Document Detail


Subacute and chronic oral toxicity of lornoxicam in cynomolgus monkeys.
MedLine Citation:
PMID:  9216745     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Lornoxicam is a novel non-steroidal anti-inflammatory compound in the same chemical class as piroxicam and tenoxicam, with potent anti-inflammatory, antipyretic and analgesic activity. As part of the preclinical safety programme, its toxicity was evaluated in a dose-range-finding and 52-wk toxicity study in cynomolgus monkeys. In the dose-range-finding study, five groups of monkeys (two per sex per group) were dosed orally by gavage for 6 wk with 0, 0.25, 0.5, 1.0 or 2.0 mg lornoxicam/kg/day. Drug-related toxicity was observed in the 1.0 and 2.0 mg/kg/day dose groups only. This included mortality, diarrhoea, prostration, decreased body weight gain and food consumption, faecal occult blood, anaemia, leucocytosis, hypoalbuminaemia, gastrointestinal erosions and ulcerations. On the basis of these results, four groups of monkeys (six per sex per group) were given the compound orally by nasogastric intubation at dose levels of 0, 0.125, 0.25 or 0.5 mg/kg/day for 52 wk. The high-dose level was increased to 0.6 mg/kg/day from wk 39 to wk 52. Treatment was followed by a 4-wk recovery period for two animals per sex per group. Histologically, drug-related changes seen were gastrointestinal erosions, ulcerations and inflammation in males and females at 0.5/0.6 mg/kg/day. Treatment-related clinicopathological findings included decreased haematocrit and hypoproteinaemia (group 0.5/0.6 mg/kg/day males), and hypoalbuminaemia (group 0.5/0.6 mg/kg/day males and females). None of these changes were present after the recovery period, thus indicating reversibility. Plasma concentration of lornoxicam measured 2 hr after dosing increased in a dose proportional manner. The estimated area under the curve (AUC) at steady state increased in a dose-proportional manner and at 0.25 mg/kg was three- to fivefold higher than the human AUC following a 16 mg dose (8 mg b.i.d.). The no-observed-effect level in the chronic toxicity study was 0.25 mg/kg/day.
Authors:
E Atzpodien; N Mehdi; D Clarke; S Radhofer-Welte
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association     Volume:  35     ISSN:  0278-6915     ISO Abbreviation:  Food Chem. Toxicol.     Publication Date:  1997 May 
Date Detail:
Created Date:  1997-07-31     Completed Date:  1997-07-31     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8207483     Medline TA:  Food Chem Toxicol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  465-74     Citation Subset:  IM    
Affiliation:
Nycomed Austria GmbH, Linz, Austria.
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MeSH Terms
Descriptor/Qualifier:
Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal / administration & dosage,  pharmacokinetics,  toxicity*
Area Under Curve
Chemistry, Clinical
Digestive System / drug effects,  pathology
Gastrointestinal Diseases / chemically induced,  pathology
Macaca fascicularis
Male
Piroxicam / administration & dosage,  analogs & derivatives*,  pharmacokinetics,  toxicity
Survival Rate
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 36322-90-4/Piroxicam; 70374-39-9/lornoxicam

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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