Luc Wouters - Academia.edu (original) (raw)

Papers by Luc Wouters

Stroke, Feb 1, 1997

Background and Purpose Cerebral ischemia may lead to glutamate-induced excitotoxic damage in vuln... more Background and Purpose Cerebral ischemia may lead to glutamate-induced excitotoxic damage in vulnerable brain areas. Lubeluzole is not an N -methyl- d -aspartate antagonist but prevents postischemic increase in extracellular glutamate concentrations. The present study examined whether lubeluzole, administered after global incomplete ischemia in rats, is capable of preserving the structural integrity of CA1 hippocampus. Methods Ischemia was induced by bilateral carotid artery occlusion and severe hypotension for a duration of 9 minutes. Delayed neuronal cell death was histologically evaluated 7 days later. This was done by scoring acidophilic cell change and coagulative necrosis and by counting the number of surviving neurons in the CA1 subfield. Experiments were performed according to a paired design (13 animals per treatment group). Results Posttreatment with lubeluzole (0.31 mg/kg IV bolus at 5 minutes and 0.31 mg/kg IV infusion during 1 hour) resulted in significant neuroprotection. Whereas in the untreated rats there were 42 (median) viable neurons per millimeter CA1 layer in the left and 69 in the right hemisphere, in the drug-treated rats 99 viable neurons per millimeter were found in the left ( P =.002) and 113 in the right hemisphere ( P =.013). Histological scores, reflecting altered staining properties of the hippocampal cells, correlated strongly with the quantitative data, reflecting the structural integrity of CA1 pyramidal neurons. Conclusions Lubeluzole, when administered after an ischemic insult in rats, protects vulnerable brain regions against delayed structural injury. The results support the potential clinical use of this new drug in stroke treatment.

PubMed, 1991

The clinically applicable formulation of the microtubule inhibitor erbulozole (R 55 104), dissolv... more The clinically applicable formulation of the microtubule inhibitor erbulozole (R 55 104), dissolved into an aqueous hydroxypropyl-beta-cyclodextrin solution (designated as R 55 104-CYCLO), exerts a similar effect on growth delay of subcutaneous MO4 fibrosarcomas in mice, with or without 10 Gy gamma-irradiation given locally to the tumors 2 h later, compared to R 55 104 in water. The drug concentration can be reduced from 80 mg/kg to 5 mg/kg without affecting the activity of this particular drug-radiation combination. Furthermore, 80 mg/kg R 55 104-CYCLO show a radioprotective effect when given 2 h before total body irradiation of non-tumor bearing mice. A radiation dose of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gy respectively was given resulting in a LD50(30) of 5.97 Gy for the irradiated mice and 7.65 Gy for the drug-radiation treated animals (Dose Effect Factor = 0.78). Therapeutic implications of both observations are discussed.

PubMed, Mar 1, 1985

The fast intravenous injection of arachidonic acid (AA) in mice produces, in a dose-related way, ... more The fast intravenous injection of arachidonic acid (AA) in mice produces, in a dose-related way, mortality due to respiratory distress. Upon electron microscopical examination an extensive oedematous damage of the capillary endothelium was found; thrombotic platelet obstructions were present in a minority of pulmonary capillaries only. Protection against this toxic AA-effect is obtained with inhibitors of fatty acid cyclo-oxygenase and of thromboxane (TXA2) synthetase, suggesting involvement of TXA2 as a causative mediator. The Ca2+-entry blockers flunarizine, niludipine and nimodipine, not affecting TXA2 synthesis by murine platelets, also provide protection, but not the antiplatelet drugs ticlopidine, dipyridamole or suloctidil; thrombocytopenia induced by busulphan does not affect the AA-induced mortality nor the protection obtained with flunarizine. Platelet-independent bronchoconstriction induced by AA in guinea-pigs is also inhibited by flunarizine. This study suggests that the AA-induced mortality test reflects pulmonary conversion of AA to TXA2 producing endothelial cell damage and respiratory smooth muscle cell contraction rather than a thrombotic phenomenon. The protective effect of flunarizine against TXA2 induced changes in vivo may contribute to its effectiveness in particular hypoxic conditions associated with liberation of AA.

Drug Development Research, May 1, 1986

The protective effects of lidoflazine and mioflazine against normothermic ischemia were evaluated... more The protective effects of lidoflazine and mioflazine against normothermic ischemia were evaluated in isolated rabbit hearts used in the working mode. Pretreatment with 0.125 mgl liter of these drugs improved recovery of cardiodynamic function during postischemic reperfusion. Functional recovery was preceded by less severe impairment of sarcolemmal structure and Ca2+ distribution at the end of the ischemic period, allowing the normalization of other substructures and the prevention of cellular Ca2+ overload during postischemic reperfusion. When cardiac output and semi-quantitative histology are taken as parameters, the protective effects of mioflazine were greater than that of lidoflazine.

