Validated LC-MS/MS method for the simultaneous determination of enalapril maleate, nitrendipine, hydrochlorothiazide, and their major metabolites in human plasma.

Hypertension is a major risk factor for atherosclerosis and ischemic heart disease. Most hypertensive patients need a combination of antihypertensive agents to achieve therapeutic goals. A rapid, sensitive, and selective liquid chromatography-tandem mass spectrometric method was developed and validated for simultaneous determination of enalapril maleate (ENA) and its major metabolite enalaprilat (ENAT), nitrendipine (NIT) and its major metabolite dehydronitrendipine (DNIT), and hydrochlorothiazide (HCT) in human plasma using felodipine as an internal standard (IS). The drugs were extracted from plasma using one-step protein precipitation. Chromatographic separation was performed on a Symmetry C18 column, with water and acetonitrile (10:90, v/v) as mobile phase. The detection was carried out using multiple reaction monitoring mode and coupled with electrospray ionization source. Multiple reaction monitoring transitions were m/z 377.1 → 234.1 for ENA, m/z 349.2 → 206.1 for ENAT, m/z 361.2 → 315.1 for NIT, m/z 359 → 331 for DNIT, m/z 295.9 → 205.1 for HCT, and m/z 384.1 → 338 for felodipine (IS). The method was linear over concentration ranges of 1-200, 20-500, 5-200, 2-100, and 5-200 ng/mL for ENA, ENAT, NIT, DNIT, and HCT, respectively, with r2 ≥ 0.99. Method validation was performed according to U.S. Food and Drug Administration guidelines. The validated method showed good sensitivity and selectivity and could be applied for therapeutic drug monitoring and bioequivalence studies.

Development and optimization of nanoemulsion based gel for enhanced transdermal delivery of nitrendipine using box-behnken statistical design.

Objective: The purpose of present research was to develop and statistically optimize nitrendipine nanoemulsion gel for transdermal delivery using box-behnken statistical design.Method: The nanoemulsion formulations bearing nitrendipine were prepared by application of ternary phase diagram and spontaneous emulsification method. Box-behnken design was employed for the optimization of nitrendipine loaded nanoemulsion. The independent variables were oil, surfactant and co-surfactant while globule size, drug content and zeta potential were dependent variables. The optimized nanoemulsion formulation was incorporated into gel and evaluated for in-vitro release, ex-vivo permeation studies, confocal laser scanning microscopy, skin irritation and histopathological studies.Results: The optimized formulation through box-behnken statistical design showed globule size of 20.43 ± 1.50 nm, drug content of 97.05 ± 1.77% and zeta potential of -15.45 ± 0.35 mV. The ex-vivo study confirmed the enhanced delivery of nitrendipine from nanoemulsion gel than compare to drug solution by virtue of better permeation and solubility. Nanoemulsion gel was proved significantly superior by confocal laser scanning microscopy for satisfactory permeation and distribution of gel, deep into the rat skin. The optimized gel was found with no allergic dermal effects and was proved safe by histopathological studies for transdermal application.Conclusions: Results reveals that developed nitrendipine nanoemulsion gel overcomes the limitation of low penetration and accentuate permeation through albino Wistar rat skin. It was concluded that nanoemulsion gel could be utilized as a potential carrier for transdermal delivery of nitrendipine.

Preparation of a Mesoporous Structure of SnO2 for Increasing the Oral Bioavailability and Dissolution Rate of Nitrendipine.

In this study, mesoporous SnO2 (MSn) with a three-dimensional mesoporous structure was prepared using MCM-48 as the template in order to increase the oral bioavailability and dissolution rate of insoluble drugs. The model drug, nitrendipine (NDP), was loaded into the MSn by the adsorption method. The structural features of MSn were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and N2 adsorption (desorption) analysis. NDP was existed in the pore channels of MSn in an amorphous state, which was characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR). MSn showed a good biocompatibility in the cell toxicity assay for Caco-2 cells. In vitro dissolution results suggested that MSn could significantly enhance the dissolution rate of NDP compared with commercial NDP tablets. Pharmacokinetic studies indicated that NDP-MSn tablets effectively enhanced the oral bioavailability of NDP. In conclusion, MSn was found to be a potential carrier for improving the solubility of insoluble drugs.

