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Influence of isradipine treatment on platelet membrane lipid alterations and aggregation in patients with essential hypertension
LOW-DOSE COMBINATIONS OF MOEXIPRIL AND HYDROCHLOROTHIAZIDE IN THE TREATMENT OF HYPERTENSION B. Koch, M. Stimpel~ O. Andersson* Clineal Research, Schwarz Pharma AG, Monheim, Germany. Medicmska Kllniken, G6teborg, Sweden g*
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Moexipfil (Moex) is a new angiotensin converting enzyme (ACE) inhibitor. Given once daily it demonstrates a potent 24 hourantihypertensive effect. Combining ACE inhibitors with diuretics results in good blood pressure (BP) responses at low risk of adverse events (AE). The purpose of this study was to determine the efficacy, safety and tolerability of low-dose combinations of Moex and hydrochlomthiazide (HCTZ) in patients with mild to moderate hypertension. Five hundred and twenty patients with sitting diastolic blood pressure (SDBP) of 95-114 mm Fig were randomized to 12-week double-blind treatment. During this period patients received~once daily placebo, Moex 3.75 or 7.5 mg, HCTZ 3.125, 6.25 or 12.5 mg or combinations of both drugs using these doses. At biweekly visits blood pressures, pulse rates and AEs were documented. At endpoint, low-dose combination treatment showed significantly larger adjusted mean reductions in SDBP from baseline than did placebo or the single agent components. Best results were obtained with Moex3.75/ HCTZt2.5, Meex7.5/HCTZ6.25 and Moex7.5/HCTZ12.5. The changes from baseline (expressed as "ram Hg") were as follows: 0 mg HCTZ 3.125 mg HCTZ 6.25 nag HCTZ 12.5 mg HCTZ
0 me Moex -3.8 -5.4 -5.5 -8.1
3.75 mg Moex 7.5 mg Moex_ -7.2 -8.9 :8.5 -9.2 -7.7 -10.4 -11.0 -I1.5
INFLUENCE OF ISRADIPINETREATMENT ON PLATELET MEMBRANE LIPID ALTERATIONS AND AGGREGATION IN PATIENTS WITH ESSENTIAL HYPERTENSION°
T.I.Bazhenova., L.I.Gapon Institute of Clinical & Preventive Cardiology,Tyumen,Russia The aim of present investigation was to study the platelet membranes lipid alterations and aggregation levels in patients with essential hypertension and to assess the possible membrane stabilisation effect by isradipine in mild essential hypertensive pts. Sistolic, diastolic blood pressure ($BP, DBP); cell membrane lipid profile - platelet membrane cholesterol (CH) content, phospholipid (PH) spectrum (phosphaUdylcholine (PC), lysophosphatidylcholine (LPC), srhingomyeline (SM) (by thin-layer chromatography method); lipid peroxydes products levels= dienes conjugates (DC) and malonic dialdehyde (MD) (by photometric method) and ADP-induced aggregation (by Borffs method)were determined in 126 males aged 16-45 yes with borderline hypertension (BH), mild and moderate essential hypertension (EH)..Effect of isradipine was estimated after four-week treatment (5 rag/day) in group with mild EH (22 pts). The progression of hypertension to accompaned the increasing CH content (p<.05), DC and MD levels (p<.01) and ADP-induced platelet aggregation (p<.001). Significant changes in main PH fraction levels were not revealed, but SM and LPH levels had tendency to increasing in moderate EH. The investigation showed the positive correlations between DBP and DC (p<.05), SBP and MD (p<.05), MD and CH content (p<.05), ADP-induced aggregation and MD (p<.05)i LPC (p<.05), PH (p<.05) and CH content (p<.01). Dynamic investigation of parametrs after isradipine treatment in pts with mild EH revealed thattheexpressive hypotensive effect (81%) of drug to aceompaned significant lowering of CH content (p<.05), and DC, MD levels (p<.01). LPC, PH and ADP-induced aggregation had
After treatment with Moex and HCTZ the most frequently reported AEs were headache, upper respiratory infection and increased cough. This study shows that low dose combinations of Moex and HCTZ have a favourable safety profile and are more efficacious in the treatment of hypertension than their individual components alone.
tendency to decreasing. Thus, we showed that isradipine causes the blood pressure lowering and positive modificates platelet membrane lipid alterations and aggregation, that may be one of the prevention factors of athero- and trombogenesis development.
