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Biomedical subjects

J Vaage

Publications and source records attributed to J Vaage.

At least 91 records · Page 5Linked to original sources
PubMed1994

Lipid peroxidation in open-heart surgery.

Production of oxygen free radicals and subsequent lipid peroxidation are thought to occur during cardiopulmonary bypass (CPB) and myocardial ischaemia-reperfusion injury. Malondialdehyde (MDA), a lipid peroxidation product, was measured simultaneously in arterial and coronary sinus blood before CPB and after release of the aortic crossclamp. Additional arterial samples were drawn pre-, per-, and postoperatively. Thirteen patients scheduled for coronary artery and/or valvular surgery were studied. Cold, crystalloid, cardioplegic arrest (54 [35-120] minutes, median [range]) was induced retrogradely. Preoperatively, arterial MDA was 0.78 +/- 0.4 (mean +/- SD) mumol/l, and increased during CPB (highest level 3.66 +/- 1.08 mumol/l, p < 0.002, 30 minutes after the start of reperfusion). Arterial MDA was still increased four hours after the end of CPB (3.17 +/- 0.88 mumol/l, p < 0.003), but had returned to normal the first postoperative day. No difference was found between arterial and coronary sinus samples at any time. In conclusion, MDA increased in arterial blood during CPB, indicating that lipid peroxidation occurred. There was no intracoronary release of MDA during reperfusion of the ischaemic heart.

Aged↗
PubMed1994

Microvascular injury induced by intravascular platelet aggregation. An experimental study.

Microvascular injury due to platelet aggregation was studied in cats for an hour after 1-hour intraaortic infusion of a suspension of collagen fibrils. Haematocrit and numbers of circulating platelets and leukocytes were repeatedly measured in arterial blood and a major cutaneous lymph vessel in the thigh was cannulated for measurement of lymph flow and erythrocyte counts in peripheral lymph. There were seven groups, each of eight cats, viz. normal cats infused with collagen (I) or vehicle (II) and collagen-infused cats which were platelet-depleted--by antiserum (III), or neutrophil-depleted--by anti-serum (IV), or decomplemented--by cobra venom (V), or pretreated with indomethacin--10 mg/kg (VI), or treated with nonimmunized serum (VII). Induced intravascular platelet aggregation reduced the numbers of circulating platelets and leukocytes, and increased haematocrit, lymph flow and numbers of red cells in peripheral lymph. These effects were inhibited by platelet depletion and indomethacin and attenuated by decomplementation and neutrophil depletion. Platelet aggregation was thus shown to induce microvascular injury and increase microvascular permeability, which is partly dependent on complement and neutrophils.

Animals↗
PubMed1993

Lipopolysaccharide induced monocyte thromboplastin synthesis and coagulation responses in patients undergoing coronary bypass surgery after preoperative supplementation with n-3 fatty acids.

Twenty patients with coronary heart disease (CHD) and elevated serum lipids were randomized into 2 groups of 10 to receive encapsulated preparations of either a concentrated ethylester form of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or corn oil in doses of 6 g per day, given double blindly for approximately two months prior to coronary bypass surgery. Lipopolysaccharide (LPS) induced monocyte thromboplastin synthesis was studied during the preoperative period and one week following surgery. The ability of n-3 fatty acids to modify tissue factor pathway inhibitor (TFPI) and tissue plasminogen activator inhibitor (PAI-1) was also evaluated along with fibrinogen and thrombin-antithrombin III (TAT) complexes. No significant changes were noted preoperatively. Monocyte reactivity, PAI-1, fibrinogen and TAT increased significantly after surgery. These changes were not modified by preoperative loading with n-3 fatty acids.

Acute-Phase Reaction↗
PubMed1993

Therapy of human ovarian carcinoma xenografts using doxorubicin encapsulated in sterically stabilized liposomes.

BACKGROUND: This study compared the therapeutic effects of doxorubicin hydrochloride in saline and in sterically stabilized, long-circulating liposomes composed of hydrogenated soy phosphatidylcholine/cholesterol/polyethylene glycol-distearoyl-phosphatidyl-ethanolamine (Doxil). METHODS: The drug formulations were injected intravenously or intraperitoneally to treat the human ovarian carcinoma HEY, which was implanted subcutaneously or intraperitoneally into mature female Swiss nude mice. RESULTS: The long-circulating liposome formulation was significantly more effective than was the free drug in inhibiting tumor growth and in producing cure. The liposome formulation was significantly less toxic than was the free drug. This is the first demonstration of the therapeutic effectiveness of doxorubicin in sterically stabilized liposomes against human tumor xenografts. CONCLUSIONS: The encapsulation of doxorubicin in long-circulating liposomes significantly enhanced the therapeutic efficacy of the drug against a human ovarian carcinoma.

