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Effect of 2,3-dimercaptosuccinic acid (DMSA) on hypertension in the Dahl salt-sensitive (SS) rat
AIH
1995; 8:131A-135A
POSTERS: Other Therapeutic Agentsor Modalities
Gl
G2
MEASUREMENT OF TROUGH·TO-PEAK RATIOS OF FOUR ANTIHYPERTENSIVE DRUGS ON THE BASIS OF 24-H AMBULATORY BLOOD PRESSURE MONITORING. DIFFERENT METHODS MAY GIVE DIFFERENT RESULTS. G. Gama, A. Sanlos, J. PoJonia· Un. Farmacol Clin, S. Medicina
3, Fac. Medicine Porto Porlugal Wilb 24·h ambulatory blood pressure monitoring (ABPM), we measured the trough-to-peak ratios (f/Pr) (corrected for placebo) of atenolol l00mg, cilazllpriJ 2.5mg, enalapril 20mg and nifedipine-GiTS 30mg (aU once-a-day • 4 weeks) in 4 comparable groups of hypertensives that responded to therapy (24-hBP fall >5mmHg). ABPM was performed after 2 weeks of placebo and after drug treatment. TIPr were calculated by 3 methods: directly from the curves that averaged hourly all individual 24·h data, (A); averaging all individual TIPr values after ABPM data were averaged for each patienl over either l-h intervals (8) or 3·h intervals, (C). Different values of TIPr were obtained by methods Band C: for eacf drug: TIPr were significantly higher wilh method C. With method A, TIPr of nlfedipine appeared to be superior to the other drugs; however, with methods B or C, although nifedipine exhibited higher values of T!Pr and highr.r percentage of patients with a TIPr > 50%, differences to the other drugs were not significant. Moreover the T/Pf determined by any of the three methods did not differ when the inclusion criteria of a minimal response to therapy changed from 5 mmHg to 10mmHg. • p
ATmOLOL ClLAZAPlUL ~ALAPIUL NIF11IJIPIN& ~
n •
TIP
TIP' TIP TIP _ • • of. ABC A
14 13 20 15
34 49 58 83
t-- 'SyrlDJic
32+26 40.±26 40.±.~8
SS±32
56'! 29' 61±30' 64±,34' 73%28'
S3 50 57
6S
TfP%
T/~
Di"lllr.•• ~ D C
40+;9 41+29 36±25 49+29
-
69+34' 70±,~'
6S±39' 67+3S'
-
We conclude that precise guidelines for measuring TIPr based on Ai3PM are needed, whereas for the comparison between drugs, b'?&v'Wo'Pcfl:n TIPr and its. variance must bedetermined. hypertension, trough-to-peak ratio, ambulatory blood pressure monitoring, methodology
G3 COMPARISON OF ~~LODIPINE AND BENAZEPRIL MONOTHERAPY '1'0 COMBINATION THERAPY IN PATIENTS WITH SYSTEMIC HYPERTENSION. NH Frishman., ~S Ram, FG McMahon, SG Chrysant, A Graff, JW Kupiec, H Hsu for the Benazepril/Amlodipine stUdy Group. Albert Einstein College of Medicine, B7"onx NY. Using a single-blind run-in, randomized, double-blind, parallel design, placebo and active control comparison trial, we assessed the safety and efficacy of low-dose amlodipine 2.5 mg daily, low-dose benazepril 10 mg daily, and the combination of the two drugs at the same doses used once daily in the management of patients (n=401) with mild to moderate systemic hypertension (Stages I and II). Both active monotherapies were shown to significantly reduce both systolic and diastolic blood pressure compared to baseline placebo values, and the combination was shown to be effective in lowering blood pressure with additive efficacy when compared to the monotherapies. The combination regimen also was shown to be associated with a similar incidence of adverse reactions as the active monotherapies or placebo. We conclude that the combination of low-dose amlodipine (2.5 mg) and benazepril (10 mg) provides greater blood pressure lowering efficacy than either monotherapy or placebo, While having an excellent side effect profile. KevWords:. amlodip~n7' benazepril,. bertazeprll-amlodlplne, hypertenslon.
