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C Bregengård

Publications and source records attributed to C Bregengård.

13 recordsLinked to original sources
PubMed1995

Recombinant lys-plasminogen, but not glu-plasminogen, improves recombinant tissue-type plasminogen activator-induced coronary thrombolysis in dogs.

OBJECTIVES: This study examined the modification of recombinant tissue-type plasminogen activator (rt-PA)-induced thrombolysis by recombinant lys-plasminogen. BACKGROUND: Recombinant tissue-type plasminogen activator restores flow in the thrombosed coronary artery, but the artery often reoccludes. The rt-PA-induced thrombolysis is a result of activation of plasminogen bound to fibrin in the thrombus and results in generation of the fibrinolytic enzyme plasmin. Small amounts of lys-plasminogen are formed when rt-PA is used. Lys-plasminogen binds to fibrin with a 10-fold greater affinity than the predominant native glu-plasminogen, leading to a loose fibrin structure. METHODS: Dogs with electrically induced occlusive intracoronary thrombus were treated with saline solution (n = 9), glu-plasminogen (2 mg/kg body weight, n = 5) or lys-plasminogen (2 mg/kg, n = 5), followed by infusion of rt-PA (1 mg/kg over 20 min) 10 min later. RESULTS: Reperfusion rates were similar in all groups of dogs, but the time to reflow was lowest in dogs given lys-plasminogen compared with those given saline solution or glu-plasminogen before rt-PA (mean [+/- SE] 14 +/- 2 vs. 22 +/- 2 and 23 +/- 3 min, respectively, p < 0.05). None of the reperfused coronary arteries reoccluded in the lys-plasminogen plus rt-PA group, whereas 75% reoccluded in dogs given saline solution plus rt-PA, and 50% reoccluded in those given glu-plasminogen plus rt-PA. Accordingly, duration of reflow was greater in the lys-plasminogen plus rt-PA group (> 120 vs. 39 +/- 7 and 82 +/- 21 min, respectively, p < 0.05). Plasminogen activator inhibitor-1 activity decreased during rt-PA infusion and thereafter increased in all dogs, but less so in dogs given lys-plasminogen (p < 0.05 vs. those given saline solution before rt-PA). CONCLUSIONS: Treatment with recombinant lys-plasminogen before rt-PA reduces time to reflow and sustains reflow after thrombolysis, whereas glu-plasminogen has no such effect.

Animals↗
PubMed1995

Primary haemostasis in thyroid disease.

OBJECTIVES: There have been reports on a bleeding tendency in hypothyroidism resembling von Willebrand's disease. The aim of the present study was to investigate whether altered primary haemostasis is a general phenomenon in thyroid disease. DESIGN/SETTING: A total of 10 patients with hyperthyroidism and nine patients with hypothyroidism were studied at diagnosis, and during treatment with carbimazole or L-thyroxine, respectively, when euthyroidism had been achieved. RESULTS: In untreated hypothyroidism, template bleeding time was prolonged (median 9.3 min, range 3.8-20.0 min) compared to that in controls (median 4.0 min, range 3.0-6.0 min; P < 0.05), whereas maximal agglutination velocity induced by ristocetin was decreased (38% min-1, range 4-52% min-1 vs. 70% min-1, range 60-81% min-1, P < 0.05). The level of von Willebrand factor antigen in plasma from hypothyroid patients was less than half of the value in hyperthyroid patients. This difference disappeared after euthyroidism was achieved. CONCLUSIONS: We found that changed primary haemostasis is a general feature of hypothyroidism, and that it is resolved after levothyroxine treatment.

Adult↗
PubMed1995

Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.

Glycoprotein 330 (gp330) is an endocytic receptor expressed in the renal proximal tubules and some other absorptive epithelia, e.g., in the inner ear. The present study shows that the antifibrinolytic polypeptide, aprotinin, and the nephro- and ototoxic antibiotics, aminoglycosides, and polymyxin B compete for binding of 125I-urokinase-plasminogen activator inhibitor type-1 complexes to purified rabbit gp330. Half maximal inhibition was measured at 4 microM for aprotinin, 50 microM for gentamicin, and 0.5 microM for polymyxin B. Drug binding to gp330 was validated by equilibrium dialysis of [3H] gentamicin-gp330 incubations and binding/uptake studies in rat proximal tubules and gp330-expressing L2 carcinoma cells. Analyses of mutant aprotinins expressed in Saccharomyces cerevisiae revealed that basic residues are essential for the binding to gp330 and renal uptake. The polybasic drugs also antagonized ligand binding to the human alpha 2-macroglobulin receptor. However, the rapid glomerular filtration of the drugs suggests kidney gp330 to be the quantitatively most important target. In conclusion, a novel role of gp330 as a drug receptor is demonstrated. The new insight into the mechanism of epithelial uptake of polybasic drugs might provide a basis for future design of drugs with reduced toxicity.

