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Biomedical subjects

O Svendsen

Publications and source records attributed to O Svendsen.

At least 37 records · Page 2Linked to original sources
PubMed1993

The effect of two-domain tissue factor pathway inhibitor on endotoxin-induced disseminated intravascular coagulation in rabbits.

Disseminated intravascular coagulation (DIC) is a common complication in sepsis, and may result from endotoxin-induced exposure of tissue factor on the surface of monocytes and endothelial cells. Tissue factor pathway inhibitor (TFPI) is a factor Xa-dependent feedback inhibitor of the tissue factor-factor VIIa complex. In the present study the effect on DIC of a two-domain TFPI analogue (2D-TFPI), consisting of the first two Kunitz domains of TFPI but lacking the third domain, was tested. DIC was induced in rabbits by two intravenous bolus injections of endotoxin from Escherichia coli (10 and 50 micrograms/kg) 24 h apart. Simultaneously with the last endotoxin injection an infusion of 2D-TFPI (0, 0.3, 1.0 or 3.0 mg/kg/h) was given. Blood samples were obtained at 0 h, 24 h and 31 h. At 31 h the animals were sacrificed and the kidneys were submitted to histological examination. The degree of fibrin deposition in glomeruli was scored blindly using an arbitrary scale from 0 to 3. Between 24 and 31 h the group receiving endotoxin alone showed a significant decrease in platelet count (65%), plasma fibrinogen (41%), antithrombin III (25%), and factor VIII (63%), and a significant prolongation of the aPTT (14%). Furthermore, massive fibrin deposition was detected in the renal glomeruli at 31 h. Infusions of 2D-TFPI inhibited all the endotoxin-induced changes in a dose-dependent manner. In conclusion, the data demonstrate that inhibition of the TF/FVIIa complex by infusion of 2D-TFPI significantly counteracts endotoxin-induced coagulopathy in rabbits, and might thus be an attractive drug for treatment of endotoxin-induced DIC in humans.

Animals↗
PubMed1992

Effect of immunosuppressive agents on the guanethidine-induced sympathectomy in athymic and euthymic rats.

Guanethidine sulphate causes destruction of peripheral sympathetic neurons and infiltration of mononuclear inflammatory cells in the sympathetic ganglia of both athymic nude (rnu/rnu) and euthymic LEW/Mol rats. The effect of guanethidine is believed to be an autoimmune reaction. To determine the effect of immunosuppressive drugs concurrently with guanethidine treatment both athymic and euthymic rats were treated with guanethidine 40 mg/kg i.p. daily for 14 days, cyclophosphamide 100 mg/kg i.p. on days 1 and 8, methylprednisolone 10 mg/kg and cyclosporin A 10 mg/kg daily from days 1 to 7, and then every other day from days 8 to 14. The number of neurons in the sympathetic ganglia was counted and four subpopulations of mononuclear inflammatory cells were identified by monoclonal antibodies MHC II, CD8 T-cells/NK-cells, CD5 T-cells, CD4 T-cells/macrophages. Our results show that the immunosuppressive drugs used were unable to prevent the guanethidine-induced reduction of sympathetic neurons, although the number, of neurons following guanethidine-methylprednisolone treatment was significantly higher compared with guanethidine alone in both athymic and euthymic rats. The identification of mononuclear cells in the sympathetic ganglia showed that the CD8/NK and CD5 populations were the populations primarily responding to guanethidine treatment. Both CD8/NK and CD5 populations were absent without guanethidine, but increased significantly following guanethidine in both athymic and euthymic animals. None of the immunosuppressive drugs used could prevent the guanethidine-induced rise in the CD8/NK population in neither athymic nor in euthymic rats. The rise in the CD5 population was suppressed following treatment with all immunosuppressive drugs in athymic rats, but only following methylprednisolone in euthymic animals. These results indicate that guanethidine induces proliferation of T-cells in euthymic rats and non-functional CD5 positive pre T-cells in athymic animals. The CD5 population in both athymic and euthymic animals appears relatively more sensitive to immunosuppressive drugs than the NK-cell population also activated by guanethidine. This relatively resistant NK-cell population seems to play an important role in the guanethidine-induced destruction of sympathetic neurons and can explain why the guanethidine-induced immunological reaction could not be fully prevented by the immunosuppressive drugs used. The conclusion is that guanethidine induces destruction of sympathetic neurons by a NK-cell-mediated reaction.

