Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new norvasc research articles will be listed here shortly after becoming available to us.
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Renal Blood Flow and Dynamic Autoregulation in Conscious Mice.
Am J Physiol Renal Physiol. 2008 Jun 25;
Iliescu R, Cazan R, McLemore Jr GR, Venegas-Pont M, Ryan MJ
Autoregulation of renal blood flow (RBF) occurs via myogenic and tubuloglomerular feedback (TGF) mechanisms that are engaged by pressure changes within preglomerular arteries and by tubular flow and content, respectively. Our understanding of autoregulatory function in the kidney largely stems from experiments in anesthetized animals where renal perfusion pressure is precisely controlled. However, normally occurring variations in blood pressure are sufficient to engage both myogenic and TGF mechanisms making the assessment of autoregulatory function in conscious animals of significant value. To our knowledge, no studies have evaluated the dynamics of RBF in conscious mice. Therefore, we used spectral analysis of blood pressure and RBF and identified dynamic operational characteristics of the myogenic and TGF mechanisms in conscious, freely moving mice instrumented with ultrasound flow probes and arterial catheters. The myogenic response generates a distinct resonance peak in transfer gain at 0.31+/-0.01 Hz. Myogenic-dependent attenuation of RBF oscillations, indicative of active autoregulation, is apparent as a trough in gain below 0.3 Hz (-6.5+/-1.3 dB) and a strong positive phase peak (93+/-9 deg), which are abolished by amlodipine infusion. Operation of TGF produces a local maximum in gain at 0.05+/-0.01 Hz and a positive phase peak (62.3+/-12.3 deg), both of which are eliminated by infusion of furosemide. Administration of amlodipine eliminated both myogenic and TGF signature peaks, whereas furosemide shifted the myogenic phase peak to a slower operational frequency. These data indicate that myogenic and TGF dynamics may be used to investigate the effectiveness of renal autoregulatory mechanisms in conscious mice. Key words: myogenic, tubuloglomerular feedback, mouse, renal blood flow, dynamics.
Rev Med Liege. 2008 Apr; 63(4): 220-4
Lancellotti P
Ivabradine (Procoralan), a new If inhibitor which acts specifically and in a dose-dependent manner on the pacemaker activity of the sinoatrial node, is a pure heart rate lowering agent. It slows the diastolic depolarization slope of sinoatrial node cells and reduces heart rate at rest and during exercise. It has shown anti-ischaemic and anti-anginal activity at recommended doses of 5 and 7.5 mg bid in patients with stable angina. Ivabradine is as effective as atenolol and amlodipine to prevent or attenuate exercise-induced ischaemia in these patients. It is well tolerated, with transient visual symptoms being the main drug-related adverse event. These symptoms may be linked to the presence in the retina of ion channels similar to cardiac If channels and did not adversely affect the tolerability of the drug for most patients. In Belgium, ivabradine is currently reimbursed in patients with stable angina and normal sinus rhythm who do not tolerate beta-blockers and non-dihydropyridine calcium antagonists or in whom these treatments are contra-indicated.
Pharmacol Res. 2008 May 21;
Aboutabl ME, Raafat M, Maklad YA, Kenawy SA, Din AG
The association of erectile dysfunction (ED) with cardiovascular diseases is so common. This study was carried out to investigate possible impact of sildenafil; the prototype phosphodiesterase 5 inhibitor used for treatment of ED, on the beneficial hemodynamic and histopathological effects of the prototype third generation calcium antagonist, amlodipine, in nitric oxide (NO)-deficient hypertensive rats. Hypertension was induced by 4-weeks treatment with N(omega)-nitro-l-arginine-methyl ester (l-NAME). Animals were allocated into five groups: normal control, hypertensive control, amlodipine-treated group, sildenafil-treated group and combined treatment group. Drug treatment was started 2 weeks after l-NAME and continued together with l-NAME to the end of the treatment period. Systolic blood pressure (SBP), plasma nitrate/nitrite (NO(x)) and plasma cGMP levels were evaluated at the end of the treatment period. Aortic and renal structural alterations were also investigated. l-NAME treatment caused elevation of SBP, reduction in plasma NO(x) and cGMP levels as well as adverse histological alterations in the tissues studied. Amlodipine normalized SBP, restored plasma NO(x) and cGMP levels and ameliorated the adverse histological changes seen in NO-deficient rats. When combined with sildenafil, both hemodynamic and histopathological effects of amlodipine were augmented with an underlying enhanced elevation of both plasma NO(x) and cGMP levels to statistically higher values than amlodipine alone. These results show that sildenafil augments the beneficial hemodynamic and histopathological effects of amlodipine in NO-deficient hypertensive rats with a pivotal role being played by NO-cGMP pathway. Whether this pharmacodynamic interaction could exist in other models of hypertension that do not share such biochemical derangement warrants further investigations.
