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I R Johnson - One of the best experts on this subject based on the ideXlab platform.
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the haemodynamic actions of zeneca zd7288 a novel sino atrial node function modulator in the exercising beagle a comparison with zatebradine and Propranolol
British Journal of Pharmacology, 1994Co-Authors: W Rouse, P J Stafford, I R JohnsonAbstract:1 ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICID7288) is a novel sino-atrial node function modulator which selectively slows heart rate. 2 The haemodynamic effects of ZD7288 (0.1, 0.3 and 1.0 mg kg−1, i.v.) have been evaluated and compared with those of placebo (physiological saline), zatebradine (ULFS 49, 0.1, 0.3 and 1.0 mg kg−1, i.v.) and propanolol (0.03, 0.1, and 0.3 mg kg−1, i.v.) in beagles chronically instrumented for measurement of heart rate, aortic pressure, aortic flow and dPLV/dtmax. The dogs were trained to run at 6.5 k h−1 on a level treadmill for 5 min at half hourly intervals over a period of 4 h. Drugs were dosed cumulatively after the second, fourth and sixth exercise periods. 3 Control experiments demonstrated a degree of accommodation to repeated exercise over a period of 4 h. Resting heart rate decreased by 21 beats min−1, but heart rate response to exercise was maintained, whereas dPLV/dtmax at rest remained steady while the response to exercise decreased significantly (by 25% after 2 h, P < 0.05). 4 ZD7288 and zatebradine both decreased heart rate during exercise in a dose-dependent manner, whilst heart rate at rest did not differ from resting heart rates in saline dosed control animals. In contrast, heart rate at rest and during exercise were lowered equally by the lowest doses of Propranolol (approximately by 30 beats min−1), and additional doses caused only minor additional decreases. The exercise-induced tachycardia was maintained within 12% of pre-dose levels, presumably by withdrawal of vagal tone. 5 Cardiac inotropism, as indicated by dPLV/dtmax, was not affected by ZD7288 or zatebradine at rest, although the inotropic response to exercise decreased in proportion to the decreases in exercise-induced tachycardia. Propranolol caused a marked dose-dependent decrease in the exercise-induced inotropic response (by 85% at 0.3 mg kg−1). 6 Whilst the sino-atrial node modulators increased stroke volume at rest, and augmented increases in response to exercise, Propranolol did not affect resting stroke volume and decreased the responses to exercise. 7 Cardiac output at rest and cardiac output increases during exercise were well maintained in the presence of ZD7288 and zatebradine in contrast to Propranolol which induced a significant depression of cardiac output, both at rest and during exercise. Propranolol also caused significant systemic vasoconstriction. 8 In conclusion, ZD7288 has haemodynamic actions comparable to those of zatebradine despite their chemical dissimilarity. ZD7288 may be of benefit in the treatment of ischaemic heart disease by reducing heart rate without impairing cardiac function.
