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Sample records for radiopharmaceutical showing pharmacokinetic

  1. 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.

  2. '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.

  3. 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.

  4. 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.

  5. 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

  6. Dithiocarbamate-thiourea hybrids useful as vaginal microbicides also show reverse transcriptase inhibition: design, synthesis, docking and pharmacokinetic studies.

    PubMed

    Bala, Veenu; Jangir, Santosh; Mandalapu, Dhanaraju; Gupta, Sonal; Chhonker, Yashpal S; Lal, Nand; Kushwaha, Bhavana; Chandasana, Hardik; Krishna, Shagun; Rawat, Kavita; Maikhuri, Jagdamba P; Bhatta, Rabi S; Siddiqi, Mohammad I; Tripathi, Rajkamal; Gupta, Gopal; Sharma, Vishnu L

    2015-02-15

    Prophylactic prevention is considered as the most promising strategy to tackle STI/HIV. Twenty-five dithiocarbamate-thiourea hybrids (14-38) were synthesized as woman controlled topical vaginal microbicides to counter Trichomonas vaginalis and sperm along with RT inhibition potential. The four promising compounds (18, 26, 28 and 33) were tested for safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. Docking study of most promising vaginal microbicide (33) revealed that it docked in a position and orientation similar to known reverse transcriptase inhibitor Nevirapine. The preliminary in vivo pharmacokinetics of compound 33 was performed in NZ-rabbits to evaluate systemic toxicity in comparison to Nonoxynol-9. PMID:25592712

  7. 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.

  8. Cyclotron produced radiopharmaceuticals

    NASA Astrophysics Data System (ADS)

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

    2003-01-01

    Some of the cyclotron-produced radionuclides may serve as important materials for the production of radiopharmaceuticals. This lecture deals with basic information relating to various aspects of these compounds. In comparison with radionuclides/compounds used for non-medical purposes, radiopharmaceuticals are subject to a broader scale of regulations, both from the safety and efficacy point of view; besides that, there are both radioactive and medical aspects that must be taken into account for any radiopharmaceutical. According to the regulations and in compliance with general rules of work with radioactivity, radiopharmaceuticals should only be prepared/manufactured under special conditions, using special areas and special equipment and applying special procedures (e.g. sterilisation, disinfection, aseptic work). Also, there are special procedures for cleaning and maintenance. Sometimes the requirements for the product safety clash with those for the safety of the personnel; several examples of solutions pertaining to these cases are given in the lecture. Also, the specific role of cyclotron radiopharmaceuticals is discussed.

  9. 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. PMID:20150978

  10. 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

  11. 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.

  12. Audits of radiopharmaceutical formulations.

    PubMed

    Castronovo, F P

    1992-03-01

    A procedure for auditing radiopharmaceutical formulations is described. To meet FDA guidelines regarding the quality of radiopharmaceuticals, institutional radioactive drug research committees perform audits when such drugs are formulated away from an institutional pharmacy. All principal investigators who formulate drugs outside institutional pharmacies must pass these audits before they can obtain a radiopharmaceutical investigation permit. The audit team meets with the individual who performs the formulation at the site of drug preparation to verify that drug formulations meet identity, strength, quality, and purity standards; are uniform and reproducible; and are sterile and pyrogen free. This team must contain an expert knowledgeable in the preparation of radioactive drugs; a radiopharmacist is the most qualified person for this role. Problems that have been identified by audits include lack of sterility and apyrogenicity testing, formulations that are open to the laboratory environment, failure to use pharmaceutical-grade chemicals, inadequate quality control methods or records, inadequate training of the person preparing the drug, and improper unit dose preparation. Investigational radiopharmaceutical formulations, including nonradiolabeled drugs, must be audited before they are administered to humans. A properly trained pharmacist should be a member of the audit team. PMID:1598931

  13. Radiopharmaceuticals for thrombus detection

    SciTech Connect

    Knight, L.C. )

    1990-01-01

    Most of the components of the thrombotic and fibrinolytic systems have at some time been evaluated as a means of carrying a radiolabel specifically to thrombi, although very few have been promising enough to emerge from investigational status to routine clinical use. New approaches are being explored, including improved methods of labeling platelets, chemically modified forms of previously tested plasma proteins, and new biomolecules, including monoclonal antibodies specific for fibrin and platelets. The current goal is to find one or more radiotracers that bind specifically and rapidly to thrombi, and that also have a rapid blood disappearance rate, permitting a clear diagnosis within a few hours after injection. Because this test may be needed to assess the course of therapy in an anticoagulated patient, the ideal radiopharmaceutical should be able to locate thrombi without interference by anticoagulants. Until a suitable thrombus-specific radiopharmaceutical becomes generally available, many hospitals will continue to attempt to make a diagnosis with nonspecific radiopharmaceuticals that can at best provide blood pool images to indicate filling defects. Several of the new approaches seem likely to provide the radiopharmaceutical sought, although clinical trials are at an early stage.137 references.

  14. 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)

  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. Pharmacovigilance in radiopharmaceuticals

    PubMed Central

    Kumar, Rishi; Kalaiselvan, Vivekanandan; Kumar, Rakesh; Verma, Ravendra; Singh, Gyanendra Nath

    2016-01-01

    Indian Pharmacopoeia Commission is Committed for maintaining the standards of drugs including Radiopharmaceuticals (RPs) by publishing Indian Pharmacopoeia. These RPs are being used in India for diagnostic or therapeutic purpose. RPs though contain relatively small quantities of active ingredient and administered in small volumes could cause some adverse reactions to the patients. The objective of presenting this article is to introduce the system of adverse drug reaction reporting to the nuclear medicine fraternity who are dealing with RPs. PMID:27095855

  17. Radiopharmaceuticals in nuclear medicine practice

    SciTech Connect

    Kowalsky, R.J.; Perry, J.R.

    1987-01-01

    This book discusses the basic principles and clinical applications of radiopharmaceuticals. Topics include atomic physics as applied to radiopharmaceuticals, radionuclide generator function, nuclear pharmacy and safety, and radiopharmaceutical use in evaluating the major organ systems of the body. For each body system the author explains rationale for use, typical procedures, current agents of choice, and interpretation of results. Images, tables, and graphs illustrate normal and abnormal studies.

  18. I-123 - FP-CIT pharmacokinetics and dosimetry show great potential for the evaluation of dopamine transporter system in clinical routine

    SciTech Connect

    Costa, D.C.; Walker, S.; Waddington, W. |

    1996-05-01

    FP-CIT is a N-fluoropropyl analogue of the [2{beta}-carbomethoxy-3{beta}-(4-iodophenyl)tropane] which has been labelled with I-123 and developed as a new marker of the pre-synaptic dopamine transporter system. Its selective uptake in the striatum of non-human primates and human volunteers has been reported with advantageous faster brain kinetics than {beta}-CIT. In this pilot work we studied the whole body imaging kinetics of FP-CIT in one normal volunteer - NV (5, 60, 100, 360 minutes and 24 hours post-injection for 20 minutes each) and a drug-free patient with well established Parkinson`s disease - PD (100 minutes) after intravenous injection of 111 MBq. Both subjects had high resolution brain SPECT at 35 minutes and 3.5 hours post-injection. Percent of whole body uptake (geometric mean of anterior and posterior projections) in different organs, including total brain and basal ganglia shows rapid clearance from blood during the first hour with no significant change from 100 minutes to 24 hours. The basal ganglia uptake is approximately 0.4% of total body from 100 minutes onwards. Striatal uptake (ratio to frontal cortex) is different between subjects, mainly at 3.5 hours and more marked in the putamen: Calculated dosimetry (mSv/MBq) showed E.D.E.-0.034, and total doses to whole body - 0.01, total brain - 0.017, basal ganglia - 0.155, small intestine - 0.06, urinary bladder - 0.05 and liver - 0.03. These data confirm that FP-CIT has acceptable dosimetry with good pharmacokinetics enabling the study of pre-synaptic dopamine transport system in nigrostriatal degeneration with clinical SPECT at 3-4 hrs p.i.

  19. [Cephalexin pharmacokinetics].

    PubMed

    Koroleva, V G; Vasil'ev, V K; Danilova, V I; Firsov, A A

    1981-03-01

    The pharmacokinetics of cephalexin monohydrate after its oral administration in a single dose was studied on rats and dogs. The analysis of the pharmacokinetic data obtained with the one-compartmental model showed that the rate of the antibiotic absorption in the rats was higher than that in the dogs. The periods of the cephalexin half-absorption and maximum concentration were 0.2 and 1.1 hour in the rats and 0.64 and 1.9 hours in the dogs respectively. The period of the antibiotic half-life was almost the same in both animal species. Selective localization of cephalexin in the kidney and liver tissues was noted. The antibiotic was mainly excreted by the kidneys (98.8 per cent for 24 hours). PMID:7235651

  20. 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)

  1. 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

  2. Instrumentation and radiopharmaceutical validation.

    PubMed

    Zigler, S S

    2009-08-01

    Although the promise of new positron emission tomography (PET) imaging agents is great, the process of bringing these agents to commercialization remains in its infancy. There are no PET products today that have gone through the full clinical and chemistry development process required to gain marketing approval by the US Food and Drug Administration (FDA). The purpose of this paper was to review validation from the perspective of the chemistry, manufacturing and controls (CMC) section of an FDA filing, as well as the validation requirements described in FDA good manufacturing practice (GMP) regulations, guidance documents and general chapters of the US Pharmacopeia (USP). The review includes discussion of validation from development to commercial production of PET radiopharmaceuticals with a special emphasis on equipment and instrumentation used in production and testing. The goal is to stimulate a dialog that leads to the standardization of industry practices and regulatory requirements for validation practices in PET. PMID:19834450

  3. Radiopharmaceuticals for diagnosis and treatment

    SciTech Connect

    Kuhl, D.E.

    1992-01-01

    We report on our efforts in PET basic radiochemistry, radiopharmaceutical synthesis, and preclinical radiopharmaceutical evaluation. These efforts are focused on three fronts. First predictive abilities in nucleophilic aromatic substitution with [[sup 18]F]fluorination of substituted aromatic rings. Although radiochemical yields can be predicted within a very similar group of compounds with similar leaving groups and substituent patterns, generalization to all nucleophilic substitutions with [[sup 18]F] fluoride is not warranted. Kinetic studies indicate significantly different rates of reactions, depending on ring substituents. Second, preclinical evaluation of new radiopharmaceuticals. We have synthesized and begun the preclinical evaluation of [[sup 11]C]tetrabenazine, a new radioligand based on the vesicular monoamine transport system. Third, our work, on [[sup 18]F]fluorination/decarbonylation reactions, structure-activity relationships in dopamine uptake inhibitors and effects of chronic drugs on radioligand binding is described.

  4. 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. PMID:25989891

  5. 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.

  6. 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.

  7. 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)

  8. 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.

  9. 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.

  10. (Radiopharmaceutical and chemotherapeutic drug technology)

    SciTech Connect

    Srivastava, P.C.

    1988-01-14

    The purpose was to undertake a TOKTEN Distinguished Scientist Award assignment sponsored by the United Nations Development Programme (UNDP) in cooperation with the Council of Scientific and Industrial Research (CSIR) of India to conduct research in the areas of nucleosides and protein labeling agents at the Central Drug Research Institute (CDRI), Lucknow, and to help research scientists develop chemotherapeutic drugs in India. His work at CDRI consisted of syntheses of imidazole nucleosides, iodination reactions of nucleosides, synthesis of a bifunctional bismaleimide protein labeling agent, coordination of protein labeling studies with the Membrane Biology Group of CDRI, and initiation of several new collaborative research projects at CDRI. In addition, as a part of the CSIR-UNDP, the traveler visited several academic and industrial research institutions in India, delivered five seminars describing various aspects of radiopharmaceutical development at ORNL, and interacted extensively with scientists in India on current drug and radiopharmaceutical develop technologies in India and abroad.

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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…

  16. Modeling Pharmacokinetics.

    PubMed

    Bois, Frederic Y; Brochot, Céline

    2016-01-01

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

  17. Hot atom chemistry and radiopharmaceuticals

    SciTech Connect

    Krohn, Kenneth A.; Moerlein, Stephen M.; Link, Jeanne M.; Welch, Michael J.

    2012-12-19

    The chemical products made in a cyclotron target are a combined result of the chemical effects of the nuclear transformation that made the radioactive atom and the bulk radiolysis in the target. This review uses some well-known examples to understand how hot atom chemistry explains the primary products from a nuclear reaction and then how radiation chemistry is exploited to set up the optimal product for radiosynthesis. It also addresses the chemical effects of nuclear decay. There are important principles that are common to hot atom chemistry and radiopharmaceutical chemistry. Both emphasize short-lived radionuclides and manipulation of high specific activity nuclides. Furthermore, they both rely on radiochromatographic separation for identification of no-carrieradded products.

  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. Pharmacokinetics of macrolides in foals.

    PubMed

    Villarino, N; Martín-Jiménez, T

    2013-02-01

    Macrolides are used for treatment of pneumonia and extrapulmonary conditions caused by Rhodococcus equi. In foals, macrolides have an extraordinary capacity to accumulate in different lung tissue compartments. These drugs show unique pharmacokinetic features such as rapid and extensive distribution and long persistence in pulmonary epithelial lining fluid (PELF) and bronchoalveolar lavage (BAL) cells from foals. This article reviews the pharmacokinetic characteristics of erythromycin, azithromycin, clarithromycin, tulathromycin, telithromycin, gamithromycin, and tilmicosin in foals, with emphasis on PELF and BAL cell concentrations. PMID:23082900

  1. 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.

  2. 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.

  3. Rational development of radiopharmaceuticals for HIV-1.

    PubMed

    Lau, Chuen-Yen; Maldarelli, Frank; Eckelman, William C; Neumann, Ronald D

    2014-04-01

    The global battle against HIV-1 would benefit from a sensitive and specific radiopharmaceutical to localize HIV-infected cells. Ideally, this probe would be able to identify latently infected host cells containing replication competent HIV sequences. Clinical and research applications would include assessment of reservoirs, informing clinical management by facilitating assessment of burden of infection in different compartments, monitoring disease progression and monitoring response to therapy. A "rational" development approach could facilitate efficient identification of an appropriate targeted radiopharmaceutical. Rational development starts with understanding characteristics of the disease that can be effectively targeted and then engineering radiopharmaceuticals to hone in on an appropriate target, which in the case of HIV-1 (HIV) might be an HIV-specific product on or in the host cell, a differentially expressed gene product, an integrated DNA sequence specific enzymatic activity, part of the inflammatory response, or a combination of these. This is different from the current approach that starts with a radiopharmaceutical for a target associated with a disease, mostly from autopsy studies, without a strong rationale for the potential to impact patient care. At present, no targeted therapies are available for HIV latency, although a number of approaches are under study. Here we discuss requirements for a radiopharmaceutical useful in strategies targeting persistently infected cells. The radiopharmaceutical for HIV should be developed based on HIV biology, studied in an animal model and then in humans, and ultimately used in clinical and research settings. PMID:24607432

  4. 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. PMID:25144560

  5. Radiopharmaceuticals for diagnosis and treatment. Progress report

    SciTech Connect

    Kuhl, D.E.

    1992-12-01

    We report on our efforts in PET basic radiochemistry, radiopharmaceutical synthesis, and preclinical radiopharmaceutical evaluation. These efforts are focused on three fronts. First predictive abilities in nucleophilic aromatic substitution with [{sup 18}F]fluorination of substituted aromatic rings. Although radiochemical yields can be predicted within a very similar group of compounds with similar leaving groups and substituent patterns, generalization to all nucleophilic substitutions with [{sup 18}F] fluoride is not warranted. Kinetic studies indicate significantly different rates of reactions, depending on ring substituents. Second, preclinical evaluation of new radiopharmaceuticals. We have synthesized and begun the preclinical evaluation of [{sup 11}C]tetrabenazine, a new radioligand based on the vesicular monoamine transport system. Third, our work, on [{sup 18}F]fluorination/decarbonylation reactions, structure-activity relationships in dopamine uptake inhibitors and effects of chronic drugs on radioligand binding is described.

  6. 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.

  7. Joint CDRH (Center for Devices and Radiological Health) and state quality-assurance surveys in nuclear medicine: Phase 2 - radiopharmaceuticals

    SciTech Connect

    Hamilton, D.R.; Evans, C.D.

    1986-08-01

    The report discusses survey results on aspects of the quality assurance of radio-pharmaceuticals from 180 nuclear-medicine facilities in the United States. Data were collected from facilities in 8 states. Demographic information about nuclear-medicine operations and quality-assurance programs was gathered by state radiation-control-program personnel. The data collected from the survey show an incomplete acceptance of quality-assurance practices for radiopharmaceuticals. Most of the facilities in the survey indicated that, because an inferior radiopharmaceutical was prepared so infrequently, they did not believe it was cost-effective to perform extensive quality-assurance testing. The Center for Devices and Radiological Health hopes that the information from the survey will stimulate nuclear-medicine professionals and their organizations to encourage appropriate testing of all radiopharmaceuticals.