European Journal of Cancer and Clinical Oncology, Oct 1, 1989

IS a more water soluble congener of the synthetic microtubule inhibitor tubulozole (R 46 846) exh... more IS a more water soluble congener of the synthetic microtubule inhibitor tubulozole (R 46 846) exhibiting a reversible antimicrotubular activity in vitro at a dose (1.56 X 10-s M) which is at least IO-fold lower. The compound also has an antiinvasive potential and shows antitumoral effects both in vitro and in vivo when administered appropriately. Eigh& mglkg R 55 104, given orally 6 h before or 3 h after radiotherapy, displays a prominent interactive effect with 10 Gy gamma irradiation in subcutaneous murk tumors which is similar to 160 mg/kg tubulozole administered 6 h before 10 Gy. The enhancing effect is also observed in a clinically relevant radiation dose fractionation schedule whereby eight fractions of 2 Gy each were pretreated 2 h before with 40 mglkg R 55 104. Further stuaj of this radiochemotherapeutic combination may lead to new clinical applications.

Cardiovascular Research, Sep 1, 1984

The cardioprotective effects of mioflazine, a recently developed cardiovascular drug, were invest... more The cardioprotective effects of mioflazine, a recently developed cardiovascular drug, were investigated in 41 anaesthetised open chest Beagle dogs subjected to 1 h normothermic global myocardial ischaemia. The severity of the model is evidenced by the finding that only one out of 20 control dogs could be weaned from extracorporeal bypass. Oral pretreatment with mioflazine (2.5 mg X kg-1) resulted in complete functional recovery in 17 out of 20 animals. Biochemical analysis of left ventricular biopsies taken before, during and after aortic cross clamping showed a preservation of purines and a better recovery of ATP, ATP/ADP X Pi ratio and energy charge (p less than 0.05) in the pretreated animals. Morphological and cytochemical assessment of the myocardium demonstrated that the ultrastructure of the sarcolemma and its calcium binding capacity is remarkably well preserved in the drug treated animals. These results indicate a strong cardioprotective effect of mioflazine. The biochemical, cytochemical and ultrastructural findings suggest an interaction of the drug with the sarcolemma.

Drug Development Research, May 1, 1986

The consequences of acute cerebral ischemia and the protective effects of post-treatment with flu... more The consequences of acute cerebral ischemia and the protective effects of post-treatment with flunarizine and nimodipine were morphologically studied in an experimental rat model allowing simple quantification of delayed neuronal damage. Global incomplete ischemia was induced by temporary clamping of both carotid arteries combined with severe hypotension. Selective damage to CA1 hippocampal neurons was quantified 7 days later. Cytochemical visualization of subcellular Ca2+ in this model revealed a correlation between irreversible cell necrosis and toxic cytosolic Ca2+-overload, the latter being a relatively slow process originating late in the reoxygenation period. Treatment with Ca2+entry blockers started at 5 min after restoration of cerebral blood flow. Flunarizine significantly protected against ischemic hippocampal damage, whereas nimodipine had no effect.

Journal of biomolecular screening, Aug 1, 2002

Annals of Vascular Surgery, Nov 1, 1986

The authors present a series of 175 femoropopliteal (below-knee) and 65 femorotibial reconstructi... more The authors present a series of 175 femoropopliteal (below-knee) and 65 femorotibial reconstructions with the human umbilical vein (HUV) graft performed over an eight year period. With a mean follow-up of 36.7 months (range one month to 84 months) the early patency rate of 89% decreased to 54% after five years. Long-term patency was found to be primarily related to the location of the distal anastomosis and the quality of the outflow, showing a statistically significant decrease after repeat revascularization. Early thrombosis, even in the absence of a technical failure and late aneurysmal degeneration remain the major problems associated with the use of the HUV graft. It is therefore recommended that these reconstructions be preserved for patients with advanced ischemia or a limited life-expectancy.

PubMed, Sep 1, 1989

The cardioprotective effects of the beta-blocking drugs (dl-nebivolol, d-nebivolol, propranolol, ... more The cardioprotective effects of the beta-blocking drugs (dl-nebivolol, d-nebivolol, propranolol, atenolol, dilevalol and pindolol) were tested in the isolated working rabbit heart. The effects of l-nebivolol, having little beta-adrenoceptor blocking activity, were also studied. The hearts were subjected to 25 min ischemia, followed by 30 min of reperfusion. In solvent-treated hearts, ischemia resulted in a considerable loss of function. The mean functional recovery of one of the most sensitive parameters, i.e. aortic flow, was only 6%. Pretreatment either with dl-nebivolol, d-nebivolol, l-nebivolol or propranol significantly improved cardiodynamic function. Recovery after pretreatment with atenolol, dilevalol and pindolol (less than 10 mg/l) was not significantly improved when compared to solvent-treated hearts. The results suggest that the protective effects of some beta-blockers are most probably not related to beta-adrenoceptor blocking activity.

