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Sample records for radiopharmaceutical showing pharmacokinetic

  1. Pharmacokinetics of SPECT radiopharmaceuticals for imaging hypoxic tissues.

    PubMed

    Wiebe, L I; Stypinski, D

    1996-09-01

    Although hypoxia has been known for decades to play an important role in the outcome of radiotherapy in oncology, and inspite of the contribution of hypoxia to a myriad of pathologies that involve vascular disease, the selective imaging of hypoxic tissue has attained prominence only within the past decade. Contemporary research in the hypoxia imaging field is based largely on radiosensitizer research of the 1960's and 1970's. Early sensitizer research identified a family of nitro-organic compounds, the N-1 substituted 2-nitroimidazoles as candidate drugs. The early champion, and still the reference standard for therapeutic radiosensitization of hypoxic tumor cells is misonidazole (MISO). Its peripheral neurotoxicity led to failure in clinical studies, but its biological, biophysical and biochemical properties have been investigated in detail and serve as a basis for further design, not only of sensitizers, but of diagnostic radiopharmaceuticals for imaging tissue hypoxia. Pharmacokinetic characterization of radiopharmaceuticals, specifically radiopharmaceuticals for imaging tissue hypoxia, has not been a central theme in their development. The advent of PET, through which quantitative determinations first became possible, opened the field for both descriptive and analytical radiopharmacokinetic studies. In SPECT, however, this approach is still undergoing refinement. This paper addresses some of the underlying issues in radiopharmaceutical pharmacokinetics. There is a paucity of published radiopharmacokinetic data for SPECT hypoxia imaging agents. Consequently, the pharmacokinetic issues for MISO are presented as a basis for development of pharmacokinetics for the chemically-related imaging agents. Properties of an hypoxia marker are described from a pharmacokinetic viewpoint, a theoretical model for descriptive pharmacokinetics is introduced and finally, recent pharmacokinetic studies from our laboratory are described.

  2. Radiopharmaceuticals

    SciTech Connect

    Theobald, A.E.

    1989-01-01

    This book is a review of the latest developments in radiopharmaceuticals. It covers the development of radiopharmaceutical compounds, the theory and practice of their synthesis, and examples of their application. Also covers safe handling of radiopharmaceuticals, legislation affecting their use, radiation monitoring, radiochromatography, and computer techniques.

  3. A comparative analysis of pharmacokinetics properties of diagnostic bone-seeking radiopharmaceuticals on the basis of phosphonic acids and technetium-99m

    NASA Astrophysics Data System (ADS)

    Tishchenko, V. K.; Petriev, V. M.; Smoryzanova, O. A.; Zavestovskaya, I. N.

    2017-01-01

    This work is devoted to comparative research of pharmacokinetics properties of four bone-seeking radiopharmaceuticals (RPP) on the basis of bi- tetra- and penta-phosphonic acids. Biodistribution studies were performed in intact rats after intravenous injections of 99mTc-hydroxyethylidenediphosphonic acid (99mTc-HEDP), 99mTc-oxabiphor (99mTc-OXB), 99mTc-ethylenediaminetetramethylenephosphonic acid (99mTc-EDTMP) or 99mTc-diethylenetriaminopentakis(methylphosphonic acid) (99mTc-PPA). In the structure of the HEDP contains two phosphonic groups, OENTMP and EDTMP – four phosphonic groups, PPA – five phosphonic groups. Radiochemical yield of labeled 99mTc HEDP, OENTMP, EDTMP, PPA is not less than 95%, the radiochemical impurities does not exceed 5%. The investigated compounds have high stability in vivo and selective accumulation in osseous tissue. The highest concentrations of labeled compounds is reached in 3–24 hours after their intravenous injections. The investigated compounds are rapidly excreted from blood and soft organs and tissues mainly through the urinary routes. So present study has showed that these RPP have properties, which making them promising candidates as a diagnostic pharmaceuticals of bone metastases.

  4. Radiopharmaceutical bacteriostats

    SciTech Connect

    Flanagan, R.J.; Tartaglia, D.

    1993-07-13

    A radiopharmaceutical has been prepared with a composition comprising: (a) a radioactive iodine-based radiopharmaceutical; (b) an auto radiolytic decomposition-inhibiting antioxidant selected from: (i) ascorbic acid (ii) nicotinamide, (iii) nicotinic acid, and (iv) a mixture of ascorbic acid and nicotinamide; (c) a bacteriostat selected from: (i) benzalkonium chloride, and (ii) benzethonium chloride.

  5. Pharmacokinetic properties of new antitumor radiopharmaceutical on the basis of diamond nanoporous composites labeled with rhenium-188

    NASA Astrophysics Data System (ADS)

    Petriev, V. M.; Tishchenko, V. K.; Kuril’chik, A. A.; Skvortsov, V. G.

    2017-01-01

    Today the development of address therapeutic radionuclide delivery systems directly to tumor tissue is of current interest. It can be achieved by the design of drug containers of specific sizes and shapes from carbon-based composite materials. It will be allowed to enhance the efficacy of anticancer therapy and avoid serious side effects. In this work we studied the pharmacokinetic properties of nanodiamond nanoporous composite labeled with rhenium-188 in rats with hepatocholangioma PC-1 after intratumoral injection. It was established that substantial part of injected radioactivity remained in tumor tissue. Within three hours after 188Re-nanoporous composites injection activity in tumor constituted 79.1–91.3% of injected dose (ID). Then activity level declined to 45.9% ID at 120 hours. No more than 1.34% ID entered the bloodstream. In soft organs and tissues, except thyroid gland, the content of compound didn’t exceed 0.3% ID/g. The highest activity in thyroid gland was 6.95% ID/g. In conclusion, received results suggest 188Re-nanoporous composites can be promising radionuclide delivery systems for cancer treatment.

  6. 'Naked' radiopharmaceuticals

    SciTech Connect

    Wallner, Paul E. . E-mail: pwallner@rtsx.com

    2006-10-01

    The term 'naked' radiopharmaceuticals, more appropriately, 'unbound' radiopharmaceuticals, refers to any radioisotope used for clinical research or clinical purposes that is not attached to a chemical or biological carrier, and that localizes in various tissues because of a physiologic or chemical propensity/affinity, or secondary to focal anatomic placement. Although they remain useful in selected clinical circumstances, the available agents (except for Iodine-131) have been relegated to an unfortunate and somewhat secondary role. The agents remain useful and worthy of consideration for new clinical investigation and clinical use.

  7. Organometallic Radiopharmaceuticals

    NASA Astrophysics Data System (ADS)

    Alberto, Roger

    Although molecular imaging agents have to be synthesized ultimately from aqueous solutions, organometallic complexes are becoming more and more important as flexible yet kinetically stable building blocks for radiopharmaceutical drug discovery. The diversity of ligands, targets, and targeting molecules related to these complexes is an essential base for finding novel, noninvasive imaging agents to diagnose and eventually treat widespread diseases such as cancer. This review article covers the most important findings toward these objectives accomplished during the past 3-4 years. The two major available organometallic building blocks will be discussed in the beginning together with constraints for market introduction as imposed by science and industry. Since targeting radiopharmaceuticals are a major focus of current research in molecular imaging, attempts toward so-called technetium essential radiopharmaceuticals will be briefly touched in the beginning followed by the main discussion about the labeling of targeting molecules such as folic acid, nucleosides, vitamins, carbohydrates, and fatty acids. At the end, some new strategies for drug discovery will be introduced together with results from organometallic chemistry in water. The majority of the new results have been achieved with the [99mTc(OH2)3(CO)3]+ complex which will, though not exclusively, be a focus of this review.

  8. Medicinal Radiopharmaceutical Chemistry of Metal Radiopharmaceuticals

    NASA Astrophysics Data System (ADS)

    Saw, Maung Maung

    2012-06-01

    Metal complexes have been used as medicinal compounds. Metals have advantageous features over organic compounds. Significant applications of metal complexes are in the field of nuclear medicine. Radiopharmaceuticals are drugs containing radioisotopes used for diagnostic and therapeutic purposes. The generalized targeting strategy for molecular imaging probe consists of three essential parts: (i) reporter unit or payload, (ii) carrier, and (iii) targeting system. Medicinal radiopharmaceutical chemistry pays special consideration to radioisotopes, as a reporter unit for diagnostic application or as a payload for therapeutic application. Targeting is achieved by a few approaches but the most common is the bifunctional chelator approach. While designing a radiopharmaceutical, a range of issues needs to be considered including properties of metal radioisotopes, bifunctional chelators, linkers, and targeting molecules. Designing radiopharmaceuticals requires consideration of two key words: "compounds of biological interest" and "fit for intended use." The ultimate goal is the development of new diagnostic methods and treatment. Diagnostic metal radiopharmaceuticals are used for SPECT and PET applications. Technetium chemistry constitutes a major portion of SPECT and gallium chemistry constitutes a major portion of PET. Therapeutic radiopharmaceuticals can be constructed by using alpha-, beta minus-, or Auger electron-emitting radiometals. Special uses of medicinal radiopharmaceuticals include internal radiation therapy, brachytherapy, immunoPET, radioimmunotherapy, and peptide receptor radionuclide imaging and therapy.

  9. Applications of click chemistry in radiopharmaceutical development.

    PubMed

    Walsh, Joseph C; Kolb, Hartmuth C

    2010-01-01

    Click chemistry, a concept that employs only practical and reliable transformations for compound synthesis, has made a significant impact in several areas of chemistry, including material sciences and drug discovery. The present article describes the use of click chemistry for the development of radiopharmaceuticals. Target templated in situ click chemistry was used for lead generation. The 1,2,3-triazole moiety was found to improve the pharmacokinetic properties of certain radiopharmaceuticals. The reliable Cu(I)-catalyzed click reaction was employed for radiolabeling of peptidic compounds without the need for protecting groups. In summary, the click chemistry approach for the discovery, optimization and labeling of new radiotracers, represents a very powerful tool for radiopharmaceutical development.

  10. Dosimetry for Radiopharmaceutical Therapy

    PubMed Central

    Sgouros, George; Hobbs, Robert F.

    2014-01-01

    Radiopharmaceutical therapy (RPT) involves the use of radionuclides that are either conjugated to tumor-targeting agents (eg, nanoscale constructs, antibodies, peptides, and small molecules) or concentrated in tissue through natural physiological mechanisms that occur predominantly in neoplastic or otherwise targeted cells (eg, Graves disease). The ability to collect pharmacokinetic data by imaging and use this to perform dosimetry calculations for treatment planning distinguishes RPT from other systemic treatment modalities. Treatment planning has not been widely adopted, in part, because early attempts to relate dosimetry to outcome were not successful. This was partially because a dosimetry methodology appropriate to risk evaluation rather than efficacy and toxicity was being applied to RPT. The weakest links in both diagnostic and therapeutic dosimetry are the accuracy of the input and the reliability of the radiobiological models used to convert dosimetric data to the relevant biologic end points. Dosimetry for RPT places a greater demand on both of these weak links. To date, most dosimetric studies have been retrospective, with a focus on tumor dose-response correlations rather than prospective treatment planning. In this regard, transarterial radioembolization also known as intra-arterial radiation therapy, which uses radiolabeled (90Y) microspheres of glass or resin to treat lesions in the liver holds much promise for more widespread dosimetric treatment planning. The recent interest in RPT with alpha-particle emitters has highlighted the need to adopt a dosimetry methodology that specifically accounts for the unique aspects of alpha particles. The short range of alpha-particle emitters means that in cases in which the distribution of activity is localized to specific functional components or cell types of an organ, the absorbed dose will be equally localized and dosimetric calculations on the scale of organs or even voxels (~5 mm) are no longer sufficient

  11. Radiopharmaceuticals in cardiology.

    PubMed

    Mikołajczak, Renata; Garnuszek, Piotr

    2012-04-24

    Myocardial perfusion studies are among the most often performed investigations in Nuclear Medicine. However, the development of radiopharmaceuticals for cardiology is an emerging discipline and several other radiotracers have been proven to be useful. Although the myocardial perfusion studies have a well established role in the management of cardiac disorders, still a number of radiopharmaceuticals are under development for a variety of specific cardiac indications and their eventual clinical role remains to be seen. The paper provides a short overview of currently used radiopharmaceuticals and potential molecular imaging radiotracers applicable in cardiology.

  12. Eleventh international symposium on radiopharmaceutical chemistry

    SciTech Connect

    1995-12-31

    This document contains abstracts of papers which were presented at the Eleventh International Symposium on Radiopharmaceutical Chemistry. Sessions included: radiopharmaceuticals for the dopaminergic system, strategies for the production and use of labelled reactive small molecules, radiopharmaceuticals for measuring metabolism, radiopharmaceuticals for the serotonin and sigma receptor systems, labelled probes for molecular biology applications, radiopharmaceuticals for receptor systems, radiopharmaceuticals utilizing coordination chemistry, radiolabelled antibodies, radiolabelling methods for small molecules, analytical techniques in radiopharmaceutical chemistry, and analytical techniques in radiopharmaceutical chemistry.

  13. [Nuclear medicine and radiopharmaceuticals].

    PubMed

    Sopena Novales, P; Plancha Mansanet, M C; Martinez Carsi, C; Sopena Monforte, R

    2014-06-01

    Nuclear Medicine is a medical specialty that allows modern diagnostics and treatments using radiopharmaceuticals original radiotracers (drugs linked to a radioactive isotope). In Europe, radiopharmaceuticals are considered a special group of drugs and thus their preparation and use are regulated by a set of policies that have been adopted by individual member countries. The radiopharmaceuticals used in diagnostic examinations are administered in very small doses. So, in general, they have no pharmacological action, side effects or serious adverse reactions. The biggest problem associated with their use are the alterations in their biodistribution that may cause diagnostic errors. Nuclear Medicine is growing considerably influenced by the appearance and development of new radiopharmaceuticals in both the diagnostic and therapeutic fields and primarily to the impact of new multimodality imaging techniques (SPECT-CT, PET-CT, PET-MRI, etc.). It's mandatory to know the limitations of these techniques, distribution and eventual physiological alterations of radiopharmaceuticals, contraindications and adverse reactions of radiological contrasts, and the possible interference of both.

  14. Method for preparing radiopharmaceutical complexes

    DOEpatents

    Jones, Alun G.; Davison, Alan; Abrams, Michael J.

    1989-05-02

    A method for preparing radiopharmaceutical complexes that are substantially free of the reaction materials used to produce the radiopharmaceutical complex is disclosed. The method involves admixing in a suitable first solvent in a container a target seeking ligand or salt or metal adduct thereof, a radionuclide label, and a reducing agent for said radionuclide, thereby forming said radiopharmaceutical complex; coating the interior walls of the container with said pharmaceutical complex; discarding the solvent containing by-products and unreacted starting reaction materials; and removing the radiopharmaceutical complex from said walls by dissolving it in a second solvent, thereby obtaining said radiopharmaceutical complex substantially free of by-products and unreacted starting materials.

  15. Process for preparing radiopharmaceuticals

    DOEpatents

    Barak, Morton; Winchell, Harry S.

    1977-01-04

    A process for the preparation of technetium-99m labeled pharmaceuticals is disclosed. The process comprises initially isolating technetium-99m pertechnetate by adsorption upon an adsorbent packing in a chromatographic column. The technetium-99m is then eluted from the packing with a biological compound to form a radiopharmaceutical.

  16. Melanin-binding radiopharmaceuticals

    SciTech Connect

    Packer, S; Fairchild, R G; Watts, K P; Greenberg, D; Hannon, S J

    1980-01-01

    The scope of this paper is limited to an analysis of the factors that are important to the relationship of radiopharmaceuticals to melanin. While the authors do not attempt to deal with differences between melanin-binding vs. melanoma-binding, a notable variance is assumed. (PSB)

  17. Astatine Radiopharmaceuticals: Prospects and Problems

    PubMed Central

    Vaidyanathan, Ganesan; Zalutsky, Michael R.

    2010-01-01

    For the treatment of minimum residual diseases such micrometastases and residual tumor margins that remain after debulking of the primary tumor, targeted radiotherapy using radiopharmaceuticals tagged with α-particle-emitting radionuclides is very attractive. In addition to the their short range in tissue, which helps minimize harmful effects on adjacent normal tissues, α-particles, being high LET radiation, have several radiobiological advantages. The heavy halogen, astatine-211 is one of the prominent α-particle-emitting radionuclides in practice. Being a halogen, it can often be incorporated into biomolecules of interest by adapting radioiodination chemistry. A wide spectrum of compounds from the simple [211At]astatide ion to small organic molecules, peptides, and large proteins labeled with 211At have been investigated with at least two reaching the stage of clinical evaluation. The chemistry, cytotoxic advantages, biodistribution studies, and microdosimetry/pharmacokinetic modeling of some of these agents will be reviewed. In addition, potential problems such as the harmful effect of radiolysis on the synthesis, lack of sufficient in vivo stability of astatinated compounds, and possible adverse effects when they are systemically administered will be discussed. PMID:20150978

  18. Astatine Radiopharmaceuticals: Prospects and Problems.

    PubMed

    Vaidyanathan, Ganesan; Zalutsky, Michael R

    2008-09-01

    For the treatment of minimum residual diseases such micrometastases and residual tumor margins that remain after debulking of the primary tumor, targeted radiotherapy using radiopharmaceuticals tagged with alpha-particle-emitting radionuclides is very attractive. In addition to the their short range in tissue, which helps minimize harmful effects on adjacent normal tissues, alpha-particles, being high LET radiation, have several radiobiological advantages. The heavy halogen, astatine-211 is one of the prominent alpha-particle-emitting radionuclides in practice. Being a halogen, it can often be incorporated into biomolecules of interest by adapting radioiodination chemistry. A wide spectrum of compounds from the simple [(211)At]astatide ion to small organic molecules, peptides, and large proteins labeled with (211)At have been investigated with at least two reaching the stage of clinical evaluation. The chemistry, cytotoxic advantages, biodistribution studies, and microdosimetry/pharmacokinetic modeling of some of these agents will be reviewed. In addition, potential problems such as the harmful effect of radiolysis on the synthesis, lack of sufficient in vivo stability of astatinated compounds, and possible adverse effects when they are systemically administered will be discussed.

  19. Radiopharmaceuticals: Progress and clinical perspectives. Volume I

    SciTech Connect

    Fritzberg, A.R.

    1986-01-01

    This volume examines the radiopharmaceuticals from both the clinical and pharmaceutical research viewpoints. Classes of radiopharmaceuticals are covered by organ type, including the heart, brain, liver, kidney, adrenal, blood, and bone. Also included are discussions of radiolabeled antibodies for cancer; cyclotron-produced radiopharmaceuticals; receptor agents; radiopharmaceutical design; and animal and human evaluation studies. VOLUME I: Contents include: Cationic Radiotracers as Myocardial Radiopharmaceuticals, Brain Radiopharmaceuticals, Antibody imaging and Therapy in Human Cancer, Advances in Renal Radiopharmaceuticals, Advances in the Development of Hepatobiliary Radiopharmaceuticals, Radiopharmaceutical Design, The Adrenal Medulla and its Diseases, and Index.

  20. Radiopharmaceuticals for diagnosis

    SciTech Connect

    Kuhl, D.E.

    1990-06-01

    During this grant period 1 January 1988--31 December 1990, we have successfully developed a number of new approaches to fluorine-18 labeled compounds, prepared several new radiotracers for both animal studies and eventual clinical trials, and explored the utility of a high-quality industrial robot in radiopharmaceutical applications. The progress during the last grant period is summarized briefly in the following sections. Publications arising from this research are listed below and can be found in Appendix I. 1 fig.

  1. Cyclotrons and positron emitting radiopharmaceuticals

    SciTech Connect

    Wolf, A.P.; Fowler, J.S.

    1984-01-01

    The state of the art of Positron Emission Tomography (PET) technology as related to cyclotron use and radiopharmaceutical production is reviewed. The paper discusses available small cyclotrons, the positron emitters which can be produced and the yields possible, target design, and radiopharmaceutical development and application. 97 refs., 12 tabs. (ACR)

  2. Unconventional Nuclides for Radiopharmaceuticals

    PubMed Central

    Holland, Jason P.; Williamson, Matthew J.; Lewis, Jason S.

    2016-01-01

    Rapid and widespread growth in the use of nuclear medicine for both diagnosis and therapy of disease has been the driving force behind burgeoning research interests in the design of novel radiopharmaceuticals. Until recently, the majority of clinical and basic science research has focused on the development of 11C-, 13N-, 15O-, and 18F-radiopharmaceuticals for use with positron emission tomography (PET) and 99mTc-labeled agents for use with single-photon emission computed tomography (SPECT). With the increased availability of small, low-energy cyclotrons and improvements in both cyclotron targetry and purification chemistries, the use of “nonstandard” radionuclides is becoming more prevalent. This brief review describes the physical characteristics of 60 radionuclides, including β+, β−, γ-ray, and α-particle emitters, which have the potential for use in the design and synthesis of the next generation of diagnostic and/or radiotherapeutic drugs. As the decay processes of many of the radionuclides described herein involve emission of high-energy γ-rays, relevant shielding and radiation safety issues are also considered. In particular, the properties and safety considerations associated with the increasingly prevalent PET nuclides 64Cu, 68Ga, 86Y, 89Zr, and 124I are discussed. PMID:20128994

  3. PASylated Coversin, a C5-Specific Complement Inhibitor with Extended Pharmacokinetics, Shows Enhanced Anti-Hemolytic Activity in Vitro.

    PubMed

    Kuhn, Nadine; Schmidt, Christoph Q; Schlapschy, Martin; Skerra, Arne

    2016-10-19

    The Ornithodoros moubata Complement Inhibitor (OmCI) binds complement component 5 (C5) with high affinity and, thus, selectively prevents proteolytic activation of the terminal lytic complement pathway. A recombinant version of OmCI (also known as Coversin and rEV576) has proven efficacious in several animal models of complement-mediated diseases and successfully completed a phase Ia clinical trial. Coversin is a small 17 kDa lipocalin protein which has a very short plasma half-life if not bound to C5; therefore, the drug requires frequent dosing. We have improved the pharmacokinetics of Coversin by N-terminal translational conjugation with a 600 residue polypeptide composed of Pro, Ala, and Ser (PAS) residues. To this end, PAS-Coversin as well as the unmodified Coversin were functionally expressed in the cytoplasm of E. coli and purified to homogeneity. Both versions showed identical affinity to human C5, as determined by surface plasmon resonance measurements, and revealed similar complement inhibitory activity, as measured in ELISAs with human serum. In line with the PEG-like biophysical properties, PASylation dramatically prolonged the plasma half-life of uncomplexed Coversin by a factor ≥50 in mice. In a clinically relevant in vitro model of the complement-mediated disease paroxysmal nocturnal hemoglobinuria (PNH) both versions of Coversin effectively reduced erythrocyte lysis. Unexpectedly, while the IC50 values were comparable, PAS-Coversin reached a substantially lower plateau of residual lysis at saturating inhibitor concentrations. Taken together, our data demonstrate two clinically relevant improvements of PASylated Coversin: markedly increased plasma half-life and considerably reduced background hemolysis of erythrocytes with PNH-induced phenotype.

  4. Preparation of radiopharmaceuticals labeled with metal radionuclides

    SciTech Connect

    Welch, M.J.

    1992-06-01

    We recently developed a useful zinc-62/copper-62 generator and are presently evaluating copper-62 radiopharmaceuticals for clinical studies. While developing these copper-62 radiopharmaceuticals, in collaboration with the University of Missouri Research Reactor, Columbia we have also explored copper-64 radiopharmaceuticals. The PET images we obtained with copper-64 tracers were of such high quality that we have developed and evaluated copper-64 labeled antibodies for PET imaging. The major research activities described herein include: the development and assessment of gallium-68 radiopharmaceuticals; the development and evaluation of a new zinc-62/copper-62 generator and the assessment of copper-62 radiopharmaceuticals; mechanistic studies on proteins labeled with metal radionuclides.

  5. Bioinorganic Activity of Technetium Radiopharmaceuticals.

    ERIC Educational Resources Information Center

    Pinkerton, Thomas C.; And Others

    1985-01-01

    Technetium radiopharmaceuticals are diagnostic imaging agents used in the field of nuclear medicine to visualize tissues, anatomical structures, and metabolic disorders. Bioavailability of technetium complexes, thyroid imaging, brain imaging, kidney imaging, imaging liver function, bone imaging, and heart imaging are the major areas discussed. (JN)

  6. Radiopharmaceuticals for diagnosis. Final report

    SciTech Connect

    Not Available

    1994-03-01

    In the period 1969-1986, this project was directed to the evolution of target-specific labeled chemicals useful for nuclear medical imaging, especially radioactive indicators suited to tracing adrenal functions and localizing tumors in the neuroendocrine system. Since 1986, this project research has focused on the chemistry of positron emission tomography (PET) ligands. This project has involved the evaluation of methods for radiochemical syntheses with fluorine-18, as well as the development and preliminary evaluation of new radiopharmaceuticals for positron emission tomography. In the radiochemistry area, the ability to predict fluorine-18 labeling yields for aromatic substitution reactions through the use of carbon-13 NMR analysis was studied. Radiochemical yields can be predicted for some structurally analogous aromatic compounds, but this correlation could not be generally applied to aromatic substrates for this reaction, particularly with changes in ring substituents or leaving groups. Importantly, certain aryl ring substituents, particularly methyl groups, appeared to have a negative effect on fluorination reactions. These observations are important in the future design of syntheses of complicated organic radiopharmaceuticals. In the radiopharmaceutical area, this project has supported the development of a new class of radiopharmaceuticals based on the monoamine vesicular uptake systems. The new radioligands, based on the tetrabenazine structure, offer a new approach to the quantification of monoaminergic neurons in the brain. Preliminary primate imaging studies support further development of these radioligands for PET studies in humans. If successful, such radiopharmaceuticals will find application in studies of the causes and treatment of neurodegenerative disorders such as Parkinson`s disease.

  7. Preparation of Radiopharmaceuticals Labeled with Metal Radionuclides

    SciTech Connect

    Welch, M.J.

    2012-02-16

    oxygen retention of the tissue and the significantly greater retention amounting in hypoxic tissue. This hypothesis was confirmed in a series of animal studies. Cu-64 can be used both as an imaging radionuclide and a therapeutic radionuclide. The therapeutic efficacy of Cu-64 ATSM was proven in hamsters bearing the CW39 human colorectal tumors. The administration of Cu-64 ATSM significantly increased the survival time of tumor-bearing animals with no acute toxicity. This copper agent therefore shows promise for radiotherapy. The flow tracer Cu-64 PTSM also demonstrates therapeutic potential by inhibiting cancer cells implanted in animal models. Again, this inhibition occurred at doses which showed no sign of toxicity to the animals. Cu-ATSM was translated to humans, under other support a series of tumors were investigated; these included head and neck cancer, non-small cell lung cancer, cervical cancer and renal cancer. Another radionuclide that was investigated was titanium 45. This radionuclide was successfully produced by radiation of a scandium foil with 15 MeV protons. The titanium 45 was processed and separated from residual scandium by high exchange chomotrophy. Titanium titanocene has been utilized as a therapeutic agent; this compound was prepared and studied in vitro and in vivo. Another project was the preparation of cyclodextrin dimers as a new pre-targeting approach for tumor uptake. Beta-cyclodextradin and two other dimers were synthesized. These dimers were studied for the in vivo application. Work continued on the application of the radionuclide already discussed. Technetium 94m, a positron emitting radionuclide of the widely used 99m Tc nuclide was also prepared. This allows the quantification of the uptake of technetium radiopharmaceuticals. In collaboration with Professor David Piwnica-Worms, technetium 94m, sestamibi was studied in animal models and in a limited number of human subjects.

  8. Prospective of 68Ga-Radiopharmaceutical Development

    PubMed Central

    Velikyan, Irina

    2014-01-01

    Positron Emission Tomography (PET) experienced accelerated development and has become an established method for medical research and clinical routine diagnostics on patient individualized basis. Development and availability of new radiopharmaceuticals specific for particular diseases is one of the driving forces of the expansion of clinical PET. The future development of the 68Ga-radiopharmaceuticals must be put in the context of several aspects such as role of PET in nuclear medicine, unmet medical needs, identification of new biomarkers, targets and corresponding ligands, production and availability of 68Ga, automation of the radiopharmaceutical production, progress of positron emission tomography technologies and image analysis methodologies for improved quantitation accuracy, PET radiopharmaceutical regulations as well as advances in radiopharmaceutical chemistry. The review presents the prospects of the 68Ga-based radiopharmaceutical development on the basis of the current status of these aspects as well as wide range and variety of imaging agents. PMID:24396515

  9. Radiopharmaceuticals for imaging the heart

    DOEpatents

    Green, Mark A.; Tsang, Brenda W.

    1994-01-01

    Radiopharmaceuticals for imaging myocardial tissues are prepared by forming lipophilic, cationic complexes of radioactive metal ions with metal chelating ligands comprising the Schiff base adducts of triamines and tetraamines with optionally substituted salicylaldehydes. The lipophilic, cationic, radioactive complexes of the invention exhibit high uptake and retention in myocardial tissues. Preferred gallium-68(III) complexes in accordance with this invention can be used to image the heart using positron emission tomography.

  10. Radiopharmaceuticals for imaging the heart

    DOEpatents

    Green, M.A.; Tsang, B.W.

    1994-06-28

    Radiopharmaceuticals for imaging myocardial tissues are prepared by forming lipophilic, cationic complexes of radioactive metal ions with metal chelating ligands comprising the Schiff base adducts of triamines and tetraamines with optionally substituted salicylaldehydes. The lipophilic, cationic, radioactive complexes of the invention exhibit high uptake and retention in myocardial tissues. Preferred gallium-68(III) complexes in accordance with this invention can be used to image the heart using positron emission tomography. 6 figures.

  11. Radiation dose estimates for radiopharmaceuticals

    SciTech Connect

    Stabin, M.G.; Stubbs, J.B.; Toohey, R.E.

    1996-04-01

    Tables of radiation dose estimates based on the Cristy-Eckerman adult male phantom are provided for a number of radiopharmaceuticals commonly used in nuclear medicine. Radiation dose estimates are listed for all major source organs, and several other organs of interest. The dose estimates were calculated using the MIRD Technique as implemented in the MIRDOSE3 computer code, developed by the Oak Ridge Institute for Science and Education, Radiation Internal Dose Information Center. In this code, residence times for source organs are used with decay data from the MIRD Radionuclide Data and Decay Schemes to produce estimates of radiation dose to organs of standardized phantoms representing individuals of different ages. The adult male phantom of the Cristy-Eckerman phantom series is different from the MIRD 5, or Reference Man phantom in several aspects, the most important of which is the difference in the masses and absorbed fractions for the active (red) marrow. The absorbed fractions for flow energy photons striking the marrow are also different. Other minor differences exist, but are not likely to significantly affect dose estimates calculated with the two phantoms. Assumptions which support each of the dose estimates appears at the bottom of the table of estimates for a given radiopharmaceutical. In most cases, the model kinetics or organ residence times are explicitly given. The results presented here can easily be extended to include other radiopharmaceuticals or phantoms.

  12. Internal dose assessment for 211At α-emitter in isotonic solution as radiopharmaceutical

    NASA Astrophysics Data System (ADS)

    Yuminov, O. A.; Fotina, O. V.; Priselkova, A. B.; Tultaev, A. V.; Platonov, S. Yu.; Eremenko, D. O.; Drozdov, V. A.

    2003-12-01

    The functional fitness of the α-emitter 211At for radiotherapy of the thyroid gland cancer is evaluated. Radiation doses are calculated using the MIRD method and previously obtained pharmacokinetic data for 211At in isotonic solution and for 123I as sodium iodide. Analysis of the 211At radiation dose to the thyroid gland suggests that this radiopharmaceutical may be predominantly used for the treatment of the thyroid cancer.

  13. Effect of blood activity on dosimetric calculations for radiopharmaceuticals

    NASA Astrophysics Data System (ADS)

    Zvereva, Alexandra; Petoussi-Henss, Nina; Li, Wei Bo; Schlattl, Helmut; Oeh, Uwe; Zankl, Maria; Graner, Frank Philipp; Hoeschen, Christoph; Nekolla, Stephan G.; Parodi, Katia; Schwaiger, Markus

    2016-11-01

    The objective of this work was to investigate the influence of the definition of blood as a distinct source on organ doses, associated with the administration of a novel radiopharmaceutical for positron emission tomography-computed tomography (PET/CT) imaging—(S)-4-(3-18F-fluoropropyl)-L-glutamic acid (18F-FSPG). Personalised pharmacokinetic models were constructed based on clinical PET/CT images from five healthy volunteers and blood samples from four of them. Following an identifiability analysis of the developed compartmental models, person-specific model parameters were estimated using the commercial program SAAM II. Organ doses were calculated in accordance to the formalism promulgated by the Committee on Medical Internal Radiation Dose (MIRD) and the International Commission on Radiological Protection (ICRP) using specific absorbed fractions for photons and electrons previously derived for the ICRP reference adult computational voxel phantoms. Organ doses for two concepts were compared: source organ activities in organs parenchyma with blood as a separate source (concept-1); aggregate activities in perfused source organs without blood as a distinct source (concept-2). Aggregate activities comprise the activities of organs parenchyma and the activity in the regional blood volumes (RBV). Concept-1 resulted in notably higher absorbed doses for most organs, especially non-source organs with substantial blood contents, e.g. lungs (92% maximum difference). Consequently, effective doses increased in concept-1 compared to concept-2 by 3-10%. Not considering the blood as a distinct source region leads to an underestimation of the organ absorbed doses and effective doses. The pronounced influence of the blood even for a radiopharmaceutical with a rapid clearance from the blood, such as 18F-FSPG, suggests that blood should be introduced as a separate compartment in most compartmental pharmacokinetic models and blood should be considered as a distinct source in

  14. Radioactive Ion Beams and Radiopharmaceuticals

    NASA Astrophysics Data System (ADS)

    Laxdal, R. E.; Morton, A. C.; Schaffer, P.

    2014-02-01

    Experiments performed at radioactive ion beam facilities shed new light on nuclear physics and nuclear structure, as well as nuclear astrophysics, materials science and medical science. The many existing facilities, as well as the new generation of facilities being built and those proposed for the future, are a testament to the high interest in this rapidly expanding field. The opportunities inherent in radioactive beam facilities have enabled the search for radioisotopes suitable for medical diagnosis or therapy. In this article, an overview of the production techniques and the current status of RIB facilities and proposals will be presented. In addition, accelerator-generated radiopharmaceuticals will be reviewed.

  15. Fourth international radiopharmaceutical dosimetry symposium

    SciTech Connect

    Schlafke-Stelson, A.T.; Watson, E.E.

    1986-04-01

    The focus of the Fourth International Radiopharmaceutical Dosimetry Symposium was to explore the impact of current developments in nuclear medicine on absorbed dose calculations. This book contains the proceedings of the meeting including the edited discussion that followed the presentations. Topics that were addressed included the dosimetry associated with radiolabeled monoclonal antibodies and blood elements, ultrashort-lived radionuclides, and positron emitters. Some specific areas of discussion were variations in absorbed dose as a result of alterations in the kinetics, the influence of radioactive contaminants on dose, dose in children and in the fetus, available instrumentation and techniques for collecting the kinetic data needed for dose calculation, dosimetry requirements for the review and approval of new radiopharmaceuticals, and a comparison of the effect on the thyroid of internal versus external irradiation. New models for the urinary blader, skeleton including the active marrow, and the blood were presented. Several papers dealt with the validity of traditional ''average-organ'' dose estimates to express the dose from particulate radiation that has a short range in tissue. These problems are particularly important in the use of monoclonal antibodies and agents used to measure intracellular functions. These proceedings have been published to provide a resource volume for anyone interested in the calculation of absorbed radiation dose.

  16. Renal radiopharmaceuticals--an update

    SciTech Connect

    Chervu, L.R.; Blaufox, M.D.

    1982-07-01

    Noninvasive radionuclide procedures in the evaluation of renal disease have been accepted increasingly as effective and valuable alternatives to older clinical methods. The development of suitable radiopharmaceuticals labeled with high photon intensity radionuclides and with /sup 99m/Tc in particular has stimulated this modality during the last few years. Currently several nearly ideal agents are available for anatomical and functional studies of kidney imparting very low absorbed radiation doses. These include /sup 99m/Tc-GHA and /sup 99m/Tc-DMSA for renal morphology and differential function evaluation, /sup 99m/Tc-DTPA for GFR and /sup 123/I orthoiodohippurate for ERPF measurements. A suitable agent as a replacement for the latter labeled with /sup 99m/Tc is actively being sought. Computer-assisted processing of dynamic renal function studies enables the observer to obtain a wealth of information related to the renal extraction, uptake, parenchymal transit and pelvic transit parameters of the agent administered into the bloodstream. Each of these parameters either globally or differentially contributes to a detailed evaluation of renal disease states. Several of these procedures have been validated against classical techniques clinically but more detailed information is being sought with the recently introduced radiopharmaceuticals. With the detailed validation and increasing recognition of the clinical utility of several of the radionuclidic procedures at many centers, it is hoped that radionuclide assessment of renal disorders ultimately will be made available routinely at all medical facilities.

  17. A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

    DTIC Science & Technology

    2014-11-01

    Naval Health Research Center A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory...Concentrations by Two Weeks After Benzathine Penicillin G Injection in the Majority of Young Adults Michael Neely Edward L. Kaplan Jeffrey L...Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in

  18. Radiopharmaceuticals for diagnosis and treatment

    SciTech Connect

    Kuhl, D.E.

    1991-01-01

    In this grant period we have continued our efforts in the areas of PE basic radiochemistry, radiopharmaceutical synthesis, and preclinical radiopharmaceutical evaluation. A new synthetic sequence, consisting, of no-carrier-added fluorine-18 labeling of substituted benzaldehydes followed by reductive decarbonylation, has been developed. This new methodology can be applied to the fluorine-18 labeling of a wide variety of drugs not previously accessible through existing fluorine-18 labeling methods. Following up on a literature report that the ability to radiolabel aromatic rings can be predicted by {sup 13}C-NMR chemical shifts, we have examined the generality of this correlation in aromatic rings bearing a variety of substituents. Although the original correlation holds for nitro substituted anisaldehydes, it cannot be extended to other rings substitution patterns. We have examined the relationship of in vivo localization of various fluorine-18 labeled dopamine uptake inhibitors to their in vitro binding affinities and lipophilicities. We have found that remarkably small decreases in binding affinity result in dramatic losses of in vivo binding to the desired high affinity binding sites. In order to probe the effects of endogenous neurotransmitter on the in vivo binding of radiolabeled dopamine uptake inhibitors, we have examined the in vivo regional localization of (18{sub F}) GBR 13119 after acute and chronic drug treatments which alter the endogenous levels of dopamine. We have found that acute changes in dopamine levels do not affect the binding of this radioligand, but chronic depletion of neurotransmitter results in down-regulation of the in vivo binding sites. 16 refs., 2 figs., 1 tab.

  19. Advancement in treatment and diagnosis of pancreatic cancer with radiopharmaceuticals

    PubMed Central

    Xu, Yu-Ping; Yang, Min

    2016-01-01

    Pancreatic cancer (PC) is a major health problem. Conventional imaging modalities show limited accuracy for reliable assessment of the tumor. Recent researches suggest that molecular imaging techniques with tracers provide more biologically relevant information and are benefit for the diagnosis of the cancer. In addition, radiopharmaceuticals also play more important roles in treatment of the disease. This review summaries the advancement of the radiolabeled compounds in the theranostics of PC. PMID:26909131

  20. Radiopharmaceuticals in PET, progress and promise

    SciTech Connect

    Wolf, A.P.; Fowler, J.S.

    1988-11-01

    It is the intention of this presentation to focus on the current state of radiopharmaceuticals for PET and where this is leading us. PET radiopharmaceuticals can be broken down into perhaps seven categories at present with each being applicable to a different aspect of human biochemistry. These are: metabolic probes, neurochemical probes, enzyme probes, ion channel blockers, blood flow agents, ethical drugs and other positron emitters. 7 refs.

  1. Radiopharmaceuticals in PET, Progress and Promise

    DOE R&D Accomplishments Database

    Wolf, A. P.; Fowler, J. S.

    1988-11-01

    It is the intention of this presentation to focus on the current state of radiopharmaceuticals for PET and where this is leading us. PET radiopharmaceuticals can be broken down into perhaps seven categories at present with each being applicable to a different aspect of human biochemistry. These are: metabolic probes, neurochemical probes, enzyme probes, ion channel blockers, blood flow agents, ethical drugs and other positron emitters.

  2. Improving radiopharmaceutical supply chain safety by implementing bar code technology.

    PubMed

    Matanza, David; Hallouard, François; Rioufol, Catherine; Fessi, Hatem; Fraysse, Marc

    2014-11-01

    The aim of this study was to describe and evaluate an approach for improving radiopharmaceutical supply chain safety by implementing bar code technology. We first evaluated the current situation of our radiopharmaceutical supply chain and, by means of the ALARM protocol, analysed two dispensing errors that occurred in our department. Thereafter, we implemented a bar code system to secure selected key stages of the radiopharmaceutical supply chain. Finally, we evaluated the cost of this implementation, from overtime, to overheads, to additional radiation exposure to workers. An analysis of the events that occurred revealed a lack of identification of prepared or dispensed drugs. Moreover, the evaluation of the current radiopharmaceutical supply chain showed that the dispensation and injection steps needed to be further secured. The bar code system was used to reinforce product identification at three selected key stages: at usable stock entry; at preparation-dispensation; and during administration, allowing to check conformity between the labelling of the delivered product (identity and activity) and the prescription. The extra time needed for all these steps had no impact on the number and successful conduct of examinations. The investment cost was reduced (2600 euros for new material and 30 euros a year for additional supplies) because of pre-existing computing equipment. With regard to the radiation exposure to workers there was an insignificant overexposure for hands with this new organization because of the labelling and scanning processes of radiolabelled preparation vials. Implementation of bar code technology is now an essential part of a global securing approach towards optimum patient management.

  3. Radiobrominated triphenylethylenes as estrogen receptor binding radiopharmaceuticals

    SciTech Connect

    Seevers, R.H.; Meese, R.C.; Friedman, A.M.; DeSombre, E.R.

    1985-05-01

    Estrogen receptor binding radiopharmaceuticals have potential for use in the diagnosis and treatment of cancers of the female reproductive system. Tamoxifen is an antiestrogen derived from the triphenylethylene skeleton which is used in the treatment of mammary carcinoma. Hydroxytamoxifen is a metabolite of tamoxifen which binds tightly to the estrogen receptor. Two triphenylethylene derivatives based on the structure of hydroxytamoxifen have been prepared: 1-bromo-1-phenyl-2- (2-dimethylamino)-4-ethoxyphenyl -2-(4-hydroxyphenyl) ethene (1) where the ethyl group of hydroxytamoxifen has been replaced by a bromine, and 1-bromo-1-phenyl-2,2-(4-hydroxyphenyl) ethene (2) with a similar substitution and also lacking the aminoethoxy side chain believed to confer antiestrogenicity. Both 1 and 2 bind strongly to the estrogen receptor. 2 has been labeled with the Auger electron emitting nuclide Br-80m in moderate yields in high specific activity using either N-bromosuccinimide or N-bromophthalimide and shows promise as a potential radiotherapy agent.

  4. In Vitro Assessment of the In Vivo Stability of Cu-64 Radiopharmaceuticals

    SciTech Connect

    Packard, Alan B

    2011-12-15

    Benefits: The FISRE method that will be used in this project, once validated, will provide researchers with a core technology by which the stability of Cu 64 radiopharmaceuticals can be accurately measured. In the short-term, we expect to produce extensive data regarding the stability of Cu-64 complexes of ligands of radiopharmaceutical interest, primarily those that are most commonly used as BFCs (e.g., DOTA, TETA). These data will provide a quantitative basis for deciding which ligands may be best suited for use as BFCs, data that is not currently available. In the intermediate term, we expect that these results will facilitate the development of new Cu-64 radiopharmaceuticals by providing a quantitative approach to assessing the stability of Cu-64 chelates. This innovative methodology will enable investigators to quantitatively compare the ability of different BFCs to retain Cu-64 in vivo. The benefits of this approach will be best seen in the development of Cu-64-labeled monoclonal antibodies where the accumulation of antibodies in the liver obviates liver uptake as an effective surrogate measure of Cu-64 lability. In the longer-term, we anticipate an improvement in the way in which various diseases (especially cancer) are detected, diagnosed, staged, and treated. This method will also enable researchers to distinguish differences in biodistribution that may arise from differences in charge, lipophilicity, etc. from those that may arise from loss of Cu-64 from the chelator. Last, this novel quantitative tool will allow investigators to evaluate the chemical factors that determine the in vivo stability of Cu-64 radiopharmaceuticals laying the groundwork for the future development of more effective Cu-64 radiopharmaceuticals. Once the feasibility of this method is established, it can also be used to evaluate the stability of other metalloradiopharmaceuticals including those based on Ga-68, a radionuclide that is showing great promise in tumor imaging.

  5. Eighth international symposium on radiopharmaceutical chemistry

    SciTech Connect

    Eckelman, W.C.

    1990-01-01

    The Eighth International Symposium on Radiopharmaceutical Chemistry was held on June 25--29, in Princeton, New Jersey. Topics covered in the meeting include: Technetium Chemistry; Perfusion Agents; Radionuclide Production; Synthetic Precursors; Analysis/Automation; Antibodies; Receptors; Metabolism, DOPA FDG; Receptors, D2 D1; Metabolism; and Metabolism, Cancer. Individual papers in each of these areas are abstracted separately. (MHB)

  6. Incorporation of radiohalogens via versatile organometallic reactions: applications in radiopharmaceutical chemistry

    SciTech Connect

    Srivastava, P.C.; Goodman, M.M.; Knapp, F.F. Jr.

    1985-01-01

    Factors that must be considered for the design of radiohalogenated radio-pharmaceuticals include the stability and availability of the substrate, the physical half-life of the radiohalogen and the in vivo stability of the radiolabel. Vinyl and phenyl radiohalogen bonds show more in vivo stability than the alkyl radiohalogen bonds. Consequently, a variety of methods suitable for the synthesis of tissue specific radiopharmaceuticals bearing a vinyl or phenyl radiohalogen have been developed involving the synthesis and halogenation of metallovinyl and phenyl intermediates. The halogens and metallation reactions include iodine and bromine and alanation, boronation, mercuration, stannylation, and thallation, respectively. 19 refs., 1 fig., 1 tab.

  7. Population pharmacokinetic analysis for 10-monohydroxy derivative of oxcarbazepine in pediatric epileptic patients shows no difference between Japanese and other ethnicities.

    PubMed

    Sugiyama, Ikuo; Bouillon, Thomas; Yamaguchi, Masayuki; Suzuki, Hikoe; Hirota, Takashi; Fink, Martin

    2015-04-01

    Oxcarbazepine is an anti-epileptic drug, which is almost completely metabolized by cytosolic enzymes in the liver to the active 10-monohyroxy metabolite (MHD) following oral administration. The pharmacokinetic (PK) profiles of MHD were evaluated in pediatric epileptic patients and a possible ethnic difference in PK of MHD between Japanese and non-Japanese pediatric patients was assessed. A non-linear mixed effect modeling approach was used to determine the PK of MHD. A one-compartment population model with first-order absorption appropriately described the PK of MHD. No clinically relevant differences were found for using body surface area or weight to explain between-patient variability, therefore the final model included the effects of body weight on apparent clearance (CL/F) and apparent volume of distribution (V/F) of MHD, and in addition, the effect of 3 concomitant anti-epileptic drugs (carbamazepine, phenobarbital and phenytoin) on CL/F of MHD. Inclusion of ethnicity as a covariate in the final model, concluded no ethnic difference with respect to CL/F of MHD between Japanese and non-Japanese patients. Hence, oxcarbazepine can be generally applied using the same dosage and administration for the treatment of partial onset seizures in pediatric patients, regardless of ethnicity.

  8. Simplification of Methods for PET Radiopharmaceutical Syntheses

    SciTech Connect

    Kilbourn, Michael, R.

    2011-12-27

    In an attempt to develop simplified methods for radiochemical synthesis of radiopharmaceuticals useful in Positron Emission Tomography (PET), current commercially available automated synthesis apparati were evaluated for use with solid phase synthesis, thin-film techniques, microwave-accelerated chemistry, and click chemistry approaches. Using combinations of these techniques, it was shown that these automated synthesis systems can be simply and effectively used to support the synthesis of a wide variety of carbon-11 and fluorine-18 labeled compounds, representing all of the major types of compounds synthesized and using all of the common radiochemical precursors available. These techniques are available for use to deliver clinically useful amounts of PET radiopharmaceuticals with chemical and radiochemical purities and high specific activities, suitable for human administration.

  9. Design of CGMP Production of 18F- and 68Ga-Radiopharmaceuticals

    PubMed Central

    Chu, Pei-Chun; Chao, Hao-Yu; Shieh, Wei-Chen; Chen, Chuck C.

    2014-01-01

    Objective. Radiopharmaceutical production process must adhere to current good manufacturing process (CGMP) compliance to ensure the quality of precursor, prodrug (active pharmaceutical ingredient, API), and the final drug product that meet acceptance criteria. We aimed to develop an automated system for production of CGMP grade of PET radiopharmaceuticals. Methods. The hardware and software of the automated synthesizer that fit in the hot cell under cGMP requirement were developed. Examples of production yield and purity for 68Ga-DOTATATE and 18F-FDG at CGMP facility were optimized. Analytical assays and acceptance criteria for cGMP grade of 68Ga-DOTATATE and 18F-FDG were established. Results. CGMP facility for the production of PET radiopharmaceuticals has been established. Radio-TLC and HPLC analyses of 68Ga-DOTATATE and 18F-FDG showed that the radiochemical purity was 92% and 96%, respectively. The products were sterile and pyrogenic-free. Conclusion. CGMP compliance of radiopharmaceuticals has been reviewed. 68Ga-DOTATATE and 18F-FDG were synthesized with high radiochemical yield under CGMP process. PMID:25276810

  10. Placental transfer of radiopharmaceuticals and dosimetry in pregnancy

    SciTech Connect

    Russell, J.R.; Stabin, M.G.; Sparks, R.B.

    1999-01-01

    The calculation of radiation dose estimates to the fetus is often important in nuclear medicine. To obtain the best estimates of radiation dose to the fetus, the best biological and physical models should be employed. In this paper, after identification of radiopharmaceuticals often administered to women of childbearing age, the most recent data available on the placental crossover of these radiopharmaceuticals was used (with standard kinetic models describing the maternal distribution and retention and with the best available physical models) to obtain fetal dose estimates for these radiopharmaceuticals were identified as those most commonly administered to women of childbearing years. The literature yielded information on placental crossover of 15 radiopharmaceuticals, from animal or human data. Radiation dose estimates are presented in early pregnancy and at 3-, 6-, and 9-months gestation for these radiopharmaceuticals, as well as for many others used in nuclear medicine (the latter considering only maternal organ contributions to fetal dose). 46 refs., 1 fig., 5 tabs.

  11. Small Molecule Radiopharmaceuticals – A Review of Current Approaches

    PubMed Central

    Chaturvedi, Shubhra; Mishra, Anil K.

    2016-01-01

    Radiopharmaceuticals are an integral component of nuclear medicine and are widely applied in diagnostics and therapy. Though widely applied, the development of an “ideal” radiopharmaceutical can be challenging. Issues such as specificity, selectivity, sensitivity, and feasible chemistry challenge the design and synthesis of radiopharmaceuticals. Over time, strategies to address the issues have evolved by making use of new technological advances in the fields of biology and chemistry. This review presents the application of few advances in design and synthesis of radiopharmaceuticals. The topics covered are bivalent ligand approach and lipidization as part of design modifications for enhanced selectivity and sensitivity and novel synthetic strategies for optimized chemistry and radiolabeling of radiopharmaceuticals. PMID:26942181

  12. Predicting the success of a radiopharmaceutical for in vivo imaging of central nervous system neuroreceptor systems.

    PubMed

    Wong, Dean F; Pomper, Martin G

    2003-01-01

    In vivo imaging of the central nervous system (CNS) neuroreceptors in humans began was used in the early 1980s. Now, some twenty years later, the success of radiopharmaceutical imaging is still often one based on empiricism and serendipity. Nevertheless, a number of factors can be identified based on the robot experience in developing these radiotracers. This article will describe some of the issues that may be useful in choosing approaches to radiolabel ligands as future imaging agents of neuroreceptors, transporters and intrasynaptic measures of neurotransmitters. A description of the current process from hypothesis to radiochemical preclinical development, non-human primate imaging development of quantitative procedures finally leading to toxicology, dosimetry and eventually human applications are provided. The role of important factors including metabolism and lipophilicity, affinity and other factors for optimizing radiolabeling strategies is dealt with. Furthermore, issues involving decision making of how far to extend efforts in developing a radiotracer and when might be an appropriate stopping place are discussed. Finally some typical examples of the use of these radiotracers, especially with emphasis on stable drug design and development, are provided. These include occupancy studies and mechanism of action studies. In summary, the prediction of tracer success includes: first, identification of appropriate targets and precursors, then systematic optimization of ligands with continuous feedback from pharmacokinetics and iterative improvement based on unsuccessful tracers. This article is intended to present a pragmatic overview of the radiopharmaceutical development process with emphasis on the CNS.

  13. Radiopharmaceutical dosage selection for pediatric nuclear medicine

    SciTech Connect

    Shore, R.M.; Hendee, W.R.

    1986-02-01

    To identify the most rational method for adjusting adult radiopharmaceutical dosages for children, four methods of dosage computation were examined from the perspectives of diagnostic adequacy and radiation absorbed dose. For static imaging, information density is the most important factor in study quality, and adjustment of dosage by body weight (Wt) for thick organs, and body surface area (BSA) for thin organs is recommended. Compared with adults, small children receive less radiation exposure if radiopharmaceutical dosages are adjusted by Wt, and slightly greater exposure if dosages are adjusted by BSA. For dynamic imaging studies, dosage requirements are governed by the spatial resolution needed for region of interest assignment, and the statistical reliability of the time-activity data. For dynamic renal imaging, renograms of similar quality are obtained if dosages are adjusted by height (Ht). Dynamic cardiac studies might appear to require dosages even larger than those adjusted by Ht which would result in higher radiation absorbed doses to pediatric patients. However, smaller dosages can be used in children by prolonging the imaging time and accepting lower temporal resolution. Dosage requirements for dynamic studies depend on which physiologic characteristics are measured from the time-activity data. Since the measurements of some characteristics demand higher count rates than others, dosage requirements ultimately depend on which measurements are clinically necessary. Close attention to the factors that determine these requirements may yield significant reduction in dosages, and thus in radiation exposure, for patients of all ages.

  14. The NIST radioactivity measurement assurance program for the radiopharmaceutical industry.

    PubMed

    Cessna, Jeffrey T; Golas, Daniel B

    2012-09-01

    The National Institute of Standards and Technology (NIST) maintains a program for the establishment and dissemination of activity measurement standards in nuclear medicine. These standards are disseminated through Standard Reference Materials (SRMs), Calibration Services, radionuclide calibrator settings, and the NIST Radioactivity Measurement Assurance Program (NRMAP, formerly the NEI/NIST MAP). The MAP for the radiopharmaceutical industry is described here. Consolidated results show that, for over 3600 comparisons, 96% of the participants' results differed from that of NIST by less than 10%, with 98% being less than 20%. Individual radionuclide results are presented from 214 to 439 comparisons, per radionuclide, for (67)Ga, (90)Y, (99m)Tc, (99)Mo, (111)In, (125)I, (131)I, and (201)Tl. The percentage of participants results within 10% of NIST ranges from 88% to 98%.

  15. Pharmacokinetic characterization of amrubicin cardiac safety in an ex vivo human myocardial strip model. II. Amrubicin shows metabolic advantages over doxorubicin and epirubicin.

    PubMed

    Salvatorelli, Emanuela; Menna, Pierantonio; Gonzalez Paz, Odalys; Surapaneni, Sekhar; Aukerman, Sharon L; Chello, Massimo; Covino, Elvio; Sung, Victoria; Minotti, Giorgio

    2012-05-01

    Anthracycline-related cardiotoxicity correlates with cardiac anthracycline accumulation and bioactivation to secondary alcohol metabolites or reactive oxygen species (ROS), such as superoxide anion (O₂·⁻) and hydrogen peroxide H₂O₂). We reported that in an ex vivo human myocardial strip model, 3 or 10 μM amrubicin [(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-napthacenedione hydrochloride] accumulated to a lower level compared with equimolar doxorubicin or epirubicin (J Pharmacol Exp Ther 341:464-473, 2012). We have characterized how amrubicin converted to ROS or secondary alcohol metabolite in comparison with doxorubicin (that formed both toxic species) or epirubicin (that lacked ROS formation and showed an impaired conversion to alcohol metabolite). Amrubicin and doxorubicin partitioned to mitochondria and caused similar elevations of H₂O₂, but the mechanisms of H₂O₂ formation were different. Amrubicin produced H₂O₂ by enzymatic reduction-oxidation of its quinone moiety, whereas doxorubicin acted by inducing mitochondrial uncoupling. Moreover, mitochondrial aconitase assays showed that 3 μM amrubicin caused an O₂·⁻-dependent reversible inactivation, whereas doxorubicin always caused an irreversible inactivation. Low concentrations of amrubicin therefore proved similar to epirubicin in sparing mitochondrial aconitase from irreversible inactivation. The soluble fraction of human myocardial strips converted doxorubicin and epirubicin to secondary alcohol metabolites that irreversibly inactivated cytoplasmic aconitase; in contrast, strips exposed to amrubicin failed to generate its secondary alcohol metabolite, amrubicinol, and only occasionally exhibited an irreversible inactivation of cytoplasmic aconitase. This was caused by competing pathways that favored formation and complete or near-to-complete elimination of 9-deaminoamrubicinol. These results characterize amrubicin

  16. [Reduction of radiation dose to the worker in preparing the radiopharmaceutical solution by a simple shielding equipment].

    PubMed

    Miyazaki, Y; Inoue, H; Shiozaki, J; Higuchi, Y; Fujioka, M; Kawaguchi, K; Miyanaga, M; Aburano, T

    1987-01-01

    In order to reduce radiation dose to the hands of examiners who prepare and aspirate radiopharmaceuticals, we made a prototype of simplified manually-operated dispense system, which the syringe and the vial shield with lead were set in the small box made of lead and lead glass. The result showed that our dispense system allowed substantial reduction of radiation dose to the hands and rapid preparation of radiopharmaceuticals compared with the conventional lead shield syringe system, and allowed closer operation, smaller dead volume and lower cost compared with the conventional automatic system.

  17. Matching chelators to radiometals for radiopharmaceuticals.

    PubMed

    Price, Eric W; Orvig, Chris

    2014-01-07

    Radiometals comprise many useful radioactive isotopes of various metallic elements. When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomography (SPECT, e.g.(67)Ga, (99m)Tc, (111)In, (177)Lu) and positron emission tomography (PET, e.g.(68)Ga, (64)Cu, (44)Sc, (86)Y, (89)Zr), as well as therapeutic applications (e.g.(47)Sc, (114m)In, (177)Lu, (90)Y, (212/213)Bi, (212)Pb, (225)Ac, (186/188)Re). A fundamental critical component of a radiometal-based radiopharmaceutical is the chelator, the ligand system that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable molecular target in vivo. This article is a guide for selecting the optimal match between chelator and radiometal for use in these systems. The article briefly introduces a selection of relevant and high impact radiometals, and their potential utility to the fields of radiochemistry, nuclear medicine, and molecular imaging. A description of radiometal-based radiopharmaceuticals is provided, and several key design considerations are discussed. The experimental methods by which chelators are assessed for their suitability with a variety of radiometal ions is explained, and a large selection of the most common and most promising chelators are evaluated and discussed for their potential use with a variety of radiometals. Comprehensive tables have been assembled to provide a convenient and accessible overview of the field of radiometal chelating agents.

  18. Radiopharmaceuticals for diagnosis and treatment. Progress report

    SciTech Connect

    Kuhl, D.E.

    1991-12-31

    In this grant period we have continued our efforts in the areas of PE basic radiochemistry, radiopharmaceutical synthesis, and preclinical radiopharmaceutical evaluation. A new synthetic sequence, consisting, of no-carrier-added fluorine-18 labeling of substituted benzaldehydes followed by reductive decarbonylation, has been developed. This new methodology can be applied to the fluorine-18 labeling of a wide variety of drugs not previously accessible through existing fluorine-18 labeling methods. Following up on a literature report that the ability to radiolabel aromatic rings can be predicted by {sup 13}C-NMR chemical shifts, we have examined the generality of this correlation in aromatic rings bearing a variety of substituents. Although the original correlation holds for nitro substituted anisaldehydes, it cannot be extended to other rings substitution patterns. We have examined the relationship of in vivo localization of various fluorine-18 labeled dopamine uptake inhibitors to their in vitro binding affinities and lipophilicities. We have found that remarkably small decreases in binding affinity result in dramatic losses of in vivo binding to the desired high affinity binding sites. In order to probe the effects of endogenous neurotransmitter on the in vivo binding of radiolabeled dopamine uptake inhibitors, we have examined the in vivo regional localization of [18{sub F}] GBR 13119 after acute and chronic drug treatments which alter the endogenous levels of dopamine. We have found that acute changes in dopamine levels do not affect the binding of this radioligand, but chronic depletion of neurotransmitter results in down-regulation of the in vivo binding sites. 16 refs., 2 figs., 1 tab.

  19. 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…

  20. Traceability from governmental producers of radiopharmaceuticals in measuring (18)F in Brazil.

    PubMed

    Oliveira, A E; Iwahara, A; Silva, C J; Cruz, P A L; Poledna, R; Silva, R L; Laranjeira, A S; Delgado, J U; Tauhata, L; Loureiro, J S; Toledo, B C; Braghirolli, A M S; Andrade, E A L; Silva, J L; Hernandes, H O K; Valente, E S; Dalle, H M; Almeida, V M; Silva, T G; Fragoso, M C F; Oliveira, M L; Nascimento, E S S; Oliveira, E M; Herrerias, R; Souza, A A; Bambalas, E; Bruzinga, W A

    2016-03-01

    Since the inception of its proficiency test program to evaluate radionuclide measurement in hospitals and clinics, the National Metrology Laboratory of Ionizing Radiation-LNMRI, that represents Brazilian National Metrology Institute (NMI) for ionizing radiation has expanded its measurement and calibration capability. Requirements from the National Health Surveillance Agency from Ministry of Health (ANVISA), to producers of radiopharmaceuticals provided an opportunity to improve the full traceability chain to the highest level. Fluorodeoxyglucose (FDG-(18)F) is the only radiopharmaceutical simultaneously produced by all Brazilian radiopharmaceutical production centers (RPCs). By running this proficiency test, LNMRI began to provide them with the required traceability. For evaluation, the ratio of RPC to reference value results and ISO/IEC17043:2010 criteria were used. The reference value established as calibration factor on the secondary standard ionization chamber was obtained from three absolute measurements systems, and routinely confirmed in each round of proficiency test by CIEMAT/NIST liquid scintillation counting. The γ-emitting impurities were checked using a High-Purity Germanium (HPGe) detector. The results show that Brazilian RPCs are in accordance with (accuracy within ±10%) the Brazilian standard for evaluation of measurements with radionuclide calibrators (CNEN NN 3.05., 2013). Nevertheless, the RPCs should improve the methodology of uncertainty estimates, essential when using the statistical criteria of ISO/IEC 17043 standard, in addition to improving accuracy to levels consistent with their position in the national traceability chain.

  1. (Coordinated research of chemotherapeutic agents and radiopharmaceuticals)

    SciTech Connect

    Srivastava, P.C.

    1991-01-14

    The traveler received a United Nations Development Program (UNDP) Award for Distinguished Scientists to visit Indian Research Institutions including Central Drug Research Institute (CDRI), Lucknow, the host institution, in cooperation with the Council of Scientific and Industrial Research (CSIR) of India. At CDRI, the traveler had meetings to discuss progress and future directions of on-going collaborative research work on nucleosides and had the opportunity to initiate new projects with the divisions of pharmacology, biopolymers, and membrane biology. As a part of this program, the traveler also visited Sanjay Gandhi Post Graduate Institute (SGPI) of Medical Sciences, Lucknow; Board of Radiation and Isotope Technology (BRIT) and Bhabha Atomic Research Center (BARC), Bombay; Variable Energy Cyclotron Center (VECC) and Indian Institute of Chemical Biology, Calcutta. He also attended the Indo-American Society of Nuclear Medicine Meeting held in Calcutta. The traveler delivered five seminars describing various aspects of radiopharmaceutical development at the Oak Ridge National Laboratory (ORNL) and discussed the opportunities for exchange visits to ORNL by Indian scientists.

  2. Stroma Targeting Nuclear Imaging and Radiopharmaceuticals

    PubMed Central

    Shetty, Dinesh; Jeong, Jae-Min; Shim, Hyunsuk

    2012-01-01

    Malignant transformation of tumor accompanies profound changes in the normal neighboring tissue, called tumor stroma. The tumor stroma provides an environment favoring local tumor growth, invasion, and metastatic spreading. Nuclear imaging (PET/SPECT) measures biochemical and physiologic functions in the human body. In oncology, PET/SPECT is particularly useful for differentiating tumors from postsurgical changes or radiation necrosis, distinguishing benign from malignant lesions, identifying the optimal site for biopsy, staging cancers, and monitoring the response to therapy. Indeed, PET/SPECT is a powerful, proven diagnostic imaging modality that displays information unobtainable through other anatomical imaging, such as CT or MRI. When combined with coregistered CT data, [18F]fluorodeoxyglucose ([18F]FDG)-PET is particularly useful. However, [18F]FDG is not a target-specific PET tracer. This paper will review the tumor microenvironment targeting oncologic imaging such as angiogenesis, invasion, hypoxia, growth, and homing, and also therapeutic radiopharmaceuticals to provide a roadmap for additional applications of tumor imaging and therapy. PMID:22685650

  3. Aptamers as radiopharmaceuticals for nuclear imaging and therapy.

    PubMed

    Gijs, Marlies; Aerts, An; Impens, Nathalie; Baatout, Sarah; Luxen, André

    2016-04-01

    Today, radiopharmaceuticals belong to the standard instrumentation of nuclear medicine, both in the context of diagnosis and therapy. The majority of radiopharmaceuticals consist of targeting biomolecules which are designed to interact with a disease-related molecular target. A plethora of targeting biomolecules of radiopharmaceuticals exists, including antibodies, antibody fragments, proteins, peptides and nucleic acids. Nucleic acids have some significant advantages relative to proteinaceous biomolecules in terms of size, production, modifications, possible targets and immunogenicity. In particular, aptamers (non-coding, synthetic, single-stranded DNA or RNA oligonucleotides) are of interest because they can bind a molecular target with high affinity and specificity. At present, few aptamers have been investigated preclinically for imaging and therapeutic applications. In this review, we describe the use of aptamers as targeting biomolecules of radiopharmaceuticals. We also discuss the chemical modifications which are needed to turn aptamers into valuable (radio-)pharmaceuticals, as well as the different radiolabeling strategies that can be used to radiolabel oligonucleotides and, in particular, aptamers.

  4. Auger Emitting Radiopharmaceuticals for Cancer Therapy

    NASA Astrophysics Data System (ADS)

    Falzone, Nadia; Cornelissen, Bart; Vallis, Katherine A.

    Radionuclides that emit Auger electrons have been of particular interest as therapeutic agents. This is primarily due to the short range in tissue, controlled linear paths and high linear energy transfer of these particles. Taking into consideration that ionizations are clustered within several cubic nanometers around the point of decay the possibility of incorporating an Auger emitter in close proximity to the cancer cell DNA has immense therapeutic potential thus making nuclear targeted Auger-electron emitters ideal for precise targeting of cancer cells. Furthermore, many Auger-electron emitters also emit γ-radiation, this property makes Auger emitting radionuclides a very attractive option as therapeutic and diagnostic agents in the molecular imaging and management of tumors. The first requirement for the delivery of Auger emitting nuclides is the definition of suitable tumor-selective delivery vehicles to avoid normal tissue toxicity. One of the main challenges of targeted radionuclide therapy remains in matching the physical and chemical characteristics of the radionuclide and targeting moiety with the clinical character of the tumor. Molecules and molecular targets that have been used in the past can be classified according to the carrier molecule used to deliver the Auger-electron-emitting radionuclide. These include (1) antibodies, (2) peptides, (3) small molecules, (4) oligonucleotides and peptide nucleic acids (PNAs), (5) proteins, and (6) nanoparticles. The efficacy of targeted radionuclide therapy depends greatly on the ability to increase intranuclear incorporation of the radiopharmaceutical without compromising toxicity. Several strategies to achieve this goal have been proposed in literature. The possibility of transferring tumor therapy based on the emission of Auger electrons from experimental models to patients has vast therapeutic potential, and remains a field of intense research.

