thromboxane-b2 and Fever

The objective was to compare the clinical and physiologic characteristics of febrile septic patients with hypothermic septic patients; and to examine plasma levels of cytokines tumor necrosis factor alpha (TNF-alpha and interleukin 6 (IL-6) and the lipid mediators thromboxane B2 (TxB2) and prostacyclin in hypothermic septic patients in comparison with febrile patients. Most importantly, we wanted to report the effect of ibuprofen treatment on vital signs, organ failure, and mortality in hypothermic sepsis.. The study was performed in the intensive care units (ICUs) of seven clinical centers in the United States and Canada.. Four hundred fifty-five patients admitted to the ICU who met defined criteria for severe sepsis and were suspected of having a serious infection.. Ibuprofen at a dose of 10 mg/kg (maximum 800 mg) was administered intravenously over 30 to 60 mins every 6 hrs for eight doses vs. placebo (glycine buffer vehicle).. Forty-four (10%) septic patients met criteria for hypothermia and 409 were febrile. The mortality rate was significantly higher in hypothermic patients, 70% vs. 35% for febrile patients. At study entry, urinary metabolites of TxB2, prostacyclin, and serum levels of TNF-alpha and IL-6 were significantly elevated in hypothermic patients compared with febrile patients. In hypothermic patients treated with ibuprofen, there was a trend toward an increased number of days free of major organ system failures and a significant reduction in the 30-day mortality rate from 90% (18/20 placebo-treated patients) to 54% (13/24 ibuprofen-treated patients).. Hypothermic sepsis has an incidence of approximately 10% and an untreated mortality twice that of severe sepsis presenting with fever. When compared with febrile patients, the hypothermic group has an amplified response with respect to cytokines TNF-alpha and IL-6 and lipid mediators TxB2 and prostacyclin. Treatment with ibuprofen may decrease mortality in this select group of septic patients.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Epoprostenol; Female; Fever; Humans; Hypothermia; Ibuprofen; Interleukin-6; Male; Middle Aged; Multiple Organ Failure; Prospective Studies; Sepsis; Survival Analysis; Thromboxane B2; Time Factors; Tumor Necrosis Factor-alpha

Salicylate is the basic therapy for Kawasaki disease, however its optimal dose is controversial. We investigated the therapeutic efficacy of high dose (100 mg/kg per day, n = 30) versus low dose (30 mg/kg per day, n = 30) salicylate. Duration of fever, SGPT, serum salicylate, plasma thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha) levels were compared before enrollment and on days 4, 7 and 14 of treatment. In the high dose group, duration of fever was significantly shorter than that of the low dose group (3.2 +/- 0.3 versus 5.4 +/- 0.8 days, P less than 0.05), however, SGPT levels were significantly elevated (157 +/- 34 versus 48 +/- 11 IU/1, P less than 0.05). No differences in the incidence of coronary artery lesions were observed (5/30 versus 7/30). Plasma TxB2 production was completely blocked in both groups, and plasma 6-keto-PGF1 alpha levels in the high dose group on day 14 was lower than that in the low dose group (39 +/- 8 versus 159 +/- 65 pg/ml, P less than 0.05). SGPT and plasma 6-keto-PGF1 alpha correlated with serum salicylate concentration. These data suggest that high dose salicylate therapy may be disadvantageous as anti-thrombotic therapy, and supports the notion that low dose therapy is safe in the acute stage of Kawasaki disease.

Topics: 6-Ketoprostaglandin F1 alpha; Alanine Transaminase; Child, Preschool; Dose-Response Relationship, Drug; Female; Fever; Humans; Infant; Male; Mucocutaneous Lymph Node Syndrome; Salicylates; Salicylic Acid; Thromboxane B2

Prostaglandin E2 (PGE2), one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2). Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1αin vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI) ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Benzothiazoles; Depression, Chemical; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fever; Guinea Pigs; Imidazoles; Indomethacin; Inflammation; Macrophages; Pain; Peptic Ulcer; Phenanthrenes; Piperidines; Stimulation, Chemical; Thromboxane B2