  8. Clinical pharmacokinetics of molsidomine.

    PubMed

    Rosenkranz, B; Winkelmann, B R; Parnham, M J

    1996-05-01

    Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t-1/2) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight. Single-dose studies (1, 2 and 4 mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2 mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4 mg 4 times daily for 4 weeks) do not show any accumulation of the drug. A study in young and elderly individuals indicated that the first-pass effect is decreased and t-1/2 prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds. A linear dose-effect relationship is observed with

  9. Dose Assessments to the Hands of Radiopharmaceutical Workers

    SciTech Connect

    Ilas, Dan; Eckerman, Keith F; Sherbini, Sami; Karagiannis, Harriet

    2008-01-01

    This paper describes the characterization of radiation doses to the hands of nuclear medicine technicians resulting from the handling of radiopharmaceuticals. Radiation monitoring using ring dosimeters indicates that finger dosimeters may overestimate or underestimate the radiation doses to the skin that are used to show compliance with applicable regulations depending on the nature of the particular procedure and the radioisotope being handled. To better understand the parameters governing the absorbed dose distributions, a detailed model of the hands was created and used in Monte Carlo simulations of selected nuclear medicine procedures. Simulations on realistic configurations typical for workers handling radiopharmaceuticals were performed for a range of energies of the source photons. The lack of charged-particle equilibrium necessitated full photon-electron coupled transport calculations. The results show that the dose to different regions of the fingers can differ substantially from the dosimeters' readings when the dosimeters are located at the base of the finger. We tried to identify consistent patterns that relate the actual dose to the dosimeter readings. These patterns depend on the specific work conditions and can be used to better assess the absorbed dose to different regions of the exposed skin.

  10. 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.

  11. Transport processes of radiopharmaceuticals and -modulators

    PubMed Central

    2011-01-01

    Radiotherapy and radiology have been indispensable components in cancer care for many years. The detection limit of small tumor foci as well as the development of radio-resistance and severe side effects towards normal tissues led to the development of strategies to improve radio-diagnostic and -therapeutic approaches by pharmaceuticals. The term "radiopharmaceutical" has been used for drugs labeled with radioactive tracers for therapy or diagnosis. In addition, drugs have been described to sensitize tumor cells to radiotherapy (radiosensitizers) or to protect normal tissues from detrimental effects of radiation (radioprotectors). The present review summarizes recent concepts on the transport of radiopharmaceuticals, radiosensitizers, and radioprotectors in cells and tissues, e.g. by ATP-binding cassette transporters such as P-glycoprotein. Strengths and weaknesses of current strategies to improve transport-based processes are discussed. PMID:21645349

  12. Advances in the robotic production of radiopharmaceuticals

    SciTech Connect

    Gaehle, G.; Welch, M.J.

    1994-12-31

    A variety of robotic systems, including Zymark, Hudson Control Group, Anotech, and Questech formerly U.M.I, have been used as a reliable and safe way to produce radiopharmaceuticals. A robotic system`s ability allows it to produce a variety of radiopharmaceuticals on a routine basis including final preparation and quality control. With proper scheduling, a single robotic system can synthesize {sup 18}F-fluorodeoxyglucose, {sup 18}F-estradiol, {sup 11}C-acetate, {sup 68}Ga-citrate and at the same time control black box type syntheses such as {sup 15}O-butanol in a single day. A robotic system`s flexibility allows it to be used in designing and testing new syntheses, thus making the development of the new radiopharmaceuticals safer for the chemist. The development of Windows, a multi-tasking operating system for PC computers, allows a robot controlled by that computer to function simultaneously with a large variety of other systems. This increases the system`s ability to communicate with other systems and it allows for change without replacing the entire system. Improvements in robot technology has increased their reliability while making them competitive in price to other means of automation. Today a robotic system to produce {sup 18}F-fluorodeoxyglucose can cost as little as $55,000 U.S. depending on the cost of the hot cell.

  13. Pitfalls and Limitations of SPECT, PET, and Therapeutic Radiopharmaceuticals.

    PubMed

    Ballinger, James R

    2015-09-01

    Radiopharmaceuticals are widely accepted to be a very safe class of drugs, with very few adverse reactions and unexpected biodistributions. However, problems can arise because of technical issues in manufacture or reconstitution, patient preparation, or drug administration. This review presents highlights of issues that have arisen in the newer classes of radiopharmaceuticals in the last 20 years and expands the scope of the previous report to include PET and therapeutic radiopharmaceuticals. Variations in the "quality" of the eluate of a (99)Mo/(99m)Tc generator remain a major issue. Several of the newer (99m)Tc tracers require a heating step in preparation that can also lead to unacceptably low radiochemical purity. Radiolytic breakdown can be a problem with all classes of radiopharmaceuticals. Many of the newer radiopharmaceuticals localize by receptor- or transporter-mediated processes and thus can be affected by other drugs, making patient preparation more important than ever. Therapeutic radiopharmaceuticals may require coadministration of radioprotectant regimens, such as the use of lysine-arginine infusions with radiopeptide therapy. Extravasation can have serious consequences with therapeutic radiopharmaceuticals. Adverse reactions to newer radiopharmaceuticals remain rare, though may increase because of coadministration of agents such as contrast media. However, there is known to be underreporting of minor adverse reactions. Knowledge of the pitfalls that can occur with radiopharmaceuticals is important in the interpretation of nuclear medicine images and optimal patient care. PMID:26278857

  14. Oritavancin Pharmacokinetics and Bone Penetration in Rabbits

    PubMed Central

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

    2015-01-01

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

  15. 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

  16. Consequences of electroplated targets on radiopharmaceutical preparations

    NASA Astrophysics Data System (ADS)

    Finn, R. D.; Tirelli, S.; Sheh, Y.; Knott, A.; Gelbard, A. S.; Larson, S. M.; Dahl, J. R.

    1991-05-01

    The staff of the cyclotron facility at Memorial Sloan-Kettering Cancer Center is involved in a comprehensive radionuclide preparation program which culminates with the formulation of numerous requested short-lived, positron-emitting radiopharmaceutical agents for clinical investigation. Both the produced radionuclide as well as the final radiolabeled compound are subjected to stringent quality control standards including assays for radiochemical and chemical purity. The subtle chemical consequences resulting from the irradiation of a nickel-plated target for 13N production serve to emphasize some of these potential technical difficulties.

  17. Stochastic Control of Pharmacokinetic Systems

    PubMed Central

    Schumitzky, Alan; Milman, Mark; Katz, Darryl; D'Argenio, David Z.; Jelliffe, Roger W.

    1983-01-01

    The application of stochastic control theory to the clinical problem of designing a dosage regimen for a pharmacokinetic system is considered. This involves defining a patient-dependent pharmacokinetic model and a clinically appropriate therapeutic goal. Most investigators have attacked the dosage regimen problem by first estimating the values of the patient's unknown model parameters and then controlling the system as if those parameter estimates were in fact the true values. We have developed an alternative approach utilizing stochastic control theory in which the estimation and control phases of the problem are not separated. Mathematical results are given which show that this approach yields significant potential improvement in attaining, for example, therapeutic serum level goals over methods in which estimation and control are separated. Finally, a computer simulation is given for the optimal stochastic control of an aminoglycoside regimen which shows that this approach is feasible for practical applications.

  18. 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

  19. 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.

  20. Radiopharmaceuticals for SPECT Cancer Detection

    NASA Astrophysics Data System (ADS)

    Chernov, V. I.; Medvedeva, A. A.; Zelchan, R. V.; Sinilkin, I. G.; Stasyuk, E. S.; Larionova, L. A.; Slonimskaya, E. M.; Choynzonov, E. L.

    2016-06-01

    The purpose of the study was to assess the efficacy of single photon emission computed tomography (SPECT) with 199Tl and 99mTc-MIBI in the detection of breast, laryngeal and hypopharyngeal cancers. Materials and Methods: a total of 220 patients were included into the study. Of them, there were 120 patients with breast lesions (100 patients with breast cancer and 20 patients with benign breast tumors) and '00 patients with laryngeal/hypopharyngeal diseases (80 patients with laryngeal/hypopharyngeal cancer and 20 patients with benign laryngeal/hypopharyngeal lesions). Results: no abnormal 199Tl uptake was seen in all patients with benign breast and laryngeal lesions, indicating a 100% specificity of 199Tl SPECT. In breast cancer patients, increased 199Tl uptake in the breast was visualized in 94.8% patients, 99mTc-MIBI in 93.4% patients. Increased 199Tl uptake in axillary lymph nodes was detected in 60% patients and 99mTc-MIBI in 93.1% patients. In patients with laryngeal/hypopharyngeal cancer, sensitivity of SPECT with 199Tl and 99mTc-MIBI were 95%. The 199Tl SPECT sensitivity in identification of regional lymph node metastases in patients with laryngeal/hypopharyngeal cancer was 75% and the 99mTc-MIBI SPECT sensitivity was 17%. Conclusion: the data obtained show that SPECT with 199Tl and 99mTc-MIBI can be used as one of the additional imaging methods in detection of tumors.

  1. Radiopharmaceuticals for SPECT cancer detection

    NASA Astrophysics Data System (ADS)

    Chernov, V. I.; Medvedeva, A. A.; Zelchan, R. V.; Sinilkin, I. G.; Stasyuk, E. S.; Larionova, L. A.; Slonimskaya, E. M.; Choynzonov, E. L.

    2016-08-01

    The purpose of the study was to assess the efficacy of single photon emission computed tomography (SPECT) with 199Tl and 99mTc-MIBI in the detection of breast, laryngeal and hypopharyngeal cancers. A total of 220 patients were included into the study: 120 patients with breast lesions (100 patients with breast cancer and 20 patients with benign breast tumors) and 100 patients with laryngeal/hypopharyngeal diseases (80 patients with laryngeal/hypopharyngeal cancer and 20 patients with benign laryngeal/hypopharyngeal lesions). No abnormal 199Tl uptake was seen in all patients with benign breast and laryngeal lesions, indicating a 100% specificity of 199Tl SPECT. In the breast cancer patients, the increased 199Tl uptake in the breast was visualized in 94.8% patients, 99mTc-MIBI—in 93.4% patients. The increased 199Tl uptake in axillary lymph nodes was detected in 60% patients, and 99mTc-MIBI—in 93.1% patients. In patients with laryngeal/hypopharyngeal cancer, the sensitivity of SPECT with 199Tl and 99mTc-MIBI was 95%. The 199Tl SPECT sensitivity in identification of regional lymph node metastases in the patients with laryngeal/hypopharyngeal cancer was 75% and the 99mTc-MIBI SPECT sensitivity was 17%. The data obtained showed that SPECT with 199Tl and 99mTc-MIBI can be used as one of the additional imaging methods in detection of tumors.

  2. 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.

  3. Lisdexamfetamine: A pharmacokinetic review.

    PubMed

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

    2016-06-30

    Lisdexamfetamine (LDX) is a d-amphetamine (d-AMPH) pro-drug used to treat Attention Deficit and Hyperactivity Disorder (ADHD) and Binge Eating Disorder (BED) symptoms. The in vivo pharmacodynamics of LDX is the same as that of its active product d-AMPH, although there are a few qualitative and quantitative differences due to pharmacokinetics. Due to the specific pharmacokinetics of the long-acting stimulants, this article revises the pharmacokinetic studies on LDX, the newest amphetamine pro-drug. The Medline/Pubmed, Science Direct and Biblioteca Virtual em Saúde (Lilacs and Ibecs) (2007-2016) databases were searched for articles and their list of references. As for basic pharmacokinetics studies, since LDX is a newly developed medication, there are few results concerning biotransformation, distribution and the use of different biological matrices for analysis. This is the first robust review on this topic, gathering data from all clinical pharmacokinetics studies available in the literature. The particular pharmacokinetics of LDX plays a major role in studying this pro-drug, since this knowledge was essential to understand some reports on clinical effects in literature, e.g. the small likelihood of reducing the effect by interactions, the effect of long duration use and the still questionable reduction of the potential for abuse. In general the already well-known pharmacokinetic properties of amphetamine make LDX relatively predictable, simplifying the use of LDX in clinical practice. PMID:27125257

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

    PubMed

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

    2015-10-01

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

  5. Relative biological effectiveness of 99mTc radiopharmaceuticals.

    PubMed

    Narra, V R; Sastry, K S; Goddu, S M; Howell, R W; Strand, S E; Rao, D V

    1994-12-01

    The radiotoxicity of three 99mTc-labeled compounds is investigated using spermatogenesis in mouse testis as the experimental model, and spermatogonial cell survival as the biological end point. The radiopharmaceuticals studied are pertechnetate (99mTcO4-), pyrophosphate (99mTc-PYP), and hydroxyethylene diphosphate (99mTc-HDP). The mean lethal doses at 37% survival (D37) are 0.70 +/- 0.06, 0.84 +/- 0.13, and 0.59 +/- 0.08 Gy for 99mTcO4-, 99mTc-PYP, and 99mTc-HDP, respectively. When these results are compared with the D37 value obtained with external x rays or internal gamma rays, the relative biological effectiveness (RBE) of these compounds are 0.94 +/- 0.09, 0.79 +/- 0.13, and 1.1 +/- 0.16, respectively. These results show that the radiotoxicity of 99mTc in mouse testis is essentially similar to that of low-LET radiations (i.e., RBE approximately 1). To understand these results, the distribution of these radiocompounds in the testis is determined and correlated with the observed RBE values. The expected range of RBE values for 99mTc radiopharmaceuticals in organs is 0.95 to 1.5, depending on the fraction of organ activity that is bound to DNA. This suggests that the Auger electrons emitted in the decay of 99mTc are not capable of causing extreme toxicity in vivo. These results provide further support for 99mTc as the radionuclide of choice for imaging in nuclear medicine. PMID:7700199

  6. 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.

  7. Manufacture of radiopharmaceuticals-recent advances

    SciTech Connect

    Krieger, J.K.

    1996-12-31

    Trends in radiopharmaceutical manufacturing have been influenced by the demands of the regulatory agencies, the demands of the customers, and the ever-increasing complexity of new products. Process improvements resulting from automation in the production of radionuclides for diagnostic imaging products, {sup 99m}/Tc generators, {sup 67}Ga, and {sup 201}Tl have been introduced to enhance compliance with current good manufacturing practices and to improve worker safety, both by reducing dose in accord with as low as reasonably achievable levels of radiation and by providing an ergonomically sound environment. Tighter process control has resulted in less lot-to-lot variability and ensures reliability of supply. Reduced manufacturing lapse time for {sup 99m}Tc generators minimizes decay and conserves the supply of {sup 99}Mo. Automation has resulted in an even greater degree of remote operation and has led to reductions in dose, improved process control, and faster throughput in the manufacture of radionuclides.

  8. Cancer-targeted therapies and radiopharmaceuticals.

    PubMed

    Rachner, Tilman D; Jakob, Franz; Hofbauer, Lorenz C

    2015-01-01

    The treatment of bone metastases remains a clinical challenge. Although a number of well-established agents, namely bisphosphonates and denosumab, are available to reduce the occurrence of skeletal-related events, additional cancer-targeted therapies are required to improve patients' prognosis and quality of life. This review focuses on novel targets and agents that are under clinical evaluation for the treatment of malignant bone diseases such as activin A, src and endothelin-1 inhibition or agents that are clinically approved and may positively influence bone, such as the mTOR inhibitor everolimus. In addition, the potential of alpharadin, a novel radiopharmaceutical approved for the treatment of prostatic bone disease, is discussed. PMID:26131359

  9. 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.

  10. Metallic radionuclides in the development of diagnostic and therapeutic radiopharmaceuticals.

    PubMed

    Bhattacharyya, Sibaprasad; Dixit, Manish

    2011-06-21

    Metallic radionuclides are the mainstay of both diagnostic and therapeutic radiopharmaceuticals. Therapeutic nuclear medicine is less advanced but has tremendous potential if the radionuclide is accurately targeted. Great interest exists in the field of inorganic chemistry for developing target specific radiopharmaceuticals based on radiometals for non-invasive disease detection and cancer radiotherapy. This perspective will focus on the nuclear properties of a few important radiometals and their recent applications to developing radiopharmaceuticals for imaging and therapy. Other topics for discussion will include imaging techniques, radiotherapy, analytical techniques, and radiation safety. The ultimate goal of this perspective is to introduce inorganic chemists to the field of nuclear medicine and radiopharmaceutical development, where many applications of fundamental inorganic chemistry can be found. PMID:21541393

  11. Application of a Small Molecule Radiopharmaceutical Concept to Improve Kinetics.

    PubMed

    Jeong, Jae Min

    2016-06-01

    Recently, large molecules or nanoparticles are actively studied as radiopharmaceuticals. However, their kinetics is problematic because of a slow penetration through the capillaries and slow distribution to the target. To improve the kinetics, a two-step targeting method can be applied by using small molecules and very rapid copper-free click reaction. Although this method might have limitations such as internalization of the first targeted conjugate, it will provide high target-to-non-target ratio imaging of radiopharmaceuticals. PMID:27275356

  12. 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)...