Cardiovascular Research, Oct 1, 1991

The aim was to evaluate the factors determining myocardial infarct size in unconscious dogs. In a... more The aim was to evaluate the factors determining myocardial infarct size in unconscious dogs. In anaesthetised open chest dogs, the left anterior descending coronary artery was occluded either by ligation or by thrombosis for different time periods (1.5 h, 4 h, 24 h), with or without reperfusion. Haemodynamic variables were recorded throughout the experiment. Radioactive microspheres (15 microns) were injected at the end of the ischaemic period to measure regional myocardial blood flow. Infarct size and area at risk were determined by the Evans blue triphenyltetrazolium staining technique followed by planimetry. Mongrel dogs of either sex (n = 16-42 per experiment), weight 18-25 kg, were used. A large interindividual variability in infarct size was observed after occlusion of the left anterior descending coronary artery at a standardised location for a well defined period. An examination of the factors responsible for this variability was carried out in order to develop a statistical model which would make it possible to predict infarct size. Using multiple regression analysis, it was found that in most protocols (except 90 min thrombosis) more than 85% of the variability in infarct size could be explained by the size of the area at risk and the amount of collateral flow. Thus, knowing the area at risk and the collateral flow, a fairly accurate prediction can be made of the size of the infarct that the dog will develop after a defined occlusion period. Furthermore, it was found that the infarct size increased with duration of occlusion, while duration of reperfusion had no effect. In the 90 min occlusion group thrombosis induced a larger final infarct than ligature. A correction for baseline variables is necessary in order to compare infarct size between experimental groups. The usefulness of this procedure is shown by an example of an experimental intervention, i.e., R 56,865, a drug with known cardioprotective effects.

Thrombosis Research, Aug 1, 1982

The anti-hypertensive effect of ketanserin, a selective 5-HT2 antagonist, both in experimental an... more The anti-hypertensive effect of ketanserin, a selective 5-HT2 antagonist, both in experimental and human pathology (1,2) could implicate the blood platelets as a source for peripherally available 5-hydroxytryptamine (5-HT), acting to increase peripheral vascular resistance (3). Therefore we examined various blood platelet parameters in spontaneously hypertensive rats in comparison with normotensive Wistar rats.

Anesthesia & Analgesia, 2010

BACKGROUND: Patient rewarming after hypothermic cardiopulmonary bypass (CPB) has been linked to b... more BACKGROUND: Patient rewarming after hypothermic cardiopulmonary bypass (CPB) has been linked to brain injury after cardiac surgery. In this study, we evaluated whether cooling and then rewarming of body temperature during CPB in adult patients is associated with alterations in cerebral blood flow (CBF)-blood pressure autoregulation. METHODS: One hundred twenty-seven adult patients undergoing CPB during cardiac surgery had transcranial Doppler monitoring of the right and left middle cerebral artery blood flow velocity. Eleven patients undergoing CPB who had arterial inflow maintained at Ͼ35°C served as controls. The mean velocity index (Mx) was calculated as a moving, linear correlation coefficient between slow waves of middle cerebral artery blood flow velocity and mean arterial blood pressure. Intact CBF-blood pressure autoregulation is associated with an Mx that approaches 0. Impaired autoregulation results in an increasing Mx approaching 1.0. Comparisons of time-averaged Mx values were made between the following periods: before CPB (baseline), during the cooling and rewarming phases of CPB, and after CPB. The number of patients in each phase of CPB with an Mx Ͼ4.0, indicative of impaired CBF autoregulation, was determined. RESULTS: During cooling, Mx (left, 0.29 Ϯ 0.18; right, 0.28 Ϯ 0.18 [mean Ϯ sd]) was greater than that at baseline (left, 0.17 Ϯ 0.21; right, 0.17 Ϯ 0.20; P Յ 0.0001). Mx increased during the rewarming phase of CPB (left, 0.40 Ϯ 0.19; right, 0.39 Ϯ 0.19) compared with baseline (P Յ 0.001) and the cooling phase (P Յ 0.0001), indicating impaired CBF autoregulation. After CPB, Mx (left, 0.27 Ϯ 0.20; right, 0.28 Ϯ 0.21) was higher than at baseline (left, P ϭ 0.0004; right, P ϭ 0.0003), no different than during the cooling phase, but lower than during rewarming (left, P Յ 0.0001; right, P Յ 0.0005). Forty-three patients (34%) had an Mx Ն0.4 during the cooling phase of CPB and 68 (53%) had an average Mx Ն0.4 during rewarming. Nine of the 11 warm controls had an average Mx Ն0.4 during the entire CPB period. There were 7 strokes and 1 TIA after surgery. All strokes were in patients with Mx Ն 0.4 during rewarming (P ϭ 0.015). The unadjusted odds ratio for any neurologic event (stroke or transient ischemic attack) for patients with Mx Ն 0.4 during rewarming was 6.57 (95% confidence interval, 0.79 to 55.0, P Ͻ 0.08). CONCLUSIONS: Hypothermic CPB is associated with abnormal CBF-blood pressure autoregulation that is worsened with rewarming. We found a high rate of strokes in patients with evidence of impaired CBF autoregulation. Whether a pressurepassive CBF state during rewarming is associated with risk for ischemic brain injury requires further investigation.

