amlodipine Norvasc
Morning versus evening amlodipine treatment: effect on circadian blood pressure profile in essential hypertensive patients.

Nold G, Strobel G, Lemmer B.

Institute of Pharmacology and Toxicology, Faculty of Clinical Medicine, Ruprecht Karls-Universitat Heidelberg, Germany.

OBJECTIVE: To determine the antihypertensive efficacy and the potential impact on circadian blood pressure pattern of morning versus evening administration of amlodipine to essential hypertensive patients. METHODS: Twelve mild-to-moderate essential hypertensives were investigated in this open, randomized cross-over study. Blood pressure and heart rate were measured by use of ambulatory blood pressure monitoring after a wash-out period of 1 week and after treatment schedules with 5 mg amlodipine once a day either at 0800 h or at 2000 h for 3 weeks. Effects were evaluated by linear and rhythm analysis using the ABPM-FIT program. RESULTS: Both morning and evening administrations of amlodipine significantly (P < 0.01) reduced the elevated systolic and diastolic blood pressures during daytime. However, due to baseline values being lower during night-time, a significant (P < 0.05) reduction was observed only in systolic, not in diastolic, blood pressure. Maximal blood pressure values were significantly (P </= 0.01) decreased by both treatment regimens, whereas nightly minimum values remained unchanged. The early morning rise in blood pressure was decreaseed after morning and slightly more pronounced aftger evening dosing of amlodipine. Though both amlodipine treatments more effectively reduced daytime blood pressure levels, the circadian profile was not greatly affected. Amlodipine treatment had no effect on heart rate. CONCLUSION: The results demonstrate that, independently from the dosing time, the long-acting calcium antagonist amlodipine sufficiently reduced blood pressure in essential hypertensive patients without increasing the nightly drop. The drug-induced decrase in the early morning rise in blood pressure may be advantageous in reducing the early morning cardiovascular risk.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10212327&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Are there differences in the effects of long-acting calcium antagonists on ambulatory blood pressure? Extended-release nisoldipine versus amlodipine as a model.

Punzi HA, Noveck R, Weiss RJ, Graf R, Ruff DA, Hutchinson HG, White WB.

Trinity Hypertension Research Center, Carrollton, Texas, USA.

BACKGROUND: Twenty-four-hour ambulatory blood pressure monitoring (ABPM), which provides important information regarding mean 24 h efficacy, variability of effect during sleeping-awake cycles, and effects on the early morning surge in blood pressure, is a sensitive method for evaluating efficacy of antihypertensive agents. Extended-release nisoldipine and amlodipine are long-acting dihydropyridine calcium antagonists used for the treatment of hypertension. Because these agents have different pharmacokinetic profiles, 24 h ABPM could provide clues regarding their different effects on blood pressure. OBJECTIVE: To assess the effects of extended-release nisoldipine and amlodipine on 24 h ambulatory blood pressure control and heart rate. METHODS: After completion of a 3-4 week placebo run-in period, 100 patients were randomly allocated to double-blind treatment with 10-40 mg extended-release nisoldipine or 2.5-10 mg amlodipine for 8 weeks, starting at the lowest dose. Medications were titrated at 2-week intervals on the basis of office blood pressures in seated patients. Twenty-four-hour ABPM was performed at placebo baseline and at the end of double-blind therapy. RESULTS: Extended-release nisoldipine and amlodipine provided equivalent mean 24 h changes in blood pressure [systolic blood pressure (SBP)/diastolic blood pressure decreases by 9.8/7.1 and 8.0/6.0 mmHg, respectively] and heart rate. These two treatments also provided similar changes in blood pressure at trough (22-24 h after dosing; decreases by 10.4/7.2 and 10.1/7.3 mmHg, respectively). The antihypertensive effects of amlodipine during the awake and sleeping intervals were similar (decreases by 9.6/5.9 and 9.9/5.8 mmHg, respectively, NS); whereas the effect of nisoldipine during the awake interval was significantly greater than its effect during the sleeping interval (decreases by 12.4/8.0 and 8.9/4.3 mmHg, respectively, P = 0.08/0.01). Furthermore, extended-release nisoldipine, but not amlodipine, blunted the rate of rise in early morning SBP. CONCLUSIONS: Extended-release nisoldipine and amlodipine have similar effects on mean 24 h and trough blood pressures. However, different effects during the sleeping and awake intervals and on the rate of rise in early morning SBP were observed with nisoldipine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10212365&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
A comparison of the efficacies and duration of action of the angiotensin II receptor blockers telmisartan and amlodipine.