Solubility and Thermodynamic Analysis of Antihypertensive Agent Nitrendipine in Different Pure Solvents at the Temperature Range of 298.15 to 318.15°K.

The aim of the present study was to ascertain the solubility of nitrendipine (NP), an antihypertensive drug in six different pure solvents such as water, ethyl acetate (EA), ethanol, isopropyl alcohol (IPA), polyethylene glycol-400 (PEG-400), and Transcutol at temperature from 298.15 to 318.15 K under atmospheric pressure (p) of 0.1 MPa. Experimental solubility data of NP was fitted with Apelblat and ideal models. The mole fraction solubility of NP was found maximum in PEG-400 (6.85 × 10-2 at 318.15 K) followed by Transcutol (4.65 × 10-2 at 318.15 K), EA (1.68 × 10-2 at 318.15 K), ethanol (2.83 × 10-3 at 318.15 K), IPA (2.69 × 10-3 at 318.15 K), and water (1.29 × 10-7 at 318.15 K). The dissolution activity of NP was observed as an endothermic, spontaneous, and an entropy-driven in most of studied pure solvents. The solubility data of NP obtained in the present study could be useful in purification, recrystallization, and dosage forms design of NP.

Preparation of starch macrocellular foam for increasing the dissolution rate of poorly water-soluble drugs.

Starch macrocellular foam (SMF), a novel natural bio-matrix material, was prepared by the hard template method in order to improve the dissolution rate and oral bioavailability of poorly water-soluble drugs. Nitrendipine (NDP) was chosen as a model drug and was loaded into SMF by the solvent evaporation method. SMF and the loaded SMF samples (NDP-SMF) were characterized by scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro drug release studies showed that SMF significantly increased the dissolution rate of NDP. In vivo studies showed that the NDP-SMF tablets clearly increased the oral bioavailability of NDP in comparison with the reference commercial tablets. All the results obtained demonstrated that SMF was a promising carrier for the oral delivery of poor water-soluble drugs.

Anti-arrhythmic and hemodynamic effects of oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine.

Our previous studies have established cardio-protective effects of furnidipine and its active metabolites. We therefore decided to compare the influence of oral and intravenous administration of furnidipine, nifedipine, nitrendipine and nimodipine to examine their effects on hemodynamics and arrhythmias. Since dihydropyridines are oxidatively metabolized in the body and the oxidized metabolites are among the final products, we studied the influence of four oxidized dihydropyridines (oxy nifedipine, oxy nimodipine, oxy nitrendipine and oxy nisoldipine) on the same parameters. In vivo model of ischemia- and reperfusion-induced arrhythmias of rats was used. Dihydropyridines were administered 5 mg/kg orally (24 and 1 h before ischemia) or 5 µg/kg intravenously (10 min before ischemia). 20 mg/kg of the oxidized dihydropyridines was given orally (24 and 1 h before ischemia). The dihydropyridines exhibited significant anti-arrhythmic actions after both forms of administration but their influence on blood pressure was differential and contrasting and depended on route of administration. The oxidized dihydropyridines imparted strong protection against lethal arrhythmias while exerting differential influences on blood pressure with oxy nifedipine and oxy nisoldipine being hypertensive and oxy nitrendipine being most normotensive. The differential effects observed with the dihydropyridines after the two routes of administration lend strength to the hypothesis that their metabolites may have a significant role in mediating the actions of the parent drug. The strong anti-arrhythmic action of the oxidized dihydropyridines along with their differential effect on blood pressure could indicate their potential use as cardio-protective drugs in certain groups of patients.

Polymer-mediated anti-solvent crystallization of nitrendipine: monodispersed spherical crystals and growth mechanism.

