title: GT160-246, a toxin binding polymer for treatment of Clostridium difficile colitis.
abstract: GT160-246, a high-molecular-weight soluble anionic polymer, was tested in vitro and in vivo for neutralization of Clostridium difficile toxin A and B activities. Five milligrams of GT160-246 per ml neutralized toxin-mediated inhibition of protein synthesis in Vero cells induced by 5 ng of toxin A per ml or 1.25 ng of toxin B per ml. In ligated rat ileal loops, 1 mg of GT160-246 neutralized fluid accumulation caused by 5 microg of toxin A. At doses as high as 80 mg/loop, cholestyramine provided incomplete neutralization of fluid accumulation caused by 5 microg of toxin A. GT160-246 protected 80% of the hamsters from mortality caused by infection with C. difficile, whereas cholestyramine protected only 10% of animals. Treatment of C. difficile-infected hamsters with metronidazole initially protected 100% of the hamsters from mortality, but upon removal of treatment, 80% of the hamsters had relapses and died. In contrast, removal of GT160-246 treatment did not result in disease relapse in the hamsters. GT160-246 showed no antimicrobial activity in tests with a panel of 16 aerobic bacteria and yeast and 22 anaerobic bacteria and did not interfere with the in vitro activities of most antibiotics. GT160-246 offers a novel, nonantimicrobial treatment of C. difficile disease in humans.
authors.affiliation: GelTex Pharmaceuticals, Inc., Waltham, Massachusetts 02451, USA. ckurtz@geltex.com
authors.forename: C B
authors.initials: CB
authors.lastname: Kurtz
authors.forename: E P
authors.initials: EP
authors.lastname: Cannon
authors.forename: A
authors.initials: A
authors.lastname: Brezzani
authors.forename: M
authors.initials: M
authors.lastname: Pitruzzello
authors.forename: C
authors.initials: C
authors.lastname: Dinardo
authors.forename: E
authors.initials: E
authors.lastname: Rinard
authors.forename: D W
authors.initials: DW
authors.lastname: Acheson
authors.forename: R
authors.initials: R
authors.lastname: Fitzpatrick
authors.forename: P
authors.initials: P
authors.lastname: Kelly
authors.forename: K
authors.initials: K
authors.lastname: Shackett
authors.forename: A T
authors.initials: AT
authors.lastname: Papoulis
authors.forename: P J
authors.initials: PJ
authors.lastname: Goddard
authors.forename: R H
authors.initials: RH
authors.lastname: Barker
authors.forename: G P
authors.initials: GP
authors.lastname: Palace
authors.forename: J D
authors.initials: JD
authors.lastname: Klinger
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors; D001427:Bacterial Toxins / Q000378:metabolism*; D002522:Chlorocebus aethiops; D002792:Cholestyramine Resin / Q000627:therapeutic use; D016360:Clostridioides difficile / Q000502:physiology*; D003015:Clostridium Infections / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D006224:Cricetinae; D004768:Enterotoxins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007477:Ions / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D007769:Lactams / Q000494:pharmacology; D008297:Male; D008795:Metronidazole / Q000627:therapeutic use; D008826:Microbial Sensitivity Tests; D011108:Polymers / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013451:Sulfonic Acids; D015996:Survival Rate; D014709:Vero Cells / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D007477:Ions; D007769:Lactams; D011108:Polymers; D013451:Sulfonic Acids; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D002792:Cholestyramine Resin; D008795:Metronidazole; C077114:styrenesulfonic acid polymer