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Black HR, Elliott WJ, Weber MA, Frishman WH, Strom JA, Liebson PR, Hwang CT, Ruff DA, Montoro R, DeQuattro V, Zhang DY, Schleman MM, Klibaner MI. One-year study of felodipine or placebo for stage 1 isolated systolic hypertension. Hypertension 2001;38(5):1118-23. The aim of this randomized, double-blind, parallel group study was to compare the effects of felodipine with placebo on blood pressure, ventricular hypertrophy and quality of life in 171 stage 1 isolated systolic hypertensive patients (84 male, 87 female; mean age 66 years) for 1 year. The patients were randomized to receive either felodipine extended-release 2.5 mg or placebo, if the sitting systolic blood pressure (SBP) was > 140 mm Hg, the dose of felodipine or placebo was doubled. Significantly more patients withdrew from the placebo than the felodipine group. After 1 year patients were receiving either felodipine or placebo at 2.5, 5 or 10 mg. Felodipine treatment was associated with significantly greater reductions from baseline in mean trough SBP at all time points. Mean reductions in trough sitting SBP at week 52 compared with baseline were 11.7 mm Hg for felodipine and 2.0 mm Hg for placebo. After 52 weeks treatment mean reductions in trough diastolic blood pressure were 3.0 and 0.1 mm Hg in felodipine and placebo groups, respectively. Patients randomized to felodipine consistently demonstrated greater mean reductions in blood pressure regardless of age, gender or ethnicity. Felodipine treatment demonstrated significant differences compared to placebo with respect to response rates, 62% vs 34%. 9 patients experienced a worsening of their hypertension, 6 of these were in the placebo group and 3 were in the felodipine group. The prevalence of blood pressure control at week 52 was significantly different, 62% felodipine vs 32% placebo. The mean left ventricular mass index did not change between the groups after 52 weeks treatment. 13% of the felodipine treated patients had left ventricular hypertrophy (LVH) after 52 weeks compared with 33% in the placebo group. 7% of patients that did not have LVH at baseline developed it during the study in the felodipine group compared with 24% in the placebo group. Felodipine treatment had significantly better scores on anxiety and depression than placebo did. 7 patients discontinued treatment due to adverse reactions, 2 patients were from the felodipine group and 5 from the placebo group. Dizziness, back pain and headache were more common in the placebo-treated patients, while hematuria, rhinitis and dyslipidemia were more common in the felodipine-treated patients. The authors conclude that felodipine treatment reduced progression to the higher stages of hypertension, reduced the incidence of LVH and improved an overall measure of the quality of life. Morgan TO, MacInnis R, Bertram D, Anderson AE. The effect of candesartan, felodipine or their combination on 24 h blood pressure and microalbuminuria. Journal of Hypertension 2001;19(Suppl 2):S174, Abs 7C.5. In this double-blind crossover study 32 patients received candesartan 16 mg, felodipine 5 mg, candesartan + felodipine or placebo. Mean 24-h ambulatory blood pressure fell 12.3/6.8 mm Hg in the candesartan group, 12.0/5.5 mm Hg in the felodipine group and 21.0/10.2 mm Hg in the candesartan + felodipine. 22 patients taking candesartan + felodipine, 5 patients taking candesartan and 5 patients taking felodipine achieved their lowest 24-h ambulatory blood pressure. The blood pressure reduction with combined therapy was additive and consistent over day and night. In the 14 patients with microalbuminuria, urinary albumin excretion rates were 192 mcg/min in the placebo group, 101 mcg/min in the candesartan group, 181 mcg/min in the felodipine group and 93 mcg/min in the candesartan + felodipine group. Falls in microalbuminuria did not correlate with falls in blood pressure. All drugs were well tolerated. The authors conclude that blood pressure is reduced more effectively by candesartan + felodipine than by either drug alone, and that candesartan reduces microalbuminuria. Morgan TO, MacInnis R, Bertram D, Anderson AE. The effect of candesartan, felodipine or their combination on 24h ambulatory blood pressure. American Journal of Hypertension 2001;14(4 Pt 2):27a, Abs O-57. In this double-blind crossover study 36 patients (all aged > 65 years) with systolic hypertension received candesartan 16 mg, felodipine 5 mg, candesartan + felodipine or placebo. 