PURPOSE: To investigate anti-solvent crystallization and growth mechanism of nitrendipine spherical crystals in an aqueous solution containing polymeric additives. METHODS: Size and shape of crystals were investigated using laser diffractometry, optical microscopy and scanning electron microscopy (SEM). Crystalline form was determined by X-ray powder diffractometer (XRPD). During crystal growth, morphological changes at different time points were observed using SEM. RESULTS: Morphology of nitrendipine crystals was affected by polymers and temperature. Monodispersed micro-spherical crystals were obtained when polyvinyl alcohol (PVA) and PEG 200 were present in crystallization medium at 2°C. During crystallization, large number of amorphous nanoparticles was first observed, followed by aggregation into a core for spherical crystals. Once crystalline state was achieved, rapid growth on core surface was observed with amorphous particles acting as a reservoir allowing formation of star-like particles with needle-like subunits. Spherical crystals were formed by filling the gap between needle-like distinct crystalline units of star-like templates with molecules from dissolved amorphous particles. CONCLUSIONS: Monodispersed nitrendipine spherical crystals were obtained using carefully controlled conditions. A mechanism for the nitrendipine spherical crystal growth is suggested. These findings provide a new insight into spherulitic crystallization of active pharmaceutical ingredients.

Preparation and characterization of nitrendipine solid lipid nanoparticles.

Nitrendipine, a dihydropyridine calcium channel blocker, has very poor oral bioavailability (10-20%) due to first pass effect. Solid lipid nanoparticle (SLN) delivery systems of nitrendipine have been developed using various triglycerides (trimyristin, tripalmitin and tristearin), soy phosphatidylcholine 95%, poloxamer 188 and charge modifiers stearylamine and dicetyl phosphate. SLNs were prepared by hot homogenization of melted lipids and aqueous phase followed by ultrasonication at temperatures above the melting point of lipids. Optimization studies of process and formulation variables were carried out. Particle size and zeta potential were measured by photon correlation spectroscopy (PCS) using Malvern zetasizer. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies were performed to characterize state of drug and lipid modification. In vitro release studies were performed in phosphate buffer pH 6.8 using modified Franz diffusion cell. Stable nitrendipine SLNs of mean size range 79 to 213 nm and zeta potential -38.2 to +34.6 mV were developed. About 99% nitrendipine was entrapped in SLNs and were stable on storage at 4 and 25 degrees C. DSC and PXRD analyses revealed that nitrendipine is dispersed in SLNs in an amorphous state. The release pattern of drug is analyzed and found to follow Weibull distribution rather than first order and Higuchi equation.

Nitrendipine nanocrystals: its preparation, characterization, and in vitro-in vivo evaluation.

The present investigation was undertaken with the objective of developing a solid formulation containing nitrendipine nanocrystals for oral delivery. Nitrendipine nanocrystals were prepared using a tandem precipitation-homogenization process. Then, spray drying, a cost-effective method very popular in industrial situations, was employed to convert the nanocrystals into a solid form. The parameters of the preparation process were investigated and optimized. The optimal process was as follows: firstly, nitrendipine/acetone solution (100 mg/ml) was added to a polyvinyl alcohol solution (1 mg/ml) at 10°C, then the pre-suspension was homogenized for 20 cycles at 1,000 bar. Both differential scanning calorimetry and X-ray diffraction analysis indicated that nitrendipine was present in crystalline form. The in vitro dissolution rate of the nanocrystals was significantly increased compared with the physical mixture and commercial tablet. The in vivo testing demonstrated that the C(max) of the nanocrystals was approximately 15-fold and 10-fold greater than that of physical mixture and commercial tablet, respectively. In addition, the AUC(0→24) of the nanocrystals was approximately 41-fold and 10-fold greater than that of physical mixture and commercial tablet, respectively.

Effect of crystal size on the in vitro dissolution and oral absorption of nitrendipine in rats.