  5. Altered biodistribution of radiopharmaceuticals used in bone scintigraphy.

    PubMed

    Zuckier, Lionel S; Martineau, Patrick

    2015-01-01

    Bone scintigraphy has remained a mainstay of clinical nuclear medicine for more than 4 decades. Extensive medical literature has developed surrounding the etiology and significance of alterations in distribution of bone radiopharmaceuticals. Altered biodistribution may be of a global nature, reflecting altered partition of radiopharmaceutical between bone and soft tissues, or more focal, reflecting regional abnormalities, including those related to bone or soft tissues. A third category of alterations in the distribution of bone radiopharmaceuticals is those due to errors and blunders, colloquially termed "artifactual" in the medical imaging literature. Being cognizant of these unexpected abnormalities, and understanding their etiology, will prepare the reader to more readily appreciate the significance of these findings when encountered in clinical practice.

  6. 188Re(V) Nitrido Radiopharmaceuticals for Radionuclide Therapy

    PubMed Central

    Boschi, Alessandra; Martini, Petra; Uccelli, Licia

    2017-01-01

    The favorable nuclear properties of rhenium-188 for therapeutic application are described, together with new methods for the preparation of high yield and stable 188Re radiopharmaceuticals characterized by the presence of the nitride rhenium core in their final chemical structure. 188Re is readily available from an 188W/188Re generator system and a parallelism between the general synthetic procedures applied for the preparation of nitride technetium-99m and rhenium-188 theranostics radiopharmaceuticals is reported. Although some differences between the chemical characteristics of the two metallic nitrido fragments are highlighted, it is apparent that the same general procedures developed for the labelling of biologically active molecules with technetium-99m can be applied to rhenium-188 with minor modification. The availability of these chemical strategies, that allow the obtainment, in very high yield and in physiological condition, of 188Re radiopharmaceuticals, gives a new attractive prospective to employ this radionuclide for therapeutic applications. PMID:28106830

  7. Newer positron emission tomography radiopharmaceuticals for radiotherapy planning: an overview

    PubMed Central

    Mukherjee, Anirban

    2016-01-01

    Positron emission tomography-computed tomography (PET-CT) has changed cancer imaging in the last decade, for better. It can be employed for radiation treatment planning of different cancers with improved accuracy and outcomes as compared to conventional imaging methods. 18F-fluorodeoxyglucose remains the most widely used though relatively non-specific cancer imaging PET tracer. A wide array of newer PET radiopharmaceuticals has been developed for targeted imaging of different cancers. PET-CT with such new PET radiopharmaceuticals has also been used for radiotherapy planning with encouraging results. In the present review we have briefly outlined the role of PET-CT with newer radiopharmaceuticals for radiotherapy planning and briefly reviewed the available literature in this regard. PMID:26904575

  8. PET/Computed Tomography Using New Radiopharmaceuticals in Targeted Therapy.

    PubMed

    Sharma, Punit; Kumar, Rakesh; Alavi, Abass

    2015-10-01

    Targeted therapy is gaining prominence in the management of different cancers. Given different mechanism of action compared with traditional chemoradiotherapy, selection of patients for targeted therapy and monitoring response to these agents is difficult with conventional imaging. Various new PET radiopharmaceuticals have been evaluated for molecular imaging of these targets to achieve specific patient selection and response monitoring. These PET/computed tomography (CT) agents target the cell surface receptors, hormone receptors, receptor tyrosine kinases, or angiogenesis components. This article reviews the established and potential role of PET/CT with new radiopharmaceuticals for guiding targeted therapy.

  9. Preparation of radiopharmaceuticals labeled with metal radionuclides. Progress report, July 1, 1988--June 30, 1992

    SciTech Connect

    Welch, M.J.

    1992-06-01

    We recently developed a useful zinc-62/copper-62 generator and are presently evaluating copper-62 radiopharmaceuticals for clinical studies. While developing these copper-62 radiopharmaceuticals, in collaboration with the University of Missouri Research Reactor, Columbia we have also explored copper-64 radiopharmaceuticals. The PET images we obtained with copper-64 tracers were of such high quality that we have developed and evaluated copper-64 labeled antibodies for PET imaging. The major research activities described herein include: the development and assessment of gallium-68 radiopharmaceuticals; the development and evaluation of a new zinc-62/copper-62 generator and the assessment of copper-62 radiopharmaceuticals; mechanistic studies on proteins labeled with metal radionuclides.

  10. Process for producing astatine-211 for radiopharmaceutical use

    DOEpatents

    Mirzadeh, Saed; Lambrecht, Richard M.

    1987-01-01

    A process for reliably and consistently producing astatine-211 in small controlled volumes of a solution, which is selected from a choice of solvents that are useful in selected radiopharmaceutical procedures in which the At-211 activities are to be applied.

  11. Harvard-MIT research program in short-lived radiopharmaceuticals

    SciTech Connect

    Adelstein, S.J.

    1991-01-01

    This report presents research on radiopharmaceuticals. The following topics are discussed: antibody labeling with positron-emitting radionuclides; antibody modification for radioimmune imaging; labeling antibodies; evaluation of technetium acetlyacetonates as potential cerebral blood flow agents; and studies in technetium chemistry. (CBS)

  12. Progress in radiopharmaceutical development in the Australasia region

    SciTech Connect

    Lambrecht, R.M.; Katsifis, A.; Kassiou, M.; Smith, S.

    1994-12-31

    Recent progress in the development of reactor and cyclotron produced radionuclides, conversion to precursors, synthesis, quality control and biomedical applications are highlighted with examples of prospective radiopharmaceuticals applicable to major diseases of the Australasia region. The merits of cyclotrons and nuclear reactors for medical radioisotopes in the region are cited.

  13. Process for producing astatine-211 for radiopharmaceutical use

    DOEpatents

    Mirzadeh, S.; Lambrecht, R.M.

    1984-04-10

    A process is described for reliably and consistently producing astatine-211 in small controlled volumes of a solution, which is selected from a choice of solvents that are useful in selected radiopharmaceutical procedures in which the At-211 activities are to be applied. 4 figures, 1 table.

  14. Pharmacokinetics of levodopa.

    PubMed

    Contin, Manuela; Martinelli, Paolo

    2010-11-01

    This paper reviews the clinically relevant determinants of levodopa peripheral pharmacokinetics and main observed changes in the levodopa concentration-effect relationship with Parkinson's disease (PD) progression. Available clinically practical strategies to optimise levodopa pharmacokinetics and pharmacodynamics are briefly discussed. Levodopa shows particular pharmacokinetics including an extensive presystemic metabolism, overcome by the combined use of extracerebral inhibitors of the enzyme L: -amino acid decarboxylase and rapid absorption in the proximal small bowel by a saturable facilitated transport system shared with other large neutral amino acids. Drug transport from plasma to the brain is mediated by the same carriers operating in the intestinal mucosa. The main strategies to assure reproducibility of both intestinal absorption and delivery to the brain, and the clinical effect include standardization of levodopa dosing with respect to meal times and a controlled dietary protein intake. Levodopa plasma half-life is very short, resulting in marked plasma drug concentration fluctuations which are matched, as the disease progresses, to swings in the therapeutic response ("wearing-off" phenomena). "Wearing-off" phenomena can also be associated, at the more advanced disease stages, with a "negative", both parkinsonism-exacerbating and dyskinetic effect of levodopa at low, subtherapeutic plasma concentrations. Dyskinesias may also be related to high-levodopa, excessive plasma concentrations. Recognition of the different levodopa toxic response patterns can be difficult on a clinical basis alone and simultaneous monitoring of the levodopa concentration-effect relationship may prove useful to disclose the underlying mechanism and in planning the correct management. Clinically practical strategies to optimise levodopa pharmacokinetics, and possibly its therapeutic response, include liquid drug solutions, controlled release formulations and the use of inhibitors

  15. Radiopharmaceutical chemistry with iodine-124: a non-standard radiohalogen for positron emission tomography.

    PubMed

    Chacko, Ann-Marie; Divgi, Chaitanya R

    2011-09-01

    Positron emission tomography (PET) is a powerful molecular imaging technology with the ability to image and monitor molecular events in vivo and in real time. With the increased application of PET radiopharmaceuticals for imaging physiological and pathological processes in vivo, there is a demand for versatile positron emitters with longer physical and biological half-lives. Traditional PET radionuclides, such as carbon-11 ((11)C) and fluorine-18 ((18)F), have relatively short half-lives (20 min and 110 min, respectively). Among the currently available positron emitters, the non-standard radiohalogen iodine-124 ((124)I) has the longest physical half-life at 4.2 d. This, combined with the well characterized radiochemistry of radioiodine, is contributing to the increasing utility of (124)I in investigating slow and complex pharmacokinetic processes in clinical nuclear medicine and small animal PET imaging studies. This review will summarize the progress to date on the potential of (124)I as a positron emitting nuclide for molecular imaging purposes, beginning with the production of (124)I. Particular emphasis will be placed on the basic radiochemistry as it applies to the production of various (124)I-labeled compounds, from small molecules, to biomolecules such as peptides and proteins, and finally to macromolecules like nanoparticles. The review will conclude by highlighting promising future directions in using (124)I as a positron emitter in PET radiochemistry and molecular imaging.

  16. Estrogen receptor binding radiopharmaceuticals: II. Tissue distribution of 17. cap alpha. -methylestradiol in normal and tumor-bearing rats

    SciTech Connect

    Feenstra, A.; Vaalburg, W.; Nolten, G.M.J.; Reiffers, S.; Talma, A.G.; Wiegman, T.; van der Molen, H.D.; Woldring, M.G.

    1983-06-01

    Tritiated 17..cap alpha..-methylestradiol was synthesized to investigate the potential of the carbon-11-labeled analog as an estrogen-receptor-binding radiopharmaceutical. In vitro, 17..cap alpha..-methylestradiol is bound with high affinity to the cytoplasmic estrogen receptor from rabbit uterus (K/sub d/ = 1.96 x 10/sup -10/M), and it sediments as an 8S hormone-receptor complex in sucrose gradients. The compound shows specific uptake in the uterus of the adult rat, within 1 h after injection. In female rats bearing DMBA-induced tumors, specific uterine and tumor uptakes were observed, although at 30 min the tumor uptake was only 23 to 30% of the uptake in the uterus. Tritiated 17..cap alpha..-methylestradiol with a specific activity of 6 Ci/mmole showed a similar tissue distribution. Our results indicate that a 17 ..cap alpha..-methylestradiol is promising as an estrogen-receptor-binding radiopharmaceutical.

  17. Quantitative autoradiography with radiopharmaceuticals, Part 2: Applications in radiopharmaceutical research: concise communication

    SciTech Connect

    Som, P.; Yonekura, Y.; Oster, Z.H.; Meyer, M.A.; Pelletteri, M.L.; Fowler, J.S.; MacGregor, R.R.; Russell, J.A.; Wolf, A.P.; Fand, I.

    1983-03-01

    We describe the application of macroautoradiography, a relatively simple, quantifiable method for the evaluation of positron-emitting and gamma-emitting radiopharmaceuticals. We have investigated the response properties of two types of film to positron (F-18) and negatron (C-14) emitters. Variations in the response of film to increasing film-to-source distance are described, along with the effects of different intensifying screens and mounting tape. Digitization of whole-body autoradiograms (WBARG) in small animals was performed by using a videodensitometry system (videocamera interfaced to a computer). Quantitation was derived from analysis of a series of step-wedge standards that covered the range of radioactivities in the sample. By using a close-up lens on the videocamera, a 2- by 2-cm field is digitized as a 128 X 128 array, each pixel representing 156 X 156 micron. The effect of chlorpromazine (CPZ) on glucose metabolism in mice was studied by giving C-14 2DG followed by CPZ and F-18 FDG in the same animal. Muscle activity decreased and brown-fat activity increased. The high spatial resolution of this technique enables quantification in structures as small as the basal ganglia in mice. The use of dual-nuclide ARG permits each animal to be its own control, which greatly increases the utility of this method.

  18. Quantitative autoradiography with radiopharmaceuticals, Part 2: Applications in radiopharmaceutical research: concise communication.

    PubMed

    Som, P; Yonekura, Y; Oster, Z H; Meyer, M A; Pelletteri, M L; Fowler, J S; MacGregor, R R; Russell, J A; Wolf, A P; Fand, I; McNally, W P; Brill, A B

    1983-03-01

    We describe the application of macroautoradiography, a relatively simple, quantifiable method for the evaluation of positron-emitting and gamma-emitting radiopharmaceuticals. We have investigated the response properties of two types of film to positron (F-18) and negatron (C-14) emitters. Variations in the response of film to increasing film-to-source distance are described, along with the effects of different intensifying screens and mounting tape. Digitization of whole-body autoradiograms (WBARG) in small animals was performed by using a videodensitometry system (videocamera interfaced to a computer). Quantitation was derived from analysis of a series of step-wedge standards that covered the range of radioactivities in the sample. By using a close-up lens on the videocamera, a 2- by 2-cm field is digitized as a 128 X 128 array, each pixel representing 156 X 156 micron. The effect of chlorpromazine (CPZ) on glucose metabolism in mice was studied by giving C-14 2DG followed by CPZ and F-18 FDG in the same animal. Muscle activity decreased and brown-fat activity increased. The high spatial resolution of this technique enables quantification in structures as small as the basal ganglia in mice. The use of dual-nuclide ARG permits each animal to be its own control, which greatly increases the utility of this method.

  19. Current status of PET imaging of differentiated thyroid cancer with second generation radiopharmaceuticals.

    PubMed

    Lauri, C; Di Traglia, S; Galli, F; Pizzichini, P; Signore, A

    2015-03-01

    Although the prognosis of differentiated thyroid cancer (DTC) is favorable, some histotypes show worst clinical outcome and higher risk of recurrence. Serum thyroglobulin (Tg) levels and 131I-whole-body-scan (WBS), together with neck ultrasound (US), represent the golden standard for DTC follow-up. Nevertheless, the relatively high frequency of patients with high Tg levels and negative WBS requires further investigations by using new imaging modalities. The availability of whole body positron emission tomography (PET) methods, in parallel with the advances in radiochemistry, offer a wide substrate for many solutions. To this day ¹⁸F-fluoro-deoxy-glucose (¹⁸F-FDG) PET/CT still represents the imaging of choice in follow-up of patients with high serum Tg and negative ¹³¹I-WBS but in the last decades the research has focused on finding "second generation" radiopharmaceuticals for PET imaging, with both diagnostic and prognostic purposes, aiming to change the way to image thyroid cancer. Moreover, the use of various PET radiopharmaceuticals, that offer the possibility to explore different pathways involved in thyroid cancer, could find important applications in the near future for clinical decision making in order to program tailored treatments and follow-up. It would be desirable to use the same radiopharmaceutical for both imaging and dosimetric purpose to achieve a tailored therapy. Many efforts are focused in this direction and ¹²⁴I-PET/CT is now emerging as a valid tool in restaging and therapy management of DTC with promising results. Although the preliminary data available in literature require a confirmation in larger studies with longer follow-up, we think that in next future ¹²⁴I-PET/CT could gain an important role for management of DTC. The aim of this review was to perform a systematic analysis of literature describing the state of art of "second generation" PET-radiopharmaceuticals for imaging DTC. Discussion is focused on the utility of

  20. A simple liquid detector for radiopharmaceutical processing systems

    SciTech Connect

    Alexoff, D.L.; Hallaba, K.; Schlyer, D.; Ferrieri, R.

    1995-03-01

    Sensing the presence of liquids in tubing and vessels in radiochemical processing equipment provides information important to the remote or automatic control of the production of clinical doses of radiopharmaceuticals. Although modern commercial automated radiopharmaceutical synthesis machines do not usually include liquid presence as a measured process variable, earlier more complex automated synthesis devices did; and the inclusion of such feedback can increase system reliability and simplify trouble-shooting tasks carried out by computer software or human operators. Commercial liquid level detectors are often designed for large-scale industrial processes and are therefore too large or expensive to be useful in many radiochemical hardware systems. An inexpensive miniature optical liquid detector originally by Kramer and Fuchs has been duplicated here for use in monitoring the presence of liquids in teflon tubing (1/16 in. O.D.) in an enriched oxygen-18 water recovery system.

  1. [Computer simulated images of radiopharmaceutical distributions in anthropomorphic phantoms

    SciTech Connect

    Not Available

    1991-05-17

    We have constructed an anatomically correct human geometry, which can be used to store radioisotope concentrations in 51 various internal organs. Each organ is associated with an index number which references to its attenuating characteristics (composition and density). The initial development of Computer Simulated Images of Radiopharmaceuticals in Anthropomorphic Phantoms (CSIRDAP) over the first 3 years has been very successful. All components of the simulation have been coded, made operational and debugged.

  2. 68Ga-Based radiopharmaceuticals: production and application relationship.

    PubMed

    Velikyan, Irina

    2015-07-16

    The contribution of 68Ga to the promotion and expansion of clinical research and routine positron emission tomography (PET) for earlier better diagnostics and individualized medicine is considerable. The potential applications of 68Ga-comprising imaging agents include targeted, pre-targeted and non-targeted imaging. This review discusses the key aspects of the production of 68Ga and 68Ga-based radiopharmaceuticals in the light of the impact of regulatory requirements and endpoint pre-clinical and clinical applications.

  3. ORGAN DOSES AND EFFECTIVE DOSE FOR FIVE PET RADIOPHARMACEUTICALS.

    PubMed

    Andersson, Martin; Johansson, Lennart; Mattsson, Sören; Minarik, David; Leide-Svegborn, Sigrid

    2016-06-01

    Diagnostic investigations with positron-emitting radiopharmaceuticals are dominated by (18)F-fluorodeoxyglucose ((18)F-FDG), but other radiopharmaceuticals are also commercially available or under development. Five of them, which are all clinically important, are (18)F-fluoride, (18)F-fluoroethyltyrosine ((18)F-FET), (18)F-deoxyfluorothymidine ((18)F-FLT), (18)F-fluorocholine ((18)F-choline) and (11)C-raclopride. To estimate the potential risk of stochastic effects (mainly lethal cancer) to a population, organ doses and effective dose values were updated for all five radiopharmaceuticals. Dose calculations were performed using the computer program IDAC2.0, which bases its calculations on the ICRP/ICRU adult reference voxel phantoms and the tissue weighting factors from ICRP publication 103. The biokinetic models were taken from ICRP publication 128. For organ doses, there are substantial changes. The only significant change in effective dose compared with previous estimations was a 46 % reduction for (18)F-fluoride. The estimated effective dose in mSv MBq(-1) was 1.5E-02 for (18)F-FET, 1.5E-02 for (18)F-FLT, 2.0E-02 for (18)F-choline, 9.0E-03 for (18)F-fluoride and 4.4E-03 for (11)C-raclopride.

  4. Radionuclides, radiotracers and radiopharmaceuticals for in vivo diagnosis

    NASA Astrophysics Data System (ADS)

    Wiebe, Leonard I.

    Radioactive tracers for in vivo clinical diagnosis fall within a narrow, strictly-defined set of specifications in respect of their physical properties, chemical and biochemical characteristics, and (approved) medical applications. The type of radioactive decay and physical half-life of the radionuclide are immutable properties which, along with the demands of production and supply, limit the choice of radionuclides used in medicine to only a small fraction of those known to exist. In use, the biochemical and physiological properties of a radiotracer are dictated by the chemical form of the radionuclide. This chemical form may range from elemental, molecular or ionic, to complex compounds formed by coordinate or covalent bonding of the radionuclide to either simple organic or inorganic molecules, or complex macromolecules. Few of the radiotracers which are tested in model systems ever become radiopharmaceuticals in the strictest sense. Radionuclides, radiotracers and radiopharmaceuticals in use are reviewed. Drug legislation and regulations concerning drug manufacture, as well as hospital ethical constraints and legislation concerning unsealed sources of radiation must all be satisfied in order to translate a radiopharmaceutical from the laboratory to clinical use.

  5. 18F-Labeled Silicon-Based Fluoride Acceptors: Potential Opportunities for Novel Positron Emitting Radiopharmaceuticals

    PubMed Central

    Bernard-Gauthier, Vadim; Wängler, Carmen; Wängler, Bjoern; Schirrmacher, Ralf

    2014-01-01

    Background. Over the recent years, radiopharmaceutical chemistry has experienced a wide variety of innovative pushes towards finding both novel and unconventional radiochemical methods to introduce fluorine-18 into radiotracers for positron emission tomography (PET). These “nonclassical” labeling methodologies based on silicon-, boron-, and aluminium-18F chemistry deviate from commonplace bonding of an [18F]fluorine atom (18F) to either an aliphatic or aromatic carbon atom. One method in particular, the silicon-fluoride-acceptor isotopic exchange (SiFA-IE) approach, invalidates a dogma in radiochemistry that has been widely accepted for many years: the inability to obtain radiopharmaceuticals of high specific activity (SA) via simple IE. Methodology. The most advantageous feature of IE labeling in general is that labeling precursor and labeled radiotracer are chemically identical, eliminating the need to separate the radiotracer from its precursor. SiFA-IE chemistry proceeds in dipolar aprotic solvents at room temperature and below, entirely avoiding the formation of radioactive side products during the IE. Scope of Review. A great plethora of different SiFA species have been reported in the literature ranging from small prosthetic groups and other compounds of low molecular weight to labeled peptides and most recently affibody molecules. Conclusions. The literature over the last years (from 2006 to 2014) shows unambiguously that SiFA-IE and other silicon-based fluoride acceptor strategies relying on 18F− leaving group substitutions have the potential to become a valuable addition to radiochemistry. PMID:25157357

  6. Radiopharmaceutical preparation in-house vs. central radiopharmacy: a make/buy decision.

    PubMed

    Cope, R H

    1987-03-01

    Under DRG reimbursement it is essential that all operational costs be considered as targets for reduction. In this article, the author presents a methodology for determining whether to prepare radiopharmaceuticals in house or purchase them from a central radiopharmacy. By using this methodology, purchasing agents may find it possible to save up to 50% of the cost of radiopharmaceuticals.

  7. Molecular Engineering of Technetium and Rhenium Based Radiopharmaceuticals

    SciTech Connect

    Zubieta, J.

    2003-06-30

    The research was based on the observation that despite the extraordinarily rich coordination chemistry of technetium and rhenium and several notable successes in reagent design, the extensive investigations by numerous research groups on a variety of N{sub 2}S{sub 2} and N{sub 3}S donor type ligands and on HYNIC have revealed that the chemistries of these ligands with Tc and Re are rather complex, giving rise to considerable difficulties in the development of reliable procedures for the development of radiopharmaceutical reagents.

  8. A Peltier thermal cycling unit for radiopharmaceutical synthesis.

    PubMed

    McKinney, C J; Nader, M W

    2001-01-01

    We have investigated the use of Peltier devices to rapidly cycle the temperature of reaction vessels in a radiopharmaceutical synthesis system. Peltier devices have the advantage that they can be actively cooled as well as heated, allowing precise and rapid control of vessel temperatures. Reaction vessel temperatures of between -6 degrees C and 110 degrees C have been obtained with commercially available devices with reasonable cycle times. Two devices have been used as the basis for a general purpose, two-pot synthesis system for production of [11C] compounds such as raclopride.

  9. A comparison of radiopharmaceutical agents used for the diagnosis of pulmonary embolism.

    PubMed

    Rizzo-Padoin, N; Farina, A; Le Pen, C; Duet, M; Mundler, O; Leverge, R

    2001-04-01

    Radioactive gas or technetium-99m aerosols are used to perform pulmonary ventilation scintigraphy. The aim of this study was to compare three radiopharmaceuticals, Kryptoscan, Technegas and Venticis II, in terms of their costs and user preferences rather than on the basis of diagnostic efficacy. For each radiopharmaceutical agent, an analysis questionnaire was sent to nuclear medicine departments setting out the criteria (and subcriteria) to be assessed: diagnosis quality: imaging quality, distribution homogeneity, examination procedures and capacity to examine particular patients (e.g. smokers); safety: for patient, paramedical and medical staff and the environment; use: availability in cases of emergency, ergonomics of the apparatus, simplicity and time of preparation. A score, ranging from 0 to 5, and a weighting (importance of one criterion with regard to the others) were assigned to each criterion. The direct cost of a ventilation (drugs, generator systems, disposable materials) was calculated for each radiopharmaceutical agent according to the number of patients examined per day (1-6) and the number of examination days per week (2-5). Fourteen questionnaires concerning at least two of the products were returned out of the 30 mailed. A 'preference score' was calculated using Pharma Decision software. The mean score of Kryptoscan was significantly higher than that of Venticis II (444 vs. 286, P < 0.001) and higher than the mean score of Technegas (444 vs. 344, P < 0.01). For Venticis II and Technegas, the changes in patient direct costs were minor and depended on the number of patients per day and the number of examination days per week. Respectively, they were: $US 117.66 (5 patients.day-1; 5 days.week-1) to $US 147.74 (2 patients.day-1; 2 days.week-1) and $US 56.60 (6 patients.day-1; 5 days.week-1) to $US 132.08 (2 patients.day-1; 2 days.week-1). The direct cost of ventilation using Kryptoscan varied only according to the number of patients examined per day

  10. Enantiopure bifunctional chelators for copper radiopharmaceuticals--does chirality matter in radiotracer design?

    PubMed

    Singh, Ajay N; Dakanali, Marianna; Hao, Guiyang; Ramezani, Saleh; Kumar, Amit; Sun, Xiankai

    2014-06-10

    It is well recognized that carbon chirality plays a critical role in the design of drug molecules. However, very little information is available regarding the effect of stereoisomerism of macrocyclic bifunctional chelators (BFC) on biological behaviors of the corresponding radiopharmaceuticals. To evaluate such effects, three enantiopure stereoisomers of a copper radiopharmaceutical BFC bearing two chiral carbon atoms were synthesized in forms of R,R-, S,S-, and R,S-. Their corresponding peptide conjugates were prepared by coupling with a model peptide sequence, c(RGDyK), which targets the αvβ3 integrin for in vitro and in vivo evaluation of their biological behaviors as compared to the racemic conjugate. Despite the chirality differences, all the conjugates showed a similar in vitro binding affinity profile to the αvβ3 integrin (106, 108, 85 and 100 nM for rac-H2-1, RR-H2-1, SS-H2-1, and RS-H2-1 respectively with all p values > 0.05) and a similar level of in vivo tumor uptake (2.72 ± 0.45, 2.60 ± 0.52, 2.45 ± 0.48 and 2.88 ± 0.59 for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 at 1 h p.i. respectively). Furthermore, they demonstrated a nearly identical biodistribution pattern in major organs (e.g. 2.07 ± 0.21, 2.13 ± 0.58, 1.70 ± 0.20 and 1.90 ± 0.46 %ID/g at 24 h p.i. in liver for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively; 1.80 ± 0.46, 2.30 ± 1.49, 1.73 ± 0.31 and 2.23 ± 0.71 at 24 h p.i. in kidneys for rac-(64)Cu-1, RR-(64)Cu-1, SS-(64)Cu-1, and RS-(64)Cu-1 respectively). Therefore we conclude that the chirality of BFC plays a negligible role in αvβ3-targeted copper radiopharmaceuticals. However, we believe it is still worthwhile to consider the chirality effects of BFCs on other targeted imaging or therapeutic agents.

  11. Current Status of Radiopharmaceuticals for the Theranostics of Neuroendocrine Neoplasms

    PubMed Central

    Fani, Melpomeni; Kolenc Peitl, Petra; Velikyan, Irina

    2017-01-01

    Nuclear medicine plays a pivotal role in the management of patients affected by neuroendocrine neoplasms (NENs). Radiolabeled somatostatin receptor analogs are by far the most advanced radiopharmaceuticals for diagnosis and therapy (radiotheranostics) of NENs. Their clinical success emerged receptor-targeted radiolabeled peptides as an important class of radiopharmaceuticals and it paved the way for the investigation of other radioligand-receptor systems. Besides the somatostatin receptors (sstr), other receptors have also been linked to NENs and quite a number of potential radiolabeled peptides have been derived from them. The Glucagon-Like Peptide-1 Receptor (GLP-1R) is highly expressed in benign insulinomas, the Cholecystokinin 2 (CCK2)/Gastrin receptor is expressed in different NENs, in particular medullary thyroid cancer, and the Glucose-dependent Insulinotropic Polypeptide (GIP) receptor was found to be expressed in gastrointestinal and bronchial NENs, where interestingly, it is present in most of the sstr-negative and GLP-1R-negative NENs. Also in the field of sstr targeting new discoveries brought into light an alternative approach with the use of radiolabeled somatostatin receptor antagonists, instead of the clinically used agonists. The purpose of this review is to present the current status and the most innovative strategies for the diagnosis and treatment (theranostics) of neuroendocrine neoplasms using a cadre of radiolabeled regulatory peptides targeting their receptors. PMID:28295000

  12. Cyclotron targets and production technologies used for radiopharmaceuticals in NPI

    NASA Astrophysics Data System (ADS)

    Fišer, M.; Kopička, K.; Hradilek, P.; Hanč, P.; Lebeda, O.; Pánek, J.; Vognar, M.

    2003-01-01

    This paper deals with some technical aspects of the development and production of cyclotronmade radiopharmaceuticals (excluding PET). In this field, nuclear chemistry and pharmacy are in a close contact; therefore, requirements of the both should be taken into account. The principles of cyclotron targetry, separation/recovery of materials and synthesis of active substances are given, as well as issues connected with formulation of pharmaceutical forms. As the radiopharmaceuticals should fulfil the requirements on in vivo preparations, there exist a variety of demands pertaining to Good Manufacturing Practice (GMP) concept, which is also briefly discussed. A typical production chain is presented and practical examples of real technologies based on cyclotron-made radionuclides are given as they have been used in Nuclear Physics Institute of CAS (NPI). Special attention is devoted to the technology of enriched cyclotron targets. Frequently used medicinal products employing cyclotron-produced active substances are characterised (Rb/Kr generators, 123I-labelled MIBG, OIH and MAB's). The cyclotron produced radioactive implants for transluminal coronary angioplasty (radioactive stents) are introduced as an example of a medical device developed for therapeutic application.

  13. Process for producing astatine-211 for radiopharmaceutical use

    SciTech Connect

    Mirzadeh, S.; Lambrecht, R.M.

    1987-07-21

    A one-step chemical manipulation is described in combination with a distillation and collection process for producing At-211 comprising; a. providing a target of irradiated Bismuth coated to a predetermined thickness of a backing member, b. providing a vapor-producing still operably connected with a condenser that has a water cooled condensate collector formed of a dry silica gel mesh maintained at a temperature above the freezing point of water, and providing an effluent gas filter that is operably connected to receive effluent gas from the condenser, c. heating the target in the still at a temperature in the range of about 630/sup 0/-680/sup 0/C for a time period in the range of 50 to 80 minutes, to evole At-211 vapor from the target, c. providing a dry carrier gas having an oxygen concentration that is sufficient to form Bi/sub 2/O/sub 3/ thereby to essentially preclude vaporization of Bi metal, passing the carrier gas through the still to carry the At-211 vapor to the condenser, and to carry effluent from the condenser to the effluent gas filter, e. eluting At-211 from the condensate collector of the condenser with a controlled volume of eluent containing predetermined solvents that are compatible with a given desired radiopharmaceutical procedure, and f. collecting the At-211 in the controlled volume of eluent for use in the given radiopharmaceutical procedure.

  14. Nuclear medicine and imaging research (quantitative studies in radiopharmaceutical science)

    SciTech Connect

    Cooper, M.D.; Beck, R.N.

    1990-09-01

    This is a report of progress in Year Two (January 1, 1990--December 31, 1990) of Grant FG02-86ER60438, Quantitative Studies in Radiopharmaceutical Science,'' awarded for the three-year period January 1, 1989--December 31, 1991 as a competitive renewal following site visit in the fall of 1988. This program addresses the problems involving the basic science and technology underlying the physical and conceptual tools of radioactive tracer methodology as they relate to the measurement of structural and functional parameters of physiologic importance in health and disease. The principal tool is quantitative radionuclide imaging. The overall objective of this program is to further the development and transfer of radiotracer methodology from basic theory to routine clinical practice in order that individual patients and society as a whole will receive the maximum net benefit from the new knowledge gained. The focus of the research is on the development of new instruments and radiopharmaceuticals, and the evaluation of these through the phase of clinical feasibility. 25 refs., 13 figs., 1 tab.

  15. 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

  16. Paediatric pharmacokinetics: key considerations.

    PubMed

    Batchelor, Hannah Katharine; Marriott, John Francis

    2015-03-01

    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.

  17. Peptide Based Radiopharmaceuticals: Specific Construct Approach

    SciTech Connect

    Som, P; Rhodes, B A; Sharma, S S

    1997-10-21

    The objective of this project was to develop receptor based peptides for diagnostic imaging and therapy. A series of peptides related to cell adhesion molecules (CAM) and immune regulation were designed for radiolabeling with 99mTc and evaluated in animal models as potential diagnostic imaging agents for various disease conditions such as thrombus (clot), acute kidney failure, and inflection/inflammation imaging. The peptides for this project were designed by the industrial partner, Palatin Technologies, (formerly Rhomed, Inc.) using various peptide design approaches including a newly developed rational computer assisted drug design (CADD) approach termed MIDAS (Metal ion Induced Distinctive Array of Structures). In this approach, the biological function domain and the 99mTc complexing domain are fused together so that structurally these domains are indistinguishable. This approach allows construction of conformationally rigid metallo-peptide molecules (similar to cyclic peptides) that are metabolically stable in-vivo. All the newly designed peptides were screened in various in vitro receptor binding and functional assays to identify a lead compound. The lead compounds were formulated in a one-step 99mTc labeling kit form which were studied by BNL for detailed in-vivo imaging using various animals models of human disease. Two main peptides usingMIDAS approach evolved and were investigated: RGD peptide for acute renal failure and an immunomodulatory peptide derived from tuftsin (RMT-1) for infection/inflammation imaging. Various RGD based metallopeptides were designed, synthesized and assayed for their efficacy in inhibiting ADP-induced human platelet aggregation. Most of these peptides displayed biological activity in the 1-100 µM range. Based on previous work by others, RGD-I and RGD-II were evaluated in animal models of acute renal failure. These earlier studies showed that after acute ischemic injury the renal cortex displays

  18. Risk assessment and economic impact analysis of the implementation of new European legislation on radiopharmaceuticals in Italy: the case of the new monograph chapter Compounding of Radiopharmaceuticals (PHARMEUROPA, Vol. 23, No. 4, October 2011).

    PubMed

    Chitto, Giuseppe; Di Domenico, Elvira; Gandolfo, Patrizia; Ria, Francesco; Tafuri, Chiara; Papa, Sergio

    2013-12-01

    An assessment of the new monograph chapter Compounding of Radiopharmaceuticals has been conducted on the basis of the first period of implementation of Italian legislation on Good Radiopharmaceuticals Practice (NBP) in the preparation of radiopharmaceuticals, in keeping with Decree by the Italian Ministry of Health dated March 30, 2005. This approach is well grounded in the several points of similarity between the two sets of regulations. The impact on patient risk, on staff risk, and on healthcare organization risk, has been assessed. At the same time, the actual costs of coming into compliance with regulations have been estimated. A change risk analysis has been performed through the identification of healthcare-associated risks, the analysis and measurement of the likelihood of occurrence and of the potential impact in terms of patient harm and staff harm, and the determination of the healthcare organization's controlling capability. In order to evaluate the economic impact, the expenses directly related to the implementation of the activities as per ministerial decree have been estimated after calculating the overall costs unrelated to NBP implementation. The resulting costs have then been averaged over the total number of patient services delivered. NBP implementation shows an extremely positive impact on risk management for both patients receiving Nuclear Medicine services and the healthcare organization. With regard to healthcare workers, instead, the implementation of these regulations has a negative effect on the risk for greater exposure and a positive effect on the defense against litigation. The economic impact analysis of NBP implementation shows a 34% increase in the costs for a single patient service. The implementation of the ministerial decree allows for greater detectability of and control over a number of critical elements, paving the way for risk management and minimization. We, therefore, believe that the proposed tool can provide basic

  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. (99m)Tc-zolmitriptan: radiolabeling, molecular modeling, biodistribution and gamma scintigraphy as a hopeful radiopharmaceutical for lung nuclear imaging.

    PubMed

    Rashed, H M; Marzook, F A; Farag, H

    2016-12-01

    Lung imaging radiopharmaceuticals are helpful agents for measuring pulmonary blood flow and allow detection of pulmonary embolism and lung cancer. The goal of this study was to develop a novel potential radiopharmaceutical for lung imaging. Zolmitriptan (a selective serotonin receptor agonist) was successfully labeled with (99m)Tc via direct labeling method under reductive conditions studying different factors affecting the labeling efficiency. (99m)Tc-zolmitriptan was obtained with a maximum labeling yield of 92.5 ± 0.61 % and in vitro stability up to 24 h. Molecular modeling was done to predict the structure of (99m)Tc-zolmitriptan and ensure that radiolabeling did not affect binding ability of zolmitriptan to its receptor. Biodistribution studies showed that maximum lung uptake of (99m)Tc-zolmitriptan was 23.89 ± 1.2 % injected dose/g tissue at 15 min post-injection and retention in lungs remained high up to 1 h, whereas the clearance from mice appeared to proceed mainly via the renal pathway. Scintigraphic images confirmed the biodistribution results showing a high resolution lung image with low accumulation of radioactivity in other organs except kidneys and urinary bladder. (99m)Tc-zolmitriptan is not a blood product and so it is more safe than the currently available (99m)Tc-MAA, and its lung uptake is higher than that of the recently discovered (123)I-IPMPD, (99m)Tc(CO)5I and (99m)Tc-DHPM. So, (99m)Tc-zolmitriptan could be used as a hopeful radiopharmaceutical for lung scintigraphic imaging.

  1. New selenium-75 labeled radiopharmaceuticals: selenonium analogues of dopamine

    SciTech Connect

    Sadek, S.A.; Basmadjian, G.P.; Hsu, P.M.; Rieger, J.A.

    1983-07-01

    Selenium-75 labeled selenonium analogues of dopamine, (2-(3,4-dimethoxyphenyl)ethyl)dimethylselenonium iodide and its dihydroxy analogue, were prepared by reducing (/sup 75/Se)selenious acid with sodium borohydride at pH 6.0 and reacting the NaSeH produced with 1-(3,4-dimethoxyphenyl)-2-(p-toluenesulfonyloxy)ethane. Tissue distribution studies in rats given the /sup 75/Se-labeled selenonium agents intravenously demonstrated high initial heart uptake. Prolonged adrenal retention and high adrenal to blood ratio of compound 4 were observed. The high uptake and adrenal to blood ratio suggest the potential use of compound 4 as a radiopharmaceutical for the adrenal gland.

  2. A rapid and efficient preparation of [123I]radiopharmaceuticals using a small HPLC (Rocket) column.

    PubMed

    Katsifis, Andrew; Papazian, Vahan; Jackson, Timothy; Loc'h, Christian

    2006-01-01

    A simplified method for the rapid and efficient preparation of [(123)I]radiopharmaceuticals is described. Three radiopharmaceuticals, [(123)I]beta-CIT, [(123)I]MIBG and [(123)I]clioquinol, were synthesised and purified as model compounds. The radiotracers were labelled with iodine-123 using electrophilic oxidative conditions and purified by a compact semi-preparative reverse phase column (C-18, 3 microm, 7 x 53 mm, Alltima Rocket, Alltech) using aqueous-ethanol as HPLC solvents that were directly used for radiopharmaceutical formulation. The radiochemical purity of the radioiodinated tracers as assessed by analytical HPLC was higher than 99% with specific activity higher than 3 GBq/nmol. The total preparation time of a radiotracer ranged from 40 to 60 min and, starting from 3.7 GBq of iodine-123, more than 2.5 GBq of formulated radiopharmaceuticals were available for clinical investigations.

  3. The Role of Non-Standard PET Radionuclides in the Development of New Radiopharmaceuticals

    SciTech Connect

    Avila-Rodriguez, M. A.; McQuarrie, S. A.

    2008-08-11

    This paper discusses the production methods of the most commonly used non-standard PET radionuclides, their decay characteristics and importance in the development of novel radiopharmaceuticals for PET-based molecular imaging and potential applications in therapy.

  4. 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.

  5. [Dalbavancin: pharmacokinetic and pharmacodynamic parameters].

    PubMed

    Azanza, José Ramón; Sádaba, Belén; Reis, Joana

    2017-01-01

    Dalbavancin is a new lipoglycopeptide antibiotic whose structure influences its pharmacokinetic profile. It is not absorbed after oral administration and is therefore administered intravenously. It is distributed through intracellular fluid, reaching adequate concentrations in the skin, bone, blister fluid and synovial fluid. Plasma protein binding is very high. Concentrations in brain tissue and cerebrospinal fluid (CSF) are inadequate. Excretion is through non-microsomal metabolism with inactive metabolites and through the kidneys by glomerular filtration. Dalbavancin is eliminated slowly, as shown by its clearance value and its terminal elimination half-life, which exceeds 300 hours. This means that adequate concentrations of the drug remain in plasma and tissues for a prolonged period and explains the dosing regimen: a first dose of 1g followed 7 days later by a 500mg dose. The pharmacokinetics are linear and show little intra- and interindividual variability. There are no pharmacokinetic interactions. Dose adjustment is not required for patients with mild or moderate renal insufficiency (creatinine clearance ≥ 30 to 79ml/min). Dosage adjustment is not required in patients regularly receiving elective haemodialysis (3 times/week) and the drug can be administered without consideration of haemodialysis times. In patients with chronic renal insufficiency, whose creatinine clearance is < 30ml/min and who are not regularly receiving elective haemodialysis, the recommended dose should be reduced to 750mg per week, followed 1 week later by 375mg. Dosage adjustment does not seem necessary in patients with liver failure or in older patients. There is no information on the most appropriate dosage in children. The pharmacokinetic/pharmacodynamics parameter that best describes the effectiveness of dalbavancin is the ratio between the area under the curve and the minimum inhibitory concentration.

  6. USE OF RADIOPHARMACEUTICALS IN DIAGNOSTIC NUCLEAR MEDICINE IN THE UNITED STATES: 1960–2010

    PubMed Central

    Drozdovitch, Vladimir; Brill, Aaron B.; Callahan, Ronald J.; Clanton, Jeffrey A.; DePietro, Allegra; Goldsmith, Stanley J.; Greenspan, Bennett S.; Gross, Milton D.; Hays, Marguerite T.; Moore, Stephen C.; Ponto, James A.; Shreeve, Walton W.; Melo, Dunstana R.; Linet, Martha S.; Simon, Steven L.

    2014-01-01

    To reconstruct reliable nuclear medicine-related occupational radiation doses or doses received as patients from radiopharmaceuticals over the last five decades, we assessed which radiopharmaceuticals were used in different time periods, their relative frequency of use, and typical values of the administered activity. This paper presents data on the changing patterns of clinical use of radiopharmaceuticals and documents the range of activity administered to adult patients undergoing diagnostic nuclear medicine procedures in the U.S. between 1960 and 2010. Data are presented for 15 diagnostic imaging procedures that include thyroid scan and thyroid uptake, brain scan, brain blood flow, lung perfusion and ventilation, bone, liver, hepatobiliary, bone marrow, pancreas, and kidney scans, cardiac imaging procedures, tumor localization studies, localization of gastrointestinal bleeding, and non-imaging studies of blood volume and iron metabolism. Data on the relative use of radiopharmaceuticals were collected using key informant interviews and comprehensive literature reviews of typical administered activities of these diagnostic nuclear medicine studies. Responses of key informants on relative use of radiopharmaceuticals are in agreement with published literature. Results of this study will be used for retrospective reconstruction of occupational and personal medical radiation doses from diagnostic radiopharmaceuticals to members of the U.S. radiologic technologist’s cohort and in reconstructing radiation doses from occupational or patient radiation exposures to other U.S. workers or patient populations. PMID:25811150

  7. Use of radiopharmaceuticals in diagnostic nuclear medicine in the United States: 1960-2010.

    PubMed

    Drozdovitch, Vladimir; Brill, Aaron B; Callahan, Ronald J; Clanton, Jeffrey A; DePietro, Allegra; Goldsmith, Stanley J; Greenspan, Bennett S; Gross, Milton D; Hays, Marguerite T; Moore, Stephen C; Ponto, James A; Shreeve, Walton W; Melo, Dunstana R; Linet, Martha S; Simon, Steven L

    2015-05-01

    To reconstruct reliable nuclear medicine-related occupational radiation doses or doses received as patients from radiopharmaceuticals over the last five decades, the authors assessed which radiopharmaceuticals were used in different time periods, their relative frequency of use, and typical values of the administered activity. This paper presents data on the changing patterns of clinical use of radiopharmaceuticals and documents the range of activity administered to adult patients undergoing diagnostic nuclear medicine procedures in the U.S. between 1960 and 2010. Data are presented for 15 diagnostic imaging procedures that include thyroid scan and thyroid uptake; brain scan; brain blood flow; lung perfusion and ventilation; bone, liver, hepatobiliary, bone marrow, pancreas, and kidney scans; cardiac imaging procedures; tumor localization studies; localization of gastrointestinal bleeding; and non-imaging studies of blood volume and iron metabolism. Data on the relative use of radiopharmaceuticals were collected using key informant interviews and comprehensive literature reviews of typical administered activities of these diagnostic nuclear medicine studies. Responses of key informants on relative use of radiopharmaceuticals are in agreement with published literature. Results of this study will be used for retrospective reconstruction of occupational and personal medical radiation doses from diagnostic radiopharmaceuticals to members of the U.S. radiologic technologists' cohort and in reconstructing radiation doses from occupational or patient radiation exposures to other U.S. workers or patient populations.

  8. 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)...

  9. Preclinical acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]fluorocholine in mice.

    PubMed

    Silveira, Marina B; Ferreira, Soraya M Z M D; Nascimento, Leonardo T C; Costa, Flávia M; Mendes, Bruno M; Ferreira, Andrea V; Malamut, Carlos; Silva, Juliana B; Mamede, Marcelo

    2016-10-01

    [(18)F]Fluorocholine ([(18)F]FCH) has been proven to be effective in prostate cancer. Since [(18)F]FCH is classified as a new radiopharmaceutical in Brazil, preclinical safety and efficacy data are required to support clinical trials and to obtain its approval. The aim of this work was to perform acute toxicity, biodistribution, pharmacokinetics, radiation dosimetry and microPET imaging studies of [(18)F]FCH. The results could support its use in nuclear medicine as an important piece of work for regulatory in Brazil.

  10. AUTOMATION FOR THE SYNTHESIS AND APPLICATION OF PET RADIOPHARMACEUTICALS.

    SciTech Connect

    Alexoff, D.L.

    2001-09-21

    The development of automated systems supporting the production and application of PET radiopharmaceuticals has been an important focus of researchers since the first successes of using carbon-11 (Comar et al., 1979) and fluorine-18 (Reivich et al., 1979) labeled compounds to visualize functional activity of the human brain. These initial successes of imaging the human brain soon led to applications in the human heart (Schelbert et al., 1980), and quickly radiochemists began to see the importance of automation to support PET studies in humans (Lambrecht, 1982; Langstrom et al., 1983). Driven by the necessity of controlling processes emanating high fluxes of 511 KeV photons, and by the tedium of repetitive syntheses for carrying out these human PET investigations, academic and government scientists have designed, developed and tested many useful and novel automated systems in the past twenty years. These systems, originally designed primarily by radiochemists, not only carry out effectively the tasks they were designed for, but also demonstrate significant engineering innovation in the field of laboratory automation.

  11. Synthesis and biological studies of positron-emitting radiopharmaceuticals

    SciTech Connect

    Dischino, D.D.

    1983-01-01

    The development and clinical evaluation of two-positron emitting radiopharmaceuticals designed to image myelin in humans is reported. Carbon-11-labeled benzyl methyl ether was synthesized by the reaction of carbon-11-labeled methanol and benzyl chloride in dimethyl sulfoxide containing powdered potassium hydroxide in a radiochemical yield of 43% and a synthesis and purification time of 40 minutes. Carbon-11-labeled diphenylmethanol was synthesized by the reaction of carbon-11-labeled carbon dioxide and phenyllithium followed by the reduction of the carbon-11-labeled intermediate to diphenylmethanol via lithium aluminum hydride in a radiochemical yield of 71% and a synthesis and purification time of 38 minutes. Carbon-11-labeled benzyl methyl ether and diphenylmethanol were each evaluated as myelin imaging agents in three patients with multiple sclerosis via positron-emission tomography. In two out of three patients studied with carbon-11-labeled benzyl methyl ether, the distribution of activity in the brain was not consistent with local lipid content. A new synthesis of carbon-11-labeled-DL-phenylalanine labeled in the benzylic position and the synthesis of fluorine-18-labeled 1-(2-nitro-1-imidazolyl)-3-fluoro-2-propanol, a potential in vivo marker of hypoxic tissue, are reported.

  12. New SPECT and PET Radiopharmaceuticals for Imaging Cardiovascular Disease

    PubMed Central

    Sogbein, Oyebola O.; Pelletier-Galarneau, Matthieu; Schindler, Thomas H.; Wei, Lihui; Wells, R. Glenn; Ruddy, Terrence D.

    2014-01-01

    Nuclear cardiology has experienced exponential growth within the past four decades with converging capacity to diagnose and influence management of a variety of cardiovascular diseases. Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) with technetium-99m radiotracers or thallium-201 has dominated the field; however new hardware and software designs that optimize image quality with reduced radiation exposure are fuelling a resurgence of interest at the preclinical and clinical levels to expand beyond MPI. Other imaging modalities including positron emission tomography (PET) and magnetic resonance imaging (MRI) continue to emerge as powerful players with an expanded capacity to diagnose a variety of cardiac conditions. At the forefront of this resurgence is the development of novel target vectors based on an enhanced understanding of the underlying pathophysiological process in the subcellular domain. Molecular imaging with novel radiopharmaceuticals engineered to target a specific subcellular process has the capacity to improve diagnostic accuracy and deliver enhanced prognostic information to alter management. This paper, while not comprehensive, will review the recent advancements in radiotracer development for SPECT and PET MPI, autonomic dysfunction, apoptosis, atherosclerotic plaques, metabolism, and viability. The relevant radiochemistry and preclinical and clinical development in addition to molecular imaging with emerging modalities such as cardiac MRI and PET-MR will be discussed. PMID:24901002

  13. "The Show"

    ERIC Educational Resources Information Center

    Gehring, John

    2004-01-01

    For the past 16 years, the blue-collar city of Huntington, West Virginia, has rolled out the red carpet to welcome young wrestlers and their families as old friends. They have come to town chasing the same dream for a spot in what many of them call "The Show". For three days, under the lights of an arena packed with 5,000 fans, the…

  14. Intelligent portal monitor for fast suppression of false positives due to radiopharmaceuticals

    SciTech Connect

    Johnson, M.W.; Butterfield, K.B.

    1985-01-01

    Monitoring the movement of radioactive material through secure or sensitive areas may be complicated by the existence of unanticipated sources of radiation carried by individuals passing through the area. Typical of such sources are radiopharmaceuticals prescribed for a medical procedure. We report here on an apparatus designed to quickly discriminate between in-vivo radiopharmaceuticals and other nuclear materials, based on a pattern-recognition algorithm and a microcomputer. Principles of operation are discussed, and the data base for the pattern-recognition algorithm is displayed. Operating experience with the apparatus in a trial location is also discussed. Our apparatus correctly identifies in-vivo radiopharmaceuticals in over 80% of all trials; challenges with radioisotopes other than radiopharmaceuticals have led the apparatus, without exception, to reject the challenge isotope as incompatible with medical practice. The apparatus thus rapidly discriminates between individuals bearing radiopharmaceuticals and those bearing illicit sources, such as special nuclear materials. Examples of applications are presented. 7 refs., 4 figs., 1 tab.

  15. SYMBOLS IN PHARMACOKINETICS1

    PubMed Central

    Rowland, Malcolm; Tucker, Geoffrey

    1982-01-01

    To encourage uniformity in the presentation of pharmacokinetic data, a general nomenclature has been developed. The system has wide application. Flexibility is achieved through the use of general variables, constants, qualifying terms and subscripts. Yet, through the use of implied terms, the symbols describing many common variables and constants are simple.

  16. Lumping in pharmacokinetics.

    PubMed

    Brochot, Céline; Tóth, János; Bois, Frédéric Y

    2005-12-01

    Pharmacokinetic (PK) models simplify biological complexity by dividing the body into interconnected compartments. The time course of the chemical's amount (or concentration) in each compartment is then expressed as a system of ordinary differential equations. The complexity of the resulting system of equations can rapidly increase if a precise description of the organism is needed. However, difficulties arise when the PK model contains more variables and parameters than comfortable for mathematical and computational treatment. To overcome such difficulties, mathematical lumping methods are new and powerful tools. Such methods aim at reducing a differential system by aggregating several variables into one. Typically, the lumped model is still a differential equation system, whose variables are interpretable in terms of variables of the original system. In practice, the reduced model is usually required to satisfy some constraints. For example, it may be necessary to keep state variables of interest for prediction unlumped. To accommodate such constraints, constrained lumping methods have are also available. After presenting the theory, we study, here, through practical examples, the potential of such methods in toxico/pharmacokinetics. As a tutorial, we first simplify a 2-compartment pharmacokinetic model by symbolic lumping. We then explore the reduction of a 6-compartment physiologically based pharmacokinetic model for 1,3-butadiene with numerical constrained lumping. The lumping methods presented here can be easily automated, and are applicable to first-order ordinary differential equation systems.

  17. 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

  18. Hepatic extraction fraction of hepatobiliary radiopharmaceuticals measured using spectral analysis.

    PubMed

    Murase, K; Tsuda, T; Mochizuki, T; Ikezoe, J

    1999-11-01

    Measuring the hepatic extraction fraction (HEF) of a hepatobiliary radiopharmaceutical helps to differentiate hepatocyte from biliary tract diseases, and it is generally performed using deconvolution analysis. In this study, we measured HEF using spectral analysis. With spectral analysis, HEF was calculated from (the sum of the spectral data obtained by spectral analysis--the highest frequency component of the spectrum) divided by (the sum of the spectral data) x 100 (%). We applied this method to dynamic liver scintigraphic data obtained from six healthy volunteers and from 46 patients with various liver diseases, using 99Tcm-N-pyridoxyl-5-methyltryptophan (PMT). We also measured HEF using deconvolution analysis, in which the modified Fourier transform technique was employed. The HEF values obtained by spectral analysis correlated closely with those obtained by deconvolution analysis (r = 0.925), suggesting our method is valid. The HEF values obtained by spectral analysis decreased as the severity of liver disease progressed. The values were 100.0 +/- 0.0%, 94.7 +/- 13.6%, 76.2 +/- 27.4%, 45.7 +/- 15.6%, 82.7 +/- 24.2% and 95.2 +/- 11.8% (mean +/- S.D.) for the normal controls (n = 6), mild liver cirrhosis (n = 16), moderate liver cirrhosis (n = 11), severe liver cirrhosis (n = 5), acute hepatitis (n = 8) and chronic hepatitis groups (n = 6), respectively. The HEF was obtained more simply and rapidly by spectral analysis than by deconvolution analysis. The results suggest that our method using spectral analysis can be used as an alternative to the conventional procedure using deconvolution analysis for measuring HEF.

  19. DOPASCAN Injection ([{sup 123}I]{beta}-CIT): A radiopharmaceutical with potential for the diagnosis of Parkinson's disease

    SciTech Connect

    Nowotnik, D. P.

    1999-06-10

    In conjunction with single photon emission computerized tomography (SPECT), the radiopharmaceutical [{sup 123}I]{beta}-CIT (DOPASCAN Injection) has demonstrated significant potential for the early diagnosis and monitoring of Parkinson's Disease. Well over 2000 patients worldwide have been studied with this product, which has completed phase II clinical studies. This review summarizes the development and clinical application of this new radiopharmaceutical product.

  20. Biokinetics and dosimetry of target-specific radiopharmaceuticals for molecular imaging and therapy

    NASA Astrophysics Data System (ADS)

    Ferro-Flores, Guillermina; Torres-García, Eugenio; Gonz&Ález-v&Ázquez, Armando; de Murphy, Consuelo Arteaga

    Molecular imaging techniques directly or indirectly monitor and record the spatiotemporal distribution of molecular or cellular processes for biochemical, biologic, diagnostic or therapeutic applications. 99mTc-HYNIC-TOC has shown high stability both in vitro and in vivo and rapid detection of somatostatin receptor-positive tumors. Therapies using radiolabeled anti-CD20 have demonstrated their efficacy in patients with B-cell non-Hodgkin's lymphoma (NHL). The aim of this study was to establish biokinetic models for 99mTc-HYNIC-TOC and 188Re-anti-CD20 and to evaluate their dosimetry as target-specific radiopharmaceuticals. The OLINDA/EXM code was used to calculate patient-specific internal radiation dose estimates. 99mTc-HYNIC-TOC images showed an average tumor/blood ratio of 4.3±0.7 in receptor-positive tumors with an average effective dose of 4.4 mSv. Dosimetric studies indicated that after administration of 5.8 to 7.5 GBq of 188Re-anti-CD20 the absorbed dose to total body would be 0.75 Gy which corresponds to the recommended dose for NHL therapies.

  1. Diagnostic and therapeutic potential of new radiopharmaceutical agents in medullary thyroid carcinoma

    SciTech Connect

    Troncone, L.; Rufini, V.; De Rosa, G.; Testa, A.

    1989-01-01

    Recently developed radiopharmaceuticals have been proposed for imaging medullary thyroid carcinoma (MTC) with some having therapeutic potential. This study compares the imaging results obtained with radioiodinated meta-iodo-benzylguanidine (MIBG), {sup 99m}Tc (V) DMSA, and {sup 131}I F(ab')2 anti-carcinoembryonic antigen (anti-CEA) in a group of MTC patients. In 23 patients {sup 131}I MIBG imaging showed a high specificity (no false-positive results) but a less satisfactory sensitivity (50%). In 12 patients {sup 99m}Tc (V) DMSA revealed a better sensitivity (77%) but a lower specificity (three false-positive results). Positive results were obtained in two of three patients studied with {sup 131}I F(ab')2 anti-CEA. These data suggest that the highly sensitive {sup 99m}Tc (V) DMSA should be considered as a first choice procedure followed by the highly specific radioiodinated MIBG to confirm the initial results. Since radioiodinated MIBG imaging may have therapeutic usefulness, {sup 131}I MIBG was evaluated in an integrated treatment protocol in four cases of proven MTC. The preliminary results obtained were encouraging.

  2. Radiopharmaceuticals for diagnosis. [Final] report, 1 January 1991--31 December 1993

    SciTech Connect

    Kuhl, D.E.

    1993-06-01

    Since 1987, this grant has supported the development of new radiochemical methods for use with short-lived, positron-emitting radionuclides; new laboratory techniques for radiochemical syntheses; and development of new radiopharmaceuticals which will be of use in Positron Emission Tomography. For the period 1 January 1991 to 31 December 1993, the authors have continued their efforts in all of these areas, as they feel that an integrated approach to the synthesis and characterization of new PET Radiopharmaceuticals is crucial to the continued growth and application of this imaging technique in modern medicine. Progress in a number of these areas is described in this report.

  3. Some statistical issues in modelling pharmacokinetic data.

    PubMed

    Lindsey, J K; Jones, B; Jarvis, P

    A fundamental assumption underlying pharmacokinetic compartment modelling is that each subject has a different individual curve. To some extent this runs counter to the statistical principle that similar individuals will have similar curves, thus making inferences to a wider population possible. In population pharmacokinetics, the compromise is to use random effects. We recommend that such models also be used in data rich situations instead of independently fitting individual curves. However, the additional information available in such studies shows that random effects are often not sufficient; generally, an autoregressive process is also required. This has the added advantage that it provides a means of tracking each individual, yielding predictions for the next observation. The compartment model curve being fitted may also be distorted in other ways. A widely held assumption is that most, if not all, pharmacokinetic concentration data follow a log-normal distribution. By examples, we show that this is not generally true, with the gamma distribution often being more suitable. When extreme individuals are present, a heavy-tailed distribution, such as the log Cauchy, can often provide more robust results. Finally, other assumptions that can distort the results include a direct dependence of the variance, or other dispersion parameter, on the mean and setting non-detectable values to some arbitrarily small value instead of treating them as censored. By pointing out these problems with standard methods of statistical modelling of pharmacokinetic data, we hope that commercial software will soon make more flexible and suitable models available.

  4. Grepafloxacin: pharmacokinetics and tissue penetration.

    PubMed

    Wise, Richard

    1998-03-01

    Pharmacokinetic and tissue penetration studies of grepafloxacin, a new broad-spectrum fluoroquinolone, show that it has useful properties for the treatment of respiratory tract infections. Grepafloxacin has a volume of distribution that is larger than those of many of the other fluoroquinolones and is concentrated in alveolar macrophages, bronchial mucosa and epithelial lining fluid to a greater extent than are certain other fluoroquinolones. Grepafloxacin concentrations achieved in plasma after a 400-mg oral dose are well in excess of those required to inhibit the respiratory pathogens Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis. Streptococcus pneumoniae is also covered for most of the dosing interval, but at normal dose levels grepafloxacin might not inhibit Enterococcus faecalis. The maximum plasma concentrations and area under the concentration---time curve achieved with grepafloxacin suggest that it will be effective for the treatment of community-acquired pneumonia and acute exacerbations of chronic bronchitis. The pharmacokinetics of fluoroquinolones are among their most useful properties. The aim of this paper is to demonstrate whether the differences between grepafloxacin and the other fluoroquinolones are of therapeutic significance.

  5. 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.

  6. Antifungal pharmacokinetics and pharmacodynamics.

    PubMed

    Lepak, Alexander J; Andes, David R

    2014-11-10

    Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including penetration into infection site, pathogen susceptibility, optimal route of drug administration, drug dose, frequency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) studies consider these variables and have been useful in drug development, optimizing dosing regimens, determining susceptibility breakpoints, and limiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studies are reviewed, with emphasis on methodology and application. The initial sections of this review focus on principles and methodology. Then the pharmacodynamics of each major antifungal drug class (polyenes, flucytosine, azoles, and echinocandins) is discussed. Finally, the review discusses novel areas of pharmacodynamic investigation in the study and application of combination therapy.

  7. Population pharmacokinetics of exenatide

    PubMed Central

    Mager, Donald E.

    2016-01-01

    Aim The aim of the present analysis was to develop a core population pharmacokinetic model for the pharmacokinetic properties of immediate‐release (IR) exenatide, which can be used in subsequent analyses of novel sustained‐release formulations. Methods Data from eight clinical trials, evaluating a wide range of doses and different administration routes, were available for analysis. All modelling and simulations were conducted using the nonlinear mixed‐effect modelling program NONMEM. External model validation was performed using data from the phase III clinical trials programme through standard visual predictive checks. Results The pharmacokinetics of IR exenatide was described by a two‐compartment model, and the absorption of subcutaneous exenatide was described with a sequential zero‐order rate constant followed by a saturable nonlinear absorption process. Drug elimination was characterized by two parallel routes (linear and nonlinear), with significant relationships between renal function and the linear elimination route, and between body weight and volume of distribution. For a subject with normal renal function, the linear clearance was estimated to be 5.06 l hr−1. The nonlinear elimination was quantified with a Michaelis–Menten constant (K m) of 567 pg ml−1 and a maximum rate of metabolism (V max) of 1.6 μg h−1. For subcutaneous administration, 37% of the subcutaneous dose is absorbed via the zero‐order process, and the remaining 63% via the nonlinear pathway. Conclusions The present analysis provides a comprehensive population pharmacokinetic model for exenatide, expanding the elimination process to include both linear and nonlinear components, providing a suitable platform for a broad range of concentrations and patient conditions that can be leveraged in future modelling efforts of sustained‐release exenatide formulations. PMID:27650681

  8. Lutetium-177 DOTATATE Production with an Automated Radiopharmaceutical Synthesis System

    PubMed Central

    Aslani, Alireza; Snowdon, Graeme M; Bailey, Dale L; Schembri, Geoffrey P; Bailey, Elizabeth A; Pavlakis, Nick; Roach, Paul J

    2015-01-01

    Objective(s): Peptide Receptor Radionuclide Therapy (PRRT) with yttrium-90 (90Y) and lutetium-177 (177Lu)-labelled SST analogues are now therapy option for patients who have failed to respond to conventional medical therapy. In-house production with automated PRRT synthesis systems have clear advantages over manual methods resulting in increasing use in hospital-based radiopharmacies. We report on our one year experience with an automated radiopharmaceutical synthesis system. Methods: All syntheses were carried out using the Eckert & Ziegler Eurotope’s Modular-Lab Pharm Tracer® automated synthesis system. All materials and methods used were followed as instructed by the manufacturer of the system (Eckert & Ziegler Eurotope, Berlin, Germany). Sterile, GMP-certified, no-carrier added (NCA) 177Lu was used with GMP-certified peptide. An audit trail was also produced and saved by the system. The quality of the final product was assessed after each synthesis by ITLC-SG and HPLC methods. Results: A total of 17 [177Lu]-DOTATATE syntheses were performed between August 2013 and December 2014. The amount of radioactive [177Lu]-DOTATATE produced by each synthesis varied between 10-40 GBq and was dependant on the number of patients being treated on a given day. Thirteen individuals received a total of 37 individual treatment administrations in this period. There were no issues and failures with the system or the synthesis cassettes. The average radiochemical purity as determined by ITLC was above 99% (99.8 ± 0.05%) and the average radiochemical purity as determined by HPLC technique was above 97% (97.3 ± 1.5%) for this period. Conclusions: The automated synthesis of [177Lu]-DOTATATE using Eckert & Ziegler Eurotope’s Modular-Lab Pharm Tracer® system is a robust, convenient and high yield approach to the radiolabelling of DOTATATE peptide benefiting from the use of NCA 177Lu and almost negligible radiation exposure of the operators. PMID:27408890

  9. 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

  10. Ofloxacin pharmacokinetics in mechanically ventilated patients.

    PubMed Central

    Martin, C; Lambert, D; Bruguerolle, B; Saux, P; Freney, J; Fleurette, J; Meugnier, H; Gouin, F

    1991-01-01

    The pharmacokinetics of ofloxacin were studied in 12 intensive care patients, 6 of whom were under controlled mechanical ventilation. All patients had a creatinine clearance of greater than 80 ml/min per 1.73 m2. They were given 3 mg of ofloxacin per kg of body weight intravenously at a constant flow rate in 30 min twice a day for 7 days. Pharmacokinetic studies were performed on days 1 and 7. Between days 1 and 7, significant increases in the alpha (distribution) and beta (elimination) phase half-lives, the area under the serum concentration-time curve, and peak and trough levels in serum were observed, together with a marked decrease (greater than 50%) in total body clearance. Possible contributing factors for alteration of ofloxacin pharmacokinetics in ventilated patients were patient age, liver dysfunction, drug interaction, and drug accumulation in a deep compartment. This study shows that in intensive care patients the pharmacokinetics of ofloxacin differ from those reported for healthy volunteers. PMID:1929329

  11. [Delta-9-tetrahydrocannabinol pharmacokinetics].

