| Full text | |
| Author(s): |
Malvar, David do C.
[1]
;
Aguiar, Fernando A.
[2]
;
Vaz, Artur de L. L.
[2]
;
Assis, Debora C. R.
[1]
;
de Melo, Miriam C. C.
[1]
;
Jabor, Valquiria A. P.
[3]
;
Kalapothakis, Evanguedes
[4]
;
Ferreira, Sergio H.
[5]
;
Clososki, Giuliano C.
[2]
;
de Souza, Gloria E. P.
[2, 1]
Total Authors: 10
|
| Affiliation: | [1] Univ Sao Paulo, Farmacol Lab, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Sao Paulo - Brazil
[2] Univ Sao Paulo, Nucleo Pesquisa Prod Nat & Sintet, Fac Ciencias Farmaceut Ribeirao Preto, BR-14040903 Sao Paulo - Brazil
[3] Univ Sao Paulo, Dept Quim & Fis, Fac Ciencias Farmaceut Ribeirao Preto, Lab Cromatog & Eletroforese Capilar, BR-14040903 Sao Paulo - Brazil
[4] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Biol Geral, Belo Horizonte, MG - Brazil
[5] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Farmacol, BR-14040903 Sao Paulo - Brazil
Total Affiliations: 5
|
| Document type: | Journal article |
| Source: | British Journal of Pharmacology; v. 171, n. 15, p. 3666-3679, AUG 2014. |
| Web of Science Citations: | 11 |
| Abstract | |
BACKGROUND AND PURPOSE The antipyretic and hypothermic prodrug dipyrone prevents PGE(2)-dependent and -independent fever induced by LPS from Escherichia coli and Tityus serrulatus venom (Tsv) respectively. We aimed to identify the dipyrone metabolites responsible for the antipyretic and hypothermic effects. EXPERIMENTAL APPROACH Male Wistar rats were treated i.p. with indomethacin (2 mg.kg(-1)), dipyrone, 4-methylaminoantipyrine (4-MAA), 4-aminoantipyrine (4-AA) (60-360 mg.kg(-1)), 4-formylaminoantipyrine, 4-acethylaminoantipyrine (120-360 mg.kg(-1)) or vehicle 30 min before i.p. injection of LPS (50 mu g.kg(-1)), Tsv (150 mu g.kg(-1)) or saline. Rectal temperatures were measured by tele-thermometry and dipyrone metabolite concentrations determined in the plasma, CSF and hypothalamus by LC-MS/MS. PGE(2) concentrations were determined in the CSF and hypothalamus by ELISA. KEY RESULTS In contrast to LPS, Tsv-induced fever was not followed by increased PGE(2) in the CSF or hypothalamus. The antipyretic time-course of 4-MAA and 4-AA on LPS-induced fever overlapped with the period of the highest concentrations of 4-MAA and 4-AA in the hypothalamus, CSF and plasma. These metabolites reduced LPS-induced fever and the PGE(2) increase in the plasma, CSF and hypothalamus. Only 4-MAA inhibited Tsv-induced fever. The higher doses of dipyrone and 4-MAA also induced hypothermia. CONCLUSIONS AND IMPLICATIONS The presence of 4-MAA and 4-AA in the CSF and hypothalamus was associated with PGE2 synthesis inhibition and a decrease in LPS-induced fever. 4-MAA was also shown to be an antipyretic metabolite for PGE(2)-independent fever induced by Tsv suggesting that it is responsible for the additional antipyretic mechanism of dipyrone. Moreover, 4-MAA is the hypothermic metabolite of dipyrone. (AU) | |
| FAPESP's process: | 08/09443-4 - Antipyretic effect of the main dipyrone metabolites on febrile response induced by LPS and Tityus serrulatus scorpion venom |
| Grantee: | David do Carmo Malvar |
| Support Opportunities: | Scholarships in Brazil - Doctorate |