Biomedical subjects

C Mattsson

Publications and source records attributed to C Mattsson.

At least 19 recordsLinked to original sources

PubMed2006

Biological monitoring of exposure to 1,5-naphthalene diisocyanate and 4,4'-methylenediphenyl diisocyanate.

OBJECTIVES: Biological monitoring of occupational sensitizers, such as 1,5-naphthalene diisocyanate (NDI) and 4,4'-methylenediphenyl diisocyanate (MDI) is of high importance. In this study, 1,5-naphthalenediamine (NDA) and 4,4'-methylenedianiline (MDA) in hydrolysed urine and plasma were evaluated as biomarkers of exposure to NDI and MDI, respectively. METHODS: The air exposure to NDI and MDI was monitored for 30 exposed workers at four different plants. In parallel, urinary as well as blood plasma samples were collected. Biomarker levels were determined in hydrolysed urine and plasma by means of gas chromatography-mass spectrometry. RESULTS: Air exposure to both MDI and NDI was correlated to their corresponding urinary and plasma biomarkers. The correlation coefficients for the associations between air and biomarker levels were in the range of 0.51-0.65 and 0.53-0.96 for MDI and NDI, respectively. For NDI, but not for MDI, the significance and correlation coefficients were increased by adjusting the urinary biomarker levels for creatinine content or density. CONCLUSIONS: Biomarker and air levels of MDI and NDI were correlated, but there was a large individual variation.

Air Pollutants, Occupational↗

PubMed2006

Cognitive-behavioural stress management does not improve biological cardiovascular risk indicators in women with ischaemic heart disease: a randomized-controlled trial.

OBJECTIVES: Psychosocial factors, such as stress and vital exhaustion, are associated with an increased risk of cardiovascular events, and women report more psychosocial ill-being after an acute myocardial infarction than men. We have earlier shown that a cognitive-behavioural intervention in women with ischaemic heart disease (IHD) improved psychosocial well-being. In the present study, we tested the hypothesis that the improvement in psychosocial well-being is associated with an improvement in biochemical indicators of cardiovascular risk. DESIGN: Randomized-controlled trial in northern Sweden. SETTING: Outpatient care. SUBJECTS: Women with IHD were randomized to either a 1-year cognitive-behavioural stress management programme or usual care. Of the 159 women who completed the study, 77 were in the intervention group, and 82 in the control group. INTERVENTIONS: A 1-year cognitive-behavioural stress management programme versus conventional care. RESULTS: Group assignment was not found to be a determinant of waist circumference, high sensitive C-reactive protein (hs-CRP), fibrinogen, von Willebrand factor (vWF), plasminogen activator inhibitor type 1 (PAI-1) activity, tissue plasminogen activator (tPA) activity, tPA antigen, tPA-PAI-1 complex, leptin, or HOMA2 insulin resistance index (HOMA2-IR) at follow up. Changes in psychosocial variables were not associated with changes in any of the biological risk indicators. CONCLUSIONS: Even if our cognitive-behavioural stress management programme had effects on proximal targets, such as stress behaviour and vital exhaustion, we found no improvement in intermediate biochemical targets related to the metabolic syndrome and IHD. Our results challenge the proposition that the relationship between psychological well-being and biological cardiovascular risk indicators is a direct cause-effect phenomenon.

Biomarkers↗

PubMed2002

Local proCPU (TAFI) activation during thrombolytic treatment in a dog model of coronary artery thrombosis can be inhibited with a direct, small molecule thrombin inhibitor (melagatran).

