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  • 11
    Electronic Resource
    Electronic Resource
    Bioavailability of repeated oral administration of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase in healthy volunteers (2000)
    Springer
    European journal of clinical pharmacology 55 (2000), S. 749-754 
    Details
    ISSN: 1432-1041
    Keywords: Key words NEP ; ACE inhibitor ; ANP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Background: MDL 100,240 (pyrido[2,1-a] [2]benzazepine-4-carboxylic acid,7-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8,12b-octahydro-6-oxo, [4S-[4α,7α(R*),12bβ]]-) is a molecule possessing an inhibiting ability on both angiotensin converting enzyme (ACE) and neutral endopeptidase, the enzyme responsible for atrial natriuretic peptide (ANP) degradation. Such a dual mechanism of action presents a potential clinical interest for the treatment of hypertension and congestive heart failure. Objectives: To evaluate the bioavailability of MDL 100,240 and its accumulation over repeated oral administration, using ACE inhibition as a surrogate for plasma drug level and determining its profile after oral and i.v. administration. Methods: First, in an open, one-period, single-dose study, the ACE inhibition profile was characterised following a 12.5 mg MDL 100,240 i.v. infusion. Second, in a three-group, parallel, randomised, double-blind study, each group of four subjects received q.d., over 8 days, 2.5, 10 or 20 mg of MDL 100,240 orally. The ACE inhibition profile was determined on day 1 and day 8. Trough plasma ACE was measured on days 2, 3 and 4. The recovery of ACE activity was monitored up to 72 h after the last dose of MDL 100,240. Results: ACE inhibition profile was similar on day 1 and day 8, and trough inhibition remained unchanged after the 8 days of treatment with 10 mg or 20 mg. Following repeated 2.5-mg ingestion, trough inhibition increased from 33% to 44% after the eighth dose. The oral bioavailability of MDL 100,240 was estimated at 85%, not statistically different from 100%. The accumulation ratio at steady state was estimated at 112%. Expressing the accumulation ratio in terms of half-life, a t1/2 of 0.31 days or 7.5 h was estimated. Conclusion: MDL 100,240 (oral solution) has a good bioavailability, as estimated by ACE inhibition, and no drug accumulation seems to occur over 8 days with the 10-mg and 20-mg doses, but a slight rise in the trough level is observed with the 2.5-mg dose.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002280050009
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  • 12
    Electronic Resource
    Electronic Resource
    Haemodynamic and pharmacological effects of the converting enzyme inhibitor CGS 14824A in normal volunteers (1985)
    Springer
    European journal of clinical pharmacology 28 (1985), S. 267-272 
    Details
    ISSN: 1432-1041
    Keywords: converting enzyme inhibitor ; CGS 14824A ; pharmacodynamics ; plasma renin ; plasma angiotensin ; aldosterone ; side-effects ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The converting enzyme inhibitor CGS 14824A was evaluated in 15 healthy male volunteers. First, the efficacy of a single 5 or 10 mg oral dose in antagonizing the pressor response to exogenous angiotensin I was tested in 2 subjects. Blood pressure and heart rate were monitored continuously through an intra-arterial catheter. CGS 14824A 5 mg reduced the response to angiotensin I within 75 min to 50%, and 10 mg within 1 h to less than 25%, and for a period of more than 4 h. Subsequently, plasma renin and converting enzyme activity, plasma angiotensin I, angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of 2, 5, 10 or 20 mg CGS 14824A to groups of 5 volunteers. Plasma converting enzyme activity fell to well below 10% of baseline within 1 h after administration of 5 mg or more CGS 14824 A. Within 2 h following 2 mg p.o., a similarly low level was reached. Twenty four hours following the 20 mg dose, plasma converting enzyme activity was still below 10%. As expected, plasma renin activity and angiotensin I rose while angiotensin II and aldosterone fell following the 2 mg dose. This pattern of effects was enhanced by increasing the dose. Nonetheless, 24 h after the 20 mg dose, plasma angiotensin II and aldosterone had returned to their baseline levels. No side-effects occurred. Thus, in normal volunteers, CGS 14824A was an effective, potent and long acting converting enzyme inhibitor.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00543322
