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Comparison of Absorbents and Drugs for Internal Decorporation

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Comparison of Absorbents and Drugs for Internal Decorporation Biological and Pharmaceutical Bulletin Advance Publication by J-STAGE Advance Publication DOI:10.1248/bpb.b15-00728 December 25, 2015 Biol. Pharm. Bull. Regular Article Comparison of Absorbents and Drugs for Internal Decorporation of Radiocesium: Advances of Polyvinyl Alcohol Hydrogel Microsphere Preparations Containing Magnetite and Prussian Blue. Izumi Tanaka, Hiroshi Ishihara*, Haruko Yakumaru, Mika Tanaka, Kazuko Yokochi, Katsushi Tajima, Makoto Akashi Internal Decorporation Research Team, Research Program for Radiation Medicine, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba-shi, Chiba 263-85555, Japan *Corresponding author. Internal Decorporation Research Team, Research Program for Radiation Medicine, Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba-shi, Chiba 263-85555, Japan. Tel: +81-43-206-3162; Fax: +81-43-284-1769; Email: [email protected] Ⓒ 2015 The Pharmaceutical Society of Japan Summary Radiocesium nuclides, used as a gamma ray source in various types of industrial equipments and found in nuclear waste, are strictly controlled to avoid their leakage into the environment. When large amounts of radiocesium are accidentally incorporated into the human body, decorporation therapy should be considered. Although standard decorporation methods have been studied since the 1960s and were established in the 1970s with the drug Radiogardase® (a Prussian blue preparation), application of recent advances in pharmacokinetics and ethical standards could improve these methods. Here we designed a modern dosage form of hydrogel containing cesium-absorbents to alleviate intestinal mucosa irritation due to the cesium-binding capacity of the absorbents. The effectiveness of the dosage form on fecal excretion was confirmed by quantitative mouse experiments. The total cesium excretion rate of the crystal form (1.37 ± 0.09) was improved by the hydrogel form (1.52 ± 0.10) at the same dose of Prussian blue, with a longer gastrointestinal tract transit time. Using a mouse model, we compared the effects of several drugs on fecal and urinary excretion of internal cesium, without the use of absorbents. Only phenylephrine hydrochloride significantly enhanced cesium excretion (excretion rate of 1.17 ± 0.08) via the urinary pathway, whereas none of the diuretic drugs tested had this Biological and Pharmaceutical Bulletin Advance Publication effect. These findings indicate that modifying the dosage form of cesium absorbents is important for the decorporation of internal radiocesium contamination. Key Words: Radiocesium; Prussian blue; Zeolite; Diuretics; Phenylephrine Biological and Pharmaceutical Bulletin Advance Publication INTRODUCTION Internal contamination with radiocesium generated by nuclear fission may occur after nuclear weapon testing and serious nuclear plant accidents 1). In addition, concentrated radiocesium is frequently used industrially as a source of gamma rays. Accidental incorporation of radiocesium may also occur due to mishandling, inadequate security, terrorism or complex disasters. 2) Studies of contamination countermeasures have been performed, but few studies have examined methods of internal contamination. Cesium is an alkaline metal and the biokinetics of cesium have been studied in detail. 3) Briefly, ingested cesium rapidly disperses throughout the whole-body in ion form without sedimentation. Cesium in body fluids is incorporated into several cell types by ionic pumps, and then leaked back to the fluid via potassium channels in the plasma membrane. Cesium particularly accumulates in skeletal muscle, because of its large influx/efflux rate, where it is retained for several months in human. Cesium in the body fluid is mainly excreted in urine. Although large amounts of cesium are released to the gastrointestinal (GI) tract, most of it is reabsorbed by the intestine and returned to the body fluid. Thus, the final rate of excretion of cesium from the body through feces, urine and sweat is estimated to be 13%, 85% and 2%, respectively, in human. 3) Biological and Pharmaceutical Bulletin Advance Publication Medical treatment for radiocesium decorporation is recommended when the committed dose is predicted to be 30 to 300 mSv. 4) The effectiveness of oral administration of Prussian blue is established based on studies of various cesium absorbents. 5) In principle, ingested Prussian blue crystals capture radiocesium ions released in the GI tract, and are excreted with the feces while blocking intestinal reabsorption, thus enhancing the fecal radiocesium decorporation rate. 3) Since the 1970s, Radiogardase®, a capsule containing Prussian blue crystals, has been sold on the market for treating serious accidental internal exposure to radiocesium. 