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

    PubMed Central

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

    2014-01-01

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

  14. 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. PMID:26688362

  15. (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.

  16. 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

  17. Skin contamination by radiopharmaceuticals and decontamination strategies.

    PubMed

    Bolzinger, M A; Bolot, C; Galy, G; Chabanel, A; Pelletier, J; Briançon, S

    2010-12-15

    The aim of the present study was to evaluate the percutaneous penetration of five common radiopharmaceuticals ((99m)Tc, (67)Ga, (125)I, (111)In and (51)Cr) and to evaluate the effect of decontamination by a detergent solution dedicated to hospital institutions for that purpose. The skin kinetic profiles were established by using the in vitro Franz cell method over 24h. The skin distribution in each skin layer was quantified after 6h exposure time and the efficacy of the detergent solution to remove radionuclides was evaluated also after 6h. The most striking result was the repartition into two classes of kinetic profiles: (125)I and (99m)Tc permeated quickly (∼60% of applied activity after 24h) while the 3 other radionuclides permeated slowly (from ∼2.75% for (67)Ga to ∼10% of applied activity for (111)In). The lag times, i.e. the time necessary to cross the skin varied from 20min for (99m)Tc to 5h for (51)Cr, which accumulated in skin compartments. Skin washings with the detergent solution were particularly efficient for this radionuclide, contrary to the others for which the washing procedure should be applied earlier. The permeation of ions was dependent on their chemical and physical forms and on their salting-in or salting-out effects (coordination state and Hofmeister series). PMID:20888404

  18. Nanodrugs: pharmacokinetics and safety.

    PubMed

    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

  19. 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. PMID:26746572

  20. 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.

  1. New radiopharmaceutical agents for the treatment of castration-resistant prostate cancer.

    PubMed

    Maffioli, L; Florimonte, L; Costa, D C; Correia Castanheira, J; Grana, C; Luster, M; Bodei, L; Chinol, M

    2015-12-01

    Prostate cancer (PCa) is the fourth most common cancer worldwide in terms of incidence and third among male, but is becoming the most common cancer in developed countries. In many patients the disease will progress despite of castration levels of testosterone, to become castration-resistant PCa (CRPC). Nearly all patients with CRPC show bone metastases. The treatment of patients with bony metastases has dramatically changed during the past three years because of new therapeutic approaches addressed to obtain pain control, reduced skeletal morbidity, and most importantly, increased survival rate. A possible therapy can be based also on the use of radiopharmaceuticals systemically administered to slow or reverse the bone metastatic progression. In facts bone-homing radiopharmaceuticals are taken up in areas of high bone turnover, including areas with high osteoblastic activity. Recently, a bone targeting radiopharmaceutical, Radium-223 dichloride was added to this group of drugs clearly representing a new generation of radiopharmaceutical in bone therapy. Clinical trials had shown that the treatment with Ra-223 allowed the reduction of the risk of death respect to placebo. No other radiometabolic treatment achieved such result, evidentiating the disease-modifying properties of this bone-homing radiopharmaceutical. In an effort to treat patients with disseminated PCa, who became resistant to hormonal therapy, molecular targets have been recently identified. Prostate specific membrane antigen (PSMA) is one attractive target for diagnosis and therapy of metastasized PCa since its expression levels are directly correlated to androgen independence, metastasis, and progression. Gastrin-releasing peptide receptors (GRPr) are also highly overexpressed in PCa. Numerous studies suggest the possibility of a high PCa-specific signal with radiolabeled bombesin analogs targeting GRPr. Low molecular weight peptides directed against these molecular targets have been radiolabeled

  2. 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

  3. Applications of quantitative whole body autoradiographic technique in radiopharmaceutical research

    SciTech Connect

    Som, P.; Oster, Z.H.; Yonekura, Y.; Meyer, M.A.; Fand, I.; Brill, A.B.

    1982-01-01

    The routine evaluation of radiopharmaceuticals involves dissecting tissue distribution studies (DTDS) and gamma or positron imaging. DTDS have the following disadvantages: since not all tissues can always be sampled, sites of radiopharmaceutical uptake may be missed and because the procedure involves weighing of dissected tissue samples, the spatial resolution of this method is low and determined by the smallest amount that can be weighed accurately. Gamma camera imaging and positron emission tomography though more comprehensive in evaluating the global distribution of a compound, have relative low spatial resolution. Whole body autoradiography of small animals has a much higher spatial resolution as compared to the above and depicts the global distribution of radiopharmaceuticals. A computer-assisted quantification method of WBARG applied to positron, beta, and gamma emitters will complement the method by producing quantitative values comparable to those obtained by dissection and direct tissue counting, with the advantages of depicting the global distribution at high spatial resolution.

  4. Pharmacokinetic evaluation of fosaprepitant dimeglumine

    PubMed Central

    Colon-Gonzalez, Francheska; Kraft, Walter K.

    2011-01-01

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

  5. Clinical pharmacokinetics of dapsone.

    PubMed

    Zuidema, J; Hilbers-Modderman, E S; Merkus, F W

    1986-01-01

    Dapsone (DDS) has for about 4 decades been the most important antileprosy drug. Concentrations of dapsone and its monoacetyl metabolite, MADDS, can be determined in biological media by high-performance liquid chromatography. After oral administration, the drug is slowly absorbed, the maximum concentration in plasma being reached at about 4 hours, with an absorption half-life of about 1.1 hours. However, the extent of absorption has not been adequately determined. The elimination half-life of dapsone is about 30 hours. The drug shows linear pharmacokinetics within the therapeutic range and the time-course after oral administration fits a 2-compartment model. The concentration-time profile of dapsone after parenteral administration is reviewed. Of clinical importance is the development of a new long acting injection, which permits monthly supervised administration as recommended by the World Health Organization. Following dapsone injection in gluteal subcutaneous adipose tissue, a sufficiently sustained absorption for this purpose has been reported. Dapsone is about 70 to 90% protein bound and its monoacetylated metabolite (MADDS) is almost completely protein bound. The volume of distribution of dapsone is estimated to be 1.5 L/kg. It is distributed in most tissues, but M. leprae living in the Schwann cells of the nerves might be unaffected. Dapsone crosses the placenta and is excreted in breast milk and saliva. Dapsone is extensively metabolised. Dapsone, some MADDS and their hydroxylated metabolites are found in urine, partly conjugated as N-glucuronides and N-sulphates. The acetylation ratio (MADDS:dapsone) shows a genetically determined bimodal distribution and allows the definition of 'slow' and 'rapid' acetylators. As enterohepatic circulation occurs, the elimination half-life of dapsone is markedly decreased after oral administration of activated charcoal. This permits successful treatment in cases of intoxication. The daily dose of dapsone in leprosy is 50 to

  6. "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 state's best…

  7. 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.

  8. Axitinib plasma pharmacokinetics and ethnic differences.

    PubMed

    Chen, Ying; Suzuki, Akiyuki; Tortorici, Michael A; Garrett, May; LaBadie, Robert R; Umeyama, Yoshiko; Pithavala, Yazdi K

    2015-04-01

    Axitinib, a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, showed improved progression-free survival over sorafenib in patients previously treated for advanced renal cell carcinoma in the AXIS trial. Although a few studies had established the efficacy and safety of axitinib in Asian patients, additional evaluation was necessary to obtain regulatory approval in several Asian countries, especially in light of ethnic differences that are known to exist in genetic polymorphisms for metabolizing enzymes such as cytochrome P450 (CYP) 3A5, CYP2C19 and uridine diphosphate glucuronosyltransferase (UGT) 1A1, which are involved in axitinib metabolism. Axitinib plasma pharmacokinetics following single or multiple administration of oral axitinib in Asian (Japanese or Chinese) healthy subjects as well as Asian patients with advanced solid tumors was compared with that obtained in Caucasians. Upon review, the data demonstrated that axitinib can be characterized as not sensitive to ethnic factors based on its pharmacokinetic and pharmacodynamic properties. Axitinib exhibited similar pharmacokinetics in Asian and non-Asian subjects. A pooled population pharmacokinetic analysis indicated lack of a clinically meaningful effect of ethnicity on axitinib disposition. Therefore, dose adjustment for axitinib on the basis of ethnicity is not currently warranted. PMID:25663295

  9. Pharmacokinetics of melatonin in preterm infants

    PubMed Central

    Merchant, Nazakat M; Azzopardi, Denis V; Hawwa, Ahmed F; McElnay, James C; Middleton, Benita; Arendt, J; Arichi, Tomoki; Gressens, Pierre; Edwards, A David

    2013-01-01

    Aims Preterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials. Methods Melatonin was administered to 18 preterm infants in doses ranging from 0.04–0.6 μg kg−1 over 0.5–6 h. Pharmacokinetic profiles were analyzed individually and by population methods. Results Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1 μg kg−1 h−1 for 2 h showed a median half-life of 15.82 h and median maximum plasma concentration of 203.3 pg ml−1. On population pharmacokinetics, clearance was 0.045 l h−1, volume of distribution 1.098 l and elimination half-life 16.91 h with gender (P = 0.047) and race (P < 0.0001) as significant covariates. Conclusions A 2 h infusion of 0.1 μg kg−1 h−1 increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can be used to guide therapeutic clinical trials of melatonin in preterm infants. PMID:23432339

  10. 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.

  11. 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.

  12. 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.

  13. Radioisotope requirements and usage in the radiopharmaceutical industry

    SciTech Connect

    Langton, M.A.

    1995-12-31

    Radioisotopes are used extensively in many different productive and beneficial human endeavors. Amersham International, a U.K.-based company originating in the British Scientific Civil Service during World War II, has been actively involved in many of these activities for more than 50 yr. Today they are one of the world`s largest suppliers of radioactive compounds and scaled radiation sources for use in industrial quality and safety assurance, life science research, and medicine. This paper outlines one of these applications: the use of radioisotopes as radiopharmaceuticals. Radiopharmaceuticals are radioactive nuclides and labeled compounds that have been developed for the diagnosis and treatment of (human) disease. They are manufactured via highly controlled processes and have gone through regulatory scrutiny and approval far in excess of other radioisotopes used in other applications. Radiopharmaceuticals can be conveniently split into two categories. One type is simply an active analog that mimics the physiological behavior of its inactive counterpart in the body. The other involves an actual pharmacological compound that exhibits the desired physiological behavior, which is then labeled with a radionuclide suitable for either imaging or the delivery of a therapeutic radiation dose as appropriate but which plays no part in the mechanism of action of the drug. The latter type, which is the more common of the two, can be supplied either as an active compounded product or as a {open_quotes}cold kit,{close_quotes} which is then labeled with the appropriate radiopharmaceutical-grade radionuclide to yield the final product.

  14. 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)

  15. Radiopharmaceuticals for single-photon emission computed tomography brain imaging.

    PubMed

    Kung, Hank F; Kung, Mei-Ping; Choi, Seok Rye

    2003-01-01

    In the past 10 years, significant progress on the development of new brain-imaging agents for single-photon emission computed tomography has been made. Most of the new radiopharmaceuticals are designed to bind specific neurotransmitter receptor or transporter sites in the central nervous system. Most of the site-specific brain radiopharmaceuticals are labeled with (123)I. Results from imaging of benzodiazepine (gamma-aminobutyric acid) receptors by [(123)I]iomazenil are useful in identifying epileptic seizure foci and changes of this receptor in psychiatric disorders. Imaging of dopamine D2/D3 receptors ([(123)I]iodobenzamide and [(123)I]epidepride) and transporters [(123)I]CIT (2-beta-carboxymethoxy-3-beta(4-iodophenyl)tropane) and [(123)I]FP-beta-CIT (N-propyl-2-beta-carboxymethoxy-3-beta(4-iodophenyl)-nortropane has proven to be a simple but powerful tool for differential diagnosis of Parkinson's and other neurodegenerative diseases. A (99m)Tc-labeled agent, [(99m)Tc]TRODAT (technetium, 2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3,2,1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethyl]amino] ethanethiolato(3-)]oxo-[1R-(exo-exo)]-), for imaging dopamine transporters in the brain has been successfully applied in the diagnosis of Parkinson's disease. Despite the fact that (123)I radiopharmaceuticals have been widely used in Japan and in Europe, clinical application of (123)I-labeled brain radiopharmaceuticals in the United States is limited because of the difficulties in supplying such agents. Development of (99m)Tc agents will likely extend the application of site-specific brain radiopharmaceuticals for routine applications in aiding the diagnosis and monitoring treatments of various neurologic and psychiatric disorders. PMID:12605353

  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. Pharmacokinetics of cannabidiol in dogs.

    PubMed

    Samara, E; Bialer, M; Mechoulam, R

    1988-01-01

    Cannabidiol (CBD) is one of the major nonpsychoactive cannabinoids produced by Cannabis sativa L. Recent studies have shown that CBD has a high protective index, comparable to that of phenobarbital and phenytoin. Because CBD has been reported to possess both anticonvulsant and antiepileptic activity, its pharmacokinetics were studied in dogs after the administration of two iv doses (45 and 90 mg) and one oral dose (180 mg) to dogs. After iv administration, CBD was rapidly distributed, followed by a prolonged elimination. It has a terminal half-life of 9 hr. CBD plasma levels declined in a triphasic fashion. The total body clearance of CBD was 17 liters/hr (after the 45-mg dose) and 16 liters/hr (after the 90-mg dose). This clearance value, after its normalization to blood clearance using mathematical equations, approaches the value of the hepatic blood flow; the extraction ratio in the liver is 0.74. CBD was observed to have a large volume of distribution, approximately 100 liters. In the dose range of 45 to 90 mg, the increase in the AUC was proportional to the dose, a fact that indicates that the pharmacokinetic profile of CBD in this dose range was not dose dependent. In three of the six dogs studied, CBD could not be detected in the plasma after oral administration. In the other three, the oral bioavailability ranged from 13 to 19%. The results of this study show that CBD is barely absorbed after oral administration to dogs. This low bioavailability may be due to a first pass effect. PMID:2900742

  18. Pharmacokinetics of pivmecillinam.

    PubMed

    Parsons, R L; Hossack, G A; Paddock, G M

    1977-06-01

    1 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam (400 and 600 mg). 2 Similar plasma concentration/time curves of ampicillin and mecillinam in the starved normal subjects followed oral administration of ampicillin (500 mg) and pivmecillinam (600 mg). 3 The plasma concentration/time curve of mecillinam was measured in the same normal subjects after oral administration of pivmecillinam (400 mg) with a reproducible standardized Lundh test meal. 4 There was no statistically significant difference in the plasma concentration/time curve of mecillinam after pivmecillinam/400 mg) and the meal compared with the plasma concentration/time curve after oral pivmecillinam (400 mg) was given to the same subjects when starved. After administration of pivmecillinam (400 mg) with meal, Tasc was significantly delayed beyond the value obtained when the subjects were starved. 5 The pharmacokinetics of pivmecillinam in coeliac disease are normal. This finding contrasts with previous studies on the pharmacokinetics of another pivaloyloxymethylpenicillin ester, pivampicillin, in this condition. PMID:197981

  19. Pharmacokinetics of pivmecillinam.

    PubMed Central

    Parsons, R L; Hossack, G A; Paddock, G M

    1977-01-01

    1 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam (400 and 600 mg). 2 Similar plasma concentration/time curves of ampicillin and mecillinam in the starved normal subjects followed oral administration of ampicillin (500 mg) and pivmecillinam (600 mg). 3 The plasma concentration/time curve of mecillinam was measured in the same normal subjects after oral administration of pivmecillinam (400 mg) with a reproducible standardized Lundh test meal. 4 There was no statistically significant difference in the plasma concentration/time curve of mecillinam after pivmecillinam/400 mg) and the meal compared with the plasma concentration/time curve after oral pivmecillinam (400 mg) was given to the same subjects when starved. After administration of pivmecillinam (400 mg) with meal, Tasc was significantly delayed beyond the value obtained when the subjects were starved. 5 The pharmacokinetics of pivmecillinam in coeliac disease are normal. This finding contrasts with previous studies on the pharmacokinetics of another pivaloyloxymethylpenicillin ester, pivampicillin, in this condition. PMID:197981

  20. Monte Carlo Assessments of Absorbed Doses to the Hands of Radiopharmaceutical Workers Due to Photon Emitters

    SciTech Connect

    Ilas, Dan; Eckerman, Keith F; Karagiannis, Harriet

    2009-01-01

    This paper describes the characterization of radiation doses to the hands of nuclear medicine technicians resulting from the handling of radiopharmaceuticals. Radiation monitoring using ring dosimeters indicates that finger dosimeters that are used to show compliance with applicable regulations may overestimate or underestimate radiation doses to the skin depending on the nature of the particular procedure and the radionuclide being handled. To better understand the parameters governing the absorbed dose distributions, a detailed model of the hands was created and used in Monte Carlo simulations of selected nuclear medicine procedures. Simulations of realistic configurations typical for workers handling radiopharmaceuticals were performedfor a range of energies of the source photons. The lack of charged-particle equilibrium necessitated full photon-electron coupled transport calculations. The results show that the dose to different regions of the fingers can differ substantially from dosimeter readings when dosimeters are located at the base of the finger. We tried to identify consistent patterns that relate the actual dose to the dosimeter readings. These patterns depend on the specific work conditions and can be used to better assess the absorbed dose to different regions of the exposed skin.