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  • 13
    Electronic Resource
    Electronic Resource
    Effect on blood pressure and the renin-angiotensin system of repeated doses of the converting enzyme inhibitor CGS 14824A (1987)
    Springer
    European journal of clinical pharmacology 31 (1987), S. 643-646 
    Details
    ISSN: 1432-1041
    Keywords: converting enzyme inhibitor (CGS 14824A) ; blood pressure ; renin-angiotensin system ; healthy volunteers ; aldosterone ; haemodynamic effects ; plasma angiotensin II ; angiotensin converting enzyme ; plasma renin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 14824A, was evaluated in 12 healthy male volunteers. Two groups each of 6 volunteers were given 5 or 10 mg once daily p.o. for 8 days. Four hours after the first and the last morning doses, plasma angiotensin II, aldosterone and plasma converting enzyme activity had fallen, while blood angiotensin I and plasma renin activity had risen. Throughout the study, more than 90% inhibition of ACE was found immediately before giving either the 5 or 10 mg dose and 50% blockade was still present 72 h following the last dose. Based on the determination of ACE, there was no evidence of drug accumulation. No significant change in blood pressure or heart rate was observed during the course of the study. CGS 14824A was an effective, orally active, long-lasting and well tolerated converting enzyme inhibitor.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00541289
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  • 14
    Electronic Resource
    Electronic Resource
    Effects of prolonged administration of the angiotensin converting enzyme inhibitor CGS 16617 in normotensive volunteers (1989)
    Springer
    European journal of clinical pharmacology 36 (1989), S. 587-591 
    Details
    ISSN: 1432-1041
    Keywords: angiotensin converting enzyme (ACE) inhibitor ; CGS 16617 ; blood pressure response ; healthy volunteers ; prolonged administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 16617, has been evaluated in normotensive subjects during acute and prolonged administration. Single ascending doses of CGS 16617 20 to 100 mg were given to 9 normotensive volunteers at one week intervals and the changes in blood pressure, plasma ACE and renin activity were examined up to 72 h after drug intake. Also, CGS 16617 50 mg/day or placebo were given for 30 days to 8 and 6 normotensive subjects, respectively, maintained on an unrestricted salt diet. Blood pressure was measured daily in the office and ambulatory blood pressure profiles were also obtained before, during and after therapy, using the Remler M 2000 blood pressure recording system. CGS 16617 was an effective and long lasting ACE inhibitor. It did not induce a consistant change in blood pressure, but, the individual responses were very variable and several subjects experienced a clear decrease in the average of the blood pressures recorded during the daytime.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00637741
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  • 15
    Electronic Resource
    Electronic Resource
    Atrial natriuretic peptides: Reproducibility of renal effects and response of liver blood flow (1986)
    Springer
    European journal of clinical pharmacology 31 (1986), S. 1-8 
    Details
    ISSN: 1432-1041
    Keywords: atrial natriuretic peptides ; renal effects ; hepatic blood flow ; normotensive volunteers ; response consistency
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To assess the variability of the response to exogenous atrial natriuretic peptide (ANP), it was infused at the rate of 1 µg/min for 2 h in 6 salt-loaded normal volunteers under controlled conditions on 2 occasions at an interval of 1 week. The effect on solute excretion and the haemodynamic and endocrine actions were highly reproducible. The constant ANP infusion caused a delayed and prolonged excretion of sodium, chloride and calcium, no change in potassium or phosphate excretion or in glomerular filtration rate but a marked decrease in renal plasma flow. Blood pressure, heart rate and the plasma levels of angiotensin II, aldosterone, arginine vasopressin and plasma renin activity were unaltered. The effect of a 2-h infusion of ANP 0.5 µg/min or its vehicle on apparent hepatic blood flow (HBF) was also studied in 14 normal volunteers by measuring the indocyanine green clearance. A 21% decrease in HBF was observed in subjects who received the ANP infusion (p〈0.01 vs vehicle). Thus, ANP infused at a dose that did not lower blood pressure decreased both renal and liver blood flow in normotensive volunteers. The renal and endocrine responses to ANP were reproducible over a 1-week interval.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00870977