To test the hypothesis that the direct thrombin inhibitor, melagatran is able to inhibit local pro-carboxypeptidase U (proCPU) activation that occurs during thrombolytic treatment, t-PA alone, or in combination with melagatran, was given to dogs with a coronary artery thrombosis. Blood samples from the great cardiac vein and aorta were collected at baseline, during thrombus formation, throughout the t-PA+/-melagatran infusion and during the patency period, for analysis of CPU activity using a novel assay. A higher CPU activity in venous compared to arterial blood (V-A difference) indicates CPU activation in coronary vessels. Efficacy was assessed by determination of time to lysis, duration of patency and blood flow during patency. Dogs (n = 26) were randomized to receive either 1) t-PA, 1 mg/kg as an intravenous 20-min infusion; 2) t-PA as in group 1, +melagatran bolus, 0.3 mg/kg, followed by a 3-h infusion (0.15 mg/kg per h); 3) sham-operated but no coronary thrombus, and administered t-PA as for Group 1. All groups had similar baseline characteristics. Significant increases in CPU activity were observed in Groups 1 and 2 during thrombus formation, with V-A differences of 5.5 and 4.5 U/L, respectively. No significant V-A difference was observed in the sham-operated group. CPU activity increased in Group 1 during the t-PA infusion (V-A difference 15.9 U/L), whereas the V-A difference in Group 2 decreased to 2.6 U/L following melagatran treatment. These results demonstrate that melagatran attenuates generation of CPU in the coronary circulation. The mechanism is probably indirect, via inhibition of thrombin-mediated activation of proCPU.

Animals↗

PubMed2001

Effect of different types of thrombin inhibitors on thrombin/thrombomodulin modulated activation of protein C in vitro.

The objectives of this study were to investigate whether the affinity of thrombin for small-molecule, active site-directed thrombin inhibitors and substrates is affected by the presence of thrombomodulin (TM), and to what extent thrombin inhibitors inhibit TM-bound thrombin. Inhibition of human alpha-thrombin was studied in the presence and absence of solubilised rabbit lung TM in a buffer containing CaCl(2). TM inhibited thrombin-induced proteolysis of human fibrinogen with a dissociation constant (K(D)) of 4 nmol/l. With at least 16-fold molar excess of TM over thrombin the affinity of thrombin both for the small thrombin substrates (S-2366 and S-2238) and the reversible, active site-directed thrombin inhibitors (inogatran and melagatran) increased twofold. In contrast, the ability of hirudin to inhibit thrombin was reduced by TM, since hirudin competes with TM in binding to thrombin. The effect of thrombin inhibitors on protein C activation by thrombin bound to human kidney cells transfected with cDNA for human TM was also studied. The mean binding capacity of the transfected cells was approximately 320,000 quantified by flow cytometry with antibodies against TM. Hirudin, inogatran and melagatran inhibited the activation of protein C by thrombin complexed with cell-bound TM in a dose-dependent manner, with mean IC(50) values+/-S.D. of 4.4+/-0.8, 20.0+/-1.1 and 6.4+/-0.2 nmol/l, respectively. Antithrombin inhibited protein C activation with an IC(50) value of 290+/-10 nmol/l, which was enhanced fourfold (IC(50) 60 nmol/l) by the addition of heparin 0.5 U/ml. Heparin alone, up to a concentration of 1 U/ml, had no effect on the activation of protein C. Small direct thrombin inhibitors thus inhibited both free and TM-bound thrombin and therefore also inhibited the activation of protein C. Whether this will influence their clinical efficacy or safety versus heparin and warfarin, which also inhibit protein activation, respectively, lowers the concentration of protein C, remains to be studied in clinical trials.

Antithrombins↗

PubMed2001

Effect of melagatran on prothrombin time assays depends on the sensitivity of the thromboplastin and the final dilution of the plasma sample.

