Clinical and blood biochemical changes after administration of low doses of endotoxin in ewes.
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Animals↗
Biomedical subjects
H Kindahl
Publications and source records attributed to H Kindahl.
A critical approach to eicosanoid assay.
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Animals↗
Effects of flunixin meglumine on endotoxin-induced prostaglandin F2 alpha secretion during early pregnancy in mares.
The role of prostaglandin F2 alpha (PGF2 alpha) in embryonic loss following induced endotoxemia was studied in mares that were 21 to 44 days pregnant. Thirteen pregnant mares were treated with a nonsteroidal anti-inflammatory drug, flunixin meglumine, to inhibit the synthesis of PGF2 alpha caused by Salmonella typhimurium endotoxin given IV. Flunixin meglumine was administered either before injection of the endotoxin (group 1, -10 min; n = 7), or after endotoxin injection into the mares (group 2, 1 hour, n = 3; group 3, 2 hours, n = 3); 12 pregnant mares (group 4) were given only S typhimurium endotoxin. In group 4, the secretion of PGF2 alpha, as determined by plasma 15-keto-13,14-dihydro-PGF2 alpha concentrations, was biphasic, initially peaking at 30 minutes followed by a second, larger peak approximately 105 minutes after the endotoxin was given IV. When flunixin meglumine was administered at -10 minutes, synthesis of PGF2 alpha was inhibited for several hours, after administration of flunixin meglumine at 1 hour, the second secretory surge of PGF2 alpha was blocked, and administration of the drug at 2 hours did not substantially modify the secretion of PGF2 alpha. Plasma progesterone concentrations were unchanged after endotoxin injections were given in group 1. In group 2, progesterone values decreased less than 2 ng/ml and remained low for several days. In group 3 and group 4, progesterone concentrations decreased to values less than 0.5 ng/ml by 48 hours after endotoxin injections were given.(ABSTRACT TRUNCATED AT 250 WORDS)
Abortion, Veterinary↗
Evaluation of progesterone deficiency as a cause of fetal death in mares with experimentally induced endotoxemia.
The role of decreased luteal activity in embryonic loss after induced endotoxemia was studied in mares 21 to 35 days pregnant. Fourteen pregnant mares were treated daily with 44 mg of altrenogest to compensate for the loss of endogenous progesterone secretion caused by prostaglandin F2 alpha (PGF2 alpha) synthesis and release following intravenous administration of Salmonella typhimurium endotoxin. Altrenogest was administered daily from the day of endotoxin injection until day 40 of gestation (group 1; n = 7), until day 70 (group 2; n = 5), or until day 50 (group 3; n = 2). In all mares, secretion of PGF2 alpha, as determined by the plasma 15-keto-13,14-dihydro-PGF2 alpha concentrations, followed a biphasic pattern, with an initial peak at 30 minutes followed by a second, larger peak at 105 minutes after endotoxin injection. Plasma progesterone concentrations decreased in all mares to values less than 1 ng/ml within 24 hours after endotoxin injection. In group 1, progesterone concentrations for all mares were less than 1 ng/ml until the final day of altrenogest treatment. In 6 of 7 mares in group 1, the fetuses died within 4 days after the end of treatment, with progesterone concentrations less than 1 ng/ml at that time. In the mare that remained pregnant after the end of treatment, plasma progesterone concentration was 1.6 ng/ml on day 41 and increased to 4.4 ng/ml on day 44. In group 2, all mares remained pregnant, even though plasma progesterone concentrations were less than 1 ng/ml in 4 of 5 mares from the day after endotoxin injection until after the end of altrenogest treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Regulation of prostaglandin biosynthesis with flunixin meglumine in the bovine species.
Flunixin meglumine (FM) was injected in 2 oophorectomized cows to follow changes in basal levels of the main circulating prostaglandin (PG)F2 alpha metabolite, 15-ketodihydro-PGF2 alpha. A rapid decrease in the levels was seen after FM and the effect was lasting for about 6 h. Thus, to obtain a full effect of the drug on prostaglandin synthesis it is recommended that FM should be injected 4 times daily. This concept was further studied in 3 cycling heifers which obtained FM 4 times daily from day 15 of the estrous cycle for 7 days (totally 28 injections). During the period of drug administration, prostaglandin metabolite levels were decreased and the expected pulsatile release seen during luteolysis was delayed. The pulsatile release started about one day after cessation of treatment and then luteolysis occurred. Progesterone levels were normal during the FM treatment and dropped concomitantly with the pulsatile release of PGF2 alpha. The levels of progesterone decreased to low levels before the heifers showed signs of estrus and ovulated. The administration of FM causes a situation resembling that seen during early pregnancy and FM can be a useful tool in understanding the mechanism behind maternal recognition of pregnancy.