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  • 16
    Electronic Resource
    Electronic Resource
    Effect of propranolol and prindolol on renin secretion in normal supine man (1975)
    Springer
    Journal of molecular medicine 53 (1975), S. 709-711 
    Details
    ISSN: 1432-1440
    Keywords: Plasma-Renin-Aktivität ; Propranolol ; Prindolol ; Plasma renin activity ; propranolol ; prindolol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary To investigate the effect of propranolol and prindolol on renin secretion plasma renin activity (PRA) was determined overnight at short-time intervals in 10 sodium-restricted normal supine subjects. 4 of them were on a 4-days medication with propranolol, 3 were treated with prindolol and 3 were used as control group. In normal controls renin was secreted episodically and showed characteristic night-day variations. Both in propranolol and in prindolol-treated subjects secretory episodes in renin secretion either did not occur or were less frequent than in normal controls. With one exception night-day variations in renin secretion were not observed. Mean PRA values were significantly lower than in the control group (p〈0.001). Our results show that both propranolol and prindolol lower PRA and eliminate or reduce the frequency of secretory episodes. It is concluded that the sympathetic nervous system plays an important role in regulating night-day variations and short-time fluctuations of renin secretion in normal supine man.
    Notes: Zusammenfassung Um den Effekt von Propranolol und Prindolol auf die Reninsekretion zu untersuchen, wurde unter natriumarmer Ernährung bei 10 liegenden Normalpersonen in kurzen Zeitabständen über Nacht die Plasma-Renin-Aktivität (PRA) bestimmt. 4 Personen standen unter einer 4tägigen Behandlung mit Propranolol, 3 wurden über denselben Zeitraum mit Prindolol behandelt und 3 Personen dienten als Kontrollgruppe. Bei Normalpersonen zeigte Renin sowohl eine episodische Sekretion als auch einen typischen Nacht-Tag-Rhythmus. Unter Propranolol und Prindolol wurden Sekretionsepisoden des Renins entweder nicht beobachtet oder traten seltener auf. Eine Nacht-TagSchwankung der Reninsekretion war mit einer Ausnahme nicht zu beobachten. Unter beiden Betablockern war die mittlere PRA signifikant niedriger als bei Kontrollpersonen (p〈0.001). Unsere Ergebnisse zeigen, daß Propranolol und Prindolol die Renin-Aktivität senken und entweder die episodische Reninsekretion aufheben oder zu einer Frequenzabnahme der Sekretionsepisoden führen. Unsere Resultate erlauben die Schlußfolgerung, daß das sympathische Nervensystem eine bedeutende Rolle in der Steuerung der Nacht-Tag-Rhythmik und in der Regulation der Kurz-ZeitSchwankungen der Reninsekretion spielt.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01468701
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  • 17
    Electronic Resource
    Electronic Resource
    The effect of the converting enzyme inhibitor HOE 498 on the renin angiotensin system of normal volunteers (1985)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 329 (1985), S. 63-69 
    Details
    ISSN: 1432-1912
    Keywords: HOE 498 ; Angiotensin converting enzyme inhibition ; Angiotensin II
