

    PubMed

    Huber, R; Hartmann, M; Bliesath, H; Lühmann, R; Steinijans, V W; Zech, K

    1996-05-01

    The proton pump inhibitor pantoprazole is a substituted benzimidazole sulphoxide for the treatment of acid-related gastrointestinal diseases such as reflux esophagitis, duodenal and gastric ulcers. Pantoprazole, administered as a 40 mg enteric coated tablet, is quantitatively absorbed. Its absolute bioavailability is 77% and does not change upon multiple dosing. Following a single oral dose of 40 mg, Cmax is approximately 2.5 mg/l, with a tmax of 2-3 h. The AUC(O,inf.) is approximately 5 mgxh/l. Pantoprazole shows linear pharmacokinetics after both i.v. and oral administration. Pantoprazole is extensively metabolized in the liver, has a total serum clearance of 0.1 l/h/kg, a serum elimination halflife of about 1.1 h, and an apparent volume of distribution of 0.15 l/kg. 98% of pantoprazole is bound to serum proteins. Elimination half-life, clearance and volume of distribution are independent of the dose. The main serum metabolite is formed by demethylation at the 4-position of the pyridine ring, followed by conjugation with sulphate. Almost 80% of an oral or intravenous dose is excreted as metabolites in urine; the remainder is found in feces and originates from biliary secretion. The pharmacokinetics of pantoprazole are unaltered in patients with renal failure. In patients with severe liver cirrhosis, the decreased rate of metabolism results in a half-life of 7-9 h. The clearance of pantoprazole is only slightly affected by age, its half-life being approximately 1.25 h in the elderly. Concomitant intake of food had no influence on the bioavailability of pantoprazole. Pantoprazole showed lack of cytochrome P450 interaction with concomitantly administered drugs in any of the studies conducted to date. Lack of interaction was also demonstrated with a coadministered antacid. The absence of inductive effects on metabolism after chronic administration was first shown by using antipyrine as a probe for mixed functional oxidative cytochrome P450 enzymes. Absence of CYP1A2

  1. Clinical pharmacokinetics of the salicylates.

    PubMed

    Needs, C J; Brooks, P M

    1985-01-01

    -order kinetics. The serum half-life of salicylic acid is dose-dependent; thus, the larger the dose employed, the longer it will take to reach steady-state. There is also evidence that enzyme induction of salicyluric acid formation occurs. No significant differences exist between the pharmacokinetics of the salicylates in the elderly or in children when compared with young adults. Apart from differences in free versus albumin-bound salicylate in various disease states and physiological conditions associated with low serum albumin, pharmacokinetic parameters in patients with rheumatoid arthritis, osteoarthritis, chronic renal failure or liver disease are essentially the same.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3888490

  2. Pregnancy influences the plasma pharmacokinetics but not the cerebrospinal fluid pharmacokinetics of raltegravir: a preclinical investigation.

    PubMed

    Mahat, Mahamad Yunnus A; Thippeswamy, B S; Khan, Farhin R; Edunuri, Ramya; Nidhyanandan, Saranya; Chaudhary, Shilpee

    2014-12-18

    Alterations in antiretroviral pharmacokinetics during pregnancy must be understood for the drugs to be used safely and effectively. Present study is an attempt to understand the potential changes in raltegravir plasma and cerebrospinal fluid pharmacokinetics during pregnancy in late pregnant and non-pregnant rats. In vitro plasma protein binding, metabolic stability, intravenous blood-brain barrier (BBB) permeability and oral pharmacokinetic studies were performed. Raltegravir concentrations in different matrices were measured using LC-MS/MS. Raltegravir plasma protein binding remained similar in both groups, whereas, metabolic stability was significantly lower in pregnant rats than the non-pregnant rats liver microsomes. In oral pharmacokinetic study, peak plasma concentrations and systemic exposures were significantly lower (∼37%) and clearance was significantly higher (∼61%) in late pregnant rats compared to non-pregnant rats. However, unlike plasma pharmacokinetics, CSF pharmacokinetic profile of raltegravir was similar in both pregnant and non-pregnant rats. Following intravenous administration, raltegravir showed higher BBB permeability in pregnant rats compared to non-pregnant rats. But the mean CSF-to-plasma ratio was significantly higher in pregnant rats compared to non-pregnant rats suggesting higher brain penetration in pregnant rats. In conclusion, pregnancy significantly affected the plasma pharmacokinetics, whereas cerebrospinal fluid pharmacokinetics remained fairly similar in pregnant and non-pregnant rats. Although current plasma pharmacokinetic data is in contradiction to the reported human data, pregnancy-specific pharmacokinetic changes observed in the current study emphasize the need for close therapeutic monitoring while treating the pregnant population and also warrants the need for additional clinical data with larger group of patients.

  3. Tools to evaluate pharmacokinetics data for establishing maximum residue limits for approved veterinary drugs: examples from JECFA's work.

    PubMed

    Sanders, P; Henri, J; Laurentie, M

    2016-05-01

    Maximum residue limits (MRLs) for residues of veterinary drugs are the maximum concentrations of residues permitted in or on a food by national or regional legislation. In the process of MRLs recommendations by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), analysis of pharmacokinetic data describing the ADME process (absorption, distribution, metabolism and excretion) is a crucial step and requires the use of different pharmacokinetic tools. The results of animal metabolism studies are the prime determinants of the residue definition in food commodities. Substances labelled with radioactive isotopes are used so that the disposition of the residue can be followed as total residue and main metabolites concentrations. Residue depletion studies with radiolabelled parent drug will lead to the estimate of the time course of the total residue and to determine a marker residue. Depletion studies with an unlabelled drug provide more information on the time course of the marker residue in raw commodities after administration under approved practical conditions of use. By use of this information and after conversion with the total/residue marker ratio, MRLs are derived by comparison of the acceptable daily intake with the daily intakes calculated with different scenarios of dietary exposure. Progress in pharmacokinetic model such as physiologically based pharmacokinetics and population pharmacokinetics will drive the future research in this field to improved veterinary drug development. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27443212

  4. Acceptability of human risk.

    PubMed Central

    Kasperson, R E

    1983-01-01

    This paper has three objectives: to explore the nature of the problem implicit in the term "risk acceptability," to examine the possible contributions of scientific information to risk standard-setting, and to argue that societal response is best guided by considerations of process rather than formal methods of analysis. Most technological risks are not accepted but are imposed. There is also little reason to expect consensus among individuals on their tolerance of risk. Moreover, debates about risk levels are often at base debates over the adequacy of the institutions which manage the risks. Scientific information can contribute three broad types of analyses to risk-setting deliberations: contextual analysis, equity assessment, and public preference analysis. More effective risk-setting decisions will involve attention to the process used, particularly in regard to the requirements of procedural justice and democratic responsibility. PMID:6418541

  5. The influence of weightlessness on pharmacokinetics.

    PubMed

    Gandia, Peggy; Saivin, Sylvie; Houin, Georges

    2005-12-01

    The primary hostile factor during a spaceflight is the lack of gravity, which can induce space motion sickness and act on bones, muscles and the cardiovascular system. These physiological effects may modify the pharmacokinetics of the drugs administered during the flight producing reduced pharmacological activity or appearance of adverse effects. Given the small number of spaceflights and the difficulties of conducting experiments during missions, pharmacokinetic data obtained in flight are insufficient to determine if drug monitoring is necessary for the drugs present in the onboard medical kit. Therefore, validated earthbound models like tail-suspension performed with animals and long-term bedrest performed with human volunteers are used to simulate weightlessness and to study the pharmacokinetic variations of either absorption, distribution, or elimination of drugs. As a result of these studies, it is possible to make some dosing recommendations but more information is necessary to predict with precision all of the pharmacokinetic variations occurring in spaceflight. To collect more pharmacokinetic information, head-down bedrest studies are still the best solution and as saliva is an appropriate substitution for plasma for some drugs, salivary sampling can be planned during flights.

  6. Pharmacokinetic modeling in aquatic animals. 1. Models and concepts

    USGS Publications Warehouse

    Barron, M.G.; Stehly, Guy R.; Hayton, W.L.

    1990-01-01

    While clinical and toxicological applications of pharmacokinetics have continued to evolve both conceptually and experimentally, pharmacokinetics modeling in aquatic animals has not progressed accordingly. In this paper we present methods and concepts of pharmacokinetic modeling in aquatic animals using multicompartmental, clearance-based, non-compartmental and physiologically-based pharmacokinetic models. These models should be considered as alternatives to traditional approaches, which assume that the animal acts as a single homogeneous compartment based on apparent monoexponential elimination.

  7. Age and Acceptance of Euthanasia.

    ERIC Educational Resources Information Center

    Ward, Russell A.

    1980-01-01

    Study explores relationship between age (and sex and race) and acceptance of euthanasia. Women and non-Whites were less accepting because of religiosity. Among older people less acceptance was attributable to their lesser education and greater religiosity. Results suggest that quality of life in old age affects acceptability of euthanasia. (Author)

  8. Pharmacokinetics of intravenous and subcutaneous cefovecin in alpacas.

    PubMed

    Cox, S; Sommardahl, C; Seddighi, R; Videla, R; Hayes, J; Pistole, N; Hamill, M; Doherty, T

    2015-08-01

    The purpose of this study was to determine the pharmacokinetics of cefovecin after intravenous and subcutaneous dose of 8 mg/kg to alpacas. Bacterial infections requiring long-term antibiotic therapy such as neonatal bacteremia, pneumonia, peritonitis, dental, and uterine infections are a significant cause of morbidity and mortality in this species. However, few antimicrobials have been evaluated and proven to have favorable pharmacokinetics for therapeutic use. Most antimicrobials that are currently used require daily injections for many days. Cefovecin is a long-acting cephalosporin that is formulated for subcutaneous administration, and its long-elimination half-life allows for 14-day dosing intervals in dogs and cats. The properties of cefovecin may be advantageous for medical treatment of camelids due to its broad spectrum, route of administration, and long duration of activity. Pharmacokinetic evaluation of antimicrobial drugs in camelids is essential for the proper treatment and prevention of bacterial disease, and to minimize development of antibiotic resistant bacterial strains due to inadequate antibiotic concentrations. Cefovecin mean half-life, volume of distribution at steady-state, and clearance after intravenous administration were 10.3 h, 86 mL/kg, and 7.07 mL·h/kg. The bioavailability was 143%, while half-life, C(max), and T(max) were 16.9 h, 108 μg/mL, and 2.8 h following subcutaneous administration. In the absence of additional microbial susceptibility data for alpaca pathogens, the current cefovecin dosage regimen prescribed for dogs (8 mg/kg SC every 14 days) may need to be optimized for the treatment of infections in this species.

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

    SciTech Connect

    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.

  10. Nanoparticles for tumor targeted therapies and their pharmacokinetics.

    PubMed

    Wang, Jianqiu; Sui, Meihua; Fan, Weimin

    2010-02-01

    Various types of nanoparticles, such as liposomes, polymeric micelles, dendrimers, superparamagnetic iron oxide crystals, and colloidal gold, have been employed in targeted therapies for cancer. Both passive and active targeting strategies can be utilized for nano-drug delivery. Passive targeting is based on the enhanced permeability and retention (EPR) effect of the vasculature surrounding tumors. Active targeting relies on ligand-directed binding of nanoparticles to receptors expressed by tumor cells. Release of loaded drugs from nanoparticles may be controlled in response to changes in environmental condition such as temperature and pH. Biodistribution profiles and anticancer efficacy of nano-drugs in vivo would be different depending upon their size, surface charge, PEGylation and other biophysical properties. This review focuses on the recent development of nanoparticles for tumor targeted therapies, including physicochemical properties, tumor targeting, control of drug release, pharmacokinetics, anticancer efficacy and safety. Future perspectives are discussed as well.

  11. Pharmacokinetic and pharmacodynamic considerations for the next generation protein therapeutics

    PubMed Central

    Shah, Dhaval K.

    2015-01-01

    Increasingly sophisticated protein engineering efforts have been undertaken lately to generate protein therapeutics with desired properties. This has resulted in the discovery of the next generation of protein therapeutics, which include: engineered antibodies, immunoconjugates, bi/multi-specific proteins, antibody mimetic novel scaffolds, and engineered ligands/receptors. These novel protein therapeutics possess unique physicochemical properties and act via a unique mechanism-of-action, which collectively makes their pharmacokinetics (PK) and pharmacodynamics (PD) different than other established biological molecules. Consequently, in order to support the discovery and development of these next generation molecules, it becomes important to understand the determinants controlling their PK/PD. This review discusses the determinants that a PK/PD scientist should consider during the design and development of next generation protein therapeutics. In addition, the role of systems PK/PD models in enabling rational development of the next generation protein therapeutics is emphasized. PMID:26373957

  12. Elucidation of arctigenin pharmacokinetics after intravenous and oral administrations in rats: integration of in vitro and in vivo findings via semi-mechanistic pharmacokinetic modeling.

    PubMed

    Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong

    2014-11-01

    Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway of AR, which occurred with V max, K m, and Clint of 47.5 ± 3.4 nmol/min/mg, 204 ± 22 μM, and 233 ± 9 μl/min/mg with intestinal microsomes and 2.92 ± 0.07 nmol/min/mg, 22.7 ± 1.2 μM, and 129 ± 4 μl/min/mg with liver microsomes, respectively. In addition, demethylation and hydrolysis of AR occurred with liver microsomes but not with intestinal microsomes. In vitro incubation of AR and its metabolites in intestinal content demonstrated that glucuronides of AR excreted in bile could be further hydrolyzed back to the parent compound, suggesting its potential enterohepatic circulation. Furthermore, rapid formation followed by fast elimination of arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was observed after both intravenous (IV) and oral administrations of AR in rats. Linear pharmacokinetics was observed at three different doses for AR, AA, and AG after IV administration of AR (0.48-2.4 mg/kg, r (2) > 0.99). Finally, an integrated semi-mechanistic pharmacokinetic model using in vitro enzyme kinetic and in vivo pharmacokinetic parameters was successfully developed to describe plasma concentrations of AR, AA, and AG after both IV and oral administration of AR at all tested doses.

  13. Elucidation of arctigenin pharmacokinetics after intravenous and oral administrations in rats: integration of in vitro and in vivo findings via semi-mechanistic pharmacokinetic modeling.

    PubMed

    Gao, Qiong; Zhang, Yufeng; Wo, Siukwan; Zuo, Zhong

    2014-11-01

    Although arctigenin (AR) has attracted substantial research interests due to its promising and diverse therapeutic effects, studies regarding its biotransformation were limited. The current study aims to provide information regarding the pharmacokinetic properties of AR via various in vitro and in vivo experiments as well as semi-mechanistic pharmacokinetic modeling. Our in vitro rat microsome incubation studies revealed that glucuronidation was the main intestinal and liver metabolic pathway of AR, which occurred with V max, K m, and Clint of 47.5 ± 3.4 nmol/min/mg, 204 ± 22 μM, and 233 ± 9 μl/min/mg with intestinal microsomes and 2.92 ± 0.07 nmol/min/mg, 22.7 ± 1.2 μM, and 129 ± 4 μl/min/mg with liver microsomes, respectively. In addition, demethylation and hydrolysis of AR occurred with liver microsomes but not with intestinal microsomes. In vitro incubation of AR and its metabolites in intestinal content demonstrated that glucuronides of AR excreted in bile could be further hydrolyzed back to the parent compound, suggesting its potential enterohepatic circulation. Furthermore, rapid formation followed by fast elimination of arctigenic acid (AA) and arctigenin-4'-O-glucuronide (AG) was observed after both intravenous (IV) and oral administrations of AR in rats. Linear pharmacokinetics was observed at three different doses for AR, AA, and AG after IV administration of AR (0.48-2.4 mg/kg, r (2) > 0.99). Finally, an integrated semi-mechanistic pharmacokinetic model using in vitro enzyme kinetic and in vivo pharmacokinetic parameters was successfully developed to describe plasma concentrations of AR, AA, and AG after both IV and oral administration of AR at all tested doses. PMID:25274606

  14. Bioelectrical impedance modelling of gentamicin pharmacokinetic parameters.

    PubMed

    Zarowitz, B J; Pilla, A M; Peterson, E L

    1989-10-01

    1. Bioelectrical impedance analysis was used to develop descriptive models of gentamicin pharmacokinetic parameters in 30 adult in-patients receiving therapy with gentamicin. 2. Serial blood samples obtained from each subject at steady state were analyzed and used to derive gentamicin pharmacokinetic parameters. 3. Multiple regression equations were developed for clearance, elimination rate constant and volume of distribution at steady state and were all statistically significant at P less than 0.05. 4. Clinical validation of this innovative technique is warranted before clinical use is recommended.

  15. Baby-Crying Acceptance

    NASA Astrophysics Data System (ADS)

    Martins, Tiago; de Magalhães, Sérgio Tenreiro

    The baby's crying is his most important mean of communication. The crying monitoring performed by devices that have been developed doesn't ensure the complete safety of the child. It is necessary to join, to these technological resources, means of communicating the results to the responsible, which would involve the digital processing of information available from crying. The survey carried out, enabled to understand the level of adoption, in the continental territory of Portugal, of a technology that will be able to do such a digital processing. It was used the TAM as the theoretical referential. The statistical analysis showed that there is a good probability of acceptance of such a system.

  16. High acceptance recoil polarimeter

    SciTech Connect

    The HARP Collaboration

    1992-12-05

    In order to detect neutrons and protons in the 50 to 600 MeV energy range and measure their polarization, an efficient, low-noise, self-calibrating device is being designed. This detector, known as the High Acceptance Recoil Polarimeter (HARP), is based on the recoil principle of proton detection from np[r arrow]n[prime]p[prime] or pp[r arrow]p[prime]p[prime] scattering (detected particles are underlined) which intrinsically yields polarization information on the incoming particle. HARP will be commissioned to carry out experiments in 1994.

  17. A Physiologically Based Pharmacokinetic Model to Describe Artemether Pharmacokinetics in Adult and Pediatric Patients.

    PubMed

    Lin, Wen; Heimbach, Tycho; Jain, Jay Prakash; Awasthi, Rakesh; Hamed, Kamal; Sunkara, Gangadhar; He, Handan

    2016-10-01

    Artemether is co-administered with lumefantrine as part of a fixed-dose combination therapy for malaria in both adult and pediatric patients. However, artemether exposure is higher in younger infants (1-3 months) with a lower body weight (<5 kg) as compared to older infants (3-6 months) with a higher body weight (≥5 to <10 kg), children, and adults. In contrast, lumefantrine exposure is similar in all age groups. This article describes the clinically observed artemether exposure data in pediatric populations across various age groups (1 month to 12 years) and body weights (<5 or ≥5 kg) using physiologically based pharmacokinetic (PBPK) mechanistic models. A PBPK model was developed using artemether physicochemical, biopharmaceutic, and metabolic properties together with known enzyme ontogeny and pediatric physiology. The model was verified using clinical data from adult patients after multiple doses of oral artemether, and was then applied to simulate the exposure in children and infants. The simulated PBPK concentration-time profiles captured observed clinical data. Consistent with the clinical data, the PBPK model simulations indicated a higher artemether exposure for younger infants with lower body weight. A PBPK model developed for artemether reliably described the clinical data from adult and pediatric patients. PMID:27506269

  18. Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039).

    PubMed

    Rorick-Kehn, Linda M; Johnson, Bryan G; Burkey, Jennifer L; Wright, Rebecca A; Calligaro, David O; Marek, Gerard J; Nisenbaum, Eric S; Catlow, John T; Kingston, Ann E; Giera, Deborah D; Herin, Marc F; Monn, James A; McKinzie, David L; Schoepp, Darryle D

    2007-04-01

    Group II metabotropic glutamate (mGlu) receptor agonists, including (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), have demonstrated efficacy in animal models of anxiety and schizophrenia, and LY354740 decreased anxiety in human subjects. Herein, we report the in vitro pharmacological profile and pharmacokinetic properties of another potent, selective, and structurally novel mGlu2/3 receptor agonist, (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) and provide comparisons with LY354740. Similar to LY354740, LY404039 is a nanomolar potent agonist at recombinant human mGlu2 and mGlu3 receptors (K(i) = 149 and 92, respectively) and in rat neurons expressing native mGlu2/3 receptors (Ki = 88). LY404039 is highly selective for mGlu2/3 receptors, showing more than 100-fold selectivity for these receptors, versus ionotropic glutamate receptors, glutamate transporters, and other receptors targeted by known anxiolytic and antipsychotic medications. Functionally, LY404039 potently inhibited forskolin-stimulated cAMP formation in cells expressing human mGlu2 and mGlu3 receptors. Electrophysiological studies indicated that LY404039 suppressed electrically evoked excitatory activity in the striatum, and serotonin-induced l-glutamate release in the prefrontal cortex; effects reversed by LY341495. These characteristics suggest LY404039 modulates glutamatergic activity in limbic and forebrain areas relevant to psychiatric disorders; and that, similar to LY354740, it works through a mechanism that may be devoid of negative side effects associated with current antipsychotics and anxiolytics. Interestingly, despite the slightly lower potency (approximately 2-5-fold) of LY404039 versus LY354740 in binding, functional, and electrophysiological assays, LY404039 demonstrated higher plasma exposure and better oral bioavailability in

  19. Ethnic and genetic factors in methadone pharmacokinetics: A population pharmacokinetic study☆

    PubMed Central

    Bart, Gavin; Lenz, Scott; Straka, Robert J.; Brundage, Richard C.

    2014-01-01

    Background Treatment of opiate use disorders with methadone is complicated by wide interindividual variability in pharmacokinetics. To identify potentially contributing covariates in methadone pharmacokinetics, we used population pharmacokinetic modeling to estimate clearance (CL/F) and volume of distribution (V/F) for each methadone enantiomer in an ethnically diverse methadone maintained population. Methods Plasma levels of the opiate-active R-methadone and opiate-inactive S-methadone were measured in 206 methadone maintained subjects approximately two and twenty-three hours after a daily oral dose of racmethadone. A linear one-compartment population pharmacokinetic model with first-order conditional estimation with interaction (FOCE-I) was used to evaluate methadone CL/F and V/F. The influence of covariates on parameter estimates was evaluated using stepwise covariate modeling. Covariates included ethnicity, gender, weight, BMI, age, methadone dose, and 21 single nucleotide polymorphisms in genes implicated in methadone pharmacokinetics. Results In the final model, for each enantiomer, Hmong ethnicity reduced CL/F by approximately 30% and the rs2032582 (ABCB1 2677G > T/A) GG genotype was associated with a 20% reduction in CL/F. The presence of the rs3745274 minor allele (CYP2B6 515G > T) reduced CL/F by up to 20% for S-methadone only. A smaller effect of age was noted on CL/F for R-methadone. Conclusion This is the first report showing the influence of the rs2032582 and rs3745274 variants on methadone pharmacokinetics rather than simply dose requirements or plasma levels. Population pharmacokinetics is a valuable method for identifying the influences on methadone pharmacokinetic variability. PMID:25456329

  20. 4,5-dihydroxypyrimidine carboxamides and N-alkyl-5-hydroxypyrimidinone carboxamides are potent, selective HIV integrase inhibitors with good pharmacokinetic profiles in preclinical species.

    PubMed

    Summa, Vincenzo; Petrocchi, Alessia; Matassa, Victor G; Gardelli, Cristina; Muraglia, Ester; Rowley, Michael; Paz, Odalys Gonzalez; Laufer, Ralph; Monteagudo, Edith; Pace, Paola

    2006-11-16

    The dihydroxypyrimidine carboxamide 4a was discovered as a potent and selective HIV integrase strand transfer inhibitor. The optimization of physicochemical properties, pharmacokinetic profiles, and potency led to the identification of 13 in the dihydroxypyrimidine series and 18 in the N-methylpyrimidinone series having low nanomolar activity in the cellular HIV spread assay in the presence of 50% normal human serum and very good pharmacokinetics in preclinical species.

  1. Obstetric Pharmacokinetic Dosing Studies are Urgently Needed

    PubMed Central

    McCormack, Shelley A.; Best, Brookie M.

    2014-01-01

    Use of pharmacotherapy during pregnancy is common and increasing. Physiologic changes during pregnancy may significantly alter the overall systemic drug exposure, necessitating dose changes. A search of PubMed for pharmacokinetic clinical trials showed 494 publications during pregnancy out of 35,921 total pharmacokinetic published studies (1.29%), from the late 1960s through August 31, 2013. Closer examination of pharmacokinetic studies in pregnant women published since 2008 (81 studies) revealed that about a third of the trials were for treatment of acute labor and delivery issues, a third included studies of infectious disease treatment during pregnancy, and the remaining third were for varied ante-partum indications. Approximately, two-thirds of these recent studies were primarily funded by government agencies worldwide, one-quarter were supported by private non-profit foundations or combinations of government and private funding, and slightly <10% were supported by pharmaceutical industry. As highlighted in this review, vast gaps exist in pharmacology information and evidence for appropriate dosing of medications in pregnant women. This lack of knowledge and understanding of drug disposition throughout pregnancy place both the mother and the fetus at risk for avoidable therapeutic misadventures – suboptimal efficacy or excess toxicity – with medication use in pregnancy. Increased efforts to perform and support obstetric dosing and pharmacokinetic studies are greatly needed. PMID:24575394

  2. Pharmacokinetics of Drug Entry into Cochlear Fluids

    ERIC Educational Resources Information Center

    Salt, Alec N.

    2005-01-01

    The inner ear is exposed to aminoglycosides or other drugs either intentionally or as a side effect of clinical treatments directed at other regions of the body. An understanding of the effects of drugs on the inner ear requires knowledge of the pharmacokinetics of the drug once it reaches the cochlear fluids, specifically how much of it reaches…

  3. Population pharmacokinetics of imipenem in burn patients.

    PubMed

    Dailly, Eric; Kergueris, Marie France; Pannier, Michel; Jolliet, Pascale; Bourin, Michel

    2003-12-01

    The interindividual variability of imipenem pharmacokinetic parameters in burn patients suggest that these parameters have to be estimated with a large number of patients. The aim of this study is (i) to estimate these parameters with a population pharmacokinetic approach, and (ii) to test the influence of factors on pharmacokinetics parameters. Data are provided by therapeutic drug monitoring (n = 47,118 samples) and analysed by a nonlinear mixed effect modelling method. Among the tested covariates (age, gender, body weight, height, size of burn and creatinine plasma level) creatinine plasma level affects imipenem pharmacokinetic parameters substantially. The best fit is obtained with a two-compartment model integrating a linear-inverse relationship between imipenem clearance and creatinine plasma level. The estimates of imipenem clearance (16.37 +/- 0.204 L/h) and of the distribution volume of the central compartment (0.376 +/- 0.039 L/kg) are higher in the population of burn patients than the estimates in healthy subjects. This result is connected with high values of glomerule filtration rate and confirms the interest of therapeutic drug monitoring of imipenem in burn patients and particularly for patients with extreme values of creatinine clearance.

  4. FIRST REPORTS OF CLINICAL PHARMACOKINETICS IN NIGERIA

    PubMed Central

    Michael, O.S.

    2015-01-01

    The German Friedrich Hartmut Dost (1910-1985) introduced the word Pharmacokinetics. Clinical pharmacokinetics is the direct application of knowledge regarding a drug's pharmacokinetics to a therapeutic situation in an individual or a population. 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 A. Salako, both of whom were affiliated to the great institutions- University of Ibadan (UI) and the Teaching Hospital, University College Hospital (UCH). Prof A.O Iyun was Nigeria's first home-trained Clinical Pharmacologist, while Prof L.A. Salako played a most significant role in the creation of the Department of Clinical Pharmacology, UCH. This edition of the Chronicles highlights a few of the first reports of this exciting branch of pharmacology in Nigeria. This historical review is based on publications listed on the United States National Library of Medicine database (PUBMED). PMID:26807087

  5. Microcomputer-Based Programs for Pharmacokinetic Simulations.

    ERIC Educational Resources Information Center

    Li, Ronald C.; And Others

    1995-01-01

    Microcomputer software that simulates drug-concentration time profiles based on user-assigned pharmacokinetic parameters such as central volume of distribution, elimination rate constant, absorption rate constant, dosing regimens, and compartmental transfer rate constants is described. The software is recommended for use in undergraduate…

  6. A Terminal Pharmaceutics Course in Clinical Pharmacokinetics.

    ERIC Educational Resources Information Center

    Reuning, Richard H.; Krautheim, Daniel

    1978-01-01

    At Ohio State University, an undergraduate course extends the course sequence in biopharmaceutics and pharmacokinetics to application to problems in optimizing drug therapy. Course content, structure, instructional methods, and student term projects are described, and a course outline, typical projects, and some behavioral objectives are appended.…

  7. Pharmacokinetics and Bioequivalence Evaluation of Cyclobenzaprine Tablets

    PubMed Central

    Brioschi, Tatiane Maria de Lima Souza; Schramm, Simone Grigoleto; Kano, Eunice Kazue; Koono, Eunice Emiko Mori; Ching, Ting Hui; Serra, Cristina Helena dos Reis

    2013-01-01

    The purpose of this study was to investigate cyclobenzaprine pharmacokinetics and to evaluate bioequivalence between two different tablet formulations containing the drug. An open, randomized, crossover, single-dose, two-period, and two-sequence design was employed. Tablets were administered to 23 healthy subjects after an overnight fasting and blood samples were collected up to 240 hours after drug administration. Plasma cyclobenzaprine was quantified by means of an LC-MS/MS method. Pharmacokinetic parameters related to absorption, distribution, and elimination were calculated. Cyclobenzaprine plasma profiles for the reference and test products were similar, as well as absorption pharmacokinetic parameters AUC (reference: 199.4 ng∗h/mL; test: 201.6 ng∗h/mL), Cmax (reference: 7.0 ng/mL; test: 7.2 ng/mL), and Tmax (reference: 4.5 h; test: 4.6 h). Bioequivalence was evaluated by means of 90% confidence intervals for the ratio of AUC (93%–111%) and Cmax (93%–112%) values for test and reference products, which were within the 80%–125% interval proposed by FDA. Cyclobenzaprine pharmacokinetics can be described by a multicompartment open model with an average rapid elimination half-life (t(1/2)β) of 3.1 hours and an average terminal elimination half-life (t(1/2)γ) of 31.9 hours. PMID:24151591

  8. Pharmacokinetics and pharmacodynamics of the triptan antimigraine agents: a comparative review.

    PubMed

    Jhee, S S; Shiovitz, T; Crawford, A W; Cutler, N R

    2001-01-01

    The current approach to antimigraine therapy comprises potent serotonin 5-HT1B/1D receptor agonists collectively termed triptans. Sumatriptan was the first of these compounds to be developed, and offered improved efficacy and tolerability over ergot-derived compounds. The development of sumatriptan was quickly followed by a number of 'second generation' triptan compounds, characterised by improved pharmacokinetic properties and/or tolerability profiles. Triptans are believed to effect migraine relief by binding to serotonin (5-hydroxy-tryptamine) receptors in the brain, where they act to induce vasoconstriction of extracerebral blood vessels and also reduce neurogenic inflammation. Although the pharmacological mechanism of the triptans is similar, their pharmacokinetic properties are distinct. For example, bioavailability of oral formulations ranges between 14% (sumatriptan) and 74% (naratriptan), and their elimination half-life ranges from 2 hours (sumatriptan and rizatriptan) to 25 hours (frovatriptan). Clearly, such diverse pharmacokinetic properties will influence the effectiveness of the compounds and favour the prescription of one over another in different patient populations. This article reviews the pharmacological properties of the triptans (time to peak plasma concentration, half-life, bioavailability and receptor binding) and relates these properties to efficacy and time of onset. It also considers the effects of concomitant medication, food, age and disease on the pharmacokinetics of the compounds. In addition, the relative merits, such as headache recurrence, tolerability and route of administration, are discussed. Finally, the performance of the triptans is considered in the context of direct head-to-head comparative trials that have assessed the efficacy profile of the compounds. PMID:11327198

  9. Influence of two commercial fibers in the pharmacokinetics of ethinylestradiol in rabbits.

    PubMed

    Fernández, N; Diez, M J; Terán, M T; García, J J; Calle, A P; Sierra, M

    1998-08-01

    Fiber formulations are used in human nutrition owing to their beneficial properties for health. It is probable that ingestion of fiber coincides with the oral administration of drugs, and a modification of its oral absorption, and therefore of its pharmacokinetics, can appear. In the present study, the compartmental and noncompartmental pharmacokinetic parameters of ethinylestradiol (EE) in rabbits after oral administration were determined. It was also studied whether the presence of two different fiber formulations [A, wheat bran (76.5%), fruit fiber (12%) and guar gum (2%) and B, Plantago ovata seeds (65%) and P. ovata seed cuticles (2.2%)] in the gastrointestinal tract modified the pharmacokinetics of EE when administered at the same time. Three groups of rabbits were used: control, fiber A and fiber B. The animals in all three groups received 1 mg/kg b. wt. EE. The estrogen was administered alone in the control group and in the presence of 4 g of fiber A and fiber B, respectively, in the other two groups. After compartmental (two-compartment open model) and noncompartmental analyses of plasma concentrations, statistical analysis revealed that the presence of fiber (both A and B) decreased between 29% and 35% the extent of EE absorbed (represented by the pharmacokinetic parameters area under the curve and the maximum plasma concentration) without affecting the rate of the absorption process (represented by the time to reach maximum concentration and the absorption rate constant). PMID:9694944

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

    PubMed

    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. PMID:23607546

  11. Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy Greyhound dogs

    PubMed Central

    KuKanich, Butch; Allen, Philip

    2014-01-01

    The purpose of this study was to compare the pharmacokinetics of two highly protein bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy Greyhound dogs (3 males and 3 females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL/min/kg) was faster than buprenorphine (10.3 mL/min/kg). The terminal half-life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including: octanol:water partition coefficient and pKa the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs. PMID:24684621

  12. Pharmacokinetic-pharmacodynamic crisis in the elderly.

    PubMed

    ElDesoky, Ehab S

    2007-01-01

    Aging is characterized by a progressive loss of functional capacities of most if not all organs, a reduction in homeostatic mechanisms, and a response to receptor stimulation. Also, loss of water content and an increase of fat content in the body are reported. Therefore, understanding the influence of age-dependent changes in composition and function of the body on the pharmacokinetics and pharmacodynamics of drugs is important before prescribing drugs to elderly patients. In this study, a Medline search for articles published in the period between 1975 and June 2006 was conducted with use of the key words aging, pharmacokinetics, and pharmacodynamics to review data related to alteration in pharmacokinetics and pharmacodynamics in elderly patients. Analysis of data revealed that the most important pharmacokinetic changes in old age include a decrease in the excretory capacity of the kidney more than the decline in the rate of hepatic drug metabolism. On the other hand, pharmacodynamic changes in the elderly are frequent and commonly ascribed to alteration in the sensitivity to drugs, irrespective of changes in drug disposition. For instance, the sensitivity of the cardiovascular system to beta-adrenergic agonists and antagonists decreases in old age, and the incidence of orthostatic episodes in response to drugs that lower blood pressure increases. However, the central nervous system becomes vulnerable in the elderly to agents that affect brain function (eg, opioids, benzodiazepines, and psychotropic drugs). Therefore, these drugs must be used very cautiously in this age group. In conclusion, the complexity of the interactions between polypharmacy, comorbidity, altered pharmacodynamic sensitivity, and even modest changes in pharmacokinetics in elderly necessitate the medical approach "start low and go slow" for aged subjects, especially if drug therapy is considered beneficial or absolutely necessary for them.

  13. Specific pharmacokinetic aspects of the urinary tract.

    PubMed

    Korstanje, Cees; Krauwinkel, Walter

    2011-01-01

    This chapter reviews the evidence for "specific" pharmacokinetics playing a role in currently marketed drugs intended to treat lower urinary tract (LUT) symptoms. Principles of drug targeting include intrinsic properties of drugs or organs as well as drug formulations to modify drug release or to create confinement of drug presence. Prodrugs and specific formulations to deliver high drug concentrations at the site(s) of action as well as other ways to manipulate drug distribution to achieve enrichment in target tissues are considered. In overactive bladder (OAB), specific formulations for oxybutynin have been introduced to reduce the level of side effects of the active drug. Extended release tablet formulations and a topical gel formulation have been introduced, with efficacy similar to immediate release (IR) tablets, but with a reduction in anticholinergic adverse effects. However, these modifications have not led to outstanding performance parameters compared to other anticholinergic drugs marketed as IR formulations. Urinary excretion is discussed as potential mechanism for targeting LUT symptoms, but no strong indications appear to exist that this mechanism would contribute for currently available drugs. Intravesical administration of drugs is not a preferred option and only considered for drugs like botulinum toxin, where the inconvenient application compensates for a reasonable degree of long-term efficacy in severe refractory OAB. Alpha acid glycoprotein binding is discussed as a potential factor to influence drug tissue distribution, and it is concluded that there is reasonable evidence that for tamsulosin this mechanism is responsible for the difference in free fraction of the drug observed in plasma and prostate, which could contribute to its relative absence of blood pressure effects in patients with LUT symptoms related to benign prostate hyperplasia (LUTS-BPH). The principle of irreversible inhibition of type II 5α-reductase as a tool to develop drugs

  14. Comparative pharmacokinetic and pharmacodynamic evaluation of branded and generic formulations of meloxicam in healthy male volunteers

    PubMed Central

    Tacca, Mario Del; Pasqualetti, Giuseppe; Gori, Giovanni; Pepe, Pasquale; Di Paolo, Antonello; Lastella, Marianna; De Negri, Ferdinando; Blandizzi, Corrado

    2013-01-01

    Purpose The primary aim of the present study was to assess the pharmacokinetic bioequivalence between a generic formulation of meloxicam 15 mg tablets (Meloxicam Hexal) and its respective brand product (Mobic), in order to verify whether the generic product conforms to the regulatory standards of bioequivalence in the postmarketing setting. As a secondary exploratory aim, the pharmacodynamic effects of the two formulations were also evaluated by means of rating scales following hyperalgesia induced by cutaneous freeze injury. Subjects and methods A single 15 mg dose of generic or branded meloxicam tablets was administered to 24 healthy male volunteers in a crossover fashion. Plasma samples, collected for 24 hours after dosing, were assayed for meloxicam concentration by a validated highperformance liquid chromatography method. Results The analysis of pharmacokinetic parameters did not show any significant difference between the two meloxicam formulations: the 90% confidence intervals fell within the acceptance range of 80%–125% (0.84–1.16 for area under the curve [0–24], and 0.89–1.23 for peak concentration). No difference in the pharmacodynamic end point was observed between the two groups. Conclusion The pharmacokinetic profiles of the two meloxicam formulations confirm the regulatory criteria for bioequivalence; pharmacodynamic data indicate a similar antihyperalgesic effect. The two formulations can be used interchangeably in the clinical setting. PMID:23901278

  15. [Interindividual variation of pharmacokinetic disposition of and clinical responses to opioid analgesics in cancer pain patients].

    PubMed

    Naito, Takafumi; Kawakami, Junichi

    2015-01-01

    Use of prescription opioids for cancer pain according to the World Health Organization analgesic ladder has been accepted in Japan. Although oxycodone and fentanyl are commonly used as first-line analgesics, a few clinical reports have been published on interindividual variations in their pharmacokinetics and clinical responses in cancer patients. (1) Some factors relating to CYP2D6, CYP3A, ATP-binding cassette sub-family B member 1 (ABCB1), and opioid receptor mu 1 (OPRM1) involve oxycodone pharmacokinetics and sensitivity in humans. The relations between their genetic variations and clinical responses to oxycodone are being revealed in limited groups. In our study, the impact of genetic variants and pharmacokinetics on clinical responses to oxycodone were evaluated in Japanese populations. (2) Opioid switching improves the opioid tolerance related to the balance between analgesia and adverse effects. Some patients have difficulty in obtaining better opioid tolerance in recommended conversion ratios. The activities of CYP3A, ABCB1, and OPRM1 contribute to the interindividual variations in clinical responses to fentanyl in cancer patients. However, the variations in opioid switching remain to be clarified in clinical settings. In our study, genetic factors related to interindividual variations in clinical responses in opioid switching to fentanyl were revealed in Japanese populations. In this symposium review, the possibility of approaches to personalized palliative care using opioids based on genetic variants of CYP2D6, CYP3A5, ABCB1, and OPRM1 is discussed.

  16. Pharmacokinetic and clinical pharmacological studies with mepivacaine and prilocaine.

    PubMed

    Arthur, G R; Scott, D H; Boyes, R N; Scott, D B

    1979-06-01

    The tolerance and pharmacokinetic properties of mepivacaine and prilocaine were compared following i.v. infusion of 250 mg (0.88 and 0.97 mmol respectively) of each drug in five healthy volunteers. Side-effects were minor and occurred in only two subjects during the infusion of mepivacaine. Plasma concentrations of mepivacaine were greater in each subject than the corresponding values for prilocaine. The elimination half-life of mepivacaine was generally longer than that for prilocaine, whereas the total body clearance of prilocaine was consistently greater than the corresponding value for mepivacaine. For each subject the clearance of prilocaine substantially exceeded normal heptic blood flow and therefore an extra-hepatic site of metabolism of prilocaine has been postulated.

