Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new plendil research articles will be listed here shortly after becoming available to us.
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Int J Cardiol. 2008 Jun 23;
Braun M, Frank E, Markus K, Steffen S, Carsten S, Gregor S, Mathias B, Christof W, Ruth S
BACKGROUND: In addition to standard therapy with ACE-inhibitors, digitalis and diuretics, beta-adrenergic receptor blockers have become a widely accepted strategy in the treatment of chronic heart failure. The role of calcium antagonists in CHF however remains controversial. To evaluate if a combination therapy of metoprolol and felodipine might improve hemodynamic parameters, a randomized and placebo-controlled study was designed. METHODS AND RESULTS: Sixty-three patients with DCMP, LVEF 3 months in NYHA II-III on standard medication were prospectively treated with either a) a combination of metoprolol+felodipine (MF group, n=20), b) metoprolol+felodipine-placebo (MP group, n=23), or c) metoprolol-placebo+felodipine-placebo (PP group, n=20). Compared to baseline, LVEF and LVEDD significantly improved after 6 months in the MP group (LVEF: 36+/-2% vs 29+/-2%, p
Eur J Pharm Biopharm. 2008 Jun 6;
Konno H, Handa T, Alonzo DE, Taylor LS
Amorphous solid dispersions are used as a strategy to improve the bioavailability of poorly water-soluble compounds. When formulating with a polymer, it is important not only for the polymer to stabilize against crystallization in the solid state, but also to improve the dissolution profile through inhibiting crystallization from the supersaturated solution generated by dissolution of the amorphous material. In this study, the dissolution profiles of solid dispersions of felodipine formulated with poly(vinylpyrrolidone) (PVP), hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMCAS) were compared. In addition, concentration versus time profiles were evaluated for the supersaturated solutions of felodipine in the presence and absence of the polymers. HPMCAS was found to maintain the highest level of supersaturation for the greatest length of time for both the dissolution and solution crystallization experiments, whereas PVP was found to be the least effective crystallization inhibitor. All polymers appeared to reduce the crystal growth rates of felodipine at an equivalent supersaturation and this mechanism most likely contributes to the enhanced solution concentration values observed during dissolution of the amorphous solid dispersions.
[Seronine effects in ocular vasculature reactivity]
Oftalmologia. 2007; 51(4): 126-33
Coman OA, Savu OR, Ghiţă I, Păunescu H, Coman L, Fulga I
INTRODUCTION: Serotonin presents specific receptors of many types and subtypes. The aim of this study was to analyze the differences in reactivity between the vessels (arteries and veins) of the iris and conjunctiva. The vascular diameter was measured using a noninvasive technique after intraocular administration of different doses of serotonin. MATERIAL AND METHODS: The tests were performed on rats, divided in control and study groups. The modifications of studied vessels' diameters before and after topical administration of the solutions were evaluated by measuring these diameters at fixed time intervals of 30 seconds, for 6 minutes. Differentiation between arteries and veins was made using topical administration of felodipine after the testing 6 minutes interval The statistical significance of differences between the values obtained in each interval of 30 seconds and the control values at the initial moment was evaluated using t-test, the "paired" variant. RESULTS: There were obtained differences in reactivity between iridian and conjunctival vessels and between iridian arteries and veins for the different concentrations of tested serotonin solutions. CONCLUSIONS: Iridian and conjunctival vessels contain serotonin receptors with different types and densities, whose activation produced vasoconstriction in both territories, but with different evolution and intensity. Differences in reactivity were found between iridian arteries and veins, probably due to a different density of receptors between those two territories. The different vascular response might be a protective mechanism against dissemination of conjunctival infections.
Felodipine Reduces Cardiac Expression of IL-18 and Perivascular Fibrosis in Fructose-fed Rats.
Mol Med. 2008 May 25;
Xing SS, Tan HW, Bi XP, Zhong M, Zhang Y, Zhang W
Metabolic syndrome (MS) is associated with accelerated macrovascular and microvascular coronary disease, cardiomyopathy and elevated inflammatory status. To determine whether MS-associated elevation of IL-18 - an inflammatory cytokine, in serum and cardiac tissue and its potential sequelae could be attenuated pharmacologically, we studied fructose-fed rats. The fructose-fed rats exhibited increases in systolic blood pressure (SBP), body weight, heart weight, left ventricular weight and blood insulin. Serum IL-18 levels in these rats were also significantly elevated. These changes were significantly different in comparing to those in control rats. Perivascular fibrosis around coronary arterioles was evident in the fructose-fed rats, which was accompanied by a paralleled increase in IL-18 by immunohistochemical analysis and real time polymerase chain reaction. Felodipine attenuated the increased levels in serum IL-18 and cardiac IL-18 mRNA as well as coronary perivascular fibrosis. Thus, augmented IL-18 in serum and cardiac tissue in metabolic syndrome may contribute to the coronary perivascular fibrosis; felodipine administration can attenuate the inflammatory and fibrosis process.
