6-ketoprostaglandin-f1-alpha and Fever

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

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