  17. Asparaginase pharmacokinetics and implications of therapeutic drug monitoring

    PubMed Central

    Asselin, Barbara; Rizzari, Carmelo

    2015-01-01

    Asparaginase is widely used in chemotherapeutic regimens for the treatment of acute lymphoblastic leukemia (ALL) and has led to a substantial improvement in cure rates, especially in children. Optimal therapeutic effects depend on a complete and sustained depletion of serum asparagine. However, pronounced interpatient variability, differences in pharmacokinetic properties between asparaginases and the formation of asparaginase antibodies make it difficult to predict the degree of asparagine depletion that will result from a given dose of asparaginase. The pharmacological principles underlying asparaginase therapy in the treatment of ALL are summarized in this article. A better understanding of the many factors that influence asparaginase activity and subsequent asparagine depletion may allow physicians to tailor treatment to the individual, maximizing therapeutic effect and minimizing treatment-related toxicity. Therapeutic drug monitoring provides a means of assessing a patient's current depletion status and can be used to better evaluate the potential benefit of treatment adjustments. PMID:25586605

  18. Pharmacokinetic study of medicinal polymers: models based on dextrans

    SciTech Connect

    Kulakov, V.N.; Pimenova, G.N.; Matveev, V.A.; Sedov, V.V.; Vasil'ev, A.E.

    1986-09-01

    The authors study the pharmacokinetics of dextrans with various molecular masses modified by fluorescein isothiocyanate (FITC) using a radioisotope method. The radionuclide /sup 125/I was selectively bound to a FITC residue attached to the polysaccharide by electrochemical iodination under potentiostatic conditions. In the experiments, dextrans modified by FITC were labeled with /sup 125/I (DF-/sup 125/I) by electrochemical iodination. The separation of DF-/sup 125/I and FITC from ionic forms of the radionuclide not bound to the polymer was carried out. The properties of the samples obtained are presented. The radioactivity accumulated in the rate organs and urine studied are shown. The features of DF-/sup 125/I behavior in the blood and liver are examined.

  19. Sonic boom acceptability studies

    NASA Astrophysics Data System (ADS)

    Shepherd, Kevin P.; Sullivan, Brenda M.; Leatherwood, Jack D.; McCurdy, David A.

    1992-04-01

    The determination of the magnitude of sonic boom exposure which would be acceptable to the general population requires, as a starting point, a method to assess and compare individual sonic booms. There is no consensus within the scientific and regulatory communities regarding an appropriate sonic boom assessment metric. Loudness, being a fundamental and well-understood attribute of human hearing was chosen as a means of comparing sonic booms of differing shapes and amplitudes. The figure illustrates the basic steps which yield a calculated value of loudness. Based upon the aircraft configuration and its operating conditions, the sonic boom pressure signature which reaches the ground is calculated. This pressure-time history is transformed to the frequency domain and converted into a one-third octave band spectrum. The essence of the loudness method is to account for the frequency response and integration characteristics of the auditory system. The result of the calculation procedure is a numerical description (perceived level, dB) which represents the loudness of the sonic boom waveform.

  20. Sonic boom acceptability studies

    NASA Technical Reports Server (NTRS)

    Shepherd, Kevin P.; Sullivan, Brenda M.; Leatherwood, Jack D.; Mccurdy, David A.

    1992-01-01

    The determination of the magnitude of sonic boom exposure which would be acceptable to the general population requires, as a starting point, a method to assess and compare individual sonic booms. There is no consensus within the scientific and regulatory communities regarding an appropriate sonic boom assessment metric. Loudness, being a fundamental and well-understood attribute of human hearing was chosen as a means of comparing sonic booms of differing shapes and amplitudes. The figure illustrates the basic steps which yield a calculated value of loudness. Based upon the aircraft configuration and its operating conditions, the sonic boom pressure signature which reaches the ground is calculated. This pressure-time history is transformed to the frequency domain and converted into a one-third octave band spectrum. The essence of the loudness method is to account for the frequency response and integration characteristics of the auditory system. The result of the calculation procedure is a numerical description (perceived level, dB) which represents the loudness of the sonic boom waveform.

  1. Preclinical pharmacology and pharmacokinetics of CERC-301, a GluN2B-selective N-methyl-D-aspartate receptor antagonist.

    PubMed

    Garner, Rachel; Gopalakrishnan, Shobha; McCauley, John A; Bednar, Rodney A; Gaul, Stanley L; Mosser, Scott D; Kiss, Laszlo; Lynch, Joseph J; Patel, Shil; Fandozzi, Christine; Lagrutta, Armando; Briscoe, Richard; Liverton, Nigel J; Paterson, Blake M; Vornov, James J; Mazhari, Reza

    2015-12-01

    The preclinical pharmacodynamic and pharmacokinetic properties of 4-methylbenzyl (3S, 4R)-3-fluoro-4-[(Pyrimidin-2-ylamino) methyl] piperidine-1-carboxylate (CERC-301), an orally bioavailable selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC-301 dose selection in clinical trials of major depressive disorder. CERC-301 demonstrated high-binding affinity (K i, 8.1 nmol L(-1)) specific to GluN2B with an IC 50 of 3.6 nmol L(-1) and no off-target activity. CERC-301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED 50) of 0.3-0.7 mg kg(-1) (RO, 30-50%); increase in locomotor activity was observed at ED 50 of 2 mg kg(-1), corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L(-1), similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L(-1), respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first-in-human study in healthy males demonstrated a dose-proportional pharmacokinetic profile, with T max of ~1 h and t 1/2 of 12-17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.

  2. Pharmacokinetics of new nootropic acylprolyldipeptide and its penetration across the blood-brain barrier after oral administration.

    PubMed

    Boiko, S S; Ostrovskaya, R U; Zherdev, V P; Korotkov, S A; Gudasheva, T A; Voronina, T A; Seredenin, S B

    2000-04-01

    Pharmacokinetics of GVS-111, a new acylprolyldipeptide with nootropic properties and its penetration across the blood-brain barrier were studied in rats using HPLC. It was found that the dipeptide is absorbed in the gastrointestinal tract, enters the circulation, and penetrates through the blood-brain barrier in an unmodified state. PMID:10977920

  3. 45 CFR 2544.150 - How will accepted donations be recorded and used?

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 4 2010-10-01 2010-10-01 false How will accepted donations be recorded and used... FOR NATIONAL AND COMMUNITY SERVICE SOLICITATION AND ACCEPTANCE OF DONATIONS § 2544.150 How will accepted donations be recorded and used? (a) All accepted donations of money and other property will...

  4. 45 CFR 2544.150 - How will accepted donations be recorded and used?

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 4 2011-10-01 2011-10-01 false How will accepted donations be recorded and used... FOR NATIONAL AND COMMUNITY SERVICE SOLICITATION AND ACCEPTANCE OF DONATIONS § 2544.150 How will accepted donations be recorded and used? (a) All accepted donations of money and other property will...

  5. 41 CFR 101-26.506-4 - Acceptance and processing of requests.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 2 2010-07-01 2010-07-01 true Acceptance and processing...-PROCUREMENT SOURCES AND PROGRAM 26.5-GSA Procurement Programs § 101-26.506-4 Acceptance and processing of... feasible, will be accepted. Upon acceptance of a request by GSA, a proposal will be furnished...

  6. Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: optimization of kinase selectivity and pharmacokinetics.

    PubMed

    Hornberger, Keith R; Chen, Xin; Crew, Andrew P; Kleinberg, Andrew; Ma, Lifu; Mulvihill, Mark J; Wang, Jing; Wilde, Victoria L; Albertella, Mark; Bittner, Mark; Cooke, Andrew; Kadhim, Salam; Kahler, Jennifer; Maresca, Paul; May, Earl; Meyn, Peter; Romashko, Darlene; Tokar, Brianna; Turton, Roy

    2013-08-15

    The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer. PMID:23856049

  7. Discovery of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1: optimization of kinase selectivity and pharmacokinetics.

    PubMed

    Hornberger, Keith R; Chen, Xin; Crew, Andrew P; Kleinberg, Andrew; Ma, Lifu; Mulvihill, Mark J; Wang, Jing; Wilde, Victoria L; Albertella, Mark; Bittner, Mark; Cooke, Andrew; Kadhim, Salam; Kahler, Jennifer; Maresca, Paul; May, Earl; Meyn, Peter; Romashko, Darlene; Tokar, Brianna; Turton, Roy

    2013-08-15

    The kinase selectivity and pharmacokinetic optimization of a series of 7-aminofuro[2,3-c]pyridine inhibitors of TAK1 is described. The intersection of insights from molecular modeling, computational prediction of metabolic sites, and in vitro metabolite identification studies resulted in a simple and unique solution to both of these problems. These efforts culminated in the discovery of compound 13a, a potent, relatively selective inhibitor of TAK1 with good pharmacokinetic properties in mice, which was active in an in vivo model of ovarian cancer.

  8. 39 CFR 777.51 - Acceptance of donations.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 39 Postal Service 1 2012-07-01 2012-07-01 false Acceptance of donations. 777.51 Section 777.51 Postal Service UNITED STATES POSTAL SERVICE SPECIAL REGULATIONS RELOCATION ASSISTANCE AND REAL PROPERTY ACQUISITION POLICIES Donations § 777.51 Acceptance of donations. Nothing in these regulations shall prevent...

  9. 39 CFR 777.51 - Acceptance of donations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 39 Postal Service 1 2011-07-01 2011-07-01 false Acceptance of donations. 777.51 Section 777.51... ACQUISITION POLICIES Donations § 777.51 Acceptance of donations. Nothing in these regulations shall prevent a person from making a gift or donation of real property or any part thereof, or any interest therein,...

  10. 39 CFR 777.51 - Acceptance of donations.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 39 Postal Service 1 2010-07-01 2010-07-01 false Acceptance of donations. 777.51 Section 777.51... ACQUISITION POLICIES Donations § 777.51 Acceptance of donations. Nothing in these regulations shall prevent a person from making a gift or donation of real property or any part thereof, or any interest therein,...

  11. 48 CFR 570.111 - Inspection and acceptance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... requirements and specifications. Document the inspection and acceptance in the contract file. ... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Inspection and acceptance... CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY General 570.111 Inspection and...

  12. Pharmacokinetics-pharmacology disconnection of herbal medicines and its potential solutions with cellular pharmacokinetic-pharmacodynamic strategy.

    PubMed

    Zhang, Jingwei; Zhou, Fang; Lu, Meng; Ji, Wei; Niu, Fang; Zha, Weibin; Wu, Xiaolan; Hao, Haiping; Wang, Guangji

    2012-06-01

    Recently, there is a global trend of using herbal medicines to treat various chronic diseases and promote health. But the controversy over the safety and efficacy of herbal medicines is a focus of attention, primarily because of the many unknown and unrevealed natures of herbal medicines, which strongly restricts their application and development. Pharmacokinetics is a bridge linking the herbal medicines and their pharmacological responses. It is assumed in traditional pharmacokinetics that an excellent drug should have appropriate pharmacokinetic behaviours and its pharmacological effect is related with plasma drug concentrations. However, most herbal medicines exhibit excellent pharmacological responses despite poor pharmacokinetic behaviours. As most drugs are intracellulartargeted, we put forward cellular pharmacokinetic-pharmacodynamic strategy, which is focused on the intracellular fate of drugs. This strategy could partially explain the marked pharmacological activities of herbal medicines from their intracellular pharmacokinetic behaviours, rather than their plasma concentrations. It is a helpful complementarity to traditional pharmacokinetics, and takes a potential role in the research and development of new herb-origined drugs. In this review, the pharmacokinetics-pharmacology disconnections of herbal medicines (such as ginseng, berberine and danshen) are retrospected. Then our proposed cellular pharmacokineticpharmacodynamic strategy, its characteristics, as well as its research procedures are described, followed by the subcellular distributions of drug transporters and metabolic enzymes which are the determinants of cellular pharmacokinetics-pharmacodynamics. Finally, our successful applications of cellular pharmacokinetic-pharmacodynamic strategy in elucidating ginsenoside Rh2 as an adjuvant agent and tanshinone IIA as an anticancer agent are illustrated.

  13. Drug Dosing in Obese Children: A Systematic Review of Current Pharmacokinetic Data

    PubMed Central

    Harskamp-van Ginkel, Margreet W.; Hill, Kevin D.; Becker, Kristian; Testoni, Daniela; Cohen-Wolkowiez, Michael; Gonzalez, Daniel; Barrett, Jeffrey S.; Benjamin, Daniel K.; Siegel, David A.; Banks, Patricia; Watt, Kevin M.

    2015-01-01

    IMPORTANCE Obesity affects nearly one sixth of U.S. children and results in alterations to body composition and physiology that can affect drug disposition, possibly leading to therapeutic failure or toxicity. The depth of available literature regarding obesity’s effect on drug safety, pharmacokinetics (PK) and dosing in obese children is unknown. OBJECTIVE To perform a systematic literature review describing the current evidence of the effect of obesity on drug disposition in children. EVIDENCE REVIEW We searched the Medline, Cochrane, and Embase databases (January 1970–December 2012) and included studies if they contained clearance, volume of distribution, or drug concentration data in obese children (age ≤18 years). We compared exposure and weight-normalized volume of distribution and clearance between obese and non-obese children. We explored the relationship between drug physicochemical properties and clearance and volume of distribution. FINDINGS Twenty studies met inclusion criteria and contained pharmacokinetic data for 21 drugs. The median number of obese children studied per drug was 10 (range 1–112), ages ranged from 0–29 years. Dosing schema varied and were based on a fixed dose (n=6, 29%), body weight (n=10, 48%), and body surface area (n=4, 19%). Clinically significant pharmacokinetic alterations were observed in obese children for 65% (11/17) of studied drugs. Pharmacokinetic alterations resulted in substantial differences in exposure between obese and non-obese children for 38% (5/13) of drugs. We found no association between drug lipophilicity or Biopharmaceutical Drug Disposition Classification System class and changes in volume of distribution or clearance due to obesity. CONCLUSIONS AND RELEVANCE Consensus is lacking on the most appropriate weight-based dosing strategy. Prospective pharmacokinetic trials in obese children are needed to ensure therapeutic efficacy and enhance drug safety. PMID:25961828

  14. Clinical pharmacokinetics of new-generation antiepileptic drugs at the extremes of age: an update.

    PubMed

    Italiano, Domenico; Perucca, Emilio

    2013-08-01

    Epilepsies occur across the entire age range, and their incidence peaks in the first years of life and in the elderly. Therefore, antiepileptic drugs (AEDs) are commonly used at the extremes of age. Rational prescribing in these age groups requires not only an understanding of the drugs' pharmacodynamic properties, but also careful consideration of potential age-related changes in their pharmacokinetic profile. The present article, which updates a review published in 2006 in this journal, focuses on recent findings on the pharmacokinetics of new-generation AEDs in neonates, infants, children, and the elderly. Significant new information on the pharmacokinetics of new AEDs in the perinatal period has been acquired, particularly for lamotrigine and levetiracetam. As a result of slow maturation of the enzymes involved in glucuronide conjugation, lamotrigine elimination occurs at a particularly slow rate in neonates, and becomes gradually more efficient during the first months of life. In the case of levetiracetam, elimination occurs primarily by renal excretion and is also slow at birth, but drug clearance increases rapidly thereafter and can even double within 1 week. In general, infants older than 2-3 months and children show higher drug clearance (normalized for body weight) than adults. This pattern was confirmed in recent studies that investigated the pediatric pharmacokinetics of several new AEDs, including levetiracetam, rufinamide, stiripentol, and eslicarbazepine acetate. At the other extreme of age, in the elderly, drug clearance is generally reduced compared with younger adults because of less efficient drug-metabolizing activity, decreased renal function, or both. This general pattern, described previously for several AEDs, was confirmed in recent studies on the effect of old age on the clearance of felbamate, levetiracetam, pregabalin, lacosamide, and retigabine. For those drugs which are predominantly eliminated by renal excretion, aging

  15. Dose selection for the investigational anticancer agent alisertib (MLN8237): Pharmacokinetics, pharmacodynamics, and exposure-safety relationships.

    PubMed

    Venkatakrishnan, Karthik; Zhou, Xiaofei; Ecsedy, Jeffrey; Mould, Diane R; Liu, Hua; Danaee, Hadi; Fingert, Howard; Kleinfield, Robert; Milton, Ashley

    2015-03-01

    We report population pharmacokinetic, pharmacodynamic, and pharmacokinetic-safety analyses to support phase II/III dose/regimen selection of alisertib, a selective Aurora A kinase (AAK) inhibitor. Phase I studies in adult cancer patients evaluated dosing on Days 1-7 in 21-day cycles or Days 1-21 in 35-day cycles, with corresponding maximum tolerated doses of 50 mg twice daily (BID) and 50 mg QD, respectively. Population pharmacokinetic analyses supported dose- and time-linear pharmacokinetics without identification of clinically meaningful covariates. Exposure-related increases in skin mitotic index and decreases in chromosomal alignment/spindle bipolarity in tumor mitotic cells confirmed AAK inhibition. Exposures in the 7-day schedule at or near 50 mg BID are expected to result in tumor AAK inhibition based on pharmacodynamic assessment in patient tumors. Exposure-safety analyses of data from patients receiving doses of 5-200 mg/day in the 7-day schedule support a low (∼7%) predicted incidence of dose-limiting toxicity at 50 mg BID. Taken together, these analyses support a pharmacologically active and acceptably tolerated dose range of alisertib for future clinical development. PMID:25302940

  16. The Holy Grail of Polymer Therapeutics for Cancer Therapy: An Overview on the Pharmacokinetics and Bio Distribution.

    PubMed

    Dyawanapelly, Sathish; Junnuthula, Vijayabhaskar Reddy; Singh, AkhileshVikram

    2015-01-01

    In recent years, multifaceted clinical benefits of polymeric therapeutics have been reported. Over the past decades, cancer has been one of the leading causes of mortality in the world. Many clinically approved chemotherapeutics encounter potential challenges against deadly cancer. Moreover, safety and efficacy of anticancer agents have been limited by undesirable pharmacokinetics and biodistribution. To address these limitations, various polymer drug conjugates are being studied and developed to improve the antitumor efficacy. Among other therapeutics, polymer therapeutics are well established platforms that circumvent anticancer therapeutics from enzymatic metabolism via direct conjugation to therapeutic molecules. Interestingly, polymer therapeutics meets an unmet need of small molecules. Further clinical study showed that polymer-drug conjugation can achieve desired pharmacokinetics and biodistribution properties of several anticancer drugs. The present retrospective review mainly enlightens the most recent preclinical and clinical studies include safety, stability, pharmacokinetic behavior and distribution of polymer therapeutics.

  17. Pharmacokinetic Screening of Soluble Epoxide Hydrolase Inhibitors in Dogs

    PubMed Central

    Tsai, Hsing-Ju; Hwang, Sung Hee; Morisseau, Christophe; Yang, Jun; Jones, Paul D.; Kasagami, Takeo; Kim, In-Hae; Hammock, Bruce D.

    2012-01-01

    Epoxyeicosatrienoic acids that have anti-hypertensive and anti-inflammatory properties are mainly metabolized by soluble epoxide hydrolase (sEH, EC 3.3.2.3). Therefore, sEH has emerged as a therapeutic target for treating various cardiovascular diseases and inflammatory pain. N,N’-Disubstituted ureas are potent sEH inhibitors in vitro. However, in vivo usage of early sEH inhibitors has been limited by their low bioavailability and poor physiochemical properties. Therefore, a group of highly potent compounds with more drug-like physiochemical properties were evaluated by monitoring their plasma profiles in dogs treated orally with sEH inhibitors. Urea compounds with an adamantyl or a 4-trifluoromethoxyphenyl group on one side and a piperidyl or a cyclohexyl ether group on the other side of the urea function showed pharmacokinetic profiles with high plasma concentrations and long half lives. In particular, the inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) not only is very potent with good physiochemical properties, but also shows high oral bioavailability for doses ranging from 0.01 to 1 mg/kg. This compound is also very potent against the sEH of several mammals, suggesting that t-AUCB will be an excellent tool to evaluate the biology of sEH in multiple animal models. Such compounds may also be a valuable lead for the development of veterinary therapeutics. PMID:20359531

  18. Pharmacokinetics of norfloxacin in the elderly.

    PubMed

    Lepage, J Y; Caillon, J; Malinowsky, J M; Lequerré, S; Cozian, A; Le Normand, Y; Potel, G; Drugeon, H; Baron, D

    1991-01-01

    9 elderly and 9 younger adult patients, with proven post-operative lower urinary tract infection were treated with 400 mg of norfloxacin twice daily for 5 days. Pharmacokinetics of norfloxacin were measured on days 1 and 5. Compared to the younger adult patients, the elderly showed a decreased creatinine clearance and, following the last dose on day 5, an increased maximum plasma concentration of norfloxacin, an increased area under the concentration-time curve and a decreased total body clearance of norfloxacin. These results confirm that in elderly, as in younger adult patients, the pharmacokinetics of norfloxacin can be described by a linear model and accumulation of the drug during repetitive multiple doses is predictable. The differences between the two groups cannot be considered as clinically significant so that no dose change would be required in elderly patients within the range of creatinine clearance studied.

  19. Pharmacokinetics of subcutaneous fentanyl in Greyhounds.

    PubMed

    KuKanich, Butch

    2011-11-01

    The purpose of the study was to describe the pharmacokinetics of subcutaneous fentanyl (15μg/kg) in six healthy Greyhound dogs. Fentanyl plasma concentrations were determined by a liquid chromatography with mass spectrometry method. Non-compartmental pharmacokinetic analysis was used. Fentanyl was rapidly absorbed with a mean peak concentration (C(MAX)) of 3.56ng/mL at 0.24h. The mean terminal half-life, volume of distribution per bioavailability, and clearance per bioavailability were 2.97h, 7.09L/kg, 27.60mL/min/kg, respectively. Pain occurred on injection in all six dogs, but addition of 8.4% sodium bicarbonate (1mL per 20mL fentanyl) resulted in no pain on injection in 3/3 dogs but similar C(MAX) values. The subcutaneous route may be an alternative route of fentanyl administration if intravenous administration is not practical.

  20. Acute pharmacokinetics of memantine in the mouse.

    PubMed

    Saab, Bechara J; Roder, John C

    2011-01-01

    The pharmacokinetics of memantine, a widely prescribed medication in the United States and the European Union for the treatment of moderate-to-severe Alzheimer's disease (AD), have not been well explored in the mouse. Memantine is a highly unspecific blocker of many channels and how memantine may be of benefit in AD remains a mystery. Therefore, the investigation of memantine in the mouse, the most commonly chosen subject for modeling AD, has strong potential to lead to better therapies. Here, we present an acute pharmacokinetic analysis of memantine in mouse brain tissue and blood serum for a variety of experimentally relevant doses. The data help shed light on the mechanism of memantine action in vivo, and demonstrate that subcutaneous doses above 10 mg/kg in the mouse are most likely not therapeutically relevant to the human.

  1. Pharmacokinetics and prescribing in the elderly.

    PubMed

    Swift, C G

    1994-08-01

    The use of prescribed medication in general is higher in the elderly than in the young and it is possible that existing patterns of antimicrobial agent prescribing may predispose to suboptimal response, certain adverse drug reactions (ADR) and the emergence of resistant strains of organisms. Age is an important variable affecting the pharmacokinetics of drugs, including many antimicrobials. Changes which may affect Cmax/MIC ratios and/or the time above MIC include reduced first-pass metabolism, altered distribution volume, reduced binding to albumin, reduced metabolic biotransformation and reduced renal elimination. Application of a knowledge of antimicrobial agent pharmacokinetic changes with age and their implications for response may enable more precise determination of dose regimens for older patients, which is probably desirable for the prevention of both ADR and bacterial resistance. PMID:7844071

  2. Recommended reading in population pharmacokinetic pharmacodynamics.

    PubMed

    Bonate, Peter L

    2005-01-01

    Developing the skills or expertise to create useful population pharmacokinetic-pharmacodynamic models can be a daunting task-the level of mathematical and statistical complexity is such that newcomers to the field are frequently overwhelmed. A good place to start in learning the field is to read articles in the literature. However, the number of articles dealing with population pharmacokinetic pharmacodynamics is exponentially increasing on a yearly basis, so choosing which articles to read can be difficult. The purpose of this review is to provide a recommended reading list for newcomers to the field. The list was chosen based on perceived impact of the article in the field, the quality of the article, or to highlight some important detail contained within the article. After reading the articles in the list, it is believed that the reader will have a broad overview of the field and have a sound foundation for more-detailed reading of the literature.

  3. Pharmacokinetic Profile of Spectinomycin in Rats

    PubMed Central

    Madhura, Dora Babu; Lee, Richard; Meibohm, Bernd

    2014-01-01

    Short Summary Following intravenous (IV) administration, the pharmacokinetics of spectinomycin in rats was found to be on par with its profile in other mammalian species including humans with respect to its overall excretion and half-life at effective concentrations. This study, however, indicates that a small fraction of the spectinomycin dose is retained in peripheral tissues for a prolonged period of time at low concentrations. PMID:24020122

  4. Pharmacokinetics of Tenofovir During Pregnancy and Postpartum

    PubMed Central

    Best, Brookie M.; Burchett, Sandra; Li, Hong; Stek, Alice; Hu, Chengcheng; Wang, Jiajia; Hawkins, Elizabeth; Byroads, Mark; Watts, D. Heather; Smith, Elizabeth; Fletcher, Courtney V.; Capparelli, Edmund V.; Mirochnick, Mark

    2016-01-01

    Objectives Tenofovir disoproxol fumarate (TDF) is increasingly used in HAART regimens of pregnant women, but limited data exist on pregnancy pharmacokinetics of chronically-dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum. Methods IMPAACT P1026s is a prospective, non-blinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at 2nd and 3rd trimester and postpartum, with maternal and umbilical cord samples at delivery. Tenofovir was measured by LC-MS. The target AUC was ≥ 1.99 mcg•hr/mL (non-pregnant historical control 10th percentile). Results Median tenofovir AUC was decreased during the 2nd (1.9 mcg•hr/mL) and 3rd (2.4 mcg•hr/mL, p=0.005) trimesters versus postpartum (3.0 mcg•hr/mL). Tenofovir AUC exceeded the target for 2/4 (50%) 2nd trimester; 27/37 (73%; 95% CI: 56%, 86%) 3rd trimester; and 27/32 (84%; 95% CI: 67%, 95%) postpartum women (p>0.05). Median 2nd/3rd trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median 3rd trimester weight was heavier for subjects below target AUC versus those above target (97.9 vs. 74.2 kg, p = 0.006). Median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected. Conclusions This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90kg) or inadequate HIV RNA response. PMID:25959631

  5. Pharmacokinetics of Oral Taurine in Healthy Volunteers

    PubMed Central

    Ghandforoush-Sattari, Mohammadreza; Mashayekhi, Siminozar; Krishna, Channarayapatna V.; Thompson, John P.; Routledge, Philipp A.

    2010-01-01

    Taurine, a sulfur-containing amino acid, is a normal constituent of the human diet. Little is known of the pharmacokinetics of taurine in man after oral administration. We studied the pharmacokinetics of 4 g taurine in eight healthy male volunteers (median age 27.5, range 22–45) following orally administration in the fasting state in the morning. Blood samples were taken at regular intervals and plasma taurine concentration was measured by a modified HPLC method. Data were subjected to noncompartmental analysis. Maximum plasma taurine concentration (Cmax) was measured at 1.5 ± 0.6 hr after administration as 86.1 ± 19.0 mg/L (0.69 ± 0.15 mmol). Plasma elimination half-life (T1/2) and the ratio of clearance/bioavailability (Cl/F) were 1.0 ± 0.3 hr and 21.1 ± 7.8 L/hr, respectively. Since taurine is occasionally used in therapeutics as a medicine, the pharmacokinetics and effects of oral taurine in healthy volunteers would be useful in the future studies of taurine in pharmacology and nutrition. PMID:22331997

  6. Ethanol Pharmacokinetics in Neonates and Infants

    PubMed Central

    Marek, Elizabeth; Kraft, Walter K.

    2014-01-01

    Introduction Ethanol has been used for years in neonatal and infant liquid medications, yet the pharmacokinetics, pharmacodynamics, and safety of ethanol in this vulnerable population have not been well characterized. The purpose of this review is to raise awareness of ethanol use as an excipient in neonatal and infant medications and to provide insight, based on the available evidence, into clearance rates of ethanol in babies. We also discuss ethanol pharmacokinetics in adults, theoretical pharmacokinetic changes in neonates and infants as it may apply to ethanol disposition, and case reports involving ethanol exposure in neonates and infants. Materials and methods This study was a narrative review in which relevant papers were selected using databases and scientific search engines such as PubMed with the key words ethanol, infant, and newborninfant. Results It remains unclear what ethanol exposure is safe for neonates and infants. The Food and Drug Administration and American Academy of Pediatrics have both taken action, by either setting limits of ethanol content in over-the-counter medications or by recommending restricted exposure to ethanol-containing pediatric formulations. Conclusions Until the short- and long-term health effects of chronic ethanol administration can be further characterized, ethanol-containing medications should be used with caution. PMID:25379066

  7. Dose dependent pharmacokinetics of naproxen in man.

    PubMed

    Niazi, S K; Alam, S M; Ahmad, S I

    1996-05-01

    The pharmacokinetics of one of the most widely used non-steroidal antiinflammatory drugs, naproxen, were studied in 28 healthy human volunteers at the two most commonly used dose levels, viz., 250 mg and 500 mg, in a cross-over design. The plasma levels of naproxen were analysed by a modified high-pressure liquid chromatography method. The plasma concentrations at higher doses were not proportional to dose, indicating a non-linearity in the pharmacokinetics at the dose levels studied; this finding is new since earlier studies had studied only higher doses and assumed that at lower doses the pharmacokinetics would be linear. There was, however, no significant difference in the elimination half-life (rate constant), time to reach peak concentration (Cmax), mean residence time (MRT), or area under first moment curve (AUMC). The clearance and distribution volume of naproxen were substantially increased at higher dose resulting in statistically lower proportional concentration and the total area under the curve (AUC). These observations are explained on the basis of a change in the plasma protein binding resulting in more free naproxen available for quicker clearance and wider penetration into tissues. These findings have several important clinical implications for the long-term use of naproxen as an antiarthritic drug. It is proposed that the clinical efficacy of naproxen can be increased and side-effects reduced by giving it in small divided doses instead of large doses.

  8. Predictive Performance of Physiologically Based Pharmacokinetic and Population Pharmacokinetic Modeling of Renally Cleared Drugs in Children

    PubMed Central

    Zhou, W; Johnson, TN; Xu, H; Cheung, SYA; Bui, KH; Li, J; Al‐Huniti, N

    2016-01-01

    Predictive performance of physiologically based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) models of drugs predominantly eliminated through kidney in the pediatric population was evaluated. After optimization using adult clinical data, the verified PBPK models can predict 33 of 34 drug clearance within twofold of the observed values in children 1 month and older. More specifically, 10 of 11 of predicted clearance values were within 1.5‐fold of those observed in children between 1 month and 2 years old. The PopPK approach also predicted 19 of 21 drug clearance within twofold of the observed values in children. In summary, our analysis demonstrated both PBPK and PopPK adult models, after verification with additional adult pharmacokinetic (PK) studies and incorporation of known ontogeny of renal filtration, could be applied for dosing regimen recommendation in children 1 month and older for renally eliminated drugs in a first‐in‐pediatric study. PMID:27566992

  9. Pre-formulation characterization and pharmacokinetic evaluation of resveratrol

    NASA Astrophysics Data System (ADS)

    Robinson-Barnes, Keila Delores

    Resveratrol, a natural compound found in grapes has potential chemotherapy effects but very low oral bioavailability in humans. The objectives of this study are to quantitatively characterized and understand the physiochemical properties and the pharmacokinetic evaluation of resveratrol. Solubility of resveratrol was measured in 10 common solvents at 25°C using HPLC. The solution state pH stability of resveratrol was assessed in various USP buffers ranging from pH 2-10 for 24 hours at 37 °C. Human plasma protein binding was determined using ultracentrifugation technique. Stability of resveratrol in human and rat plasma was also assessed at 37°C. Aliquots of blank plasma were spiked with a standard drug concentration to yield final plasma concentration of 50 mug/mL. Samples were analyzed for resveratrol concentration up to 96 hours. A group (n=8) of jugular vein-cannulated adult male Sprague-Dawley rats were evaluated and received intravenous dose of 20 mg/kg resveratrol. Serial blood samples were collected up to 8 hours after the dose. Plasma concentrations of resveratrol were measured by an established LC-MS/MS method. Pharmacokinetic parameters were assessed using noncompartmental methods. Resveratrol is more soluble in alcohol and PEG-400, and stable in acidic pH. It binds highly to plasma proteins, and degrades slower in human then rat plasma. Resveratrol exhibits bioexponential disposition after intravenous administration and has a short elimination half-life. Resveratrol displays bioexponential disposition following intravenous administration. The estimated mean maximum concentration was 1045.5 ng/mL and rapidly dropped below 100 ng/mL within 30 minutes. The area under the concentration time curve (AUC) for resveratrol was 13888.7 min*ng/mL The mean terminal elimination half-life was 50.9 minutes. The mean total body clearance (Cl) and volume of distribution of trans-resveratrol were 1711.9mL/min/kg and 91087.8 mL/kg, respectively. Pre

  10. Bioavailability, pharmacokinetics and residues of chloramphenicol in the chicken.

    PubMed

    Anadón, A; Bringas, P; Martinez-Larrañaga, M R; Diaz, M J

    1994-02-01

    The pharmacokinetic properties of chloramphenicol were determined in broiler chickens after two single oral doses (30 and 50 mg/kg body weight) and after a single intravenous (i.v.) dose (30 mg/kg body weight). After oral and i.v. administration, the plasma concentration-time graph was characteristic of a two-compartment open model. After oral administration (30 and 50 mg/kg), chloramphenicol was absorbed rapidly (time to maximal concentration of 0.72 or 0.60 h) and eliminated with a mean half-life (t1/2 beta) of 6.87 or 7.41 h, respectively. The bioavailability was 29% at 30 mg/kg chloramphenicol and 38% at 50 mg/kg chloramphenicol. Concentrations greater than 5 micrograms/ml were achieved at 15 min and persisted up to 2 or 4 h post-administration, respectively. Statistically significant differences between the two routes of administration were found for the pharmacokinetic variables, half-lives of both distribution and elimination phases (t1/2 alpha, t1/2 beta) and apparent volume of distribution [Vd(area)]. The mean t1/2 beta of chloramphenicol and i.v. administration was 5.23 h. Chloramphenicol was extensively metabolized into dehydrochloramphenicol (DH-CAP), nitrophenylaminopropanedione (NPAP) and nitroso-chloramphenicol (NO-CAP) derivatives. Residues of chloramphenicol (CAP) and the three metabolites DH-CAP, NPAP and NO-CAP in kidney, liver and muscle were measured in chickens that received an oral dose of 50 mg/kg once daily for 4 days. The results indicate that CAP and DH-CAP residues were cleared slowly and were at or below the detection limit of 0.005 microgram/ml within 12 days after dosing. However, at the time of slaughter (12 days), the NPAP and NO-CAP residues were detected in the tissue.

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

    PubMed Central

    Mehta, Piyush; Shah, Rishi; Lohidasan, Sathiyanarayanan; Mahadik, K.R.

    2015-01-01

    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. PMID:26587392

  12. Pharmacokinetics of 2 Formulations of Transdermal Fentanyl in Cynomolgus Macaques (Macaca fascicularis).

    PubMed

    Carlson, Amy M; Kelly Iii, Richard; Fetterer, David P; Rico, Pedro J; Bailey, Emily J

    2016-01-01

    Fentanyl is a μ-opioid agonist that often is used as the analgesic component for balanced anesthesia in both human and veterinary patients. Minimal information has been published regarding appropriate dosing, and the pharmacokinetics of fentanyl are unknown in NHP. The pharmacokinetic properties of 2 transdermal fentanyl delivery methods, a solution (2.6 and 1.95 mg/kg) and a patch (25 μg/h), were determined when applied topically to the dorsal scapular area of cynomolgus macaques (Macaca fascicularis). Serum fentanyl concentrations were analyzed by using liquid chromatography-mass spectrometry. Compared with the patch, the transdermal fentanyl solution generated higher drug concentrations over longer time. Adverse reactions occurred in the macaques that received the transdermal fentanyl solution at 2.6 mg/kg. Both preparations showed significant interanimal variability in the maximal serum drug levels, time to achieve maximal fentanyl levels, elimination half-life, and AUC values. Both the maximal concentration and the time at which this concentration occurred were increased in macaques compared with most other species after application of the transdermal fentanyl patch and compared with dogs after application of the transdermal fentanyl solution. The pharmacokinetic properties of transdermal fentanyl in macaques are markedly different from those in other veterinary species and preclude its use as a long-acting analgesic drug in NHP. PMID:27423151

  13. Pharmacokinetic profile of phytoconstituent(s) isolated from medicinal plants-A comprehensive review.

    PubMed

    Mehta, Piyush; Shah, Rishi; Lohidasan, Sathiyanarayanan; Mahadik, K R

    2015-10-01

    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.

  14. Cone penetrometer acceptance test report

    SciTech Connect

    Boechler, G.N.

    1996-09-19

    This Acceptance Test Report (ATR) documents the results of acceptance test procedure WHC-SD-WM-ATR-151. Included in this report is a summary of the tests, the results and issues, the signature and sign- off ATP pages, and a summarized table of the specification vs. ATP section that satisfied the specification.

  15. Pharmacokinetics of quercetin-loaded nanodroplets with ultrasound activation and their use for bioimaging

    PubMed Central

    Chang, Li-Wen; Hou, Mei-Ling; Hung, Shuo-Hui; Lin, Lie-Chwen; Tsai, Tung-Hu

    2015-01-01

    Bubble formulations have both diagnostic and therapeutic applications. However, research on nanobubbles/nanodroplets remains in the initial stages. In this study, a nanodroplet formulation was prepared and loaded with a novel class of chemotherapeutic drug, ie, quercetin, to observe its pharmacokinetic properties and ultrasonic bioimaging of specific sites, namely the abdominal vein and bladder. Four parallel groups were designed to investigate the effects of ultrasound and nanodroplets on the pharmacokinetics of quercetin. These groups were quercetin alone, quercetin triggered with ultrasound, quercetin-encapsulated in nanodroplets, and quercetin encapsulated in nanodroplets triggered with ultrasound. Spherical vesicles with a mean diameter of 280 nm were formed, and quercetin was completely encapsulated within. In vivo ultrasonic imaging confirmed that the nanodroplets could be treated by ultrasound. The results indicate that the initial 5-minute serum concentration, area under the concentration–time curve, elimination half-life, and clearance of quercetin were significantly enhanced by nanodroplets with or without ultrasound. PMID:25945049

  16. Development of a human physiologically based pharmacokinetic (PBPK) model for dermal permeability for lindane.

    PubMed

    Sawyer, Megan E; Evans, Marina V; Wilson, Charles A; Beesley, Lauren J; Leon, Lider S; Eklund, Chris R; Croom, Edward L; Pegram, Rex A

    2016-03-14

    Lindane is a neurotoxicant used for the treatment of lice and scabies present on human skin. Due to its pharmaceutical application, an extensive pharmacokinetic database exists in humans. Mathematical diffusion models allow for calculation of lindane skin permeability coefficients using human kinetic data obtained from in vitro and in vivo experimentation as well as a default compound-specific calculation based on physicochemical characteristics used in the absence of kinetic data. A dermal model was developed to describe lindane diffusion into the skin, where the skin compartment consisted of homogeneous dermal tissue. This study utilized Fick's law of diffusion along with chemical binding to protein and lipids to determine appropriate dermal absorption parameters which were then incorporated into a physiologically based pharmacokinetic (PBPK) model to describe in vivo kinetics. The estimation of permeability coefficients using chemical binding in combination with in vivo data demonstrates the advantages of combining physiochemical properties with a PBPK model to predict dermal absorption.

  17. Dissolution test acceptance sampling plans.

    PubMed

    Tsong, Y; Hammerstrom, T; Lin, K; Ong, T E

    1995-07-01

    The U.S. Pharmacopeia (USP) general monograph provides a standard for dissolution compliance with the requirements as stated in the individual USP monograph for a tablet or capsule dosage form. The acceptance rules recommended by USP have important roles in the quality control process. The USP rules and their modifications are often used as an industrial lot release sampling plan, where a lot is accepted when the tablets or capsules sampled are accepted as proof of compliance with the requirement. In this paper, the operating characteristics of the USP acceptance rules are reviewed and compared to a selected modification. The operating characteristics curves show that the USP acceptance rules are sensitive to the true mean dissolution and do not reject a lot or batch that has a large percentage of tablets that dissolve with less than the dissolution specification.