Journal of Urology, 1994

We examined the in vivo antitumoral effects of liarozole against androgen-dependent and independe... more We examined the in vivo antitumoral effects of liarozole against androgen-dependent and independent Dunning rat prostatic tumors. Liarozole, applied as a dietary admixture, at a dose of 120 mg./100 gm. food, equivalent to 100 mg./kg. per day, inhibited the growth of the slow growing, well-differentiated, androgen-dependent Dunning-H tumor (median tumor volume decrease of60%). At the same dose it also significantly reduced the growth of the androgen-independent, moderately differentiated PIF-1 (-60%) and androgen-independent, anaplastic AT-6 tumors (-73%). The growth of AT-6 sq tumor showing squamous metaplasia was unaffected by liarozole. When administered by oral gavage, liarozole at 40 (-82%) mg./kg. twice a day was as effective as castration (-92%) in reducing the androgen-dependent, poorly differentiated Dunning R3327-G tumor. Liarozole, administered by gavage, twice a day, also significantly reduced median tumor volume in the androgen-independent, AT-6 sq (-90% at 60 mg./kg., twice a day). This difference between liarozole administration by gavage and food admixture will have to be taken into account in further experimental studies. Inhibition of the growth of several androgen-dependent and, chiefly, androgen-independent Dunning prostate carcinoma sublines that differ widely in their histological degree of differentiation and growth :rate suggests that liarozole may be a suitable agent for evaluation in second line treatment of hormone refractory prostate carcinoma in patients who relapse after androgen ablation.

Archives internationales de pharmacodynamie et de thérapie, 1984

Collateral arteries can clearly be visualized in corrosion cast material after ligation of the fe... more Collateral arteries can clearly be visualized in corrosion cast material after ligation of the femoral artery in rats. To characterize the influence of serotonin on the blood circulation under the experimental condition of unilateral ligation, we performed intermuscular thermoflow measurements. The data showed that intraperitoneal serotonin (8.7 and 20 mg.kg-1) injection markedly reduced the muscle temperature in both hindlegs. However, the effect was significantly more pronounced on the ligated side, where the blood was supplied through a collateral circulation, than on the non-ligated side with its normal arterial vasculature. Almost identical changes were obtained in rats with an early as well as in animals with a more advanced stage of collateral development (challenge with 8.7 mg.kg-1 serotonin). Evans blue dye experiments and angiographic data further revealed that, after challenge with 20 mg.kg-1 serotonin, the severe temperature decrease at the ligated side probably reflecte...

The Journal of cardiovascular surgery

Graft limb patency was studied retrospectively in a consecutive series of 912 patients (1605 limb... more Graft limb patency was studied retrospectively in a consecutive series of 912 patients (1605 limbs), who received an aorto(bi)femoral Dacron graft for occlusive disease over a 25 years period (1963-1987). The mean follow-up for the series was 5.35 years (range 1 month to 23 years) and 18.5% of the patients were followed for at least 10 years. Primary patency decreased progressively to 83% at 10 years and 77% at 15 years. It was significantly improved to 90% (at 10 years) and 84% (at 15 years) by means of operative thrombectomy (secondary patency). Factors influencing patency (univariate analysis) were (1) concomitant femoropopliteal occlusive disease, (2) the site of the femoral anastomosis and (3) the date of the operation. Multivariate analysis in relation to the femoral anastomosis stressed the importance of profunda femoris artery disease and the date of operation. It is concluded that the negative effects of concomitant superficial femoral artery disease may be completely relie...

SummaryThe effect of nebivolol treatment on the survival of cardiomyopathic hamsters (BIO82.62) w... more SummaryThe effect of nebivolol treatment on the survival of cardiomyopathic hamsters (BIO82.62) who had developed congestive heart failure was investigated. Five percent of the hamsters included in the study had died between 200 and 220 days of age, indicating development of congestive heart failure. At age 220 days, a treatment protocol was initiated and the remaining animals received either nonmedicated food (n = 34) or food supplemented with nebivolol (1 mg/kg/day, n = 33). The death rate was similar in both groups during the first 27 days of treatment, after which nebivolol significantly delayed mortality (p = 0.011). The median survival time was 293 days in controls vs 321 days in the nebivolol group. It is concluded that nebivolol prolongs survival in this animal model of congestive heart failure, although further investigation is needed to clarify the mechanism of action.

