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Objective: Objective of the study was the comparison of two nifedipine sustained-release products marketed in Europe. Maximum plasma concentration (C(max)) and area under the plasma-concentration curve (AUC) values were derived after administration of single doses (60 mg) of test product and reference product, both approved for once-a-day administration, to 24 healthy male volunteers either after an overnight fast or immediately after a high-fat American breakfast. The study was performed with a randomised, non-blinded, four-period crossover design. Within- and between-product comparisons were determined for fed versus fasted administration considering bioavailability and tolerability of all treatments. Furthermore, in vitro dissolution characteristics of both products were evaluated., Methods: Plasma samples were assayed using a liquid chromatography-mass spectrometry method, and resulting pharmacokinetic parameters were determined model independently according to international requirements and the current European guidelines., Results: Under fasted conditions the comparison of test and reference products showed a similar extent of bioavailability with a mean ratio of AUC((0-)(infinity)()) of 99% [95% confidence interval (CI) 86%, 114%], but significantly higher C(max) values resulting in a mean ratio of 169% (95% CI 139%, 206%). Accordingly, mean residence time and half-value duration values were smaller for the test product than the reference product. Under fed conditions, a pronounced food effect could be observed for the test product resulting in a pronounced increase of C(max) values. The affiliating point estimate was calculated as 340% with a 95% CI of 279%, 413%. However no remarkable influence of food intake was observed for the reference product., Conclusion: Under fasting conditions the modified-release characteristics of the test product are less pronounced than the reference product. No relevant impact of food intake could be observed for the reference product when switching from fasted to fed state, whereas a significant loss of modified-release characteristics could be detected for the test product under fed conditions resulting in much higher maximum concentrations. Such a phenomenon has been described in literature as "dose-dumping effect".

The effect of the intake of 200 g of grapefruit pulp (corresponding to one grapefruit) on the pharmacokinetics of the calcium antagonists nifedipine (NF) and nisoldipine (NS) were investigated in 8 healthy Japanese male volunteers. A crossover design was used for the study: group I did not ingest any grapefruit (control group); group II ingested grapefruit 1 h after drug administration; and group III ingested grapefruit 1 h before drug administration. The intake of grapefruit pulp increased the plasma concentrations of both NF and NS, an effect that has previously been reported with grapefruit juice. The increase was most marked when grapefruit was eaten before drug administration. For both NF and NS, subjects who ingested grapefruit 1 h before drug administration exhibited a greater Cmax and AUC0-24 than did subjects in the control group. For NF, the Cmax was 1.4 times higher and the AUC0-24 1.3 times larger in group III than in group I. For NS, the Cmax was 1.5 times higher and the AUC0-24 1.3 times larger in group III than in group I. The increase in the AUC0-24 was significant for both drugs (p < 0.05). The finding that the ratios of Cmax and AUC0-24 for unchanged drug and metabolites did not vary greatly among the three groups for either drug suggests that the increase in serum concentration produced by grapefruit intake may be due to other factors than an inhibitory effect on drug metabolism. Also, the increases in Cmax and AUC0-24 of NS produced by grapefruit intake were smaller than those produced by grapefruit juice intake, indicating that grapefruit pulp and juice have different effects on the pharmacokinetics.

Grapefruit juice is known to increase the oral bioavailability of dihydropyridine calcium channel blockers, including nifedipine, by reducing presystemic clearance. The nature and magnitude of this interaction has not been studied in black Africans. Previous studies have reported reduced systemic clearance of nifedipine in this population, suggesting altered risk from the interaction of grapefruit juice and nifedipine. We report a case of a nifedipine-grapefruit juice adverse interaction in a Nigerian to draw attention to the problem and further sensitize practitioners.

The long-term oral ketoconazole (KTZ) treatment extensively inhibits hepatic CYP3A activity. We investigated the effect of the KTZ treatment on hepatic and intestinal extraction of nifedipine (NIF) using beagle dogs. Four dogs were given orally KTZ for 20 days (200 mg, bid). NIF was administered either intravenously (0.5 mg/kg) or orally (20 mg) 10 and 20 days before the KTZ treatment and 10 and 20 days after start of KTZ treatment. CLtot of NIF after intravenous administration decreased to about 50% during the KTZ treatment. C(max) and AUC after oral administration increased to 2.5-fold and fourfold, respectively, by the KTZ treatment. The hepatic extraction ratio of NIF decreased to about a half by KTZ. A significant decrease in intestinal extraction ratio was not observed. In conclusion, the KTZ treatment inhibits hepatic extraction more profoundly than intestinal extraction of NIF. Therefore, inhibition of hepatic extraction of NIF by the KTZ treatment mainly results in substantial increase in systemic bioavailability in dogs. Because KTZ inhibits human CYP3A activities similar to canine CYP3A activities, the long-term oral KTZ treatment may dramatically increase bioavailability of NIF or other CYP3A substrates in humans., (Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association.)

Nifedipine (N) and nifedipine. Pluronic F-68 solid dispersion (SD) pellets were developed and characterizedfor drug release mechanisms from a multi-unit erosion matrix system for controlled release. Nifedipine was micronized using a jet mill. Solid dispersion with Pluronic F-68 was prepared by the fusion method. Nifedipine and SD were characterized by particle size analysis, solubility, differential scanning calorimetry (DSC), and x-ray diffraction (XRD) studies. Samples were subsequently processed into matrix pellets by extrusion/spheronization using Eudragit L 100-55 and Eudragit S 100 as release rate-controlling polymers. Drug release mechanisms from pellets were characterized by microscopy and mercury intrusion porosimetry; DSC and XRD studies indicated no polymorphic changes in N after micronization and also confirmed the formation of SD of N with Pluronic F-68. Pellets of N showed a 24-hr drug release profile following zero-order kinetics. Pellets of SD showed a 12-hr release profile followingfirst-order kinetics. Aqueous solubility of N after SD formation was found to be increased 10-fold. Due to increased solubility of N in SD, the drug release mechanism from the multi-unit erosion matrix changed from pure surface erosion to an erosion/diffusion mechanism, thereby altering the release rate and kinetics.

Aims: To study the effects of rifampicin on the pharmacokinetics and pharmacodynamics of nilvadipine., Methods: Five healthy adult volunteers received nilvadipine (4 mg) orally before and after a 6 day treatment with rifampicin. Blood and urine were collected and assayed for plasma nilvadipine and urinary 6beta-hydroxycortisol and cortisol., Results: The treatment with rifampicin reduced the mean (+/- s.d.) AUC of nilvadipine from 17.4 +/- 8.4 to 0.6 +/- 0.4 microg l-1 h (mean difference -16.8 microg l-1 h, 95% CI -9.4, 24.2 microg l-1 h). While the administration of nilvadipine alone elicited a significant (P < 0.05) hypotensive (mean difference for diastolic blood pressure -8 mmHg, 95% CI -4, -12 mmHg) and reflex tachycardia (mean difference 5 beats min-1, 95% CI 1, 9 beats min-1), the treatment with rifampicin abolished these responses. The urinary 6beta-hydroxycortisol/cortisol ratio showed a significant (P < 0.05) increase from 10.3 +/- 4.0 to 50.3 +/- 24.6 by rifampicin: mean difference 40.1, 95% CI 20.4, 59.8., Conclusions: Because rifampicin may greatly decrease the oral bioavailability of nilvadipine, caution is needed when these two drugs are to be coadministered.