Prothrombin time (PT) assays are clotting methods that measure the activity of vitamin K-dependent coagulation factors (F) II, VII, and X. There are three main types of PT assays in general usage, namely the Quick assay, Owren's assay and PT dry chemistry test cards. PT assays were initially developed to monitor dose-adjustments of vitamin K antagonists such as warfarin. The aim of the present study was to investigate whether commercially available PT assays are suitable for evaluating the anticoagulant activity of direct thrombin inhibitors. Melagatran, a reversible direct thrombin inhibitor, was added to human plasma at concentrations ranging from 0.1 to 2.0 micromol/l. Seventeen different commercially available PT kits were used, including thirteen Quick reagents, two Owren reagents and two PT test cards. The sensitivity of the different reagents, expressed as the concentration of melagatran that doubled the prothrombin time (IC50) varied widely, with Thromboplastin S and Thromboplastin HS being the most sensitive (IC50 = 0.9 micromol/l). The reagents with apparently the lowest sensitivity were the two Owren reagents Nycotest PT and SPA 50 with an IC50 of 2.2 and 2.9 micromol/L, respectively. This is most likely due to a higher dilution of melagatran in these assays compared to the dilution in the Quick assays. The results were also dependent on the International Sensitivity Index (ISI) of each reagent. The concentration of melagatran that produced an International Normalized Ratio (INR) of 2 was calculated from dose-response curves for each assay, and these results revealed that reagents with a high ISI value gave an INR of 2 at much lower concentrations of melagatran (0.5-0.7 micromol/L) than those with an ISI-values around one (0.9-1.2 micromol/L). It was found that INR depends not only on the plasma concentration of melagatran, but also on the sensitivity of the PT reagent and on the final dilution of the plasma sample in the prothrombin time assay. Thus, since the same melagatran concentration can be associated with widely varying PT/INR results depending on the specific assay used it is concluded that PT assays and INR can not be used to monitor melagatran activity.

Anticoagulants↗

PubMed2000

Effects of melagatran, an inhibitor of thrombin, on fibrin deposits, haemodynamics, and platelet count in endotoxaemic pigs.

BACKGROUND: Thrombin plays a pivotal role in the development of septic shock. Porcine endotoxaemia can replicate this condition. We wanted to evaluate whether melagatran, a novel inhibitor of thrombin, would counteract some of the endotoxin-induced changes in this model. METHODS: Fifteen pigs were anaesthetised, monitored (circulatory and respiratory variables) and subjected to an infusion of E. coli endotoxin at 10 microg x kg(-1) x h(-1). Six pigs were given melagatran during the first 3 h of the 6-h endotoxaemic period. Nine controls were given the corresponding volume of saline instead of melagatran. Specimens from the liver and the left lung were taken for light microscopy post mortem. RESULTS: The endotoxin-induced increase in pulmonary capillary wedge pressure and drop in platelet count were significantly less pronounced in the melagatran-treated pigs. Deposits of pulmonary fibrin were significantly reduced in the melagatran group, without improving oxygenation. Light microscopy revealed no hepatic fibrin in the pigs treated with melagatran in contrast to the endotoxaemic controls. Hepatic neutrophil accumulation was reduced in the melagatran group as compared to controls. Hepatocellular degeneration and plasma levels of tumour necrosis factor alpha (TNF alpha) and bilirubin were of the same magnitude in both groups. CONCLUSION: Melagatran reduced pulmonary capillary wedge pressure, a retrograde reflection of the left ventricular end-diastolic filling pressure, and also pulmonary stasis in pigs subjected to endotoxaemic challenge. Pulmonary and hepatic fibrin depositions were reduced, but PaO2 levels or liver function markers were not affected by melagatran during the early phase of endotoxaemia. Obstruction of the intrahepatic bile ducts, by fibrin depositions, is not responsible for reduced excretion of conjugated bilirubin during endotoxaemia. The beneficial effects of melagatran during endotoxaemia were not due to any reduction of plasma TNF alpha.

Animals↗

PubMed2000

Effects of melagatran, a novel direct thrombin inhibitor, during experimental septic shock.