Animals↗
PubMed1992

Athymic experimental animals in pharmaco-immunological research.

Immunodeficient animals--the nude mouse and the nude rat--allow studies of drug action and possible side effects without interference from the immune system. Comparative investigations in athymic and euthymic animals allowed us to elucidate the role of T-lymphocytes in the pathogenesis of streptozotocin-induced diabetes mellitus in mice, and the importance of NK-cells as effectors in guanethidine-induced sympathectomy in the rat. It is suggested that immunodeficient animals should be included in toxicological studies of xenobiotics.

Animals↗
PubMed1992

Anti-asialo GM1 antibodies prevents guanethidine-induced sympathectomy in athymic rats.

Guanethidine sulphate induces destruction of peripheral sympathetic neurons and infiltration of mononuclear cells in rat sympathetic ganglia. The effect of guanethidine is believed to be an autoimmune reaction. In order to determine the effect of anti-asialo GM1, an antibody that binds to the glycolipid asialo GM1 expressed on rodent natural killer cells, athymic Lewis rats received guanethidine 40 mg/kg i.p. daily from day 1 to 14 and anti-asialo GM1 i.p. 1 mg/rat on day -2, 0, 2, 6, and 10 in the study period. Saline and anti-asialo GM1 were given alone in the same doses as control. The number of neurons in the sympathetic ganglia were counted and the ganglionic volume determined. The presence of natural killer cells in the ganglia were determined by immunohistochemical methods. Our results shows that anti-asialo GM1 can prevent guanethidine-induced reduction of sympathetic neurons, but not prevent the initiation of an immunological reaction in the ganglia. Natural killer cells could only be identified in ganglia following guanethidine treatment alone. It is concluded that anti-asialo GM1 treatment can prevent the guanethidine-induced sympathectomy by eliminating the natural killer cells from the ganglia.

Animals↗
PubMed1992

Rederivation of rat colonies seropositive for Bacillus piliformis and the subsequent screening for antibodies.

Latent infection of rats in a breeding colony with Bacillus piliformis detectable by antibodies to the agent in an immunofluorescence assay was eliminated by a combination of traditional rederivation techniques, using animal units not previously used for rat breeding, and the use of specific disinfection procedures. The success rate was apparently correlated with the use of peracetic acid instead of aldehyde products to decontaminate the animal unit.

Animal Husbandry↗
PubMed1991

Pretreatment with steroids before intravenous injection of diatrizoate or iohexol. Effects on urine and serum profiles.

The effects on urine and serum profiles of intravenous injection of diatrizoate, iohexol, or saline were studied in male rats pretreated with steroids or saline. Using urinary albumin, glucose, sodium, and the enzymes lactate dehydrogenase (LDH), gamma-glutamyltransferase (GGT), and N-acetyl-beta-D-glucosaminidase (NAG) as markers of glomerular and tubular function, it was found that diatrizoate caused temporary glomerular and tubular dysfunction; the effect was independent of the kind of pretreatment. Iohexol did not cause increased glomerular permeability in steroid- and saline-pretreated rats. When used following saline, iohexol induced increased excretion of three tubular components, whereas iohexol plus steroids caused increased excretion of all five tubular components. The dysfunctional effect of iohexol plus steroids was less than that of diatrizoate plus steroids. The serum components revealed no abnormalities induced by either contrast media or methylprednisolone. Pretreatment with steroids has no effect on the glomerular or tubular dysfunctional effect of diatrizoate, whereas it worsens the temporary tubular dysfunctional effect of iohexol in rats.

Acetylglucosaminidase↗
PubMed1991

Effect of human growth hormone on the reproduction of female rats.

Female rats were treated with human growth hormone (hGH) 0.3, 1.0 and 3.3 IU/kg daily for two weeks before mating, throughout mating and during the first seven days of pregnancy. Treatment with 1.0 and 3.3 IU/kg hGH caused a significant prolongation of the oestrous cycle. As a consequence the number of mating days was more than doubled compared to placebo treatment. The number of implantation sites and corpora lutea was significantly higher in hGH treated rats than in placebo treated rats. The number of early resorptions was increased in the rats given 3.3 IU/kg. The number of foetuses in rats sacrificed on day 20 of pregnancy and the number of viable offspring from the rats allowed to give birth were significantly increased by treatment with 1.0 IU/kg hGH. In a study of 4-day cyclic rats, treatment with 3.3 IU/kg hGH caused a prolongation of the cycle length to an average of 10.1 days, and the plasma progesterone levels tended to be higher in those rats in which the cyclic patterns had been most deranged. Foetal body weights were increased in the hGH groups, and a study with 125I-hGH indicated that hGH administered to pregnant rats will to some extent pass the placenta.