Journal of Molecular and Cellular Cardiology, 1992

Stroke, Feb 1, 1997

Background and Purpose Cerebral ischemia may lead to glutamate-induced excitotoxic damage in vuln... more Background and Purpose Cerebral ischemia may lead to glutamate-induced excitotoxic damage in vulnerable brain areas. Lubeluzole is not an N -methyl- d -aspartate antagonist but prevents postischemic increase in extracellular glutamate concentrations. The present study examined whether lubeluzole, administered after global incomplete ischemia in rats, is capable of preserving the structural integrity of CA1 hippocampus. Methods Ischemia was induced by bilateral carotid artery occlusion and severe hypotension for a duration of 9 minutes. Delayed neuronal cell death was histologically evaluated 7 days later. This was done by scoring acidophilic cell change and coagulative necrosis and by counting the number of surviving neurons in the CA1 subfield. Experiments were performed according to a paired design (13 animals per treatment group). Results Posttreatment with lubeluzole (0.31 mg/kg IV bolus at 5 minutes and 0.31 mg/kg IV infusion during 1 hour) resulted in significant neuroprotection. Whereas in the untreated rats there were 42 (median) viable neurons per millimeter CA1 layer in the left and 69 in the right hemisphere, in the drug-treated rats 99 viable neurons per millimeter were found in the left ( P =.002) and 113 in the right hemisphere ( P =.013). Histological scores, reflecting altered staining properties of the hippocampal cells, correlated strongly with the quantitative data, reflecting the structural integrity of CA1 pyramidal neurons. Conclusions Lubeluzole, when administered after an ischemic insult in rats, protects vulnerable brain regions against delayed structural injury. The results support the potential clinical use of this new drug in stroke treatment.

PubMed, 1991

The clinically applicable formulation of the microtubule inhibitor erbulozole (R 55 104), dissolv... more The clinically applicable formulation of the microtubule inhibitor erbulozole (R 55 104), dissolved into an aqueous hydroxypropyl-beta-cyclodextrin solution (designated as R 55 104-CYCLO), exerts a similar effect on growth delay of subcutaneous MO4 fibrosarcomas in mice, with or without 10 Gy gamma-irradiation given locally to the tumors 2 h later, compared to R 55 104 in water. The drug concentration can be reduced from 80 mg/kg to 5 mg/kg without affecting the activity of this particular drug-radiation combination. Furthermore, 80 mg/kg R 55 104-CYCLO show a radioprotective effect when given 2 h before total body irradiation of non-tumor bearing mice. A radiation dose of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 Gy respectively was given resulting in a LD50(30) of 5.97 Gy for the irradiated mice and 7.65 Gy for the drug-radiation treated animals (Dose Effect Factor = 0.78). Therapeutic implications of both observations are discussed.

PubMed, Mar 1, 1985

The fast intravenous injection of arachidonic acid (AA) in mice produces, in a dose-related way, ... more The fast intravenous injection of arachidonic acid (AA) in mice produces, in a dose-related way, mortality due to respiratory distress. Upon electron microscopical examination an extensive oedematous damage of the capillary endothelium was found; thrombotic platelet obstructions were present in a minority of pulmonary capillaries only. Protection against this toxic AA-effect is obtained with inhibitors of fatty acid cyclo-oxygenase and of thromboxane (TXA2) synthetase, suggesting involvement of TXA2 as a causative mediator. The Ca2+-entry blockers flunarizine, niludipine and nimodipine, not affecting TXA2 synthesis by murine platelets, also provide protection, but not the antiplatelet drugs ticlopidine, dipyridamole or suloctidil; thrombocytopenia induced by busulphan does not affect the AA-induced mortality nor the protection obtained with flunarizine. Platelet-independent bronchoconstriction induced by AA in guinea-pigs is also inhibited by flunarizine. This study suggests that the AA-induced mortality test reflects pulmonary conversion of AA to TXA2 producing endothelial cell damage and respiratory smooth muscle cell contraction rather than a thrombotic phenomenon. The protective effect of flunarizine against TXA2 induced changes in vivo may contribute to its effectiveness in particular hypoxic conditions associated with liberation of AA.

Drug Development Research, May 1, 1986

The protective effects of lidoflazine and mioflazine against normothermic ischemia were evaluated... more The protective effects of lidoflazine and mioflazine against normothermic ischemia were evaluated in isolated rabbit hearts used in the working mode. Pretreatment with 0.125 mgl liter of these drugs improved recovery of cardiodynamic function during postischemic reperfusion. Functional recovery was preceded by less severe impairment of sarcolemmal structure and Ca2+ distribution at the end of the ischemic period, allowing the normalization of other substructures and the prevention of cellular Ca2+ overload during postischemic reperfusion. When cardiac output and semi-quantitative histology are taken as parameters, the protective effects of mioflazine were greater than that of lidoflazine.