    PubMed

    Goullé, J-P; Saussereau, E; Lacroix, C

    2008-08-01

    Delta-9-tetrahydrocannabinol (Delta-9-THC) is the main psychoactive ingredient of cannabis. Smoking is currently most common use of cannabis. The present review focuses on the pharmacokinetics of THC. The variability of THC in plant material which has significantly increased in recent years leads to variability in tissue THC levels from smoking, which is, in itself, a highly individual process. This variability of THC content has an important impact on drug pharmacokinetics and pharmacology. After smoking THC bioavailability averages 30%. With a 3.55% THC cigarette, a peak plasma level near 160 ng/mL occurs approximately 10 min after inhalation. THC is eliminated quickly from plasma in a multiphasic manner and is widely distributed to tissues, which is responsible for its pharmacologic effects. Body fat then serves as a long-term storage site. This particular pharmacokinetics explains the noncorrelation between THC blood level and clinical effects as is observed for ethanol. A major active 11-hydroxy metabolite is formed after both inhalation and oral dosing (20 and 100% of parent, respectively). The elimination of THC and its many metabolites, mainly THC-COOH, occurs via the feces and urine for several weeks. Thus, to confirm abstinence, urine THC-COOH analysis would be a useful tool. A positive result could be checked by gas chromatography-mass spectrometry THC blood analysis, indicative of a recent cannabis exposure.

  12. Pharmacokinetics of grepafloxacin.

    PubMed

    Efthymiopoulos, C

    1997-12-01

    Grepafloxacin is a fluoroquinolone antibiotic which is rapidly absorbed in healthy volunteers following oral dosing. It reaches peak plasma levels around 2 h after administration, then declines bi-exponentially, with an extended half-life of around 12 h. Grepafloxacin is eliminated primarily through metabolism and is excreted mainly in the faeces. Renal clearance accounts for only 10-15% of the administered dose. Grepafloxacin plasma concentrations increase disproportionately with increasing doses, but this is unlikely to be of clinical significance over the range of therapeutic doses. The rate and extent of absorption are not affected by food or elevated intragastric pH. The pharmacokinetics of grepafloxacin are affected by gender, with these differences relating to variations in body weight. No effect of age on the pharmacokinetics of grepafloxacin was found. Renal impairment does not affect grepafloxacin pharmacokinetics, whereas peak plasma concentrations, areas under plasma concentration-time curves and renal excretion are increased in patients with hepatic impairment. Grepafloxacin can be co-administered with warfarin and theophylline, though reduction of the theophylline dose is necessary. Following oral administration, higher grepafloxacin concentrations are achieved in lung and genital tissues than in serum, indicating its potential in the treatment of respiratory and sexually transmitted diseases. In addition, it exceeds therapeutically effective levels in bile and gall-bladder tissues, and accumulates in polymorphonuclear leucocytes such that it may be useful against intracellular pathogens.

  13. Harvard-MIT research program in short-lived radiopharmaceuticals. Technical progress report, 1991

    SciTech Connect

    Adelstein, S.J.

    1991-12-31

    This report presents research on radiopharmaceuticals. The following topics are discussed: antibody labeling with positron-emitting radionuclides; antibody modification for radioimmune imaging; labeling antibodies; evaluation of technetium acetlyacetonates as potential cerebral blood flow agents; and studies in technetium chemistry. (CBS)

  14. A simple computer programme for biokinetic study of 99Tcm-radiopharmaceuticals.

    PubMed

    Imran, M B; Khurshid, S J; Anwar, K

    1994-02-01

    A simple programme has been written in GW BASIC to calculate the percentage activity of 99Tcm-radiopharmaceuticals in different tissues after biodistribution. The programme is efficient, easy to handle and produces a permanent record in terms of a final report.

  15. Counting Rate Characteristics and Image Distortion in Preclinical PET Imaging During Radiopharmaceutical Therapy.

    PubMed

    Mellhammar, Emma; Dahlbom, Magnus; Axelsson, Johan; Strand, Sven-Erik

    2016-12-01

    PET may provide important information on the response during radiopharmaceutical therapy (RPT). Emission of radiation from the RPT radionuclide may disturb coincidence detection and impair image resolution. In this study, we tested the feasibility of performing intratherapeutic PET on 3 preclinical PET systems.

  16. Harvard-MIT research program in short-lived radiopharmaceuticals. Progress report, March 1, 1983-February 29, 1984

    SciTech Connect

    Adelstein, S.J.; Brownell, G.L.

    1984-02-01

    This report describes research efforts towards the achievement of a clearer understanding of the solution chemistry of technetium in order to facilitate the design of future clinical agents labeled with Tc-99m, the development of new receptor binding radiopharmaceuticals for the in vivo assessment of insulin receptors and for imaging the adrenal medulla and the brain, the examination of the utility of monoclonal antibodies and liposomes in the design of radiopharmaceuticals for diagnosis and therapy, and the synthesis of short-lived positron-emitting radiopharmaceuticals for transverse imaging of regional physiological processes.

  17. Understanding radioxenon isotopical ratios originating from radiopharmaceutical facilities

    NASA Astrophysics Data System (ADS)

    Saey, P. R. J.; Ringbom, A.; Bowyer, T. W.; Becker, A.; de Geer, L.-E.; Nikkinen, M.; Payne, R. F.

    2009-04-01

    It was recently shown that radiopharmaceutical facilities (RPF) are major contributors to the general background of 133Xe and other xenon isotopes both in the northern and southern hemisphere. To distinguish a nuclear explosion signal from releases from civil nuclear facilities, not only the activity concentrations but also the ratios of the four different CTBT relevant radioxenon isotopes (131mXe, 133mXe, 133Xe and 135Xe) have to be well understood. First measurements taken recently in and around two of the world's largest RPF's: NTP at Pelindaba, South Africa and IRE at Fleurus, Belgium have been presented. At both sites, also stack samples were taken in close cooperation with the facility operators. The radioxenon in Belgium could be classified in four classes: the normal European background (133Xe activity between 0 - 5 mBq/m3) on one hand and then the samples where all four isotopes were detected with 133mXe/131mXe > 1. In northern South Africa the Pelindaba RPF is in practice the sole source of radioxenon. It generated a background of 133Xe at the measurement site some 230 km to the west of the RPF of 0 - 5 mBq/m3. In the cases where the air from the Pelindaba facility reached the measurement site directly and in a short time period, the 133Xe was higher, also 135Xe was present and in some samples 133mXe as well. The ratios of the activity concentrations of 135Xe/133Xe vs. 133mXe/131mXe (Multiple Isotope Ratio Plot - MIRC) have been analysed. For both facilities, the possible theoretical ratio's for different scenarios were calculated with the information available and compared with the measurements. It was found that there is an excess of 131mXe present in the European samples compared to theoretical calculations. A similar excess has also been seen in samples measured in northern America. In South Africa, neither the environmental samples nor the stack ones contained 131mXe at measurable levels. This can probably be explained by different processes and

  18. Nonlinear Population Pharmacokinetics of Sirolimus in Patients With Advanced Cancer

    PubMed Central

    Wu, K; Cohen, E E W; House, L K; Ramírez, J; Zhang, W; Ratain, M J; Bies, R R

    2012-01-01

    Sirolimus, the prototypical inhibitor of the mammalian target of rapamycin, has substantial antitumor activity. In this study, sirolimus showed nonlinear pharmacokinetic characteristics over a wide dose range (from 1 to 60 mg/week). The objective of this study was to develop a population pharmacokinetic (PopPK) model to describe the nonlinearity of sirolimus. Whole blood concentration data, obtained from four phase I clinical trials, were analyzed using a nonlinear mixed-effects modeling (NONMEM) approach. The influence of potential covariates was evaluated. Model robustness was assessed using nonparametric bootstrap and visual predictive check approaches. The data were well described by a two-compartment model incorporating a saturable Michaelis–Menten kinetic absorption process. A covariate analysis identified hematocrit as influencing the oral clearance of sirolimus. The visual predictive check indicated that the final pharmacokinetic model adequately predicted observed concentrations. The pharmacokinetics of sirolimus, based on whole blood concentrations, appears to be nonlinear due to saturable absorption. PMID:23887441

  19. Clinical pharmacokinetics of levetiracetam.

    PubMed

    Patsalos, Philip N

    2004-01-01

    Since 1989, eight new antiepileptic drugs (AEDs) have been licensed for clinical use. Levetiracetam is the latest to be licensed and is used as adjunctive therapy for the treatment of adult patients with partial seizures with or without secondary generalisation that are refractory to other established first-line AEDs. Pharmacokinetic studies of levetiracetam have been conducted in healthy volunteers, in adults, children and elderly patients with epilepsy, and in patients with renal and hepatic impairment. After oral ingestion, levetiracetam is rapidly absorbed, with peak concentration occurring after 1.3 hours, and its bioavailability is >95%. Co-ingestion of food slows the rate but not the extent of absorption. Levetiracetam is not bound to plasma proteins and has a volume of distribution of 0.5-0.7 L/kg. Plasma concentrations increase in proportion to dose over the clinically relevant dose range (500-5000 mg) and there is no evidence of accumulation during multiple administration. Steady-state blood concentrations are achieved within 24-48 hours. The elimination half-life in adult volunteers, adults with epilepsy, children with epilepsy and elderly volunteers is 6-8, 6-8, 5-7 and 10-11 hours, respectively. Approximately 34% of a levetiracetam dose is metabolised and 66% is excreted in urine unmetabolised; however, the metabolism is not hepatic but occurs primarily in blood by hydrolysis. Autoinduction is not a feature. As clearance is renal in nature it is directly dependent on creatinine clearance. Consequently, dosage adjustments are necessary for patients with moderate to severe renal impairment. To date, no clinically relevant pharmacokinetic interactions between AEDs and levetiracetam have been identified. Similarly, levetiracetam does not interact with digoxin, warfarin and the low-dose contraceptive pill; however, adverse pharmacodynamic interactions with carbamazepine and topiramate have been demonstrated. Overall, the pharmacokinetic characteristics of

  20. Development of a Web-Accessible Population Pharmacokinetic Service—Hemophilia (WAPPS-Hemo): Study Protocol

    PubMed Central

    Foster, Gary; Navarro-Ruan, Tamara; McEneny-King, Alanna; Edginton, Andrea N; Thabane, Lehana

    2016-01-01

    (available at www.wapps-hemo.org, version 2.4), with core functionalities allowing hemophilia treaters to obtain individual pharmacokinetic estimates on sparse data points after 1 or more infusions of a factor concentrate, was launched for use within the research network in July 2015. Conclusions The WAPPS-Hemo project and research network aims to make it easier to perform individual pharmacokinetic assessments on a reduced number of plasma samples by adoption of a population pharmacokinetics approach. The project will also gather data to substantially enhance the current knowledge about factor concentrate pharmacokinetics and sources of its variability in target populations. Trial Registration ClinicalTrials.gov NCT02061072; https://clinicaltrials.gov/ct2/show/NCT02061072 (Archived by WebCite at http://www.webcitation.org/6mRK9bKP6) PMID:27977390

  1. Evaluation of deoxyribonucleic acid toxicity induced by the radiopharmaceutical 99mTechnetium-Methylenediphosphonic acid and by stannous chloride in Wistar rats.

    PubMed

    Mattos, José Carlos Pelielo De; Matos, Vanessa Coutinho de; Rodrigues, Michelle Pinheiro; Oliveira, Marcia Betânia Nunes de; Dantas, Flavio José S; Santos-Filho, Sebastião David; Bernardo-Filho, Mario; Caldeira-de-Araujo, Adriano

    2012-11-01

    Radiopharmaceuticals are employed in patient diagnostics and disease treatments. Concerning the diagnosis aspect, technetium-99m (99mTc) is utilized to label radiopharmaceuticals for single photon computed emission tomography (SPECT) due to its physical and chemical characteristics. 99mTc fixation on pharmaceuticals depends on a reducing agent, stannous chloride (SnCl(2)) being the most widely-utilized. The genotoxic, clastogenic and anegenic properties of the 99mTc-MDP(methylene diphosphonate used for bone SPECT) and SnCl(2) were evaluated in Wistar rat blood cells using the Comet assay and micronucleus test. The experimental approach was to endovenously administer NaCl 0.9% (negative control), cyclophosphamide 50 mg/kg b.w. (positive control), SnCl(2) 500 μg/mL or 99mTc-MDP to animals and blood samples taken immediately before the injection, 3, and 24 h after (in the Comet assay) and 36 h after, for micronucleus test. The data showed that both SnCl(2) and 99mTc-MDP-induced deoxyribonucleic acid (DNA) strand breaks in rat total blood cells, suggesting genotoxic potential. The 99mTc-MDP was not able to induce a significant DNA strand breaks increase in in vivo assays. Taken together, the data presented here points to the formation of a complex between SnCl(2) in the radiopharmaceutical 99mTc-MDP, responsible for the decrease in cell damage, compared to both isolated chemical agents. These findings are important for the practice of nuclear medicine.

  2. [Pharmacokinetics of carbapenems].

    PubMed

    Suchánková, H; Rychlíčková, J; Urbánek, K

    2012-06-01

    Carbapenems, beta-lactam antibiotics, are ideal candidates for the treatment of serious nosocomial infections including sepsis for their exceptionally broad antibacterial spectrum and high efficiency. They are administered parenterally by intravenous infusion. Carbapenems penetrate well and rapidly into many different tissue compartments and the interstitial fluid. They are metabolized by renal dihydropeptidase-1. Therefore, imipenem must be co-administered with an inhibitor of dihydropeptidase-1. Other carbapenems registered in the Czech Republic (meropenem, ertapenem and doripenem) are more stable to this enzyme. Carbapenems are mainly eliminated via the kidneys and dose adjustment in patients with renal impairment is necessary. The elimination half-life of most carbapenems is around 1 hour with the exception of ertapenem, with 3.8-hour half-life, which allows its once-daily use. Carbapenems are a group of antibiotics with time-dependent effect. Their typical pharmaceutical property is a limited stability in solution after dilution. Administration in the prolonged infusion appears to be a convenient strategy to achieve higher efficiency. Pharmacokinetic parameters of carbapenems may vary individually, especially in critically ill patients and those treated by renal replacement therapy. Therefore, individualization of dosing regimens based on knowledge of pharmacokinetic parameters of individual patients may be useful.

  3. Identifying 24 h variation in the pharmacokinetics of levofloxacin: a population pharmacokinetic approach

    PubMed Central

    Kervezee, Laura; Stevens, Jasper; Birkhoff, Willem; Kamerling, Ingrid M. C.; de Boer, Theo; Dröge, Melloney; Meijer, Johanna H.

    2015-01-01

    Aim The objective of this study was to investigate whether the pharmacokinetics of orally administered levofloxacin show 24 h variation. Levofloxacin was used as a model compound for solubility and permeability independent absorption and passive renal elimination. Methods In this single centre, crossover, open label study, 12 healthy subjects received an oral dose of 1000 mg levofloxacin at six different time points equally divided over the 24 h period. Population pharmacokinetic modelling was used to identify potential 24 h variation in the pharmacokinetic parameters of this drug. Results The pharmacokinetics of levofloxacin could be described by a one compartment model with first order clearance and a transit compartment to describe drug absorption. The fit of the model was significantly improved when the absorption rate constant was described as a cosine function with a fixed period of 24 h, a relative amplitude of 47% and a peak around 08.00 h in the morning. Despite this variation in absorption rate constant, simulations of a once daily dosing regimen showed that t max, C max and the area under the curve at steady‐state were not affected by the time of drug administration. Conclusion The finding that the absorption rate constant showed considerable 24 h variation may be relevant for drugs with similar physicochemical properties as levofloxacin that have a narrower therapeutic index. Levofloxacin, however, can be dosed without taking into account the time of day, at least in terms of its pharmacokinetics. PMID:26852745

  4. 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

  5. Pharmacokinetics of Tyrosol Metabolites in Rats.

    PubMed

    Lee, Da-Hye; Kim, Yang-Ji; Kim, Min Jung; Ahn, Jiyun; Ha, Tae-Youl; Lee, Sang Hee; Jang, Young Jin; Jung, Chang Hwa

    2016-01-21

    Tyrosol is considered a potential antioxidant; however, little is known regarding the pharmacokinetics of its metabolites. To study the pharmacokinetics of tyrosol-derived metabolites after oral administration of a single dose of tyrosol, we attempted to identify tyrosol metabolites in rat plasma by using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Two tyrosol metabolites (M1 and M2) were detected in the plasma. M1 was identified as tyrosol-4-sulfate (T4S) with an [M - H](-) ion at m/z 217. While M2 showed an [M - H](-) ion at m/z 151.0, its metabolite was not identified. Pharmacokinetic analysis of T4S and M2 showed rapid uptake after oral administration of tyrosol within 1 h. The metabolites were rapidly distributed in most organs and tissues and eliminated within 4 h. The greatest T4S deposition by tissue weight was observed in the liver, followed by the kidney and spleen, while M2 was most concentrated in the kidney followed by the liver and spleen. These findings indicate that T4S and M2 were distributed mainly in tissues with an abundant blood supply and were rapidly excreted in urine.

  6. Diagnostic radiopharmaceuticals for localization in target tissues exhibiting a regional PH shift relative to surrounding tissues

    SciTech Connect

    Blau, M.; Kung, H. F.

    1984-10-02

    A radiopharmaceutical chemical compound comprising a radioactive isotope, other than an isotope of iodine, in chemical combination with at least one amine group. The compound has a lipophilicity sufficiently high at a pH of 7.6 to permit passage of the compound from the blood of a mammal into a target organ or tissue and sufficiently low at a pH of 6.6 to prevent rapid return of the compound from the target organ or tissue to the blood. The compound has a percent protein binding of less than ninety percent. A method for selectively depositing a radiopharmaceutical compound in at least one target tissue or organ of a mammal, which tissue or organ has a significantly different intracellular pH than the blood of the mammal, by introducing the compound of the invention into the bloodstream of the mammal.

  7. Radiopharmaceutical stannic Sn-117m chelate compositions and methods of use

    DOEpatents

    Srivastava, Suresh C.; Meinken, George E.

    2001-01-01

    Radiopharmaceutical compositions including .sup.117m Sn labeled stannic (Sn.sup.4+) chelates are provided. The chelates are preferably polyhydroxycarboxylate, such as oxalates, tartrates, citrates, malonates, gluconates, glucoheptonates and the like. Methods of making .sup.117m Sn-labeled (Sn.sup.4+) polyhydroxycarboxylic chelates are also provided. The foregoing pharmaceutical compositions can be used in methods of preparing bone for scintigraphical analysis, for radiopharmaceutical skeletal imaging, treatment of pain resulting from metastatic bone involvement, treatment of primary bone cancer, treatment of cancer resulting from metastatic spread to bone from other primary cancers, treatment of pain resulting from rheumatoid arthritis, treatment of bone/joint disorders and to monitor radioactively the skeletal system.

  8. Development of a modular system for the synthesis of PET [(11)C]labelled radiopharmaceuticals.

    PubMed

    Boschi, Stefano; Lodi, Filippo; Cicoria, Gianfranco; Raul Ledesma, Jorge; Knopp, Roger; Rizzello, Anna; Di Pierro, Donato; Trespidi, Silvia; Marengo, Mario

    2009-10-01

    [((11))C]labelled radiopharmaceuticals as N-[(11)C]methyl-choline ([(11)C]choline), l-(S-methyl-[(11)C])methionine ([(11)C]methionine) and [(11)C]acetate have gained increasing importance in clinical PET and for the routine production of these radiopharmaceuticals, simple and reliable modules are needed to produce clinically relevant radioactivity. On the other hand, flexible devices are needed not only for the routine synthesis but also for more complex applications as the development of new tracers. The aim of this work was the adaptation of an Eckert Ziegler modular system for easy routine synthesis of [(11)C]choline, [(11)C]methionine and [(11)C]acetate using components that account for straightforward scaling up and upgrades.

  9. [Activities of administered radiopharmaceuticals and population dose from nuclear medicine in Czechoslovakia].

    PubMed

    Gushak, V; Rzhichkova, G

    1991-01-01

    The authors assessed by means of questionnaires the activities of radiopharmaceuticals administered in departments of nuclear medicine in Czechoslovakia. The mean activities of individual radiopharmaceuticals are roughly equal as in Great Britain but lower than in the Canadian province of Manitoba. The differences of activities used in different departments are approximately equal in all compared countries. In the Czech Republic the annual collective effective dose equivalent from nuclear medicine was 433 Sv in 1983 and 609 Sv in 1987. The mean effective dose equivalent per examination was 2.23 mSv in 1983 and 2.44 mSv in 1987. The mean effective dose equivalent per inhabitant of the Czech Republic was 0.042 mSv in 1983 and 0.059 mSv in 1987. The radiation dose of the Czech population from nuclear medicine amounts approximately to one tenth of the load from radiodiagnostics.

  10. An overview of translational (radio)pharmaceutical research related to certain oncological and non-oncological applications.

    PubMed

    Cona, Marlein Miranda; de Witte, Peter; Verbruggen, Alfons; Ni, Yicheng

    2013-12-26

    Translational medicine pursues the conversion of scientific discovery into human health improvement. It aims to establish strategies for diagnosis and treatment of diseases. Cancer treatment is difficult. Radio-pharmaceutical research has played an important role in multiple disciplines, particularly in translational oncology. Based on the natural phenomenon of necrosis avidity, OncoCiDia has emerged as a novel generic approach for treating solid malignancies. Under this systemic dual targeting strategy, a vascular disrupting agent first selectively causes massive tumor necrosis that is followed by iodine-131 labeled-hypericin ((123)I-Hyp), a necrosis-avid compound that kills the residual cancer cells by crossfire effect of beta radiation. In this review, by emphasizing the potential clinical applicability of OncoCiDia, we summarize our research activities including optimization of radioiodinated hypericin Hyp preparations and recent studies on the biodistribution, dosimetry, pharmacokinetic and, chemical and radiochemical toxicities of the preparations. Myocardial infarction is a global health problem. Although cardiac scintigraphy using radioactive perfusion tracers is used in the assessment of myocardial viability, searching for diagnostic imaging agents with authentic necrosis avidity is pursued. Therefore, a comparative study on the biological profiles of the necrosis avid (123)I-Hyp and the commercially available (99m)Tc-Sestamibi was conducted and the results are demonstrated. Cholelithiasis or gallstone disease may cause gallbladder inflammation, infection and other severe complications. While studying the mechanisms underlying the necrosis avidity of Hyp and derivatives, their naturally occurring fluorophore property was exploited for targeting cholesterol as a main component of gallstones. The usefulness of Hyp as an optical imaging agent for cholelithiasis was studied and the results are presented. Multiple uses of automatic contrast injectors may reduce

  11. An overview of translational (radio)pharmaceutical research related to certain oncological and non-oncological applications

    PubMed Central

    Cona, Marlein Miranda; de Witte, Peter; Verbruggen, Alfons; Ni, Yicheng

    2013-01-01

    Translational medicine pursues the conversion of scientific discovery into human health improvement. It aims to establish strategies for diagnosis and treatment of diseases. Cancer treatment is difficult. Radio-pharmaceutical research has played an important role in multiple disciplines, particularly in translational oncology. Based on the natural phenomenon of necrosis avidity, OncoCiDia has emerged as a novel generic approach for treating solid malignancies. Under this systemic dual targeting strategy, a vascular disrupting agent first selectively causes massive tumor necrosis that is followed by iodine-131 labeled-hypericin (123I-Hyp), a necrosis-avid compound that kills the residual cancer cells by crossfire effect of beta radiation. In this review, by emphasizing the potential clinical applicability of OncoCiDia, we summarize our research activities including optimization of radioiodinated hypericin Hyp preparations and recent studies on the biodistribution, dosimetry, pharmacokinetic and, chemical and radiochemical toxicities of the preparations. Myocardial infarction is a global health problem. Although cardiac scintigraphy using radioactive perfusion tracers is used in the assessment of myocardial viability, searching for diagnostic imaging agents with authentic necrosis avidity is pursued. Therefore, a comparative study on the biological profiles of the necrosis avid 123I-Hyp and the commercially available 99mTc-Sestamibi was conducted and the results are demonstrated. Cholelithiasis or gallstone disease may cause gallbladder inflammation, infection and other severe complications. While studying the mechanisms underlying the necrosis avidity of Hyp and derivatives, their naturally occurring fluorophore property was exploited for targeting cholesterol as a main component of gallstones. The usefulness of Hyp as an optical imaging agent for cholelithiasis was studied and the results are presented. Multiple uses of automatic contrast injectors may reduce costs

  12. [Computer simulated images of radiopharmaceutical distributions in anthropomorphic phantoms]. Performance report

    SciTech Connect

    Not Available

    1991-05-17

    We have constructed an anatomically correct human geometry, which can be used to store radioisotope concentrations in 51 various internal organs. Each organ is associated with an index number which references to its attenuating characteristics (composition and density). The initial development of Computer Simulated Images of Radiopharmaceuticals in Anthropomorphic Phantoms (CSIRDAP) over the first 3 years has been very successful. All components of the simulation have been coded, made operational and debugged.

  13. The role of exploratory investigational new drugs for translating radiopharmaceuticals into first-in-human studies.

    PubMed

    Schwarz, Sally W; Oyama, Reiko

    2015-04-01

    The Food and Drug Administration has provided a mechanism to reduce time and resources expended on new pharmaceuticals, including radiopharmaceuticals, in order to identify the most promising agents for further development. The exploratory investigational new drug guidance describes early phase 1 exploratory approaches involving microdoses of potential drug candidates that are consistent with regulatory requirements while maintaining the safety needed for human subjects, allowing sponsors to move ahead more quickly with the development of new agents.

  14. Development new radiopharmaceutical based on 5-thio-d- glucose labeled technetium-99m

    NASA Astrophysics Data System (ADS)

    Stasyuk, E. S.; Skuridin, V. S.; Ilina, E. A.; Rogov, A. S.; Nesterov, E. A.; Sadkin, V. L.; Larionova, L. A.; Varlamova, N. V.; Zelchan, R.

    2016-06-01

    The article considers the obtaining and possibility of using 5-thio-D-glucose labeled technetium-99m for the diagnosis of malignant tumors by single photon emission computed tomography. The analysis of the level of international developments of radiopharmaceuticals based on derivatives of glucose has been carried out. Also the article provides information on of using experimental batches of lyophilisate on the basis of 5-thio-D-glucose for preliminary biomedical testing on the mice.

  15. Quantitative studies in radiopharmaceutical science. Progress report, April 1-August 31, 1986

    SciTech Connect

    Cooper, M.

    1986-09-01

    This report covers progress made during the first reporting period since the redirection of the project. In radiochemistry, achievements in fluorine-18 tracer studies including purification and reaction kinetics of 2-fluorodeoxyglucose and production of 6-fluoroDOPA. Radiopharmaceuticals have been prepared and tested for studies on CNS dopaminergic systems. By use of dynamic positron emission tomography the cerebral transport and metabolism of glucose continues to be studied. 6 figs.

  16. Diagnostic and Therapeutic Radiopharmaceutical Agents for Selective Discrimination of Prostate Cancer

    DTIC Science & Technology

    2009-10-01

    Therapeutic Radiopharmaceutical Agents for Selective Discrimination of Prostate Cancer 5b. GRANT NUMBER W81XWH-05-1-0556 5c. PROGRAM ELEMENT NUMBER 6...Bottenus, Brienne N.∞; Fugate, Glenn A.†; Benny, Paul*. Actinides Separations, Conference Pacific Northwest National Lab 6/2006 In situ formation of...Bottenus, Brienne N.∞; Benny, Paul*. Actinides Separations, Conference Pacific Northwest National Lab 3/12/2006 S-functionalized cysteine ligands

  17. Harvard-MIT research program in short-lived radiopharmaceuticals. Final report

    SciTech Connect

    Adelstein, S.J.

    1995-02-01

    The Harvard-MIT Research Program in Short-lived Radiopharmaceuticals was established in 1977 to foster interaction among groups working in radiopharmaceutical chemistry at Harvard Medical School, the Massachusetts Institute of Technology, and the Massachusetts General Hospital. To this was added a group at The Childrens Hospital. From these collaborations and building upon the special strengths of the participating individuals, laboratories and institutions, it was hoped that original approaches would be found for the design of new, clinically useful, radiolabeled compounds. The original thrust of this proposal included: (a) examination of the coordination chemistry of technetium as a basis for rational radiopharmaceutical design, (b) development of an ultrashort-lived radionuclide generator for the diagnosis of congenital heart disease in newborns, (c) synthesis of receptor-site-directed halopharmaceuticals, (d) improved facile labeling of complex molecules with positron-emitting radionuclides. The authors` 1986 proposal was oriented toward organs and disease, emphasizing radiolabeled agents that delineate specific functions and the distribution of receptors in brain, heart, and tumors. In 1989, they further refined their purposes and focused on two major aims: (a) synthesis and utilization of neutral technetium and rhenium complexes of high specific activity, and (b) development of new approaches to the radiolabeling of proteins, peptides, immunoglobulins, and their fragments. In 1992, the authors amended this proposal to concentrate their efforts on biologically active peptides and proteins for targeted radiodiagnosis and therapy.

  18. Preparation of gallium-68 radiopharmaceuticals for positron tomography. Progress report, November 1, 1977-October 31, 1980

    SciTech Connect

    Welch, M.J.

    1980-06-01

    Although the germanium-68 ..-->.. gallium-68 generator is probably the only source of positron-emitting radionuclides that could enable the widespread application of positron tomography, the commercially available /sup 68/Ga//sup 68/Ge generator system suffers from several major disadvantages. The most important of these is that the generator is eluted with EDTA, which forms a very strong chelate with gallium. In order to produce radiopharmaceuticals other than /sup 68/Ga-EDTA, it is first necessary to break the stable EDTA complex and remove all traces of EDTA. This procedure adds several steps and a significant amount of time to procedures for preparing /sup 68/Ga-radiopharmaceuticals. We have developed a new generator using a solvent extraction system which will produce /sup 68/Ga-oxine (8-hydroxyquinoline), a weak chelate. Using this agent we have synthesized several /sup 68/Ga-radiopharmaceuticals and tested them in vitro and in vivo. We have also carried out some preliminary studies to compare generator systems which produce /sup 68/Ga in an ionic form. Attempts have been made using polarographic and chromatographic techniques, and in vivo distribution data to investigate the stability of radiogallium complexes with a series of potentially lipophilic complexing agents.

  19. Use of pressure-hold test for sterilizing filter membrane integrity in radiopharmaceutical manufacturing.

    PubMed

    Belanger, Anthony P; Byrne, John F; Paolino, Justin M; DeGrado, Timothy R

    2009-11-01

    The bubble point test is the de facto standard for postproduction filter membrane integrity test in the radiopharmaceutical community. However, the bubble point test depends on a subjective visual assessment of bubbling rate that can be obscured by significant diffusive gas flows below the manufacturer's prescribed bubble point. To provide a more objective means to assess filter membrane integrity, this study evaluates the pressure-hold test as an alternative to the bubble point test. In our application of the pressure-hold test, the nonsterile side of the sterilizing filter is pressurized to 85% of the predetermined bubble point with nitrogen, the filter system is closed off from the pressurizing gas and the pressure is monitored over a prescribed time interval. The drop in pressure, which has a known relationship with diffusive gas flow, is used as a quantitative measure of membrane integrity. Characterization of the gas flow vs. pressure relationship of each filter/solution combination provides an objective and quantitative means for defining a critical value of pressure drop over which the membrane is indicated to be nonintegral. The method is applied to sterilizing filter integrity testing associated with the commonly produced radiopharmaceuticals, [(18)F]FDG and [(11)C]PIB. The method is shown to be robust, practical and amenable to automation in radiopharmaceutical manufacturing environments (e.g., hot cells).

  20. Synthetic techniques of radiopharmaceuticals production labeled with C-11 for PET in cardiology

    NASA Astrophysics Data System (ADS)

    Dyubkov, V. S.; Ekaeva, I. V.; Katunina, T. A.; Rumyantsev, A. S.; Silchenkov, A. V.; Tuflina, T. V.

    2017-01-01

    Positron emission tomography (PET) and PET-Computerised Tomography (CT) are unique, non-invasive diagnostic techniques, in which the local, temporal and quantitative distributions of radioactive labelled substances are measured to investigate physiological processes. It is well known that PET centre of Bakulev Scientific Centre for Cardiovascular Surgery is the oldest one in Moscow. During more than fifteen years a large number of patients have received PET scans. Due to main stream of Scientific Centre, emphasis is placed on examining the heart functioning. For the diagnosis innervation of the heart muscle a number of radiopharmaceuticals are used, including PET radiopharmaceuticals such as 11C-CGP 12177, 11C-meta-hydroxyephedrine as well as its synthetic analogues labelled with other PET radionuclides (18F, 68Ga). 11C-meta-hydroxyephedrine is one of the most perspective radiopharmaceutical for an investigation of cardiac receptors function due to required materials availability for a radio synthesis in Russia. The main advantage of proposed 11C-meta-hydroxyephedrine synthesis technique is the use of a catalyst which allows one decrease reaction time from 5 minutes to 30 seconds. Obtained results allow one decrease reaction time of methylation and increase radiochemical and technological yields.

  1. Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: samarium-153-EDTMP and radium-223.

    PubMed

    Anderson, Peter M; Subbiah, Vivek; Rohren, Eric

    2014-01-01

    Osteosarcoma is a cancer characterized by formation of bone by malignant cells. Routine bone scan imaging with Tc-99m-MDP is done at diagnosis to evaluate primary tumor uptake and check for bone metastases. At time of relapse the Tc-99m-MDP bone scan also provides a specific means to assess formation of bone by malignant osteosarcoma cells and the potential for bone-seeking radiopharmaceuticals to deliver radioactivity directly into osteoblastic osteosarcoma lesions. This chapter will review and compare a bone-seeking radiopharmaceutical that emits beta-particles, samarium-153-EDTMP, with an alpha-particle emitter, radium-223. The charged alpha particles from radium-223 have far more mass and energy than beta particles (electrons) from Sm-153-EDTMP. Because radium-223 has less marrow toxicity and more radiobiological effectiveness, especially if inside the bone forming cancer cell than samarium-153-EDTMP, radium-223 may have greater potential to become widely used against osteosarcoma as a targeted therapy. Radium-223 also has more potential to be used with chemotherapy against osteosarcoma and bone metastases. Because osteosarcoma makes bone and radium-223 acts like calcium, this radiopharmaceutical could possibly become a new targeted means to achieve safe and effective reduction of tumor burden as well as facilitate better surgery and/or radiotherapy for difficult to resect large, or metastatic tumors.

  2. Radiopharmaceuticals for metastatic bone pain palliation: available options in the clinical domain and their comparisons.

    PubMed

    Das, Tapas; Banerjee, Sharmila

    2017-01-01

    Bone pain arising due to skeletal metastases is one of the common complications experienced by the majority of patients suffering from prostate, breast and lung cancer at the advanced stage of the disease. These patients are subjected to palliative care in order to improve the quality of their remaining life. With the gradually increasing number of cancer cases, palliation of metastatic bone pain is gaining importance. Bone-seeking radiopharmaceuticals play a pivotal role in the management of cancer pain, particularly in patients with multiple metastases, as these agents are proven to be effective in controlling the bone pain with minimum side effects. Although a plethora of such radiopharmaceuticals have been developed and evaluated in animal models, only a few are regularly used in clinics while some of these agents are at different stages of clinical evaluations. The present article describes only those bone-seeking radiopharmaceuticals, which have been reported to be clinically administered till date, along with their relative merits and drawbacks.

  3. Interaction of licorice on glycyrrhizin pharmacokinetics.

    PubMed Central

    Cantelli-Forti, G; Maffei, F; Hrelia, P; Bugamelli, F; Bernardi, M; D'Intino, P; Maranesi, M; Raggi, M A

    1994-01-01

    The effects of components of aqueous licorice root extract (LE) on the pharmacokinetics of glycyrrhizin (G) and glycyrrhetic acid (GA) were investigated in rats and humans. The aim of this work was to define the role of pharmacokinetics in G toxicity. In the procedure, G and GA were detected in biological fluids by means of recently improved HPLC methods. Significantly lower G and GA plasma levels were found in rats and humans treated with LE compared to the levels obtained with those in which G alone was administered. The pharmacokinetic curves showed significant differences in the areas under the plasma-time curve (AUC), Cmax, and Tmax parameters. The data obtained from urine samples are in agreement with the above results and confirm a reduced bioavailability of G present in LE compared to pure G. This should be attributed to the interaction during intestinal absorption between the G constituent and the several components in LE. The modified bioavailability could explain the various clinical adverse effects resulting from the chronic oral administration of G alone as opposed to LE. PMID:7698088

  4. ( sup 111 In-DTPA-D-Phe sup 1 )-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: Synthesis, radiolabeling and in vitro validation

    SciTech Connect

    Bakker, W.H.; Albert, R.; Bruns, C.; Breeman, W.A.P.; Hofland, L.J.; Marbach, P.; Pless, J.; Pralet, D.; Stolz, B.; Koper, J.W.; Lamberts, S.W.J.; Visser, T.J.; Krenning, E.P. Sandoz Pharma AG, Basel )

    1991-01-01

    As starting material for a potentially convenient radiopharmaceutical, a diethylenetriaminopentaacetic acid (DTPA) conjugated derivative of octreotide (SMS 201-995) was prepared. This peptide, (DTPA-D-Phe{sup 1})-octreotide (SDZ 215-811) binds more than 95% of added {sup 111}In in an easy, single-step labeling procedure without necessity of further purification. The specific somatostatin-like biologic effect of these analogues was proven by the inhibition of growth hormone secretion by cultured rat pituitary cells in a dose-dependent fashion by octreotide, (DTPA-D-Phe{sup 1})-octreotide and non-radioactive ({sup 115}In-DTPA-D-Phe{sup 1})-octreotide. The binding of ({sup 111}In-DTPA-D-Phe{sup 1})-octreotide to rat brain cortex membranes proved to be displaced similarly by natural somatosatin as well as by octreotide, suggesting specific binding of ({sup 111}In-DTPA-D-Phe{sup 1})-octreotide to somatostatin receptors. The binding of the indium-labeled compound showed a somewhat lower affinity when compared with the iodinated (Tyr{sup 3})-octreotide, but indium-labeled (DTPA-D-Phe{sup 1})-octreotide still binds with nanomolar affinity. In conjunction with in vivo studies, these results suggest that ({sup 111}In-DTPA-D-Phe{sup 1})-octreotide is a promising radiopharmaceutical for scintigraphic imaging of somatostatin receptor-positive tumors.

  5. SU-E-I-82: PET Radiopharmaceuticals for Prostate Cancer Imaging: A Review

    SciTech Connect

    Fernandes, F; Silva, D da; Rodrigues, L

    2015-06-15

    Purpose: The aim of this work was to review new and clinical practice PET radiopharmaceuticals for prostate cancer imaging. Methods: PET radiopharmaceuticals were reviewed on the main databases. Availability, dosimetry, accuracy and limitations were considered. Results: The following radioisotopes with respective physical half-life and mean positron energy were found: {sup 18}F (109,7 min, 249,8 keV), {sup 89}Zr (78,4 hs, 395,5 keV), {sup 11}C (20,4 min, 385,7 keV) and {sup 68}Ga (67,8 min, 836 keV). {sup 68}Ga was the only one not produced by cyclotron. Radiopharmaceuticals uptake by glucose metabolism ({sup 18}F-FDG), lipogenesis ({sup 11}C-Choline and {sup 11}C-Acetate), amino acid transport (Anti-{sup 18}F-FACBC), bone matrix ({sup 18}F-NaF), prostatespecific membrane antigen ({sup 68}Ga-PSMA and {sup 89}Zr-J591), CXCR receptors ({sup 89}Ga-Pentixafor), adrenal receptors ({sup 18}F-FDHT) and gastrin release peptide receptor (bombesin analogue). Most of radiopharmaceuticals are urinary excretion, so bladder is the critical organ. 11C-choline (pancreas), Anti-{sup 18}FFACBC (liver) and {sup 18}F-FBDC (stomach wall) are the exception. Higher effective dose was seen {sup 18}F-NaF (27 μSv/MBq) while the lowest was {sup 11}CAcetate (3,5 μSv/MBq). Conclusion: Even though {sup 18}F-FDG has a large availability its high urinary excretion and poor uptake to slow growing disease offers weak results for prostate cancer. Better accuracy is obtained when {sup 18}F-NaF is used for bone metastatic investigation although physicians tend to choose bone scintigraphy probably due to its cost and practice. Many guidelines in oncology consider {sup 11}C or {sup 18}F labeled with Choline the gold standard for biochemical relapse after radical treatment. Local, lymph node and distant metastatic relapse can be evaluated at same time with this radiopharmaceutical. There is no consensus over bigger urinary excretion for {sup 18}F labeling. Anti-{sup 18}F-FACBC, {sup 68}Ga-PSMA and {sup

  6. Radiolabeled tirofiban – a potential radiopharmaceutical for detection of deep venous thrombosis

    PubMed Central

    Darkovska-Serafimovska, Marija; Janevik-Ivanovska, Emilija; Djorgoski, Icko; Arsova-Sarafinovska, Zorica; Zdravkovska, Milka; Balkanov, Trajan; Ugresic, Nenad

    2016-01-01

    Aim The aim of this study was to investigate the possibility of using 99mtechnetium (99mTc)-labeled tirofiban (a reversible antagonist of glycoprotein IIb/IIIa) for detection of deep venous thrombosis (DVT) in rats without causing an antiplatelet effect. Methods The ability of in vitro tirofiban to inhibit adenosine 5′-diphosphate (ADP)-induced platelet aggregation was evaluated using optical aggregometer. Binding of 99mTc-tirofiban to platelets was evaluated. Serum levels of unlabeled (a validated high performance liquid chromatography method) and 99mTc-tirofiban after single intravenous injection were evaluated in male Wistar rats with or without induced DVT (femoral vein ligation model), and the rats were also subjected to whole body scintigraphy. Results Tirofiban in vitro inhibits ADP-induced aggregation of human platelets in a dose- and concentration-dependent manner (10 nM to 2 μM), but only if it is added before ADP and not after ADP. 99mTc labeling did not affect the ability of tirofiban to bind to either human or rat platelets, nor did it affect tirofiban pharmacokinetics in intact rats or in animals with induced DVT. When 99mTc-tirofiban was injected to rats after induction of DVT, at a molar dose lower than the one showing only a weak antiaggregatory effect in vitro, whole body scintigraphy indicated localization of 99mTc-tirofiban around the place of the induced DVT. Conclusion 99mTc labeling of tirofiban does not affect its ability to bind to glycoprotein IIb/IIIa or its in vivo pharmacokinetics in rats, either intact or with DVT. A low, nonantiaggregatory dose of 99mTc-tirofiban may be used to visualize DVT at an early stage. PMID:27713618

  7. 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

  8. 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

  9. Pharmacokinetics Application in Biophysics Experiments

    NASA Astrophysics Data System (ADS)

    Millet, Philippe; Lemoigne, Yves

    Among the available computerised tomography devices, the Positron Emission Tomography (PET) has the advantage to be sensitive to pico-molar concentrations of radiotracers inside living matter. Devices adapted to small animal imaging are now commercially available and allow us to study the function rather than the structure of living tissues by in vivo analysis. PET methodology, from the physics of electron-positron annihilation to the biophysics involved in tracers, is treated by other authors in this book. The basics of coincidence detection, image reconstruction, spatial resolution and sensitivity are discussed in the paper by R. Ott. The use of compartment analysis combined with pharmacokinetics is described here to illustrate an application to neuroimaging and to show how parametric imaging can bring insight on the in vivo bio-distribution of a radioactive tracer with small animal PET scanners. After reporting on the use of an intracerebral β+ radiosensitive probe (βP), we describe a small animal PET experiment used to measure the density of 5HT 1 a receptors in rat brain.

  10. Pharmacokinetic study of sulbactomax.

    PubMed

    Payasi, Anurag; Chaudhary, Manu; Gupta, Ankush; Dwivedi, Vivek Kumar; Bhatnagar, Anuj

    2010-08-01

    We have evaluated pharmacokinetics of a fixed dose combination (FDC) of ceftriaxone and sulbactam (2:1) or sulbactomax in eight healthy volunteers. A 1.5 g dose of sulbactomax, 1 g dose of ceftriaxone and 0.5 g sulbactam were given intravenously in a balanced two-ways cross-over study. Serially collected plasma sample was analyzed for ceftriaxone and sulbactam by high performance liquid chromatography (HPLC). The mean peaks of ceftriaxone and sulbactam concentrations in plasma were 152.06+/-6.65 microg/ml and 21.32+/-1.80 microg/ml, respectively and plasma half-lives for ceftriaxone and sulbactam were 5.2+/-0.35 hr and 0.94+/-0.038 hr, respectively. The AUC0-24 for ceftriaxone and sulbactam was 760.16+/-27.68 microg.hr/ml and 20.74+/-2.34 microg.hr/ml, respectively, with elimination rate constant of 0.133+/-0.009 hr(-1) and 0.732+/-0.029 hr(-1), respectively. The kinetics of ceftriaxone and sulbactum did not change in combination as compared to the alone treatment. Also, concentration of the ceftriaxone after 24 hr is higher than the minimum inhibitory concentration (MIC) of the most of the gram positive and gram negative bacteria indicating that one dose in a day is sufficient to treat the disease caused by these organisms.

  11. Population pharmacokinetics of daptomycin.

    PubMed

    Dvorchik, Barry; Arbeit, Robert D; Chung, Julia; Liu, Susan; Knebel, William; Kastrissios, Helen

    2004-08-01

    Data from subjects in nine phase 1 (n = 153) and six phase 2/3 (n = 129) clinical trials were combined to identify factors contributing to interindividual variability in daptomycin pharmacokinetics (PK). Over 30 covariates were considered. A two-compartment model with first-order elimination provided the best fit for data on daptomycin concentrations in plasma over time. In the final population PK model, daptomycin plasma clearance (CL) was a function of renal function, body temperature, and sex. Of these factors, renal function contributed most significantly to interindividual variability. CL varied linearly with the estimated creatinine clearance. CL among dialysis subjects was approximately one-third that of healthy subjects (0.27 versus 0.81 liter/h). CL in females was 80% that in males; however, in clinical trials, the outcome was not affected by sex and therefore this effect is not considered clinically meaningful. The relationship with body temperature should be interpreted cautiously since the analysis included only a limited number of subjects who were hyperthermic. The volume of distribution of the peripheral compartment (V2) and intercompartmental clearance (Q) were linearly related to body weight. V2 increased approximately twofold in the presence of an acute infection. No factors were identified that significantly impacted V1. This analysis supports the dosing of daptomycin on a milligram-per-kilogram-of-body-weight basis and suggests that modified dosing regimens are indicated for patients with severe renal disease and for those undergoing dialysis.

  12. Preparation and biological evaluation of (99m)Tc-ropinirole as a novel radiopharmaceutical for brain imaging.

    PubMed

    Motaleb, M A; Ibrahem, I T; Ayoub, V R; Geneidi, A S

    2016-04-01

    Noninvasive brain imaging is a process that allows scientists and physicians to view and monitor the areas of the brain. The aim of this study was to formulate a novel radiopharmaceutical for the detection of brain disorders at early stages in susceptible patients. (99m) Tc-ropinirole was prepared by the direct complexation of ropinirole with technetium-99m. The results showed that the radiochemical yield (99m) Tc-ropinirole was 92 ± 2.87% and the radiochemical yield was evaluated by paper chromatography and HPLC. In vitro studies showed that the formed complex was stable for up to 6 h. In vivo uptake of (99m) Tc-ropinirole in the brain was 4.87 ± 0.15% injected dose/g organ at 30 min post-injection, which cleared from the brain with time till it reaches 2.3% at 2 h post-injection indicating that the brain uptake of (99m) Tc-ropinirole is higher than that of the commercially available (99m) Tc-HMPAO, which is 2.25% at 30 min. Pre-dosing mice with cold ropinirole reduced the brain uptake to 0.26 ± 0.01% injected dose/g organ, so this confirms the high specificity and selectivity of this radiotracer for the assessment of the dopamine receptors.

  13. 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.

  14. Low energy cyclotron production and separation of yttrium-86 for evaluation of monoclonal antibody pharmacokinetics and dosimetry

    SciTech Connect

    Shoner, S.; Link, J.; Krohn, K.; Schlyer, D.

    1999-06-01

    Although an excellent radionuclide for application to systemic isotopic therapy when complexed to various monoclonal antibodies, the lack of photon emission from yttrium-90 makes the determination of the pharmacokinetics and dosimetry of the resultant radiopharmaceutical difficult. The introduction of the positron-emitting radionuclide yttrium-86 (T{sub 1/2}=14.7&hthinsp;h,&hthinsp;{beta}{sup +}=33{percent}) provides the non-invasive quantitation for the biodistribution of the chelated complex. The yttrium-86 radionuclide is produced at Memorial Sloan-Kettering using the CS-15 cyclotron via the (p,n) nuclear reaction on an enriched strontium-86 target. The separation is effectively achieved through a combination of solvent extraction and ion exchange chromatography. Once investigational new drug approval has been received, the mixed nuclides, Y-90 and Y-86, are to be used to formulate the HuM195 labeled monoclonal antibody, a radiopharmaceutical under active investigation against hematopoietic progenitor cells. {copyright} {ital 1999 American Institute of Physics.}

  15. [Elements of pharmacodynamics and pharmacokinetics].

    PubMed

    Piette, F; Soubrie, C

    1990-05-21

    A knowledge of pharmacokinetic data is particularly important with drugs that have a narrow margin of safety. Exhaustive pre-marketing pharmacokinetic investigations and pharmacokinetic studies in populations are the two principal means of acquiring such knowledge. Although popular, the concept of half-life which decreases with age for many drugs is insufficient to calculate dosage in elderly people. Measurements of creatinine clearance provide an almost mathematical approach to the dosage of drugs that are excreted exclusively by the kidneys. In contrast, changes in hepatic metabolism with age and pathology are difficult to evaluate, and their consequences are often vaguely perceived. Our knowledge of relationships between age and pharmacodynamics is still in infancy. Owing to the wide consumption of medicine by elderly people, drug interactions are frequent at all stages, including absorption, metabolization, transport and site of action.

  16. 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

  17. Environmental effects on the structure of metal ion-DOTA complexes: An ab initio study of radiopharmaceutical metals.

    SciTech Connect

    Lau, E Y; Lightstone, F C; Colvin, M E

    2006-02-10

    Quantum mechanical calculations were performed to study the differences between the important radiopharmaceutical metals yttrium (Y) and indium (In) bound by DOTA and modified DOTA molecules. Energies were calculated at the MP2/6-31+G(d)//HF/6-31G(d) levels, using effective core potentials on the Y and In ions. Although the minimum energy structures obtained are similar for both metal ion-DOTA complexes, changes in coordination and local environment significantly affect the geometries and energies of these complexes. Coordination by a single water molecule causes a change in the coordination number and a change in the position of the metal ion in In-DOTA; but, Y-DOTA is hardly affected by water coordination. When one of the DOTA carboxylates is replaced by an amide, the coordination energy for the amide arm shows a large variation between the Y and In ions. Optimizations including water and guandinium moieties to approximate the effects of antibody binding indicate a large energy cost for the DOTA-chelated In to adopt the ideal conformation for antibody binding.

  18. Improving production of 11C to achieve high specific labelled radiopharmaceuticals

    NASA Astrophysics Data System (ADS)

    Savio, E.; García, O.; Trindade, V.; Buccino, P.; Giglio, J.; Balter, H.; Engler, H.

    2012-12-01

    Molecular imaging is usually based on the recognition by the radiopharmaceuticals of specific sites which are present in limited number or density in the cells or biological tissues. Thus is of high importance to label the radiopharmaceuticals with high specific activity to be able to achieve a high target to non target ratio. The presence of carbon dioxide (CO2) from the air containing 98,88% of 12C and 1,12% 13C compete with 11CO2 produced at the cyclotron. In order to minimize the presence of these isotopes along the process of irradiation, transferring and synthesis of radiopharmaceuticals labelled with 11C, we applied this method: previous to the irradiation the target was 3-4 times flushed with He (5.7) as a cold cleaning, followed by a similar conditioning of the line, from the target up to the module, and finally a hot cleaning in order to desorb 12CO2 and 13CO2, this was performed by irradiation during 1 min at 5 uA (3 times). In addition, with the aim of improving quality of gases in the target and in the modules, water traps (Agilent) were incorporated in the inlet lines of the target and modules. Target conditioning process (cold and hot flushings) as well as line cleaning, allowing the desorption of unlabelled CO2, together with the increasing of gas purity in the irradiation and in the synthesis, were critical parameters that enable to achieve 11C-radiopharamaceuticals with high specific activity, mainly in the case of 11C-PIB.

  19. Computational Opioid Prescribing: A Novel Application of Clinical Pharmacokinetics

    PubMed Central

    Linares, Oscar A; Linares, Annemarie L

    2011-01-01

    We implemented a pharmacokinetics-based mathematical modeling technique using algebra to assist pre-scribers with point-of-care opioid dosing. We call this technique computational opioid prescribing (COP). Because population pharmacokinetic parameter values are needed to estimate drug dosing regimen designs for individual patients using COP, and those values are not readily available to prescribers because they exist scattered in the vast pharmacology literature, we estimated the population pharmacokinetic parameter values for 12 commonly prescribed opioids from various sources using the bootstrap resampling technique. Our results show that opioid dosing regimen design, evaluation, and modification is feasible using COP. We conclude that COP is a new technique for the quantitative assessment of opioid dosing regimen design evaluation and adjustment, which may help prescribers to manage acute and chronic pain at the point-of-care. Potential benefits include opioid dose optimization and minimization of adverse opioid drug events, leading to potential improvement in patient treatment outcomes and safety. PMID:21657860

  20. The Radiopharmaceuticals Production and Research Centre established by the Heavy Ion Laboratory of the University of Warsaw

    NASA Astrophysics Data System (ADS)

    Choiński, J.; Jastrzębskia, J.; Kilian, K.; Mazur, I.; Napiorkowski, P. J.; Pękal, A.; Szczepaniak, D.

    2014-03-01

    The Radiopharmaceuticals Production and Research Centre was recently installed on the premises of the Heavy Ion Laboratory, University of Warsaw. Equipped with a medical PETtrace p/d cyclotron , radiochemistry synthesis and dispensing units and a modern quality control laboratory the Centre is intended to produce regularly for commercial purposes the classic PET radiopharmaceuticals ( such -as e.g. FDG- ). Situated on the largest Warsaw scientific campus OCHOTA, an important part of the Centre's activities will also be devoted to the production of known species for preclinical studies and research into innovative radiopharmaceuticals in collaboration with other scientific units of this Campus as well as with members of the Warsaw Consortium for PET Collaboration. Research into the accelerator production route of 99mTc will also begin shortly.

  1. Quality control of 99mTc-radiopharmaceuticals. Evaluation of GCS minicolumns in routine clinical work with scintillation cameras.

    PubMed

    Darte, L; Persson, B R

    1980-12-01

    Gel chromatography columnm scanning (GCS) is a rapid and reliable method for the quality control of 99mTc-radiopharmaceuticals. With this method the labelled compound and various impurities such as free pertechnetate, hydrolyzed reduced technetium or other 99mTc-complexes are obtained in one testing procedure. Using minicolumns results can be obtained with a simple testing procedure within a few minutes after the sample is taken; this is significant in routine radiopharmaceutical work. The resolution of the recording system is important, so as to be able to utilize fully the good separation ability of the minicolumn. Minicolumns were studied with some commonly used radiopharmaceuticals. A scintillation camera was used to record minicolumn data under various conditions and the results were conpared to those obtained using a scanner to reveal optimal recording conditions for the scintillation camera.

  2. 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

  3. Radio-UHPLC: a tool for rapidly determining the radiochemical purity of technetium-99m radiopharmaceuticals?

    PubMed

    Kryza, David; Janier, Marc

    2013-08-01

    Determining the radiochemical purity (RCP) of technetium-99m ((99m)Tc) radiopharmaceuticals using the method described in the package insert is a time-consuming process, requiring particular attention in order to achieve accurate RCP results. The purpose of this study was to evaluate whether radio-ultra high performance liquid chromatography (radio-UHPLC) may be an alternative method for RCP testing of (99m)Tc-tetrofosmin, (99m)Tc-MAG3 and (99m)Tc-sestamibi. Results obtained using radio-UHPLC were in excellent agreement with the standard method, with total analysis time being reduced to less than 3 min.

  4. High--valent technetium chemistry-new opportunities for radiopharmaceutical developments.

    PubMed

    Braband, Henrik

    2014-04-01

    The rich coordination chemistry of (99m) Tc distinguishes this radiometal from other radiolabels applied for single-photon emission computed tomography (SPECT) or positron emission tomography (PET). This potential should be used to create novel opportunities for the development of effective imaging probes. In this context, the field of high-valent technetium chemistry has received much interest. It has been shown that fac-{(99m) TcO3 }(+) complexes are potential new synthons for radiopharmaceutical developments, due to their unique physicochemical properties and unprecedented reactivity. In this article, recent developments and the 'state of the art' in this field of technetium chemistry will be reviewed comprehensively.

  5. Refurbishing of a Freeze Drying Machine, used in Nuclear Medicine for Radiopharmaceuticals Production

    NASA Astrophysics Data System (ADS)

    Gaytán-Gallardo, E.; Desales-Galeana, G.

    2006-09-01

    The refurbishing of a freeze drying machine used in the radiopharmaceuticals production, applied in nuclear medicine in the Radioactive Materials Department of the Nuclear Research National Institute in México (ININ in Spanish), is presented. The freeze drying machine was acquired in the 80's decade and some components started having problems. Then it was necessary to refurbish this equipment by changing old cam-type temperature controllers and outdated recording devices, developing a sophisticated software system that substitutes those devices. The system is composed by a freeze drying machine by Hull, AC output modules for improved temperature control, a commercial data acquisition card, and the software system.

  6. Proliferation dangers associated with nuclear medicine: getting weapons-grade uranium out of radiopharmaceutical production.

    PubMed

    Williams, Bill; Ruff, Tilman A

    2007-01-01

    Abolishing the threat of nuclear war requires the outlawing of nuclear weapons and dismantling current nuclear weapon stockpiles, but also depends on eliminating access to fissile material (nuclear weapon fuel). The near-universal use of weapons-grade, highly enriched uranium (HEU) to produce radiopharmaceuticals is a significant proliferation hazard. Health professionals have a strategic opportunity and obligation to progress the elimination of medically-related commerce in HEU, closing one of the most vulnerable pathways to the much-feared 'terrorist bomb'.

  7. A Generator-Produced Gallium-68 Radiopharmaceutical for PET Imaging of Myocardial Perfusion

    PubMed Central

    Sharma, Vijay; Sivapackiam, Jothilingam; Harpstrite, Scott E.; Prior, Julie L.; Gu, Hannah; Rath, Nigam P.; Piwnica-Worms, David

    2014-01-01

    Lipophilic cationic technetium-99m-complexes are widely used for myocardial perfusion imaging (MPI). However, inherent uncertainties in the supply chain of molybdenum-99, the parent isotope required for manufacturing 99Mo/99mTc generators, intensifies the need for discovery of novel MPI agents incorporating alternative radionuclides. Recently, germanium/gallium (Ge/Ga) generators capable of producing high quality 68Ga, an isotope with excellent emission characteristics for clinical PET imaging, have emerged. Herein, we report a novel 68Ga-complex identified through mechanism-based cell screening that holds promise as a generator-produced radiopharmaceutical for PET MPI. PMID:25353349

  8. Reliability of eye lens dosimetry in workers of a positron emission tomography radiopharmaceutical production facility.

    PubMed

    da Silva, Teógenes A; Guimarães, Margarete C; Meireles, Leonardo S; Teles, Luciana L D; Lacerda, Marco Aurélio S

    2016-11-01

    A new regulatory statement was issued concerning the eye lens radiation protection of persons in planned exposures. A debate was raised on the adequacy of the dosimetric quantity and on its method of measurement. The aim of this work was to establish the individual monitoring procedure with the EYE-D™ holder and a MCP-N LiF:Mg,Cu,P thermoluminescent chip detector for measuring the personal dose equivalent Hp(3) in workers of a Positron Emission Tomography Radiopharmaceutical Production Facility.

  9. USCEA/NIST measurement assurance programs for the radiopharmaceutical and nuclear power industries

    SciTech Connect

    Golas, D.B.

    1993-12-31

    In cooperation with the U.S. Council for Energy Awareness (USCEA), the National Institute of Standards and Technology (NIST) supervises and administers two measurement assurance programs for radioactivity measurement traceability. One, in existence since the mid 1970s, provides traceability to suppliers of radiochemicals and radiopharmaceuticals, dose calibrators, and nuclear pharmacy services. The second program, begun in 1987, provides traceability to the nuclear power industry for utilities, source suppliers, and service laboratories. Each program is described, and the results of measurements of samples of known, but undisclosed activity, prepared at NIST and measured by the participants are presented.

  10. Guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals

    PubMed Central

    Elsinga, Philip; Todde, Sergio; Penuelas, Ivan; Meyer, Geerd; Farstad, Brit; Faivre-Chauvet, Alain; Mikolajczak, Renata; Westera, Gerrit; Gmeiner-Stopar, Tanja

    2010-01-01

    This guidance is meant as a guidance to Part B of the EANM “Guidelines on Good Radiopharmacy Practice (GRPP)” issued by the Radiopharmacy Committee of the EANM (see www.eanm.org), covering the small-scale “in house” preparation of radiopharmaceuticals which are not kit procedures. The aim is to provide more detailed and practice-oriented guidance to those who are involved in the small-scale preparation of, for example, PET, therapeutic or other radiopharmaceuticals which are not intended for commercial purposes or distribution. PMID:20306035

  11. Pharmacokinetics of chlorpromazine and key metabolites.

    PubMed

    Yeung, P K; Hubbard, J W; Korchinski, E D; Midha, K K

    1993-01-01

    A study was carried out in 11 healthy young men to investigate the pharmacokinetics of chlorpromazine (CPZ) after a bolus intravenous (i.v.) dose (10 mg) and three single oral doses (25, 50 and 100 mg), with a washout period of two weeks between doses. Plasma levels of CPZ, CPZ N-oxide (CPZNO), CPZ sulfoxide (CPZSO) and both free and conjugated 7-hydroxy-CPZ (7-HOCPZ) were measured by extraction radioimmunoassays. CPZ exhibited multicompartmental pharmacokinetics in most subjects. There was wide between-subject variability in half life (11.05 h), volume of distribution (1215 l), volume of distribution at steady state (642 l) and mean residence time (8.88 h), whereas systemic clearance was somewhat less variable (76.6 l.h-1). All metabolites were present in measurable concentrations in the plasma of 9 of 11 subjects after i.v. CPZ, whereas free 7-HOCPZ was not detected in the other 2 individuals. With the exception of CPZNO, the biological half lives of the primary metabolites were longer than the half life of CPZ. After oral administration, the percentage of CPZ reaching the systemic circulation intact (F%) was very low (4-38%) and dose dependent. Moreover, both within-subject and between-subject variances were very high. The maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve extrapolated to infinite time (AUC) showed evidence of nonlinearity, whereas half life did not appear to be dose dependent. These data suggest that the high degree of variability in the pharmacokinetics of CPZ is a result of extensive first pass metabolism rather than variation in half life.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide.

    PubMed

    Chen, Nianhang; Zhou, Simon; Palmisano, Maria

    2017-02-01

    Lenalidomide is a lead therapeutic in multiple myeloma and deletion 5q myelodysplastic syndromes and shows promising activities in other hematologic malignancies. This article presents a comprehensive review of the clinical pharmacokinetics and pharmacodynamics of lenalidomide. Oral lenalidomide is rapidly and highly absorbed (>90 % of dose) under fasting conditions. Food affects oral absorption, reducing area under the concentration-time curve (AUC) by 20 % and maximum concentration (C max) by 50 %. The increase in AUC and C max is dose proportional, and interindividual variability in plasma exposure is low to moderate. Lenalidomide distributes into semen but is undetectable 3 days after stopping treatment. Biotransformation of lenalidomide in humans includes chiral inversion, trivial hydroxylation, and slow non-enzymatic hydrolysis. Approximately 82 % of an oral dose is excreted as lenalidomide in urine within 24 h. Lenalidomide has a short half-life (3-4 h) and does not accumulate in plasma upon repeated dosing. Its pharmacokinetics are consistent across patient populations, regardless of the type of hematologic malignancy. Renal function is the only important factor affecting lenalidomide plasma exposure. Lenalidomide has no QT prolongation risk at approved doses, and higher plasma exposure to lenalidomide is associated with increased risk of neutropenia and thrombocytopenia. Despite being a weak substrate of P-glycoprotein (P-gp) in vitro, lenalidomide does not have clinically significant pharmacokinetic interactions with P-gp substrates/inhibitors in controlled studies. The AUC-matched dose adjustment is recommended for patients with renal impairment at the start of therapy. No dose adjustment for lenalidomide is needed on the basis of age, ethnicity, mild hepatic impairment, or drug-drug interactions.

  13. Aztreonam pharmacokinetics in burn patients.

    PubMed Central

    Friedrich, L V; White, R L; Kays, M B; Brundage, D M; Yarbrough, D

    1991-01-01

    The pharmacokinetics of aztreonam in eight adult patients with severe burn injuries (total body surface area burn, 49% +/- 21% [mean +/- standard deviation]) were studied. The time of initiation of study following burn injury was 7.0 +/- 1.4 days. Four patients at first dose and at steady state were studied. Aztreonam concentrations were measured by high-performance liquid chromatography, and a two-compartment model was used to fit the data. No significant differences in any pharmacokinetic parameters between first dose and steady state were observed. Volume of distribution of the central compartment after first dose (0.14 liters/kg) and volume of distribution at steady state (0.31 liters/kg) were approximately 30% higher than those reported for other patient populations. Total drug clearance and renal drug clearance when normalized to creatinine clearance (CLCR) were similar to those previously reported for other critically ill patients. CLCR was strongly correlated with renal drug clearance (r = 0.94) and total drug clearance (r = 0.95). The extent and degree of burn (percent second or third degree burn) were poorly correlated with all pharmacokinetic parameters with the exception of the volume of distribution at steady state, which was correlated with both total body surface area burn (r = 0.95) and percent second degree burn (r = 0.83). Aztreonam pharmacokinetics are altered as a result of thermal injury; however, CLCR can be used to assess the clearance of aztreonam in burn patients. PMID:2014982

  14. Development of copper based drugs, radiopharmaceuticals and medical materials.

    PubMed

    Szymański, Paweł; Frączek, Tomasz; Markowicz, Magdalena; Mikiciuk-Olasik, Elżbieta

    2012-12-01

    Copper is one of the most interesting elements for various biomedical applications. Copper compounds show vast array of biological actions, including anti-inflammatory, anti-proliferative, biocidal and other. It also offers a selection of radioisotopes, suitable for nuclear imaging and radiotherapy. Quick progress in nanotechnology opened new possibilities for design of copper based drugs and medical materials. To date, copper has not found many uses in medicine, but number of ongoing research, as well as preclinical and clinical studies, will most likely lead to many novel applications of copper in the near future.

  15. Comparative evaluation of glutamate-sensitive radiopharmaceuticals: Technetium-99m-glutamic acid and technetium-99m-diethylenetriaminepentaacetic acid-bis(glutamate) conjugate for tumor imaging.

    PubMed

    Kakkar, Dipti; Tiwari, Anjani K; Chuttani, Krishna; Kaul, Ankur; Singh, Harpal; Mishra, Anil K

    2010-12-01

    Single-photon emission computed tomography has become a significant imaging modality with huge potential to visualize and provide information of anatomic dysfunctions that are predictive of future diseases. This imaging tool is complimented by radiopharmaceuticals/radiosubstrates that help in imaging specific physiological aspects of the human body. The present study was undertaken to explore the utility of technetium-99m (⁹⁹(m)Tc)-labeled glutamate conjugates for tumor scintigraphy. As part of our efforts to further utilize the application of chelating agents, glutamic acid was conjugated with a multidentate ligand, diethylenetriaminepentaacetic acid (DTPA). The DTPA-glutamate conjugate [DTPA-bis(Glu)] was well characterized by IR, NMR, and mass spectroscopy. The biological activity of glutamic acid was compared with its DTPA conjugate by radiocomplexation with ⁹⁹(m)Tc (labeling efficiency ≥98%). In vivo studies of both the radiolabeled complexes ⁹⁹(m)Tc-Glu and ⁹⁹(m)Tc-DTPA-bis(Glu) were then carried out, followed by gamma scintigraphy in New Zealand albino rabbits. Improved serum stability of ⁹⁹(m)Tc-labeled DTPA conjugate indicated that ⁹⁹(m)Tc remained bound to the conjugate up to 24 hours. Blood clearance showed a relatively slow washout of the DTPA conjugate when compared with the labeled glutamate. Biodistribution characteristics of the conjugate in Balb/c mice revealed that DTPA conjugation of glutamic acid favors less accumulation in the liver and bone and rapid renal clearance. Tumor scintigraphy in mice showed increasing tumor accumulation, stable up to 4 hours. These preliminary studies show that ⁹⁹(m)Tc-DTPA-bis(Glu) can be a useful radiopharmaceutical for diagnostic applications in single-photon emission computed tomography imaging.