  18. What is meant by the term acceptance of technology and locating the acceptance of the CCS Technology?

    NASA Astrophysics Data System (ADS)

    Harz, Mario; Vesper, Anton

    2013-04-01

    abstract: The formal language of logic expresses concepts and statements exactly. The logic of relations can serve as an important ressource for the philosophical analysis of technology and the construction of philosophical propositions about acceptance of technology. The theory of logical relations is used to investigate the theoretical structure of how acceptance of technologies can be revealed. The term "ordered tuple" helps to define the basis of the concept of logical relations. The term "acceptance of technology" refers to neither a thing nor a property; but to a complex relationship. The research refers to the study of the properties of this complex relationship. It examines the properties of reflexivity, total reflexivity, symmetry, transitivity, irreflexivity and asymmetry. Using these properties and the rules for forming converses-relations and partial-relations the question is analyzed: What, in general, is meant by the term "acceptance of technology?" These properties have been observed empirically at a discussion forum for the key players in the Brandenburg discourse on the acceptance of CCS technology. The meeting was held on the 8th of May 2012 in St. Nicholas Church, Cottbus (GER). The pragma-dialectical theory of argumentation is used to locate the acceptance of the CCS technology. With the ideal model of critical discussion as the methodological starting point the term "acceptance" can be defined in terms of the four meta-theoretical principles of the theory. That boils down to the findings that acceptance is the externalization of a positive commitment towards a proposition, acceptance is expressed by the speech act "to accept" and acceptance occurs in the dialogical, interactional setting of a critical discussion with the aim of resolving a difference of opinion. In the study differences of opinion about (descriptive, normative, evaluative) standpoints about the CCS technology from everyday problem-solving discussions are investigated. The

  19. Property.

    ERIC Educational Resources Information Center

    Piele, Philip K.

    Several court cases involving acquisition, use, and disposal of property by institutions of higher education are briefly summarized in this chapter. Cases discussed touch on such topics as municipal annexation of university property; repurchase of properties temporarily allocated to faculty members; implications of zoning laws and zoning board…

  20. Pharmacokinetics of chlorogenic acid and corydaline in DA-9701, a new botanical gastroprokinetic agent, in rats.

    PubMed

    Jung, Ji Won; Kim, Ju Myung; Jeong, Jin Seok; Son, Miwon; Lee, Hye Suk; Lee, Myung Gull; Kang, Hee Eun

    2014-07-01

    1.Few studies describing the pharmacokinetic properties of chlorogenic acid (CA) and corydaline (CRD) which are marker compounds of a new prokinetic botanical agent, DA-9701, have been reported. The aim of the present study is to evaluate the pharmacokinetic properties CA and CRD following intravenous and oral administration of pure CA (1-8 mg/kg) or CRD (1.1-4.5 mg/kg) and their equivalent dose of DA-9701 to rats. 2.  Dose-proportional AUC and dose-independent clearance (10.3-12.1 ml/min/kg) of CA were observed following its administration. Oral administration of CA as DA-9701 did not influence the oral pharmacokinetic parameters of CA. Incomplete absorption of CA, its decomposition in the gastrointestinal tract, and/or pre-systemic metabolism resulted in extremely low oral bioavailability (F) of CA (0.478-0.899%). 3.  CRD showed greater dose-normalized AUC in the higher dose group than that in lower dose group(s) after its administration due to saturation of its metabolism via decreased non-renal clearance (by 51.3%) and first-pass extraction. As a result, the F of CRD following 4.5 mg/kg oral CRD (21.1%) was considerably greater than those of the lower dose groups (9.10 and 13.8%). However, oral administration of CRD as DA-9701 showed linear pharmacokinetics as a result of increased AUC and F in lower-dose groups (by 182% and 78.5%, respectively) compared to those of pure CRD. The greater oral AUC of CRD for DA-9701 than for pure CRD could be due to decreased hepatic and/or GI first-pass extraction of CRD by other components in DA-9701.

  1. Population Pharmacokinetics of Benznidazole in Adult Patients with Chagas Disease

    PubMed Central

    Aldasoro, E.; Guerrero, L.; Posada, E.; Serret, N.; Mejía, T.; Urbina, J. A.; Gascón, J.

    2015-01-01

    The aim of the present study was to build a population pharmacokinetic (popPK) model to characterize benznidazole (BNZ) pharmacokinetics in adults with chronic Chagas disease. This study was a prospective, open-label, single-center clinical trial approved by the local ethics committee. Patients received BNZ at 2.5 mg/kg of body weight/12 h (Abarax, Elea Laboratory, Argentina) for 60 days. Plasma BNZ samples were taken several times during the study and analyzed by high-performance liquid chromatography with UV-visible detection (HPLC-UV). The popPK analysis was done with NONMEMv.7.3. Demographic and biological data were tested as covariates. Intraindividual, interoccasion, and residual variabilities were modeled. Internal and external validations were completed to assess the robustness of the model. Later on, simulations were performed to generate BNZ concentration-time course profiles for different dosage regimens. A total of 358 plasma BNZ concentrations from 39 patients were included in the analysis. A one-compartment PK model characterized by clearance (CL/F) and the apparent volume of distribution (V/F), with first-order absorption (Ka) and elimination, adequately described the data (CL/F, 1.73 liters/h; V/F, 89.6 liters; and Ka, 1.15 h−1). No covariates were found to be significant for CL/F and V/F. Internal and external validations of the final model showed adequate results. Data from simulations revealed that a dose of 2.5 mg/kg/12 h might lead to overexposure in most patients. A lower dose (2.5 mg/kg/24 h) was able to achieve trough BNZ plasma concentrations within the accepted therapeutic range of 3 to 6 mg/liter. In summary, we developed a population PK model for BNZ in adults with chronic Chagas disease. Dosing simulations showed that a BNZ dose of 2.5 mg/kg/24 h will adequately keep BNZ trough plasma concentrations within the recommended target range for the majority of patients. (This study has been registered at EudraCT under number 2011

  2. Pharmacokinetics and pharmacodynamics of a new reformulated microemulsion and the long-chain triglyceride emulsion of propofol in beagle dogs

    PubMed Central

    Lee, S-H; Ghim, J-L; Song, M-H; Choi, H-G; Choi, B-M; Lee, H-M; Lee, E-K; Roh, Y-J; Noh, G-J

    2009-01-01

    Background and purpose: Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations. Experimental approach: The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg·kg−1·min−1) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling. Key results: Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUClast and AUCinf between both formulations were acceptable for bioequivalence, whereas that of Cmax was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E0 (baseline ApEn)–Emax (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V1 of both formulations and sex for k21 of microemulsion propofol. The blood-brain equilibration rate constants (ke0, min−1) were 0.476 and 0.696 for microemulsion and LCT propofol respectively. Conclusions and implications: Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges. PMID:19925493

  3. GLP principles and their role in supporting pharmacokinetic and residue depletion studies for drug registration and licensing.

    PubMed

    Croubels, Siska; De Backer, Patrick; Devreese, Mathias

    2016-05-01

    Good Laboratory Practice (GLP) is a quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived, and reported. This paper focuses on the GLP principles applicable for veterinary drug registration and licensing purposes. First, a general overview of the GLP requirements is given, followed by a more specific comparison and discussion of the analytical method validation parameters and acceptance criteria of different international guidelines applied in the context of veterinary drug pharmacokinetic and residue depletion studies. Finally, some needs with respect to method validation and new developments in pharmacokinetic and residue depletion studies are highlighted. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27443213

  4. Quantitative determination of sirolimus in dog blood using liquid chromatography-tandem mass spectrometry, and its applications to pharmacokinetic studies.

    PubMed

    Lee, Jong-Hwa; Cha, Kwang-Ho; Cho, Wonkyung; Park, Junsung; Park, Hee Jun; Cho, Youngseok; Hwang, Sung-Joo

    2010-12-01

    A rapid, sensitive method of detecting sirolimus in blood was developed and applied in pharmacokinetic studies employing deionized water for hemolysis and a weakly basic mobile phase to enhance chromatographic peak intensity. Dog blood samples were processed via liquid-liquid extraction and the amounts of sirolimus and tacrolimus, an internal standard, were quantified by LC-MS/MS. Specificity, the lower limit of quantification, linearity, accuracy, precision, dilution, recovery, matrix effects, robustness and stability were within the acceptable range for assay validation. The concentration of sirolimus was quantifiable in blood samples for up to 36 h after the dog had received a 3 mg/kg dose of sirolimus. These observations suggest that sirolimus can be detected at low levels in dog blood using a basic mobile phase and metal-free hemolysis. This method is therefore applicable to pharmacokinetic studies in dogs. PMID:20674213

  5. Pharmacometric Models for Characterizing the Pharmacokinetics of Orally Inhaled Drugs.

    PubMed

    Borghardt, Jens Markus; Weber, Benjamin; Staab, Alexander; Kloft, Charlotte

    2015-07-01

    During the last decades, the importance of modeling and simulation in clinical drug development, with the goal to qualitatively and quantitatively assess and understand mechanisms of pharmacokinetic processes, has strongly increased. However, this increase could not equally be observed for orally inhaled drugs. The objectives of this review are to understand the reasons for this gap and to demonstrate the opportunities that mathematical modeling of pharmacokinetics of orally inhaled drugs offers. To achieve these objectives, this review (i) discusses pulmonary physiological processes and their impact on the pharmacokinetics after drug inhalation, (ii) provides a comprehensive overview of published pharmacokinetic models, (iii) categorizes these models into physiologically based pharmacokinetic (PBPK) and (clinical data-derived) empirical models, (iv) explores both their (mechanistic) plausibility, and (v) addresses critical aspects of different pharmacometric approaches pertinent for drug inhalation. In summary, pulmonary deposition, dissolution, and absorption are highly complex processes and may represent the major challenge for modeling and simulation of PK after oral drug inhalation. Challenges in relating systemic pharmacokinetics with pulmonary efficacy may be another factor contributing to the limited number of existing pharmacokinetic models for orally inhaled drugs. Investigations comprising in vitro experiments, clinical studies, and more sophisticated mathematical approaches are considered to be necessary for elucidating these highly complex pulmonary processes. With this additional knowledge, the PBPK approach might gain additional attractiveness. Currently, (semi-)mechanistic modeling offers an alternative to generate and investigate hypotheses and to more mechanistically understand the pulmonary and systemic pharmacokinetics after oral drug inhalation including the impact of pulmonary diseases.

  6. PHARMACOKINETIC/PHARMACODYNAMIC MODELING OF PERMETHRIN IN THE RAT

    EPA Science Inventory

    A physiologically-based pharmacokinetic (PBPK) model was used to describe pharmacokinetics of permethrin and calibrated using experimental data on the concentration time-course of cis- and trans-permethrin in rat blood and brain tissues following oral administration...

  7. Multiple-Dose Pharmacokinetics of Fluvoxamine in Children and Adolescents.

    ERIC Educational Resources Information Center

    Labellarte, Michael; Biederman, Joseph; Emslie, Graham; Ferguson, James; Khan, Arifulla; Ruckle, Jon; Sallee, Randy; Riddle, Mark

    2004-01-01

    Objective: To determine the pharmacokinetics of fluvoxamine in children and adolescents and to compare pharmacokinetic data from adolescents to adults from a previous study. Method: Fluvoxamine was titrated to a target dose of 100 mg b.i.d. in children (6-11 years) and 150 mg b.i.d. in adolescents (12-17 years) with obsessive-compulsive disorder…

  8. PHARMACOKINETIC MODELING FOR PERFLUORINATED CHEMICALS USED IN HOUSEHOLD CONSUMER PRODUCTS

    EPA Science Inventory

    PHARMACOKINETIC MODELING FOR PERFLUORONATED CHEMICALS USED IN HOUSEHOLD CONSUMER PRODUCTS
    Leona H. Clark and Hugh A. Barton
    US Environmental Protection Agency, ORD, NHEERL, ETD, Research Triangle Park, NC

    The physiologically-based pharmacokinetic model to be presente...

  9. KINPLOT: An Interactive Pharmacokinetics Graphics Program for Digital Computers.

    ERIC Educational Resources Information Center

    Wilson, Robert C.; And Others

    1982-01-01

    Inability to see the relevance of mathematics to understanding the time course of drugs in the body may discourage interest in pharmacokinetics. A UNC-developed computer graphics simulation program helps visualize the nature of pharmacokinetic-patient interactions, generates classroom handouts, and is used in the pharmaceuticals industry to…

  10. Extending the Technology Acceptance Model: Policy Acceptance Model (PAM)

    NASA Astrophysics Data System (ADS)

    Pierce, Tamra

    There has been extensive research on how new ideas and technologies are accepted in society. This has resulted in the creation of many models that are used to discover and assess the contributing factors. The Technology Acceptance Model (TAM) is one that is a widely accepted model. This model examines people's acceptance of new technologies based on variables that directly correlate to how the end user views the product. This paper introduces the Policy Acceptance Model (PAM), an expansion of TAM, which is designed for the analysis and evaluation of acceptance of new policy implementation. PAM includes the traditional constructs of TAM and adds the variables of age, ethnicity, and family. The model is demonstrated using a survey of people's attitude toward the upcoming healthcare reform in the United States (US) from 72 survey respondents. The aim is that the theory behind this model can be used as a framework that will be applicable to studies looking at the introduction of any new or modified policies.

  11. Pharmacokinetics and pharmacodynamics of intravenous inotropic agents.

    PubMed

    Lehtonen, Lasse A; Antila, Saila; Pentikäinen, Pertti J

    2004-01-01

    Positive inotropic drugs have various mechanisms of action. Long-term use of cyclic adenosine monophosphate (cAMP)-dependent drugs has adverse effects on the prognosis of heart failure patients, whereas digoxin has neutral effect on mortality. There are, however, little data on the effects of intravenous inotropic drugs on the outcome of patients. Intravenous inotropic agents are used to treat cardiac emergencies and refractory heart failure. beta-Adrenergic agonists are rapid acting and easy to titrate, with short elimination half-life. However, they increase myocardial oxygen consumption and are thus hazardous during myocardial ischaemia. Furthermore they may promote myocyte apoptosis. Phosphodiesterase (PDE) III inhibiting drugs (amrinone, milrinone and enoximone) increase contractility by reducing the degradation of cAMP. In addition, they reduce both preload and afterload via vasodilation. Short-term use of intravenous milrinone is not associated with increased mortality, and some symptomatic benefit may be obtained when it is used in refractory heart failure. Furthermore, PDE III inhibitors facilitate weaning from the cardiopulmonary bypass machine after cardiac surgery. Levosimendan belongs to a new group of positive inotropic drugs, the calcium sensitisers. It has complex pharmacokinetics and long-lasting haemodynamic effects as a result of its active metabolites. In comparative trials, it has been better tolerated than the most widely used beta-agonist inotropic drug, dobutamine. The pharmacokinetics of the intravenous inotropic drugs might sometimes greatly modify and prolong the response to the therapy, for example because of long-acting active metabolites. These drugs display considerable differences in their pharmacokinetics and pharmacodynamics, and the selection of the most appropriate inotropic drug for each patient should be based on careful consideration of the clinical status of the patient and on the pharmacology of the drug.

  12. Pharmacokinetics of a nicotine polacrilex lozenge.

    PubMed

    Choi, Jae H; Dresler, Carolyn M; Norton, Michele R; Strahs, Kenneth R

    2003-10-01

    To evaluate the pharmacokinetic characteristics of the 2-mg and 4-mg nicotine polacrilex lozenges, the following four separate studies were conducted in healthy adult smokers: (a) A single-dose, four-way crossover (replicate design) study to compare the 4-mg lozenge and the 4-mg nicotine polacrilex gum, (b) a single-dose, two-way crossover study to compare the 2-mg lozenge and the 2-mg gum, (c) a multiple-dose, four-way crossover study to compare the lozenges administered every 90 min and the gums administered every 60 min at 2- and 4-mg dose levels, and (d) a single-dose, three-way crossover study to compare the pharmacokinetic profiles of the 4-mg lozenge when administered in three different ways: (i) Used as directed, (ii) chewed and immediately swallowed, and (iii) chewed, retained in the mouth for 5 min, and then swallowed. The single-dose studies consistently demonstrated 8%-10% higher maximal plasma concentrations and 25%-27% higher AUC values (area under the concentration-time curve) from the lozenges compared with the gums at the 2- and 4-mg dose levels, probably owing to the residual nicotine retained in the gum. The multiple-dose study applying different dosing intervals (i.e., every 90 min for the lozenges and every 60 min for the gums) resulted in approximately 30% lower AUC(0-t) values for the lozenges compared with those for the gums. Administration of the lozenge contrary to the label-specified instructions for use did not lead to a faster or higher absorption of nicotine. These pharmacokinetic characteristics should allow the lozenge to become an effective and safe therapeutic alternative for smoking cessation.

  13. The pharmacokinetics of meloxicam in vultures.

    PubMed

    Naidoo, V; Wolter, K; Cromarty, A D; Bartels, P; Bekker, L; McGaw, L; Taggart, M A; Cuthbert, R; Swan, G E

    2008-04-01

    Vulture populations across the Asian subcontinent have declined dramatically in the last 15 years and are now on the verge of extinction. Although the cause of the population decline was initially unknown, the decrease has recently been conclusively linked to the use of the nonsteroidal anti-inflammatory drug diclofenac in cattle that inadvertently ended up in the vulture food chain. With the vulture numbers continuing to decline by up to 48% a year, the Indian, Nepali and Pakistan governments have recently banned the manufacture and importation of veterinary diclofenac. They have also suggested meloxicam as an alternate anti-inflammatory for use in cattle. This recommendation was based on extensive acute safety studies in the African White-backed vulture (Gyps africanus), which evaluated worst case scenarios of maximum intake based on a once in three day feeding pattern. However, the possible cumulative pharmacokinetic and pharmacodynamic effects in vultures receiving multiple daily doses of meloxicam over time were not assessed. At present very little pharmacokinetic or pharmacodynamic information is available to add further support for the safety of meloxicam in this animal species. This article discusses the oral and intramuscular pharmacokinetics of meloxicam in Cape Griffon vultures (Gyps coprotheres). Therapeutic drug monitoring was also undertaken in White-backed, Egyptian (Neophron pernopterus) and one Lappet Faced vulture (Torgos tracheliotos). In all these species, meloxicam was characterized by a short half-life of elimination. The rapid metabolism of meloxicam in combination with a short duration of effect in the studied species Gyps vultures shown in this study makes it unlikely that the drug could accumulate. This confirms the safety of repeated exposure to meloxicam in vultures of this genus.

  14. Pharmacokinetics of a nicotine polacrilex lozenge.

    PubMed

    Choi, Jae H; Dresler, Carolyn M; Norton, Michele R; Strahs, Kenneth R

    2003-10-01

    To evaluate the pharmacokinetic characteristics of the 2-mg and 4-mg nicotine polacrilex lozenges, the following four separate studies were conducted in healthy adult smokers: (a) A single-dose, four-way crossover (replicate design) study to compare the 4-mg lozenge and the 4-mg nicotine polacrilex gum, (b) a single-dose, two-way crossover study to compare the 2-mg lozenge and the 2-mg gum, (c) a multiple-dose, four-way crossover study to compare the lozenges administered every 90 min and the gums administered every 60 min at 2- and 4-mg dose levels, and (d) a single-dose, three-way crossover study to compare the pharmacokinetic profiles of the 4-mg lozenge when administered in three different ways: (i) Used as directed, (ii) chewed and immediately swallowed, and (iii) chewed, retained in the mouth for 5 min, and then swallowed. The single-dose studies consistently demonstrated 8%-10% higher maximal plasma concentrations and 25%-27% higher AUC values (area under the concentration-time curve) from the lozenges compared with the gums at the 2- and 4-mg dose levels, probably owing to the residual nicotine retained in the gum. The multiple-dose study applying different dosing intervals (i.e., every 90 min for the lozenges and every 60 min for the gums) resulted in approximately 30% lower AUC(0-t) values for the lozenges compared with those for the gums. Administration of the lozenge contrary to the label-specified instructions for use did not lead to a faster or higher absorption of nicotine. These pharmacokinetic characteristics should allow the lozenge to become an effective and safe therapeutic alternative for smoking cessation. PMID:14577980

  15. The pharmacokinetics of meloxicam in vultures.

    PubMed

    Naidoo, V; Wolter, K; Cromarty, A D; Bartels, P; Bekker, L; McGaw, L; Taggart, M A; Cuthbert, R; Swan, G E

    2008-04-01

    Vulture populations across the Asian subcontinent have declined dramatically in the last 15 years and are now on the verge of extinction. Although the cause of the population decline was initially unknown, the decrease has recently been conclusively linked to the use of the nonsteroidal anti-inflammatory drug diclofenac in cattle that inadvertently ended up in the vulture food chain. With the vulture numbers continuing to decline by up to 48% a year, the Indian, Nepali and Pakistan governments have recently banned the manufacture and importation of veterinary diclofenac. They have also suggested meloxicam as an alternate anti-inflammatory for use in cattle. This recommendation was based on extensive acute safety studies in the African White-backed vulture (Gyps africanus), which evaluated worst case scenarios of maximum intake based on a once in three day feeding pattern. However, the possible cumulative pharmacokinetic and pharmacodynamic effects in vultures receiving multiple daily doses of meloxicam over time were not assessed. At present very little pharmacokinetic or pharmacodynamic information is available to add further support for the safety of meloxicam in this animal species. This article discusses the oral and intramuscular pharmacokinetics of meloxicam in Cape Griffon vultures (Gyps coprotheres). Therapeutic drug monitoring was also undertaken in White-backed, Egyptian (Neophron pernopterus) and one Lappet Faced vulture (Torgos tracheliotos). In all these species, meloxicam was characterized by a short half-life of elimination. The rapid metabolism of meloxicam in combination with a short duration of effect in the studied species Gyps vultures shown in this study makes it unlikely that the drug could accumulate. This confirms the safety of repeated exposure to meloxicam in vultures of this genus. PMID:18307504

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

    PubMed

    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.

  17. Pharmacokinetic parameters of bevantolol in volunteers.

    PubMed

    Vermeij, P; van Brummelen, P

    1986-01-01

    The pharmacokinetics of the new beta-adrenoceptor blocking drug bevantolol and some aspects of its beta-blocking effect have been studied in healthy volunteers. Bevantolol had a short serum half-life (86 +/- 33 min) and high systemic availability after oral administration. The observed changes in heart rate, systolic blood pressure during exercise and plasma renin activity were all compatible with beta-adrenoceptor blockade. After 200 mg p.o. in the morning, the effects lasted for less than 24 h.

  18. MEGen: A Physiologically Based Pharmacokinetic Model Generator

    PubMed Central

    Loizou, George; Hogg, Alex

    2011-01-01

    Physiologically based pharmacokinetic models are being used in an increasing number of different areas. However, they are perceived as complex, data hungry, resource intensive, and time consuming. In addition, model validation and verification are hindered by the relative complexity of the equations. To begin to address these issues a web application called MEGen for the rapid construction and documentation of bespoke deterministic PBPK model code is under development. MEGen comprises a parameter database and a model code generator that produces code for use in several commercial software packages and one that is freely available. Here we present an overview of the current capabilities of MEGen, and discuss future developments. PMID:22084631

  19. Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5-hydroxytryptamine 1B receptor antagonist.

    PubMed

    Zhang, Minli; Zhou, Diansong; Wang, Yi; Maier, Donna L; Widzowski, Daniel V; Sobotka-Briner, Cynthia D; Brockel, Becky J; Potts, William M; Shenvi, Ashok B; Bernstein, Peter R; Pierson, M Edward

    2011-11-01

    The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8-(4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation-induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients.

  20. L-286 Acceptance Test Record

    SciTech Connect

    HARMON, B.C.

    2000-01-14

    This document provides a detailed account of how the acceptance testing was conducted for Project L-286, ''200E Area Sanitary Water Plant Effluent Stream Reduction''. The testing of the L-286 instrumentation system was conducted under the direct supervision

  1. Accepted scientific research works (abstracts).

    PubMed

    2014-01-01

    These are the 39 accepted abstracts for IAYT's Symposium on Yoga Research (SYR) September 24-24, 2014 at the Kripalu Center for Yoga & Health and published in the Final Program Guide and Abstracts. PMID:25645134

  2. Lipid nanoparticles: effect on bioavailability and pharmacokinetic changes.

    PubMed

    Souto, Eliana B; Müller, Rainer H

    2010-01-01

    The main aim of pharmaceutical technology research is the design of successful formulations for effective therapy, taking into account several issues including therapeutic requirements and patient compliance. In this regard, several achievements have been reported with colloidal carriers, in particular with lipid nanoparticles, due to their unique physicochemical properties. For several years these carriers have been showing potential success for several administration routes, namely oral, dermal, parenteral, and, more recently, for pulmonary and brain targeting. The present chapter provides a review of the use of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) to modify the release profile and the pharmacokinetic parameters of active pharmaceutical ingredients (APIs) incorporated in these lipid matrices, aiming to modify the API bioavailability, either upwards or downwards depending on the therapeutic requirement. Definitions of the morphological characteristics, surface properties, and polymorphic structures will also be given, emphasizing their influence on the incorporation parameters of the API, such as yield of production, loading capacity, and encapsulation efficiency. PMID:20217528

  3. Lipid nanocarriers: influence of lipids on product development and pharmacokinetics.

    PubMed

    Pathak, Kamla; Keshri, Lav; Shah, Mayank

    2011-01-01

    Lipid nanocarriers are on the forefront of the rapidly developing field of nanotechnology with several potential applications in drug delivery. Owing to their size-dependent properties, lipid nanoparticles offer the possibility for development of new therapeutics and an alternative system to other colloidal counterparts for drug administration. An important point to be considered in the selection of a lipid for the carrier system is its effect on the properties of the nanocarrier and also its intended use, as different types of lipids differ in their nature. Researchers around the globe have tapped the potential of solid lipid nanoparticles (SLNs) in developing formulation(s) that can be administered by various routes such as oral, ocular, parenteral, topical, and pulmonary. Since the start of this millennium, a new generation of lipid nanoparticles, namely nanostructured lipid carriers (NLCs), lipid drug conjugates (LDCs), and pharmacosomes, has evolved that have the potential to overcome the limitations of SLNs. The current review article presents broad considerations on the influence of various types of lipids on the diverse characteristics of nanocarriers, encompassing their physicochemical, formulation, pharmacokinetic, and cytotoxic aspects. PMID:21967401

  4. Ginkgo biloba extracts: a review of the pharmacokinetics of the active ingredients.

    PubMed

    Ude, Christian; Schubert-Zsilavecz, Manfred; Wurglics, Mario

    2013-09-01

    Ginkgo biloba is among the most favourite and best explored herbal drugs. Standardized extracts of Ginkgo biloba represent the only herbal alternative to synthetic antidementia drugs in the therapy of cognitive decline and Alzheimer's diseases. The clinical efficiency of such standardized Ginkgo biloba extracts (GBE) is still controversial, but authors of numerous international clinical studies recommended the use of GBE in the described therapies.Extracts of Ginkgo biloba are a mixture of substances with a wide variety of physical and chemical properties and activities. Numerous pharmacological investigations lead to the conclusion that the terpene trilactones (TTL) and the flavonoids of GBE are responsible for the main pharmacological effects of the extract in the therapy of cognitive decline. Therefore, the quality of GBE products must be oriented on a defined quantity of TTL and flavonoids. Furthermore, because of their toxic potential the amount of ginkgolic acid should be less than 5 ppm.However, data on pharmacokinetics and bioavailability, especially related to the central nervous system (CNS), which is the target tissue, are relatively rare. A few investigations characterize the TTL and flavonoids of Ginkgo biloba pharmacokinetically in plasma and in the brain. Recent investigations show that significant levels of TTL and Ginkgo biloba flavonoids cross the blood-brain barrier and enter the CNS of rats after oral application of GBE. Knowledge about the pharmacokinetic behaviour of these substances is necessary to discuss the pharmacological results on a more realistic basis.

  5. Comparison of the pharmacokinetics of linezolid in burn and non-burn rabbits.

    PubMed

    Ma, Jian-Li; Gao, Lei; Li, Xiang; Chu, Wan-Li; Feng, Yong-Qiang; Wang, Xiao-Qin; Zhang, Qing-Zhe

    2015-09-01

    Linezolid is effective on many resistant organisms for the treatment of severe infections in burns. However, its pharmacokinetics was difficult to predict after major burns. The study aimed to describe the pharmacokinetic properties of linezolid administered intravenously at a dose of 10 mg/kg in severely burned rabbits in comparison to that in non-burns. Linezolid concentrations were quantitatively analyzed by high-performance liquid chromatography. The direct consequence of the physiological changes after burn injury was lower plasma linezolid concentrations. In addition, burn injury induced significantly altered pharmacokinetic parameters with higher inter-individual variability. The distribution volume and clearance rate were increased (2.88 vs. 1.92 L/kg, P > 0.05; 0.28 vs. 0.20 L/h/kg, P < 0.05), and the AUC0-∞ was significantly lower (37.99 vs. 51.47 mg/L h, P < 0.05). However, there were almost no changes in half-life and mean residence time. These results suggested that therapeutic drug monitoring and dosage individualization of linezolid in patients with severe burns were necessary.

  6. In vitro/in vivo phototoxic risk assessments of griseofulvin based on photobiochemical and pharmacokinetic behaviors.

    PubMed

    Seto, Yoshiki; Onoue, Satomi; Yamada, Shizuo

    2009-09-10

    The present investigation aims to establish efficacious screening strategy to clarify the phototoxic potential of pharmaceutical substances and its possible pathways by characterizing both photobiochemical properties and pharmacokinetic profiles. Photochemical behavior of griseofulvin, as model compounds, was evaluated by reactive oxygen species (ROS) assay, and the photogenotoxic potential was also assessed by DNA binding assay, DNA photocleavage assay, and atomic force microscopy. Pharmacokinetic (PK) study was also carried out after dermal and oral administration of griseofulvin in rats. ROS assay suggested the phototoxic potential of griseofulvin via type II photochemical pathways, and the photogenotoxic risk of griseofulvin was also proposed as evidenced by high affinity toward DNA and potent DNA photocleaving activity. PK profiling and in vivo phototoxicity testing demonstrated that a highly concentrated griseofulvin in the skin might cause phototoxic skin reactions in rats, whereas oral administration of griseofulvin in single dosing regimen (20mg/kg) resulted in 10(3)-fold less skin deposition than phototoxic skin concentration of griseofulvin. Upon these findings, the phototoxic potential of griseofulvin might not be severe at least in a single oral dosing regimen, whereas it might be phototoxic in dermal administration. The combination use of photobiochemical and pharmacokinetic data would be valuable to provide reliable prediction on phototoxic risk and possible toxic pathways of new drug entities in the early stage of drug discovery.

  7. Pharmacokinetic Interactions between Primaquine and Pyronaridine-Artesunate in Healthy Adult Thai Subjects

    PubMed Central

    Jittamala, Podjanee; Pukrittayakamee, Sasithon; Ashley, Elizabeth A.; Nosten, François; Hanboonkunupakarn, Borimas; Lee, Sue J.; Thana, Praiya; Chairat, Kalayanee; Blessborn, Daniel; Panapipat, Salwaluk; White, Nicholas J.; Day, Nicholas P. J.

    2014-01-01

    Pyronaridine-artesunate is a newly introduced artemisinin-based combination treatment which may be deployed together with primaquine. A single-dose, randomized, three-sequence crossover study was conducted in healthy Thai volunteers to characterize potential pharmacokinetic interactions between these drugs. Seventeen healthy adults received a single oral dose of primaquine alone (30 mg base) and were then randomized to receive pyronaridine-artesunate alone (540−180 mg) or pyronaridine-artesunate plus primaquine in combination, with intervening washout periods between all treatments. The pharmacokinetic properties of primaquine, its metabolite carboxyprimaquine, artesunate, its metabolite dihydroartemisinin, and pyronaridine were assessed in 15 subjects using a noncompartmental approach followed by a bioequivalence evaluation. All drugs were well tolerated. The single oral dose of primaquine did not result in any clinically relevant pharmacokinetic alterations to pyronaridine, artesunate, or dihydroartemisinin exposures. There were significantly higher primaquine maximum plasma drug concentrations (geometric mean ratio, 30%; 90% confidence interval [CI], 17% to 46%) and total exposures (15%; 6.4% to 24%) during coadministration with pyronaridine-artesunate than when primaquine was given alone. Pyronaridine, like chloroquine and piperaquine, increases plasma primaquine concentrations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01552330.) PMID:25385096

  8. Enantioselective pharmacokinetics of ketoprofen in calves after intramuscular administration of a racemic mixture.

    PubMed

    Plessers, E; Watteyn, A; Wyns, H; Pardon, B; De Baere, S; De Backer, P; Croubels, S

    2015-08-01

    The pharmacokinetic properties of ketoprofen were determined in 4-week-old calves after intramuscular (i.m.) injection of a racemic mixture at a dose of 3 mg/kg body weight. Due to possible enantioselective disposition kinetics and chiral inversion, the plasma concentrations of the R(-) and S(+) enantiomer were quantified separately, using a stereospecific HPLC-UV assay. A distinct predominance of the S(+) enantiomer was observed, as well as significantly different pharmacokinetic parameters between R(-) and S(+) ketoprofen. More in specific, a greater value for the mean area under the plasma concentration-time curve (AUC(0→∞)) (46.92 ± 7.75 and 11.13 ± 2.18 μg·h/mL for the S(+) and R(-) enantiomer, respectively), a lower apparent clearance (Cl/F) (32.8 ± 5.7 and 139.0 ± 25.1 mL/h·kg for the S(+) and R(-) enantiomer, respectively) and a lower apparent volume of distribution (V(d)/F) (139 ± 14.7 and 496 ± 139.4 mL/kg for the S(+) and R(-) enantiomer, respectively) were calculated for the S(+) enantiomer, indicating enantioselective pharmacokinetics for ketoprofen in calves following i.m. administration.

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

    PubMed

    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.

  10. Development of a Physiologically-Based Pharmacokinetic Model of the Rat Central Nervous System

    PubMed Central

    Badhan, Raj K. Singh; Chenel, Marylore; Penny, Jeffrey I.

    2014-01-01

    Central nervous system (CNS) drug disposition is dictated by a drug’s physicochemical properties and its ability to permeate physiological barriers. The blood–brain barrier (BBB), blood-cerebrospinal fluid barrier and centrally located drug transporter proteins influence drug disposition within the central nervous system. Attainment of adequate brain-to-plasma and cerebrospinal fluid-to-plasma partitioning is important in determining the efficacy of centrally acting therapeutics. We have developed a physiologically-based pharmacokinetic model of the rat CNS which incorporates brain interstitial fluid (ISF), choroidal epithelial and total cerebrospinal fluid (CSF) compartments and accurately predicts CNS pharmacokinetics. The model yielded reasonable predictions of unbound brain-to-plasma partition ratio (Kpuu,brain) and CSF:plasma ratio (CSF:Plasmau) using a series of in vitro permeability and unbound fraction parameters. When using in vitro permeability data obtained from L-mdr1a cells to estimate rat in vivo permeability, the model successfully predicted, to within 4-fold, Kpuu,brain and CSF:Plasmau for 81.5% of compounds simulated. The model presented allows for simultaneous simulation and analysis of both brain biophase and CSF to accurately predict CNS pharmacokinetics from preclinical drug parameters routinely available during discovery and development pathways. PMID:24647103

  11. Property.

    ERIC Educational Resources Information Center

    Piele, Philip K.; Johnson, Margaret M.

    This chapter deals with 1981 cases involving disputes over property. Cases involving the detachment and attachment of land continue to dominate the property chapter with 11 cases reported, the same number summarized in last year's chapter. One case involving school board referenda raised the interesting question of whether or not a state could…

  12. Property.

    ERIC Educational Resources Information Center

    Bickel, Robert D.; Zeller, Trisha A.

    A number of cases related to property issues involving institutions of higher education are examined in this chapter. Cases discussed touch on such topics as funding for property and equipment acquisition; opposition to building construction or demolition; zoning issues; building construction and equipment contracts; and lease agreements. Current…

  13. Pharmacokinetics of oral ivabradine in healthy cats.

    PubMed

    Riesen, S C; Ni, W; Carnes, C A; Lindsey, K J; Phelps, M A; Schober, K E

    2011-10-01

    A liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method for the measurement of the novel heart rate-lowering drug ivabradine and its major metabolite, S-18982, was cross-validated in the plasma of eight healthy cats. Plasma concentrations were then determined after single and repeated oral administration of ivabradine. Individual plasma concentrations versus time from each cat were used in compartmental analysis using the commercially available software WinNonlin. Both ivabradine and S-18982 reached their maximum concentrations of 103.33 and 3.86 ng/mL within 1 h. Following repeated administration, areas under the plasma concentration-time curves for ivabradine and S-18982 did not significantly increase. Two-compartmental and one-compartmental models with first-order input and elimination provided the best fit to the data for ivabradine and S-18982, respectively. Both models were combined to produce a single 4-compartment model characterizing ivabradine and S-18982 pharmacokinetics. The results of this study indicate that repeated oral doses of ivabradine produced plasma drug concentrations suitable for 12-h dosing intervals in healthy cats. Furthermore, the analytical assay and combined ivabradine/S-18982 model provide tools for further evaluation of ivabradine pharmacokinetics and pharmacodynamics in future studies in cats.

  14. Pharmacokinetics of sevoflurane uptake into the brain.

    PubMed

    Turner, M J; McCulloch, T J; Kennedy, R R; Baker, A B

    2004-12-01

    Two recent studies have examined the pharmacokinetics of sevoflurane in adults. Lu et al.(Pharmacokinetics of sevoflurane uptake into the brain and body, Anaesthesia 2003; 58: 951-6) observed that jugular bulb sevoflurane concentration initially rose unexpectedly rapidly and then approached arterial concentrations unexpectedly slowly, suggesting that a blood-brain diffusion barrier exists. They also observed a large alveolar-arterial sevoflurane gradient, suggesting that an alveolar-arterial diffusion barrier exists. Nakamura et al. (Predicted sevoflurane partial pressure in the brain with an uptake and distribution model: Comparison with the measured value in internal jugular vein blood. Journal of Clinical Monitoring and Computing 1999; 15: 299-305) found no diffusion barriers. We used a computer model to analyse both data sets and show that the observations of Lu et al. can be explained by contamination of jugular samples with extracerebral blood. It is possible that the alveolar-arterial gradients observed by Lu et al. are due to discrepancies in conversions between blood concentrations and gas partial pressures. Our study suggests that there is no blood-brain diffusion barrier for sevoflurane and that the data of Lu et al. must be interpreted with caution.

