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In 1722 hypertensives recruited for the European Lacidipine Study on Atherosclerosis and treated with atenolol or lacidipine (±additional drugs) during 4 years, we evaluated the long-term reproducibility of dipping, nondipping, extreme dipping, and reverse dipping, an information of key relevance for defining the prognostic impact of these blood pressure (BP) phenotypes. Ambulatory BP was measured at baseline and every year during treatment, allowing repeated classifications of these conditions. Based on systolic BP, at baseline 50.1%, 37.5 %, 4.5 %, and 7.9 % were dippers, nondippers, extreme dippers, and reverse dippers, respectively. Antihypertensive drug treatment reduced the number of dippers and extreme dippers in favor of nondippers and reverse dippers. During treatment, the dipping and nondipping phenotypes were markedly unstable and shifts from one to other phenotypes were even more common in reverse and extreme dippers In only a very small fraction of patients, a given nighttime BP phenotype was persistently found throughout the 4 years. Data were similar for diastolic BP and in subgroups differing for the type of treatment, the treatment complexity, and the achieved on-treatment BP value Poor reproducibility characterized also the absolute nighttime BP reduction as measured by the nighttime BP fall and the night/day BP ratio. Thus nighttime BP phenotypes are all largely inconsistent, their detection over the entire treatment period involving just a minute fraction of the entire patients’ cohort.

Changes in myocardial expression of Na+/K+-ATPase alpha-subunit isoforms have been demonstrated in different models of cardiac hypertrophy and hypertension. Here we studied the expression of these isozymes in stroke-prone spontaneously hypertensive rats (SHRSP) and the influence of high salt diet and treatment with the dihydropyridine lacidipine. Adult SHRSP were offered either 1% NaCl or water as drinking solution for 6 weeks. Salt-loaded SHRSP were treated or not with I mg/kg/day lacidipine. Compared to Wistar Kyoto (WKY) rats, non-salt-loaded SHRSP presented significant hypertension and cardiac hypertrophy. Salt intake markedly enhanced cardiac hypertrophy, an effect blunted by lacidipine. [H-3]Ouabain binding assays on total particulate fractions from heart ventricles revealed the existence of two high-affinity sites with K-d similar to 25 and similar to 200 nM, ascribed to the alpha(3) and alpha(2) isoforms, respectively. B-max of alpha(3) was unexpectedly high (40% of total high-affinity binding) in ventricles from WKY rats but very low in all groups of SHRSP. On the other hand, B-max of alpha(2) was similar in WKY and non-salt-loaded SHRSP; however, salt loading of SHRSP resulted in a B-max reduction of 20% (P < 0.05), an effect blocked by lacidipine. These effects were largely confirmed by inummoblotting analysis, which, in addition, demonstrated that the density of the ubiquitous (x, isoform was comparable among the experimental groups. In conclusion, WKY rats showed a high myocardial expression of the Na+/K+-ATPase alpha(3) subunit, which was not found in SHRSP; the level of the alpha(2) isoform was similar in untreated SHRSP and WKY, salt-loading of SHRSP promoted reduction of the a, isoform, and this effect was completely hampered by lacidipine. (c) 2007 Elsevier B.V. All rights reserved.

The aim of this study was to determine the miscibility of drug and excipient to predict if glass solutions are likely to form when drug and excipient are melt extruded. Two poorly water-soluble drugs, indomethacin and lacidipine, were selected along with 11 excipients (polymeric and non-polymeric). Estimation of drug/excipient miscibility was performed using a combination of the Hoy and Hoftzyer/Van Krevelen methods for Hansen solubility parameter calculation. Miscibility was experimentally investigated with differential scanning calorimetry (DSC) and hot stage microscopy (HSM). Studies were performed at drug/excipient ratios, 1:4, 1:1 and 4:1. Analysis of the glass transition temperature (Tg) was performed by quench cooling drug/excipient melts in the DSC. Differences in the drug/excipient solubility parameters of <7.0 MPa1/2 were predicted to indicate significant miscibility and, therefore, glass solution formation on melt extrusion. In comparison, differences of <10 MPa1/2 were expected to indicate a lack of miscibility and not form glass solutions when melt extruded. Experimentally, miscibility was shown by changes in drug/excipient melting endotherms and confirmed by HSM investigations. Experimental results were in agreement with solubility parameter predictions. In addition, drug/excipient combinations predicted to be largely immiscible often exhibited more than one Tg upon reheating in the DSC. Melt extrusion of miscible components resulted in amorphous solid solution formation, whereas extrusion of an 'immiscible' component led to amorphous drug dispersed in crystalline excipient. In conclusion, combining calculation of Hansen solubility parameters with thermal analysis of drug/excipient miscibility can be successfully applied to predict formation of glass solutions with melt extrusion.