  16. A physiologically based pharmacokinetic model for lactational transfer of Na-131I

    NASA Astrophysics Data System (ADS)

    Turner, Anita Loretta

    The excretion of radionuclides in human breast milk after administration of radiopharmaceuticals is a concern as a radiation risk to nursing infants. It is not uncommon to administer radiopharmaceuticals to lactating patients due to emergency nuclear medicine investigations such as thyroid complications, kidney failure, and pulmonary embolism. There is a need to quantify the amount of radioactivity translocated into breast milk in cases of ingestion by a breast-fed infant. A physiologically based pharmacokinetic model (PBPK) and a modified International Commission on Radiological Protection (ICRP) model have been developed to predict iodine concentrations in breast milk after ingestion of radioiodine by the mother. In the PBPK model, all compartments are interconnected by blood flow and represent real anatomic tissue regions in the body. All parameters involved are measurable values with physiological or physiochemical meaning such as tissue masses, blood flow rates, partition coefficients and cardiac output. However, some of the parameters such as the partition coefficients and metabolic constants are not available for iodine and had to be inferred from other information. The structure of the PBPK model for the mother consists of the following tissue compartments: gastrointestinal tract, blood, kidney, thyroid, milk, and other tissues. With the exception of the milk compartment, the model for the nursing infant is structured similarly to the mother. The ICRP model describing iodine metabolism in a standard 70-kg man was modified to represent iodine metabolism in a lactating woman and nursing infant. The parameters involved in this model are transfer rates and biological half-lives which are based on experimental observations. The results of the PBPK model and the modified ICRP model describing the lactational transfer of iodine were compared. When administering 1 mCi of Na131I to the lactating mother, the concentration reaches a maximum of 0.1 mCi/liter in 24

  17. Radiopharmaceuticals for radiation synovectomy: Evaluation of two yttrium-90 particulate agents

    SciTech Connect

    Davis, M.A.; Chinol, M.

    1989-06-01

    Radiation synovectomy, a noninvasive therapeutic alternative to surgical synovectomy, has not gained widespread acceptance in the United States because of the lack of a suitable radiopharmaceutical. Two new radioactive particles, (/sup 90/Y)Ca oxalate and (/sup 90/Y)ferric hydroxide macroaggregates (FHMA), were developed in our laboratory and evaluated for size, stability, and joint leakage. More than 90% of the (/sup 90/Y)Ca oxalate particles were in the optimal size range of 1-10 microns, and the unbound activity in serum and synovial fluid was 3.7% to 5.0%. Following injection in rabbit knees, leakage of (/sup 90/Y)Ca oxalate was 5 +/- 2%, with localization primarily in the bone and virtually no uptake by the lymph nodes or liver. Yttrium-90 FHMA particles were larger (95% greater than 10 microns), and at least on a microscopic level, appeared to distribute homogeneously over the articular surface. Leakage of (/sup 90/Y)FHMA was initially less but eventually slightly exceeded that of (/sup 90/Y)Ca oxalate. Nevertheless, both radiopharmaceuticals can provide a satisfactory therapeutic dose to the knee with less than half the leakage and a marked reduction in absorbed dose to nontarget tissues compared to previously tested agents. Ease of preparation, physical characteristics of the /sup 90/Y beta ray, and apparent lack of substantial leakage from the joint make these agents extremely attractive for clinical evaluation in rheumatoid arthritis patients who are unresponsive to medical therapy.

  18. Evaluation of a measurement system for Uranium electrodeposition control to radiopharmaceuticals production

    SciTech Connect

    Tufic Madi Filho; Adonis Marcelo Saliba Silva; Jose Patricio Nahuel Cardenas; Maria da Conceicao Costa Pereira; Valdir Maciel Lopes; Alexandre, P. S.; Diogo, F. S.; Rafael, T. P.; Vitor, O. A; Anderson, F. L.; Lucas, R. S.; Brianna, S.; Eduardo, L. C.

    2015-07-01

    For 2016, studies by international bodies forecast a crisis in the supply of Molybdenum ({sup 99}Mo), which is the generator of {sup 99m}Tc, widely used for medical diagnoses and treatments. As a result, many countries are making efforts to prevent this crisis. Brazil is developing the Brazilian Multipurpose Reactor (RMB) project, under the responsibility of the National Nuclear Energy Commission (CNEN). The RMB is a nuclear reactor for research and production of radioisotopes used in the production of radiopharmaceuticals and radioactive sources, broadly used in industrial and research areas in Brazil. Electrodeposition of uranium is a common practice to create samples for alpha spectrometry and this methodology may be an alternative way to produce targets of low enriched uranium (LEU) to fabricate radiopharmaceuticals, as {sup 99}Mo, used for cancer diagnosis. To study the electrodeposition, a solution of 10 mM uranyl nitrate, in 2-propanol, containing uranium enriched to 2.4% in {sup 235}U, with pH = 1, was prepared and measurements with an alpha spectrometer were performed. These studies are justified by the need to produce {sup 99}Mo since, despite using molybdenum in bulk, Brazil is totally dependent on its import. In this project, we intend to obtain a process that may be technologically feasible to control the radiation targets for {sup 99}Mo production. (authors)

  19. European regulatory framework on the use and development of pharmaceuticals and radiopharmaceuticals for pediatrics.

    PubMed

    Mensonides-Harsema, Marguérite; Otte, Andreas

    2011-01-01

    A survey in 2000 revealed that only about 30% of the prescriptions in the European pediatric population were on the basis of evidence-based medicine (EbM). Less for radiopharmaceuticals and principally for diagnostics, radiologists throughout Europe are referred to the pediatric guidelines of the European Association of Nuclear Medicine (EANM), as none of the frequently used tracers have been evaluated in clinical trials in the different pediatric subgroups. Following a resolution to address the lack of EbM in children, the European Commission published the Pediatric Regulation EC 1901/2006 and its amendment EC 1902/2006, effective from 2007. This regulation foresees the development of evidence-based medicine in the pediatric population. This is effected through a set of principles like the mandatory pediatric investigation plan (PIP) to be included with the market authorization application (MAA), and the pediatric use market authorization (PUMA) for off-patent pharmaceuticals, and to a very small part radiopharmaceuticals with funding possibilities for pediatric-specific research through the 7th Framework Programme (7FP) of the European Union.

  20. Relationship between lipophilicity and brain extraction of C-11-labeled radiopharmaceuticals. [Baboons

    SciTech Connect

    Dischino, D.D.; Welch, M.J.; Kilbourn, M.R.; Raichle, M.E.

    1983-11-01

    The brain extraction of fifteen C-11-labeled compounds during a single capillary transit was studied in adult baboons by external detection of these tracers after injection into the internal carotid artery. The log P/sub oct/ (partition coefficient for octanol/water) values of these compounds range from -0.7 to greater than 4.0. A parabolic relationship was found between the log P/sub oct/value of the C-11-labeled compounds and the fraction of the radiopharmaceutical entering the brain. Compounds with log P/sub oct/ values between 0.9 and 2.5 were found to pass freely across the blood-brain barrier at a cerebral blood flow of 100 ml-min/sup -1/-hg/sup -1/. An apparently decreased extraction of very lipophilic compounds was shown to be related to binding of the tracer to blood components and macromolecules (red blood cells, albumin, etc.). These data suggest that a radiopharmaceutical designed to measure blood flow should have a log P/sub oct/ value of between 0.9 and 2.5.

  1. Technetium-99m-alendronate: a new radiopharmaceutical for bone scanning.

    PubMed

    Arteaga de Murphy, C; Meléndez-Alafort, L; Montoya-Molina, C; Sepúlveda-Méndez, J

    1996-01-01

    The purpose of this paper is to report the preparation of a new technetium-99m-radiopharmaceutical for bone scanning. The chelating agent for 99mTc is a new bisphosphonate, alendronate, 4-amino-1-hydroxy-butylidene-1, 1-bisphosphonate (ABP) used as a treatment for osteoporosis. ABP, because of its amino group, seems to be better suited to form a strong and stable complex with technetium-99m and therefore might be better than 99mTc-etidronate (HEDP) or 99mTc-medronate (MDP) for bone scanning. A sterile dry kit containing APB, a reducing agent and a stabilizer was prepared. The parameters studied were molar concentrations, pH, shelf life, labeling efficiency and radiochemical purity. The oven dried sterile kit was formulated with 5 mg ABP, 0.25 mg stannous fluoride and 0.025 mg gentisic acid at pH 2.5-3.5. The labeling efficiency with 20-1500 MBq of pertechnetate (99mTcO4-) was over 95% at room temperature and was stable for 5 h. Technetium-99m-alendronate was tested in two rabbits and it proved to be a promising new radiopharmaceutical for bone scanning. Work is underway to study 99mTc-ABP biodistribution in a statistically significant number of laboratory animals and, later on, to determine radiopharmacokinetic parameters in normal volunteers.

  2. 11C=O Bonds Made Easily for Positron Emission Tomography Radiopharmaceuticals

    PubMed Central

    Rotstein, Benjamin H.; Liang, Steven H.; Placzek, Michael S.; Hooker, Jacob M.; Gee, Antony D.; Dollé, Frédéric; Wilson, Alan A.; Vasdev, Neil

    2016-01-01

    The positron-emitting radionuclide carbon-11 (11C, t1/2 = 20.3 minutes) possesses the unique potential for radiolabeling of any biological, naturally occurring, or synthetic organic molecule for in vivo positron emission tomography (PET) imaging. Carbon-11 is most often incorporated into small molecules by methylation of alcohol, thiol, amine or carboxylic acid precursors using [11C]methyl iodide or [11C]methyl triflate (generated from [11C]CO2). Consequently, small molecules that lack an easily substituted 11C-methyl group are often considered to have non-obvious strategies for radiolabeling and require a more customized approach. [11C]Carbon dioxide, [11C]carbon monoxide, [11C]cyanide, and [11C]phosgene represent alternative carbon-11 reactants to enable 11C-carbonylation. Methodologies developed for preparation of 11C-carbonyl groups have had a tremendous impact on the development of novel PET radiopharmaceuticals and provided key tools for clinical research. 11C-Carbonyl radiopharmaceuticals based on labeled carboxylic acids, amides, carbamates, and ureas now account for a substantial number of important imaging agents that have seen translation to higher species and clinical research of previously inaccessible targets, which is a testament to the creativity, utility, and practicality of the underlying radiochemistry. PMID:27276357

  3. Grepafloxacin pharmacokinetics in individuals with hepatic dysfunction.

    PubMed

    Efthymiopoulos, C; Bramer, S L; Maroli, A; Flaherty, J F; Wolfe, E; Bass, N; Somberg, K

    1997-01-01

    The pharmacokinetics of grepafloxacin, a new broad spectrum fluoroquinolone antibiotic, were studied in 2 trials involving 14 healthy volunteers, 10 individuals with mild (Child-Pugh Class A) impairment of liver function, and 12 with moderate (Child-Pugh Class B or C) hepatic impairment. All participants received an oral dose of grepafloxacin 400 mg, daily for 7 days, and plasma and urine grepafloxacin concentrations were measured over 7 days. The pooled data from participants with impaired liver function showed that, compared with healthy individuals, peak plasma grepafloxacin concentrations, area under the plasma concentration-time curve and proportion of the dose excreted in the urine were increased. In addition, apparent total clearance was reduced in the presence of hepatic dysfunction. Peak concentrations were increased by 36% and 48% in individuals with Class A and B disease, respectively; the corresponding reductions in clearance were 33% and 55%, respectively. Child-Pugh scores and components of the scores showed no correlation with any pharmacokinetic variables. Based on these findings, we recommend a daily grepafloxacin dose of 400 mg in patients with mild hepatic impairment, irrespective of the severity of infection. Grepafloxacin should not be used in patients with moderate or severe liver disease.

  4. New calculations for internal dosimetry of beta-emitting radiopharmaceuticals.

    PubMed

    Zankl, M; Petoussi-Henss, N; Janzen, T; Uusijärvi, H; Schlattl, H; Li, W B; Giussani, A; Hoeschen, C

    2010-01-01

    The calculation of absorbed dose from internally incorporated radionuclides is based on the so-called specific absorbed fractions (SAFs) which represent the fraction of energy emitted in a given source region that is absorbed per unit mass in a specific target organ. Until recently, photon SAFs were calculated using MIRD-type mathematical phantoms. For electrons, the energy released was assumed to be absorbed locally ('ICRP 30 approach'). For this work, photon and electron SAFs were derived with Monte Carlo simulations in the new male voxel-based reference computational phantom adopted by the ICRP and ICRU. The present results show that the assumption of electrons being locally absorbed is not always true at energies above 300-500 keV. For source/target organ pairs in close vicinity, high-energy electrons escaping from the source organ may result in cross-fire electron SAFs in the same order of magnitude as those from photons. Examples of organ absorbed doses per unit activity are given for (18)F-choline and (123)I-iodide. The impact of the new electron SAFs used for absorbed dose calculations compared with the previously used assumptions was found to be small. The organ dose coefficients for the two approaches differ by not more than 6 % for most organs. Only for irradiation of the urinary bladder wall by activity in the contents, the ICRP 30 approach presents an overestimation of approximately 40-50%.

  5. Rhenium and technetium tricarbonyl, {M(CO)3} (+) (M = Tc, Re), binding to mammalian metallothioneins: new insights into chemical and radiopharmaceutical implications.

    PubMed

    Lecina, Joan; Palacios, Òscar; Atrian, Sílvia; Capdevila, Mercè; Suades, Joan

    2015-04-01

    This paper deals with the binding of the four mammalian metallothioneins (MTs) to the organometallic metal fragment {fac-M(CO)3}(+) (M = (99)Tc, Re), which is highly promising for the preparation of second-generation radiopharmaceuticals. The study of the transmetallation reaction between zinc and rhenium in Zn7-MT1 by means of UV-vis and CD spectroscopy demonstrated the incorporation of the {fac-Re(CO)3}(+) fragment to the MTs. This reaction should be performed at 70 °C to accelerate the reaction rate, a result that is consistent with the reported reactivity of the rhenium fragment. ESI-TOF MS demonstrated the formation of mixed-metal species as Zn6,{Re(CO)3}-MT, Zn6,{Re(CO)3}2-MT, and Zn5,{Re(CO)3}3-MT, as well as the different reactivity of the four MT isoforms. Hence, Zn-MT3 showed the highest reactivity, in agreement with its high Cu-thionein character, whereas Zn-MT2 exhibited the lowest reactivity, in line with its high Zn-thionein character. The reactivity of the Zn-loaded forms of MT1 and MT4 is intermediate between those of MT3 and MT2. The study of the binding of the {fac-(99)Tc(CO)3}(+) fragment to MTs showed a significant and very interesting different reactivity in relation to rhenium. The transmetallation reaction is much more effective with technetium than with rhenium and significant amounts of mixed Zn x ,{(99)Tc(CO)3} y -MT species were formed with the four MT isoforms whereas only MT3 rendered similar amounts of rhenium derivatives. The results obtained in this study support the possible use of technetium for labelling mammalian metallothioneins and also for possible radiopharmaceutical applications.

  6. Harvard--MIT research program in short-lived radiopharmaceuticals

    SciTech Connect

    Not Available

    1991-03-01

    This report describes progress on five projects. The first project showed a 1000 fold concentration of the cationic complex {sup 99m}Tc (MIBI) in heart cell mitochondria vs heart cell cytoplasm, as determined by high resolution electron probe microanalysis. Additional technetium-99m based complexes are being developed and tested. The second project involves evaluating technetium acetylacteonates as potential indicators of cerebral blood flow. An intermediate in the synthesis of a technetium porphyrin complex has been synthesized; an oxotechnetium(V)-2,4-pentanedione complex has been prepared and is currently being characterized. The third project involves using radio labelled antibodies for diagnosis and treatment of cancer. An early discovery was that chloramine-T based iodination protocols resulted in a reversal of the charge on mouse lgGs. Immunoperoxidase-labelled monoclonal antibody MOv 18 was shown to bind specifically to the most frequent ovarian aderon carcinomas, and not to healthy tissue, making this antibody a good candidate for immunotherapy or immunodetection. Work on a specific immunotherapy protocol suffered a setback when one reagent, a {sup 125}I-biotin complex, proved to be unstable in vivo. The fourth project involves labelling antibodies with positron emitting radionuclides. Radiofluorination was accomplished through reductive alkylation of {sup 18}F-aldehyde, or pentafluorophenyl esters. Radioiodination was accomplished using alkyl-tin derivation exchange. The fifth project examined antibody modification for use in radioimmune imaging. Technetium-99m-labelled lgG was shown to be biologically equivalent to Indium-III-labelled lgG for imaging focal sites of inflamation. Also, Indium III labelling of small bioactive peptides was examined as a means of imaging important physiological processes. 44 refs., 2 figs.

  7. Chemistry and biology of Tc-99m renal function radiopharmaceuticals. Final report, May 1, 1982-January 15, 1983

    SciTech Connect

    Not Available

    1983-01-01

    Progress is reported on research conducted during the period May 1, 1982 to January 15, 1983. The chemistry and biology of two possible renal function radiopharmaceuticals, Tc-99m N, N'-bis (mercaptoacetyl)-2,3-diamino-propanoate (Tc-99m CO/sub 2/DADS, 1(X=OH)) and the Tc-99m complex of penicillamine. (ACR)

  8. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling.

    PubMed

    Moss, Darren Michael; Siccardi, Marco

    2014-09-01

    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.

  9. Development of a rhenium-186-labeled MAG3-conjugated bisphosphonate for the palliation of metastatic bone pain based on the concept of bifunctional radiopharmaceuticals.

    PubMed

    Ogawa, Kazuma; Mukai, Takahiro; Arano, Yasushi; Ono, Masahiro; Hanaoka, Hirofumi; Ishino, Seigo; Hashimoto, Kazuyuki; Nishimura, Hiroshi; Saji, Hideo

    2005-01-01

    Rhenium-186-1-hydroxyethylidene-1,1-diphosphonate (186Re-HEDP) has been used for the palliation of metastatic bone pain. Delayed blood clearance and high gastric uptake of radioactivity have been observed upon injection, due to the instability of (186)Re-HEDP in vivo. In this study, on the basis of the concept of bifunctional radiopharmaceuticals, we designed a stable 186Re-mercaptoacetylglycylglycylglycine (MAG3) complex-conjugated bisphosphonate, [[[[(4-hydroxy-4,4-diphosphonobutyl)carbamoylmethyl]carbamoylmethyl]carbamoylmethyl]carbamoylmethanethiolate]oxorhenium(V) (186Re-MAG3-HBP). As a precursor, [1-hydroxy-1-phosphono-4-[2-[2-[2-(2-tritylmercaptoacetylamino)acetylamino]acetylamino]acetylamino]butyl]phosphonic acid (Tr-MAG3-HBP) was synthesized by the conjugation of N-[(tritylmercapto)acetyl]glycylglycylglycine (Tr-MAG3) with the bisphosphonate analogue. After deprotection of the trityl group of Tr-MAG3-HBP, 186Re-labeling was performed by reacting 186ReO4- with SnCl2 in citrate buffer. After purification by HPLC, 186Re-MAG3-HBP showed a radiochemical purity of over 95%. To compare the stability of 186Re-MAG3-HBP and 186Re-HEDP, these (186)Re complexes were incubated in phosphate buffer. No measurable decomposition of 186Re-MAG3-HBP occurred over a 24-h period, while only approximately 30% of 186Re-HEDP remained intact 24 h postincubation. In biodistribution experiments, the radioactivity level of 186Re-MAG3-HBP in bone was significantly higher than that of (186)Re-HEDP. Blood clearance of 186Re-MAG3-HBP was faster than that of 186Re-HEDP. In addition, the gastric accumulation of 186Re-MAG3-HBP radioactivity was lower than that of 186Re-HEDP. In conclusion, 186Re-MAG3-HBP is expected to be a useful radiopharmaceutical for the palliation of metastatic bone pain.

  10. Current activities in the ICRP concerning estimation of radiation doses to patients from radiopharmaceuticals for diagnostic use

    NASA Astrophysics Data System (ADS)

    Mattsson, S.; Johansson, L.; Leide-Svegborn, S.; Liniecki, J.; Nosske, D.; Riklund, K.; Stabin, M.; Taylor, D.

    2011-09-01

    A Task Group within the ICRP Committees 2 and 3 is continuously working to improve absorbed dose estimates to patients investigated with radiopharmaceuticals. The work deals with reviews of the literature, initiation of new or complementary studies of the biokinetics of a compound and dose estimates. Absorbed dose calculations for organs and tissues have up to now been carried out using the MIRD formalism. There is still a lack of necessary biokinetic data from measurements in humans. More time series obtained by nuclear medicine imaging techniques such as whole-body planar gamma-camera imaging, SPECT or PET are highly desirable for this purpose. In 2008, a new addendum to ICRP Publication 53 was published under the name of ICRP Publication 106 containing biokinetic data and absorbed dose information to organs and tissues of patients of various ages for radiopharmaceuticals in common use. That report also covers a number of generic models and realistic maximum models covering other large groups of substances (e.g. "123I-brain receptor substances"). Together with ICRP Publication 80, most radiopharmaceuticals in clinical use at the time of publication were covered except the radioiodine labeled compounds for which the ICRP dose estimates are still found in Publication 53. There is an increasing use of new radiopharmaceuticals, especially PET-tracers and the TG has recently finished its work with biokinetic and dosimetric data for 18F-FET, 18F-FLT and 18F-choline. The work continues now with new data for 11C-raclopride, 11C-PiB and 123I-ioflupan as well as re-evaluation of published data for 82Rb-chloride, 18F-fluoride and radioiodide. This paper summarises published ICRP-information on dose to patients from radiopharmaceuticals and gives some preliminary data for substances under review.

  11. Improved dose-volume histogram estimates for radiopharmaceutical therapy by optimizing quantitative SPECT reconstruction parameters

    NASA Astrophysics Data System (ADS)

    Cheng, Lishui; Hobbs, Robert F.; Segars, Paul W.; Sgouros, George; Frey, Eric C.

    2013-06-01

    In radiopharmaceutical therapy, an understanding of the dose distribution in normal and target tissues is important for optimizing treatment. Three-dimensional (3D) dosimetry takes into account patient anatomy and the nonuniform uptake of radiopharmaceuticals in tissues. Dose-volume histograms (DVHs) provide a useful summary representation of the 3D dose distribution and have been widely used for external beam treatment planning. Reliable 3D dosimetry requires an accurate 3D radioactivity distribution as the input. However, activity distribution estimates from SPECT are corrupted by noise and partial volume effects (PVEs). In this work, we systematically investigated OS-EM based quantitative SPECT (QSPECT) image reconstruction in terms of its effect on DVHs estimates. A modified 3D NURBS-based Cardiac-Torso (NCAT) phantom that incorporated a non-uniform kidney model and clinically realistic organ activities and biokinetics was used. Projections were generated using a Monte Carlo (MC) simulation; noise effects were studied using 50 noise realizations with clinical count levels. Activity images were reconstructed using QSPECT with compensation for attenuation, scatter and collimator-detector response (CDR). Dose rate distributions were estimated by convolution of the activity image with a voxel S kernel. Cumulative DVHs were calculated from the phantom and QSPECT images and compared both qualitatively and quantitatively. We found that noise, PVEs, and ringing artifacts due to CDR compensation all degraded histogram estimates. Low-pass filtering and early termination of the iterative process were needed to reduce the effects of noise and ringing artifacts on DVHs, but resulted in increased degradations due to PVEs. Large objects with few features, such as the liver, had more accurate histogram estimates and required fewer iterations and more smoothing for optimal results. Smaller objects with fine details, such as the kidneys, required more iterations and less

  12. 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.

  13. 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.

  14. Pharmacokinetics and pharmacodynamics of intrathecal ziconotide in chronic pain patients.

    PubMed

    Wermeling, Daniel; Drass, Michael; Ellis, David; Mayo, Martha; McGuire, Dawn; O'Connell, Damian; Hale, Victoria; Chao, Stella

    2003-06-01

    The pharmacokinetics and pharmacodynamics of ziconotide were assessed over a 48-hour period following intrathecal (i.t.) administration (1, 5, 7.5, or 10 micrograms) to 22 patients with chronic, nonmalignant pain. Plasma and cerebrospinal fluid (CSF) samples were obtained over a 24-hour period. Analgesic efficacy was monitored using Visual Analog Scale of Pain Intensity (VASPI) and Category Pain Relief Scores (CPRS) measurements. Pharmacokinetic (PK) parameters were calculated by noncompartmental methods. Plasma ziconotide data were insufficient for PK calculations. In CSF, the median half-life of ziconotide was 4.5 hours. The median CSF clearance and volume of distribution were 0.26 mL/min and 99 mL, respectively. CSF pharmacokinetics of ziconotide were linear, based on cumulative exposure and peak CSF concentrations. A dose-related analgesia was observed. Pharmacokinetic-pharmacodynamic efficacy and safety analyses showed that higher CSF ziconotide concentrations were generally associated with analgesia and increased incidence of nervous system adverse events following a 1-hour i.t. infusion.

  15. The pharmacokinetics of intravenous fenoldopam in healthy, awake cats.

    PubMed

    O'Neill, K E; Labato, M A; Court, M H

    2016-04-01

    Fenoldopam is a selective dopamine-1 receptor agonist that improves diuresis by increasing renal blood flow and perfusion and causing peripheral vasodilation. Fenoldopam has been shown to induce diuresis and be well-tolerated in healthy cats. It is used clinically in cats with oliguric kidney injury at doses extrapolated from human medicine and canine studies. The pharmacokinetics in healthy beagle dogs has been reported; however, pharmacokinetic data in cats are lacking. The goal of this study was to determine pharmacokinetic data for healthy, awake cats receiving an infusion of fenoldopam. Six healthy, awake, client-owned cats aged 2-6 years old received a 120-min constant rate infusion of fenoldopam at 0.8 μg/kg/min followed by a 20-min washout period. Ascorbate stabilized plasma samples were collected during and after the infusion for the measurement of fenoldopam concentration by HPLC with mass spectrometry detection. This study showed that the geometric mean of the volume of distribution, clearance, and half-life (198 mL/kg, 46 mL/kg/min, and 3.0 mins) is similar to pharmacokinetic parameters for humans. No adverse events were noted. Fenoldopam at a constant rate infusion of 0.8 μg/kg per min was well tolerated in healthy cats. Based on the results, further evaluation of fenoldopam in cats with kidney disease is recommended.

  16. Pharmacokinetics of drugs in pregnancy

    PubMed Central

    Feghali, Maisa; Venkataramanan, Raman; Caritis, Steve

    2016-01-01

    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. PMID:26452316

  17. Highway accident involving radiopharmaceuticals near Brookhaven, Mississippi on December 3, 1983

    SciTech Connect

    Mohr, P.B.; Mount, M.E.; Schwartz, M.W.

    1985-04-01

    A rear-end collision occurred between a passenger automobile and a luggage trailer carrying 84 packages, 76 of which contained radiopharmaceuticals, on US Highway 84 near Brookhaven, Mississippi on the afternoon of December 3, 1983. The purpose of this report is to document the mechanical circumstances of the accident, confirm the nature and quantity of radioactive materials involved, and assess the nature of the physical environment to which the packages were exposed and the response of the packages. The report consists of three major sections. The first deals wth the nature and circumstances of the accident and findings of fact. The second gives an accounting and description of the materials involved and the consequences of their exposure. The third gives an assessment and analysis of the mechanisms of damage and the conclusions which may be drawn from the investigation. 4 refs., 24 figs., 4 tabs.

  18. Click-to-Chelate: development of technetium and rhenium-tricarbonyl labeled radiopharmaceuticals.

    PubMed

    Kluba, Christiane A; Mindt, Thomas L

    2013-03-12

    The Click-to-Chelate approach is a highly efficient strategy for the radiolabeling of molecules of medicinal interest with technetium and rhenium-tricarbonyl cores. Reaction of azide-functionalized molecules with alkyne prochelators by the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC; click reaction) enables the simultaneous synthesis and conjugation of tridentate chelating systems for the stable complexation of the radiometals. In many cases, the functionalization of (bio)molecules with the ligand system and radiolabeling can be achieved by convenient one-pot procedures. Since its first report in 2006, Click-to-Chelate has been applied to the development of numerous novel radiotracers with promising potential for translation into the clinic. This review summarizes the use of the Click-to-Chelate approach in radiopharmaceutical sciences and provides a perspective for future applications.

  19. Evaluation of alternative rapid thin layer chromatography systems for quality control of technetium-99m radiopharmaceuticals.

    PubMed

    Mang'era, Kennedy; Wong, Derek; Douglas, David; Franz, Kellie; Biru, Taddese

    2014-04-01

    Whatman 3MM™ and Tec-Control™ systems were evaluated as ITLC-SG alternatives for 99mTc-radiopharmaceuticals. They compare well in accuracy and reproducibility, and are faster and more convenient than ITLC-SG. Tec-Control™ radiochemical purity values for 99mTc-sestamibi were more conservative than ITLC-SG. Full solvent migration was not reproduced for 99mTc-tetrofosmin in Tec-Control™, and for this Whatman 3MM™ is preferred. Developing times were 10-15 min, 7-9 min and ~1min for ITLC-SG, Whatman 3MM™ and Tec-Control™, respectively. Overall, Tec-Control™ strips are preferred due to speed and ease of use.

  20. Cage-like bifunctional chelators, copper-64 radiopharmaceuticals and PET imaging using the same

    SciTech Connect

    Conti, Peter S.; Cai, Hancheng; Li, Zibo; Liu, Shuanglong

    2016-08-02

    Disclosed is a class of versatile Sarcophagine based bifunctional chelators (BFCs) containing a hexa-aza cage for labeling with metals having either imaging, therapeutic or contrast applications radiolabeling and one or more linkers (A) and (B). The compounds have the general formula ##STR00001## where A is a functional group selected from group consisting of an amine, a carboxylic acid, an ester, a carbonyl, a thiol, an azide and an alkene, and B is a functional group selected from the group consisting of hydrogen, an amine, a carboxylic acid, and ester, a carbonyl, a thiol, an azide and an alkene. Also disclosed are conjugate of the BFC and a targeting moiety, which may be a peptide or antibody. Also disclosed are metal complexes of the BFC/targeting moiety conjugates that are useful as radiopharmaceuticals, imaging agents or contrast agents.

  1. Theranostic Radiopharmaceuticals Based on Gold Nanoparticles Labeled with (177)Lu and Conjugated to Peptides.

    PubMed

    Ferro-Flores, Guillermina; Ocampo-García, Blanca E; Santos-Cuevas, Clara L; de María Ramírez, Flor; Azorín-Vega, Erika P; Meléndez-Alafort, Laura

    2015-01-01

    Gold nanoparticles (AuNPs) have been proposed for a variety of medical applications such as localized heat sources for cancer treatment and drug delivery systems. The conjugation of peptides to AuNPs produces stable multimeric systems with target-specific molecular recognition. Lutetium- 177 ((177)Lu) has been successfully used in peptide radionuclide therapy. Recently, (177)Lu-AuNPs conjugated to different peptides have been proposed as a new class of theranostic radiopharmaceuticals. These radioconjugates may function simultaneously as molecular imaging agents, radiotherapy systems and thermal-ablation systems. This article covers advancements in the design, synthesis, physicochemical characterization, molecular recognition assessment and preclinical therapeutic efficacy of gold nanoparticles radiolabeled with (177)Lu and conjugated to RGD (-Arg-Gly-Asp-), Lys(3)-Bombesin and Tat(49-57) peptides.

  2. Complexation study on no-carrier-added astatine with insulin: a candidate radiopharmaceutical.

    PubMed

    Lahiri, Susanta; Roy, Kamalika; Sen, Souvik

    2008-12-01

    No-carrier-added astatine radionuclides produced in the (7)Li-irradiated lead matrix were separated from bulk lead nitrate target by complexing At with insulin, followed by dialysis. The method offers simultaneous separation of At from lead as well as its complexation with insulin. The At-insulin complex might be a potential radiopharmaceutical in the treatment of hepatocellular carcinoma. The stability of At-insulin complex was checked by dialysis against deionized water and Ringer lactate (RL) solution. It has been found that the half-life of At-insulin complex is about approximately 12h, when dialyzed against deionized water and is only 6h, when dialyzed against RL solution having the same composition as blood serum. The 6h half-life of this Insulin-At complex is perfect for killing cancer cells from external cell surfaces as the half-life of internalization of insulin molecule inside the cell is 7-12h.

  3. Scaling animal to human biodistribution of the radiopharmaceutical [68Ga]Ga-PSMA-HBED-CC

    NASA Astrophysics Data System (ADS)

    Parra, Pamela Ochoa; Veloza, Stella

    2016-07-01

    The radiotracer called 68Ga-labelled Glu-urea-Lys(Ahx)-HBED-CC ([68Ga]Ga-PSMA-HBED-CC) is a novel radiophar-maceutical for the detection of prostate cancer lesions by positron emission tomography (PET) imaging. Setting up a cost-effective manual synthesis of this radiotracer and making its clinical translation in Colombia will require two important elements: the evaluation of the procedure to yield a consistent product, meeting standards of radio-chemical purity and low toxicity and then, the evaluation of the radiation dosimetry. In this paper a protocol to extrapolate the biokinetic model made in normal mice to humans by using the computer software for internal dose assessment OLINDA/EXM® is presented as an accurate and standardized method for the calculation of radiation dosimetry estimates.

  4. The role of coordination chemistry in the development of copper and rhenium radiopharmaceuticals.

    PubMed

    Donnelly, Paul S

    2011-02-07

    There are several isotopes of copper and rhenium that are of interest in the development of new molecular imaging or radiotherapeutic agents. This perspective article highlights the role of coordination chemistry in the design of copper and rhenium radiopharmaceuticals engineered to selectively target tissue of interest such as cancer cells or pathological features associated with Alzheimer's disease. The coordination chemistry of copper bis(thiosemicarbazone) derivatives and copper macrocyclic complexes is discussed in terms of their potential application as targeted positron emission tomography tracers for non-invasive diagnostic imaging. A range of rhenium complexes with different ligands with rhenium in different oxidation states are introduced and their potential to be translated to new radiotherapeutic agents discussed.

  5. Simple method to quantitate iodine-124 contamination in iodine-123 radiopharmaceuticals

    SciTech Connect

    Palmer, D.W.; Rao, S.A.

    1985-08-01

    Iodine-123 (/sup 123/I) produced by the /sup 124/Te(p,2n)/sup 123/I reaction contains several percent /sup 124/I radionuclidic contamination at the time of imaging. Since /sup 124/I degrades the quality of the images and causes unnecessary radiation absorbed dose to the patient, it is important to know the amount present in radiopharmaceuticals at the time of administration. A simple approach is described which uses a radionuclide dose calibrator and lead shield. The sample is assayed both shielded and unshielded and the ratio of readings depends uniquely upon the percent /sup 124/I present. The technique can be adopted for any type of dose calibrator, sample container, and Pb shield, but use of the numeric constants reported here should be restricted to the specified equipment.

  6. In vivo nanoparticle-mediated radiopharmaceutical-excited fluorescence molecular imaging

    NASA Astrophysics Data System (ADS)

    Hu, Zhenhua; Qu, Yawei; Wang, Kun; Zhang, Xiaojun; Zha, Jiali; Song, Tianming; Bao, Chengpeng; Liu, Haixiao; Wang, Zhongliang; Wang, Jing; Liu, Zhongyu; Liu, Haifeng; Tian, Jie

    2015-06-01

    Cerenkov luminescence imaging utilizes visible photons emitted from radiopharmaceuticals to achieve in vivo optical molecular-derived signals. Since Cerenkov radiation is weak, non-optimum for tissue penetration and continuous regardless of biological interactions, it is challenging to detect this signal with a diagnostic dose. Therefore, it is challenging to achieve useful activated optical imaging for the acquisition of direct molecular information. Here we introduce a novel imaging strategy, which converts γ and Cerenkov radiation from radioisotopes into fluorescence through europium oxide nanoparticles. After a series of imaging studies, we demonstrate that this approach provides strong optical signals with high signal-to-background ratios, an ideal tissue penetration spectrum and activatable imaging ability. In comparison with present imaging techniques, it detects tumour lesions with low radioactive tracer uptake or small tumour lesions more effectively. We believe it will facilitate the development of nuclear and optical molecular imaging for new, highly sensitive imaging applications.

  7. The growing impact of bioorthogonal click chemistry on the development of radiopharmaceuticals.

    PubMed

    Zeng, Dexing; Zeglis, Brian M; Lewis, Jason S; Anderson, Carolyn J

    2013-06-01

    Click chemistry has become a ubiquitous chemical tool with applications in nearly all areas of modern chemistry, including drug discovery, bioconjugation, and nanoscience. Radiochemistry is no exception, as the canonical Cu(I)-catalyzed azide-alkyne cycloaddition, strain-promoted azide-alkyne cycloaddition, inverse electron demand Diels-Alder reaction, and other types of bioorthogonal click ligations have had a significant impact on the synthesis and development of radiopharmaceuticals. This review will focus on recent applications of click chemistry ligations in the preparation of imaging agents for SPECT and PET, including small molecules, peptides, and proteins labeled with radionuclides such as (18)F, (64)Cu, (111)In, and (99m)Tc.

  8. Receptor-specific positron emission tomography radiopharmaceuticals: /sup 75/Br-labeled butyrophenone neuroleptics

    SciTech Connect

    Moerlein, S.M.; Stoecklin, G.; Weinhard, K.; Pawlik, G.; Heiss, W.D.

    1985-11-01

    Cerebral dopaminergic D/sub 2/ receptors are involved in several common disease states, such as schizophrenia, Parkinson's disease, and Huntington's chorea. The use of radiolabeled D/sub 2/ receptor-binding ligands with positron emission tomography (PET) to noninvasively quantitate D/sub 2/ receptor densities thus has potential application in medicine. Butyrophenone neuroleptics have a high in vitro and in vivo binding affinity for cerebral D/sub 2/ receptors, and due to the useful chemical and nuclear decay properties of /sup 74/Br (76% ..beta../sup +/, half-life = 1.6 h), the authors have evaluated radiobrominated bromospiperone (BSP), brombenperidol (BBP), and bromperidol (BP) as radiopharmaceuticals for use with PET.

  9. Hydroxypyridinone Chelators: From Iron Scavenging to Radiopharmaceuticals for PET Imaging with Gallium-68

    PubMed Central

    Cusnir, Ruslan; Imberti, Cinzia; Hider, Robert C.; Blower, Philip J.; Ma, Michelle T.

    2017-01-01

    Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe3+ sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of iron overload disease. Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe3+ at very low iron concentrations, and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the positron emitting radiometal, 68Ga3+, which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex 68Ga3+ at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of 68Ga PET radiopharmaceuticals. 68Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images. PMID:28075350

  10. Design Features Of Microfluidic Reactor For [18F]FDG Radiopharmaceutical Synthesis

    NASA Astrophysics Data System (ADS)

    Oh, J. H.; Lee, B. N.; Nam, K. R.; Attla, G. A.; Lee, K. C.; Cjai, J. S.

    2011-06-01

    Microfluidic reactor exhibits advantages for radiopharmaceutical synthesis. Microfluidic chips can reduce the time for radiosynthesis using tiny quantities of chemical compounds. It also has a good heat transfer, performance and provides an integrated system including synthesis, separation, and purification. These advantages make FDG production. So we have designed a microreactor chip which included the whole chemical processing; water evaporation, solvent exchange, radiofluorination and so on. It was designed by using a commercial 3D CAD modeling program CATIA V5, heat transfer performance was analyzed by ANSYS, and CFX was used for analyzing fluid performance. This paper described the design of FDG synthesis system on a microchip, the relevant locations of its parts, both heat and fluid performance efficiency analysis.

  11. Effect of altered thyroid status on the transport of hepatobiliary radiopharmaceuticals

    SciTech Connect

    Pahuja, D.N.; Noronha, O.P.

    1985-10-01

    The effect of induced hypothyroidism (by feeding an antithyroid drug-propylthiouracil) on the transport and clearance of the routinely used hepatobiliary radiopharmaceuticals--radioiodinated iodine- T (131I) rose bengal and technetium-99m-N-(4-n-butylphenylcarbamoylmethyl) iminodiacetate, was studied in the rats. Hypothyroidism was associated with depressed growth and retarded clearance of these radiotracers from the in vivo system. Treatment of the hypothyroid rats with thyroxine (2-5 micrograms/100 g b.w. day) for 6 wk, restored these parameters towards normal values. These data suggest that delayed clearance of these hepatobiliary tracers could be related to reduced metabolic rate accompanied with the hypotonia and hypomotility of intestine normally observed in the hypothyroid state.

  12. Generators and automated generator systems for production and on-line injections of pet radiopharmaceuticals

    NASA Astrophysics Data System (ADS)

    Shimchuk, G.; Shimchuk, Gr; Pakhomov, G.; Avalishvili, G.; Zavrazhnov, G.; Polonsky-Byslaev, I.; Fedotov, A.; Polozov, P.

    2017-01-01

    One of the prospective directions of PET development is using generator positron radiating nuclides [1,2]. Introduction of this technology is financially promising, since it does not require expensive special accelerator and radiochemical laboratory in the medical institution, which considerably reduces costs of PET diagnostics and makes it available to more patients. POZITOM-PRO RPC LLC developed and produced an 82Sr-82Rb generator, an automated injection system, designed for automatic and fully-controlled injections of 82RbCl produced by this generator, automated radiopharmaceutical synthesis units based on generated 68Ga produced using a domestically-manufactured 68Ge-68Ga generator for preparing two pharmaceuticals: Ga-68-DOTA-TATE and Vascular Ga-68.

  13. Differential renal function in unilateral renal injury: possible effects of radiopharmaceutical choice. [Rats

    SciTech Connect

    Taylor, A. Jr.; Lallone, R.

    1985-01-01

    An abnormal filtration fraction or a significant divergence between a kidney's ability to extract Tc-99m dimercaptosuccinic acid (DMSA) and other function parameters, such as the glomerular filtration rate (GFR) or the effective renal plasma flow (ERPF, could lead to different estimates of relative or absolute renal function, depending on the radiopharmaceutical administered. To evaluate this possible divergence, the authors measured the relative GFR (I-125 iothalamate), ERPF (I-131 hippurate), and Tc-99m DMSA accumulation in adult male Sprague-Dawley rats with unilateral ureteral obstruction or unilateral ischemia at various times after renal injury. The relative ERPF of the obstructed kidney was significantly greater than the relative GFR at all time periods studied; significant but less dramatic differences were noted comparing DMSA with GFR in obstruction and DMSA and ERPF with GRF in ischemia.

  14. Radioprotective effect of the Barbados Cherry (Malpighia glabra L.) against radiopharmaceutical Iodine-131 in Wistar rats in vivo

    PubMed Central

    2014-01-01

    Background The increasing consumption of fruits and vegetables has contributed to the improvement of populational health, due in part, to the abundance of antioxidants in these foods. Antioxidants reduce the level of oxidative damage to DNA caused by free radicals and ionizing radiation, including the radioisotope iodine-131 (131I). This isotope is used for the diagnosis and treatment of thyroid injuries, such as hyperthyroidism and cancer. Methods This study aimed to evaluate the radioprotective and cytotoxic activity of acute and subchronic treatments with Barbados Cherry (BC) (Malpighia glabra L.) fruit juice (5 mg), which is rich in potent antioxidants such as vitamin C, phenols, carotenoids, anthocyanins and yellow flavonoids and its activity against the mutagenic activity of the therapeutic dose of 25 μCi of radioiodine for hyperthyroidism. The test system used was the bone marrow cells of Wistar rats (Rattus norvegicus) that were treated in vivo by gavage. Results BC showed radioprotective activity in acute treatments, which is most likely due to the joint action of its antioxidant components. In subchronic treatments, the continuous treatment presented an effective radioprotective activity, which was significantly different from treatment with the radiopharmaceutical only. Treatment with BC prior to (PRE) and simultaneous with (SIM) ionizing radiation decreased the number of induced chromosomal alterations, while post-treatment produced no protective effect. In addition, BC exhibited no cytotoxic activity. Conclusions These data serve as evidence that BC can be used as a preventive health measure to improve public health quality by countering the action of inevitable exposure to mutagens, such as 131I. PMID:24479389

  15. Implementation and validation of collapsed cone superposition for radiopharmaceutical dosimetry of photon emitters.

    PubMed

    Sanchez-Garcia, Manuel; Gardin, Isabelle; Lebtahi, Rachida; Dieudonné, Arnaud

    2015-10-21

    Two collapsed cone (CC) superposition algorithms have been implemented for radiopharmaceutical dosimetry of photon emitters. The straight CC (SCC) superposition method uses a water energy deposition kernel (EDKw) for each electron, positron and photon components, while the primary and scatter CC (PSCC) superposition method uses different EDKw for primary and once-scattered photons. PSCC was implemented only for photons originating from the nucleus, precluding its application to positron emitters. EDKw are linearly scaled by radiological distance, taking into account tissue density heterogeneities. The implementation was tested on 100, 300 and 600 keV mono-energetic photons and (18)F, (99m)Tc, (131)I and (177)Lu. The kernels were generated using the Monte Carlo codes MCNP and EGSnrc. The validation was performed on 6 phantoms representing interfaces between soft-tissues, lung and bone. The figures of merit were γ (3%, 3 mm) and γ (5%, 5 mm) criterions corresponding to the computation comparison on 80 absorbed doses (AD) points per phantom between Monte Carlo simulations and CC algorithms. PSCC gave better results than SCC for the lowest photon energy (100 keV). For the 3 isotopes computed with PSCC, the percentage of AD points satisfying the γ (5%, 5 mm) criterion was always over 99%. A still good but worse result was found with SCC, since at least 97% of AD-values verified the γ (5%, 5 mm) criterion, except a value of 57% for the (99m)Tc with the lung/bone interface. The CC superposition method for radiopharmaceutical dosimetry is a good alternative to Monte Carlo simulations while reducing computation complexity.

  16. Pharmacokinetics and radiation dosimetry of 99Tcm-labelled monoclonal antibody B43.13 in ovarian cancer patients.

    PubMed

    McQuarrie, S A; Baum, R P; Niesen, A; Madiyalakan, R; Korz, W; Sykes, T R; Sykes, C J; Hör, G; McEwan, A J; Noujaim, A A

    1997-09-01

    OVAREX MAb B43.13 is a new radiopharmaceutical based on a monoclonal antibody (MAb-B43.13) known to recognize CA 125, a tumour antigen associated with epithelial ovarian cancer. This MAb is capable of facile radiolabelling with 99Tcm and has been shown previously to localize in the tumours of ovarian cancer patients. The present study was initiated to measure the pharmacokinetics of this MAb in the serum of 10 patients with primary or metastatic ovarian cancer. A two-compartment model was found to be best at representing the biodistribution of the 99Tcm-labelled MAb, yielding a 2.6 h distribution phase half-life and a 31.3 h elimination phase half-life. The serum and renal clearances for 99Tcm-MAb-B43.13 were 121 and 53 ml h-1 respectively. These parameters were compared with a similar model developed from the serum values of the MAb itself (determined using an ELISA detection method). Based on the serum pharmacokinetics of 99Tcm-MAb-B43.13 and whole-body planar gamma camera images, an estimate of the radiation dose from 99Tcm was calculated using standard MIRD schema. The organs demonstrating significant 99Tcm uptake included the liver, kidneys, heart and spleen. The whole-body dose was similar to other 99Tcm-labelled MAbs.

  17. Dynamic 99mTc-MAG3 renography: images for quality control obtained by combining pharmacokinetic modelling, an anthropomorphic computer phantom and Monte Carlo simulated scintillation camera imaging

    NASA Astrophysics Data System (ADS)

    Brolin, Gustav; Sjögreen Gleisner, Katarina; Ljungberg, Michael

    2013-05-01

    In dynamic renal scintigraphy, the main interest is the radiopharmaceutical redistribution as a function of time. Quality control (QC) of renal procedures often relies on phantom experiments to compare image-based results with the measurement setup. A phantom with a realistic anatomy and time-varying activity distribution is therefore desirable. This work describes a pharmacokinetic (PK) compartment model for 99mTc-MAG3, used for defining a dynamic whole-body activity distribution within a digital phantom (XCAT) for accurate Monte Carlo (MC)-based images for QC. Each phantom structure is assigned a time-activity curve provided by the PK model, employing parameter values consistent with MAG3 pharmacokinetics. This approach ensures that the total amount of tracer in the phantom is preserved between time points, and it allows for modifications of the pharmacokinetics in a controlled fashion. By adjusting parameter values in the PK model, different clinically realistic scenarios can be mimicked, regarding, e.g., the relative renal uptake and renal transit time. Using the MC code SIMIND, a complete set of renography images including effects of photon attenuation, scattering, limited spatial resolution and noise, are simulated. The obtained image data can be used to evaluate quantitative techniques and computer software in clinical renography.

  18. Dynamic (99m)Tc-MAG3 renography: images for quality control obtained by combining pharmacokinetic modelling, an anthropomorphic computer phantom and Monte Carlo simulated scintillation camera imaging.

    PubMed

    Brolin, Gustav; Gleisner, Katarina Sjögreen; Ljungberg, Michael

    2013-05-21

    In dynamic renal scintigraphy, the main interest is the radiopharmaceutical redistribution as a function of time. Quality control (QC) of renal procedures often relies on phantom experiments to compare image-based results with the measurement setup. A phantom with a realistic anatomy and time-varying activity distribution is therefore desirable. This work describes a pharmacokinetic (PK) compartment model for (99m)Tc-MAG3, used for defining a dynamic whole-body activity distribution within a digital phantom (XCAT) for accurate Monte Carlo (MC)-based images for QC. Each phantom structure is assigned a time-activity curve provided by the PK model, employing parameter values consistent with MAG3 pharmacokinetics. This approach ensures that the total amount of tracer in the phantom is preserved between time points, and it allows for modifications of the pharmacokinetics in a controlled fashion. By adjusting parameter values in the PK model, different clinically realistic scenarios can be mimicked, regarding, e.g., the relative renal uptake and renal transit time. Using the MC code SIMIND, a complete set of renography images including effects of photon attenuation, scattering, limited spatial resolution and noise, are simulated. The obtained image data can be used to evaluate quantitative techniques and computer software in clinical renography.

  19. Pharmacokinetic interactions of flunixin meglumine and enrofloxacin in ICR mice.

    PubMed

    Ogino, Tomoe; Arai, Toshiro

    2007-04-01

    We examined the pharmacokinetic interactions of enrofloxacin and flunixin in male ICR mice that were subcutaneously (SC) administered with both or either one of the drugs. The experiments were performed on the following three groups: flunixin alone (2 mg/kg, SC), combination of flunixin (2 mg/kg, SC) and enrofloxacin (10 mg/kg, SC), and enrofloxacin alone (10 mg/kg, SC). Blood samples were collected at 5, 15 and 30 min, and 1, 2, 3, 4, 5 and 6 h after the drug administration, and the pharmacokinetic parameters of flunixin and enrofloxacin were evaluated from the plasma drug concentrations. Significant changes were detected in the pharmacokinetics of flunixin following its coadministration with enrofloxacin. Coadministration of flunixin and enrofloxacin resulted in a 41% increase of the area under the curve (AUC) and a 53% extension of the terminal half-life of flunixin; moreover, flunixin attained the maximum plasma drug concentration 2.75 times faster than when administered alone. The terminal rate constant and the maximum plasma drug concentration showed significant decreases of 34% and 33%, respectively, following the coadministration of enrofloxacin and flunixin as compared to those following the administration of flunixin alone. In contrast, no significant difference in the pharmacokinetics of enrofloxacin was detected following its coadministration with flunixin, as compared to those following the administration of enrofloxacin alone. Following the administration of enrofloxacin alone or its coadministration with flunixin, the plasma level of ciprofloxacin, the metabolite of enrofloxacin, was very low or undetectable. In conclusion, the pharmacokinetics of flunixin in ICR mice are altered by the coadministration of flunixin and enrofloxacin.

  20. 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

  1. A Treatment Planning Method for Sequentially Combining Radiopharmaceutical Therapy and External Radiation Therapy;External beam therapy; Radiopharmaceutical therapy; Three-dimensional dosimetry; Treatment planning

    SciTech Connect

    Hobbs, Robert F.; McNutt, Todd; Baechler, Sebastien; He Bin; Esaias, Caroline E.; Frey, Eric C.; Loeb, David M.; Wahl, Richard L.; Shokek, Ori; Sgouros, George

    2011-07-15

    Purpose: Effective cancer treatment generally requires combination therapy. The combination of external beam therapy (XRT) with radiopharmaceutical therapy (RPT) requires accurate three-dimensional dose calculations to avoid toxicity and evaluate efficacy. We have developed and tested a treatment planning method, using the patient-specific three-dimensional dosimetry package 3D-RD, for sequentially combined RPT/XRT therapy designed to limit toxicity to organs at risk. Methods and Materials: The biologic effective dose (BED) was used to translate voxelized RPT absorbed dose (D{sub RPT}) values into a normalized total dose (or equivalent 2-Gy-fraction XRT absorbed dose), NTD{sub RPT} map. The BED was calculated numerically using an algorithmic approach, which enabled a more accurate calculation of BED and NTD{sub RPT}. A treatment plan from the combined Samarium-153 and external beam was designed that would deliver a tumoricidal dose while delivering no more than 50 Gy of NTD{sub sum} to the spinal cord of a patient with a paraspinal tumor. Results: The average voxel NTD{sub RPT} to tumor from RPT was 22.6 Gy (range, 1-85 Gy); the maximum spinal cord voxel NTD{sub RPT} from RPT was 6.8 Gy. The combined therapy NTD{sub sum} to tumor was 71.5 Gy (range, 40-135 Gy) for a maximum voxel spinal cord NTD{sub sum} equal to the maximum tolerated dose of 50 Gy. Conclusions: A method that enables real-time treatment planning of combined RPT-XRT has been developed. By implementing a more generalized conversion between the dose values from the two modalities and an activity-based treatment of partial volume effects, the reliability of combination therapy treatment planning has been expanded.

  2. 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

  3. Population pharmacokinetics of abacavir in pregnant women.

    PubMed

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

    2014-10-01

    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.

  4. 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…

  5. Applying pharmacokinetics to veterinary clinical practice.

    PubMed

    Trepanier, Lauren A

    2013-09-01

    This article describes clinical examples in which pharmacokinetic parameters can be used to optimize veterinary patient care. Specific applications include extrapolating drug dosages, optimizing therapy with therapeutic drug monitoring, interpreting pharmacokinetic information provided by drug labels and pharmaceutical companies, and adjusting drug dosages in patients with hepatic or renal failure.

  6. Absence of pharmacokinetic interaction between intravenous peramivir and oral oseltamivir or rimantadine in humans.

    PubMed

    Atiee, George; Lasseter, Kenneth; Baughman, Sharon; McCullough, Amy; Collis, Phil; Hollister, Alan; Hernandez, Jaime

    2012-09-01

    Peramivir, an intravenously administered neuraminidase inhibitor, may be used concomitantly with other influenza antivirals. Two studies were conducted to assess the potential for pharmacokinetic interactions of peramivir when coadministered with oseltamivir or rimantadine. Twenty-one healthy subjects were enrolled in each randomized, open-label, crossover study, and they received 1 intravenous dose of peramivir (600 mg), 1 oral dose of oseltamivir (75 mg) or rimantadine (100 mg), or a combination of peramivir with oseltamivir or rimantadine. Assessment of the 90% confidence interval for the geometric mean ratio of peramivir and oseltamivir carboxylate or rimantadine pharmacokinetic parameters showed no effect of oseltamivir or rimantadine on the pharmacokinetics of peramivir and no effect of peramivir on the pharmacokinetics of oseltamivir carboxylate or rimantadine. The drugs were well tolerated. These results suggest no reason to expect an effect of concomitant administration of oseltamivir or rimantadine on the safety profile of peramivir in patients with influenza.

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

    PubMed

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

    2013-10-01

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

  8. Elucidating the Plasma and Liver Pharmacokinetics of Simeprevir in Special Populations Using Physiologically Based Pharmacokinetic Modelling.

    PubMed

    Snoeys, Jan; Beumont, Maria; Monshouwer, Mario; Ouwerkerk-Mahadevan, Sivi

    2016-11-29

    The disposition of simeprevir (SMV) in humans is characterised by cytochrome P450 3A4 metabolism and hepatic uptake by organic anion transporting polypeptide 1B1/3 (OATP1B1/3). This study was designed to investigate SMV plasma and liver exposure upon oral administration in subjects infected with hepatitis C virus (HCV), in subjects of Japanese or Chinese origin, subjects with organ impairment and subjects with OATP genetic polymorphisms, using physiologically based pharmacokinetic modelling. Simulations showed that compared with healthy Caucasian subjects, SMV plasma exposure was 2.4-, 1.7-, 2.2- and 2.0-fold higher, respectively, in HCV-infected Caucasian subjects, in healthy Japanese, healthy Chinese and subjects with severe renal impairment. Further simulations showed that compared with HCV-infected Caucasian subjects, SMV plasma exposure was 1.6-fold higher in HCV-infected Japanese subjects. In subjects with OATP1B1 genetic polymorphisms, no noteworthy changes in SMV pharmacokinetics were observed. Simulations suggested that liver concentrations in Caucasians with HCV are 18 times higher than plasma concentrations.

  9. Obstetric analgesia. Clinical pharmacokinetic considerations.

    PubMed

    Kanto, J

    1986-01-01

    All drugs used in obstetric analgesia are more or less lipophilic, their site of action is in the central nervous system, and they have good membrane penetrability in the fetomaternal unit. Thus the dose and method of administration as well as the duration of treatment are important clinical determinants of drug effects in the fetus and newborn. In the past, too much emphasis has been placed on fetomaternal blood concentration ratios of different agents; it is now appreciated that the extent of fetal tissue distribution and the neonatal elimination rate are pharmacokinetically much more important. Extensive fetal tissue distribution is reflected in a low fetomaternal drug concentration ratio, which may be followed by prolonged neonatal elimination of the drug. Currently, the most effective and safest method for obstetric analgesia is regional epidural administration of bupivacaine or lignocaine (lidocaine); only low doses are needed and the newborn is able to handle these agents efficiently. On the basis of pharmacokinetic and neurobehavioural assessments, inhalational anaesthetic agents appear to be more attractive than pethidine (meperidine) or benzodiazepines. Intermittent administration and fast pulmonary elimination of inhalational agents ensure that long-lasting residual effects are unlikely to occur. The kinetics of epidural and intrathecal opiates explain the problems associated with their use in obstetrics. Among the newer drugs used in obstetric analgesia, the properties of meptazinol and isoflurane appear interesting and these agents warrant further study. All drugs used in obstetric analgesia have a potentially detrimental effect on the neonate and, therefore, knowledge of fetal and neonatal pharmacokinetics is of importance to the clinician.

  10. Microdosing: the new pharmacokinetic paradigm?

    PubMed

    Zanni, Guido R; Wick, Jeannette Y

    2006-10-01

    Numerous market factors have converged to create a need for change in the drug development process. Public scrutiny, high failure rates for investigational agents, and concern about the use of animals in research, are just a few. In response, some changes in this process are being made. Microdosing--administering very small, radiolabeled doses of investigational agents to humans--is one change that has the potential to save time and money. It is used to elucidate the pharmacokinetic profile of agents. Not all experts agree that it will live up to its promise, but the potential is great.

  11. A new approach to the analysis of radiopharmaceuticals. Final technical report, January 15, 1987--June 30, 1991

    SciTech Connect

    Jones, A.G.; Davison, A.; Costello, C.E.

    1998-03-01

    The objective of this research was to investigate analytical techniques that could be used in the study of both the basic chemistry and the radiopharmaceutical chemistry of {sup 99m}Tc. First funded in 1981, the work focused initially upon the use of high performance liquid chromatography (HPLC) and various forms of mass spectrometry for the identification of technetium species. This funding allowed the authors to combine HPLC and mass spectrometry to identify radiopharmaceuticals which, although in clinical use, had not previously been characterized. Other techniques that have been examined include resonance Raman spectroscopy and, more significantly, {sup 99}Tc nuclear magnetic resonance spectroscopy (NMR), with the latter not only being used in purely chemical experiments but also in biologic studies. In 1985 a grant to the Department of Chemistry at MIT from DOE allowed the purchase of an X-ray diffractometer and access to this instrument has enabled them to broaden the analytical base with routine structural determinations.

  12. Modeling of Corneal and Retinal Pharmacokinetics after Periocular Drug Administration

    PubMed Central

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

    2012-01-01

    Purpose To develop pharmacokinetics models to describe the disposition of small lipophilic molecules in the cornea and retina after periocular (subconjunctival or posterior subconjunctival) administration. Methods Compartmental pharmacokinetics analysis was performed on the corneal and retinal data obtained after periocular administration of 3 mg of celecoxib (a selective COX-2 inhibitor) to Brown Norway (BN) rats. Berkeley Madonna, a differential and difference equation–based modeling software, was used for the pharmacokinetics modeling. The data were fit to different compartment models with first-order input and disposition, and the best fit was selected on the basis of coefficient of regression and Akaike information criteria (AIC). The models were validated by using the celecoxib data from a prior study in Sprague-Dawley (SD) rats. The corneal model was also fit to the corneal data for prednisolone at a dose of 2.61 mg in albino rabbits, and the model was validated at two other doses of prednisolone (0.261 and 26.1 mg) in these rabbits. Model simulations were performed with the finalized model to understand the effect of formulation on corneal and retinal pharmacokinetics after periocular administration. Results Celecoxib kinetics in the BN rat cornea can be described by a two-compartment (periocular space and cornea, with a dissolution step for periocular formulation) model, with parallel elimination from the cornea and the periocular space. The inclusion of a distribution compartment or a dissolution step for celecoxib suspension did not lead to an overall improvement in the corneal data fit compared with the two-compartment model. The more important parameter for enhanced fit and explaining the apparent lack of an increase phase in the corneal levels is the inclusion of the initial leak-back of the dose from the periocular space into the precorneal area. The predicted celecoxib concentrations from this model also showed very good correlation (r = 0

  13. (18)F-labeled positron emission tomographic radiopharmaceuticals in oncology: an overview of radiochemistry and mechanisms of tumor localization.

    PubMed

    Vallabhajosula, Shankar

    2007-11-01

    Molecular imaging is the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in a living system. At present, positron emission tomography/computed tomography (PET/CT) is one the most rapidly growing areas of medical imaging, with many applications in the clinical management of patients with cancer. Although [(18)F]fluorodeoxyglucose (FDG)-PET/CT imaging provides high specificity and sensitivity in several kinds of cancer and has many applications, it is important to recognize that FDG is not a "specific" radiotracer for imaging malignant disease. Highly "tumor-specific" and "tumor cell signal-specific" PET radiopharmaceuticals are essential to meet the growing demand of radioisotope-based molecular imaging technology. In the last 15 years, many alternative PET tracers have been proposed and evaluated in preclinical and clinical studies to characterize the tumor biology more appropriately. The potential clinical utility of several (18)F-labeled radiotracers (eg, fluoride, FDOPA, FLT, FMISO, FES, and FCH) is being reviewed by several investigators in this issue. An overview of design and development of (18)F-labeled PET radiopharmaceuticals, radiochemistry, and mechanism(s) of tumor cell uptake and localization of radiotracers are presented here. The approval of clinical indications for FDG-PET in the year 2000 by the Food and Drug Administration, based on a review of literature, was a major breakthrough to the rapid incorporation of PET into nuclear medicine practice, particularly in oncology. Approval of a radiopharmaceutical typically involves submission of a "New Drug Application" by a manufacturer or a company clearly documenting 2 major aspects of the drug: (1) manufacturing of PET drug using current good manufacturing practices and (2) the safety and effectiveness of a drug with specific indications. The potential routine clinical utility of (18)F-labeled PET radiopharmaceuticals depends also on

  14. Species differences in pharmacokinetics and drug teratogenesis

    SciTech Connect

    Nau, H.

    1986-12-01

    Interspecies differences in regard to the teratogenicity of drugs can be the result of differing pharmacokinetic processes that determine the crucial concentration-time relationships in the embryo. Maternal absorption, as well as distribution, of the drugs does not usually show great species differences. The first-pass effect after oral application is often more pronounced in animals than man (e.g., valproic acid, 13-cis-retinoic acid), although in some cases the reverse was found (e.g., hydrolysis of valpromide). Existing differences can be adjusted by appropriate choice of the administration route and measurements of drug levels. Many variables determine the placental transfer of drugs: developmental stage, type of placenta, properties of the drug. Even closely related drugs (e.g., retinoids) may differ greatly in regard to placental transfer. Maternal protein binding is an important determinant of placental transfer, since only the free concentration in maternal plasma can equilibrate with the embryo during organogenesis; this parameter differs greatly across species. Laboratory animals usually have a much higher rate of drug elimination than man. Drastic drug level fluctuations are therefore present during teratogenicity testing in animals, but not to do the same degree in human therapy. It must, therefore, be investigated if peak concentrations (such as for valproic acid and possibly caffeine) or the area under the concentration-time curve (AUC) (such as for cyclophosphamide and possibly retinoids) correlate with the teratogenic response. Only then is a rational and scientific basis for interspecies comparison possible. It is concluded that the prediction of the human response based on animal studies can be improved by consideration of the appropriate pharmacokinetic determinants.

  15. Species differences in pharmacokinetics and drug teratogenesis.

    PubMed Central

    Nau, H

    1986-01-01

    Interspecies differences in regard to the teratogenicity of drugs can be the result of differing pharmacokinetic processes that determine the crucial concentration-time relationships in the embryo. Maternal absorption, as well as distribution, of the drugs does not usually show great species differences. The first-pass effect after oral application is often more pronounced in animals than man (e.g., valproic acid, 13-cis-retinoic acid), although in some cases the reverse was found (e.g., hydrolysis of valpromide). Existing differences can be adjusted by appropriate choice of the administration route and measurements of drug levels. Many variables determine the placental transfer of drugs: developmental stage, type of placenta, properties of the drug. Even closely related drugs (e.g., retinoids) may differ greatly in regard to placental transfer. Maternal protein binding is an important determinant of placental transfer, since only the free concentration in maternal plasma can equilibrate with the embryo during organogenesis; this parameter differs greatly across species (e.g., valproic acid: five times higher free fractions in mouse and hamster than in monkey and man). The metabolic pattern has not yet been demonstrated to be a major cause of species differences, although recent evidence on phenytoin and thalidomide support the hypothesis that some species differences can be the result of differing activation/deactivation pathways. Laboratory animals usually have a much higher rate of drug elimination than man. Drastic drug level fluctuations are therefore present during teratogenicity testing in animals, but not to the same degree in human therapy. It must, therefore, be investigated if peak concentrations (such as for valproic acid and possibly caffeine) or the area under the concentration-time curve (AUC) (such as for cyclophosphamide and possibly retinoids) correlate with the teratogenic response. Only then is a rational and scientific basis for interspecies

  16. Pharmacokinetics of fenoterol in pregnant women.

    PubMed

    von Mandach, U; Böni, R; Danko, J; Huch, R; Huch, A

    1995-02-01

    The beta 2-sympathomimetic drug fenoterol (fenoterol hydrobromide, CAS 1944-12-3, Partusisten) is routinely used to inhibit uterine contractions (tocolysis). Investigations of plasma concentrations of those receiving i.v. or oral tocolysis often show different results, both within particular groups of pregnant women and in comparison with non-pregnant persons. The aim of this study was to determine the pharmacokinetics of fenoterol in pregnant women, an important factor which so far had not been known. Four healthy pregnant women with similar weight and gestational age and all with premature labor were administered a continuous intravenous infusion of 4 micrograms fenoterol/min. During and up to 24 hours after the end of the infusion, venous blood samples were taken in order to determine the fenoterol plasma concentrations by radioimmunoassay. From a steady state concentration (css) of 2242 +/- 391 pg/ml (x +/- S.E.), a non-linear two-phased plasma elimination was seen with half-lives t1/2 of 11.40 min and 4.87 h. The area under the plasma concentration-time curve (AUC0-12h) was 6.27 ng/ml x h. The total clearance (Cltot) was 114.8 l/h. These data are nearly the same as the data already known for healthy non-pregnant (male) volunteers. The deviations which are seen in the plasma concentrations in pregnant women in comparison to non-pregnant persons during or after continuous i.v. infusion can therefore not be caused by differences in the pharmacokinetics. Other factors, however, such as body weight and/or gestational age, might influence the results.