EFFECT OF A CHRONIC TREATMENT WITH ACE INHIBITORS ON RAT TISSUE ACE CHARACTERISTICS F. Brde I. M.C. Martiska 1, G. Hamon 2, S. Jouquey2, J.P. Tillcment I (1) Drpartement de Phannacologie, Facult6 de Mrdecine de Paris XII, 94010 Crrteil, France. (21 Roussel-Ucla£ 93230 RomainviUe, France.
PASSAGE OF B L O O D B R A I N BARRIER BY TRANDOLAPRIL A N D E N A L A P R I L IN S H R A T S AFTER C H R O N I C T R E A T M E N T .C. Chevillard*, S. Jouquey, M-N. Mathieu* and G. Hamon *INSERM U.300, Montpellier & Roussel Uclaf, Romainville, France.
The importance of tissue angiotensin converting enzyme (ACE) rather than its soluble isofonn in plasma, in determining long-term antihypertensive efficacy of ACE inhibitors has been largely demonstrated by several investigators. Indeed the antihypertensivc response appeared to correlate better with the inhibition of tissue ACE activity. Interruption of a chronic treatment with ACE inhibitors has also been shown to be associated with a rapid rise in plasma ACE activky even leading to a rebound of activity above basal level. However some compounds like trandolapril do not lead to such a phenomenon. At the end of a trandolapril treatment the enzymatic ACE activity recovers slowly, three weeks washout being necessary for a full recovery. [n order to explain this umque property of trandolapril, wc have measured the binding characteristics to the ACE after a chronic treatment with two different inhibitors. Increasing doses of trandolapril (0.3 - 1000 gg/kg) or coalapril (0.3 - 30 mg/kg) were administered intrapcritoneally for 14 days to normotensivc rats. ACE characteristics were measured in hmg and heart plasma membranes and compared according to the drug dose regimen during the treatment. The ACE activity being progressively inhibited, the affinity of the enzyme for anglotensin I was considerably decreased whereas that for the active metabolite trandolaprilat did not vary. No variation of the number of binding sites occurred after treatment with enalapril, but a significant decrease of this parameter was observed with trandolapril from the dose of 30 lag/kg. We cenclude that the ACE inhibitor trandolapril causes after chronic treatment doses, an inhibition of the membrane bound enzyme biosynthesis.
Data concerning the passage of the blood brain barrier (BBB) by ACE inhibitors are conflicting. This is probably due to the different modes of administration, strains of animals and the state of the BBB but also to differences in chemical nature of the molecules. Therefore, the aim of the present study was to determine whether the new ACE inhibitor trrandolapril was able to cross the BBB in spontaneously hypertensive (SH) rats. For that purpose, we have measured ex vivo ACE activity in different brain areas of SH rats after a 2 week oral treatment with trandolapril (0.001, 0.01, 0.1 and 1 mg/kg/day). The effects of trandolapril were compared with those of enalapril (10 mg/kg/day) used as a reference compound. ACE activity was assayed in homogenates of punched specific brain areas by a radiometric enzymatic method using radiolabeled hippuryl-histidyl-leucine as substrate. Enalapril induced a decrease in ACE activity in brain areas not protected by the BBB (organon subfomicalis and eminentia mediana) and in cerebral cortex. Conversely trandolapril at a dose of 0.01 mg/kg/day and above induced a dose-dependent inhibition of ACE activity in all brain areas assayed, including hypothalamic supraopticus and paraventricularis nuclei, septum, amygdala, hippocampus, cerebellar and cerebral cortex, nucleus tractus solitarii and nucleus caudatus. The inhibition was roughly similar in all brain areas studied with ID50s close to 0.1 mg/kg/day. These data show that after chronic oral administration trandolapril or its metabolite, in contrast to enalapril can reach all brain areas of SH rats including those protected by the BBB.
