The Experts below are selected from a list of 312 Experts worldwide ranked by ideXlab platform
Henning Schröder - One of the best experts on this subject based on the ideXlab platform.
-
The Nitric Oxide Donor SIN-1 Is Free of Tolerance and Maintains Its Cyclic GMP Stimulatory Potency in Nitrate-Tolerant LLC-PK1 Cells
Pharmaceutical Research, 1999Co-Authors: Burkhard Hinz, Henning SchröderAbstract:Purpose . Using an established cell culture model, the present study investigates whether Linsidomine (SIN-1), a spontaneous donor of nitric oxide and active metabolite of the antianginal drug molsidomine, induces tolerance to its own cyclic GMP stimulatory action or shows a diminished response after tolerance induction with glyceryl trinitrate. Methods . Incubations with nitric oxide donors were carried out in LLC-PK_1, kidney epithelial cells. Intracellular levels of cyclic GMP, the vasodilatory second messenger of nitric oxide, were determined by radioimmunoassay. Results . A 5-h preincubation with glyceryl trinitrate (0.01−100 μM) led to complete inhibition of a subsequent cyclic GMP stimulation by glyceryl trinitrate but left the cyclic GMP response to SIN-1 unaltered. Similarly, cyclic GMP elevations by the spontaneous nitric oxide donors sodium nitroprusside and spermine NONOate were not affected after pretreatment with glyceryl trinitrate. Moreover, pretreatment with SIN-1 (1−1000 μM) had no significant effect on SIN-1-dependent cyclic GMP stimulation. Conclusions . Our results show that in LLC-PK_1, cells, SIN-1 is free of tolerance induction and not cross-tolerant to glyceryl trinitrate. This may be due to the spontaneous nitric oxide release from SIN-1, which in contrast to nitric acid esters does not require enzymatic bioactivation and may therefore be unaffected by nitrate tolerance.
-
The nitric oxide donor SIN-1 is free of tolerance and maintains its cyclic GMP stimulatory potency in nitrate-tolerant LLC-PK1 cells.
Pharmaceutical research, 1999Co-Authors: Burkhard Hinz, Henning SchröderAbstract:Purpose. Using an established cell culture model, the present study investigates whether Linsidomine (SIN-1), a spontaneous donor of nitric oxide and active metabolite of the antianginal drug molsidomine, induces tolerance to its own cyclic GMP stimulatory action or shows a diminished response after tolerance induction with glyceryl trinitrate.
-
Ferritin may mediate SIN-1-induced protection against oxidative stress.
Nitric oxide : biology and chemistry, 1997Co-Authors: Stefanie Oberle, Henning SchröderAbstract:Abstract In porcine aortic endothelial cells, a 20-h incubation with hydrogen peroxide (0.5 m m ) markedly reduced the number of viable cells. A 6-h preincubation with Linsidomine (SIN-1, 0.5 m m ) protected endothelial cells from hydrogen peroxide-dependent cytotoxicity and increased the surviving endothelial cell fraction by 85%. This protection was associated with a 2.5-fold induction of ferritin heavy chain mRNA and ferritin protein by SIN-1. The nitric oxide donor glyceryl trinitrate was also found to induce transcriptional and translational expression of ferritin heavy chain. A protective effect comparable to SIN-1 was observed when preincubating the cells with iron-free apoferritin (1 mg/ml). These findings suggest that ferritin induction, presumably via release of nitric oxide, may be a mechanism underlying long-term cytoprotection by SIN-1 against oxidative stress.
-
THE NITRIC OXIDE DONOR SIN-1 PROTECTS ENDOTHELIAL CELLS FROM TUMOR NECROSIS FACTOR-ALPHA -MEDIATED CYTOTOXICITY: POSSIBLE ROLE FOR CYCLIC GMP AND HEME OXYGENASE
Journal of molecular and cellular cardiology, 1997Co-Authors: Tobias Polte, Stefanie Oberle, Henning SchröderAbstract:In cultured endothelial cells, incubation with TNF-alpha (50 ng/ml) for 72 h markedly reduced viability of endothelial cells. A 6-h pre-incubation with the nitric oxide (NO) donor Linsidomine (SIN-1, 10-150 microM) protected endothelial cells in a concentration-dependent manner and increased viability by up to 59% of control. The unmetabolized parent compound molsidomine and the NO-free metabolite of SIN-1 3-morpholinoiminoacetonitrile (SIN-1C) were without cytoprotective effect. Cytoprotection by SIN-1 was completely abolished by the NO scavenger 2-phenyl-4,4,5,5, -tetramethylimidazoline-1-oxyl-3-oxide (PTIO, 30 microM). A cytoprotective effect comparable to SIN-1 was observed when preincubating the cells with dibutyryl cyclic GMP (10-100 microM). Moreover, no protection by SIN-1 occurred in the presence of cycloheximide (1 microM) or 1H--1,2,4-oxadiazole-4, 3-a-quinoxalin-1-one (ODQ, 0.1 microM), a selective inhibitor of soluble guanylyl cyclase. Tin protoporphyrin-IX (SnPP, 25 microM), an inhibitor of heme oxygenase, was found to attenuate SIN-1-induced cytoprotection. Our results demonstrate that SIN-1 produces a long-term endothelial protection against cellular injury by TNF-alpha, presumably via a cyclic GMP-dependent pathway leading to up-regulation of protective proteins such as heme oxygenase.