A 59-year-old male who had suffered from hypertension for 21 years was admitted because of manic and delusional symptoms. He was treated with 12 mg/day of haloperidol for psychotic symptoms and 8 mg/day of nilvadipine for hypertension. Due to insufficient effect of haloperidol on the patient's manic symptoms, carbamazepine was added to these medications. Abnormally high blood pressure was observed during carbamazepine coadministration, and it returned gradually to normal range after its discontinuation. Retrospective analyses revealed that the plasma concentrations of nilvadipine were undetectable during carbamazepine treatment. The clinical course and laboratory findings suggest that carbamazepine decreased the plasma concentration and hence the antihypertensive effect of nilvadipine probably via CYP3A induction. This interaction between nilvadipine and carbamazepine should be kept in mind when these drugs are administered concomitantly.

Introduction: Short-acting nifedipine (SA-NIF) is widely prescribed for acute hypertension (HTN) in children despite reports of ischemic complications in adults. We describe two children with neurologic events caused by rebound hypertension following SA-NIF use., Cases: Patient 1 is a 7-year-old with acute nephritis and blood pressure (BP) of 185/130. She received SA-NIF which decreased BP to 114/79. When BP rebounded to 160/103, she developed severe cortical visual impairment. Head CT demonstrated edema and petechial hemorrhages in the watershed region. Patient 2 is a 10-year-old renal transplant recipient who received SA-NIF for a BP of 155/98, which resulted in a prompt decrease to 114/74. Two hours later he developed aphasia and right-sided neglect. His BP increased to 168/88 and he developed partial complex seizures. Brain MRI showed high signal intensity in the watershed areas with early gadolinium enhancement., Discussion: The temporal association of the neurologic events with the rebound increase in BP suggests a possible role for the SA-NIF, consistent with its pharmacokinetic profile. Although the adult literature has focused on the unpredictable decline in BP after SA-NIF treatment, these cases suggest that rapid increases in BP following the maximal SA-NIF effect may be associated with impaired cerebral autoregulation and encephalopathy in children. These cases underscore the need for frequent blood pressure determinations and therapy to prevent rebound hypertension.

Objective: Our objective was to investigate ethnic differences in the oral pharmacokinetics of nifedipine and erythromycin, both typical cytochrome P4503A (CYP3A) substrates, in Koreans and Caucasians and to identify the nature of any correlations between the pharmacokinetic parameters of the two drugs., Methods: Twenty healthy male volunteers (10 Koreans and 10 Caucasians) received single oral doses of nifedipine (10 mg) or erythromycin (500 mg) in a randomized 2-way crossover study. Pharmacokinetic evaluations were performed, and parameters were compared for the two ethnic groups. During the nifedipine study period, hemodynamic measurements were conducted to determine the pharmacodynamic relevance of the pharmacokinetic differences., Results: Koreans showed area under the concentration-time curves (AUCs) for both drugs that were 1.6 to 1.7 times higher than those of Caucasians. This difference decreased to 1.3 when normalized for body weight. Significant correlation between the AUCs of the two drugs was not evident. Hemodynamic changes after nifedipine administration paralleled those of the pharmacokinetic differences, with significantly greater decreases in blood pressure and total peripheral resistance noted in Koreans., Conclusions: Koreans showed significantly lower oral clearances of nifedipine and erythromycin, probably because of genetic differences attributed to the CYP3A enzymes.

Purpose: To develop a high performance liquid chromatography system for the determination of a new 1,4-dihydropyridine, mebudipine, in rabbit plasma., Methods: To 1 ml of rabbit plasma was added internal standard (dibudipine) and 0.5 ml of 1 M NaOH. Mebudipine and internal standard were extracted to 5 ml ethyl acetate, evaporated under slow stream of nitrogen. The residue was reconstituted in 200 microl mobile phase and 20 microl of aliquots were injected into a HPLC system equipped with 4.6 x 250 mm i.d. C18 analytical column. Mobile phase consisted of methanol (70%), water (25%) and acetonitril (5%) and its flow rate was 1 ml/min., Results: There were no interfering peaks from endogenous components in blank plasma chromatograms. Standard curves were linear (r(2)>0.99) over 10 to 500 ng/ml. The extraction efficiency was >90% and the minimum quantifiable concentration was 10 ng/ml (CV<10%)., Conclusion: A suitable, convenient and simple HPLC assay for pharmacokinetic study of mebudipine in rabbits was developed.

Objective: To evaluate the use of short-acting nifedipine for treatment of severe hypertension in children., Study Design: A retrospective chart review of 520 nifedipine doses given for severe hypertension in 117 pediatric patients was completed. Nifedipine dose, systolic and diastolic blood pressures before and within 2 hours of the dose, and side effects were recorded. Pre- and post-dose mean arterial pressure (MAP) and percent reductions in MAP and systolic and diastolic blood pressure were calculated. Age, dose, primary diagnosis, and use of other antihypertensive agents were examined with respect to blood pressure reduction., Results: Of the doses received, 35% were associated with > or =25% reduction in MAP, a degree of MAP reduction previously associated with hypertension treatment complications. MAP percent reduction was correlated with nifedipine dose adjusted for weight (r = 0.24, P<.001). Mean nifedipine doses per kilogram were larger in patients who had > or =25% MAP reduction compared with those who had <25% MAP reduction (0.26 +/- 0.12 mg/kg vs. 0.21 +/- 0.11 mg/kg, F = 29.01, P <.001). Adolescents received lower nifedipine doses per kilogram and had lower percent reduction in blood pressure compared with younger children. No clinically significant side effects were noted after administration of nifedipine., Conclusion: Precipitous reductions in blood pressure are ameliorated by decreasing the initial nifedipine dose to < or =0.25 mg/kg in pediatric patients. Short-acting nifedipine use in pediatric patients with hypertension in a hospital setting is safe.

Objective: The pharmacokinetic and dynamic interactions of the angiotensin-converting enzyme (ACE) inhibitor imidapril with other therapeutic principles used in hypertension and heart failure were evaluated., Methods: In three separate, double-blind, placebo-controlled, four-way cross-over studies in healthy volunteers (n = 16 each), single oral doses of imidapril 10 mg (I), hydrochlorothiazide 12.5 mg (H), bisoprolol 5 mg (B) and nilvadipine 8 mg (N) were administered as monotherapies, and in IH, IB and IN combinations. Plasma concentrations of imidaprilat and H were followed up to 48 h, those of B and N up to 24 h and area under the concentration time curve (AUC), maximum plasma concentration (Cmax) and time to Cmax (tmax) were determined. Blood pressure (BP), heart rate (HR) and non-invasive haemodynamics [total peripheral resistance (TPR, N and H), systolic time intervals (STI, N and H), and plasma renin activity (PRA)] were assessed up to 24 h., Results: There were no pharmacokinetic interactions between I plus H, B or N. Bioequivalence between single and combined administrations was verified for all investigational compounds [AUC point estimates (90% confidence interval CI): imidaprilat IH 109% (97.8, 122.8); IB 99.6% (91.2, 109.4); IN 105.7% (92.1, 121.3); H 96.6% (92.5, 100.8); B 103% (100.2, 105.8); N 98% (89, 108)]. The haemodynamic effects were mostly additive and without relevant pharmacodynamic interactions. I significantly reduced the BP by 5-8 mmHg, B by 4-8 mmHg and N by 4-6 mmHg. In addition, H induced a significant reduction of the preload as seen from STI, and B significantly reduced HR (-5 bpm). N induced a significant decrease in TPR (about 15% of baseline values) and showed corresponding changes in STI. PRA increased significantly following I alone (1.5-2.0 ng/ml/h), as well as combined with N (2.5 ng/ ml/h) or H (3.1 ng/ml/h). This increase was clearly blunted by the co-administration of B (0.6 ng/ml/h)., Conclusions: The combination of imidapril with a diuretic, beta-adrenoceptor antagonist or calcium-channel blocker seems a reasonable and safe treatment option when striving for additive pharmacodynamic effects not accompanied by relevant pharmacokinetic interactions.