Sepsis and endotoxaemia initiate the generation of thrombin, which is responsible for the conversion of fibrinogen to fibrin, platelet aggregation and acts as an inflammatory mediator affecting numerous types of cells, including myocardial, smooth muscle and endothelial cells. Human Gram-negative septic shock, frequently seen in intensive care units, is a condition with high mortality. This condition can be replicated in the endotoxaemic pig. As many of the toxic effects of sepsis are due to thrombin generation, it was of interest to study, using this porcine experimental septic shock model, whether inhibition of thrombin could alleviate the effects of endotoxaemia. For this purpose melagatran, a direct synthetic thrombin inhibitor with a molecular weight of 429 Da, was employed. Melagatran does not significantly interact with any other enzymes in the coagulation cascade or fibrinolytic enzymes aside from thrombin. Furthermore, melagatran does not require endogenous co-factors such as antithrombin or heparin co-Factor II for its antithrombin effect, which is important, as these inhibitors are often consumed in septic patients. We have shown that melagatran exerts a beneficial effect on renal function, as evaluated by plasma creatinine and urinary output, during experimental septic shock. These effects were most pronounced during the later phase of the experimental period, after the infusion of melagatran had been discontinued. Prevention of intrarenal coagulation may be attributable to this finding. In addition, melagatran had beneficial effects on systemic haemodynamics (left ventricular stroke work index, pulmonary capillary wedge pressure and systemic vascular resistance index) in endotoxaemic pigs. This result may be explained by the ability of melagatran to inhibit thrombin, thereby counteracting thrombin's cellular effects. Thus, it can be seen, using this experimental model of septic shock, that melagatran may help to alleviate some of the damaging effects of endotoxaemia, although more research is required to test this further.

Animals↗

PubMed2000

Treatment with dexamethasone arrests the development of myringosclerosis after myringotomy.

HYPOTHESIS: To attempt to inhibit the development of myringosclerosis by intraperitoneal injection of dexamethasone. BACKGROUND: The authors' earlier report showed that the development of myringosclerosis after myringotomy was associated with an inflammatory reaction. The present study was performed to secure evidence for this hypothesis. METHODS: Three groups of bilaterally myringotomized rats were treated at 12-hour intervals with intraperitoneal injection of dexamethasone, RU486 (a glucocorticoid receptor antagonist), and saline, respectively. At 6, 12, 24, and 48 hours after the myringotomy, 2 animals were anesthetized on each occasion and examined otomicroscopically. The animals were then killed, and the tympanic membranes were excised and prepared for light microscopic studies. RESULTS: Dexamethasone treatment retarded and diminished the development of sclerotic lesions markedly. Moreover, no inflammatory signs were seen in the flaccida specimens. When the RU486-treated animals were compared with the animals in the control group, there were no evident differences concerning the development of myringosclerosis or the extent of the inflammatory reaction. CONCLUSION: These findings confirm the earlier hypothesis that an inflammatory reaction in collagen tissue is involved in the mechanism that causes the development of myringosclerosis.

Animals↗

PubMed1999

Structure of the human uvula.

Eleven uvular biopsies were investigated for their morphology, the presence of mast cells and the distribution of hyaluronan and its major ligand CD44. Three microanatomical sites--surface epithelium, subepithelial area and area of glands--were examined. The oral side of the uvula was covered by a 15-20 cell thick layer of keratinized/parakeratinized surface epithelium, firmly anchored to the underlying connective tissue by connective tissue papillae. The width of the intercellular spaces in the epithelium increased toward the basal lamina, a location that exhibited intense hyaluronan and anti-CD44 staining. Most mast cells were located in the vicinity of blood vessels, at which sites there was high staining intensity of hyaluronan. Tissue mast cells could also be observed in the connective tissue septa enclosing the acini. Glands and muscle fibres became more sparse from the proximal part of the uvula to the distal end, while the amount of connective tissue increased. The localization and architecture of connective tissue elements and mast cells are consistent with the ability of the uvula to resist mechanical stresses and to develop oedema and fibrosis, respectively.

Adult↗

PubMed1998

Coronary thrombosis/thrombolysis in pigs: effects of heparin, ASA, and the thrombin inhibitor inogatran.