Animals↗
PubMed1991

Muscle toxicity of diatrizoate and iohexol in rabbits. A model for local tissue damage.

The potential tissue irritating effect of diatrizoate and iohexol was studied by injecting the contrast media into the right longissimus dorsi muscle of rabbits. The left muscle served as control. The animals were sacrificed 3 days after the injection, at which time muscle tissue was examined for macroscopic changes and loss of the muscle enzyme creatine kinase (CK) from the injection site was determined. An irregular area of necrotic muscle tissue and a hemorrhage was found at the injection site in rabbits given diatrizoate, whereas iohexol only caused hemorrhage. The local loss of CK activity following diatrizoate (0.64 g muscle tissue) was statistically significantly greater than following iohexol (0.18 g muscle tissue). It is concluded that this model seems to be useful for identification of the irritating potential of contrast media. It is also concluded that diatrizoate caused more damage to the local muscle tissue than iohexol.

Animals↗
PubMed1990

Identification of the mononuclear cell infiltrate in the superior cervical ganglion of athymic nude and euthymic rats after guanethidine-induced sympathectomy.

Guanethidine sulphate 40 mg/kg intraperitoneally for 14 days induced chromatolysis and nerve cell death in the superior cervical ganglia of athymic nude (rnu/rnu) LEW/Mol rats and their euthymic (+/rnu) LEW/Mol heterozygous littermates. Histologically the sympathetic ganglia were dominated by an infiltration of small inflammatory cells. By means of monoclonal antibodies these cells were identified. The number of B-lymphocytes increased following guanethidine in both athymic and euthymic rats. The number of T-lymphocytes increased to a great extent in euthymic rats, but was virtually missing in athymic rats. The number of NK-cells and monocytes/macrophages increased in both athymic and euthymic rats. The conclusion is, that guanethidine exerts a direct effect on sympathetic ganglion cells followed by a thymus-independent immune response.

Animals↗
PubMed1990

Epidemiological studies of Bacillus piliformis infection and Tyzzer's disease in laboratory rats.

Characteristics in connection with the presence of Bacillus piliformis in the barrier-protected animal rooms of a breeding centre for laboratory rats are discussed. The incidence of antibodies against B. piliformis in IFA test is high -77.8% for the total breeding centre. Clinical and pathological changes are, however, rare and mainly connected with certain rat strains. Immunosuppression with prednisolone and subsequent histopathological tests of liver sections indicate that rats with MHC-type RT1.A-u have an increased risk of developing Tyzzer's disease, while RT1.A-1-carriers seem to be resistant to this disease.

Animals↗
PubMed1988

Biosynthetic human growth hormone: subchronic toxicity studies in rats and monkeys.

Biosynthetic human growth hormone was injected subcutaneously in rats for 90 days and in cynomolgus monkeys for 30 days. The daily doses were 0.5, 3.3 and 25 IU kg-1 (rats) and 0.3 and 15 IU kg-1 (monkeys). The growth hormone was tolerated well in both rats and monkeys. No drug related deaths occurred and all animals appeared to be normal and also behaved normally throughout the dosing period. Increased body weight gain, increased food utilisation and increased organ weights were seen in the rats in the high and intermediate dose groups. The higher doses of human growth hormone (3.3 and 25 IU kg-1) caused a glandular hyperplasia of the mammary gland in male and female rats with evidence of secretory activity. In the female monkeys secretory activity was seen without any sign of mammary gland hyperplasia. Mucification of the vaginal epithelium and stress induced prostatitis was observed in the rats. Additional treatment related changes in the rats were an increased haematopoietic activity in the spleen and an increase in the amounts of calcium and phosphate excreted in urine. An increase in fasting plasma glucose levels was seen in the male monkeys on the high dose level. The changes observed during the treatment periods presumably represent exaggerated pharmacological effects of the growth hormone.

Animals↗
PubMed1986

Microscopic epidural lesions in goats given repeated epidural injections of morphine: use of a modified autopsy procedure.