Animals↗
PubMed1993

Therapy of mouse mammary carcinomas with vincristine and doxorubicin encapsulated in sterically stabilized liposomes.

This study tested the therapeutic effects of vincristine sulfate and doxorubicin hydrochloride, each drug in 2 different formulations: (i) as a solution in saline, and (ii) encapsulated in sterically stabilized, long-circulating liposomes composed of hydrogenated soy-phosphatidylcholine/cholesterol/polyethylene-glycerol-disteroyl++ +- phosphatidylethanolamine. The 4 drug preparations were used to treat s.c. implants of the mouse mammary carcinoma MC2. The drugs were given by i.v. injection over 15 to 18 days, starting 3 days after tumor implantation. The single-drug therapeutic effects of vincristine (S-VCR) and doxorubicin (Doxil) in liposomes were compared, and the 2 preparations were also tested in alternate and in simultaneous combinations. These new liposome formulations of vincristine and doxorubicin were significantly more effective than the free drugs in curing the mice. Alternate, semi-weekly injection of both drugs gave the best therapeutic effect. Prolonged circulation time with increased accumulation in tumors are considered likely reasons for the improved therapeutic efficacy of both drugs when encapsulated in these liposomes.

Animals↗
PubMed1993

Reactive oxygen intermediates and ischemia-reperfusion injury release tissue plasminogen activator from isolated rat hearts.

Tissue plasminogen activator (t-PA) is a marker of endothelial cell injury or activation. The release of t-PA from isolated rat hearts (Langendorff model) subjected to ischemia-reperfusion or reactive oxygen intermediates (ROI) generated by H2O2 was investigated. H2O2 (200 microM) increased t-PA activity in the coronary effluent to 305 +/- 84% of initial value (mean +/- SEM, p < 0.04 vs controls) at the end of a 10 min intervention. The hydroxyl radical scavenger thiourea (10 mM) only partially inhibited the increase (175 +/- 27%, p < 0.01 compared to controls). 20 min normothermic ischemia increased t-PA activity to 416 +/- 108% (p < 0.005 compared to controls) at the start of reperfusion. In conclusion, cardiac injury by ischemia-reperfusion or ROI increases release of t-PA.

Animals↗
PubMed1993

Toxic oxygen metabolites and ischemia-reperfusion increase histamine synthesis and release in the isolated rat heart.

Histamine is synthetized in the heart, and released by ischemia-reperfusion injury in several species. Histamine has arrhythmogenic, chronotropic, inotropic and vasoactive effects. Cardiac histamine release during ischemia-reperfusion may be mediated by toxic oxygen metabolites. We studied the effect of ischemia-reperfusion and toxic oxygen metabolites on release and synthesis of histamine in the isolated rat heart (Langendorff model). The following groups were included: I, (n = 10) control perfusion for 60 min; II, (n = 7) H2O2 (200 microM) was given for 10 min followed by 50 min recovery; III, (n = 7) thiourea (15 mM) was given in addition to H2O2; IV, (n = 7) thiourea given alone; V, (n = 7) catalase (150 U/ml) plus H2O2; VI, (n = 7) 20 min ischemia followed by 40 min reperfusion. The contents of histamine in the coronary effluent and in cardiac tissue were measured repeatedly (radioenzymatic method). Ischemia-reperfusion and toxic oxygen metabolites increased release of histamine in the coronary effluent. Concomitantly the histamine contents in cardiac tissue increased, indicating increased synthesis of histamine.

Animals↗
PubMed1993

Release of histamine from isolated rat hearts during reperfusion is not dependent on length of ischemic insult, or contents of histamine in cardiac tissue.

Release of histamine (H) by ischemia-reperfusion injury was investigated in isolated rat hearts (Langendorff model). The effect of 10, 15, 20, 25, 30, 40 and 60 min ischemia (n = 10 each) on H in the coronary effluent and in cardiac tissue was studied after 4 min reperfusion. Release of creatine kinase and lactate dehydrogenase in the coronary effluent increased with time of ischemia. Tissue H increased from 95 +/- 10 ng/g rat heart (mean +/- SEM) before ischemia to max 148 +/- 10 ng/g after 20 min ischemia (p < 0.002), and increased also after 15 (p < 0.01), 25 (p < 0.01), and 30 min (p < 0.045). H in the coronary effluent increased after 15 (from 16 +/- 3 to 26 +/- 2 pmol/min, p < 0.044), 30 (26 +/- 6 pmol/min, p < 0.027), and 60 min ischemia (47 +/- 6 pmol/min, p < 0.0044). Release of H during ischemia-reperfusion is neither dependent on the severity of the ischemic insult, nor on the level of tissue H.