  17. Production and Clinical Applications of Radiopharmaceuticals and Medical Radioisotopes in Iran.

    PubMed

    Jalilian, Amir Reza; Beiki, Davood; Hassanzadeh-Rad, Arman; Eftekhari, Arash; Geramifar, Parham; Eftekhari, Mohammad

    2016-07-01

    During past 3 decades, nuclear medicine has flourished as vibrant and independent medical specialty in Iran. Since that time, more than 200 nuclear physicians have been trained and now practicing in nearly 158 centers throughout the country. In the same period, Tc-99m generators and variety of cold kits for conventional nuclear medicine were locally produced for the first time. Local production has continued to mature in robust manner while fulfilling international standards. To meet the ever-growing demand at the national level and with international achievements in mind, work for production of other Tc-99m-based peptides such as ubiquicidin, bombesin, octreotide, and more recently a kit formulation for Tc-99m TRODAT-1 for clinical use was introduced. Other than the Tehran Research Reactor, the oldest facility active in production of medical radioisotopes, there is one commercial and three hospital-based cyclotrons currently operational in the country. I-131 has been one of the oldest radioisotope produced in Iran and traditionally used for treatment of thyrotoxicosis and differentiated thyroid carcinoma. Since 2009, (131)I-meta-iodobenzylguanidine has been locally available for diagnostic applications. Gallium-67 citrate, thallium-201 thallous chloride, and Indium-111 in the form of DTPA and Oxine are among the early cyclotron-produced tracers available in Iran for about 2 decades. Rb-81/Kr-81m generator has been available for pulmonary ventilation studies since 1996. Experimental production of PET radiopharmaceuticals began in 1998. This work has culminated with development and optimization of the high-scale production line of (18)F-FDG shortly after installation of PET/CT scanner in 2012. In the field of therapy, other than the use of old timers such as I-131 and different forms of P-32, there has been quite a significant advancement in production and application of therapeutic radiopharmaceuticals in recent years. Application of (131)I

  18. New rhenium complexes with ciprofloxacin as useful models for understanding the properties of [99mTc]-ciprofloxacin radiopharmaceutical.

    PubMed

    Lecina, Joan; Cortés, Pilar; Llagostera, Montserrat; Piera, Carlos; Suades, Joan

    2014-07-01

    Rhenium complexes with the antibiotic ciprofloxacin have been prepared to be studied as models of technetium radiopharmaceuticals. With this aim, the new rhenium complexes 1 {[ReO(Cpf)2]Cl}, 2 {[ReO(CpfH)2]Cl3} and 3 {fac-[Re(CO)3(H2O)(Cpf)]} with ciprofloxacin (CpfH=ciprofloxacin; Cpf=conjugated base of ciprofloxacin) have been synthesised and characterised by elemental analyses, IR, NMR ((1)H, (19)F and (13)C CP-MAS) spectroscopy, as well as MS measurements. All spectroscopic data are consistent with the coordination of ciprofloxacin in all these complexes through the carbonyl and the carboxylate oxygen atoms with the formation of a six member chelate ring. The study of a Tc-ciprofloxacin solution by ESI-MS reveals the presence of [TcO(Cpf)2](+) cations, which agrees with the hypothesis that complexes 1 and 2 can be seen as model rhenium complexes of this radiopharmaceutical. Antimicrobial and DNA gyrase inhibition studies performed with complexes 2 and 3 have shown a very similar behaviour between complex 2 and the free antibiotic, whereas complex 3 exhibit a lower antimicrobial activity. Based on a joint analysis of the data reported in the literature and the chemical and biological results obtained in this study, a tentative proposal to explain some aspects of the behaviour of Tc-ciprofloxacin radiopharmaceutical has been made.

  19. Cardiac blood-pool scintigraphy in rats and hamsters: comparison of five radiopharmaceuticals and three pinhole collimator apertures

    SciTech Connect

    Pieri, P.; Fischman, A.J.; Ahmad, M.; Moore, R.H.; Callahan, R.J.; Strauss, H.W. )

    1991-05-01

    Preclinical evaluation of cardiac drugs may require evaluation of cardiac function in intact animals. To optimize the quality of radionuclide measurements of ventricular function in small animals, a comparison was made of gated blood-pool scans recorded with five blood-pool radiopharmaceuticals ({sup 99}mTc-labeled human polyclonal IgG, {sup 99}mTc-human serum albumin labeled by two methods, and red blood cells radiolabeled with {sup 99}mTc via in vivo and in vitro methods) in rats and three pinhole apertures in hamsters. The quality of the radiopharmaceuticals was evaluated by comparing count density ratios (LV/BACKGROUND and LV/LIVER) and ejection fractions recorded with each agent. The edge definition of the left ventricle and count rate performance of the 1-, 2-, and 3-mm apertures was evaluated in hamsters. In general, the images obtained with the radiolabeled cells were superior to those obtained with the labeled proteins and no significant differences between the protein preparations were detected. Left ventricular ejection fractions calculated with all five radiopharmaceuticals were not significantly different. The best quality images were obtained with the 1-mm pinhole collimator. Ejection fraction and acquisition time were inversely related to aperture size. A good compromise between resolution and sensitivity was obtained with the 2-mm pinhole collimator.

  20. Development of more efficacious [Tc]-99m organ imaging agents for use in nuclear medicine by analytical characterization of radiopharmaceuticals

    SciTech Connect

    Heineman, W.R.

    1993-05-03

    This research program is detailed at development of more efficacious technetium-99m radiopharmaceuticals for use as imaging agents in diagnostic nuclear medicine. We seek to isolate and develop distinct site imaging agents to provide diagnostic information concerning a given pathological condition. Analytical techniques are being developed to enable complete analysis of radiopharmaceutical preparations so that individual complexes can be characterized with respect to imaging efficacy and to enable a radiopharmaceutical to be monitored after injection into a test animal to determine the species that actually accumulates in an organ to provide the image. Administration of the isolated, single most effective imaging complex, rather than a mixture of technetium-containing complexes, wi-11 minimize radiation exposure to the patient and maximize diagnostic information available to the clinician. This report specifically describes the development of capillary electrophoresis (CE) for characterizating diphosphonate skeletal imaging agents. Advances in the development of electrochemical and fiber optic sensors for Tc and Re imaging agents are described. These sensors will ultimately be capable of monitoring a specific chemical state of an imaging agent in vivo after injection into a test animal by implantation in the organ of interest.

  1. Pharmacokinetic enhancers in HIV therapeutics.

    PubMed

    Larson, Kajal B; Wang, Kun; Delille, Cecile; Otofokun, Igho; Acosta, Edward P

    2014-10-01

    Maximal and durable viral load suppression is one of the most important goals of HIV therapy and is directly related to adequate drug exposure. Protease inhibitors (PIs), an important component of the antiretroviral armada, were historically associated with poor oral bioavailability and high pill burden. However, because the PIs are metabolized by cytochrome P450 (CYP) 3A enzymes, intentional inhibition of these enzymes leads to higher drug exposure, lower pill burden, and therefore simplified dosing schedules with this class of drug. This is the basis of pharmacokinetic enhancement. In HIV therapy, two pharmacokinetic enhancers or boosting agents are used: ritonavir and cobicistat. Both agents inhibit CYP3A4, with cobicistat being a more specific CYP inhibitor than ritonavir. Unlike ritonavir, cobicistat does not have antiretroviral activity. Cobicistat has been evaluated in clinical trials and was recently approved in the USA as a fixed-dose combination with the integrase inhibitor, elvitegravir and two nucleos(t)ide analogs. Additional studies are examining cobicistat in fixed-dose combinations with various PIs. In this review, we summarize current knowledge of these agents and clinically relevant drug regimens and ongoing trials. Studies with elvitegravir and the novel PI TMC319011 are also discussed.

  2. A comprehensive physiologically based pharmacokinetic ...

    EPA Pesticide Factsheets

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

  3. [The pharmacokinetics of monoclonal antibodies].

    PubMed

    Keizer, R J; Huitema, A D R; Damen, C W N; Schellens, J H M; Beijnen, J H

    2007-03-24

    Monoclonal antibodies (MOABs) are, due to their specificity, increasingly being deployed for therapeutic purposes. MOABs are derived from immunoglobulins and are fully or partially of murine or human origin. They are administered parenterally: mostly intravenously, but subcutaneous or intramuscular administration is also possible, in which case absorption probably occurs through the lymphatic system. The distribution of MOABs from the bloodstream into the tissues is slow and is hampered by the high molecular size of the MOABs, which is a lesser problem for fragments of antibodies (Fab fragments). MOABs are metabolised to peptides and amino acids. This process takes place in many tissues of the body, but probably predominantly in epithelial cells. As a consequence of the saturable binding of the MOAB to its target, a dose-dependent (non-linear) elimination is often observed. Immune reactions can accelerate the elimination of antibodies, partially depending on the degree ofhumanisation of the antibody. Antibodies and endogenous immunoglobulins are protected from elimination by binding to protective receptors (neonatal Fc-receptor; FcRn), which explains their long half-lives (up to 4 weeks). Metabolic pharmacokinetic interactions with other drugs have not been reported and are not expected. It is expected that in the years to come, new MOABs directed towards new targets will appear on the market, as well as existing antibodies with improved pharmacokinetic properties.

  4. Study of potential utility of new radiopharmaceuticals based on technetium-99m labeled derivative of glucose

    NASA Astrophysics Data System (ADS)

    Zeltchan, R.; Medvedeva, A.; Sinilkin, I.; Chernov, V.; Stasyuk, E.; Rogov, A.; Il'ina, E.; Larionova, L.; Skuridin, V.

    2016-08-01

    Purpose: to study the potential utility of 1-thio-D-glucose labeled with 99mTc for cancer imaging in laboratory animals. Materials and method: the study was carried out in cell cultures of normal CHO (Chinese hamster ovary cells CHO) and malignant tissues MCF-7 (human breast adenocarcinoma MCF-7). To evaluate the uptake of 99mTc-1-thio-D-glucose in normal and tumor tissue cells, 25 MBq of 1-thio-D-glucose labeled with 99mTc was added to the vials with 3 million cells and incubated for 30 min at room temperature. After centrifugation of the vials with cells, the supernatant was removed. The radioactivity in vials with normal and tumor cells was then measured. In addition, the study included 40 mice of C57B1/6j lines with tumor lesion of the right femur. For neoplastic lesions, Lewis lung carcinoma model was used. Following anesthesia, mice were injected intravenously with 25 MBq of 99mTc-1-thio-D-glucose. Planar scintigraphy was performed 15 minutes later in a matrix of 512x512 pixels for 5 min. Results: when measuring the radioactivity of normal and malignant cells after incubation with 99mTc-1-thio-D-glucose, it was found that the radioactivity of malignant cells was higher than that of normal cells. The mean values of radioactivity levels in normal and malignant cells were 0.3 ± 0.15 MBq and 1.07 ± 0.6 MBq, respectively. All examined animals had increased accumulation of 99mTc-1-thio-D-glucose at the tumor site. The accumulation of 99mTc-1-thio-D-glucose in the tumor was on average twice as high as compared to the symmetric region. Conclusion: The present study demonstrated that 99mTc-1-thio-D-glucose is a prospective radiopharmaceutical for cancer visualization. In addition, high accumulation of 99mTc-1-thio-D-glucose in the culture of cancer cells and in tumor tissue of animals demonstrates tumor tropism of the radiopharmaceutical.

  5. Experimental study of radiopharmaceuticals based on technetium-99m labeled derivative of glucose for tumor diagnosis

    NASA Astrophysics Data System (ADS)

    Zeltchan, R.; Medvedeva, A.; Sinilkin, I.; Bragina, O.; Chernov, V.; Stasyuk, E.; Rogov, A.; Il'ina, E.; Larionova, L.; Skuridin, V.; Dergilev, A.

    2016-06-01

    Purpose: to study the potential utility of 1-thio-D-glucose labeled with 99mTc for cancer imaging in laboratory animals. Materials and method: the study was carried out in cell cultures of normal CHO (Chinese hamster ovary cells CHO) and malignant tissues MCF-7 (human breast adenocarcinoma MCF-7). To evaluate the uptake of 99mTc-1-thio-D-glucose in normal and tumor tissue cells, 25 MBq of 1-thio-D-glucose labeled with 99mTc was added to the vials with 3 million cells and incubated for 30 minutes at room temperature. After centrifugation of the vials with cells, the supernatant was removed. Radioactivity in vials with normal and tumor cells was then measured. In addition, the study included 40 mice of C57B 1/6j lines with tumor lesion of the right femur. For neoplastic lesions, Lewis lung carcinoma model was used. Following anesthesia, mice were injected intravenously with 25MBq of 99mTc-1-thio-D-glucose. Planar scintigraphy was performed 15 minutes later in a matrix of 512x512 pixels for 5 minutes. Results: when measuring the radioactivity of normal and malignant cells after incubation with 99mTc-1-thio-D- glucose, it was found that the radioactivity of malignant cells was higher than that of normal cells. The mean values of radioactivity levels in normal and malignant cells were 0.3±0.15MBq and 1.07±0.6MBq, respectively. All examined animals had increased accumulation of 99mTc-1-thio- D-glucose at the tumor site. The accumulation of 99mTc-1-thio-D-glucose in the tumor was on average twice as high as compared to the symmetric region. Conclusion: The present study demonstrated that 99mTc-1-thio-D-glucose is a prospective radiopharmaceutical for cancer visualization. In addition, high accumulation of 99mTc-1-thio-D-glucose in the culture of cancer cells and in tumor tissue of animals demonstrates tumor tropism of the radiopharmaceutical.

  6. To Apply Microdosing or Not? Recommendations to Single Out Compounds with Non-Linear Pharmacokinetics.

    PubMed

    Bosgra, Sieto; Vlaming, Maria L H; Vaes, Wouter H J

    2016-01-01

    Microdosing studies allow clinical investigation of pharmacokinetics earlier in drug development, before all high-dose safety concerns have been sorted out. Furthermore, microdosing allows inclusion of target groups that are inadmissible in high-dose phase I trials. A potential concern when considering a microdosing study is that a particular drug candidate may display non-linear pharmacokinetics. Saturation of, for example, membrane transport or metabolism at exposure levels between the microdose and therapeutic dose may limit the predictivity of high-dose pharmacokinetics from microdose observations. Guidance on the likelihood of appreciable non-linear pharmacokinetics based on preclinical information can be helpful in staging the clinical phase and the place of microdosing in it. We present a decision tree that evaluates concerns about non-linearities raised in the preclinical phase and their potential impact on the proportionality between microdose and intended therapeutic dose as predicted from preclinical information. The expected maximum concentrations at relevant sites are estimated by non-compartmental methods. These are compared with dissolution, Michaelis constants for active or enzymatic processes, and binding protein concentrations to assess the potential saturation of the processes below therapeutic doses. The decision tree was applied to ten published cases comparing microdose and therapeutic dose pharmacokinetics, for which concerns about non-linear pharmacokinetics were raised a priori. The decision tree was able to discriminate cases showing substantial non-linearities from cases displaying dose-proportional pharmacokinetics. The recommendations described in this paper may be useful in deciding whether a microdosing study is a sensible option to gain early insight in clinical pharmacokinetics of drug candidates.

  7. Evaluation of microdosing to assess pharmacokinetic linearity in rats using liquid chromatography-tandem mass spectrometry.

    PubMed

    Balani, Suresh K; Nagaraja, Nelamangala V; Qian, Mark G; Costa, Arnaldo O; Daniels, J Scott; Yang, Hua; Shimoga, Prakash R; Wu, Jing-Tao; Gan, Liang-Shang; Lee, Frank W; Miwa, Gerald T

    2006-03-01

    The microdosing strategy allows for early assessment of human pharmacokinetics of new chemical entities using more limited safety assessment requirements than those requisite for a conventional phase I program. The current choice for evaluating microdosing is accelerator mass spectrometry (AMS) due to its ultrasensitivity for detecting radiotracers. However, the AMS technique is still expensive to be used routinely and requires the preparation of radiolabeled compounds. This report describes a feasibility study with conventional liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology for oral microdosing assessment in rats, a commonly used preclinical species. The nonlabeled drugs fluconazole and tolbutamide were studied because of their similar pharmacokinetics characteristics in rats and humans. We demonstrate that pharmacokinetics can be readily characterized by LC-MS/MS at a microdose of 1 microg/kg for these molecules in rats, and, hence, LC-MS/MS should be adequate in human microdosing studies. The studies also exhibit linearity in exposure between the microdose and >or=1000-fold higher doses in rats for these drugs, which are known to show a linear dose-exposure relationship in the clinic, further substantiating the potential utility of LC-MS/MS in defining pharmacokinetics from the microdose of drugs. These data should increase confidence in the use of LC-MS/MS in microdose pharmacokinetics studies of new chemical entities in humans. Application of this approach is also described for an investigational compound, MLNX, in which the pharmacokinetics in rats were determined to be nonlinear, suggesting that MLNX pharmacokinetics at microdoses in humans also might not reflect those at the therapeutic doses. These preclinical studies demonstrate the potential applicability of using traditional LC-MS/MS for microdose pharmacokinetic assessment in humans.

  8. Quantitative structure-pharmacokinetic relationships (QSPR) of beta blockers derived using neural networks.

    PubMed

    Gobburu, J V; Shelver, W H

    1995-07-01

    This study demonstrates the application of neural networks to predict the pharmacokinetic properties of beta-adrenoreceptor antagonists in humans. A congeneric series of 10 beta-blockers, whose critical pharmacokinetic parameters are well established, was selected for the study. An appropriate neural network system was constructed and tested for its ability to predict the pharmacokinetic parameters from the octanol/water partition coefficient (shake flask method), the pKa, or the fraction bound to plasma proteins. Neural networks successfully trained and the predicted pharmacokinetic values agreed well with the experimental values (average difference = 8%). The neural network-predicted values showed better agreement with the experimental values than those predicted by multiple regression techniques (average difference = 47%). Because the neural networks had a large number of connections, two tests were conducted to determine if the networks were memorizing rather than generalizing. The "leave-one-out" method verified the generalization of the networks by demonstrating that any of the compounds could be deleted from the training set and its value correctly predicted by the new network (average error = 19%). The second test involved the prediction of pharmacokinetic properties of compounds never seen by the network, and reasonable results were obtained for three out of four compounds tested. The results indicate neural networks can be a powerful tool in exploration of quantitative structure-pharmacokinetic relationships.

  9. Contribution of electrospray mass spectrometry for the characterization, design, and development of nitrido technetium and rhenium heterocomplexes as potential radiopharmaceuticals.

    PubMed

    Tisato, Francesco; Bolzati, Cristina; Porchia, Marina; Refosco, Fiorenzo

    2004-01-01

    Diagnostic nuclear medicine (NM) is among the imaging procedures (together with X-ray, computerized tomography, magnetic resonance, and echography) the clinicians can routinely adopt to image organs or tissues and related disorders. (99m)Tc-based agents are the radiopharmaceuticals of election in diagnostic NM because of the ideal physical properties of the 99mTc nuclide (t1/2 6.01 hr; Egamma 142 keV), low cost, and easy availability through the commercial 99Mo/99mTc generator, and chemical versatility of the element. In the last two decades the synergistic work of clinics, pharmacologists, and coordination chemists has had a tremendous impact in the development of new 99mTc-based radiopharmaceuticals through the recognition of the structure at the molecular level of the agent utilized. This has been achieved by studying the physico-chemical properties of the long-lived 99gTc (t1/2 2.11 x 10(5) year; Ebeta 292 keV) and third-row congener Re isostructural compounds. Electrospray ionization mass spectrometry (ESI-MS) and collision experiments (MS/MS) represent valuable analytical techniques suitable for the characterization of both technetium and rhenium complexes relevant to NM. Unequivocal structural identification of these bioinorganic compounds, either simple coordination complexes ("essential radiopharmaceuticals") or more sophisticated structures carrying bioactive fragments ("receptor-specific" radiopharmaceuticals), can be realized in combination with multinuclear NMR spectroscopy. MS/MS experiments provide useful information on the different metal-ligand bond strength, and comparison of the fragmentation profiles of isostructural technetium and rhenium compounds give additional details on the role played by the metal in determining preferred decomposition channels. The analysis of these data contribute to design novel synthetic strategies for the obtainment of technetium and rhenium compounds relevant to NM. The chemistry underlying the production of a new

  10. Pyrimethamine nanosuspension with improved bioavailability: in vivo pharmacokinetic studies.

    PubMed

    Dhapte, Vividha; Kadam, Vivek; Pokharkar, Varsha

    2013-10-01

    Pyrimethamine is a standard antiprotozoal drug recommended for prophylaxis and treatment of malarial infections. Limited bioavailability, slow onset of action, and life-threatening side effects restrict its use. Hence, in the present study, pyrimethamine nanosuspension was prepared with the objective to improve its dissolution rate and pharmacokinetic profile. Stable pyrimethamine nanosuspension with submicron particle size was prepared by nanoprecipitation and high-pressure homogenization techniques. Nanosizing and stabilizers modified the surface characteristics of drug particles resulting in considerable increase in the dissolution rate. The in vivo pharmacokinetic studies of the prepared nanosuspension were carried out and compared with plain pyrimethamine suspension and marketed pyrimethamine suspension. The in vivo pharmacokinetic profiling of pyrimethamine nanosuspension in rats showed higher AUC0-24 h and C max compared to the plain and marketed pyrimethamine suspensions. In contrast to its plain and marketed formulation, pyrimethamine nanosuspension showed rapid onset of action (T max 0.5 h vs. 2 h). Also, the low volume of distribution and reduced elimination half-life of the developed nanosuspension can lead to reduced side effects. Thus, improved in vitro-in vivo kinetics indicated that nanosuspension proved to be a suitable strategy for elevating the therapeutic profile of pyrimethamine.

  11. Optimisation of sampling windows design for population pharmacokinetic experiments.

    PubMed

    Ogungbenro, Kayode; Aarons, Leon

    2008-08-01

    This paper describes an approach for optimising sampling windows for population pharmacokinetic experiments. Sampling windows designs are more practical in late phase drug development where patients are enrolled in many centres and in out-patient clinic settings. Collection of samples under the uncontrolled environment at these centres at fixed times may be problematic and can result in uninformative data. Population pharmacokinetic sampling windows design provides an opportunity to control when samples are collected by allowing some flexibility and yet provide satisfactory parameter estimation. This approach uses information obtained from previous experiments about the model and parameter estimates to optimise sampling windows for population pharmacokinetic experiments within a space of admissible sampling windows sequences. The optimisation is based on a continuous design and in addition to sampling windows the structure of the population design in terms of the proportion of subjects in elementary designs, number of elementary designs in the population design and number of sampling windows per elementary design is also optimised. The results obtained showed that optimal sampling windows designs obtained using this approach are very efficient for estimating population PK parameters and provide greater flexibility in terms of when samples are collected. The results obtained also showed that the generalized equivalence theorem holds for this approach.

  12. Preparation and In Vivo Pharmacokinetics of the Tongshu Suppository.

    PubMed

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

    2016-01-01

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

  13. Preparation and In Vivo Pharmacokinetics of the Tongshu Suppository

    PubMed Central

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

    2016-01-01

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

  14. Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals.

    PubMed

    Hashimoto, Kenji; Ishiwata, Kiichi

    2006-01-01

    Sigma receptors are classified into sigma(1) and sigma(2) subtypes. These subtypes display a different tissue distribution and a distinct physiological and pharmacological profile in the central and peripheral nervous system. The characterization of these subtypes and the discovery of new specific sigma receptor ligands demonstrated that sigma receptors are novel targets for the therapeutic treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition), brain ischemia, and cocaine addiction. Furthermore, imaging of sigma(1) receptors in the human brain using specific PET radioligands has started. In addition, the two sigma receptor subtypes are also expressed on tumor cells, where they could be of prognostic relevance. The ability of sigma(2) receptor agonists to inhibit tumor cell proliferation through mechanisms that might involve apoptosis, intracellular Ca(2+), and sphingolipids has promoted the development of sigma(2) receptor agonists as novel therapeutic drugs for treating cancer. Consequently, sigma(2) receptor ligands have been demonstrated to be potentially useful tumor imaging ligands. In this article, we focus on the sigma receptor ligands as therapeutic agents and as radiopharmaceuticals.

  15. APTAMER DELIVERY OF siRNA, RADIOPHARMACEUTICS AND chemotherapy agents IN CANCER.

    PubMed

    de Almeida, Carlos E B; Alves, Lais Nascimento; Paulino, Enrique T; Cabral-Neto, Januário Bispo; Missailidis, Sotiris

    2017-03-31

    Aptamers are oligonucleotide reagents with high affinity and specificity, which among other therapeutic and diagnostic applications have the capability of acting as delivery agents. Thus, aptamers are capable of carrying small molecules, nanoparticles, radiopharmaceuticals or fluorescent agents as well as nucleic acid therapeutics specifically to their target cells. In most cases, the molecules may possess interesting therapeutic properties, but their lack of specificity for a particular cell type, or ability to internalise in such a cell, hinders their clinical development, or cause unwanted side effects. Thus, chemotherapy or radiotherapy agents, famous for their side effects, can be coupled to aptamers for specific delivery. Equally, siRNA have great therapeutic potential and specificity, but one of their shortcomings remain the delivery and internalisation into cells. Various methodologies have been proposed to date, including aptamers, to resolve this problem. Therapeutic or imaging reagents benefit from the adaptability and ease of chemical manipulation of aptamers, their high affinity for the specific marker of a cell type, and their internalisation ability via cell mediated endocytosis. In this review paper, we explore the potential of the aptamers as delivery agents and offer an update on current status and latest advancements.

  16. Production of 64Cu and 67Cu radiopharmaceuticals using zinc target irradiated with accelerator neutrons

    NASA Astrophysics Data System (ADS)

    Kawabata, Masako; Hashimoto, Kazuyuki; Saeki, Hideya; Sato, Nozomi; Motoishi, Shoji; Nagai, Yasuki

    2014-09-01

    Copper radioisotopes have gained a lot of attention in radiopharmaceuticals owing to their unique decay characteristics. The longest half-life β emitter, 67Cu, is thought to be suitable for targeted radio-immunotherapy. Adequate production of 67Cu to meet the demands of clinical studies has not been fully established. Another attractive copper isotope, 64Cu has possible applications as a diagnostic imaging tracer combined with a therapeutic effect. This work proposes a production method using accelerator neutrons in which two copper radioisotopes can be produced: 1) 68Zn(n,x)67Cu and 2) 64Zn(n,p)64Cu using ~14 MeV neutrons generated by natC(d, n) reaction, both from natural or enriched zinc oxides. The generated 64,67Cu were separated from the target zinc oxide using a chelating and an anion exchange columns and were labelled with two widely studied chelators where the labelling efficiency was found to be acceptably good. The major advantage of this method is that a significant amount of 64,67Cu with a very few impurity radionuclides are produced which also makes the separation procedure simple. Provided an accelerator supplying an Ed = ~ 40 MeV, a wide application of 64,67Cu based drugs in nuclear medicine is feasible in the near future. We will present the characteristics of this production method using accelerator neutrons including the chemical separation processes.

  17. PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence

    PubMed Central

    Lopci, Egesta; Grassi, Ilaria; Chiti, Arturo; Nanni, Cristina; Cicoria, Gianfranco; Toschi, Luca; Fonti, Cristina; Lodi, Filippo; Mattioli, Sandro; Fanti, Stefano

    2014-01-01

    Hypoxia is a pathological condition arising in living tissues when oxygen supply does not adequately cover the cellular metabolic demand. Detection of this phenomenon in tumors is of the utmost clinical relevance because tumor aggressiveness, metastatic spread, failure to achieve tumor control, increased rate of recurrence, and ultimate poor outcome are all associated with hypoxia. Consequently, in recent decades there has been increasing interest in developing methods for measurement of oxygen levels in tumors. Among the image-based modalities for hypoxia assessment, positron emission tomography (PET) is one of the most extensively investigated based on the various advantages it offers, i.e., broad range of radiopharmaceuticals, good intrinsic resolution, three-dimensional tumor representation, possibility of semiquantification/quantification of the amount of hypoxic tumor burden, overall patient friendliness, and ease of repetition. Compared with the other non-invasive techniques, the biggest advantage of PET imaging is that it offers the highest specificity for detection of hypoxic tissue. Starting with the 2-nitroimidazole family of compounds in the early 1980s, a great number of PET tracers have been developed for the identification of hypoxia in living tissue and solid tumors. This paper provides an overview of the principal PET tracers applied in cancer imaging of hypoxia and discusses in detail their advantages and pitfalls. PMID:24982822

  18. Development of dopamine receptor radiopharmaceuticals for the study of neurological and psychiatric disorders

    SciTech Connect

    Dr. Jogeshwar Mukherjee

    2009-01-02

    Our goals in this grant application are directed towards the development of radiotracers that may allow the study of the high-affinity state (functional state) of the dopamine receptors. There have been numerous reports on the presence of two inter-convertible states of these (G-protein coupled) receptors in vitro. However, there is no report that establishes the presence of these separate affinity states in vivo. We have made efforts in this direction in order to provide such direct in vivo evidence about the presence of the high affinity state. This understanding of the functional state of the receptors is of critical significance in our overall diagnosis and treatment of diseases that implicate the G-protein coupled receptors. Four specific aims have been listed in the grant application: (1). Design and syntheses of agonists (2). Radiosyntheses of agonists (3). In vitro pharmacology of agonists (4). In vivo distribution and pharmacology of labeled derivatives. We have accomplished the syntheses and radiosyntheses of three agonist radiotracers labeled with carbon-11. In vitro and in vivo pharmacological experiments have been accomplished in rats and preliminary PET studies in non-human primates have been carried out. Various accomplishments during the funded years, briefly outlined in this document, have been disseminated by several publications in various journals and presentations in national and international meetings (Society of Nuclear Medicine, Society for Neuroscience and International Symposium on Radiopharmaceutical Chemistry).

  19. Multi-scale hybrid models for radiopharmaceutical dosimetry with Geant4.

    PubMed

    Marcatili, S; Villoing, D; Garcia, M P; Bardiès, M

    2014-12-21

    The accuracy of radiopharmaceutical absorbed dose distributions computed through Monte Carlo (MC) simulations is mostly limited by the low spatial resolution of 3D imaging techniques used to define the simulation geometry. This issue also persists with the implementation of realistic hybrid models built using polygonal mesh and/or NURBS as they require to be simulated in their voxel form in order to reduce computation times. The existing trade-off between voxel size and simulation speed leads on one side, in an overestimation of the size of small radiosensitive structures such as the skin or hollow organs walls and, on the other, to unnecessarily detailed voxelization of large, homogeneous structures.We developed a set of computational tools based on VTK and Geant4 in order to build multi-resolution organ models. Our aim is to use different voxel sizes to represent anatomical regions of different clinical relevance: the MC implementation of these models is expected to improve spatial resolution in specific anatomical structures without significantly affecting simulation speed. Here we present the tools developed through a proof of principle example. Our approach is validated against the standard Geant4 technique for the simulation of voxel geometries.

  20. Development of radiodetection systems towards miniaturised quality control of PET and SPECT radiopharmaceuticals.

    PubMed

    Taggart, Matthew P; Tarn, Mark D; Esfahani, Mohammad M N; Schofield, Daniel M; Brown, Nathaniel J; Archibald, Stephen J; Deakin, Tom; Pamme, Nicole; Thompson, Lee F

    2016-04-26

    The ability to detect radiation in microfluidic devices is important for the on-chip analysis of radiopharmaceuticals, but previously reported systems have largely suffered from various limitations including cost, complexity of fabrication, and insufficient sensitivity and/or speed. Here, we present the use of sensitive, low cost, small-sized, commercially available silicon photomultipliers (SiPMs) for the detection of radioactivity inside microfluidic channels fabricated from a range of conventional microfluidic chip substrates. We demonstrate the effects of chip material and thickness on the detection of the positron-emitting isotope, [(18)F]fluoride, and find that, while the SiPMs are light sensors, they are able to detect radiation even through opaque chip materials via direct positron and gamma (γ) ray interaction. Finally, we employed the SiPM platform for analysis of the PET (positron emission tomography) radiotracers 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) and [(68)Ga]gallium-citrate, and highlight the ability to detect the γ ray emitting SPECT (single photon emission computed tomography) radiotracer, [(99m)Tc]pertechnetate.

  1. Noninvasive measurement of radiopharmaceutical time–activity data using external thermoluminescent dosimeters (TLDs)

    NASA Astrophysics Data System (ADS)

    Lu, Cheng-Chang; Dong, Shang-Lung; Lin, Hsin-Hon; Ni, Yu-Ching; Jan, Meei-Ling; Chuang, Keh-Shih

    2017-02-01

    In this study, we present a new method for estimating the time–activity data using serial timely measurements of thermoluminescent dosimeters (TLDs). The approach is based on the combination of the measurement of surface dose using TLD and Monte Carlo (MC) simulation to estimate the radiopharmaceutical time–activity data. It involves four steps: (1) identify the source organs and outline their contours in computed tomography images; (2) compute the S values on the body surface for each source organ using a MC code; (3) obtain a serial measurement of the dose with numerous TLDs placed on the body surface; (4) solve the dose–activity equation to generate organ cumulative activity for each period of measurement. The activity of each organ at the time of measurement is simply the cumulative activity divided by the timespan between measurements. The usefulness of this method was studied using a MC simulation based on an Oak Ridge National Laboratory mathematical phantom with 18F-FDG filled in six source organs. Numerous TLDs were placed on different locations of the surface and were repeatedly read and replaced. The time–activity curves (TACs) of all organs were successfully reconstructed. Experiments on a physical phantom were also performed. Preliminary results indicate that it is an effective, robust, and simple method for assessing the TAC. The proposed method holds great potential for a range of applications in areas such as targeted radionuclide therapy, pharmaceutical research, and patient-specific dose estimation.

  2. Correction Factors Applied to Finger Dosimetry: A Theoretical Assessment of Appropriate Values for Use in Handling Radiopharmaceuticals

    SciTech Connect

    Sherbini, Sami; Ilas, Dan; Eckerman, Keith F; DeCicco, Joseph

    2011-01-01

    United States Nuclear Regulatory Commission (USNRC) regulations limit the dose to the skin to 500 mSv per year. This is also the dose limit recommended by the International Commission on Radiological Protection (ICRP). The operational quantity recommended by ICRP for quantifying dose to the skin is the personal dose equivalent, Hp(0.07) and is identical to NRC s shallow dose equivalent, Hs, also measured at a skin depth of 7 mg cm 2. However, whereas ICRP recommends averaging the dose to the skin over an area of 1 cm2 regardless of the size of the exposed area of skin, USNRC requires the shallow dose equivalent to be averaged over 10 cm2. To monitor dose to the skin of the hands of workers handling radioactive materials and particularly in radiopharmaceutical manufacturing facilities, which is the focus of this work, workers are frequently required to wear finger ring dosimeters. The dosimeters monitor the dose at the location of the sensitive element, but this is not the dose required to show compliance (i.e., the dose averaged over the highest exposed contiguous 10 cm2 of skin). Therefore, it may be necessary to apply a correction factor that enables estimation of the required skin dose from the dosimeter reading. This work explored the effects of finger ring placement and of the geometry of the radioactive materials being handled by the worker on the relationship between the dosimeter reading and the desired average dose. A mathematical model of the hand was developed for this purpose that is capable of positioning the fingers in any desired grasping configuration, thereby realistically modeling manipulation of any object. The model was then used with the radiation transport code MCNP to calculate the dose distribution on the skin of the hand when handling a variety of radioactive vials and syringes, as well as the dose to the dosimeter element. Correction factors were calculated using the results of these calculations and examined for any patterns that may be

  3. Pharmacokinetics of indomethacin in poultry.

    PubMed

    Cristòfol, C; Valladares, J E; Martí, G; Arboix, M

    2000-01-01

    Indomethacin (INDO) is a nonsteroidal antiinflammatory drug widely used since the 1970s. The pharmacokinetic behavior of INDO (2 mg/kg) has been studied after intravenous (i.v.) and oral administration to broiler chickens. After i.v. administration, a first fast distribution phase and a later and slower elimination phase were observed. The elimination half-life and mean residence time (MRT) obtained were 1.0 hr and 0.8 hr, respectively. After oral administration, a flip-flop phenomenon was observed giving an elimination half-life and MRT approximately three times and six times higher, respectively, than the i.v. administration. The plasma concentrations after oral administration were sustained during 8-10 hr, giving an antinflammatory cover over the dose producing 50% of maximal effect during this time period.

  4. Oxazepam pharmacokinetics in thyroid disease.

    PubMed Central

    Scott, A K; Khir, A S; Bewsher, P D; Hawksworth, G M

    1984-01-01

    The pharmacokinetics of oxazepam, a drug mainly eliminated by a single step glucuronidation reaction, were studied in seven hyperthyroid and six hypothyroid patients before and after treatment. Oxazepam elimination half-life was shorter and apparent oral clearance higher in untreated hyperthyroid patients than after treatment. There was no significant change in oxazepam elimination in hypothyroid subjects. Time to peak concentration (tmax) was reduced in the hyperthyroid state. Hypothyroidism had no significant effect on tmax. Serum bilirubin concentration was lower in the patients while hyperthyroid before treatment than when euthyroid and also lower than in the hypothyroid patients. There was no significant correlation between serum bilirubin concentrations and oxazepam elimination. These results suggest that glucuronyl transferase activity is increased in hyperthyroidism but is not altered in most patients with hypothyroidism. The extent of increase in glucuronyl transferase activity is similar to that produced by enzyme inducing drugs. PMID:6419761

  5. 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

  6. Population pharmacokinetic analysis of bisoprolol.

    PubMed

    Grevel, J; Thomas, P; Whiting, B

    1989-07-01

    The technique of population pharmacokinetic analysis was employed to study the variability in the dose concentration relationship of bisoprolol during its clinical development. The influence of demographic factors on the variability of clearance was investigated in 3 different populations: group I, patients (including an elderly group) with essential hypertension receiving multiple oral doses of bisoprolol 10 or 20mg for 3 months; group II, patients with different degrees of renal impairment and healthy controls; and group III, patients with different types of hepatic impairment and healthy controls. Patients and controls in groups II and III received only a single oral dose of bisoprolol 10mg. The 3 data sets were analysed separately, using a non-linear mixed effects model (the NONMEM program). A 2-compartment pharmacokinetic model with first-order absorption described the data adequately. The typical values of volume of central compartment, volume of distribution at steady-state and the absorption rate constant for the 3 populations were: for group I, 68L, 235L, and 0.7h-1; for group II, 28L, 179L, and 0.3h-1; and for group III, 55L, 256L, and 0.4h-1, respectively. Plasma clearance was related to age in group I, to serum creatinine in group II and to aspartate transaminase activity in group III. The 68% confidence limits for clearance and elimination half-life were 8.2 to 21.5 L/h and 7.6 to 19.7h, respectively, for 50-year-old patients in group I. The analysis predicted that progressive increases in serum creatinine or aspartate transaminase activity will result in only a 50% reduction of clearance.

  7. 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.

  8. 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...

  9. Gestation Time-Dependent Pharmacokinetics of Intravenous (+)-Methamphetamine in Rats

    PubMed Central

    White, Sarah; Laurenzana, Elizabeth; Hendrickson, Howard; Gentry, W. Brooks

    2011-01-01

    We tested the hypothesis that differences in (+)-methamphetamine (METH) disposition during late rat pregnancy could lead to increased vulnerability to acute METH effects. The disposition of a single 1 mg/kg i.v. METH dose was studied during early (gestation day 7, GD7) and late (GD21) gestation. Results showed gestation time-dependent pharmacokinetics, characterized by a significantly higher area under the METH serum concentration versus time curve and a lower clearance on GD21 (p < 0.05; total, renal, and nonrenal clearance). The terminal elimination half-life (t1/2λz) of METH and (+)-amphetamine (AMP; a pharmacologically active metabolite of METH) were not different on GD7, but by GD21, AMP t1/2λz was 37% longer than METH t1/2λz (p < 0.05). To identify the mechanism for AMP metabolite changes, intravenous AMP pharmacokinetics on GD21 were compared with AMP metabolite pharmacokinetics after intravenous METH. The intravenous AMP t1/2λz was significantly shorter than metabolite AMP t1/2λz (p < 0.05), which suggested AMP metabolite formation (not elimination) was the rate-limiting process. To understand the medical consequence of METH use during late-stage pregnancy, timed-pregnant rats received an intravenous dose of saline or METH (1, 3, or 5.6 mg/kg) on GD21, 0 to 2 days antepartum. Although one rat died and another had stillbirths at term after the 5.6-mg/kg dose, the pharmacokinetic values for all of the other animals were not significantly different. In conclusion, late-gestational clearance reductions lengthen METH exposure time, possibly increasing susceptibility to adverse effects, including death. PMID:21632964

  10. Effect of renal impairment on the pharmacokinetics of grepafloxacin.

    PubMed

    Efthymiopoulos, C; Bramer, S L; Maroli, A; Gambertoglio, J G

    1997-01-01

    Grepafloxacin is mainly (approximately 90%) excreted by nonrenal mechanisms. The effect of renal impairment on the pharmacokinetics of grepafloxacin was evaluated in an open-label study involving 20 adults, 15 of whom had some degree of renal impairment (creatinine clearance 7.5 to 64.0 ml/min). Of these 15, 3 had mild renal impairment, 6 had moderate renal impairment, and 6 had severe renal impairment. Grepafloxacin 400 mg was administered orally once daily for 7 days, and pharmacokinetic parameters were measured on days 1 and 7. The results show that both renal clearance and the amount of grepafloxacin excreted unchanged in urine, on day 1 and day 7, were significantly lower in individuals with severe renal impairment compared with those who were healthy. Renal clearance was 0.50 +/- 0.05 ml/min/kg in healthy individuals vs 0.15 +/- 0.05 ml/min/kg in patients with severe renal impairment on day 1, while the corresponding values on day 7 were 0.46 +/- 0.04 ml/min/kg vs 0.14 +/- 0.08 ml/min/kg, respectively. The percentage of grepafloxacin excreted unchanged in urine on day 1 was 5.1 +/- 3.0 in the healthy individuals and 1.5 +/- 0.7 in those with severe renal impairment. On day 7, the corresponding values were 7.9 +/- 1.9 and 2.9 +/- 2.2. No other significant pharmacokinetic differences occurred between the 2 groups. Accumulation during multiple dose administration did not vary with the degree of renal impairment. We conclude that the pharmacokinetics of grepafloxacin are not significantly different in individuals with varying degrees of renal impairment. Hence, dose adjustment is not necessary during treatment of patients with renal dysfunction.

  11. Gestation time-dependent pharmacokinetics of intravenous (+)-methamphetamine in rats.

    PubMed

    White, Sarah; Laurenzana, Elizabeth; Hendrickson, Howard; Gentry, W Brooks; Owens, S Michael

    2011-09-01

    We tested the hypothesis that differences in (+)-methamphetamine (METH) disposition during late rat pregnancy could lead to increased vulnerability to acute METH effects. The disposition of a single 1 mg/kg i.v. METH dose was studied during early (gestation day 7, GD7) and late (GD21) gestation. Results showed gestation time-dependent pharmacokinetics, characterized by a significantly higher area under the METH serum concentration versus time curve and a lower clearance on GD21 (p < 0.05; total, renal, and nonrenal clearance). The terminal elimination half-life (t(1/2λz)) of METH and (+)-amphetamine (AMP; a pharmacologically active metabolite of METH) were not different on GD7, but by GD21, AMP t(1/2λz) was 37% longer than METH t(1/2λz) (p < 0.05). To identify the mechanism for AMP metabolite changes, intravenous AMP pharmacokinetics on GD21 were compared with AMP metabolite pharmacokinetics after intravenous METH. The intravenous AMP t(1/2λz) was significantly shorter than metabolite AMP t(1/2λz) (p < 0.05), which suggested AMP metabolite formation (not elimination) was the rate-limiting process. To understand the medical consequence of METH use during late-stage pregnancy, timed-pregnant rats received an intravenous dose of saline or METH (1, 3, or 5.6 mg/kg) on GD21, 0 to 2 days antepartum. Although one rat died and another had stillbirths at term after the 5.6-mg/kg dose, the pharmacokinetic values for all of the other animals were not significantly different. In conclusion, late-gestational clearance reductions lengthen METH exposure time, possibly increasing susceptibility to adverse effects, including death.

  12. A model to resolve organochlorine pharmacokinetics in migrating humpback whales.

    PubMed

    Cropp, Roger; Nash, Susan Bengtson; Hawker, Darryl

    2014-07-01

    Humpback whales are iconic mammals at the top of the Antarctic food chain. Their large reserves of lipid-rich tissues such as blubber predispose them to accumulation of lipophilic contaminants throughout their lifetime. Changes in the volume and distribution of lipids in humpback whales, particularly during migration, could play an important role in the pharmacokinetics of lipophilic contaminants such as the organochlorine pesticide hexachlorobenzene (HCB). Previous models have examined constant feeding and nonmigratory scenarios. In the present study, the authors develop a novel heuristic model to investigate HCB dynamics in a humpback whale and its environment by coupling an ecosystem nutrient-phytoplankton-zooplankton-detritus (NPZD) model, a dynamic energy budget (DEB) model, and a physiologically based pharmacokinetic (PBPK) model. The model takes into account the seasonal feeding pattern of whales, their energy requirements, and fluctuating contaminant burdens in the supporting plankton food chain. It is applied to a male whale from weaning to maturity, spanning 20 migration and feeding cycles. The model is initialized with environmental HCB burdens similar to those measured in the Southern Ocean and predicts blubber HCB concentrations consistent with empirical concentrations observed in a southern hemisphere population of male, migrating humpback whales. Results show for the first time some important details of the relationship between energy budgets and organochlorine pharmacokinetics.

  13. Preclinical pharmacokinetic analysis of NOV-002, a glutathione disulfide mimetic.

    PubMed

    Uys, J D; Manevich, Y; Devane, L C; He, L; Garret, T E; Pazoles, C J; Tew, K D; Townsend, D M

    2010-09-01

    NOV-002 is a glutathione disulfide (GSSG) mimetic that is the subject of clinical investigation in oncology indications. GSSG is reduced by glutathione reductase (GR) to form glutathione (GSH), thereby maintaining redox homeostasis. The purpose of the study was to report the pharmacokinetic properties of NOV-002 and evaluate the effect that NOV-002 elicits in redox homeostasis. The pharmacokinetic analysis and tissue distribution of NOV-002 and GSH was evaluated in mice following a dose of 250 mg/kg, i.p. The redox potential and total protein thiol status was calculated. Here we show that NOV-002 is a substrate for GR and that GSH is a primary metabolite. Non-linear pharmacokinetic modeling predicted that the estimated absorption and elimination rate constants correspond to a half-life of approximately 13 min with an AUC of 1.18 μgh/mL, a C(max) of 2.16 μg/ml and a volume of distribution of 42.61 L/kg. In addition, measurement of the redox potential and total protein thiol status indicated the generation of a transient oxidative signal in the plasma compartment after administration of NOV-002. These results indicate that NOV-002 exerts kinetic and dynamic effects in mice consistent with the GSSG component as the active pharmacological constituent of the drug. A longer-lasting decrease in total plasma free thiol content was also seen, suggesting that the oxidative effect of the GSSG from NOV-002 was impacting redox homeostasis.

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

    PubMed

    Ambrose, P J; Smith, W E; Palarea, E R

    1988-09-01

    The development, operation, and functions of the pharmacokinetics service at Memorial Medical Center of Long Beach (MMCLB) are described, and the data used to determine the quality and cost-effectiveness of the service are presented. Current functions of the pharmacokinetics service at MMCLB include making brief written comments about the interpretations of serum drug concentrations (SDCs) and oral recommendations to physicians on dosage adjustment; provision of written consultations with dosage recommendations; provision of drug information, education, and research; and development of drug dosing guidelines for the pharmacy and medical staff. During the 10-year existence of this service, costs have been justified on the basis of not only revenue generated by the service (in the form of "drug concentration scheduling" and "drug concentration evaluation" fees charged to patients) but also by cost savings resulting from the prevention of inappropriate, misleading, and potentially dangerous SDCs. An audit conducted in 1986 showed that the policy of having pharmacists schedule the sampling times for SDCs saves about $500,000 annually. Quality assurance has been documented by auditing compliance with and therapeutic effectiveness of dosing guidelines and by working with laboratory personnel to identify and prevent spurious SDC results and assay errors. The methods used by the pharmacokinetics service at MMCLB to document the benefits of the service have been vital in proving both its cost-effectiveness and its positive effect on patient care.

  15. Cetirizine in horses: pharmacokinetics and pharmacodynamics following repeated oral administration.

    PubMed

    Olsén, Lena; Bondesson, Ulf; Broström, Hans; Tjälve, Hans; Ingvast-Larsson, Carina

    2008-08-01

    The pharmacokinetics of the histamine H(1)-antagonist cetirizine and its effect on histamine-induced cutaneous wheal formation were studied in six healthy horses following repeated oral administration. After three consecutive administrations of cetirizine (0.2 mg/kg body weight, bw) every 12h, the trough plasma concentration of cetirizine was 16+/-4 ng/mL (mean+/-SD) and the wheal formation was inhibited by 45+/-23%. After four additional administrations of cetirizine (0.4 mg/kg bw) every 12 h, the trough plasma concentration was 48+/-15 ng/mL and the wheal formation was inhibited by 68+/-11%. The terminal half-life was about 5.8 h. A pharmacokinetic/pharmacodynamic link model showed that the maximal inhibition of wheal formation was about 95% and the EC(50) about 18 ng/mL. It is concluded that cetirizine in doses of 0.2-0.4 mg/kg bw administered at 12 h intervals exhibits favourable pharmacokinetic and pharmacodynamic properties without causing visible side effects, and the drug may therefore be a useful antihistamine in equine medicine.

  16. Television Quiz Show Simulation

    ERIC Educational Resources Information Center

    Hill, Jonnie Lynn

    2007-01-01

    This article explores the simulation of four television quiz shows for students in China studying English as a foreign language (EFL). It discusses the adaptation and implementation of television quiz shows and how the students reacted to them.

  17. Pharmacokinetics of oral amantadine in greyhound dogs.

    PubMed

    Norkus, C; Rankin, D; Warner, M; KuKanich, B

    2015-06-01

    This study reports the pharmacokinetics of amantadine in greyhound dogs after oral administration. Five healthy greyhound dogs were used. A single oral dose of 100 mg amantadine hydrochloride (mean dose 2.8 mg/kg as amantadine hydrochloride) was administered to nonfasted subjects. Blood samples were collected at predetermined time points from 0 to 24 h after administration, and plasma concentrations of amantadine were measured by liquid chromatography with triple quadrupole mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Amantadine was well tolerated in all dogs with no adverse effects observed. The mean (range) amantadine CMAX was 275 ng/mL (225-351 ng/mL) at 2.6 h (1-4 h) with a terminal half-life of 4.96 h (4.11-6.59 h). The results of this study can be used to design dosages to assess multidose pharmacokinetics and dosages designed to achieve targeted concentrations in order to assess the clinical effects of amantadine in a variety of conditions including chronic pain. Further studies should also assess the pharmacokinetics of amantadine in other dog breeds or using population pharmacokinetics studies including multiple dog breeds to assess potential breed-specific differences in the pharmacokinetics of amantadine in dogs.

  18. Physiologically-based pharmacokinetic analysis of grepafloxacin.

    PubMed

    Nakajima, Y; Hattori, K; Shinsei, M; Matsunaga, N; Iizasa, H; Sasabe, H; Akiyama, H; Miyanmoto, G; Nakashima, E

    2000-09-01

    Grepafloxacin (GPFX) is a synthetic new quinolone antimicrobial agent that possesses an extensive tissue distribution and exhibits a strong antibacterial activity in vivo. In this study, the tissue distribution characteristics of GPFX were examined using tissue concentration-time profiles following intravenous administration to rats. Subsequently, the pharmacokinetics of GPFX were analyzed based on the physiological pharmacokinetic model. The tissue-to-plasma partition coefficients (Kp) of GPFX in rats were high in all tissues except brain. A pharmacokinetic model for rabbits, monkeys and dogs was constructed using the tissue-to-plasma free concentration ratio (Kp,f) of GPFX in rats to simulate the GPFX concentration-time profile in plasma following intravenous administration of GPFX to each animal. The calculation-derived concentrations correlated well with the experimentally-derived data, suggesting that there are no interspecies differences in the high tissue distribution characteristics of GPFX. The clearance rates of GPFX in humans were predicted from the pharmacokinetic parameters of rats, rabbits, monkeys and dogs by an animal scale-up method and a pharmacokinetic model for humans was constructed. The GPFX concentration-time profiles in plasma, following oral administration of GPFX to humans, were predicted within 0.5-1.0 h of mean absorption time and the calculation-derived results were in good agreement with the experimental data. Thus, it is suggested that the concentration-time profile in plasma and all human organs can be predicted from the pharmacokinetic data of animals.

  19. Clinical Predictors of Venetoclax Pharmacokinetics in Chronic Lymphocytic Leukemia and Non-Hodgkin's Lymphoma Patients: a Pooled Population Pharmacokinetic Analysis.

    PubMed

    Jones, Aksana K; Freise, Kevin J; Agarwal, Suresh K; Humerickhouse, Rod A; Wong, Shekman L; Salem, Ahmed Hamed

    2016-09-01

    Venetoclax (ABT-199/GDC-0199) is a selective, potent, first-in-class BCL-2 inhibitor that restores apoptosis in cancer cells and has demonstrated clinical efficacy in a variety of hematological malignancies. The objective of this analysis was to characterize the population pharmacokinetics of venetoclax and identify demographic, pathophysiologic, and treatment factors that influence its pharmacokinetics. Plasma concentration samples from 505 subjects enrolled in 8 clinical studies were analyzed using non-linear mixed-effects modeling. Venetoclax plasma concentrations were best described by a two-compartment PK model with first-order absorption and elimination. The terminal half-life in cancer subjects was estimated to be approximately 26 h. Moderate and strong CYP3A inhibitors decreased venetoclax apparent clearance by 19% and 84%, respectively, while weak CYP3A inhibitors and inducers did not affect clearance. Additionally, concomitant rituximab administration was estimated to increase venetoclax apparent clearance by 21%. Gastric acid-reducing agent co-administration had no impact on the rate or extent of venetoclax absorption. Females had 32% lower central volume of distribution when compared to males. Food increased the bioavailability by 2.99- to 4.25-fold when compared to the fasting state. Mild and moderate renal and hepatic impairment, body weight, age, race, weak CYP3A inhibitors and inducers as well as OATP1B1 transporter phenotype and P-gp, BCRP, and OATP1B1/OATP1B3 modulators had no impact on venetoclax pharmacokinetics. Venetoclax showed minimal accumulation with accumulation ratio of 1.30-1.44. In conclusion, the concomitant administration of moderate and strong CYP3A inhibitors and rituximab as well as food were the main factors impacting venetoclax pharmacokinetics, while patient characteristics had only minimal impact.

  20. Pharmacokinetic population study to describe cefepime lung concentrations.

    PubMed

    Breilh, D; Saux, M C; Delaisement, C; Fratta, A; Ducint, D; Velly, J F; Couraud, L

    2001-01-01

    Pharmacokinetic parameters of cefepime in 2 g plasma and lung tissue bid over 3 days to achieve the steady-state was studied in 16 patients (15 male, one female) subjected to lung surgery for bronchial epithelioma. The aims of this study were firstly to quantify cefepime lung diffusion with cefepime lung concentrations in comparison with cefepime serum concentrations, and secondly to estimate population pharmacokinetic parameters of cefepime in lung tissue using NONMEM. The mean characteristics of patients were: age, 60 years (range, 51-69 years), weight, 73 kg (range, 62-87 kg) and creatinine clearance, 77 ml/min (range, 62-92 ml/min). Both serum sample (two per patient) and lung sample (one per patient) cefepime concentrations were analysed by HPLC with UV detection. Five groups were made according to the time of sampling after the last cefepime intravenous infusion at the fifth infusion: 0.5 h (n=2), 2 h (n=5), 4 h (n=3), 8 h (n=3) and 12 h (n=3). The cefepime concentration ratio between lung and serum was calculated for each group and statistical analysis show no significant difference between groups. The mean concentration ratio between lung and serum was 101% (range, 70-130%). To explain this observation a two-compartment pharmacokinetic model with a population approach was used to describe pharmacokinetic parameters of cefepime both in lung and in serum. Serum was assimilated at the central compartment and lung was the peripheral compartment. NONMEM was used to estimate the mean and the variance of the pharmacokinetic parameters. Central volume of distribution (V(d)), steady-state volume of distribution (V(ss)), central clearance (CL) and transfer constants (K(cp)) from serum to lung and (K(pc)) from lung to serum were estimated. Central elimination half-life t(1/2Kbeta)was extrapolated from elimination constant beta. Results were: V(d)= 15.62 +/- 2.56 l, V(ss)= 17.58 +/- 2.58 l, CL = 3.65 +/- 1.25 l/h, beta = 0.234 h(-1), t(1/2beta)= 2.96 hours, K(cp)= 12

  1. Development of a radiopharmaceutical dose calculator for pediatric patients undergoing diagnostic nuclear medicine studies

    PubMed Central

    Pandey, Anil Kumar; Sharma, Sanjay Kumar; Sharma, Punit; Gupta, Priyanka; Kumar, Rakesh

    2013-01-01

    Objective: It is important to ensure that as low as reasonably achievable (ALARA) concept during the radiopharmaceutical (RPH) dose administration in pediatric patients. Several methods have been suggested over the years for the calculation of individualized RPH dose, sometimes requiring complex calculations and large variability exists for administered dose in children. The aim of the present study was to develop a software application that can calculate and store RPH dose along with patient record. Materials and Methods: We reviewed the literature to select the dose formula and used Microsoft Access (a software package) to develop this application. We used the Microsoft Excel to verify the accurate execution of the dose formula. The manual and computer time using this program required for calculating the RPH dose were compared. Results: The developed application calculates RPH dose for pediatric patients based on European Association of Nuclear Medicine dose card, weight based, body surface area based, Clark, Solomon Fried, Young and Webster's formula. It is password protected to prevent the accidental damage and stores the complete record of patients that can be exported to Excel sheet for further analysis. It reduces the burden of calculation and saves considerable time i.e., 2 min computer time as compared with 102 min (manual calculation with the calculator for all seven formulas for 25 patients). Conclusion: The software detailed above appears to be an easy and useful method for calculation of pediatric RPH dose in routine clinical practice. This software application will help in helping the user to routinely applied ALARA principle while pediatric dose administration. PMID:24163510

  2. High Yield Production and Radiochemical Isolation of Isotopically Pure Arsenic-72 and Novel Radioarsenic Labeling Strategies for the Development of Theranostic Radiopharmaceuticals

    PubMed Central

    Ellison, Paul A.; Barnhart, Todd E.; Chen, Feng; Hong, Hao; Zhang, Yin; Theuer, Charles P.; Cai, Weibo; Nickles, Robert J.; DeJesus, Onofre T.

    2016-01-01

    Radioisotopes of arsenic are of considerable interest to the field of nuclear medicine with unique nuclear and chemical properties making them well-suited for use in novel theranostic radiopharmaceuticals. However, progress must still be made in the production of isotopically pure radioarsenic and in its stable conjugation to biological targeting vectors. This work presents the production and irradiation of isotopically enriched 72Ge(m) discs in an irrigation-cooled target system allowing for the production of isotopically pure 72As with capability on the order of 10 GBq. A radiochemical separation procedure isolated the reactive trivalent radioarsenic in a small volume buffered aqueous solution, while reclaiming 72Ge target material. The direct thiol-labeling of a monoclonal antibody resulted in a conjugate exhibiting exceptionally poor in vivo stability in a mouse model. This prompted further investigations to alternative radioarsenic labeling strategies, including the labeling of the dithiol-containing chelator dihydrolipoic acid, and thiol-modified mesoporous silica nanoparticles (MSN-SH). Radioarsenic-labeled MSN-SH showed exceptional in vivo stability toward dearsenylation. PMID:26646989

  3. cGMP Production of the Radiopharmaceutical [(18) F]MK-6240 for PET imaging of Human Neurofibrillary Tangles.

    PubMed

    Collier, Thomas Lee; Yokell, Daniel L; Livni, Eli; Rice, Peter A; Celen, Sofie; Serdons, Kim; Neelamegam, Ramesh; Bormans, Guy; Harris, Dawn; Walji, Abbas; Hostetler, Eric D; Bennacef, Idriss; Vasdev, Neil

    2017-02-09

    Fluorine-18 labelled 6-(fluoro)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([(18) F]MK-6240) is a novel potent and selective PET radiopharmaceutical for detecting human neurofibrillary tangles, which are made up of aggregated tau protein. Herein, we report the fully automated two-step radiosynthesis of [(18) F]MK-6240 using a commercially available radiosynthesis module, GE Healthcare Tracerlab(TM) FXFN . Nucleophilic fluorination of the 5-diBoc-6-nitro precursor with potassium cryptand [(18) F]fluoride (K[(18) F]/K222 ) was carried out by conventional heating, followed by acid deprotection and semi-preparative HPLC under isocratic conditions. The isolated product was diluted with formulation solution and sterile filtered under Current Good Manufacturing Practices (cGMPs), and quality control procedures were established to validate this radiopharmaceutical for human use. At the end of synthesis, 6.3 - 9.3 GBq (170 - 250 mCi) of [(18) F]MK-6240 was formulated and ready for injection, in an uncorrected radiochemical yield of 7.5 ± 1.9% (relative to starting [(18) F]fluoride) with a specific activity of 222 ± 67 GBq/µmol (6.0 ± 1.8 Ci/µmol) at the end of synthesis (90 min; n = 3). [(18) F]MK-6240 was successfully validated for human PET studies meeting all FDA and USP requirements for a PET radiopharmaceutical. The present method can be easily adopted for use with other radiofluorination modules for widespread clinical research use.

  4. Analysis of radionuclide concentration in air released through the stack of a radiopharmaceutical production facility based on a medical cyclotron

    NASA Astrophysics Data System (ADS)

    Giardina, M.; Tomarchio, E.; Greco, D.

    2015-11-01

    Positron emitting radionuclides are increasingly used in medical diagnostics and the number of radiopharmaceutical production facilities have been estimated to be growing worldwide. During the process of production and/or patient administration of radiopharmaceuticals, an amount of these radionuclides might become airborne and escape into the environment. Therefore, the analysis of radionuclide concentration in the air released to the stack is a very important issue to evaluate the dose to the population living around the plant. To this end, sampling and measurement of radionuclide concentration in air released through the stack of a Nuclear Medicine Center (NMC), provided with a cyclotron for radiopharmaceuticals production, must be routinely carried out with an automatic measurement system. In this work is presented the air monitoring system realized at "San Gaetano" NMC at Bagheria (Italy) besides the analysis of the recorded stack relesead air concentration data. Sampling of air was carried out continuously and gamma-ray spectrometric measurement are made on-line and for a short time by using a shielded Marinelli beaker filled with sampled air and a gamma detector. The use of this system allows to have 1440 values of air concentration per day from 2002, year of the start of operation with the cyclotron. Therefore, the concentration values are very many and an analysis software is needed to determine the dose to the population. A comparison with the results of a simulation code based on a Gaussian Plume air dispersion modelling allow us to confirm the no-radiological significance of the stack effluent releases in terms of dose to population and to evaluate possible improvements in the plant devices to reduce the air concentration at stack.

  5. An internal radiation dosimetry computer program, IDAC 2.0, for estimation of patient doses from radiopharmaceuticals.

    PubMed

    Andersson, M; Johansson, L; Minarik, D; Mattsson, S; Leide-Svegborn, S

    2014-12-01

    The internal dosimetry computer program internal dose assessment by computer (IDAC) for calculations of absorbed doses to organs and tissues as well as effective doses to patients from examinations with radiopharmaceuticals has been developed. The new version, IDAC2.0, incorporates the International Commission on Radiation Protection (ICRP)/ICRU computational adult male and female voxel phantoms and decay data from the ICRP publication 107. Instead of only 25 source and target regions, calculation can now be made with 63 source regions to 73 target regions. The major advantage of having the new phantom is that the calculations of the effective doses can be made with the latest tissue weighting factors of ICRP publication 103. IDAC2.0 uses the ICRP human alimentary tract (HAT) model for orally administrated activity and for excretion through the gastrointestinal tract and effective doses have been recalculated for radiopharmaceuticals that are orally administered. The results of the program are consistent with published data using the same specific absorption fractions and also compared with published data from the same computational phantoms but with segmentation of organs leading to another set of specific absorption fractions. The effective dose is recalculated for all the 34 radiopharmaceuticals that are administered orally and has been published by the ICRP. Using the new HAT model, new tissue weighting factors and the new adult computational voxel phantoms lead to an average effective dose of half of its earlier estimated value. The reduction mainly depends on electron transport simulations to walled organs and the transition from the stylised phantom with unrealistic interorgan distances to more realistic voxel phantoms.

  6. Population pharmacokinetic modeling and simulation of huperzine A in elderly Chinese subjects

    PubMed Central

    Sheng, Lei; Qu, Yi; Yan, Jing; Liu, Gang-yi; Wang, Wei-liang; Wang, Yi-jun; Wang, Hong-yi; Zhang, Meng-qi; Lu, Chuan; Liu, Yun; Jia, Jing-yin; Hu, Chao-ying; Li, Xue-ning; Yu, Chen; Xu, Hong-rong

    2016-01-01

    Aim: Our preliminary results show that huperzine A, an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD) patients in China, exhibits different pharmacokinetic features in elderly and young healthy subjects. However, its pharmacokinetic data in elderly subjects remains unavailable to date. Thus, we developed a population pharmacokinetic (PPK) model of huperzine A in elderly Chinese people, and identified the covariate affecting its pharmacokinetics for optimal individual administration. Methods: A total of 341 serum huperzine A concentration records was obtained from 2 completed clinical trials (14 elderly healthy subjects in a phase I pharmacokinetic study; 35 elderly AD patients in a phase II study). Population pharmacokinetic analysis was performed using the non-linear mixed-effect modeling software Phoenix NLME1.1.1. The effects of age, gender, body weight, height, creatinine, endogenous creatinine clearance rate as well as drugs administered concomitantly were analyzed. Bootstrap and visual predictive checks were used simultaneously to validate the final population pharmacokinetics models. Results: The plasma concentration-time profile of huperzine A was best described by a one-compartment model with first-order absorption and elimination. Age was identified as the covariate having significant influence on huperzine A clearance. The final PPK model of huperzine A was: CL (L/h)=2.4649*(age/86)(−3.3856), Ka=0.6750 h−1, V (L)=104.216. The final PPK model was demonstrated to be suitable and effective by the bootstrap and visual predictive checks. Conclusion: A PPK model of huperzine A in elderly Chinese subjects is established, which can be used to predict PPK parameters of huperzine A in the treatment of elderly AD patients. PMID:27180987

  7. MIRD Pamphlet No. 26: Joint EANM/MIRD Guidelines for Quantitative 177Lu SPECT Applied for Dosimetry of Radiopharmaceutical Therapy.