European Journal of Cancer and Clinical Oncology, Oct 1, 1989

IS a more water soluble congener of the synthetic microtubule inhibitor tubulozole (R 46 846) exh... more IS a more water soluble congener of the synthetic microtubule inhibitor tubulozole (R 46 846) exhibiting a reversible antimicrotubular activity in vitro at a dose (1.56 X 10-s M) which is at least IO-fold lower. The compound also has an antiinvasive potential and shows antitumoral effects both in vitro and in vivo when administered appropriately. Eigh& mglkg R 55 104, given orally 6 h before or 3 h after radiotherapy, displays a prominent interactive effect with 10 Gy gamma irradiation in subcutaneous murk tumors which is similar to 160 mg/kg tubulozole administered 6 h before 10 Gy. The enhancing effect is also observed in a clinically relevant radiation dose fractionation schedule whereby eight fractions of 2 Gy each were pretreated 2 h before with 40 mglkg R 55 104. Further stuaj of this radiochemotherapeutic combination may lead to new clinical applications.

Cardiovascular Research, Sep 1, 1984

The cardioprotective effects of mioflazine, a recently developed cardiovascular drug, were invest... more The cardioprotective effects of mioflazine, a recently developed cardiovascular drug, were investigated in 41 anaesthetised open chest Beagle dogs subjected to 1 h normothermic global myocardial ischaemia. The severity of the model is evidenced by the finding that only one out of 20 control dogs could be weaned from extracorporeal bypass. Oral pretreatment with mioflazine (2.5 mg X kg-1) resulted in complete functional recovery in 17 out of 20 animals. Biochemical analysis of left ventricular biopsies taken before, during and after aortic cross clamping showed a preservation of purines and a better recovery of ATP, ATP/ADP X Pi ratio and energy charge (p less than 0.05) in the pretreated animals. Morphological and cytochemical assessment of the myocardium demonstrated that the ultrastructure of the sarcolemma and its calcium binding capacity is remarkably well preserved in the drug treated animals. These results indicate a strong cardioprotective effect of mioflazine. The biochemical, cytochemical and ultrastructural findings suggest an interaction of the drug with the sarcolemma.

Drug Development Research, May 1, 1986

The consequences of acute cerebral ischemia and the protective effects of post-treatment with flu... more The consequences of acute cerebral ischemia and the protective effects of post-treatment with flunarizine and nimodipine were morphologically studied in an experimental rat model allowing simple quantification of delayed neuronal damage. Global incomplete ischemia was induced by temporary clamping of both carotid arteries combined with severe hypotension. Selective damage to CA1 hippocampal neurons was quantified 7 days later. Cytochemical visualization of subcellular Ca2+ in this model revealed a correlation between irreversible cell necrosis and toxic cytosolic Ca2+-overload, the latter being a relatively slow process originating late in the reoxygenation period. Treatment with Ca2+entry blockers started at 5 min after restoration of cerebral blood flow. Flunarizine significantly protected against ischemic hippocampal damage, whereas nimodipine had no effect.

Journal of biomolecular screening, Aug 1, 2002

Annals of Vascular Surgery, Nov 1, 1986

The authors present a series of 175 femoropopliteal (below-knee) and 65 femorotibial reconstructi... more The authors present a series of 175 femoropopliteal (below-knee) and 65 femorotibial reconstructions with the human umbilical vein (HUV) graft performed over an eight year period. With a mean follow-up of 36.7 months (range one month to 84 months) the early patency rate of 89% decreased to 54% after five years. Long-term patency was found to be primarily related to the location of the distal anastomosis and the quality of the outflow, showing a statistically significant decrease after repeat revascularization. Early thrombosis, even in the absence of a technical failure and late aneurysmal degeneration remain the major problems associated with the use of the HUV graft. It is therefore recommended that these reconstructions be preserved for patients with advanced ischemia or a limited life-expectancy.

PubMed, Sep 1, 1989

The cardioprotective effects of the beta-blocking drugs (dl-nebivolol, d-nebivolol, propranolol, ... more The cardioprotective effects of the beta-blocking drugs (dl-nebivolol, d-nebivolol, propranolol, atenolol, dilevalol and pindolol) were tested in the isolated working rabbit heart. The effects of l-nebivolol, having little beta-adrenoceptor blocking activity, were also studied. The hearts were subjected to 25 min ischemia, followed by 30 min of reperfusion. In solvent-treated hearts, ischemia resulted in a considerable loss of function. The mean functional recovery of one of the most sensitive parameters, i.e. aortic flow, was only 6%. Pretreatment either with dl-nebivolol, d-nebivolol, l-nebivolol or propranol significantly improved cardiodynamic function. Recovery after pretreatment with atenolol, dilevalol and pindolol (less than 10 mg/l) was not significantly improved when compared to solvent-treated hearts. The results suggest that the protective effects of some beta-blockers are most probably not related to beta-adrenoceptor blocking activity.