Prostaglandins (PGs) are important lipid mediators involved in the development of inflammatory associated pain and fever. PGE2 is a well-established endogenous pyrogen activated by proinflammatory cytokine interleukin (IL)-1β. P2X7 receptors (P2X7Rs) expressed by inflammatory cells are stimulated by the danger signal extracellular ATP to activate the inflammasome and release IL-1β. Here we show that P2X7R activation is required for the release of PGE2 and other autacoids independent of inflammasome activation, with an ATP EC(50) for PGE2 and IL-1β release of 1.58 and 1.23 mM, respectively. Furthermore, lack of P2X7R or specific antagonism of P2X7R decreased the febrile response in mice triggered after intraperitoneal LPS or IL-1β inoculation. Accordingly, LPS inoculation caused intraperitoneal ATP accumulation. Therefore, P2X7R antagonists emerge as novel therapeutics for the treatment for acute inflammation, pain and fever, with wider anti-inflammatory activity than currently used cyclooxygenase inhibitors.-Barberà-Cremades, M., Baroja-Mazo, A., Gomez, A. I., Machado, F., Di Virgilio, F., Pelegrín, P. P2X7 receptor-stimulation causes fever via PGE2 and IL-1β release.

Topics: Adenosine Triphosphate; Animals; Calcium Signaling; Cyclooxygenase 2; Dinoprostone; Fever; Humans; In Vitro Techniques; Inflammation Mediators; Injections, Intraperitoneal; Interleukin-1beta; Leukotriene B4; Lipopolysaccharides; Macrophages; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Purinergic P2X Receptor Agonists; Purinergic P2X Receptor Antagonists; Receptors, Purinergic P2X4; Receptors, Purinergic P2X7; Recombinant Proteins; Thromboxane B2

1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified COX-1 and COX-2 with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for COX-2 and 67 microM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Biological Availability; Blood Platelets; Cell Line; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Disease Models, Animal; Drug Evaluation, Preclinical; Edema; Female; Fever; Fibroblasts; Humans; Hyperalgesia; Male; Membrane Proteins; Organic Chemicals; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Rats, Wistar; Skin; Thromboxane B2

The pharmacological profile of celecoxib (CAS 169590-42-5, SC-58635), a specific cyclooxygenase-2 (COX-2) inhibitor, was investigated. Celecoxib inhibited COX-2-mediated prostaglandin E2 (PGE2) production in human dermal fibroblasts (IC50 = 91 nmol/l), whereas it was a weak inhibitor of COX-1-mediated PGE2 production in human lymphoma cells (IC50 = 2800 nmol/l). In in vivo studies, the effects of celecoxib were compared with those of nonsteroidal anti-inflammatory drugs (NSAIDs) in acute rat models of hyperalgesia and pyrexia. Celecoxib abrogated carrageenan-induced hyperalgesia in the hind paw accompanied by a decrease in PGE2 content in paw exudates and cerebrospinal fluid in a dose-related manner, with an ED30 = 0.81 mg/kg. Its analgesic potency was comparable to those of NSAIDs. In lipopolysaccharide-induced pyrexia, the anti-pyretic potency of celecoxib was equal to that of NSAIDs. On the other hand, in a gastric toxicity study in rats, single oral administration of celecoxib had no effect on gastric mucosa or mucosal PGE2 content at doses up to 200 mg/kg. Additionally, celecoxib did not inhibit thromboxane B2 production of calcium ionophore-stimulated peripheral blood of rats or arachidonic acid-induced aggregation of human platelets. These findings suggest that celecoxib might be a safe and effective alternative to NSAIDs for clinical use.

Topics: Animals; Carrageenan; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Fever; Fibroblasts; Humans; Hyperalgesia; In Vitro Techniques; Interleukin-1; Lipopolysaccharides; Lymphoma; Male; Membrane Proteins; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Sulfonamides; Thromboxane B2; Tumor Cells, Cultured

It has been proposed that ciliary neurotrophic factor (CNTF) belongs to the group of cytokines causing fever in response to infectious and inflammatory noxae. The present investigation was undertaken in the conscious cat to verify whether CNTF (human type, hCNTF) is pyrogenic when given either intravenously (i.v.) or intracerebroventricularly (i.c.v.) and correlate at the same time body temperature with cerebrospinal fluid (CSF) levels of prostaglandin (PG) E2 (i.e., the putative fever mediator in brain) and thromboxane (TX) B2 (the stable TXA2 byproduct) in untreated vs. treated animals. hCNTF (10 microg/kg i.v.; 1 microg i.c.v.) caused fever by both routes and the increase in body temperature was associated with an upward change in CSF PGE2. Conversely, CSF TXB2 showed no elevation. Similarly unaffected was CSF TXB2 by human interleukin 6 (hIL-6, 1 microg i.c.v.), a cytokine with known pyrogenic and PGE2-promoting actions sharing the signal-transducing mechanism with hCNTF. We conclude that CNTF lends itself to a role in the pathogenesis of fever. The modest PGE2 elevation relatively to other cytokines, specifically hIL-1, is ascribed to the fact that CNTF activates the inducible isoform of arachidonate cyclooxygenase, which is constitutively expressed in brain, without concomitantly promoting the formation of new enzyme.