Epidural catheterization was performed in six goats. Five days later either saline or 20 mg (5 mg/ml) preservative free morphine was injected epidurally once daily for 8 days. The goats were sacrificed 4, 24 or 48 hours after the last injection. The lumbar part of columna was removed in toto for microscopic examination of the spinal cord and the entire epidural space after decalcification and transverse sectioning. After saline, minimal changes including a fibrous membrane surrounding the catheter, scattered fat cell necrosis, scattered small focal cell infiltrations and occasionally focal haemorrhages were seen. After morphine the changes were considerably more severe including diffuse cellular inflammatory reaction in the epidural space, fat cell necrosis, occasionally focal exudative inflammation and chronic inflammatory reaction in the vicinity of the fibrous membrane demarcating position of the catheter. It is concluded that the present modified autopsy procedure permits microscopic examination of the epidural space. It has been shown that repeated administration of morphine caused tissue damage in the epidural space of goats. The human predictability of the results obtained is unknown. However, the results are encouraging for investigations with similar procedure in humans.

Animals↗
PubMed1985

Pharmacological differentiation of dopamine D-1 and D-2 antagonists after single and repeated administration.

In single-dose experiments neuroleptics antagonize dopamine (DA)-agonist-induced stereotypies in animals. The antagonistic potency correlates with their clinical antipsychotic effects. In a series of experiments where DA-agonist-induced stereotyped gnawing in mice and rats was inhibited by neuroleptics it was shown that the antagonistic effect of butyrophenones was greatly attenuated by concomitant treatment with anticholinergics. The effect of phenothiazines was slightly attenuated and that of thioxanthenes and SCH 23390 remained unchanged. After repeated administration a differentiation is also seen in the ability of the antagonists to suppress DA-agonist-induced stereotypies. The differentiation in these experiments is similar to that seen in dopamine D-1 and D-2 receptor binding. The compounds can be classified into three pharmacological subgroups: butyrophenones (e.g., haloperidol) with affinity for D-2 receptors; phenothiazines (e.g., fluphenazine and perphenazine) with affinity for both D-2 and D-1 receptors but with preference for the D-2 receptors; and thioxanthenes (e.g., cis(Z)-flupentixol and cis(Z)-clopenthixol) with equal affinity for D-1 and D-2 receptors, and the selective D-1 antagonist SCH 23390. This compound has the same antistereotypic effect as is seen with the neuroleptics. We have also investigated the effect of the above-mentioned neuroleptics and SCH 23390 after 12 days' treatment and 3-5 days withdrawal. They were given either alone or in combination. When they were given alone a clear differentiation was seen between the groups when mice were tested for methylphenidate antagonism. The thioxanthenes and SCH 23390 retain their ability to antagonize the stereotyped gnawing; the phenothiazines show a reduced effect; and the butyrophenones have almost lost their ability to antagonize the stereotyped behavior.

Animals↗
PubMed1985

Down-regulation of dopamine D-2, 5-HT2 receptors and beta-adrenoceptors in rat brain after prolonged treatment with a new potential antidepressant, Lu 19-005.

Lu 19-005 is a new phenylindan derivative with strong and equipotent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake. The adaptive effects of 2 weeks treatment with Lu 19-005, on receptor binding in vitro and on d-amphetamine responsiveness in vivo have been investigated in rats. One or 3 days after the final dose the number of beta-adrenoceptors and of 5-HT2 and DA D-2 receptors was decreased by 20-30%, whereas alpha 1-adrenoceptor number was slightly decreased only 1 day after withdrawal. The DA D-2 receptor number remained decreased at 7 days withdrawal, but returned to normal after another 3 days. The brain levels of DA, NA and 5-HT were not changed by 2 weeks' Lu 19-005 treatment. The down-regulation of DA D-2 receptors was accompanied by tolerance to d-amphetamine-induced hypermotility (after low doses) and stereotyped licking or biting (after a high dose). The tolerance to d-amphetamine-induced hypermotility was maximal at 3-5 days withdrawal time, and remained significant also 15 days after the last dose. An acute dose of Lu 19-005 did not modify the effects of d-amphetamine. The results are discussed in relation to the effect of prolonged treatment with other antidepressant drugs.

Animals↗
PubMed1985

Local toxicity of different drugs after intramuscular or intralipomatous injection in pigs: serum concentrations after three different formulations of cis(Z)-clopenthixol.