Udo Jonas - One of the best experts on this subject based on the ideXlab platform.
-
Effects of various nitric oxide-donating drugs on adrenergic tension of human seminal vesicles in vitro.
Urology, 2003Co-Authors: S. Machtens, Christian G. Stief, Stefan Ckert, Dimitrios Tsikas, J.rgen C Frlich, Udo JonasAbstract:Abstract Objectives To evaluate the effects of the nitric oxide (NO)-donating compounds sodium nitroprusside (SNP), S-nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteine (SNAC), S-nitroso-N-acetylcysteine-ethylester (SNACET), and Linsidomine (SIN-1) on the adrenergic tension of isolated human seminal vesicle strip preparations. The significance of the NO-cyclic guanosine monophosphate (cGMP) pathway in the regulation of smooth muscle tone in the human genitourinary tract has been well established. However, information on the significance of NO-mediated signal transduction in the functional control of the mammalian seminal vesicles is still sparse. Methods Seminal vesicle strip preparations were applied to an organ bath system under standard conditions. Tension was induced by the addition of 10 μM norepinephrine. After stable tension plateaus had been reached, the drugs were added in a cumulative manner (0.01 to 100 μM) and the isometric responses of the tissue registered. The effects of the compounds on the phasic contractility of the tissue preparations were also evaluated. The adenylyl cyclase-stimulating agent forskolin was used as a reference compound known to interfere with the cyclic adenosine monophosphate pathway. Results Adrenergic tension was dose dependently attenuated by the drugs. The rank order of potency, from greater to lesser, was GSNO, SNAC, SNP, SIN-1, forskolin, and SNACET. The rank order (from greater to lesser) with regard to the inhibitory effects of the compounds on the frequency of phasic contractions of the tissue induced by the addition of norepinephrine was GSNO, SNAC, SNP, and SIN-1; the effects of SIN-1, forskolin, and SNACET on the frequency of contractions were nearly equipotent. Conclusions Our results strongly support the hypothesis that the contractility of the human seminal vesicle is under the control of the NO-cGMP pathway. This finding may give a rationale for the use of S-nitrosothiols, such as GSNO and SNAC, in the pharmacotherapy of hyperexcitatory disturbances of ejaculation (premature ejaculation).
-
Effects of various nitric oxide donating agents on the contractility and cyclic nucleotide turnover of human seminal vesicles in vitro.
Urology, 2002Co-Authors: Olaf Heuer, Christian G. Stief, Stefan Uckert, Jürgen C. Frölich, S. Machtens, Dimitrios Tsikas, Udo JonasAbstract:Abstract Objectives. To evaluate the effects of the nitric oxide (NO)-donating drugs sodium nitroprusside, S-nitroso-glutathione (GSNO), S-nitroso-N-acetylcysteineetylester (SNACET), and Linsidomine (SIN-1), as well as the adenylyl cyclase-stimulating agent forskolin, on electrically induced contractions and on tissue levels of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) of isolated human seminal vesicle strip preparations. The significance of the l -arginine-NO-cGMP pathway in the regulation of smooth muscle tone in the human genitourinary tract has been well established; however, information on the relevance of NO-mediated signal transduction in the functional control of mammalian seminal vesicles is still sparse. Methods. Seminal vesicle strip preparations were applied to an organ bath system under standard conditions. Phasic contractions were induced by electrical field stimulation (frequency 80 Hz, amplitude 10 V, single pulse 1 ms, total pulse duration 1 second, pause 90 seconds). After stable contraction amplitudes had been reached, the drugs were added in a cumulative manner (0.001 to 10 μM), and the isometric responses were registered. After drug exposure, freezing, tissue homogenization, and extraction of cyclic nucleotides, cAMP and cGMP were measured by means of enzyme-linked immunosorbent assays. Results. Electrical field stimulation-induced amplitudes were attenuated by the drugs in a dose-dependent manner. The rank order of potency was GSNO > sodium nitroprusside > forskolin > SNACET ≥ SIN-1. The relaxing effect of GSNO was antagonized in the presence of 10 μM of guanylyl cyclase inhibitor methylene blue. The inhibitory effects of GSNO, sodium nitroprusside, and forskolin on the contractile activity were paralleled by an increase in tissue cGMP (2 to 100-fold) and cAMP (7 to 9-fold). Conclusions. Our results strongly support the hypothesis that the contractility of human seminal vesicles is in part regulated by the NO-cGMP-cascade. This may give a rationale for the use of S-nitrosothiols, such as GSNO, in the pharmacotherapy of hyperexcitatory disturbances of ejaculation.