PURPOSE: To investigate the effect of crystal size on the dissolution and oral absorption of nitrendipine, a poorly soluble drug, in rats. METHODS: Five types of nitrendipine crystal suspensions with different particle sizes (200 nm, 620 nm, 2.7 microm, 4.1 microm, 20.2 microm) were prepared either by the precipitation-ultrasonication or the anti-solvent precipitation method. The simulated intestinal fluid in the fasted state (FaSSIF) was selected as the dissolution medium, and the dissolution behaviors of different nitrendipine crystals were simulated based on a Noyes-Whitney type equation. The in vivo absorption and the absolute bioavailability of the different nitrendipine crystals were evaluated in Wistar rats. RESULTS: The dissolution rate of nitrendipine was significantly increased by a reduction in particle size. The dissolution test in FaSSIF could discriminate between the differences in the dissolution rates of the different particle sizes, and the simulated results were in agreement with the observed dissolution curves. From the simulated T(50%) values (50% dissolution time), the dissolution rates of crystals with particle sizes of 200 nm, 620 nm, 2.7 microm, 4.1 microm and 20.2 microm were calculated to be 5.1 x 10(4), 1.0 x 10(4), 237, 64 and 11-fold greater than that of the raw crystals and resulted in absolute bioavailability of 61.4% 51.5%, 29.4%, 26.7%, 24.7%, respectively. The reduction in the drug particle size correlated well with incremental improvements in oral absorption. A good linear relationship was observed between the Log (T(50%)) and the absolute bioavailability of nitrendipine. CONCLUSIONS: The dissolution rate and the oral bioavailability of nitrendipine were significantly affected by the crystal size, and the oral bioavailability could be improved significantly by preparing it as nanocrystals. FaSSIF can be used to predict differences in oral absorption of crystals with different particle sizes.

Application of a self-modeling curve resolution method for studying the photodegradation kinetics of nitrendipine and felodipine.

Dihydropyridine (DHP) derivatives, as calcium channel blockers with cardiovascular activity, are highly photosensitive and converted in the presence of light to compounds that are inactive. In this work, a self-modeling curve resolution method was applied to study the photodegradation kinetics of nitrendipine and felodipine by spectrophotometric method. The methanolic solutions of drugs were separately exposed to UV and daylight, respectively. A fully soft-modeling multivariate curve resolution method based on the combination of iterative target transformation and Kubista methods were used to analyze the recorded absorbance data, extracting the concentration profiles and pure spectra of the drugs and their photodegradation products. By fitting the concentration profiles of the studied DHP drugs to different kinetic equations, it was found that at the beginning of lighting, the reaction is zero-order and in the case of nitrendipine it changes to a first-order kinetic when the concentration of products exceeded than that of the initial compounds.

Crystallization rate of amorphous nifedipine analogues unrelated to the glass transition temperature.

To examine the relative contributions of molecular mobility and thermodynamic factor, the relationship between glass transition temperature (T(g)) and the crystallization rate was examined using amorphous dihydropyridines (nifedipine (NFD), m-nifedipine (m-NFD), nitrendipine (NTR) and nilvadipine (NLV)) with differing T(g) values. The time required for 10% crystallization, t(90), was calculated from the time course of decreases in the heat capacity change at T(g). The t(90) of NLV and NTR decreased with decreases in T(g) associated with water sorption. The t(90) versus T(g)/T plots almost overlapped for samples of differing water contents, indicating that the crystallization rate is determined by molecular mobility as indicated by T(g). In contrast, differences in the crystallization rate between these four drugs cannot be explained only by molecular mobility, since the t(90) values at a given T(g)/T were in the order: NLV>NTR>NFD approximately m-NFD. A lower rate was obtained for amorphous drugs with lower structural symmetry and more bulky functional groups, suggesting that these factors are also important. Furthermore, the crystallization rate of NTR in solid dispersions with poly(vinylpyrrolidone) (PVP) and hydroxypropyl methylcellulose (HPMC) decreased to a greater extent than expected from the increased T(g). This also suggests that factors other than molecular mobility affect the crystallization rate.

Development and evaluation of nitrendipine loaded solid lipid nanoparticles: influence of wax and glyceride lipids on plasma pharmacokinetics.