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The converting enzyme inhibitor HOE 498 was evaluated in 12 normotensive male volunteers aged 21 to 26. The efficacy of single 5, 10 or 20 mg oral doses in blocking the pressor response to exogenous angiotensin I was tested in 3 of the subjects. All 3 doses of HOE 498 reduced the pressor response to exogenous angiotensin I to below 50% of control within 1,5 h following administration of the drug. Plasma renin and converting enzyme activity, blood angiotensin I, as well as plasma angiotensin II and aldosterone were measured serially before and up to 72 h following oral administration of a single dose of 2.5, 5, 10 or 20 mg of HOE 498 to groups of 5 volunteers each. As expected, blood angiotensin I levels and plasma renin activity rose while plasma converting enzyme activity, plasma angiotensin II and aldosterone concentration fell after administration of the drug. While the dose of 2.5 mg did not reduce plasma converting enzyme activity below 20% of control, the higher doses all resulted in plasma converting enzyme inhibition exceeding 90%. No side-effects were observed. It is concluded that in normal volunteers HOE 498 is an effective potent and long-acting converting enzyme inhibitor. Based on these preliminary findings it is expected that 5 mg HOE 948 will turn out to be adequate for therapeutic use.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00695194
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  • 18
    Electronic Resource
    Electronic Resource
    Influence of the renin-angiotensin system on sympathetic neurotransmission in canine skeletal muscle in vivo (1991)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 343 (1991), S. 166-172 
    Details
    ISSN: 1432-1912
    Keywords: Angiotensin II ; Prejunctional ; Noradrenaline ; Benazeprilat ; α-Adrenoceptors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The physiological importance of interactions between angiotensin II and sympathetic neurotransmission was studied in an in vivo model with constant flow blood perfused gracilis muscle in situ in dogs pretreated with desipramine and atropine. Sympathetic nerve stimulation- (2 and 8 Hz, 480 pulses) evoked overflow of endogenous noradrenaline and vasoconstriction, and vasoconstrictor responses to exogenous noradrenaline (0.5 nmol, locally i. a.) were evaluated. Angiotensin converting enzyme inhibition by benazeprilat (10 mg i. v.; n = 8) reduced arterial angiotensin II levels from 26 ± 8 to 2 +- 1 pM and reduced mean arterial and basal muscle perfusion pressures. Subsequent resubstitution of angiotensin II (3, 30 and 90 ng kg−1 min−1 i.v.) elevated arterial angiotensin II dose-dependently (to 67 ± 14, 622 ± 63 and 1940 ± 251 pM, respectively), as well as mean arterial and muscle perfusion pressures. Nerve stimulation-evoked noradrenaline overflow was unchanged following benazeprilat (−4 ± 4 and + 1 ± 8% at 2 and 8 Hz, respectively) and during subsequent infusions of angiotensin II. Vasoconstrictor responses to nerve stimulation and exogenous noradrenaline were also uninfluenced by these treatments. Thus, angiotensin II did not enhance sympathetic neurotransmission at the postjunctional level. Another group of animals was pretreated with noncompetitive α-adrenoceptor blockade locally by phenoxybenzamine and benextramine (0.5 mg kg−1 i. a. of each; n = 7), which abolished vasoconstrictor responses to nerve stimulation. The effects of benazeprilat and subsequent angiotensin II infusions (3 and 30 ng kg−1 min−1 i.v.) on circulating angiotensin II levels, mean arterial and muscle perfusion pressures were similar in this group. Following α-adrenoceptor blockade, however, inhibition of angiotensin converting enzyme reduced sympathetic nerve stimulation-evoked noradrenaline overflow by 23 ± 4 and 21 ± 5% at 2 and 8 Hz, respectively (P 〈 0.01 for both). Angiotensin II infusions failed to enhance evoked noradrenaline overflow (−5 ± 10 and −18 ± 10% at 2 Hz; +6 ± 13% and −3 ± 14% at 8 Hz) also under these conditions. It is concluded that circulating angiotensin II does not influence sympathetic vascular control in canine skeletal muscle even at very high levels in arterial plasma. Angiotensin converting enzyme inhibition reduces nerve stimulation-evoked noradrenaline overflow only in the presence of α-adrenoceptor blockade, suggesting that prejunctional α-adrenoceptors have an overriding importance over prejunctional angiotensin II-receptors in the modulation of noradrenaline release in this model. The effect of converting enzyme inhibition may be related to merely local changes in angiotensin II concentration or — unrelated to the renin-angiotensin system — to other consequences of the blockade of this unspecific enzyme.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00168605
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