Biomedical subjects

O Roeise

Publications and source records attributed to O Roeise.

13 recordsLinked to original sources

PubMed1994

Effects of a combined drug regimen on tumour necrosis factor and plasma kallikrein activity in experimental endotoxaemia.

OBJECTIVE: To clarify the relationship between changes in haemodynamics, liberation of tumour necrosis factor and generation of plasma kallikrein, and to see if treatment with a combination of drugs was successful in preventing activation of tumour necrosis factor and plasma kallikrein in experimental endotoxic shock. DESIGN: Controlled study. MATERIAL: 22 juvenile pigs. INTERVENTIONS: 15 animals received 0.01 mg/kg endotoxin infusion, the rest being given the same volume of saline. 10 received no treatment, and 5 were given a combination of methylprednisolone, naloxone, ketanserin, promethazine, C1 esterase inhibitor, antithrombin III and aprotinin. MAIN OUTCOME MEASURES: Assessment of the liberation of tumour necrosis factor, generation of plasma kallikrein, and haemodynamic and cellular effects of endotoxaemia. RESULTS: There was a linear statistical relationship between decreases in cardiac output and increases in packed cell volume, and between increases in packed cell volume and plasma kallikrein activity. The combination treatment totally blocked all the effects of the infusion of endotoxin. CONCLUSION: Endotoxin affects several mediators, but combination treatment can prevent some of these effects.

Animals↗

PubMed1992

Hemodynamic and proteolytic effects of intravenous injection of purified human plasma kallikrein.

To investigate the precise hemodynamic effects of purified human plasma kallikrein, small doses (0.3 U/kg) of this proteolytic enzyme were infused over 10 s in five pigs. Hemodynamic performance was evaluated by means of a Swan-Ganz catheter, and parameters of the plasma kallikrein-kinin, coagulation, and fibrinolytic systems were determined by means of chromogenic peptide substrate assays. The infusions of plasma kallikrein were followed by rapid decreases in mean arterial pressure (to 43 +/- 2% of baseline values) and increases in cardiac output (to 145 +/- 6% of baseline values), accounting for marked decreases in systemic vascular resistance, to 28 +/- 1% of initial values. Heart rate, mean pulmonary arterial, central venous, and pulmonary capillary wedge pressures did not change after the injection. Pulmonary vascular resistance decreased to 69 +/- 3% of baseline values. The hemodynamic changes gradually normalized during the following 10 min. Functional levels of prekallikrein, kallikrein, kallikrein inhibition, prothrombin, antithrombin III, plasmin, and antiplasmin were not affected by the injection or the resulting hemodynamic changes; the hematocrit and the number of circulating leukocytes or platelets were also unaffected.

Animals↗

PubMed1992

On the value of giving a combination of drugs for the treatment of endotoxaemia in pigs.

OBJECTIVE: To see if treatment with a combination of drugs each directed at a different mediator was successful in preventing activation of those mediators in experimental endotoxic shock. DESIGN: Controlled study. MATERIAL: 40 juvenile pigs. INTERVENTIONS: 33 animals received 0.01 mg/kg endotoxin infusion, the rest being given the same volume of saline; 10 of the 33 received no treatment. Of the remaining 23, 5 were given combination treatment with methylprednisolone, naloxone, ketanserin, promethazine, C1 esterase inhibitor, antithrombin III and aprotinin; 7 were given methylprednisolone only; 6 were given the three protease inhibitors (C1 esterase inhibitor, antithrombin III and aprotinin); and 5 were given naloxone, ketanserin and promethazine. MAIN OUTCOME MEASURES: Assessment of haemodynamic, proteolytic, and cellular effects of endotoxaemia. RESULTS: Only the combination treatment totally blocked all the effects of the infusion of endotoxin. CONCLUSION: As endotoxin affects several mediators, combination treatment is necessary to block all its deleterious effects in pigs.

Animals↗

PubMed1991

Plasma kallikrein generation in endotoxemia is abolished by ultra high doses of methyl-prednisolone: in vivo studies in a pig model.

