Pii: s0166-3542(98)00015-

Long-term stability of the anti-influenza A Christoph Scholtissek, Robert G. Webster * Department of Virology and Molecular Biology, St. Jude Childrens Research Hospital, 332 N. Lauderdale, P.O. Box 318, Memphis, Received 14 June 1997; accepted 5 September 1997 Abstract
Amantadine and rimantadine hydrochloride were tested for stability after storage at different temperatures and under different conditions for extended periods of time. Both compounds were quite stable after storage for at least25 years at ambient temperature; they both retained full antiviral activity after long-term storage or after boiling andholding at 65 – 85°C for several days. Thus, amantadine and rimantadine could be synthesized in large quantities andstored for at least one generation without loss of activity in preparation for the next influenza A pandemic in humans.
1998 Elsevier Science B.V. All rights reserved.
Keywords: Anti-influenza compounds; Amantadine; Rimantadine Amantadine is a derivative of adamantane that necessary for fusion of the endosomal and viral efficiently inhibits replication of influenza A membranes (Daniels et al., 1985; Steinhauer et al., viruses (Davies et al., 1964). This drug inhibits 1991). Because influenza viruses (like other RNA replication by interfering with the ion channel viruses) have a relatively error-prone polymerase activity of the matrix (M)-2 protein (Sugrue and and no repair system, drug-resistant variants can Hay, 1991; Pinto et al., 1992; Schroeder et al., be obtained easily by passing the virus in the 1994) and/or with the pH-dependent conforma- presence of amantadine (Cochran et al., 1965; tional change of the hemagglutinin (HA), which is Appleyard, 1977). The strains obtained by passingthe virus in the presence of relatively low concen-trations of amantadine ( * Corresponding author. Tel.: + 1 901 4953400; fax: + 1 901 5232622; e-mail: robert.webster@stjude.org amino acid replacements at one of four specific 0166-3542/98/$19.00 1998 Elsevier Science B.V. All rights reserved.
C. Scholtissek, R.G. Webster / Anti6iral Research 38 (1998) 213–215 Table 1Inhibition of plaque formation by amantadine and rimantadine hydrochloride Amantadine or rimantadine hydrochloride in overlay (vg/ml) Number of plaque-forming units (log ) after treatment with the following amantadine or rimantadine hydrochloride prepa-rations Preparations: 1, newly purchased amantadine hydrochloride (Sigma); 2, amantadine stored at room temperature ( :20°C) atSJCRH for at least 25 years; 3, amantadine stored at 4°C in Giessen for at least 20 years; 4, amantadine hydrochloride (Giessen)made up to 1 mg/ml in PBS, heated at 100°C for 60 min and held at 65°C for 5 days; 5, newly purchased rimantadine hydrochloride(Forest Pharmaceuticals); 6, rimantadine stored at room temperature ( :20°C) at SJCRH for at least 25 years; and 7, rimantadineheated at 100°C for 120 min and held at 80°C for 4 days.
A/Singapore/1/57 (H2N2) was diluted to produce approximately 8.0 (log ) plaques in MDCK cells and treated with amantadine and rimantadine hydrochloride in the overlay at the above concentrations.
NT, not tested.
aVery small plaques (:95% reduction) in all drug preparations tested.
bPlaques reduced in size by :50% or more in all drug preparations tested.
cA few minute plaques in each drug preparation tested.
dPlaques reduced in size by :75% or more in all drug preparations tested.
sites in the membrane-spanning region of the M2 ture ( :20°C) at St. Jude Children’s Research Hospital (SJCRH), Memphis, TN, and another In preparation for the next human influenza A batch of amantadine hydrochloride (Sigma, St.
pandemic, strategic plans have been developed in Louis, MO) was kept at 4°C for at least 20 years many countries on steps that can be taken to at the Institute of Virology in Giessen, Germany.
prepare for this event. One possibility considered These drugs were compared with freshly pur- was the preparation and storage of the two li- chased amantadine (Sigma, St. Louis, MO) and censed anti-influenza A compounds — amantadine rimantadine hydrochloride (Forest Pharmaceuti- and rimantadine. At a symposium entitled Pan- cals, USA). Stock solutions of 1 mg/ml in phos- phate buffered saline (PBS) were prepared and 1 Threat, held in Bethesda, MD in December 1995, ml of the Giessen amantadine stock solution was questions were raised about the stability of aman- boiled for 1 h and kept for 5 days at 65°C, and 1 tadine and rimantadine. Currently these two ml of the Memphis rimantadine stock solution drugs have a short FDA approval time of only 2 was boiled for 2 h and kept for 4 days at 80°C.
