Pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers.

WHAT IS KNOWN AND OBJECTIVE: Ivabradine is a novel heart rate-lowering agent that selectively and specifically inhibits the depolarizing cardiac pacemaker If current in the sinus node. Our objective was to evaluate a possible pharmacokinetic interaction between ivabradine and carbamazepine in healthy volunteers. METHODS: The study consisted of two periods: Period 1 (Reference), when each volunteer received a single dose of 10 mg ivabradine and Period 2 (Test), when each volunteer received a single dose of 10 mg ivabradine and 400 mg carbamazepine. Between the two periods, the subjects were treated for 15 days with a single daily dose of 400 mg carbamazepine. Plasma concentrations of ivabradine were determined during a 12-h period following drug administration, using a high-throughput liquid chromatography with mass spectrometry analytical method. Pharmacokinetic parameters of ivabradine administered in each treatment period were calculated using non-compartmental and compartmental analysis to determine if there were statistically significant differences. RESULTS AND DISCUSSION: In the two periods of treatments, the mean peak plasma concentrations (C(max)) were 16·25 ng/mL (ivabradine alone) and 3·69 ng/mL (ivabradine after pretreatment with carbamazepine). The time taken to reach C(max), t(max), were 0·97 and 1·14 h, respectively, and the total areas under the curve (AUC(0-∞)) were 52·49 and 10·33 ng h/mL, respectively. These differences were statistically significant for C(max) and AUC(0-∞) when ivabradine was administered with carbamazepine, whereas they were not for t(max), half-life and mean residence time. WHAT IS NEW AND CONCLUSION: T Carbamazepine interacts with ivabradine in healthy volunteers, and lowers its bioavailability by about 80%. This magnitude of effect is likely to be clinically significant.

Oxaliplatin in patients with metastatic colorectal cancer: efficacy and pharmacokinetics parameters.

PURPOSE: The aim of this study was to investigate the efficiency of the FOLFOX-4 regimen and to evaluate the pharmacokinetics of oxaliplatin in untreated patients with metastatic colorectal cancer. METHODS: 43 patients were enrolled in the study. Patients received oxaliplatin 85 mg/m(2) as 2-h i.v. infusion, on day 1, and bolus 5-fluorouracil (5FU) 400 mg/m(2) plus leucovorin (LV) 200 mg/m(2) followed by 5FU 600 mg/m(2) as 22-h infusion on day 1 and 2, every 2 weeks. The pharmacokinetics of oxaliplatin evaluated in 4 patients was performed in blood, plasma and ultrafiltered plasma (UFT) by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). RESULTS: The overall response rate and the median time to progression (TTP) were 53.49% and 7.1 months, respectively. Grade 3-4 toxic effects were observed in 11 (25.5%) patients. Grade 3 neuropathy was observed in 13.95% of the cases. In univariate analysis only Eastern Cooperative Oncology Group (ECOG) performance status (PS) was correlated with response. No correlation was found between grade 3-4 adverse events and the patient characteristics. The area under the time-concentration curve (AUC) in UFT was 4.8 + or - 0.72 standard deviation (SD) microg h/ml and the total clearance 30.17 + or - 7.75 l/min. The values for volume of distribution and the maximum concentration were 567 + or - 20 liters and 0.38 + or - 0.17 ug/ml, respectively. CONCLUSION: FOLFOX-4 was an effective regimen with good tolerability in previously untreated metastatic colorectal cancer patients. The pharmacokinetics of oxaliplatin was triphasic with a short initial distribution phase and a long terminal elimination phase.

Optimization of fluid bed formulations of metoprolol granules and tablets using an experimental design.

BACKGROUND: The granulation process of a metoprolol tartrate (very difficult to process active pharmaceutical ingredient) formulation in laboratory scale fluid bed equipment was studied. AIM: To study the influence of two formulation factors and three process parameters on the characteristics of the granules and subsequently of the tablets, in the case of fluid bed granulating of a powder mix containing metoprolol tartrate. METHOD: In order to study the influence of formulation factors (binder solution concentration and the silicon dioxide ratio) and process factors (atomizing pressure, the length of the final drying phase, and the inlet air temperature) on the technological and pharmaceutical properties of granules and tablets, a fractional factorial experimental design resolution V+ with five factors and two levels was used. RESULTS: A high atomizing pressure allows us to obtain fine granules with large poly-dispersion index and granules with high tapped and untapped density, tablets with short disintegration time, short mean dissolution time, and a high percentage metoprolol tartrate release in the first 15 minutes. A lower concentration of binder solution allows us to obtain granules with very good flow properties, tablets which have no tendency to stick on the set punch of tabletting machine and no capping. The final drying time of granules has an influence only on the granule's relative humidity and tapped and untapped density, without any influence on the granules flow properties. CONCLUSIONS: The practical experimental results from the formulation processed in optimal working conditions were close to the predicted ones by Modde 6.0 software.

