title: Efficacy of intracolonic administration of low-molecular-weight heparin CB-01-05, compared to other low-molecular-weight heparins and unfractionated heparin, in experimentally induced colitis in rat.
abstract: OBJECTIVE
  Parenteral administration of low-molecular-weight heparins (LMWHs) and unfractionated heparin (UFH) resulted effective in improving the symptoms of experimental colitis in rat. Today, there is little information about their activity by intracolonic instillation. The scope of this study was to evaluate the ability of CB-01-05 (a LMWH with a mean molecular weight of about 5,700), compared to a series of other LMWHs and to UFH, directly instilled into the distal colon of the rat, to ameliorate dinitrobenzene (DNB)-induced experimental colitis.
  
  
  METHODS
  Adult male Wistar rats underwent colitis induction by intracolonic instillation of DNB. Starting 24 h after colitis induction, CB-01-05 (0.005-0.9 mg), other LMWHs (0.3-0.6 mg), and UFH (0.6 mg) were instilled, by rectal route, into the distal colon once a day for three consecutive days. On the day following the last administration, the animals were sacrificed and the distal colon was isolated, weighed, macroscopically examined, and processed for histology. Additional experiments in rat splenocytes, performed in order to elucidate the anti-inflammatory mechanisms of CB-01-05, were performed.
  
  
  RESULTS
  Among the tested items, only CB-01-05 at doses ranging from 0.2 to 0.9 mg was significantly effective in reducing colon weight increase and in improving both the mucosal damaged area and the histological score. The other LMWHs resulted far less effective, showing decreasing activity closely related with the decrease of their molecular weight, thus demonstrating their biological nonequivalence. CB-01-05 resulted also more active than UFH. CB-01-05 was shown to interfere with cytokines production by rat splenocytes, mainly inhibiting interferon (IFN)-gamma expression.
  
  
  CONCLUSIONS
  CB-01-05 instilled into the colon is well tolerated, has strong anti-inflammatory effect on DNB-induced colitis in rat, and is the most effective agent among other LMWHs and UFH. These results suggest that the anti-inflammatory activity of CB-01-05, together with its topical administration, could represent a new approach in the management of ulcerative colitis.
authors.affiliation: Cosmo Research and Development Srl, Via C. Colombo 1, 20020, Lainate, MI, Italy. giuseppe.celasco@cosmopharmaceuticals.com
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Celasco
authors.forename: Luigi
authors.initials: L
authors.lastname: Moro
authors.forename: Roberta
authors.initials: R
authors.lastname: Bozzella
authors.forename: Katia
authors.initials: K
authors.lastname: Mangano
authors.forename: Cinzia
authors.initials: C
authors.lastname: Quattrocchi
authors.forename: Caterina
authors.initials: C
authors.lastname: Aiello
authors.forename: Marco
authors.initials: M
authors.lastname: Donia
authors.forename: Paolo
authors.initials: P
authors.lastname: Fagone
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Marco
mesh_terms: D000285:Administration, Rectal; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D004136:Dinitrobenzenes; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000378:metabolism
chemical_list: D004136:Dinitrobenzenes; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D007371:Interferon-gamma; C080945:parnaparin