Objective: To evaluate the use of calcium-channel-blockers (CCBs) for tocolysis., Methods: We reviewed the literature retrieved from the Medline database from 1967 to 200 dealing with fetal toxicity and efficacy of CCBs compared with beta-adrenergic agonists., Results: Data on fetal toxicity in animals were inconsistent. A teratologic effect has been observed during early pregnancy at supratherapeutic dosage. At usual therapeutic dosage, no fetal abnormalities have been observed. The efficacy of CBs for tocolysis is superior to that of beta-adrenergic drugs and allows a reduction of neonatal morbidity. Calcium channel blockers are better tolerated than beta-adrenergic agonists., Conclusion: Published data suggest that CCBs could be used a first line tocolytic agents. Although use of CCBs is extremely simple, they should not be prescribed in low-risk outpatients.

Nifedipine is frequently used for patients who require an immediate reduction of blood pressure elevated temporarily by various administration techniques including sublingual route without administrating intravenous infusion of vasodilator. A cross-over clinical study was conducted to investigate the optimal administration method of nifedipine for rapid management of hypertension. Four method of administering 10 mg nifedipine (the capsule was bitten and swallowed, sublingually with a hole in it or the contents administered orally or intranasally with a syringe) were evaluated with regarded efficacy, safety, and usefulness in 6 normal volunteers. Systolic and diastolic blood pressures were correlated with the nifedipine serum concentration in each method. Nifedipine pharmacokinetic parameters differed among the 4 administration methods. Nifedipine was absorbed rapidly by not only intestinal mucosa but also the nasal or oral mucosa. The pharmacological effect of intranasal or sublingual administration was superior. However, mint oil which is present in nifedipine capsules stimulates nasal mucosa when administered intranasally. For clinical usage, nifedipine capsules in which a hole is made with a needle, administered sublingually, can be effectively and safely used for rapid management of systemic hypertension.

The absorption process of nifedipine in aqueous NaCl solutions with additions of the following surfactants: egg lecithin, sodium lauryl sulphate and Tween-80 was studied in vitro. A flow-through apparatus containing a piece of small intestine (ileum) of a rat was used for the absorption rate measurements. The surfactants were added in two concentrations, i.e., below and above their critical micellar concentrations respectively. The small additions of the studied surfactants to the aqueous nifedipine solutions (i.e. in the concentrations below the critical micellar point) notably increased the absorption rate of nifedipine. However, when the mentioned surfactants were added in higher concentrations (i.e., above their critical micellar points), a important decrease of the absorption of nifedipine was observed.

This study is an attempt to prepare microspheres loaded with two antihypertensive drugs viz., nifedipine (NFD) and verapamil hydrochloride (VRP) using cellulose-based polymers viz., ethyl cellulose (EC) and cellulose acetate (CA). Emulsification and solvent evaporation methods were optimized using ethyl acetate as a dispersing solvent. The particles are spherical in shape and have smooth surfaces, as evidenced by the scanning electron microscopy. The microspheres were characterized for their particle size and distribution, tapped density and encapsulation efficiency. Smaller sized particles with a narrow size distribution were produced with EC when compared to CA matrices. Molecular level drug distribution in the microspheres was confirmed by differential scanning calorimetry. The microspheres were directly compressed into tablets using different excipients. The drug release from CA was faster than EC microspheres and, also, the VRP release was faster than NFD. The excipients used in tableting showed an effect on the release as well as the physical properties of the tablets.

Purpose: It has been reported that grapefruit juice (GJ) causes a pharmacokinetic interaction with many drugs after co-ingestion. It is postulated that the substances in GJ may inhibit the first-pass metabolism during the intestinal absorption process. In recent years, several furanocoumarin derivatives that inhibit P450 activity in intestinal microsomes were isolated from GJ. In this study, we report the effects of the furanocoumarin derivatives in GJ on the nifedipine (NFP) pharmacokinetics in rats., Methods: Three furanocoumarin derivatives (bergaptol [BT], bergamottin [BG], and 6',7'-dihydroxybergamottin [DHB]) found in GJ were used in this study. Each furanocoumarin was reconstituted in orange juice at the same concentration as in the GJ. Two milliliters of each sample was administered into the rat duodenum. After 30 min, NFP was intraduodenally administered at a dose of 3 mg/kg body weight. The NFP concentrations in the plasma samples were determined by HPLC., Results: A significant increase in the AUC of NFP was observed only in the rats administered BG; 1.5 times that of the control group. The result was quite identical with that of the group that was administered GJ. BT and DHB had no significant effects on the NFP pharmacokinetics., Conclusions: The results strongly suggested that BG in GJ might be the substance that elevates the NFP plasma concentrations.

Bamidipine is an antihypertensive drug belonging to the dihydropyridine (DHP) group of calcium antagonists. It is available in a modified-release formulation which has a gradual onset of action and is effective in a single daily oral dose of 10 to 20 mg. Bamidipine has selective action against cardiovascular calcium antagonist receptors and its antihypertensive action is related to the reduction of peripheral vascular resistance secondary to its vasodilatory action. The clinical antihypertensive efficacy of barnidipine is similar to that of other DHP calcium antagonists such as nitrendipine and amlodipine, and antihypertensives belonging to other drug classes such as atenolol and enalapril. Barnidipine has been found to be as efficacious and well tolerated as hydrochlorothiazide in the management of hypertension in elderly patients. Barnidipine is generally well tolerated. As with other DHP calcium antagonists, vasodilator adverse events such as headache, flushing and peripheral oedema account for most of the adverse events reported with its use and are usually transient. Oedema is less frequent than with amlodipine and nitrendipine. Its use is not associated with reflex tachycardia.

Short-term (by hour) intracerebroventricular (i.c.v.) or i.v. infusion of nifedipine at low rates evokes parallel decreases in renal sympathetic nerve activity (RSNA) and blood pressure (BP) in spontaneously hypertensive rats (SHR). In the present study, effects of long-term administration of nifedipine on BP and control of sympathetic tone were examined in SHR on a high-salt (8%) diet. From 6 to 8 weeks of age, for 2 weeks concomitant with taking a high-salt diet, rats were also treated with subcutaneous infusion of nifedipine at 10, 50, or 100 microg/kg/h or vehicle solvent as control using osmotic minipumps. At the end of the 2-week treatment period, mean arterial pressure (MAP), heart rate (HR), and RSNA at rest and in response to air-jet stress, i.c.v. injection of the alpha-adrenoceptor agonist guanabenz (25 microg), and i.v. injection of the ganglionic blocker hexamethonium were recorded in conscious rats. In rats on nifedipine 50 or 100 microg/kg/h, resting MAP was significantly lower (136+/-4 or 130+/-4 vs. 145+/-2 mm Hg in control rats, p < 0.05 for both), the sympathoinhibitory and depressor responses to i.c.v. guanabenz were significantly decreased, and the absolute decreases in MAP in response to i.v. injection of hexamethonium were significantly smaller. Sympathoexcitatory and pressor responses to air-jet stress, however, were not affected by nifedipine. Infusion of nifedipine at the three rates for 2 weeks caused concentrations of plasma nifedipine in a dose-related manner. Nifedipine was not detected in tissues of rats treated with 10 microg/kg/h nifedipine but was present in brain and other tissues of rats treated with nifedipine at the two higher rates. Thus in SHR on high-salt intake long-term treatment with nifedipine at 50 or 100 microg/kg/h decreased resting BP and the sympathetic component in BP control. In addition to possible peripheral effects, long-term administration of nifedipine may also act centrally to decrease sympathetic activity and BP, likely by increasing activity in central pathways involving sympathoinhibition, but not in pathways involving sympathoexcitation as evaluated by air-stress.

