PRELIMINARY SAFETY EVALUATION OF PARENTERALLY ADMINISTERED SULFOALKYL ETHER BETA-CYCLODEXTRIN DERIVATIVES

被引:121
|
作者
RAJEWSKI, RA
TRAIGER, G
BRESNAHAN, J
JABERABOANSARI, P
STELLA, VJ
THOMPSON, DO
机构
[1] UNIV KANSAS,HIGUCHI BIOSCI CTR DRUG DELIVERY RES,LAWRENCE,KS 66047
[2] UNIV KANSAS,DEPT PHARMACOL & TOXICOL,LAWRENCE,KS 66047
[3] UNIV KANSAS,ANIM CARE UNIT,LAWRENCE,KS 66047
[4] CYDEX LC,OVERLAND PK,KS 66212
关键词
D O I
10.1002/jps.2600840805
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Parenteral administration of beta-cyclodextrin (beta-CD) results in renal and/or local toxicity dependent on the mode of administration. In an attempt to alleviate these properties, a series of anionically charged sulfoalkyl ether cyclodextrin (SAE;-beta-CD) derivatives have been developed. The parenteral safety of these derivatives was determined by survival of male mice after intraperitoneal (ip) injection, kidney histopathology, plasma urea nitrogen levels of mice determined 24 h after injection, relative in vitro hemolytic potential and activated partial thromboplastin times (APTT). In addition, the 24-h renal excretion behavior of the derivatives was measured. Where appropriate, the results obtained with these cyclodextrin derivatives were compared with results obtained for beta-CD and (hydroxypropyl)-beta-cyclodextrin (HP-beta-CD). The SAE-beta-CD derivatives did not produce mortality in mice following ip injection at doses exceeding 5.45 mmol/kg. No significant histological lesions were observed in the kidney tissue of mice receiving the cyclodextrin derivatives. The SAE-beta-CD derivatives were excreted faster and to a greater extent than beta-CD and at rates comparable to HP-beta-CD. The hemolytic potential of these derivatives was less than that of beta-CD and comparable to or better than that of HP-beta-CD. The SAE-beta-CD derivatives did not increase APTT clotting times indicating that these derivatives have no significant anticoagulant activity. The toxicological profile of these derivatives suggests that these molecules may have application as biologically safe beta-CD derivatives.
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收藏
页码:927 / 932
页数:6
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