Topics: Animals; Body Temperature; Body Temperature Regulation; Cats; Cerebral Ventricles; Ciliary Neurotrophic Factor; Dinoprostone; Female; Fever; Humans; Injections, Intravenous; Injections, Intraventricular; Interleukin-1; Male; Nerve Growth Factors; Nerve Tissue Proteins; Recombinant Proteins; Skin Temperature; Thromboxane A2; Thromboxane B2; Time Factors

1. DFU (5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulphonyl)phenyl-2(5H)-furan one) was identified as a novel orally active and highly selective cyclo-oxygenase-2 (COX-2) inhibitor. 2. In CHO cells stably transfected with human COX isozymes, DFU inhibited the arachidonic acid-dependent production of prostaglandin E2 (PGE2) with at least a 1,000 fold selectivity for COX-2 (IC50 = 41 +/- 14 nM) over COX-1 (IC50 > 50 microM). Indomethacin was a potent inhibitor of both COX-1 (IC50 = 18 +/- 3 nM) and COX-2 (IC50 = 26 +/- 6 nM) under the same assay conditions. The large increase in selectivity of DFU over indomethacin was also observed in COX-1 mediated production of thromboxane B2 (TXB2) by Ca2+ ionophore-challenged human platelets (IC50 > 50 microM and 4.1 +/- 1.7 nM, respectively). 3. DFU caused a time-dependent inhibition of purified recombinant human COX-2 with a Ki, value of 140 +/- 68 microM for the initial reversible binding to enzyme and a kappa 2 value of 0.11 +/- 0.06 s-1 for the first order rate constant for formation of a tightly bound enzyme-inhibitor complex. Comparable values of 62 +/- 26 microM and 0.06 +/- 0.01 s-1, respectively, were obtained for indomethacin. The enzyme-inhibitor complex was found to have a 1:1 stoichiometry and to dissociate only very slowly (t1/2 = 1-3 h) with recovery of intact inhibitor and active enzyme. The time-dependent inhibition by DFU was decreased by co-incubation with arachidonic acid under non-turnover conditions, consistent with reversible competitive inhibition at the COX active site. 4. Inhibition of purified recombinant human COX-1 by DFU was very weak and observed only at low concentrations of substrate (IC50 = 63 +/- 5 microM at 0.1 microM arachidonic acid). In contrast to COX-2, inhibition was time-independent and rapidly reversible. These data are consistent with a reversible competitive inhibition of COX-1. 5. DFU inhibited lipopolysaccharide (LPS)-induced PGE2 production (COX-2) in a human whole blood assay with a potency (IC50 = 0.28 +/- 0.04 microM) similar to indomethacin (IC50 = 0.68 +/- 0.17 microM). In contrast, DFU was at least 500 times less potent (IC50 > 97 microM) than indomethacin at inhibiting coagulation-induced TXB2 production (COX-1) (IC50 = 0.19 +/- 0.02 microM). 6. In a sensitive assay with U937 cell microsomes at a low arachidonic acid concentration (0.1 microM), DFU inhibited COX-1 with an IC50 value of 13 +/- 2 microM as compared to 20 +/- 1 nM for indomethacin. CGP 28238, etodo

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; CHO Cells; Cricetinae; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Digestive System; Dinoprostone; Dose-Response Relationship, Drug; Edema; Fever; Furans; Humans; Hyperalgesia; Indomethacin; Isoenzymes; Lipopolysaccharides; Male; Membrane Proteins; Peroxidases; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Saimiri; Structure-Activity Relationship; Thromboxane B2; Transfection

Topics: Blood Platelets; Calcium; Cell Membrane; Cold Temperature; Cytosol; Fever; Humans; In Vitro Techniques; Membrane Fluidity; Platelet Aggregation; Spectroscopy, Fourier Transform Infrared; Thromboxane B2

Topics: Animals; Dinoprostone; Fever; Humans; Hypothalamus; Pyrogens; Thromboxane B2