32 patients completed all treatment periods and underwent 24-h ambulatory blood pressure measurements and clinic blood pressure measurements at the end of each treatment period. Systolic and diastolic ambulatory and clinic blood pressure readings for felodipine, candesartan, felodipine + candesartan and placebo are shown in a table. Blood pressures were lower in the felodipine and candesartan groups than in the placebo groups. Felodipine + candesartan treatment had an additive effect, causing a fall in blood pressure greater than that achieved by either drug alone. All treatments were well tolerated. The authors conclude that candesartan + felodipine is a more effective treatment for hypertension than either drug alone due to an additive effect of the 2 drugs. Dopp JM, Ernst ME, Dellsperger KC, Phillips BG. Comparison of amlodipine and felodipine on 24-hour ambulatory blood pressure in hypertensive patients. American Journal of Hypertension 2001;14(4 Pt 2):118a, Abs P-267. Heart rate and 24-h ambulatory blood pressure values were compared in 50 patients (mean age 56 years) with mild-to-moderate hypertension who were randomized to 8 weeks of amlodipine 5 mg/day (n = 24) or felodipine 5 mg/day (n = 26). Doses of both drugs could be doubled if needed to obtain blood pressure control. Mean daily doses at the end of the study were amlodipine 8 mg and felodipine 7 mg. Mean 24-h ambulatory blood pressure values were significantly lower in felodipine than in amlodipine patients after 1 week of therapy, but both drugs significantly and similarly decreased mean 24-h ambulatory blood pressure as well as daytime and nighttime ambulatory blood pressure after 8 weeks of therapy. The authors conclude that felodipine decreased blood pressure sooner than did amlodipine, but that both agents have similar antihypertensive effects after 8 weeks of therapy. Mancia G, Omboni S, Parati G, Clement DL, Haley WE, Rahman SN, Hoogma RPLM. Twenty-four hour ambulatory blood pressure in the Hypertension Optimal Treatment (HOT) study. Journal of Hypertension 2001;19(10):1755-63. In this Hypertension Optimal Treatment (HOT) sub-study, patients (n = 277, 54% male; mean age 62 years) underwent both office measurements and 24 h ambulatory blood pressure measuring to determine the extent of which antihypertensive treatment modifies daily life blood pressure. All patients were randomized to reach a target diastolic blood pressure < = 90 mm Hg, < = 85 mm Hg or < = 80 mm Hg by administering a 5 step drug treatment. Step 1 consisted of administration of felodipine 5 mg plus a low dose of ACE inhibitor or beta-blocker. Step 2 involved felodipine 10 mg plus the previous dose of ACE inhibitor or beta blocker. Step 3 included felodipine 10 mg administration plus a higher ACE inhibitor or beta-blocker dose. Step 4 equated to step 3 with the addition of hydrochlorothiazide. Step 5 equated to step 3 plus other hypertensive drugs. When these steps were completed the patients were randomized to take a daily dose of acetylsalicylic acid 75 mg or placebo in a double-blind fashion. Significantly when patients were taking felodipine only, it was found that heart rate was not increased. It is evident from the results of this study that, before treatment, 24 h diastolic and systolic average blood pressures were substantially less than the corresponding office values; and this is consistent with similar studies. Yang ZH, Madinova A, Kozai T, Joch H, Aebi U, Luscher TF. Felodipine inhibits nuclear translocation of p42/44 mitogen-activated protein kinase and human smooth muscle cell growth. Cardiovascular Research 2002;53(1):227-31. The aim of this study was to determine whether felodipine interferes with the p42/44 mitogenactivated protein kinases pathway, and thereby arrest cell growth. As part of the DNA synthesis study section of the study, smooth muscle cells were stimulated with platelet-derived growth factor for 24 h in the presence or absence of felodipine. For the activation of p42/44 mitogen-activated protein kinases and Elk-1 activation part of the study smooth muscle cells were stimulated with platelet-derived growth factor for 15 rnin in the presence or absence of felodipine and then harvested in extraction buffer. The results of the study showed that stimulation of human smooth muscle cells with platelet-derived growth factor for 24 h enhanced thymidine incorporation. This process was prevented in the presence of felodipine. Activation of p42/44 mitogen-activated protein kinases was not influenced