Adv Ther. 2008 May 8;
Brachmann J, Ansari A, Mahla G, Handrock R, Klebs S
INTRODUCTION: The addition of an angiotensin II receptor blocker to calcium channel blocker-based antihypertensive therapy may be associated with enhanced efficacy and reduced risk of adverse events. METHODS: This 8-week, open-label, single-arm trial evaluated the efficacy and tolerability of the combination of amlodipine and valsartan in patients not responding adequately to treatment with amlodipine or felodipine alone. Patients aged >/=18 years with moderate essential hypertension (defined as mean sitting systolic blood pressure [MSSBP] >/=160 and
Biosens Bioelectron. 2008 Jul 15; 23(12): 1862-8
Ahmad F, Yusof AP, Bainbridge M, Ab Ghani S
The mechanisms involving insulin and anti-hypertensive drugs regulation for in vivo cerebral glucose metabolism are not well-understood. This might be due to lack of direct means of measuring cerebral glucose. It is known that the continuous delivery of glucose to the brain is critical for its normal metabolic function. In this study, we report the effect of insulin and anti-hypertensive drugs on glucose level in the striatum of rats. The rats were divided into two groups, i.e. hyperglycemia (14.8+/-0.3mM plasma glucose) and diabetic (10.8+/-0.2mM plasma glucose). A custom-built glucose microsensor was implanted at coordinates A/P 1.0 from bregma, M/L +2.5 and D/V -5.0 (from dura) in the striatum. The amperometric response obtained at +0.23V vs. Ag|AgCl corresponded to the glucose level in striatum. By varying the concentrations of protaminc zinc insulin infused into the rats, striatum glucose level was found to remain constant throughout, i.e. 9.8+/-0.1 and 4.7+/-0.1mM for hyperglycemic rats and for diabetic rats, respectively. However, infusion of valsartan and felodipine has lowered the striatum glucose level significantly. These findings agreed with the hypothesis that suggested striatum glucose uptake do not depend on insulin but is clearly dependant on anti-hypertensive drugs administration.
J Biol Chem. 2008 Jun 20; 283(25): 17227-37
Schoch GA, Yano JK, Sansen S, Dansette PM, Stout CD, Johnson EF
Although a crystal structure and a pharmacophore model are available for cytochrome P450 2C8, the role of protein flexibility and specific ligand-protein interactions that govern substrate binding are poorly understood. X-ray crystal structures of P450 2C8 complexed with montelukast (2.8 A), troglitazone (2.7 A), felodipine (2.3 A), and 9-cis-retinoic acid (2.6 A) were determined to examine ligand-protein interactions for these chemically diverse compounds. Montelukast is a relatively large anionic inhibitor that exhibits a tripartite structure and complements the size and shape of the active-site cavity. The inhibitor troglitazone occupies the upper portion of the active-site cavity, leaving a substantial part of the cavity unoccupied. The smaller neutral felodipine molecule is sequestered with its dichlorophenyl group positioned close to the heme iron, and water molecules fill the distal portion of the cavity. The structure of the 9-cis-retinoic acid complex reveals that two substrate molecules bind simultaneously in the active site of P450 2C8. A second molecule of 9-cis-retinoic acid is located above the proximal molecule and can restrain the position of the latter for more efficient oxygenation. Solution binding studies do not discriminate between cooperative and noncooperative models for multiple substrate binding. The complexes with structurally distinct ligands further demonstrate the conformational adaptability of active site-constituting residues, especially Arg-241, that can reorient in the active-site cavity to stabilize a negatively charged functional group and define two spatially distinct binding sites for anionic moieties of substrates.