Nitrendipine is an antihypertensive drug with poor oral bioavailability ranging from 10 to 20% due to the first pass metabolism. For improving the oral bioavailability of nitrendipine, nitrendipine loaded solid lipid nanoparticles have been developed using triglyceride (tripalmitin), monoglyceride (glyceryl monostearate) and wax (cetyl palmitate). Poloxamer 188 was used as surfactant. Hot homogenization of melted lipids and aqueous phase followed by ultrasonication at temperature above the melting point of lipid was used to prepare SLN dispersions. SLN were characterized for particle size, zeta potential, entrapment efficiency and crystallinity of lipid and drug. In vitro release studies were performed in phosphate buffer of pH 6.8 using Franz diffusion cell. Pharmacokinetics of nitrendipine loaded solid lipid nanoparticles after intraduodenal administration to conscious male Wistar rats was studied. Bioavailability of nitrendipine was increased three- to four-fold after intraduodenal administration compared to that of nitrendipine suspension. The obtained results are indicative of solid lipid nanoparticles as carriers for improving the bioavailability of lipophilic drugs such as nitrendipine by minimizing first pass metabolism.

Development of nitrendipine transdermal patches: in vitro and ex vivo characterization.

OBJECTIVE: The aim of the investigation was to develop and evaluate matrix type transdermal drug delivery systems (TDDS) of nitrendipine (NTDP). EXPERIMENTAL: The matrix type TDDS of NTDP were prepared by solvent evaporation technique. Ten formulations (composed of Eudragit RL 100 and Hydroxypropyl methyl cellulose in the ratios of 5:0, 4:1, 3:2, 2:3, 1:4 in formulations A1, A2, A3, A4, A5 and Eudragit RS 100 and Hydroxypropyl methyl cellulose in the same ratios in formulation B1, B2, B3, B4, B5 respectively) were prepared. All formulations carried 6 % v/w of carvone as penetration enhancer and 15% v/w of propylene glycol as plasticizer in dichloromethane and methanol as solvent system. The prepared TDDS were evaluated for in vitro release, ex vivo permeation, moisture absorption, moisture content and mechanical properties. The physicochemical interactions between nitrendipine and polymers were investigated by Fourier Transform Infrared (FTIR) Spectroscopy. RESULTS: The maximum drug release in 24 hrs for A series formulations was 89.29% (A4) and 86.17% for B series (B5), which are significantly (p < 0.01) different to the lowest values (57.58 for A1 and 50.64 for B1). Again formulations A4 (flux 23.51 microg/hr/cm(2)) and B5 (flux 22.98 microg/hr/cm(2)) showed maximum skin permeation in the respective series. The flux obtained with formulation A4 and B5 meets the required flux (19.10 microg/hr/cm(2)). The mechanical properties, tensile strength, elastic modulus (3.42 kg/mm(2) for A4 and 4.25 kg/mm(2) for B5) reveal that the formulations were found to be strong but not brittle. FTIR studies did not show any evidence of interaction between the drug and the polymers. CONCLUSION: Nitrendipine matrix type transdermal therapeutic systems could be prepared with the required flux having suitable mechanical properties.

The novel application of tertiary butyl alcohol in the preparation of hydrophobic drug-HPbetaCD complex.

This report describes a novel application of tertiary butyl alcohol (TBA) in the preparation of hydrophobic drug-hydroxypropyl beta-cyclodextrin (HPbetaCD) complex. The straightforward, economic preparation procedure consists of dissolving both the hydrophobic drug and HPbetaCD in TBA, which is subsequently freeze-dried to give the hydrophobic drug-HPbetaCD complex in the form of a porous powder. TBA was selected as the medium due to it being a good solvent for hydrophobic drug and HPbetaCD; in addition, it is also a versatile lyophilization medium and is widely used in pharmaceutical processes. In this study, ketoprofen and nitrendipine were used as model drugs and their HPbetaCD complexes were prepared by lyophilization of the TBA system. Based on the data from differential scanning calorimetry (DSC) and X-ray diffractometry (XRD), the drugs were amorphous in freeze-dried samples. The infra-red (IR) spectrum indicated that a drug-HPbetaCD interaction took place in the freeze-dried complex. Dissolution experiments showed that the hydrophobic drug dissolved rapidly from the HPbetaCD complex in both simulated gastric juice and simulated intestinal fluid. These results confirmed that this technique produced a hydrophobic drug-HPbetaCD complex. TBA was found to be a suitable freeze-drying medium for the preparation of hydrophobic drug-HPbetaCD complex. This approach is versatile, energy-conserving and can easily be scaled up. It is expected to have further application in modifying the physicochemical characteristics of hydrophobic drugs and improving their absorption and pharmacodynamic properties.