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The haemodynamic actions of ZENECA ZD7288, a novel sino‐atrial node function modulator, in the exercising beagle: a comparison with zatebradine and Propranolol
British Journal of Pharmacology, 1994Co-Authors: W Rouse, P J Stafford, I R JohnsonAbstract:1 ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICID7288) is a novel sino-atrial node function modulator which selectively slows heart rate. 2 The haemodynamic effects of ZD7288 (0.1, 0.3 and 1.0 mg kg−1, i.v.) have been evaluated and compared with those of placebo (physiological saline), zatebradine (ULFS 49, 0.1, 0.3 and 1.0 mg kg−1, i.v.) and propanolol (0.03, 0.1, and 0.3 mg kg−1, i.v.) in beagles chronically instrumented for measurement of heart rate, aortic pressure, aortic flow and dPLV/dtmax. The dogs were trained to run at 6.5 k h−1 on a level treadmill for 5 min at half hourly intervals over a period of 4 h. Drugs were dosed cumulatively after the second, fourth and sixth exercise periods. 3 Control experiments demonstrated a degree of accommodation to repeated exercise over a period of 4 h. Resting heart rate decreased by 21 beats min−1, but heart rate response to exercise was maintained, whereas dPLV/dtmax at rest remained steady while the response to exercise decreased significantly (by 25% after 2 h, P < 0.05). 4 ZD7288 and zatebradine both decreased heart rate during exercise in a dose-dependent manner, whilst heart rate at rest did not differ from resting heart rates in saline dosed control animals. In contrast, heart rate at rest and during exercise were lowered equally by the lowest doses of Propranolol (approximately by 30 beats min−1), and additional doses caused only minor additional decreases. The exercise-induced tachycardia was maintained within 12% of pre-dose levels, presumably by withdrawal of vagal tone. 5 Cardiac inotropism, as indicated by dPLV/dtmax, was not affected by ZD7288 or zatebradine at rest, although the inotropic response to exercise decreased in proportion to the decreases in exercise-induced tachycardia. Propranolol caused a marked dose-dependent decrease in the exercise-induced inotropic response (by 85% at 0.3 mg kg−1). 6 Whilst the sino-atrial node modulators increased stroke volume at rest, and augmented increases in response to exercise, Propranolol did not affect resting stroke volume and decreased the responses to exercise. 7 Cardiac output at rest and cardiac output increases during exercise were well maintained in the presence of ZD7288 and zatebradine in contrast to Propranolol which induced a significant depression of cardiac output, both at rest and during exercise. Propranolol also caused significant systemic vasoconstriction. 8 In conclusion, ZD7288 has haemodynamic actions comparable to those of zatebradine despite their chemical dissimilarity. ZD7288 may be of benefit in the treatment of ischaemic heart disease by reducing heart rate without impairing cardiac function.
W Rouse - One of the best experts on this subject based on the ideXlab platform.
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the haemodynamic actions of zeneca zd7288 a novel sino atrial node function modulator in the exercising beagle a comparison with zatebradine and Propranolol
British Journal of Pharmacology, 1994Co-Authors: W Rouse, P J Stafford, I R JohnsonAbstract:1 ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICID7288) is a novel sino-atrial node function modulator which selectively slows heart rate. 2 The haemodynamic effects of ZD7288 (0.1, 0.3 and 1.0 mg kg−1, i.v.) have been evaluated and compared with those of placebo (physiological saline), zatebradine (ULFS 49, 0.1, 0.3 and 1.0 mg kg−1, i.v.) and propanolol (0.03, 0.1, and 0.3 mg kg−1, i.v.) in beagles chronically instrumented for measurement of heart rate, aortic pressure, aortic flow and dPLV/dtmax. The dogs were trained to run at 6.5 k h−1 on a level treadmill for 5 min at half hourly intervals over a period of 4 h. Drugs were dosed cumulatively after the second, fourth and sixth exercise periods. 3 Control experiments demonstrated a degree of accommodation to repeated exercise over a period of 4 h. Resting heart rate decreased by 21 beats min−1, but heart rate response to exercise was maintained, whereas dPLV/dtmax at rest remained steady while the response to exercise decreased significantly (by 25% after 2 h, P < 0.05). 4 ZD7288 and zatebradine both decreased heart rate during exercise in a dose-dependent manner, whilst heart rate at rest did not differ from resting heart rates in saline dosed control animals. In contrast, heart rate at rest and during exercise were lowered equally by the lowest doses of Propranolol (approximately by 30 beats min−1), and additional doses caused only minor additional decreases. The exercise-induced tachycardia was maintained within 12% of pre-dose levels, presumably by withdrawal of vagal tone. 5 Cardiac inotropism, as indicated by dPLV/dtmax, was not affected by ZD7288 or zatebradine at rest, although the inotropic response to exercise decreased in proportion to the decreases in exercise-induced tachycardia. Propranolol caused a marked dose-dependent decrease in the exercise-induced inotropic response (by 85% at 0.3 mg kg−1). 6 Whilst the sino-atrial node modulators increased stroke volume at rest, and augmented increases in response to exercise, Propranolol did not affect resting stroke volume and decreased the responses to exercise. 7 Cardiac output at rest and cardiac output increases during exercise were well maintained in the presence of ZD7288 and zatebradine in contrast to Propranolol which induced a significant depression of cardiac output, both at rest and during exercise. Propranolol also caused significant systemic vasoconstriction. 8 In conclusion, ZD7288 has haemodynamic actions comparable to those of zatebradine despite their chemical dissimilarity. ZD7288 may be of benefit in the treatment of ischaemic heart disease by reducing heart rate without impairing cardiac function.
