title: Nonsteroidal anti-inflammatory drug and phospholipid prodrugs: combination therapy with antisecretory agents in rats.
abstract: OBJECTIVE
  The gastrointestinal side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are reduced by antisecretory agents. The effects of combination therapy on the gastrointestinal toxicity and therapeutic activity of free and phospholipid-associated NSAIDs were investigated in rats.
  
  
  METHODS
  Fasted rats, pretreated with either saline or an antisecretory dose of omeprazole, ranitidine, or cimetidine, were intragastrically administered saline, aspirin, or indomethacin. In ulcer models, gastric lesions in aspirin-treated rats and intestinal bleeding in indomethacin-treated rats were measured. For antipyretic and analgesic activity, rectal body temperature in febrile rats and the rats' pain sensitivity to pressure applied to an inflamed limb were measured, respectively.
  
  
  RESULTS
  NSAID-induced gastrointestinal ulceration and bleeding were reduced in rats pretreated with antisecretory agents and abolished in rats administered phospholipid-associated NSAIDs in combination with inhibitors of acid secretion. The antipyretic and analgesic activity of both NSAIDs was attenuated in rats pretreated with an antisecretory agent. This pH-dependent block in therapeutic activity was overcome if the NSAID was preassociated with a phospholipid to enhance the drug's lipophilic characteristics.
  
  
  CONCLUSIONS
  Combination therapy of antisecretory agents and NSAIDs, chemically associated with phospholipids, has distinct advantages with regard to both low gastrointestinal toxicity and restored therapeutic activity.
authors.affiliation: Department of Integrative Biology, University of Texas-Houston Medical School, Houston, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Lichtenberger
authors.forename: C
authors.initials: C
authors.lastname: Ulloa
authors.forename: J J
authors.initials: JJ
authors.lastname: Romero
authors.forename: A L
authors.initials: AL
authors.lastname: Vanous
authors.forename: P A
authors.initials: PA
authors.lastname: Illich
authors.forename: E J
authors.initials: EJ
authors.lastname: Dial
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000008:administration & dosage*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000633:toxicity; D000897:Anti-Ulcer Agents / Q000008:administration & dosage*; D002927:Cimetidine / Q000008:administration & dosage; D004064:Digestive System / Q000187:drug effects*; D004359:Drug Therapy, Combination; D008297:Male; D009853:Omeprazole / Q000008:administration & dosage; D011355:Prodrugs / Q000008:administration & dosage*; D011899:Ranitidine / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D011355:Prodrugs; D015060:1,2-Dipalmitoylphosphatidylcholine; D002927:Cimetidine; D011899:Ranitidine; D009853:Omeprazole