-
Intracavernous pharmacotherapy
World Journal of Urology, 1997Co-Authors: Michael C. Truss, Armin J. Becker, Dirk Schultheiss, Udo JonasAbstract:Intracavernous application of vasoactive substances not only has enhanced our understanding of penile hemodynamics, the physiology of penile erection, and the pathophysiology of erectile dysfunction but also has revolutionized the diagnosis and treatment of erectile dysfunction in the last 15 years. Virag was the first to report on the erectile effect of papaverine in humans, and Brindley later reported the effect of intracavernous application of alpha-receptor-blocking agents on cavernous tissue. These reports led to numerous basic and clinical investigations and ultimately established a new treatment alternative for patients with erectile dysfunction that is now considered to be the treatment of choice for most patients. Changes in penile hemodynamics include the relaxation of cavernous smooth musculature and arteries, which leads to an increase in arterial blood flow and a restriction of venous outflow through a compression of subtunical veins. These hemodynamic changes are the prerequisite for the induction and maintenance of penile erection. With the intracavernous application of vasoactive substances it was possible to influence penile hemodynamics at a local level and to induce an erection despite alterations in the nervous system, penile arterial blood flow, cavernous musculature, or neurotransmitter status. In addition, the localapplication of pharmacologically active substances directly to the end organ enabled the achievement of high local drug concentrations without severe systemic side effects. The commonly used substances are papaverine, the combination of papaverine and phentolamine, and prostaglandin E1 (alprostadil). In addition to these established substances, several other regimens, such as Linsidomine (SIN-1), calcitonin gene-related peptide (CGRP), moxisylyte, and various triple- or quadruple drug mixtures have been described. In addition, several other compounds as well as different routes of administration are on the horizon and may prove to be effective in the future diagnosis and treatment of erectile dysfunction.
-
Pharmacological therapy in erectile dysfunction--current standards and new viewpoint
Wiener medizinische Wochenschrift (1946), 1997Co-Authors: Dirk Schultheiss, Michael C. Truss, Udo JonasAbstract:Intracavernous pharmacotherapy of erectile dysfunction has been established for over 10 years, with prostaglandin E1 (PGE1) being the standard substance with the lowest rate of side effects. Recent investigations deal with the identification of intracellular mechanisms of smooth muscle relaxation in cavernous tissue as the most important aspect of penile erection. Nitric oxide and specific phosphodiesterase-isoenzymes seem to play a central role. This resulted in clinical studies with the intracavernous injected nitric oxide-donor Linsidomine (SIN 1) and the orally given phosphodiesterase-inhibitor sildenafil. Furthermore new ways of pharmaco-application are tested, e.g. transdermal treatment with nitroglycerin, minoxidil or papaverine, as well as intraurethral injection of prostaglandin E1.
-
Initial Clinical Experience with the Intracavernous Application of the Nitric Oxide Donor Sin 1 in the Treatment of Patients with Erectile Dysfunction
Biochemical Pharmacological and Clinical Aspects of Nitric Oxide, 1995Co-Authors: Michael C. Truss, Armin J. Becker, Christian G. Stief, Udo JonasAbstract:Penile erection requires a series of events that includes cavernous and vascular smooth muscle relaxation, increased arterial inflow and subsequent venous outflow restriction. Recent work suggests that the initial step, cavernous and vascular smooth muscle relaxation, is mediated by the synthesis and release of nitric oxide from nerves innervating vascular and cavernous smooth muscles (Ignarro et al., 1990; Holmquist et al., 1991; Rajfer et al., 1992; Burnett et al., 1992). Therefore, the use of the L-arginine/nitric oxide pathway seems to be a possible approach in the treatment of erectile dysfunction. Linsidomine chlorhydrate (SIN-1, Corvasal intracoronaire®), the active hepatic metabolite of molsidomine (N-ethoxycarbomyl-3-morpholino- sydninimine), is believed to liberate nitric oxide nonenzymatically (nitric oxide donor). Theoretically, a nitric oxide donor may be superior to other vasoactive drugs because it may resemble more closely the physiologic sequence of events in penile erection. Our preliminary results with the intracavernous application of SIN-1 suggested a possible role in the treatment of patients with erectile dysfunction (Stief et al., 1992). We now report our extended follow up with SIN-1 in the diagnosis and treatment of patients with erectile dysfunction.
Jean Luc Dubois-randé - One of the best experts on this subject based on the ideXlab platform.