  1. Pharmacokinetics of melatonin in human sexual maturation.

    PubMed

    Cavallo, A; Ritschel, W A

    1996-05-01

    To determine whether melatonin pharmacokinetics change during puberty, we infused melatonin iv in 9 prepubertal, 8 pubertal, and 16 adult subjects and measured melatonin in serum and saliva, and 6-hydroxymelatonin sulfate in urine. A pilot study of 3 adult males showed dose linearity, absence of saturation kinetics, and unaltered metabolism and urinary excretion for doses of 0.1, 0.5, and 5.0 micrograms/kg. All other subjects received 0.5 microgram/kg melatonin. The results of pharmacokinetic parameters calculated from serum melatonin showed no significant gender differences in adults. However, developmental differences were significant between prepubertal children and adults for terminal elimination rate constant (1.08 +/- 0.25 vs. 0.89 +/- 0.11 h-1), elimination half-life (0.67 +/- 0.12 vs. 0.79 +/- 0.10 h), and area under the concentration-time curve (250.9 +/- 91.8 vs. 376.9 +/- 154.3 (pg/mL).h, respectively). At all time points melatonin levels were higher in serum than in saliva, and the ratio between serum and salivary melatonin varied up to 55-fold within and between individuals. Results based on salivary melatonin showed significant differences between prepubertal children and adults for the terminal elimination rate constant (1.90 +/- 0.95 vs. 1.06 +/- 0.28 h-1). The described group differences in pharmacokinetic parameters suggest that prepubertal children metabolize melatonin faster than adults. The inconsistent ratio between serum and salivary melatonin calls for caution in the use of salivary melatonin for pharmacokinetic studies or to infer pineal function. The present findings, suggestive of faster melatonin metabolism in prepubertal children, combined with the known decline of serum melatonin with age and higher excretion rate of the metabolite in prepubertal children lead us to conclude that the prepubertal pineal gland has a higher melatonin secretion rate than the adult gland. PMID:8626852

  2. 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.

  3. Freeware for reporting radiation dosimetry following the administration of radiopharmaceuticals.

    PubMed

    Gómez Perales, Jesús Luis; García Mendoza, Antonio

    2015-09-01

    This work describes the development of a software application for reporting patient radiation dosimetry following radiopharmaceutical administration. The resulting report may be included within the patient's medical records. The application was developed in the Visual Basic programming language. The dosimetric calculations are based on the values given by the International Commission on Radiological Protection (ICRP). The software is available in both Spanish and English and can be downloaded at no cost from www.radiopharmacy.net. PMID:26092354

  4. [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.

  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. Pharmacokinetics of cefixime

    SciTech Connect

    Tonelli, A.P.

    1987-01-01

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

  7. Clinical pharmacokinetics of anticonvulsants.

    PubMed

    Hvidberg, E F; Dam, M

    1976-01-01

    Anticonvulsant therapy was among the first areas to benefit from clinical pharmacokinetic studies. The most important advantage is that the frequent interindividual variation in the plasma level/dose ratio for these drugs can be circumvented by plasma level monitoring. For several anticonvulsants the brain concentration is shown to parallel the plasma concentration. Phenytoin (diphenylhydantoin) is stil the most important anticonvulsant and the one for which kinetics have been thoroughly investigated in man. These investigations have revealed several reasons for the wellknown difficulties in using this drug clinically. The absorption rate and fraction are very much dependent on the pharmaceutical preparation, and changes of brand may alter the plasma level of phenytoin in spite of unaltered dose. The elimination capacity is saturable causing dose dependent kinetics, which again means disproportional changes in plasma level with changes in dose. Great individual variations exist in the rate of metabolism, and several pharmacokinetic drug interactions are known. As an optimum therapeutic plasma concentration range has been established monitoring plasma levels must be strongly advocated. Interpretation of plasma levels in uraemic patients must take into account decreased protein binding of the drug. Carbamazepine is probably as effective as phenytoin. The elimination is a first order process, but the rate of metabolism increases after a few weeks' treatment. An active metabolite (epoxide) may be the cause of some side-effects. Combined treatment with other anticonvulsant drugs decreases the half-life and more frequent dosing may be necessary. An optimum therapeutic concentration range has been suggested and plasma monitoring is advocated, along with that of the active metabolite, the epoxide. Phenobarbitone is still much used but its kinetics have been investigated to a lesser extent. The main problem is the variability in the rate of elimination. In children the half

  8. Pharmacokinetics of Hoasca alkaloids in healthy humans.

    PubMed

    Callaway, J C; McKenna, D J; Grob, C S; Brito, G S; Raymon, L P; Poland, R E; Andrade, E N; Andrade, E O; Mash, D C

    1999-06-01

    N,N-Dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine (THH) are the characteristic alkaloids found in Amazonian sacraments known as hoasca, ayahuasca, and yajè. Such beverages are characterized by the presence of these three harmala alkaloids, where harmine and harmaline reversibly inhibit monoamine oxidase A (MAO-A) while tetrahydroharmine weakly inhibits the uptake of serotonin. Together, both actions increase central and peripheral serotonergic activity while facilitating the psychoactivity of DMT. Though the use of such 'teas' has be known to western science for over 100 years, little is known of their pharmacokinetics. In this study, hoasca was prepared and administered in a ceremonial context. All four alkaloids were measured in the tea and in the plasma of 15 volunteers, subsequent to the ingestion of 2 ml hoasca/kg body weight, using gas (GC) and high pressure liquid chromatographic (HPLC) methods. Pharmacokinetic parameters were calculated and peak times of psychoactivity coincided with high alkaloid concentrations, particularly DMT which had an average Tmax of 107.5 +/- 32.5 min. While DMT parameters correlated with those of harmine, THH showed a pharmacokinetic profile relatively independent of harmine's. PMID:10404423

  9. [Pharmacokinetics--pharmacodynamics of modafinil in mice].

    PubMed

    Ma, Zhang-Qing; Hong, Zong-Yuan; Wang, Wu-San; Tao, Fang

    2012-01-01

    To guide the reasonable clinical application of modafinil (MOD), pharmacokinetics and pharmacodynamics of MOD in mice and the correlation between them were investigated. Male mice (Kunming strain) were given a single oral dose of MOD (120 mg x kg(-1)). The plasma concentration of MOD was measured by HPLC and the pharmacokinetic parameters were calculated with DAS 3.0 software. For another batch of male Kunming strain mice, their locomotor activities were recorded by an infrared ray passive sensor after a same oral dose of MOD, and the synchronization and correlation between the changes of MOD plasma concentration and the locomotor activity induced by MOD were compared and analyzed. The results showed that the plasma concentration-time curve of MOD was fitted to two-compartment open model with a first order absorption. The main pharmacokinetic parameters t1/2alpha, t1/2beta, t(max), C(max) and AUC(0-inifinity) were 0.42 h, 3.10 h, 1.00 h, 41.34 mg x L(-1) and 142.22 mg x L(-1) x h, respectively. MOD significantly increased locomotor activity and the effect lasted for about 4 h. The changes of MOD plasma concentration and the locomotor activity induced by MOD were synchronous. In conclusion, there is a significant correlation between the effect of MOD and its plasma concentration after administration of 120 mg x kg(-1) in mice. PMID:22493813

  10. Auger Radiopharmaceutical Therapy Targeting Prostate-Specific Membrane Antigen

    PubMed Central

    Kiess, Ana P.; Hobbs, Robert; Sgouros, George; Mease, Ronnie C.; Pullambhatla, Mrudula; Shen, Colette J.; Foss, Catherine A.; Pomper, Martin G.

    2015-01-01

    Auger electron emitters such as 125I have a high linear energy transfer and short range of emission (<10 μm), making them suitable for treating micrometastases while sparing normal tissues. We used a highly specific small molecule targeting the prostate-specific membrane antigen (PSMA) to deliver 125I to prostate cancer cells. Methods The PSMA-targeting Auger emitter 2-[3-[1-carboxy-5-(4-125I-iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid (125I-DCIBzL) was synthesized. DNA damage (via phosphorylated H2A histone family member X staining) and clonogenic survival were tested in PSMA-positive (PSMA+) PC3 PIP and PSMA-negative (PSMA−) PC3 flu human prostate cancer cells after treatment with 125I-DCIBzL. Subcellular drug distribution was assessed with confocal microscopy using a related fluorescent PSMA-targeting compound YC-36. In vivo antitumor efficacy was tested in nude mice bearing PSMA+ PC3 PIP or PSMA− PC3 flu flank xenografts. Animals were administered (intravenously) 111 MBq (3 mCi) of 125I-DCIBzL, 111 MBq (3 mCi) of 125I-NaI, an equivalent amount of nonradiolabeled DCIBzL, or saline. Results After treatment with 125I-DCIBzL, PSMA+ PC3 PIP cells exhibited increased DNA damage and decreased clonogenic survival when compared with PSMA− PC3 flu cells. Confocal microscopy of YC-36 showed drug distribution in the perinuclear area and plasma membrane. Animals bearing PSMA+ PC3 PIP tumors had significant tumor growth delay after treatment with 125I-DCIBzL, with only 1 mouse reaching 5 times the initial tumor volume by 60 d after treatment, compared with a median time to 5 times volume of less than 15 d for PSMA− PC3 flu tumors and all other treatment groups (P = 0.002 by log-rank test). Conclusion PSMA-targeted radiopharmaceutical therapy with the Auger emitter 125I-DCIBzL yielded highly specific antitumor efficacy in vivo, suggesting promise for treatment of prostate cancer micrometastases. PMID:26182968

  11. Symbol-and-Arrow Diagrams in Teaching Pharmacokinetics.

    ERIC Educational Resources Information Center

    Hayton, William L.

    1990-01-01

    Symbol-and-arrow diagrams are helpful adjuncts to equations derived from pharmacokinetic models. Both show relationships among dependent and independent variables. Diagrams show only qualitative relationships, but clearly show which variables are dependent and which are independent, helping students understand complex but important functional…

  12. Estimation of pharmacokinetic model parameters.

    PubMed

    Timcenko, A; Reich, D L; Trunfio, G

    1995-01-01

    This paper addresses the problem of estimating the depth of anesthesia in clinical practice where many drugs are used in combination. The aim of the project is to use pharmacokinetically-derived data to predict episodes of light anesthesia. The weighted linear combination of anesthetic drug concentrations was computed using a stochastic pharmacokinetic model. The clinical definition of light anesthesia was based on the hemodynamic consequences of autonomic nervous system responses to surgical stimuli. A rule-based expert system was used to review anesthesia records to determine instances of light anesthesia using hemodynamic criteria. It was assumed that light anesthesia was a direct consequence of the weighted linear combination of drug concentrations in the patient's body that decreased below a certain threshold. We augmented traditional two-compartment models with a stochastic component of anesthetics' concentrations to compensate for interpatient pharmacokinetic and pharmacodynamic variability. A cohort of 532 clinical anesthesia cases was examined and parameters of two compartment pharmacokinetic models for 6 intravenously administered anesthetic drugs (fentanyl, thiopenthal, morphine, propofol, midazolam, ketamine) were estimated, as well as the parameters for 2 inhalational anesthetics (N2O and isoflurane). These parameters were then prospectively applied to 22 cases that were not used for parameter estimation, and the predictive ability of the pharmacokinetic model was determined. The goal of the study is the development of a pharmacokinetic model that will be useful in predicting light anesthesia in the clinically relevant circumstance where many drugs are used concurrently. PMID:8563327

  13. Pharmacokinetics of pantoprazole in man.

    PubMed

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

    1996-05-01

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

  14. Pharmacokinetics of pantoprazole in man.

    PubMed

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

    1996-05-01

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

  15. 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

  16. 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

  17. 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. PMID:20686332

  18. Applied Pharmacokinetics: Course Description and Retrospective Evaluation.

    ERIC Educational Resources Information Center

    Beck, Diane E.

    1984-01-01

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

  19. Silver-coated monolithic columns for separation in radiopharmaceutical applications.

    PubMed

    Sedlacek, Ondrej; Kucka, Jan; Svec, Frantisek; Hruby, Martin

    2014-04-01

    In this study, we demonstrate the preparation of a macroporous monolithic column containing anchored silver nanoparticles and its use for the elimination of excess radioiodine from the radiolabeled pharmaceutical. The poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith was first functionalized with cystamine and the free thiol groups liberated by reaction with borohydride. In-house-prepared silver nanoparticles were then attached by interaction with the surface thiols. The deiodization process was demonstrated with the commonly used radiopharmaceutical m-iodobenzylguanidine labeled with radionuclide iodine-125. PMID:24478196

  20. 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.

  1. (177) Lu-5-Fluorouracil a potential theranostic radiopharmaceutical: radiosynthesis, quality control, biodistribution, and scintigraphy.

    PubMed

    Rasheed, Rashid; Tariq, Saleha; Naqvi, Syed Ali Raza; Gillani, Syed Jawad Hussain; Rizvi, Faheem Askari; Sajid, Muhammad; Rasheed, Shahid

    2016-08-01

    The aim of this study is to develop (177) Lu-5-Flourouracil as a potential cancer therapeutic radiopharmaceutical. 5-Flourouracil (5-FU) is widely accepted as an anticancer drug of broad spectrum fame. The labeling of 5-FU was carried out at different set of experimental conditions using high specific activity of (177) LuCl3 . The optimum conditions for maximum radiochemical yield was set: 5-FU (5 mg), (177) LuCl3 (185 MBq), diethylenetriaminepentaacetic acid (10 µg), reaction volume (2 mL), pH (5.5), temperature (80°C), and reaction time (20 min). The radiochemical labeling was assessed with Whatman No. 2 paper, instant thin layer chromatographic, and radio-HPLC, which revealed >94% labeling results with sufficient stability up to 6 h. Serum stability study also showed (177) Lu-5-FU promising stability. Biodistribution study in normal rats and rabbits showed liver, stomach, kidney, and heart as area of increased tracer accumulation just after injection, which decreased to 1.4%, 0.4%, 0.2%, and 0.39% ID/g, respectively, after 72 h. Glomerular filtration rate and cytotoxicity study results of (177) Lu-5-FU showed it had no adverse effect on renal function and nontoxic to blood cells. The promising characteristics of (177) Lu-5-FU, that is, clever elimination from kidney and nontoxic nature toward blood cells make it the radiopharmaceutical for further testing in patients for therapeutic purposes. PMID:27444959

  2. Pirbenicillin: Pharmacokinetic Parameters in Mice

    PubMed Central

    English, Arthur R.; Girard, Dennis; Retsema, James A.

    1976-01-01

    The rapid intravenous administration to mice of pirbenicillin, carbenicillin, and ampicillin produced biexponential blood concentration-time curves when assessed by frequent blood samplings at short intervals. The pharmacokinetic behavior of pirbenicillin and the other penicillins was analyzed by the two-compartment open model. This is thought to be the first study giving detailed pharmacokinetic values of penicillins in mice. Some significant differences were noted between the pharmacokinetic values of pirbenicillin, ampicillin, and carbenicillin. These values suggest that the interchange of pirbenicillin between the central and peripheral body compartments of the mouse was slower than that of either carbenicillin or ampicillin and indicated that a greater fraction of the pirbenicillin than the ampicillin dose reached the peripheral compartment. PMID:984791

  3. Clinical pharmacokinetics of metformin.

    PubMed

    Graham, Garry G; Punt, Jeroen; Arora, Manit; Day, Richard O; Doogue, Matthew P; Duong, Janna K; Furlong, Timothy J; Greenfield, Jerry R; Greenup, Louise C; Kirkpatrick, Carl M; Ray, John E; Timmins, Peter; Williams, Kenneth M

    2011-02-01

    Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean ± SD fractional oral bioavailability (F) of metformin is 55 ± 16%. It is absorbed predominately from the small intestine. Metformin is excreted unchanged in urine. The elimination half-life (t(½)) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CL(R)) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 ± 130 mL/min and 1140 ± 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CL(R) and CL/F of metformin are 4.3 ± 1.5 and 10.7 ± 3.5 times as great, respectively, as the clearance of creatinine (CL(CR)). As the CL(R) and CL/F decrease approximately in proportion to CL(CR), the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CL(CR). The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural

  4. PET Pharmacokinetic Modelling

    NASA Astrophysics Data System (ADS)

    Müller-Schauenburg, Wolfgang; Reimold, Matthias

    Positron Emission Tomography is a well-established technique that allows imaging and quantification of tissue properties in-vivo. The goal of pharmacokinetic modelling is to estimate physiological parameters, e.g. perfusion or receptor density from the measured time course of a radiotracer. After a brief overview of clinical application of PET, we summarize the fundamentals of modelling: distribution volume, Fick's principle of local balancing, extraction and perfusion, and how to calculate equilibrium data from measurements after bolus injection. Three fundamental models are considered: (i) the 1-tissue compartment model, e.g. for regional cerebral blood flow (rCBF) with the short-lived tracer [15O]water, (ii) the 2-tissue compartment model accounting for trapping (one exponential + constant), e.g. for glucose metabolism with [18F]FDG, (iii) the reversible 2-tissue compartment model (two exponentials), e.g. for receptor binding. Arterial blood sampling is required for classical PET modelling, but can often be avoided by comparing regions with specific binding with so called reference regions with negligible specific uptake, e.g. in receptor imaging. To estimate the model parameters, non-linear least square fits are the standard. Various linearizations have been proposed for rapid parameter estimation, e.g. on a pixel-by-pixel basis, for the prize of a bias. Such linear approaches exist for all three models; e.g. the PATLAK-plot for trapping substances like FDG, and the LOGAN-plot to obtain distribution volumes for reversibly binding tracers. The description of receptor modelling is dedicated to the approaches of the subsequent lecture (chapter) of Millet, who works in the tradition of Delforge with multiple-injection investigations.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. Population Pharmacokinetics and Therapeutic Efficacy of Febuxostat in Patients with Severe Renal Impairment.