Animals↗
The effect of Toxoplasma gondii infection in flunixin meglumine treated pregnant ewes as monitored by plasma levels of 15-ketodihydroprostaglandin F2 alpha, progesterone, oestrone sulphate and ultrasound scanning.
The aim of this study was to examine the endocrinological response (15-ketodihydro-PGF2 alpha, progesterone and oestrone sulphate) of pregnant ewes which were constantly treated with flunixin meglumine (FM) after infection with Toxoplasma gondii. Seven Swedish Peltsheep ewes were dosed orally with 2,000 T. gondii oocysts at 90.5 (82-94) days of pregnancy. The ewes were treated with FM, 1 mg/kg, intramuscularly twice a day, starting one day before infection until the end of the gestation period. Further three ewes were treated with FM alone during the corresponding time of pregnancy. Another four ewes were used as uninfected and untreated controls. All infected ewes developed antibodies to T. gondii and aborted, but the FM treated control group and the non-treated control group, which remained seronegative, delivered the lambs in the normal gestation range. No early abortions (less than 10 days after infection) were seen in the infected group. The endocrinological changes reflected the pathological changes in the uterus and foetuses. FM could neither completely inhibit prostaglandin release during abortion nor the physiological change of the hormone before parturition even though it depressed prostaglandin release before abortion or parturition and eliminated fever. The infectious process caused by the organism was probably not affected. FM treatment alone had no observed negative effects on pregnant ewes and their foetuses.
Animals↗
The effect of Toxoplasma gondii infection in unvaccinated and iscom-vaccinated pregnant ewes as monitored by plasma levels of 15-ketodihydroprostaglandin F2 alpha, progesterone, and oestrone sulphate.
In order to study the effect of Toxoplasma infection on hormonal levels in pregnant ewes, twenty-eight Scottish Blackface ewes were dosed orally with Toxoplasma gondii oocytes at 91 +/- 1 days of gestation. Fifteen of these ewes were vaccinated with an experimental Toxoplasma iscom vaccine prior to inoculation. Further three ewes were used as non-infected controls. All challenged ewes became infected. Plasma was analysed for the content of 15-ketodihydro-PGF2 alpha, progesterone and oestrone sulphate. The endocrinological changes appeared to reflect the pathological changes in the uterus. Infected animals tended to show an increase in the levels of the prostaglandin metabolite between two and eleven days after challenge, followed by a decrease in progesterone and later also of oestrone sulphate levels. Following the initial phase, the pattern was more variable but related to the outcome of gestation. There was a marked tendency towards more normal endocrinological patterns in the vaccinated animals in comparison to unvaccinated challenged ones.
Adjuvants, Immunologic↗
A clinical and endocrine study on the effect of orally administered bacterial endotoxin in adult pigs and goats.
Endotoxin of Gram-negative bacteria was orally administered in 5 female pigs and 8 male goats. Two of the gilts were pregnant. A solution of lipopolysaccharide (LPS) of Enterobacter agglomerans was mixed into the feed ration of the pigs (40 mg/animal), and given by gastric tube into the rumen of the goats (1-20 mg/animal). Jugular venous blood was collected and clinical signs, rectal temperature and WBC counts were recorded for 12-24 hours. Plasma concentrations of the major plasma metabolite of PGF2 alpha, 15-keto-13,14-dihydro-PGF2 alpha were determined in both species, progesterone concentration only in pigs. The pigs showed slight to severe signs of endotoxemia. Increases in rectal temperature and levels of the PGF2 alpha metabolite occurred in 3 gilts. Progesterone level and the total WBC counts remained unchanged. Differential counts followed irregular patterns mostly within the normal range. The goats showed slight signs of discomfort. Temperature increased in one animal. No other parameters were altered after the intake of LPS. The observations in pigs indicate that endotoxin either penetrated the intestinal barrier causing systemic endotoxemia or induced inflammatory reactions in the intestine activating inflammatory mediators.
