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Postmarketing surveillance study of amlodipine in hypertensive patients with hypertension not controlled with other antihypertensive agents. (Preliminary results)
A]H-APRIL
1999-VOL.
12, NO. 4, PART
POSTERS:
2
Antihypertensive
DO33
DO34
ACE-INHIBITION BUT NOT ANGIOTENSIN II ANTAGONISM IMPROVES FIBRINOLYSIS AND INSULIN SENSITIVITY IN HYPERTENSIVE POST-MENOPAUSAL WOMEN. P. -3 Preti A. Banderali, A. zOppl*, L. Corradi’, A. Mugellini, R.M. Pace. R. Fogari’. Department of Internal Medicine and Therapeutics, University of Pavla, Pawa (Italy).
COMBINATION THERAPY OF CALCIUM ANTAGONISTS AND ACE INHIBITORS-THE INCIDENCE OF VASODILATORY EDEMA. FH Messerli’, Z_&g. and Gradman AH. Ochsner Clinic and Alton Ochsner Medical Fowxiation, New Orleans, LA, and Western Pennsylvania Hospital, Pittsburgh, PA. Vasodilatory edema is a common adverse effect of calcium antagonists (CA). It occurs more commonly with the dlbydropyidine derivatives than with the nondihydropydiie. in women than in men, and is dose dependent, thereby limiting the tolerability of higher doses of CA. The present study assessed tbe incidence of all forms of edema in a cohort of 1189 patients with essential hypertension who were treated either witb placebo, a diiydropyridine CA alone (amlodipine or felodipine) in the dose of either 5 mg (CA 5) or 10 mg (CA IO) once a day or with the combination of an ACE inhibitor (ACEI) (benazapril or enalapril) with the 5 mg dose of the calcium antagonist (CA S/ACE& Results were as follows:
Aim: To compare the effect of an Ace-InhIbitor vs an Anglo II antagonIst on PAI-I and insulin sensitivity in hypertensive postmenopausal women. Methods : We studied 64 hypertensive (DBP>90 and
IKlfll IOlf6 39+14 6.88+0,42
144*9** 88f6” 30*13* 8,07?0.54*
159+11 lOlf7 381tl6 6,97x%.43
148flO’* 92f6** 40fl7 7,14io,40
n (total) Edema &inBP (m8) Xofedemal &10 m&g
Placebo 194 5.1 (2.6%) -4.31-3.2 -
CA5 338 18 (5.3%) -8.21-5.6
CA 10 188 46 (24.5%) -8.11-8.6
CA S/ACE1 469 16 (3.4%) -7.81-10
6.8%
27%
3.2%
GIR (mgirmnlkg) * p < 0,05 ; ** p< 0,Ol vs placebo. In-the Trandol&l group PAI-I decrease correlated wth GIR increase (r=0,42; p < 0.01) Conclusion : Both Trandolapril and Losartan significantly reduced BP. However, Trandolaprll decreased PAI-I and improved Insulin Sensitivity while Losartan did not. These data suggest that PAI-I decrease produced by Ace-Inhibitors IS related to then action on insulin sensltlvity and is not dependent on Angiotensin II antagonism but rather on other mechamsms
The incidence of edema was significantly higher in patients on the 10 mg (but not in those on the 5 mg) CA dose tima in those on placebo (p
Key Words:
Key words:
Fibrinolysis, Ace-Inhibition, Anglo II antagonism.
Drugs
Edema, calcium antagonist, ACE lnbibitors, combination therapy. hypertension
DO35
DO36
Title: OF POS?MARKETINo SURVEILLANCE STUDY AMLODIPlNE IN HYPERTENSIVE PATIENTS WITH HYPER’fENSION NOT OTHER CONTROLLED WITH ANTIHYPBRTENSIVE AGENTS.(PRELIMINARYRESULTS)
IN VIVO lNHlBlTlON OF ANGIOTENSIN CONVERTING ENZYME AND NEUTRAL ENDOPEPTIDASE BY A DUAL VASOPEPTIDASE INHIBITOR L.M. BurrelI M.D. Rockell, J. Powell’, C.I. Johnston’ -of Medicine, University of Melbourne, Melbourne, AUSTRALIA and Bristol-Myers Squibb, Princeton, NJ.