Lacourciere Y, Lenis J, Orchard R, Lewanczuk R, Houde M, Pesant Y, Wright J, Wilson T, Martin K.

Department of Medicine, Universite Laval, Ste-Foy, Montreal, Canada.

OBJECTIVES: To compare the antihypertensive effects and duration of action of the angiotensin II receptor antagonist, telmisartan, amlodipine, and placebo in patients with mild-to-moderate hypertension using both conventional clinic blood pressures and ambulatory blood pressure monitoring (ABPM). METHODS: After a 4-week single-blind, placebo run-in period, qualifying patients were randomly allocated in double-blind manner to be administered 40 mg telmisartan (n = 73; increased to 80 and 120 mg as necessary for patients whose diastolic blood pressure (DBP) remained > 90 mmHg); 5 mg amlodipine (n = 78; titrated to 5 mg and titrated to 10 mg for patients whose DBP remained > 90 mmHg); or placebo (n = 81). ABPM was performed at the end of the baseline period and again at the end of 12 weeks of double-blind treatment. RESULTS: Telmisartan and amlodipine treatments significantly decreased trough supine systolic blood pressure and DBP (P < 0.001, measured conventionally) to a similar extent (by 13.1/7.1 and 14.0/7.1 mmHg, respectively, at the end of 12 weeks' treatment) compared with placebo. Both drugs also significantly reduced 24 h mean systolic blood pressures and DBP compared with placebo (P < 0.0001), measured using ABPM, maintaining control of blood pressure throughout the dosing period. Reductions in DBP with telmisartan were greater (P < 0.05) than those with amlodipine during the night-time interval and the last 4 h of the dosing period. Twenty-four-hour mean ABPM DBP < 85 mmHg were observed in 71% of telmisartan patients and in 55% of patients administered amlodipine. In addition, heart rates in patients treated with telmisartan were lower than heart rates in those treated with amlodipine during the final 4 h of the dosing period (P = 0.0003) and during the morning interval (P = 0.005). Generally, both telmisartan and amlodipine were well tolerated, however, drug-related edema occurred significantly more commonly (P < 0.05) among the patients administered amlodipine than it did among patients administered either telmisartan or placebo. CONCLUSIONS: Clinic blood pressure measurements detected no difference between the antihypertensive effects and durations of action of telmisartan and amlodipine, both agents producing statistically significant reductions compared with placebo. ABPM measurements, however, revealed differences between the efficacies at specific time points within the dosing periods. These findings highlight the potential importance of the use of ABPM for evaluating and comparing efficacies of antihypertensive agents.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10212369&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Pharmacologic characterization of FR172516: a new combined calcium channel-blocking and beta-adrenoceptor-blocking agent.

Yamamoto N, Nomura M, Okubo K, Maeda K, Goto T.

Medicinal Biology Research Laboratory, Fujisawa Pharmaceutical Co., Osaka, Japan.

The pharmacologic characterization of FR172516, a new combined calcium channel-blocking and beta-adrenoceptor-blocking agent, was studied and compared with amlodipine in receptor-binding assay and in vivo studies. In the binding assay, Ki values of FR172516 for calcium channel and beta-receptor were 29.3 nM and 44.1 nM, respectively. In the in vivo studies with pithed rats, FR172516 shifted the dose-response curves of isoproterenol in heart rate to the right, suggesting that this compound has a antiadrenoceptor effect in vivo. The hypotensive effect of FR172516, which could be mainly attributed to its calcium channel-blocking action, was compared with that of amlodipine in normotensive Wistar rats (NTRs), spontaneously hypertensive rats (SHRs), and renal hypertensive dogs (RHDs). FR172516 showed more potent hypotensive action than amlodipine when administered intravenously to NTRs, and apparent bradycardia was seen only with FR172516. In SHRs, FR172516 showed a long-lasting hypotensive action and dose-dependently decreased heart rate, whereas amlodipine scarcely affected heart rate. In RHDs, oral administration of FR172516 once daily for 5 days decreased blood pressure without reflex tachycardia or an increase of plasma renin activity. On the other hand, amlodipine, in the dose at which hypotensive effects equipotent to those of FR172516 were observed, produced apparent reflex tachycardia and concomitant increase of plasma renin. These results indicate that FR172516 has a potent long-lasting antihypertensive effect without activating sympathetic tone by calcium channel-blocking and beta-adrenoceptor-blocking actions.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10218729&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
An economic evaluation of the JNC hypertension guidelines using data from a randomized controlled trial. Joint National Committee.