Administration, Oral↗
Reproductive hormones during termination of early pregnancy with mifepristone.
Thirteen women received a single oral dose of 600 mg mifepristone (RU486; Roussel-Uclaf, Paris, France) on day 0 to induce first-trimester abortion. Eleven women had a complete abortion, and 2 had a continuing pregnancy and were considered as failures. Plasma levels of human chorionic gonadotropin (hCG) increased from day 0 in all women, but dropped sharply after day 3 in women with successfully induced abortion. In these women, the levels of progesterone, 17 alpha-hydroxyprogesterone and estradiol-17 beta increased from day 0 to day 1 and then dropped. In the 2 failed inductions, the steroid levels remained virtually unchanged. In the complete abortions, the main prostaglandin F2 alpha metabolite, 15-keto-13,14-dihydro-PGF2 alpha, increased to a significant peak at day 6 followed by a significant fall to day 14. These findings supports a direct effect of mifepristone on the decidua, initiating prostaglandin synthesis. It is also suggested that there is a luteolytic effect of prostaglandin F2 alpha, as the levels of corpus luteum steroids started to fall before the drop in hCG.
17-alpha-Hydroxyprogesterone↗
Endotoxin-induced abortion in early pregnant gilts and its prevention by flunixin meglumine.
The objective of the study was to examine the effect of endotoxin on early pregnancy in gilts and to test the potential of flunixin meglumine (FM), a cyclooxygenase inhibitor, to counteract abortifacient action of the endotoxin. Ten gilts at 30 days gestation were used in the experiment. Eight were injected with lipopolysaccharide (LPS) of Salmonella typhimurium, while 2 were treated with 500 micrograms cloprostenol (CP). Six of the LPS-injected gilts were treated with a total of 4 mg/kg body weight FM in 2 different dose regimens. Clinical observations were recorded and plasma levels of 15-keto-13, 14-dihydro-PGF2 alpha, progesterone and estrone sulfate (ES) were determined with radioimmunoassay. LPS induced typical signs of endotoxemia and a monophasic fever in all LPS-treated gilts. No antipyretic effect of FM was observed. The CP-treated gilts aborted within 34 h as did the gilts treated by LPS only. Of the 6 LPS + FM-treated gilts, 1 aborted within 34 h, while 5 maintained gestation. These were aborted about a week later by CP and the aborted fetuses anatomically examined. Two of the litters were lost (devoured by the dams), 2 showed no signs of earlier death and 1 showed extensive fetal death. The PGF2 alpha metabolite concentrations increased at least 10 fold immediately after the LPS injection. Progesterone plasma concentration decreased rapidly. A 5-10 fold increase in the plasma metabolite levels accompanied all abortions. CP caused no immediate change in the PGF2 alpha metabolite levels, but the abortion-related response was similar to that in LPS-injected gilts. In the FM-treated gilts, the LPS-induced PGF2 alpha metabolite response was rudimentary and the progesterone decrease temporary in nonaborting gilts. The elevated concentrations of ES decreased within 48 h in gilts aborting at 30 days gestation, while in nonaborting gilts a slow, graduate decrease of ES occurred within 3-5 days of the LPS injection. These results indicate that FM apparently suppressed LPS-induced prostaglandin synthesis and thus prevented luteolysis and abortion in early pregnant gilts.
Abortion, Veterinary↗
Clinical and blood biochemical changes during induction of endotoxaemia in heifers.
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Animals↗
Endotoxin concentrations in the blood following intravenous injection and effect on prostaglandin F2 alpha release, calcium and bile acids in goats.
Injection of endotoxin from Salmonella typhimurium in male goats resulted in a biphasic release pattern of PGF2 alpha, as determined by 15-ketodihydro-PGF2 alpha concentrations in plasma. A small initial peak at 30 minutes was followed by a second peak one hour after injection. The rectal temperature increased three to five hours after endotoxin injection and calcium concentrations started to decrease soon after injection; a significant decrease was seen from 105 minutes. Endotoxin concentrations varied among the animals but had a tendency to increase three hours after injection, simultaneously with a decrease in bile acid concentrations three hours after injection. The decrease in bile acids indicated alimentary stasis. Therefore, the raised endotoxin levels could be of endogenous origin. This study also shows that the prostaglandin metabolite is a very reliable parameter for estimating the effect of endotoxin.