Authors: m Vega,J.E+jo.
R Jim-
M. Go&la,
M San Martin, E. Becerril, A.
Bstlhltloo and locatIon: Dcpmtment School. Univnsidad ObJetivcr:
Complutensc
of Preventive de Madrid.
Medicine.
To asses the safety and efficacy of andodipine
Medical
in monotherapy
and as a combination tbaapy for the treatmnt of hypxtensive patie& &nwiouslyunanhulled despite pkumacological trcatmmt. hi@: A p”ospeCtive.m”hice”ter, pOstm‘&tb,g .m,w&mce st”dy wit,, hypertensivepatients in Rimary Care sening. Methods: 1569 hypertaive patients @BP2140 and/or DBPZO “,“,Hg) uncontrolled despite phwnacolc+xl treatment were assigned to receive either amlodipine in monotbemphy(73%) w amlodipine as pmt of a two antihyprteneve drugs regimen (27%). The follow up period lasted four months and each cadent should have at least tbrec visita durinc this osiod. The initial daily hose of amlodipine was 5 mg, then this &.s &Id be in& to 10 m&&y in order to achieve hyprtsnsirm wnhvl. The main outcome m-s included blocd press&&mpliance and incidence of adverse events. Rerulb: Ihe mean aae for the studied woulation uas 62.04 -
(SD=IO.S).76 patients &t&d adverse eve& i4,8%). Most of the ad&se events appearedin the firrt two maths (6%). None of t&se events were classified as saiow There was no signiticant diffin the incidence of adverse events between tbosc tits in monotba-at,v and those in
combinationtherapy.The mean v&m of SBP 8nd DBP f&the group with monotherapywere 165.8 and 97.3 m&Ig at baseline, 148.5 md 87.03 mmHgafter hvo months,and 141.4and 83.07 mmBg after four months of treatment There wae significant di!T.erencesin the mtan SBP and DBP redtions finm baseline to the second month of batmeat and 6um the swmd month to the fourth mm& of hahneat in the monotherapygroup (p
H-ion,
safety, amlcdipine.
Angiotensin Converting Enzyme (ACE) and Net&al Endopeptidase (NEP) are cell membrane bound zinc metallopeptidases, wfth close homology at their catalytic sites and several common substrates. Whereas ACE produces the vasoconstrictor angiotensin II, NEP degrades the vascdilator natriuretk peptides. Omapatrilat is a mercaptoacyl derivative of a dipeptide surrogate that in vitro inhibits both ACE (Ki 6.0 nM) and NEP (Ki 6.9nM). This study investigated the dose response and time course of inhibition of these two enzymes in vivo by omapatrilat. In vivo inhibition of renal ACE and NEP was determined by quantitative autoradiography employing specifc radioligands for ACE and NEP. Sprague Dawley rats were gavaged with 0, 0.1, 1 or 10 mgikg of omapatrilat and killed 1 hour later or gavaged with 10 mgikg and killed after 0, 1,2,4.8,24 hours. Kidneys were snap frozen and processed for autoradiography and blood sampled for plasma ACE and renin activity Marked inhibition of ACE and NEP in their precise renal anatomical localisatton was seen with the 10 mgikg dose. On the other hand, plasma ACE was inhibited significantly by all 3 doses. The increase in plasma renin similar to renal ACE inhibitton was only significant after the 10 mg/kg dose. Kidney ACE was inhibited at 1 hour and was still significantly depressed after 24 hours. Renal NEP inhibition was suppressed for 6 hours but returned towards normal by 24 hours. Plasma ACE and PRA showed reciprocal changes with both returning towards normal at 24 hours. Omapatrilat is a potent and long lasting inhibitor of both plasma ACE and tksue ACE and NEP in viva. Inhibition of the RAS with potentiatton of the natdurettc peptides offer potential benefits in hypertension and heart failure.