Animals↗
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↗
PubMed1993

Evidence that the C-terminus of tissue factor pathway inhibitor (TFPI) is essential for its in vitro and in vivo interaction with lipoproteins.

We have previously shown that the C-terminus of TFPI is essential for its anticoagulant activity. In the present study we have assessed the role of this region in the binding of TFPI to lipoproteins. We found that full length TFPI, but not C-terminal degraded TFPI, was capable of coeluting with the plasma lipoprotein fraction on a Superose-6 column. The importance of the TFPI C-terminus in lipoprotein interactions was also assessed using a microtitre plate binding assay. We found that full-length TFPI was capable of binding to VLDL or LDL coated microtitre plates. C-terminal degraded TFPI also bound to VLDL, but with a ten-fold lower affinity than full length TFPI. Interestingly, removal of the C-terminus along with the third Kunitz-type domain resulted in a TFPI form incapable of lipoprotein binding. Since heparin shows strong binding to the C-terminus of TFPI, we also tested its effect on the binding of full length TFPI to VLDL. We found that co-incubation of TFPI with heparin inhibited this binding in a dose-dependent manner. Heparin was also capable of releasing TFPI from a preformed TFPI:VLDL complex, although this reaction required unphysiological amounts of heparin. To assess the physiological function of heparin on FL-TFPI:lipoprotein interactions we also performed gel filtration chromatography of rabbit plasma immediately following i.v. administration of FL-TFPI with and without heparin. Previous experiments indicated that heparin has a protective effect on exogenously added FL-TFPI, increasing its recovery by ten-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1989

[Hypophyseal hyperthyroidism. Non-tumoral hypersecretion of thyroid stimulating hormone with clinical hyperthyroidism].

A case of hyperthyroidism due to inappropriate TSH secretion in a 45-year-old man is presented. The diagnosis was confirmed by measurement of increased serum TSH values using three different assays, increased T4 and T3 values, the clinical picture, and the effect of anti-thyroid treatment. Nuclear magnetic resonance and computerized tomographic scans of the pituitary fossa showed no abnormalities. Treatment with long-term oral thyrotropin-releasing hormone, oral triiodothyronine, and short-term subcutaneous Sandostatin injections resulted in partial suppression of TSH without however adequate clinical effect. Treatment with thyroxin, bromocriptine, and triiodothyroacetic acid did not alter the parameters. It is concluded, that the inappropriate TSH secretion may be due to a pituitary microadenoma.

Humans↗
PubMed1989

[Severe adverse effects of low-dose carbimazole treatment in hyperthyroidism. A retrospective study of 476 patients].

A material of 476 hyperthyroid patients treated with carbimazole and 69 patients treated with PTU in the period from 1978 to 1986 were studied retrospectively. The antithyroid treatment was given in low dosage without supplementary thyroxine. The total frequency of adverse effects, defined as symptoms leading to discontinuance of the treatment, was 8.0% for carbimazole and 2.9% for PTU. There were no cases of agranulocytosis in the group treated with carbimazole, and one case in the group treated with PTU. No relationship between age and adverse effects could be demonstrated. The relationship between adverse effects and dosage is discussed, and it is concluded that low dosage treatment with carbimazole has a very low frequency of adverse effects in terms of agranulocytosis and toxic hepatitis.

Adult↗
PubMed1989

Thyroid hormone metabolism in hypermetabolic patients with haematological disorders.

Turnover tracer studies of T4 and T3 using the single injection, noncompartmental approach were performed in 6 hypermetabolic patients with haematological disorders (HHD) (basal metabolic rate (BMR): median 141%, range 122-166%), in 10 controls with stable, nonthyroidal illness (NTIC), and in 14 healthy controls (HC). The main finding was an increase of approximately 30% of the production rate (PR) of both T4 and T3 in patients with HHD. Median PR of T4 was 134 nmol/day x 70 kg in HHD, compared to 78 nmol/day x 70 kg in NTIC (P less than 0.05) and 98 nmol/day X 70 kg in HC (p less than 0.1), whereas median PR of T3 was 40.3 nmol/day x 70 kg in HHD, compared to 25.6 nmol/day x 70 kg in NTIC (P less than 0.01) and 31.1 nmol/day x 70 kg in HC (P less than 0.1). An increase of similar magnitude was found for the apparent distribution volume and the pool size of both T4 and T3. In contrast, the mean transit times of the hormones were similar in the 3 groups. Patients with HHD had normal levels of basal serum TSH as well as of the TSH response to TRH. Only PR of T3 correlated to the BMR (R = 1.00, P less than 0.02). The data are compatible with an increased consumption of thyroid hormones by malignant haematologic cells, and the increase of BMR seems to be dependent on the production of T3.