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.
.
.
Moexipfil (Moex) is a new angiotensin converting enzyme (ACE) inhibitor. Given once daily it demonstrates a potent 24 hourantihypertensive effect. Combining ACE inhibitors with diuretics results in good blood pressure (BP) responses at low risk of adverse events (AE). The purpose of this study was to determine the efficacy, safety and tolerability of low-dose combinations of Moex and hydrochlomthiazide (HCTZ) in patients with mild to moderate hypertension. Five hundred and twenty patients with sitting diastolic blood pressure (SDBP) of 95-114 mm Fig were randomized to 12-week double-blind treatment. During this period patients received~once daily placebo, Moex 3.75 or 7.5 mg, HCTZ 3.125, 6.25 or 12.5 mg or combinations of both drugs using these doses. At biweekly visits blood pressures, pulse rates and AEs were documented. At endpoint, low-dose combination treatment showed significantly larger adjusted mean reductions in SDBP from baseline than did placebo or the single agent components. Best results were obtained with Moex3.75/ HCTZt2.5, Meex7.5/HCTZ6.25 and Moex7.5/HCTZ12.5. The changes from baseline (expressed as "ram Hg") were as follows: 0 mg HCTZ 3.125 mg HCTZ 6.25 nag HCTZ 12.5 mg HCTZ
0 me Moex -3.8 -5.4 -5.5 -8.1
3.75 mg Moex 7.5 mg Moex_ -7.2 -8.9 :8.5 -9.2 -7.7 -10.4 -11.0 -I1.5
INFLUENCE OF ISRADIPINETREATMENT ON PLATELET MEMBRANE LIPID ALTERATIONS AND AGGREGATION IN PATIENTS WITH ESSENTIAL HYPERTENSION°
T.I.Bazhenova., L.I.Gapon Institute of Clinical & Preventive Cardiology,Tyumen,Russia The aim of present investigation was to study the platelet membranes lipid alterations and aggregation levels in patients with essential hypertension and to assess the possible membrane stabilisation effect by isradipine in mild essential hypertensive pts. Sistolic, diastolic blood pressure ($BP, DBP); cell membrane lipid profile - platelet membrane cholesterol (CH) content, phospholipid (PH) spectrum (phosphaUdylcholine (PC), lysophosphatidylcholine (LPC), srhingomyeline (SM) (by thin-layer chromatography method); lipid peroxydes products levels= dienes conjugates (DC) and malonic dialdehyde (MD) (by photometric method) and ADP-induced aggregation (by Borffs method)were determined in 126 males aged 16-45 yes with borderline hypertension (BH), mild and moderate essential hypertension (EH)..Effect of isradipine was estimated after four-week treatment (5 rag/day) in group with mild EH (22 pts). The progression of hypertension to accompaned the increasing CH content (p<.05), DC and MD levels (p<.01) and ADP-induced platelet aggregation (p<.001). Significant changes in main PH fraction levels were not revealed, but SM and LPH levels had tendency to increasing in moderate EH. The investigation showed the positive correlations between DBP and DC (p<.05), SBP and MD (p<.05), MD and CH content (p<.05), ADP-induced aggregation and MD (p<.05)i LPC (p<.05), PH (p<.05) and CH content (p<.01). Dynamic investigation of parametrs after isradipine treatment in pts with mild EH revealed thattheexpressive hypotensive effect (81%) of drug to aceompaned significant lowering of CH content (p<.05), and DC, MD levels (p<.01). LPC, PH and ADP-induced aggregation had
After treatment with Moex and HCTZ the most frequently reported AEs were headache, upper respiratory infection and increased cough. This study shows that low dose combinations of Moex and HCTZ have a favourable safety profile and are more efficacious in the treatment of hypertension than their individual components alone.
tendency to decreasing. Thus, we showed that isradipine causes the blood pressure lowering and positive modificates platelet membrane lipid alterations and aggregation, that may be one of the prevention factors of athero- and trombogenesis development.