  15. Salicylate pharmacokinetics in patients with rheumatoid arthritis.

    PubMed Central

    Owen, S G; Roberts, M S; Friesen, W T; Francis, H W

    1989-01-01

    1. The pharmacokinetics of salicylic acid (SA) and its major metabolite salicyluric acid (SU) were studied in nine patients with rheumatoid arthritis following a 900 mg oral dose of acetylsalicylic acid and during 6 weeks of chronic administration of enteric coated aspirin (3,900 mg day). Response to therapy was also monitored. 2. The various pharmacokinetic parameters determined in the study were similar to those observed in other single dose salicylate studies amongst healthy volunteers but were not predictive of salicylate concentration in the chronic dose study. 3. Plasma concentrations of SA (total and unbound) were found to decline significantly over the 6 weeks and plasma SU concentrations increased. 4. During the chronic dosing study, there was a significant increase in the Vmax (total and unbound) for the formation of SU, whilst the Km and SU clearance remained constant. Also, the elimination rate constant (k) for salicylate was not significantly affected. 5. Therapeutic response to salicylate therapy was not significantly affected by the decline in SA concentrations. PMID:2590603

  16. Virtual modelling of compartmental pharmacokinetic systems.

    PubMed

    Prado, Manuel; Roa, Laura

    2005-01-01

    This paper presents an analysis of different methodologies for modelling pharmacokinetic systems under the context of a telemedicine system oriented to the on-line and personalized knowledge generation. We use a simplified 3-pool kinetic system for a better clarification of several relevant modelling formalisms. A more complete 3-pool urea kinetic model is built simply connecting EL components pertaining to a pharmacokinetic library previously developed. The evolution of the urea concentration during the dialysis of a patient provided by this model was compared successfully to the evolution computed by a 2-pool model experimentally validated. The 3-pool model provides more information regarding the interstice and a high capacity to be modified for attending to the knowledge needs of physicians, as well as biomedicine advances. As a major conclusion, our outcomes suggest that virtual modelling is an excellent methodology in biomedical engineering to support the on-line generation of personalized health knowledge for telemedicine systems. This is due to its capacity for reusing components at horizontal and vertical level, and for implementing multiformalism and multidomain models, what simplifies the task to represent complex physiological and artificial systems. PMID:17282097

  17. The Pharmacokinetics and Pharmacodynamics of Iron Preparations

    PubMed Central

    Geisser, Peter; Burckhardt, Susanna

    2011-01-01

    Standard approaches are not appropriate when assessing pharmacokinetics of iron supplements due to the ubiquity of endogenous iron, its compartmentalized sites of action, and the complexity of the iron metabolism. The primary site of action of iron is the erythrocyte, and, in contrast to conventional drugs, no drug-receptor interaction takes place. Notably, the process of erythropoiesis, i.e., formation of new erythrocytes, takes 3–4 weeks. Accordingly, serum iron concentration and area under the curve (AUC) are clinically irrelevant for assessing iron utilization. Iron can be administered intravenously in the form of polynuclear iron(III)-hydroxide complexes with carbohydrate ligands or orally as iron(II) (ferrous) salts or iron(III) (ferric) complexes. Several approaches have been employed to study the pharmacodynamics of iron after oral administration. Quantification of iron uptake from radiolabeled preparations by the whole body or the erythrocytes is optimal, but alternatively total iron transfer can be calculated based on known elimination rates and the intrinsic reactivity of individual preparations. Degradation kinetics, and thus the safety, of parenteral iron preparations are directly related to the molecular weight and the stability of the complex. High oral iron doses or rapid release of iron from intravenous iron preparations can saturate the iron transport system, resulting in oxidative stress with adverse clinical and subclinical consequences. Appropriate pharmacokinetics and pharmacodynamics analyses will greatly assist our understanding of the likely contribution of novel preparations to the management of anemia. PMID:24310424

  18. Pharmacokinetics of subcutaneous fentanyl in Greyhounds.

    PubMed

    KuKanich, Butch

    2011-11-01

    The purpose of the study was to describe the pharmacokinetics of subcutaneous fentanyl (15μg/kg) in six healthy Greyhound dogs. Fentanyl plasma concentrations were determined by a liquid chromatography with mass spectrometry method. Non-compartmental pharmacokinetic analysis was used. Fentanyl was rapidly absorbed with a mean peak concentration (C(MAX)) of 3.56ng/mL at 0.24h. The mean terminal half-life, volume of distribution per bioavailability, and clearance per bioavailability were 2.97h, 7.09L/kg, 27.60mL/min/kg, respectively. Pain occurred on injection in all six dogs, but addition of 8.4% sodium bicarbonate (1mL per 20mL fentanyl) resulted in no pain on injection in 3/3 dogs but similar C(MAX) values. The subcutaneous route may be an alternative route of fentanyl administration if intravenous administration is not practical. PMID:21388844

  19. Pharmacokinetic study of copper (II) acetylsalicylate.

    PubMed

    Iqbal, Mohammad S; Sher, Muhammad; Pervez, Humayun; Saeed, Maryiam

    2008-09-01

    This study was aimed at determination of pharmacokinetic parameters of copper (II) acetylsalicylate (CAS). Ten volunteers received a 60-mg dose of CAS. Blood samples were collected just before and after 0.25, 0.5, 0.75, 1.0, 1.5, 2.5, 3.0, 3.5, 4.0, 4.5, 5.5, 7.0, 10, and 12.0 h of administration of the drug. The plasma samples were analyzed for CAS and its metabolites by a validated high-performance liquid chromatography method having a suitable lower limit of quantification. The dose of 60 mg was well tolerated without any adverse effect. The maximum plasma concentration of CAS was found to be 0.38 mg L(-1) with t (max) of 0.72 h. The plasma half-life, clearance, and volume of distribution of CAS were 8.67 h, 66.30 L h(-1) and 829 L kg(-1), respectively. The elimination of CAS, acetylsalicylic acid, copper salicylate, and salicylic acid follows the first order kinetics with r (2) 0.979, 0.880, 0.991, and 0.998, respectively. The study provided for the first time the pharmacokinetic data for CAS after oral administration of CAS. The data were found to be useful in understanding the claimed enhanced anti-inflammatory activity of the drug as compared with that of acetylsalicylic acid. PMID:18478192

  20. Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans

    PubMed Central

    Huestis, M.A.; Cone, E.J.; Pirnay, S.O.; Umbricht, A.; Preston, K.L.

    2013-01-01

    Background Prescribed sublingual (SL) buprenorphine is sometimes diverted for intravenous (IV) abuse, but no human pharmacokinetic data are available following high-dose IV buprenorphine. Methods Plasma was collected for 72 h after administration of placebo or 2, 4, 8, 12, or 16 mg IV buprenorphine in escalating order (single-blind, double-dummy) in 5 healthy male non-dependent opioid users. Buprenorphine and its primary active metabolite, norbuprenorphine, were quantified by liquid chromatography tandem mass spectrometry with limits of quantitation of 0.1 μg/L. Results Maximum buprenorphine concentrations (mean ± SE) were detected 10 min after 2, 4, 8, 12, 16 mg IV: 19.3±1.0, 44.5±4.8, 85.2±7.7, 124.6±16.6, and 137.7±18.8 μg/L, respectively. Maximum norbuprenorphine concentrations occurred 10–15 min (3.7±0.7 μg/L) after 16 mg IV administration. Conclusions Buprenorphine concentrations increased in a significantly linear dose-dependent manner up to 12 mg IV buprenorphine. Thus, previously demonstrated pharmacodynamic ceiling effects (over 2–16 mg) are not due to pharmacokinetic adaptations within this range, although they may play a role at doses higher than 12 mg. PMID:23246635

  1. Colistin: understanding and applying recent pharmacokinetic advances.

    PubMed

    Ortwine, Jessica K; Kaye, Keith S; Li, Jian; Pogue, Jason M

    2015-01-01

    Colistin, the most widely used polymyxin antibiotic, was originally introduced in the late 1950s before the establishment of the present-day drug approval process. Originally shelved due to toxicity concerns, colistin, in the form of its inactive prodrug colistin methanesulfonate, has undergone a renaissance in the past 15 years. Unfortunately, this is not because of an improved adverse-effect profile but because colistin is among the only remaining antibiotics with activity against multidrug-resistant gram-negative bacilli. Pharmacokinetic and pharmacodynamic data are limited to guide the appropriate use of colistin; however, important advances have occurred over the past 5 years. Since its reintroduction, published reports regarding colistin have produced discordant results in terms of both efficacy and safety. Because the efficacy and toxicity of colistin are dose dependent, the impact of discordant dosing recommendations cannot be understated. This review highlights the issues leading to differing and often conflicting dosing recommendations, reviews the recent pharmacokinetic advances, and provides recommendations for the optimal use of colistin.

  2. Physiologically based pharmacokinetics and cancer risk assessment.

    PubMed Central

    Andersen, M E; Krishnan, K

    1994-01-01

    Physiologically based pharmacokinetic (PBPK) modeling involves mathematically describing the complex interplay of the critical physicochemical and biological determinants involved in the disposition of chemicals. In this approach, the body is divided into a number of biologically relevant tissue compartments, arranged in an anatomically accurate manner, and defined with appropriate physiological characteristics. The extrapolation of pharmacokinetic behavior of chemicals from high dose to low dose for various exposure routes and species is possible with this approach because these models are developed by integrating quantitative information on the critical determinants of chemical disposition under a biological modeling framework. The principal application of PBPK models is in the prediction of tissue dosimetry of toxic moiety (e.g., parent chemical, reactive metabolite, macromolecular adduct) of a chemical. Such an application has been demonstrated with dichloromethane, a liver and lung carcinogen in the B6C3F1 mouse. The PBPK model-based risk assessment approach estimated a cancer risk to people of 3.7 x 10(-8) for a lifetime inhalation exposure of 1 micrograms/m3, which is lower by more than two orders of magnitude than that calculated by the U.S. Environmental Protection Agency using the linearized multistage model (for low-dose extrapolation) and body surface correction factor (for interspecies scaling). The capability of predicting the target tissue exposure to toxic moiety in people with PBPK models should help reduce the uncertainty associated with the extrapolation procedures adopted in conventional dose-response assessment. PMID:8187697

  3. Pharmacokinetics of Antiretrovirals in Mucosal Tissue

    PubMed Central

    Cottrell, M.L.; Srinivas, N.; Kashuba, A.D.M.

    2015-01-01

    Introduction In the absence of an HIV vaccine or cure, antiretroviral (ARV) based prevention strategies are being investigated to reduce HIV incidence. These prevention strategies depend on achieving effective drug concentrations at the site HIV exposure which is most commonly the mucosal tissues of the lower gastrointestinal tract and the female genital tract. Areas covered This article collates all known data regarding drug exposure in these vulnerable mucosal tissues, and reviews important mechanisms of ARV drug distribution. Research papers and abstracts describing antiretroviral pharmacokinetics in the female genital tract and lower gastrointestinal mucosal tissues available in MEDLINE® or presented at scientific conferences prior to December 2014 are reviewed in detail. Important influences on ARV mucosal tissue distribution, including protein binding, active drug transport, and endogenous hormones, are also reviewed. Expert opinion ARVs exhibit highly variable pharmacokinetics in mucosal tissues. In general, antiretroviral exposure is higher in the lower gastrointestinal tract compared to the female genital tract, but concentrations required for protective efficacy are largely unknown. The expected site of HIV exposure represents an important consideration when designing and optimizing antiretroviral based prevention strategies. PMID:25797064

  4. Pharmacokinetic/pharmacodynamic-based optimization of levofloxacin administration in the treatment of MDR-TB.

    PubMed

    Ghimire, Samiksha; Van't Boveneind-Vrubleuskaya, Natasha; Akkerman, Onno W; de Lange, Wiel C M; van Soolingen, Dick; Kosterink, Jos G W; van der Werf, Tjip S; Wilffert, Bob; Touw, Daniel J; Alffenaar, Jan-Willem C

    2016-10-01

    The emergence of MDR-TB and XDR-TB has complicated TB treatment success. Among many factors that contribute to the development of resistance, low drug exposure is not the least important. This review summarizes the available information on pharmacokinetic properties of levofloxacin in relation to microbial susceptibilities, in order to optimize the dose and make general treatment recommendations. A total of 37 studies on adult (32 studies) and paediatric (5 studies) MDR-TB patients were included. Among the 32 adult studies, 19 were on susceptibility of Mycobacterium tuberculosis isolates to levofloxacin by MIC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by MBC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by mutant prevention concentration and 4 were on pharmacokinetics of levofloxacin, and 7 others were included. Likewise, out of five studies on children, two dealt with levofloxacin pharmacokinetic parameters, one reviewed CSF concentrations and two dealt with background information. In adult MDR-TB patients, standard dosing of once-daily 1000 mg levofloxacin in TB treatment did not consistently attain the target concentration (i.e. fAUC/MIC >100 and fAUC/MBC >100) in 80% of the patients with MIC and MBC of 1 mg/L, leaving them at risk of developing drug resistance. However, with an MIC of 0.5 mg/L, 100% of the patients achieved the target concentration. Similarly, paediatric patients failed consistently in achieving given pharmacokinetic/pharmacodynamic targets due to age-related differences, demanding a shift towards once daily dosing of 15-20 mg/kg. Therefore, we recommend therapeutic drug monitoring for patients with strains having MICs of ≥0.5 mg/L and suggest revising the cut-off value from 2 to 1 mg/L.

  5. Pharmacokinetics and immunogenicity of a recombinant human butyrylcholinesterase bioscavenger in macaques following intravenous and pulmonary delivery.

    PubMed

    Rosenberg, Yvonne J; Adams, Robert J; Hernandez-Abanto, Segundo; Jiang, Xiaoming; Sun, Wei; Mao, Lingjun; Lee, K David

    2015-12-01

    Recombinant (r) and native butyrylcholinesterse (BChE) are potent bioscavengers of organophosphates (OPs) such as nerve agents and pesticides and are undergoing development as antidotal treatments for OP-induced toxicity. Because of the lethal properties of such agents, regulatory approval will require extensive testing under the Animal Rule. However, human (Hu) glycoprotein biologicals, such as BChE, present a challenge for assessing immunogenicity and efficacy in heterologous animal models since any immune responses to the small species differences in amino acids or glycans between the host and biologic may alter pharmacodynamics and preclude accurate efficacy testing; possibly underestimating their potential protective value in humans. To establish accurate pharmacokinetic and efficacy data, an homologous animal model has been developed in which native and PEGylated forms of CHO-derived rMaBChE were multiply injected into homologous macaques with no induction of antibody. These now serve as controls for assessing the pharmacokinetics and immunogenicity in macaques of multiple administrations of PEGylated and unmodified human rBChE (rHuBChE) by both intravenous (IV) and pulmonary routes. The results indicate that, except for maximal concentration (Cmax), the pharmacokinetic parameters following IV injection with heterologous PEG-rHuBChE were greatly reduced even after the first injection compared with homologous PEG-rMaBChE. Anti-HuBChE antibody responses were induced in all monkeys after the second and third administrations regardless of the route of delivery; impacting rates of clearance and usually resulting in reduced endogenous MaBChE activity. These data highlight the difficulties inherent in assessing pharmacokinetics and immunogenicity in animal models, but bode well for the efficacy and safety of rHuBChE pretreatments in homologous humans. PMID:26415620

  6. Pharmacokinetic/pharmacodynamic-based optimization of levofloxacin administration in the treatment of MDR-TB.

    PubMed

    Ghimire, Samiksha; Van't Boveneind-Vrubleuskaya, Natasha; Akkerman, Onno W; de Lange, Wiel C M; van Soolingen, Dick; Kosterink, Jos G W; van der Werf, Tjip S; Wilffert, Bob; Touw, Daniel J; Alffenaar, Jan-Willem C

    2016-10-01

    The emergence of MDR-TB and XDR-TB has complicated TB treatment success. Among many factors that contribute to the development of resistance, low drug exposure is not the least important. This review summarizes the available information on pharmacokinetic properties of levofloxacin in relation to microbial susceptibilities, in order to optimize the dose and make general treatment recommendations. A total of 37 studies on adult (32 studies) and paediatric (5 studies) MDR-TB patients were included. Among the 32 adult studies, 19 were on susceptibility of Mycobacterium tuberculosis isolates to levofloxacin by MIC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by MBC, 1 was on susceptibility of M. tuberculosis isolates to levofloxacin by mutant prevention concentration and 4 were on pharmacokinetics of levofloxacin, and 7 others were included. Likewise, out of five studies on children, two dealt with levofloxacin pharmacokinetic parameters, one reviewed CSF concentrations and two dealt with background information. In adult MDR-TB patients, standard dosing of once-daily 1000 mg levofloxacin in TB treatment did not consistently attain the target concentration (i.e. fAUC/MIC >100 and fAUC/MBC >100) in 80% of the patients with MIC and MBC of 1 mg/L, leaving them at risk of developing drug resistance. However, with an MIC of 0.5 mg/L, 100% of the patients achieved the target concentration. Similarly, paediatric patients failed consistently in achieving given pharmacokinetic/pharmacodynamic targets due to age-related differences, demanding a shift towards once daily dosing of 15-20 mg/kg. Therefore, we recommend therapeutic drug monitoring for patients with strains having MICs of ≥0.5 mg/L and suggest revising the cut-off value from 2 to 1 mg/L. PMID:27231277

  7. Bioappearance and pharmacokinetics of bioactives upon coffee consumption.

    PubMed

    Lang, Roman; Dieminger, Natalie; Beusch, Anja; Lee, Yu-Mi; Dunkel, Andreas; Suess, Barbara; Skurk, Thomas; Wahl, Anika; Hauner, Hans; Hofmann, Thomas

    2013-10-01

    Habitual consumption of medium amounts of coffee over the whole life-span is hypothesized to reduce the risk to develop diabetes type 2 (DM2) and Alzheimer's disease (AD). To identify putative bioactive coffee-derived metabolites, first, pooled urine from coffee drinkers and non-coffee drinkers were screened by UPLC-HDMS. After statistical data analysis, trigonelline, dimethylxanthines and monomethylxanthines, and ferulic acid conjugates were identified as the major metabolites found after coffee consumption. For quantitative analysis of these markers in body fluids, targeted methods based on stable-isotope dilution and UPLC-MS/MS were developed and applied to plasma samples from a coffee intervention study (n = 13 volunteers) who consumed a single cup of caffeinated coffee brew after a 10-day washout period. Chlorogenic acid-derived metabolites were found to be separated into two groups showing different pharmacokinetic properties. The first group comprised, e.g., ferulic acid and feruloyl sulfate and showed early appearance in the plasma (~1 h). The second group contained particularly chlorogenic acid metabolites formed by the intestinal microflora, appearing late and persisting in the plasma (>6 h). Trigonelline appeared early but persisted with calculated half-life times ~5 h. The plasma levels of caffeine metabolites significantly and progressively increased 2-4 h after coffee consumption and did not reach c max within the time frame of the study. The pharmacokinetic profiles suggest that particularly trigonelline, caffeine, its metabolites, as well as late appearing dihydroferulic acid, feruloylglycine and dihydroferulic acid sulfate formed from chlorogenic acid by the intestinal microflora accumulate in the plasma due to their long half-life times during habitual consumption of several cups of coffee distributed over the day. Since some of these metabolites have been reported to show antioxidant effects in vivo, antioxidant-response-element activating

  8. Bioappearance and pharmacokinetics of bioactives upon coffee consumption.

    PubMed

    Lang, Roman; Dieminger, Natalie; Beusch, Anja; Lee, Yu-Mi; Dunkel, Andreas; Suess, Barbara; Skurk, Thomas; Wahl, Anika; Hauner, Hans; Hofmann, Thomas

    2013-10-01

    Habitual consumption of medium amounts of coffee over the whole life-span is hypothesized to reduce the risk to develop diabetes type 2 (DM2) and Alzheimer's disease (AD). To identify putative bioactive coffee-derived metabolites, first, pooled urine from coffee drinkers and non-coffee drinkers were screened by UPLC-HDMS. After statistical data analysis, trigonelline, dimethylxanthines and monomethylxanthines, and ferulic acid conjugates were identified as the major metabolites found after coffee consumption. For quantitative analysis of these markers in body fluids, targeted methods based on stable-isotope dilution and UPLC-MS/MS were developed and applied to plasma samples from a coffee intervention study (n = 13 volunteers) who consumed a single cup of caffeinated coffee brew after a 10-day washout period. Chlorogenic acid-derived metabolites were found to be separated into two groups showing different pharmacokinetic properties. The first group comprised, e.g., ferulic acid and feruloyl sulfate and showed early appearance in the plasma (~1 h). The second group contained particularly chlorogenic acid metabolites formed by the intestinal microflora, appearing late and persisting in the plasma (>6 h). Trigonelline appeared early but persisted with calculated half-life times ~5 h. The plasma levels of caffeine metabolites significantly and progressively increased 2-4 h after coffee consumption and did not reach c max within the time frame of the study. The pharmacokinetic profiles suggest that particularly trigonelline, caffeine, its metabolites, as well as late appearing dihydroferulic acid, feruloylglycine and dihydroferulic acid sulfate formed from chlorogenic acid by the intestinal microflora accumulate in the plasma due to their long half-life times during habitual consumption of several cups of coffee distributed over the day. Since some of these metabolites have been reported to show antioxidant effects in vivo, antioxidant-response-element activating

  9. Physiologically-based pharmacokinetic modeling to predict the clinical pharmacokinetics of monoclonal antibodies.

    PubMed

    Glassman, Patrick M; Balthasar, Joseph P

    2016-08-01

    Accurate prediction of the clinical pharmacokinetics of new therapeutic entities facilitates decision making during drug discovery, and increases the probability of success for early clinical trials. Standard strategies employed for predicting the pharmacokinetics of small-molecule drugs (e.g., allometric scaling) are often not useful for predicting the disposition monoclonal antibodies (mAbs), as mAbs frequently demonstrate species-specific non-linear pharmacokinetics that is related to mAb-target binding (i.e., target-mediated drug disposition, TMDD). The saturable kinetics of TMDD are known to be influenced by a variety of factors, including the sites of target expression (which determines the accessibility of target to mAb), the extent of target expression, the rate of target turnover, and the fate of mAb-target complexes. In most cases, quantitative information on the determinants of TMDD is not available during early phases of drug discovery, and this has complicated attempts to employ mechanistic mathematical models to predict the clinical pharmacokinetics of mAbs. In this report, we introduce a simple strategy, employing physiologically-based modeling, to predict mAb disposition in humans. The approach employs estimates of inter-antibody variability in rate processes of extravasation in tissues and fluid-phase endocytosis, estimates for target concentrations in tissues derived through use of categorical immunohistochemical scores, and in vitro measures of the turnover of target and target-mAb complexes. Monte Carlo simulations were performed for four mAbs (cetuximab, figitumumab, dalotuzumab, trastuzumab) directed against three targets (epidermal growth factor receptor, insulin-like growth factor receptor 1, human epidermal growth factor receptor 2). The proposed modeling strategy was able to predict well the pharmacokinetics of cetuximab, dalotuzumab, and trastuzumab at a range of doses, but trended towards underprediction of figitumumab concentrations

  10. Single-Ascending-Dose Pharmacokinetic Study of Tribendimidine in Opisthorchis viverrini-Infected Patients

    PubMed Central

    Duthaler, Urs; Sayasone, Somphou; Vanobbergen, Fiona; Penny, Melissa A.; Odermatt, Peter; Huwyler, Jörg

    2016-01-01

    Praziquantel is the only drug available for the treatment of Opisthorchis viverrini infections. Tribendimidine has emerged as a potential treatment alternative; however, its pharmacokinetic (PK) properties have not been sufficiently studied to date. Via two phase IIa dose-finding studies, 68 O. viverrini patients were treated with 25- to 600-mg doses of tribendimidine using 50- and 200-mg tablet formulations. Plasma, blood, and dried blood spots (DBS) were sampled at selected time points. The two main metabolites of tribendimidine, active deacetylated amidantel (dADT) and acetylated dADT (adADT), were analyzed in plasma, blood, and DBS. PK parameters were estimated by noncompartmental analysis. An acceptable agreement among plasma and DBS concentrations was observed, with a mean bias of ≤10%, and 60% dADT and 74% adADT concentrations being within ±20% margins. We found that 200-mg tribendimidine tablets possess immediate floating characteristics, which led to variable time to maximal concentration of drug (Tmax) values (2 to 24 h) between individuals. Dose proportionality was observed for dADT from 25 to 200 mg using 50-mg tablets, but at higher dosages (200 to 600 mg), saturation occurred. The median ratio of the area under the plasma concentration-time curve from 0 to 24 h (AUC0–24) of dADT to the AUC0–24 of adADT ranged from 0.8 to 26.4, suggesting substantial differences in acetylation rates. Cure rates ranged from 11% (25-mg dose) to 100% (400-mg dose). Cured patients showed significantly higher dADT maximal serum concentrations (Cmax) and AUC0–24 values than uncured patients. Tribendimidine is a promising drug for the treatment of opisthorchiasis. However, the tablet formulation should be optimized to achieve consistent absorption among patients. Further studies are warranted to assess the large differences between individuals in the rate of metabolic turnover of dADT to adADT. (This study has been registered with the ISRCTN Registry under no. ISRCTN

  11. Pharmacokinetic and pharmacogenetic predictive markers of irinotecan activity and toxicity.

    PubMed

    Di Paolo, Antonello; Bocci, Guido; Polillo, Marialuisa; Del Re, Marzia; Di Desidero, Teresa; Lastella, Marianna; Danesi, Romano

    2011-12-01

    After the rapid development of new classes of antineoplastic drugs, research activities have focused their efforts to the identification of predictive markers of drug activity and tolerability. Irinotecan (CPT-11) may induce severe toxicities (diarrhea, neutropenia) that limit its clinical use, but the increasing knowledge of its pharmacokinetics offered a potential approach to treatment optimization. Pharmacokinetics, the first area of investigation, has identified markers such as biliary index, the relative extent of conversion and the glucuronidation ratio, which are capable to define the risk for severe adverse effects. Because of the existence of some issues concerning the adoption of pharmacokinetic strategies to optimize CPT-11 dose and schedule, analyses of genetic polymorphisms seemed to offer a more reliable and safer approach for the identification of patients at risk than pharmacokinetics. In this view, the uridine diphosphate glucuronosil transferase isoform 1A1 (UGT1A1) was associated with significant changes in disposition of CPT-11 and its metabolites, and consequently with treatment-induced toxicities. However, the complex pharmacokinetics of irinotecan and the involvement of several enzymes other than UGT (i.e., carboxyl estherases, CYP450 isoforms), and transmembrane transporters (ABCB1, ABCC1, ABCG2, SLCO1B1) make difficult the identification of patients with an optimal sensitivity and specificity, and a large part of variability among patients still remains unexplained. Furthermore, prospective clinical studies that should demonstrate the reliability of those pharmacokinetic and pharmacogenetic markers are still lacking. In the present review, pharmacokinetic and pharmacogenetic markers will be discussed. PMID:21787264

  12. Physiologically Based Pharmacokinetic Modeling in Pediatric Oncology Drug Development.

    PubMed

    Rioux, Nathalie; Waters, Nigel J

    2016-07-01

    Childhood cancer represents more than 100 rare and ultra-rare diseases, with an estimated 12,400 new cases diagnosed each year in the United States. As such, this much smaller patient population has led to pediatric oncology drug development lagging behind that for adult cancers. Developing drugs for pediatric malignancies also brings with it a number of unique trial design considerations, including flexible enrollment approaches, age-appropriate formulation, acceptable sampling schedules, and balancing the need for age-stratified dosing regimens, given the smaller patient populations. The regulatory landscape for pediatric pharmacotherapy has evolved with U.S. Food and Drug Administration (FDA) legislation such as the 2012 FDA Safety and Innovation Act. In parallel, regulatory authorities have recommended the application of physiologically based pharmacokinetic (PBPK) modeling, for example, in the recently issued FDA Strategic Plan for Accelerating the Development of Therapies for Pediatric Rare Diseases. PBPK modeling provides a quantitative and systems-based framework that allows the effects of intrinsic and extrinsic factors on drug exposure to be modeled in a mechanistic fashion. The application of PBPK modeling in drug development for pediatric cancers is relatively nascent, with several retrospective analyses of cytotoxic therapies, and latterly for targeted agents such as obatoclax and imatinib. More recently, we have employed PBPK modeling in a prospective manner to inform the first pediatric trials of pinometostat and tazemetostat in genetically defined populations (mixed lineage leukemia-rearranged and integrase interactor-1-deficient sarcomas, respectively). In this review, we evaluate the application of PBPK modeling in pediatric cancer drug development and discuss the important challenges that lie ahead in this field.

  13. Pharmacokinetic Properties of a New Glutamic Acid Derivative Glutaron.

    PubMed

    Smirnova, L A; Ryabukha, A F; Kuznetsov, K A; Suchkov, E A; Perfilova, V N; Tyurenkov, I N

    2015-06-01

    Inhomogenous distribution of glutaron in organs and tissues was found after intravenous and peroral administration: the agent demonstrated high affinity to organs with high degree of vascularization (lungs and heart) and elimination (kidney). Glutaron easily penetrates through the blood-brain barrier, which is consistent with its concentration in the adipose tissue.

  14. Aligning Potency and Pharmacokinetic Properties for Pyridine-Based NCINIs.

    PubMed

    Fader, Lee D; Bailey, Murray; Beaulieu, Eric; Bilodeau, François; Bonneau, Pierre; Bousquet, Yves; Carson, Rebekah J; Chabot, Catherine; Coulombe, René; Duan, Jianmin; Fenwick, Craig; Garneau, Michel; Halmos, Ted; Jakalian, Araz; James, Clint; Kawai, Stephen H; Landry, Serge; LaPlante, Steven R; Mason, Stephen W; Morin, Sebastien; Rioux, Nathalie; Simoneau, Bruno; Surprenant, Simon; Thavonekham, Bounkham; Thibeault, Carl; Trinh, Thao; Tsantrizos, Youla; Tsoung, Jennifer; Yoakim, Christiane; Wernic, Dominik

    2016-08-11

    Optimization of pyridine-based noncatalytic site integrase inhibitors (NCINIs) based on compound 2 has led to the discovery of molecules capable of inhibiting virus harboring N124 variants of HIV integrase (IN) while maintaining minimal contribution of enterohepatic recirculation to clearance in rat. Structure-activity relationships at the C6 position established chemical space where the extent of enterohepatic recirculation in the rat is minimized. Desymmetrization of the C4 substituent allowed for potency optimization against virus having the N124 variant of integrase. Combination of these lessons led to the discovery of compound 20, having balanced serum-shifted antiviral potency and minimized excretion in to the biliary tract in rat, potentially representing a clinically viable starting point for a new treatment option for individuals infected with HIV. PMID:27563405

  15. From requirements to acceptance tests

    NASA Technical Reports Server (NTRS)

    Baize, Lionel; Pasquier, Helene

    1993-01-01

    From user requirements definition to accepted software system, the software project management wants to be sure that the system will meet the requirements. For the development of a telecommunication satellites Control Centre, C.N.E.S. has used new rules to make the use of tracing matrix easier. From Requirements to Acceptance Tests, each item of a document must have an identifier. A unique matrix traces the system and allows the tracking of the consequences of a change in the requirements. A tool has been developed, to import documents into a relational data base. Each record of the data base corresponds to an item of a document, the access key is the item identifier. Tracing matrix is also processed, providing automatically links between the different documents. It enables the reading on the same screen of traced items. For example one can read simultaneously the User Requirements items, the corresponding Software Requirements items and the Acceptance Tests.

  16. Cyclosporine pharmacokinetics in pancreas transplant recipients.

    PubMed

    Munda, R; Schroeder, T J; Pedersen, S A; Clardy, C W; Wadhwa, N K; Myre, S A; Stephens, G W; Pesce, A J; Alexander, J W; First, M R

    1988-04-01

    Ten CsA pharmacokinetic studies were performed on five pancreas transplant recipients to determine proper doses and dosing intervals. These cadaver pancreas transplants were performed with exocrine ductal drainage into the urinary tract through a bladder anastomosis in four cases and into the bowel in one case. Four CsA pharmacokinetic studies were performed on diabetic renal transplant recipients and an additional six studies were performed while with pancreas transplant patients taking metoclopramide in an effort to enhance absorption of CsA. Mean CsA dose was 3.7 mg/kg/dose (range 2.1 to 7.5 mg/kg/dose). All patients but one were on twice daily dosing intervals yielding an average daily dose of 7.4 mg/kg/d. Noncompartmental pharmacokinetic analyses were used. The adequacy of a 1-, 2-, or 3-exponential model was determined by breakpoint analysis of the log concentration v time curve using the F statistic. The terminal rate constant was calculated by nonlinear regression analysis. The AUC and AUMC were calculated by the trapezoidal method with exponential extrapolation and these were used to calculate the MRT and Vdss. The unknown fractional absorption, F, was used to correct the oral data. The average CsA concentration maximum (Cmax) was 528 ng/mL with an average time to maximum concentration (Tmax) of 4.7 hours, a mean residence time of 7.75 hours, with a Vdss/%F of 9.61 L/kg in the pancreas transplant recipients. Additional studies of six patients receiving metoclopramide with CsA revealed an average Cmax of 723 ng/mL, an average Tmax of 2.3 hours, an average MRT of 6.08 hours, and an average Vdss/%F of 5.7% L/kg. These results indicate that coexistent gastroparesis in diabetic recipients of either pancreatic or renal transplants may result in reduced bioavailability of CsA. PMID:3284095

  17. Covariates of intravenous paracetamol pharmacokinetics in adults

    PubMed Central

    2014-01-01

    Background Pharmacokinetic estimates for intravenous paracetamol in individual adult cohorts are different to a certain extent, and understanding the covariates of these differences may guide dose individualization. In order to assess covariate effects of intravenous paracetamol disposition in adults, pharmacokinetic data on discrete studies were pooled. Methods This pooled analysis was based on 7 studies, resulting in 2755 time-concentration observations in 189 adults (mean age 46 SD 23 years; weight 73 SD 13 kg) given intravenous paracetamol. The effects of size, age, pregnancy and other clinical settings (intensive care, high dependency, orthopaedic or abdominal surgery) on clearance and volume of distribution were explored using non-linear mixed effects models. Results Paracetamol disposition was best described using normal fat mass (NFM) with allometric scaling as a size descriptor. A three-compartment linear disposition model revealed that the population parameter estimates (between subject variability,%) were central volume (V1) 24.6 (55.5%) L/70 kg with peripheral volumes of distribution V2 23.1 (49.6%) L/70 kg and V3 30.6 (78.9%) L/70 kg. Clearance (CL) was 16.7 (24.6%) L/h/70 kg and inter-compartment clearances were Q2 67.3 (25.7%) L/h/70 kg and Q3 2.04 (71.3%) L/h/70 kg. Clearance and V2 decreased only slightly with age. Sex differences in clearance were minor and of no significance. Clearance, relative to median values, was increased during pregnancy (FPREG = 1.14) and decreased during abdominal surgery (FABDCL = 0.715). Patients undergoing orthopaedic surgery had a reduced V2 (FORTHOV = 0.649), while those in intensive care had increased V2 (FICV = 1.51). Conclusions Size and age are important covariates for paracetamol pharmacokinetics explaining approximately 40% of clearance and V2 variability. Dose individualization in adult subpopulations would achieve little benefit in the scenarios explored. PMID:25342929

  18. Enantioselective pharmacokinetics of doxazosin and pharmacokinetic interaction between the isomers in rats.

    PubMed

    Li, Qing; Kong, Dezhi; Du, Qian; Zhao, Jing; Zhen, Yaqin; Li, Tonghui; Ren, Leiming

    2015-10-01

    In this study, the stereoselective pharmacokinetics of doxazosin enantiomers and their pharmacokinetic interaction were studied in rats. Enantiomer concentrations in plasma were measured using chiral high-pressure liquid chromatography (HPLC) with fluorescence detection after oral or intravenous administration of (-)-(R)-doxazosin 3.0 mg/kg, (+)-(S)-doxazosin 3.0 mg/kg, and rac-doxazosin 6.0 mg/kg. AUC values of (+)-(S)-doxazosin were always larger than those of (-)-(R)-doxazosin, regardless of oral or intravenous administration. The maximum plasma concentration (Cmax ) value of (-)-(R)-doxazosin after oral administration was significantly higher when given alone (110.5 ± 46.4 ng/mL) versus in racemate (53.2 ± 19.7 ng/mL), whereas the Cmax value of (+)-(S)-doxazosin did not change significantly. The area under the curve (AUC) and Cmax values for (+)-(S)-doxazosin after intravenous administration were significantly lower, and its Cl value significantly higher, when given alone versus in racemate. We speculate that (-)-(R)-doxazosin increases (+)-(S)-doxazosin exposure probably by inhibiting the elimination of (+)-(S)-doxazosin, and the enantiomers may be competitively absorbed from the gastrointestinal tract. In conclusion, doxazosin pharmacokinetics are substantially stereospecific and enantiomer-enantiomer interaction occurs after rac-administration.

  19. The influence of cardiovascular physiology on dose/pharmacokinetic and pharmacokinetic/pharmacodynamic relationships.

    PubMed

    Fagiolino, Pietro; Eiraldi, Rosa; Vázquez, Marta

    2006-01-01

    Inter- and intraindividual variability in the relationship between dose and clinical--or pharmacodynamic--response of a drug can be analysed in two steps: firstly, by considering the plasma pharmacokinetic response to a given dose and, secondly, by the connection between both pharmacokinetic and pharmacodynamic responses. As the cardiovascular system is the means of transport of endogenous and exogenous substances, blood flow fraction destined to each organ determines the relative mass of solute in plasma, which is constantly in contact with the tissue. Hence, not only the rate but also the extent of drug transfer would be increased when tissues are irrigated by a higher fraction of cardiac output. Aging and circadian rhythms present similar cardiac output distribution patterns when moving from young to aged adult and from nocturnal to diurnal hours. These two changes lead to an increased blood flow delivery to the extra-splanchnic-renal region in the elderly and in the morning, but with a decreased cardiac output in aged individuals and an increased one during the day. This scenario allows us to forecast substance concentrations outside the blood vessels, which are responsible for the extent of drug elimination and the intensity of drug effect. So available data on disposition and pharmacodynamics of drugs might be explained from another point of view that challenges current knowledge. Furthermore, the administration of cardiovascular active drugs might reverse the chronological sequence between pharmacokinetic and pharmacodynamic responses, since they could modify blood flow distribution.

  20. Pharmacokinetics and interactions of headache medications, part I: introduction, pharmacokinetics, metabolism and acute treatments.

    PubMed

    Sternieri, Emilio; Coccia, Ciro Pio Rosario; Pinetti, Diego; Ferrari, Anna

    2006-12-01

    Recent progress in the treatment of primary headaches has made available specific, effective and safe medications for these disorders, which are widely spread among the general population. One of the negative consequences of this undoubtedly positive progress is the risk of drug-drug interactions. This review is the first in a two-part series on pharmacokinetic drug-drug interactions of headache medications. Part I addresses acute treatments. Part II focuses on prophylactic treatments. The overall aim of this series is to increase the awareness of physicians, either primary care providers or specialists, regarding this topic. Pharmacokinetic drug-drug interactions of major severity involving acute medications are a minority among those reported in literature. The main drug combinations to avoid are: i) NSAIDs plus drugs with a narrow therapeutic range (i.e., digoxin, methotrexate, etc.); ii) sumatriptan, rizatriptan or zolmitriptan plus monoamine oxidase inhibitors; iii) substrates and inhibitors of CYP2D6 (i.e., chlorpromazine, metoclopramide, etc.) and -3A4 (i.e., ergot derivatives, eletriptan, etc.), as well as other substrates or inhibitors of the same CYP isoenzymes. The risk of having clinically significant pharmacokinetic drug-drug interactions seems to be limited in patients with low frequency headaches, but could be higher in chronic headache sufferers with medication overuse. PMID:17125411

  1. 41 CFR 102-75.1150 - What happens to the gift if GSA determines it to be acceptable?

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... if GSA determines it to be acceptable? 102-75.1150 Section 102-75.1150 Public Contracts and Property...-75.1150 What happens to the gift if GSA determines it to be acceptable? When GSA determines that the gift is acceptable and can be accepted and used in the form in which it was offered, GSA must...

  2. Improved pharmacokinetics of Yttrium-90 delivery with multivalent Fab{prime} fragments

    SciTech Connect

    Turner, A.; Boyce, B.A.; Antoniw, P.

    1994-05-01

    Humanised monoclonal antibodies have circulating half-lives in man of many days and one of the problems in using Yttrium-90 labelled versions for tumor therapy is the level of consequent whole body radiation. F(ab`){sub 2} fragments are rapidly cleared from the circulation but have relatively poor tumor uptake in biodistribution experiments. We initially developed a chemically cross-linked F(ab`)2 species (divalent Fab` maleimide or DFM) capable of carrying Yttrium-90 complexed to a 12N4 macrocycle. Although the DFM derived from the Fab` of cB72.3 had the desired pharmacokinetics of blood clearance with good tumor uptake in athymic nude mice carrying human tumor xenografts, significant retention of radioactivity by the kidneys was observed. We then progressed to higher oligomers and found that the trivalent Fab` maleimide (TFM), obtained via the structure below (n=3), when labelled with Y-90 possessed acceptable pharmacokinetics and good tumor uptake without kidney accumulation of radioactivity. The clinical evaluation of this technology is in progress.

  3. Assessments of pharmacokinetic drug interactions and tolerability of albendazole, praziquantel and ivermectin combinations.

    PubMed

    Na-Bangchang, K; Kietinun, S; Pawa, K K; Hanpitakpong, W; Na-Bangchang, C; Lazdins, J

    2006-04-01

    The pharmacokinetic interactions and tolerability of albendazole, praziquantel and ivermectin combinations were assessed in 23 healthy Thai volunteers (12 males and 11 females). The study was an open, randomised, three-way crossover design in which each subject attended the study on three separate occasions (Phases I, II and III), of 4 d or 8 d each, with at least 1 or 2 weeks (but not longer than 2 months) between each phase. All subjects received the three study drug regimens as follows: regimen I, oral praziquantel (40 mg/kg body weight); regimen II, oral ivermectin (200 microg/kg body weight) given concurrently with an oral dose of albendazole (400 mg); and regimen III, oral ivermectin given concurrently with albendazole and praziquantel. All treatment regimens showed acceptable tolerability profiles. The incidence of overall drug-related adverse events was significantly higher following regimens I (12/23) and III (7/23) compared with that following regimen II (0/23). Six statistically significant changes in the pharmacokinetic parameters of albendazole sulphoxide (Cmax, AUC0-infinity, Vz/F, CL/F), praziquantel (Vz/F) and ivermectin (AUC0-infinity) were observed when the three drugs were given concurrently. However, based on US Food and Drug Administration criteria, these changes were not considered of clinical relevance. PMID:16271272

  4. Benzoxazole and benzothiazole amides as novel pharmacokinetic enhancers of HIV protease inhibitors.

    PubMed

    Jonckers, Tim H M; Rouan, Marie-Claude; Haché, Geerwin; Schepens, Wim; Hallenberger, Sabine; Baumeister, Judith; Sasaki, Jennifer C

    2012-08-01

    A new class of benzoxazole and benzothiazole amide derivatives exhibiting potent CYP3A4 inhibiting properties was identified. Extensive lead optimization was aimed at improving the CYP3A4 inhibitory properties as well as overall ADME profile of these amide derivatives. This led to the identification of thiazol-5-ylmethyl (2S,3R)-4-(2-(ethyl(methyl)amino)-N-isobutylbenzo[d]oxazole-6-carboxamido)-3-hydroxy-1-phenylbutan-2-ylcarbamate (C1) as a lead candidate for this class. This compound together with structurally similar analogues demonstrated excellent 'boosting' properties when tested in dogs. These findings warrant further evaluation of their properties in an effort to identify valuable alternatives to Ritonavir as pharmacokinetic enhancers.