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The haemodynamic actions of ZENECA ZD7288, a novel sino‐atrial node function modulator, in the exercising beagle: a comparison with zatebradine and Propranolol
British Journal of Pharmacology, 1994Co-Authors: W Rouse, P J Stafford, I R JohnsonAbstract:1 ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICID7288) is a novel sino-atrial node function modulator which selectively slows heart rate. 2 The haemodynamic effects of ZD7288 (0.1, 0.3 and 1.0 mg kg−1, i.v.) have been evaluated and compared with those of placebo (physiological saline), zatebradine (ULFS 49, 0.1, 0.3 and 1.0 mg kg−1, i.v.) and propanolol (0.03, 0.1, and 0.3 mg kg−1, i.v.) in beagles chronically instrumented for measurement of heart rate, aortic pressure, aortic flow and dPLV/dtmax. The dogs were trained to run at 6.5 k h−1 on a level treadmill for 5 min at half hourly intervals over a period of 4 h. Drugs were dosed cumulatively after the second, fourth and sixth exercise periods. 3 Control experiments demonstrated a degree of accommodation to repeated exercise over a period of 4 h. Resting heart rate decreased by 21 beats min−1, but heart rate response to exercise was maintained, whereas dPLV/dtmax at rest remained steady while the response to exercise decreased significantly (by 25% after 2 h, P < 0.05). 4 ZD7288 and zatebradine both decreased heart rate during exercise in a dose-dependent manner, whilst heart rate at rest did not differ from resting heart rates in saline dosed control animals. In contrast, heart rate at rest and during exercise were lowered equally by the lowest doses of Propranolol (approximately by 30 beats min−1), and additional doses caused only minor additional decreases. The exercise-induced tachycardia was maintained within 12% of pre-dose levels, presumably by withdrawal of vagal tone. 5 Cardiac inotropism, as indicated by dPLV/dtmax, was not affected by ZD7288 or zatebradine at rest, although the inotropic response to exercise decreased in proportion to the decreases in exercise-induced tachycardia. Propranolol caused a marked dose-dependent decrease in the exercise-induced inotropic response (by 85% at 0.3 mg kg−1). 6 Whilst the sino-atrial node modulators increased stroke volume at rest, and augmented increases in response to exercise, Propranolol did not affect resting stroke volume and decreased the responses to exercise. 7 Cardiac output at rest and cardiac output increases during exercise were well maintained in the presence of ZD7288 and zatebradine in contrast to Propranolol which induced a significant depression of cardiac output, both at rest and during exercise. Propranolol also caused significant systemic vasoconstriction. 8 In conclusion, ZD7288 has haemodynamic actions comparable to those of zatebradine despite their chemical dissimilarity. ZD7288 may be of benefit in the treatment of ischaemic heart disease by reducing heart rate without impairing cardiac function.
P J Stafford - One of the best experts on this subject based on the ideXlab platform.