Cardiovascular Research, Oct 1, 1991

The aim was to evaluate the factors determining myocardial infarct size in unconscious dogs. In a... more The aim was to evaluate the factors determining myocardial infarct size in unconscious dogs. In anaesthetised open chest dogs, the left anterior descending coronary artery was occluded either by ligation or by thrombosis for different time periods (1.5 h, 4 h, 24 h), with or without reperfusion. Haemodynamic variables were recorded throughout the experiment. Radioactive microspheres (15 microns) were injected at the end of the ischaemic period to measure regional myocardial blood flow. Infarct size and area at risk were determined by the Evans blue triphenyltetrazolium staining technique followed by planimetry. Mongrel dogs of either sex (n = 16-42 per experiment), weight 18-25 kg, were used. A large interindividual variability in infarct size was observed after occlusion of the left anterior descending coronary artery at a standardised location for a well defined period. An examination of the factors responsible for this variability was carried out in order to develop a statistical model which would make it possible to predict infarct size. Using multiple regression analysis, it was found that in most protocols (except 90 min thrombosis) more than 85% of the variability in infarct size could be explained by the size of the area at risk and the amount of collateral flow. Thus, knowing the area at risk and the collateral flow, a fairly accurate prediction can be made of the size of the infarct that the dog will develop after a defined occlusion period. Furthermore, it was found that the infarct size increased with duration of occlusion, while duration of reperfusion had no effect. In the 90 min occlusion group thrombosis induced a larger final infarct than ligature. A correction for baseline variables is necessary in order to compare infarct size between experimental groups. The usefulness of this procedure is shown by an example of an experimental intervention, i.e., R 56,865, a drug with known cardioprotective effects.

Thrombosis Research, Aug 1, 1982

The anti-hypertensive effect of ketanserin, a selective 5-HT2 antagonist, both in experimental an... more The anti-hypertensive effect of ketanserin, a selective 5-HT2 antagonist, both in experimental and human pathology (1,2) could implicate the blood platelets as a source for peripherally available 5-hydroxytryptamine (5-HT), acting to increase peripheral vascular resistance (3). Therefore we examined various blood platelet parameters in spontaneously hypertensive rats in comparison with normotensive Wistar rats.

Anesthesia & Analgesia, 2010

BACKGROUND: Patient rewarming after hypothermic cardiopulmonary bypass (CPB) has been linked to b... more BACKGROUND: Patient rewarming after hypothermic cardiopulmonary bypass (CPB) has been linked to brain injury after cardiac surgery. In this study, we evaluated whether cooling and then rewarming of body temperature during CPB in adult patients is associated with alterations in cerebral blood flow (CBF)-blood pressure autoregulation. METHODS: One hundred twenty-seven adult patients undergoing CPB during cardiac surgery had transcranial Doppler monitoring of the right and left middle cerebral artery blood flow velocity. Eleven patients undergoing CPB who had arterial inflow maintained at Ͼ35°C served as controls. The mean velocity index (Mx) was calculated as a moving, linear correlation coefficient between slow waves of middle cerebral artery blood flow velocity and mean arterial blood pressure. Intact CBF-blood pressure autoregulation is associated with an Mx that approaches 0. Impaired autoregulation results in an increasing Mx approaching 1.0. Comparisons of time-averaged Mx values were made between the following periods: before CPB (baseline), during the cooling and rewarming phases of CPB, and after CPB. The number of patients in each phase of CPB with an Mx Ͼ4.0, indicative of impaired CBF autoregulation, was determined. RESULTS: During cooling, Mx (left, 0.29 Ϯ 0.18; right, 0.28 Ϯ 0.18 [mean Ϯ sd]) was greater than that at baseline (left, 0.17 Ϯ 0.21; right, 0.17 Ϯ 0.20; P Յ 0.0001). Mx increased during the rewarming phase of CPB (left, 0.40 Ϯ 0.19; right, 0.39 Ϯ 0.19) compared with baseline (P Յ 0.001) and the cooling phase (P Յ 0.0001), indicating impaired CBF autoregulation. After CPB, Mx (left, 0.27 Ϯ 0.20; right, 0.28 Ϯ 0.21) was higher than at baseline (left, P ϭ 0.0004; right, P ϭ 0.0003), no different than during the cooling phase, but lower than during rewarming (left, P Յ 0.0001; right, P Յ 0.0005). Forty-three patients (34%) had an Mx Ն0.4 during the cooling phase of CPB and 68 (53%) had an average Mx Ն0.4 during rewarming. Nine of the 11 warm controls had an average Mx Ն0.4 during the entire CPB period. There were 7 strokes and 1 TIA after surgery. All strokes were in patients with Mx Ն 0.4 during rewarming (P ϭ 0.015). The unadjusted odds ratio for any neurologic event (stroke or transient ischemic attack) for patients with Mx Ն 0.4 during rewarming was 6.57 (95% confidence interval, 0.79 to 55.0, P Ͻ 0.08). CONCLUSIONS: Hypothermic CPB is associated with abnormal CBF-blood pressure autoregulation that is worsened with rewarming. We found a high rate of strokes in patients with evidence of impaired CBF autoregulation. Whether a pressurepassive CBF state during rewarming is associated with risk for ischemic brain injury requires further investigation.