-
Sympathetic Stimulation Overrides Flow-Mediated Endothelium-Dependent Epicardial Coronary Vasodilation in Transplant Patients
Circulation, 1996Co-Authors: Eduardo Aptecar, Patrick Dupouy, Herbert J. Geschwind, Alain Castaigne, Christophe Benvenuti, Emmanuel Teiger, Daniel Loisance, Jean Luc Dubois-randéAbstract:Background Abnormal coronary vasomotor responses have been described in transplant patients. The aim of this study was to evaluate the graft epicardial vasomotor responses to different stimuli that increase coronary blood flow. Methods and Results Twelve heart transplant recipients with angiographically normal epicardial coronary arteries were compared 2.7±1.2 months after surgery with 6 control subjects. Coronary flow velocity was measured with a guidewire Doppler. Coronary diameter changes of the proximal and midportion of the left anterior descending coronary artery were assessed by quantitative coronary angiography during rapid atrial pacing, cold pressor test, supine exercise, and subselective infusion of papaverine and after intracoronary injection of Linsidomine (SIN-1). Catecholamine plasmatic levels were determined at the different stages of the protocol. In 6 other transplant patients, a cold pressor test was performed before and after intracoronary infusion of phentolamine (10 μg·kg−1·min−1). Coronary flow velocity increased significantly in both groups during each phase of the protocol. In control subjects, dilation was observed in response to atrial pacing (8.7±7.6%; P
-
Evaluation of coronary vasomotricity by intracoronary ultrasonography
Archives des maladies du coeur et des vaisseaux, 1994Co-Authors: Patrick Dupouy, Gabriel Pelle, Dominique Gallot, Geschwind H, Larrazet F, A El Ghalid, Jean Luc Dubois-randéAbstract:Coronary vasomotion dependent on the endothelium and on the smooth muscle has been intensively studied by quantitative angiography and intracoronary Doppler. Intracoronary ultrasound is a new imaging technique which allows precise measurement of the section of the coronary artery. This study was undertaken to assess the value of intracoronary ultrasound in the investigation of epicardial coronary artery vasomotion. Twenty hypercholesterolaemic patients with irregularity of the arterial lumen on angiography and 6 normo-cholesterolaemic subjects with normal coronary angiogram (control group) were included. An intracoronary ultrasonic catheter with a rotating mirror (4.3 French, CVIS) emitting at 30 MHz was positioned in the proximal segment of a coronary artery. Endothelial function was studied during sympathetic stimulation by a cold pressor test and during increased coronary flow by local injection of papaverine. The intima of the coronary arteries of the patient group was significantly thicker than that of the control group. The cold test induced significant paradoxical vasoconstriction of the atheromatous coronary arteries and a significant vasodilatation of the coronary arteries of the control group. The increased coronary flow tended to constrict the ateromatous arteries but significantly dilated the normal arteries. Administration of Linsidomine (SIN-1) induced vasodilatation by direct relaxation of the smooth muscle in both groups. No correlation was observed between the thickness of the intima measured by intracoronary ultrasound and the abnormal vasomotor response to the vasomotion different stimuli. The results of this study concord with those of studies of coronary by quantitative angiography. Intracoronary ultrasound provides an accurate method of studying coronary endothelial function and the vasomotor tone of the epicardial coronary arteries.
-
Assessment of coronary vasomotion by intracoronary ultrasound
Diagnostic and Therapeutic Cardiovascular Interventions III, 1993Co-Authors: Patrick Dupouy, Jean Luc Dubois-randé, Gabriel Pelle, Dominique Gallot, Herbert J. GeschwindAbstract:Recently, new intravascular ultrasound devices for intracoronary use became available. The aim of the study was to evaluate the accuracy of intravascular ultrasound for the assessment of coronary artery vasomotion and endothelial function in patients with atherosclerosis. Twenty patients with luminal irregularities on coronary angiogram and a high cholesterol level (287 +/- 19 mg/dl) (group 1) and 6 patients with angiographically smooth arteries and a minimally elevated cholesterol level (197 +/- 12 mg/dl) (group 2) were studied. A mechanical intravascular ultrasound probe (4.3 French, 30 MHz, Cardiovascular Imaging Systems) was placed into the proximal segment of the coronary artery. Off-line measurements of the lumen area and calculation of mean intimal thickness indice was performed using digitized ultrasound images. Endothelial function was studied during a sympathetic stimulation by a cold pressor test and after intracoronary administration of papaverine and Linsidomine. Mean intimal thickness was higher in group 1 than in group 2 (1.52 +/- 0.64 mm vs. 0.18 +/- 0.08 mm, p < 0.001). Linsidomine infusion induced a significant vasodilating effect in both groups (p < 0.001).