Introduction: Barnidipine is a new dihydropyridine calcium antagonist that is presented in modified-release capsules containing a single S-S optical isomer of the molecule. Its characteristics are of interest, as there is evidence of differences in kinetics, dynamics, interactions and safety of individual enantiomers in traditional racemic preparations of calcium antagonists. The safety of barnidipine and its interaction profile are reviewed., Safety: Adverse events with barnidipine are of mild to moderate intensity, most commonly of type I and occur in the early phase of treatment. Furthermore, safety results in elderly patients are comparable with those in the general population, indicating that barnidipine can be used without dose adjustment in elderly hypertensive patients., Interactions: Barnidipine has a pharmacokinetic interaction profile that compares favourably with those from other calcium antagonists. The pharmacokinetic properties of barnidipine are unaffected by food. Minor increases in its availability may occur with concomitant use of alcohol or grapefruit juice, but these are unlikely to have clinical relevance. In contrast with several other calcium antagonists, barnidipine does not affect the steady-state kinetics of digoxin, whereas, like other calcium antagonists its bioavailability may be increased by the concomitant administration of cimetidine. In addition, the potential of barnidipine and its major metabolites to affect the metabolism of concomitant medication is unlikely to be of clinical relevance., Conclusion: The interaction and tolerability profile of barnidipine is well established in all age groups.

Objective: To estimate oral clearance of nifedipine and to determine demographic and clinical covariates that affect nifedipine clearance in a clinical population., Methods: Apparent oral clearance of nifedipine and protein binding were measured in 226 patients receiving sustained-release nifedipine formulations for hypertension and coronary artery disease (black men, n = 111; black women, n = 27; white men, n = 64; white women, n = 24). Mean age +/- SD was 71 +/- 11 years, and mean weight was 86 +/- 17 kg. Nifedipine concentrations were analyzed by HPLC, protein binding was measured by equilibrium dialysis, clearance and covariate effects were estimated by a nonlinear mixed effects population model, and statistical analyses were performed by a nonlinear mixed-effects model (clearance) and ANOVA (protein binding)., Results: Clearance was significantly slower in black subjects (8.9 +/- 0.7 mL/min/kg; mean +/- SE) compared with white subjects (11.6 +/- 0.8 mL/min/kg; P = .00004) and in men compared with women (9.3 +/- 0.6 versus 12.1 +/- 1.5 mL/min/kg; P = .0021). Reported alcohol use (alcohol, 8.6 +/- 1.1 versus no alcohol, 10.8 +/- 0.6 mL/min/kg; P = .0002) and smoking status (smoker, 8.8 +/- 2.0 versus nonsmoker, 10.2 +/- 0.6 mL/min/kg; P = .0362) also affected nifedipine clearance. Race and sex had no effect on protein binding of nifedipine (P = .29 and P = .44, respectively). No effects of age, stable coronary artery disease, or reported intake of beta-blockers on nifedipine clearance were detected in this primarily elderly population with hypertension., Conclusions: The data suggest that race, sex, and environmental factors are identifiable sources of interindividual variation in the oral clearance of nifedipine, a CYP3A substrate. Our experience also suggests that data from clinical populations may be biased with regard to age, sex, and formulation selection, and covariates may not be independently distributed, which can limit analyses.

The aim of the present study was to investigate the effect of hydroxypropylmethylcellulose (HPMC-2208), used as an excipient for controlled release of drug, on the release profiles and bioavailability of the poorly water-soluble nifedipine (NP) from a tablet prepared using macrogol 6000 (PEG) and HPMC. The crushing tolerance of the NP tablet prepared using PEG and HPMC (NP-PEG-HPMC tablet) was markedly increased with increasing compression force used during the preparation from 20 to 200 MPa. The values reached their maximal levels (approximately 13 kg for the NP-PEG-HPMC tablet and 8 kg for the PEG tablet) at the compression force of 100 MPa. Although NP is a poorly water-soluble drug, it was rapidly dissolved from the NP-PEG tablet (without HPMC) due to the improvement of its dissolution rate in the presence of PEG. NP dissolution was complete at the latest within 1 h. On the other hand, dissolution of NP from the NP-PEG-HPMC tablet was significantly delayed with an increase in the concentration of HPMC in the tablet. The dissolution of NP from the NP-PEG-HPMC tablet containing 50% HPMC-2208 was markedly delayed as the viscosity of HPMC also increased. Interestingly, the same peak plasma NP concentration (C(max)) and the area under the plasma NP concentration-time curve (AUC(0-10)) were observed for both the NP-PEG tablet and NP-PEG-HPMC tablets, however, the time to C(max) (t(max)) for the NP-PEG-HPMC tablet was significantly higher when the NP-PEG-HPMC tablet was orally administered to rabbits. We describe here a preparation method of a new sustained-release NP-PEG-HPMC tablet using a mixture of NP-PEG granules (prepared with PEG) and HPMC.

A rapid, simple, specific and sensitive high performance liquid chromatographic method has been developed for the determination of nifedipine (adalate) in human serum using diazepam (valium) as an internal standard (I.S.). The method utilized a 5 microm nonpolar C18 reversed phase Hypersil (ODS) column (250 x 3 mm i.d.). The mobile phase consisted of 60% v/v, acetonitrile in water, adjusted to pH 3.7 with glacial acetic acid and ammonium acetate, and pumped at a flow rate of 2 ml/min. The effluent was monitored by UV detection at 340 nm and a sensitivity fixed at 0.02 aufs. Each analysis required no longer than 4 min. The minimum detectable amount of nifedipine in serum was 3 ng/ml, and the mean absolute recovery was 93.5%. The within and between-day coefficients of variation at three different concentrations from 15-160 ng/ml ranged from 2.07 to 7.76%, and from 3.15 to 7.98% respectively. Calibration graphs for 10 to 200 ng/ml were linear with a mean correlation coefficient, r (n = 36) of 0.9991. The method was validated for accuracy, sensitivity, selectivity and reproducibility and finally was utilized and proved to be suitable in a bioavailability study of two products of nifedipine following oral administration to healthy male subjects.

