The Experts below are selected from a list of 75 Experts worldwide ranked by ideXlab platform
Willem Flameng - One of the best experts on this subject based on the ideXlab platform.
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requested comment concerning Lidoflazine
The Journal of Thoracic and Cardiovascular Surgery, 1995Co-Authors: Willem FlamengAbstract:Lidoflazine is a drug that was developed by the Janssen Research Laboratories (Janssen Pharmaceutics, Beerse, Belgium) several decades ago but never became available on the international market. It has strong nucleoside transport inhibitory properties and can be classified as an ARA or adenosine regulating agent. 1 Recently, there has been increasing interest in this type of drugs for myocardial protection, because they all enhance the tissue content of adenosine in the myocardium. Adenosine is widely known for its cardioprotective properties against ischemic damage. 2 Accumulation of adenosine in the myocardium can be obtained by prevention of its breakdown (for example, by inhibition of its transport from the myocyte to the endothelial cell where adenosine is catabolized) or by stimulating its production. The latter can be done by infusing the precursor AICA riboside (5-amino-4-imidazole carboxamide riboside). This drug is now under clinical investigation in large multicenter studies in the United States, Canada, and Europe. The study of Akpinar, Vanerman, and Wellens is interesting in so far as it demonstrates that extensive coronary bypass grafting can safely be done on the fibrillating heart using one single period of aortic crossclamping combined with lidosazine pretreatment. The clinical outcome was the same as when cardioplegia was used. However, the study does not provide scientific proof
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nucleoside transport inhibition mediates Lidoflazine induced cardioprotection during intermittent aortic crossclamping
The Journal of Thoracic and Cardiovascular Surgery, 1992Co-Authors: Chen Changchun, Munetaka Masuda, Zoltan Szabo, Thomas Szerafin, J Szecsi, Herman Van Belle, Willem FlamengAbstract:The effects of pretreatment with the nucleoside transport inhibitor Lidoflazine on repeated ischemia-reperfusion injury induced by normothermic intermittent aortic crossclamping were studied in canine hearts. Eighteen mongrel dogs were allocated to three groups: placebo (n = 6), Lidoflazine (1 mg/kg) (n = 6), and Lidoflazine (1 mg/kg) plus the adenosine receptor blocker aminophylline (7 mg/kg) (n = 6). Pretreatment was performed intravenously during 15 minutes before extracorporeal circulation. All hearts were subjected to four intervals of 15 minutes of global ischemia each followed by 10 minutes of reperfusion. After weaning from extracorporeal circulation, functional recovery was followed for 1 hour. In the Lidoflazine group, myocardial adenosine content (0.25 +/- 0.06 mumol/gm dry weight) was 3.5 times higher than that in the control group (0.07 +/- 0.03 mumol/gm dry weight; p < 0.05) at the end of the last aortic crossclamping. The release of adenosine from the myocardium during each reperfusion period was significantly higher than that in the control group (p < 0.05). Myocardial extraction of lactate was normalized at every reperfusion interval in the Lidoflazine group but not in the control group (p < 0.05). In the Lidoflazine group functional recovery was significantly better than that in the control group. Positive rate of rise of pressure, negative rate of rise of pressure, and cardiac output recovered to, respectively, 150% +/- 19%, 82% +/- 8%, and 131% +/- 15% in the Lidoflazine group versus, respectively, 37% +/- 9%, 23% +/- 7%, and 29% +/- 8% in the control group (p < 0.001) at 1 hour after extracorporeal circulation. When the adenosine receptor blocker aminophylline was administered in association with Lidoflazine, protection dropped significantly: positive and negative rate of rise of pressure and cardiac output were, respectively, 58% +/- 8%, 46% +/- 9%, and 67% +/- 16% at 1 hour after extracorporeal circulation (p < 0.05 versus Lidoflazine alone). These results suggest that the cardioprotective effects of Lidoflazine are at least in part mediated by adenosine receptor stimulation via nucleoside transport inhibition-induced accumulation of endogenous adenosine in the myocardium.
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evaluation of myocardial protection by combination of Lidoflazine pretreatment and st thomas hospital cardioplegia in aorto coronary bypass grafting
European Journal of Cardio-Thoracic Surgery, 1992Co-Authors: Luc Noyez, J T A Knape, B J Arnold, P M Vermeulen, T Van Der Werf, J Gimbrere, L K Lacquet, Willem FlamengAbstract:The concept of pretreatment of the myocardium with a pharmacological agent protecting the cell against ischemic and reperfusion injury is very attractive. Lidoflazine, a calcium overload blocker, predominantly membrane stabilizing, is able to prevent cell damage during ischemic arrest and reperfusion. The purpose of this study was to determine whether the combination of Lidoflazine pretreatment and St. Thomas' Hospital cardioplegia can provide, in clinical practice, better myocardial protection in aorto-coronary bypass grafting than St. Thomas' Hospital cardioplegia alone. As indices for myocardial protection, recovery of cardiac function, enzyme release, and clinical outcome were registered. Ninety-three patients undergoing aorto-coronary bypass surgery were studied. These patients were randomized into two groups in a double blind fashion. Patients in group A (n = 48) received Lidoflazine 1 mg/kg intravenously over a period of 20 min before initiation of cardiopulmonary bypass. Group B (n = 45) receiving placebo, acted as a control group. Myocardial protection consisted of intermittent infusion of cold 4 degrees C St. Thomas' Hospital cardioplegia, topical slush ice, and systemic hypothermia (28 degrees C rectal). No significant differences between the two groups were noted in terms of recovery of cardiac function, enzyme release, incidence of myocardial infarction, low cardiac output, rhythm, and conduction disturbances. In conclusion, our data suggest that the combination of intravenous pretreatment with Lidoflazine and St. Thomas' Hospital cardioplegia did not provide significant additional myocardial protection in the clinical situation.