-
Assessment of coronary vasomotion by intracoronary ultrasound.
American heart journal, 1993Co-Authors: Patrick Dupouy, Gabriel Pelle, Dominique Gallot, Herbert J. Geschwind, Jean Luc Dubois-randéAbstract:This study was performed to evaluate the accuracy of intravascular ultrasound for the assessment of coronary artery vasomotion and endothelial function in patients with atherosclerosis. Twenty patients with luminal irregularities on the coronary angiogram and a high cholesterol level (287 ± 19 mg/dl) (group 1) and six patients with angiographically smooth arteries and a minimally elevated cholesterol level (197 ± 12 mg/dl) (group 2) were studied. A mechanical intravascular ultrasound probe (4.3F) was placed into the proximal segment of the coronary artery. The ultrasound images were recorded on super VHS videotape and were then digitized allowing the measurement of the lumen area and then the calculation of a mean intimal thickness index. Endothelial function was studied during sympathetic stimulation by a cold pressor test and, after increasing coronary blood flow, by intracoronary papaverine administration; a 1 mg bolus of Linsidomine was then administered into the coronary artery. Patients in group 1 had a higher mean intimal thickness (1.52 ± 0.64 mm) than those in group 2 (0.18 ± 0.08 mm) ( p 2 vs 11.4 ± 1.2 mm 2 at baseline, p 2 vs 10.4 ± 1.8 mm 2 at baseline, p 2 vs 11.4 ± 1.2 mm 2 at baseline, p 2 vs 8.9 ± 1.9 mm 2 , p = NS). Linsidomine infusion induced a significant vasodilating effect in both groups ( p
-
Intracoronary Linsidomine abolishes acetylcholine-induced vasoconstriction of epicardial coronary arteries
Journal of cardiovascular pharmacology, 1993Co-Authors: Jean Luc Dubois-randé, Patrick Dupouy, Herbert J. Geschwind, Alain Castaigne, Serge AdnotAbstract:If the vasodilation of the epicardial coronary arteries caused by Linsidomine (SIN-1), the active metabolite of molsidomine, is well established, few data are available concerning the effects of SIN-1 on the acetylcholine (ACh)-induced vasoconstriction of epicardial coronary arteries. Fourteen patients with mild lesions of the left anterior descending artery (LAD) were studied. Intracoronary blood flow velocity was measured by a Doppler probe placed in the proximal segment of the LAD, and cross-sectional arterial area was assessed by quantitative angiography. After initial hemodynamic parameters were measured, 12 mg papaverine was injected into the left main coronary artery. When hemodynamic parameters returned to baseline values, three increasing concentrations of ACh (5 x 10(-7), 10(-6), and 5 x 10(-6) M) were selectively administered into the LAD in a 3 min period for each concentration. While the infusion of ACh 5 x 10(-6) M was continued, 1 mg SIN-1 was injected as a bolus in the ostium of the left coronary artery. After the injection of papaverine, blood flow increased by 197 +/- 8%, with a trend toward vasoconstriction of the proximal and distal segments of the LAD (p = NS). The ACh injection induced a dose-dependent vasoconstriction, reaching 51 +/- 20% on the distal segment of the LAD at the maximum concentration (p < 0.001). After an initial increase in coronary blood flow of 47 +/- 10 and 28 +/- 11% during the first two concentrations of ACh, respectively, the values decreased after the last injection to the level of baseline values. The infusion of SIN-1 antagonized the ACh-induced vasoconstriction, leading to vasodilation of 7.5 +/- 3% (p < 0.005) and 16 +/- 7% (p < 0.001) of the proximal and distal segments of the LAD, respectively; this was associated with an increase in intracoronary blood flow by 42 +/- 8%. We conclude that intracoronary administration of SIN-1 can antagonize the ACh-induced vasoconstriction of epicardial coronary arteries.