Objective: To assess the bioequivalence of two oral formulations containing 10 mg of nifedipine. The test preparation were Macorel tablets, the reference preparation were Adalat tablets., Subjects, Material and Methods: The study was designed as a single-dose, three-period crossover randomized design to 18 non-smoker, healthy male volunteers under fasting conditions. Seventeen volunteers completed the study. Plasma samples were analyzed for nifedipine by HPLC after solid-phase extraction. The pharmacokinetic parameters used to assess the bioequivalence of the two formulations were AUC(0-infinite) and AUC(0-t) for the extent of absorption and Cmax and Tmax for the rate of absorption. Statistical comparisons of AUC(0-infinite) AUC(0-t), and Cmax data were evaluated after logarithmic transformation by two-way analysis of variance (ANOVA), and differences of Tmax were tested non-parametricaly., Results: Point estimates (90% confidence intervals) of the test/reference ratios were 97.4% (87.6%-108.3%) for AUC(0-infinite) 97.0% (85.6%-110.1%) for AUC0-t, and 107.7% (89.1%-130.7%) for Cmax. No statistically significant difference was found for Tmax and elimination half-life values., Conclusion: Therefore, in accordance with the European Union bioequivalence requirements, the test and reference nifedipine preparations are bioequivalent for both the extent and the rate of absorption.

The impact of acute phase response (APR) on the plasma clearances of antipyrine, theophylline, phenytoin and nifedipine was studied using 50 female rabbits. APR was induced by a bolus intramuscular injection of Escherichia coli lipopolysaccharide (LPS, 50 microg/kg). No abnormal findings, other than an increase in rectal body temperature and the plasma concentration of interleukin-6 (IL-6), were observed in the LPS-treated animals. Twenty-four hours after LPS injection, the pharmacokinetic parameters of the four drugs were obtained following intravenous administrations of antipyrine (7 mg/kg), theophylline (5 mg/kg), phenytoin (10 mg/kg) and nifedipine (1 mg/kg). Total body clearances of antipyrine, theophylline, phenytoin and nifedipine in LPS-treated rabbits decreased, and terminal elimination half-life and the mean residence time of these drugs increased compared with those in the control rabbits. The apparent volume of distribution for phenytoin and nifedipine increased after the LPS injection, although the binding percentage of the drugs with plasma protein did not change. These results suggested that APR appears to decrease the plasma clearances of these drugs in rabbits, which may be due to the suppression of the activity of cytochrome P450 enzymes.

A nifedipine (NF) polyethylene glycol (PEG) solid dispersion was prepared. Using this solid dispersion, NF hydroxypropylmethylcellulose (HPMC) matrix tablets were prepared. Both the high-viscosity grade HPMC (Methocel K15M) and low-viscosity grade HPMC (Methocel K100) were applied in the tablets to form the matrix. The dissolution and absorption of NF from the tablet were evaluated as a formulation that had a sustained release over 24 hr. The Hixson-Crowell equation and Higuchi equation were used to investigate the dissolution mechanism, and the erosion and diffusion codependent mechanism was established. Adalat GITS 30 was used as a reference dosage form. Each beagle dog was also administered an intravenous injection to obtain the pharmacokinetics parameters. The Loo-Riegelman method was applied to study the in vitro/in vivo correlation of the tested tablets and Adalat GITS 30, and significant correlation was proved. Absolute bioavailability and comparative bioavailability of the tested tablet were studied. The results indicated that the NF HPMC tablet could be an ideal 24-hr sustained-release formulation.

The calcium antagonist nifedipine absorbs ultraviolet A (UVA) radiation and readily photodegrades in vitro to a toxic nitroso-pyridine photoproduct. We examined whether whole body exposure of normal subjects to sunbed UVA radiation would affect the pharmacokinetics of nifedipine. Eight healthy, male, Caucasian volunteers (phototypes I-III) participated in this ethically approved, randomised, cross-over study. Each subject attended on 2 occasions, one week apart, and on each occasion was given a single oral dose (10 mg) of nifedipine following which blood samples were collected at 0, 0.5, 1. 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 7 h. During one of the visits, 15 min after nifedipine ingestion, a whole-body UVA (sunbed comprising Philips R-UVA lamps) dose of 70% of the individual's predetermined minimal phototoxic dose was delivered over a period of 17-36 min. Plasma nifedipine levels were measured using a standard reverse-phase high-performance liquid chromatography method. The area under the plasma concentration-time curve (AUC) of nifedipine during the UVA irradiation session (median 206 ng x ml(-1) x h(-1)) was significantly higher than during the non-irradiation control session (median 174.5 ng x ml(-1) x h(-1)) (P=0.03; 95% C.I. for difference in medians 9.9 to 55.9 ng x ml(-1) x h(-1)). UVA irradiation did not significantly affect any of the other measured pharmacokinetic parameters (Cmax, t 1/2, tmax). We demonstrate that sunbed UVA irradiation does not lead to in vivo photodegradation of nifedipine in healthy humans after a single dose. The apparent increase in AUC during UVA irradiation may be due to slightly slower metabolism of nifedipine in the presence of toxic photoproduct(s) or due to blood distribution changes affecting liver blood flow.

Experimental controlled release nifedipine microcapsules composed of ethylcellulose and eudragit RL were explored for the assessment of bioavailability on rabbit. The pharmacokinetic parameters were compared between the formulations and with the pure drug material. A statistically significant difference between the formulations was noticed in the parameters, K, T1/2, AUC (0-->infinity), MRT and bioavailability but not in Vd, Cmax and Tmax and in each case a highly significant difference was observed with reference drug material. Controlled release absorption profiles in vivo were observed from the experimental microcapsules as revealed by the Wagner-Nelson method. The absorption lag time, absorption rate constant, and absorption half life were calculated by using the back projection method of residuals. A good correlation demonstrated between in vivo absorption and in vitro release data for both the products merits specific attention. There was no loss in bioavailability of the experimental ethylcellulose microcapsule (drug content 75.8%), even though nifedipine undergoes extensive first pass metabolism.

We studied the effects of short- and long-term ingestion of grapefruit juice (GJ) on nifedipine (NFP) pharmacokinetics in rats. Thirty minutes after intraduodenal (id) administration of 2.0 ml of GJ or saline, NFP was i.v. or id administered at a dose of 3 mg/kg b. wt. No significant differences were observed in pharmacokinetic values between the two groups after i.v. administrations of NFP. By contrast, after id administration, the mean AUC value in the GJ group was approximately 1.62 times that in the control group, and the mean apparent clearance (CL) decreased by approximately 40%. In addition, 2.0 ml of GJ was orally administered twice a day (9:00 AM and 7:00 PM) for 10 consecutive days; on the 11th day the pharmacokinetics of NFP were examined again. Irrespective of route of administration (i.v. or id), NFP CL from plasma in these GJ-treated rats was considerably faster than that in the rats treated with GJ for a short (30-min) period. In microsomes prepared from the intestinal mucosa of animals receiving long-term administration of GJ, NFP oxidation activity (0.21 +/- 0.02 nmol/mg/min) and P-450 content (0.045 +/- 0.009 nmol/mg) were significantly lower than those in untreated rats (0.32 +/- 0.05 nmol/mg/min and 0.060 +/- 0.007 nmol/mg). In hepatic microsomes from the same rats, however, NFP oxidation activity (1.43 +/- 0.17 nmol/mg/min) and P-450 content (0.66 +/- 0.07 nmol/mg) were distinctly greater than those in untreated rats (1.00 +/- 0.06 nmol/mg/min and 0.51 +/- 0.04 nmol/mg). In conclusion, short-term id exposure to GJ resulted in increased NFP bioavailability, whereas long-term administration of GJ resulted in reduced bioavailability and increased CL.