    PubMed

    Hira, Daiki; Chisaki, Yugo; Noda, Satoshi; Araki, Hisazumi; Uzu, Takashi; Maegawa, Hiroshi; Yano, Yoshitaka; Morita, Shin-Ya; Terada, Tomohiro

    2015-01-01

    The aim of the present study was to determine the influence of severe renal dysfunction (estimated glomerular filtration rate <30 ml/min/1.73 m(2), including hemodialysis) on the pharmacokinetics and therapeutic effects of febuxostat using a population pharmacokinetic analysis. This study recruited patients with hyperuricemia who were initially treated with allopurinol, but were switched to febuxostat, and it consists of 2 sub-studies: a pharmacokinetic study (26 patients) and retrospective efficacy evaluation study (51 patients). The demographic and clinical data of patients were collected from electronic medical records. Plasma febuxostat concentrations were obtained at each hospital visit. Population pharmacokinetic modeling was performed with NONMEM version 7.2. A total of 128 plasma febuxostat concentrations from 26 patients were used in the population pharmacokinetic analysis. The data were best described by a 1-compartment model with first order absorption. Covariate analysis revealed that renal function did not influence the pharmacokinetics of febuxostat, whereas actual body weight significantly influenced apparent clearance and apparent volume of distribution. The retrospective efficacy analysis showed the favorable therapeutic response of febuxostat switched from allopurinol in patients with moderate to severe renal impairment. No serious adverse event associated with febuxostat was observed irrespective of renal function. The population pharmacokinetic analysis and therapeutic analysis of febuxostat revealed that severe renal dysfunction had no influence on the pharmacokinetic parameters of febuxostat. These results suggest that febuxostat is tolerated well by patients with severe renal impairment. PMID:26183164

  10. 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

  11. [A new radiopharmaceutical for bone imaging: experimental study of 99mTc-HEDTMP].

    PubMed

    Hu, Shu; Deng, Houfu; Jiang, Shubin; Luo, Shunzhong; Lei, Yong

    2010-08-01

    The purpose of this study is to prepare 99mTc-HEDTMP [N-(2-hydroxyethyl) ethlenediamine-1,1,2-tri (methylene phosphonic acid), a new kind of bone seeking compound; to investigate its biological properties; and to explore the possibility of using it as a potential radiopharmaceutical for skeleton scintigraphy. HEDTMP was labeled with 99mTc by "pretinning" method, the radiochemical purity was 97.00% +/- 0.34%. 99mTc-HEDTMP was found to be stable in 5 hours in vitro with the radiochemical purity over 95% even after being diluted by physiological saline with the factor of dilution 100. The plane bone scanning of rabbits showed that 99mTc-HEDTMP was principally absorbed by skeletal system. Skull, spine and legs could be observed clearly, and were more legible than the images of 99mTc-MDP. Mice trial also indicated the high bone seeking of 99mTc-HEDTMP. The skeletal uptake was 11.92% ID/g, 13.19% ID/g, 10.14% ID/g, 10.04% ID/g, 7.71% ID/g separately at 30 minutes, 1 hour, 3 hours, 6 hours and 24 hours after the injection. Kidney seemed to be the major excretory organ. The clearance of blood was quick and the retaining amount in non-target organs was small. These results indicate that 99mTc-HEDTMP can be prepared easily, and its biological properties can be compared favorably with the commonly used bone imaging agent, and it is well worth further researching as a promising potential radiopharmaceutical in nuclide diagnosis for skeleton diseases. PMID:20842850

  12. Ocular pharmacokinetics of cephalosporins using microdialysis.

    PubMed

    Macha, S; Mitra, A K

    2001-10-01

    The purpose of this study was to delineate the ocular pharmacokinetics of cephalosporins and investigate the presence of peptide transporters in the retina. New Zealand albino rabbits were kept under anesthesia. A concentric microdialysis probe was implanted in the vitreous chamber and linear probe across the cornea in the aqueous humor. Isotonic phosphate buffer saline was perfused through the probes, and samples were collected every 20 min over a period of 10 hr. A 500 microg dose of cephalexin, cephazolin, and cephalothin was administered intravitreally. Inhibition experiments were carried out in vivo, using gly-pro and gly-sar. The vitreal half-lives of cephalexin, cefazolin, and cephalothin were 185.38 +/- 27.25 min, 111.40 +/- 17.17 min, and 146.68 +/- 47.52 min, respectively. Cephalexin generated higher aqueous humor concentrations compared to cefazolin. The pharmacokinetic parameters of cephalexin in the presence of gly-pro, i.e., AUC (44452.06 +/- 3326.55 microg x min/ml), clearance (0.0013 +/- 0.0004 ml/min) and vitreal half-life (825.12 +/- 499.95 min) were different from that of the control (14612.83 +/- 4036.47 microg x min/ml, 0.0036 +/- 0.0011 ml/min, and 187.96 +/- 65.12 min, respectively). Gly-pro did not inhibit cefazolin, and gly-sar showed no effect on the pharmacokinetics of both drugs. These studies indicate the involvement of a peptide carrier in the transport of cephalosporins across the retina. Although gly-pro inhibited the elimination of cephalexin from the vitreous, the effect of an alpha-amino group on peptide carriers was not clearly evident. PMID:11765153

  13. PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING

    EPA Science Inventory

    Physiologically-based pharmacokinetic (PB-PK) models attempt to provide both a realistic anatomic description of the animal to which a drug or toxic chemical has been administered and a biologically accurate representation of the physiological pathways for chemical storage, metab...

  14. 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

  15. Clinical pharmacokinetics of ibuprofen arginine.

    PubMed

    Cattaneo, Dario; Clementi, Emilio

    2010-11-01

    Currently, several ibuprofen compounds are available on the market, mainly differing in terms of pharmaceutical composition that influence the pharmacokinetic profile and eventually the onset of drug action. This review will mainly deal with the clinical pharmacokinetics of ibuprofen arginine, an alternative formulation specifically designed to improve the absorption of ibuprofen. Indeed, available data from studies in healthy volunteers have consistently shown that the formulation of ibuprofen arginine is characterized by prompt absorption of ibuprofen as compared to the conventional formulation at all tested doses with higher peak plasma concentration and lower Tmax values. This trend has been confirmed also in studies dealing with chiral ibuprofen pharmacokinetics. Most importantly, the shortening in the absorption time observed either with racemic mixture or with the S(+)-enantiomer of ibuprofen arginine did not imply a faster drug elimination eventually leading to inadequate daily drug exposure, as documented by T1/2 and AUC values being comparable to those measured with the free acid form. Taken together, the pharmacokinetic/dynamic characteristics of ibuprofen arginine can be considered particularly favorable for several clinical conditions, such as moderate/severe pain, in which a rapid pharmacologic effect is required. PMID:20925647

  16. Pharmacokinetics of ricobendazole in calves.

    PubMed

    Formentini, E A; Mestorino, O N; Mariño, E L; Errecalde, J O

    2001-06-01

    The pharmacokinetics of ricobendazole (RBZ) and its major metabolite albendazole sulphone (ABZSO2) were studied in six calves, after administration of RBZ (7.5 mg/kg), using a 10% experimental solution by the intravenous (i.v.) route, a 10% commercial solution by the subcutaneous (s.c.) route, and a 10% experimental suspension by the intraruminal (i.r.) route. Blood samples were drawn during a 60-h period. Plasma drug and metabolite concentrations were determined by HPLC. The pharmacokinetic evaluation in each case was prepared by weighted least-squares nonlinear regression analysis. Ricobendazole i.v. data were best fitted by a two-compartment model. The best pharmacokinetic exponents and coefficients were estimated, and the pharmacokinetic variables for RBZ and ABZSO2 were calculated from them. Similar patterns of plasma disposition were found for RBZ after i.r. and s.c. administration, suggesting delayed release from the s.c. site resembling the slow release of the drug from the rumen. PMID:11442798

  17. [Pharmacokinetics and pharmacodynamics of ceftaroline].

    PubMed

    Grau, Santiago; Sorlí, Luisa; Luque, Sonia

    2014-03-01

    Ceftaroline is administered intravenously in the form of a prodrug, ceftaroline fosamil, which is rapidly hydrolyzed by plasma phosphatases to its active form, ceftaroline. In general, the pharmacokinetics of ceftaroline differ little from those of other cephalosporins. A proportional increase in both the peak plasma concentration (Cmax) and the area under the curve (AUC) have been observed when the drug is administered in increasing doses, which demonstrates its linear pharmacokinetics. Half the dose of ceftaroline is excreted actively through the kidneys. The pharmacokinetic parameters of ceftaroline administered through the intramuscular route in diverse animal species were similar to those observed when the drug was administered intravenously and consequently clinical research into ceftaroline administered through this alternative route would be appropriate. Patients with moderate-severe alterations of renal function and those undergoing hemodialysis require dose adjustments. There is limited experience of the pharmacokinetics of ceftaroline in children, which has given rise to several schedules stratified by age groups. The pharmacodynamics of the drug have been studied in models of animal infection and in in vitro infections caused mainly by Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA], strains with intermediate vancomycin sensitivity [hVISA or hGISA]) and by Streptococcus pneumoniae strains with distinct sensitivities to penicillin. Because ceftaroline is a time-dependent antibiotic, the most widely studied pharmacokinetic/pharmacodynamic (PK/PD) indicator is the time interval during which drug concentrations are maintained above the minimum inhibitory concentration (MIC), calculated both as total drug (T > MIC) and as free fraction of the drug (fT > MIC). The PK/PD simulations carried out in these models, developed on the basis of the concentrations obtained with routine doses in humans, have shown that ceftaroline has a good PK

  18. Duloxetine: clinical pharmacokinetics and drug interactions.

    PubMed

    Knadler, Mary Pat; Lobo, Evelyn; Chappell, Jill; Bergstrom, Richard

    2011-05-01

    Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (C(max)) of approximately 47 ng/mL (40 mg twice-daily dosing) to 110 ng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10-12 hours and the volume of distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on concomitant medications and their clinical implications. Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and C(max) of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate

  19. 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.

  20. Deterioration of stannous ion in radiopharmaceutical kits during storage.

    PubMed

    McBride, M H; Shaw, S M; Kessler, W V

    1979-10-01

    The deterioration of stannous ion (Sn++) in inhouse-prepared and commercial radiopharmaceutical kits was studied. Sn++ content of three types of nonlyophilized, deoxygenated, aqueous inhouse-prepared kits [diethylenetriamine pentaacetic acid (DTPA), pyrophosphate and glucoheptonate] and of three commercially prepared kits (two lyophilized pyrophosphate kits and one diphosphonate in sealed glass ampul kit) was measured by differential pulse polarography. Inhouse-prepared kits were assayed initially and after storage for 6, 12, 24 and 48 days at 24, 5 and -18 C. Commercial kits were assayed initially and after storage for 12, 24 and 48 days at 5 and 24 C. Of the inhouse-prepared kits, Sn++ stability when stored for 48 days at 5 and 24 C. Freezer storage should be used, when possible, to insure maximum stability of Sn++ in inhouse-prepared, nonlyophilized ratiopharmaceutical kits. The commercial procedures of lyophilization and of sealing the reagent in a sealed glass ampul prolong Sn++ stability. PMID:507080

  1. 175Yb-TTHMP as a good candidate for bone pain palliation and substitute of other radiopharmaceuticals

    PubMed Central

    Safarzadeh, Laleh

    2014-01-01

    Bone metastasis is one of the most frequent causes of pain in cancer patients. Different radioisotopes such as P-32, Sm-153, Ho-166, Lu-177, and Re-186 with several chemical ligands as ethylenediaminetetramethylene phosphonic acid (EDTMP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP), and propylenediaminetetramethylene phosphonate (PDTMP) are recommended for bone pain palliation. In this work, 175Yb-triethylenetetraminehexamethylene phosphonic acid (TTHMP) was produced as a proper alternative to other radiopharmaceuticals. Relatively long half-life (T1/2 = 4.18 days), maximum energy beta particle Eβ =470 keV (86.5%), low abundance gamma emission 396 keV (6.4%), 286 keV (3.01%), 113.8 keV (1.88%) and low cost are considered advantageous of Yb-175 are to wider usage of this isotope; in addition, TTHMP is an ideal carrier moiety for bone metastases. Production, quality control, and biodistribution studies of 175Yb-TTHMP were targeted. Yb-175 chloride was obtained by thermal neutron bombardment of a natural Yb2O3 sample at Tehran Research Reactor (TRR), radiolabeling was completed in 1 h by the addition of TTHMP at the room temperature and pH was 7.5-8, radiochemical purity was higher than 95%. Biodistribution studies in normal rats were carried out. The results showed favorable biodistribution features of 175Yb-TTHMP, indicating significant accumulation in bone tissues compared with clinically used bone-seeking radiopharmaceuticals. This research presents 175Yb-TTHMP can be a good candidate for bone pain palliation and substitute of other radiopharmaceuticals, however, further biological studies in other mammals are still needed. PMID:25210277

  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. PMID:16129607

  3. [Interspecies differences of noopept pharmacokinetics].

    PubMed

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

    2004-01-01

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

  4. 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.

  5. Pregnancy-related pharmacokinetic changes.

    PubMed

    Tasnif, Y; Morado, J; Hebert, M F

    2016-07-01

    The pharmacokinetics of many drugs are altered by pregnancy. Drug distribution and protein binding are changed by pregnancy. While some drug metabolizing enzymes have an apparent increase in activity, others have an apparent decrease in activity. Not only is drug metabolism affected by pregnancy, but renal filtration is also increased. In addition, pregnancy alters the apparent activities of multiple drug transporters resulting in changes in the net renal secretion of drugs. PMID:27082931

  6. 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

  7. Multiple-dose acetaminophen pharmacokinetics.

    PubMed

    Sahajwalla, C G; Ayres, J W

    1991-09-01

    Four different treatments of acetaminophen (Tylenol) were administered in multiple doses to eight healthy volunteers. Each treatment (325, 650, 825, and 1000 mg) was administered five times at 6-h intervals. Saliva acetaminophen concentration versus time profiles were determined. Noncompartmental pharmacokinetic parameters were calculated and compared to determine whether acetaminophen exhibited linear or dose-dependent pharmacokinetics. For doses less than or equal to 18 mg/kg, area under the curve (AUC), half-life (t1/2), mean residence time (MRT), and ratio of AUC to dose for the first dose were compared with the last dose. No statistically significant differences were observed in dose-corrected AUC for the first or last dose among subjects or treatments. Half-lives and MRT were not significantly different among treatments for the first or the last dose. Statistically significant differences in t1/2 and MRT were noted (p less than 0.05) among subjects for the last dose. A plot of AUC versus dose for the first and the last doses exhibited a linear relationship. Dose-corrected saliva concentration versus time curves for the treatments were superimposable. Thus, acetaminophen exhibits linear pharmacokinetics for doses of 18 mg/kg or less. Plots of AUC versus dose for one subject who received doses higher than 18 mg/kg were curved, suggesting nonlinear behavior of acetaminophen in this subject. PMID:1800709

  8. 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

  9. Pharmacokinetic interactions of cimetidine 1987.

    PubMed

    Somogyi, A; Muirhead, M

    1987-05-01

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

  10. Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling

    PubMed Central

    Moss, Darren Michael; Siccardi, Marco

    2014-01-01

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

  11. 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

  12. 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…

  13. Population Pharmacokinetics of Abacavir in Pregnant Women

    PubMed Central

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

    2014-01-01

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

  14. COMPUTATIONAL PHARMACOKINETICS DURING DEVELOPMENTAL WINDOWS OF SUSPECTIBILITY

    EPA Science Inventory

    ABSTRACT

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

  15. Radiopharmaceutical Therapy in the Era of Precision Medicine*

    PubMed Central

    Sgouros, George; Goldenberg, David M.