EFFECT OF 2,3-DIKERCAPTOSUCCINIC ACID CDMSA) ON HYPERTENSION IN THE DAHL SALTSENSITIVE (SS) RAT. H Gonick*, F KhalilKanesh, L Saldanba, Q Ren, E Weiler, and A Cohen. cedars-sinai Med. etr. and UCLA School of Medicine, LOB Angeles, CA. We have previously reported that the chelato~, DHSA, reduces mean blood preesure (MBP) in lead-treated rats (Environ. Res. ~:86-99, 1994). The effect appeared to be the consequence of a si~ultaneous decrease in endothelin-3 (ET-3) and an increase in endothelial-derived relaxing factor (EDRF), In the present stUdy, we have demonstrated that DMSA (~.5t for 5 days every 2 w~eks) also reduces MB~ in the Dahl SS rat. After 2 weeks on a 0.3t NaCl diet followed by 4 weeks on an 8t NaCl diet, MBP in the untreated SS rats was 141 ± 14 in comparison to 126 ± 8 mmHg in DM5A-treated rate (p
G4 EFFECl' OF CI~ ON pROS'i:AcYcr.m SECRETIC!'I BY HtJrm ENDCYmELIAL CELLS IN VI'I'P..o. A HornYch, B Oravec, Ml' Droy-Lefaix # and E I>brin #, U-28 INSERM Broussais Hospital and # IPSEN Institute,
Paris, France . CicletClo'1ine (CIC, IPSEN, France) is a new antihypertensive drug whose mechanism of action appears to be linked to prostacyclin (PGr2 } release from srrooth muscles and from the kidney. We were interested whether C1C and its enantiomers (EN) stimulate WI; release also from human umbilical vein endothelial cells (HUVEC) cultivated in vitro. Confluent HUVEC were coincubated in 48 well micro-titer plates for 24 h \~ith increasing ;:oncentrations (10'10 M - 10" M) of cre D,L (t) and its sulphoconjugated metabolites ere-so, (t), (+) and (-Y. '!be concentration of 6-k-F1, in the supernatant was then measured by radioinmunoassay after the previous SEP-PAK C 18 extraction. Basal control 6-k-F1• secretion was 4825 t 997 pg/lO's cellsl24 h (n = 5). C1C increased significantly 6-k-Fl i secretion (p < 0.05 - 0.005) with a maximum at 10" M (+ 34 11;), but followed by decreasing release at higher concentrations : at 10-7 M + 28 %", at 10" M + 14 %, cre-so. (t) increased 6-kFl. release at 10" M (+ 33 11;), but with the inhibition at 10" l>f r- 7S %', P < 0.05). ere-so, (+) had a significant stimulatory effect on 6-kFlo release at 10.9 , " M (+ 66 %, + 67 %) (p < 0.50.02) I but also inhibitory effect at high concentrations . crc-so. (-) was without significant effect . As the plasma concentrations of therapeutic doses of cre (t) in man (50-100 !l9'/day) are in the range of 10" M, therefore our results in vitro confirm these doses have optimum effect on 001: release by endothelial cells. Cicletanine (t) and its sulphoconjugated metab::llites especially ere-so, (+) stimulate 001: release from human endothelial cells in biphasic lMJ'U1er. The naximum stimulatory effect is observed at clinically used therapeutic doses. Cicletanine-dependent endothelial OOI: release may rr~diate, at least partially, the antihypertensive effect of cicletanine. KeyWords: . Cicletanine, !?rostacyclin, endothehum, antihyperten51ve effect -
1995; 8:131A-135A
POSTERS: Other Therapeutic Agentsor Modalities
Gl
G2
MEASUREMENT OF TROUGH·TO-PEAK RATIOS OF FOUR ANTIHYPERTENSIVE DRUGS ON THE BASIS OF 24-H AMBULATORY BLOOD PRESSURE MONITORING. DIFFERENT METHODS MAY GIVE DIFFERENT RESULTS. G. Gama, A. Sanlos, J. PoJonia· Un. Farmacol Clin, S. Medicina
3, Fac. Medicine Porto Porlugal Wilb 24·h ambulatory blood pressure monitoring (ABPM), we measured the trough-to-peak ratios (f/Pr) (corrected for placebo) of atenolol l00mg, cilazllpriJ 2.5mg, enalapril 20mg and nifedipine-GiTS 30mg (aU once-a-day • 4 weeks) in 4 comparable groups of hypertensives that responded to therapy (24-hBP fall >5mmHg). ABPM was performed after 2 weeks of placebo and after drug treatment. TIPr were calculated by 3 methods: directly from the curves that averaged hourly all individual 24·h data, (A); averaging all individual TIPr values after ABPM data were averaged for each patienl over either l-h intervals (8) or 3·h intervals, (C). Different values of TIPr were obtained by methods Band C: for eacf drug: TIPr were significantly higher wilh method C. With method A, TIPr of nlfedipine appeared to be superior to the other drugs; however, with methods B or C, although nifedipine exhibited higher values of T!Pr and highr.r percentage of patients with a TIPr > 50%, differences to the other drugs were not significant. Moreover the T/Pf determined by any of the three methods did not differ when the inclusion criteria of a minimal response to therapy changed from 5 mmHg to 10mmHg. • p
ATmOLOL ClLAZAPlUL ~ALAPIUL NIF11IJIPIN& ~
n •
TIP
TIP' TIP TIP _ • • of. ABC A
14 13 20 15
34 49 58 83
t-- 'SyrlDJic
32+26 40.±26 40.±.~8
SS±32
56'! 29' 61±30' 64±,34' 73%28'
S3 50 57
6S
TfP%
T/~