A highly sensitive, selective and reproducible reversed-phase high-performance liquid chromatographic method has been developed for the determination of nifedipine in human plasma with minimum sample preparation. The method is sensitive to 3 ng/ml in plasma, with acceptable within- and between-day reproducibilities and linearity (r2 > 0.99) over a concentration range from 10-200 ng/ml. Acidified plasma samples were extracted using diethyether containing diazepam as internal standard and chromatographic separation was accomplished on C18 column using a mobile phase consisting of acetonitrile, methanol and water (35:17:48, v/v). The within-day precision ranged from 2.22 to 4.64% and accuracy ranged from 102.4-106.4%. The day-to-day precision ranged from 2.34-7.07% and accuracy from 95.1-100.1%. The relative recoveries of nifedipine from plasma ranged from 91.0-107.3% whereas extraction recoveries were 88.6-93.3%. Following eight 6-week freeze-thaw cycles, nifedipine in plasma samples proved to be stable with accuracy ranging from 0.64 to 3.0% and precision ranging from 3.6 to 4.15%. Nifedipine was also found to be photostable for at least 120 min in plasma, 30 min in blood and for 60 min in aqueous solutions after exposure to light. The method is sensitive and reliable for pharmacokinetic studies and therapeutic drug monitoring of nifedipine in humans after the oral administration of immediate-release capsules and sustained-release tablets to five healthy subjects.

The synthesis and antihypertensive activity of racemates and enantiomers of substituted 2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridinedicarboxylates have been reported.

Objective: To discuss some controversial aspects and special situations which should be considered when assessing the use of generic drugs, especially those frequently used in neurology., Development: We discuss the difference between the concept of average bio-equivalence and individual bio-equivalence, and the implications the selection of one or other criterion may have in the treatment of individual patients with carbamazepine. We also discuss the peculiarities and problems concerning bio-equivalence in the case of drugs with non-linear pharmacokinetics, controlled-release formulations, racemic drugs with two or more stereo-isomers and when there are differences in the excipients of different formulations of the same drug., Conclusions: There are drugs in which it may be very difficult to show the bio-equivalence of a generic formulation because of its pharmacokinetic characteristics as occurs in the case of controlled-release drugs, the presence of active metabolites or differences in their enantiomers or even due to problems with the excipients used, although if the therapeutic range is wide and these variables are controlled in the studies done, the conclusions regarding bio-equivalence may be valid.

Poly(vinyl alcohol)-guar gum interpenetrating network microspheres were prepared by cross-linking with glutaraldehyde. Nifedipine, an antihypertensive drug, was loaded into these matrices before and after cross-linking to study its release patterns. The extent of cross-linking was analyzed by Fourier transform infrared spectroscopy and differential scanning calorimetry. Furthermore, the microspheres were characterized for drug entrapment efficiency, particle size, transport of water into the matrix and drug release kinetics. Scanning electron microscopic photographs confirmed the spherical nature and surface morphology. The mean particle size of the microspheres was found to be around 300 microm. The molecular transport phenomenon, as studied by the dynamic swelling experiments, indicated that an increase in cross-linking affected the transport mechanism from Fickian to non-Fickian. The in vitro release study indicated that the release from these microspheres is not only dependent upon the extent of cross-linking, but also on the amount of the drug loaded as well as the method of drug loading.

To examine the effects of repeat oral dosing of rosiglitazone on the pharmacokinetics of nifedipine, a prototype CYP3A4 substrate, a randomized, open-label, crossover study was performed with two treatment phases separated by a washout period of at least 14 days. Twenty-eight healthy male volunteers received either a single 20 mg oral nifedipine dose or rosiglitazone 8 mg orally once daily for 14 days with a single 20 mg oral nifedipine dose administered on day 14. Plasma nifedipine concentrations were determined over the 24-hour period following administration of the nifedipine doses. Lack of effect was defined as the demonstration that the 90% CI was contained entirely within a symmetrical 30% range either side of unity on the loge-scale. Following rosiglitazone + nifedipine administration, the area under the nifedipine concentration-time curve from time zero to infinity (AUC(0-infinity)) was 13% lower than that after administration of nifedipine alone. This difference in nifedipine AUC(0-infinity) was not deemed to be clinically significant since the 90% CI was contained within the protocol-defined 30% range (point estimate for ratio of geometric means 0.87; 90% CI: 0.79, 0.96). Rosiglitazone had no marked effect on nifedipine peak plasma concentration (point estimate: 0.99; 90% CI: 0.73, 1.34) or time to peak concentration compared with nifedipine alone. Rosiglitazone coadministration produced a small decrease in the mean nifedipine half-life (point estimate: -0.77; 90% CI: mean difference -1.29 h, -0.25 h). Both treatment regimens were well tolerated and associated with a favorable safety profile. Rosiglitazone, at the highest dose used in clinical studies, produced a small, clinically insignificant decrease in nifedipine exposure. The very small effect on nifedipine pharmacokinetics suggests that rosiglitazone is an extremely weak inducer of CYP3A4, a characteristic that distinguishes rosiglitazone from troglitazone.

Objective: The extrapolated area under the concentration-time curve (AUC0-infinity) for any drug is considered by operating guidelines as the primary parameter related to the extent of absorption in single-dose bioavailability and bioequivalence trials. Not more than 20% should be added to the experimental AUC (AUC0-t) in the extrapolating procedure. However, in certain specific cases, it is problematic and, in other cases, impossible to respect the above requirement. It was intended to demonstrate that truncated AUC or AUC0-t would be used in bioequivalence trials when the AUC cannot be extrapolated., Methods: AUC0-t and truncated AUC were compared at various time intervals with AUC0-infinity in a series of 19 single-dose bioequivalence trials covering 15 different drugs, each carried out on 12-24 healthy volunteers. Point estimators and 90% confidence intervals in the 0.80-1.25 and 0.70-1.43 ranges were statistically processed using log-transformed parameters., Results: In all the trials considered, overlapping point estimators and 90% confidence intervals were invariably obtained, regardless of the AUC used., Conclusion: The use of AUC0-t or truncated AUC may be considered an ancillary procedure in bioequivalence trials when AUC cannot be extrapolated. This occurs with most extended-release formulations, endogenous substances, and poorly absorbed drugs. It also occurs in trials with one or more poor metabolisers, with drugs possessing very long elimination half-lives, and with bioassays having problems of sensitivity that preclude sufficiently precise plasma concentration measurement over the required sampling period.

Nifedipine, a hypertensive calcium channel blocker, is commonly administered to subjects with coronary heart disease who often exhibit hyperlipidemia. In general, the pharmacokinetic consequences of hyperlipidemia include increased total drug concentrations and decreased unbound fraction in plasma. However, the pharmacodynamic consequences of hyperlipidemia are conflicting; unaltered, increased, or decreased pharmacological effects are reported. In this study, the effect of experimental hyperlipidemia on pharmacokinetic and pharmacodynamic consequences of nifedipine was studied. After establishing a dose (0.05-0.3 mg.kg(-1))-effect relationship, single 0.1 mg.kg(-1) i.v. doses of nifedipine were administered to control and poloxamer 407-induced hyperlipidemic (with and without cholesterol-lowering agent atorvastatin) rats. Mean arterial pressure, total as well as unbound nifedipine plasma concentrations, and total cholesterol were monitored. Hyperlipidemia significantly decreased systemic clearance of nifedipine by 40% and increased T(1/2) and area under the plasma concentration-time curve by 85 and 65%, respectively. Compared with the hyperlipidemic group, atorvastatin-treated rats had significantly lower total plasma cholesterol (0-70%), increased systemic clearance (39%), and decreased T(1/2) (27%) and area under the plasma concentration-time curve (24%). Hyperlipidemia prolonged pharmacological T(1/2) of nifedipine by 300%. Atorvastatin treatment significantly reduced this prolongation to 46%. There was a significant correlation between mean blood pressure and the total but not unbound nifedipine plasma concentrations. Hyperlipidemia potentiates the hypotensive effect of nifedipine by increasing its total plasma concentrations despite decreased unbound drug concentration.