Prolonged severe hypotension following combined amlodipine and valsartan ingestion.
Clin Toxicol (Phila). 2008 Jun; 46(5): 470-4
Smith SW, Ferguson KL, Hoffman RS, Nelson LS, Greller HA
INTRODUCTION: Compared to other calcium channel blockers (CCBs), overdose with dihydropyridine CCBs are considered relatively benign due to their vascular selectivity. Although not a sustained-release preparation, amlodipine's prolonged duration of effect is concerning following overdose. In addition, angiotensin II receptor blocker blunting of vasoconstrictive and sympathetic compensatory responses could exacerbate calcium channel blocker toxicity. We describe severe toxicity associated with an overdose of amlodipine and valsartan. CASE REPORT: A 75-year-old woman presented to the ED 45 minutes after a witnessed suicidal ingestion of a "handful" of amlodipine and valsartan tablets. Hypotension, which appeared two hours after ingestion, was refractory to crystalloids and colloids, calcium gluconate, epinephrine, norepinephrine, phenylephrine, and vasopressin infusions. High-dose insulin euglycemia (HIE) therapy, and treatment with glucagon and naloxone were successful in improving her hemodynamic status. In this combined overdose, right heart catheterization demonstrated both negative inotropic effects and decreased systemic vascular resistance. CONCLUSION: Co-ingestion of amlodipine with valsartan produced profound toxicity. Early institution of HIE therapy may be beneficial to reverse these effects.
Cardiovasc J Afr. 2008 May-Jun; 19(3): 163
Am J Hypertens. 2008 Jun 19;
Fogari R, Derosa G, Ferrari I, Corradi L, Zoppi A, Lazzari P, Santoro T, Preti P, Mugellini A
BackgroundThis study compared the effect of antihypertensive treatment with valsartan or ramipril on atrial fibrillation (AF) recurrence, on P-wave dispersion, (PWD) and on serum procollagen type I carboxy terminal peptide (PIP).MethodsA total of 369 mild hypertensive (systolic blood pressure (SBP) >140 and/or 90 < diastolic blood pressure (DBP) < 110 mm Hg) outpatients in sinus rhythm but with at least two episodes of AF in the previous 6 months were randomized to valsartan (n = 122), ramipril (n = 124), or amlodipine (n = 123) for 1 year. Clinic blood pressure (BP) and a 24-h electrocardiogram (ECG) were evaluated monthly. Patients were asked to report any episode of symptomatic AF and to perform an ECG as early as possible. PWD and serum PIP levels were evaluated before and after each treatment period.ResultsSBP and DBP were significantly reduced by the three treatments (P < 0.001). A total of 46 (47.4%) patients treated with amlodipine had a recurrence of AF as did 26 (27.9%) patients treated with ramipril (P < 0.01 vs. amlodipine) and 16 (16.1%) patients treated with valsartan (P < 0.01 vs. amlodipine and P < 0.05 vs. ramipril). The Kaplan-Meyer analysis showed a significant reduction of AF episodes in the valsartan group (P = 0.005 log-rank test) as well as in the ramipril group (P = 0.021), even if at a lesser degree. PWD values were significantly reduced by ramipril (-4.2 ms, P < 0.05) and even more by valsartan (-11.2 ms, P < 0.01), the difference being significant (P < 0.01). Serum PIP levels were reduced by ramipril (-49.7 mug, P < 0.001) and valsartan (-49.3 mug, P < 0.001).ConclusionsDespite similar BP lowering, valsartan and ramipril were more effective than amlodipine in preventing new episodes of AF, but the effect of valsartan was greater than that of ramipril. This could be related to the greater PWD reduction observed with valsartan.American Journal of Hypertension (2008). doi:10.1038/ajh.2008.217American Journal of Hypertension (2008). doi:10.1038/ajh.2008.217.