EFFECT OF A CHRONIC TREATMENT WITH ACE INHIBITORS ON RAT TISSUE ACE CHARACTERISTICS F. Brde I. M.C. Martiska 1, G. Hamon 2, S. Jouquey2, J.P. Tillcment I (1) Drpartement de Phannacologie, Facult6 de Mrdecine de Paris XII, 94010 Crrteil, France. (21 Roussel-Ucla£ 93230 RomainviUe, France.
PASSAGE OF B L O O D B R A I N BARRIER BY TRANDOLAPRIL A N D E N A L A P R I L IN S H R A T S AFTER C H R O N I C T R E A T M E N T .C. Chevillard*, S. Jouquey, M-N. Mathieu* and G. Hamon *INSERM U.300, Montpellier & Roussel Uclaf, Romainville, France.
The importance of tissue angiotensin converting enzyme (ACE) rather than its soluble isofonn in plasma, in determining long-term antihypertensive efficacy of ACE inhibitors has been largely demonstrated by several investigators. Indeed the antihypertensivc response appeared to correlate better with the inhibition of tissue ACE activity. Interruption of a chronic treatment with ACE inhibitors has also been shown to be associated with a rapid rise in plasma ACE activky even leading to a rebound of activity above basal level. However some compounds like trandolapril do not lead to such a phenomenon. At the end of a trandolapril treatment the enzymatic ACE activity recovers slowly, three weeks washout being necessary for a full recovery. [n order to explain this umque property of trandolapril, wc have measured the binding characteristics to the ACE after a chronic treatment with two different inhibitors. Increasing doses of trandolapril (0.3 - 1000 gg/kg) or coalapril (0.3 - 30 mg/kg) were administered intrapcritoneally for 14 days to normotensivc rats. ACE characteristics were measured in hmg and heart plasma membranes and compared according to the drug dose regimen during the treatment. The ACE activity being progressively inhibited, the affinity of the enzyme for anglotensin I was considerably decreased whereas that for the active metabolite trandolaprilat did not vary. No variation of the number of binding sites occurred after treatment with enalapril, but a significant decrease of this parameter was observed with trandolapril from the dose of 30 lag/kg. We cenclude that the ACE inhibitor trandolapril causes after chronic treatment doses, an inhibition of the membrane bound enzyme biosynthesis.
Data concerning the passage of the blood brain barrier (BBB) by ACE inhibitors are conflicting. This is probably due to the different modes of administration, strains of animals and the state of the BBB but also to differences in chemical nature of the molecules. Therefore, the aim of the present study was to determine whether the new ACE inhibitor trrandolapril was able to cross the BBB in spontaneously hypertensive (SH) rats. For that purpose, we have measured ex vivo ACE activity in different brain areas of SH rats after a 2 week oral treatment with trandolapril (0.001, 0.01, 0.1 and 1 mg/kg/day). The effects of trandolapril were compared with those of enalapril (10 mg/kg/day) used as a reference compound. ACE activity was assayed in homogenates of punched specific brain areas by a radiometric enzymatic method using radiolabeled hippuryl-histidyl-leucine as substrate. Enalapril induced a decrease in ACE activity in brain areas not protected by the BBB (organon subfomicalis and eminentia mediana) and in cerebral cortex. Conversely trandolapril at a dose of 0.01 mg/kg/day and above induced a dose-dependent inhibition of ACE activity in all brain areas assayed, including hypothalamic supraopticus and paraventricularis nuclei, septum, amygdala, hippocampus, cerebellar and cerebral cortex, nucleus tractus solitarii and nucleus caudatus. The inhibition was roughly similar in all brain areas studied with ID50s close to 0.1 mg/kg/day. These data show that after chronic oral administration trandolapril or its metabolite, in contrast to enalapril can reach all brain areas of SH rats including those protected by the BBB.
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