J Renin Angiotensin Aldosterone Syst. 2008 Mar; 9(1): 1-9
Gojanovic B, Feihl F, Liaudet L, Waeber B
Pharmacological treatment of hypertension is effective in preventing cardiovascular and renal complications. Calcium antagonists (CAs) and blockers of the renin-angiotensin system [angiotensin-converting enzyme (ACE) inhibitors and angiotensin II antagonists (ARBs)] are widely used today to initiate antihypertensive treatment but, when given as monotherapy, do not suffice in most patients to normalise blood pressure (BP). Combining a CA and either an ACE-inhibitor or an ARB considerably increases the antihypertensive efficacy, but not at the expense of a deterioration of tolerability. Several fixed-dose combinations are available (CA + ACE-inhibitors: amlodipine + benazepril, felodipine + ramipril, verapamil + trandolapril; CA + ARB: amlodipine + valsartan). They are expected not only to improve BP control, but also to facilitate long-term adherence with antihypertensive therapy, thereby providing maximal protection against the cardiovascular and renal damage caused by high BP.
Am J Clin Nutr. 2008 Apr; 87(4): 863-71
Paine MF, Widmer WW, Pusek SN, Beavers KL, Criss AB, Snyder J, Watkins PB
BACKGROUND: We previously established furanocoumarins as mediators of the interaction between grapefruit juice (GFJ) and the model CYP3A4 substrate felodipine in healthy volunteers using a GFJ devoid of furanocoumarins. It remains unclear whether furanocoumarins mediate drug-GFJ interactions involving CYP3A4 substrates that are also P-glycoprotein substrates. OBJECTIVE: The effects of furanocoumarin-free GFJ on drug disposition were further characterized by using the dual CYP3A4/P-glycoprotein substrate cyclosporine. DESIGN: By randomized crossover design, 18 healthy volunteers received cyclosporine (5 mg/kg) with 240 mL orange juice (control), GFJ, or furanocoumarin-free GFJ. Blood was collected over 24 h. Juice treatments were separated by > or = 1 wk. The effects of diluted extracts of each juice and of purified furanocoumarins on [3H]cyclosporine translocation in Caco-2 cells were then compared. RESULTS: The median (range) dose-corrected cyclosporine area under the curve and the maximum concentration with GFJ (P < or = 0.007), but not with furanocoumarin-free GFJ (P > or = 0.50), were significantly higher than those with orange juice [15.6 (6.7-33.5) compared with 11.3 (4.8-22.0) x 10(-3) h/L and 3.0 (1.6-5.8) compared with 2.4 (1.1-3.1) mL(-1), respectively]. The median time to reach maximum concentration and terminal elimination half-life were not significantly different between the juices (2-3 and 7-8 h, respectively; P > or = 0.08). Relative to vehicle, the GFJ extract, orange juice extract, and purified furanocoumarins partially increased apical-to-basolateral and decreased basolateral-to-apical [3H]cyclosporine translocation in Caco-2 cells, whereas the furanocoumarin-free GFJ extract had negligible effects. Reanalysis of the clinical juices identified polymethoxyflavones as candidate P-glycoprotein inhibitors in orange juice but not in GFJ. CONCLUSIONS: Furanocoumarins mediate, at least partially, the cyclosporine-GFJ interaction in vivo. A plausible mechanism involves the combined inhibition of enteric CYP3A4 and P-glycoprotein.
Clin Chem Lab Med. 2008; 46(3): 393-5
Song H, Bao W, Wang H, An G, Feng J, Wang R, Zhang Y, An F
BACKGROUND: Endothelial dysfunction plays a significant role in the pathogenesis of essential hypertension (EH). This trial was undertaken to reveal the effects of extended-release felodipine on endothelial vasoactive substances in EH patients. METHODS: A colorimetric chemical method was employed to measure the level of nitric oxide (NO) and nitric oxide synthase (NOS), while radioimmunoassay was employed to measure endothelin (ET), angiotensin-II (Ang-II), thromboxane A2 (TXA(2)) and prostacyclin I(2) (PGI(2)) in plasma of the subjects. Group 1 consisted of 120 patients who were treated with a 4-week mono-therapy of felodipine. Group 2 consisted of 70 patients who were participating in fitness programs during this period. Another group comprising 80 individuals was selected as controls. Data from both the starting point and the ending point were collected and analyzed. RESULTS: After a 4-week mono-therapy of extended-release felodipine in Group 1, the levels of plasma ET, Ang-II and TXA(2) decreased significantly, while levels of NO, NOS and PGI(2) did not noticeably change. In Group 2, there were almost no changes in levels of ET, Ang-II, TXA(2), NO, NOS and PGI(2). Conclusions: From these results, we conclude that felodipine reduced blood pressure by decreasing the secretion of ET, Ang-II and TXA(2). Consequently, felodipine can revitalize the endothelial function in EH patients.