Di"lllr.•• ~ D C
40+;9 41+29 36±25 49+29
-
69+34' 70±,~'
6S±39' 67+3S'
-
We conclude that precise guidelines for measuring TIPr based on Ai3PM are needed, whereas for the comparison between drugs, b'?&v'Wo'Pcfl:n TIPr and its. variance must bedetermined. hypertension, trough-to-peak ratio, ambulatory blood pressure monitoring, methodology
G3 COMPARISON OF ~~LODIPINE AND BENAZEPRIL MONOTHERAPY '1'0 COMBINATION THERAPY IN PATIENTS WITH SYSTEMIC HYPERTENSION. NH Frishman., ~S Ram, FG McMahon, SG Chrysant, A Graff, JW Kupiec, H Hsu for the Benazepril/Amlodipine stUdy Group. Albert Einstein College of Medicine, B7"onx NY. Using a single-blind run-in, randomized, double-blind, parallel design, placebo and active control comparison trial, we assessed the safety and efficacy of low-dose amlodipine 2.5 mg daily, low-dose benazepril 10 mg daily, and the combination of the two drugs at the same doses used once daily in the management of patients (n=401) with mild to moderate systemic hypertension (Stages I and II). Both active monotherapies were shown to significantly reduce both systolic and diastolic blood pressure compared to baseline placebo values, and the combination was shown to be effective in lowering blood pressure with additive efficacy when compared to the monotherapies. The combination regimen also was shown to be associated with a similar incidence of adverse reactions as the active monotherapies or placebo. We conclude that the combination of low-dose amlodipine (2.5 mg) and benazepril (10 mg) provides greater blood pressure lowering efficacy than either monotherapy or placebo, While having an excellent side effect profile. KevWords:. amlodip~n7' benazepril,. bertazeprll-amlodlplne, hypertenslon.
EFFECT OF 2,3-DIKERCAPTOSUCCINIC ACID CDMSA) ON HYPERTENSION IN THE DAHL SALTSENSITIVE (SS) RAT. H Gonick*, F KhalilKanesh, L Saldanba, Q Ren, E Weiler, and A Cohen. cedars-sinai Med. etr. and UCLA School of Medicine, LOB Angeles, CA. We have previously reported that the chelato~, DHSA, reduces mean blood preesure (MBP) in lead-treated rats (Environ. Res. ~:86-99, 1994). The effect appeared to be the consequence of a si~ultaneous decrease in endothelin-3 (ET-3) and an increase in endothelial-derived relaxing factor (EDRF), In the present stUdy, we have demonstrated that DMSA (~.5t for 5 days every 2 w~eks) also reduces MB~ in the Dahl SS rat. After 2 weeks on a 0.3t NaCl diet followed by 4 weeks on an 8t NaCl diet, MBP in the untreated SS rats was 141 ± 14 in comparison to 126 ± 8 mmHg in DM5A-treated rate (p
G4 EFFECl' OF CI~ ON pROS'i:AcYcr.m SECRETIC!'I BY HtJrm ENDCYmELIAL CELLS IN VI'I'P..o. A HornYch, B Oravec, Ml' Droy-Lefaix # and E I>brin #, U-28 INSERM Broussais Hospital and # IPSEN Institute,
Paris, France . CicletClo'1ine (CIC, IPSEN, France) is a new antihypertensive drug whose mechanism of action appears to be linked to prostacyclin (PGr2 } release from srrooth muscles and from the kidney. We were interested whether C1C and its enantiomers (EN) stimulate WI; release also from human umbilical vein endothelial cells (HUVEC) cultivated in vitro. Confluent HUVEC were coincubated in 48 well micro-titer plates for 24 h \~ith increasing ;:oncentrations (10'10 M - 10" M) of cre D,L (t) and its sulphoconjugated metabolites ere-so, (t), (+) and (-Y. '!be concentration of 6-k-F1, in the supernatant was then measured by radioinmunoassay after the previous SEP-PAK C 18 extraction. Basal control 6-k-F1• secretion was 4825 t 997 pg/lO's cellsl24 h (n = 5). C1C increased significantly 6-k-Fl i secretion (p < 0.05 - 0.005) with a maximum at 10" M (+ 34 11;), but followed by decreasing release at higher concentrations : at 10-7 M + 28 %", at 10" M + 14 %, cre-so. (t) increased 6-kFl. release at 10" M (+ 33 11;), but with the inhibition at 10" l>f r- 7S %', P < 0.05). ere-so, (+) had a significant stimulatory effect on 6-kFlo release at 10.9 , " M (+ 66 %, + 67 %) (p < 0.50.02) I but also inhibitory effect at high concentrations . crc-so. (-) was without significant effect . As the plasma concentrations of therapeutic doses of cre (t) in man (50-100 !l9'/day) are in the range of 10" M, therefore our results in vitro confirm these doses have optimum effect on 001: release by endothelial cells. Cicletanine (t) and its sulphoconjugated metab::llites especially ere-so, (+) stimulate 001: release from human endothelial cells in biphasic lMJ'U1er. The naximum stimulatory effect is observed at clinically used therapeutic doses. Cicletanine-dependent endothelial OOI: release may rr~diate, at least partially, the antihypertensive effect of cicletanine. KeyWords: . Cicletanine, !?rostacyclin, endothehum, antihyperten51ve effect -