Marcel Borgers - One of the best experts on this subject based on the ideXlab platform.
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protection of human rat and guinea pig atrial muscle by mioflazine Lidoflazine and verapamil against the destructive effects of high concentrations of ca2
Cardiovascular Drugs and Therapy, 1992Co-Authors: Ursula Ravens, G Vandeplassche, Liu Guoshu, Marcel BorgersAbstract:In right atrial trabeculae from humans and in left atria from rat and guinea-pig hearts, the protective effects of mioflazine, Lidoflazine, and verapamil against the accumulation of cellular calcium were investigated. Two consecutive, cumulative increases in the extracellular calcium concentration, [Ca2+]0 (1–25 mmol/l), were induced, in between which the muscles were exposed for at least 30 minutes to solvent or drug. When using solvent in the 30-minute interval, the force of contraction was much lower during the second Ca2+ challenge, while the aftercontractions and the increase in passive tension at high [Ca2+]0 tended to be larger. These signs of functional impairment were prevented by exposure to mioflazine or Lidoflazine (3μmol/l each) but not to verapamil (3 μmol/l). Muscles were fixed with glutaraldehyde at the end of the second Ca2+ challenge for morphological and cytochemical examination. After solvent treatment, more than half of the cells were severely damaged, showing cellular edema, contraction-band necrosis, mitochondrial swelling, and nuclear pyknosis; the sarcolemma was devoid of calcium deposits, damaged mitochondria contained either large deposits of calcium or flocculent densities, and in some cells, the cytoplasm was filled with calcium deposits. Following exposure to mioflazine and Lidoflazine, but not to verapamil, the number of intact cells after the second Ca2+ challenge was not different from time-matched controls (80–90%). Furthermore, the shifts in cellular calcium distribution were prevented with mioflazine and Lidoflazine, whereas verapamil was less effective. There were no species differences with respect to either morphological or contractile changes. In conclusion, exposure of atria to high [Ca2+]0 induced similar ultrastructural and cytochemical changes as seen after ischemia-reperfusion induced damage. Indeed, under the mentioned conditions the sarcolemma lost its capacity to exclude Ca2+ after a challenge with high [Ca2+]0 and allowed excessive Ca2+ entry. The pathway for this extra Ca2+ remains to be elucidated. L-type calcium channels are probably no involved, since verapamil cannot prevent the Ca2+ overload.
Simon M. Jarvis - One of the best experts on this subject based on the ideXlab platform.
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Nucleoside influx and efflux in guinea-pig ventricular myocytes. Inhibition by analogues of Lidoflazine.
Biochemical pharmacology, 1994Co-Authors: Alan R. Conant, Simon M. JarvisAbstract:Abstract Adenosine influx and formycin B influx and efflux were characterized in guinea-pig ventricular myocytes at 22°. Transport by both modes was saturable and inhibited by nitrobenzylthionosine (NBMPR), indicating the presence of an equilibrative NBMPR-sensitive nucleoside transporter in the cardiomyocytes. The kinetic constants for influx aand efflux for formycin B, a non-metabolitezed nucleoside, were similar, suggesting that the nucleoside transporter exhibits symmetrical kinetics (apparent K m 490 ± 160 and 700 ± 140 μ M; V max 6.5 ± 0.3 nmol./10 6 cells per min for influx and efflux, respectively). No evidence was found of either NBMPR-insensitive equilibrative nucleoside transport or sodium-dependent concentrative nucleoside transport. Inhibition of adenosine influx (apparent K m 100 ± 33 μ M), by Lidoflazine and the analogues mioflazine soluflazine and R73-335, gave average K i values of 730, 100, 64 and 2.9 nM, respectively. These compounds inhibitied formycin B efflux with a similar potency to that of adenosine influx. NBMPR-sensitive nucleoside transport was associated with high affinity binding of NBMPR (apparent K d ∼1 nM; 9.6 × 10 5 sites/cells). Specific binding of NBMPR was also inhibited by Lidoflazine and its analogues. Mioflazine and soluflazine were 20–30-fold more potent at inhibiting NBMPR-sensitive nucleoside influx in guinea-pig erythrocytes than ventricular myocytes, indicating that the potency of some of the compounds studied is tissue dependent.
Jeanette Jacobsson - One of the best experts on this subject based on the ideXlab platform.