Conscious cats were used to study the local release of prostaglandin (PG) E2 and thromboxane (Tx) B2 (the stable TxA2 by-product) from the preoptic-anterior hypothalamus (AH-POA) and the tuberal-posterior hypothalamus (PH-Tu) using a modified "push-pull" perfusion procedure. In the absence of fever, PGE2 release was steady from the 2nd h of perfusion onward, its rate at either site ranging between 0.08 and 0.12 pg/min. Local treatment with probenecid (1 mM) increased PGE2 release about threefold. Compared with PGE2, basal release of TxB2 was greater (0.15-0.43 pg/min) and, occasionally, tended to fall with time. Both compounds were found in higher amounts (2- to 10-fold increase) after locally injecting endotoxin, and the effect was greater in AH-POA than PH-Tu. Conversely, intravenous endotoxin (bolus) or interleukin 1 (IL-1) (bolus plus infusion) at doses causing a sustained fever selectively stimulated the formation of PGE2, but the response itself did not differ between AH-POA and PH-Tu. In either region, the degree of enhancement in PGE2 release correlated with the magnitude of the fever. Intravenous indomethacin (2 mg/kg) reversed both the fever and PGE2 elevation. These findings support an intermediary role for PGE2 in the central action of pyrogens and the ensuing fever. Blood-borne pyrogens may act at multiple sites in brain, which are tentatively identified with the circumventricular organs.

Topics: Animals; Body Temperature; Cats; Dinoprostone; Endotoxins; Female; Fever; Hypothalamus; Indomethacin; Interleukin-1; Male; Probenecid; Pyrogens; Recombinant Proteins; Reference Values; Thromboxane B2

Conscious cats were used to study the effects of endotoxin and interleukin 1 (IL 1) on levels of prostaglandin (PG) E2 and thromboxane (TX) B2 (the stable TXA2 byproduct) in cerebrospinal fluid (CSF) from the third ventricle. Pyrogens were given intravenously or intraventricularly and prostanoids were measured by radioimmunoassay. PGE2 was normally less abundant than TXB2 (mean, 37 vs. 528 pg/ml), and its level increased severalfold during the sustained fever following intravenous endotoxin (bolus) or IL 1 (bolus plus infusion). PGE2 elevation preceded the fever and was maintained thereafter. Likewise, intraventricular pyrogens promoted PGE2 formation, and their effect was also manifest during the latent period of the fever. The PGE2 metabolite, 13,14-dihydro-15-keto-PGE2, was not measurable in CSF from either afebrile or febrile animals. Basal content of PGE2, on the other hand, was higher in animals pretreated with probenecid (30 mg/kg ip or iv; 50 or 100 micrograms ivt), confirming the importance of transport processes in removing prostanoids from brain. Unlike PGE2, TXB2 levels did not change during the fever to intravenous endotoxin. TXB2 rose instead in response to intraventricular endotoxin, although the elevation did not extend beyond fever uprise. Furthermore, a TXA2 analog (ONO-11113;2 or 4 micrograms ivt) had inconsistent effects on body temperature, while a TXA2 antagonist (ONO-11120;2 micrograms ivt) did not interfere with endotoxin fever. These findings strongly support a causative role for PGE2 in the onset and progression of pyrogen fever. No evidence of a similar role was obtained for TXA2.

Topics: Animals; Brain; Cats; Dinoprostone; Endotoxins; Escherichia coli; Female; Fever; Injections, Intraventricular; Interleukin-1; Male; Prostaglandins E; Pyrogens; Thromboxane A2; Thromboxane B2

