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Title: Interaction of steroidal and non-steroidal anti-inflammatory agents with pyrogenic immunomodulators
Author: Abul, Habib T.
ISNI:       0000 0001 3392 6908
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 1988
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The objective of the study was to investigate the possibility that the synthetic glucocorticoid analogue, dexamethasone was antipyretic. In addition, the possible involvement of peripheral PGE2 during fever and the mechanism by which ketoprofen, dexamethasone and the neuropeptide ACTH1-24 interact with fever in response to pyrogenic immunomodulators such as Poly I:C, LPS and IL-1/EP and their effect on PGE2 biosynthesis both in vivo and in vitro in the rabbit was also investigated. The febrile response was measured as changes in rectal temperatures and CSF levels of PGE2 were estimated by collecting samples from the third cerebral ventricle by using a push-pull perfusion system. PGE2 release was also measured in vitro from rabbit monocytes prepared by Percoll density gradient centrifugation. PGE2 was estimated by RIA. Ketoprofen (3 mg/Kg s.c.) administered prior to or after the onset of fever completely inhibited the febrile response to all pyrogens. Dexamethasone (1 mg/kg i.v.) attenuated the febrile response to Poly I:C (5 μ g/Kg i.v.) but only if administered between 0.5 - 2 hours before Poly I:C and a maximum effect was observed with 3 mg/Kg. Fever in response to LPS (50 - 200 ng/Kg i.v.), IL-1/EP (50 μl/animal = 5 x 108 cell equivalents i.v.), TNF (15 μg/animal i.v.) or Poly I:C (5 μg i.c.v.) was also attenuated by pretreatment for 1 hour with dexamethasone. ACTH1-24 (1 - 10 μg/Kg i.v.) produced a dose-related hypothermia at an ambient temperature of 22 ± 2oC. A non-hypothermic dose of ACTH1-24 (5 μg/Kg i.v.) significantly reduced the febrile response to Poly I:C (5 μg/Kg i.v.) or IL-1/EP (50 μl/animal i.v.). Poly I:C, LPS and IL-1/EP administered i.v. were found to produce a significant increase in the plasma PGE_2 level (in order of 6 - 8 fold) which occurred simultaneously with the rise in body temperature. Ketoprofen (3 mg/Kg s.c.) abolished both the rise in body temperature and the increase in plasma PGE_2 level. Dexamethasone (3 mg/Kg i.v.) pretreatment (1 hour) attenuated the pyrogen-stimulated increase in both parameters. If dexamethasone was administered after the onset of fever in response to Poly I:C, it potentiated both the increase in body temperature and plasma PGE_2. ACTH_1-24 (5 μg/Kg i.v.) significantly reduced the febrile response to Poly I:C and IL-1/EP but had no effect on plasma PGE2 levels. Poly I:C and IL-1/EP increased the amount of PGE2 detected in the perfusate collected from the third cerebral ventricle. The increase was in the order of 2 - 4 fold compared with control levels which parallelled the increase in body temperature. Ketoprofen abolished the fever and the increase in CSF PGE2 level. Dexamethasone also significantly attenuated the febrile response and reduced the amount of PGE2 in the CSF perfusate. Experiments were also carried out on rabbit monocytes in vitro. Poly I:C, LPS and IL-1/EP all increased the concentration of PGE2 in culture supernatants. Ketoprofen and dexamethasone significantly reduced pyrogen-stimulated release of PGE2, but ACTH1-24 had no effect. The protein synthesis inhibitor anisomycin reduced Poly I:C and LPS-stimulated release of PGE2 but had no effect on IL-1/EP-stimulated release of PGE2. In addition, anisomycin antagonised the inhibitory effect of dexamethasone on the PGE2 released from monocytes in the presence of IL-1/EP. These results suggest that the increase in plasma PGE2 levels in response to the pyrogenic agents may contribute to their pyrogenicity. In addition, the antipyretic actions of dexamethasone and ketoprofen may involve a reduction in circulating levels of PGE2 and this action of dexamethasone may occur via the induction of a protein intermediate possibly the PLA2 inhibitory protein, lipocortin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pharmacology & pharmacy & pharmaceutical chemistry