Thirty-one healthy young pigs were studied to evaluate the effects of methylprednisolone sodium succinate (MP) on cellular, proteolytic, and hemodynamic parameters in normal and endotoxin-exposed animals. Fourteen animals served as controls, whereas 17 test animals received a continuous infusion of endotoxin, 0.01 mg/kg/3hr. Seven of the test animals and seven of the control group received a total of 200 mg/kg body weight over 5 hr of MP, 100 mg/kg as pretreatment before the endotoxin infusion was started. The administration of MP to control animals did not cause changes in the plasma kallikrein-kinin system, as determined with chromogenic peptide substrate assays. Only temporary effects, which normalized during the observation period, were seen in hemodynamic parameters. The pretreatment with MP significantly counteracted the increases in plasma kallikrein activity (KK) and the decreases in functional kallikrein inhibition capacity (KKI) seen after endotoxin infusion in untreated animals. Marked reductions in the number of circulating leukocytes and platelets were observed in untreated endotoxemia, together with increases in hematocrit. Furthermore, increases in pulmonary vascular resistance (PVR) and decreases in cardiac output (CO), left ventricular stroke work (LVSW), and mixed venous oxygen saturation (SvO2) ensued. The changes in circulating cells, PVR, and SvO2 were significantly counteracted by MP treatment, whereas changes in hematocrit, CO, and LVSW were only moderately improved.

Animals↗

PubMed1990

Studies on components of the contact phase system in patients with advanced gastrointestinal cancer.

The authors have studied components of the contact system in plasma obtained from patients with advanced gastrointestinal cancer. Plasma samples from 118 healthy blood donors served as controls. Plasma prekallikrein (PKK) values, evaluated by chromogenic peptide substrate technique, were significantly decreased in patients with cancer compared with healthy blood donors. High molecular weight kininogen (HMwK) and Hageman factor (FXII) values, assayed by immunochemical techniques, were also decreased in the patients with cancer. The changes of contact factors were most pronounced in patients with liver metastasis. The most striking observation in our study, however, was the elevated inhibitor values in patients with cancer. Alpha-2-macroglobulin (alpha 2-M) and C1 inhibitor (C1INH) values, determined both by functional and immunochemical techniques, were markedly increased in patients with cancer. In conclusion, this study shows that patients with intestinal cancer have reduced values of contact factors and markedly elevated inhibitor values which indicate that development of malignant tumors in the gastrointestinal tract is associated with changes in the contact system of plasma.

Aged↗

PubMed1990

Methylprednisolone induces activation of the contact system in a dose-dependent manner. An in vitro study.

The effect of methylprednisolone sodium succinate (MP) on the contact system of plasma was studied in human citrated pool plasma. Contact activation was demonstrated by the presence of plasma kallikrein (KK) activity and activated Hageman factor (FXIIa) and/or KK in complex with C1 inhibitor (C1inh), detected by chromogenic peptide substrates or radioimmunoassays, using monoclonal antibodies directed to neodeterminants exposed on complexed C1inh, respectively. When plasma and different doses of MP were incubated for a period of 24 hours, the highest dose of MP (10 mg/ml) gave rapid and marked increases in KK activities and concentrations of C1inh complexes. MP at 5 mg/ml plasma also induced activation of the contact system, although this activation was less pronounced. Even the lower dose of MP (1 mg/ml), which is equivalent to doses used in humans, increased plasma concentrations of KK-C1inh complexes. In conclusion, this in vitro study shows that MP in a dose-dependent way activates the contact system of plasma.

Complement C1 Inactivator Proteins↗

PubMed1990

Methylprednisolone in high doses gives different effects on the early and the late part of complement.

The effects of methylprednisolone (MP) on endotoxin-induced activation of complement were studied in citrated pool plasma. Complement activation was tested in two immunoassays: one evaluating C3 activation fragments (C3act) and the other the terminal complement complex (TCC). These components are indicators of initial and terminal complement activation, respectively. Plasma samples were obtained at 1, 2, 4 and 6 h of incubation. Plasma containing endotoxin (2.10(9) ng/l) without MP revealed a marked increase of both C3act and TCC after 1 h. MP in high doses (10 mg/ml) gave an additive effect on activation of the initial part of the complement cascade compared to test plasma containing only endotoxin. In contrast, endotoxin-induced activation of the terminal part of the complement cascade was inhibited by the same dose of MP. The influence of lower doses of MP (0.1 and 1 mg/ml) on endotoxin-induced activation of complement was insignificant. Interestingly, MP without endotoxin induced activation of the initial part of complement. In test plasmas containing 5 and 10 mg/ml of MP (without endotoxin) marked increases of C3act values were seen. Despite this obvious activation of the early part of complement, only insignificant changes were found in TCC values. Test plasmas containing 0.1 and 1 mg/ml of MP revealed only minor changes in both C3act and TCC. In conclusion, the present study shows that high doses of MP activate the initial part of complement and that the endotoxin-induced activation of this cascade system was facilitated by MP. The terminal part of complement was, on the other hand, inhibited by high doses of MP.