by felodipine. The results also showed that platelet-derived growth factor induced translocation of p42/44 mitogen-activated protein kinases from the cytoplasm to the cell nucleus, this was inhibited by felodipine. Furthermore, 1 of the nuclear protein substrates of p42/44 mitogen-activated protein kinases, Elk-1, was phosphorylated by platelet-derived growth factor, a process which was inhibited by felodipine. This further confirmed that the entry of p42/44 mitogen-activated protein kinases into the nucleus was prevented by felodipine. Zabalgoitia M, Rahman SNU, Haley WE, Yarows S, Krause L, Anderson LC, Oraby MA, Amarena J. Effect of regression of left ventricular hypertrophy from systemic hypertension on systolic function assessed by midwall shortening (HOT echocardiographic study). American Journal of Cardiology 2001;88(5):521-5. A study was carried out in order to determine whether regression of left ventricular (LV) hypertrophy is associated with an improvement in the ventricular mechanics in patients with pressure-overload hypertrophy. A number of patients from the HOT trial (n=508, 58% male; mean age 60 years) were entered into this study and underwent serial echocardiographic examinations. These patients were given felodipine, followed by the addition of either an ACE inhibitor or a betaadrenergic blocking agent, and hydrochlorothiazide until the target diastolic blood pressure was reached. Echocardiograms were carried out at baseline during the 2-week washout phase before starting therapy with felodipine at year 1, year 2, and at the end of the study. Over the course of the study, there was a large reduction in both systolic and diastolic blood pressure. The authors conclude that midwall shortening is a more sensitive index of systolic function in patients with pressure-overload hypertrophy, and it identifies high-risk patients who may benefit from a more aggressive antihypertensive program. Ruzicka M, Leenen FHH. Monotherapy versus combination therapy as first line treatment of uncomplicated arterial hypertension. Drugs 2001;61(7):943-54. This review discusses the treatment options available for uncomplicated arterial hypertension and compares monotherapy with combination therapy for control of this condition. The current recommendation for the treatment of uncomplicated hypertension is mono-drug therapy involving stepwise dose increases and the addition of a second agent if high doses of the original drug fail to normalise blood pressure. Combination drug therapy has only recently come under focus. Single drug regimens address only 1 pathophysiological mechanism of hypertension and the reasons for the lower response rate to single drug therapy may be because the role of the particular pathophysiological mechanism may vary from patient to patient. Previous studies involving single drug therapy with either a diuretic, beta-blocker (atenolol), calcium antagonist or ACE inhibitor showed that response rates were only around 55%. Another possible contributor to the low response achieved by single drug therapy for hypertension may be poor adherence to the single drug regimen, and possible factors which affect patient compliance include cognitive, social and behavioural elements as well as adverse effects and the complexity of the regimen. Combination therapy has several advantages over monotherapy especially in terms of antihypertensive effectiveness at lower doses and thus has a lower incidence of adverse effects. A beta-blocker and calcium antagonist may complement each other in terms of decreasing peripheral vascular resistance and cardiac output and in terms of tolerability. The results of several studies have shown a calcium antagonist/beta-blocker combination to have superior antihypertensive efficacy compared to each agent alone. One such study involved randomization of patients (n=159) with mild hypertension to treatment with felodipine 10 mg/day, metoprolol 100 mg/day or a combination of both for 12 weeks. The response rate, defined as diastolic blood pressure (DBP) lt90mm Hg, was higher with the combination therapy (71%) than with either agent alone (49% for felodipine, 34% for metoprolol). A similar study using both these agents for the treatment of patients with mild to moderate hypertension (n=58) but at lower doses of metoprolol 50 mg/day, felodipine 5 mg/day, or in combination also showed similar results. After 6 weeks of treatment dose titration was performed involving an increase in felodipine from 5 to 10 mg/day and metoprolol