  5. Comparison of the dissolution and pharmacokinetic profiles of two galenical formulations of the endothelin receptor antagonist macitentan.

    PubMed

    Kummer, Oliver; Haschke, Manuel; Hammann, Felix; Bodmer, Michael; Bruderer, Shirin; Regnault, Yann; Dingemanse, Jasper; Krähenbühl, Stephan

    2009-11-01

    Macitentan (ACT-064992) is an orally active endothelin receptor antagonist. We first compared the in vitro dissolution characteristics of uncoated and film-coated tablets with hard gelatin capsules containing 10mg ACT-064992. Subsequently, we compared the oral pharmacokinetics of ACT-064992 and its active metabolite ACT-132577 of the coated tablet and the gelatin capsule formulation in 11 male volunteers. The dissolution profile showed a rapid disintegration of all formulations with >90% dissolution of ACT-064992 within 45 min. The pharmacokinetics of ACT-064992 and its metabolite ACT-132577 were comparable for the two formulations. ACT-064992 revealed a slow absorption (median t(max) 8h) and a terminal half-life of approximately 13 h. Bioequivalence criteria were met for AUC(0-t) and AUC(0-infinity). Mean C(max) was 19% lower after ingestion of the tablet compared to capsules with its lower 90% confidence limit below the accepted bioequivalence range. The pharmacokinetics of the metabolite ACT-132577, characterized by a t(max) of approximately 48 h and a terminal half-life of approximately 45 h, was not different between the two formulations. We conclude that the absorption profile of the tablet differs from the capsule in peak but not in total exposure, which is not expected to be of clinical significance.

  6. Preliminary pharmacokinetics of a new pyridopyrimidine derivative.

    PubMed

    Pérez, M J; Roch, M J; Ochoa, M C

    1991-06-01

    This paper describes the preliminary pharmacokinetic studies of 4-anilino-2-methylthiopyrido[2,3-d]pyrimidine (MD-39-AM) following a single administration of the compound to male rats via different routes (intravenous and oral) in the dose range of 6-24 mg.kg-1. The plasma level versus time plots after intravenous and oral administration to male rats can well be described by an open two-compartment model. The product was rapidly absorbed and peak concentrations in plasma were reached before 1 h after a single oral administration whatever the dose studied. The absolute bioavailability calculated on the basis of AUC0-infinity after intravenous and oral administration was estimated to be about 90%. Plasma levels found at higher doses than 6 mg/kg suggest that the product kinetics is dose dependent.

  7. Application of queueing theory to pharmacokinetics.

    PubMed

    Brill, P H; Moon, R E

    1980-05-01

    This paper considers the steady-state plasma drug concentration in a one-compartment, open pharmacokinetic model with multiple doses and first-order kinetics using a classical deterministic technique as well as a queueing theoretical stochastic analysis. The stochastic analysis employs a new method for obtaining the steady-state probability distribution of the content of a dam with compound Poisson input and a general release rule. It is shown that if the deterministic steady-state average concentration exists, it is equal to the mean value of the steady-state concentration, the probability distribution of which is obtained using the stochastic model. Moreover, the steady-state probability distribution of the concentration and its mean always exist in the stochastic model. Ramifications of the stochastic method of analysis are discussed.

  8. Influence of liver cirrhosis on sertraline pharmacokinetics

    PubMed Central

    DÉMOLIS, JEAN-LOUIS; ANGEBAUD, PASCAL; GRANGÉ, JEAN-DIDIER; COATES, PETER; FUNCK-BRENTANO, CHRISTIAN; JAILLON, PATRICE

    1996-01-01

    Sertraline is a serotonin reuptake inhibitor. The enhancement of serotoninergic transmission is associated with antidepressant activity. In order to determine the pharmacokinetics of sertraline in patients with chronic stable hepatic insufficiency, 10 patients were matched (age, weight, sex) with 10 healthy subjects in an open study. Each participant received a single capsule containing the equivalent of 100 mg sertraline base. Blood samples were taken during 264 h after administration for measurement of plasma concentrations of sertraline. The results confirm that the oral clearance of sertraline is reduced with a 1.7-fold increase in Cmax and a significant prolongation in elimination half-life in hepatically impaired patients PMID:8877033

  9. Sex Differences in Pharmacokinetics and Pharmacodynamics

    PubMed Central

    Soldin, OP; Mattison, DR

    2013-01-01

    Males and females differ in their response to drug treatment. These differences can be critical in response to drug treatment. It is therefore essential to understand those differences to appropriately conduct risk assessment and to design safe and effective treatments. Even from that modest perspective, how and when we use drugs can result in unwanted and unexpected outcomes. We summarize the sex differences that impact pharmacokinetics and pharmacodynamics and include a general comparison of clinical pharmacology as it applies to men, pregnant and non-pregnant women. Since this is an area rapidly evolving, it is essential for the practitioner to review drug prescribing information and recent literature to understand fully the impact of sex differences in clinical therapeutics. PMID:19385708

  10. Factors Controlling the Pharmacokinetics, Biodistribution and Intratumoral Penetration of Nanoparticles

    PubMed Central

    Ernsting, Mark J.; Murakami, Mami; Roy, Aniruddha; Li, Shyh-Dar

    2014-01-01

    Nanoparticle drug delivery to the tumor is impacted by multiple factors: nanoparticles must evade clearance by renal filtration and the reticuloendothelial system, extravasate through the enlarged endothelial gaps in tumors, penetrate through dense stroma in the tumor microenvironment to reach the tumor cells, remain in the tumor tissue for a prolonged period of time, and finally release the active agent to induce pharmacological effect. The physicochemical properties of nanoparticles such as size, shape, surface charge, surface chemistry (PEGylation, ligand conjugation) and composition affect the pharmacokinetics, biodistribution, intratumoral penetration and tumor bioavailability. On the other hand, tumor biology (blood flow, perfusion, permeability, interstitial fluid pressure and stroma content) and patient characteristics (age, gender, tumor type, tumor location, body composition and prior treatments) also have impact on drug delivery by nanoparticles. It is now believed that both nanoparticles and the tumor microenvironment have to be optimized or adjusted for optimal delivery. This review provides a comprehensive summary of how these nanoparticle and biological factors impact nanoparticle delivery to tumors, with discussion on how the tumor microenvironment can be adjusted and how patients can be stratified by imaging methods to receive the maximal benefit of nanomedicine. Perspectives and future directions are also provided. PMID:24075927

  11. Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities

    PubMed Central

    Zhang, Yong; Jiang, Peixin; Ye, Min; Kim, Sung-Hoon; Jiang, Cheng; Lü, Junxuan

    2012-01-01

    Tanshinones are a class of abietane diterpene compound isolated from Salvia miltiorrhiza (Danshen or Tanshen in Chinese), a well-known herb in Traditional Chinese Medicine (TCM). Since they were first identified in the 1930s, more than 40 lipophilic tanshinones and structurally related compounds have been isolated from Danshen. In recent decades, numerous studies have been conducted to investigate the isolation, identification, synthesis and pharmacology of tanshinones. In addition to the well-studied cardiovascular activities, tanshinones have been investigated more recently for their anti-cancer activities in vitro and in vivo. In this review, we update the herbal and alternative sources of tanshinones, and the pharmacokinetics of selected tanshinones. We discuss anti-cancer properties and identify critical issues for future research. Whereas previous studies have suggested anti-cancer potential of tanshinones affecting multiple cellular processes and molecular targets in cell culture models, data from in vivo potency assessment experiments in preclinical models vary greatly due to lack of uniformity of solvent vehicles and routes of administration. Chemical modifications and novel formulations had been made to address the poor oral bioavailability of tanshinones. So far, human clinical trials have been far from ideal in their design and execution for the purpose of supporting an anti-cancer indication of tanshinones. PMID:23202971

  12. A Systems Approach for Tumor Pharmacokinetics

    PubMed Central

    Thurber, Greg Michael; Weissleder, Ralph

    2011-01-01

    Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design. PMID:21935441

  13. A systems approach for tumor pharmacokinetics.

    PubMed

    Thurber, Greg Michael; Weissleder, Ralph

    2011-01-01

    Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design. PMID:21935441

  14. Pharmacokinetics of intrarectal omeprazole in alpacas.

    PubMed

    Marmulak, T; Stanley, S; Kass, P H; Wiebe, V; McKemie, D; Pusterla, N

    2010-08-01

    The purpose of this study was to evaluate the pharmacokinetics of omeprazole in three different vehicles when administered rectally to six alpacas. Alpacas were given single doses of omeprazole (4 mg/kg) in a double-blinded, randomized cross-over design with a 1 week washout period. Omeprazole formulations consisted of (1) Treatment A: omeprazole paste mixed in surgical lubricant (2) Treatment B: omeprazole capsule contents in 8.4% sodium bicarbonate and (3) Treatment C: omeprazole capsule contents in surgical lubricant and 8.4% sodium bicarbonate solution. Plasma samples were drawn at 0, 5, 10, 15, 30, 45, 60, 90, 120, 180, 300 and 480 min. Omeprazole plasma concentrations were determined by high-pressure liquid chromatography-mass spectrometry. Pharmacokinetic results demonstrated median peak plasma concentrations (C(max)) of 7.35 (3.2-15.2), 7.30 (1.7-10.9) and 8.65 (1.8-19.3) ng/mL and median area under the concentration curve (AUC((0-180))) of 747 (237-1681) min x ng/mL, 552.9 (39-1063) min x ng/mL, and 972 (107-1841) min x ng/mL for treatments A, B and C, respectively. The median half-lives were similar between groups: 38, 50, and 53 min. As a result of the low measured omeprazole plasma concentrations, it is assumed that rectal absorption of omeprazole is poor in alpacas and not an effective route of administration. PMID:20646199

  15. Pharmacokinetics of Intranasal Scopolamine Gel Formulation (Inscop)

    NASA Technical Reports Server (NTRS)

    Boyd, Jason L.; Du, Brian; Daniels, Vernie; Simmons, Rita; Buckey, Jay; Putcha, Lakshmi

    2009-01-01

    Space Motion Sickness (SMS) is commonly experienced by astronauts and often requires treatment with medications during early flight days of space missions. Orally administered scopolamine is commonly used by astronauts to prevent SMS. Bioavailability of oral (PO) SMS medications is often low and highly variable. Intranasal (IN) administration of medications achieves higher and more reliable bioavailability than from an equivalent PO dose. Methods: To test the safety and reliability of INSCOP, two clinical studies were performed, a dose escalation study and a comparison study administering INSCOP during normal ambulation and head down tilt bedrest. Efficacy was evaluated by testing INSCOP with two, different motion sickness inducing paradigms. Results: Preliminary results indicate that INSCOP demonstrates linear pharmacokinetics and a low side effect profile. In head down tilt bedrest, relative bioavailability of INSCOP was increased for females at both doses (0.2 and 0.4 mg) and for males at the higher dose (0.4 mg) but is reduced at the lower dose (0.2 mg) compared to normal ambulation. INSCOP displays gender specific differences during ABR. One of the treatment efficacy trials conducted at Dartmouth Hitchcock Medical Center demonstrated that INSCOP is efficacious at both doses (0.2 and 0.4 mg) in suppressing motion sickness symptoms as indicated by longer chair ride times with INSCOP administration than with placebo, and efficacy increases with dose. Similar results were seen using another motion sickness simulator, the motion simulator dome, at the Naval Aerospace Medical Research Laboratory, with significantly increased time in the dome in motion-susceptible subjects when using INSCOP compared to untreated controls. Conclusion: Higher bioavailability, linear pharmacokinetics, a low incidence of side effects, and a favorable efficacy profile make INSCOP a desirable formulation for prophylactic and rescue treatment of astronauts in space and military personnel on

  16. PREDICTIVE PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE FLOATING TABLETS.

    PubMed

    Wang, Jianming; Zhang, Yanzhen; Guo, Zhiling; Tao, Qingwen; Wang, Yongjun; Zhou, Wei; Ma, Xiao; Li, Zhihong

    2016-01-01

    The purpose of this study was to propose the effectiveness of convolution approach to predict pharmacokinetics of tramadol hydrochloride floating tablets, prepared by using various ratios of carbopol, HPMC K100M, and Hibiscus rosa Sinensis as excipient. The in vitro dissolution test was conducted using paddle method in 900 mL of HCl buffer with pH 1.2 to simulate the gastric condition. The stirring speed of paddles was set at 70 rpm. Temperature of dissolution medium was adjusted at 37 ± 5 °C. At predetermined time points, 5 mL of dissolution samples were taken with a replacement of same volume using fresh medium. The obtained samples were analyzed at 271 nm using UV visible spectrophotometer. The values of predicted pharmacokinetic parameters like Cmax (maximum blood drug level), Tmax (time required to attain maximum blood drug level), and AUC (area under blood drug concentration curve) ranged between 80.8 ± 3.2-119.6 ± 4.7 ng/mL, 11.4 ± 0.2-12.2 ± 0.2 h, and 1430.5 ± 209.5-1970.6 ± 287.4 ng.h/mL, respectively. This certainly is a desired feature required at the formulation development step, where the formulator requires the development of a formulation using desired in vivo features on the basis of only accessible in vitro data. It can be concluded from the results that convolution method is a practical method for the prediction of drug concentration in blood and for quality control. PMID:27476294

  17. Reporting guidelines for population pharmacokinetic analyses.

    PubMed

    Dykstra, Kevin; Mehrotra, Nitin; Tornøe, Christoffer Wenzel; Kastrissios, Helen; Patel, Bela; Al-Huniti, Nidal; Jadhav, Pravin; Wang, Yaning; Byon, Wonkyung

    2015-08-01

    The purpose of this work was to develop a consolidated set of guiding principles for the reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting, and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (in which population PK frequently serves as preparatory analysis for exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider 2 main purposes of population PK reports: (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified 2 main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results; and (2) a scientifically literate but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with 6 questions that need to be addressed throughout the report. We recommend 8 sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step toward industrialization of the field of pharmacometrics such that a nontechnical audience also understands the role of pharmacometric analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports

  18. Clinical Pharmacokinetics of Alamifovir and Its Metabolites

    PubMed Central

    Chan, Clark; Abu-Raddad, Eyas; Golor, Georg; Watanabe, Hikari; Sasaki, Akira; Yeo, Kwee Poo; Soon, Danny; Sinha, Vikram P.; Flanagan, Shawn D.; He, Minxia M.; Wise, Stephen D.

    2005-01-01

    Alamifovir, a purine nucleotide analogue prodrug, and its hydrolyzed derivatives have shown preclincal efficacy activity against wild-type and lamivudine-resistant hepatitis B virus. Two studies were conducted to examine the single- and multiple-dose alamifovir pharmacokinetics after oral administration in healthy males. In study 1, subjects were given single doses (0.2 to 80 mg), with a subset receiving 20 mg in a fed state. Study 2 subjects were dosed with 2.5 to 15 mg twice daily for 15 days. Plasma samples were collected over 72 h in study 1 and over 24 h on days 1 and 15 in study 2. Concentrations of alamifovir and its major metabolites were determined using liquid chromatography/tandem mass spectrometry methods. The data were analyzed using a noncompartmental technique. Although alamifovir was rapidly absorbed, there was limited systemic exposure due to its rapid hydrolysis and formation of at least three metabolites, suggesting that alamifovir acts as a prodrug. The major metabolites detected were 602074 and 602076, with 602075 detectable only in higher-dose groups. Maximum 602074 plasma concentration was achieved at approximately 0.5 h (Tmax) and declined with a 1- to 2-h terminal half-life (t1/2). Maximum concentrations of 602076 (Cmax) averaged 10% of the 602074 Cmax and reached Tmax in 2.5 h with a 4-h t1/2. Food appeared to decrease the extent of absorption of the compound. Multiple dosing resulted in minimal accumulation, and the concentrations following multiple doses could be predicted using the single-dose data. Alamifovir was well tolerated and the pharmacokinetics were characterized in these studies. PMID:15855501

  19. Clinical population pharmacokinetics and toxicodynamics of linezolid.

    PubMed

    Boak, Lauren M; Rayner, Craig R; Grayson, M Lindsay; Paterson, David L; Spelman, Denis; Khumra, Sharmila; Capitano, Blair; Forrest, Alan; Li, Jian; Nation, Roger L; Bulitta, Jurgen B

    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 <100 ×10(9)/liter. The risk for toxicity did not differ noticeably between 14 and 28 days of therapy and was significantly higher for patients with lower baseline platelet counts. Due to the increased risk of toxicity after longer durations 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

  20. Synthesis, activity and pharmacokinetics of novel antibacterial 15-membered ring macrolones.

    PubMed

    Fajdetić, Andrea; Vinter, Adrijana; Paljetak, Hana Čipčić; Padovan, Jasna; Jakopović, Ivana Palej; Kapić, Samra; Alihodžić, Sulejman; Filić, Darko; Modrić, Marina; Košutić-Hulita, Nada; Antolović, Roberto; Schoenfeld, Zrinka Ivezić; Mutak, Stjepan; Eraković Haber, Vesna; Spaventi, Radan

    2011-08-01

    Synthesis, antibacterial activity and pharmacokinetic properties of a novel class of macrolide antibiotics-macrolones-derived from azithromycin, comprising oxygen atom(s) in the linker and either free or esterified quinolone 3-carboxylic group, are reported. Selected compounds showed excellent antibacterial potency towards key erythromycin resistant respiratory pathogens. However, the majority of compounds lacked good bioavailability. The isopropyl ester, compound 35, and a macrolone derivative with an elongated linker 29 showed the best oral bioavailability in rats, both accompanied with an excellent overall microbiology profile addressing inducible and constitutive MLSb as well as efflux mediated macrolide resistance in streptococci, while compound 29 is more potent against staphylococci.

  1. Phenylethanoid Glycosides: Research Advances in Their Phytochemistry, Pharmacological Activity and Pharmacokinetics.

    PubMed

    Xue, Zhenzhen; Yang, Bin

    2016-01-01

    Phenylethanoid glycosides (PhGs) are widely distributed in traditional Chinese medicines as well as in other medicinal plants, and they were characterized by a phenethyl alcohol (C₆-C₂) moiety attached to a β-glucopyranose/β-allopyranose via a glycosidic bond. The outstanding activity of PhGs in diverse diseases proves their importance in medicinal chemistry research. This review summarizes new findings on PhGs over the past 10 years, concerning the new structures, their bioactivities, including neuroprotective, anti-inflammatory, antioxidant, antibacterial and antivirus, cytotoxic, immunomodulatory, and enzyme inhibitory effects, and pharmacokinetic properties.

  2. Imaginary Companions and Peer Acceptance

    ERIC Educational Resources Information Center

    Gleason, Tracy R.

    2004-01-01

    Early research on imaginary companions suggests that children who create them do so to compensate for poor social relationships. Consequently, the peer acceptance of children with imaginary companions was compared to that of their peers. Sociometrics were conducted on 88 preschool-aged children; 11 had invisible companions, 16 had personified…

  3. Acceptance of Others (Number Form).

    ERIC Educational Resources Information Center

    Masters, James R.; Laverty, Grace E.

    As part of the instrumentation to assess the effectiveness of the Schools Without Failure (SWF) program in 10 elementary schools in the New Castle, Pa. School District, the Acceptance of Others (Number Form) was prepared to determine pupil's attitudes toward classmates. Given a list of all class members, pupils are asked to circle a number from 1…

  4. W-025, acceptance test report

    SciTech Connect

    Roscha, V.

    1994-10-04

    This acceptance test report (ATR) has been prepared to establish the results of the field testing conducted on W-025 to demonstrate that the electrical/instrumentation systems functioned as intended by design. This is part of the RMW Land Disposal Facility.

  5. Euthanasia Acceptance: An Attitudinal Inquiry.

    ERIC Educational Resources Information Center

    Klopfer, Fredrick J.; Price, William F.

    The study presented was conducted to examine potential relationships between attitudes regarding the dying process, including acceptance of euthanasia, and other attitudinal or demographic attributes. The data of the survey was comprised of responses given by 331 respondents to a door-to-door interview. Results are discussed in terms of preferred…

  6. Helping Our Children Accept Themselves.

    ERIC Educational Resources Information Center

    Gamble, Mae

    1984-01-01

    Parents of a child with muscular dystrophy recount their reactions to learning of the diagnosis, their gradual acceptance, and their son's resistance, which was gradually lessened when he was provided with more information and treated more normally as a member of the family. (CL)

  7. Acceptance and Commitment Therapy: Introduction

    ERIC Educational Resources Information Center

    Twohig, Michael P.

    2012-01-01

    This is the introductory article to a special series in Cognitive and Behavioral Practice on Acceptance and Commitment Therapy (ACT). Instead of each article herein reviewing the basics of ACT, this article contains that review. This article provides a description of where ACT fits within the larger category of cognitive behavior therapy (CBT):…

  8. Who accepts first aid training?

    PubMed

    Pearn, J; Dawson, B; Leditschke, F; Petrie, G; Nixon, J

    1980-09-01

    The percentage of individuals trained in first aid skills in the general community is inadequate. We report here a study to investigate factors which influence motivation to accept voluntary training in first aid. A group of 700 randomly selected owners of inground swimming pools (a parental high-risk group) was offered a course of formal first aid instruction. Nine per cent attended the offered training course. The time commitment involved in traditional courses (eight training nights spread over four weeks) is not a deterrent, the same percentage accepting such courses as that who accept a course of one night's instruction. Cost is an important deterrent factor, consumer resistance rising over 15 cost units (one cost unit = the price of a loaf of bread). The level of competent first aid training within the community can be raised by (a) keeping to traditional course content, but (b) by ensuring a higher acceptance rate of first aid courses by a new approach to publicity campaigns, to convince prospective students of the real worth of first aid training. Questions concerning who should be taught first aid, and factors influencing motivation, are discussed.

  9. Applications of a Pharmacokinetic Simulation Program in Pharmacy Courses.

    ERIC Educational Resources Information Center

    Ingram, D.; And Others

    1979-01-01

    Presents a multicompartment model which illustrates aspects of drug absorption, distribution, and elimination in the human body for a course in pharmacokinetics. The course work consists of the interpretation of computer generated simulated data. (Author/CMV)

  10. Explicit Pharmacokinetic Modeling: Tools for Documentation, Verification, and Portability

    EPA Science Inventory

    Quantitative estimates of tissue dosimetry of environmental chemicals due to multiple exposure pathways require the use of complex mathematical models, such as physiologically-based pharmacokinetic (PBPK) models. The process of translating the abstract mathematics of a PBPK mode...

  11. Population Pharmacokinetic and Pharmacodynamic Modeling of Amodiaquine and Desethylamodiaquine in Women with Plasmodium vivax Malaria during and after Pregnancy

    PubMed Central

    Chotsiri, Palang; Jullien, Vincent; Rijken, Marcus J.; Bergstrand, Martin; Cammas, Mireille; McGready, Rose; Singhasivanon, Pratap; Day, Nicholas P. J.; White, Nicholas J.; Nosten, Francois; Lindegardh, Niklas

    2012-01-01

    Amodiaquine is effective for the treatment of Plasmodium vivax malaria, but there is little information on the pharmacokinetic and pharmacodynamic properties of amodiaquine in pregnant women with malaria. This study evaluated the population pharmacokinetic and pharmacodynamic properties of amodiaquine and its biologically active metabolite, desethylamodiaquine, in pregnant women with P. vivax infection and again after delivery. Twenty-seven pregnant women infected with P. vivax malaria on the Thai-Myanmar border were treated with amodiaquine monotherapy (10 mg/kg/day) once daily for 3 days. Nineteen women, with and without P. vivax infections, returned to receive the same amodiaquine dose postpartum. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine. Amodiaquine plasma concentrations were described accurately by lagged first-order absorption with a two-compartment disposition model followed by a three-compartment disposition of desethylamodiaquine under the assumption of complete in vivo conversion. Body weight was implemented as an allometric function on all clearance and volume parameters. Amodiaquine clearance decreased linearly with age, and absorption lag time was reduced in pregnant patients. Recurrent malaria infections in pregnant women were modeled with a time-to-event model consisting of a constant-hazard function with an inhibitory effect of desethylamodiaquine. Amodiaquine treatment reduced the risk of recurrent infections from 22.2% to 7.4% at day 35. In conclusion, pregnancy did not have a clinically relevant impact on the pharmacokinetic properties of amodiaquine or desethylamodiaquine. No dose adjustments are required in pregnancy. PMID:22926572

  12. Preclinical pharmacokinetics, tissue distribution and excretion studies of a novel anti-candidal agent-thiosemicarbazide derivative of isoniazid (TSC-INH) by validated UPLC-MS/MS assay.

    PubMed

    Iqbal, Muzaffar; Ezzeldin, Essam; Bhat, Mashooq A; Raish, Mohammad; Al-Rashood, Khalid A

    2016-01-01

    A simple and sensitive UPLC-MS/MS assay was developed and validated for rapid determination of thiosemicarbazide derivative of isoniazid (TSC-INH), a potent anti-candidal agent in rat plasma, tissues, urine and feces. All biological samples were prepared by protein precipitation method using celecoxib as an internal standard (IS). Chromatographic separation was achieved on Acquity BEH™ C18 (50×2.1 mm, 1.7 μm) column using gradient mobile phase of acetonitrile and water (containing 0.1% formic acid) at flow rate of 0.3 mL/min. The MRM transitions were monitored at m/z 305.00→135.89 for TSC-INH and m/z 380.08→316.03 for IS in ESI negative mode. All validation parameter results were within the acceptable range described in guideline for bioanalytical method validation. The pharmacokinetic study showed that the compound TSC-INH was orally active with 66% absolute bioavailability in rats. It was rapidly absorbed with peak plasma concentration of 1985.92 ng/mL achieved within 1 h after single oral dose (10 mg/kg) administration. TSC-INH exhibited rapid distribution across the body with highest levels in liver and lungs. Penetration in brain tissues suggests that TSC-INH crossed the blood brain barrier. Only 5.23% of the orally administered drug was excreted as unconverted form in urine and feces implying that TSC-INH was metabolized extensively before excretion. With the preliminary knowledge of in vivo pharmacokinetics and disposition properties, this study will be beneficial for further development of compound TSC-INH in future studies.

  13. Simultaneous multi-component quantitation of Chinese herbal injection Yin-zhi-huang in rat plasma by using a single-tube extraction procedure for mass spectrometry-based pharmacokinetic measurement.

    PubMed

    Zeng, Le; Wang, Meiling; Yuan, Yu; Guo, Bin; Zhou, Jing; Tan, Zhen; Ye, Meiling; Ding, Li; Chen, Bo

    2014-09-15

    Ying-zhi-huang injection (YZH-I) is an injectable multi-herbal prescription derived from the ancient Chinese remedy "Yin-chen-hao-tang", which is widely used in the clinic for the treatment of jaundice and chronic liver diseases. To date, little information is available on the pharmacokinetic properties of this poly-herbal formulation. Herein, we reported a simple, rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantitative multiple reaction monitoring (MRM) of eight major ingredients of YZH-I (including baicalin, baicalein, wogonoside, geniposide, geniposidic acid, chlorogenic acid, neochlorogenic acid, and caffeic acid) in rat plasma. A fast single-tube multi-impurity precipitation extraction ("SMIPE") procedure was introduced for straightforward plasma preparation, based on one-pot deproteinization precipitation with acidified methanol extraction and in-situ multifunction impurity removal by a solid sorbent mixture (anh. magnesium sulfate plus octadecylsilane). Particularly, the addition of ascorbic acid in methanol (10 mg/mL) was found to exhibit a pronounced protective effect and significantly increase extraction effectiveness of the herbal phenolic components. Some pretreatment variables (protein precipitating solvent, acidifying agent and sorbent) were optimized with acceptable matrix effect (-18 to 7.7%), extraction recovery (65-88%) and process efficiency (62-91%) for the SMIPE-based LC-MRM multi-analyte quantitation using matrix-matched calibration (5-1000 ng/mL) without using internal standard. Mean accuracies were obtained in the range of 83-114% at three different fortification levels, with intra- and inter-day variations within 13%. This validated method was successfully applied to the simultaneous measurement and pharmacokinetic investigation of the chemical constituents in rats following an intravenous administration of YZH-I.

  14. Simultaneous multi-component quantitation of Chinese herbal injection Yin-zhi-huang in rat plasma by using a single-tube extraction procedure for mass spectrometry-based pharmacokinetic measurement.

    PubMed

    Zeng, Le; Wang, Meiling; Yuan, Yu; Guo, Bin; Zhou, Jing; Tan, Zhen; Ye, Meiling; Ding, Li; Chen, Bo

    2014-09-15

    Ying-zhi-huang injection (YZH-I) is an injectable multi-herbal prescription derived from the ancient Chinese remedy "Yin-chen-hao-tang", which is widely used in the clinic for the treatment of jaundice and chronic liver diseases. To date, little information is available on the pharmacokinetic properties of this poly-herbal formulation. Herein, we reported a simple, rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantitative multiple reaction monitoring (MRM) of eight major ingredients of YZH-I (including baicalin, baicalein, wogonoside, geniposide, geniposidic acid, chlorogenic acid, neochlorogenic acid, and caffeic acid) in rat plasma. A fast single-tube multi-impurity precipitation extraction ("SMIPE") procedure was introduced for straightforward plasma preparation, based on one-pot deproteinization precipitation with acidified methanol extraction and in-situ multifunction impurity removal by a solid sorbent mixture (anh. magnesium sulfate plus octadecylsilane). Particularly, the addition of ascorbic acid in methanol (10 mg/mL) was found to exhibit a pronounced protective effect and significantly increase extraction effectiveness of the herbal phenolic components. Some pretreatment variables (protein precipitating solvent, acidifying agent and sorbent) were optimized with acceptable matrix effect (-18 to 7.7%), extraction recovery (65-88%) and process efficiency (62-91%) for the SMIPE-based LC-MRM multi-analyte quantitation using matrix-matched calibration (5-1000 ng/mL) without using internal standard. Mean accuracies were obtained in the range of 83-114% at three different fortification levels, with intra- and inter-day variations within 13%. This validated method was successfully applied to the simultaneous measurement and pharmacokinetic investigation of the chemical constituents in rats following an intravenous administration of YZH-I. PMID:25129410

  15. Application of a novel liquid chromatography/tandem mass spectrometry method for the determination of antazoline in human plasma: Result of ELEPHANT-I [ELEctrophysiological, pharmacokinetic and hemodynamic effects of PHenazolinum (ANTazoline mesylate)] human pharmacokinetic study.

    PubMed

    Giebułtowicz, Joanna; Piotrowski, Roman; Baran, Jakub; Kułakowski, Piotr; Wroczyński, Piotr

    2016-05-10

    Antazoline is a first-generation antihistaminic agent with antiarrhythmic quinidine-like properties. In some countries, it is widely used for termination of cardiac arrhythmias, especially atrial fibrillation (AF). However, no human pharmacokinetic studies have been conducted with intravenous antazoline. The aim of our study was to develop and validate a novel liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the determination of antazoline in human plasma: the ELEPHANT-I [ELEctrophysiological, pharmacokinetic and hemodynamic effects of PHenazolinum (ANTazoline mesylate)] human pharmacokinetic study. Antazoline was extracted from plasma using liquid-liquid extraction. The concentration of the analyte was measured by LC-MS/MS with xylometazoline as an internal standard. The method was validated for linearity, precision, accuracy, stability (freeze/thaw stability, stability in autosampler, short and long term stability), dilution integrity and matrix effect. The analyzed validation criteria were fulfilled. The method was applied to a pharmacokinetic study involving 10 healthy volunteers. Following a single intravenous dose of antazoline mesylate (100 mg), the plasma concentration profile showed a relative fast elimination with a terminal elimination half-life of 2.29 h. A relatively high volume of distribution was observed (Vss=315 L). The values of mean residence time (MRT∞), area under the curve (AUC∞) and clearance were 3.45 h, 0.91 mg h L(-1) and 80.5 L h(-1), respectively. One volunteer showed significant differences in pharmacokinetic parameters. In conclusion, the proposed new LC-MS/MS method was successfully used for the first time for the determination of antazoline in human plasma. PMID:26895496

  16. Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I.

    PubMed

    McCune, Jeannine S; Bemer, Meagan J

    2016-05-01

    Although immunosuppressive treatments and target concentration intervention (TCI) have significantly contributed to the success of allogeneic haematopoietic cell transplantation (alloHCT), there is currently no consensus on the best immunosuppressive strategies. Compared with solid organ transplantation, alloHCT is unique because of the potential for bidirectional reactions (i.e. host-versus-graft and graft-versus-host). Postgraft immunosuppression typically includes a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate after high-dose myeloablative conditioning, or a calcineurin inhibitor and mycophenolate mofetil after reduced-intensity conditioning. There are evolving roles for the antithymyocyte globulins (ATGs) and sirolimus as postgraft immunosuppression. A review of the pharmacokinetics and TCI of the main postgraft immunosuppressants is presented in this two-part review. All immunosuppressants are characterized by large intra- and interindividual pharmacokinetic variability and by narrow therapeutic indices. It is essential to understand immunosuppressants' pharmacokinetic properties and how to use them for individualized treatment incorporating TCI to improve outcomes. TCI, which is mandatory for the calcineurin inhibitors and sirolimus, has become an integral part of postgraft immunosuppression. TCI is usually based on trough concentration monitoring, but other approaches include measurement of the area under the concentration-time curve (AUC) over the dosing interval or limited sampling schedules with maximum a posteriori Bayesian personalization approaches. Interpretation of pharmacodynamic results is hindered by the prevalence of studies enrolling only a small number of patients, variability in the allogeneic graft source and variability in postgraft immunosuppression. Given the curative potential of alloHCT, the pharmacodynamics of these immunosuppressants deserves to be explored in depth. Development of

  17. Impact of release characteristics of sinomenine hydrochloride dosage forms on its pharmacokinetics in beagle dogs

    PubMed Central

    Sun, Jin; Shi, Jie-Ming; Zhang, Tian-Hong; Gao, Kun; Mao, Jing-Jing; Li, Bing; Sun, Ying-Hua; He, Zhong-Gui

    2005-01-01

    AIM: To investigate the effect of release behavior of sustained-release dosage forms of sinomenine hydrochloride (SM•HCl) on its pharmacokinetics in beagle dogs. METHODS: The in vitro release behavior of two SM•HCl dosage forms, including commercial 12-h sustained-release tablets and 24-h sustained-release pellets prepared in our laboratory, was examined. The two dosage forms were orally administrated to beagle dogs, and then the in vivo SM•HCl pharmacokinetics was investigated and compared. RESULTS: The optimal SM•HCl sustained-release formulation was achieved by mixing slow- and rapid-release pellets (9:1, w/w). The SM•HCl release profiles of the sustained-release pellets were scarcely influenced by the pH of the dissolution medium. Release from the 12-h sustained-release tablets was markedly quicker than that from the 24-h sustained-release pellets, the cumulative release up to 12-h was 99.9% vs 68.7%. From a pharmacokinetic standpoint, the 24-h SM•HCl sustained-release pellets had longer tmax and lower Cmax compared to the 12-h sustained-release tablets, the tmax being 2.67×0.52 h vs 9.83×0.98 h and the Cmax being 1 334.45±368.76 ng/mL vs 893.12±292.55 ng/mL, respectively. However, the AUC0-tn of two SM•HCl dosage forms was comparable and both preparations were statistically bioequivalent. Furthermore, the two preparations had good correlations between SM•HCl percentage absorption in vivo and the cumulative percentage release in vitro. CONCLUSION: The in vitro release properties of the dosage forms strongly affect their pharmacokinetic behavior in vivo. Therefore, managing the in vitro release behavior of dosage forms is a promising strategy for obtaining the optimal in vivo pharmacokinetic characteristics and safe therapeutic drug concentration-time curves. PMID:16052686

  18. Pharmacokinetics of a new ivermectin/praziquantel oil suspension after intramuscular administration in pigs.

    PubMed

    Tang, Shusheng; Chen, Linlin; Guo, Zhaoxu; Hu, Xiuzhi; He, Jiakang; Wang, Gang; Zhao, Tingting; Xiao, Xilong

    2012-04-30

    A new oil suspension containing 0.15% ivermectin and 15% praziquantel for intramuscular injection was developed, and corresponding pharmacokinetics studies were conducted in swine. The combination product is a white- to cream-colored oil suspension and its physical properties such as settling volume ratio, redispersibility, syringeability and flowability are well consistent with the Technical Standards by the Ministry of Agriculture of the People's Republic of China. The pharmacokinetic study consists of two parts. First, the experiments were carried out to compare the pharmacokinetic parameters of the combination product and those same products with praziquantel or ivermectin removed merely. The results showed that no significant change in the major pharmacokinetic parameters (t(1/2z), T(max), C(max), AUC(INF), TimeDur) was observed when either of the component was removed from the combination product, indicating that ivermectin and praziquantel do not interfere with each other when being used together. Second, the pharmacokinetics of the combination product were compared with those of their respective single product. The results showed that the C(max) (15.94 ng/mL) of ivermectin in combination product was 9.01 times higher than the single product, while the AUC(INF) (1925.61 ng h/mL) was 6.02 times higher. Meanwhile, the C(max) (1.48 μg/mL), AUC(INF) (17.08μgh/mL), t(1/2z) (20.25 h), TimeDur3 (42.01 h) and TimeDur4 (16.60 h) of praziquantel in combination product were improved with a factor of 5.48, 13.66, 8.58, 10.10 and 7.31 times when compared with the single product, respectively. Therefore, the efficacy of the combination product was significantly prolonged, especially for praziquantel, so that comprehensive efficacy of controlling parasites sensitive to ivermectin and praziquantel can be achieved with one-single use of it. PMID:22075041

  19. Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I.