    PubMed

    Ljungberg, Michael; Celler, Anna; Konijnenberg, Mark W; Eckerman, Keith F; Dewaraja, Yuni K; Sjögreen-Gleisner, Katarina; Bolch, Wesley E; Brill, A Bertrand; Fahey, Frederic; Fisher, Darrell R; Hobbs, Robert; Howell, Roger W; Meredith, Ruby F; Sgouros, George; Zanzonico, Pat; Bacher, Klaus; Chiesa, Carlo; Flux, Glenn; Lassmann, Michael; Strigari, Lidia; Walrand, Stephan

    2016-01-01

    The accuracy of absorbed dose calculations in personalized internal radionuclide therapy is directly related to the accuracy of the activity (or activity concentration) estimates obtained at each of the imaging time points. MIRD Pamphlet no. 23 presented a general overview of methods that are required for quantitative SPECT imaging. The present document is next in a series of isotope-specific guidelines and recommendations that follow the general information that was provided in MIRD 23. This paper focuses on (177)Lu (lutetium) and its application in radiopharmaceutical therapy.

  8. Determination of 125I impurities in [ 123I]labelled radiopharmaceuticals, by liquid scintillation counting: sensitivity of the method

    NASA Astrophysics Data System (ADS)

    Bonardi, M. L.; Birattari, C.; Groppi, F.; Gini, L.; Mainardi, C. H. S.; Menapace, E.

    2004-01-01

    Iodine-125 is a radioisotopic impurity "always" present in iodine-123, produced by nuclear reactions induced either on natural or "highly" enriched targets. Liquid scintillation counting is a very sensitive tool to determine low level impurities of both low energy electrons and photons in aqueous and organic solutions of radiopharmaceutical compounds. With this technique it was possible to determine, on commercial samples, that the content of 125I was of the order of not less than 0.1% for 123I produced via 127I(p,5n) reactions and not less than 0.01% for 123I produced via "highly" enriched 124Xe(p,X) nuclear reactions.

  9. Preclinical assessment of dopaminergic system in rats by MicroPET using three positron-emitting radiopharmaceuticals

    NASA Astrophysics Data System (ADS)

    Lara-Camacho, V. M.; Ávila-García, M. C.; Ávila-Rodríguez, M. A.

    2014-11-01

    Different diseases associated with dysfunction of dopaminergic system such as Parkinson, Alzheimer, and Schizophrenia are being widely studied with positron emission tomography (PET) which is a noninvasive method useful to assess the stage of these illnesses. In our facility we have recently implemented the production of [11C ]-DTBZ, [11C ]-RAC, and [18F ]-FDOPA, which are among the most common PET radiopharmaceuticals used in neurology applications to get information about the dopamine pathways. In this study two healthy rats were imaged with each of those radiotracers in order to confirm selective striatum uptake as a proof of principle before to release them for human use.

  10. Preclinical assessment of dopaminergic system in rats by MicroPET using three positron-emitting radiopharmaceuticals

    SciTech Connect

    Lara-Camacho, V. M. Ávila-García, M. C. Ávila-Rodríguez, M. A.

    2014-11-07

    Different diseases associated with dysfunction of dopaminergic system such as Parkinson, Alzheimer, and Schizophrenia are being widely studied with positron emission tomography (PET) which is a noninvasive method useful to assess the stage of these illnesses. In our facility we have recently implemented the production of [{sup 11}C]-DTBZ, [{sup 11}C]-RAC, and [{sup 18}F]-FDOPA, which are among the most common PET radiopharmaceuticals used in neurology applications to get information about the dopamine pathways. In this study two healthy rats were imaged with each of those radiotracers in order to confirm selective striatum uptake as a proof of principle before to release them for human use.

  11. Untangling the web of European regulations for the preparation of unlicensed radiopharmaceuticals: a concise overview and practical guidance for a risk-based approach.

    PubMed

    Lange, Rogier; ter Heine, Rob; Decristoforo, Clemens; Peñuelas, Iván; Elsinga, Philip H; van der Westerlaken, Monique M L; Hendrikse, N Harry

    2015-05-01

    Radiopharmaceuticals are highly regulated, because they are controlled both as regular medicinal products and as radioactive substances. This can pose a hurdle for their development and clinical use. Radiopharmaceuticals are fundamentally different from other medicinal products and these regulations are not always adequate for their production. Strict compliance may have a huge resource impact, without further improving product quality. In this paper we give an overview of the applicable legislation and guidelines and propose a risk-based approach for their implementation. We focus on a few controversial Good Manufacturing Practice topics: cleanroom classification, air pressure regime, cleanroom qualification and microbiological monitoring. We have developed an algorithm to assess the combined risk of microbiological contamination of a radiopharmaceutical preparation process and propose corresponding Good Manufacturing Practice classification levels. In our opinion, the risk of carry-over of radiopharmaceuticals by individuals cannot be contained by pressure differences, and complicated regimes with underpressured rooms are not necessary in most situations. We propose a sterility assurance level of 10 for radiopharmaceuticals that are administered within a working day, irrespective of their use. We suggest the adoption of limits for environmental monitoring of microbial contamination, as proposed by Bruel and colleagues, on behalf of the French Society of Radiopharmacy. Recently launched regulatory documents seem to breathe a more liberal spirit than current legislation and recognize the need for the use of risk assessment. We argue that future legislation be further harmonized and state risk assessment as the gold standard for implementation of drug quality regulations for the preparation of unlicensed radiopharmaceuticals.

  12. Leptin pharmacokinetics in male mice

    PubMed Central

    Dobos, Robin C; Agnew, Linda L; Smart, Neil A; McFarlane, James R

    2017-01-01

    Pharmacokinetics of leptin in mammals has not been studied in detail and only one study has examined more than one time point in non-mutant mice and this was in a female mice. This is the first study to describe leptin distribution over a detailed time course in normal male mice. A physiologic dose (12 ng) of radiolabelled leptin was injected into adult male mice via the lateral tail vein and tissues were dissected out and measured for radioactivity over a time course of up to two hours. Major targets were the digestive tract, kidneys, skin and lungs. The brain was not a major target, and 0.15% of the total dose was recovered from the brain 5 min after administration. Major differences appear to exist in the distribution of leptin between the male and female mice, indicating a high degree of sexual dimorphism. Although the half-lives were similar between male and female mice, almost twice the proportion of leptin was recovered from the digestive tract of male mice in comparison to that reported previously for females. This would seem to indicate a major difference in leptin distribution and possibly function between males and females. PMID:27998953

  13. Piperacillin pharmacokinetics in pediatric patients.

    PubMed Central

    Wilson, C B; Koup, J R; Opheim, K E; Adelman, L A; Levy, J; Stull, T L; Clausen, C; Smith, A L

    1982-01-01

    The pharmacokinetics of piperacillin were studied in 15 pediatric patients (age range, 3.3 to 14.3 years). Piperacillin was administered in a dosage of 1.5 +/- 0.4 g/m2 (mean +/- standard deviation) every 4 to 6 h. Peak serum concentrations ranged from 69 to 354 micrograms/ml. The mean elimination half-life was 37.0 +/- 13.3 min, which is shorter than that observed in most adults with normal renal function. The mean elimination half-life in three patients with renal impairment was 60.1 +/- 12.4 min, and the mean ratio of renal clearance to total clearance was 0.57. These results suggest a significant nonrenal elimination of piperacillin. Based on these data, a dosage of 1.5 g/m2 given as a 30-min infusion every 4 h is suggested for children with normal renal function. For patients with renal impairment, the daily dosage could be calculated as follows: corrected dose = normal dose x (0.35 + [0.65 x (ClCr/0.06)]), where ClCr is the creatinine clearance expressed as liters per minute per square meter. PMID:6215893

  14. Showing What They Know

    ERIC Educational Resources Information Center

    Cech, Scott J.

    2008-01-01

    Having students show their skills in three dimensions, known as performance-based assessment, dates back at least to Socrates. Individual schools such as Barrington High School--located just outside of Providence--have been requiring students to actively demonstrate their knowledge for years. The Rhode Island's high school graduating class became…

  15. The Ozone Show.

    ERIC Educational Resources Information Center

    Mathieu, Aaron

    2000-01-01

    Uses a talk show activity for a final assessment tool for students to debate about the ozone hole. Students are assessed on five areas: (1) cooperative learning; (2) the written component; (3) content; (4) self-evaluation; and (5) peer evaluation. (SAH)

  16. What Do Maps Show?

    ERIC Educational Resources Information Center

    Geological Survey (Dept. of Interior), Reston, VA.

    This curriculum packet, appropriate for grades 4-8, features a teaching poster which shows different types of maps (different views of Salt Lake City, Utah), as well as three reproducible maps and reproducible activity sheets which complement the maps. The poster provides teacher background, including step-by-step lesson plans for four geography…

  17. Show Me the Way

    ERIC Educational Resources Information Center

    Dicks, Matthew J.

    2005-01-01

    Because today's students have grown up steeped in video games and the Internet, most of them expect feedback, and usually gratification, very soon after they expend effort on a task. Teachers can get quick feedback to students by showing them videotapes of their learning performances. The author, a 3rd grade teacher describes how the seemingly…

  18. Chemistry Game Shows

    NASA Astrophysics Data System (ADS)

    Campbell, Susan; Muzyka, Jennifer

    2002-04-01

    We present a technological improvement to the use of game shows to help students review for tests. Our approach uses HTML files interpreted with a browser on a computer attached to an LCD projector. The HTML files can be easily modified for use of the game in a variety of courses.

  19. Honored Teacher Shows Commitment.

    ERIC Educational Resources Information Center

    Ratte, Kathy

    1987-01-01

    Part of the acceptance speech of the 1985 National Council for the Social Studies Teacher of the Year, this article describes the censorship experience of this honored social studies teacher. The incident involved the showing of a videotape version of the feature film entitled "The Seduction of Joe Tynan." (JDH)

  20. Talk Show Science.

    ERIC Educational Resources Information Center

    Moore, Mitzi Ruth

    1992-01-01

    Proposes having students perform skits in which they play the roles of the science concepts they are trying to understand. Provides the dialog for a skit in which hot and cold gas molecules are interviewed on a talk show to study how these properties affect wind, rain, and other weather phenomena. (MDH)

  1. Stage a Water Show

    ERIC Educational Resources Information Center

    Frasier, Debra

    2008-01-01

    In the author's book titled "The Incredible Water Show," the characters from "Miss Alaineus: A Vocabulary Disaster" used an ocean of information to stage an inventive performance about the water cycle. In this article, the author relates how she turned the story into hands-on science teaching for real-life fifth-grade students. The author also…

  2. Understanding pharmacokinetics to improve tuberculosis treatment outcome

    PubMed Central

    Reynolds, Jonathan; Heysell, Scott K

    2014-01-01

    Introduction Tuberculosis (TB) remains the leading cause of death from a curable infectious disease; drug-resistant TB threatens to dismantle all prior gains in global control. Suboptimal circulating anti-TB drug concentrations can lead to lack of cure and acquired drug resistance. Areas covered This review will introduce pharmacokinetic parameters for key anti-TB drugs, as well as the indications and limitations of measuring these parameters in clinical practice. Current and novel methodologies for delivering anti-TB pharmacokinetic-pharmacodynamic data are highlighted and gaps in operational research described. Expert opinion Individual pharmacokinetic variability is commonplace, underappreciated and difficult to predict without therapeutic drug monitoring (TDM). Pharmacokinetic thresholds associated with poor TB treatment outcome in drug-susceptible TB have recently been described and may now guide the application of TDM, but require validation in a variety of settings and comorbidities. Dried blood spots for TDM and prepackaged multidrug plates for minimum inhibitory concentration testing will overcome barriers of accessibility and represent areas for innovation. Operationalizing pharmacokinetics has the potential to improve TB outcomes in the most difficult-to-treat forms of the disease such as multidrug resistance. Clinical studies in these areas are eagerly anticipated and we expect will better define the rational introduction of novel therapeutics. PMID:24597717

  3. 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.

  4. 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

  5. Pharmacokinetics and Saturable Absorption of Gabapentin in Nursing Home Elderly Patients.

    PubMed

    Ahmed, Ghada F; Bathena, Sai Praneeth R; Brundage, Richard C; Leppik, Ilo E; Conway, Jeannine M; Schwartz, Janice B; Birnbaum, Angela K

    2017-03-01

    Pharmacokinetic data of gabapentin (GBP) in community-dwelling elderly patients show a significant effect of advanced age on GBP pharmacokinetics due to altered renal function. However, there are no data in elderly nursing home (NH) patients to evaluate gabapentin absorption and elimination. Our objective was to characterize the pharmacokinetics of GBP in elderly nursing home patients maintained on GBP therapy. This was a prospective pharmacokinetic study in elderly nursing home patients (≥60 years) receiving GBP for the management of chronic pain or epilepsy from seven nursing homes. Pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling. A one-compartment model described the data and clearance (CL) was associated with estimated glomerular filtration rate (eGFR) (p < 0.0001). The GBP CL in elderly nursing home patients was 2.93 L/h. After adjusting for the effect of GFR, GBP CL was not affected by age, sex, body weight, or comorbidity scores. No significant effects of body size measures, age, and sex were detected on volume of distribution. Dose-dependent bioavailability of GBP was demonstrated, and the saturable absorption profile was described by a nonlinear hyperbolic function. Prediction-corrected visual predictive check (pc-VPC) suggests adequate fixed- and random-effects models that successfully simulated the mean trend and variability in gabapentin concentration-time profiles. In this analysis, the parameters of the hyperbolic nonlinearity appear to be similar between elderly and younger adults.

  6. Radiation absorbed dose estimates for oxygen-15 radiopharmaceuticals (H2( V)O, C VO, O VO) in newborn infants

    SciTech Connect

    Powers, W.J.; Stabin, M.; Howse, D.; Eichling, J.O.; Herscovitch, P.

    1988-12-01

    In preparation for measurement of regional cerebral oxygen metabolism by positron emission tomography, radiation absorbed dose estimates for 19 internal organs, blood, and total body were calculated for newborn infants following bolus intravenous administration of H2( V)O and brief inhalation of C VO and O VO. Cumulated activity for each radiopharmaceutical was calculated from a compartmental model based on the known biologic behavior of the compound. Values for mean absorbed dose/unit cumulated activity (S) for internal organs and total body were based on a newborn phantom. S was separately calculated for blood. Total radiopharmaceutical absorbed dose estimates necessary to measure cerebral oxygen metabolism in a 3.51-kg infant based on 0.7 mCi/kg H2( V)O and 1 mCi/kg C VO and O VO were determined to be 1.6 rad to the lung (maximum organ dose), 0.28 rad to the marrow, 0.46 rad to the gonads, and 0.22 rad to total body. These values are similar to those for current clinical nuclear medicine procedures employing /sup 99m/Tc in newborn infants.

  7. The effect of radiopharmaceutical choice on the determination of relative renal function in rats with unilateral renal obstruction

    SciTech Connect

    Taylor, A.; Lallone, R.

    1984-01-01

    A significant divergence of GFR and ERPF within a single kidney could lead to different estimates of relative renal function depending on which radiopharmaceutical is administered. To address this question, the authors studied adult male Sprague-Dawley rats with unilateral ureteral obstruction by giving each animal an intravenous injection of 10 ..mu..Ci of I-125 iothalamate (GFR), I-131 hippurate (ERPF), and TC-99m DMSA and measuring the 30 minute clearance (renal uptake and urine excretion) of each agent. Normal control animals were sham operated; 25 experimental animals were subjected to permanent unilateral ureteral occlusion and studied at 6 hours, 1, 3, 7 and 14 days. Acute ureteral obstruction impaired the clearance of iothalamate to a much greater degree than OIH or DMSA at 6 hours and 1 day (rho<.005) and 3 days (rho<.05). The decline in DMSA clearance reflected ERPF more closely than GFR. In evaluating renal disease, one should consider the functional parameter reflected by the radiopharmaceutical as well as the underlying disease state.

  8. Design of site specific radiopharmaceuticals for tumor imaging. (Parts I and II)

    SciTech Connect

    Van Dort, M.E.

    1983-01-01

    Part I. Synthetic methods were developed for the preparation of several iodinated benzoic acid hydrazides as labeling moieties for indirect tagging of carbonyl-containing bio-molecules and potential tumor-imaging agents. Biodistribution studies conducted in mice on the derivatives having the I-125 label ortho to a phenolic OH demonstrated a rapid in vivo deiodination. Part II. The reported high melanin binding affinity of quinoline and other heterocyclic antimalarial drugs led to the development of many analogues of such molecules as potential melanoma-imaging agents. Once such analogue iodochloroquine does exhibit high melanin binding, but has found limited clinical use due to appreciable accumulation in non-target tissues such as the adrenal cortex and inner ear. This project developed a new series of candidate melanoma imaging agents which would be easier to radio-label, could yield higher specific activity product, and which might demonstrate more favorable pharmacokinetic and dosimetric characteristics compared to iodochloroquine.

  9. Synthesis and evaluation of Lys¹(α,γ-Folate)Lys³(¹⁷⁷Lu-DOTA)-Bombesin(1-14) as a potential theranostic radiopharmaceutical for breast cancer.

    PubMed

    Aranda-Lara, Liliana; Ferro-Flores, Guillermina; Azorín-Vega, Erika; Ramírez, Flor de María; Jiménez-Mancilla, Nallely; Ocampo-García, Blanca; Santos-Cuevas, Clara; Isaac-Olivé, Keila

    2016-01-01

    The aim of this work was to synthesize Lys(1)(α,γ-Folate)-Lys(3)((177)Lu-DOTA)-Bombesin (1-14) ((177)Lu-Folate-BN), as well as to assess its potential for molecular imaging and targeted radiotherapy of breast tumors expressing folate receptors (FR) and gastrin-releasing peptide receptors (GRPR). Radiation absorbed doses of (177)Lu-Folate-BN (74 MBq, i.v.) estimated in athymic mice with T47D-induced breast tumors (positive to FR and GRPR), showed tumor doses of 23.9±2.1 Gy. T47D-tumors were clearly visible (Micro-SPECT/CT images). (177)Lu-Folate-BN demonstrated properties suitable as a theranostic radiopharmaceutical.

  10. 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.

  11. Optimisation of immunosuppressive therapy using pharmacokinetic principles.

    PubMed

    Grevel, J

    1992-11-01

    Clinical experience with immunosuppressive therapy is more extensive in the area of preventing the rejection of transplanted organs than in the treatment of autoimmune diseases. Among the many pharmacological agents presently in use, only prednisone (or methylprednisolone) and cyclosporin require dosage individualisation. Sources of interindividual variability in the pharmacokinetics of prednisone have been identified and are guiding the selection of individual dosage rates. As an alternative, a single timed concentration can determine an apparent value for prednisone clearance from which an individual dosage can be calculated. In contrast, numerous sources of inter- and intraindividual variability in cyclosporin pharmacokinetics prevent the easy selection of safe and effective starting dose rates. Indeed, test doses of cyclosporin followed by series of blood samples and the calculation of individual pharmacokinetic parameters are needed to assure successful immunosuppression right from the start. Furthermore, only continued monitoring sustains immunotherapy vis-à-vis intraindividual variability and a narrow therapeutic range of cyclosporin concentrations.

  12. In vitro kinetic studies on the mechanism of oxygen-dependent cellular uptake of copper radiopharmaceuticals

    NASA Astrophysics Data System (ADS)

    Holland, Jason P.; Giansiracusa, Jeffrey H.; Bell, Stephen G.; Wong, Luet-Lok; Dilworth, Jonathan R.

    2009-04-01

    The development of hypoxia-selective radiopharmaceuticals for use as therapeutic and/or imaging agents is of vital importance for both early identification and treatment of cancer and in the design of new drugs. Radiotracers based on copper for use in positron emission tomography have received great attention due to the successful application of copper(II) bis(thiosemicarbazonato) complexes, such as [60/62/64Cu(II)ATSM] and [60/62/64Cu(II)PTSM], as markers for tumour hypoxia and blood perfusion, respectively. Recent work has led to the proposal of a revised mechanism of hypoxia-selective cellular uptake and retention of [Cu(II)ATSM]. The work presented here describes non-steady-state kinetic simulations in which the reported pO2-dependent in vitro cellular uptake and retention of [64Cu(II)ATSM] in EMT6 murine carcinoma cells has been modelled by using the revised mechanistic scheme. Non-steady-state (NSS) kinetic analysis reveals that the model is in very good agreement with the reported experimental data with a root-mean-squared error of less than 6% between the simulated and experimental cellular uptake profiles. Estimated rate constants are derived for the cellular uptake and washout (k1 = 9.8 ± 0.59 × 10-4 s-1 and k2 = 2.9 ± 0.17 × 10-3 s-1), intracellular reduction (k3 = 5.2 ± 0.31 × 10-2 s-1), reoxidation (k4 = 2.2 ± 0.13 mol-1 dm3 s-1) and proton-mediated ligand dissociation (k5 = 9.0 ± 0.54 × 10-5 s-1). Previous mechanisms focused on the reduction and reoxidation steps. However, the data suggest that the origins of hypoxia-selective retention may reside with the stability of the copper(I) anion with respect to protonation and ligand dissociation. In vitro kinetic studies using the nicotimamide adenine dinucleotide (NADH)-dependent ferredoxin reductase enzyme PuR isolated from the bacterium Rhodopseudomonas palustris have also been conducted. NADH turnover frequencies are found to be dependent on the structure of the ligand and the results confirm

  13. A PHARMACOKINETIC MODEL FOR ESTIMATING ...

    EPA Pesticide Factsheets

    Empirical evidence suggests that exposure of Americans to dioxin-like compounds was low during the early decades of the 20th century, then increased during the 1940s and 1950s reaching a peak in the 1960s and 1970s, and progressively decreased to lower levels in the 1980s and 1990s. Such evidence includes dioxin analysis of carbon-dated sediment cores of lakes and rivers, preserved meat samples from different decades of the 20th century, and limited body burden measurements of dioxin-like compounds. Pinsky and Lorber (1998) summarized studies measuring 2,3,7,8-TCDD in blood and adipose tissue finding a range of 10-20 pg/g (ppt) lipid during the 1970s, and 2-10 ppt lipid during the 1980s. This study reviews body burdens of dioxin toxic equivalents, TEQs, to find a range from about 50-80 ppt lipid during the 1970s, 30-50 ppt lipid during the 1980s, and 10-20 ppt lipid during the 1990s (TEQs comprised of the 17 dioxin and furan congeners only). Pinsky and Lorber (1998) investigated historical exposure trends for 2,3,7,8-TCDD by using a single-compartment, first-order pharmacokinetic model. The current study extends this prior effort by modeling dioxin TEQs instead of the single compound, 2,3,7,8-TCDD. TEQs are modeled as though they are a single compound, in contrast to an approach where the individual dioxin and furan congeners are modeled separately. It was found that body burdens of TEQs during the 1970s, 80s, and 90s could be modeled by assuming a histor

  14. Pharmacokinetics of enrofloxacin in turkeys.

    PubMed

    Dimitrova, D J; Lashev, L D; Yanev, S G; Pandova, B

    2007-06-01

    The pharmacokinetics of enrofloxacin (EFL) and its active metabolite ciprofloxacin (CIP) was investigated in 7-8 month old turkeys (6 birds per sex). EFL was administered intravenously (i.v.) and orally (p.o.) at a dose 10 mg kg(-1) body weight. Blood was taken prior to and at 0.17, 0.33, 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 h following drug administration. The concentrations of EFL and CIP in blood serum were determined by high-performance liquid chromatography (HPLC). Serum concentrations versus time were analysed by a noncompartmental analysis. The elimination half-live and the mean residence time of EFL after i.v. injection for the serum were after oral administration 6.64+/-0.90 h, 8.96+/-1.18 h and 6.92+/-0.97 h, 11.91+/-1.87 h, respectively. After single p.o. administration, EFL was absorbed slowly (MAT=2.76+/-0.48 h) with time to reach maximum serum concentrations of 6.33+/-2.54 h. Maximum serum concentrations was 1.23+/-0.30 microg mL(-1). Oral bioavailability for for EFL after oral administration was found to be 69.20+/-1.49%. The ratios C(max)/MIC and AUC(0 --> 24)/MIC were respectively from 161.23+/-5.9 h to 12.90+/-0.5 h for the pharmacodynamic predictor C(max)/MIC, and from 2153.44+/-66.6 h to 137.82+/-4.27 h for AUC(0 --> 24)/MIC, for the different clinically significant microorganisms, whose values for MIC varies from 0.008 microg L(-1) to 0.125 microg mL(-1).

  15. Pharmacokinetics of amantadine in cats.

    PubMed

    Siao, K T; Pypendop, B H; Stanley, S D; Ilkiw, J E

    2011-12-01

    This study reports the pharmacokinetics of amantadine in cats, after both i.v. and oral administration. Six healthy adult domestic shorthair female cats were used. Amantadine HCl (5 mg/kg, equivalent to 4 mg/kg amantadine base) was administered either intravenously or orally in a crossover randomized design. Blood samples were collected immediately prior to amantadine administration, and at various times up to 1440 min following intravenous, or up to 2880 min following oral administration. Plasma amantadine concentrations were determined by liquid chromatography-mass spectrometry, and plasma amantadine concentration-time data were fitted to compartmental models. A two-compartment model with elimination from the central compartment best described the disposition of amantadine administered intravenously in cats, and a one-compartment model best described the disposition of oral amantadine in cats. After i.v. administration, the apparent volume of distribution of the central compartment and apparent volume of distribution at steady-state [mean ± SEM (range)], and the clearance and terminal half-life [harmonic mean ± jackknife pseudo-SD (range)] were 1.5 ± 0.3 (0.7-2.5) L/kg, 4.3 ± 0.2 (3.7-5.0) L/kg, 8.2 ± 2.1 (5.9-11.4) mL·min/kg, and 348 ± 49 (307-465) min, respectively. Systemic availability [mean ± SEM (range)] and terminal half-life after oral administration [harmonic mean ± jackknife pseudo-SD (range)] were 130 ± 11 (86-160)% and 324 ± 41 (277-381) min, respectively.

  16. Naproxen pharmacokinetics in the elderly.

    PubMed Central

    Upton, R A; Williams, R L; Kelly, J; Jones, R M

    1984-01-01

    While naproxen pharmacokinetics appear to be altered in the presence of both diminished renal and hepatic function, the degree to which naproxen disposition might be influenced in the elderly by concurrent alteration in these functions is not obvious. Total plasma clearance/bioavailability (CL/F) of naproxen after a single 375 mg oral dose was found to be less in a group of 10 healthy men between 66 and 81 years of age than in 10 healthy men between 22 and 39 years (0.318 +/- 0.078, 0.416 +/- 0.061 l/h). At steady state (375 mg, 12 hourly), however, CL/F was statistically indistinguishable between the two groups. The fraction of naproxen unbound to plasma protein was doubled in elderly subjects, both at peak and trough drug concentrations. The lowered protein binding tended to obscure a 50% decrement in the intrinsic clearance of naproxen in the elderly as estimated by unbound clearance/bioavailability (213 +/- 64, 396 +/- 155 l/h). As a result, mean steady-state plasma concentrations of naproxen were indistinguishable between the elderly and young (64.2 +/- 8.5, 58.2 +/- 8.1 mg/l) but the elderly generated twice the mean steady-state unbound plasma drug concentration (0.157 +/- 0.039, 0.0859 +/- 0.0212 mg/l). Since it is the unbound drug concentration which appears in general to relate more closely to pharmacological and toxic effect, it may be advisable to reduce naproxen doses by half in the elderly, pending plasma drug concentration-response studies in this age group. If a similar perturbation with age occurs in benoxaprofen protein binding as was observed with naproxen, benoxaprofen intrinsic clearance in the elderly might be only one quarter of that in younger individuals; a factor which may contribute to the toxicity of this drug in the elderly. PMID:6487459

  17. Compartmental analysis and its manifold applications to pharmacokinetics.

    PubMed

    Rescigno, Aldo

    2010-03-01

    In this paper, I show how the concept of compartment evolved from the simple dilution of a substance in a physiological volume to its distribution in a network of interconnected spaces. The differential equations describing the fate of a substance in a living being can be solved, qualitatively and quantitatively, with the help of a number of mathematical techniques. A number of parameters of pharmacokinetic interest can be computed from the experimental data; often, the data available are not sufficient to determine some parameters, but it is possible to determine their range.

  18. Not a "reality" show.

    PubMed

    Wrong, Terence; Baumgart, Erica

    2013-01-01

    The authors of the preceding articles raise legitimate questions about patient and staff rights and the unintended consequences of allowing ABC News to film inside teaching hospitals. We explain why we regard their fears as baseless and not supported by what we heard from individuals portrayed in the filming, our decade-long experience making medical documentaries, and the full un-aired context of the scenes shown in the broadcast. The authors don't and can't know what conversations we had, what documents we reviewed, and what protections we put in place in each televised scene. Finally, we hope to correct several misleading examples cited by the authors as well as their offhand mischaracterization of our program as a "reality" show.

  19. Single-dose oral pharmacokinetics of pergolide mesylate in healthy adult mares.

    PubMed

    Gehring, Ronette; Beard, Laurie; Wright, Abra; Coetzee, Johann; Havel, James; Apley, Michael

    2010-01-01

    Pituitary pars intermedia dysfunction (PPID) is probably the most common disease of geriatric horses. Affected horses show a variety of clinical signs, including hirsutism, polyuria/polydipsia, immunosuppression, muscle wasting, and laminitis. The most common treatment for PPID is pergolide, a dopamine agonist; however, there are no pharmacokinetic data about the use of this drug in horses. This article describes a study designed to address this complete lack of pharmacokinetic information. The pharmacokinetics of pergolide are described in a small group of relatively young, healthy mares (n = 6), with the objective of generating data on which to base larger studies in the future. To make definitive dosing recommendations to clinicians, more studies will be needed to investigate the relationship between plasma pergolide concentrations and clinical outcomes, as well as the effect of gender, age, and concomitant disease on the absorption and disposition of this drug.

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

    PubMed

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

    2005-06-01

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

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

    PubMed Central

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

    2013-01-01

    Pharmacokinetic analysis at the organ level provides insight into how drugs distribute throughout the body but cannot explain how drugs work at the cellular level. Here we demonstrate in vivo single cell pharmacokinetic imaging of PARP-1 inhibitors (PARPi) and model drug behavior under varying conditions. We visualize intracellular kinetics of PARPi distribution in real time, showing that PARPi reaches its cellular target compartment, the nucleus, within minutes in vivo both in cancer and normal cells in various cancer models. We also use these data to validate predictive finite element modeling. Our theoretical and experimental data indicate that tumor cells are exposed to sufficiently high PARPi concentrations in vivo and suggest that drug inefficiency is likely related to proteomic heterogeneity or insensitivity of cancer cells to DNA repair inhibition. This suggests that single cell pharmacokinetic imaging and derived modeling improves our understanding of drug action at single cell resolution in vivo. PMID:23422672

  2. Clinical pharmacokinetics of amoxycillin and theophylline during cotreatment with both medicaments.

    PubMed

    Jonkman, J H; van der Boon, W J; Schoenmaker, R; Holtkamp, A H; Hempenius, J

    1985-01-01

    The influence of amoxycillin and theophylline on their mutual steady-state pharmacokinetics was studied in healthy adults by comparing the pharmacokinetic parameters as obtained during a 10-day course of each drug alone and after giving the drugs in combination. Amoxycillin and theophylline plasma concentrations were measured by means of HPLC methods. On the 9th day of each of the two periods of drug administration, a concentration-time curve was evaluated. These showed no influence of theophylline on absorption, elimination or volume of distribution of amoxycillin, demonstrating that the mean steady-state plasma concentrations were not significantly different during the two treatments. Amoxycillin also has no significant effect on theophylline steady-state pharmacokinetics. It is concluded that both drugs can be given concomitantly without any dosage adjustment.

  3. A Population Pharmacokinetic Model for Vancomycin in Adult Patients Receiving Extracorporeal Membrane Oxygenation Therapy

    PubMed Central

    Healy, JR; Thoma, BN; Peahota, MM; Ahamadi, M; Schmidt, L; Cavarocchi, NC; Kraft, WK

    2016-01-01

    The literature on the pharmacokinetics of vancomycin in patients undergoing extracorporeal membrane oxygenation (ECMO) therapy is sparse. A population pharmacokinetic (PK) model for vancomycin in ECMO patients was developed using a nonlinear mixed effects modeling on the concentration–time profiles of 14 ECMO patients who received intravenous vancomycin. Model selection was based on log‐likelihood criterion, goodness of fit plots, and scientific plausibility. Identification of covariates was done using a full covariate model approach. The pharmacokinetics of vancomycin was adequately described with a two‐compartment model. Parameters included clearance of 2.83 L/hr, limited central volume of distribution 24.2 L, and low residual variability 0.67%. Findings from the analysis suggest that standard dosing recommendations for vancomycin in non‐ECMO patients are adequate to achieve therapeutic trough concentrations in ECMO patients. This further shows that ECMO minimally affects the PK of vancomycin in adults including in higher‐weight patients. PMID:27639260

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

    PubMed Central

    Eugene, Andy R.

    2016-01-01

    Recent meta-analyses and publications over the past 15 years have provided evidence showing there are considerable gender differences in the pharmacokinetics of metoprolol. Throughout this time, there have not been any research articles proposing a gender stratified dose-adjustment resulting in an equivalent total drug exposure. Metoprolol pharmacokinetic data was obtained from a previous publication. Data was modeled using nonlinear mixed effect modeling using the MONOLIX software package to quantify metoprolol concentration–time data. Gender-stratified dosing simulations were conducted to identify equivalent total drug exposure based on a 100 mg dose in adults. Based on the pharmacokinetic modeling and simulations, a 50 mg dose in adult women provides an approximately similar metoprolol drug exposure to a 100 mg dose in adult men. PMID:28035289

  5. [Pharmacokinetics and pharmacodynamics of antibiotic therapy].

    PubMed

    Beck, S; Wicha, S G; Kloft, C; Kees, M G

    2014-10-01

    Antibiotic agents are crucial pillars in intensive care medicine and must be used rationally and sensibly. In the case of critically ill patients optimal dosing with respect to pharmacokinetic and pharmacodynamic principles (PK/PD) can be vital. Preclinical results demonstrated important differences between antibiotic classes and gave rise to differing clinical dosing strategies, e.g. high dose once daily regimens for aminoglycosides or extended/continuous infusion of betalactams. Critically ill patients with altered pharmacokinetic parameters and infections by pathogens with low susceptibility are most likely to benefit from PK/PD-guided therapy.

  6. Pharmacokinetics of three different injectable zuclopenthixol preparations.

    PubMed

    Aaes-Jørgensen, T

    1989-01-01

    1. The zuclopenthixol concentrations in serum has been investigated in man and dog after injection of three different zuclopenthixol preparations. These were zuclopenthixol dihydrochloride in aqueous solution, zuclopenthixol acetate in oil and zuclopenthixol decanoate in oil. 2. The pharmacokinetic profiles of the three injectable zuclopenthixol preparations are very different. Maximum serum levels are obtained after about 1 hour for zuclopenthixol dihydrochloride, after 36 hours for zuclopenthixol acetate and after one week for zuclopenthixol decanoate. 3. The different pharmacokinetics of the three injectable zuclopenthixol preparations are reflected in their clinical properties.

  7. Pharmacokinetic Comparative Study of Gastrodin and Rhynchophylline after Oral Administration of Different Prescriptions of Yizhi Tablets in Rats by an HPLC-ESI/MS Method

    PubMed Central

    Ge, Zhaohui; Liang, Qionglin; Wang, Yiming; Luo, Guoan

    2014-01-01

    Pharmacokinetic characters of rhynchophylline (RIN), gastrodin (GAS), and gastrodigenin (p-hydroxybenzyl alcohol, HBA) were investigated after oral administration of different prescriptions of Yizhi: Yizhi tablets or effective parts of tianma (total saponins from Gastrodiae, EPT) and gouteng (rhynchophylla alkaloids, EPG). At different predetermined time points after administration, the concentrations of GAS, HBA, and RIN in rat plasma were determined by an HPLC-ESI/MS method, and the main pharmacokinetic parameters were investigated. The results showed that the pharmacokinetic parameters Cmax and AUC0–∞ (P < 0.05) were dramatically different after oral administration of different prescriptions of Yizhi. The data indicated that the pharmacokinetic processes of GAS, HBA, and RIN in rats would interact with each other or be affected by other components in Yizhi. The rationality of the compatibility of Uncaria and Gastrodia elata as a classic “herb pair” has been verified from the pharmacokinetic viewpoint. PMID:25610474

  8. Developing population pharmacokinetic parameters for high-dose methotrexate therapy: implication of correlations among developed parameters for individual parameter estimation using the Bayesian least-squares method.

    PubMed

    Watanabe, Masahiro; Fukuoka, Noriyasu; Takeuchi, Toshiki; Yamaguchi, Kazunori; Motoki, Takahiro; Tanaka, Hiroaki; Kosaka, Shinji; Houchi, Hitoshi

    2014-01-01

    Bayesian estimation enables the individual pharmacokinetic parameters of the medication administrated to be estimated using only a few blood concentrations. Due to wide inter-individual variability in the pharmacokinetics of methotrexate (MTX), the concentration of MTX needs to be frequently determined during high-dose MTX therapy in order to prevent toxic adverse events. To apply the benefits of Bayesian estimation to cases treated with this therapy, we attempted to develop an estimation method using the Bayesian least-squares method, which is commonly used for therapeutic monitoring in a clinical setting. Because this method hypothesizes independency among population pharmacokinetic parameters, we focused on correlations among population pharmacokinetic parameters used to estimate individual parameters. A two-compartment model adequately described the observed concentration of MTX. The individual pharmacokinetic parameters of MTX were estimated in 57 cases using the maximum likelihood method. Among the available parameters accounting for a 2-compartment model, V1, k10, k12, and k21 were found to be the combination showing the weakest correlations, which indicated that this combination was best suited to the Bayesian least-squares method. Using this combination of population pharmacokinetic parameters, Bayesian estimation provided an accurate estimation of individual parameters. In addition, we demonstrated that the degree of correlation among population pharmacokinetic parameters used in the estimation affected the precision of the estimates. This result highlights the necessity of assessing correlations among the population pharmacokinetic parameters used in the Bayesian least-squares method.

  9. The effects of cefonicid on the pharmacokinetics of a once-a-day theophylline formulation.

    PubMed

    Cazzola, M; Lobefalo, G; Lupis, F; Vanacore, L; Martucci, P; D'Amato, G

    1989-01-01

    The authors have explored the effects of cefonicid on the steady-state pharmacokinetics of a new sustained-release theophylline formulation in 12 adult patients suffering from chronic obstructive lung disease, by comparing the pharmacokinetic data obtained following four days of medication with theophylline alone with those found at the end of seven days of combined treatment with the same theophylline preparation plus cefonicid. Blood theophylline levels were assessed in duplicate by polarized immunofluorescence with a TDx analyser. Theophylline kinetics were totally unaffected by simultaneous cefonicid treatment, showing that the two drugs may be administered together without any need for adjustment of the theophylline dosage.

  10. Pharmacokinetics and ocular penetration of grepafloxacin in albino and pigmented rabbits.

    PubMed

    Perez, S; Solans, C; Bregante, M A; Pinilla, I; García, M A; Honrubia, F

    2002-10-01

    The pharmacokinetics of grepafloxacin were determined in albino and pigmented rabbits following a single 10 mg/kg intravenous administration. The penetration of grepafloxacin into various ocular tissues was also determined after continuous intravenous infusion in both types of animal. Grepafloxacin showed a bicompartmental model of distribution in both pigmented and albino rabbits with significant differences in the pharmacokinetics between the two types of animal. After continuous intravenous infusion, significantly greater penetration of grepafloxacin was found in the iris, cornea and chorioretina of pigmented rabbits compared with albino rabbits.

  11. Public medical shows.

    PubMed

    Walusinski, Olivier

    2014-01-01

    In the second half of the 19th century, Jean-Martin Charcot (1825-1893) became famous for the quality of his teaching and his innovative neurological discoveries, bringing many French and foreign students to Paris. A hunger for recognition, together with progressive and anticlerical ideals, led Charcot to invite writers, journalists, and politicians to his lessons, during which he presented the results of his work on hysteria. These events became public performances, for which physicians and patients were transformed into actors. Major newspapers ran accounts of these consultations, more like theatrical shows in some respects. The resultant enthusiasm prompted other physicians in Paris and throughout France to try and imitate them. We will compare the form and substance of Charcot's lessons with those given by Jules-Bernard Luys (1828-1897), Victor Dumontpallier (1826-1899), Ambroise-Auguste Liébault (1823-1904), Hippolyte Bernheim (1840-1919), Joseph Grasset (1849-1918), and Albert Pitres (1848-1928). We will also note their impact on contemporary cinema and theatre.

  12. The Great Cometary Show

    NASA Astrophysics Data System (ADS)

    2007-01-01

    its high spatial and spectral resolution, it was possible to zoom into the very heart of this very massive star. In this innermost region, the observations are dominated by the extremely dense stellar wind that totally obscures the underlying central star. The AMBER observations show that this dense stellar wind is not spherically symmetric, but exhibits a clearly elongated structure. Overall, the AMBER observations confirm that the extremely high mass loss of Eta Carinae's massive central star is non-spherical and much stronger along the poles than in the equatorial plane. This is in agreement with theoretical models that predict such an enhanced polar mass-loss in the case of rapidly rotating stars. ESO PR Photo 06c/07 ESO PR Photo 06c/07 RS Ophiuchi in Outburst Several papers from this special feature focus on the later stages in a star's life. One looks at the binary system Gamma 2 Velorum, which contains the closest example of a star known as a Wolf-Rayet. A single AMBER observation allowed the astronomers to separate the spectra of the two components, offering new insights in the modeling of Wolf-Rayet stars, but made it also possible to measure the separation between the two stars. This led to a new determination of the distance of the system, showing that previous estimates were incorrect. The observations also revealed information on the region where the winds from the two stars collide. The famous binary system RS Ophiuchi, an example of a recurrent nova, was observed just 5 days after it was discovered to be in outburst on 12 February 2006, an event that has been expected for 21 years. AMBER was able to detect the extension of the expanding nova emission. These observations show a complex geometry and kinematics, far from the simple interpretation of a spherical fireball in extension. AMBER has detected a high velocity jet probably perpendicular to the orbital plane of the binary system, and allowed a precise and careful study of the wind and the shockwave

  13. Stretched View Showing 'Victoria'

    NASA Technical Reports Server (NTRS)

    2006-01-01

    [figure removed for brevity, see original site] Stretched View Showing 'Victoria'

    This pair of images from the panoramic camera on NASA's Mars Exploration Rover Opportunity served as initial confirmation that the two-year-old rover is within sight of 'Victoria Crater,' which it has been approaching for more than a year. Engineers on the rover team were unsure whether Opportunity would make it as far as Victoria, but scientists hoped for the chance to study such a large crater with their roving geologist. Victoria Crater is 800 meters (nearly half a mile) in diameter, about six times wider than 'Endurance Crater,' where Opportunity spent several months in 2004 examining rock layers affected by ancient water.

    When scientists using orbital data calculated that they should be able to detect Victoria's rim in rover images, they scrutinized frames taken in the direction of the crater by the panoramic camera. To positively characterize the subtle horizon profile of the crater and some of the features leading up to it, researchers created a vertically-stretched image (top) from a mosaic of regular frames from the panoramic camera (bottom), taken on Opportunity's 804th Martian day (April 29, 2006).

    The stretched image makes mild nearby dunes look like more threatening peaks, but that is only a result of the exaggerated vertical dimension. This vertical stretch technique was first applied to Viking Lander 2 panoramas by Philip Stooke, of the University of Western Ontario, Canada, to help locate the lander with respect to orbiter images. Vertically stretching the image allows features to be more readily identified by the Mars Exploration Rover science team.

    The bright white dot near the horizon to the right of center (barely visible without labeling or zoom-in) is thought to be a light-toned outcrop on the far wall of the crater, suggesting that the rover can see over the low rim of Victoria. In figure 1, the northeast and southeast rims are labeled

  14. The hydrazide/hydrazone click reaction as a biomolecule labeling strategy for M(CO)3 (M = Re, (99m)Tc) radiopharmaceuticals.

    PubMed

    Ganguly, Tanushree; Kasten, Benjamin B; Bučar, Dejan-Krešimir; MacGillivray, Leonard R; Berkman, Clifford E; Benny, Paul D

    2011-12-28

    Facile reactivity of hydrazides and aldehydes was explored as potential coupling partners for incorporation into M(CO)(3) (M = Re, (99m)Tc) based radiopharmaceuticals. Both 'click, then chelate' and 'prelabel, then click' synthetic routes produced identical products in high yields and lacked metal-hydrazide/-hydrazone interactions, highlighting the potential of this click strategy.

  15. Potential pitfalls in the nuclear medicine imaging: Experimental models to evaluate the effect of natural products on the radiolabeling of blood constituents, bioavailability of radiopharmaceutical and on the survival of Escherichia coli strains submitted to the treatment with stannous ion

    NASA Astrophysics Data System (ADS)

    Soares, Scheila F.; Brito, Lavínia C.; Souza, Deise E.; Bernardo, Luciana C.; Oliveira, Joelma F.; Bernardo-Filho, Mario

    2006-12-01

    Single photon emission computed tomography (SPECT) allows studies of physiological or pathological processes. Red blood cells labeled with technetium-99m ( 99mTc-RBC) are used as a radiopharmaceutical in several evaluations. The radiolabeling efficiency and bioavailability of radiopharmaceuticals can be altered by natural/synthetic drugs and may induce pitfalls in the analysis of the nuclear medicine imaging. The labeling with 99mTc requires a reducing agent and stannous chloride (SnCl 2) is widely utilized. However, SnCl 2 presents a citotoxic and/or genotoxic potential in Escherichia coli ( E. coli) strains. The aim of this work was to evaluate the influence of aqueous extracts of Baccharis genistelloides (BG), Terminalia chebula (TC), Maytenus ilicifolia (MI), Cassia angustifolia (CA) and Equisetum arvense (EA) on (i) radiolabeling of blood constituents, (ii) bioavailability of sodium pertechnetate(Na 99mTcO 4) radiopharmaceutical, (iii) survival of E. coli. In vitro labeling of RBC was performed with blood ( Wistar rats) incubated with each extract, SnCl 2 and Na 99mTcO 4. Plasma (P) and blood cells (BC) were isolated, another aliquots precipitated and soluble (SF) and insoluble (IF) fractions isolated and counted. In the bioavailability of Na 99mTcO 4, Wistar rats were treated (7 days) with aqueous extract or with 0.9%NaCl, the radiopharmaceutical was administered, the animals sacrificed, the organs isolated, weighted and radioactivity counted. To evaluate the effect on the bacterial survival, E. coli was treated with: (a) SnCl 2; (b) 0.9% NaCl; (c) vegetal extract; or (d) SnCl 2 and vegetal extract. Radiolabeling efficiency showed a significantly decrease (ANOVA/Tukey post-test, p<0.05) after treatment with BG, TC, MI and CA extracts. The bioavailability results showed that the uptake of Na 99mTcO 4 was altered significantly (unpaired t-student test, p<0.05) in blood, lungs (CA/TC extracts), bone, heart, ovary (EA /TC), spleen, kidney (TC) , pancreas, thyroid

  16. Pharmacokinetics of conivaptan use in patients with severe hepatic impairment

    PubMed Central

    Marbury, Thomas; Fox, Jerry; Kaelin, Byron; Pavliv, Leo

    2017-01-01

    Purpose Conivaptan is an intravenous dual V1A/V2 vasopressin antagonist approved for the treatment of euvolemic and hypervolemic hyponatremia. Earlier studies showed that patients with moderate liver disease could be safely treated with conivaptan by reducing the dose by 50%, whereas patients with mild hepatic impairment needed no dose adjustment. The objective of this Phase 1, open-label study was to assess the pharmacokinetics, protein binding, and safety of 48 h of conivaptan infusion in individuals with severe hepatic impairment. Patients and methods Eight subjects with severe hepatic impairment (Child–Pugh score 10–15) and nine subjects with normal liver function were enrolled. Intravenous conivaptan (20 mg) was given as a 30 min loading dose on Day 1 followed by two consecutive 20 mg continuous infusions over 24 h each. Subjects were monitored for adverse events and changes in clinical laboratory parameters. Plasma and urine pharmacokinetic samples were collected at defined times. Subjects were followed through Study Day 5. Results Hepatically impaired individuals exhibited higher concentrations of plasma conivaptan throughout the treatment period. Overall exposure, as measured by area under the plasma conivaptan concentration-time curve from time zero through infinity (AUCINF), was ~60% higher in impaired individuals compared to those with normal liver function. Terminal elimination half-life was slightly longer in impaired subjects (12 h) as compared to normal subjects (9 h), and clearance was 65% higher in subjects with normal liver function, while urinary excretion was higher in impaired individuals. Albumin levels directly, and alkaline phosphatase inversely, correlated with conivaptan clearance. Conclusion A 20 mg conivaptan loading dose given >30 min followed by two daily infusions of 20 mg each was well tolerated by patients with severe hepatic impairment as monitored by adverse events and clinical laboratory values. Based on pharmacokinetic data

  17. Preclinical Pharmacokinetic Analysis of NOV-002, a Glutathione Disulfide Mimetic

    PubMed Central

    Uys, Joachim D.; Manevich, Yefim; DeVane, Lindsay C.; He, Lin; Garret, Tracy E.; Pazoles, Christopher J.; Tew, Kenneth D.; Townsend, Danyelle M.

    2010-01-01

    Summary NOV-002 is a glutathione disulfide (GSSG) mimetic that is in Phase III clinical trials for the treatment of advanced non-small cell lung cancer and other oncology indications. GSSG is reduced by glutathione reductase (GR) to form glutathione (GSH), thereby maintaining redox homeostasis. The purpose of the study was to report the pharmacokinetic properties of NOV-002 and evaluate the effect that NOV-002 elicits in redox homeostasis. The pharmacokinetic analysis and tissue distribution of NOV-002 and GSH was evaluated in mice following a dose of 250 mg/kg, i.p. The redox potential and total protein thiol status was calculated. Here we show that NOV-002 is a substrate for GR and that GSH is a primary metabolite. Nonlinear pharmacokinetic modeling predicted that the estimated absorption and elimination rate constants correspond to a half-life of ~13 mins with an AUC of 1.18 μg.h/ml, a Cmax of 2.16 μg/ml and a volume of distribution of 42.61 L/kg. In addition, measurement of the redox potential and total protein thiol status indicated the generation of a transient oxidative signal in the plasma compartment after administration of NOV-002. These results indicate that NOV-002 exerts kinetic and dynamic effects in mice consistent with the GSSG component as the active pharmacological constituent of the drug. A longer-lasting decrease in total plasma free thiol content was also seen, suggesting that the oxidative effect of the GSSG from NOV-002 was impacting redox homeostasis. PMID:20359856

  18. Maraviroc Pharmacokinetics in HIV-1–Infected Pregnant Women

    PubMed Central

    Colbers, Angela; Best, Brookie; Schalkwijk, Stein; Wang, Jiajia; Stek, Alice; Hidalgo Tenorio, Carmen; Hawkins, David; Taylor, Graham; Kreitchmann, Regis; Burchett, Sandra; Haberl, Annette; Kabeya, Kabamba; van Kasteren, Marjo; Smith, Elizabeth; Capparelli, Edmund; Burger, David; Mirochnick, Mark

    2015-01-01

    Objective. To describe the pharmacokinetics of maraviroc in human immunodeficiency virus (HIV)–infected women during pregnancy and post partum. Methods. HIV-infected pregnant women receiving maraviroc as part of clinical care had intensive steady-state 12-hour pharmacokinetic profiles performed during the third trimester and ≥2 weeks after delivery. Cord blood samples and matching maternal blood samples were taken at delivery. The data were collected in 2 studies: P1026 (United States) and PANNA (Europe). Pharmacokinetic parameters were calculated. Results. Eighteen women were included in the analysis. Most women (12; 67%) received 150 mg of maraviroc twice daily with a protease inhibitor, 2 (11%) received 300 mg twice daily without a protease inhibitor, and 4 (22%) had an alternative regimen. The geometric mean ratios for third-trimester versus postpartum maraviroc were 0.72 (90% confidence interval, .60–.88) for the area under the curve over a dosing interval (AUCtau) and 0.70 (0.58–0.85) for the maximum maraviroc concentration. Only 1 patient showed a trough concentration (Ctrough) below the suggested target of 50 ng/mL, both during pregnancy and post partum. The median ratio of maraviroc cord blood to maternal blood was 0.33 (range, 0.03–0.56). The viral load close to delivery was <50 copies/mL in 13 women (76%). All children were HIV negative at testing. Conclusions. Overall maraviroc exposure during pregnancy was decreased, with a reduction in AUCtau and maximum concentration of about 30%. Ctrough was reduced by 15% but exceeded the minimum Ctrough target concentration. Therefore, the standard adult dose seems sufficient in pregnancy. Clinical Trials Registration. NCT00825929 and NCT000422890. PMID:26202768

  19. Ceftazidime in cystic fibrosis: pharmacokinetics and therapeutic response.

    PubMed

    Kercsmar, C M; Stern, R C; Reed, M D; Myers, C M; Murdell, D; Blumer, J L

    1983-07-01

    The pharmacokinetics of ceftazidime were assessed following a single-dose in 20 patients (8 to 30 years) with cystic fibrosis. All patients received 50 mg/kg (0.9 to 3.5 g) bolus over 30 to 60 sec. Multiple timed samples were obtained over 8 h and analysed by a sensitive HPLC technique. Two-compartment pharmacokinetic analysis revealed means (+/- S.D.) T 1/2 alpha, 0.45 (0.20) h; T 1/2 beta, 1.74 (0.63) h; Vd, 270.0 (50.0) ml/kg; Vc, 190.0 (50.0) ml/kg and Cl beta, 133.7 (22.8) ml/min/1.73 m2. Probenecid pretreatment in six patients was without effect on T 1/2 beta and Cl beta. Urinary excretion was (% of dose) 0 to 2 h, 65.4 (11.1); 2 to 4 h, 14.9 (3.4) and 4 to 8 h, 9.8 (5.8). Ceftazidime was used to treat pulmonary exacerbations in 12 adult cystic fibrosis patients with multiply-resistant Pseudomonas species. Each patient received 2 g iv 8-hourly for 14 to 35 days. Ten of 12 patients showed dramatic improvement as determined by increased appetite and weight gain and arterial pCO2. No hepatic, renal or bone-marrow toxicity was noted. Ceftazidime is an effective antipseudomonal agent possessing favourable pharmacokinetic characteristics with potential use in the treatment of pulmonary exacerbations in cystic fibrosis.

  20. FIRST REPORTS OF CLINICAL PHARMACOKINETICS IN NIGERIA.

    PubMed

    Michael, O S

    2015-06-01

    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).

  1. 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

  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. Heritability of metoprolol and torsemide pharmacokinetics.

    PubMed

    Matthaei, J; Brockmöller, J; Tzvetkov, M V; Sehrt, D; Sachse-Seeboth, C; Hjelmborg, J B; Möller, S; Halekoh, U; Hofmann, U; Schwab, M; Kerb, R

    2015-12-01

    Genetic variation in the pharmacokinetics of metoprolol and torsemide due to polymorphisms in CYP2D6, CYP2C9, and OATP1B1 has been extensively studied. However, it is still unknown how much of the variation in pharmacokinetics of these two clinically important drugs in total is due to genetic factors. Metoprolol and torsemide were intravenously administered to 44 monozygotic and 14 dizygotic twin pairs. Metoprolol area under the curve (AUC) varied 4.7-fold and torsemide AUC 3.5-fold. A very high fraction of AUC variations, 91% of metoprolol and 86% of torsemide, were found to be due to additive genetic effects. However, known genetic variants of CYP2D6, -2C9, and OATP1B1 explained only 39%, 2%, and 39% of that variation, respectively. Comparable results for genetically explained variation in pharmacokinetics and pharmacodynamics have been found for other substrates of these enzymes earlier. These findings indicate that a substantial fraction of the heritable variability in the pharmacokinetics of metoprolol and torsemide remains to be elucidated.

  4. Pharmacokinetics and safety of intravitreal caspofungin.

    PubMed

    Shen, Ying-Cheng; Liang, Chiao-Ying; Wang, Chun-Yuan; Lin, Keng-Hung; Hsu, Min-Yen; Yuen, Hon-Leung; Wei, Li-Chen

    2014-12-01

    Caspofungin exhibits potent antifungal activities against Candida and Aspergillus species. The elimination rate and retinal toxicity of caspofungin were determined in this study to assess its pharmacokinetics and safety in the treatment of fungal endophthalmitis. Intravitreal injections of 50 μg/0.1 ml of caspofungin were administered to rabbits. Levels of caspofungin in the vitreous and aqueous humors were determined using high-performance liquid chromatography (HPLC) at selected time intervals (10 min and 1, 2, 4, 8, 16, 24, and 48 h), and the half-lives were calculated. Eyes were intravitreally injected with caspofungin to obtain concentrations of 10 μg/ml, 50 μg/ml, 100 μg/ml, and 200 μg/ml. Electroretinograms were recorded 4 weeks after injections, and the injected eyes were examined histologically. The concentrations of intravitreal caspofungin at various time points exhibited an exponential decay with a half-life of 6.28 h. The mean vitreous concentration was 6.06 ± 1.76 μg/ml 1 h after intravitreal injection, and this declined to 0.47 ± 0.15 μg/ml at 24 h. The mean aqueous concentration showed undetectable levels at all time points. There were no statistical differences in scotopic a-wave and b-wave responses between control eyes and caspofungin-injected eyes. No focal necrosis or other abnormality in retinal histology was observed. Intravitreal caspofungin injection may be considered to be an alternative treatment for fungal endophthalmitis based on its antifungal activity, lower retinal toxicity, and lower elimination rate in the vitreous. More clinical data are needed to determine its potential role as primary therapy for fungal endophthalmitis.

  5. Population Pharmacokinetics of Ciprofloxacin in Neonates and Young Infants Less than Three Months of Age

    PubMed Central

    Zhao, Wei; Hill, Helen; Le Guellec, Chantal; Neal, Tim; Mahoney, Sarah; Paulus, Stephane; Castellan, Charlotte; Kassai, Behrouz; van den Anker, Johannes N.; Kearns, Gregory L.; Turner, Mark A.

    2014-01-01

    Ciprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation. PMID:25155587

  6. Population pharmacokinetics of ciprofloxacin in neonates and young infants less than three months of age.

    PubMed

    Zhao, Wei; Hill, Helen; Le Guellec, Chantal; Neal, Tim; Mahoney, Sarah; Paulus, Stephane; Castellan, Charlotte; Kassai, Behrouz; van den Anker, Johannes N; Kearns, Gregory L; Turner, Mark A; Jacqz-Aigrain, Evelyne

    2014-11-01

    Ciprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.

  7. Assessing Predictive Performance of Published Population Pharmacokinetic Models of Intravenous Tobramycin in Pediatric Patients

    PubMed Central

    Bloomfield, Celeste; Staatz, Christine E.; Unwin, Sean

    2016-01-01

    Several population pharmacokinetic models describe the dose-exposure relationship of tobramycin in pediatric patients. Before the implementation of these models in clinical practice for dosage adjustment, their predictive performance should be externally evaluated. This study tested the predictive performance of all published population pharmacokinetic models of tobramycin developed for pediatric patients with an independent patient cohort. A literature search was conducted to identify suitable models for testing. Demographic and pharmacokinetic data were collected retrospectively from the medical records of pediatric patients who had received intravenous tobramycin. Tobramycin exposure was predicted from each model. Predictive performance was assessed by visual comparison of predictions to observations, by calculation of bias and imprecision, and through the use of simulation-based diagnostics. Eight population pharmacokinetic models were identified. A total of 269 concentration-time points from 41 pediatric patients with cystic fibrosis were collected for external evaluation. Three models consistently performed best in all evaluations and had mean errors ranging from −0.4 to 1.8 mg/liter, relative mean errors ranging from 4.9 to 29.4%, and root mean square errors ranging from 47.8 to 66.9%. Simulation-based diagnostics supported these findings. Models that allowed a two-compartment disposition generally had better predictive performance than those that used a one-compartment disposition model. Several published models of the pharmacokinetics of tobramycin showed reasonable low levels of bias, although all models seemed to have some problems with imprecision. This suggests that knowledge of typical pharmacokinetic behavior and patient covariate values alone without feedback concentration measurements from individual patients is not sufficient to make precise predictions. PMID:27001806

  8. Multiple-dose pharmacokinetics and safety of an ibuprofen-pseudoephedrine cold suspension in children.

    PubMed

    Gelotte, Cathy K; Prior, Mary Jane; Pendley, Charles; Zimmerman, Brenda; Lavins, Bernard J

    2010-07-01

    Two studies were conducted to characterize multiple-dose pharmacokinetics and potential drug interactions of ibuprofen and pseudoephedrine combined in a suspension and to evaluate safety of this combination in children with common cold, flu, or sinusitis. In the pharmacokinetic study, 24 healthy children aged 4-11 years were administered ibuprofen -pseudoephedrine suspension at 7.5 and 1.125 mg/kg, respectively, every 6 hours for 5 doses. Serial blood samples were drawn over 6 hours after final dose for assessment of steady-state pharmacokinetics. In the open-label, multicenter safety study, more than 100 children aged 2-11 years experiencing symptomatic rhinitis were enrolled. Ibuprofen -pseudoephedrine suspension was administered as needed at similar mg/kg doses every 6-8 hours for up to 3 days. Subjects enrolled in the pharmacokinetic study showed no accumulation of either drug; their weight-adjusted clearances were independent of age, and results were comparable with those from previous single-ingredient studies. For ibuprofen, oral clearance (Cl/F) was 77.5 + or - 16.4 mL/kg/h and volume of distribution (Vd/F) was 0.147 + or - 0.037 L/kg. For pseudoephedrine, Cl/F was 12.3 + or - 2.2 mL/kg/min and Vd/F was 2.52 + or - 0.47 L/kg. In the safety study, adverse events were reported for 18.4% of subjects; most were mild to moderate intensity. There was little difference in incidence of adverse events among different age and weight groups. In conclusion, administration of combined ibuprofen and pseudoephedrine in children demonstrated similar pharmacokinetics when compared with reports of the pharmacokinetics for the single-ingredient products, consistent with no apparent drug interactions. The combination suspension was generally well tolerated.

  9. Population pharmacokinetics. Theory and clinical application.

    PubMed

    Whiting, B; Kelman, A W; Grevel, J

    1986-01-01

    Good therapeutic practice should always be based on an understanding of pharmacokinetic variability. This ensures that dosage adjustments can be made to accommodate differences in pharmacokinetics due to genetic, environmental, physiological or pathological factors. The identification of the circumstances in which these factors play a significant role depends on the conduct of pharmacokinetic studies throughout all stages of drug development. Advances in pharmacokinetic data analysis in the last 10 years have opened up a more comprehensive approach to this subject: early traditional small group studies may now be complemented by later population-based studies. This change in emphasis has been largely brought about by the development of appropriate computer software (NONMEM: Nonlinear Mixed Effects Model) and its successful application to the retrospective analysis of clinical data of a number of commonly used drugs, e.g. digoxin, phenytoin, gentamicin, procainamide, mexiletine and lignocaine (lidocaine). Success has been measured in terms of the provision of information which leads to increased efficiency in dosage adjustment, usually based on a subsequent Bayesian feedback procedure. The application of NONMEM to new drugs, however, raises a number of interesting questions, e.g. 'what experimental design strategies should be employed?' and 'can kinetic parameter distributions other than those which are unimodal and normal be identified?' An answer to the later question may be provided by an alternative non-parametric maximum likelihood (NPML) approach. Population kinetic studies generate a considerable amount of demographic and concentration-time data; the effort involved may be wasted unless sufficient attention is paid to the organisation and storage of such information. This is greatly facilitated by the creation of specially designed clinical pharmacokinetic data bases, conveniently stored on microcomputers. A move towards the adoption of population

  10. Population Pharmacokinetic Model Characterizing 24-Hour Variation in the Pharmacokinetics of Oral and Intravenous Midazolam in Healthy Volunteers

    PubMed Central

    van Rongen, A; Kervezee, L; Brill, MJE; van Meir, H; den Hartigh, J; Guchelaar, H-J; Meijer, JH; Burggraaf, J; van Oosterhout, F

    2015-01-01

    Daily rhythms in physiology may affect the pharmacokinetics of a drug. The aim of this study was to evaluate 24-hour variation in the pharmacokinetics of the CYP3A substrate midazolam. Oral (2 mg) and intravenous (1 mg) midazolam was administered at six timepoints throughout the 24-hour period in 12 healthy volunteers. Oral bioavailability (population mean value [RSE%] of 0.28 (7.1%)) showed 24-hour variation that was best parameterized as a cosine function with an amplitude of 0.04 (17.3%) and a peak at 12:14 in the afternoon. The absorption rate constant was 1.41 (4.7%) times increased after drug administration at 14:00. Clearance (0.38 L/min (4.8%)) showed a minor 24-hour variation with an amplitude of 0.03 (14.8%) L/min and a peak at 18:50. Simulations show that dosing time minimally affects the concentration time profiles after intravenous administration, while concentrations are higher during the day compared to the night after oral dosing, reflecting considerable variation in intestinal processes. PMID:26380154

  11. Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

    PubMed

    Heuberger, Jules A A C; Guan, Zheng; Oyetayo, Olubukayo-Opeyemi; Klumpers, Linda; Morrison, Paul D; Beumer, Tim L; van Gerven, Joop M A; Cohen, Adam F; Freijer, Jan

    2015-02-01

    Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.

  12. Inferring biochemical reaction pathways: the case of the gemcitabine pharmacokinetics

    PubMed Central

    2012-01-01

    minimal a priori knowledge. In fact, the inference model presented in this paper is completely unsupervised. It takes as input the time series of the concetrations of the parent drug and its metabolites. The method, applied to the case study of the gemcitabine pharmacokinetics, shows good accuracy and sensitivity. PMID:22640931

  13. Sucralose sweetener in vivo effects on blood constituents radiolabeling, red blood cell morphology and radiopharmaceutical biodistribution in rats.

    PubMed

    Rocha, G S; Pereira, M O; Benarroz, M O; Frydman, J N G; Rocha, V C; Pereira, M J; Fonseca, A S; Medeiros, A C; Bernardo-Filho, M

    2011-01-01

    Effects of sucralose sweetener on blood constituents labelled with technetium-99m ((99m)Tc) on red blood cell (RBC) morphology, sodium pertechnetate (Na(99m)TcO(4)) and diethylenetriaminepentaacetic acid labeled with (99m)Tc ((99m)Tc-DTPA) biodistribution in rats were evaluated. Radiolabeling on blood constituents from Wistar rats was undertaken for determining the activity percentage (%ATI) on blood constituents. RBC morphology was also evaluated. Na(99m)TcO(4) and (99m)Tc-DTPA biodistribution was used to determine %ATI/g in organs. There was no alteration on RBC blood constituents and morphology %ATI. Sucralose sweetener was capable of altering %ATI/g of the radiopharmaceuticals in different organs. These findings are associated to the sucralose sweetener in specific organs.

  14. Food and Drug Administration process for development and approval of drugs and radiopharmaceuticals: treatments in urologic oncology.

    PubMed

    Ning, Yang-Min; Maher, V Ellen

    2015-03-01

    Regulatory advice and assessment play an important role in the successful development of new drugs and radiopharmaceuticals for the treatment of urologic malignancies. Cooperation between the US Food and Drug Administration (FDA) and the pharmaceutical industry has led to the approval of more than 20 new urologic oncology products in the last 2 decades. Despite these advances, more effective treatments need to be developed and approved for the treatment of urologic malignancies. This review provides general information about the FDA's role in the development of investigational new drugs, with an emphasis on the regulatory process and the requirements for marketing approval. In addition, this review summarizes the products for the treatment of urologic malignancies that were approved by the FDA in the last 30 years and the key issues concerning urologic oncology products that were discussed publicly at Oncologic Drug Advisory Committee meetings in the past 10 years.