Animals↗
PubMed1993

Inhibition of lipoxygenase and cyclooxygenase augments cardiac injury by H2O2.

The role of arachidonic acid metabolites in the cardiac effects of toxic oxygen metabolites (TOM) was investigated in buffer-perfused rat hearts (Langendorff model). Hydrogen peroxide (H2O2, 200 microM) was given for 10 min to generate TOM, followed by 30 min recovery. H2O2 reduced left ventricular developed pressure (LVDP), increased left ventricular end-diastolic pressure (LVEDP), and increased coronary flow (CF). The hydroxyl radical scavenger thiourea inhibited the H2O2-induced effects. Perfusion with three lipoxygenase inhibitors, AA861, BWA4C, and diethylcarbamazine, in addition to H2O2, augmented the decrease of LVDP and the increase of LVEDP induced by H2O2. The cyclooxygenase inhibitor indomethacin had the same effects. The H2O2-induced increase in CF was not influenced by diethylcarbamazine, but inhibited by all other drugs. Control perfusion with drugs alone did not influence cardiac function. In conclusion, inhibition of lipoxygenase and cyclooxygenase augmented the depression of cardiac function induced by TOM. Leukotrienes and prostanoids appear to be protective against H2O2-induced cardiac injury.

Animals↗
PubMed1993

Ischaemia-reperfusion and toxic oxygen metabolites do not induce release of immunoreactive atrial natriuretic factor from isolated rat hearts.

Secretion of immunoreactive atrial natriuretic factors (ANF) after injury by ischaemia-reperfusion and toxic oxygen metabolites (TOM) was investigated in the following groups of Langendorff-perfused rat hearts: 1.1., control perfusion; 1.2., hearts perfused with H2O2 (200 mumol l-1) as a TOM-generating agent for 10 min, followed by recovery for 30 min; 1.3., thiourea (10 mmol l-1), a hydroxyl radical scavenger, was given together with H2O2; 2.1., control perfusion; 2.2., ischaemia (37 degrees C) for 20 min followed by reperfusion for 40 min. Ischaemia-reperfusion and TOM temporarily decreased left ventricular developed pressure and increased left ventricular end-diastolic pressure. The cardiac effects of H2O2 were inhibited by thiourea. Coronary flow (CF) was increased by TOM and decreased by ischaemia-reperfusion. Immunoreactive ANF was measured sequentially in the coronary effluent by radioimmunoassay. Basal secretion of immunoreactive ANF for all groups pooled was 0.45 +/- 0.02 pmol min-1 (mean +/- SEM), and did not change significantly with time in any group. In conclusion, ischaemia-reperfusion and TOM do not influence secretion of immunoreactive ANF.

Animals↗
PubMed1993

Thromboplastin activities and monocytes in the coronary circulation of reperfused human myocardium. No effect of preoperative treatment with n-3 fatty acids.

In a double-blind study 18 patients were randomized to receive a daily dietary supplement of concentrated ethyl ester compound of n-3 fatty acids or placebo (corn oil) for at least 6 weeks before coronary bypass surgery. Three-fold increase of serum eicosapentaenoic acid and 20% reduction of triglyceride levels were found preoperatively in the n-3 group, while the two groups were similar as regards monocyte and platelet counts, mean platelet volume and monocyte activation as expressed by thromboplastin activities. For determination of transcardiac gradients, coronary sinus and aortic blood were sampled preoperatively 5, 10 and 30 minutes after release of the aortic cross-clamp. In both patient groups the monocyte count was lower in coronary sinus than in aortic blood at 5 and 10 minutes, but the differences were not significant. The platelet counts showed no significant change. In vitro stimulation of monocytes, however, evoked significantly (p < 0.05) less thromboplastin activity in coronary sinus blood than in aortic blood at all three sampling times, without significant intergroup difference. The monocytes most sensitive to activation presumably were trapped in the reperfused myocardium, and this sequestration was not hindered by pretreatment with n-3 fatty acids.

Aged↗
PubMed1993

Pathophysiology and mediators of ischemia-reperfusion injury with special reference to cardiac surgery. A review.

Although necessary for the ultimate tissue survival, reperfusion may paradoxically exacerbate the ischemic injury. Ischemia and reperfusion injury is intimately woven together. The relative role of reperfusion injury is not clarified and probably varies with the ischemic insult: Reperfusion is always preceded by ischemia, and some of the reperfusion-related events may represent a process continuing from the ischemic period; thus the proper designation should be ischemia-reperfusion injury. The reperfusion-related events are: arrhythmias, myocardial stunning with both systolic and diastolic dysfunction, and low reflow and microvascular stunning. Of pathogenetic importance are the mode and speed of reperfusion as well as the initiation of an intracoronary inflammatory reaction during reperfusion, including endothelium-leukocyte interaction, platelets, generation of oxygen free radical, generation and release of arachidonic acid metabolites, platelet activating factor, endothelium derived relaxing factor, endothelins, kinins, and histamine, complement activation, disturbances in calcium homeostasis, and disturbances in lipid and fatty acid metabolism.