Intravenous infusion of Pasteurella hemolytica endotoxin caused marked increases in the plasma levels of thromboxane B2 (TxB2), prostaglandins (PG) and serotonin in sheep. The control values for TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin before endotoxin infusion averaged 283 +/- 53 (standard error of mean), 281 +/- 14 and 199 +/- 27 pg/ml and 57 +/- 3 ng/ml, respectively. At 50 min during endotoxin infusion, these values were increased to their maximum of 376, 339, 325 and 202% of control, respectively. Body temperature increased from the control value of 39.5 +/- 0.1 degrees C to a maximum of 41.5 +/- 0.1 degrees C at 200-300 min of infusion. In the second part of this study, we have examined the effects of ibuprofen on endotoxin-induced increases in plasma PG, TxB2, and serotonin levels and body temperature. The control values for TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and temperature prior to ibuprofen and endotoxin infusion averaged 238 +/- 35, 335 +/- 44 and 248 +/- 28 pg/ml, 65 +/- 3 ng/ml and 40.1 +/- 0.2 degrees C, respectively. A loading dose (15 mg/kg) of ibuprofen was followed by infusion of endotoxin (12 micrograms/kg) and ibuprofen (43.3 mg/kg) over 500 min. Plasma levels of 6-keto-PGF1 alpha and serotonin increased only to 131 and 149% of control at 50 min of infusion, and levels of PGF2 alpha and TxB2 decreased to 50 and 80% of control at 100 and 150 min of infusion, respectively. Temperature remained unchanged. Ibuprofen effectively suppressed endotoxin-induced increases in the plasma levels of TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin and body temperature. It was concluded from the present study that nonsteroidal anti-inflammatory drugs as an adjunct to antibiotic therapy might have a rational basis in treatment of endotoxin toxicity.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Endotoxins; Female; Fever; Ibuprofen; Pasteurella; Pasteurella Infections; Prostaglandins; Prostaglandins F; Serotonin; Sheep; Sheep Diseases; Thromboxane B2; Thromboxanes

The effects of cyclooxygenase inhibition on the reaction to a toxin isolated from group B beta-hemolytic streptococci, type III, were studied in seven sheep instrumented for chronic measurement of pulmonary lymph flow, pulmonary artery and left atrial pressures. Each sheep was infused with toxin alone on one day and with indomethacin plus toxin on a different day in random order. The toxin alone caused a two-phased reaction. After the infusion of toxin, alone, in the initial phase, pulmonary artery pressure increased from 16.5 +/- 1.2 mmHg to 47.1 +/- 4.8 mmHg and the rectal temperature rose from 39.7 +/- 0.13 degree C to 40.9 +/- 0.16 degree C. During the second phase, the granulocyte count decreased to less than 10% of baseline values and the lymph protein clearance increased from 4.8 +/- 1.2 ml/h to 10.02 +/- 1.4 ml/h, suggesting increased pulmonary vascular permeability. Indomethacin pretreatment prevented the initial phase of pulmonary hypertension, the increases in thromboxane and prostacyclin metabolites in lung lymph, and the febrile response to toxin infusion but did not modify the granulocytopenia or the increased pulmonary vascular permeability. It appears that the hemodynamic changes are independent from the pulmonary vascular changes, and that prostaglandin endoperoxides or their metabolites are necessary for the fever and the acute pulmonary hypertension.

Topics: Animals; Bacterial Toxins; Capillary Permeability; Cyclooxygenase Inhibitors; Fever; Granulocytes; Hypertension, Pulmonary; Indomethacin; Lung; Lymph; Lymphopenia; Prostaglandins F; Sheep; Streptococcus agalactiae; Thromboxane B2

Levels of prostaglandin (PG) E2 and thromboxane (TX) B2, the stable metabolite of TXA2, were measured by radioimmunoassay in cerebrospinal fluid (CSF) collected from the third ventricle and the cisterna magna of conscious cats. In the absence of fever, PGE2 was usually below the threshold of the assay (0.05-0.37 ng/ml), while TXB2 was measurable in the majority of cases and its concentration was greater in the third ventricle (about 0.7 ng/ml) than in the cisterna magna (about 0.2 ng/ml). At either site, TXB2 content rose if any manipulation was required for the collection of samples. PGE2 levels increased to measurable values (max 1.1-1.4 ng/ml) during fever produced by intrathecal or intravenous administration of leucocytic pyrogen. In contrast, TXB2 concentration rose to an average of 2.2-4 ng/ml only when pyrogen (bacterial or leukocytic) was given intrathecally. Moreover, TXB2 elevation, unlike PGE2 elevation, was limited to the uprise phase of the fever. Imidazole, given either intraperitoneally (50 mg/kg) or intrathecally (3 mg), attenuated the pyrogen fever and suppressed any rise in TXB2 levels. At the same time, the drug tended to increase the PGE2 content of the CSF. Evidence was also obtained suggesting that a fraction of PGE2 is bound to CSF protein, and this event may be important to the inactivation of the compound. These findings are consistent with the concept that PGE2 is involved in the sequence of events underlying pyrogen fever. A role for thromboxane A2 in this process remains to be established.

Topics: Animals; Body Temperature; Cats; Dinoprostone; Female; Fever; Imidazoles; Interleukin-1; Male; Prostaglandins E; Proteins; Pyrogens; Radioimmunoassay; Reference Values; Thromboxane B2; Thromboxanes