    PubMed

    McCune, Jeannine S; Bemer, Meagan J

    2016-05-01

    Although immunosuppressive treatments and target concentration intervention (TCI) have significantly contributed to the success of allogeneic haematopoietic cell transplantation (alloHCT), there is currently no consensus on the best immunosuppressive strategies. Compared with solid organ transplantation, alloHCT is unique because of the potential for bidirectional reactions (i.e. host-versus-graft and graft-versus-host). Postgraft immunosuppression typically includes a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate after high-dose myeloablative conditioning, or a calcineurin inhibitor and mycophenolate mofetil after reduced-intensity conditioning. There are evolving roles for the antithymyocyte globulins (ATGs) and sirolimus as postgraft immunosuppression. A review of the pharmacokinetics and TCI of the main postgraft immunosuppressants is presented in this two-part review. All immunosuppressants are characterized by large intra- and interindividual pharmacokinetic variability and by narrow therapeutic indices. It is essential to understand immunosuppressants' pharmacokinetic properties and how to use them for individualized treatment incorporating TCI to improve outcomes. TCI, which is mandatory for the calcineurin inhibitors and sirolimus, has become an integral part of postgraft immunosuppression. TCI is usually based on trough concentration monitoring, but other approaches include measurement of the area under the concentration-time curve (AUC) over the dosing interval or limited sampling schedules with maximum a posteriori Bayesian personalization approaches. Interpretation of pharmacodynamic results is hindered by the prevalence of studies enrolling only a small number of patients, variability in the allogeneic graft source and variability in postgraft immunosuppression. Given the curative potential of alloHCT, the pharmacodynamics of these immunosuppressants deserves to be explored in depth. Development of

  20. Pharmacokinetics and safety of JTE-522, a novel selective cyclooxygenase-2 inhibitor, in healthy male volunteers

    PubMed Central

    Ikeda, Yasuhiko; Umemura, Kazuo; Kondo, Kazunao; Nakashima, Mitsuyoshi; Kobayashi, Takuo; Takahashi, Mitsuru

    2002-01-01

    Aims The pharmacokinetics and safety profile of JTE-522, 4-(4-cyclohexyl-2 methyloxazol-5-yl)-2-fluorobenzensulphonamide, a novel selective cyclooxygenase-2 inhibitor were investigated in healthy male volunteers. Methods Initially, as a pilot study, five groups of two subjects were given oral doses of 3–100 mg of JTE-522. After safety assessment, subjects were given 150 and 200 mg of JTE-522. The effect of food-intake on the pharmacokinetics of JTE-522 at a dose of 150 mg was examined. In the multiple-dose study, subjects were given 150 mg of JTE-522 once a day for 7 days. Concentrations of unchanged JTE-522 in plasma, blood and urine were determined by high performance liquid chromatography (h.p.l.c.). Concentrations of metabolites were estimated with h.p.l.c. chromatograms and calibration curves for quantification of unchanged JTE-522. Results In the course of this study, no serious abnormality attributable to the test drug was observed, suggesting that JTE-522 was well tolerated in healthy subjects. In a single-dose study, the concentrations of JTE-522 in blood were much higher than the corresponding concentrations in plasma. JTE-522 was readily distributed to blood cells and percentage distribution into blood cells was more than 99.0%. However, the values of Cmax in blood at doses of 100, 150, 200 mg JTE-522 were 15241, 20445 ± 3918 (16333–24556), 20965 ± 3260 (17544–24386) ng ml−1, respectively. These findings suggest that JTE-522 has a high affinity for blood cells and the distribution into blood cells is limited at the higher doses of over 100 mg. In a multiple dose study, pharmacokinetic parameters including t1/2 and AUC after the fourth administration were comparable with that of the seventh administration. Thus, these findings suggest the absence of accumulation on the multiple-dosing of JTE-522. Conclusions These results indicate that JTE-522 has an acceptable pharmacokinetic profile for clinical use without any serious adverse events as we

  1. Prodrug oncrasin-266 improves the stability, pharmacokinetics, and safety of NSC-743380

    PubMed Central

    Wu, Shuhong; Wang, Li; Huang, Xiao; Cao, Mengru; Hu, Jing; Li, Hongyu; Zhang, Hui; Sun, Xiaoping; Meng, Qing H.; Hofstetter, Wayne L.; Roth, Jack A.; Swisher, Stephen G.; Fang, Bingliang

    2014-01-01

    Through synthetic lethality screening of isogenic cell lines with and without the oncogenic KRAS gene and through lead compound optimization, we recently developed a novel anticancer agent designated NSC-743380 (oncrasin-72) that has promising in vitro and in vivo anticancer activity in a subset of cancer cell lines, including KRAS-mutant cancer cells. However, NSC-743380 tends to form dimers, which dramatically reduces its anticancer activity. To improve the physicochemical properties of NSC-743380, we synthesized a prodrug of NSC-743380, designated oncrasin-266, by modifying NSC-743380 with cyclohexylacetic acid and evaluated its in vitro and in vivo properties. Oncrasin-266 spontaneously hydrolyzed in phosphate-buffered saline in a time-dependent manner and was more stable than NSC-743380 in powder or stock solutions. In vivo administration of oncrasin-266 in mice led to the release of NSC-743380 which improved the pharmacokinetics of NSC-743380. Tissue distribution analysis revealed that oncrasin-266 was deposited in liver, whereas released NSC-743380 was detected in liver, lung, kidney, and subcutaneous tumor. Oncrasin-266 was better tolerated in mice at a higher dose level treatment (150–300mg/kg, i.p.) than the parent agent was, suggesting that the prodrug reduced the acute toxicity of the parent agent. Our results demonstrated that the prodrug strategy could improve the stability, pharmacokinetic properties, and safety of NSC-743380. PMID:25182964

  2. Population Pharmacokinetics of Peramivir in Healthy Volunteers and Influenza Patients

    PubMed Central

    Matsuo, Yumiko; Ishibashi, Toru; Hollister, Alan S.

    2015-01-01

    Peramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. subjects. Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function. PMID:26282420

  3. A First-in-Human Study To Assess the Safety and Pharmacokinetics of Monoclonal Antibodies against Human Cytomegalovirus in Healthy Volunteers.

    PubMed

    Dole, Kiran; Segal, Florencia Pereyra; Feire, Adam; Magnusson, Baldur; Rondon, Juan C; Vemula, Janardhana; Yu, Jing; Pang, Yinuo; Pertel, Peter

    2016-05-01

    Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the function of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. Here, we evaluated the safety, tolerability, and pharmacokinetics of a single intravenous dose of LJP538 or LJP539 or their combination in healthy volunteers. Adverse events and laboratory abnormalities occurred sporadically with similar incidence between antibody and placebo groups and without any apparent relationship to dose. No subject who received antibody developed a hypersensitivity, infusion-related reaction or anti-drug antibodies. After intravenous administration, both LJP538 and LJP539 demonstrated typical human IgG1 pharmacokinetic properties, with slow clearances, limited volumes of distribution, and long terminal half-lives. The pharmacokinetic parameters were linear and dose proportional for both antibodies across the 50-fold range of doses evaluated in the study. There was no apparent impact on pharmacokinetics when the antibodies were administered alone or in combination. CSJ148 and the individual monoclonal antibodies were safe and well tolerated, with pharmacokinetics as expected for human immunoglobulin.

  4. Comparative bioavailability and pharmacokinetics of two oral formulations of flurbiprofen: a single-dose, randomized, open-label, two-period, crossover study in Pakistani subjects.

    PubMed

    Qayyum, Aisha; Najmi, Muzammil Hasan; Abbas, Mateen

    2013-11-01

    Comparative bioavailability studies are conducted to establish the bioequivalence of generic formulation with that of branded reference formulation, providing confidence to clinicians to use these products interchangeably. This study was carried out to compare a locally manufactured formulation of flurbiprofen with that of a branded product. Twenty two healthy male adults received a single dose of flurbiprofen (100mg) either generic or branded product according to randomization scheme on each of 2 periods. Blood samples were collected and plasma flurbiprofen concentration was determined by a validated HPLC method. Pharmacokinetic parameters like AUC(0-t), AUC(0-oo), Cmax, Tmax, t½, Vd and clearance were determined. The 90% CI for the ratio of geometric means of test to reference product's pharmacokinetic variables was calculated. Pharmacokinetic parameters for two formulations were comparable. Ratio of means of AUC(0-24), AUC(0-oo) and Cmax for test to reference products and 90% CI for these ratios were within the acceptable range. The p-values calculated by TOST were much less than the specified value (p-0.05). ANOVA gave p-values which were more than the specified value (p-0.05) for sequence, subject, period and formulation. Test formulation of flurbiprofen (tablet Flurso) was found to meet the criteria for bioequivalence to branded product (tablet Ansaid) based on pharmacokinetic parameters.

  5. 41 CFR 101-27.506 - Determination of acceptability for credit.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...-INVENTORY MANAGEMENT 27.5-Return of GSA Stock Items § 101-27.506 Determination of acceptability for credit... 41 Public Contracts and Property Management 2 2010-07-01 2010-07-01 true Determination of acceptability for credit. 101-27.506 Section 101-27.506 Public Contracts and Property Management...

  6. Accepting the T3D

    SciTech Connect

    Rich, D.O.; Pope, S.C.; DeLapp, J.G.

    1994-10-01

    In April, a 128 PE Cray T3D was installed at Los Alamos National Laboratory`s Advanced Computing Laboratory as part of the DOE`s High-Performance Parallel Processor Program (H4P). In conjunction with CRI, the authors implemented a 30 day acceptance test. The test was constructed in part to help them understand the strengths and weaknesses of the T3D. In this paper, they briefly describe the H4P and its goals. They discuss the design and implementation of the T3D acceptance test and detail issues that arose during the test. They conclude with a set of system requirements that must be addressed as the T3D system evolves.

  7. Sweeteners: consumer acceptance in tea.

    PubMed

    Sprowl, D J; Ehrcke, L A

    1984-09-01

    Sucrose, fructose, aspartame, and saccharin were compared for consumer preference, aftertaste, and cost to determine acceptability of the sweeteners. A 23-member taste panel evaluated tea samples for preference and aftertaste. Mean retail cost of the sweeteners were calculated and adjusted to take sweetening power into consideration. Sucrose was the least expensive and most preferred sweetener. No significant difference in preference for fructose and aspartame was found, but both sweeteners were rated significantly lower than sucrose. Saccharin was the most disliked sweetener. Fructose was the most expensive sweetener and aspartame the next most expensive. Scores for aftertaste followed the same pattern as those for preference. Thus, a strong, unpleasant aftertaste seems to be associated with a dislike for a sweetener. From the results of this study, it seems that there is no completely acceptable low-calorie substitute for sucrose available to consumers.

  8. Acceptability of reactors in space

    SciTech Connect

    Buden, D.

    1981-01-01

    Reactors are the key to our future expansion into space. However, there has been some confusion in the public as to whether they are a safe and acceptable technology for use in space. The answer to these questions is explored. The US position is that when reactors are the preferred technical choice, that they can be used safely. In fact, it does not appear that reactors add measurably to the risk associated with the Space Transportation System.

  9. Acceptability of reactors in space

    SciTech Connect

    Buden, D.

    1981-04-01

    Reactors are the key to our future expansion into space. However, there has been some confusion in the public as to whether they are a safe and acceptable technology for use in space. The answer to these questions is explored. The US position is that when reactors are the preferred technical choice, that they can be used safely. In fact, it dies not appear that reactors add measurably to the risk associated with the Space Transportation System.

  10. 48 CFR 12.402 - Acceptance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Acceptance. 12.402 Section... Acceptance. (a) The acceptance paragraph in 52.212-4 is based upon the assumption that the Government will rely on the contractor's assurances that the commercial item tendered for acceptance conforms to...

  11. Pharmacokinetics prediction and drugability assessment of diphenylheptanoids from turmeric (Curcuma longa L).

    PubMed

    Balaji, S; Chempakam, B

    2009-03-01

    Cheminformatics approaches are currently not employed in any of the spices to study the medicinal properties traditionally attributed to them. The aim of this study is to find the most efficacious molecule which do not have toxic effects but at the same time have desired pharmacokinetic profile. In the present study of the class 'diphenylheptanoids' from turmeric, cheminformatics methods were employed to predict properties such as physicochemical properties, Absorption, Distribution, Metabolism, Toxicity (mutagenicity, rodent carcinogenicity and human hepatotoxicity). These studies confirmed that curcumin and its derivatives cause dose-dependent hepatotoxicity. The results of these studies indicate that, in contrast to curcumin, few other compounds in turmeric such as compounds (8) and (9) [refer text], exhibit better activities and are drugable and do not have any side-effects.

  12. Population pharmacokinetic analysis of voriconazole from a pharmacokinetic study with immunocompromised Japanese pediatric subjects.

    PubMed

    Muto, Chieko; Shoji, Satoshi; Tomono, Yoshiro; Liu, Ping

    2015-01-01

    A population pharmacokinetic (PK) analysis was conducted to characterize the voriconazole pharmacokinetic profiles in immunocompromised Japanese pediatric subjects and to compare them to those in immunocompromised non-Japanese pediatric subjects. A previously developed two-compartment pharmacokinetic model with first-order absorption and mixed linear and nonlinear elimination adequately described the voriconazole intravenous and oral data from Japanese pediatric subjects with few modifications. Bayesian priors were applied to this analysis by using the NONMEM routine NWPRI, which allowed priors for the fixed-effect parameter vector and variance matrix of the random-effect parameters to be a normal distribution and an inverse Wishart distribution, respectively. Large intersubject variabilities in oral bioavailability and voriconazole exposure were observed in these pediatric subjects. The mean oral bioavailability estimated in Japanese pediatric subjects was 73% (range, 17% to 99%), which is consistent with the reported estimates of 64% in the previous model and less than what was originally estimated for healthy adults-96%. Voriconazole exposures in Japanese pediatric subjects were generally comparable to those in non-Japanese pediatric subjects receiving the same dosing regimens, given the large intersubject variability. Consistent with the previous findings, the CYP2C19 genotyping status did not have a clinically relevant effect on voriconazole exposure in Japanese pediatric subjects, although it was identified as a covariate in the model to help explain the intersubject variability in voriconazole exposure. The CYP2C19 genotyping status alone does not warrant dose adjustment of voriconazole. No other factors besides age and weight were identified to explain the PK variability of voriconazole. PMID:25801557

  13. Population pharmacokinetic analysis of voriconazole from a pharmacokinetic study with immunocompromised Japanese pediatric subjects.

    PubMed

    Muto, Chieko; Shoji, Satoshi; Tomono, Yoshiro; Liu, Ping

    2015-01-01

    A population pharmacokinetic (PK) analysis was conducted to characterize the voriconazole pharmacokinetic profiles in immunocompromised Japanese pediatric subjects and to compare them to those in immunocompromised non-Japanese pediatric subjects. A previously developed two-compartment pharmacokinetic model with first-order absorption and mixed linear and nonlinear elimination adequately described the voriconazole intravenous and oral data from Japanese pediatric subjects with few modifications. Bayesian priors were applied to this analysis by using the NONMEM routine NWPRI, which allowed priors for the fixed-effect parameter vector and variance matrix of the random-effect parameters to be a normal distribution and an inverse Wishart distribution, respectively. Large intersubject variabilities in oral bioavailability and voriconazole exposure were observed in these pediatric subjects. The mean oral bioavailability estimated in Japanese pediatric subjects was 73% (range, 17% to 99%), which is consistent with the reported estimates of 64% in the previous model and less than what was originally estimated for healthy adults-96%. Voriconazole exposures in Japanese pediatric subjects were generally comparable to those in non-Japanese pediatric subjects receiving the same dosing regimens, given the large intersubject variability. Consistent with the previous findings, the CYP2C19 genotyping status did not have a clinically relevant effect on voriconazole exposure in Japanese pediatric subjects, although it was identified as a covariate in the model to help explain the intersubject variability in voriconazole exposure. The CYP2C19 genotyping status alone does not warrant dose adjustment of voriconazole. No other factors besides age and weight were identified to explain the PK variability of voriconazole.

  14. Pharmacokinetics and bioavailability of percutaneous ibuprofen.

    PubMed

    Kleinbloesem, C H; Ouwerkerk, M; Spitznagel, W; Wilkinson, F E; Kaiser, R R

    1995-10-01

    The absorption, pharmacokinetics and bioavailability of ibuprofen (CAS 15687-27-1) were investigated for an ibuprofen gel preparation (ibugel) for percutaneous application, and compared to a standard oral ibuprofen tablet preparation. The monocentric, randomised, 2-way cross-over study with 7-day wash-out period was performed on 18 healthy female volunteers with an average age of 26.3 +/- 4.8 years (range: 20-38 years), average weight 60.4 +/- 7.6 kg, and average height 164.7 +/- 5.9 cm. Blood samples were taken from the volunteers before administration of the tablet or gel, and periodically during 24 h after administration. The ibuprofen content in these samples was determined using a validated HPLC method. Main pharmacokinetic parameters derived from individual plasma concentration-time courses included: Cmax, tmax, AUCO-->24, AUCO-->infinity, MRTO-->infinity, t1/2 and Frel. For percutaneous application of 500 mg ibuprofen (10 g 5% gel on the back, area of 20 x 20 cm) with occlusion for 2 h, a Cmax of 7.1 +/- 4.4 micrograms/ml (95% confidence interval (CI): 5.0-9.1) was obtained at 2.4 +/- 0.8 h (95% CI: 2.0-2.8). For oral administration of 400 mg, Cmax was 36.7 +/- 7.5 micrograms/ml (95% CI: 33.2-40.1) at 1.1 +/- 0.8 h (95% CI: 0.7-1.5). The (dose-corrected) relative bioavailability of the topical ibuprofen was found to be 22 +/- 12% (95% CI: 14-30%) of that after oral administration. The plasma elimination half-life was 2.5 +/- 1.4 h (95% CI: 1.9-3.2) for topical administration, and 1.8 +/- 0.5 h (95% CI: 1.6-2.1) after oral administration (not significant, p > 0.05). The surprisingly high levels of ibuprofen found in the plasma after percutaneous application are still below the threshold where systemic side effects might be expected (10 micrograms/ml). The high peak plasma concentration and relative bioavailability of percutaneous ibuprofen are likely due to the galenical formation of the gel preparation, which contains isopropyl alcohol and propylene glycol

  15. Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials.

    PubMed

    Lamp, K C; Freeman, C D; Klutman, N E; Lacy, M K

    1999-05-01

    Metronidazole, the prototype nitroimidazole antimicrobial, was originally introduced to treat Trichomonas vaginalis, but is now used for the treatment of anaerobic and protozoal infections. The nitroimidazoles are bactericidal through toxic metabolites which cause DNA strand breakage. Resistance, both clinical and microbiological, has been described only rarely. Metronidazole given orally is absorbed almost completely, with bioavailability > 90% for tablets; absorption is unaffected by infection. Rectal and intravaginal absorption are 67 to 82%, and 20 to 56%, of the dose, respectively. Metronidazole is distributed widely and has low protein binding (< 20%). The volume of distribution at steady state in adults is 0.51 to 1.1 L/kg. Metronidazole reaches 60 to 100% of plasma concentrations in most tissues studied, including the central nervous system, but does not reach high concentrations in placental tissue. Metronidazole is extensively metabolised by the liver to 5 metabolites. The hydroxy metabolite has biological activity of 30 to 65% and a longer elimination half-life than the parent compound. The majority of metronidazole and its metabolites are excreted in urine and faeces, with less than 12% excreted unchanged in urine. The pharmacokinetics of metronidazole are unaffected by acute or chronic renal failure, haemodialysis, continuous ambulatory peritoneal dialysis, age, pregnancy or enteric disease. Renal dysfunction reduces the elimination of metronidazole metabolites; however, no toxicity has been documented and dosage alterations are unnecessary. Liver disease leads to a decreased clearance of metronidazole and dosage reduction is recommended. Recent pharmacodynamic studies of metronidazole have demonstrated activity for 12 to 24 hours after administration of metronidazole 1 g. The post-antibiotic effect of metronidazole extends beyond 3 hours after the concentration falls below the minimum inhibitory concentration (MIC). The concentration

  16. Developing a New Instrument for Assessing Acceptance of Change

    PubMed Central

    Di Fabio, Annamaria; Gori, Alessio

    2016-01-01

    This article focuses on the usefulness of going beyond the concept of resistance to change and capitalizing on the use of a model that includes positivity and acceptance of change. We first discuss the theoretical background of this new construct in the work and organizational fields and then evaluate the psychometric properties of a new measure for assessing acceptance of change. The results of exploratory factor analysis indicated a factor structure with five principal dimensions; besides confirmatory factor analysis (CFA) goodness of fit indices indicated a good fit of the model to the data. All the dimensions showed good values of internal consistency. The results of the present study indicate that the Acceptance of Change Scale (ACS) is a brief and easily administered instrument with good psychometric properties that can promote the development of clients' strengths and the growth of a sense of Self, thereby helping them choose their own way without losing any opportunities in their lives and their work. PMID:27303356

  17. Pharmacokinetic simulations to explore dissolution criteria of BCS I and III biowaivers with and without MDR-1 efflux transporter.

    PubMed

    Kortejärvi, H; Malkki, J; Shawahna, R; Scherrmann, J-M; Urtti, A; Yliperttula, M

    2014-09-30

    In this study, a pharmacokinetic simulation model was used to explore the dissolution acceptance criteria for BCS I and III biowaivers and to examine the risk of MDR-1 efflux transporter on bioequivalence of substrates. The compartmental absorption and transit (CAT) model with one- or two systemic compartments was used. The parameter values used in the simulations were based on the pharmacokinetics of existing 70 BCS I and III drugs. Based on the simulations BCS I drug products with Tmax of >0.9 h, both dissolution criteria "very rapid" and "rapid and similar" were acceptable. For rapidly absorbed and distributed BCS I drug products with Tmax of 0.6-0.9 h, the dissolution criterion "very rapid" is preferred. If Tmax is less than 0.6 h there is a risk of bioinequivalence for the BCS I drug products regardless of the dissolution criteria. Based on the simulations, all BCS III drug products were good biowaiver candidates with both dissolution criteria. Almost all the BCS III drug products (>89%) and many BCS I products (9-57%) showed risks of bioinequivalence, if an excipient in either product inhibits MDR1-efflux transport of the drug. To eliminate these risks excipients with prior use in bioequivalent products should be used for MDR-1 efflux substrates.

  18. Physico-chemical properties, probiotic survivability, microstructure, and acceptability of a yogurt-like symbiotic oats-based product using pre-polymerized whey protein as a gelation agent.

    PubMed

    Walsh, Helen; Ross, Jane; Hendricks, Gregory; Guo, Mingruo

    2010-06-01

    Consumption of a food product containing prebiotics and probiotics has been recognized as an important factor in lowering risk of intestinal cancer and gastrointestinal diseases and risks associated with high cholesterol. An oats-based symbiotic yogurt-like food (Oagurt) was developed using oats and probiotics (Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium), with pre-polymerized whey protein (PWP) as a gelation agent. The product was also fortified with inulin to increase soluble fiber, minerals, and vitamins. Physico-chemical analyses and 9 wk shelf life for viability of probiotics and changes in pH and viscosity were carried out for formulations with (F) and without (C) fortification. Results of the shelf life study showed that both L. casei and Bifidobacterium remained at therapeutic levels: 4.8 x 10(6) CFU/g (F), 4.3 x 10(6) CFU/g (C) and 3.1 x 10(6) CFU/g (F), 3.17 x 10(6) CFU/g (C) after 9 wk. However L. acidophilus did not survive after 3 wk. Viscosity and pH decreased significantly during the study with the difference between formulations also significant for pH (P < 0.0001). Scanning electron microscopy of samples revealed that the pre-polymerized whey protein played a major role in the structure of the gel with an increased protein network structure visible at higher PWP levels. A consumer acceptability study showed that the product was "fair" for all organoleptic attributes.

  19. Potential of aerosolized rifampicin lipospheres for modulation of pulmonary pharmacokinetics and bio-distribution.

    PubMed

    Singh, Charan; Koduri, L V Seshu Kumar; Dhawale, Vaibhav; Bhatt, Tara Datt; Kumar, Rajdeo; Grover, Vikas; Tikoo, Kulbhushan; Suresh, Sarasija

    2015-11-30

    The aim of the present study was to establish the potential of rifampicin loaded phospholipid lipospheres carrier for pulmonary application. Lipospheres were prepared with rifampicin and phospholipid in the ratio of 1:1 using spray drying method. Further, lipospheres were evaluated for flow properties and surface area measurement. The formulated lipospheres were evaluated in vitro for aerodynamic characterization and in vivo for lung pharmacokinetics and biodistribution studies in Sprague Dawley rats. Powder flow properties finding suggested the free flowing nature of the lipospheres. In-vitro aerosol performance study indicated more than 80±5% of the emitted dose (ED) and 77.61±3% fine particles fraction (FPF). Mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were found to be 2.72±0.13 μm and 3.28±0.12, respectively. In-vitro aerosol performance study revealed the higher deposition at 3, 4 and 5 stages which simulates the trachea-primary bronchus, secondary and terminal bronchus of the human lung, respectively. The drug concentration from nebulized lipospheres in the non-targeted tissues was lesser than from rifampicin-aqueous solution. The pulmonary pharmacokinetic study demonstrated improved bioavailability, longer residence of drug in the lung and targeting factor of 8.03 for lipospheres as compared to rifampicin-aqueous solution. Thus, the results of the study demonstrated the potential of rifampicin lipospheres formulation would be of use as an alternative to existing oral therapy.

  20. Sensitivity Analysis of a Pharmacokinetic Model of Vaginal Anti-HIV Microbicide Drug Delivery.

    PubMed

    Jarrett, Angela M; Gao, Yajing; Hussaini, M Yousuff; Cogan, Nicholas G; Katz, David F

    2016-05-01

    Uncertainties in parameter values in microbicide pharmacokinetics (PK) models confound the models' use in understanding the determinants of drug delivery and in designing and interpreting dosing and sampling in PK studies. A global sensitivity analysis (Sobol' indices) was performed for a compartmental model of the pharmacokinetics of gel delivery of tenofovir to the vaginal mucosa. The model's parameter space was explored to quantify model output sensitivities to parameters characterizing properties for the gel-drug product (volume, drug transport, initial loading) and host environment (thicknesses of the mucosal epithelium and stroma and the role of ambient vaginal fluid in diluting gel). Greatest sensitivities overall were to the initial drug concentration in gel, gel-epithelium partition coefficient for drug, and rate constant for gel dilution by vaginal fluid. Sensitivities for 3 PK measures of drug concentration values were somewhat different than those for the kinetic PK measure. Sensitivities in the stromal compartment (where tenofovir acts against host cells) and a simulated biopsy also depended on thicknesses of epithelium and stroma. This methodology and results here contribute an approach to help interpret uncertainties in measures of vaginal microbicide gel properties and their host environment. In turn, this will inform rational gel design and optimization. PMID:27012224

  1. Virtual pharmacokinetic model of human eye.

    PubMed

    Kotha, Sreevani; Murtomäki, Lasse

    2014-07-01

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

  2. Pharmacokinetic interaction of intravenous fentanyl with ketoconazole.

    PubMed

    Ziesenitz, Victoria C; König, Sonja K; Mahlke, Nina S; Skopp, Gisela; Haefeli, Walter E; Mikus, Gerd

    2015-06-01

    Fentanyl is primarily metabolized by CYP3A, but has also been suggested to act as a weak inhibitor of CYP3A. We investigated the influence of CYP3A inhibition by ketoconazole on the pharmacokinetics of intravenously administered fentanyl and the effect of fentanyl on CYP3A activity. A prospective, open-label, randomized, monocentre, crossover study was conducted in 16 healthy volunteers. They received fentanyl alone (5 microgram per kilogram) or fentanyl plus ketoconazole (200 milligram orally B.I.D. over 2 days). Naloxone (2 × 0.2 milligram i.v.) was given simultaneously with fentanyl to mitigate any opioid effect. Midazolam was administered as a CYP3A probe drug. Fentanyl and its metabolites were quantified by LC/MS/MS in blood and urine samples obtained over 24 hour. Exposure of fentanyl (AUC0- ∞ ) was significantly increased to 133% and systemic clearance was reduced to 78% by ketoconazole, norfentanyl formation was significantly delayed and partial metabolic clearance decreased to 18%. Fentanyl had no influence on midazolam exposure and CYP3A activity whereas ketoconazole decreased CYP3A activity to 13%. Although fentanyl N-dealkylation is substantially inhibited by ketoconazole, exposure of fentanyl itself increased by one third only. Clinically fentanyl dosage adjustments may become necessary when ketoconazole or other strong CYP3A inhibitors are given simultaneously. Fentanyl itself does not influence CYP3A activity.

  3. Modeling of pharmacokinetic systems using stochastic deconvolution.

    PubMed

    Kakhi, Maziar; Chittenden, Jason

    2013-12-01

    In environments where complete mechanistic knowledge of the system dynamics is not available, a synergy of first-principle concepts, stochastic methods and statistical approaches can provide an efficient, accurate, and insightful strategy for model development. In this work, a system of ordinary differential equations describing system pharmacokinetics (PK) was coupled to a Wiener process for tracking the absorption rate coefficient, and was embedded in a nonlinear mixed effects population PK formalism. The procedure is referred to as "stochastic deconvolution" and it is proposed as a diagnostic tool to inform on a mapping function between the fraction of the drug absorbed and the fraction of the drug dissolved when applying one-stage methods to in vitro-in vivo correlation modeling. The goal of this work was to show that stochastic deconvolution can infer an a priori specified absorption profile given dense observational (simulated) data. The results demonstrate that the mathematical model is able to accurately reproduce the simulated data in scenarios where solution strategies for linear, time-invariant systems would assuredly fail. To this end, PK systems that are representative of Michaelis-Menten kinetics and enterohepatic circulation were investigated. Furthermore, the solution times are manageable using a modest computer hardware platform.

  4. Pharmacokinetics and biodegradation of chitosan in rats

    NASA Astrophysics Data System (ADS)

    Li, Hui; Jiang, Zhiwen; Han, Baoqin; Niu, Shuyi; Dong, Wen; Liu, Wanshun

    2015-10-01

    Chitosan, an excellent biomedical material, has received a widespread in vivo application. In contrast, its metabolism and distribution once being implanted were less documented. In this study, the pharmacokinetics and biodegradation of fluorescein isothiocyanate (FITC) labeled and muscle implantation administrated chitosan in rats were investigated with fluorescence spectrophotometry, histological assay and gel chromatography. After implantation, chitosan was degraded gradually during its distribution to diverse organs. Among the tested organs, liver and kidney were found to be the first two highest in chitosan content, which was followed by heart, brain and spleen. Urinary excretion was believed to be the major pathway of chitosan elimination, yet 80% of chitosan administered to rats was not trackable in their urine. This indicated that the majority of chitosan was degraded in tissues. In average, the molecular weight of the degradation products of chitosan in diverse organs and urine was found to be <65 kDa. This further confirmed the in vivo degradation of chitosan. Our findings provided new evidences for the intensive and safe application of chitosan as a biomedical material.

  5. Virtual pharmacokinetic model of human eye.

    PubMed

    Kotha, Sreevani; Murtomäki, Lasse

    2014-07-01

    A virtual pharmacokinetic 3D model of the human eye is built using Comsol Multiphysics® software, which is based on the Finite Element Method (FEM). The model considers drug release from a polymer patch placed on sclera. The model concentrates on the posterior part of the eye, retina being the target tissue, and comprises the choroidal blood flow, partitioning of the drug between different tissues and active transport at the retina pigment epithelium (RPE)-choroid boundary. Although most straightforward, in order to check the mass balance, no protein binding or metabolism is yet included. It appeared that the most important issue in obtaining reliable simulation results is the finite element mesh, while time stepping has hardly any significance. Simulations were extended to 100,000 s. The concentration of a drug is shown as a function of time at various points of retina, as well as its average value, varying several parameters in the model. This work demonstrates how anybody with basic knowledge of calculus is able to build physically meaningful models of quite complex biological systems. PMID:24721554

  6. Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib.

    PubMed

    Abbas, Richat; Hsyu, Poe-Hirr

    2016-10-01

    Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disorder. Bosutinib is an oral, once-daily SRC/ABL tyrosine kinase inhibitor with very potent inhibitory activity. Bosutinib is effective against all phases of intolerant or resistant Philadelphia chromosome-positive CML that do not harbor the T315I or V299LABL kinase domain mutations. Peak plasma concentrations of bosutinib occur at 4-6 h following oral administration, and dose-proportional increases in exposure are observed at doses ranging from 200 to 800 mg. Absorption of bosutinib increases with food. Bosutinib is distributed extensively into the tissues. It is highly plasma protein bound (94 %) and is primarily metabolized in the liver by cytochrome P450 3A4. Bosutinib is well tolerated overall and has a unique but manageable toxicity profile. This article provides a review of the available clinical pharmacokinetic, pharmacodynamic, and drug-drug interaction data on bosutinib in healthy subjects, patients with CML, and special populations.

  7. Pharmacokinetics of gentamicin in birds of prey.

    PubMed

    Bird, J E; Miller, K W; Larson, A A; Duke, G E

    1983-07-01

    The pharmacokinetics of gentamicin, including half-life, apparent volume of distribution, total body clearance, and fraction of drug absorbed from IM injection sites, were determined in 3 species of birds of prey (red-tailed hawks, great horned owls, and golden eagles). Significant differences (P less than 0.05) between species were found for the half-life and total body clearance values for this broad-spectrum antibiotic. The values for apparent volume of distribution and fraction absorbed did not differ among species and were similar to those reported in mammals. Rapid and relatively complete absorption from IM injection sites resulted in high bioavailability. After IV administration of 10 mg of gentamicin/kg of body weight, serum concentrations greater than 12 micrograms/ml were present for at least 2 hours and greater than 2 micrograms/ml for 4 to 6 hours. On the basis of the various determinations, an IM dose of 2.5 mg of gentamicin/kg given every 8 hours should provide therapeutic serum concentrations of gentamicin in the 3 species. PMID:6881663

  8. 48 CFR 570.402-5 - Potential acceptable locations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... ADMINISTRATION SPECIAL CONTRACTING PROGRAMS ACQUIRING LEASEHOLD INTERESTS IN REAL PROPERTY Special Aspects of Contracting for Continued Space Requirements 570.402-5 Potential acceptable locations. If the contracting... cost-benefit analysis following the procedures in 570.402-6. Based on the results of the...

  9. Pharmacokinetics of Anti-VEGF Agent Aflibercept in Cancer Predicted by Data-Driven, Molecular-Detailed Model.

    PubMed

    Finley, S D; Angelikopoulos, P; Koumoutsakos, P; Popel, A S

    2015-11-01

    Mathematical models can support the drug development process by predicting the pharmacokinetic (PK) properties of the drug and optimal dosing regimens. We have developed a pharmacokinetic model that includes a biochemical molecular interaction network linked to a whole-body compartment model. We applied the model to study the PK of the anti-vascular endothelial growth factor (VEGF) cancer therapeutic agent, aflibercept. Clinical data is used to infer model parameters using a Bayesian approach, enabling a quantitative estimation of the contributions of specific transport processes and molecular interactions of the drug that cannot be examined in other PK modeling, and insight into the mechanisms of aflibercept's antiangiogenic action. Additionally, we predict the plasma and tissue concentrations of unbound and VEGF-bound aflibercept. Thus, we present a computational framework that can serve as a valuable tool for drug development efforts. PMID:26783500

  10. Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction

    EPA Science Inventory

    Developing physiologically-based pharmacokinetic (PBPK) models for chemicals can be resource-intensive, as neither chemical-specific parameters nor in vivo pharmacokinetic data are easily available for model construction. Previously developed, well-parameterized, and thoroughly-v...

  11. The relevance of pharmacokinetics in the development of biotechnology products.

    PubMed

    Toon, S

    1996-01-01

    Biotechnology derived medicines will have an increasing impact not only upon medical practice but also upon the working lives of many pharmaceutical scientists. Whilst such medicines may be viewed as highly sophisticated to the clinician and scientist, the computer will still rightly demand that they are both efficacious and safe. Impacting as it does upon all phases of drug development and facilitating quantitative relationship between administered dose and systemic drug concentration, pharmacokinetics has an important role to play in the development of all medicines. Bioanalysis is an essential prelude to any pharmacokinetic investigation. For many biotechnology products the immunoassay and bioassay methodologies employed are often relatively non-specific and imprecise and yield assay dependent pharmacokinetic parameters. Other factors may also confound the pharmacokinetic evaluation of biotechnological products. In vivo binding proteins (including antibodies) may not only interfere with bioanalytical methodology but also have a significant effect on the pharmacokinetics and biological activity of certain macromolecules. Antibody formation is a particular problem in the preclinical evaluation of human proteins. Unlike most conventional pharmaceuticals, the rate and time of delivery into the systemic circulation is a fundamental component of the biological activity of many biological molecules. PMID:8839682

  12. Pharmacokinetics of ambroxol and clenbuterol tablets in healthy Chinese volunteers

    PubMed Central

    Yang, Yong-Ge; Song, Li-Xue; Jiang, Nan; Xu, Xue-Ting; Di, Xiao-Hui; Zhang, Mei

    2015-01-01

    Objective: To investigate the pharmacokinetics of Ambroxol and Clenbuterol Tablets in Chinese healthy volunteers after a single or multiple dosages oral administration. Methods: A total of 9 healthy adult subjects were given Ambroxol and Clenbuterol Tablets in a single dosage or multiple dosages respectively. LC/MS/MS were used for the determination of Ambroxol and Clenbuterol of in plasma. The important pharmacokinetic parameters were calculated by DAS 2.0 software (compartment model). Results: Single and multiple dosage groups of Ambroxol and Clenbuterol were all fitted two-compartment model. The pharmacokinetics fitted first order kinetics process. No difference in pharmacokinetics of Ambroxol in single and multiple dosage groups volunteers was observed, Which showed no marked changes, suggesting that multiple dosing did not influence the velocity of drug metabolism. Moreover, parameters of Clenbuterol had significant difference between the single and multiple dosage groups (P<0.05), showing there was accumulation in the body. 9 subjects had completed single or multiple dosages oral administration test, with no adverse drug reactions appeared during the test. Conclusion: There was no obvious accumulation of Ambroxol after repeated dosing. But obvious accumulation of Clenbuterol was noted in multiple-dose administration. The established method is sensitive, accurate, reliable and specific, and it can meet the requirement of clinical pharmacokinetic trial. PMID:26770490

  13. Clinical evidence of pharmacokinetic changes in thalidomide therapy.

    PubMed

    Nakamura, Katsunori; Matsuzawa, Naoki; Ohmori, Shigeru; Ando, Yuichi; Yamazaki, Hiroshi; Matsunaga, Tamihide

    2013-01-01

    The teratogenic effects of thalidomide have been studied for more than 50 years. However, there have been few studies of the pharmacokinetic changes occurring during thalidomide therapy. Thalidomide was originally developed as a sedative. However, thalidomide induces multiple birth defects when used in pregnant women. Thalidomide is now used in the treatment of multiple myeloma (MM) and erythema nodosum leprosum (ENL) in Japan. Rational use of thalidomide is problematic due to a lack of basic research regarding its mechanism of action and serum concentration/effect relationships. There are a number of hypotheses for pharmacokinetic changes in thalidomide therapy. Genetic factors including single nucleotide polymorphisms (SNPs) that change cytochrome P450 (CYP) activity and epigenetic regulation that modifies CYP expression levels may contribute to the changes in pharmacokinetics and adverse drug reactions (ADRs) of thalidomide. Environmental factors include the pharmacological context of drug-drug interactions and the physiological context of liver diseases. Liver and kidney diseases do not play important roles in pharmacokinetic changes or ADRs in thalidomide therapy. To date, most research has focused on teratogenic activity, while the impact of polymorphisms in genes encoding drug metabolic enzymes and drug-drug interactions could mediate ADRs. Here, we discuss clinical evidence of pharmacokinetic changes in thalidomide therapy.

  14. Allometric scaling of marbofloxacin pharmacokinetics: a retrospective analysis.

    PubMed

    Yohannes, S; Hossain, Md Akil; Kim, J Y; Lee, S J; Kwak, D M; Suh, J W; Park, S C

    2014-01-01

    The association between physiologically dependent pharmacokinetic parameters (CL(B), T1/2beta, Vd(ss)) of marbofloxacin and body weight was studied in eight animal species based on allometric equation Y = aWb, where 'Y' is the pharmacokinetic parameter, 'W' is body weight, 'a' is allometric coefficient (intercept) and 'b' is the exponent that describes relation between pharmacokinetic parameter and body weight. The body clearance of marbofloxacin has shown significant (P < 0.0001) relation with size (Bwt) in various animal species. However, half-life and volume of distribution were not in association with body weight. Although half-life and volume of distribution were not in a good correlation with body weight, statistically significant association between the body clearance and body weight suggests validity of allometric scaling for predicting pharmacokinetic parameters of marbofloxacin in animal species that have not been studied yet. However further study considering large sample size and other parameters influencing pharmacokinetics of marbofloxacin is recommended.

  15. Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844).

    PubMed

    Ugolini, Antonio; Kenigsberg, Mireille; Rak, Alexey; Vallée, Francois; Houtmann, Jacques; Lowinski, Maryse; Capdevila, Cécile; Khider, Jean; Albert, Eva; Martinet, Nathalie; Nemecek, Conception; Grapinet, Sandrine; Bacqué, Eric; Roesner, Manfred; Delaisi, Christine; Calvet, Loreley; Bonche, Fabrice; Semiond, Dorothée; Egile, Coumaran; Goulaouic, Hélène; Schio, Laurent

    2016-08-11

    The HGF/MET pathway is frequently activated in a variety of cancer types. Several selective small molecule inhibitors of the MET kinase are currently in clinical evaluation, in particular for NSCLC, liver, and gastric cancer patients. We report herein the discovery of a series of triazolopyridazines that are selective inhibitors of wild-type (WT) MET kinase and several clinically relevant mutants. We provide insight into their mode of binding and report unprecedented crystal structures of the Y1230H variant. A multiparametric chemical optimization approach allowed the identification of compound 12 (SAR125844) as a development candidate. In this chemical series, absence of CYP3A4 inhibition was obtained at the expense of satisfactory oral absorption. Compound 12, a promising parenteral agent for the treatment of MET-dependent cancers, promoted sustained target engagement at tolerated doses in a human xenograft tumor model. Preclinical pharmacokinetics conducted in several species were predictive for the observed pharmacokinetic behavior of 12 in cancer patients.

  16. Discovery and Pharmacokinetic and Pharmacological Properties of the Potent and Selective MET Kinase Inhibitor 1-{6-[6-(4-Fluorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea (SAR125844).