The aim of this study was to determine the miscibility of drug and excipient to predict if glass solutions are likely to form when drug and excipient are melt extruded. Two poorly water-soluble drugs, indomethacin and lacidipine, were selected along with 11 excipients (polymeric and non-polymeric). Estimation of drug/excipient miscibility was performed using a combination of the Hoy and Hoftzyer/Van Krevelen methods for Hansen solubility parameter calculation. Miscibility was experimentally investigated with differential scanning calorimetry (DSC) and hot stage microscopy (HSM). Studies were performed at drug/excipient ratios, 1:4, 1:1 and 4:1. Analysis of the glass transition temperature (Tg) was performed by quench cooling drug/excipient melts in the DSC. Differences in the drug/excipient solubility parameters of <7.0 MPa1/2 were predicted to indicate significant miscibility and, therefore, glass solution formation on melt extrusion. In comparison, differences of <10 MPa1/2 were expected to indicate a lack of miscibility and not form glass solutions when melt extruded. Experimentally, miscibility was shown by changes in drug/excipient melting endotherms and confirmed by HSM investigations. Experimental results were in agreement with solubility parameter predictions. In addition, drug/excipient combinations predicted to be largely immiscible often exhibited more than one Tg upon reheating in the DSC. Melt extrusion of miscible components resulted in amorphous solid solution formation, whereas extrusion of an 'immiscible' component led to amorphous drug dispersed in crystalline excipient. In conclusion, combining calculation of Hansen solubility parameters with thermal analysis of drug/excipient miscibility can be successfully applied to predict formation of glass solutions with melt extrusion.

We have examined the effects of lacidipine, a new dihydropyridine calcium antagonist, on cardiohemodynamics in comparison with those of nifedipine. Experiments were performed in open- and close-chest dogs anesthetized with morphine-α-chloralose-urethane and nitrous oxide. Lacidipine and nifedipine were administered intravenously at 1～30μg/kg. In open-chest dogs, both lacidipine and nifedipine produced dose-dependent decreases in diastolic and mean blood pressures (DBP and MBP) and increases in heart rate (HR) and left ventricular max dP/dt (LV max dP/dt). The decrease in MBP produced by nifedipine was transient; the MBP recovered to a level almost equal to the predrug level in a few minutes. In contrast, the effects of lacidipine were more prolonged except at low dose levels. On the basis of half-life assessed at a dose causing a decrement of MBP of a similar magnitude the hypotensive effect of lacidipine was >9 times longer-lasting than that of nifedipine. Both nifedipine and lacidipine decreased systolic blood pressure (SBP), left ventricular pressure (LVP) and left ventricular end-diastolic pressure (LVEDP) and increased cardiac output (CO). Lacidipine and nifedipine decreased total peripheral resistance (TPR) dose-dependently. The decreases were 20～50% for lacidipine and 15～40 % for nifedipine. Coronary blood flow (Cor-F) was increased to 50～175 % of the control after lecidipine and coronary vascular resistance (Cor-R) was decreased to 25～75%, while the changes were 40～240% and 35～70% after nifedipine. Decreases and increases were dose-dependent with both drugs. The increases in Cor-F exceeded those expected from the increases in MVO_2 observed simultaneously. In close-chest dogs, both nifedipine and lacidipine increased carotid and femoral blood flow (Car-F and Fern-F) and dose-dependently decreased carotid and femoral vascular resistance (Car-R and Fem-R). Coincident with the fall in BP renal blood flow (Ren-F) was decreased. Renal vascular resistance (Ren-R)

1. The present experiments were undertaken in order to characterize further the apparently irreversible inhibition of the contraction of depolarized rat aorta caused by lacidipine, a 1,4-dihydropyridine calcium antagonist. 2. We studied the effect of lacidipine on contraction evoked by 100 mM KCl solution in rat aorta, treated by N omega-nitro-L-arginine (0.1 mM), an inhibitor of nitric oxide (NO) synthesis. We compared the effect of prolonged depolarization on lacidipine and (+)-isradipine inhibition and the reversal of this inhibition after washout in the absence of dihydropyridines. Assuming that the onset of lacidipine-evoked inhibition was a pseudo-first order association kinetics, we estimated the dissociation rate constant (k-1 = 0.031 min-1), the association rate constant (k1 = 2.70 x 10(8) M-1 min-1) and the dissociation constant (KD = k-1/k1 = 115 pM) which was close to the IC50 value in steady-state conditions (160 pM). 3. The inhibitory effects of lacidipine and (+)-isradipine on rat aorta contraction were reversibly enhanced after preincubation with the drug in a 40 mM KCl-solution. Washout with drug-free 40 mM K(+)-depolarizing solution reversed inhibition in the (+)-isradipine-treated preparations, but not in the lacidipine-treated ones. 4. Radioligand binding studies were performed with [3H]-lacidipine and [3H]-isradipine in microsomes from rat aorta and rat ileum.(ABSTRACT TRUNCATED AT 250 WORDS)