Animals↗
Some effects of gram-negative bacterial endotoxin and its importance as a contaminator of biological preparations.
The purpose of this study was to establish a model which can be used to examine the biological response to Salmonella typhimurium endotoxin in both anaesthetized and unanaesthetized rabbits, and then compare this response to that of rabbits injected with an endotoxin-contaminated biological preparation. The parameters used to evaluate the biological response included total white blood cell and differential counts, 15-ketodihydro-PGF2 alpha concentration, and rectal temperature. Unanaesthetized groups of rabbits received 1000, 100, 10, or 1 ng/kg of the endotoxin via intravenous injection (i.v.); the anaesthetized group of rabbits received 100 ng/kg endotoxin i.v. (anaesthesia induced with Hypnorm). In addition, groups of rabbits were treated under anaesthesia with Pharmacia-Chiron's recombinant human Cu/Zn superoxide dismutase (SOD) (10 mg/kg body weight = 1.6 endotoxin units (EU)/kg) or Grünenthal's bovine SOD (two doses: 10 mg/kg = 400 EU/kg, or 50 mg/kg = 2000 EU/kg). Results demonstrated that at the lower doses of endotoxin (10 and 1 ng/kg) and r-hSOD (10 mg/kg), no leukopenia was observed. There was however a slight shift in the leukocyte population so that polymorphonucleocytes increased and monocytes decreased in number. Rabbits treated with higher doses of endotoxin (1000 and 100 ng/kg) showed many of the common signs of endotoxemia, including leukopenia, increased prostaglandin metabolite levels, and increased body temperature, as did the rabbits treated with endotoxin-contaminated bSOD. There was a definite dose-dependency, with the higher dose of bSOD giving a more marked rise in all parameters. These findings indicate that use of this or other endotoxin-contaminated biological preparations in live-animal experiments could produce erratic, and therefore unreliable, results.
Animals↗
Biological responses of sheep treated with endotoxin-contaminated superoxide dismutase and endotoxin preparations.
The purpose of this study was to evaluate the biological response of sheep to different doses of endotoxin and endotoxin-contaminated enzyme preparations. The enzyme used in this experiment was superoxide dismutase (SOD), as it is currently being used in many different experiments and because several preparations were found to be heavily contaminated with endotoxin. A group of ewes were injected intravenously with a variety of different treatments. Peripheral blood was used to determine the total number of leukocytes, a differential cell count to find out the numbers of polymorphonucleocytes (PMN) and monocytes (M), and to measure the concentration of 15-ketodihydro-PGF2 alpha. In addition, rectal temperature was recorded. Treatments included saline (control), Pharmacia-Chiron's Cu/Zn-SOD (r-hSOD, 8 mg/kg), Sigma's bovine SOD (bSOD, 8 mg/kg), Grünenthal's bSOD (8 mg/kg), various doses of Salmonella typhimurium endotoxin (1000, 200, 100, 50, 20, 10, 5, and 1 ng/kg), and a mixture of endotoxin (200 ng/kg) plus r-hSOD (8 mg/kg). Results indicate that sheep react to endotoxin-contaminated SOD preparations with an endotoxemia which is similar to that seen in animals receiving endotoxin alone. This endotoxemia includes, among other things, a rise in rectal temperature, a peak in the PGF2 alpha metabolite, and an increased PMN/M ratio. Endotoxin administered at doses of 50 to 200 ng/kg also caused the expected signs of endotoxemia. At 1000 ng/kg endotoxin actually led to a decreased rectal temperature. This may be due to a type of endotoxemic shock, resulting in a decrease in peripheral blood circulation. Low doses of endotoxin (10, 5, and 1 ng/kg) caused a leukocytosis via increases in PMN; no greater changes in rectal temperature or the PGF2 alpha metabolite were noted. The combination of r-hSOD with 200 ng/kg of endotoxin caused an endotoxemia similar to that caused by 200 ng/kg of endotoxin alone. In conclusion, if an endotoxin-contaminated SOD-preparation was used to study the efficacy of SOD, there would be a serious risk of interaction by the endotoxins. In such a case it would be impossible to distinguish the effects of the endotoxin from those of the preparation itself. It is therefore important that researchers are alert to the problem of endotoxin contamination.
Animals↗
15-Keto-13,14-dihydroprostaglandin E2- and F2 alpha-metabolite levels in blood from men and women given prostaglandin E2 orally.