from 50 to 100 mg/day. 65% of patients had a positive response to the low dose combination which was significantly higher than either agent alone at the lower or standard dose. Another study investigated 12 weeks of treatment with a combination of felodipine 5 mg/day combined with metoprolol 50 mg/day to treatment with the ACE inhibitor enalapril 10 mg/day and placebo. Dose adjustment was required in 38% of patients receiving the combination because their DPB remained above 90mm Hg compared to 61% of those receiving enalapril and overall response rates were highest in the group that received the combination, being 72%, compared to 49% for enalapril and 30% for placebo. In addition the overall incidence of peripheral oedema with calcium antagonists was also lower when the calcium antagonist was combined with a beta-blocker. The overall conclusion is that fixed low-dose combination therapies offer superior initial antihypertensive efficacy and improved tolerability but whether this will lead to better control of arterial hypertension and thus a further reduction in cardiovascular/cerebrovascular morbidity and mortality remains to be seen. Miczke A, Cymerys M, Bryl W, Luczak M, Pupek Musialik D. The influence of hypertensive drugs on circadian rhythm of blood pressure. Journal of Hypertension 2001;19(Suppl 2):S81, Abs P1.228. In this study 39 patients (aged 20-55 years) with mild-to-moderate essential hypertension received trandolapril, felodipine ER or rilmenidine once daily in the morning for 1 month and in the evening for 1 month. Office blood pressure and ambulatory blood pressure readings showed significant reductions of blood pressure in each treatment group. 24-h mean, daytime and nighttime ambulatory blood pressure readings within each treatment group did not differ between morning treatment and evening treatment periods. The authors conclude that the effect of time of drug administration on blood pressure variability is less pronounced than the effect of antihypertensive treatment itself. Ahmad S, Keeley PA, Stout MJ, Davidson RC. Pretreatment hemodynamics predict response to therapy in essential hypertension: HOT substudy. American Journal of Hypertension 2001;14(4 Pt 2):182a, Abs P-451. The effects of baseline hemodynamics on response to antihypertensive therapy were examined in this sub-study of the Hypertensive Optimum Therapy (HOT) clinical trial involving 10 patients with hypertension well-controlled by felodipine monotherapy and 51 patients randomized to the addition of enalapril or metoprolol to the felodipine. Patients with poor responses to the addition of enalapril or metoprolol after 3 months were crossed over to the other therapy. Baseline cardiac indices were significantly higher and total peripheral resistance was significantly lower among patients who required metoprolol for blood pressure control (n = 16) compared with those whose blood pressure was controlled by felodipine alone or with enalapril initially or after crossover (n = 45). The authors conclude that baseline hemodynamics appear to predict responsiveness to antihypertensive therapy. Coca A, Calvo C, Sobrino J, Olivan J, Garcia Puig J, Otero A, Alberti F, Martin Hidalgo A, Ocon J. Low-dose fixed combination therapy is superior to dose increase in patients not controlled by monotherapy. American Journal of Hypertension 2001;14(4 Pt 2):175a, Abs P-428. This multicenter study examined 24-h ambulatory blood pressure levels in 154 patients (53% male, 47% female; mean age 54 years) with uncontrolled essential hypertension who were randomized double-blind to 12 weeks of once-daily treatment with a fixed-dose of felodipine 5 mg/ramipril 5 mg or to monotherapy with once-daily felodipine 10 mg or ramipril 10 mg. These patients had previously failed therapy with 4 weeks of once-daily felodipine 5 mg or ramipril 5 mg and with ACE inhibitors and calcium channel blockers, respectively. 24-h systolic and diastolic pressures were decreased significantly more by the combination therapy and by felodipine 10 mg than by ramipril 10 mg. Office blood pressure control was significantly greater with combination therapy than with either monotherapy. Fewer side effects occurred in patients treated with the combination therapy than in those treated with felodipine 10 mg (28% vs 41%). The authors conclude that lowdose fixed combination therapy is a better treatment option than dose increase for patients with uncontrolled hypertension. Coca A, Calvo C, Sobrino J, Olivan J, Garcia Puig J, Otero A, Alberti F, Martin Hidalgo A, Ocon J. Combination therapy is a better strategy than increasing the dose in hypertensive patients not controlled by monotherapy. A double-blind randomized study. Hypertension 2001;37(3):996. In this multicenter, double-blind study 210 patients with essential hypertension received either felodipine 5 mg/day or ramipril 5 mg/day for 4 weeks followed by placebo for 2 weeks. 