    2014-01-01

    Precision medicine is the selection of a treatment modality that is specifically tailored to the genetic and phenotypic characteristics of a particular patient’s disease. In cancer, the objective is to treat with agents that inhibit cell signaling pathways that drive uncontrolled proliferation and dissemination of the disease. To overcome the eventual resistance to pathway inhibition therapy, this treatment modality has been combined with chemotherapy. We propose that pathway inhibition therapy is more rationally combined with radiopharmaceutical therapy (RPT), a cytotoxic treatment that is also targeted. RPT exploits pharmaceuticals that either bind specifically to tumors or accumulate by a broad array of physiological mechanisms indigenous to the neoplastic cells to deliver radiation specifically to these cells. Consistent with pathway inhibition therapy and in contrast to chemotherapy, RPT is well tolerated. However, the potential of RPT has not been fully exploited; for the most part, treatment has been implemented without using the ability to customize RPT by imaging and deriving individual patient tumor and normal organ radiation absorbed doses. These are more closely related to biological response and their determination should enable RPT treatment administration to maximum therapeutic benefit by treating to normal organ tolerance or demonstrating futility via tumor dosimetry. This is the essence of precision medicine. PMID:24953565

  16. 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.

  17. 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.

  18. 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

  19. The Next Generation of Positron Emission Tomography Radiopharmaceuticals in Oncology

    PubMed Central

    Rice, Samuel L.; Roney, Celeste A.; Daumar, Pierre; Lewis, Jason S.

    2015-01-01

    Although 18F-fluorodeoxyglucose (18F-FDG) is still the most widely used positron emission tomography (PET) radiotracer, there are a few well-known limitations to its use. The last decade has seen the development of new PET probes for in vivo visualization of specific molecular targets, along with important technical advances in the production of positron-emitting radionuclides and their related labeling methods. As such, a broad range of new PET tracers are in preclinical development or have recently entered clinical trials. The topics covered in this review include labeling methods, biological targets, and the most recent preclinical or clinical data of some of the next generation of PET radiopharmaceuticals. This review, which is by no means exhaustive, has been separated into sections related to the PET radionuclide used for radiolabeling: fluorine-18, for the labeling of agents such as FACBC, FDHT, choline, and Galacto-RGD; carbon-11, for the labeling of choline; gallium-68, for the labeling of peptides such as DOTATOC and bombesin analogs; and the long-lived radionuclides iodine-124 and zirconium-89 for the labeling of monoclonal antibodies cG250, and J591 and trastuzumab, respectively. PMID:21624561

  20. PET - radiopharmaceutical facilities at Washington University Medical School - an overview

    SciTech Connect

    Dence, C.S.; Welch, M.J.

    1994-12-31

    The PET program at Washington University has evolved over more than three decades of research and development in the use of positron-emitting isotopes in medicine and biology. In 1962 the installation of the first hospital cyclotron in the USA was accomplished. This first machine was an Allis Chalmers (AC) cyclotron and it was operated until July, 1990. Simultaneously with this cyclotron the authors also ran a Cyclotron Corporation (TCC) CS-15 cyclotron that was purchased in 1977. Both of these cyclotrons were maintained in-house and operated with a relatively small downtime (approximately 3.5%). After the dismantling of the AC machine in 1990, a Japanese Steel Works 16/8 (JSW-16/8) cyclotron was installed in the vault. Whereas the AC cyclotron could only accelerate deuterons (6.2 MeV), the JSW - 16/8 machine can accelerate both protons and deuterons, so all of the radiopharmaceuticals can be produced on either of the two presently owned accelerators. At the end of May 1993, the medical school installed the first clinical Tandem Cascade Accelerator (TCA) a collaboration with Science Research Laboratories (SRL) of Somerville, MA. Preliminary target testing, design and development are presently under way. In 1973, the University installed the first operational PETT device in the country, and at present there is a large basic science and clinical research program involving more than a hundred staff in nuclear medicine, radiation sciences, neurology, neurosurgery, psychiatry, cardiology, pulmonary medicine, oncology, and surgery.

  1. 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. PMID:23852614

  2. 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

  3. Azithromycin pharmacokinetics and penetration to lymph.

    PubMed

    Bergan, T; Jørgensen, N P; Olszewski, W; Zhang, Y

    1992-01-01

    The study of pharmacokinetics of azithromycin and penetration to peripheral human lymph was carried out in 14 healthy male volunteers taking 1 g orally after overnight fasting. Samples were analyzed by microbiological assay. The mean peak concentrations were 0.82 +/- 0.23 mg/l after 1.7 +/- 0.5 h in serum and 0.22 +/- 0.07 mg/l after 3.1 h in lymph. Nine of the 14 subjects showed a second and lower serum peak indicating the existence of enterohepatic circulation. The total areas under the serum concentrations curves (AUCs) till infinity were 7.9 +/- 3.1 mg. h/l compared to 4.4 +/- 1.2 mg.h/l in lymph. The mean lymph AUC was 68.1 +/- 20.7% of the serum AUC indicating a penetration ratio of 0.68. However, the actual amounts penetrating the tissues were much higher than this ratio suggests. Thus, after 6 h 81% of the drug was within the tissue compartment and after 120 h, 63% of the azithromycin was still present in the tissue compartment. The urinary recovery of azithromycin was 14.7 +/- 7.7% during the first 48 h. The serum curves and lymph curves displayed a distinctly slower phase of elimination after 12 h. The mean serum half-life was 5.4 +/- 3.4 h during the first 12 h (after the peak), whereas the value was 44.2 +/- 10.1 h during the interval 12-120 h. The corresponding half-life values for the peripheral lymph were 5.4 +/- 2.2 h and 50.8 +/- 11.6 h. Azithromycin possesses key pharmacokinetic properties that are prerequisites for a convenient once-daily dosage schedule which may improve patient compliance. PMID:1336891

  4. Pharmacokinetics of procaterol in thoroughbred horses.

    PubMed

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

    2016-06-01

    Procaterol (PCR) is a beta-2-adrenergic bronchodilator widely used in Japanese racehorses for treating lower respiratory disease. The pharmacokinetics of PCR following single intravenous (0.5 μg/kg) and oral (2.0 μg/kg) administrations were investigated in six thoroughbred horses. Plasma and urine concentrations of PCR were measured using liquid chromatography-mass spectrometry. Plasma PCR concentration following intravenous administration showed a biphasic elimination pattern. The systemic clearance was 0.47 ± 0.16 L/h/kg, the steady-state volume of the distribution was 1.21 ± 0.23 L/kg, and the elimination half-life was 2.85 ± 1.35 h. Heart rate rapidly increased after intravenous administration and gradually decreased thereafter. A strong correlation between heart rate and plasma concentration of PCR was observed. Plasma concentrations of PCR after oral administration were not quantifiable in all horses. Urine concentrations of PCR following intravenous and oral administrations were quantified in all horses until 32 h after administration. Urine PCR concentrations were not significantly different on and after 24 h between intravenous and oral administrations. These results suggest that the bioavailability of orally administrated PCR in horses is very poor, and the drug was eliminated from the body slowly based on urinary concentrations. This report is the first study to demonstrate the pharmacokinetic character of PCR in thoroughbred horses. PMID:26538319

  5. 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.

  6. Pharmacokinetics of peginterferons.

    PubMed

    Zeuzem, Stefan; Welsch, Christoph; Herrmann, Eva

    2003-01-01

    Two polyethylene glycol (PEG)-modified interferons are approved for the treatment of chronic hepatitis C. The pharmocokinetic properties of the branched 40 kDa pegylated interferon alfa-2a differ from the linear 12 kDa pegylated interferon alfa-2b. The absorption half-life of standard interferon alfa is 2.3 hours, while absorption half-lives for peginterferon alfa-2a and alfa-2b are 50 hours and 4.6 hours, respectively. The volume of distribution for peginterferon alfa-2a is considerably restricted, while the volume of distribution for peginterferon alfa-2b is only approximately 30% lower than that for conventional interferon. Because of its large size, the 40 kD peginterferon alfa-2a has a more than 100-fold reduction in renal clearance compared with conventional interferon alfa. Clearance of peginterferon alfa-2b is about one-tenth that of unmodified interferon alfa. Although data are limited, both drugs appear to show differences in the initial viral decay pattern in patients with chronic hepatitis C. However, it remains unknown whether these differences in the initial viral decline predict differences in the primary clinical endpoint, sustained virological response. PMID:12934165

  7. Pharmacokinetics of ciprofloxacin in ponies.

    PubMed

    Dowling, P M; Wilson, R C; Tyler, J W; Duran, S H

    1995-02-01

    The pharmacokinetics of ciprofloxacin was investigated in healthy, mature ponies. Ciprofloxacin was administered intravenously to six ponies at a dose of 5 mg per kg body weight. Seven days later, ciprofloxacin was administered orally to each pony at the same dose. Intravenous ciprofloxacin concentration vs. time data best fit a two-compartment open model with first-order elimination from the central compartment. Mean plasma half-life, based on the terminal phase, was 157.89 min (harmonic mean). Total body clearance of ciprofloxacin was 18.12 +/- 3.99 mL/min/kg. Volume of distribution at steady-state was 3.45 +/- 0.72 L/kg. From the pharmacokinetic data and reported minimum inhibitory concentrations for equine gram-negative pathogens, the appropriate dosage of ciprofloxacin was determined to be 5.32 mg per kg body weight at 12 h intervals. Bioavailability of oral ciprofloxacin in ponies was 6.8 +/- 5.33%. Owing to the poor bioavailability, a dosage regimen could not be proposed for oral ciprofloxacin administration in horses. Ciprofloxacin concentrations were determined in tissues and body fluids at 1, 2 and 4 h after intravenous administration. At all times, tissue concentrations exceeded plasma concentrations of ciprofloxacin. Highest concentrations were achieved in kidneys and urine. Potentially therapeutic concentrations were obtained in cerebrospinal and joint fluid, but low concentrations were achieved in aqueous humour. PMID:7752310

  8. Pharmacokinetics of Indomethacin in Pregnancy

    PubMed Central

    Rytting, Erik; Nanovskaya, Tatiana N.; Wang, Xiaoming; Vernikovskaya, Daria I.; Clark, Shannon M.; Cochran, Marlo; Abdel-Rahman, Susan M.; Venkataramanan, Raman; Caritis, Steve N.; Hankins, Gary D. V.; Ahmed, Mahmoud S.

    2014-01-01

    Background and objectives Although indomethacin has been widely used for the treatment of preterm labor over the past 40 years, there are few reports regarding its pharmacokinetics in pregnant women. Methods This opportunistic study assessed the steady-state pharmacokinetics of indomethacin in pregnant subjects to whom an oral dose of 25 mg every 6 h was prescribed. Indomethacin concentrations in plasma and urine were analyzed by a validated high-performance liquid chromatography method with mass spectrometric detection. Results The mean area under the plasma concentration versus time curve at steady state (AUCss) was 1.91 ± 0.53 lg h/mL, mean peak plasma concentration (Cmax) was 1.02 ± 0.49 lg/mL, and mean time to reach Cmax (tmax) was 1.3 ± 0.7 h. The mean apparent clearance at steady state was 14.5 ± 5.5 L/h, which is higher than the apparent clearance reported in the literature for non-pregnant subjects. Indomethacin crosses the placenta; the mean fetal/maternal ratio from five sets of cord blood samples collected at delivery was 4.0 ± 1.1. Conclusions Further studies are needed to determine whether any dose adjustments are necessary as a result of the increased clearance of indomethacin during pregnancy. PMID:24493205

  9. 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. PMID:25164142

  10. Technetium Tc-99m pyrophosphate for cerebrospinal fluid leaks: radiopharmaceutical considerations.

    PubMed

    Ponto, James A; Graham, Michael M

    2014-01-01

    OBJECTIVE To confirm the anticipated image quality and absence of adverse reactions in patients undergoing clinical practice cerebrospinal fluid (CSF) leak imaging procedures using technetium Tc-99m pyrophosphate (PYP). METHODS Following the recent discontinuation of preservative-free calcium trisodium diethylene triamine pentaacetic acid kits, PYP was selected as a suitable alternative for CSF leak imaging procedures. Procedures were established for its preparation and dispensing, paying special attention to safety considerations, and its use in clinical practice was implemented. Medical records, including images, were reviewed for the first 15 patients undergoing clinical practice CSF imaging procedures using Tc-99m PYP to confirm anticipated image quality and absence of adverse effects. RESULTS Review of CSF leak imaging procedures using Tc-99m PYP in 15 patients showed images to be of uniformly high quality. The vast majority of injected radiopharmaceutical remained in the CSF throughout the duration of the imaging procedure, allowing visualization of CSF leaks. Only a small amount of Tc-99m PYP diffused into the blood with resultant uptake on the skeleton and excretion into the urine, which did not interfere with image interpretation. No adverse reactions were noted in any of the patients. CONCLUSION With proper attention to safety considerations, Tc-99m PYP is a safe and effective alternative for performing CSF leak imaging procedures. PMID:24257695

  11. 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.

  12. 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. PMID:10572914

  13. Circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients.

    PubMed

    Binkhorst, Lisette; Kloth, Jacqueline S L; de Wit, Annelieke S; de Bruijn, Peter; Lam, Mei H; Chaves, Ines; Burger, Herman; van Alphen, Robbert J; Hamberg, Paul; van Schaik, Ron H N; Jager, Agnes; Koch, Birgit C P; Wiemer, Erik A C; van Gelder, Teun; van der Horst, Gijsbertus T J; Mathijssen, Ron H J

    2015-07-01

    The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen C(max )and area under the curve (AUC)0-8 h were 20 % higher (P < 0.001), and tamoxifen t(max) was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0-24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen. PMID:26050156

  14. 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

  15. 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. PMID:27610366

  16. 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

  17. 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.

  18. Studying the General Toxicity and Cumulative Properties of a Radiopharmaceutical Nanocolloid, (99m)Tc-Al2O3.

    PubMed

    Varlamova, N V; Churin, A A; Fomina, T I; Ermolaeva, L A; Vetoshkina, T V; Dubskaya, T Yu; Lamzina, T Yu; Fedorova, E P; Neupokoeva, O V; Skuridin, V S; Nesterov, E A; Larionova, L A; Chernov, V I

    2016-07-01

    We studied toxicity of a new Russian radiopharmaceutical Nanocolloid, (99m)Tc-Al2O3. Tests for acute toxicity showed that this agent belongs to a class of moderate-toxicity substances and does not have cumulative properties. The evaluation of subchronic toxicity after subcutaneous injection of this product to rats (0.04, 0.2, and 0.4 ml/kg) and rabbits (0.02 and 0.2 ml/kg) for 7 days did not reveal changes in the general state, temperature, body weight, indices of the peripheral blood and bone marrow, functions of the heart, liver, kidneys, and nervous system, and morphological characteristics of the internal organs in animals. The drug does not produce a local irritant effect. PMID:27502539

  19. Performance of a Lanthanum Bromide Detector and a New Conception Collimator for Radiopharmaceuticals Molecular Imaging in Oncology

    NASA Astrophysics Data System (ADS)

    Pani, Roberto; Pellegrini, Rosanna; Bennati, Paolo; Cinti, Maria Nerina; Scafè, Raffaele; De Vincentis, Giuseppe; Navarria, Francesco; Moschini, Giuliano; Cencelli, Valentino Orsolini; De Notaristefani, Francesco; Rossi, Paolo

    2009-03-01

    We have realized and tested a new-design compact gamma camera for high resolution SPET (Single Photon Emission Tomography), and small animals' radio-pharmaceutical molecular imaging. The camera is based on a "continuous" Lanthanum tri-Bromide crystal, and a new Low Energy (LE) collimator. The crystal is interfaced to a 2×2 array of Hamamatsu-H8500 position sensitive photo-multipliers. The lead collimator features parallel hexagonal 1.0 mm holes, 18 mm length, 0.2 mm septa and 10×10 cm2 detection area. It was newly designed to fully exploit the high spatial resolution a Lanthanum crystal may provide. To better evaluate its role, we have compared our camera to three other systems with similar crystals and photomultipliers, but employing traditional collimators, either pinhole or parallel. The new camera seems to be complementary to pinhole systems and shows a very attractive trade-off between spatial resolution and detection area.

  20. Data sharing for pharmacokinetic studies.

    PubMed

    Anderson, Brian J; Merry, Alan F

    2009-10-01

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

  1. 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.

  2. Molecular pharmacokinetics of catharanthus (vinca) alkaloids.

    PubMed

    Levêque, Dominique; Jehl, François

    2007-05-01

    This review focuses on the published data regarding the molecular determinants (enzymes, transporters, orphan nuclear receptors) of Catharanthus (vinca) alkaloids pharmacokinetics in humans. The clinical impact of these determinants (drug disposition, drug-drug interactions) is also discussed. PMID:17442684

  3. 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...

