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Titolo:
Absorption, distribution, metabolism, and excretion of a respirable antisense oligonucleotide for asthma
Autore:
Ali, S; Leonard, SA; Kukoly, CA; Metzger, WJ; Wooles, WR; McGinty, JF; Tanaka, M; Sandrasagra, A; Nyce, JW;
Indirizzi:
EpiGenesis Pharmaceut Inc, Dept Mol Pharmacol & Therapeut, Princeton, NJ USA EpiGenesis Pharmaceut Inc Princeton NJ USA Therapeut, Princeton, NJ USA Asthma & Allergy Ctr Eastern N Carolina, Sch Med, Greenville, NC USA Asthma & Allergy Ctr Eastern N Carolina Greenville NC USA nville, NC USA Natl Jewish Med & Res Ctr, Denver, CO USA Natl Jewish Med & Res Ctr Denver CO USA sh Med & Res Ctr, Denver, CO USA E Carolina Univ, Sch Med, Dept Pharmacol, Greenville, NC USA E Carolina Univ Greenville NC USA ed, Dept Pharmacol, Greenville, NC USA Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA MedUniv S Carolina Charleston SC USA 29425 sci, Charleston, SC 29425 USA Taisho Pharmaceut Co Ltd, Sci Evaluat Grp, Toshima Ku, Tokyo, Japan TaishoPharmaceut Co Ltd Tokyo Japan luat Grp, Toshima Ku, Tokyo, Japan
Titolo Testata:
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
fascicolo: 4, volume: 163, anno: 2001,
pagine: 989 - 993
SICI:
1073-449X(200103)163:4<989:ADMAEO>2.0.ZU;2-L
Fonte:
ISI
Lingua:
ENG
Soggetto:
PHOSPHOROTHIOATE OLIGONUCLEOTIDE; GENE-EXPRESSION; IN-VIVO; PHARMACOKINETICS; THERAPY; RATS; THERAPEUTICS; INHIBITION; DELIVERY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
25
Recensione:
Indirizzi per estratti:
Indirizzo: Nyce, JW EpiGenesis Pharmaceut Inc, 7 Clarke Dr, Cranbury, NJ 08512 USA EpiGenesis Pharmaceut Inc 7 Clarke Dr Cranbury NJ USA 08512 2 USA
Citazione:
S. Ali et al., "Absorption, distribution, metabolism, and excretion of a respirable antisense oligonucleotide for asthma", AM J R CRIT, 163(4), 2001, pp. 989-993

Abstract

EPI-2010 is a respirable antisense oligonucleotide (RASON), which selectively attenuates discordantly overexpressed adenosine A, receptors in allergic lung (Nature 1997;385:721). In the present study, aerosolized [S-35]-labeled EPI-2010 (5 mg exposure; specific activity 0.055 Ci/mmol) was administered to normal rabbits by endotracheal tube to assess biodistribution, routeof elimination, and potential cardiovascular toxicity. The animals were killed at 0, 6, 24, 48, and 72 h after inhalation of EPI-2010. Duplicate aliquots from different tissues and samples were solubilized and assessed for radioactivity. Approximately 1.4% of the total aerosolized EPI-2010 was deposited into the lung. The concentration of the drug in the lung at 0, 6, 24 48, and 72 h was 64.0 +/- 1.5, 67.0 +/- 4.4, 32.0 +/- 3.7, 23.4 +/- 1.4, and 2.1 +/- 0.5 mug equivalents, respectively. Only a small amount of the radioactivity was detected in extrapulmonary tissues. By 72 h, 67.5% of the administered dose was excreted in the urine, which represented the major pathway of elimination. In postlabeling studies, intact full-length EPI-2010 could only be detected in the lung. Autoradiographic analysis after inhalation of [35S]-labeled EPI-2010 showed a relatively uniform deposition of drug throughout the lung. The aerosolized EPI-2010 did not have any significant systemic effects on the cardiovascular system as determined by Cardiomax-IIanalysis. This pattern of distribution and the lack of effect on cardiovascular function support the concept that RASONs offer the potential to safely address respiratory targets for which systemic distribution and systemic bioavailability may be contraindicated.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/03/20 alle ore 19:52:06