Purpose: To further characterize CYP3A4-transfected Caco-2 cells with regard to morphological, transport, and metabolic properties, and to evaluate a different Caco-2 cell strain transfected with both CYP3A4 and oxidoreductase (OR)., Methods: Transfected Caco-2 cells, Caco-2 TC7 cells, and wild-type Caco-2 cells grown onto Millicell were used. We determined the morphological characteristics of transfected cell monolayers using light and transmission electron microscope. We determined the transport and metabolic capabilities of the transfected cells, TC7 cells, and wild-type cells with a variety of drugs, nutrients, and marker compounds., Results: The transfected Caco-2 cells formed a tight monolayer with TEER values and mannitol transport similar to the untransfected parent cell strain (wild type). However, the transfected cells (grown onto Millicell) reached maturity approximately 33% faster than the wild-type cells. Permeabilities of propranolol, nifedipine, testosterone, linopirdine, mannitol, and cephalexin were similar in transfected and wild-type Caco-2 cells. On the other hand, the transfected cells of early passages were much more metabolically active, and metabolized standard CYP3A4 substrates (e.g., testosterone and nifedipine) as much as 100 times faster than untransfected cells. In addition, metabolism of standard substrates was inhibitable by ketoconazole and TAO. Using comparable data, the transfected cells metabolized testosterone the fastest, followed by linopirdine and nifedipine (approximate ratio: 10:6:2). The metabolites of standard substrates were generally preferably excreted to the apical membrane., Conclusion: The monolayers of newly transfected cells (CYP3A4 + OR) have a significantly increased level of CYP3A4 activities compared to untransfected cells. These cell monolayers also have desirable morphological and transport characteristics that are similar to untransfected cells.

Particles from gas saturated solutions, a novel method for high pressure material processing, has been used for micronization of practically insoluble calcium-channel blockers nifedipine and felodipine and the hypolipidemic agent fenofibrate with the aim of increasing their dissolution rate and hence their bioavailability. Dependent on the pre-expansion conditions, a mean particle size of between 15 and 30 microm was achieved for micronized nifedipine and 42 microm for micronized felodipine. The particle size of processed fenofibrate, on the other hand, increased due to agglomeration. The highest dissolution rate was achieved by preparation of drug coprecipitates with PEG 4000., (Copyright.)

Purpose: The effect of hyperlipidemia on nifedipine pharmacokinetics was studied. The mechanisms by which hyperlipidemia affects pharmacokinetics of drugs are mainly undetermined. Hyperlipidemia may decrease the fraction of unbound drug in plasma and/or decrease intrinsic ability of the cytochrome P-450 systems due to excess membrane cholesterol. Hyperlipidemia is a primary risk factor for coronary artery disease leading to hypertension and ischemic heart disease, for which nifedipine, a calcium channel blocker, is used., Methods: Poloxamer 407 (P407)-induced hyperlipidemic rat model was used to study the effects of hyperlipidemia on the pharmacokinetics of nifedipine (6 mg kg-1 given i.v., i.p. and p.o.). Total plasma cholesterol levels increased from 0.82-2.02 to 5.27-11.05 mmol L-1 48 h post P407 administration (1 g kg-1, i.p.). Protein binding studies were conducted by an ultrafiltration method., Results: Hyperlipidemia significantly decreased CLTB by 38% and CLTB/F by 45 and 42% following po and i.p. doses, respectively, thereby increasing AUC0-infinity, Cmax and half-life. Absolute bioavailability and Vdss remained unchanged. AUC0-infinity was affected to the same extent in each route of administration, therefore, the effect was mainly systemic rather than presystemic. Hyperlipidemia significantly lowered the fraction unbound in plasma by approximately 31%., Conclusions: The altered pharmacokinetics of nifedipine by P407-induced HYPERLIPIDEMIA may be, at least in part, due to the decrease in fraction unbound in plasma. A decrease in intrinsic clearance, however, cannot be ruled out.

Genetic polymorphisms in the cytochrome P450 (CYP) family are widely known to contribute to interindividual differences in the pharmacokinetics of many drugs. Several alleles for the CYP2C9 gene have been reported. Individuals homozygous for the Leu359 variant (CYP2C9*3) have been shown to have significantly lower drug clearances compared with Ile359 (CYP2C9*1) homozygous individuals. A male Caucasian who participated in six bioavailability studies in our laboratory over a period of several years showed extremely low clearance of two drugs: phenytoin and glipizide (both substrates of CYP2C9), but not for nifedipine (a CYP3A4 substrate) and chlorpheniramine (a CYP2D6 substrate). His oral clearance of phenytoin was 21% of the mean of the other 11 individuals participating in the study, and his oral clearance of glipizide, a second generation sulfonylurea structurally similar to tolbutamide, was only 188% of the mean of the other 10 individuals. However, his oral clearance of nifedipine and chlorpheniramine did not differ from individuals in other studies performed at our laboratories. An additional blood sample was obtained from this individual to determine if he possessed any of the known CYP2C9 or CYP2C19 allelic variants that would account for his poor clearance of the CYP2C9 substrates (phenytoin and glipizide) compared with the CYP3A4 (nifedipine) and CYP2D6 (chlorpheniramine) substrates. The results of the genotype testing showed that this individual was homozygous for the CYP2C9*3 allele and did not possess any of the known defective CYP2C19 alleles. This study establishes that the Leu359 mutation is responsible for the phenytoin and glipizide/tolbutamide poor metabolizer phenotype.

Study Objective: To evaluate 24-hour blood pressure control and frequency of adverse effects in patients with mild to moderate hypertension switched from nifedipine gastrointestinal therapeutic system (Nif-GITS) to nifedipine coat core (Nif-CC)., Design: Open-label, prospective, switch study, Setting: University-affiliated outpatient cardiology clinic., Subjects: Twenty patients with mild to moderate essential hypertension, who were taking Nif-GITS 30, 60, or 90 mg/day for 8 weeks or longer., Interventions: Patients stabilized with Nif-GITS 30, 60, or 90 mg were monitored over 24 hours with an ambulatory blood pressure monitor and were then switched to an equivalent dosage of Nif-CC. After 8 weeks+/-1 week taking Nif-CC, they were again monitored with a 24-hour blood pressure monitor. The 24-hour blood pressure load (percentage of values > 135/85 mm Hg for 24 hrs), daytime blood pressure load (percentage of values > 140/90 mm Hg from 7:00 A.M.-10:00 P.M.), nighttime blood pressure load (percentage of values > 120/80 mm Hg from 10:00 P.M.-7:00 A.M.), diurnal blood pressure variation, average 24-hour blood pressure, daytime blood pressure, nighttime blood pressure, mean blood pressure for the first 4 hours, and last 8 hours of the dosing interval were measured. Adverse effects such as headache, dizziness, and edema were also reported., Measurements and Main Results: No differences in average 24 hour-blood pressure readings were observed but significant differences in blood pressure control during the first 4 and last 8 hours of the dosing interval were seen. Systolic and diastolic blood pressures were higher after approximately 16 hours in patients switched from Nif-GITS to Nif-CC. Although Nif-CC caused a greater initial response, it was less effective than Nif-GITS after 16 hours. This could explain the lack of differences in average 24-hour blood pressure values between formulations. Of the 20 patients, 20% experienced increased headaches, 20% showed signs of increased peripheral edema, and 10% reported occasional dizziness after switching agents. Three patients discontinued Nif-CC, two as ordered by their primary care physician and one on his own due to headache., Conclusion: This study suggests that patients switched from Nif-GITS to Nif-CC could experience increased blood pressure during the night or toward the end of the dosing interval. They could also experience adverse effects such as headache, edema, and dizziness, which could result in more physician visits and put patients with other disease states such as coronary heart disease at increased risk.