Ramsey SD, Neil N, Sullivan SD, Perfetto E.

Department of Medicine, University of Washington, Seattle, USA.

BACKGROUND: We wanted to determine the clinical cost of managing hypertension when following the Joint National Committee on Hypertension (JNC) guidelines, including drug therapy, the cost of monitoring for and treating side effects, compliance, and the cost of switching after therapeutic failures. METHODS: The base-case analysis considers antihypertensive agents from four therapeutic classes that were recently evaluated in a large randomized trial: enalapril, amlodipine, acebutolol, and chlorthalidone. Clinical evaluation, therapy, and monitoring for hypertension are modeled with an incidence-based Markov model. Clinical inputs include agent efficacy, side effects, and compliance with dosing schedules. JNC-recommended clinical and laboratory monitoring schedules are followed for each agent. Switches between classes occur for therapeutic failures. Drug and medical care costs are valued in 1995 US dollars. RESULTS: Although patients whose hypertension was initially treated with amlodipine achieved control more readily than patients who were given the other agents, the initial costs to achieve and maintain hypertension control were lowest for chlorthalidone ($641), followed by acebutolol ($920), amlodipine ($946), and enalapril ($948). Maintenance costs were lowest for chlorthalidone. For all agents except chlorthalidone, drug costs were the largest component of overall costs, followed by the costs of office visits, laboratory monitoring, and switching between classes for therapeutic failures. CONCLUSIONS: By following JNC guidelines, a slightly higher percentage of patients will achieve hypertension control with a newer class calcium channel blocker (amlodipine) but at a substantially higher cost than with a generic diuretic (chlorthalidone).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10220232&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
The effects of missing a dose of enalapril versus amlodipine on ambulatory blood pressure.

Hernandez-Hernandez R, Armas de Hernandez MJ, Armas-Padilla MC, Carvajal AR, Guerrero-Pajuelo J.

Clinical Pharmacology Unit, School of Medicine, Universidad Centro Occidental Lisandro Alvarado, Barquisimeto, Venezuela.

OBJECTIVE: To compare the antihypertensive actions of amlodipine and enalapril in a double-blind, randomized, parallel-group study during treatment and when missing a dose. METHOD: After a single-blind run-in 4-week placebo period, patients were randomly allocated to receive enalapril (15 patients) or amlodipine (15 patients). Patients received active treatment for 4 weeks (20 mg enalapril or 5 mg amlodipine). For those with sitting diastolic office pressure not below 90 mmHg the dosage was doubled and continued up to week 12. Ambulatory blood pressure monitoring was performed at the end of the placebo run-in period for 24 h and at the end of week 12 for 48 h; in this case, patients took the active tablet at 0700 h of the first day and a placebo tablet on the next day to stimulate a missing dose in a single-blind manner. RESULTS: Of the patients, 60% had office blood pressure controlled by enalapril therapy and 80% had amlodipine therapy. The average dosage was 30.7 mg a day for enalapril and 7.3 mg a day for amlodipine. Reductions in blood pressures were higher for the amlodipine group. Ambulatory blood pressure measurement shows a reduction in systolic and in diastolic blood pressure during the 24 h when patients from both groups were receiving their medication with respect to placebo values. During the second day of ambulatory blood pressure recording, when the patient had taken a placebo tablet instead of an active one, the antihypertensive effect was progressively lost with enalapril, but not with amlodipine. CONCLUSION: Enalapril and amlodipine reduced ambulatory systolic and diastolic blood pressure during treatment; however, when patients missed an enalapril dose, control of blood pressure was progressively lost, whereas patients receiving amlodipine maintained their blood pressure under control up to 48 h after the last dose.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10226213&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Vasoactive agents modulate matrix metalloproteinase-2 activity by mesangial cells.

Singhal PC, Sagar S, Garg P, Bansal V.

Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York 11040, USA.