Re: Amlodipine for migraine prophylaxis.
Headache. 1999 Feb; 39(2): 138
Haugh MJ
The effect of ion pairing on the skin permeation of amlodipine.
Pharmazie. 2008 May; 63(5): 356-60
Jiang Y, Fang L, Niu X, Rui M, He Z
The purpose of the present study was to evaluate the effect of ion pairing on the skin permeation of amlodipine. Amlodipine base (AM) was first prepared from amlodipine besilate (AM-B), then amlodipine adipate (AM-A), amlodipine oxalate (AM-O) and amlodipine maleate (AM-M) were prepared using AM and the corresponding organic acids. Differential scanning calorimetry (DSC) thermogram studies demonstrated the formation of complexes between AM and the various acids. In vitro percutaneous absorption of AM and its complexes was evaluated through excised rat skin using 2-chamber diffusion cells. The results showed that AM had the greatest steady-state flux and lowest permeability coefficient of the five compounds from the El system (ethanol:isopropyl myristate (IPM)= 2:8), and its four complexes all exhibited a lower flux and higher permeability coefficient than AM.
Clin Ther. 2008 May; 30(5): 845-57
Kim SA, Park S, Chung N, Lim DS, Yang JY, Oh BH, Tahk SJ, Ahn TH
Background: "Chiral switching" from an existing racemate to a pure enantiomeric compound is a popular theme in drug development, especially when the enantiomer is found to have better efficacy and safety profiles. Amlodipine is a racemic mixture, composed of the S(-)-enantiomer, which is the pharmacologically active isomer, and the R(+)-enantiomer, which is 1000-fold less active. S(-)-amlodipine nicotinate, a chirally switched form of amlodipine nicotinate, has been developed and found to be bioequivalent to amlodipine besylate in Phase I clinical trials in Korea. Objective: The aim of this study was to compare the efficacy and safety profiles of S(-)-amlodipine nicotinate with those of amlodipine besylate in adult Korean patients with mild to moderate hypertension (diastolic blood pressure [DBP] >/=90 mm Hg and /=90 and /=90 mm Hg). The primary end point was noninferiority of the difference in mean SiDBP from baseline to week 8 for S(-)-amlodipine nicotinate compared with amlodipine besylate. Secondary end points were as follows: (1) noninferiority of the difference in mean sitting systolic blood pressure (SiSBP) from baseline to week 8 between the study groups; and (2) SiDBP response rate (defined as the proportion of patients whose SiDBP was /=10 mm Hg from baseline) after the 8-week treatment. Also, the incidence and severity of adverse events (AEs) and adverse drug reactions (ADRs) were reported. Severe AEs/ADRs were defined as those associated with any of the following: death; an event associated with a high risk of mortality; an event requiring hospitalization; or development of a permanent disability or congenital malformation. Results: One hundred fifty-seven patients were assessed for inclusion in the study. Of these, 124 patients were randomly allocated to receive S(-)-amlodipine nicotinate (42 men, 21 women; mean [SD] age, 52.4 [10.3] years [range, 23-70 years]; weight, 67.7 [10.8] kg [range, 44-92 kg]) or amlodipine besylate (45 men, 16 women; mean [SD] age, 54.5 [10.0] years [range, 30-73]; weight, 68.9 [9.8] kg [range, 49-95 kg]). One hundred sixteen patients completed the study, but 11 patients (8.9%) were dropped from the per-protocol analysis due to violations; therefore, 105 patients were included in the modified intent-to-treat population analysis (S[-]-amlodipine nicotinate, 55 patients; amlodipine besylate, 50 patients). There were no significant between-group differences in the baseline characteristics. Baseline mean (SD) SiSBP and SiDBP were 142.6 (11.3) and 94.9 (4.8) mm Hg in the S(-)-amlodipine nicotinate group, and 141.8 (8.3) and 96.1 (4.9) mm Hg in the amlodipine besylate group. Mean (SD) changes in SiSBP were 17.6 (11.2) mm Hg in the S(-)-amlodipine nicotinate group and 18.6 (12.3) mm Hg in the amlodipine besylate group. The SiDBP response rates were 92.7% in the S(-)-amlodipine nicotinate group and 88.0% in the amlodipine besylate group. There were no significant between-group differences in the prevalence of AEs and ADRs. In the S(-)-amlodipine nicotinate group, 15 patients (23.8%) reported a total of 28 AEs, and 19 patients (31.1%) reported a total of 27 AEs in the amlodipine besylate group. Six patients (9.5%) in the S(-)-amlodipine nicotinate group and 7 patients (11.4%) in the amlodipine besylate group experienced a total of 19 ADRs (11 and 8, respectively). The most common ADRs were liver enzyme elevation (3/63 [4.8%]) in the S(-)-amlodipine nicotinate group and facial flushing (3/61 [4.9%]) in the amlodipine besylate group. No cases of severe AEs or ADRs were reported in either group. Conclusions: The reduction of SiDBP after 8 weeks of treatment with S(-)-amlodipine nicotinate was noninferior compared with that of racemic amlodipine besylate in these adult Korean patients with mild to moderate hypertension. The SiDBP response rate and the reduction of SiSBP after 8 weeks of treatment with S(-)-amlodipine nicotinate were not significantly different from those with racemic amlodipine besylate. Both treatments were generally well tolerated.
Olmesartan medoxomil : a review of its use in the management of hypertension.
Drugs. 2008; 68(9): 1239-72
Scott LJ, McCormack PL
Olmesartan medoxomil (Olmetec((R)), Benicar((R))) is an angiotensin II type 1 (AT(1)) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system, which plays a key role in the pathogenesis of hypertension. Oral olmesartan medoxomil 10-40 mg once daily is recommended for the treatment of adult patients with hypertension. In those with inadequate BP control using monotherapy, fixed-dose olmesartan medoxomil/hydrochlorothiazide (HCTZ) [Olmetec plus((R)), Benicar-HCT((R))] combination therapy may be initiated.Extensive clinical evidence from several large well designed trials and the clinical practice setting has confirmed the antihypertensive efficacy and good tolerability profile of oral olmesartan medoxomil, as monotherapy or in combination with HCTZ, in patients with hypertension, including elderly patients with isolated systolic hypertension (ISH). Notably, BP control is sustained throughout the 24-hour dosage interval, including during the last 4 hours of this period. In clinical trials, olmesartan medoxomil monotherapy provided better antihypertensive efficacy than losartan, candesartan cilexetil or irbesartan monotherapy, and was at least as effective as valsartan treatment, with a faster onset of action than other ARBs in terms of reductions from baseline in diastolic BP (DBP) and, in most instances, systolic BP (SBP). Combination therapy with olmesartan medoxomil plus HCTZ was superior to that with benazepril plus amlodipine, as effective as that with losartan plus HCTZ, noninferior to that with atenolol plus HCTZ, but less effective than that with telmisartan plus HCTZ, in individual trials. Data from ongoing clinical outcome trials are required to more fully determine the relative position of olmesartan medoxomil therapy in the management of hypertension. In the meantime, the consistent antihypertensive efficacy during the entire 24-hour dosage interval and good tolerability profile of olmesartan medoxomil, with or without HCTZ, make it a valuable option for the treatment of adult patients with hypertension, including the elderly.