154 patients (mean age 54 years) were eventually randomized to receive felodipine 5 mg/day + ramipril 5 mg/day, felodipine 10 mg/day or ramipril 10 mg/day for 12 weeks. 24-h ambulatory monitoring was performed before randomization and at 12 weeks. Systolic blood pressure was reduced by 16.5 mm Hg in the felodipine + ramipril group, 16.7 mm Hg in the felodipine group and 9.3 mm Hg in the ramipril group. Diastolic blood pressure was reduced by 11.4 mm Hg in the felodipine + ramipril group, 11.9 mm Hg in the felodipine group and 7.2 mm Hg in the ramipril group. Blood pressure control was achieved by 46% of patients taking felodipine + ramipril, 28% of patients taking felodipine and 25% of patients taking ramipril. 28% of patients taking felodipine + ramipril and 41% of patients taking felodipine experienced adverse events. The authors conclude that lowdose fixed-combination therapy is better than increased dosage for essential hypertension not controlled by monotherapy. Zebekakis PE, Tziolas J, Lasaridis AN, Tourkantonis AA. Treatment of isolated systolic hypertension in a comparative study of four antihypertensive drugs. American Journal of Hypertension 2001;14(4 Pt 2):99a, Abs P-209. Blood pressure was monitored in 106 patients (mean age 62.9 years) with isolated systolic hypertension who were randomized to once-daily treatment with amiloride 2.5-5 mg/chlorthalidone 25-50 mg, atenolol 50-100 mg, perindopril 2-4 mg or felodipine 5-10 mg in this parallel group study. If target blood pressure (systolic pressure < 140 mm Hg) was not met after 4 weeks of monotherapy, dual therapy and then triple with a combination of the study drugs were instituted, each for an additional 4 weeks. 96 patients completed the study. 2 patients withdrew due to cough and 8 due to peripheral edema. All of the treatments significantly reduced blood pressure. The target blood pressure was achieved by 88% of the patients receiving felodipine, 65% of the patients receiving atenolol, 75% of the patients receiving amiloride/chlorthalidone and 62% of the patients receiving perindopril. Dual and triple therapy was required by 27% and 9.3% of the patients, respectively. The authors conclude that the drugs studied were effective as mono- and combination therapy, with a rank order of felodipine, amiloride/chlorthalidone, atenolol and perindopril. Schleman MM, Hwang C, Plendil HF Study Group. Acute and chronic hemodynamic effects of felodipine ER in patients with chronic heart failure (NYHA Class II-IV). Journal of Cardiac Failure 2001;7(3)(Suppl 2):66, Abs 243. In this study 151 patients (aged 27-78 years) with heart failure received Plendil (felodipine ER) 1.25 mg, 2.5 mg, 5 mg or 10 mg or placebo single dose and twice daily for 12 weeks. Cardiac index and stroke volume index increased significantly after both acute and chronic felodipine dosing compared with placebo. Systemic vascular resistance decreased after acute dosing. Pulmonary artery pressure and pulmonary capillary wedge pressure were not affected by felodipine. Heart rate and mean blood pressure were affected only by felodipine 10 mg. No significant improvements in heart failure symptoms and no changes in assessment of global response by physicians or patients were seen after felodipine treatment. 12% of patients taking placebo, 19% of patients taking felodipine 1.25 mg, 20% of patients taking felodipine 2.5 mg, 16% of patients taking felodipine 5 mg and 37% of patients taking felodipine 10 mg discontinued the study due to adverse events. More weight gain, edema and orthopnea were seen in the felodipine 10 mg group. The authors conclude that felodipine ER produces acute hemodynamic changes that are sustained for 12 weeks and is well tolerated up to 5 mg twice daily. Morgan TO, Anderson AIE, MacInnis RJ. ACE inhibitors, beta-blockers, calcium blockers, and diuretics for the control of systolic hypertension American Journal of Hypertension 2001;14(3):241-7. The intent of this balanced randomized crossover study of 74 elderly patients with untreated hypertension (56 male, 18 female; aged 77.3 years mean) was to determine which