Complement Activation↗

PubMed1990

Combined drug therapy in porcine endotoxemia. Hemodynamic and proteolytic effects of antagonists against histamine, serotonin and endorphin.

In order to investigate the importance of potential mediators of pathophysiologic derangements in endotoxemia, we have examined the effects of the combined administration of antagonists against histamine, serotonin and endorphins in a porcine model of endotoxemia. The treatment regimen significantly reduced the increase in pulmonary artery pressure, pulmonary vascular resistance and systemic arterial pressure seen in the early stages of endotoxemia. Also, cardiac output was better maintained. However, the hemodynamic performance after an observation period of 5 h was not statistically different from untreated animals. The treatment regimen did not hinder the activation of the kallikreinkinin and fibrinolytic systems of plasma, which was evident in both treated and untreated animals, and could not counteract the increase in hematocrit or leukopenia seen in this model. This study shows that the combined blocking of histamine, serotonin and endorphines is not enough to abrogate the detrimental effects of endotoxin in a porcine model.

Animals↗

PubMed1989

Methylprednisolone affects inhibitors of the complement and the contact systems; functional and immunochemical studies on alpha 2-macroglobulin and C1 inhibitor.

The effects of methylprednisolone sodium succinate (MP) on main inhibitors of the classical pathway of complement and on the contact system were studied in citrated pool plasma. Endotoxin (2.10(9) ng/l, lipopolysaccharide B, E. coli 026: B6 Difco Laboratories, Detroit, Michigan, USA) and/or MP in doses of 0.1, 1, 5 and 10 mg/ml were incubated with plasma at 37 degrees C. Plasma samples were obtained at timed intervals up to 24 hours for determination of C1 inhibitor (C1inh) and alpha 2-macroglobulin (alpha 2M) values using both functional and immunochemical assays. Plasma containing endotoxin without MP revealed decreases of C1inh and alpha 2M values after 12 hours. Addition of MP in high doses (10 mg/ml) gave an additive effect on the endotoxin-induced decreases of C1inh and alpha 2M values, evident 1 and 12 hours after the beginning of incubation, respectively. When MP alone was added to plasma (5 and 10 mg/ml) also significant decreases in C1inh and alpha 2M values were seen. MP in low doses (0.1 and 1 mg/ml) did not either influence the endotoxin-induced changes in the protease inhibitor functions, or induce significant changes in C1inh and alpha 2M values when incubated in plasma without endotoxin. This study demonstrates that MP in high doses induces marked decreases in plasma C1inh and alpha 2M inhibitory functions and that MP has an additive effect on the endotoxin-induced decreases of these inhibitors.

Blood↗

PubMed1989

Peritoneal lavage efficiently eliminates protease-alpha-2-macroglobulin complexes and components of the contact system from the peritoneal cavity in patients with severe acute pancreatitis.

Trypsin (Try), plasma kallikrein (KK) and plasmin activities together with coagulation factor XII (F XII, Hageman factor), high-molecular-weight kininogen (HMWK), plasma prekallikrein (PKK), alpha 2-macroglobulin (alpha 2-M), C1 inhibitor (C1Inh), and functional plasma kallikrein inhibition (KKI) values were studied in peritoneal fluid and lavage taps of 9 patients with severe acute pancreatitis treated with peritoneal lavage. Both immunochemical methods and functional techniques based on chromogenic peptide substrate assays were used. In the exudate obtained before peritoneal lavage was performed, F XII was 52%, HMWK was 30%, PKK was 40%, alpha 2-M was 29% and C1Inh was 57% of standard plasma pool values, determined by immunochemical technique. Functional plasma KKI values were zero, whereas Try activities determined by chromogenic peptide substrate technique were markedly elevated in the exudate. Using a prepacked HR 10/30 Superose Tm 12 column (Pharmacia, Uppsala, Sweden) and chromogenic peptide substrate assays, Try and KK activities were detected in the alpha 2-M containing fractions of the peritoneal exudate demonstrating KK-alpha 2-M and Try-alpha 2-M complex formation. The peritoneal lavage procedure efficiently eliminated components of the contact system and protease activities. In the first lavage tap, Try activities were markedly reduced compared to values found in the exudate and concentrations of F XII, HMWK, PKK, alpha 2-M and C1Inh were all zero. In consecutive lavage taps Try values were also zero. The study shows that the lavage procedures efficiently clears the peritoneal cavity for protease-alpha 2-M complexes generated during acute pancreatitis. Also, components of the contact system found in peritoneal exudate, and which might serve as substrates for the protease-alpha 2-M complexes, are rapidly eliminated by the procedure.