Animals↗
PubMed1993

Toxic oxygen metabolites and leukocytes in reperfusion injury. A review.

Toxic oxygen metabolites (TOM) are generated by activated leukocytes and ischemic tissue upon reperfusion, and are cardiotoxic in vitro. Generation of TOM during reperfusion in vivo has been measured directly and indirectly. TOM contribute to myocardial stunning, causing systolic and diastolic dysfunction. TOM may also play a role in the pathogenesis of reperfusion arrhythmias. It is uncertain if TOM cause cell death during reperfusion. Inhibition of TOM with antioxidants may be important for myocardial protection during cardiac surgery.

Cardiac Surgical Procedures↗
PubMed1993

Retrograde cardioplegia: when and how. A review.

With the introduction of balloon catheters enabling blind transatrial cannulation of the coronary sinus, retrograde cardioplegia is gaining increasing popularity. In several situations retrograde cardioplegia offers distinct technical advantages. Although not yet clinically documented, some patient subgroups with severe coronary stenoses/occlusion may probably benefit from retrograde cardioplegia. This technique is a valuable addendum to the technical repertoire of cardiac surgeons.

Heart Arrest, Induced↗
PubMed1992

Therapy of primary and metastatic mouse mammary carcinomas with doxorubicin encapsulated in long circulating liposomes.

The purpose of our study was to compare the therapeutic effects of doxorubicin in 3 different formulations: (1) in PBS, (2) in conventional liposomes composed of egg phosphatidylglycerol/egg phosphatidylcholine/cholesterol/dl-alpha tocopherol, and (3) in sterically stabilized, long-circulating "Stealth" liposomes composed of hydrogenated soy phosphatidylcholine/cholesterol/polyethylene glycol-distearoylphosphatidylethanolamine. The doxorubicin formulations were used to treat recently implanted and well-established, growing primary mouse mammary carcinomas, and to inhibit the development of spontaneous metastases from intra-mammary tumor implants. In the treatment of recently implanted primary tumors, the formulations were given in 3 i.v. injections over 15 days, starting 3 or 10 days after tumor implantation. In the treatment of well-established primary tumors, the mice received 4 i.v. injections over 22 days, starting an average 38 days after tumor implantation. In the preventive treatment against metastases, the formulations were given in 4 i.v. injections over 22 days, starting 22 days or 58 days after primary tumor implantation. The Stealth liposome formulation was significantly more effective than the conventional liposome formulation or the free drug in reducing the incidence of metastases from intra-mammary implants of tumor MC19 and tumor MC65, in curing mice with recent implants of tumor MC2A, tumor MC2B, and tumor MC65, and in increasing the 8-week survival of mice with well-established implants of tumor MC2B. It is concluded that the long circulation time of the Stealth liposome doxorubicin formulation accounts for its superior therapeutic effectiveness.

Animals↗
PubMed1992

Fibrosis in immune control of mammary-tumor growth.

In malignancies, an interruption of growth (dormancy) is sometimes observed. In the immunogenic mammary carcinoma MC2, dormancy followed by regression after a period of growth was observed in 18% of s.c. implants in normal mice. Dormant implants removed for histologic examination were invariably found to be completely surrounded by a highly fibrous stroma. Fibrosis was enhanced in immunized mice, and reduced in immuno-deficient mice. Surgical disruption of the fibrous capsule around dormant tumors early (19 +/- 3 days) in the immune response led more frequently to resumed growth, while later (32 +/- 3 days) disruption of the capsule led more frequently to complete regressions. This showed that fibrous capsules that could destroy tumors could also shield them against well-developed systemic immune mechanisms.

Animals↗
PubMed1992

Immunologic aspects of fibrosis in mouse mammary carcinomas.

The nature of the fibrosis associated with mammary carcinomas MC2 and MC3 was investigated in syngeneic C3H mice. Accelerated and enhanced peri-tumor cellular and fibrotic responses and retarded tumor growth were observed in actively immunized and in adoptively immunized mice, and in mice treated with IL-2. T lymphocytes and, particularly, macrophages were closely associated with collagen deposition at the tumors. The collagen deposition frequently resulted in the encapsulation and regression of the less invasive tumor MC2. A cellular fibrous response was not observed at tumors implanted into athymic C3Hnu/nu mice. The results suggest that tumor fibrosis may in some circumstances be promoted by an immune response.

Animals↗