J. Delonca - One of the best experts on this subject based on the ideXlab platform.
-
Comparative efficacy of the intravenous administration of Linsidomine, a direct nitric oxide donor, and isosorbide dinitrate in severe unstable angina A French multicentre study
European heart journal, 1997Co-Authors: J. Delonca, T. Giraud, P. Beaufils, B. Dupuis, R. Haïat, C. ThéryAbstract:Aims Although Linsidomine shares common properties with nitrovasodilators, it releases nitric oxide directly without catalytic involvement by thiols. We conducted a prospective, randomized, multicentre, parallel group, single-blind study to compare the efficacy of intravenous administration of Linsidomine with that of isosorbide dinitrate in unstable angina. Methods and results Between November 1990 and July 1992, 568 patients with suspected unstable angina (class IIIB of the Braunwald classification) received a continuous infusion of either Linsidomine (1 mg.h−1 on average) or isosorbide dinitrate (2·5 mg. h−1 on average) for 72 h. All patients received concomitant aspirin and intravenous heparin, 81% beta-blockers and 38% calcium antagonists. Holter monitoring was performed in all patients and analysed blindly. Only 25% of the patients had at least one episode of chest pain during the study (24·6% vs 25·8% in the Linsidomine and isosorbide dinitrate groups, P =0·74), of which 12% were associated with ECG changes. Holter criteria yielded similar results in both groups: 33% of patients presented episodes of myocardial ischaemia (32·6% vs 33·9% in the Linsidomine and isosorbide dinitrate groups, P =0·74), while 45% showed episodes of ventricular arrhythmia (43·5% vs 46·5% in the Linsidomine and isosorbide dinitrate groups, P =0·48). The incidence of serious clinical events at 72 h (death, myocardial infarction or myocardial revascularization) was 6·5% (5% vs 8% in the Linsidomine and isosorbide dinitrate groups, P =0·17). Conclusion Intravenous Linsidomine is at least as efficacious as isosorbide dinitrate in the stabilization of patients with severe unstable angina.
-
Linsidomine direct donor of edrf no a new treatment for unstable angina
Archives Des Maladies Du Coeur Et Des Vaisseaux, 1996Co-Authors: J. Delonca, T. Giraud, E. Lennuyeux, O. CharansonneyAbstract:Linsidomine 10 mg, administered intravenously, has become available for the treatment of unstable angina since the beginning of 1996. It reinforces a range which consists of oral molsidomine, 2 and 4 mg, and the 1 mg intracoronary Linsidomine dosage, thereby providing a more complete management of symptomatic coronary patients. Linsidomine is a direct donor of EDRF/NO which has an action on blood vessels (reduction of preload and dilatation of the large epicardial coronary vessels) and on platelets (inhibition of aggregation) without risk of tolerance. Linsidomine was compared with parenteral isosorbide dinitrate in a large scale French trial in patients with severe unstable angina (Braunwald's Class IIIb). The results showed Linsidomine to be an effective treatment of unstable angina, controlling 75% of patients with a low incidence of severe clinical events (death, myocardial infarction, emergency myocardial revascularisation). In addition, intravenous Linsidomine was well tolerated clinically, especially in terms of symptomatic hypotension.
-
Linsidomine, direct donor of EDRF/NO: a new treatment for unstable angina
Archives des maladies du coeur et des vaisseaux, 1996Co-Authors: J. Delonca, T. Giraud, E. Lennuyeux, O. CharansonneyAbstract:Linsidomine 10 mg, administered intravenously, has become available for the treatment of unstable angina since the beginning of 1996. It reinforces a range which consists of oral molsidomine, 2 and 4 mg, and the 1 mg intracoronary Linsidomine dosage, thereby providing a more complete management of symptomatic coronary patients. Linsidomine is a direct donor of EDRF/NO which has an action on blood vessels (reduction of preload and dilatation of the large epicardial coronary vessels) and on platelets (inhibition of aggregation) without risk of tolerance. Linsidomine was compared with parenteral isosorbide dinitrate in a large scale French trial in patients with severe unstable angina (Braunwald's Class IIIb). The results showed Linsidomine to be an effective treatment of unstable angina, controlling 75% of patients with a low incidence of severe clinical events (death, myocardial infarction, emergency myocardial revascularisation). In addition, intravenous Linsidomine was well tolerated clinically, especially in terms of symptomatic hypotension.
-
Linsidomine donneur direct d edrf no un nouveau traitement de l angor instable
Archives Des Maladies Du Coeur Et Des Vaisseaux, 1996Co-Authors: J. Delonca, T. Giraud, E. Lennuyeux, O. CharansonneyAbstract:La Linsidomine, dosee a 10 mg et administree par vole Intraveineuse, a ete mise a la disposition du corps medical au debut de l'annee 1996 dans le traitement de l'angor Instable. Elle vient renforcer une gamme qui comporte la molsidomine per os, dosee a 2 et 4 mg, et la Linsidomine administree par vole intracoronaire, dosee a 1 mg, permettant ainsi une prise en charge plus complete des patients coronariens symptomatiques. La Linsidomine est un donneur direct d'EDRF/N0 qui possede une action vasculaire (reduction de la precharge et dilatation des gros troncs coronaires epicardiques) et plaquettaire (inhibition de l'agregation), sans risque d'echappement therapeutique. La Linsidomine a ete comparee au dinitrate d'isosorbide injectable dans une grande etude d'equivalence francaise, chez des patients en angor Instable severe (classe III B de la classification de Braunwald). Les resultats de cette etude indiquent que la Linsidomine est un traitement efficace de l'angor instable, puisqu'elle permet de controler plus de 75 % des patients, avec une Incidence faible d'evenements cliniques graves (deces, infarctus du myocarde, revascularisation myocardlque en urgence). Par ailleurs la Linsidomine administree par vole intraveineuse presente une bonne tolerance clinique, en particulier en termes d'hypotension symptomatique.