Findings made by computerized tomography scanning of pelvis of patients suggested that the majority of injections intended to be intramuscular in fact are delivered in the fat tissue. This finding has raised the question what difference it makes when drugs are injected intramuscularly or intralipomatously. We have studied local toxicity after intramuscular or intralipomatous injection of different drugs in pigs, which have a subcutaneous layer of fat comparable to that of man. The pigs were killed 1, 3, 7 or 14 days after injection of antibiotics, vitamins, neuroleptics, diazepam, digoxin, pentazocine, sulphadimidine and vehicles. The tissues at the injection site were examined macro- and microscopically. In another series of experiments an aqueous or two different oily preparations of the neuroleptic drug cis(Z)-clopenthixol were given intramuscularly or intralipomatously to pigs and a series of blood samples were taken for drug level determination. The tissue examinations showed that all drugs causing local muscle damage after intramuscular injection caused considerably less extensive damage with a faster regeneration after intralipomatous injection. The pharmacokinetic study showed that there was virtually no difference between plasma-concentration-time curves after intramuscular or intralipomatous injection. Our findings indicate that intralipomatous injection of irritating drugs is better tolerated than intramuscular injection since intralipomatous injection causes less local toxicity. Our findings also suggest that the pharmacokinetics are not different. However, further studies are required to substantiate whether the findings are of general relevance.

Absorption↗
PubMed1985

Tests for local toxicity of intramuscular drug preparations: comparison of in vivo and in vitro methods.

Different concentrations of aqueous preparations of metoclopramide, gaboxadol, cis(Z)-clopenthixol, digoxin and chlorpromazine and of cis(Z)-clopenthixol acetate in Viscoleo have been tested for local toxicity after intramuscular injection in rabbits. The weight of macroscopically changed muscle tissue isolated 3 days after injection was determined. In addition, homogenized injection site muscle tissue was analysed for creatine kinase (CK) activity and by comparison with the CK activity of contralateral muscle tissue, the amount of injection site muscle tissue totally depleted for CK activity was calculated. The substances have also been tested for in vitro toxicity. The concentrations of the substances which caused 100% haemolysis of human erythrocytes or minimal cytotoxicity in cell culture assays using MRC-5 fibroblasts were estimated. Metoclopramide and gaboxadol caused no or only minimal local muscle damage in the rabbits. Metoclopramide caused local bleeding. The four other substances caused concentration-dependent muscle damage. Although there was some deviations, the two in vitro tests reflected reasonably well the in vivo findings. The results of this study suggest that the in vitro tests employed can be useful as screening tests for local toxic effect of intramuscular drug preparations. However, further studies are required before conclusion as to predictability can be drawn. The in vitro methods are inexpensive and quick, especially the haemolysis test.

Animals↗
PubMed1984

Effects of S (+)-3-phenethyl-PP, a putative dopamine autoreceptors agonist with greater autoreceptor selectivity than 3-PPP enantiomers.

The experiments concerned the pharmacology of the enantiomers of the phenethyl-analogue (3-phenethyl-PP) of the putative dopamine (DA) autoreceptor agonist 3-PPP. In contrast to the almost equipotency of 3-PPP enantiomers, the phenethyl enantiomers showed marked stereoselectivity. S(+)-3-Phenethyl-PP had 25 times higher affinity to D-2 DA receptors in vitro than the R(-)-enantiomer. In vivo a similar potency difference was seen for the inhibition of motility, induction of circling behaviour in 6-OHDA-lesioned rats and emetic effect in dogs. None of the enantiomers induced stereotypy and hypermotility in normal rats or in rats pretreated with reserpine and alpha-methyl-p-tyrosine. In test models for antidopaminergic activity only slight activity of either enantiomer was observed. The S(+)-enantiomer had no antagonistic effect against apomorphine- and amphetamine-induced stereotypies, no cataleptogenic activity and only partially antagonized amphetamine-induced hypermotility. Apomorphine-induced emesis was weakly antagonized. The results indicate a greater and higher selectivity of S(+)-3-phenethyl-PP for DA receptors mediating sedation compared with 3-PPP enantiomers which previously have been shown to exert significant effects on postsynaptic DA receptors. Thus S(+)-3-phenethyl-PP may be a more selective model compound for the differential study of effects elicited by stimulation of pre- and postsynaptic DA receptors.

Adenylyl Cyclases↗