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the haemodynamic actions of zeneca zd7288 a novel sino atrial node function modulator in the exercising beagle a comparison with zatebradine and Propranolol
British Journal of Pharmacology, 1994Co-Authors: W Rouse, P J Stafford, I R JohnsonAbstract:1 ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICID7288) is a novel sino-atrial node function modulator which selectively slows heart rate. 2 The haemodynamic effects of ZD7288 (0.1, 0.3 and 1.0 mg kg−1, i.v.) have been evaluated and compared with those of placebo (physiological saline), zatebradine (ULFS 49, 0.1, 0.3 and 1.0 mg kg−1, i.v.) and propanolol (0.03, 0.1, and 0.3 mg kg−1, i.v.) in beagles chronically instrumented for measurement of heart rate, aortic pressure, aortic flow and dPLV/dtmax. The dogs were trained to run at 6.5 k h−1 on a level treadmill for 5 min at half hourly intervals over a period of 4 h. Drugs were dosed cumulatively after the second, fourth and sixth exercise periods. 3 Control experiments demonstrated a degree of accommodation to repeated exercise over a period of 4 h. Resting heart rate decreased by 21 beats min−1, but heart rate response to exercise was maintained, whereas dPLV/dtmax at rest remained steady while the response to exercise decreased significantly (by 25% after 2 h, P < 0.05). 4 ZD7288 and zatebradine both decreased heart rate during exercise in a dose-dependent manner, whilst heart rate at rest did not differ from resting heart rates in saline dosed control animals. In contrast, heart rate at rest and during exercise were lowered equally by the lowest doses of Propranolol (approximately by 30 beats min−1), and additional doses caused only minor additional decreases. The exercise-induced tachycardia was maintained within 12% of pre-dose levels, presumably by withdrawal of vagal tone. 5 Cardiac inotropism, as indicated by dPLV/dtmax, was not affected by ZD7288 or zatebradine at rest, although the inotropic response to exercise decreased in proportion to the decreases in exercise-induced tachycardia. Propranolol caused a marked dose-dependent decrease in the exercise-induced inotropic response (by 85% at 0.3 mg kg−1). 6 Whilst the sino-atrial node modulators increased stroke volume at rest, and augmented increases in response to exercise, Propranolol did not affect resting stroke volume and decreased the responses to exercise. 7 Cardiac output at rest and cardiac output increases during exercise were well maintained in the presence of ZD7288 and zatebradine in contrast to Propranolol which induced a significant depression of cardiac output, both at rest and during exercise. Propranolol also caused significant systemic vasoconstriction. 8 In conclusion, ZD7288 has haemodynamic actions comparable to those of zatebradine despite their chemical dissimilarity. ZD7288 may be of benefit in the treatment of ischaemic heart disease by reducing heart rate without impairing cardiac function.
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The haemodynamic actions of ZENECA ZD7288, a novel sino‐atrial node function modulator, in the exercising beagle: a comparison with zatebradine and Propranolol
British Journal of Pharmacology, 1994Co-Authors: W Rouse, P J Stafford, I R JohnsonAbstract:1 ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICID7288) is a novel sino-atrial node function modulator which selectively slows heart rate. 2 The haemodynamic effects of ZD7288 (0.1, 0.3 and 1.0 mg kg−1, i.v.) have been evaluated and compared with those of placebo (physiological saline), zatebradine (ULFS 49, 0.1, 0.3 and 1.0 mg kg−1, i.v.) and propanolol (0.03, 0.1, and 0.3 mg kg−1, i.v.) in beagles chronically instrumented for measurement of heart rate, aortic pressure, aortic flow and dPLV/dtmax. The dogs were trained to run at 6.5 k h−1 on a level treadmill for 5 min at half hourly intervals over a period of 4 h. Drugs were dosed cumulatively after the second, fourth and sixth exercise periods. 