UNLABELLED: The aim of the present study was to develop a coronary thrombolysis model using the copper coil technique in closed-chest pigs. The first goal (protocol I) was to obtain a reproducible size of myocardial infarction by controlling the coronary occlusion period, a prerequisite for evaluation of myocardioprotective interventions. The second goal (protocol II) was to study if thrombin and platelet aggregation inhibitors influence the rate of thrombolysis, the degree of reocclusion, and the time of coronary patency when added to a thrombolytic regimen (recombinant tissue-type plasminogen activator, rt-PA). Coronary thrombosis was produced by insertion of a thrombogenic copper coil into the LAD of 40 anesthetized pigs. The animals were divided into six groups as follows: Protocol I, group 1: Open-chest, lysis initiated with intracoronary rt-PA (50 mg) concomitant with intravenous heparin and acetylsalicylic acid (ASA) (n=6). Group 2: Closed-chest, lysis initiated with intracoronary rt-PA concomitant with intravenous heparin and ASA (n=10). Protocol II, group 3: Closed-chest, lysis initiated with intravenous rt-PA (n=6). Group 4: Closed-chest, lysis initiated with intravenous rt-PA concomitant with heparin (n=6). Group 5: Closed-chest, lysis initiated with intravenous rt-PA concomitant with inogatran, a low molecular weight thrombin inhibitor (n=6). Group 6: Closed-chest, lysis initiated with intravenous rt-PA immediately after intravenous administration of ASA (n=6). Protocol 1; Reperfusion was achieved in all closed- and open-chest pigs. The time to thrombolysis was 5+/-1.6 and 6+/-3.0 min (mean+/-SD) for closed- and open-chest pigs, respectively. Reocclusions were rare (one in group 1). The size of the ischemic myocardial area was 21+/-11% of the left ventricular area in group 1 and 22+/-6% in group 2. The corresponding values for infarct size as a proportion of the ischemic area were 58+/-10% and 68+/-14%, respectively. The closed-chest model was subsequently used to study the effect of the thrombin and platelet aggregation inhibitors (inogatran, heparin, and ASA) as conjunctive agents to rt-PA-induced thrombolysis (groups 3-6). To mimic its clinical use, rt-PA was administered intravenously. Time to lysis after rt-PA only (group 3) was 33+/-24 min. Concomitant treatment with heparin (group 4), inogatran (group 5), and ASA (group 6) did not significantly influence time to lysis. All adjunctive compounds did, however, prolong the time to reocclusion, which occurred in 100%, 75%, 67%, and 20% of the animals in groups 3, 4, 5, and 6. Thus, concomitant treatment with heparin and inogatran did not shorten time to lysis or reduce the reocclusion rate, and ASA turned out to be the only effective adjunct to rt-PA, significantly reducing both time to and frequency of reocclusion (p < 0.05). CONCLUSION: The described closed-chest pig model was feasible as regards the induction and lysis of a thrombus in the left coronary artery, giving reproducible areas of myocardial ischemia and infarction. This model was useful for the evaluation of pharmacological interventions in the thrombolysis process.

Animals↗

PubMed1998

Melagatran, an oral active-site inhibitor of thrombin, prevents or delays formation of electrically induced occlusive thrombus in the canine coronary artery.

Intravenous administration of thrombin inhibitors, such as hirudin, has been shown to decrease the frequency of coronary artery reocclusion after thrombolysis. However, recent findings in large clinical trials in patients with unstable angina and myocardial infarction have failed to demonstrate a sustained antithrombotic effect after cessation of drug treatment. These findings indicate a need for a prolonged antithrombotic regimen, preferably an orally active thrombin inhibitor. To test the hypothesis that a regimen consisting of oral thrombin inhibitor will delay or prevent the formation of occlusive clot, anesthetized dogs were given saline (n = 9) or a single dose of a novel active site low-molecular-weight thrombin inhibitor melagatran by nasogastric tube (1.5 mg/kg, n = 6; 2.5 mg/kg, n = 6), and 15 min later, a potent thrombogenic stimulus in the form of anodal current (100 microA) was applied to the intimal surface of the narrowed left anterior descending coronary artery (LAD). All saline-treated dogs developed stable thrombus, indicated by zero flow at 34 +/- 7 min after initiation of direct current. On the other hand, one of the six dogs given high-dose melagatran did not develop thrombotic occlusion of the LAD during the entire 4 h of observation. Mean time to occlusive thrombus formation in 11 other dogs was prolonged 4-5 times as compared with that in the saline-treated dogs (p < 0.001). Spontaneous thrombolysis was observed in three of 11 dogs after initial clot formation. Overall, the coronary artery was patent for 68% (low dose) and 75% (high dose) of the observation period in melagatran-treated dogs (vs. 14% of observation period in saline-treated dogs). Peak plasma concentration was 0.87 +/- 0.22 microM in dogs given low-dose and 1.38 +/- 0.30 microM in dogs given high-dose melagatran. The activated partial thromboplastin time (aPTT) increased 1.5-fold at peak plasma concentration of melagatran. These observations imply (a) thrombin generation plays a critical role in thrombus formation in narrowed coronary arteries, (b) oral melagatran prevents or delays thrombus formation, whereas the aPTT is only modestly prolonged, and (c) the thrombus formed in the presence of melagatran is prone to spontaneous lysis in this canine model of coronary thrombosis.