Quantitative analysis of therapeutic compounds and their metabolites in biological matrix (such as plasma, serum or urine) nowadays requires sensitive and selective methods to allow the determination of concentrations in the ng/ml range. A new on-line LC-MS-MS method using atmospheric pressure chemical ionisation (APCI) as interface for the simultaneous determination of nifedipine (NIF) and its metabolite in human plasma, dehydronifedipine (DNIF) has been developed. The compounds were extracted from plasma using solid-phase extraction (SPE) on disposable extraction cartridges (DECs). The SPE operations were performed automatically by means of a sample processor equipped with a robotic arm (ASPEC system). The DEC filled with phenyl modified silica was first conditioned with methanol and water. The washing step was performed with water. Finally, the analytes were successively eluted with methanol and water. The liquid chromatographic (LC) separation of NIF and DNIF was achieved on a RP-18 stationary phase (4 microm). The mobile phase consisted of methanol-50 mM ammonium acetate solution (50:50, v/v). The LC was then coupled to tandem mass spectrometry with an APCI interface in the positive ion mode. The method developed was validated. The absolute recoveries evaluated over the whole concentration range were 95+/-2% and 95+/-4% for NIF and DNIF, respectively. The method was found to be linear in the 0.5-100 ng/ml concentration range for the two analytes (r2 = 0.999 for both NIF and DNIF). The mean R.S.D. values for repeatability and intermediate precision were 2.9 and 3.0% for NIF and 2.2-4.7% for the metabolite. The method developed was successfully used to investigate the plasma concentration of NIF and DNIF in the pharmacokinetic studies.

This paper describes the preparation of new buccal bilayered devices comprising a drug-containing mucoadhesive layer and a drug-free backing layer, by two different methods. Bilaminated films were produced by a casting/solvent evaporation technique and bilayered tablets were obtained by direct compression. The mucoadhesive layer was composed of a mixture of drug and chitosan, with or without an anionic crosslinking polymer (polycarbophil, sodium alginate, gellan gum), and the backing layer was made of ethylcellulose. The double-layered structure design was expected to provide drug delivery in a unidirectional fashion to the mucosa and avoid loss of drug due to wash-out with saliva. Using nifedipine and propranolol hydrochloride as slightly and highly water-soluble model drugs, respectively, it was demonstrated that these new devices show promising potential for use in controlled delivery of drugs to the oral cavity. The uncrosslinked chitosan-containing devices absorbed a large quantity of water, gelled and then eroded, allowing drug release. The bilaminated films showed a sustained drug release in a phosphate buffer (pH 6.4). Furthermore, tablets that displayed controlled swelling and drug release and adequate adhesivity were produced by in situ crosslinking the chitosan with polycarbophil.

Raynaud's phenomenon (RP) is a peripheral circulatory disorder characterized by sudden episodes of digital artery spasm, often precipitated by cold temperature or emotional stress. Although the cause of RP is not fully known, it appears to involve inappropriate adrenergic response to cold stimuli. Treatment of RP is conservative in most patients, but in patients with severe disease includes the use of agents that promote digital vasodilation. The calcium-channel antagonists, particularly the dihydropyridine derivative nifedipine, are the most thoroughly studied drug class for the treatment of RP. Approximately two thirds of patients respond favorably, with significant reductions in the frequency and severity of vasospastic attacks. Nifedipine use is often limited by the appearance of adverse vasodilatory effects such as headache or peripheral edema. The newer second-generation dihydropyridines such as amlodipine, isradipine, nicardipine, and felodipine also appear to be effective in patients with RP and may be associated with fewer adverse effects.

Objective: To investigate the influence of oral contraceptives on cytochrome P450 3A4 (P450NF) activity., Methods: In 23 healthy women, the pharmacokinetics of nifedipine and its main metabolite dehydronifedipine in plasma were assessed after a single oral dose, prior to and after intake of one of two oral contraceptive formulations, one containing 2 mg dienogest and 0.03 mg ethinylestradiol (group A) and the other containing 0.125 mg levonorgestrel and 0.03 mg ethinylestradiol (group B)., Results: While the intake of two oral contraceptives for 21 days did not influence the plasma concentration-time curve of unchanged nifedipine, mean AUC0-23.5 h and the mean Cmax values of dehydronifedipine were significantly lower in both groups tested/(24% in group A and 25% in group B). This observation may indicate a reduced formation rate of metabolites and reflects an inhibition of cytochrome P450 3A4 activity. The activation of the same or other metabolic degradation mechanism(s) could explain this result., Conclusion: The investigation presented demonstrates the importance of metabolite measurement when in vivo studies are undertaken to investigate different influences on drug metabolizing ability.

The in vitro percutaneous fluxes of propylene glycol (PG), cis-oleic acid (OA) and dimethyl isosorbide (DI) were determined and their effect on nifedipine (N) flux and lag time evaluated. PG, OA and DI flux through hairless mouse (HM) skin was measured in vitro by beta-scintigraphy and N permeation was measured by HPLC under finite and infinite dose conditions. Evaluation of each of the solvents separately showed that pure DI possessed the inherent ability to traverse the skin (12% in 24 h). For the tested formulation after 24 h, 57% of the PG and 40% of the DI had permeated across the skin with nearly linear permeation between 4 and 18 h and the relative order of permeation was PG > DI > N. DI permeation was further aided in the presence of PG and OA. N flux was dependent on concomitant solvent permeation. Over a 24-h test period a dose dependent response was observed for N, with 4.9-15.6 mg of N delivered from the lowest and highest doses, respectively, and the highest dose yielding zero-order flux of 146 (g/h per cm2)., (Copyright 1998 Elsevier Science B.V.)

Oral combinations of nifedipine and atenolol are widely used in the treatment of hypertension, proving particularly effective when the atenolol is released immediately and the nifedipine is released in a sustained manner. This work examined the potential of combining nifedipine and atenolol in a tablet, which would be easier to manufacture than currently available combined formulations. The results indicated that a 40:60 (w/w) nifedipine-atenolol mixture forms a eutectic melting at 140 degrees C. Nevertheless, both drugs were stable when incorporated in tablets elaborated using cellulose ethers as base excipients. Tablets prepared from atenolol-lactose granules and solid dispersions of nifedipine-hydroxypropylmethylcellulose (100 cP) had more adequate dissolution profiles than a more complex reference formulation in hard capsules.