3 Control experiments demonstrated a degree of accommodation to repeated exercise over a period of 4 h. Resting heart rate decreased by 21 beats min−1, but heart rate response to exercise was maintained, whereas dPLV/dtmax at rest remained steady while the response to exercise decreased significantly (by 25% after 2 h, P < 0.05). 4 ZD7288 and zatebradine both decreased heart rate during exercise in a dose-dependent manner, whilst heart rate at rest did not differ from resting heart rates in saline dosed control animals. In contrast, heart rate at rest and during exercise were lowered equally by the lowest doses of Propranolol (approximately by 30 beats min−1), and additional doses caused only minor additional decreases. The exercise-induced tachycardia was maintained within 12% of pre-dose levels, presumably by withdrawal of vagal tone. 5 Cardiac inotropism, as indicated by dPLV/dtmax, was not affected by ZD7288 or zatebradine at rest, although the inotropic response to exercise decreased in proportion to the decreases in exercise-induced tachycardia. Propranolol caused a marked dose-dependent decrease in the exercise-induced inotropic response (by 85% at 0.3 mg kg−1). 6 Whilst the sino-atrial node modulators increased stroke volume at rest, and augmented increases in response to exercise, Propranolol did not affect resting stroke volume and decreased the responses to exercise. 7 Cardiac output at rest and cardiac output increases during exercise were well maintained in the presence of ZD7288 and zatebradine in contrast to Propranolol which induced a significant depression of cardiac output, both at rest and during exercise. Propranolol also caused significant systemic vasoconstriction. 8 In conclusion, ZD7288 has haemodynamic actions comparable to those of zatebradine despite their chemical dissimilarity. ZD7288 may be of benefit in the treatment of ischaemic heart disease by reducing heart rate without impairing cardiac function.
André Grimaldi - One of the best experts on this subject based on the ideXlab platform.
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Propranolol in hypoglycaemia unawareness.
Diabetes & metabolism, 1999Co-Authors: S Chalon, Ivan Berlin, C Sachon, F. Bosquet, André GrimaldiAbstract:Propranolol dans l'hypoglycemie non ressentie Objectif: Evaluer l'effet du Propranolol a faibles doses sur l'apparition des symptomes d'hypoglycemie chez les diabetiques insulino-dependants ne percevant pas les hypoglycemies. Plan experimental: Etude randomisee Propranolol versus placebo (2:1), en double aveugle et groupes paralleles, sur 4 semaines. Le groupe Propranolol (N = 9) recevait 20 mg (semaine 1-2) puis 30 mg (semaine 3-4) matin et soir. L'autre groupe (N = 5) recevait du placebo pendant 4 semaines. Principaux criteres d'inclusion: au moins 2 episodes d'hypoglycemie severe (coma ou convulsions avec recours a une tierce personne) et absence de symptome adrenergique d'hypoglycemie. Resultats: Le nombre moyen d'hypoglycemie sur la duree totale de l'essai etait comparable dans les 2 groupes (placebo: 13 ± 2, Propranolol: 11 ± 1), le nombre d'hypoglycemies (< 0.6 g/l) asymptomatiques etait plus faible sous Propranolol (3 ± 1) que sous placebo (8 ± 3, NS) tandis que le nombre d'hypoglycemies symptomatiques etait plus eleve (7.2 ± 2 contre 4.6 + 1, NS). L'evaluation subjective des benefices lies au traitement par les investigateurs, montrait 0 succes/5 dans le groupe placebo et 5/9 dans le groupe Propranolol (Chi2 = 4.32, p = 0.038). L'avantage du Propranolol sur le placebo etait essentiellement du a l'apparition plus frequente des sueurs: le rapport [nombre d'hypoglycemies avec sueurs/nombre total d'hypoglycemies] etait augmente sous Propranolol (0.28 ± 0.08 contre 0.06 ± 0.02, p = 0.06). Conclusion. Cette etude pilote suggere un effet benefique du Propranolol a faibles doses chez les diabetiques insulino-dependants ne ressentant pas les symptomes d'hypoglycemie. Les resultats indiquent que le Propranolol pourrait agir en augmentant l'incidence des sueurs provoquees par l'hypoglycemie. Une etude portant sur des effectifs plus importants devrait confirmer ou infirmer ces resultats preliminaires.