Journal of Urology, 1994

We examined the in vivo antitumoral effects of liarozole against androgen-dependent and independe... more We examined the in vivo antitumoral effects of liarozole against androgen-dependent and independent Dunning rat prostatic tumors. Liarozole, applied as a dietary admixture, at a dose of 120 mg./100 gm. food, equivalent to 100 mg./kg. per day, inhibited the growth of the slow growing, well-differentiated, androgen-dependent Dunning-H tumor (median tumor volume decrease of60%). At the same dose it also significantly reduced the growth of the androgen-independent, moderately differentiated PIF-1 (-60%) and androgen-independent, anaplastic AT-6 tumors (-73%). The growth of AT-6 sq tumor showing squamous metaplasia was unaffected by liarozole. When administered by oral gavage, liarozole at 40 (-82%) mg./kg. twice a day was as effective as castration (-92%) in reducing the androgen-dependent, poorly differentiated Dunning R3327-G tumor. Liarozole, administered by gavage, twice a day, also significantly reduced median tumor volume in the androgen-independent, AT-6 sq (-90% at 60 mg./kg., twice a day). This difference between liarozole administration by gavage and food admixture will have to be taken into account in further experimental studies. Inhibition of the growth of several androgen-dependent and, chiefly, androgen-independent Dunning prostate carcinoma sublines that differ widely in their histological degree of differentiation and growth :rate suggests that liarozole may be a suitable agent for evaluation in second line treatment of hormone refractory prostate carcinoma in patients who relapse after androgen ablation.

Archives internationales de pharmacodynamie et de thérapie, 1984

Collateral arteries can clearly be visualized in corrosion cast material after ligation of the fe... more Collateral arteries can clearly be visualized in corrosion cast material after ligation of the femoral artery in rats. To characterize the influence of serotonin on the blood circulation under the experimental condition of unilateral ligation, we performed intermuscular thermoflow measurements. The data showed that intraperitoneal serotonin (8.7 and 20 mg.kg-1) injection markedly reduced the muscle temperature in both hindlegs. However, the effect was significantly more pronounced on the ligated side, where the blood was supplied through a collateral circulation, than on the non-ligated side with its normal arterial vasculature. Almost identical changes were obtained in rats with an early as well as in animals with a more advanced stage of collateral development (challenge with 8.7 mg.kg-1 serotonin). Evans blue dye experiments and angiographic data further revealed that, after challenge with 20 mg.kg-1 serotonin, the severe temperature decrease at the ligated side probably reflecte...

The Journal of cardiovascular surgery

Graft limb patency was studied retrospectively in a consecutive series of 912 patients (1605 limb... more Graft limb patency was studied retrospectively in a consecutive series of 912 patients (1605 limbs), who received an aorto(bi)femoral Dacron graft for occlusive disease over a 25 years period (1963-1987). The mean follow-up for the series was 5.35 years (range 1 month to 23 years) and 18.5% of the patients were followed for at least 10 years. Primary patency decreased progressively to 83% at 10 years and 77% at 15 years. It was significantly improved to 90% (at 10 years) and 84% (at 15 years) by means of operative thrombectomy (secondary patency). Factors influencing patency (univariate analysis) were (1) concomitant femoropopliteal occlusive disease, (2) the site of the femoral anastomosis and (3) the date of the operation. Multivariate analysis in relation to the femoral anastomosis stressed the importance of profunda femoris artery disease and the date of operation. It is concluded that the negative effects of concomitant superficial femoral artery disease may be completely relie...

SummaryThe effect of nebivolol treatment on the survival of cardiomyopathic hamsters (BIO82.62) w... more SummaryThe effect of nebivolol treatment on the survival of cardiomyopathic hamsters (BIO82.62) who had developed congestive heart failure was investigated. Five percent of the hamsters included in the study had died between 200 and 220 days of age, indicating development of congestive heart failure. At age 220 days, a treatment protocol was initiated and the remaining animals received either nonmedicated food (n = 34) or food supplemented with nebivolol (1 mg/kg/day, n = 33). The death rate was similar in both groups during the first 27 days of treatment, after which nebivolol significantly delayed mortality (p = 0.011). The median survival time was 293 days in controls vs 321 days in the nebivolol group. It is concluded that nebivolol prolongs survival in this animal model of congestive heart failure, although further investigation is needed to clarify the mechanism of action.

Journal of Molecular and Cellular Cardiology, 1992