  4. Development of quantitative structure-pharmacokinetic relationships.

    PubMed Central

    Mayer, J M; van de Waterbeemd, H

    1985-01-01

    Quantitative structure-activity relationships (QSAR) relating biological activity to physiochemical descriptors have been successfully used for a number of years. It is also long recognized that pharmacokinetic parameters may play an important and even determinant role in drug action. This prompted several researchers to focus attention to pharmacokinetic parameters as potential descriptors in quantitative drug design. A number of examples of quantitative structure-pharmacokinetic relationships (QSPR) have appeared in the literature. The present contribution reviews some developments in this field. In particular, a number of concepts and problems are critically discussed, rather than compilations of examples already published in recent reviews. Attention will be paid to the main processes of the pharmacokinetic or toxicokinetic phase in drug action, including absorption, distribution and elimination (biotransformation and excretion). It is clear that quantitative approaches are of considerable interest to toxicologists, since these methods may contribute to the development of real predictive toxicology. PMID:3905378

  5. 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

  6. 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. PMID:3147596

  7. 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. PMID:24733631

  8. Clinical Pharmacokinetics: A Simplified Approach, Part 2

    PubMed Central

    Perlin, Elliott; Taylor, Robert E.; Peck, Carl C.

    1986-01-01

    Part 1 of this two-part series in clinical pharmacokinetics (J Natl Med Assoc 1985; 77:475-482) introduced the clinician to the basic principles required for rational therapeutic drug management at the bedside. Practical problems were included that demonstrated how these principles could be put to clinical use. In Part 2 the clinical pharmacology of three commonly used drugs (theophylline, digoxin and gentamicin) are discussed, and practical problems are presented to illustrate the use of their pharmacokinetic profiles. PMID:3783759

  9. 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. PMID:25427541

  10. Implementing and maintaining a private pharmacokinetics practice.

    PubMed

    Murphy, J E; Ward, E S; Job, M L

    1990-03-01

    The development and maintenance of a private-practice pharmacokinetics service is described. A contracted pharmacokinetics service has been in place at Georgia Baptist Medical Center, a 525-bed hospital, for the past eight years. Physician support, inhouse study results, and literature documentation of the benefits of scheduling drug concentration determinations were used to convince hospital administrators of the value of a pharmacokinetics service. Services were reimbursed by increasing the fee charged for each drug concentration determination, with payment made to the pharmacokinetics service on a monthly basis. The service is associated with the pathology department for administrative purposes. Each member of the pharmacokinetics service is credentialed by the medical staff. The group trains part-time personnel to provide services when needed. Services provided by the group but not required by the contract include collecting quality assurance data, conducting research, serving on hospital committees, writing newsletter articles, conducting inservice-education programs, and providing clinical interventions for nonconsultation patients. This private-practice pharmacokinetics service provides high-quality services and is well accepted within the institution. PMID:2316544

  11. 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. PMID:27233802

  12. Synthesis and radioiodination of ergoline derivatives: potential in-vivo dopamine receptor site mapping radiopharmaceuticals

    SciTech Connect

    Mikhail, E.A.

    1985-01-01

    The need of a dopamine-receptor based radiopharmaceutical for brain imaging is apparent. If such an agent is made available to physicians, it could provide means for detecting brain tumors, and diagnose such mental disorders as parkinsonism, schizophrenia and psychosis. Currently, such agents are yet to be discovered. Procedures were developed to synthesize and label four ergoline derivatives which could potentially exhibit affinity to dopamine receptors. Labelling with /sup 125/I was accomplished in some cases by displacing a suitably positioned leaving group with /sup 125/I-anion, while in other cases iodine exchange procedures were utilized. Formulations of the labeled derivatives were achieved via the formation of their water soluble tartarate salts. Biodistribution studies in mature Sprague-Dawley rats showed that of the four radioactive compounds injected, the highest uptake in the brain and adrenals was achieved with 8 ..beta..-(I-125)-iodomethyl-6-propylergoline. In addition, high target/nontarget ratios were obtained with the above mentioned compound. On the other hand, the least brain and adrenal uptake as well as the lowest target/nontarget ratios were exhibited by 8 ..beta..-(I-125)-(p-iodobenzenesulfonyl)-lysergol presumably due to its in-vivo instability. A comparative biodistribution study for ergoline derivatives and N-isopropyl-(I-123)-p-iodoamphetamine was conducted. The biodistribution studies showed that the brain to blood ratio for the ergoline derivative 8 ..beta..-(I-125)-iodomethyl-6-propylergoline to be very close to that for /sup 125/I-IMP at 1 minute after dose administration. However after 15 minutes the brain/blood ratio of compound XLVI was half the value of /sup 123/I-IMP. Different mechanisms of brain influx and efflux are known to occur with the amphetamine and ergoline derivatives.

  13. 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.

  14. Systemic metabolic radiopharmaceutical therapy in the treatment of metastatic bone pain.

    PubMed

    Paes, Fabio M; Serafini, Aldo N

    2010-03-01

    Bone pain due to skeletal metastases constitutes the most common type of chronic pain among patients with cancer. It significantly decreases the patient's quality of life and is associated with comorbidities, such as hypercalcemia, pathologic fractures and spinal cord compression. Approximately 65% of patients with prostate or breast cancer and 35% of those with advanced lung, thyroid, and kidney cancers will have symptomatic skeletal metastases. The management of bone pain is extremely difficult and involves a multidisciplinary approach, which usually includes analgesics, hormone therapies, bisphosphonates, external beam radiation, and systemic radiopharmaceuticals. In patients with extensive osseous metastases, systemic radiopharmaceuticals should be the preferred adjunctive therapy for pain palliation. In this article, we review the current approved radiopharmaceutical armamentarium for bone pain palliation, focusing on indications, patient selection, efficacy, and different biochemical characteristics and toxicity of strontium-89 chloride, samarium-153 lexidronam, and rhenium-186 etidronate. A brief discussion on the available data on rhenium-188 is presented focusing on its major advantages and disadvantages. We also perform a concise appraisal of the other available treatment options, including pharmacologic and hormonal treatment modalities, external beam radiation, and bisphosphonates. Finally, the available data on combination therapy of radiopharmaceuticals with bisphosphonates or chemotherapy are discussed. PMID:20113678

  15. 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)

  16. Pharmacokinetics of Ethanol - Issues of Forensic Importance.

    PubMed

    Jones, A W

    2011-07-01

    A reliable method for the quantitative analysis of ethanol in microvolumes (50-100 μL) of blood became available in 1922, making it possible to investigate the absorption, distribution, metabolism, and excretion (ADME) of ethanol in healthy volunteers. The basic principles of ethanol pharmacokinetics were established in the 1930s, including the notion of zero-order elimination kinetics from blood and distribution of the absorbed dose into the total body water. The hepatic enzyme alcohol dehydrogenase (ADH) is primarily responsible for the oxidative metabolism of ethanol. This enzyme was purified and characterized in the early 1950s and shown to have a low Michaelis constant (km), being about ~0.1 g/L. Liver ADH is therefore saturated with substrate after the first couple of drinks and for all practical purposes the concentration-time (C-T) profiles of ethanol are a good approximation to zero-order kinetics. However, because of dose-dependent saturation kinetics, the entire postabsorptive declining part of the blood-alcohol concentration (BAC) curve looks more like a hockey stick rather than a straight line. A faster rate of ethanol elimination from blood in habituated individuals (alcoholics) is explained by participation of a high km microsomal enzyme (CYP2E1), which is inducible after a period of chronic heavy drinking. Owing to the combined influences of genetic and environmental factors, one expects a roughly threefold difference in elimination rates of ethanol from blood (0.1-0.3 g/L/h) between individuals. The volume of distribution (Vd) of ethanol, which depends on a person's age, gender, and proportion of fat to lean body mass, shows a twofold variation between individuals (0.4-0.8 L/kg). This forensic science review traces the development of forensic pharmacokinetics of ethanol from a historical perspective, followed by a discussion of important issues related to the disposition and fate of ethanol in the body, including (a) quantitative evaluation of

  17. Clinical pharmacokinetics of the salicylates.

    PubMed

    Needs, C J; Brooks, P M

    1985-01-01

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

  18. Pharmacokinetic drug interactions of macrolides.

    PubMed

    Periti, P; Mazzei, T; Mini, E; Novelli, A

    1992-08-01

    The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline

  19. 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

  20. Pharmaceutical and clinical development of phosphonate-based radiopharmaceuticals for the targeted treatment of bone metastases.

    PubMed

    Lange, Rogier; Ter Heine, Rob; Knapp, Russ Ff; de Klerk, John M H; Bloemendal, Haiko J; Hendrikse, N Harry

    2016-10-01

    Therapeutic phosphonate-based radiopharmaceuticals radiolabeled with beta, alpha and conversion electron emitting radioisotopes have been investigated for the targeted treatment of painful bone metastases for >35years. We performed a systematic literature search and focused on the pharmaceutical development, preclinical research and early human studies of these radiopharmaceuticals. The characteristics of an ideal bone-targeting therapeutic radiopharmaceutical are presented and compliance with these criteria by the compounds discussed is verified. The importance of both composition and preparation conditions for the stability and biodistribution of several agents is discussed. Very few studies have described the characterization of these products, although knowledge on the molecular structure is important with respect to in vivo behavior. This review discusses a total of 91 phosphonate-based therapeutic radiopharmaceuticals, of which only six agents have progressed to clinical use. Extensive clinical studies have only been described for (186)Re-HEDP, (188)Re-HEDP and (153)Sm-EDTMP. Of these, (153)Sm-EDTMP represents the only compound with worldwide marketing authorization. (177)Lu-EDTMP has recently received approval for clinical use in India. This review illustrates that a thorough understanding of the radiochemistry of these agents is required to design simple and robust preparation and quality control methods, which are needed to fully exploit the potential benefits of these theranostic radiopharmaceuticals. Extensive biodistribution and dosimetry studies are indispensable to provide the portfolios that are required for assessment before human administration is possible. Use of the existing knowledge collected in this review should guide future research efforts and may lead to the approval of new promising agents. PMID:27496068

  1. 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

  2. [Pharmacokinetics of cefatrizine administered in repeated doses].

    PubMed

    Couet, W; Reigner, B G; Lefebvre, M A; Bizouard, J; Fourtillan, J B

    1988-05-01

    Twelve healthy volunteers received cefatrizine orally at doses equal to 500 mg every 12 h for 5 days. Cefatrizine was assayed by high performance liquid chromatography in plasma and urines collected after the first and/or the last administration. Cefatrizine absorption was rapid; its peak plasma level was reached at time 1.79 +/- 0.07 h following the first dose, it was equal to 7.37 +/- 0.31 micrograms.ml-1. Its apparent elimination half-life was equal to 1.50 +/- 0.05 h, it explains the lack of accumulation with time during multiple administrations every 12 hours. Comparisons between peak plasma concentration and area under curves following the first and last dosing showed significant (p less than 0.01) but weak (close to 15%) reduction of these 2 parameters with time which could be explained by a slight reduction of cefatrizine absorption with time. In conclusion, cefatrizine does not accumulate when administered repeatedly at a dose equal to 500 mg every 12 h in young adult, and its pharmacokinetics is virtually linear with time. PMID:3043350

  3. Exploring Population Pharmacokinetic Modeling with Resampling Visualization

    PubMed Central

    Zuo, Fenghua

    2014-01-01

    Background. In the last decade, population pharmacokinetic (PopPK) modeling has spread its influence in the whole process of drug research and development. While targeting the construction of the dose-concentration of a drug based on a population of patients, it shows great flexibility in dealing with sparse samplings and unbalanced designs. The resampling approach has been considered an important statistical tool to assist in PopPK model validation by measuring the uncertainty of parameter estimates and evaluating the influence of individuals. Methods. The current work describes a graphical diagnostic approach for PopPK models by visualizing resampling statistics, such as case deletion and bootstrap. To examine resampling statistics, we adapted visual methods from multivariate analysis, parallel coordinate plots, and multidimensional scaling. Results. Multiple models were fitted, the information of parameter estimates and diagnostics were extracted, and the results were visualized. With careful scaling, the dependencies between different statistics are revealed. Using typical examples, the approach proved to have great capacity to identify influential outliers from the statistical perspective, which deserves special attention in a dosing regimen. Discussion. By combining static graphics with interactive graphics, we are able to explore the multidimensional data from an integrated and systematic perspective. Complementary to current approaches, our proposed method provides a new way for PopPK modeling analysis. PMID:24877118

  4. 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

  5. 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

    2012-01-01

    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. PMID:23117436

  6. 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.

  7. 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.

  8. 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

  9. Steady-state pharmacokinetics of lithium carbonate in healthy subjects.

    PubMed Central

    Hunter, R

    1988-01-01

    1. The pharmacokinetics of lithium in six healthy volunteers stabilised on lithium were investigated and appropriate pharmacokinetic parameters calculated. 2. The results illustrate important differences in single and multiple dose lithium pharmacokinetics; the implications for minimising lithium-induced renal damage are discussed. PMID:3129009

  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. Clinical pharmacokinetics of camptothecin topoisomerase I inhibitors.

    PubMed

    Herben, V M; Ten Bokkel Huinink, W W; Schellens, J H; Beijnen, J H

    1998-08-01

    In this review the clinical pharmacokinetics of camptothecin topoisomerase I inhibitors, an important new class of anticancer drugs, is discussed. Two prototypes, topotecan and irinotecan, are currently marketed in many European countries and the USA for the treatment of patients with ovarian and colorectal cancer, respectively. Other camptothecin derivatives, including lurtotecan, 9-aminocamptothecin (9-AC) and 9-nitrocamptothecin (9-NC), are at different stages of clinical development. The common property of camptothecin analogues is their action against DNA topoisomerase I, but beyond this similarity the compounds differ widely in terms of antitumour efficacy, pharmacology, pharmacokinetics and metabolism. We review chemistry, mechanism of action, stability and bioanalysis of the camptothecins. Dosage and administration, status of clinical application, pharmacokinetics, pharmacodynamics and drug interactions are discussed. PMID:9762728

  12. Radiobiological Optimization of Combination Radiopharmaceutical Therapy Applied to Myeloablative Treatment of Non-Hodgkin’s Lymphoma

    PubMed Central

    Hobbs, Robert F; Wahl, Richard L; Frey, Eric C; Kasamon, Yvette; Song, Hong; Huang, Peng; Jones, Richard J; Sgouros, George

    2014-01-01

    Combination treatment is a hallmark of cancer therapy. Although the rationale for combination radiopharmaceutical therapy was described in the mid ‘90s, such treatment strategies have only been implemented clinically recently, and without a rigorous methodology for treatment optimization. Radiobiological and quantitative imaging-based dosimetry tools are now available that enable rational implementation of combined targeted radiopharmaceutical therapy. Optimal implementation should simultaneously account for radiobiological normal organ tolerance while optimizing the ratio of two different radiopharmaceuticals required to maximize tumor control. We have developed such a methodology and applied it to hypothetical myeloablative treatment of non-hodgkin’s lymphoma (NHL) patients using 131I-tositumomab and 90Y-ibritumomab tiuxetan. Methods The range of potential administered activities (AA) is limited by the normal organ maximum tolerated biologic effective doses (MTBEDs) arising from the combined radiopharmaceuticals. Dose limiting normal organs are expected to be the lungs for 131I-tositumomab and the liver for 90Y-ibritumomab tiuxetan in myeloablative NHL treatment regimens. By plotting the limiting normal organ constraints as a function of the AAs and calculating tumor biological effective dose (BED) along the normal organ MTBED limits, the optimal combination of activities is obtained. The model was tested using previously acquired patient normal organ and tumor kinetic data and MTBED values taken from the literature. Results The average AA values based solely on normal organ constraints was (19.0 ± 8.2) GBq with a range of 3.9 – 36.9 GBq for 131I-tositumomab, and (2.77 ± 1.64) GBq with a range of 0.42 – 7.54 GBq for 90Y-ibritumomab tiuxetan. Tumor BED optimization results were calculated and plotted as a function of AA for 5 different cases, established using patient normal organ kinetics for the two radiopharmaceuticals. Results included AA ranges

  13. A minor possibility of pharmacokinetic interaction between enoxacin and fenbufen in rats.

    PubMed

    Naora, K; Katagiri, Y; Ichikawa, N; Hayashibara, M; Iwamoto, K

    1990-02-01

    In order to clarify the possibility of pharmacokinetic interaction between quinolone and fenbufen, the plasma concentration-time profiles and serum protein binding of enoxacin, fenbufen and its active metabolite, felbinac, were investigated in rats. The rats were administered an intravenous dose of enoxacin (5 mg/kg) and fenbufen (10 mg/kg) alone or concomitantly. Coadministration with fenbufen tended to prolong the plasma elimination half-life of enoxacin by about 20%, whereas it showed no effect on the area under plasma concentration-time curve, total body clearance or distribution volume of enoxacin. The extent of enoxacin binding to rat serum tended to be slightly reduced by fenbufen in vivo and in vitro. Plasma concentration-time curves, pharmacokinetic parameters and serum protein binding of fenbufen and felbinac were not affected at all by the coadministration with enoxacin. These aspects suggest that there may be only a minor possibility of the pharmacokinetic interaction between enoxacin and fenbufen. PMID:2384853