Jose Luis Calleja - One of the best experts on this subject based on the ideXlab platform.
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Propranolol plus placebo versus Propranolol plus isosorbide 5 mononitrate in the prevention of a first variceal bleed a double blind rct
Hepatology, 2003Co-Authors: M Juan Carlos D Garciapagan, Rafael Banares, Agustin Albillos, R Morillas, C Villanueva, Carme Vila, Joan Genesca, M Jimenez, Manuel S Rodriguez, Jose Luis CallejaAbstract:Abstract Nonselective β-blockers are very effective in preventing first variceal bleeding in patients with cirrhosis. Treatment with isosorbide-5-mononitrate (IS-MN) plus Propranolol achieves a greater reduction in portal pressure than Propranolol alone. The present multicenter, prospective, double-blind, randomized, controlled trial evaluated whether combined drug therapy could be more effective than Propranolol alone in preventing variceal bleeding. A total of 349 consecutive cirrhotic patients with gastroesophageal varices were randomized to receive Propranolol + placebo (n = 174) or Propranolol + IS-MN (n = 175). There were no significant differences in the 1- and 2-year actuarial probability of variceal bleeding between the 2 groups (Propranolol + placebo, 8.3% and 10.6%; Propranolol + IS-MN, 5% and 12.5%). The only independent predictor of variceal bleeding was a variceal size greater than 5 mm. However, among patients with varices greater than 5 mm (n = 196), there were no significant differences in the incidence of variceal bleeding between the 2 groups. Survival was also similar. Adverse effects were significantly more frequent in the Propranolol + IS-MN group due to a greater incidence of headache. There were no significant differences in the incidence of new-onset or worsening ascites or in impairment of renal function. In conclusion, Propranolol effectively prevents variceal bleeding. Adding IS-MN does not further decrease the low residual risk of bleeding in patients receiving Propranolol. However, the long-term use of this combination drug therapy is safe and may be an alternative in clinical conditions associated with a greater risk of bleeding. (H epatology 2003;37:1260-1266.)
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Propranolol plus prazosin compared with Propranolol plus isosorbide 5 mononitrate in the treatment of portal hypertension
Gastroenterology, 1998Co-Authors: Agustin Albillos, Juan Carlos Garcia Pagan, Jeronimo Iborra, Juan Carlos Bandi, Guillermo Cacho, Maria Perez Paramo, Angels Escorsell, Jose Luis Calleja, P Escartin, Jaime BoschAbstract:Abstract Background & Aims: The association of prazosin to Propranolol enhances the decrease in portal pressure but may cause hypotension and sodium retention. The aim of this study was to compare the portal pressure reduction and safety of the combination of Propranolol plus prazosin with that of Propranolol plus isosorbide-5-mononitrate (ISMN). Methods: Fifty-six portal-hypertensive cirrhotics received randomly Propranolol plus prazosin (n = 28) or Propranolol plus ISMN (n = 28) orally for 3 months. Hemodynamics and liver and renal function were assessed at baseline and after 3 months. Results: Propranolol plus prazosin caused a greater reduction in hepatic venous pressure gradient (HVPG) than Propranolol plus ISMN (−24.2% ± 11% vs. −16.1% ± 11%; P 20% was significantly more frequent in the Propranolol plus prazosin group than in the Propranolol plus ISMN group (85% vs. 53%; P P = 0.16). Conclusions: Propranolol plus prazosin has a greater portal pressure–lowering effect than Propranolol plus ISMN. Both therapies were safe for liver and renal function. However, the combination of Propranolol plus prazosin caused a greater decrease in arterial pressure and was less well tolerated than Propranolol plus ISMN. GASTROENTEROLOGY 1998;115:116-123