  15. Evaluation of H2CHXdedpa, H2dedpa- and H2CHXdedpa-N,N'-propyl-2-NI ligands for (64)Cu(ii) radiopharmaceuticals.

    PubMed

    Ramogida, Caterina F; Boros, Eszter; Patrick, Brian O; Zeisler, Stefan K; Kumlin, Joel; Adam, Michael J; Schaffer, Paul; Orvig, Chris

    2016-08-16

    The chiral acyclic "pa" ligand (pa = picolinic acid) H2CHXdedpa (N4O2) and two NI-containing dedpa analogues (H2CHXdedpa-N,N'-propyl-2-NI, H2dedpa-N,N'-propyl-2-NI, NI = nitroimidazole) were studied as chelators for copper radiopharmaceuticals (CHX = cyclohexyl, H2dedpa = 1,2-[[carboxypyridin-2-yl]methylamino]ethane). The hexadentate ligand H2CHXdedpa was previously established as a superb system for (67/68)Ga radiochemistry. The solid state X-ray crystal structures of [Cu(CHXdedpa-N,N'-propyl-2-NI)] and [Cu(dedpa-N,N'-propyl-2-NI)] reveal the predicted hexadentate, distorted octahedral binding of the copper(ii) ion. Cyclic voltammetry of [Cu(dedpa-N,N'-propyl-2-NI)] shows that there is one reversible couple associated with the NI redox, and one irreversible but reproducible couple attributed to the Cu(ii)/Cu(i) redox cycle. Quantitative radiolabeling (>99%) of CHXdedpa(2-) and (dedpa-N,N'-propyl-2-NI)(2-) with (64)Cu was achieved under fast and efficient labeling conditions (10 min, RT, 0.5 M sodium acetate buffer, pH 5.5) at ligand concentrations as low as 10(-6) M. In vitro kinetic inertness studies of the (64)Cu labelled complexes were studied in human serum at 37 °C over 24 hours; [(64)Cu(CHXdedpa)] was found to be 98% stable compared to previously investigated [(64)Cu(dedpa)] which was only 72% intact after 24 hours.

  16. Binding of ReO4(-) with an engineered MoO4(2-)-binding protein: towards a new approach in radiopharmaceutical applications.

    PubMed

    Aryal, Baikuntha P; Brugarolas, Pedro; He, Chuan

    2012-01-01

    Radiolabeled biomolecules are routinely used for clinical diagnostics. (99m)Tc is the most commonly used radioactive tracer in radiopharmaceuticals. (188)Re and (186)Re are also commonly used as radioactive tracers in medicine. However, currently available methods for radiolabeling are lengthy and involve several steps in bioconjugation processes. In this work we present a strategy to engineer proteins that may selectively recognize the perrhenate (ReO(4)(-)) ion as a new way to label proteins. We found that a molybdate (MoO(4)(2-))-binding protein (ModA) from Escherichia coli can bind perrhenate with high affinity. Using fluorescence and isothermal titration calorimetry measurements, we determined the dissociation constant of ModA for ReO(4)(-) to be 541 nM and we solved a crystal structure of ModA with a bound ReO(4)(-). On the basis of the structure we created a mutant protein containing a disulfide linkage, which exhibited increased affinity for perrhenate (K(d) = 104 nM). High-resolution crystal structures of ModA (1.7 Å) and A11C/R153C mutant (2.0 Å) were solved with bound perrhenate. Both structures show that a perrhenate ion occupies the molybdate binding site using the same amino acid residues that are involved in molybdate binding. The overall structure of the perrhenate-bound ModA is unchanged compared with that of the molybdate-bound form. In the mutant protein, the bound perrhenate is further stabilized by the engineered disulfide bond.

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

    PubMed

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

    2005-12-15

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

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

    SciTech Connect

    Milesi-Halle, Alessandra; Hendrickson, Howard P.; Laurenzana, Elizabeth M.; Gentry, W. Brooks; Owens, S. Michael . E-mail: mowens@uams.edu

    2005-12-15

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

  19. A Pharmacometabonomic Approach To Predicting Metabolic Phenotypes and Pharmacokinetic Parameters of Atorvastatin in Healthy Volunteers.

    PubMed

    Huang, Qing; Aa, Jiye; Jia, Huning; Xin, Xiaoqing; Tao, Chunlei; Liu, Linsheng; Zou, Bingjie; Song, Qinxin; Shi, Jian; Cao, Bei; Yong, Yonghong; Wang, Guangji; Zhou, Guohua

    2015-09-04

    Genetic polymorphism and environment each influence individual variability in drug metabolism and disposition. It is preferable to predict such variability, which may affect drug efficacy and toxicity, before drug administration. We examined individual differences in the pharmacokinetics of atorvastatin by applying gas chromatography-mass spectrometry-based metabolic profiling to predose plasma samples from 48 healthy volunteers. We determined the level of atorvastatin in plasma using liquid chromatography-tandem mass spectrometry. With the endogenous molecules, which showed a good correlation with pharmacokinetic parameters, a refined partial least-squares model was calculated based on predose data from a training set of 36 individuals and exhibited good predictive capability for the other 12 individuals in the prediction set. In addition, the model was successfully used to predictively classify individual pharmacokinetic responses into subgroups. Metabolites such as tryptophan, alanine, arachidonic acid, 2-hydroxybutyric acid, cholesterol, and isoleucine were indicated as candidate markers for predicting by showing better predictive capability for explaining individual differences than a conventional physiological index. These results suggest that a pharmacometabonomic approach offers the potential to predict individual differences in pharmacokinetics and therefore to facilitate individualized drug therapy.

  20. Effect of Catnip Charcoal on the In Vivo Pharmacokinetics of the Main Alkaloids of Rhizoma Coptidis

    PubMed Central

    He, Yanfei; Chen, Siyu; Yu, Hai; Zhu, Long; Liu, Yayun; Han, Chunyang; Liu, Cuiyan

    2016-01-01

    This study aims to explore the effect of catnip Nepeta cataria (CNC) charcoal on the pharmacokinetics of the main alkaloids of Rhizoma Coptidis in vivo. Twenty-four rabbits were randomly divided into four groups and given oral administration of an aqueous extract of Rhizoma Coptidis (RCAE), RCAE plus CNC, RCAE plus activated carbon (AC), or distilled water, respectively. Plasma samples were collected after administration. The concentrations of berberine, coptisine, palmatine, and epiberberine in plasma were measured by high-performance liquid chromatography (HPLC). The pharmacokinetics data were calculated using pharmacokinetic DAS 2.0 software. The results showed that the area under the concentration-time curve (AUC) of berberine increased, while the AUC of coptisine, palmatine, and epiberberine decreased in the rabbits that received RCAE plus CNC. Meanwhile, the AUC of berberine, coptisine, palmatine, and epiberberine decreased in the group given RCAE plus AC. The difference of main pharmacokinetics parameters among the four groups was significant (P < 0.05). This study showed that CNC improved the bioavailability of berberine in comparison to AC and prolonged its release in comparison to RCAE alone. However, it decreased the bioavailability of coptisine, palmatine, and epiberberine. In comparison, AC uniformly declined the bioavailability of berberine, coptisine, palmatine, and epiberberine. PMID:27313645

  1. Effect of Catnip Charcoal on the In Vivo Pharmacokinetics of the Main Alkaloids of Rhizoma Coptidis.

    PubMed

    He, Yanfei; Chen, Siyu; Yu, Hai; Zhu, Long; Liu, Yayun; Han, Chunyang; Liu, Cuiyan

    2016-01-01

    This study aims to explore the effect of catnip Nepeta cataria (CNC) charcoal on the pharmacokinetics of the main alkaloids of Rhizoma Coptidis in vivo. Twenty-four rabbits were randomly divided into four groups and given oral administration of an aqueous extract of Rhizoma Coptidis (RCAE), RCAE plus CNC, RCAE plus activated carbon (AC), or distilled water, respectively. Plasma samples were collected after administration. The concentrations of berberine, coptisine, palmatine, and epiberberine in plasma were measured by high-performance liquid chromatography (HPLC). The pharmacokinetics data were calculated using pharmacokinetic DAS 2.0 software. The results showed that the area under the concentration-time curve (AUC) of berberine increased, while the AUC of coptisine, palmatine, and epiberberine decreased in the rabbits that received RCAE plus CNC. Meanwhile, the AUC of berberine, coptisine, palmatine, and epiberberine decreased in the group given RCAE plus AC. The difference of main pharmacokinetics parameters among the four groups was significant (P < 0.05). This study showed that CNC improved the bioavailability of berberine in comparison to AC and prolonged its release in comparison to RCAE alone. However, it decreased the bioavailability of coptisine, palmatine, and epiberberine. In comparison, AC uniformly declined the bioavailability of berberine, coptisine, palmatine, and epiberberine.

  2. Effect of pregnancy on emtricitabine pharmacokinetics*

    PubMed Central

    Stek, AM; Best, BM; Luo, W; Capparelli, E; Burchett, S; Hu, C; Li, H; Read, JS; Jennings, A; Barr, E; Smith, E; Rossi, SS; Mirochnick, M

    2012-01-01

    Objectives The aim of the study was to describe emtricitabine pharmacokinetics during pregnancy and postpartum. Methods The International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT), formerly Pediatric AIDS Clinical Trials Group (PACTG), study P1026s is a prospective pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including a cohort taking emtricitabine 200 mg once daily. Intensive steady-state 24-hour emtricitabine pharmacokinetic profiles were performed during the third trimester and 6–12 weeks postpartum, and on maternal and umbilical cord blood samples collected at delivery. Emtricitabine was measured by liquid chromatography–mass spectrometry with a quantification limit of 0.0118 mg/L. The target emtricitabine area under the concentration versus time curve, from time 0 to 24 hours post dose (AUC0-24), was ≥7 mg h/L (≤30% reduction from the typical AUC of 10 mg h/L in nonpregnant historical controls). Third-trimester and postpartum pharmacokinetics were compared within subjects. Results Twenty-six women had pharmacokinetics assessed during the third trimester (median 35 weeks of gestation) and 22 postpartum (median 8 weeks postpartum). Mean [90% confidence interval (CI)] emtricitabine pharmacokinetic parameters during the third trimester vs. postpartum were, respectively: AUC: 8.0 (7.1–8.9) vs. 9.7 (8.6–10.9) mg h/L (P = 0.072); apparent clearance (CL/F): 25.0 (22.6–28.3) vs. 20.6 (18.4–23.2) L/h (P = 0.025); 24 hour post dose concentration (C24): 0.058 (0.037–0.063) vs. 0.085 (0.070–0.010) mg/L (P = 0.006). The mean cord:maternal ratio was 1.2 (90% CI 1.0–1.5). The viral load was <400 HIV-1 RNA copies/mL in 24 of 26 women in the third trimester, in 24 of 26 at delivery, and in 15 of 19 postpartum. Within-subject comparisons demonstrated significantly higher CL/F and significantly lower C24 during pregnancy; however, the C24 was well above the inhibitory

  3. [Pharmacokinetics of a long-circulating PEGylated Radix Ophiopogonis polysaccharide].

    PubMed

    Wang, Zhuo-jun; Lin, Xiao; Shen, Lan; Feng, Yi; Xu, De-sheng; Ruan, Ke-feng

    2011-10-01

    The pharmacokinetics of a long-circulating PEGylated Radix Ophiopogonis polysaccharide (ROP) was investigated in rats following i.v. or s.c. administration at three dose levels (9, 20, 50 mg x kg(-1)). A moderate coupling reaction between the hydroxyl-activated ROP and the amino-terminated mPEG was chosen to produce PEGylate ROP. The grafting degree of the prepared conjugate was 1.03, and the molecular mass of mPEG used was 20 kDa. High-performance gel permeation chromatorgraphy with fluorescein isothiocyanate prelabeling was established to determine levels of the conjugate in plasma. The results showed that the elimination half-life of the conjugate following s.c. administration was basically identical to that after iv administration. An accurate linear correlation was observed between administration doses and areas under the curve of plasma conjugate level vs. time profile, regardless of the administration route. The absolute bioavailability of the conjugate following sc administration was approximately 56%, and the mean in vivo residence time was 52.1 h, increased 2.4 times compared to those of iv administration. In general, linear pharmacokinetics was observed for the conjugate within the dose range studied, and sc should be a promising administration route for the conjugate.

  4. Pharmacokinetics of theophylline: a dose-range study.

    PubMed Central

    Rovei, V; Chanoine, F; Strolin Benedetti, M

    1982-01-01

    1 Pharmacokinetics of theophylline were investigated in a group of healthy adult volunteers (non smokers and on xanthine-free diet) following single oral administration of 125, 250, 375 and 500 mg doses as tablets (Theodel). 2 Absorption of theophylline was rapid and followed first-order kinetics. Plasma curves were fitted according to a one compartment open model. 3 There was a linear relationship (P less than 0.001) between plasma Cmax or AUCx values and the administered dose. The analysis of variance showed that the pharmacokinetic parameters of theophylline (t1/2 abs, tmax, t1/2 beta, CL, CLR, Vd and F) were not modified at any dose. 4 Absorption of the drug was complete since the recovery in urine of theophylline (13.7 to 16.8% of the dose) and its major metabolites, 1,3-dimethyluric acid (35 to 42%), 1-methyluric acid (21.3 to 26.7%) and 3-methylxanthine (11.5 to 13.7%), accounted for the administered dose. Some impairment of demethylation to 3-methylxanthine was observed in two subjects, however the percentage of theophylline and its major metabolites excreted in urine was constant for all the four doses. 5 On the basis of these results, after single oral administration, elimination of theophylline followed first-order kinetics in the range of doses investigated (1.62 to 10.42 mg/kg). PMID:7150456

  5. Pharmacokinetics of posaconazole prophylaxis of patients with acute myeloid leukemia.

    PubMed

    Mattiuzzi, Gloria; Yilmaz, Musa; Kantarjian, Hagop; Borthakur, Gautam; Konopleva, Marina; Jabbour, Elias; Brown, Yolanda; Pierce, Sherry; Cortes, Jorge

    2015-09-01

    Antifungal prophylaxis is routinely given to patients with hematologic malignancies at high risk for invasive fungal infections (IFI), yet breakthrough IFI may still occur. Posaconazole emerged as an excellent alternative for fungal prophylaxis in high-risk patients. There is limited data about pharmacokinetics and plasma concentrations of posaconazole when given as prophylaxis in patients with hematologic malignancies. We recruited 20 adult patients for prospective, open label trial of posaconazole given as a prophylaxis in patients with newly diagnosed acute myeloid leukemia (AML) undergoing induction chemotherapy or first salvage therapy. The median age of all patients was 65 years and received prophylaxis for a median of 38 days (range: 5-42 days).Ten patients (50%) completed 42 days on posaconazole prophylaxis. Median plasma posaconazole levels showed no statistical difference across gender, body surface area, patients developing IFI, and patients acquiring grade 3 or 4 elevation of liver enzymes. However, there was an overall trend for higher trough concentrations among patients with no IFI than those with IFI. Pharmacokinetics of posaconazole varies from patient to patient, and AML patients receiving induction chemotherapy who never develop IFI tend to have higher plasma concentrations after oral administration of posaconazole.

  6. Impact of pregnancy on zonisamide pharmacokinetics in rabbits.

    PubMed

    Matar, Kamal M

    2013-01-01

    Pregnancy is associated with various physiological changes which may lead to significant alterations in the pharmacokinetics of many drugs. The present study was aimed to investigate the potential effects of pregnancy on the pharmacokinetic profile of zonisamide (ZNM) in the rabbit. Seven female rabbits were used in this study. The pregnant and nonpregnant rabbits received ZNM orally at a dose of 10 mg/kg and blood samples were collected from the animals just before receiving the drug and then serially for up to 24 h. The plasma samples were analyzed using tandem mass spectrometric method. Following a single oral dose of ZNM to the rabbits, the mean values of ZNM plasma concentrations at different times were consistently low in pregnant compared to nonpregnant rabbits. The mean values of ZNM's Cmax and AUC0-∞ were significantly (P < 0.05) decreased, whereas the CL/F exhibited substantial increase (P < 0.05) in pregnant compared to nonpregnant rabbits. Tmax, t1/2abs, t1/2el, MRT, and Vd/F showed no significant differences between the two groups. The present study demonstrates that pregnancy decreased ZNM plasma concentrations in rabbits and that the decrease could be due to decreased extent of gastrointestinal absorption, induced hepatic metabolism, or enhanced renal elimination of the drug.

  7. Pharmacokinetics and biodegradation performance of a hydroxypropyl chitosan derivative

    NASA Astrophysics Data System (ADS)

    Shao, Kai; Han, Baoqin; Dong, Wen; Song, Fulai; Liu, Weizhi; Liu, Wanshun

    2015-10-01

    Hydroxypropyl chitosan (HP-chitosan) has been shown to have promising applications in a wide range of areas due to its biocompatibility, biodegradability and various biological activities, especially in the biomedical and pharmaceutical fields. However, it is not yet known about its pharmacokinetics and biodegradation performance, which are crucial for its clinical applications. In order to lay a foundation for its further applications and exploitations, here we carried out fluorescence intensity and GPC analyses to determine the pharmacokinetics mode of fluorescein isothiocyanate-labeled HP-chitosan (FITC-HP-chitosan) and its biodegradability. The results showed that after intraperitoneal administration at a dose of 10 mg per rat, FITC-HP-chitosan could be absorbed rapidly and distributed to liver, kidney and spleen through blood. It was indicated that FITC-HP-chitosan could be utilized effectively, and 88.47% of the FITC-HP-chitosan could be excreted by urine within 11 days with a molecular weight less than 10 kDa. Moreover, our data indicated that there was an obvious degradation process occurred in liver (< 10 kDa at 24 h). In summary, HP-chitosan has excellent bioavailability and biodegradability, suggesting the potential applications of hydroxypropyl-modified chitosan as materials in drug delivery, tissue engineering and biomedical area.

  8. Lack of pharmacokinetic interaction between dipyridamole and zalcitabine in rats.

    PubMed

    Abobo, C V; Xian, Y

    1997-11-01

    Resistance usually manifests following long-term dideoxynucleoside therapy of HIV-1 infection. This period appears to coincide with reduced dosage regimens. Resistance that is associated with long-term monotherapy may, in part, be due to decreased intracellular drug concentrations. It has been reported that intracellular uptake of the dideoxynucleosides is enhanced by dipyridamole. Hence, dipyridamole may potentially be used to optimize the effects of zalcitabine in HIV-1 antiretroviral "cocktail". The purpose of this study was to characterize the pharmacokinetics of zalcitabine when administered alone and concomitantly with dipyridamole. Also, we determined, indirectly, whether dipyridamole modulated the intracellular uptake of zalcitabine. Rats were intravenously administered either zalcitabine 100 mg/kg alone or with dipyridamole 15 mg/kg. Except renal clearance (CIR), there were no statistically significant differences in the pharmacokinetic parameters including the steady-state volume of distribution and distribution coefficient. Zalcitabine plasma concentrations declined rapidly in a bi-exponential fashion, with a terminal half-life of 1.03 +/- 0.18 hr. alone versus 1.08 +/- 0.22 hr. with dipyridamole. The area under the concentration-time curve was not significantly different with or without dipyridamole. ClR, was 1.42 +/- 0.37 l/hr./kg for zalcitabine alone versus 1.09 +/- 0.28 l/hr./kg with dipyridamole. Our single dose study show that zalcitabine disposition kinetics were not significantly modulated by dipyridamole.

  9. Pharmacokinetic strategies for cyclosporin therapy in organ transplantation.

    PubMed

    Kahan, B D; Welsh, M; Knight, R; Katz, S; Lewis, R; Grevel, J; Van Buren, C T

    1992-04-01

    Marked interindividual variations in cyclosporin (CsA) produce disparate clinical results in organ transplant recipients. In an attempt to eliminate marked deviations of insufficient or excessive CsA concentrations consequent to the administration of uniform drug doses, test dose pharmacokinetics were performed on each potential organ transplant candidate. An intravenous 3 mg/kg test dose delivered over 3 h proved to be readily performed, namely 53% perfect studies, and relatively reliable, namely 73% of observed concentrations within 10% of the predicted values. Furthermore, the use of CsA doses predicted by pretransplant studies reduces the incidence of delayed graft function, early rejection episodes and transplant loss. The oral test dose study predicted a suitable amount of CsA to achieve sufficient gastrointestinal absorption but was less accurate than the iv prediction method: namely, 40% of observed post-transplant concentrations were within 10% of the predicted target value. Furthermore, patients who received oral doses predicted by the test dose strategy showed no improvement in the incidence of acute rejection episodes between 7 and 60 days, and only modestly improved serum creatinine values. The lower accuracy of predictions from oral test dose studies may reflect the impact of non-linear oral (as opposed to iv) drug pharmacokinetics, of variable diet, and/or of altered postoperative gastrointestinal function.

  10. 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.

  11. Radiosynthesis and pharmacokinetics of high specific activity /sup 75,77/Br-bromperidol, a potent butyrophenone neuroleptic

    SciTech Connect

    Moerlein, S.M.; Stocklin, G.

    1984-01-01

    Bromperidol, 4-(4-(4-bromophenyl)-4-hydroxypiperidino)-4'- fluorobutyrophenone, is a potent neuroleptic which has found clinical use in the treatment of schizophrenia. Of the major dopaminergic receptor-binding ligands, bromperidol has the greatest specificity for binding to cerebral dopamine receptors (K/sub i/ = 3.7 nM) relative to competitive cerebral serotonin (K/sub i/ = 26 nM), ..cap alpha..-adrenergic (K/sub i/ = 100 nM) or histamine (K/sub i/ = 700 nM) receptors. The authors have therefore prepared bromperidol labelled with no-carrier-added (n.c.a.) /sup 75/Br (t/sub 1/2/ = 1.6 hr ..beta../sup +/) or /sup 77/Br (t/sub 1/2/ = 52 hr EC) for evaluation as a radiopharmaceutical for mapping cerebral dopamine receptor areas with PECT technology, as well as for non-invasive pharmacodynamic studies in man with conventional nuclear medicine equipment. 4-(4-(4-trimethylstannylphenyl)-4-hydroxypiperidino)-4'- fluorobutyrophenone, TMSn-P, was synthesized in 40% chemical yield by reaction of trimethylstannyl sodium with bromperidol. TMSn-P was purified by preparative HPLC and characterized by /sup 1/H-NMR and GC-MS. TMSn-P was radiobrominated in methanol using n.c.a. /sup 75/Br/sup -/ or /sup 77/Br/sup -/ and dichloramine-T as oxidizing agent. Product /sup 75,77/Br-bromperidol was separated from impurities, including chlorinated side-product halo-peridol, using HPLC (RP-18; MeOH/H/sub 2/O/Et/sub 3/N = 70/30/0.3). For a reaction time of 5 minutes, and an overall radiopharmaceutical production time of 30 minutes, /sup 75,77/Br-bromperidol was obtained in physiological saline solution with 40% radiochemical yield and a specific activity > 10,000 Ci/mmole. The pharmacokinetics in rodents and PECT studies in primates using /sup 75,77/Br-bromperidol are compared with that of previously-reported /sup 75,77/Br-brombenperidol.

  12. Pharmacokinetics of oral ketorolac in the rat.

    PubMed

    Granados-Soto, V; Flores-Murrieta, F J

    1995-10-01

    The pharmacokinetics of ketorolac, a potent analgesic agent used for relief of moderate to severe pain, has been studied in rats who received oral doses of 1, 3.2 or 5.6 mg/kg of ketorolac tromethamine. Blood samples were obtained at selected times during 24 h after medication, and ketorolac concentrations were determined by high performance liquid chromatography. After administration of ketorolac, blood concentrations increased rapidly reaching a dose-dependent maximal concentration in about 20 min. Then, concentrations decayed with a half-life of about 6 h. A linear increase in Cmax and AUC as a function of the dose was observed, and not statistically significant difference was observed in AUC/dose or Cmax/dose between doses, indicating that pharmacokinetics of ketorolac is linear in the range of doses studied.

  13. Physiologically Based Pharmacokinetic (PBPK) Models for Ethanol

    PubMed Central

    Plawecki, Martin H.; Han, Jae-Joon; Doerschuk, Peter C.; Ramchandani, Vijay A.; O'Connor, Sean J.

    2012-01-01

    Physiologically based pharmacokinetic models have been used to describe the distribution and elimination of ethanol after intravenous administration. These models have been used to estimate the ethanol infusion profile that is sufficient for achieving a prescribed breath ethanol concentration time course in individuals, providing a useful platform for several pharmacokinetic and pharmacodynamic investigations. Mathematical foundations of these models are examined, including the derivation of an explicit set of governing equations in the form of a system of nonlinear ordinary differential equations. These equations can then be used to formulate and refine parameter identification and control strategies. Finally, a framework in which models related to this model can be constructed and analyzed is described. PMID:19126448

  14. Whatever happened to cassette-dosing pharmacokinetics?

    PubMed

    Manitpisitkul, Prasarn; White, Ronald E

    2004-08-01

    Cassette dosing is a procedure that is used for rapidly assessing the pharmacokinetics of a series of discovery drug candidates by dosing a mixture of compounds rather than a single compound. Cassette dosing has advantages and disadvantages associated with its use, which leads to controversy about how and if it should be used. To assess the current practices of the pharmaceutical industry regarding cassette dosing, a survey of several pharmaceutical companies was conducted. Analysis of the survey revealed that opinion on this subject is divided within the pharmaceutical industry. In addition, it was determined that approximately only a half of those companies that perform in vivo pharmacokinetic screening use cassette dosing for this purpose.

  15. Pharmacokinetics and bioavailability of drotaverine in humans.

    PubMed

    Bolaji, O O; Onyeji, C O; Ogundaini, A O; Olugbade, T A; Ogunbona, F A

    1996-01-01

    The pharmacokinetics and bioavailability of drotaverine was studied in 10 healthy volunteers after administration of single 80 mg oral and intravenous doses of the HCl salt of the drug, in a crossover fashion. Plasma and urine samples were analyzed for the unchanged drug by HPLC. The pharmacokinetic parameters, such as elimination half-life, plasma clearance, renal clearance and apparent volume of distribution, were not influenced by the route of drug administration. The drug was mainly eliminated by non-renal routes since renal clearance accounted for only 0.31 +/- 0.13% of the total plasma clearance. The absolute bioavailability was variable and ranged from 24.5-91% with a mean of 58.2 +/- 18.2% (mean +/- SD). It is suggested that the high variation in the bioavailability of drotaverine HCl after oral administration may result in significant interindividual differences in therapeutic response.

  16. Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury

    DTIC Science & Technology

    2015-10-01

    AWARD NUMBER: W81XWH-14-1-0373 TITLE: Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury PRINCIPAL INVESTIGATOR: Philip C...Tranexamic Acid Mechanisms and Pharmacokinetics In Traumatic Injury 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0373 5c. PROGRAM ELEMENT NUMBER...Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 8 Title: Tranexamic Acid Mechanisms and Pharmacokinetics In Traumatic Injury (TAMPITI Trial

  17. Clinical Pharmacokinetics and Pharmacodynamics of Afatinib.

    PubMed

    Wind, Sven; Schnell, David; Ebner, Thomas; Freiwald, Matthias; Stopfer, Peter

    2017-03-01

    Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20-50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration-time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug-drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the

  18. 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

  19. Pharmacokinetic analysis of cefquinome in healthy chickens.

    PubMed

    Xie, W; Zhang, X; Wang, T; Du, S

    2013-01-01

    1. The pharmacokinetics of cefquinome (CEQ) in chickens was determined after intravenous (IV) and intramuscular (IM) administration of 2 mg/kg body weight. Plasma concentrations were measured by high performance liquid chromatography assay with an ultraviolet detector at 265 nm wavelength. 2. Plasma concentration-time data after IV administration were best fitted by a two-compartment model. The pharmacokinetic parameters following IV injection were distribution half-life 0·43 ± 0·19 h, elimination half-life 1·29 ± 0·10 h, total body clearance 0·35 ± 0·04 l/kg/h, area under curve 5·33 ± 0·55 µg/h/ml and volume of distribution at steady state 0·49 ± 0·05 l/kg. 3. Plasma concentration-time data after IM administration were best described by a two-compartment model. The pharmacokinetic parameters after IM administration were absorption half-life 0·07 ± 0·02 h, distribution half-life 0·58 ± 0·27 h, elimination half-life 1·35 ± 0·20 h, peak concentration 3·04 ± 0·71 µg/ml and bioavailability 95·81 ± 5·81%. 4. Cefquinome kinetics in chicken and data from other species were summarised and analysed to provide a comprehensive understanding of CEQ pharmacokinetics.

  20. Population pharmacokinetics of micafungin in adult patients.

    PubMed

    Gumbo, Tawanda; Hiemenz, John; Ma, Lei; Keirns, James J; Buell, Donald N; Drusano, George L

    2008-03-01

    We performed population pharmacokinetic analysis of micafungin in adult patients treated with doses between 12.5 and 200 mg/day. Our analysis identified a breakpoint patient weight of 66.3 kg above which serum clearance increased by approximately 50%. Patients with weight >66.3 kg may need larger doses to achieve similar exposures to those <66.3 kg. However, the clinical implications are still unknown.

  1. Pharmacokinetics and Metabolism of Allopurinol Riboside,

    DTIC Science & Technology

    1991-05-01

    095 Pharmacokinetics and metabolism of allopurinol riboside T"ere are no safe and effective oral drugs to treat leishmaniasis and Chagas ’ disease. Thc...leishmaniasis and Chagas ’ disease. 2 .3 typically require muLltiple parenteral doses. are e\\pen- [hese diseases occur in millions of people on a world- sive...40 ° C until analysis. Urine samples and perchloric allopurinol riboside were quantitated (in 85 determina acid extracts of plasma were analyzed for

  2. Application of biplot methods to the multivariate analysis of toxicological and pharmacokinetic data.

    PubMed

    Shy-Modjeska, J S; Riviere, J E; Rawlings, J O

    1984-01-01

    The biplot technique was applied to aminoglycoside renal toxicological and pharmacokinetic data in beagles. The biplot obtains a two-dimensional approximation to a matrix and plots row effects and column effects jointly, depicting relationships among different observed variables and simultaneously showing the relationship of experimental units as individuals and as treatment groups to those variables. This graphical representation of the matrix allows inspection of relationships, trends, clusters, approximate correlations, and variances existing in the data. Biplots were generated from gentamicin dosage regimen nephrotoxicity data. Six dogs classified as being intoxicated by established indicators of renal toxicity were a distinct cluster. A cluster of nonintoxicated dogs was separated into two groups approximating nephrectomized and normal dogs, thus revealing variables significant in separating toxic and nontoxic as well as nephrectomized and normal dogs. Biplots from pharmacokinetic data were able to separate different renal disease states on the basis of disease-induced changes in gentamicin pharmacokinetic parameters. In conclusion, the biplot technique proved to be a very useful tool in exploring this type of data by revealing clear relationships between nephrotoxicity and physiological and pharmacokinetic variables and by separating different disease states based on these data.

  3. Effects of FMO3 Polymorphisms on Pharmacokinetics of Sulindac in Chinese Healthy Male Volunteers

    PubMed Central

    Tang, Yong-Jun; Hu, Kai; Liu, Zhi; Chen, Yao; Ouyang, Dong-Sheng; Zhou, Hong-Hao

    2017-01-01

    Sulindac is a nonsteroidal anti-inflammatory drug, which is clinically used for the ailments of various inflammations. This study investigated the allele frequencies of FMO3 E158K and E308G and evaluated the influences of these two genetic polymorphisms on the pharmacokinetics of sulindac and its metabolites in Chinese healthy male volunteers. Eight FMO3 wild-type (FMO3 HHDD) subjects and seven FMO3 homozygotes E158K and E308G mutant (FMO3 hhdd) subjects were recruited from 247 healthy male volunteers genotyped by PCR-RFLP method. The plasma concentrations of sulindac, sulindac sulfide, and sulindac sulfone were determined by UPLC, while the pharmacokinetic parameters of the two different FMO3 genotypes were compared with each other. The frequencies of FMO3 E158K and E308G were 20.3% and 20.1%, respectively, which were in line with Hardy-Weinberg equilibrium (D′ = 0.977, r2 = 0.944). The mean values of Cmax, AUC0–24, and AUC0–∞ of sulindac were significantly higher in FMO3 hhdd group than those of FMO3 HHDD group (P < 0.05), while the pharmacokinetic parameters except Tmax of sulindac sulfide and sulindac sulfone showed no statistical difference between the two groups. The two FMO3 mutants were in close linkage disequilibrium and might play an important role in the pharmacokinetics of sulindac in Chinese healthy male volunteers. PMID:28331852

  4. Riociguat (BAY 63-2521) and aspirin: a randomized, pharmacodynamic, and pharmacokinetic interaction study

    PubMed Central

    Reber, Michael; Krätzschmar, Jörn; Unger, Sigrun; Mück, Wolfgang; Wensing, Georg

    2016-01-01

    Abstract In preclinical studies, drugs that increase cyclic guanosine monophosphate levels have been shown to influence platelet function/aggregation; however, the effect of riociguat on human platelets is unclear. Aspirin, a platelet inhibitor, is likely to be given concomitantly in patients receiving riociguat. It is therefore important to establish clinically whether (1) riociguat affects platelet function and (2) aspirin and riociguat interact. This randomized, open-label, crossover study investigated potential pharmacodynamic and pharmacokinetic interactions between these drugs in healthy male volunteers (N = 18). There were 3 treatment regimens: a single morning dose of riociguat 2.5 mg, aspirin 500 mg on 2 consecutive mornings, and both treatments together, with riociguat given on the second morning. Fifteen participants were available for pharmacodynamic/pharmacokinetic analysis. There was no effect of riociguat alone on bleeding time, platelet aggregation, and serum thromboxane B2 levels. The effects of aspirin on these parameters were not influenced by concomitant administration of riociguat. The pharmacokinetic profile of riociguat showed interindividual variability, which was independent of aspirin coadministration. Six of 17 participants available for safety evaluation reported at least 1 treatment-emergent adverse event. All adverse events were of mild severity, apart from 1 report of moderate headache. No serious adverse events occurred. In conclusion, riociguat demonstrated no clinically relevant pharmacodynamic or pharmacokinetic interactions with aspirin at the doses used in this study in healthy men; coadministration of riociguat and aspirin should therefore not require any dose adjustment for either drug. PMID:27162625

  5. Pharmacokinetics of a new ivermectin/praziquantel suspension after intramuscular administration in sheep.

    PubMed

    Tang, Shusheng; Chen, Linlin; Qian, Minyi; Hao, Lihua; Xiao, Xilong

    2016-05-15

    A new oil suspension containing 0.10% ivermectin (IVM) and 15% praziquantel (PZQ) (Tivm+pzq) for intramuscular injection was developed for sheep, and its pharmacokinetics was investigated in sheep. The quality of the new product met the technical standards set by the Ministry of Agriculture of the People's Republic of China. In pharmacokinetics, the commercially available single-component products approved by the Chinese Ministry of Agriculture and widely used in the livestock industry in China were selected as reference products (Rivm and Rpzq). The results showed that all of the IVM pharmacokinetic parameters of Tivm+pzq were similar to those of the reference. However, after adminstration of Tivm+pzq, mean residence time (MRT) and plasma elimination half-life (t1/2z) were 20.36h and 11.65h, which were 2.61 and 3.22 times longer than those of Rpzq (7.81h and 3.62h). In summary, the MRT and t1/2z of PZQ in Tivm+pzq were prolonged and IVM pharmacokinetic parameters were similar to commercial product, therefore the new injection may be an alternative choice for sheep to control parasites sensitive to IVM and PZQ.

  6. Clinical pharmacokinetics of levodopa in parkinson's disease.

    PubMed

    Bianchine, J R; Shaw, G M

    1976-01-01

    Although levodopa has provided a major advance in the treatment of parkinsonism, its maximum benefits have not yet been realised, in part because of its complicated pharmacokinetics. This review summarises that available pharmacokinetic data involving levodopa, especially as it relates to therapeutic response of parkinsonian patients. A large number of factors, including protein intake, gastric emptying time, pyridoxine ingestion, and dopa decarboxylase activity, affect plasma levels of levodopa attained following oral administration of this drug. Other variables influence the rate of brain uptake of levodopa from the blood. Even so, plasma levodopa concentration correlates significantly with dosage size in a large parkinsonian population and also coincides with therapeutic response in many, but not all, patients. Therefore, in certain instances, valuable information may be derived by correlating clinical response with plasma levodopa concentration. Cerebrospinal fluid levels of homovanillic acid, a major metabolite of dopamine, may have some value in predicting clinical response to levodopa. This relationship, however, has not been firmly established. Concentration of homovanillic acid or levodopa in body fluids may also be closely related to certain adverse side-effects, including abnormal involuntary movements, gastric discomfort and psychiatric disturbances. Evidence indicates that a clearer understanding of levodopa pharmacokinetics may improve the clinical management of parkinsonism.

  7. 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

  8. Pharmacokinetics of oral terbinafine in adult horses.

    PubMed

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

    2016-11-24

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

  9. 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

  10. Pharmacokinetics of formulated tenoxicam transdermal delivery systems.

    PubMed

    Kim, Taekyung; Kang, Eunyoung; Chun, Inkoo; Gwak, Hyesun

    2008-01-01

    To investigate the feasibility of developing a new tenoxicam transdermal delivery system (TDS), the pharmacokinetics of tenoxicam from various formulated TDS were evaluated and compared with values following oral administration of tenoxicam and with application of a piroxicam plaster (Trast) marketed in Korea. Based on previous in-vitro study results, a mixture of diethylene glycol monoethyl ether (DGME) and propylene glycol monolaurate (PGML) (40:60) was used as a vehicle, and caprylic acid, capric acid, lauric acid, oleic acid or linoleic acid (each at 3%) was added as an enhancer. Triethanolamine (5%) was used as a solubilizer, and Duro-Tak 87-2510 as a pressure-sensitive adhesive. Among these fatty acids used for the formulation of tenoxicam TDS, caprylic acid showed the greatest enhancing effect; the area under the plasma concentration-time profile (AUC) decreased in the order of caprylic acid>linoleic acid>or=oleic acid>lauric acid>capric acid. Compared with oral administration, maximum plasma concentration (Cmax) was significantly lower, and time to reach Cmax (Tmax) delayed with all formulated tenoxicam TDS. All formulated TDS resulted in a lower AUC than with the oral formulation, except for TDS containing caprylic acid, although the difference was statistically significant only with capric acid. The AUC for all the formulated tenoxicam TDS was significantly higher than that of the piroxicam plaster; TDS with caprylic acid increased AUC 8.53-fold compared with the piroxicam plaster. Even though the Tmax of tenoxicam TDS was not significantly different from that of the piroxicam plaster, Cmax was higher; formulations containing caprylic acid and linoleic acid increased Cmax by 7.39- and 8.76-fold, respectively. In conclusion, a formulation containing 1.5 mL DGME-PGML (40:60) with 3% caprylic acid and 5% triethanolamine mixed with 6 g Duro-Tak 87-2510 could be a good candidate for developing a new tenoxicam TDS to maintain a comparable extent of absorption

  11. Application of back-propagation artificial neural network and curve estimation in pharmacokinetics of losartan in rabbit.

    PubMed

    Lin, Bin; Lin, Gaotong; Liu, Xianyun; Ma, Jianshe; Wang, Xianchuan; Lin, Feiyan; Hu, Lufeng

    2015-01-01

    In order to develop pharmacokinetic model, a well-known multilayer feed-forward algorithm back-propagation artificial neural networks (BP-ANN) was applied to the pharmacokinetics of losartan in rabbit. The plasma concentrations of losartan in twelve rabbits, which were divided into two groups and given losartan 2 mg/kg by intravenous (Iv) and intragastrical (Ig) administration, were determined by LC-MS. The BP-ANN model included one input layer, hidden layers, and one output layer was constructed and compared with curve estimation based on the time-concentration data of losartan. The results showed the BP-ANN model had high goodness of fit index and good coherence (R > 0.99) between forecasted concentration and measured concentration both in Iv and Ig administration. The residuals of each concentrations generated by BP-ANN model were all smaller than Curve estimation. The pharmacokinetic result showed there was no significant difference between measured and simulated pharmacokinetic parameters including AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞), T1/2 V and Cmax (P > 0.05). In conclusion, the BP-ANN model has remarkably accurate predictions ability, which better than Curve estimation, and can be used as a utility tool in pharmacokinetic experiment.

  12. Application of back-propagation artificial neural network and curve estimation in pharmacokinetics of losartan in rabbit

    PubMed Central

    Lin, Bin; Lin, Gaotong; Liu, Xianyun; Ma, Jianshe; Wang, Xianchuan; Lin, Feiyan; Hu, Lufeng

    2015-01-01

    In order to develop pharmacokinetic model, a well-known multilayer feed-forward algorithm back-propagation artificial neural networks (BP-ANN) was applied to the pharmacokinetics of losartan in rabbit. The plasma concentrations of losartan in twelve rabbits, which were divided into two groups and given losartan 2 mg/kg by intravenous (Iv) and intragastrical (Ig) administration, were determined by LC-MS. The BP-ANN model included one input layer, hidden layers, and one output layer was constructed and compared with curve estimation based on the time-concentration data of losartan. The results showed the BP-ANN model had high goodness of fit index and good coherence (R > 0.99) between forecasted concentration and measured concentration both in Iv and Ig administration. The residuals of each concentrations generated by BP-ANN model were all smaller than Curve estimation. The pharmacokinetic result showed there was no significant difference between measured and simulated pharmacokinetic parameters including AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞), T1/2 V and Cmax (P > 0.05). In conclusion, the BP-ANN model has remarkably accurate predictions ability, which better than Curve estimation, and can be used as a utility tool in pharmacokinetic experiment. PMID:26885213

  13. Radiopharmaceuticals in the elderly cancer patient: Practical considerations, with a focus on prostate cancer therapy: A position paper from the International Society of Geriatric Oncology Task Force.

    PubMed

    Prior, John O; Gillessen, Silke; Wirth, Manfred; Dale, William; Aapro, Matti; Oyen, Wim J G

    2017-04-06

    Molecular imaging using radiopharmaceuticals has a clear role in visualising the presence and extent of tumour at diagnosis and monitoring response to therapy. Such imaging provides prognostic and predictive information relevant to management, e.g. by quantifying active tumour mass using positron emission tomography/computed tomography (PET/CT). As these techniques require only pharmacologically inactive doses, age and potential frailty are generally not important. However, this may be different for therapy involving radionuclides because the radiation can impact normal bodily function (e.g. myelosuppression). Since the introduction of Iodine-131 as a targeted therapy in thyroid cancer, several radiopharmaceuticals have been widely used. These include antibodies and peptides targeting specific epitopes on cancer cells. Among therapeutic bone seeking agents, radium-223 ((223)Ra) stands out as it results in survival gains in patients with castration-resistant prostate cancer and symptomatic bone metastases. The therapeutic use of radiopharmaceuticals in elderly cancer patients specifically has received little attention. In elderly prostate cancer patients, there may be advantages in radionuclides' ease of use and relative lack of toxicity compared with cytotoxic and cytostatic drugs. When using radionuclide therapies, close coordination between oncology and nuclear medicine is needed to ensure safe and effective use. Bone marrow reserve has to be considered. As most radiopharmaceuticals are cleared renally, dose adjustment may be required in the elderly. However, compared with younger patients there is less, if any, concern about adverse long-term radiation effects such as radiation-induced second cancers. Issues regarding the safety of medical staff, care givers and the wider environment can be managed by current precautions.

  14. A simple low-cost of liquid I-131 dispenser for routine radiopharmaceutical dispensing at nuclear medicine department, Institut Kanser Negara

    SciTech Connect

    Said, M. A.; Suhaimi, N. E. F.; Ashhar, Z. N.; Zainon, R.

    2016-01-22

    In routine radiopharmaceutical Iodine-131 ({sup 131}I) dispensing, the amount of radiation dose received by the personnel depends on the distance between the personnel and the source, the time spent manipulating the source and the amount of shielding used to reduce the dose rate from the source. The novel iRAD-I131 dispenser using recycle {sup 131}I liquid lead pot will lead into low cost production, less maintenance and low dose received by the personnel that prepared the {sup 131}I. The new fabricated of low cost {sup 131}I dispenser was tested and the dose received by personnel were evaluated. The body of lead material is made from 2.5 cm lead shielded coated with epoxy paint to absorb the radiation dose up to 7.4 GBq of {sup 131} I. The lead pot was supported with two stainless steel rod. The Optically Stimulated Luminescence (OSL) nanodot was used in this study to measure the dose rate at both extremities for every personnel who prepared the {sup 131}I. Each OSL nanodot was attached at the fingertip. Three different personnel (experienced between one to ten years above in preparing the radiopharmaceuticals) were participated in this study. The average equivalent dose at right and left hand were 122.694 ± 121.637 µSv/GBq and 77.281 ± 62.146 µSv/GBq respectively. This study found that the dose exposure received using iRAD-I131 was less up to seven times compared to the conventional method. The comparison of experimental data using iRAD-I131 and established radiopharmaceutical dispenser was also discussed. The innovation of {sup 131}I dispenser is highly recommended in a small radiopharmaceutical facility with limited budget. The novel iRAD-I131 enables implementation of higher output liquid dispensing with low radiation dose to the personnel.

  15. A simple low-cost of liquid I-131 dispenser for routine radiopharmaceutical dispensing at nuclear medicine department, Institut Kanser Negara

    NASA Astrophysics Data System (ADS)

    Said, M. A.; Ashhar, Z. N.; Suhaimi, N. E. F.; Zainon, R.

    2016-01-01

    In routine radiopharmaceutical Iodine-131 (131I) dispensing, the amount of radiation dose received by the personnel depends on the distance between the personnel and the source, the time spent manipulating the source and the amount of shielding used to reduce the dose rate from the source. The novel iRAD-I131 dispenser using recycle 131I liquid lead pot will lead into low cost production, less maintenance and low dose received by the personnel that prepared the 131I. The new fabricated of low cost 131I dispenser was tested and the dose received by personnel were evaluated. The body of lead material is made from 2.5 cm lead shielded coated with epoxy paint to absorb the radiation dose up to 7.4 GBq of 131 I. The lead pot was supported with two stainless steel rod. The Optically Stimulated Luminescence (OSL) nanodot was used in this study to measure the dose rate at both extremities for every personnel who prepared the 131I. Each OSL nanodot was attached at the fingertip. Three different personnel (experienced between one to ten years above in preparing the radiopharmaceuticals) were participated in this study. The average equivalent dose at right and left hand were 122.694 ± 121.637 µSv/GBq and 77.281 ± 62.146 µSv/GBq respectively. This study found that the dose exposure received using iRAD-I131 was less up to seven times compared to the conventional method. The comparison of experimental data using iRAD-I131 and established radiopharmaceutical dispenser was also discussed. The innovation of 131I dispenser is highly recommended in a small radiopharmaceutical facility with limited budget. The novel iRAD-I131 enables implementation of higher output liquid dispensing with low radiation dose to the personnel.

  16. Investigation using an advanced extremity gamma instrumentation system of options for shielding the hand during the preparation and injection of radiopharmaceuticals.

    PubMed

    Whitby, M; Martin, C J

    2003-03-01

    Staff preparing and injecting radiopharmaceuticals in hospitals may receive significant radiation doses to their hands. These doses may be high enough to warrant that they be classified as radiation workers. The influence of local shielding on finger doses has been investigated. Staff preparing radioactive liquids in a radionuclide dispensary and drawing up and injecting radiopharmaceuticals in a nuclear medicine department have been studied. Measurements have been recorded with an electronic extremity dose monitor, an advanced extremity gamma instrumentation system (AEGIS), worn near to the finger tip. The electronic dosimeter allows the pattern of doses received during different procedures to be determined. Doses received for individual manipulations during many routine sessions have been recorded for different staff members. Dose distributions around shielded vials and syringes have also been measured using AEGIS. In the radionuclide dispensary the vials from which radioactive liquids are dispensed are held in tungsten shields, whereas in nuclear medicine simple lead pots are used. Syringe shields are employed for some parts of dispensing and patient injections. Data on dose distributions have been used in interpretation of results from monitoring. Use of syringe shields during dispensing reduced the finger dose by 75-85%. The peaks in dose rate were 60% lower, and periods of exposure to high dose rates were reduced in length by a third because of the restriction in the region of high dose rate. The extremity doses to staff dispensing and injecting radiopharmaceuticals in nuclear medicine were of similar magnitude. Doses received during dispensing varied from 10 to 555 microGy depending upon whether the vial containing the radiopharmaceutical was directly handled or not. Dose received from individual injections varied from 1 to 150 microGy depending on the degree of difficulty experienced during the injection.

  17. 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

  18. The role of digitalis pharmacokinetics in converting atrial fibrillation and flutter to regular sinus rhythm.

    PubMed

    Jelliffe, Roger W

    2014-05-01

    This report examined the role of digitalis pharmacokinetics in helping to guide therapy with digitalis glycosides with regard to converting atrial fibrillation (AF) or flutter to regular sinus rhythm (RSR). Pharmacokinetic models of digitoxin and digoxin, containing a peripheral non-serum effect compartment, were used to analyze outcomes in a non-systematic literature review of five clinical studies, using the computed concentrations of digitoxin and digoxin in the effect compartment of these models in an analysis of their outcomes. Four cases treated by the author were similarly examined. Three literature studies showed results no different from placebo. Dosage regimens achieved ≤11 ng/g in the model's peripheral compartment. However, two other studies achieved significant conversion to RSR. Their peripheral concentrations were 9-14 ng/g. In the four patients treated by the author, three converted using classical clinical titration with incremental doses, plus therapeutic drug monitoring and pharmacokinetic guidance from the models for maintenance dosage. They converted at peripheral concentrations of 9-18 ng/g, similar to the two studies above. No toxicity was seen. Successful maintenance was achieved, using the models and their pharmacokinetic guidance, by giving somewhat larger than average recommended dosage regimens in order to maintain peripheral concentrations present at conversion. The fourth patient did not convert, but only reached peripheral concentrations of 6-7 ng/g, similar to the studies in which conversion was no better than placebo. Pharmacokinetic analysis and guidance play a highly significant role in converting AF to RSR. To the author's knowledge, this has not been specifically described before. In my experience, conversion of AF or flutter to RSR does not occur until peripheral concentrations of 9-18 ng/g are reached. Results in the four cases correlated well with the literature findings. More work is needed to further evaluate these

  19. The Role of Digitalis Pharmacokinetics in Converting Atrial Fibrillation and Flutter to Sinus Rhythm

    PubMed Central

    Jelliffe, Roger

    2014-01-01

    This report examined the role of digitalis pharmacokinetics in helping to guide therapy with digitalis glycosides with regard to converting atrial fibrillation (AF) or flutter to regular sinus rhythm (RSR). Pharmacokinetic models of digitoxin and digoxin, containing a peripheral nonserum effect compartment, were used to analyze outcomes in a nonsystematic literature review of five clinical studies, using the computed concentrations of digitoxin and digoxin in the effect compartment of these models in an analysis of their outcomes. Four cases treated by the author were similarly examined. Three literature studies showed results no different from placebo. Dosage regimens achieved ≤ 11 ng/gm in the model’s peripheral compartment. However, two other studies achieved significant conversion to RSR. Their peripheral concentrations were 9 to14 ng/gm. In addition, four patients were treated by the author. Three converted using classical clinical titration with incremental doses, plus therapeutic drug monitoring and pharmacokinetic guidance from the models for maintenance dosage. They converted at peripheral concentrations of 9 to 18 ng/gm, similar to the two studies above. No toxicity was seen. Successful maintenance was achieved, using the models and their pharmacokinetic guidance, by giving somewhat larger than average recommended dosage regimens in order to maintain peripheral concentrations present at conversion. The fourth patient did not convert, but only reached peripheral concentrations of 6–7 ng/gm, similar to the studies in which conversion was no better than placebo. Pharmacokinetic analysis and guidance play a highly significant role in converting AF to RSR. To the author’s knowledge, this has not been specifically described before. In my experience, conversion of AF or flutter to RSR does not occur until peripheral concentrations of 9 –18 ng/gm are reached. Results in the four cases correlated well with the literature findings. More work is needed to

  20. Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis

    PubMed Central

    Sturkenboom, Marieke G. G.; Mulder, Leonie W.; de Jager, Arthur; van Altena, Richard; Aarnoutse, Rob E.; de Lange, Wiel C. M.; Proost, Johannes H.; Kosterink, Jos G. W.; van der Werf, Tjip S.

    2015-01-01

    Rifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0–24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0–24 values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n = 1,000). The geometric mean AUC0–24 value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with an r2 value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of −0.4%. This study showed that the rifampin AUC0–24 in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h. PMID:26055359

  1. MIRD pamphlet no. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates.

    PubMed

    Siegel, J A; Thomas, S R; Stubbs, J B; Stabin, M G; Hays, M T; Koral, K F; Robertson, J S; Howell, R W; Wessels, B W; Fisher, D R; Weber, D A; Brill, A B

    1999-02-01

    This report describes recommended techniques for radiopharmaceutical biodistribution data acquisition and analysis in human subjects to estimate radiation absorbed dose using the Medical Internal Radiation Dose (MIRD) schema. The document has been prepared in a format to address two audiences: individuals with a primary interest in designing clinical trials who are not experts in dosimetry and individuals with extensive experience with dosimetry-based protocols and calculational methodology. For the first group, the general concepts involved in biodistribution data acquisition are presented, with guidance provided for the number of measurements (data points) required. For those with expertise in dosimetry, highlighted sections, examples and appendices have been included to provide calculational details, as well as references, for the techniques involved. This document is intended also to serve as a guide for the investigator in choosing the appropriate methodologies when acquiring and preparing product data for review by national regulatory agencies. The emphasis is on planar imaging techniques commonly available in most nuclear medicine departments and laboratories. The measurement of the biodistribution of radiopharmaceuticals is an important aspect in calculating absorbed dose from internally deposited radionuclides. Three phases are presented: data collection, data analysis and data processing. In the first phase, data collection, the identification of source regions, the determination of their appropriate temporal sampling and the acquisition of data are discussed. In the second phase, quantitative measurement techniques involving imaging by planar scintillation camera, SPECT and PET for the calculation of activity in source regions as a function of time are discussed. In addition, nonimaging measurement techniques, including external radiation monitoring, tissue-sample counting (blood and biopsy) and excreta counting are also considered. The third phase, data

  2. New peptide deformylase inhibitors design, synthesis and pharmacokinetic assessment.

    PubMed

    Lv, Fengping; Chen, Chen; Tang, Yang; Wei, Jianhai; Zhu, Tong; Hu, Wenhao

    2016-08-01

    The docking approach for the screening of designed small molecule ligands, led to the identification of a critical arginine residue in peptide deformylase for spiro cyclopropyl PDF inhibitor's extra hydrophobic binding, providing us a useful tool for searching more efficient PDF inhibitors to fight for horrifying antibiotics resistance. Further synthetic modification was undertaken to optimize the potency of amide compounds. To lower metabolic susceptibility and in turn reduce unwanted metabolic toxicity that was observed clinically, while retaining desired antibacterial activity, the use of azoles as amide bioisosteres had also been investigated. After the completion of chemical synthesis, all the compounds were evaluated through in vitro antibacterial activity assay, some of which were further subject to in vivo rat pharmacokinetic assessment. Those findings in this letter showed that spiro cyclopropyl proline N-formyl hydroxylamines, and especially the bioisosteric azoles, can represent a promising class of PDF inhibitors.

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

    PubMed Central

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

    2016-01-01

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

  4. Change in pharmacokinetics of mycophenolic acid as a function of age in rats and effect of coadministered amoxicillin/clavulanate.

    PubMed

    Ishizaki, Junko; Tsuda, Tomoko; Suga, Yukio; Ito, Satsuki; Arai, Kunizo; Sai, Yoshimichi; Miyamoto, Ken-Ichi

    2012-01-01

    Changes of mycophenolic acid (MPA) pharmacokinetics with aging were investigated in rats. We also compared the effect of concomitant amoxicillin/clavulanate combination (CVA/AMPC) on the pharmacokinetics of MPA in 4-week-old and 12-week-old rats (the package insert of CVA/AMPC warns of possible interaction with MPA). Four-week-old rats showed a 1.4-fold higher total body clearance of MPA and a lower volume of distribution of MPA (65%), compared to the values in 12-week-old rats. However, the difference in MPA pharmacokinetics disappeared when enterohepatic circulation was eliminated by bile duct cannulation (BDC). Concomitant CVA/AMPC significantly reduced plasma MPA concentration in intact rats of both age groups, and the age-dependent difference of MPA pharmacokinetics was no longer apparent. The effect of CVA/AMPC was not seen in rats that had undergone BDC, suggesting that the drug-drug interaction can be attributed to inhibition of enterohepatic circulation by CVA/AMPC. These results indicate that the aging-related alteration of MPA pharmacokinetics is a consequence of immature enterohepatic circulation in 4-week-old rats. Higher doses of MPA may be necessary in juveniles.

  5. Synergistic Effects of Clopidogrel and Fufang Danshen Dripping Pills by Modulation of the Metabolism Target and Pharmacokinetics

    PubMed Central

    Ma, Shitang; Ju, Wenzheng; Dai, Guoliang; Zhao, Wenzhu; Cheng, Xiaogui; Fang, Zhuyuan; Tan, Hengshan; Wang, Xiaoxiao

    2014-01-01

    Background and Objective. The aim was to evaluate the synergistic effects of clopidogrel and FDDP by modulating the metabolism target and the pharmacokinetics. Methods. The inhibition effect of FDDP on the CES1 was first investigated by the molecular simulation method, and the synergistic effects on the pharmacokinetics of CPGS were studied as follows: SD rats were treated with oral clopidogrel alone at a dosage of 30 mg/kg or the combination of clopidogrel and FDDP at dosages of 30 mg/kg and 324 mg/kg, respectively, for 21 days. The concentrations of CPGS in the blood plasma samples were determined and the calculated concentrations were used to determine the pharmacokinetic parameters. Results. 20 compounds in FDDP potentially interacted with CES1 target. The CPGS showed a two-compartment model pharmacokinetic profile. The concentration-time course of CPGS was not changed by FDDP, but FDDP decreased the peak plasma concentration and area under the curve of CPGS. Conclusion. The CES1's activity could be partly inhibited by FDDP through the molecular simulation investigation. The concentration-time course of CPGS was altered slightly by FDDP. The results demonstrated the synergistic effects of clopidogrel and FDDP by modulating both the pharmacokinetics and the target metabolism. PMID:25530790

  6. Clinical pharmacokinetic/pharmacodynamic and physiologically based pharmacokinetic modeling in new drug development: the capecitabine experience.

    PubMed

    Blesch, Karen S; Gieschke, Ronald; Tsukamoto, Yuko; Reigner, Bruno G; Burger, Hans U; Steimer, Jean-Louis

    2003-05-01

    Preclinical studies, along with Phase I, II, and III clinical trials demonstrate the pharmacokinetics, pharmacodynamics, safety and efficacy of a new drug under well controlled circumstances in relatively homogeneous populations. However, these types of studies generally do not answer important questions about variability in specific factors that predict pharmacokinetic and pharmacodynamic (PKPD) activity, in turn affecting safety and efficacy. Semi-physiological and clinical PKPD modeling and simulation offer the possibility of utilizing data obtained in the laboratory and the clinic to make accurate characterizations and predictions of PKPD activity in the target population, based on variability in predictive factors. Capecitabine is an orally administered pro-drug of 5-fluorouracil (5-FU), designed to exploit tissue-specific differences in metabolic enzyme activities in order to enhance efficacy and safety. It undergoes extensive metabolism in multiple physiologic compartments, and presents particular challenges for predicting pharmacokinetic and pharmacodynamic activity in humans. Clinical and physiologically based pharmacokinetic (PBPK) and pharmacodynamic models were developed to characterize the activity of capecitabine and its metabolites, and the clinical consequences under varying physiological conditions such as creatinine clearance or activity of key metabolic enzymes. The results of the modeling investigations were consistent with capecitabine's rational design as a triple pro-drug of 5-FU. This paper reviews and discusses the PKPD and PBPK modeling approaches used in capecitabine development to provide a more thorough understanding of what the key predictors of its PBPK activity are, and how variability in these predictors may affect its PKPD, and ultimately, clinical outcomes.

  7. 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…

  8. 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…

  9. 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...

  10. Population Pharmacokinetics of Pyronaridine in Pediatric Malaria Patients

    PubMed Central

    Ayyoub, Amal; Methaneethorn, Janthima; Ramharter, Michael; Djimde, Abdoulaye A.; Tekete, Mamadou; Duparc, Stephan; Borghini-Fuhrer, Isabelle; Shin, Jang-Sik

    2015-01-01

    Pyramax is a pyronaridine (PYR)-artesunate (PA) combination for the treatment of uncomplicated malaria in adult and pediatric patients. A granule formulation of this combination is being developed for treatment of uncomplicated P. falciparum and P. vivax malaria in pediatric patients. The aims of this study were to describe the pharmacokinetics of PYR using a total of 1,085 blood PYR concentrations available from 349 malaria patients younger than 16 years of age with mild to moderate uncomplicated malaria and to confirm the dosing regimen for the pediatric granule formulation. Nonlinear mixed-effects modeling using NONMEM software was used to obtain the pharmacokinetic and inter- and intraindividual variability parameter estimates. The population pharmacokinetics of PYR were described by a two-compartment model with first-order absorption and elimination. Allometric scaling was implemented to address the effect of body weight on clearance and volume parameters. The final parameter estimates of PYR apparent clearance (CL/F), central volume of distribution (V2/F), peripheral volume of distribution (V3/F), intercompartmental clearance (Q/F), and absorption rate constant (Ka) were 377 liters/day, 2,230 liters, 3,230 liters, 804 liters/day and 17.9 day−1, respectively. Covariate model building conducted using forward addition (P < 0.05) followed by backward elimination (P < 0.001) yielded two significant covariate-parameter relationships, i.e., age on V2/F and formulation on Ka. Evaluation of bootstrapping, visual predictive check, and condition number indicated that the final model displayed satisfactory robustness, predictive power, and stability. Simulations of PYR concentration-time profiles generated from the final model show similar exposures across pediatric weight ranges, supporting the proposed labeling for weight-based dosing of Pyramax granules. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00331136 [phase II study] and

  11. Insights into drug discovery from natural medicines using reverse pharmacokinetics.

    PubMed

    Hao, Haiping; Zheng, Xiao; Wang, Guangji

    2014-04-01

    Natural medicines (NMs) are indispensable sources for the development of modern drugs. However, the targets for most natural compounds are unknown and the current pharmacokinetic evaluation systems developed for target-defined drugs may not be directly applicable to NM-based drug discovery, which is a major hindrance in bringing natural compounds to the clinic. Here, we propose the concept of 'reverse pharmacokinetics' and discuss how a 'reverse pharmacokinetics' perspective could help clarify key questions in modern drug discovery from NMs with validated clinical benefits, thereby strengthening the translational potential. Reverse pharmacokinetics can provide physiologically relevant clues to the target identification and mechanistic study of NMs, which may also innovate drug discovery for complex diseases. We anticipate that an evolving deep understanding of the novel mode of action of natural compounds with a reverse pharmacokinetic insight may improve discovery of both single ingredient and multiple-component modern drugs from NMs.

  12. A Pharmacokinetics Module Taught Within a Pediatrics Pharmacotherapy Course

    PubMed Central

    Carr, Roxane

    2013-01-01

    Objective. To review the effectiveness of a pedagogical approach and methods used to teach pediatric pharmacokinetics to a large class of pharmacy students in a required course in the third-year of a bachelor of science in pharmacy program. Design. The pharmacokinetic sessions emphasized facilitating student understanding of the basic pharmacokinetic principles learned in earlier courses and applying that knowledge to pediatric case scenarios. This was accomplished using lectures with PowerPoint slides followed by small-group, context-focused discussions that required students to apply the principles outlined in the lecture. Evaluation. Student understanding of the pharmacokinetics concepts discussed within the course was assessed via a written examination. Conclusion. The small-group context-focused approach to teaching pediatric pharmacokinetics in a large class size with minimal resources allowed opportunities for students to apply their foundational knowledge in an interactive and engaging atmosphere. PMID:23966729

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

    PubMed

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

    2014-08-01

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

  14. 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.

  15. Fenbendazole pharmacokinetics, metabolism, and potentiation in horses.

    PubMed

    McKellar, Q A; Gokbulut, C; Muzandu, K; Benchaoui, H

    2002-11-01

    The present study was designed to describe the pharmacokinetics and fecal excretion of fenbendazole (FBZ) and fenbendazole sulphoxide (FBZSO) and their metabolites in horses, to investigate the effects which concurrent feeding has on the absorption and pharmacokinetics of FBZ, and to determine the effect of coadministration of the metabolic inhibitor piperonyl-butoxide on the in vivo pharmacokinetics and in vitro liver microsomal metabolism of sulfide and sulfoxide benzimidazoles. The effect of piperonyl-butoxide on the enantiomeric genesis of the sulfoxide moiety was also investigated. Following administration of FBZSO and FBZ, the fenbendazole sulphone metabolite predominated in plasma, and the C(max) and area under the plasma curve (AUC) values for each moiety were larger (P < 0.001) following FBZSO than FBZ. In feces the administered parent molecule predominated. The combined AUC for active benzimidazole moieties following oral administration of FBZ (10 mg/kg) in horses was almost 4 times as high in unfed horses (2.19 microg x h/ml) than in fed horses (0.59 microg x h/ml), and coadministration of piperonyl-butoxide significantly increased the AUC and C(max) of active moieties following intravenous administration of FBZSO and oral administration of FBZ. When FBZSO was administered i.v. as a racemate, the first enantiomer of oxfendazole (FBZSO-1) predominated in plasma, however, following coadministration with piperonyl-butoxide, the second enantiomer of oxfendazole (FBZSO-2) predominated for 10 h. Piperonyl-butoxide significantly reduced the oxidative metabolism of FBZSO and FBZ in equine liver microsomes and altered the ratio of enantiomers FBZSO-1/FBZSO-2 from >4:1 to 1:1. It is concluded that in horses efficacy of FBZSO and FBZ could be improved by administration to unfed animals and coadministration with piperonyl-butoxide.

  16. Clinical pharmacokinetic and pharmacodynamic profile of lacosamide.

    PubMed

    Cawello, Willi

    2015-09-01

    Lacosamide-a third-generation antiepileptic drug available in multiple formulations-was first approved in 2008 as adjunctive therapy for partial-onset seizures (POS) in adults. In 2014, lacosamide was approved as monotherapy for POS by the US Food and Drug Administration (FDA). A loading dose administration was approved in 2013 by the European Medicines Agency and in 2014 by the FDA. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing and reduction in long-term channel availability without affecting physiological function. Lacosamide is rapidly absorbed, with maximum plasma concentrations reached 0.5-4 h after intake. Oral bioavailability is high (100 %) for a dose up to 800 mg. Bioavailability is irrespective of food intake. Variability in pharmacokinetic parameters is low (coefficients of variation almost all <20 %). The pharmacokinetic profile of lacosamide is consistent in healthy subjects and across different patient populations studied. Lacosamide elimination from plasma occurs with a terminal half-life of approximately 13 h in young subjects and 14-16 h in elderly subjects; this difference does not impact the dose regimen. Lacosamide produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for reduction of seizure frequency can be described by a maximum effect (E max) model. Lacosamide does not induce or inhibit cytochrome P450 enzymes or known drug transporter systems, has low protein binding of less than 15 % and, because it has multiple elimination pathways, it has no clinically relevant interactions with commonly prescribed medications.