Thermal stability of 1,4-dihydropyridine derivatives in solid state.

The effect of temperature and air humidity on the stability of 7 derivatives of 1,4-dihydropyridine (nifedipine, nisoldipine, nitrendipine, nimodipine, nicardipine, felodipine and amlodipine) in solid state has been studied by accelerated testing. Quantitative analysis of the compounds studied was made by UV spectrophotometry, identification of the thermodegradation products and reference to the standard were made by thin layer chromatography (TLC), UV spectra and the reaction with KMnO4. Thermodegradation of the derivatives studied was found not to occur in dry air, whereas at air humidity it occurred according to the first order reaction at a similar rate for all derivatives. The main product of thermodegradation of the derivatives with the nitro substituent was a nitrozoderivative formed as a result of dihydropyridine ring aromatisation accompanied by water molecule elimination.

In search of the mutual relationship between the structure, solid-state spectroscopy and molecular dynamics in selected calcium channel blockers.

Three isostructural 1,4-dihydropyridines (DHPs), namely, nifedipine, nitrendipine and nimodipine were selected to characterize their structure, intermolecular interactions and molecular dynamics. The studied samples were analyzed using powder X-ray diffraction (XRD), neutron (INS) and infrared spectroscopy (FT-IR) as well as solid-state nuclear magnetic resonance (NMR), where each technique was supported by the state-of-the-art theoretical calculations for solid-state. By combining multiple experimental techniques with advanced theoretical calculations we were able to shed light on the mutual relation between the structure, stabilizing intermolecular interactions and their spectral response. For the first time, unambiguous computationally-supported assignment of the most prominent spectral features in DHPs is presented to give a valuable support for polymorph screening and drug control. Molecular motions were interpreted in details, revealing that a dynamic reservoir of each compound is dominated by intra-molecular reorientations of methyl groups and large-amplitude oscillations in terminal chains. Our study successfully validates the realm of applicability of first-principles solid-state calculations in search of the mutual relation between the structure and spectroscopy in this important class of drugs. Such approach gives a first necessary step to gather combined structure-dynamics data on functionalized DHPs, which are of importance to better understand crystallization and binding tendency. The NMR relaxation experiments reveal that nitro groups significantly hinder the reorientation of methyl rotors and provide the first evidence of low-temperature methyl-group tunneling in DHPs, an intriguing quantum-effect which is to be further explored.

Nanovesicles of nitrendipine with lipid complex for transdermal delivery: pharmacokinetic and pharmacodynamic studies.

CONTEXT: Vesicular transdermal delivery can enhance the bioavailability of a drug especially affected by first-pass metabolism, e.g. nitrendipine. However effective transdermal delivery employs permeation enhancer, e.g oleic acid (OA) with ceramide 2, stearic acid, behenic acid, and cholesteryl sulfate lipid complex. OBJECTIVE: This study investigated the preparation, characterization of physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential in rats, of nitrendipine-loaded nanovesicles of ceramide 2, stearic acid, behenic acid and cholesteryl sulfate containing oleic acid gel (NOVG). MATERIALS AND METHODS: The nanovesicles were made using film hydration method and characterized for physicochemical properties, ex vivo permeation using human skin, pharmacokinetic parameters and antihypertensive potential. RESULTS: Nitrendipine-loaded nanovesicles of ceramide-2 containing oleic acid (NOV-5) have shown fluxes in the range of 4.88-24.72 µg/cm(2)/h nitrendipine oral suspension (NOS) at equal dose. NOVG-5 has shown almost 33% reduction in blood pressure in the first hour and a further decrease of 25% in the second hour to restore the normal pressure. DISCUSSION: The permeation increases with increase in OA content. OA gets integrated in vesicle wall and enhances its permeability, whereas ceramide content makes sure that skin does not become damaged even after permeation. CONCLUSION: NOVG-5 has shown the most favorable physicochemical properties and good permeation through skin providing good management of hypertension during crucial initial hours.