  14. The Wordpath Show.

    ERIC Educational Resources Information Center

    Anderton, Alice

    The Intertribal Wordpath Society is a nonprofit educational corporation formed to promote the teaching, status, awareness, and use of Oklahoma Indian languages. The Society produces "Wordpath," a weekly 30-minute public access television show about Oklahoma Indian languages and the people who are teaching and preserving them. The show aims to…

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

    SciTech Connect

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

    1982-03-01

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

  16. 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

    Ge, Zhaohui; Xie, Yuanyuan; 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 C max 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

  17. 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

  18. Inhalation pharmacokinetics of isoprene in rats and mice.

    PubMed Central

    Peter, H; Wiegand, H J; Filser, J G; Bolt, H M; Laib, R J

    1990-01-01

    Studies on inhalation pharmacokinetics of isoprene were conducted in rats (Wistar) and mice (B6C3F1) to investigate possible species differences in metabolism of this compound. Pharmacokinetic analysis of isoprene inhaled by rats and mice revealed saturation kinetics of isoprene metabolism in both species. For rats and mice, linear pharmacokinetics apply at exposure concentrations below 300 ppm isoprene. Saturation of isoprene metabolism is practically complete at atmospheric concentrations of about 1000 ppm in rats and about 2000 ppm in mice. In the lower concentration range where first-order metabolism applies, metabolic clearance (related to the concentration in the atmosphere) of inhaled isoprene per kilogram body weight was 6200 mL/hr for rats and 12,000 mL/hr for mice. The estimated maximal metabolic elimination rates were 130 mumole/hr/kg for rats and 400 mumole/hr/kg for mice. This shows that the rate of isoprene metabolism in mice is about two or three times that in rats. When the untreated animals are kept in a closed all-glass exposure system, the exhalation of isoprene into the system can be measured. This shows that the isoprene endogenously produced by the animals is systemically available within the animal organism. From such experiments the endogenous production rate of isoprene was calculated to be 1.9 mumole/hr/kg for rats and 0.4 mumole/hr/kg for mice. Our data indicate that the endogenous production of isoprene should be accounted for when discussing a possible carcinogenic or mutagenic risk of this compound. PMID:2401276

  19. Pharmacokinetic properties of tandem d-peptides designed for treatment of Alzheimer's disease.

    PubMed

    Leithold, Leonie H E; Jiang, Nan; Post, Julia; Niemietz, Nicole; Schartmann, Elena; Ziehm, Tamar; Kutzsche, Janine; Shah, N Jon; Breitkreutz, Jörg; Langen, Karl-Josef; Willuweit, Antje; Willbold, Dieter

    2016-06-30

    Peptides are more and more considered for the development of drug candidates. However, they frequently exhibit severe disadvantages such as instability and unfavourable pharmacokinetic properties. Many peptides are rapidly cleared from the organism and oral bioavailabilities as well as in vivo half-lives often remain low. In contrast, some peptides consisting solely of d-enantiomeric amino acid residues were shown to combine promising therapeutic properties with high proteolytic stability and enhanced pharmacokinetic parameters. Recently, we have shown that D3 and RD2 have highly advantageous pharmacokinetic properties. Especially D3 has already proven promising properties suitable for treatment of Alzheimer's disease. Here, we analyse the pharmacokinetic profiles of D3D3 and RD2D3, which are head-to-tail tandem d-peptides built of D3 and its derivative RD2. Both D3D3 and RD2D3 show proteolytic stability in mouse plasma and organ homogenates for at least 24h and in murine and human liver microsomes for 4h. Notwithstanding their high affinity to plasma proteins, both peptides are taken up into the brain following i.v. as well as i.p. administration. Although both peptides contain identical d-amino acid residues, they are arranged in a different sequence order and the peptides show differences in pharmacokinetic properties. After i.p. administration RD2D3 exhibits lower plasma clearance and higher bioavailability than D3D3. We therefore concluded that the amino acid sequence of RD2 leads to more favourable pharmacokinetic properties within the tandem peptide, which underlines the importance of particular sequence motifs, even in short peptides, for the design of further therapeutic d-peptides. PMID:27086111

  20. A Holographic Road Show.

    ERIC Educational Resources Information Center

    Kirkpatrick, Larry D.; Rugheimer, Mac

    1979-01-01

    Describes the viewing sessions and the holograms of a holographic road show. The traveling exhibits, believed to stimulate interest in physics, include a wide variety of holograms and demonstrate several physical principles. (GA)

  1. Developing reimbursable clinical pharmacy programs: pharmacokinetic dosing service.

    PubMed

    Moore, T D; Schneider, P J; Nold, E G

    1979-11-01

    The development, operation and evaluation of a pharmacy-conducted pharmacokinetic dosing service is described. Pharmacists recommend individualized drug dosing regimens based on pharmacokinetic models and equations clinically tested for accuracy by the pharmacy department. Pharmacokinetic values are determined with the aid of online computer programs developed by the department. Drug assays are provided by the hospital's laboratory. All of the department's pharmacists were trained to provide the 24-hour service. The pharmacy department's $20 pharmacokinetic dosing service fee is reimbursed by Blue Cross. The pharmacokinetic dosing service is the first nonteaching, nonproduct-oriented pharmaceutical service whose cost-effectiveness has been recognized by a third-party payer. PMID:517538

  2. 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.

  3. 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. PMID:19535255

  4. 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.

  5. [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.

  6. 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.

  7. Radiopharmaceutical evaluation of (131)I-protohypericin as a necrosis avid compound.

    PubMed

    Liu, Xuejiao; Feng, Yuanbo; Jiang, Cuihua; Lou, Bin; Li, Yue; Liu, Wei; Yao, Nan; Gao, Meng; Ji, Yun; Wang, Qingqing; Huang, Dejian; Yin, Zhiqi; Sun, Ziping; Ni, Yicheng; Zhang, Jian

    2015-06-01

    Hypericin is a necrosis avid agent useful for nuclear imaging and tumor therapy. Protohypericin, with a similar structure to hypericin except poorer planarity, is the precursor of hypericin. In this study, we aimed to investigate the impact of this structural difference on self-assembly, and evaluate the necrosis affinity and metabolism in the rat model of reperfused hepatic infarction. Protohypericin appeared less aggregative in solution compared with hypericin by fluorescence analysis. Biodistribution data of (131)I-protohypericin showed the percentage of injected dose per gram of tissues (%ID/g) increased with time and reached to the maximum of 7.03 at 24 h in necrotic liver by gamma counting. The maximum ratio of target/non-target tissues was 11.7-fold in necrotic liver at 72 h. Pharmacokinetic parameters revealed that the half-life of (131)I-protohypericin was 14.9 h, enabling a long blood circulation and constant retention in necrotic regions. SPECT-CT, autoradiography, and histological staining showed high uptake of (131)I-protohypericin in necrotic tissues. These results suggest that (131)I-protohypericin is a promising necrosis avid compound with a weaker aggregation tendency compared with hypericin and it may have a broad application in imaging and oncotherapy. PMID:25655506

  8. Pharmacokinetics and pharmacodynamics of cannabinoids.

    PubMed

    Grotenhermen, Franjo

    2003-01-01

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

  9. In vitro assays for assessing the potential for copper complexes to function as radiopharmaceutical agents.

    PubMed

    Barnard, P J; Bayly, S R; Holland, J P; Dilworth, J R; Waghorn, P A

    2008-09-01

    A series of chemical in vitro assays are described to provide a rapid initial assessment of the in vivo stability and biological behaviour of potential new copper(II) based radiopharmaceutical agents. Chemical challenges using an excess of cysteine, glutathione (GSH) and histidine, which are models of S- and N-donor molecules found in vivo, are used to provide a measure of the potential for loss of the copper(II) ion from the radiopharmaceutical as a result of ligand dissociation. In addition, thiol containing molecules such as cysteine and GSH provide a redox challenge, whereby the copper(II) complex may be reduced to give a copper(I) species. The stability of the copper(I) species toward oxidation, protonation, and ligand dissociation may be crucial in determining the biodistribution, the biological half-life and excretion mechanisms of a potential radiopharmaceutical. Further evaluation of the redox stability is assessed using the ubiquitous biological reductant ascorbic acid. The relative stability of a complex with respect to ligand dissociation in human serum provides one of the most important experiments assessing the potential of a complex to be used in vivo. Further challenge experiments with serum proteins such as thioredoxin and serum albumin can be used to provide more detailed information on the probable fate of the complex in serum. Evaluation of complex stability and speciation over a range of pH values may also be used to obtain information on potential biodistribution. PMID:18551094

  10. 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.

  11. 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.

  12. 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. PMID:24924181

  13. Species Dependence of [64Cu]Cu-Bis(thiosemicarbazone) Radiopharmaceutical Binding to Serum Albumins

    PubMed Central

    Basken, Nathan E.; Mathias, Carla J.; Lipka, Alexander E.; Green, Mark A.

    2008-01-01

    Introduction Interactions of three copper(II) bis(thiosemicarbazone) PET radiopharmaceuticals with human serum albumin, and the serum albumins of four additional mammalian species, were evaluated. Methods 64Cu-labeled diacetyl bis(N4-methylthiosemicarbazonato)copper(II) (Cu-ATSM), pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II) (Cu-PTSM), and ethylglyoxal bis(thiosemicarbazonato)copper(II) (Cu-ETS) were synthesized and their binding to human, canine, rat, baboon, and porcine serum albumins quantified by ultrafiltration. Protein binding was also measured for each tracer in human, porcine, rat, and mouse serum. Results The interaction of these neutral, lipophilic copper chelates with serum albumin is highly compound- and species-dependent. Cu-PTSM and Cu-ATSM exhibit particularly high affinity for human serum albumin (HSA), while the albumin binding of Cu-ETS is relatively insensitive to species. At HSA concentrations of 40 mg/mL, “% Free” (non-albumin-bound) levels of radiopharmaceutical were 4.0 ± 0.1%; 5.3 ± 0.2%; and 38.6 ± 0.8% for Cu-PTSM; Cu-ATSM; and Cu-ETS, respectively. Conclusions Species-dependent variations in radiopharmaceutical binding to serum albumin may need to be considered when using animal models to predict the distribution and kinetics of these compounds in humans. PMID:18355683

  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. Show What You Know

    ERIC Educational Resources Information Center

    Eccleston, Jeff

    2007-01-01

    Big things come in small packages. This saying came to the mind of the author after he created a simple math review activity for his fourth grade students. Though simple, it has proven to be extremely advantageous in reinforcing math concepts. He uses this activity, which he calls "Show What You Know," often. This activity provides the perfect…

  16. 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)

  17. 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…

  18. 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)

  19. 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)

  20. Population pharmacokinetic analysis of meloxicam in rheumatoid arthritis patients

    PubMed Central

    Meineke, Ingolf; Türck, Dietrich

    2003-01-01

    Aim To perform a nonlinear mixed effect modelling (NONMEM) population pharmacokinetic analysis of meloxicam plasma concentrations in rheumatoid arthritis (RA) patients participating in three clinical trials, and to evaluate the effects of age, weight, gender and concomitant medications on meloxicam pharmacokinetics. Methods Meloxicam was administered to RA patients once daily for 3 weeks or 6 months at doses between 7.5 and 60 mg. Plasma samples were obtained at least 7 days after the first dose and meloxicam plasma concentrations were quantified by h.p.l.c.. Results NONMEM analysis was conducted on plasma samples derived from 586 patients. A one-compartmental model was found to describe the data adequately. For a typical subject in the population, a clearance of 0.377 l h−1 (95% confidence interval (CI) 0.0304–0.449) in males and 0.347 l h−1 (95% CI 0.274-0.419) in females was obtained. The volume of distribution was estimated to be 14.9 l. The findings were corroborated by subsequent analysis using WinBUGS. Analysis of covariates showed that age and gender both significantly (P < 0.005) affected clearance. The effect of age was relatively small and a dose adjustment of <10% was deemed unnecessary. Differences between males and females were attributed to differences in weight. No clinically relevant drug-drug interactions were found, although sulphasalazine and glucocorticoids both significantly (P < 0.005) affected meloxicam clearance (+19% and −12%, respectively). The mechanisms by which these agents affect meloxicam clearance remain to be elucidated. Conclusions The population pharmacokinetic meloxicam data from patients with RA gave similar results to those obtained from phase I trials. However, uncommon drug interactions may not be detected in phase I trials because of the small number of observations made. PMID:12534638

  1. 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

  2. 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. PMID:20359856

  3. Pharmacokinetics of Epsilon-Aminocaproic Acid in Neonates

    PubMed Central

    Eaton, Michael P.; Alfieris, George M; Sweeney, Dawn M; Angona, Ronald E; Cholette, Jill M; Venuto, Charles; Anderson, Brian

    2016-01-01

    Background Antifibrinolytic medications such as epsilon-aminocaproic acid (EACA) are used in pediatric heart surgery to decrease surgical bleeding and transfusion. Dosing schemes for neonates are often based on adult regimens, or are simply empiric, in part due to the lack of neonatal pharmacokinetic information. We sought to determine the pharmacokinetics of EACA in neonates undergoing cardiac surgery and to devise a dosing regimen for this population. Methods Ten neonates undergoing cardiac surgery with cardiopulmonary bypass were given EACA according to standard practice, and blood was drawn at 10 time points to determine drug concentrations. Time-concentration profiles were analyzed using nonlinear mixed effects models. Parameter estimates (standardized to a 70 kg person) were used to develop a dosing regimen intended to maintain a target concentration shown to inhibit fibrinolysis in neonatal plasma (50 mg/L). Results Pharmacokinetics were described using a two compartment model plus an additional compartment for the cardiopulmonary bypass pump. First order elimination was described with a clearance of 5.07 L/h*(WT/70) 0.75. Simulation showed a dosing regimen with a loading dose of 40 mg/kg, and an infusion of 30 mg/kg/h, with a pump prime concentration of 100 mg/L maintained plasma concentrations above 50 mg/L in 90% of neonates during cardiopulmonary bypass surgery. Conclusions EACA clearance, expressed using allometry, is reduced in neonates compared to older children and adults. Loading dose and infusion dose are approximately half those required in children and adults. PMID:25723765

  4. Developmental pharmacokinetics of propylene glycol in preterm and term neonates

    PubMed Central

    De Cock, Roosmarijn F W; Knibbe, Catherijne A J; Kulo, Aida; de Hoon, Jan; Verbesselt, Rene; Danhof, Meindert; Allegaert, Karel

    2013-01-01

    AIM Propylene glycol (PG) is often applied as an excipient in drug formulations. As these formulations may also be used in neonates, the aim of this study was to characterize the pharmacokinetics of propylene glycol, co-administered intravenously with paracetamol (800 mg PG/1000 mg paracetamol) or phenobarbital (700 mg PG/200 mg phenobarbital) in preterm and term neonates. METHODS A population pharmacokinetic analysis was performed based on 372 PG plasma concentrations from 62 (pre)term neonates (birth weight (bBW) 630–3980 g, postnatal age (PNA) 1–30 days) using NONMEM 6.2. The model was subsequently used to simulate PG exposure upon administration of paracetamol or phenobarbital in neonates (gestational age 24–40 weeks). RESULTS In a one compartment model, birth weight and PNA were both identified as covariates for PG clearance using an allometric function (CLi= 0.0849 × {(bBW/2720)1.69× (PNA/3)0.201}). Volume of distribution scaled allometrically with current bodyweight (Vi= 0.967 × {(BW/2720)1.45}) and was estimated 1.77 times higher when co-administered with phenobarbital compared with paracetamol. By introducing these covariates a large part of the interindividual variability on clearance (65%) as well as on volume of distribution (53%) was explained. The final model shows that for commonly used dosing regimens, the population mean PG peak and trough concentrations range between 33–144 and 28–218 mg l−1 (peak) and 19–109 and 6–112 mg l−1 (trough) for paracetamol and phenobarbital formulations, respectively, depending on birth weight and age of the neonates. CONCLUSION A pharmacokinetic model was developed for PG co-administered with paracetamol or phenobarbital in neonates. As such, large variability in PG exposure may be expected in neonates which is dependent on birth weight and PNA. PMID:22536830

  5. Pharmacokinetics and Safety of Intravitreal Caspofungin

    PubMed Central

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

    2014-01-01

    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. PMID:25246398

  6. 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). PMID:26807087

  7. Pharmacokinetic Modeling of Perfluoroalkyl Acids in Rodents

    EPA Science Inventory

    Perfluorooctanoic acid (PFOA) has pharmacokinetic properties that appear consistent with a number of processes that are currently not well understood. Studies in mice exposed orally at lower doses (1 and 10 mg/kg) demonstrated blood, liver, and kidney concentration time courses ...

  8. 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. PMID:26344676

  9. Microcomputer-Based Programs for Pharmacokinetic Simulations.

    ERIC Educational Resources Information Center

    Li, Ronald C.; And Others

    1995-01-01

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

  10. A Terminal Pharmaceutics Course in Clinical Pharmacokinetics.

    ERIC Educational Resources Information Center

    Reuning, Richard H.; Krautheim, Daniel

    1978-01-01

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