Adult↗
PubMed1988

Assessment of the clinically significant TSH response to TRH in patients with nodular goitre.

Twenty-five patients with nodular goitre who had thyroid hormone levels within normal ranges and an absent thyrotropin (TSH) response to TSH releasing hormone (TRH) as measured by a conventional radioimmunoassay with a lower detection limit of 0.6 mU/l were studied. Based on these data, and the clinical evaluation patients were divided into a hyperthyroid group (n = 12) and a euthyroid group (n = 13). The samples from the TRH test were reanalyzed by an immunoradiometric TSH assay with a detection limit of 0.05 mU/l. Basal serum TSH showed a considerable overlap between the two groups, but values above 0.10 mU/l were always associated with euthyroidism. Using this level of discrimination 76% of the patients were correctly classified. A TSH response to TRH of 0.10 mU/l provided a better discrimination allowing a correct diagnosis in 92% of the patients. It is concluded that serum TSH as measured by a sensitive assay is suitable as a first line test in patients with nodular goitre. However, patients with basal serum TSH levels below 0.10 mU/l need further investigation with a TRH-test. A TSH response to TRH above 0.10 mU/l seems to secure euthyroidism, whereas lower responses almost always are associated with hyperthyroidism.

Adult↗
PubMed1987

Relationships between serum thyrotropin, serum free thyroxine (T4), and 3,5,3'-triiodothyronine (T3) and the daily T4 and T3 production rates in euthyroid patients with multinodular goiter.

Serum TSH, as measured by a sensitive assay, and serum free T4 and T3, as measured by an ultrafiltration technique, were compared in 14 euthyroid patients with multinodular goiter and 14 normal subjects. T4 and T3 turnover studies also were performed, using the single injection, noncompartmental approach. The goitrous patients had serum free T3 levels within the normal range, but their median serum T3 level was increased compared to that in the normal subjects [goitrous patients, 5.48 pmol/L (range, 4.41-9.03); normal subjects, 4.12 pmol/L (range, 2.58-5.78); P less than 0.01]. The T3 production rate (PR) also was elevated in the patients (median, 39.4 nmol/day X 70 kg; range, 28.7-70.5) compared to that in the normal subjects 31.1 nmol/day X 70 kg; range, 24.4-45.2); P less than 0.05). No differences were found between the two groups with regard to serum free T4 levels or T4 PRs. Serum TSH levels in the patients were reduced (median, 0.20 mU/L; range, less than 0.05-1.6) compared to those in normal subjects (1.8 mU/L; range, 0.36-5.1; P less than 0.01). A significant inverse correlation was found between serum TSH levels and free T3 levels (r = 0.70; P less than 0.001), whereas serum TSH did not correlate with serum free T4 or the PR of T4 or T3. Our data suggest that clinically and biochemically euthyroid patients with multinodular goiter have slight T3 hyperproduction, and TSH secretion in the patients studied was more closely related to serum free T3 levels than to serum free T4 levels or the T3 or T4 PR.

Adult↗
PubMed1987

The influence of free fatty acids on the free fraction of thyroid hormones in serum as estimated by ultrafiltration.

Thyroid hormones are displaced from their binding proteins in serum during nonthyroidal somatic illness, and FFA have been claimed to contribute. It seems mandatory to evaluate this effect using techniques for the measurements of serum free thyroid hormones in which serum remains undiluted. We measured the effect of 7 common human FFA on the free fraction of T4, T3 and rT3 in serum from healthy subjects using an ultrafiltration technique by which serum is diluted only minimally. In addition we measured the effect of oleic acid on the free fractions of the iodothyronines in pooled serum from healthy subjects and in pooled serum from patients with nonthyroidal illness. All FFA tested were able to displace both T4, T3 and rT3, but to a varying degree, arachidonic and linoleic acid being the most potent ones. A 20% increase in the free fractions of T4, T3 and rT3, respectively, was obtained by adding between 1.7-3.3 mmol/l, 1.3-4.6 mmol/l and 1.0-2.4 mmol/l of the different FFA. A serum pool obtained from patients with nonthyroidal somatic illness was more sensitive to oleic acid than a serum pool obtained from healthy subjects, since 2-3 times less oleic acid was necessary to induce a 20% increase in the free fractions of thyroid hormones. It is concluded that FFA are able to displace both T4, T3 and rT3 from their serum binding proteins in healthy subjects as well as in patients with nonthyroidal illness. However, serum from patients with nonthyroidal illness was more sensitive to the displacing activity of oleic acid than serum from healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrovascular Disorders↗