  17. Clinical pharmacokinetics of therapeutic monoclonal antibodies.

    PubMed

    Keizer, Ron J; Huitema, Alwin D R; Schellens, Jan H M; Beijnen, Jos H

    2010-08-01

    Monoclonal antibodies (mAbs) have been used in the treatment of various diseases for over 20 years and combine high specificity with generally low toxicity. Their pharmacokinetic properties differ markedly from those of non-antibody-type drugs, and these properties can have important clinical implications. mAbs are administered intravenously, intramuscularly or subcutaneously. Oral administration is precluded by the molecular size, hydrophilicity and gastric degradation of mAbs. Distribution into tissue is slow because of the molecular size of mAbs, and volumes of distribution are generally low. mAbs are metabolized to peptides and amino acids in several tissues, by circulating phagocytic cells or by their target antigen-containing cells. Antibodies and endogenous immunoglobulins are protected from degradation by binding to protective receptors (the neonatal Fc-receptor [FcRn]), which explains their long elimination half-lives (up to 4 weeks). Population pharmacokinetic analyses have been applied in assessing covariates in the disposition of mAbs. Both linear and nonlinear elimination have been reported for mAbs, which is probably caused by target-mediated disposition. Possible factors influencing elimination of mAbs include the amount of the target antigen, immune reactions to the antibody and patient demographics. Bodyweight and/or body surface area are generally related to clearance of mAbs, but clinical relevance is often low. Metabolic drug-drug interactions are rare for mAbs. Exposure-response relationships have been described for some mAbs. In conclusion, the parenteral administration, slow tissue distribution and long elimination half-life are the most pronounced clinical pharmacokinetic characteristics of mAbs.

  18. 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.

  19. Comparison of four technetium-99m radiopharmaceuticals for detection and localization of gastrointestinal bleeding in a sheep model

    SciTech Connect

    Owunwanne, A.; Al-Wafai, I.; Vallgren, S.; Sadek, S.; Abdel-Dayem, H.M.; Yacoub, T.

    1988-01-01

    Four Tc-99 radiopharmaceuticals, Tc-99m sulphur colloid, Tc-99m red blood cells (RBCs), Tc-99m mercaptoacetyltriglycine (MAG3), and Tc-99m DTPA, were studied in an experimental animal model for detection and localization of gastrointestinal (GI) bleeding site in both the upper and lower abdomen. With Tc-99m sulphur colloid and Tc-99m RBCs, it was possible to detect and localize the GI bleeding site in the lower abdomen. With Tc-99m MAG3, it was possible to visualize the bleeding site in both the upper and lower abdomen. However, Tc-99m MAG3 is partially excreted by the liver into the bile, hence it will be difficult to use Tc-99m MAG3 to localize the GI bleeding site in the lower abdomen. With Tc-99m DTPA, it was possible to detect and localize the GI bleeding site simultaneously in both upper and lower abdomen. The overall background radioactivity was reduced considerably by diuresis with frusemide and catheterization of the urinary bladder.

  20. 99mTc-imidodiphosphonate: a superior radio-pharmaceutical for in vivo positive myocardial infarct imaging. II: Clinical data.

    PubMed Central

    Joseph, S P; Ell, P J; Ross, P; Donaldson, R; Elliott, A T; Brown, N J; Williams, E S

    1978-01-01

    99mTc-Imidodiphosphonate was investigated as a new myocardial infarct imaging agent. In the acute phase, 50 patients admitted to the coronary care unit were serially scanned over a period of 7 days. A mobile gamma camera linked on line to a remote data processor was used. Because of higher uptake in infarcted myocardium and faster blood clearance, superior images than those recorded with 99mTc-pyrophosphate were obtained. Its ease of preparation, low cost, and favourable dosimetry (because of its label with conventional 99mTc) transforms this agent into the present radiopharmaceutical of choice for acute infarct imaging in particular if sizing and follow-up is intended versus time and type of treatment. In this series, no false positive cases were seen. The sensitivity of the method in the detection of full thickness myocardial infarction was 95%. It dropped to 70% in the detection of subendocardial infarction. However, some of these apparent false negative cases may reflect severe ischaemia without infarction. It is postulated that this discrimination may not always be realistic. Images PMID:637976

  1. Molecular modeling in the development of metal radiopharmaceuticals. Final progress report, July 15, 1989--July 14, 1993

    SciTech Connect

    Green, M.A.

    1993-10-01

    We began this project with a compilation of a structural library to serve as a data base containing descriptions of the molecular features of metal-labeled radiopharmaceuticals known to efficiently cross the blood-brain barrier. Such a data base is needed in order to identify structural features (size, shape, molecular surface areas and volumes) that are critical in allowing blood-brain barrier penetration. Nine metal complexes have been added to this structural library. We have completed a detailed comparison of four molecular mechanics computer programs QUANTA, SYBYL, BOYD, and MM2DREW to assess their applicability to modeling the structures of low molecular weight metal complexes. We tested the ability of each program to reproduce the crystallographic structures of 38 complexes between nickel(II) and saturated N-donor ligands. The programs were evaluated in terns of their ability to reproduce structural features such as bond lengths, bond angles, and torsion angles. Recently, we investigated the synthesis and characterization of lipophilic cationic gallium complexes with hexadentate bis(salicylaldimine) ligands. This work identified the first gallium-68 radiopharrnaceuticals that can be injected intravenously and that subsequently exhibit significant myocardial uptake followed by prolonged myocardial retention of {sup 68}Ga radioactivity. Tracers of this type remain under investigation as agents for evaluation of myocardial perfusion with positron emission tomography.

  2. SU-C-303-03: Dosimetric Model of the Beagle Needed for Pre-Clinical Testing of Radiopharmaceuticals

    SciTech Connect

    Shang, M; Sands, M; Bolch, W

    2015-06-15

    Purpose: Large animal models, most popularly beagles, have been crucial surrogates to humans in determining radiation safety levels of radiopharmaceuticals. This study aims to develop a detailed beagle phantom to accurately approximate organ absorbed doses for therapy nuclear medicine preclinical studies. Methods: A 3D NURBS model was created subordinate to a whole body CT of an adult beagle. Bones were harvested and CT imaged to offer macroscopic skeletal detail. Samples of trabecular spongiosa were cored and imaged to offer microscopic skeletal detail for bone trabeculae and marrow volume fractions. Results: Organ masses in the model are typical of an adult beagle. Trends in volume fractions for skeletal dosimetry are fundamentally similar to those found in existing models of other canine species. Conclusion: This work warrants its use in further investigations of radiation transport calculation for electron and photon dosimetry. This model accurately represents the anatomy of a beagle, and can be directly translated into a useable geometry for a voxel-based Monte Carlo radiation transport program such as MCNP6. Work supported by a grant from the Hyundai Hope on Wheels Foundation for Pediatric Cancer Research.

  3. 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.

  4. Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis.

    PubMed

    Hennig, Stefanie; Naiker, Suhashni; Reddy, Tarylee; Egan, Deirdre; Kellerman, Tracy; Wiesner, Lubbe; Owen, Andrew; McIlleron, Helen; Pym, Alexander

    2015-10-19

    Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.).

  5. Effect of SLCO1B1 Polymorphisms on Rifabutin Pharmacokinetics in African HIV-Infected Patients with Tuberculosis

    PubMed Central

    Naiker, Suhashni; Reddy, Tarylee; Egan, Deirdre; Kellerman, Tracy; Wiesner, Lubbe; Owen, Andrew; McIlleron, Helen; Pym, Alexander

    2015-01-01

    Rifabutin, used to treat HIV-infected tuberculosis, shows highly variable drug exposure, complicating dosing. Effects of SLCO1B1 polymorphisms on rifabutin pharmacokinetics were investigated in 35 African HIV-infected tuberculosis patients after multiple doses. Nonlinear mixed-effects modeling found that influential covariates for the pharmacokinetics were weight, sex, and a 30% increased bioavailability among heterozygous carriers of SLCO1B1 rs1104581 (previously associated with low rifampin concentrations). Larger studies are needed to understand the complex interactions of host genetics in HIV-infected tuberculosis patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00640887.) PMID:26482301

  6. [Pharmacokinetic study of pyrazinamide and pyrazinoic acid in subjects with normal renal function and patients with renal failure].

    PubMed

    Vayre, P; Chambraud, E; Fredj, G; Thuillier, A

    1989-01-01

    The main pharmacokinetic parameters of pyrazinamide and pyrazinoïc acid (its major metabolite) were determined after oral administration of 1,500 mg/d in 10 patients with normal renal function and of 1,000 mg/d in 10 patients with impaired renal function (renal insufficiency). This study shows that, with these dosage regimens, almost all the pharmacokinetic parameters are identical for pyrazinamide and pyrazinoic acid in patients with normal renal function and patients with impaired renal function. Comparison of results between patients allows us to propose a dosage regimen of 1,000 mg/d as maintenance in patients with renal insufficiency.

  7. Pharmacokinetic evaluation and antitumor activity of 2-methoxyestradiol nanosuspension.

    PubMed

    Du, Shuzhang; Zhu, Ling; Du, Bin; Shi, Xiufang; Zhang, Zhenzhong; Wang, Shuyu; Zhang, Chaofeng

    2012-04-01

    The aim of the present study was to evaluate the pharmacokinetic and antitumor activity of 2-methoxyestradiol (2-ME) nanosuspension relative to 2-ME solution both in vitro and in vivo. The pharmacokinetics of 2-ME administered either as a nanosuspension or as a solution were compared after I.V. administration to rats. In plasma, 2-ME nanosuspension exhibited a significantly (p < 0.01) reduced C(max) (1022.8 ± 467.4 ng/mL versus 2559.2 ± 775.8 ng/mL) and AUC(0-240min) (41566.8 ± 965.5 ng/mL min versus 79557.7 ± 256.2 ng/mL min), and a significantly (p < 0.01) greater volume of distribution (3.18-fold), clearance (1.85-fold), and elimination half-life (156.6 ± 33.5 min versus 70.0 ± 22.6 min) compared to the 2-ME solution. Methyl tetrazolium (MTT) assay showed that nanosuspension could significantly enhance the cytotoxicity of 2-ME on EC9706 cells in vitro. After 72 h exposure, the IC(50) value of 2-ME nanosuspension was much lower than that of 2-ME solution (1.81 ± 0.15 μmol/L versus 4.14 ± 0.30 μmol/L). Studies on BALB/c mice with EC9706 solid tumors demonstrated significantly greater inhibition of tumor growth following treatment with 2-ME nanosuspension than 2-ME solution at the same dosage. These results suggest that the delivery of 2-ME nanosuspension is a promising approach for the treatment of tumors.

  8. Hepatic Dipeptidyl Peptidase-4 Controls Pharmacokinetics of Vildagliptin In Vivo.

    PubMed

    Asakura, Mitsutoshi; Fukami, Tatsuki; Nakajima, Miki; Fujii, Hideaki; Atsuda, Koichiro; Itoh, Tomoo; Fujiwara, Ryoichi

    2017-02-01

    The main route of elimination of vildagliptin, which is an inhibitor of dipeptidyl peptidase-4 (DPP-4), in humans is cyano group hydrolysis to produce a carboxylic acid metabolite M20.7. Our in vitro study previously demonstrated that DPP-4 itself greatly contributed to the hydrolysis of vildagliptin in mouse, rat, and human livers. To investigate whether hepatic DPP-4 contributes to the hydrolysis of vildagliptin in vivo, in the present study, we conducted in vivo pharmacokinetics studies of vildagliptin in mice coadministered with vildagliptin and sitagliptin, which is another DPP-4 inhibitor, and also in streptozotocin (STZ)-induced diabetic mice. The area under the plasma concentration-time curve (AUC) value of M20.7 in mice coadministered with vildagliptin and sitagliptin was significantly lower than that in mice administered vildagliptin alone (P < 0.01). Although plasma DPP-4 expression level was increased 1.9-fold, hepatic DPP-4 activity was decreased in STZ-induced diabetic mice. The AUC values of M20.7 in STZ-induced diabetic mice were lower than those in control mice (P < 0.01). Additionally, the AUC values of M20.7 significantly positively correlated with hepatic DPP-4 activities in the individual mice (Rs = 0.943, P < 0.05). These findings indicated that DPP-4 greatly contributed to the hydrolysis of vildagliptin in vivo and that not plasma, but hepatic DPP-4 controlled pharmacokinetics of vildagliptin. Furthermore, enzyme assays of 23 individual human liver samples showed that there was a 3.6-fold interindividual variability in vildagliptin-hydrolyzing activities. Predetermination of the interindividual variability of hepatic vildagliptin-hydrolyzing activity might be useful for the prediction of blood vildagliptin concentrations in vivo.

  9. Repeated dose pharmacokinetics of pancopride in human volunteers.

    PubMed

    Salva, P; Costa, J; Pérez-Campos, A; Martínez-Tobed, A

    1994-11-01

    The aim of this study was to assess the pharmacokinetic profile of pancopride after repeated oral dose administration of 20 mg pancopride in tablet form once a day for 5 d in 12 healthy male volunteers. Plasma levels were measured by HPLC using a solid phase extraction method and automated injection. The minimum quantification limit of pancopride in plasma was 2 ng mL-1. The maximum plasma concentration (mean +/- SD) after the first dose was 92.5 +/- 41.5 ng ML-1 and tmax was 1.7 +/- 0.9 h. The elimination half-life (t1/2) was 14.3 +/- 6.9 h. The area under the concentration-time curve from zero to infinity (AUC) was 997 +/- 396 ng h mL-1. The maximum plasma concentration (mean +/- SD) at steady state (day 5) was 101.8 +/- 36.9 ng mL-1 and tmax was 2.2 +/- 1.2 h. The elimination half-life (t1/2) was 16.3 +/- 2.7 h and the minimum plasma concentration (Cssmin) was 16.6 +/- 6.9 ng mL-1. The area under the concentration-time curve during the dosing interval (AUCss tau) was 995 +/- 389 ng h mL-1. The average plasma concentration at steady state (Cssav) was 43.3 +/- 16.1 ng mL-1 and the experimental accumulation ratio (RAUC) was 1.34 +/- 0.19, whereas the mean theoretical value (R) was 1.40 +/- 0.29. The results obtained showed a good correlation between the experimental plasma levels and the expected values calculated using a repeated dose two-compartment model assessed by means of the Akaike value. It is concluded that the pharmacokinetics of pancopride are not modified after repeated dose administration.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Pharmacokinetics of Lipophilic Agents Following Preexposure: Non-Cytochrome P-450 Mediated Mechanisms

    DTIC Science & Technology

    1990-05-30

    FOLLOWING PREEXPOSUR G - AFOSR-87- 185 U’) NON -CYTOCHROME P-450 MEDIATED MECHAN’ICS PE - 61102F (NJ . AUTHOKS) PR - 2312 N TA - A5 Dr Lawrence R Curtis, Dr...Z39- I*. PHARMACOKINETICS OF LIPOPHILIC AGENTS FOLLOWING PREEXPOSURE: NON -CYTOCHROME P-450 MEDIATED MECHANISMS Air Force Grant No. 87-0185 Hillary M...amounts located in non -hepatic tissues. These studies showed that, despite the differences in PDR, the systems involved respond in a dose related manner

  11. [Clinical studies on the effect of pregnancy and labor on the pharmacokinetics of ampicillin].

    PubMed

    Voigt, R; Schröder, S; Meinhold, P; Zenner, I; Nöschel, H

    1978-01-01

    After giving 5 g Ampicillin intravenously to a total of 33 women (gravidae during the VIII. month pregnancy, women in labor and health controll persons) the serum levels of the mothers were analysed according to the pharmacokinetic parameter half-life of elimination.--Our results show that only the delivery cause significant differences of the kinetic of ampicillin.--Our results are discussed with the data given by literature.

  12. Modulation of the pharmacokinetics of zinc oxide nanoparticles and their fates in vivo

    NASA Astrophysics Data System (ADS)

    Paek, Hee-Jeong; Lee, Youn-Joung; Chung, Hea-Eun; Yoo, Nan-Hui; Lee, Jeong-A.; Kim, Mi-Kyung; Lee, Jong Kwon; Jeong, Jayoung; Choi, Soo-Jin

    2013-11-01

    In the present study, the effects of particle size (20 nm or 70 nm) and surface charge (negative or positive) on the pharmacokinetics, tissue distributions, and excretion of ZnO nanoparticles were examined following the administration of a single oral dose to rats. Pharmacokinetic profiles and biodistributions were not affected by particle size or gender. However, ZnO (-) particles were markedly more absorbed by the systemic circulation than ZnO (+) particles. Furthermore, the kinetic behaviors of ZnO nanoparticles differed from those of zinc ions, as evidenced by the low dissolution (13-14%) of ZnO nanoparticles under gastric conditions. The kidneys, liver, and lungs were found to be target organs. However, the major biological fate of ZnO nanoparticles in tissues was the ionic form, not the particulate form, and this was independent of exposure routes (oral and intravenous). Particle size was only found to affect excretion kinetics, and 20 nm particles were more rapidly eliminated. Most nanoparticles were excreted via the biliary and fecal routes, but a small amount of the nanoparticles was excreted via urine. The study shows that surface charge, rather than particle size or gender, is the critical modulator of the pharmacokinetic behavior of ZnO nanoparticles.In the present study, the effects of particle size (20 nm or 70 nm) and surface charge (negative or positive) on the pharmacokinetics, tissue distributions, and excretion of ZnO nanoparticles were examined following the administration of a single oral dose to rats. Pharmacokinetic profiles and biodistributions were not affected by particle size or gender. However, ZnO (-) particles were markedly more absorbed by the systemic circulation than ZnO (+) particles. Furthermore, the kinetic behaviors of ZnO nanoparticles differed from those of zinc ions, as evidenced by the low dissolution (13-14%) of ZnO nanoparticles under gastric conditions. The kidneys, liver, and lungs were found to be target organs. However

  13. Influence of cirrhosis on lamotrigine pharmacokinetics

    PubMed Central

    Marcellin, P; de Bony, F; Garret, C; Altman, C; Boige, V; Castelnau, C; Laurent-Puig, P; Trinchet, J C; Rolan, P; Chen, C; Mamet, J P; Bidault, R

    2001-01-01

    Aims Lamotrigine, an antiepileptic drug, is cleared from the systemic circulation mainly by glucuronidation. The possibility of changes in the pharmacokinetics of lamotrigine in plasma owing to hepatic dysfunction has been evaluated. Methods Thirty-six subjects, including 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers received a single 100 mg dose of lamotrgine. Blood samples were taken for 7 days in all subjects, except nine with severe cirrhosis, who had a 29 day blood sampling period. Results The pharmacokinetics of lamotrigine were comparable between the patients with moderate cirrhosis (corresponding to Child-Pugh grade A) and the healthy subjects. Plasma oral clearance mean ratios (90% confidence interval) in patients with severe cirrhosis without or with ascites (corresponding, respectively, to Child-Pugh grade B and C) to healthy subjects were, respectively, 60% (44%, 83%) and 36% (25%, 52%). Plasma half-life mean ratios (90% confidence interval) in these two patient groups to healthy subjects were, respectively, 204% (149%, 278%) and 287% (202%, 408%). Conclusions Lamotrigine administered as a single oral dose of 100 mg was well tolerated in all groups. Initial, escalation and maintenance doses should generally be reduced by approximately 50 or 75% in patients with Child-Pugh Grade B or C cirrhosis. Escalation and maintenance doses should be adjusted according to clinical response. PMID:11421997

  14. Fractional dynamics pharmacokinetics-pharmacodynamic models.

    PubMed

    Verotta, Davide

    2010-06-01

    While an increasing number of fractional order integrals and differential equations applications have been reported in the physics, signal processing, engineering and bioengineering literatures, little attention has been paid to this class of models in the pharmacokinetics-pharmacodynamic (PKPD) literature. One of the reasons is computational: while the analytical solution of fractional differential equations is available in special cases, it this turns out that even the simplest PKPD models that can be constructed using fractional calculus do not allow an analytical solution. In this paper, we first introduce new families of PKPD models incorporating fractional order integrals and differential equations, and, second, exemplify and investigate their qualitative behavior. The families represent extensions of frequently used PK link and PD direct and indirect action models, using the tools of fractional calculus. In addition the PD models can be a function of a variable, the active drug, which can smoothly transition from concentration to exposure, to hyper-exposure, according to a fractional integral transformation. To investigate the behavior of the models we propose, we implement numerical algorithms for fractional integration and for the numerical solution of a system of fractional differential equations. For simplicity, in our investigation we concentrate on the pharmacodynamic side of the models, assuming standard (integer order) pharmacokinetics.

  15. 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.

  16. 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.

  17. Pharmacokinetics of tilidine in terminal renal failure.

    PubMed

    Seiler, K U; Jähnchen, E; Trenk, D; Brennscheidt, U; Heintz, B

    2001-01-01

    The aim of the present study was to investigate the pharmacokinetics of tilidine and its metabolites during the dialysis procedure and in the dialysis-free interval. Tilidine is a prodrug that is metabolized presystemically into the active metabolite nortilidine. Nortilidine is degraded thereafter to bisnortilidine and several polar metabolites. Nine patients with a creatinine clearance < 5 ml/min were treated in a crossover design with single oral doses of 1.5 mg/kg on the day of dialysis (dialysis performed from 3 to 6 hours after drug administration) and on a day in the dialysis-free interval. Blood samples were taken frequently and analyzed for tilidine, nortilidine, and bisnortilidine. Drug and metabolite concentrations were also measured in aliquots of dialysate collected during dialysis. Only negligible amounts of tilidine, nortilidine, and bisnortilidine (about 0.9% of the dose) were recovered from the dialysate. The pharmacokinetics of nortilidine and its inactive metabolite bisnortilidine was not affected by dialysis. The presystemic apparent clearance of the prodrug tilidine was decreased significantly during the dialysis-free interval. A significant decrease of the rate of elimination and an increase of the AUC of bisnortilidine were observed if these parameters were compared with data obtained from healthy volunteers. The plasma concentrations of nortilidine were comparable in patients and normal volunteers. Thus, a reduction of the dose of tilidine in patients with severely impaired kidney function seems not to be required. Tilidine and its metabolites cannot be removed from the body by dialysis.

  18. Single dose pharmacokinetics of terbinafine in cats.

    PubMed

    Wang, Ang; Ding, Huanzhong; Liu, Yiming; Gao, Yan; Zeng, Zhenling

    2012-08-01

    The pharmacokinetics of terbinafine was studied in six healthy fasted cats following a single intravenous and oral administration at a dose of 10 mg/kg and 30 mg/kg, respectively, according to a two-period crossover design. Plasma terbinafine concentrations were determined using a reverse phase liquid chromatographic method. The pharmacokinetic parameters were calculated by non-compartmental analysis with WinNonlin 5.2.1 software. After intravenous administration, the terminal half-life and area under the curve from time 0 to infinity were 10.40 ± 4.56 h, 15.20 ± 3.61 h·µg/ml, respectively. After oral dosing, the mean maximum concentration was 3.22 ± 0.60 µg/ml, reached at 1.33 ± 0.41 h. The terminal half-life, area under the curve from time 0 to infinity and apparent volume of distribution were 8.01 ± 3.46 h, 13.77 ± 4.99 h·µg/ml, 25.63 ± 6.29 l/kg, respectively. The absolute bioavailability of terbinafine hydrochloride tablets after oral administration was 31.00 ± 10.85%. Although bioavailability was low, excellent penetration at the site of infection and low minimum inhibitory concentrations values provided terbinafine with good efficacy against dermatophyte infections.

  19. The pharmacokinetics and pharmacodynamics of iron preparations.

    PubMed

    Geisser, Peter; Burckhardt, Susanna

    2011-01-04

    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.

  20. Pharmacokinetic study of Noni fruit extract.

    PubMed

    Issell, Brian F; Franke, Adrian; Fielding, Robert M

    2008-01-01

    Many different products containing Noni (Morinda citrifolia) fruit extracts are sold throughout the world for health restoration and maintenance. Despite a large business enterprise fueling Noni's popularity, there is a lack of standardization of products and no scientific evidence of Noni's clinical efficacy and safety. There is also no evidence to indicate an optimal therapeutic dose or dosing interval. In an initial volunteer, scopoletin was identified as a bioactive marker of Noni exposure and a candidate for product standardization and pharmacokinetic studies. Subsequently, capsules containing the whole freeze-dried fruit of Noni were orally administered to nine healthy volunteers (3 per group) at doses of 1,500 mg (3 × 500 mg), 2,000 mg (4 × 500 mg) and 2,500 mg (5 × 500 mg). Plasma and urine samples were obtained from each subject prior to dosing and at 0.5, 1, 2, 4 and 8 h after dosing. Concentrations of scopoletin were determined by HPLC with PDA (scanning at 200-700 nm) and MS detection. Scopoletin rapidly enters the plasma after Noni ingestion, maintaining levels in the range of 0.5 to 5 ng/mL for at least 8 h after dosing. Scopoletin bioavailability appears to be low, with significant intersubject variability. We conclude that scopoletin can be used as a relatively specific marker of Noni exposure in the blood and particularly in urine when its pharmacokinetics is considered appropriately.

  1. [Pharmacokinetics and interactions of raltegravir].

    PubMed

    Placeres Alsina, Maria Mercè; Tuset Creus, Montse; Miró, José M

    2008-11-01

    Raltegravir is the first integrase inhibitor approved for the treatment of HIV-1 infection in pretreated adults with evidence of viral replication despite receiving antiretroviral therapy. Raltegravir is administered orally at a dose of 400 mg every 12 hours, with or without food. This drug is mainly eliminated through UGT1A1-mediated glucuronidation and is not an inhibitor or inducer of the main liver cytochrome P450 isoenzymes; consequently there is virtually no risk of pharmacological interactions with most commonly used drugs such as methadone, azole antifungal agents or drugs used to treat erectile dysfunction. Studies of interaction with other antiretroviral agents show that raltegravir can be used in combination with tenofovir, efavirenz, atazanavir, ritonavir or tipranavir/ritonavir without the need for dose adjustments. When combined with rifampicin, the dose of raltegravir should be increased to 800 mg/12 h. Proton pump inhibitors increase plasma levels of raltegravir (a 3-fold increase in exposure or AUC levels), and consequently their combined use should be avoided as far as posible. Raltegravir is well tolerated and does not require dose adjustments in patients with severe renal impairment or mild-to-moderate liver impairment. There are no studies in patients with severe liver impairment.

  2. Clinical pharmacokinetics and pharmacodynamics of linagliptin.

    PubMed

    Graefe-Mody, Ulrike; Retlich, Silke; Friedrich, Christian

    2012-07-01

    Linagliptin is an orally active small-molecule inhibitor of dipeptidyl peptidase (DPP)-4, which was first licensed in the US, Europe, Japan and other territories in 2011 to improve glycaemic control in adults with type 2 diabetes mellitus. Linagliptin is the first and thus far the only DPP-4 inhibitor, and oral antihyperglycaemic drug in general, to be approved as a single-strength once-daily dose (5 mg). Compared with other available DPP-4 inhibitors, linagliptin has a unique pharmacokinetic/pharmacodynamic profile that is characterized by target-mediated nonlinear pharmacokinetics, concentration-dependent protein binding, minimal renal clearance and no requirements for dose adjustment for any intrinsic or extrinsic factor. After single or multiple oral doses of 1-10 mg, linagliptin displays less than dose-proportional increases in maximum plasma concentration (C(max)) and area under the plasma concentration-time curve (AUC). Linagliptin is rapidly absorbed after oral administration, with C(max) occurring after approximately 90 minutes, and reaches steady-state concentrations within 4 days. With the therapeutic dose, steady-state C(max) (11-12 nmol/L) and AUC (∼150 nmol · h/L) are approximately 1.3-fold greater than after a single dose, indicating little drug accumulation with repeat dosing. Linagliptin exhibits concentration-dependent protein binding in human plasma in vitro (99% at 1 nmol/L to 75-89% at >30 nmol/L) and has a large apparent volume of distribution, demonstrating extensive distribution into tissues. The nonlinear pharmacokinetics of linagliptin are best described by a two-compartmental model that incorporates target-mediated drug disposition resulting from high-affinity, saturable binding to DPP-4. The oral bioavailability of linagliptin estimated with this model is approximately 30%. Linagliptin has a long terminal half-life (>100 hours); however, its accumulation half-life is much shorter (approximately 10 hours), accounting for the rapid

  3. Development of safety profile evaluating pharmacokinetics, pharmacodynamics and toxicity of a combination of pioglitazone and olmesartan medoxomil in Wistar albino rats.

    PubMed

    Sengupta, Pinaki; Nandi, Utpal; Pal, Tapan Kumar

    2012-02-01

    Pioglitazone (PIO), an antidiabetic drug and olmesartan medoxomil (OLM), an antihypertensive drug were administered orally alone and in combination to Wistar albino rats for evaluation of pharmacokinetics, pharmacodynamics and repeated dose 28-day oral toxicity of individual drugs and their combination. Pharmacokinetic study was performed by orally administering PIO and OLM at single dose of 3 and 2mg/kg, respectively alone and in combination analyzing the plasma samples using LC-MS/MS. Antidiabetic activity evaluation was done in type-2 diabetes mellitus induced animals at same dose level as in pharmacokinetic study daily for 30 days. PIO and/or OLM were administered orally to animals at daily doses of 50, 100 and 150 mg/kg for 28 days for toxicity study. There was no significant alteration in the pharmacokinetic parameters of either drug indicating absence of any pharmacokinetic interaction when co-administered. Positive pharmacodynamic interaction between PIO and OLM was established in this study. Two drugs in combination showed no evidence of potentiation of 28-day repeated dose toxicity in animals. Again, drugs, alone and in combination, caused only minor changes in clinical-laboratory tests and histopathological change was not found in the experiment performed. In conclusion, PIO and OLM combination can primarily be stated as safe in terms of present toxicity and pharmacokinetics findings.

  4. Pharmacokinetics of PSC 833 (valspodar) in its Cremophor EL formulation in rat.

    PubMed

    Binkhathlan, Z; Hamdy, D A; Brocks, D R; Lavasanifar, A

    2010-01-01

    Valspodar is a P-glycoprotein inhibitor widely used in preclinical and clinical studies for overcoming multidrug resistance. Despite this, the pharmacokinetics of valspodar in rat, a commonly used animal model, have not been reported. Here, we report on the pharmacokinetics of valspodar in Sprague-Dawley rats following intravenous and oral administration of its Cremophor EL formulation, which has been used for humans in clinical trials. After intravenous doses, valspodar displayed properties of slow clearance and a large volume of distribution. Its plasma unbound fraction was around 15% in the Cremophor EL formulation used in the study. After 10 mg kg(-1) orally it was rapidly absorbed with an average maximal plasma concentration of 1.48 mg l(-1) within approximately 2 h. The mean bioavailability of valspodar was 42.8%. In rat, valspodar showed properties of low hepatic extraction and wide distribution, similar to that of its structural analogue cyclosporine A.

  5. Design evaluation and optimisation in crossover pharmacokinetic studies analysed by nonlinear mixed effects models.

    PubMed

    Nguyen, Thu Thuy; Bazzoli, Caroline; Mentré, France

    2012-05-20

    Bioequivalence or interaction trials are commonly studied in crossover design and can be analysed by nonlinear mixed effects models as an alternative to noncompartmental approach. We propose an extension of the population Fisher information matrix in nonlinear mixed effects models to design crossover pharmacokinetic trials, using a linearisation of the model around the random effect expectation, including within-subject variability and discrete covariates fixed or changing between periods. We use the expected standard errors of treatment effect to compute the power for the Wald test of comparison or equivalence and the number of subjects needed for a given power. We perform various simulations mimicking crossover two-period trials to show the relevance of these developments. We then apply these developments to design a crossover pharmacokinetic study of amoxicillin in piglets and implement them in the new version 3.2 of the r function PFIM.

  6. Pharmacokinetics and tolerance of nicotinamide combined with radiation therapy in patients with glioblastoma multiforme.

    PubMed

    Cartei, F; Danesi, R; Ducci, F; Fatigante, L; Caciagli, P G; Tacca, M; Laddaga, M

    1994-01-01

    The pharmacokinetic properties of nicotinamide and its tolerance were studied in seven patients affected by glioblastoma multiforme and treated with two fractions per day of radiation therapy. Nicotinamide was given orally at two daily doses of 4 g and then 2 g separated by a 6-h-interval. The treatment was well tolerated in almost all patients and had no effect on blood pressure, cardiac rhythm or body temperature. Pharmacokinetic analysis showed peak plasma levels (Cmax) above 100 mg/l 45 minutes after the administration of both doses. This was followed by a biexponential decay of plasma concentrations with a thermal half life of 9.4h. Tumours were irradiated 1 hour after each drug dose to match with drug Cmax in plasma, and although it is too early to evaluate the tumour response, the drug levels achieved should be sufficient to improve radiation therapy.

  7. 15. Detail showing lower chord pinconnected to vertical member, showing ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    15. Detail showing lower chord pin-connected to vertical member, showing floor beam riveted to extension of vertical member below pin-connection, and showing brackets supporting cantilevered sidewalk. View to southwest. - Selby Avenue Bridge, Spanning Short Line Railways track at Selby Avenue between Hamline & Snelling Avenues, Saint Paul, Ramsey County, MN

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

    PubMed

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

    2006-01-01

    This article reviews the pharmacokinetics of heroin after intravenous, oral, intranasal, intramuscular and rectal application and after inhalation in humans, with a special focus on heroin maintenance therapy in heroin dependent patients. In heroin maintenance therapy high doses pharmaceutically prepared heroin (up to 1000 mg/day) are prescribed to chronic heroin dependents, who do not respond to conventional interventions such as methadone maintenance treatment. Possible drug-drug interactions with the hydrolysis of heroin into 6-monoacetylmorphine and morphine, the glucuronidation of morphine and interactions with drug transporting proteins are described. Since renal and hepatic impairment is common in the special population of heroin dependent patients, specific attention was paid on the impact of renal and hepatic impairment. Hepatic impairment did not seem to have a clinically relevant effect on the pharmacokinetics of heroin and its metabolites. However, some modest effects of renal impairment have been noted, and therefore control of the creatinine clearance during heroin-assisted treatment seems recommendable.

  9. The posology of oseltamivir in infants with influenza infection using a population pharmacokinetic approach.

    PubMed

    Kamal, M A; Acosta, E P; Kimberlin, D W; Gibiansky, L; Jester, P; Niranjan, V; Rath, B; Clinch, B; Sánchez, P J; Ampofo, K; Whitley, R; Rayner, C R

    2014-09-01

    Infants are at increased risk for morbidity and mortality due to influenza. Until recently, few data were available with which to optimize oseltamivir dosing in this high-risk population. Here, data for 133 infants were pooled from two prospective pharmacokinetic/pharmacodynamic safety studies to develop a population pharmacokinetic model. A three-compartment model with allometric scaling of all clearance and volume parameters described the disposition of oseltamivir and its carboxylate metabolite (OC). Weight dependence, OC clearance, and volume of distribution increased linearly with age. Analyses showed no association between OC exposure and viral clearance, the development of resistance (phenotypic/genotypic), normalization of body temperature, or safety endpoints. Pharmacokinetic bridging showed that a 3 mg/kg dose yielded acceptable OC exposure and good tolerability while minimizing the risk of underexposure and resistance/treatment failure. These pharmacological analyses formed the basis of the US Food and Drug Administration's recent approval of oseltamivir treatment for infants with influenza aged as young as 2 weeks.

  10. Abnormal clinical pharmacokinetics of the developmental radiosensitizers pimonidazole (Ro 03-8799) and etanidazole (SR 2508)

    SciTech Connect

    Maughan, T.S.; Newman, H.F.; Bleehen, N.M.; Ward, R.; Workman, P. )

    1990-05-01

    The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) are under evaluation as single agents (Phase III) and in combination (Phase I). Ro 03-8799 produces an acute, transient central nervous system syndrome, whereas SR 2508 causes cumulative, peripheral neurotoxicity; both effects are dose-limiting. Pharmacokinetic studies have shown the importance of area under the plasma drug concentration versus time curve (AUC) in predicting the risk of peripheral neuropathy. Most patients have very similar pharmacokinetic parameters. This study reports 2/25 patients receiving 0.75 g/m2 Ro 03-8799 plus 2.0 g/m2 SR 2508 who showed significant discrepancies in drug handling. One patient exhibited a markedly elevated AUC and prolonged t1/2 beta for SR 2508 and this was associated with an unusually rapid onset of peripheral neuropathy. A second patient showed normal handling of SR 2508 but prolonged values for both t1/2 alpha and t1/2 beta for Ro 03-8799 and unusually low levels of its N-oxide metabolite. In addition a low peak Ro 03-8799 concentration combined with a very high volume of distribution was found in this patient, leading to a normal AUC value and toxicity profile. Both patients exhibited a relatively low creatinine clearance. The mechanisms which may underlie these findings are discussed, and the importance of pharmacokinetic monitoring in the use of these agents is emphasized.

  11. Comparative pharmacokinetics of ampicillin-sulbactam combination in calves and sheep.

    PubMed

    Montesissa, C; Villa, R; Sonzogni, O; Belloli, C; Carli, S

    1994-10-01

    The pharmacokinetics of ampicillin and sulbactam administered in combination were studied in calves and sheep. The animals were administered an aqueous solution of ampicillin/sulbactam (2:1, w/w) intravenously and intramuscularly at doses of 13.2 and 6.6 mg.kg-1, respectively. A microbiological method was used to detect ampicillin, and HPLC was used to detect sulbactam in serum. Following intravenous (i.v.) administration, the distribution phases were rapid and similar (about 15 min) for both drugs in both species, whereas sulbactam in calves and ampicillin in sheep showed a faster elimination rate. After intramuscular (i.m.) administration both drugs showed peak concentrations higher in calves than in sheep; the peak time of sulbactam was shorter in calves than in sheep. No other significant differences in the pharmacokinetics of the combination were observed between the species after i.m. injection. The mean residence and absorption times, calculated by non-compartmental analysis, for both calves and sheep suggested that the differences in ampicillin and sulbactam pharmacokinetics could be attributable to the different molecular structures.

  12. 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.

  13. Pharmacokinetics of tilidine and naloxone in patients with severe hepatic impairment.

    PubMed

    Brennscheidt, Ulrich; Brunnmüller, Ulrike; Proppe, Dietfried; Thomann, Peter; Seiler, Klaus-Ulrich

    2007-01-01

    The objective of the present study was to evaluate the pharmacokinetics of tilidine (CAS 20380-58-9), naloxone (CAS 465-65-6) and tilidine metabolites after administration of a single oral dose of a solution containing 100 mg tilidine hydrochloride and 8 mg naloxone hydrochloride (equivalent to 1.44 ml Valoron N solution) to patients with severe hepatic impairment. The investigation was carried out as an open single-dose study in 8 patients suffering from liver cirrhosis. Patients qualified for study enrollment if they had a Child-Pugh score of > or = 7 and a mono-ethyl-glycine-xylidide (MEGX) 15-min test value < 50 ng/ ml. Blood samples were taken over a period of 28 h and analyzed for the prodrug tilidine, its active metabolite nortilidine, bisnortilidine, and naloxone (total and non-glucuronidated fraction). Pharmacokinetic parameters were compared with data from a previous study performed in healthy volunteers. Tilidine, nortilidine and unconjugated naloxone pharmacokinetic parameters showed a high variability between patients. Compared to previous results obtained in healthy volunteers, maximum plasma concentration (Cmax) of nortilidine was reduced by 44%, whereas elimination half-life (t1/2) was prolonged by factor 2. The area under the curve (AUC) showed a slight reduction of approximately 20%. For total naloxone, no relevant change was observed. However, in contrast to the results obtained in healthy subjects, unconjugated naloxone could be measured in plasma from patients with cirrhosis, possibly due to a reduced glucuronidation capacity of the liver in these patients. In conclusion, severe hepatic impairment has a relatively minor influence on the exposure (AUC) to the active metabolite of tilidine (i.e., nortilidine). However, a straightforward interpretation of the results was confounded by pronounced variability in nortilidine pharmacokinetics. In individual patients with severely affected liver function, satisfactory analgesia with tilidine

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

    PubMed

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

    2015-01-01

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

  15. Effects of Chungsinoryungsan, a polyherbal complex, on the pharmacokinetic profiles of perindopril in rats

    PubMed Central

    KANG, SEOK-BONG; SHON, HO-SANG; PARK, SOO-JIN; SONG, CHANG-HYUN; KU, SAE-KWANG

    2014-01-01

    For sufficient antihypertension with less adverse effects, numerous clinical trials have recommended combination therapy using two or more hypertensive drugs. Chungsinoryungsan (CSORS) is a polyherbal complex based on oriental medicine, which has shown therapeutic potentials for antihypertension and additional renal improvement. Therefore, the affect of CSORS on the pharmacokinetic profiles of perindopril, an antihypertensive drug, was analyzed as a novel combination of hypertensive drugs. Rats received perindopril with CSORS as the combination or distilled water as the control. The co-administration of perindopril with CSORS or distilled water was performed by single dosing or repeated dosing for a week at a 2-h interval. The analyzed pharmacokinetic parameters included peak concentration (Cmax), time to reach the Cmax (Tmax), area under the plasma concentration-time curve, terminal half-life (t1/2) and mean residence time to infinity (MRTinf). In the single oral co-administration within 5 min, the pharmacokinetics of perindopril demonstrated an increased Tmax and MRTinf but reduced t1/2 in the combination compared to the control treatment, indicating drug-drug interactions between perindopril and CSORS. However, in the repeated co-administration for a week at a 2-h interval, which was more than perindopril MRTinf in the control treatment (1.5±0.1 h), the initial co-administration showed no differences in the pharmacokinetics between the combination and control treatments. Furthermore, the repeated co-administration also showed no differences between the combination and control treatment. The results indicate that CSORS can be co-administered at a 2-h interval that was more than perindopril MRTinf and further clinical studies may provide detailed information for developing a drug regimen that generates enhanced combination effects of CSORS with hypertensive drugs. PMID:25279159

  16. Click-chemistry reactions in radiopharmaceutical chemistry: fast & easy introduction of radiolabels into biomolecules for in vivo imaging.

    PubMed

    Wängler, C; Schirrmacher, R; Bartenstein, P; Wängler, B

    2010-01-01

    Today the term "click chemistry" is often used equivalent with the copper-catalyzed 1,3-dipolar Huisgen cycloaddition. Originally, the concept was introduced in 2001 to describe reactions fulfilling a set of criteria that are most useful for chemical syntheses in drug research. In radiopharmaceutical chemistry where short lived radioisotopes are introduced into various different substance classes for in vivo imaging of biochemical processes, the expanding field of radioactive bioconjugation has become predominant. Labeled biomolecules such as peptides, proteins and oligonucleotides generated via bioconjugation of chelators for radiometal introduction as well as novel valuable secondary precursors for (18)F labeling have enriched the growing field of molecular imaging substantially. When introducing radioactive nuclides with a very short half-life into biomolecules, some of the typical criteria defined by click-chemistry are more crucial than others. Time is always the most important issue, whereas avoiding the formation of by-products that have to be removed without chromatography is of minor importance. The short-lived radionuclide (11)C for example has a physical half-life of only 20 min so that the labeling procedure cannot exceed 40-60 minutes (2-3 half-lifes). In this contribution, we outline reactions and molecules which meet the requirements of click chemistry reactions and are suitable for radiosyntheses of short lived SPECT ((99m)Tc: t(1/2) = 6 h, (111)In: t(1/2) = 2.81 d) and PET ((11)C: t(1/2) = 20.3 min to (64)Cu: t(1/2) = 12.7 h) radiotracers for in vivo imaging of biological processes and review the contributions in the field of radiochemical "click-reactions" - 1,3-dipolar Huisgen cycloadditions and beyond.

  17. Inter-species extrapolation of pharmacokinetic data of three prostacyclin-mimetics.

    PubMed

    Hildebrand, M

    1994-11-01

    Cica-, eptalo- and iloprost are chemically and metabolically stabilized derivatives of prostacyclin which maintain the pharmacodynamic profile of the endogenous precursor. While iloprost is still subject to beta-oxidative degradation of the upper side chain, cicaprost is highly metabolically stable. Eptaloprost was synthesized to realize the pro-drug concept in PGI2-mimetics and was designed to be activated to cicaprost by single beta-oxidation. All three prostacyclin-mimetics were studied in various animal species (mouse, rat, rabbit, monkey, dog and pig) and in man to determine their pharmacokinetic profiles. Based upon this data, it was of interest whether an inter-species extrapolation of pharmacokinetic parameters can be performed to show the predictive value of animal experimentation. Allometric inter-species extrapolation is performed by modelling pharmacokinetic data (Y) as exponential functions (x) of species characteristics (e.g. body weight, W) as: Y = .aWx. For total clearance and volumes of distribution at steady state, a clear-cut correlation with x-values of 0.6-0.8 and 1.0-1.1 could be shown for all three compounds. For cicaprost, which was excreted unchanged in several species, renal and non-renal clearance was also mathematically scalable. Due to the use of different compartment models to describe plasma disposition, different sets of half-life data were obtained and could not be extrapolated reasonably. However, mean residence time showed a dependency on body weight with 0.25 as power function. In case of cicaprost, only the dog, which extensively metabolizes the compound, could not be enrolled in inter-species extrapolation. Excretion half-lives or residence times did not show a significant correlation to body weight or maximum life time potential. The present inter-species extrapolation showed a dependency from species body weight for model-independent pharmacokinetic data, e.g. clearance, volume of distribution at steady state and

  18. Cu(II) Bis(thiosemicarbazone) Radiopharmaceutical Binding to Serum Albumin: Further Definition of Species-Dependence and Associated Substituent Effects

    PubMed Central

    Basken, Nathan E.; Green, Mark A.

    2009-01-01

    Introduction The Cu-PTSM (pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II)) and Cu-ATSM (diacetyl bis(N4-methylthiosemicarbazonato)copper(II)) radiopharmaceuticals exhibit strong, species-dependent binding to the IIA site of human serum albumin (HSA), while the related Cu-ETS (ethylglyoxal bis(thiosemicarbazonato)copper(II)) radiopharmaceutical appears to only exhibit non-specific binding to human and animal serum albumins. Methods To further probe the structural basis for the species-dependence of this albumin binding interaction, protein binding of these three radiopharmaceuticals was examined in solutions of albumin and/or serum from a broader array of mammalian species (rat, sheep, donkey, rabbit, cow, pig, dog, baboon, mouse, cat, elephant). We also evaluated the albumin binding of several copper(II) bis(thiosemicarbazone) chelates offering more diverse substitution of the ligand backbone. Results Cu-PTSM and Cu-ATSM exhibit a strong interaction with HSA that is not apparent with the albumins of other species, while the binding of Cu-ETS to albumin is much less species-dependent. The strong interaction of Cu-PTSM with HSA does not appear to simply correlate with variation, relative to the animal albumins, of a single amino acid lining HSA's IIA site. Those agents that selectively interact with HSA share the common feature of only methyl or hydrogen substitution at the carbon atoms of the diimine fragment of the ligand backbone. Conclusions The interspecies variations in albumin binding of Cu-PTSM and Cu-ATSM are not simply explained by unique amino acid substitutions in the IIA binding pocket of the serum albumins. However, the specific affinity for this region of HSA is disrupted when substituents bulkier than a methyl group appear on the imine carbons of the copper bis(thiosemicarbazone) chelate. PMID:19520290

  19. Pharmacokinetics and metabolism of brotizolam in humans

    PubMed Central

    Bechtel, W. D.

    1983-01-01

    1 Pharmacokinetic studies were performed in healthy young volunteers and in elderly patients after oral administration of single doses (0.5 mg), increasing doses (0.5-1.5 mg), and multiple doses (1.0 mg) of brotizolam. 2 Brotizolam was absorbed quickly from the gastro-intestinal tract. Elimination half-lives were in the range of 3.6-7.9 h. 3 In healthy young volunteers as well as in elderly patients, there was neither a tendency for brotizolam to accumulate nor was there any indication of enzyme induction. 4 Brotizolam was metabolized almost completely into hydroxylated compounds which were conjugated prior to renal excretion. 5 After oral administration of [14C]-brotizolam, two-thirds of excretion of radioactivity was renal and was completed within 4 days. PMID:6661373

  20. Pharmacokinetics of flunixin meglumine in dogs.

    PubMed

    Hardie, E M; Hardee, G E; Rawlings, C A

    1985-01-01

    The pharmacokinetics of flunixin meglumine, a potent nonsteroidal anti-inflammatory agent, were studied in 6 intact, awake dogs. Plasma samples were obtained up to 12 hours after IV administration of flunixin meglumine. Flunixin concentration was determined, using high performance liquid chromatography. Plasma data best fit a 2-compartment model. Distribution half-life was 0.55 hour; elimination half-life was 3.7 hours; volume of distribution (area) was 0.35 L/kg; volume of distribution at steady state was 0.18 L/kg; volume of the central compartment was 0.079 L/kg; and total body clearance was 0.064 L/hr/kg. Flunixin concentrations obtained over a 6-hour period in 3 dogs with septic peritonitis did not differ significantly from those obtained from healthy dogs.

  1. Liposomal anticancer therapy: pharmacokinetic and clinical aspects.

    PubMed

    Di Paolo, A

    2004-11-01

    Liposomes, which are vesicles composed of a phospholipid bilayer surrounding an aqueous milieu, represent a new strategy for anticancer drug delivery. Extravasation and accumulation of liposomal drugs within neoplastic tissues are possible because of the leaky vasculature and scarce lymphatic vessels of tumours (the enhanced permeability and retention effect). Furthermore, liposomal chemotherapeutic agents display distinctive pharmacokinetic characteristics, because they possess longer elimination half-lives, reduced clearance and smaller volume of distribution with respect to corresponding free drugs. Taken together, these features lead to highest levels of cytotoxic agents in tumours, as demonstrated in preclinical models and clinical trials, whereas healthy tissues are spared from toxicity. In fact, liposomal drugs (i.e., doxorubicin), alone or in combination with other cytotoxic agents, lead to improved clinical effectiveness and ameliorated toxicity profile with respect to corresponding free drugs when they are used for the treatment of metastatic breast and ovarian cancers, and Kaposi's sarcoma.

  2. Pharmacokinetics of moxidectin and doramectin in goats.

    PubMed

    Escudero, E; Carceles, C M; Diaz, M S; Sutra, J F; Galtier, P; Alvinerie, M

    1999-10-01

    The pharmacokinetic behaviour of doramectin after a single subcutaneous administration and moxidectin following a single subcutaneous or oral drench were studied in goats at a dosage of 0.2 mg kg(-1). The drug plasma concentration-time data were analysed by compartmental pharmacokinetics and non-compartmental methods. Maximum plasma concentrations of moxidectin were attained earlier and to a greater extent than doramectin (shorter t(max) and greater C(max) and AUC than doramectin). MRT of doramectin (4.91 +/- 0.07 days) was also significantly shorter than that of moxidectin (12.43 +/- 1.28 days). Then, the exposure of animals to doramectin in comparison with moxidectin was significantly shorter. The apparent absorption rate of moxidectin was not significantly different after oral and subcutaneous administration but the extent of absorption, reflected in the peak concentration (C(max)) and the area under the concentration-time curve (AUC), of the subcutaneous injection (24.27 +/- 1.99 ng ml(-1) and 136.72 +/- 7.35 ng d ml(-1) respectively) was significantly greater than that of the oral administration (15.53 +/- 1.27 ng ml(-1) and 36.72 +/- 4.05 ng d ml(-1) respectively). The mean residence time (MRT) of moxidectin didn't differ significantly when administered orally or subcutaneously. Therefore low oral bioavailability and the early emergence of resistance in this minor species may be related. These results deserve to be correlated with efficacy studies for refining dosage requirements of endectocides in this species.

  3. Pharmacokinetics of metoprolol during pregnancy and lactation.

    PubMed

    Ryu, Rachel J; Eyal, Sara; Easterling, Thomas R; Caritis, Steve N; Venkataraman, Raman; Hankins, Gary; Rytting, Erik; Thummel, Kenneth; Kelly, Edward J; Risler, Linda; Phillips, Brian; Honaker, Matthew T; Shen, Danny D; Hebert, Mary F

    2016-05-01

    The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25-750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P < .05) and late pregnancy (568 ± 273 L/h, n = 8, P < .05) compared with ≥3 months postpartum (200 ± 131 and 192 ± 98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P < .05). Relative infant exposure to metoprolol through breast milk was <1.0% of maternal weight-adjusted dose (n = 3). Because of the large, pregnancy-induced changes in metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta-blocker.

  4. 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.

  5. 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

  6. Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib.

    PubMed

    Lacy, Steven A; Miles, Dale R; Nguyen, Linh T

    2017-05-01

    Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq(®)) is approved for the treatment of progressive metastatic medullary thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx™, 60-mg free base equivalent dose) is approved for the treatment of renal cell carcinoma following anti-angiogenic therapy. Cabozantinib displays a long terminal plasma half-life (~120 h) and accumulates ~fivefold by day 15 following daily dosing based on area under the plasma concentration-time curve (AUC). Four identified inactive metabolites constitute >65 % of total cabozantinib-related AUC following a single 140-mg free base equivalent dose. Cabozantinib AUC was increased by 63-81 % or 7-30 % in subjects with mild/moderate hepatic or renal impairment, respectively; by 34-38 % with concomitant cytochrome P450 3A4 inhibitor ketoconazole; and by 57 % following a high-fat meal. Cabozantinib AUC was decreased by 76-77 % with concomitant cytochrome P450 3A4 inducer rifampin, and was unaffected following administration of proton pump inhibitor esomeprazole. Cabozantinib is a potent in vitro inhibitor of P-glycoprotein, and multidrug and toxin extrusion transporter 1 and 2-K, and is a substrate for multidrug resistance protein 2. No clinically significant covariates affecting cabozantinib pharmacokinetics were identified in a population pharmacokinetic analysis. Patients with medullary thyroid cancer with low model-predicted apparent clearance were more likely to dose hold/reduce cabozantinib early, and had a lower average dose through day 85. However, longitudinal tumor modeling suggests that cabozantinib dose reductions from 140 to 60 mg/day did not markedly reduce tumor growth inhibition in medullary thyroid cancer patients.

  7. Impact of physiochemical properties on pharmacokinetics of protein therapeutics.

    PubMed

    Swami, Rajan; Shahiwala, Aliasgar

    2013-12-01

    Physicochemical properties, such as molecular weight, size, partition coefficient, acid dissociation constant and solubility have a great impact on pharmacokinetics of traditional small molecule drugs and substantially used in development of small drugs. However, predicting pharmacokinetic fate (absorption, distribution, metabolism and elimination) of protein therapeutics from their physicochemical parameters is extremely difficult due to the macromolecular nature of therapeutic proteins and peptides. Their structural complexity and immunogenicity are other contributing factors that determine their biological fate. Therefore, to develop generalized strategies concerning development of therapeutic proteins and peptides are highly challenging. However, reviewing the literature, authors found that physiochemical properties, such as molecular weight, charge and structural modification are having great impact on pharmacokinetics of protein therapeutics and an attempt is made to provide the major findings in this manuscript. This manuscript will serve to provide some bases for developing protein therapeutics with desired pharmacokinetic profile.

  8. Enhancing the Modeling of PFOA Pharmacokinetics with Bayesian Analysis

    EPA Science Inventory

    The detail sufficient to describe the pharmacokinetics (PK) for perfluorooctanoic acid (PFOA) and the methods necessary to combine information from multiple data sets are both subjects of ongoing investigation. Bayesian analysis provides tools to accommodate these goals. We exa...

  9. 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...

  10. Application of a Physiologically Based Pharmacokinetic Model to Study Theophylline Metabolism and Its Interactions With Ciprofloxacin and Caffeine.

    PubMed

    Navid, A; Ng, D M; Wong, S E; Lightstone, F C

    2016-02-01

    Theophylline is a commonly used bronchodilator. However, due to its narrow therapeutic range, moderate elevation of serum concentration can result in adverse drug reactions (ADRs). ADRs occur because of interhuman pharmacokinetic variability and interactions with coprescribed medicines. We developed a physiologically based pharmacokinetic (PBPK) model of theophylline, caffeine, and ciprofloxacin metabolisms to: examine theophylline pharmacokinetic variability, and predict population-level outcomes of drug-drug interactions (DDIs). A simulation-based equation for personalized dosing of theophylline was derived. Simulations of DDI show that calculated personalized doses are safe even after cotreatment with large doses of strong inhibitors. Simulations of adult populations indicate that the elderly are most susceptible to ADRs stemming from theophylline-ciprofloxacin and theophylline-caffeine interactions. Females, especially Asians, due to their smaller average size, are more susceptible to DDI-induced ADRs following typical dosing practices. Our simulations also show that the higher adipose and lower muscle fractions in females significantly alter the pharmacokinetics of theophylline or ciprofloxacin.

  11. Pharmacokinetic Profile of µSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats.

    PubMed

    Russo, Rosario; Mancinelli, Angelo; Ciccone, Michele; Terruzzi, Fabio; Pisano, Claudio; Severino, Lorella

    2015-09-01

    Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (µSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t½), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with µSMIN Plus™ compared with animals treated with micronized diosmin. In particular, µSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for µSMIN Plus™, which may represent a new tool for CVI management.

  12. Population pharmacokinetics model of THC used by pulmonary route in occasional cannabis smokers.

    PubMed

    Marsot, A; Audebert, C; Attolini, L; Lacarelle, B; Micallef, J; Blin, O

    2017-02-04

    Cannabis is the most widely used illegal drug in the world. Delta-9-tetrahydrocannabinol (THC) is the main source of the pharmacological effect. Some studies have been carried out and showed significant variability in the described models as the values of the estimated pharmacokinetic parameters. The objective of this study was to develop a population pharmacokinetic model for THC in occasional cannabis smokers. Twelve male volunteers (age: 20-28years, body weight: 62.5-91.0kg), tobacco (3-8 cigarette per day) and cannabis occasional smokers were recruited from the local community. After ad libitum smoking cannabis cigarette according a standardized procedure, 16 blood samples up to 72h were collected. Population pharmacokinetic analysis was performed using a non-linear mixed effects model, with NONMEM software. Demographic and biological data were investigated as covariates. A three-compartment model with first-order elimination fitted the data. The model was parameterized in terms of micro constants and central volume of distribution (V1). Normal ALT concentration (6.0 to 45.0IU/l) demonstrated a statistically significant correlation with k10. The mean values (%Relative Standard Error (RSE)) for k10, k12, k21, k23, k32 and V1 were 0.408h(-1) (48.8%), 4.070h(-1) (21.4%), 0.022h(-1) (27.0%), 1.070h(-1) (14.3%), 1.060h(-1) (16.7%) and 19.10L (39.7%), respectively. We have developed a population pharmacokinetic model able to describe the quantitative relationship between administration of inhaled doses of THC and the observed plasma concentrations after smoking cannabis. In addition, a linear relationship between ALT concentration and value of k10 has been described and request further investigation.

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

    PubMed Central

    Yu, Yang; Zhou, Yu-Feng; Li, Xiao; Chen, Mei-Ren; Qiao, Gui-Lin; Sun, Jian; Liao, Xiao-Ping; Liu, Ya-Hong

    2016-01-01

    This work aimed to characterize the mammary gland pharmacokinetics of cefquinome after an intramammary administration and integrate pharmacokinetic/pharmacodynamic model. The pharmacokinetic profiles of cefquinome in gland tissue were measured using high performance liquid chromatograph. Therapeutic regimens covered various dosages ranging from 25 to 800 μg/gland and multiple dosing intervals of 8, 12, and 24 h. The in vivo bacterial killing activity elevated when dosage increased or when dosing intervals were shortened. The best antibacterial effect was demonstrated by a mean 1.5 log10CFU/gland visible count reduction. On the other hand, the results showed that the percentage of time duration of drug concentration exceeding the MIC during a dose interval (%T > MIC) was generally 100% because of the influence of drug distribution caused by the blood-milk barrier. Therefore, pharmacokinetic/pharmacodynamic parameter of the ratio of area under the concentration-time curve over 24 h to the MIC (AUC0-24/MIC) was used to describe the efficacy of cefquinome instead of %T > MIC. When the magnitude of AUC0-24/MIC exceeding 16571.55 h⋅mL/g, considerable activity of about 1.5 log10CFU/g gland bacterial count reduction was observed in vivo. Based on the Monte Carlo simulation, the clinical recommended regimen of three infusions of 75 mg per quarter every 12 h can achieve a 76.67% cure rate in clinical treatment of bovine mastitis caused by Staphylococcus aureus infection. PMID:27774090

  14. Vatalanib population pharmacokinetics in patients with myelodysplastic syndrome: CALGB 10105 (Alliance)

    PubMed Central

    Wang, Xiaofeng; Owzar, Kouros; Gupta, Pankaj; Larson, Richard A; Mulkey, Flora; Miller, Antonius A; Lewis, Lionel D; Hurd, David; Vij, Ravi; Ratain, Mark J; Murry, Daryl J

    2014-01-01

    Aims Vatalanib is an oral anti-angiogenesis agent that inhibits vascular endothelial growth factor receptor tyrosine kinases, which in patients showed auto induction of metabolism and variability in pharmacokinetic (PK) disposition. The objective was to characterize the population PK and time-dependent change in vatalanib clearance and assess exposure–toxicity relationship in patients with myelodysplastic syndrome (MDS). Methods This was an open-label phase II study of vatalanib in MDS patients receiving 750–1250 mg once daily in 28-day cycles. Serial blood samples were obtained and plasma vatalanib concentrations measured by HPLC. Population PK analysis was performed using nonmem 7.2 with FO estimation since FOCE failed. The final model was evaluated using goodness-of-fit plots, bootstrap analysis, and visual predictive check. Results Pharmacokinetic data were complete for 137 patients (86 M, 51 F), of median age 70 years (range 20–91). A one-compartment model with lagged first-order absorption and time-dependent change in oral clearance was fitted to the vatalanib plasma concentration versus time data. The population means for pre-induction and post-induction oral clearance were 24.1 l h–1 (range: 9.6–45.5) and 54.9 l h–1 (range: 39.8–75.6), respectively. The apparent oral clearance increased 2.3-fold, (range: 1.7–4.1-fold) from first dose to steady state. Our data did not identify a significant relationship of the predefined covariates with vatalanib pharmacokinetics, although power to detect such a relationship was limited. Conclusions Vatalanib pharmacokinetics were highly variable and the extent of auto induction was not determined to correlate with any of the pre-defined covariates. PMID:24838014

  15. 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

  16. 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.

  17. Effect of verapamil on the pharmacokinetics of pasireotide in healthy volunteers.

    PubMed

    Kornberger, Ruediger; Ting, Lillian S L; Tripathi, Anadya P; Rodrigues, Heidi; Nesheiwat, Dalal; Passos, Vanessa Q; Hu, Ke

    2014-11-01

    We evaluated the drug-drug interaction between pasireotide SC and verapamil, a known P-glycoprotein inhibitor. Subjects received pasireotide SC (single dose, 600 μg) on day 1, and samples for pharmacokinetics evaluation were collected from days 1 to 8. Subjects received an oral dose of verapamil 240 mg/d for 10 days (days 15-24). On day 18, subjects also received pasireotide SC 600 μg. Pharmacokinetic sampling for pasireotide SC and verapamil was done during days 18 to 25 and days 15 to 21, respectively. Safety evaluations were performed throughout the study period, including a 30-day post-treatment follow-up. Pharmacokinetic profiles of pasireotide SC alone and in combination with verapamil sustained-release (SR) were superimposable with the geometric mean ratios (90% confidence interval [CI]) of 0.98 (0.91-1.06) for C(max), 0.97 (0.90-1.04) for AUC(last), and 0.98 (0.92-1.05) for AUC(inf). Exploratory analyses showed a 17% (90% CI, 0.72-0.94) reduction in C(trough) and 31% (0.58-0.82) reduction in C(max) (8 hours post-dose) for verapamil SR with pasireotide SC versus verapamil alone. Pasireotide SC with or without verapamil was well tolerated. In conclusion, there was no change in the rate of pasireotide absorption and elimination or extent of exposure following concomitant administration with verapamil.

  18. Pharmacological interaction between 3,4-methylenedioxymethamphetamine (ecstasy) and paroxetine: pharmacological effects and pharmacokinetics.

    PubMed

    Farré, Magí; Abanades, Sergio; Roset, Pere N; Peiró, Ana M; Torrens, Marta; O'Mathúna, Bryan; Segura, Mireia; de la Torre, Rafael

    2007-12-01

    3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is increasingly used by young people for its euphoric and empathic effects. MDMA can be used in combination with other drugs such as selective serotonin reuptake inhibitors. A clinical trial was designed where subjects pretreated with paroxetine, one of the most potent inhibitors of both 5-hydroxytryptamine reuptake and CYP2D6 activity, were challenged with a single dose of MDMA. The aim of the study was to evaluate the pharmacodynamic and pharmacokinetic interaction between paroxetine and MDMA in humans. A randomized, double-blind, crossover, placebo-controlled trial was conducted in 12 healthy male subjects. Variables included physiological parameters, psychomotor performance, subjective effects, and pharmacokinetics. Subjects received 20 mg/day paroxetine (or placebo) orally for the 3 days before MDMA challenge (100 mg oral). MDMA alone produced the prototypical effects of the drug. Pretreatment with paroxetine was associated with marked decreases of both physiological and subjective effects of MDMA, despite a 30% increase in MDMA plasma concentrations. The decreases of 3-methoxy-4-hydroxymethamphetamine plasma concentrations suggest a metabolic interaction of paroxetine and MDMA. These data show that pretreatment with paroxetine significantly attenuates MDMA-related physiological and psychological effects. It seems that paroxetine could interact with MDMA at pharmacodynamic (serotonin transporter) and pharmacokinetic (CYP2D6 metabolism) levels. Marked decrease in the effects of MDMA could lead users to take higher doses of MDMA and to produce potential life-threatening toxic effects.

  19. Pharmacokinetic Study and Optimal Formulation of New Anti-Parkinson Natural Compound Schisantherin A

    PubMed Central

    Sa, Fei; Guo, Bao Jian; Li, Sai; Zhang, Zai Jun; Chan, Hok Man; Zheng, Ying; Lee, Simon Ming Yuen

    2015-01-01

    Our recent studies showed that schisantherin A (StA) is a promising candidate for PD treatment, but the pharmacokinetic profile of StA is largely unknown. The effects of different formulations on the pharmacokinetics and bioavailability of StA were investigated by HPLC equipped with a vacuum degasser, a quaternary pump, a manual sampler, and an ultraviolet detector. The absolute bioavailability of StA in nanoemulsion formulation was significantly increased from 4.3% to 47.3%. To the best of our knowledge, this is the first report of absolute bioavailability for StA in rats and successful increase of bioavailability of StA by nanoemulsion formulation. The pharmacokinetic profiles of StA could be significantly improved by a safe nanoemulsion formulation. This study provides a successful example of advanced delivery system for improving the bioavailability of potential central nervous system (CNS) drug candidate with poor solubility. This novel approach could be an effective alternative solution to overcome the shortcomings of conventional poor drug delivery of CNS drugs. The results of present study not only indicate that StA has potential to be developed as a promising oral therapeutic agent for the management of PD but also shed light on novel way to improve bioavailability of PD drugs. PMID:26075137

  20. Pharmacokinetics of a multicomponent herbal preparation in healthy Chinese and African volunteers

    PubMed Central

    Alolga, Raphael N.; Fan, Yong; Zhang, Gang; Li, Jin; Zhao, Yi-Jing; Lelu Kakila, Jimmy; Chen, Yan; Li, Ping; Qi, Lian-Wen

    2015-01-01

    K-601 is an herbal formulation for influenza consisting of Lonicera japonica, Isatis indigotica, Rheum palmatum, Phellodendron chinense, and Scutellaria baicalensis. In this work, we characterized the chemical constituents in K-601, identified the absorbed compounds and determined their pharmacokinetics in 6 Chinese and African volunteers by liquid chromatography with time-of-flight mass spectrometry. Similarity evaluation for chromatographic fingerprint of nine different batches showed values above 0.983. Totally, 50 components were identified in K-601. Then, 15 major prototype compounds and 17 metabolites were identified in human plasma. Major metabolic pathways included glucuronidation, sulfation, methylation, demethylation, and reduction. The pharmacokinetics of the most abundant prototype compounds, berberine, jatrorrhizine, palmatine and magnoflorine were determined. Significant pharmacokinetic differences were observed between the African and Chinese subjects. The AUCs of the African is about 4–10 fold higher than that of the Chinese for the three benzylisoquinoline alkaloids. Magnoflorine, an aporphine alkaloid, was absorbed better in the Chinese than in the African. The biotransformation of K-601 by human intestinal microflora was also investigated. The major reactions included hydroxylation, methylation, demethylation, acetylation and reduction. Glucuronidation and sulfation were not observed with fecal flora. These results may be important and useful in linking data from pharmacological assays and clinical effects. PMID:26268432