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Dissociation of antihyperglycaemic and adverse effects of partial perioxisome proliferator-activated receptor (PPAR-gamma) agonist balaglitazone.

Abstract
Balaglitazone is a novel thiazolidinedione in clinical development for the treatment of type 2 diabetes. Common side effects associated with PPARgamma receptor agonists are weight gain, oedema and adipogenesis. Balaglitazone is a selective partial PPARgamma agonist and it has been speculated that such compounds have a more favourable safety margin than full agonists. We have compared impact of equi-efficacious antihyperglycaemic doses of balaglitazone with full PPARgamma agonist rosiglitazone on body fluid accumulation, cardiac enlargement, and adipogenesis. Equi-efficacious antihyperglycaemic doses (ED(90)) of balaglitazone (3 mg/kg/day) and rosiglitazone (6 mg/kg/day) were determined in male diabetic db/db mice. In adult male rats treated for up to 42 days, feeding, drinking, anthropometry, and plasma volumes were measured. Total plasma volume was measured with dye dilution technique. Compared to vehicle, rosiglitazone consistently increased food intake throughout the 42 day treatment period. In contrast, balaglitazone increased food intake in the last week of the experiment. However, both rosiglitazone and balaglitazone increased water intake. After 42 days, rosiglitazone treated rats displayed significantly elevated adiposity. Rosiglitazone increased total blood and plasma volumes throughout the treatment. Twenty-one days of balaglitazone treatment had no significant impact on blood or plasma volumes, whilst 42 days of balaglitazone increased plasma volume but to a significantly lesser extent than seen for rosiglitazone (vehicle: 46.1+/-1.5; balaglitazone: 50.8+/-1.21; rosiglitazone: 54.6+/-1.6 ml/kg). Heart weight was significantly elevated only in rosiglitazone treated animals. At doses inducing comparable antihyperglycaemic control, the full PPARgamma agonist, rosiglitazone, induces more pronounced body fluid retention and heart enlargement than seen for the partial PPARgamma agonist, balaglitazone. Thus, partial agonists may pose safer alternative to current anti-diabetic therapy with full PPARgamma agonist.
AuthorsPhilip J Larsen, Kirsten Lykkegaard, Leif K Larsen, Jan Fleckner, Per Sauerberg, Karsten Wassermann, Erik Max Wulff
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 596 Issue 1-3 Pg. 173-9 (Oct 31 2008) ISSN: 0014-2999 [Print] Netherlands
PMID18761337 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • Hypoglycemic Agents
  • PPAR gamma
  • Quinazolines
  • Thiazolidinediones
  • Rosiglitazone
  • balaglitazone
Topics
  • Adipogenesis (drug effects)
  • Adipose Tissue (drug effects)
  • Animals
  • Blood Volume (drug effects)
  • Body Weight (drug effects)
  • Drinking (drug effects)
  • Eating (drug effects)
  • Heart (anatomy & histology, drug effects)
  • Humans
  • Hypoglycemic Agents (adverse effects, pharmacology)
  • Male
  • Mice
  • Organ Size (drug effects)
  • PPAR gamma (agonists, genetics)
  • Quinazolines (adverse effects, pharmacology)
  • Rats
  • Rosiglitazone
  • Thiazolidinediones (adverse effects, pharmacology)

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