Prostaglandins in Fever and the Mode of Action of Antipyretic Drugs

Milton, A. S.

doi:10.1007/978-3-642-68569-9_10

Cited by 55 publications

(25 citation statements)

References 77 publications

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“…The ability of hIFN to stimulate PGE2 production from rabbit hypothalamus in vitro supports the hypothesis that the agent, like LP, causes fever by raising the thermoregulatory set-point via a change in arachidonate cyclooxygenase products (28). LP induces a dose-related release of PGE2 from rabbit hypothalamic tissue (17); hIFN, on the other hand, while causing the release of PGE2 from rabbit brain tissue, differs from LP in its effectiveness over a narrow dose range.…”

Section: Discussionsupporting

confidence: 55%

“…For these experiments, rabbits were injected with 1 X 107 U/kg intravenously; and at the time of peak fever (80-1 10 min postinjection) they were bled from the central ear artery into heparinized tubes. The plasma was then injected into another set of rabbits 5 mechanism by which fever is initiated (28). Furthermore, LP given intrathecally, and to a lesser degree systemically, increases POE2 levels in the CSF (14,29).…”

Section: Resultsmentioning

confidence: 99%

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Mechanisms of fever induced by recombinant human interferon.

Dinarello¹,

Bernheim²,

Duff³

et al. 1984

J. Clin. Invest.

200

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Abstract. Since the early trials using human interferon (hIFN) derived from blood leukocytes or cell lines, fever has been a prominent component of IFN therapy. Human protein impurities might account for the fever to cell-derived hIFN, but recombinant hIFN, free of extraneous human proteins, has produced fever in nearly all recipients during clinical trials. Our present studies were carried out to determine the mechanisms of fever due to recombinant hIFN currently being used in humans. Because recombinant hIFN is produced in Escherichia coli, in these experiments we considered contaminating endotoxin as the cause of fever. Polymyxin B, which blocks endotoxin, had no effect on the pyrogenicity of hIFN in rabbits. In addition, hIFN injected into an endotoxin-resistant strain of mice produced fever. The pyrogenicity of hIFN does not appear to involve production of leukocytic pyrogen (LP), since no circulating LP was detected in rabbits during IFN fever. Furthermore, human mononuclear cells incubated with hIFN in vitro at 104_106 U/ml did not release LP. However, hIFN stimulated prostaglandin E2 (PGE2) release from rabbit hypothalamic tissue in vitro. Intracerebroventricular injection of hIFN into the awake cat also produced fever and a rise in PGE2 levels in the cerebrospinal fluid; both effects were reversed by treatment with indomethacin. We conclude that the fever of recombinant hIFN is not due to endotoxin but that

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Section: Discussionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Mechanisms of fever induced by recombinant human interferon.

Dinarello¹,

Bernheim²,

Duff³

et al. 1984

J. Clin. Invest.

200

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show abstract

“…The major findings to support this are (1) the increased release of PGE2 in the hypothalamus and into the cerebrospinal fluid (CSF) during EPs/IL-1 induced fever (Feldberg, Gupta, Milton & Wendlandt, 1973;Bernheim, Gilbert & Stitt, 1980), (2) the antipyretic actions of cyclo-oxygenase inhibitors associated with the decreased release of PGE2 in the brain (Feldberg et at. 1973) and (3) the ability to produce fever promptly by minute amounts of PGE2 microinjected into the rostral hypothalamus (see review, Milton, 1982). However, the brain site which senses blood-borne EPs/ IL-1 and the type of cells which are responsible for the release of PGE2 in response to EPs/IL-1 have not yet been determined.…”

Section: Itmentioning

confidence: 99%

Thermal and PGE2 sensitivity of the organum vasculosum lamina terminalis region and preoptic area in rat brain slices.