6, 7) Although standard treatment using domestic stockpiles of Radiogardase® is established, 8) medical concepts are evolving to enhance the effectiveness and reduce patient discomfort. Recent findings and technologic advancements reveal room for improvement of the radiocesium decorporation method. In this paper, we describe an improved radiocesium decorporation treatment based on modifications of the form of cesium absorbents, and confirmed by comparison with the present absorbents. The effects were quantified by decorporation tests in mice. We also examined the effect of drugs that act to facilitate urinary and fecal excretion of body fluids. Biological and Pharmaceutical Bulletin Advance Publication MATERIALS AND METHODS Cesium-absorbents and Reagents The ferrocyanides used as cesium absorbents in the present study comprised water-soluble colloidal preparations of Prussian blue III II [KFe Fe (CN)6], microcrystal preparations less than 1 μm in diameter of Prussian blue III II II II II II [Fe 4Fe 3(CN)18-KCl-nH2O], K2Ni Fe (CN)6 and K2Co Fe (CN)6. The preparations III II were made by mixing 0.25 mol/L solutions of Fe Cl3, CoCl2, NiCl2, or K4[Fe (CN)6] (Wako Pure Chemical Industries, Ltd). Dialysis was performed to purify the preparations or to substitue the alkali metals. Insoluble Prussian blue with 14 to 16 water molecules corresponding to Radiogardase® was prepared by freeze-drying or dehydrating the microcrystals at 80°C. The sizes of the microcrystals and colloid were measured using the dynamic and static light-scattering method with a DelsaTM Max (Beckman-Coulter Inc.), supported by Beckman Coulter K.K. Japan. Synthetic zeolite with a mean particle size of 2 to 4 μm (Wako Pure Chemical Industries, Ltd.), and apple pectin (Wako) were also used. Drugs for Mouse Experiments The following drugs were used in this study: Radiogardase® (HEYL Chemisch-Pharmazeutische Fabrik GmbH und Co., KG), phenylephrine hydrochloride (Neo-Synesin Kowa, Kowa Pharmaceutical Co., Ltd.), adrenaline (Bosmin® injection, Dai-ichi Sankyo Co. Ltd), clonidine hydrochloride (Wako), phentolamine mesilate (Regitin® injection, Novartis Pharma), nisoldipine (Baymycard®, Bayer HealthCare), and hydralazine hydrochloride (Apresoline®, Novartis Pharma). As a cathartic, D-sorbitol (Wako) and magnesium succinate (Magcorol®, Horii Pharmaceutical Ind., Ltd.) were used. As diuretics, acetazolamide sodium (Diamox®, Biological and Pharmaceutical Bulletin Advance Publication Sanwa Kagaku Kenkyusho Co., Ltd.), furosemide (Lasix®, Nichi-Iko Pharmaceutical Co., Ltd.), trichlormethiazide (Fluitran®, Shionogi & Co., Ltd.), indapamide (Natrix®, Kyoto Pharmaceutical Ind., Ltd), potassium canrenoate (Soldactone®, Pfizer Japan Inc.), eplerenone (Selara®, Pfizer Japan Inc.) and isosorbide (Isobide®, Kowa Pharmaceutical Co., Ltd.) were used. Their administration doses (per kg-body weight) in mice corresponded to the upper limit dose in humans. Preparation of Polyvinyl Alcohol Hydrogel A mixture of 5% polyvinyl alcohol (PVA, polymerization degree ~500, Wako) in 0.25 mol/L HCl containing magnetite silica particles (final conc. = 20mg/mL of sicastarR-M plain, diameter of 350nm, Micromod Partikeltechnologie GmbH) and Prussian blue or metal-ferrocyanide microcrystals of II II II II K2Ni Fe (CN)6 and K2Co Fe (CN)6 (final conc. = 66.3 μmol/mL of ferrocyanide) was kept on ice. After adding 50% glutaraldehyde (Wako) to a final concentration of 1.5%, the mixture was emulsified with a 4-fold volume of mineral oil (Sigma-Aldrich Co., LLC.) containing 2.5% sorbitan sesquioleate (Sigma-Aldrich). Polymerization of PVA was achieved by keeping the mixture at 50°C. The PVA gel was isolated, purified by sequential extractions with ether, ethanol and water, and sieved. The microsphere of the magnetic PVA preparations of cesium-absorbents with diameters ranging from 10 to 50 μm were freeze-dried to insolubilize the ferrocyanides and for storage. The freeze-dried preparations were hydrated before use. Cesium Absorption Test in vitro To evaluate the absorption of cesium in vitro, solid absorbents (corresponding to 1 μmol ferrocyanide) were mixed with 2.5-fold molar amounts (2.5 μmol) of cesium chloride containing 440.5 Bq (1.0 pmole) of 137Cs (Eckert & Ziegler Isotope Products). Radioactivity in the supernatant was measured to calculate Biological and Pharmaceutical Bulletin Advance Publication radiocesium binding in the solid. For water-soluble absorbents, the solution was put into a dialyzed membrane and immersed in solution containing 2.5-fold molar amounts of the expected absorbance capacity of cesium chloride with 137Cs. After incubation at 37°C simulating in vivo treatment for the appropriate
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