Key Words:
vasopepttdase inhibitors, omapatdlat, angiotensin, nabfuretic peptldes
119A
1999-VOL.
12, NO. 4, PART
POSTERS:
2
Antihypertensive
DO33
DO34
ACE-INHIBITION BUT NOT ANGIOTENSIN II ANTAGONISM IMPROVES FIBRINOLYSIS AND INSULIN SENSITIVITY IN HYPERTENSIVE POST-MENOPAUSAL WOMEN. P. -3 Preti A. Banderali, A. zOppl*, L. Corradi’, A. Mugellini, R.M. Pace. R. Fogari’. Department of Internal Medicine and Therapeutics, University of Pavla, Pawa (Italy).
COMBINATION THERAPY OF CALCIUM ANTAGONISTS AND ACE INHIBITORS-THE INCIDENCE OF VASODILATORY EDEMA. FH Messerli’, Z_&g. and Gradman AH. Ochsner Clinic and Alton Ochsner Medical Fowxiation, New Orleans, LA, and Western Pennsylvania Hospital, Pittsburgh, PA. Vasodilatory edema is a common adverse effect of calcium antagonists (CA). It occurs more commonly with the dlbydropyidine derivatives than with the nondihydropydiie. in women than in men, and is dose dependent, thereby limiting the tolerability of higher doses of CA. The present study assessed tbe incidence of all forms of edema in a cohort of 1189 patients with essential hypertension who were treated either witb placebo, a diiydropyridine CA alone (amlodipine or felodipine) in the dose of either 5 mg (CA 5) or 10 mg (CA IO) once a day or with the combination of an ACE inhibitor (ACEI) (benazapril or enalapril) with the 5 mg dose of the calcium antagonist (CA S/ACE& Results were as follows:
Aim: To compare the effect of an Ace-InhIbitor vs an Anglo II antagonIst on PAI-I and insulin sensitivity in hypertensive postmenopausal women. Methods : We studied 64 hypertensive (DBP>90 and
IKlfll IOlf6 39+14 6.88+0,42
144*9** 88f6” 30*13* 8,07?0.54*
159+11 lOlf7 381tl6 6,97x%.43
148flO’* 92f6** 40fl7 7,14io,40
n (total) Edema &inBP (m8) Xofedemal &10 m&g
Placebo 194 5.1 (2.6%) -4.31-3.2 -
CA5 338 18 (5.3%) -8.21-5.6
CA 10 188 46 (24.5%) -8.11-8.6
CA S/ACE1 469 16 (3.4%) -7.81-10
6.8%
27%
3.2%
GIR (mgirmnlkg) * p < 0,05 ; ** p< 0,Ol vs placebo. In-the Trandol&l group PAI-I decrease correlated wth GIR increase (r=0,42; p < 0.01) Conclusion : Both Trandolapril and Losartan significantly reduced BP. However, Trandolaprll decreased PAI-I and improved Insulin Sensitivity while Losartan did not. These data suggest that PAI-I decrease produced by Ace-Inhibitors IS related to then action on insulin sensltlvity and is not dependent on Angiotensin II antagonism but rather on other mechamsms
The incidence of edema was significantly higher in patients on the 10 mg (but not in those on the 5 mg) CA dose tima in those on placebo (p
Key Words:
Key words:
Fibrinolysis, Ace-Inhibition, Anglo II antagonism.
Drugs
Edema, calcium antagonist, ACE lnbibitors, combination therapy. hypertension
DO35
DO36
Title: OF POS?MARKETINo SURVEILLANCE STUDY AMLODIPlNE IN HYPERTENSIVE PATIENTS WITH HYPER’fENSION NOT OTHER CONTROLLED WITH ANTIHYPBRTENSIVE AGENTS.(PRELIMINARYRESULTS)
IN VIVO lNHlBlTlON OF ANGIOTENSIN CONVERTING ENZYME AND NEUTRAL ENDOPEPTIDASE BY A DUAL VASOPEPTIDASE INHIBITOR L.M. BurrelI M.D. Rockell, J. Powell’, C.I. Johnston’ -of Medicine, University of Melbourne, Melbourne, AUSTRALIA and Bristol-Myers Squibb, Princeton, NJ.