Prostaglandin E2 (PGE2) was administered orally in a dose of 1 mg to healthy males (n = 20) and females (n = 10). Blood levels of 15-keto-13,14-dihydroprostaglandin F2 alpha (PGF2 alpha-M) and 15-keto-13,14-dihydroprostaglandin E2 (PGE2-M), determined as the rearrangement product 11-deoxy-15-keto-13,14-dihydro-11 beta, 16-cycloprostaglandin E2 (PGE2-cyclo-M), were measured. The levels of the two PG metabolites increased already 10 minutes after ingestion of the tablet and the mean peak value for PGE2-cyclo-M in the men was 4.64 nmol/l which was reached 50 minutes after PGE2 administration. The mean peak value in women was 4.99 nmol/l which was obtained after 30 minutes. The increase in PGE2-cyclo-M concentration was significantly faster (p less than 0.05) in women than in the men. The mean plasma concentration of PGF2 alpha in males were 0.20 nmol/l prior to treatment and rose after PGE2 ingestion to mean peak level of 0.84 nmol/l after 70 minutes. The corresponding values for the females were 0.18 nmol/l and 0.88 nmol/l 50 minutes into treatment. When the data from both sexes were amalgamated PGE2-cyclo-M peak levels were reached significantly (p = 0.004) sooner than the PGF2 alpha-M peak. The two PG metabolites returned to baseline levels in 70% of the individuals after 240 minutes. The increase in PGF2 alpha-M concentration following oral administration of PGE2 indicates that part of the PGE2 was reduced to PGF2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Effect of flunixin meglumine on prostaglandin F2 alpha synthesis and metabolism in the pig.
The effect of flunixin meglumine on prostaglandin synthesis and metabolism was evaluated in the pig in vivo. It was found that the prostaglandin metabolite, 15-ketodihydro-PGF2 alpha, was decreased in the peripheral circulation within 20 min of injection of the drug. In therapeutic doses in the pig the drug had no effect on the metabolism of PGF2 alpha. Flunixin was compared with some other non-steroidal anti-inflammatory drugs in an in vitro test system utilizing sheep vesicular gland microsomes. It was concluded that this drug is a potent inhibitor of prostaglandin synthesis.
Animals↗
Bovine virus diarrhoea virus, a cause of early pregnancy failure in the cow.
In the present report attention is drawn to clinical and hormonal changes in heifers following experimental or natural infection with bovine virus diarrhoea virus in early pregnancy. Three heifers were infected experimentally and one naturally at pregnancy stages from 29-41 days. A leukopenia was seen 5-7 days after infection. All four animals experienced foetal death. Two of them aborted and in two the foetus was resorbed. Oestrus was observed at the expulsion of the foetus or in connection with vaginal discharge. Peripheral blood plasma levels of progesterone and the main blood plasma metabolite of prostaglandin F2 alpha (15-keto-13,14-dihydro-PGF2 alpha) were analysed. Diagnosis of pregnancy and embryonic/foetal viability were monitored by ultrasound. The interrelationship between infection and reproductive endocrinology is discussed and the importance of avoiding infection in early gestation is pointed out. It may easily pass unobserved and can thereby cause serious economic loss.
Abortion, Veterinary↗
Clinical, endocrinological and spermatological studies after endotoxin in the ram.
Eight rams were injected intravenously with endotoxin from Salmonella typhimurium. Blood plasma was analysed for the contents of 15-ketodihydro-PGF2 alpha, LH, testosterone, calcium and total amount of white blood cells. Semen was examined for motility, concentration, volume and morphological appearance. After castration at 4 or 16 weeks the testes were examined histologically. The total white blood cells and the calcium levels as well as LH and testosterone decreased and the levels of 15-ketodihydro-PGF2 alpha rose after the endotoxin administration. The examination of the semen showed a significant decrease in motility and a significant increase in abnormal sperm heads. The histological examination showed a slight degeneration in the seminiferous epithelium in the rams castrated at 4 weeks after the endotoxin administration; this degeneration was not seen in the rams castrated at 16 weeks. The present results indicate that endotoxin seems to exert a negative effect on the genital functions of the ram; the changes in LH and testosterone are very similar to those seen after heat induced stress. The histological changes indicate a short-lasting mild degeneration in the seminiferous epithelium.
Animals↗