    PubMed

    Ugolini, Antonio; Kenigsberg, Mireille; Rak, Alexey; Vallée, Francois; Houtmann, Jacques; Lowinski, Maryse; Capdevila, Cécile; Khider, Jean; Albert, Eva; Martinet, Nathalie; Nemecek, Conception; Grapinet, Sandrine; Bacqué, Eric; Roesner, Manfred; Delaisi, Christine; Calvet, Loreley; Bonche, Fabrice; Semiond, Dorothée; Egile, Coumaran; Goulaouic, Hélène; Schio, Laurent

    2016-08-11

    The HGF/MET pathway is frequently activated in a variety of cancer types. Several selective small molecule inhibitors of the MET kinase are currently in clinical evaluation, in particular for NSCLC, liver, and gastric cancer patients. We report herein the discovery of a series of triazolopyridazines that are selective inhibitors of wild-type (WT) MET kinase and several clinically relevant mutants. We provide insight into their mode of binding and report unprecedented crystal structures of the Y1230H variant. A multiparametric chemical optimization approach allowed the identification of compound 12 (SAR125844) as a development candidate. In this chemical series, absence of CYP3A4 inhibition was obtained at the expense of satisfactory oral absorption. Compound 12, a promising parenteral agent for the treatment of MET-dependent cancers, promoted sustained target engagement at tolerated doses in a human xenograft tumor model. Preclinical pharmacokinetics conducted in several species were predictive for the observed pharmacokinetic behavior of 12 in cancer patients. PMID:27355974

  17. Pharmacokinetics of fluralaner in dogs following a single oral or intravenous administration

    PubMed Central

    2014-01-01

    Background Fluralaner is a novel systemic insecticide and acaricide. The purpose of these studies was to investigate the pharmacokinetic properties of fluralaner in Beagle dogs following single oral or intravenous (i.v.) administration. Methods Following the oral administration of 12.5, 25 or 50 mg fluralaner/kg body weight (BW), formulated as chewable tablets or i.v. administration of 12.5 mg fluralaner/kg BW, formulated as i.v. solution to 24 Beagles, plasma samples were collected until 112 days after treatment. Plasma concentrations of fluralaner were measured using HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods. Results After oral administration, maximum plasma concentrations (Cmax) were reached within 1 day on average. Fluralaner was quantifiable in plasma for up to 112 days after single oral and i.v. treatment. The apparent half-life of fluralaner was 12–15 days and the mean residence time was 15–20 days. The apparent volume of distribution of fluralaner was 3.1 L/kg, and clearance was 0.14 L/kg/day. Conclusions Fluralaner is readily absorbed after single-dose oral administration, and has a long elimination half-life, long mean residence time, relatively high apparent volume of distribution, and low clearance. These pharmacokinetic characteristics help to explain the prolonged activity of fluralaner against fleas and ticks on dogs after a single oral dose. PMID:24606874

  18. Pharmacokinetics and bioavailability of orbifloxacin oral suspension in New Zealand White rabbits (Oryctolagus cuniculus).

    PubMed

    Watson, Megan K; Wittenburg, Luke A; Bui, Christine T; Jarosz, Kira A; Gustafson, Daniel L; Johnston, Matthew S

    2015-11-01

    OBJECTIVE To evaluate the pharmacokinetics and bioavailability of 2 doses of orbifloxacin in rabbits. ANIMALS 6 healthy purpose-bred adult female New Zealand White rabbits (Oryctolagus cuniculus). PROCEDURES Each of 3 rabbits received orbifloxacin at either 10 or 20 mg/kg, PO. Then, after a 1-week washout period, they received the same dose IV. Blood samples were collected from each rabbit at 0, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 hours after drug administration. Plasma orbifloxacin concentration was measured with liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis for data obtained following PO administration and noncompartmental and compartmental analyses for data obtained following IV administration. RESULTS Following oral administration, the mean ± SD peak plasma orbifloxacin concentration was 1.66 ± 0.51 μg/mL for rabbits administered the 10 mg/kg dose and 3.00 ± 0.97 μg/mL for rabbits administered the 20 mg/kg dose and was attained at 2 hours after drug administration. The mean ± SD half-life of orbifloxacin in plasma was 7.3 ± 1.1 hours for rabbits administered the 10 mg/kg dose and 8.6 ± 0.55 hours for rabbits administered the 20 mg/kg dose. Mean bioavailability was 52.5% for rabbits administered the 10 mg/kg dose and 46.5% for rabbits administered the 20 mg/kg dose. CONCLUSIONS AND CLINICAL RELEVANCE Results provided pharmacokinetic properties for 2 doses (10 mg/kg and 20 mg/kg) of orbifloxacin oral suspension in rabbits. Further studies are necessary to determine the protein-binding activity of orbifloxacin in rabbits before dosages for the treatment of common pathogens in this species are recommended. PMID:26512539

  19. The influence of different long-circulating materials on the pharmacokinetics of liposomal vincristine sulfate

    PubMed Central

    Zhang, Jing; Chen, Yingchong; Li, Xiang; Liang, Xinli; Luo, Xiaojian

    2016-01-01

    Purpose This study was designed to improve the in vivo pharmacokinetics of long-circulating vincristine sulfate (VS)-loaded liposomes; three different long-circulating materials, chitosan, poly(ethylene glycol)-1,2-distearoyl sn-glycero-3-phosphatidylethanolamine (PEG-DSPE), and poly(ethylene glycol)-poly-lactide-co-glycolide (PEG-PLGA), were evaluated at the same coating molar ratio with the commercial product Marqibo® (vincristine sulfate liposome injection [VSLI]). Materials and methods VS-loaded liposomes were prepared by a pH gradient method and were then coated with chitosan, PEG-DSPE, or PEG-PLGA. Physicochemical properties, including the morphology, particle size, zeta potential, encapsulation efficiency (EE%), pH, drug loading, and in vitro release, were determined. Preservation stability and pharmacokinetic studies were performed to compare the membrane-coated liposomes with either commercially available liposomes or the VS solution. Results The sphere-like morphology of the vesicles was confirmed by transmission electron microscope. Increased particle size, especially for the chitosan formulation, was observed after the coating process. However, the EE% was ~99.0% with drug loading at 2.0 mg/mL, which did not change after the coating process. The coating of long-circulation materials, except for chitosan, resulted in negatively charged and stable vesicles at physiological pH. The near-zero zeta potential exhibited by the PEG-DSPE formulation leads to a longer circulation lifetime and improved absorption for VS, when compared with the PEG-PLGA formulation. Compared with the commercial product, PEG was responsible for a higher plasma VS concentration and a longer half-life. Conclusion PEG-DSPE coating may be related to better absorption, based on the stability and a pharmacokinetic improvement in the blood circulation time. PMID:27616886

  20. Pharmacokinetics and bioavailability of orbifloxacin oral suspension in New Zealand White rabbits (Oryctolagus cuniculus).

    PubMed

    Watson, Megan K; Wittenburg, Luke A; Bui, Christine T; Jarosz, Kira A; Gustafson, Daniel L; Johnston, Matthew S

    2015-11-01

    OBJECTIVE To evaluate the pharmacokinetics and bioavailability of 2 doses of orbifloxacin in rabbits. ANIMALS 6 healthy purpose-bred adult female New Zealand White rabbits (Oryctolagus cuniculus). PROCEDURES Each of 3 rabbits received orbifloxacin at either 10 or 20 mg/kg, PO. Then, after a 1-week washout period, they received the same dose IV. Blood samples were collected from each rabbit at 0, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 hours after drug administration. Plasma orbifloxacin concentration was measured with liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis for data obtained following PO administration and noncompartmental and compartmental analyses for data obtained following IV administration. RESULTS Following oral administration, the mean ± SD peak plasma orbifloxacin concentration was 1.66 ± 0.51 μg/mL for rabbits administered the 10 mg/kg dose and 3.00 ± 0.97 μg/mL for rabbits administered the 20 mg/kg dose and was attained at 2 hours after drug administration. The mean ± SD half-life of orbifloxacin in plasma was 7.3 ± 1.1 hours for rabbits administered the 10 mg/kg dose and 8.6 ± 0.55 hours for rabbits administered the 20 mg/kg dose. Mean bioavailability was 52.5% for rabbits administered the 10 mg/kg dose and 46.5% for rabbits administered the 20 mg/kg dose. CONCLUSIONS AND CLINICAL RELEVANCE Results provided pharmacokinetic properties for 2 doses (10 mg/kg and 20 mg/kg) of orbifloxacin oral suspension in rabbits. Further studies are necessary to determine the protein-binding activity of orbifloxacin in rabbits before dosages for the treatment of common pathogens in this species are recommended.

  1. Pharmacokinetics of single oral dose of pimobendan in Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Guzman, David Sanchez-Migallon; Beaufrère, Hugues; KuKanich, Butch; Barker, Steven A; Brandão, João; Paul-Murphy, Joanne; Tully, Thomas N

    2014-06-01

    Pimobendan is a phosphodiesterase (PDE) inhibitor and calcium sensitizer with inotropic, lusitropic, and rasodilator properties used in the treatment of congestive heart failure. The mechanism of action is by inhibition of PDE III and V and by increasing intracellular calcium sensitivity in the cardiac myocardium. Pharmacokinetic and pharmacodynamic studies have been published in humans, dogs, and cats, but there are no studies in avian species. Pimobendan has been used in birds at the empirical dosage of 0.25 mg/kg q12h. To determine the pharmacokinetic parameters of pimobendan in Hispaniolan Amazon parrots (Amazona ventralis), 3 pilot studies with 2 birds, each receiving 1, 3, and 10 mg/kg PO, provided the basis for the pivotal trials with 6 birds, each receiving 10 mg/kg PO using 2 different suspensions. Blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, and 18 hours after drug administration. Plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (HPLC/MS) by use of electrospray ionization. Because of the erratic and low concentrations of pimobendan, pharmacokinetic parameters were calculated using naive averaged analysis. Plasma concentrations after commercial pimobendan tablet suspension at 10 mg/kg reached a Cmax of 8.26 ng/mL at 3 hours with a terminal half-life of 2.1 hours, while concentrations after the bulk chemical suspension reached a Cmax of 1.28 ng/mL at 12 hours and had a terminal half-life of 2.3 hours. Further studies evaluating the effect of oral pimobendan in parrots are needed.

  2. Population Pharmacokinetic Modeling of Tribendimidine Metabolites in Opisthorchis viverrini-Infected Adults

    PubMed Central

    Penny, Melissa A.; Duthaler, Urs; Odermatt, Peter; Sayasone, Somphou; Keiser, Jennifer

    2016-01-01

    There is a pressing need for alternative treatments against the liver fluke Opisthorchis viverrini. Oral tribendimidine is a promising candidate, but its population pharmacokinetic properties are unknown. Two phase IIa trials were conducted in Laos in O. viverrini-infected adults receiving single oral doses of 25 to 600 mg tribendimidine administered as different formulations in each study (study 1 used 200-mg tablets, and study 2 used 50-mg tablets). Venous whole blood, plasma, and capillary dried blood spots were sampled frequently from 68 adults, and concentrations of the tribendimidine metabolites dADT (deacetylated amidantel) and adADT (acetylated dADT) were measured. Population pharmacokinetics were assessed by using nonlinear mixed-effects modeling. The relationship between drug exposure and cure (assessed at 21 days posttreatment) was evaluated by using univariable logistic regression. A six-transit compartment absorption model with a one-disposition compartment for each metabolite described the data well. Compared to the 50-mg formulation (study 2), the 200-mg formulation (study 1) had a 40.1% higher mean transit absorption time, a 113% higher dADT volume of distribution, and a 364% higher adADT volume of distribution. Each 10-year increase in age was associated with a 12.7% lower dADT clearance and a 21.2% lower adADT clearance. The highest cure rates (≥55%) were observed with doses of ≥100 mg. Higher dADT, but not adADT, peak concentrations and exposures were associated with cure (P = 0.004 and 0.003, respectively). For the first time, population pharmacokinetics of tribendimidine have been described. Known differences in the 200-mg versus 50-mg formulations were captured by covariate modeling. Further studies are needed to validate the structural model and confirm covariate relationships. (This study has been registered with the ISRCTN Registry under no. ISRCTN96948551.) PMID:27431233

  3. The influence of different long-circulating materials on the pharmacokinetics of liposomal vincristine sulfate

    PubMed Central

    Zhang, Jing; Chen, Yingchong; Li, Xiang; Liang, Xinli; Luo, Xiaojian

    2016-01-01

    Purpose This study was designed to improve the in vivo pharmacokinetics of long-circulating vincristine sulfate (VS)-loaded liposomes; three different long-circulating materials, chitosan, poly(ethylene glycol)-1,2-distearoyl sn-glycero-3-phosphatidylethanolamine (PEG-DSPE), and poly(ethylene glycol)-poly-lactide-co-glycolide (PEG-PLGA), were evaluated at the same coating molar ratio with the commercial product Marqibo® (vincristine sulfate liposome injection [VSLI]). Materials and methods VS-loaded liposomes were prepared by a pH gradient method and were then coated with chitosan, PEG-DSPE, or PEG-PLGA. Physicochemical properties, including the morphology, particle size, zeta potential, encapsulation efficiency (EE%), pH, drug loading, and in vitro release, were determined. Preservation stability and pharmacokinetic studies were performed to compare the membrane-coated liposomes with either commercially available liposomes or the VS solution. Results The sphere-like morphology of the vesicles was confirmed by transmission electron microscope. Increased particle size, especially for the chitosan formulation, was observed after the coating process. However, the EE% was ~99.0% with drug loading at 2.0 mg/mL, which did not change after the coating process. The coating of long-circulation materials, except for chitosan, resulted in negatively charged and stable vesicles at physiological pH. The near-zero zeta potential exhibited by the PEG-DSPE formulation leads to a longer circulation lifetime and improved absorption for VS, when compared with the PEG-PLGA formulation. Compared with the commercial product, PEG was responsible for a higher plasma VS concentration and a longer half-life. Conclusion PEG-DSPE coating may be related to better absorption, based on the stability and a pharmacokinetic improvement in the blood circulation time.

  4. Pharmacokinetic and Pharmacodynamic Integration and Modeling of Enrofloxacin in Swine for Escherichia coli

    PubMed Central

    Wang, Jianyi; Hao, Haihong; Huang, Lingli; Liu, Zhenli; Chen, Dongmei; Yuan, Zonghui

    2016-01-01

    The aim of this study was to optimize the dose regimens of enrofloxacin to reduce the development of fluoroquinolone resistance in Escherichia coli (E.coli) using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. The single dose (2.5 mg/kg body weight) of enrofloxacin was administered intramuscularly (IM) to the healthy pigs. Using cannulation, the pharmacokinetic properties, including peak concentration (Cmax), time to reach Cmax (Tmax), and area under the curve (AUC), were determined in plasma and ileum content. The Cmax, Tmax, and AUC in the plasma were 1.09 ± 0.11 μg/mL, 1.27 ± 0.35 h, and 12.70 ± 2.72 μg·h/mL, respectively. While in ileum content, the Cmax, Tmax, and AUC were 7.07 ± 0.26 μg/mL, 5.54 ± 0.42 h, and 136.18 ± 12.50 μg·h/mL, respectively. Based on the minimum inhibitory concentration (MIC) data of 918 E. coli isolates, an E. coli O101/K99 strain (enrofloxacin MIC = 0.25 μg/mL) was selected for pharmacodynamic studies. The in vitro minimum bactericidal concentration (MBC), mutant prevention concentration (MPC), and ex vivo time-killing curves for enrofloxacin in ileum content were established against the selected E. coli O101/K99 strain. Integrating the in vivo pharmacokinetic data and ex vivo pharmacodynamic data, a sigmoid Emax (Hill) equation was established to provide values for ileum content of AUC24h/MIC producing, bactericidal activity (52.65 h), and virtual eradication of bacteria (78.06 h). A dosage regimen of 1.96 mg/kg every 12 h for 3 days should be sufficient in the treatment of E. coli. PMID:26870006

  5. Pharmacokinetics and atherosclerotic lesions targeting effects of tanshinone IIA discoidal and spherical biomimetic high density lipoproteins.

    PubMed

    Zhang, Wenli; He, Hongliang; Liu, Jianping; Wang, Ji; Zhang, Suyang; Zhang, Shuangshuang; Wu, Zimei

    2013-01-01

    High density lipoproteins (HDL) have been successfully reconstructed to deliver a large number of lipophilic drugs. Here, discoidal and spherical recombinant HDL loaded with cardiovascular drug tanshinone IIA (TA) were constructed (TA-d-rHDL and TA-s-rHDL), respectively. And next their in vitro physiochemical and biomimetic properties were characterized. Furthermore, pharmacokinetics, atherosclerotic lesions targeting effects and antiatherogenic efficacies were elaborately performed and compared in atherosclerotic New Zealand White (NZW) rabbits. In vitro characterizations results showed that both TA-d-rHDL and TA-s-rHDL had nano-size diameter, high entrapment efficiency (EE) and drug-loading capacity (DL). Additionally, similar to their native counterparts, TA-d-rHDL maintained remodeling behaviors induced by lecithin cholesterol acyltransferase (LCAT), and TA leaked during remodeling behaviors. Pharmacokinetic studies manifested that both TA-d-rHDL and TA-s-rHDL markedly improved pharmacokinetic behaviors of TA in vivo. Ex vivo imaging demonstrated that both d-rHDL and s-rHDL bound more avidly to atherosclerotic lesions than to normal vessel walls, and s-rHDL had better targeting effect than d-rHDL. Pharmacodynamic tests illustrated that both TA-d-rHDL and TA-s-rHDL had much stronger antiatherogenic efficacies than conventional TA nanostructured lipid carriers (TA-NLC), TA liposomes (TA-L) and commercially available preparation Sulfotanshinone Sodium Injection (SSI). Moreover, TA-s-rHDL had more potent antiatherogenic efficacies than TA-d-rHDL. Collectively our studies indicated that rHDL could be exploited as potential delivery vehicles of TA targeting atherosclerotic lesions as well as synergistically improving efficacies, especially for s-rHDL. PMID:23069716

  6. Physicochemistry, pharmacokinetics, and pharmacodynamics of S-nitrosocaptopril crystals, a new nitric oxide donor.

    PubMed

    Jia, L; Young, X; Guo, W

    1999-10-01

    S-nitrosocaptopril (CapNO) has been proposed as a compound possessing capacities of both a nitric oxide (NO) donor and an inhibitor of angiotensin converting enzyme (ACE). In the present study, we characterized the physicochemical, pharmacokinetic, and pharmacological properties of the crystalline CapNO. The novel stable crystals are in a red flake form. Spectroscopic analyses of CapNO revealed its UV/visible lambda(max) and the corresponding extinction coefficients, and characteristic infrared frequencies for the N=O and S-N stretch. The NMR signals corresponding to the protons attached to the carbon (C-S) and the carbon itself were remarkably shifted downfield upon S-nitrosylation. Mass and HPLC analyses, solubility, and melting point of CapNO were determined. Simultaneous on-line analyses of pharmacodynamic and pharmacokinetic profiles of CapNO in catheterized awake rats of spontaneous hypertension (SHR) showed acute decreases in mean arterial pressure (MAP), concomitant with the corresponding increases in plasma levels of CapNO after po or iv administration. The pharmacokinetic parameters for CapNO, i.e., t(1/2), T(max), C(max), V(d), AUC, and oral bioavailability were analyzed to understand the dose-dependent potency and effective period of CapNO. The highest concentrations of oral CapNO distributed in tissues were found in kidney, liver, lung, and small intestine. CapNO was excreted predominantly via urine, and second via feces in the detectable forms of thiols and nitrogen oxide although a small portion of CapNO was found in bile. The results provide the evidence of in vivo cleavage of the S-N bond and biotransformation of CapNO. PMID:10514343

  7. Study to Evaluate the Effect of Rifampicin, Ketoconazole, and Omeprazole on the Pharmacokinetics of Sativex

    ClinicalTrials.gov

    2013-06-13

    Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a Known Inducer of CYP3A4; Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a Potent Inhibitor of CYP3A4; Evaluation of Pharmacokinetics of Sativex in the Absence and Presence of a CYP2C19 Inhibitor.

  8. Clinical implications of NSAID pharmacokinetics: special populations, special considerations.

    PubMed

    Adelizzi, R A

    1994-05-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are the centerpiece of pharmacologic therapy for most rheumatic disorders and related conditions, and as such are used in great numbers. These drugs are relatively safe and effective, but the pharmacokinetics of NSAIDs can be substantially altered in certain groups of patients, including the elderly and patients with renal and hepatic disease. In these patients, the risk of NSAID toxicity is increased. An understanding of NSAID pharmacokinetics in these groups can help physicians to adjust therapeutic regimens in order to limit the potentially serious complications of long-term NSAID therapy. The author discusses the age-related physiologic changes that may affect the various areas of drug pharmacokinetics and ways in which NSAIDs may interact with other drugs. Risk assessment and monitoring methods are also discussed.

  9. A Bayesian approach to tracking patients having changing pharmacokinetic parameters

    NASA Technical Reports Server (NTRS)

    Bayard, David S.; Jelliffe, Roger W.

    2004-01-01

    This paper considers the updating of Bayesian posterior densities for pharmacokinetic models associated with patients having changing parameter values. For estimation purposes it is proposed to use the Interacting Multiple Model (IMM) estimation algorithm, which is currently a popular algorithm in the aerospace community for tracking maneuvering targets. The IMM algorithm is described, and compared to the multiple model (MM) and Maximum A-Posteriori (MAP) Bayesian estimation methods, which are presently used for posterior updating when pharmacokinetic parameters do not change. Both the MM and MAP Bayesian estimation methods are used in their sequential forms, to facilitate tracking of changing parameters. Results indicate that the IMM algorithm is well suited for tracking time-varying pharmacokinetic parameters in acutely ill and unstable patients, incurring only about half of the integrated error compared to the sequential MM and MAP methods on the same example.

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

    PubMed

    Brown, Jacob T; Bishop, Jeffrey R

    2015-01-01

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

  11. Cardiovascular Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics for the Clinical Practitioner.

    PubMed

    Sleder, Anna T; Kalus, James; Lanfear, David E

    2016-01-01

    Current clinical cardiovascular practice requires a clinician to have a strong foundation in multiple aspects of pharmacology. Modern cardiovascular regimens are complex, and optimal management, application of evolving guidelines, and adoption of new therapies build off a more basic understanding of pharmacokinetics and pharmacodynamics. In addition, it is likely time to add a third pillar into this discussion, the expanding field of pharmacogenomics referring to the genetic influences on drug response. This field has increasing applications in medicine and clearly holds significant promise for cardiovascular disease management. Awareness of pharmacogenomic advances and the fundamentals of pharmacokinetics and pharmacodynamics can help the clinician more easily deliver great care. Here we attempt to briefly summarize and simplify key concepts of pharmacokinetics, pharmacodynamics, and pharmacogenomics relevant to the cardiovascular disease practitioner.

  12. Pharmacokinetics of the penicillins in man.

    PubMed

    Barza, M; Weinstein, L

    1976-01-01

    The purpose of this article is to review and summarise those aspects of the pharmacokinetic behaviour of the penicillins that may be of particular interest to the clinician. While these antibiotics differ markedly in their acid stability and oral absorption, misleading inferences may be drawn from simple inspection of the maximal serum concentrations produced by a given dose administered orally. A more accurate picture emerges when serum protein binding and intrinsic activity of the drugs are taken into account. All of the penicillins are readily and actively secreted by the renal tubles and most are eliminated, almost completely unchanged, in the urine. The majority are excreted in small quantities in the bile, but this is a major route for elimination of nafcillin from the body. Distribution of the penicillins in 'non-specialised' sites is excellent. In contrast, penetration of the central nevous system and eye are poor, and of the prostate, minimal. Inflammation reduces the barries to penetration of these areas. However, quantitative data related to this phenomenon in man are few. Probenecid actively competes with the 'export' pump of the meninges and renal tubular cells. This results in an increase in concentrations of the penicillins in the blood and cerebrospinal fluid. The effect of this agent on active secretion of these antibiotics from the eye and biliary tract is minimal. While elimination of the penicillins from the body takes place largely via renal excretion, penicillin V and oxacillin are extensively degraded as well. In contrast to the situation with respect to 'natural' and 'broad-spectrum' penicillins, the serum half-life of the isoxazolyl congeners and nafcillin is only minimally prolonged in the presence of renal failure. These agents are only weakly haemodialyzable, while the other penicillins are rapidly removed from the circulation by this procedure. PMID:797501

  13. Pharmacokinetics of heparin and related polysaccharides

    SciTech Connect

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

    1989-01-01

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

  14. Theophylline pharmacokinetics in black Zimbabwean males.

    PubMed

    Jameson, J P; Munyika, A

    1990-01-01

    Theophylline pharmacokinetics were studied in 16 black Zimbabwean volunteers aged 20-41 years. Following a single intravenous dose of 5 mg/kg, four serum levels were collected over 24 h. Data were analyzed using a one-compartment open model. The correlation coefficient was 0.995 +/- 0.004. The mean extrapolated peak level was 8.5 +/- 0.9 mg/L. The mean half-life and volume of distribution were 10.1 +/- 3.1 h and 0.55 +/- 0.7 L/kg, respectively. The mean clearance was 0.62 +/- 0.17 ml/kg/min. The mean weight was 7 kg less than the calculated ideal body weight. These data suggest a larger volume of distribution and longer half-life than in other reported populations. The clearance is on the low end of previously reported values. We postulate that the primary cause of the large volume is the decreased body fat and consequent increase in body water per kilogram. The slightly decreased clearance may have been partially due to the high carbohydrate, low protein diet of our subjects. The long half-life is simply a reflection of a large volume and a moderately low clearance. We suggest that standard per kilogram maintenance doses can be employed in this population. A larger loading dose of 8 mg/kg aminophylline is recommended. Finally, the lack of sustained release theophylline in Zimbabwe may not be a problem, given the longer half lives observed in this study.

  15. Population pharmacokinetics of valnemulin in swine.

    PubMed

    Zhao, D H; Zhang, Z; Zhang, C Y; Liu, Z C; Deng, H; Yu, J J; Guo, J P; Liu, Y H

    2014-02-01

    This study was carried out in 121 pigs to develop a population pharmacokinetic (PPK) model by oral (p.o.) administration of valnemulin at a single dose of 10 mg/kg. Serum biochemistry parameters of each pig were determined prior to drug administration. Three to five blood samples were collected at random time points, but uniformly distributed in the absorption, distribution, and elimination phases of drug disposition. Plasma concentrations of valnemulin were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The concentration-time data were fitted to PPK models using nonlinear mixed effect modeling (NONMEM) with G77 FORTRAN compiler. NONMEM runs were executed using Wings for NONMEM. Fixed effects of weight, age, sex as well as biochemistry parameters, which may influence the PK of valnemulin, were investigated. The drug concentration-time data were adequately described by a one-compartmental model with first-order absorption. A random effect model of valnemulin revealed a pattern of log-normal distribution, and it satisfactorily characterized the observed interindividual variability. The distribution of random residual errors, however, suggested an additive model for the initial phase (<12 h) followed by a combined model that consists of both proportional and additive features (≥ 12 h), so that the intra-individual variability could be sufficiently characterized. Covariate analysis indicated that body weight had a conspicuous effect on valnemulin clearance (CL/F). The featured population PK values of Ka , V/F and CL/F were 0.292/h, 63.0 L and 41.3 L/h, respectively. PMID:23617793

  16. Pharmacokinetics of iothalamate in endstage renal disease

    SciTech Connect

    Evans, J.R.; Cutler, R.E.; Forland, S.C.

    1988-09-01

    Some nephrologists make alterations in routine peritoneal and hemodialysis schedules after diagnostic studies that use radiographic contrast agents. A study to determine the pharmacokinetics of one contrast agent, iothalamate, is reported. The plasma (total body) clearance of iothalamate was measured in seven patients who had endstage renal disease (ESRD) and who received maintenance hemodialysis. During an interdialytic period, plasma clearance of iothalamate varied from 0.7 to 5.2 mL/min (3.1 +/- 1.8 mL/min, mean +/- SD) with an elimination rate constant (beta) of 0.0164 +/- 0.01 hr-1, a terminal half-life of 61 +/- 42 hours, and an estimated distribution volume of 11 +/- 3.9 L. Hemodialysis clearance of iothalamate was 104 +/- 54 mL/min. With the assumption that iothalamate is mainly distributed in the extracellular fluid (ECF) compartment, the theoretical fluid shift from the intracellular fluid (ICF) compartment to the ECF compartment was 323 mL after administration of the largest dose (2.1 mL/kg or 1.6 mmol/kg of body weight) of 60% meglumine iothalamate solution. The average maximum serum osmolarity change was less than expected, suggesting some type of internal buffering of meglumine iothalamate. In the first few hours after radiocontrast administration in four patients, the average change in serum osmolarity was 5 mmol/L; the average change in serum sodium concentration during this same time was a decrease of 0.5 mmol/L. The minor increase in ECF volume induced by hyperosmolar contrast agents does not require immediate dialysis in most patients. When needed, however, for contrast-related adverse effects, hemodialysis is efficient in rapidly removing iothalamate.

  17. Reporting guidelines for population pharmacokinetic analyses.

    PubMed

    Dykstra, Kevin; Mehrotra, Nitin; Tornøe, Christoffer Wenzel; Kastrissios, Helen; Patel, Bela; Al-Huniti, Nidal; Jadhav, Pravin; Wang, Yaning; Byon, Wonkyung

    2015-06-01

    The purpose of this work was to develop a consolidated set of guiding principles for reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (where population PK frequently serves as preparatory analysis to exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider two main purposes of population PK reports (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified two main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results, and (2) a scientifically literate, but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with six questions that need to be addressed throughout the report. We recommend eight sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step towards industrialization of the field of pharmacometrics such that non-technical audience also understands the role of pharmacometrics analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports

  18. Carboplatin pharmacokinetics in a patient receiving hemodialysis.

    PubMed

    Fong, Mei Ka; Fetterly, Gerald J; McDougald, Lori J; Iyer, Renuka V

    2014-02-01

    With refinements and advances in hemodialysis techniques, survival for patients with end-stage renal disease has improved significantly. To our knowledge, however, no prospective trials have been performed in patients receiving hemodialysis who are also diagnosed with cancer and are candidates for chemotherapy. We describe a 73-year-old man who was diagnosed with high-grade neuroendocrine carcinoma, metastatic to the bone and lymph nodes, and was undergoing hemodialysis. Although cisplatin is more commonly used in the treatment of metastatic neuroendocrine cancers, it may not be the best option in patients who suffer from renal insufficiency. Carboplatin is a second-generation, nonnephrotoxic platinum analog that can be hemodialyzed, although no formal guidelines are available regarding the dosing for patients receiving hemodialysis. This case describes a patient who was treated with five cycles of combination carboplatin 115 mg/m(2) on day 1 and etoposide 50 mg/m(2) on day 1 and day 3 of a 28-day cycle. Dialysis was performed for 3.5 hours starting 90 minutes after completion of carboplatin on day 1. Pharmacokinetic assessments were performed at 1, 2, 4, and 12 hours after chemotherapy infusion on day 1 of cycle 1. Total carboplatin concentrations in plasma and platinum ultrafiltrate were measured. The plasma concentration of free platinum at the end of the infusion was 31,000 ng/ml, and the area under the plasma concentration-time curve was 2.9 minute·mg/ml. No significant carboplatin-related toxicities were reported. This case report indicates that carboplatin can be safely administered in patients receiving hemodialysis.

  19. Reporting guidelines for population pharmacokinetic analyses.

    PubMed

    Dykstra, Kevin; Mehrotra, Nitin; Tornøe, Christoffer Wenzel; Kastrissios, Helen; Patel, Bela; Al-Huniti, Nidal; Jadhav, Pravin; Wang, Yaning; Byon, Wonkyung

    2015-06-01

    The purpose of this work was to develop a consolidated set of guiding principles for reporting of population pharmacokinetic (PK) analyses based on input from a survey of practitioners as well as discussions between industry, consulting and regulatory scientists. The survey found that identification of population covariate effects on drug exposure and support for dose selection (where population PK frequently serves as preparatory analysis to exposure-response modeling) are the main areas of influence for population PK analysis. The proposed guidelines consider two main purposes of population PK reports (1) to present key analysis findings and their impact on drug development decisions, and (2) as documentation of the analysis methods for the dual purpose of enabling review of the analysis and facilitating future use of the models. This work also identified two main audiences for the reports: (1) a technically competent group responsible for in-depth review of the data, methodology, and results, and (2) a scientifically literate, but not technically adept group, whose main interest is in the implications of the analysis for the broader drug development program. We recommend a generalized question-based approach with six questions that need to be addressed throughout the report. We recommend eight sections (Synopsis, Introduction, Data, Methods, Results, Discussion, Conclusions, Appendix) with suggestions for the target audience and level of detail for each section. A section providing general expectations regarding population PK reporting from a regulatory perspective is also included. We consider this an important step towards industrialization of the field of pharmacometrics such that non-technical audience also understands the role of pharmacometrics analyses in decision making. Population PK reports were chosen as representative reports to derive these recommendations; however, the guiding principles presented here are applicable for all pharmacometric reports

  20. The interplay of non-specific binding, target-mediated clearance and FcRn interactions on the pharmacokinetics of humanized antibodies

    PubMed Central

    Datta-Mannan, Amita; Lu, Jirong; Witcher, Derrick R; Leung, Donmienne; Tang, Ying; Wroblewski, Victor J

    2015-01-01

    The application of protein engineering technologies toward successfully improving antibody pharmacokinetics has been challenging due to the multiplicity of biochemical factors that influence monoclonal antibody (mAb) disposition in vivo. Physiological factors including interactions with the neonatal Fc receptor (FcRn) and specific antigen binding properties of mAbs, along with biophysical properties of the mAbs themselves play a critical role. It has become evident that applying an integrated approach to understand the relative contribution of these factors is critical to rationally guide and apply engineering strategies to optimize mAb pharmacokinetics. The study presented here evaluated the influence of unintended non-specific interactions on the disposition of mAbs whose clearance rates are governed predominantly by either non-specific (FcRn) or target-mediated processes. The pharmacokinetics of 8 mAbs representing a diverse range of these properties was evaluated in cynomolgus monkeys. Results revealed complementarity-determining region (CDR) charge patch engineering to decrease charge-related non-specific binding can have a significant impact on improving the clearance. In contrast, the influence of enhanced in vitro FcRn binding was mixed, and related to both the strength of charge interaction and the general mechanism predominant in governing the clearance of the particular mAb. Overall, improved pharmacokinetics through enhanced FcRn interactions were apparent for a CDR charge-patch normalized mAb which was affected by non-specific clearance. The findings in this report are an important demonstration that mAb pharmacokinetics requires optimization on a case-by-case basis to improve the design of molecules with increased therapeutic application. PMID:26337808

  1. Colistin Pharmacokinetics in Burn Patients during Continuous Venovenous Hemofiltration

    PubMed Central

    Rowan, Matthew P.; Niece, Krista L.; Stewart, Ian J.; Mende, Katrin; Cota, Jason M.; Murray, Clinton K.; Chung, Kevin K.

    2014-01-01

    While colistin is considered a last resort for the treatment of multidrug-resistant Gram-negative bacterial infections, there has been an increase in its use due to the increasing prevalence of drug-resistant infections worldwide. The pharmacology of colistin is complex, and pharmacokinetic data are limited, especially in patients requiring renal replacement therapy. As a result, dosing for patients who require renal replacement remains a challenge. Here, we present pharmacokinetic data for colistin from two burn patients (37 and 68 years old) infected with colistin-susceptible isoclonal Acinetobacter baumannii and receiving continuous venovenous hemofiltration (CVVH). To our knowledge, we are the first to examine data from before and during CVVH (for one patient), allowing analysis of the effect of CVVH on colistin pharmacokinetics. Pharmacokinetic/pharmacodynamic analysis indicated that a dose increase from 1.5 to 2.2 mg/kg of body weight colistin base activity on CVVH was insufficient to satisfy the target parameter of an AUC24/MIC (area under the concentration-time curve over 24 h in the steady state divided by the MIC) of ≥60 at an MIC of ≥1 μg/ml in one patient with residual endogenous renal function. Plasma concentrations of colistin ranged from 0 to 15 μg/ml, with free colistin levels ranging from 0.4 to 2.2 μg/ml. While both patients resolved their clinical infections and survived to discharge, colistin-resistant colonizing isolates resulted from therapy in one patient. The variabilities observed in colistin concentrations and pharmacokinetic characteristics highlight the importance of pharmacokinetic monitoring of antibiotics in patients undergoing renal replacement therapy. PMID:25313211

  2. Computer acceptance of older adults.

    PubMed

    Nägle, Sibylle; Schmidt, Ludger

    2012-01-01

    Even though computers play a massive role in everyday life of modern societies, older adults, and especially older women, are less likely to use a computer, and they perform fewer activities on it than younger adults. To get a better understanding of the factors affecting older adults' intention towards and usage of computers, the Unified Theory of Acceptance and Usage of Technology (UTAUT) was applied as part of a more extensive study with 52 users and non-users of computers, ranging in age from 50 to 90 years. The model covers various aspects of computer usage in old age via four key constructs, namely performance expectancy, effort expectancy, social influences, and facilitating conditions, as well as the variables gender, age, experience, and voluntariness it. Interestingly, next to performance expectancy, facilitating conditions showed the strongest correlation with use as well as with intention. Effort expectancy showed no significant correlation with the intention of older adults to use a computer.

  3. Raltegravir Pharmacokinetics in Patients on Asunaprevir-Daclatasvir

    PubMed Central

    Vincent, Corine; Furlan, Valérie; Rosa, Isabelle; Rosenthal, Eric; Cheret, Antoine; Molina, Jean-Michel; Taburet, Anne-Marie; Piroth, Lionel

    2015-01-01

    Raltegravir pharmacokinetics was studied in 20 patients included in the ANRS HC30 QUADRIH Study before and after addition of anti-hepatitis C virus (anti-HCV) quadritherapy, including pegylated-interferon–ribavirin and asunaprevir plus daclatasvir. Raltegravir pharmacokinetic parameters remained unchanged whether administered on or off anti-HCV therapy. In addition, concentrations of raltegravir, asunaprevir, and daclatasvir were not affected by liver cirrhosis. These data suggest that in human immunodeficiency virus (HIV)-HCV-coinfected patients, whether cirrhotic or not, asunaprevir and daclatasvir could be administered safely with raltegravir. PMID:26438504

  4. Prospective evaluation of pharmacokinetically guided dosing of carboplatin in Japanese patients with cancer.

    PubMed

    Shimokata, Tomoya; Ando, Yuichi; Yasuda, Yoshinari; Hamada, Akinobu; Kawada, Kenji; Saito, Hideyuki; Matsuo, Seiichi; Kondo, Masashi; Imaizumi, Kazuyoshi; Hasegawa, Yoshinori

    2010-12-01

    The Calvert formula, that is, carboplatin dose (mg) = target area under the concentration versus time curve (AUC) × (glomerular filtration rate [GFR] + 25), has not been validated in Japanese subjects in whom the GFR was accurately measured. The purpose of this study is to evaluate the validity of this formula for Japanese patients with cancer and modify it for this population. The GFR was measured on the basis of inulin clearance, which is considered to reflect the accurate GFR. Inulin clearance was measured in 28 patients with cancer. The adjusted 24-h creatinine clearance (24-h Ccr) was unbiased (mean prediction error [MPE] ± SE = -2.3 ± 4.5%) and acceptably precise (root mean squared error = 23.7%) for GFR assessment. The pharmacokinetics of carboplatin were analyzed in 21 patients with a GFR of 17.2-91.4 mL/min. The original Calvert formula overestimated carboplatin clearance, resulting in an MPE of 14.3%. When we revised the Calvert formula for Japanese patients by substituting a non-renal clearance of 15 for 25, that is, dose = target AUC × (GFR + 15), the MPE decreased to -0.1% (P < 0.001). We conclude that the adjusted 24-h Ccr is acceptably precise for GFR assessment, and the non-renal clearance of carboplatin is suggested to be lower in Japanese patients with cancer than in their Western counterparts.

  5. Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats.