drug class lowered blood pressure most effectively, the percentage of patients controlled with single or sequential monotherapy, and if response to 1 drug class determined response to other drug classes. The ACE inhibitors used included enalapril 20-40 mg (n=24) and perindopril 4-8 mg (n=38). Calcium channel-blocking drugs included felodipine (n=26) and amlodipine 5-10 mg (n=39). Atenolol 25-50 mg was the beta-blocker included. The diuretic used was hydrochlorothiazide 25-50 mg. Patients received the low dose for 1 month and the high dose for 1 month. Only calcium channel blockers showed a dose-dependent increase in response. Systolic blood pressure (SBP) was lower than placebo with all drug classes, but this difference was not significant for the beta-blocker. Pulse rate decreased with beta-blocker use. The decrease in SBP was ACE inhibitors = beta-blocker < diuretics = calcium channel-blocking drugs. The decrease in diastolic blood pressure (DBP) was < the decrease in SBP and no significant differences were noted in the DBP among the drug classes. A total of 21-35% and 16-18% of the patients were universal responders and nonresponders, respectively, to the drugs used. The patient's well being was lower with betablockers. Adverse effects included headache, faintness, lethargy, flushing, cough, wheeze, breathlessness, sexual dysfunction, itch, cramps, ankle swelling, nausea, sleep disturbances, skin rash, and hypertension. Only beta-blockers had more side effects than placebo. The authors conclude that elderly patients with essential hypertension are recommended to start a low dose calcium-channel blocker or diuretic regimen. Butani L, Berg G, Makker SP. Effect of felodipine on tacrolimus pharmacokinetics in a renal transplant recipient. Transplantation 2002;73(1):159-60. This letter reports the case of 13-year-old boy for whom pharmacokinetic interactions occurred between felodipine and tacrolimus. The patient underwent a renal transplantation. He was treated with prednisolone 50 mg/day, tacrolimus 4 mg bid, mycophenolate mofetil 500 mg bid, oral ganciclovir 1 g tid, trimethoprim-cotrimoxazole 80 mg/day and fluconazole 100 mg/day. On postoperative day 15, felodipine (2.5 mg/day) was initiated to treat hypertension. In the following weeks tacrolimus levels became very high necessitating several dose reductions. After fluconazole discontinuation, tacrolimus dose was increased again to maintain target trough levels. Normalization of blood pressure was observed 8 months after transplantation inducing a discontinuation of felodipine. A week later levels of tacrolimus dropped and the dose had to be increased. According to the authors, the changes in the levels of tacrolimus were the results of a significant interaction between felodipine and tacrolimus. The authors report a study conducted by Cohen with felodipine and cyclosporine which showed no effect of the coadministration of the 2 drugs on cyclosporine trough levels. Dresser GK, Wacher V, Ramtoola Z, Cumming K, Bailey D. Peppermint oil increases the oral bioavailability of felodipine and simvastatin. Clinical Pharmacology & Therapeutics 2002;71(2):P67. The pharmacokinetics of felodipine and simvastatin, when administered in combination with peppermint oil, grapefruit juice or water, were compared in 2 3-way crossover studies involving 12 healthy volunteers. Subjects received felodipine 10 mg extended release tablet or simvastatin, with either water, peppermint oil capsules or grapefruit juice. AUC's for felodipine were found to be 23, 30 and 37 with water, peppermint oil and grapefruit juice, respectively. Cmax's for felodipine were 5, 7 and 9 with water, peppermint oil and grapefruit juice, respectively. The authors suggest that a lower interaction with felodipine than with simvastatin was expected, based on the idea that the oral bioavailabilities of felodipine (15%) and simvastatin (2%) were correlated with cytochrome CYP3A4 activity. The AUC's of both felodipine and simvastatin were increased by 30% with the addition of peppermint oil. The addition of grapefruit juice increased the AUC's of felodipine and simvastatin by 60% and 300%, respectively. It is suggested that both CYP3A4 and "P-gp" efflux transport are limited by grapefruit juice. It is thought that simvastatin, but not felodipine, is a "Pgp" substrate. The authors conclude that peppermint oil selectively blocks CYP3A4 activity and may be used to increase oral bioavailability of a drug if CYP3A4 activity reduces systemic availability.