Vasoactive agents alter proteinuria by modulating glomerular hemodynamics. The authors hypothesized that vasoactive agents may be altering degradation of the collagen component of glomerular basement membrane, which also may be contributing to proteinuria. Mesangial cells treated with 10(-6) M angiotensin II had higher (P < 0.01) metalloproteinase activity (MA) when compared with control cells. This effect of angiotensin II was dose dependent. Amlodipine (10(-6) M), a calcium channel blocker, inhibited MA (control, 5.86 +/- 0.08 microgram versus 4.13 +/- 0.06 microgram gelatin degraded/mg protein, P < 0.001). The decrease in mesangial MA caused by amlodipine also occurred in a dose dependent manner. Amlodipine attenuated (P < 0.05) angiotensin II-stimulated MA (control, 6.69 +/- 0.30 micrograms, angiotensin II, 10.68 +/- 0.49 micrograms, angiotensin II+amlodipine 8.29 +/- 0.30 micrograms gelatin degraded/mg protein). Prostaglandin E2 increased (P < 0.001) MA (control, 10.22 +/- 0.9 micrograms versus prostaglandin E2, 17.9 +/- 0.9 micrograms gelatin degraded/mg protein), whereas indomethacin, a prostaglandin inhibitor, attenuated the metalloproteinase activity (control, 9.67 +/- 0.32 micrograms vs. 10(-6) M indomethacin, 4.22 +/- 0.31 micrograms gelatin degraded/mg protein, P < 0.001). Indomethacin also inhibited angiotensin II-stimulated MA (angiotensin II, 18.66 +/- 0.46 vs. angiotensin II+indomethacin, 11.86 +/- 0.56 micrograms degraded/mg protein, P < 0.001). Similarly, meclofenamate, another prostaglandin inhibitor, attenuated (P < 0.001) angiotensin II-induced MA. Because angiotensin II increases prostaglandin E2 synthesis by mesangial cells, it appears that increased MA, induced by angiotensin II, may be mediated partly through the generation of prostaglandin E2.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7503103&dopt=Abstract amlodipine Norvasc



amlodipine Norvasc
Protein synthesis in the hypertrophied heart of spontaneously hypertensive rats and a comparison of the effects of an ACE-inhibitor and a calcium channel antagonist.

Patel VB, Siddiq T, Richardson PJ, Preedy VR.

Department of Clinical Biochemistry, King's College School of Medicine & Dentistry, London, U.K.

The aim of the investigation was to assess and compare the effects of a calcium channel antagonist, (i.e. amlodipine) and an ACE-inhibitor (i.e. lisinopril) in reducing chronic left ventricular hypertrophy in 15-week old spontaneously hypertensive rats (SHR). Changes in cardiac hypertrophy were assessed after 8 weeks by measuring the fractional rates of protein synthesis using a 'flooding dose' of [3H]-phenylalanine for 10 min. Blood pressure was monitored throughout the treatment period in both SHR and Wistar-Kyoto control rats (WKY). The results showed a decrease in blood pressure by amlodipine after 1 week of treatment which was further reduced at 4 to 8 weeks. Lisinopril caused immediate and sustained reductions in blood pressure (190 mmHg to 130 mmHg, P < 0.001). After 8 weeks of treatment in SHR rats, amlodipine had no significant effect on left ventricular weight (P > 0.05), whereas lisinopril caused a marked reduction. The protein content and RNA were also not changed by amlodipine. In contrast, lisinopril significantly lowered the tissue protein, RNA and DNA content (P < 0.001). The changes in the left ventricles of lisinopril-treated SHR rats were accompanied by an increase in the fractional synthesis rate of left ventricular myofibrillar proteins (+12 per cent, P < 0.025). The synthesis rate per unit RNA was also increased in right ventricular tissue of lisinopril-treated SHR rats. However, amlodipine had no effect on the fractional synthesis rates of any of the left-ventricular fractions of SHR rats (P > 0.05). The cellular efficiency in the right ventricle was also increased in amlodipine-treated SHR rats, indicating a moderate effect on protein metabolism. In conclusion, amlodipine had minimal effects in the reduction of established left ventricular hypertrophy (LVH), despite reducing the blood pressure, whereas lisinopril caused regression of LVH. These events were associated with small changes in protein synthesis rates, with the contractile protein showing an increase.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7538913&dopt=Abstract amlodipine Norvasc