Administration, Oral↗

PubMed1998

Myringotomy: a prerequisite for the development of myringosclerosis?

Streptococcus pneumoniae was inoculated into the left middle-ear cavity in two groups of rats, resulting in purulent otitis media. After 3 days, one group of infected animals and a third group of noninfected animals were subjected to left-sided myringotomy. The tympanic membranes were examined both otomicroscopically and histologically 1 and 3 months later. On otomicroscopic examination the noninfected myringotomized animals had developed extensive myringosclerotic lesions, whereas only minimal sclerotic deposits were noted in the myringotomized animals with acute otitis media (AOM). On histologic examination both the noninfected myringotomized animals and the myringotomized animals with AOM were similar in the frequency and extension of sclerotic lesions in the tympanic membrane. The nonmyringotomized rats with AOM were free of sclerotic lesions, except for minor changes found in one animal.

Acute Disease↗

PubMed1998

Effects of melagatran, a new low-molecular-weight thrombin inhibitor, on thrombin and fibrinolytic enzymes.

Melagatran, a new, competitive and rapid inhibitor of thrombin with a molecular mass of 429 Da is described. Melagatran is well tolerated when administered in very high doses, and the oral bioavailability in the dog is relatively high. The aim of the study was to determine, in the preclinical setting, the degree of selectivity against the fibrinolytic system required for entering the clinical development phase. Melagatran was compared with two structurally similar thrombin inhibitors, inogatran and H 317/86. The potent inhibition of thrombin by melagatran was demonstrated by a low inhibition constant (Ki) for thrombin (0.002 micromol/l) and prolongation of clotting time to twice the control value in coagulation assays at low concentrations (0.010, 0.59 and 2.2 micromol/l for thrombin time, activated partial thromboplastin time and prothrombin time, respectively). Furthermore, thrombin-induced platelet aggregation was inhibited at the same concentration (IC50-value 0.002 micromol/l) as the Ki-value for thrombin. In two assays of global fibrinolysis, inhibition was observed at a concentration of 1.1 micromol/l in a euglobulin plasma fraction model, while no inhibition was observed at a concentration of < or = 10 micromol/l in a plasma model. In an in vivo model of endogenous fibrinolysis in the rat, inhibition of fibrinolysis was observed at > or = 1.0 micromol/l. In all assays, except the Ki-ratio determinations, the compounds could be graded with regard to selectivity against the fibrinolytic system: inogatran > melagatran > H 317/86. For melagatran, inhibition of fibrinolysis was not observed at concentrations below the upper limit of the proposed therapeutic plasma concentration interval (< 0.5 micromol/l). Thus, melagatran seems to have a sufficient selectivity against the fibrinolytic system, while H 317/86 was considered to be insufficient for clinical development.

Administration, Oral↗

PubMed1998

Melagatran, a low molecular weight thrombin inhibitor, counteracts endotoxin-induced haemodynamic and renal dysfunctions in the pig.

Coagulation and fibrinolysis are crucial in septic shock and inhibition of thrombin may be beneficial in this circumstance. Since porcine endotoxaemia has been found to replicate severe septic shock, a low molecular weight thrombin inhibitor, melagatran, was infused during the first 3 out of 6 h of endotoxaemia in pigs. Plasma creatinine (p <0.01) and urinary output (p <0.05) were less affected in the melagtran + endotoxin group (n=6) as compared to endotoxaemic controls (n=9). The left ventricular stroke work index, systemic vascular resistance index and oxygen extraction were all less affected (p <0.05) by endotoxin during the infusion of melagatran. The plasma concentration of melagatran declined with an apparent plasma half-life of 5 h as soon as the infusion was stopped. APTT, however, continued to increase after the infusion of melagatran had stopped and reached a maximum of 113 s at 5 h (baseline 17 s). APTT in endotoxaemic control pigs reached a maximum of 22 s. Thus, melagatran may counteract some consequences of endotoxaemia.