Matsuda

Hori

Nakashima

1992

The Journal of Physiology

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SUMMARY1. The effects of local applications of prostaglandin E2 (PGE2) on the unit activity of fifty-one neurones in the organum vasculosum lamina terminalis (OVLT) region and fifty-eight neurones in the preoptic area (POA) were investigated in small tissue slices from the rat hypothalamus containing the OVLT and POA isolated from each other.2. Of these, thirty OVLT and twenty-eight POA neurones were warm sensitive and increased their discharge rate in response to a rise in tissue temperature. One OVLT neurone and one POA neurone were cold sensitive and showed the opposite type of responses to changes in temperature. The thermosensitivity of these neurones was still observed in a Ca21 free-high Mg2+ solution.3. Perfusion with PGE2 in doses between 1 and 250 nm changed the discharge rate in forty-two of fifty-one OVLT neurones and in thirty-two of fifty-eight POA neurones in a dose-dependent manner. The responses to PGE2 were not lost during synaptic blockade. The threshold dose of PGE2 to alter the discharge rate of the OVLT neurones (4-8+1-1 (S.E.M.) nM, n = 16) was significantly lower than that of the POA neurones (40 9 + 12 2 nm, n = 16).4. Fifteen of forty-two OVLT neurones exhibited the responses with a slower onset (latency 5-13 min) and a longer duration (20 min to 3 h), but such responses were observed in only one of thirty-two POA neurones.5. The responses of OVLT and POA neurones to PGE2 (50-250 nm) were reversibly blocked by a concurrent application of AH6809. a prostanoid EP, and/or a DP receptor antagonist.6. While there was no clear correlation between the type of thermosensitivity and the type of response to PGE2 among the POA neurones, a significantly higher incidence of inhibitory response to PGE2 was found among the warm-sensitive neurones in the OVLT region.7. The lower threshold responses to PGE2 and the higher incidence of PGE2 responsiveness among OVLT neurones are consistent with previous findings which showed that the highest density of PGE2 receptor binding and the highest pyrogenic sensitivity to microinjected PGE2 were observed in the OVLT region. The results MS 9526

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“…Three of the infectious strains (the H 1 N l strains) stimulated biphasic pyrexial responses which were not produced by the equivalent u.v.-inactivated viruses; it is possible that the second peak represents the action of another pyrogen other than EP, e.g. interferon (Dinarello et al, 1984) or prostaglandin (Milton, 1982), the production of which is not stimulated by the u.v.-inactivated strains. This second peak may also be present, but masked, within the overall much greater pyrexial responses to the three H3N2 infectious clones (see Fig.…”

Section: Discussionmentioning

confidence: 99%

Severity of Fever in Influenza: Differential Pyrogenicity in Ferrets Exhibited by H1N1 and H3N2 Strains of Differing Virulence

Coates

Sweet

Smith

1986

Journal of General Virology

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SUMMARYIntracardial inoculation of large quantities (200 ~g viral protein/kg body weight) of infectious or u.v.-inactivated purified influenza viruses into ferrets resulted in a rapid febrile response which was significantly lower for two recently isolated H 1N 1 viruses, A/USSR/90/77 and A/Fiji/15899/83, than for two virulent clones, 7a and 64c, of the A/Puerto Rico/8/34 A/England/939/69 (H3N2) reassortant virus system. These results, which are in accord with the severity of fever produced by these strains in intranasally infected ferrets, show that influenza virus strains can differ in their capacity to induce fever (probably reflecting a differential capacity to induce endogenous pyrogen from phagocytes) and indicate, since u.v.-inactivated strains are pyrogenic, that this may be due to differences between strains in the nature or amount of certain virion components.

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Prostaglandins in Fever and the Mode of Action of Antipyretic Drugs

Cited by 55 publications

References 77 publications

Mechanisms of fever induced by recombinant human interferon.

Mechanisms of fever induced by recombinant human interferon.

Thermal and PGE2 sensitivity of the organum vasculosum lamina terminalis region and preoptic area in rat brain slices.

Severity of Fever in Influenza: Differential Pyrogenicity in Ferrets Exhibited by H1N1 and H3N2 Strains of Differing Virulence

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