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liver preservation with Lidoflazine and the university of wisconsin solution a dose finding study
Transplantation, 1993Co-Authors: Jeanette Jacobsson, Ralf Sundberg, L A Valdivia, Thomas E. StarzlAbstract:Over the last decade, two major advances have made liver transplantation a widely applied and successful treatment of endstage liver disease. First, improvements in immunosuppression made possible by cyclosporine (1) and the recently introduced, even more powerful, immunosuppressant FK 506 (2) have reduced graft loss due to rejection. Second, a breakthrough in preservation of the liver for transplantation was recently achieved by the University of Wisconsin cold storage solution (UW)* (3). Thus, it is now possible to safely preserve a human liver for up to 24 hr (4). This has simplified the logistics in liver transplantation and also contributed to an improved quality of the organs that are transplanted. In spite of this, there is still a need for methods to further improve both the duration and the quality of preservation.
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Protective effects of the lazaroid U74500A and Lidoflazine on liver preservation with UW solution
Transplant international : official journal of the European Society for Organ Transplantation, 1993Co-Authors: Jeanette Jacobsson, Thomas E. Starzl, R. Sundberg, H. L R Rilo, A. Gasbarrini, D. H. Van ThielAbstract:The effect of adding a 21-aminosteroid, U74500A, and a Ca2+ antagonist, Lidoflazine, alone and together to UW solution was assessed in a rat liver preservation model. Following preservation, the livers were reperfused using a closed circuit, and the release of hepatocellular enzymes (ASAT, ALAT, and LDH) into the perfusate was determined with increasing time. Both drugs reduced the amount of enzymes lost from the liver. The combination of the two drugs was better than either drug alone. These data suggest that both agents may be of value in organ preservation for clinical liver transplantation.
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improvement of renal preservation by adding Lidoflazine to university of wisconsin solution an experimental study in the rat
Cryobiology, 1992Co-Authors: Jeanette Jacobsson, Bo Odlind, Gunnar Tufveson, Jan WahlbergAbstract:The purpose of this study was to investigate the possibility of improving the organ preservation properties of the University of Wisconsin (UW) solution by adding the calcium entry blocker Lidoflazine. We also investigated the possibility of decreasing the cold ischemia and reperfusion damage by pretreatment with Lidoflazine of the donor and/or recipient. The protective effects of Lidoflazine treatment were estimated by measuring the amount of trapped erythrocytes in the rat renal medulla after 48 h of cold storage, subsequent transplantation, and 20 min of reperfusion. Lidoflazine (20 mg/liter) added to the UW solution decreased the amount of erythrocyte trapping from 14.8 ± 3.1% in controls to 8.6 ± 1.7% (P < 0.01). The flow rate of the flush-out solution during the harvesting procedure was also significantly (P < 0.01). increased when Lidoflazine was included in the UW solution (1.10 ± 0.21 ml/min vs 0.75 ± 0.22 ml/min). Administration of Lidoflazine (0.28 mg/kg body wt) to the donor and/or the recipient did not further reduce the postischemia/reperfusion damage as estimated by the degree of erythrocyte trapping. In conclusion, the results indicate that the preservation properties of the UW solution can be significantly improved by adding Lidoflazine to the solution.
Thomas E. Starzl - One of the best experts on this subject based on the ideXlab platform.
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liver preservation with Lidoflazine and the university of wisconsin solution a dose finding study
Transplantation, 1993Co-Authors: Jeanette Jacobsson, Ralf Sundberg, L A Valdivia, Thomas E. StarzlAbstract:Over the last decade, two major advances have made liver transplantation a widely applied and successful treatment of endstage liver disease. First, improvements in immunosuppression made possible by cyclosporine (1) and the recently introduced, even more powerful, immunosuppressant FK 506 (2) have reduced graft loss due to rejection. Second, a breakthrough in preservation of the liver for transplantation was recently achieved by the University of Wisconsin cold storage solution (UW)* (3). Thus, it is now possible to safely preserve a human liver for up to 24 hr (4). This has simplified the logistics in liver transplantation and also contributed to an improved quality of the organs that are transplanted. In spite of this, there is still a need for methods to further improve both the duration and the quality of preservation.
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Protective effects of the lazaroid U74500A and Lidoflazine on liver preservation with UW solution
Transplant international : official journal of the European Society for Organ Transplantation, 1993Co-Authors: Jeanette Jacobsson, Thomas E. Starzl, R. Sundberg, H. L R Rilo, A. Gasbarrini, D. H. Van ThielAbstract:The effect of adding a 21-aminosteroid, U74500A, and a Ca2+ antagonist, Lidoflazine, alone and together to UW solution was assessed in a rat liver preservation model. Following preservation, the livers were reperfused using a closed circuit, and the release of hepatocellular enzymes (ASAT, ALAT, and LDH) into the perfusate was determined with increasing time. Both drugs reduced the amount of enzymes lost from the liver. The combination of the two drugs was better than either drug alone. These data suggest that both agents may be of value in organ preservation for clinical liver transplantation.