Stereoselectivity in cardiovascular and biochemical action of calcium antagonists: studies with the enantiomers of the dihydropyridine nitrendipine.

OBJECTIVES: The cardiovascular and biochemical effects of R- and S-nitrendipine were studied in six healthy subjects in a single-blind placebo-controlled study. METHODS: After received oral doses of placebo, 20 mg R-, 80 mg R- (n = 5), 20 mg S-, and 20 mg racemic nitrendipine, heart rate, systolic, diastolic, and mean arterial blood pressure, leg blood flow, peripheral vascular resistance, plasma renin activity, norepinephrine, epinephrine, dopamine, and aldosterone plasma levels were measured before and up to 3 hours after administration. RESULTS: Neither placebo nor 20 or 80 mg R-nitrendipine caused significant changes of cardiovascular and biochemical parameters. After 20 mg S-nitrendipine and 20 mg racemic nitrendipine, significant changes in diastolic blood pressure (-9.1/-7.4 mm Hg), heart rate (+21.9/+17.3 beats/min), leg blood flow (+6.8 ml.min-1.gm tissue-1), peripheral vascular resistance (-16.9 mm Hg.min.gm tissue.ml-1), norepinephrine (+476/+281 ng.L-1), and plasma renin activity (+9.5/+3.6 ng.ml-1.hr-1) were observed. The changes in cardiovascular and biochemical parameters were closely related to the serum S-nitrendipine concentrations. CONCLUSIONS: It can be concluded that, after administration of the racemate, the S-enantiomer is responsible for the cardiovascular and biochemical effects observed and that S-nitrendipine is at least an order of magnitude more potent than the R-enantiomer.

Antioxidant effects of calcium antagonists on rat myocardial membrane lipid peroxidation.

We studied the antioxidant effects of nine calcium antagonists (nisoldipine, benidipine, nilvadipine, felodipine, nicardipine, nitrendipine, nifedipine, verapamil, and diltiazem) by means of rat myocardial membrane lipid peroxidation with a nonenzymatic active oxygen-generating system (DHF/FeCl3-ADP). The order of antioxidant potency of these agents was nilvadipine > nisoldipine > felodipine > nicardipine > verapamil > benidipine. Their IC50 values (microM) were 25.1, 28.2, 42.0, 150.0, 266.1, and 420.0, respectively. In contrast, nitrendipine, nifedipine, and diltiazem had little inhibitory effect on lipid peroxidation. These six calcium antagonists could be divided into four types on the basis of their antioxidant mechanisms. Nilvadipine, nisoldipine, and verapamil, which showed antioxidant effects both before and after the addition of active oxygen, and reduced the dihydroxyfumarate (DHF) auto-oxidation rate, were chain-breaking and preventive antioxidants. Felodipine, which showed antioxidant effects both before and after exposure to active oxygen and increased the DHF auto-oxidation rate, was only a chain-breaking antioxidant. Nicardipine, which showed an antioxidant effect only before exposure to active oxygen and reduced the DHF auto-oxidation rate, was mainly a preventive antioxidant. Benidipine, which showed an antioxidant effect only before exposure to active oxygen and had no appreciable effect on the DHF auto-oxidation rate, could interrupt the chain reaction of lipid peroxidation at the initial step alone. Although these results suggest that the antioxidant properties of some calcium antagonists may be beneficial clinically in protecting against cellular damage caused by lipid peroxidation, further studies are required to establish the antioxidant effects of these agents in vivo.