Authors: m Vega,J.E+jo.
R Jim-
M. Go&la,
M San Martin, E. Becerril, A.
Bstlhltloo and locatIon: Dcpmtment School. Univnsidad ObJetivcr:
Complutensc
of Preventive de Madrid.
Medicine.
To asses the safety and efficacy of andodipine
Medical
in monotherapy
and as a combination tbaapy for the treatmnt of hypxtensive patie& &nwiouslyunanhulled despite pkumacological trcatmmt. hi@: A p”ospeCtive.m”hice”ter, pOstm‘&tb,g .m,w&mce st”dy wit,, hypertensivepatients in Rimary Care sening. Methods: 1569 hypertaive patients @BP2140 and/or DBPZO “,“,Hg) uncontrolled despite phwnacolc+xl treatment were assigned to receive either amlodipine in monotbemphy(73%) w amlodipine as pmt of a two antihyprteneve drugs regimen (27%). The follow up period lasted four months and each cadent should have at least tbrec visita durinc this osiod. The initial daily hose of amlodipine was 5 mg, then this &.s &Id be in& to 10 m&&y in order to achieve hyprtsnsirm wnhvl. The main outcome m-s included blocd press&&mpliance and incidence of adverse events. Rerulb: Ihe mean aae for the studied woulation uas 62.04 -
(SD=IO.S).76 patients &t&d adverse eve& i4,8%). Most of the ad&se events appearedin the firrt two maths (6%). None of t&se events were classified as saiow There was no signiticant diffin the incidence of adverse events between tbosc tits in monotba-at,v and those in
combinationtherapy.The mean v&m of SBP 8nd DBP f&the group with monotherapywere 165.8 and 97.3 m&Ig at baseline, 148.5 md 87.03 mmHgafter hvo months,and 141.4and 83.07 mmBg after four months of treatment There wae significant di!T.erencesin the mtan SBP and DBP redtions finm baseline to the second month of batmeat and 6um the swmd month to the fourth mm& of hahneat in the monotherapygroup (p
H-ion,
safety, amlcdipine.
Angiotensin Converting Enzyme (ACE) and Net&al Endopeptidase (NEP) are cell membrane bound zinc metallopeptidases, wfth close homology at their catalytic sites and several common substrates. Whereas ACE produces the vasoconstrictor angiotensin II, NEP degrades the vascdilator natriuretk peptides. Omapatrilat is a mercaptoacyl derivative of a dipeptide surrogate that in vitro inhibits both ACE (Ki 6.0 nM) and NEP (Ki 6.9nM). This study investigated the dose response and time course of inhibition of these two enzymes in vivo by omapatrilat. In vivo inhibition of renal ACE and NEP was determined by quantitative autoradiography employing specifc radioligands for ACE and NEP. Sprague Dawley rats were gavaged with 0, 0.1, 1 or 10 mgikg of omapatrilat and killed 1 hour later or gavaged with 10 mgikg and killed after 0, 1,2,4.8,24 hours. Kidneys were snap frozen and processed for autoradiography and blood sampled for plasma ACE and renin activity Marked inhibition of ACE and NEP in their precise renal anatomical localisatton was seen with the 10 mgikg dose. On the other hand, plasma ACE was inhibited significantly by all 3 doses. The increase in plasma renin similar to renal ACE inhibitton was only significant after the 10 mg/kg dose. Kidney ACE was inhibited at 1 hour and was still significantly depressed after 24 hours. Renal NEP inhibition was suppressed for 6 hours but returned towards normal by 24 hours. Plasma ACE and PRA showed reciprocal changes with both returning towards normal at 24 hours. Omapatrilat is a potent and long lasting inhibitor of both plasma ACE and tksue ACE and NEP in viva. Inhibition of the RAS with potentiatton of the natdurettc peptides offer potential benefits in hypertension and heart failure.
Key Words:
vasopepttdase inhibitors, omapatdlat, angiotensin, nabfuretic peptldes
119A