Acute Disease↗

PubMed1989

Studies on the dose dependence of endotoxin-induced in vitro activation of the complement system.

The dose and time dependence of in vitro endotoxin-induced activation of complement was studied in citrated pool plasma at 37 degrees C. C3 activation fragments (C3act) and the fluid-phase terminal complement complex (TCC) were used as indicators of initial and terminal activation, respectively. At 1 h marked elevation of C3act and TCC were found in plasma tested with the highest doses of endotoxin (2.10(9) and 2.10(8) ng/l). In test plasmas with 2.10(7) and 2.10(6) ng/l of endotoxin, no sign of activation was seen during the first 4 h, whereas both C3act and TCC values were increased at 12 h. In thest plasma with 2.10(5) ng/l of endotoxin and in control plasma no elevation of TCC values were seen during the observation period (24 h), whereas C3act values increased slightly and to the same extent in both at 24 h. Parallel to the increases in C3act and TCC concentrations, the functional C1 inhibitor (C1INH) values decreased. Changes in C1INH values, however, occurred with a time lag of approximately 6 h compared to the increases in C3act and TCC. Our in vitro study showed a dose-dependent endotoxin-induced activation of both the initial and the terminal part of the complement cascade evaluated by C3act and TCC.

Complement Activation↗

PubMed1989

Plasma proteolysis and circulating cells in relation to varying endotoxin concentrations in porcine endotoxemia.

Ten juvenile pigs receiving a continuous infusion of 0.01 mg/kg of endotoxin over 3 hr and seven animals infused with sterile saline (serving as controls) were studied for 5 hr. Endotoxin concentrations in plasma as determined with a chromogenic Limulus amoebocyte lysate (LAL) test reached a steady state of about 1,000 ng/liter after 1 hr and declined rapidly as the infusion was discontinued. Preinfusion values were reached at the end of the observation period. Endotoxin concentrations found during the infusion period were comparable with those seen in humans with septicemia. The endotoxin infusion was followed by hemoconcentration, leukocytopenia, and thrombocytopenia. Using chromogenic peptide substrate assays, activation of the plasma kallikrein-kinin, fibrinolytic, and coagulation systems was detected. Although the endotoxin concentrations reached preinfusion values within the last 2 hr of the observation period, changes found in circulating cells and components of the plasma cascade systems did not normalize, and the hemodynamic situation did not change.

Animals↗

PubMed1988

Dose dependence of endotoxin-induced activation of the plasma contact system: an in vitro study.

The dose and time dependence of endotoxin-induced activation of the plasma contact system have been studied. Citrated pool plasma was incubated at 37 degrees C with endotoxin doses of 2.10(5), 2.10(6), 2.10(7), and 2.10(9) ng/l (lipopolysaccharide B, E. coli 026: B6, Difco Laboratories, Detroit, MI) for 24 hr. Samples for determination of components of the contact system were obtained prior to incubation and at 1, 2, 4, 6, 12, and 24 hr. Plasma kallikrein (KK) activity markedly increased at 12 hr in test plasma containing the highest dose of endotoxin (2.10(9) ng/l). Coincident with the elevated KK activity, reductions of both plasma prekallikrein (PKK) and functional kallikrein inhibition (KKI) were seen as assayed by chromogenic peptide substrate analyses. Also, functionally determined alpha 2-macroglobulin (alpha 2-M) and C1 inhibitor (C1INH) values were decreased, confirming the reduction of KKI values. Changes of Hageman factor (FXII), PKK, and high molecular weight kininogen (HMWK) values were also found at the same time point when assayed by immunochemical techniques. The same pattern of changes was seen in test plasma containing 2.10(7) and 2.10(6) ng/l of endotoxin. These changes, however, were less pronounced and not seen until 24 hr after beginning incubation. In control plasma and in plasma containing the lowest dose of endotoxin (2.10(5) ng/l), no changes were seen in any factors of the contact system. Our study shows that in vitro endotoxin-induced activation of the contact system is a slow process that is both time and dose dependent.

Chromogenic Compounds↗