-
Hemodynamics, tolerability, and pharmacokinetics of Linsidomine (SIN-1) infusion during the acute phase of uncomplicated myocardial infarction.
Journal of cardiovascular pharmacology, 1993Co-Authors: A Foucher-lavergne, J. Delonca, H. Kolsky, O Spreux-varoquaux, Ph BeaufilsAbstract:To determine a dose regimen and evaluate the hemodynamic effects of Linsidomine administered by continuous intravenous (i.v.) infusion, 10 patients were studied during the acute phase of uncomplicated myocardial infarction (MI). Systolic, diastolic, and mean (SBP, DBP, MBP) systemic blood pressure and heart rate (HR) were measured noninvasively. Pulmonary artery pressures were monitored after insertion of a Swan-Ganz catheter, which also enabled measurement of cardiac output (CO) and cardiac index (CI) by thermodilution. After baseline hemodynamic values (period A) were determined, Linsidomine (SIN-1) was infused at a rate of 0.8 mg/h and subsequently adjusted to obtain a 10% decrease in MBP from its baseline value (period B). The infusion was then continued for 3 h at a constant rate (period C), and pressures were monitored for 1 h after the infusion was discontinued (period D). There were no significant changes in systemic or pulmonary arterial pressures or in HR between period B and period C. In contrast, CI decreased moderately (p < 0.05), with no clinical consequences. Return to baseline hemodynamics was obtained at the end of period D. Our findings indicate that continuous i.v. administration of SIN-1 (at a mean flow rate of 1 mg/h) is well tolerated and appears to be suitable for use in acute coronary syndromes.
Michael C. Truss - One of the best experts on this subject based on the ideXlab platform.
-
ADULT UROLOGY ROLE OF THE NITRIC OXIDE DONOR Linsidomine CHLORHYDRATE (SIN-l) IN THE DIAGNOSIS AND TREATMENT OF ERECTILE DYSFUNCTION*
2015Co-Authors: Michael C. Truss, Armin J. Becker, Mohamad H. Djamilian, Christian Stiee G. M. DAbstract:ABSTRACT--Objectives. Recently, nitric oxide was shown to be a mediator of penile erection in men and the nitric oxide donor Linsidomine chlorhydrate (StN-1) was intro-duced as a novel treatment option i patients with erectile dysfunction. We now present our follow-up results with the intracavernous application of SIN-1. Methods. One hundred thirteen patients with erectile dysfunction of various etiologies and 10 normal control subjects underwent intracavernous pharmacotesting with 1 mg SIN-1. Of the 113 patients, 71 (62.8%) underwent additional pharmacotesting with a mixture of papaverine (15 mg/mL) and phentolamine (0.5 mg/mL) (P/P). Forty-eight re-sponders to SIN-1 were enrolled in an autoinjection program with this substance. Results. All normal control subjects had full rigid erections lasting 40 to 70 minutes. Of 113 patients, 78 (69%) had responses sufficient for intercourse with SIN-l, and the other 35 patients (31%) demonstrated inadequate responses. All 44 responders to SIN-1 who also received P/P had erections sufficient for intercourse with P/P in doses of 0.25 to 2 mL (mean, 0.6 + 0.3 mL). Six patients (13.6%) had prolonged erections with minimal to moderate doses of P/P. From the total of 27 patients who had erections insufficient fo
-
in vitro functional responses of isolated normal human prostatic tissue to compounds interacting with the cyclic guanosine monophosphate pathway
Urology, 2006Co-Authors: G T Kedia, Stefan Uckert, Friedemann Scheller, T Chigogidze, L Managadze, U Jonas, Michael C. TrussAbstract:Abstract Objectives To examine the effects of some nitric oxide-donating agents, as well as the C-type natriuretic peptide (CNP), on isolated human prostatic tissue. To date, guanylyl cyclases and cyclic guanosine monophosphate (cGMP)-degrading phosphodiesterases represent important target proteins for the development of new drugs for the treatment of lower urinary tract symptoms and benign prostatic hyperplasia. Methods Using the organ bath technique, the effects of sodium nitroprusside, S-nitrosoglutathione, S-nitrosocysteine, Linsidomine, and CNP (1 nM to 1.0/10 μM) on the tension induced by norepinephrine of prostatic tissue strips were investigated. The tissue was also exposed to three different concentrations of the drugs, and the production of cGMP and cyclic adenosine monophosphate (cAMP) was determined. Results The tension induced by 40 μM norepinephrine of the isolated prostatic tissue was dose dependently reversed by the drugs. The rank order of potency was sodium nitroprusside more than S-nitrosoglutathione more than Linsidomine more than S-nitrosocysteine, which was equal to CNP (1 μM). The reversal of tension induced by the greatest drug concentrations ranged from 50% relaxation with sodium nitroprusside to 42% relaxation with CNP. The relaxing effects of the drugs were paralleled by a 2-fold to 40-fold and 2-fold to 45-fold increase in tissue levels of cAMP and cGMP, respectively. Conclusions Our results provide further evidence that cGMP and cAMP are involved in the control of the normal function of human prostatic smooth muscle. Our findings may provide new strategies for future therapeutics used in the treatment of lower urinary tract symptoms and bladder outlet obstruction secondary to benign prostatic hyperplasia.