To investigate the stability of these two com- were used throughout the study and were infected pounds, studies were done on drug preparations with A/Singapore/1/57 (H2N2) at appropriate di- available in two different laboratories. One batch lutions starting with approximately 108 plaque- of amantadine hydrochloride and one of riman- forming units/ml and overlaid with agar in Eagle’s tadine hydrochloride (Dupont, Wilmington, DE) minimal essential medium containing 4% bovine were kept for at least 25 years at room tempera- serum albumin, 0.5 vg/ml trypsin, and the drugs C. Scholtissek, R.G. Webster / Anti6iral Research 38 (1998) 213–215 at various concentrations as given in Table 1. For tute of Allergy and Infectious Disease, Cancer each dilution one monolayer was used. Each ex- Center Support (CORE) Grant CA-21765 from periment was conducted at least twice. The maxi- the National Cancer Institute, and the American mal difference in two independent experiments Lebanese Syrian Associated Charities. We thank Janice Cole and Dayna Baker for typing the Each of the preparations of amantadine hy- drochloride inhibited plaque formation by A/Sin-gapore/1/57 (H2N2) influenza virus and therewere no detectable differences between the prepa- References
rations (Table 1). It is noteworthy that each of thepreparations caused plaque size reduction at the Appleyard, G., 1977. Amantadine-resistance as genetic marker same concentrations and that heating to 100°C for influenza viruses. J. Gen. Virol. 36, 249 – 255.
and storage at 65°C for 5 days also failed to Cochran, K.W., Maassab, H.R., Tsunoda, A., Berlin, B.S., 1965. New studies of the antiviral activity of amantadine decrease the biological activity of amantadine hy- hydrochloride. Ann. NY Acad. Sci. 130, 432 – 439.
drochloride. Comparable results were obtained Daniels, R.S., Downie, J.C., Hay, A.J., Knossow, M., Skehel, with rimantadine. At the lowest dose tested (0.05 J.J., Wang, M.L., Wiley, D.C., 1985. Fusion mutants of vg/ml), only a few micro plaques were observed the influenza virus hemagglutinin glycoprotein. Cell 40, with all three samples. Higher doses completely Davies, W.L., Grunert, R.R., Haff, R.F., McGahen, J.W., inhibited plaque formation by A/Singapore/1/57 Neumayer, E.M., Paulshok, M., Watts, J.C., Wood, T.R., Herrmann, E.C., Hoffmann, C.E., 1964. Antiviral activity These results indicate that both amantadine of 1-adamantanamine (amantadine). Science 144, 862 – 863.
and rimantadine are extraordinarily stable, and Hay, A.J., Wolstenholm, A.J., Skehel, J.J., Smith, M.H., 1985.
would be ideal for long-term storage for use in the The molecular basis of the specific anti-influenza action ofamantadine. EMBO J. 4, 3021 – 3024.
initial stages of a new influenza A pandemic.
Pinto, L.H., Holsinger, L.J., Lamb, R.A., 1992. Influenza According to our estimates, it would be difficult virus M2 protein has ion channel activity. Cell 69, 517 – even for our grandchildren to determine the ex vivo decay time of these compounds. After a new Schroeder, C., Ford, C.M., Wharton, S.A., Hay, A.J., 1994.
influenza A pandemic has appeared, and while a Functional reconstitution in lipid vesicles of influenza virus vaccine is under development, amantadine and M2 protein expressed by baculovirus: evidence of protontransfer activity. J. Gen. Virol. 75, 3477 – 3484.
rimantadine are the only FDA-approved drugs Steinhauer, D.A., Wharton, S.W., Skehel, J.J., Wiley, D.C., Hay, A.J., 1991. Amantadine selection of a mutant influ-enza virus containing an acid-stable hemagglutinin glyco-protein: evidence for virus-specific regulation of the pH of Acknowledgements
glycoprotein transport vesicles. Proc. Natl. Acad. Sci. USA88, 11525 – 11529.
Sugrue, R.J., Hay, A.J., 1991. Structural characteristics of the This work was supported by US Public Health M2 protein of influenza A viruses: evidence that it forms a Service Grants AI-08831 from the National Insti- tetrameric channel. Virology 180, 617 – 624.

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