Animals↗

PubMed1997

Inhibition of the development of myringosclerosis by local administration of fenspiride, an anti-inflammatory drug.

Earlier studies have revealed a relationship between the development of myringosclerosis and oxygen-derived free radicals. The latter can be blocked by the anti-inflammatory drug fenspiride. The present study was undertaken to test the ability of fenspiride to prevent myringosclerosis from developing during healing of the tympanic membrane. Myringotomized rats were treated with either topical applications or intraperitoneal injections of fenspiride for 12 days, after which the tympanic membranes were examined by otomicroscopy and studied histologically by light microscopy. Topically applied fenspiride was found to inhibit the development of sclerotic lesions, whereas intraperitoneal injections were ineffective.

Administration, Topical↗

PubMed1997

Myringotomized mice develop myringosclerosis in the pars flaccida and not in the pars tensa.

The development of myringosclerosis has been correlated with increased production of oxygen-derived free radicals. For the present study, we used a null mutant mouse lacking extracellular superoxide dismutase to test the hypothesis that increased production of free radicals can cause the development of myringosclerosis. Null mutant mice and wild-type, control mice were myringotomized and kept in ambient air for 3 weeks. Both groups developed myringosclerosis in the pars flaccida, but not in the pars tensa. The sclerotic lesions were visible in both the light and the electron microscope but not in the otomicroscope. In particular, the localization of the sclerotic deposits was found beneath both the inner and outer epidermal epithelium. No difference concerning the extent or number of sclerotic lesions between the null mutant and the wild-type mice could be distinguished.

Animals↗

PubMed1997

Application of oxygen free radical scavengers to diminish the occurrence of myringosclerosis.

The present study was designed to establish whether or not an increased production of oxygen-derived free radicals is involved in the causation of myringosclerosis. Sclerotic lesions in the tympanic membrane were experimentally elicited by keeping rats with perforated tympanic membranes in an atmosphere containing roughly 40% oxygen. The animals were treated daily with a solution containing either copper zinc-superoxide dismutase plus catalase, deferoxamine, or copper sulfate plus iron chloride, applied to the traumatized area. After 1 week the extension of myringosclerotic plaques was determined otomicroscopically. The pars tensa and pars flaccida were then dissected free and prepared for light microscopic studies. The results showed that treatment with copper zinc-superoxide dismutase plus catalase and deferoxamine inhibited or reduced the development of myringosclerosis, whereas the ears treated with copper sulfate plus iron chloride appeared unaffected. Consequently, the findings support the hypothesis that the formation of oxygen free radicals contributes significantly to the development of myringosclerosis.

Animals↗

PubMed1997

Antithrombotic effect of two low molecular weight thrombin inhibitors and a low-molecular weight heparin in a caval vein thrombosis model in the rat.

A sensitive thrombosis model with a high reproducibility was developed in the rat, utilizing stasis of the caval vein and a standardized surgical trauma as the only thrombogenic stimuli. Since no procoagulant substances were used, the results of the present study might be relevant in a clinical situation. The antithrombotic effect of two recently synthesized low-molecular-weight thrombin inhibitors have been compared to dalteparin, (Fragmin) a low-molecular-weight heparin fragment. Each compound was studied at 8 different doses with 10 rats in each group. On a gravimetric basis, the thrombin inhibitor melagatran was twice as potent as dalteparin (ED50 16 and 33 microg/kg per h, respectively). The second thrombin inhibitor, inogatran, had an intermediate effect, with an ED50 of 24 microg/kg per h. No differences in antithrombotic effect were, however, found when the compounds were compared at anticoagulant equivalent doses (same APTT prolongation). A 50% reduction in the mean thrombus weight was obtained when APTT was prolonged to 1.2 to 1.3 times the pretreatment value.

Animals↗