-
Intracavernous pharmacotherapy
World Journal of Urology, 1997Co-Authors: Michael C. Truss, Armin J. Becker, Dirk Schultheiss, Udo JonasAbstract:Intracavernous application of vasoactive substances not only has enhanced our understanding of penile hemodynamics, the physiology of penile erection, and the pathophysiology of erectile dysfunction but also has revolutionized the diagnosis and treatment of erectile dysfunction in the last 15 years. Virag was the first to report on the erectile effect of papaverine in humans, and Brindley later reported the effect of intracavernous application of alpha-receptor-blocking agents on cavernous tissue. These reports led to numerous basic and clinical investigations and ultimately established a new treatment alternative for patients with erectile dysfunction that is now considered to be the treatment of choice for most patients. Changes in penile hemodynamics include the relaxation of cavernous smooth musculature and arteries, which leads to an increase in arterial blood flow and a restriction of venous outflow through a compression of subtunical veins. These hemodynamic changes are the prerequisite for the induction and maintenance of penile erection. With the intracavernous application of vasoactive substances it was possible to influence penile hemodynamics at a local level and to induce an erection despite alterations in the nervous system, penile arterial blood flow, cavernous musculature, or neurotransmitter status. In addition, the localapplication of pharmacologically active substances directly to the end organ enabled the achievement of high local drug concentrations without severe systemic side effects. The commonly used substances are papaverine, the combination of papaverine and phentolamine, and prostaglandin E1 (alprostadil). In addition to these established substances, several other regimens, such as Linsidomine (SIN-1), calcitonin gene-related peptide (CGRP), moxisylyte, and various triple- or quadruple drug mixtures have been described. In addition, several other compounds as well as different routes of administration are on the horizon and may prove to be effective in the future diagnosis and treatment of erectile dysfunction.
-
Pharmacological therapy in erectile dysfunction--current standards and new viewpoint
Wiener medizinische Wochenschrift (1946), 1997Co-Authors: Dirk Schultheiss, Michael C. Truss, Udo JonasAbstract:Intracavernous pharmacotherapy of erectile dysfunction has been established for over 10 years, with prostaglandin E1 (PGE1) being the standard substance with the lowest rate of side effects. Recent investigations deal with the identification of intracellular mechanisms of smooth muscle relaxation in cavernous tissue as the most important aspect of penile erection. Nitric oxide and specific phosphodiesterase-isoenzymes seem to play a central role. This resulted in clinical studies with the intracavernous injected nitric oxide-donor Linsidomine (SIN 1) and the orally given phosphodiesterase-inhibitor sildenafil. Furthermore new ways of pharmaco-application are tested, e.g. transdermal treatment with nitroglycerin, minoxidil or papaverine, as well as intraurethral injection of prostaglandin E1.
-
A possible role for nitric oxide in the regulation of human ureteral smooth muscle tone in vitro
Urological Research, 1996Co-Authors: C. G. Stief, Michael C. Truss, S. Ückert, A. J. Becker, S. Machtens, U JonasAbstract:There is ample evidence that nitric oxide (NO) is an important neurotransmitter in many tissues of the urogenital tract. The aim of the present study was to examine the possible role of NO in ureteral relaxation. Human ureteral rings were mounted in organ bath chambers and precontracted with KCl. Increasing doses of the NO donor Linsidomine (SIN-1) were added with and without prior blockade of the NO/cGMP pathway by methylene blue and protein kinase (PK) inhibitors Rp-8-pCPT-cGMPS and Rp-8-CPT-cAMPS. Electrical field stimulation (EFS) was done before and after incubation with L -NOARD ( N ^G-nitro- L -arginine) and TTX (tetratodoxin). For detection of neuronal NO synthase (NOS), ureters were stained immunohistochemically. Ureteral strips were dose dependently relaxed by SIN-1; preincubation with methylene blue and protein kinase G inhibitor significantly reduced the SIN-1-induced relaxations. No effects of L -NOARG and TTX on EFS-induced tone alterations were found. NOS-positive neuronal axons and nerve-ending-like structures were found in the muscular layers. Our in vitro findings suggest that ureteral relaxation may involve the NO pathway.