    PubMed

    Gáll, Zsolt; Vancea, Szende; Szilágyi, Tibor; Gáll, Orsolya; Kolcsár, Melinda

    2015-02-20

    Rufinamide is a third-generation antiepileptic drug, approved recently as an orphan drug for the treatment of Lennox-Gastaut syndrome. Although extensive research was conducted, its pharmacokinetics in rats was not described. This work addresses that area by describing in a rapid pharmacokinetic study the main pharmacokinetic properties of rufinamide at three different doses of 1 mg/kg body weight (bw), 5 mg/kg bw, and 20 mg/kg bw. Furthermore, total brain concentrations of the drug were determined in order to characterize its brain-to-plasma partition coefficient. Adult Wistar male rats, weighing 200-450 g, were administered rufinamide by intravenous and oral routes. Rufinamide concentrations from plasma samples and brain tissue homogenate were determined using a liquid chromatography-mass spectrometric method and pharmacokinetic parameters were calculated. The mean half-life was between 7 and 13 h, depending on route of administration--intravenously administered drug was eliminated faster than orally administered drug. Mean (S.E.M.) total plasma clearance was 84.01 ± 3.80 ml/h/kg for intravenous administration, while the apparent plasma clearance for oral administration was 95.52 ± 39.45 ml/h/kg. The mean (S.E.M.) maximum plasma concentration reached after oral administration of 1 mg/kg bw and 5 mg/kg bw was 0.89 ± 0.09 μg/ml and 3.188 ± 0.71 μg/ml, respectively. The median (range) time to reach maximum plasma concentration (t(max)) was 4 (2-8)h. Mean (S.E.M.) brain-to-plasma concentration ratio of rufinamide was 0.514 ± 0.036, consistent with the brain-to-plasma ratio calculated from the area under curves (AUC(0-t)) of 0.441 ± 0.047. No influence of dose, route of administration, or post-dosing time was observed on brain-to-plasma ratio. PMID:25530452

  6. Pharmacokinetics of butorphanol after intravenous, intramuscular, and oral administration in Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Guzman, David Sanchez-Migallon; Flammer, Keven; Paul-Murphy, Joanne R; Barker, Steven A; Tully, Thomas N

    2011-09-01

    Previous studies have validated the clinical use of opioids with kaap-receptor affinities for pain management in birds. Butorphanol, a kappa opioid receptor agonist and a mu opioid receptor antagonist, is currently considered by many clinicians to be the opioid of choice for this use. However, despite studies reporting the analgesic properties of butorphanol in psittacine birds, dosing intervals have not been established for any psittacine species. The goals of this study in the Hispaniolan Amazon parrot (Amazona ventralis) were to evaluate the pharmacokinetics of butorphanol tartrate after intravenous (IV), intramuscular (IM), and oral (PO) administration and to determine the bioavailability of butorphanol tartrate after oral administration. Twelve Hispaniolan Amazon parrots were used in the study, with a complete-crossover experimental design and a 3-month period separating each part of the study. The birds were randomly assigned to 3 groups (n = 4) for each stage. Butorphanol tartrate was administered once at a dose of 5 mg/kg in the basilic vein or pectoral muscles or as an oral solution delivered via feeding tube into the crop for the IV, IM, and PO studies, respectively. After butorphanol administration, blood samples were collected at 1, 5, 15, 30, 60, 90, 120, 180, and 240 minutes for the IV and IM studies and at 5, 15, 30, 60, 90, 120, 180, 240, and 300 minutes for the PO study. Because of the size limitation of the birds, naive pooling of datum points was used to generate a mean plasma butorphanol concentration at each time point. For each study, birds in each group (n = 4) were bled 3 times after dosing. Plasma butorphanol concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry, and pharmacokinetic parameters were calculated. Butorphanol tartrate was found to have high bioavailability and rapid elimination following IM administration. In contrast, oral administration resulted in low bioavailability (< 10%), thus

  7. Pharmacokinetics of butorphanol after intravenous, intramuscular, and oral administration in Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Guzman, David Sanchez-Migallon; Flammer, Keven; Paul-Murphy, Joanne R; Barker, Steven A; Tully, Thomas N

    2011-09-01

    Previous studies have validated the clinical use of opioids with kaap-receptor affinities for pain management in birds. Butorphanol, a kappa opioid receptor agonist and a mu opioid receptor antagonist, is currently considered by many clinicians to be the opioid of choice for this use. However, despite studies reporting the analgesic properties of butorphanol in psittacine birds, dosing intervals have not been established for any psittacine species. The goals of this study in the Hispaniolan Amazon parrot (Amazona ventralis) were to evaluate the pharmacokinetics of butorphanol tartrate after intravenous (IV), intramuscular (IM), and oral (PO) administration and to determine the bioavailability of butorphanol tartrate after oral administration. Twelve Hispaniolan Amazon parrots were used in the study, with a complete-crossover experimental design and a 3-month period separating each part of the study. The birds were randomly assigned to 3 groups (n = 4) for each stage. Butorphanol tartrate was administered once at a dose of 5 mg/kg in the basilic vein or pectoral muscles or as an oral solution delivered via feeding tube into the crop for the IV, IM, and PO studies, respectively. After butorphanol administration, blood samples were collected at 1, 5, 15, 30, 60, 90, 120, 180, and 240 minutes for the IV and IM studies and at 5, 15, 30, 60, 90, 120, 180, 240, and 300 minutes for the PO study. Because of the size limitation of the birds, naive pooling of datum points was used to generate a mean plasma butorphanol concentration at each time point. For each study, birds in each group (n = 4) were bled 3 times after dosing. Plasma butorphanol concentrations were determined by high-performance liquid chromatography/tandem mass spectrometry, and pharmacokinetic parameters were calculated. Butorphanol tartrate was found to have high bioavailability and rapid elimination following IM administration. In contrast, oral administration resulted in low bioavailability (< 10%), thus

  8. [Strategy of molecular design of drugs: the unification of macro-properties and micro-structures of a molecule].

    PubMed

    Guo, Zong-Ru

    2008-03-01

    destined by molecular scaffolds and/or side chain(s) apart from pharmacophore. The features of micro-structures contributing to specific activity contain hydrogen bonding donor and acceptor, positive and negative charge centers, hydrophobic centers and centers of aromatic rings. Different combinations and spacial arrangements of these features determine the distinct activity presented. The macro-property and micro-structure are integrated into a single molecule, and are inseparable. The macro-property reflects overall contribution of atoms and groups in the micro-structure. On the other hand, structural changes aimed to adjust macroscopic property usually alter the relative position of the microscopic structure. The goal of molecular drug design is to integrate the macroscopic and microscopic factors in optimized manner. In the early stage of molecular design, both macroscopic property and microscopic structure should be considered to make pharmacodynamics, pharmacokinetics, and physico-chemical properties in optimal match. Therefore, it required the existence of structural overlapping among acceptable pharmacokinetics, visible developing potential and specific pharmacodynamics. The larger the scope of overlapping, the higher the possibility to be a drug. PMID:18630256

  9. [Strategy of molecular design of drugs: the unification of macro-properties and micro-structures of a molecule].

    PubMed

    Guo, Zong-Ru

    2008-03-01

    destined by molecular scaffolds and/or side chain(s) apart from pharmacophore. The features of micro-structures contributing to specific activity contain hydrogen bonding donor and acceptor, positive and negative charge centers, hydrophobic centers and centers of aromatic rings. Different combinations and spacial arrangements of these features determine the distinct activity presented. The macro-property and micro-structure are integrated into a single molecule, and are inseparable. The macro-property reflects overall contribution of atoms and groups in the micro-structure. On the other hand, structural changes aimed to adjust macroscopic property usually alter the relative position of the microscopic structure. The goal of molecular drug design is to integrate the macroscopic and microscopic factors in optimized manner. In the early stage of molecular design, both macroscopic property and microscopic structure should be considered to make pharmacodynamics, pharmacokinetics, and physico-chemical properties in optimal match. Therefore, it required the existence of structural overlapping among acceptable pharmacokinetics, visible developing potential and specific pharmacodynamics. The larger the scope of overlapping, the higher the possibility to be a drug.

  10. 48 CFR 2911.103 - Market acceptance.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... offered have either achieved commercial market acceptance or been satisfactorily supplied to an agency... 48 Federal Acquisition Regulations System 7 2010-10-01 2010-10-01 false Market acceptance. 2911... DESCRIBING AGENCY NEEDS Selecting And Developing Requirements Documents 2911.103 Market acceptance....

  11. 48 CFR 11.103 - Market acceptance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Market acceptance. 11.103... DESCRIBING AGENCY NEEDS Selecting and Developing Requirements Documents 11.103 Market acceptance. (a) Section... either— (i) Achieved commercial market acceptance; or (ii) Been satisfactorily supplied to an...

  12. 48 CFR 2911.103 - Market acceptance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 7 2011-10-01 2011-10-01 false Market acceptance. 2911... DESCRIBING AGENCY NEEDS Selecting And Developing Requirements Documents 2911.103 Market acceptance. The... offered have either achieved commercial market acceptance or been satisfactorily supplied to an...

  13. Older Adults' Acceptance of Information Technology

    ERIC Educational Resources Information Center

    Wang, Lin; Rau, Pei-Luen Patrick; Salvendy, Gavriel

    2011-01-01

    This study investigated variables contributing to older adults' information technology acceptance through a survey, which was used to find factors explaining and predicting older adults' information technology acceptance behaviors. Four factors, including needs satisfaction, perceived usability, support availability, and public acceptance, were…

  14. Apollo experience report environmental acceptance testing

    NASA Technical Reports Server (NTRS)

    Laubach, C. H. M.

    1976-01-01

    Environmental acceptance testing was used extensively to screen selected spacecraft hardware for workmanship defects and manufacturing flaws. The minimum acceptance levels and durations and methods for their establishment are described. Component selection and test monitoring, as well as test implementation requirements, are included. Apollo spacecraft environmental acceptance test results are summarized, and recommendations for future programs are presented.

  15. 46 CFR 28.73 - Accepted organizations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 1 2012-10-01 2012-10-01 false Accepted organizations. 28.73 Section 28.73 Shipping... INDUSTRY VESSELS General Provisions § 28.73 Accepted organizations. An organization desiring to be designated by the Commandant as an accepted organization must request such designation in writing. As...

  16. 46 CFR 28.73 - Accepted organizations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 1 2011-10-01 2011-10-01 false Accepted organizations. 28.73 Section 28.73 Shipping... INDUSTRY VESSELS General Provisions § 28.73 Accepted organizations. An organization desiring to be designated by the Commandant as an accepted organization must request such designation in writing. As...

  17. 46 CFR 28.73 - Accepted organizations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 1 2010-10-01 2010-10-01 false Accepted organizations. 28.73 Section 28.73 Shipping... INDUSTRY VESSELS General Provisions § 28.73 Accepted organizations. An organization desiring to be designated by the Commandant as an accepted organization must request such designation in writing. As...

  18. 46 CFR 28.73 - Accepted organizations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 1 2013-10-01 2013-10-01 false Accepted organizations. 28.73 Section 28.73 Shipping... INDUSTRY VESSELS General Provisions § 28.73 Accepted organizations. An organization desiring to be designated by the Commandant as an accepted organization must request such designation in writing. As...

  19. 46 CFR 28.73 - Accepted organizations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 1 2014-10-01 2014-10-01 false Accepted organizations. 28.73 Section 28.73 Shipping... INDUSTRY VESSELS General Provisions § 28.73 Accepted organizations. An organization desiring to be designated by the Commandant as an accepted organization must request such designation in writing. As...

  20. Pharmacokinetic behavior and pharmacokinetic/pharmacodynamic integration of marbofloxacin after subcutaneous administration in goats.

    PubMed

    Dova, Samanta Waxman; San Andrés, M Dolores; González, Fernando; San Andrés, Manuel I; De Lucas, José J; Rodríguez, Casilda

    2007-09-01

    The pharmacokinetic behavior of marbofloxacin was studied in goats after single-dose subcutaneous (SC) administration of 2mg/kg bodyweight. Drug concentration in plasma was determined by high performance liquid chromatography and the data obtained were subjected to non-compartmental kinetic analysis. Marbofloxacin peak plasma concentration (C(max)=1.77+/-0.24microg/mL) was reached 1.25+/-0.50h (T(max)) after SC administration. The elimination half-life (t(1/2beta)) and area under curve (AUC) were 5.74+/-1.21h and 8.15 vs 2.33microg h/mL, respectively. Taking into account the values obtained for the efficacy indices, it was concluded that a SC dose of 2mg/kg/24h of marbofloxacin could be adequate to treat infections caused by high susceptible bacteria like Escherichia coli or Salmonella spp.

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

    PubMed Central

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

    2016-01-01

    Background 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. Methods 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®. Results and Discussion 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

  2. Pharmacokinetics and metabolism of hydroxytyrosol, a natural antioxidant from olive oil.

    PubMed

    D'Angelo, S; Manna, C; Migliardi, V; Mazzoni, O; Morrica, P; Capasso, G; Pontoni, G; Galletti, P; Zappia, V

    2001-11-01

    3,4-Dihydroxyphenylethanol (DOPET) is the major o-diphenol detectable in extra virgin olive oil, either in free or esterified form. Despite its relevant biological effects, mainly related to its antioxidant properties, little data have been reported so far on its toxicity and metabolism. The aim of the present work is to evaluate DOPET toxicity and to investigate its molecular pharmacokinetics by using the (14)C-labeled diphenol. When orally administered to rats, the molecule does not show appreciable toxicity up to 2 g/kg b.wt. To identify and quantify its metabolites, [(14)C]DOPET has been synthesized and intravenously injected in rats. The pharmacokinetic analysis indicates a fast and extensive uptake of the molecule by the organs and tissues investigated, with a preferential renal uptake. Moreover, 90% of the administered radioactivity is excreted in urine collected up to 5 h after injection, and about 5% is detectable in feces and gastrointestinal content. The characterization of the labeled metabolites, extracted from the organs and urine, has been performed by high-pressure liquid chromatography analysis. In all the investigated tissues, DOPET is enzymatically converted in four oxidized and/or methylated derivatives. Moreover, a significant fraction of total radioactivity is associated with the sulfo-conjugated forms, which also represent the major urinary excretion products. On the basis of the reported results, an intracellular metabolic pathway of exogenously administered DOPET, implying the involvement of catechol-O-methyltransferase, alcohol dehydrogenase, aldehyde dehydrogenase, and phenolsulfotransferase, has been proposed. PMID:11602527

  3. Pharmacokinetic Behaviors of Intravenously Administered siRNA in Glandular Tissues.

    PubMed

    Huang, Yuanyu; Cheng, Qiang; Ji, Jia-Li; Zheng, Shuquan; Du, Lili; Meng, Lingwei; Wu, Yidi; Zhao, Deyao; Wang, Xiaoxia; Lai, Li; Cao, Huiqing; Xiao, Kai; Gao, Shan; Liang, Zicai

    2016-01-01

    The pharmacokinetics of small interfering RNAs (siRNAs) is a pivotal issue for siRNA-based drug development. In this study, we comprehensively investigated the behavior of siRNAs in vivo in various tissues and demonstrated that intravenously-injected naked siRNA accumulated remarkably in the submandibular gland, bulbourethral gland, and pancreas, with a respective half-life of ~22.7, ~45.6, and ~30.3 h. This was further confirmed by gel separation of tissue homogenates and/or supernatants. In vivo imaging and cryosectioning suggested that delivery carriers significantly influence the distribution and elimination profiles of siRNA. Gene-silencing assays revealed that neither naked nor liposome-formulated siRNA resulted in gene knockdown in the submandibular and bulbourethral glands after systemic administration, suggesting that these glands function as drug reservoirs that enable slow siRNA release into the circulation. But robust gene-silencing was achieved by local injection of liposome-encapsulated siRNA into the submandibular gland. Our results enhance understanding of the pharmacokinetic properties of siRNAs and we believe that they will facilitate the development of siRNA therapy, especially for the submandibular gland. PMID:27446488

  4. Characterization and pharmacokinetic analysis of crystalline versus amorphous rapamycin dry powder via pulmonary administration in rats.

    PubMed

    Carvalho, Simone R; Watts, Alan B; Peters, Jay I; Liu, Sha; Hengsawas, Soraya; Escotet-Espinoza, Manuel S; Williams, Robert O

    2014-09-01

    The pharmacokinetics of inhaled rapamycin (RAPA) is compared for amorphous versus crystalline dry powder formulations. The amorphous formulation of RAPA and lactose (RapaLac) was prepared by thin film freezing (TFF) using lactose as the stabilizing agent in the weight ratio 1:1. The crystalline formulation was prepared by wet ball milling RAPA and lactose and posteriorly blending the mixture with coarse lactose (micronized RAPA/micronized lactose/coarse lactose=0.5:0.5:19). While both powders presented good aerosolization performance for lung delivery, TFF formulation exhibited better in vitro aerodynamic properties than the crystalline physical mixture. Single-dose 24h pharmacokinetic studies were conducted in Sprague-Dawley rats following inhalation of the aerosol mist in a nose-only inhalation exposure system. Lung deposition was higher for the crystalline group than for the TFF group. Despite higher pulmonary levels of drug that were found for the crystalline group, the systemic circulation (AUC₀₋₂₄) was higher for the amorphous group (8.6 ngh/mL) than for crystalline group (2.4 ngh/mL) based on a five-compartmental analysis. Lung level profiles suggest that TTF powder stays in the lung for the same period of time as the crystalline powder but it presented higher in vivo systemic bioavailability due to its enhanced solubility, faster dissolution rate and increased FPF at a more distal part of the lungs. PMID:24859653

  5. The Subcellular Distribution of Small Molecules: from Pharmacokinetics to Synthetic Biology

    PubMed Central

    Zheng, Nan; Tsai, Hobart Ng; Zhang, Xinyuan; Rosania, Gus R.

    2011-01-01

    The systemic pharmacokinetics and pharmacodynamics of small molecules are determined by subcellular transport phenomena. Although approaches used to study the subcellular distribution of small molecules have gradually evolved over the past several decades, experimental analysis and prediction of cellular pharmacokinetics remains a challenge. In this article, we surveyed the progress of subcellular distribution research since the 1960s, with a focus on the advantages, disadvantages and limitations of the various experimental techniques. Critical review of the existing body of knowledge pointed to many opportunities to advance the rational design of organelle-targeted chemical agents. These opportunities include: 1) development of quantitative, nonfluorescence-based, whole cell methods and techniques to measure the subcellular distribution of chemical agents in multiple compartments; 2) exploratory experimentation with nonspecific transport probes that have not been enriched with putative, organelle-targeting features; 3) elaboration of hypothesis-driven, mechanistic and modeling-based approaches to guide experiments aimed at elucidating subcellular distribution and transport; and 4) introduction of revolutionary conceptual approaches borrowed from the field of synthetic biology combined with cutting edge experimental strategies. In our laboratory, state-of-the-art subcellular transport studies are now being aimed at understanding the formation of new intracellular membrane structures in response to drug therapy, exploring the function of drug-membrane complexes as intracellular drug depots, and synthesizing new organelles with extraordinary physical and chemical properties. PMID:21805990

  6. Docetaxel-loaded liposomes: preparation, pH sensitivity, pharmacokinetics, and tissue distribution*

    PubMed Central

    Zhang, Hong; Li, Rui-ying; Lu, Xia; Mou, Zhen-zhen; Lin, Gui-mei

    2012-01-01

    Docetaxel (DTX), as a member of taxoid family, has been widely used in the treatment of cancers. The present study prepared pH-sensitive DTX-loaded liposomes (DTX-Lips) by thin-film dispersion method and various physico-chemical and morphological properties were examined. The pH sensitivity of in vitro DTX release and the in vivo pharmacokinetics and tissue distribution using Kunming mice were also investigated. The mean particle size and zeta potential of DTX liposomes were (277±2) nm and (−32.60±0.26) mV, respectively. Additionally, in vitro drug release study showed that the cumulative release rate was 1.3 times more at pH 5.0 than at pH 7.4, suggesting a pH-dependent release ability of DTX-Lips. Pharmacokinetic and pharmaceutical studies in comparison with Duopafei® showed that the half-time period (t 1/2) and area under the curve (AUC) of DTX-Lips in mouse plasma were 1.8 times longer and 2.6 times higher, respectively, and that DTX-Lips selectively accumulated in macrophage-rich organs such as liver and spleen. These results together suggest that the DTX-Lips could be a promising formulation for the clinical administration of DTX. PMID:23225853

  7. Pharmacokinetics and metabolism of hydroxytyrosol, a natural antioxidant from olive oil.

    PubMed

    D'Angelo, S; Manna, C; Migliardi, V; Mazzoni, O; Morrica, P; Capasso, G; Pontoni, G; Galletti, P; Zappia, V

    2001-11-01

    3,4-Dihydroxyphenylethanol (DOPET) is the major o-diphenol detectable in extra virgin olive oil, either in free or esterified form. Despite its relevant biological effects, mainly related to its antioxidant properties, little data have been reported so far on its toxicity and metabolism. The aim of the present work is to evaluate DOPET toxicity and to investigate its molecular pharmacokinetics by using the (14)C-labeled diphenol. When orally administered to rats, the molecule does not show appreciable toxicity up to 2 g/kg b.wt. To identify and quantify its metabolites, [(14)C]DOPET has been synthesized and intravenously injected in rats. The pharmacokinetic analysis indicates a fast and extensive uptake of the molecule by the organs and tissues investigated, with a preferential renal uptake. Moreover, 90% of the administered radioactivity is excreted in urine collected up to 5 h after injection, and about 5% is detectable in feces and gastrointestinal content. The characterization of the labeled metabolites, extracted from the organs and urine, has been performed by high-pressure liquid chromatography analysis. In all the investigated tissues, DOPET is enzymatically converted in four oxidized and/or methylated derivatives. Moreover, a significant fraction of total radioactivity is associated with the sulfo-conjugated forms, which also represent the major urinary excretion products. On the basis of the reported results, an intracellular metabolic pathway of exogenously administered DOPET, implying the involvement of catechol-O-methyltransferase, alcohol dehydrogenase, aldehyde dehydrogenase, and phenolsulfotransferase, has been proposed.

  8. Improved dissolution and pharmacokinetic behavior of cyclosporine A using high-energy amorphous solid dispersion approach.

    PubMed

    Onoue, Satomi; Sato, Hideyuki; Ogawa, Kumiko; Kawabata, Yohei; Mizumoto, Takahiro; Yuminoki, Kayo; Hashimoto, Naofumi; Yamada, Shizuo

    2010-10-31

    The aim of the present investigation is to develop solid dispersion (SD) formulations of cyclosporine A (CsA) for improving the oral bioavailability of CsA. Amorphous SDs of CsA with eight hydrophilic polymers were prepared with wet-mill employing zirconia beads. The physicochemical properties were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, and interaction of CsA with co-existing polymer. Although CsA molecules were found to be amorphous in all wet-milled formulations, some SD formulations failed to improve the dissolution. Of all CsA formulations, SD using polymer with HPC(SSL) exhibited the largest improvement in dissolution behavior. Pharmacokinetic profiling of orally dosed CsA in rats was carried out using UPLC/ESI-MS. After the oral administration of HPC(SSL)-based SD, enhanced CsA exposure was observed with increases in C(max) and AUC of ca. 5-fold, and the variation in AUC was ca. 40% less than that of amorphous CsA. Infrared spectroscopic studies suggested an interaction between CsA and HPC(SSL), as evidenced by the conformational transition of CsA. From the improved dissolution and pharmacokinetic data, the amorphous SD approach using wet-milling technology should lead to consistent and enhanced bioavailability, leading to an improved therapeutic potential of CsA. PMID:20705124

  9. Pharmacokinetics and Pharmacodynamics of Oral Heparin Solid Dosage Form in Healthy Human Subjects

    PubMed Central

    Mousa, Shaker A.; Zhang, Fuming; Aljada, Ahmad; Chaturvedi, Seema; Takieddin, Majde; Zhang, Haifeng; Chi, Lianli; Castelli, M. Cristina; Friedman, Kristen; Goldberg, Michael M.; Linhardt, Robert J.

    2014-01-01

    The present investigation determined the molecular structure and the pharmacokinetic and pharmacodynamic profiles of oral unfractionated heparin containing oral absorption enhancer sodium N-[8-(2-hydroxybenzoyl) amino]caprylate, salcaprozate sodium (SNAC) and assessed the safety and tolerability of the orally dosed heparin solid dosage form versus other routes. Sixteen healthy men were included in this single-dose, 3-way crossover, randomized, open-label study. Disaccharide compositional analysis was performed using capillary high-performance liquid chromatography with electrospray ionization mass spectrometry detection. The pharmacodynamics of heparin were obtained from analysis of plasma anti–factor Xa, anti–factor IIa, activated partial thromboplastin time, and total tissue factor pathway inhibitor data. The molecular weight properties and the disaccharide composition of orally administered unfractionated heparin/SNAC and parenterally administered unfractionated heparin are identical and consistent with the starting pharmaceutical standard heparin. Furthermore, the anti–factor Xa/anti–factor IIa ratio achieved is of approximately 1:1. This is the first true pharmacokinetic study to measure the chemical compositions of heparin administered by different routes. PMID:18048572

  10. Pharmacokinetic Behaviors of Intravenously Administered siRNA in Glandular Tissues

    PubMed Central

    Huang, Yuanyu; Cheng, Qiang; Ji, Jia-Li; Zheng, Shuquan; Du, Lili; Meng, Lingwei; Wu, Yidi; Zhao, Deyao; Wang, Xiaoxia; Lai, Li; Cao, Huiqing; Xiao, Kai; Gao, Shan; Liang, Zicai

    2016-01-01

    The pharmacokinetics of small interfering RNAs (siRNAs) is a pivotal issue for siRNA-based drug development. In this study, we comprehensively investigated the behavior of siRNAs in vivo in various tissues and demonstrated that intravenously-injected naked siRNA accumulated remarkably in the submandibular gland, bulbourethral gland, and pancreas, with a respective half-life of ~22.7, ~45.6, and ~30.3 h. This was further confirmed by gel separation of tissue homogenates and/or supernatants. In vivo imaging and cryosectioning suggested that delivery carriers significantly influence the distribution and elimination profiles of siRNA. Gene-silencing assays revealed that neither naked nor liposome-formulated siRNA resulted in gene knockdown in the submandibular and bulbourethral glands after systemic administration, suggesting that these glands function as drug reservoirs that enable slow siRNA release into the circulation. But robust gene-silencing was achieved by local injection of liposome-encapsulated siRNA into the submandibular gland. Our results enhance understanding of the pharmacokinetic properties of siRNAs and we believe that they will facilitate the development of siRNA therapy, especially for the submandibular gland. PMID:27446488

  11. Pharmacokinetics of marbofloxacin in loggerhead sea turtles (Caretta caretta) after single intravenous and intramuscular doses.

    PubMed

    Lai, Olimpia R; Marín, Pedro; Laricchiuta, Pietro; Marzano, Giacomo; Crescenzo, Giuseppe; Escudero, Elisa

    2009-09-01

    The disposition kinetics of marbofloxacin at a single dose of 2 mg/kg bodyweight were determined in a crossover trial with five clinically healthy loggerhead sea turtles (Caretta caretta) after i.v. and i.m. administration. Marbofloxacin plasma concentrations were determined by high-performance liquid chromatography (LOD/LOQ 0.05 microg/ml). Data were subjected to noncompartmental analysis. The integrated pharmacokinetic/pharmacodynamic variables showed that optimal area under the curve (AUC(0-24 h)): minimal inhibitory concentration (MIC) (>125) and Cmax: MIC (>8) ratios, as reported for concentration-dependent bactericidal antimicrobials (e.g., fluoroquinolones), were achievable with both a once daily i.v. or i.m. dose for microorganisms with MIC < or = 0.5 microg/ml, while a Cmax: MIC > 8 for MIC > or = 1 microg/ml was achievable only after the i.v. administration. The absence of adverse reactions in the animals after i.v. or i.m. administration of marbofloxacin and the favorable pharmacokinetic/pharmacodynamic properties after a single dose of 2 mg/kg suggest the possibility of its safe and effective clinical use in loggerhead sea turtles.

  12. Preparation and pharmacokinetics study on gastro-floating sustained-release tablets of troxipide.

    PubMed

    Gao, Yunyun; Gao, Yang; Yin, Fei; Wang, Mi; Wang, Zhenhong; Ye, Tiantian; Yang, Yonggang; Pan, W S; Yang, Xinggang

    2015-01-01

    The purpose of this research aimed at preparing gastro-floating sustained-release tablets of troxipide and a further study on in vitro release and in vivo bioavailability. Under the circumstances of direct powder compression, the floating tablets were successfully prepared with HPMC as main matrix material, Carbopol as assistant matrix material, octadecanol as floating agent and sodium bicarbonate as foaming agent to float by gas-forming. The floating time and accumulative release amount as evaluation indexes were utilized to perform pre-experiment screening and single-factor test, respectively, while central composite design response surface method was applied for formulation optimization, followed by in vivo pharmacokinetic study in beagles after oral administration for floating tablets and commercial tablets used as the control. The results indicated that the floating sustained-release tablets held a better capability for floating and drug release and more satisfactory pharmacokinetic parameters, such as a lower Cmax, a prolonged Tmax, but an equivalent bioavailability calculated by AUC0-24 compared to commercial tablets. So a conclusion was finally drawn that the floating sustained-release tablets possessing a good release property could be suitable for demands of design.

  13. Pharmacokinetic studies of novel berberine derivatives with ultra-performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Wang, Wenchao; Shen, Qin; Liang, Hui; Hua, Changlong; Liu, Yuhui; Li, Fengzhi; Li, Qingyong

    2016-09-15

    An ultra-performance liquid chromatography with tandem mass spectrometric detection method was developed for the detection of berberine and its derivatives (A4, B4) in rat plasma and other organs. This validated method was successfully applied to our pharmacokinetic study of BBR derivatives in rats. At the same dose of administration, the Cmax of B4 was about eight times higher than BBR, and its half-life was approximately two times longer than BBR, according to the bigger areas under plasma concentration curves. Inversely, the pharmacokinetic parameter levels of A4 were all inferior to BBR, suggesting a tight structure-activity relationship of these compounds. Small dose of parenteral administration was used for the study of absolute oral bioavailability of A4, B4, and BBR, and the results calculated were 0.12%, 3.4% and 0.7%, respectively. The accumulations of B4 among all organs were intestine>liver>heart>kidney>lung>spleen>plasma, proving a deeply targeting property of B4, which met our experimental assumption. Together, the experimental results proved that compared with BBR and A4, the derivative B4 had higher absolute oral bioavailability and the ability of deeply targeting so that can be likely used in some organ-targeted diseases. PMID:27494281

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

    PubMed

    Sverrisdóttir, Eva; Lund, Trine Meldgaard; Olesen, Anne Estrup; Drewes, Asbjørn Mohr; Christrup, Lona Louring; Kreilgaard, Mads

    2015-07-10

    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 be used to quantify dose-response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation. This review provides 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 of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.

  15. Interspecies allometric meta-analysis of the comparative pharmacokinetics of 85 drugs across veterinary and laboratory animal species.

    PubMed

    Huang, Q; Gehring, R; Tell, L A; Li, M; Riviere, J E

    2015-06-01

    Allometric scaling is widely used for the determination of first dosage regimen and the interpolation or extrapolation of pharmacokinetic parameters across many animal species during drug development. In this article, 85 drugs used in veterinary medicine obtained from the Food Animal Residue Avoidance Databank database were selected for allometric scaling analysis. Outlier species were identified by statistical methods. The results showed that 77% and 88% of drugs displayed significant correlations between total systemic clearance (CL) and volume of distribution at steady status (Vss) vs. body weight (P < 0.05) on a log-log scale, respectively. The distribution of the allometric exponent b for CL and Vss displays approximate normal distribution, with means (0.87 and 0.99) and standard deviations (0.143 and 0.157) for CL and Vss, respectively. Twelve drugs were identified to have at least one outlier species for CL and ten drugs for Vss. The human CL and Vss were predicted for selected drugs by the obtained allometric equations. The predicted CL and Vss were within a threefold error compared to observed values, except the predicted CL values for antipyrine, warfarin and diazepam. The results can be used to estimate cross-species pharmacokinetic profiles for predicting drug dosages in veterinary species, and to identify those species for which interpolation or extrapolation of pharmacokinetics properties may be problematic.

  16. Intravitreal clearance and volume of distribution of compounds in rabbits: In silico prediction and pharmacokinetic simulations for drug development.

    PubMed

    del Amo, Eva M; Vellonen, Kati-Sisko; Kidron, Heidi; Urtti, Arto

    2015-09-01

    The aims of this research were to (1) create a curated universal database of intravitreal volumes of distribution (Vss, ivt) and clearances (CL ivt) of small molecular weight compounds and macromolecules and (2) to develop quantitative structure property relationship (QSPR) and pharmacokinetic models for the estimation of vitreal drug concentrations based on the compound structure. Vss, ivt and CL ivt values were determined from the available literature on intravitreal drug administration using compartmental models and curve fitting. A simple QSPR model for CL ivt of small molecular weight compounds was obtained with two descriptors: Log D7.4 and hydrogen bond donor capacity. The model predicted the internal and external test sets reliably with a mean fold error of 1.50 and 1.33, respectively (Q(2)Y=0.62). For 80% of the compounds the Vss, ivt was 1.18-2.28 ml; too narrow range for QSPR model building. Integration of the estimated Vss, ivt and predicted CL ivt parameters into pharmacokinetic simulation models allows prediction of vitreous drug concentrations after intravitreal administration. The present work presents for the first time a database of CL ivt and Vss, ivt values and the dependence of the CL ivt values on the molecular structure. The study provides also useful in silico tools to investigate a priori the intravitreal pharmacokinetic profiles for intravitreally injected candidate compounds and drug delivery systems.

  17. Effect of Piperazine Dithioctate on the Oral Pharmacokinetics of Glimepiride in Rats.

    PubMed

    Kim, Eun-Yeong; Yu, Keewon; Choi, Kyungmi; Yu, Hyung Eun; Oh, Soo Jin; Lee, Kiho

    2015-01-01

    The objective of the present work was to investigate the potential for pharmacokinetic drug-drug interactions between glimepiride (GMP) and piperazine dithioctate (PDT) in rats to support the development of an orally combined product of the two drugs. An LC-MS/MS bioanalytical method was developed for simultaneous quantification of GMP and thioctic acid (TA) in rat plasma. The accuracy, precision, linearity, selectivity, and recovery were all within an acceptable range. The oral plasma exposure of the GMP solution was more than 14-times greater than that of the GMP suspension at a dose of 0.5 mg/kg, suggesting a dissolution-limited absorption of the GMP suspension. Oral co-administration of PDT (72 mg/kg) with GMP suspension (0.5 mg/kg) reduced the plasma GMP exposure by approximately 80% without a significant change in t1/2 and tmax. Oral co-administration of PDT with GMP solution had no significant effect on the plasma pharmacokinetics of GMP. PDT lowered the pH (from ca. 7 to 5.6) and the dissolved GMP concentration in the GMP suspension. It was also shown that GMP was more soluble at pH 7 than at 5.7 in an aqueous solution, and the oral plasma exposure of a GMP suspension at pH 7.0 was substantially higher than that of a suspension at pH 5.7. These results suggest that the pH-dependent solubility of GMP was likely responsible for PDT's effect on the oral absorption of GMP. In conclusion, the current work suggests a possibility of drug-drug interaction between GMP and PDT upon oral co-administration. PMID:26235578

  18. Angiogenesis of uterine cervical carcinoma: characterization by pharmacokinetic magnetic resonance parameters and histological microvessel density with correlation to lymphatic involvement.

    PubMed

    Hawighorst, H; Knapstein, P G; Weikel, W; Knopp, M V; Zuna, I; Knof, A; Brix, G; Schaeffer, U; Wilkens, C; Schoenberg, S O; Essig, M; Vaupel, P; van Kaick, G

    1997-11-01

    Dynamic studies of Gd-based contrast agents in magnetic resonance imaging (MRI) are increasingly being used for tumor characterization as well as therapy response monitoring. Because detailed knowledge regarding the pathophysiological properties, which in turn are responsible for differences in contrast enhancement, remains fairly undetermined, it was the aim of this project to: (a) examine the relationship between contrast-enhanced dynamic MRI-derived characteristics and histological microvessel density counts, a recognized surrogate of tumor angiogenesis, from primary or recurrent cancers of the uterine cervix; and (b) correlate these parameters with lymphatic involvement to characterize tumor aggressiveness in terms of lymphatic spread. Pharmacokinetic parameters (amplitude, A; exchange rate constant, k21) were calculated from a contrast-enhanced dynamic MRI series in 55 patients (ages 25-72 years; mean, 50 years) with biopsy-proven primary (n = 42) or recurrent (n = 13) uterine cervical cancer. Both pharmacokinetic parameters were correlated to histologically determined microvessel density counts (factor VIII-related antigen) and other pathological tumor characteristics obtained from the operative specimens after radical surgery. In addition, the magnetic resonance and histological data were correlated to the presence or absence of lymphatic system involvement. Pharmacokinetic MRI-derived parameters (A and k21) increased with increasing histological microvessel density counts with r = 0.41 and 0.50, respectively. Lymphatic involvement was more comprehensibly assessed by the pharmacokinetic parameter k21 compared with histological microvessel density, resulting in a higher sensitivity, overall accuracy, and comparable specificity. Contrast-enhanced MRI parameters might prove to be applicable for estimation of tumor angiogenesis in uterine cervical cancer; thus, MRI may become an additional tool to characterize malignant progression in terms of lymphatic

  19. Pharmacokinetics of memantine in rats and mice.

    PubMed

    Beconi, Maria G; Howland, David; Park, Larry; Lyons, Kathryn; Giuliano, Joseph; Dominguez, Celia; Munoz-Sanjuan, Ignacio; Pacifici, Robert

    2011-12-15

    To evaluate the potential of memantine as a therapeutic agent for Huntington's disease (HD) we have undertaken a series of in vitro, ex vivo and whole animal studies to characterize its pharmacokinetics (PK) and pharmacodynamics (PD) in rats and mice. Results from these studies will enable determination of memantine exposures needed to engage the related functional PD marker and help predict the dose regimen for clinical trials to test its proposed mechanism of action; the selective blockade of extrasynaptic, but not synaptic, NMDA receptors. The studies reported here describe the PK of memantine in rats and mice at low (1 mg/kg) and high (10 mg/kg) doses. Our studies indicate that the clearance mechanisms of memantine in rats and mice are different from those in human, and that clearance needs to be taken into account when extrapolating to the human. In rats only, there is a significant metabolic contribution to memantine clearance at lower dose levels. While memantine is primarily cleared renally in all three species, the proportion of total systemic clearance above the glomerular filtration rate (GFR) is much higher in rats and mice (~13, 4.5, and 1.4 times higher than GFR in rats, mice, and humans, respectively), suggesting that the contribution of active transport to memantine elimination in rats and mice is more significant than in the human. In rats and mice, memantine had a short half-life (<4 h) and steep Cmax/Cmin ratios (>100). In the human, the half-life of memantine was reported to be very long (60-80 h) with a Cmax/Cmin ratio at steady state concentrations of ~1.5. A small change in the clearance of memantine - for example due to renal impairment or competition for the elimination pathway with a co-administered drug - will likely affect exposure and, therefore, the selectivity of memantine on NMDA receptors . The PK differences observed between these species demonstrate that the PK in mice and rats cannot be directly extrapolated to the human. Further

  20. Population pharmacokinetics of teicoplanin in children.

    PubMed

    Ramos-Martín, V; Paulus, S; Siner, S; Scott, E; Padmore, K; Newland, P; Drew, R J; Felton, T W; Docobo-Pérez, F; Pizer, B; Pea, F; Peak, M; Turner, M A; Beresford, M W; Hope, W W

    2014-11-01

    Teicoplanin is frequently administered to treat Gram-positive infections in pediatric patients. However, not enough is known about the pharmacokinetics (PK) of teicoplanin in children to justify the optimal dosing regimen. The aim of this study was to determine the population PK of teicoplanin in children and evaluate the current dosage regimens. A PK hospital-based study was conducted. Current dosage recommendations were used for children up to 16 years of age. Thirty-nine children were recruited. Serum samples were collected at the first dose interval (1, 3, 6, and 24 h) and at steady state. A standard 2-compartment PK model was developed, followed by structural models that incorporated weight. Weight was allowed to affect clearance (CL) using linear and allometric scaling terms. The linear model best accounted for the observed data and was subsequently chosen for Monte Carlo simulations. The PK parameter medians/means (standard deviation [SD]) were as follows: CL, [0.019/0.023 (0.01)] × weight liters/h/kg of body weight; volume, 2.282/4.138 liters (4.14 liters); first-order rate constant from the central to peripheral compartment (Kcp), 0.474/3.876 h(-1) (8.16 h(-1)); and first-order rate constant from peripheral to central compartment (Kpc), 0.292/3.994 h(-1) (8.93 h(-1)). The percentage of patients with a minimum concentration of drug in serum (Cmin) of <10 mg/liter was 53.85%. The median/mean (SD) total population area under the concentration-time curve (AUC) was 619/527.05 mg · h/liter (166.03 mg · h/liter). Based on Monte Carlo simulations, only 30.04% (median AUC, 507.04 mg · h/liter), 44.88% (494.1 mg · h/liter), and 60.54% (452.03 mg · h/liter) of patients weighing 50, 25, and 10 kg, respectively, attained trough concentrations of >10 mg/liter by day 4 of treatment. The teicoplanin population PK is highly variable in children, with a wider AUC distribution spread than for adults. Therapeutic drug monitoring should be a routine requirement to