The influence of formulation factors on the kinetic release of metoprolol tartrate from prolong release coated minitablets.

The aim of this work was to study the possibility to obtain an oral extended-release dosage forms with zero order kinetic release by coating minitablets (containing metoprolol tartrate) with insoluble methacrylate film coating (Eudragit NE 40D) in a fluidized bed system. To achieve this aim a full factorial experimental design with two factors and three levels was used in order to study de influence of the amount of polymer film formatting (Eudragit NE 40D) and the amount of pore generating excipient in polymeric insoluble film (low viscosity hydroxypropyl methylcellulose-Methocel E 15LV) on the in vitro drug release profile.

Preliminary HPLC study on some polyphenols of Geranium robertianum L. (Geraniaceae).

In order to continue our previous studies concerning Geranium robertianum L., herb Robert (Geraniaceae), we have realised a HPLC study of some polyphenols using an original method created by a group of young researchers from the University of Medicine and Pharmacy of Cluj-Napoca. We have identified and measured in the dried Geranii robertiani herba (harvested from Valea Runcului, district of Alba-Iulia) the following compounds: hyperoside (3.64 microg/100 mg), ellagic acid (7599.76 microg/100 mg), isoquercitrin (49.49 microg/100 mg), quercetrin (83.92 microg/100 mg), kaempferols (143.43 microg/100 mg), caftaric acid (166.92 microg/100 mg), rutoside (72.23 microg/100 mg). We have also analysed a hydrolysed sample of the same drug in which we have identified and measured: caffeic acid (6.62 microg/100 mg), ellagic acid (10550.65 microg/100 mg), quercetrin (203.44 microg/100 mg), kaempferols (231.80 microg/100 mg), caftaric acid (47.41 microg/100 mg). We have indirectly proved the presence of ellagic tannins (the amount of ellagic acid increases after acid hydrolise) and the existence of bi- or polycaffeoil derivatives (the caffeic acid is present only in the hydrolysed sample). The flavonoid aglycones exist in both forms: as free compounds and as part of the flavonoid molecules.

Oxprenolol-loaded bioadhesive microspheres: preparation and in vitro/in vivo characterization.

Biologically adhesive delivery systems offer important advantages over conventional drug-delivery systems. In this paper, microspheres intended as a sustained release carrier for oral or nasal administration have been prepared by associating a known bioadhesive polymer, poly(acrylic acid), in gelatin microspheres. A model drug oxprenolol hydrochloride was chosen. It was found that some of the formulation variables can influence the characteristics of the beads in a controlled manner. The internal structure of the microspheres studied by X-ray diffraction, thermal analysis and optical microscopy showed the absence of drug crystals in microspheres and a lowering in the glass transition temperature. The dynamic swelling of the beads obeyed the square root of time and a shift from the diffusional to the relaxational process dependent on the content of poly(acrylic acid) in gelatin microspheres was observed. As expected, drug release from gelatin/poly(acrylic acid) microspheres was influenced by the poly(acrylic acid) content in beads, by the particle size of microspheres and by the pH of the medium. The mechanism of release was analysed by applying the empirical exponential equation and by calculation of the approximate contribution of the diffusional and relaxational mechanisms to the anomalous release process by fitting the data to the coupled Fickian/Case II equation. In vitro and in vivo experiments in rats showed good adhesive characteristics of the gelatin/poly(acrylic acid) microspheres, which were greater if the poly(acrylic acid) content was greater. A significant retardation in gastric and intestinal emptying time of the beads was observed. This was also suggested by the bioavailability of the model drug after intragastric and intranasal administration of the microspheres. The pharmacokinetic parameters after microsphere administration were more appropriate to a slow release drug-delivery system. The work suggests the potential of this pharmaceutical delivery system as an alternative controlled-release dosage form, either for oral or nasal administration.

Effects of long-term administration of lithium and hydrochlorothiazide in rats.

The biochemical and histological changes following 60 days administration of daily doses equivalent to 1/20 LD(50) of lithium lactate and hydrochlorothiazide, as such and in association, were studied in male Wistar rats. No mortality or overt signs of toxicity were observed during the experiment and the serum activities of transaminases, alkaline phosphatase and cholinesterase were not significantly modified compared to controls. The histopathological examination of all the investigated organs: kidney, liver, brain and spleen, revealed significant lesions which were time-dependant and more pronounced in the association group. Although the changes were mostly inflammatory and conqestive, it was proved that the concomitant administration of lithium and hydrochlorothiazid is potentially dangerous, increasing lithium's nephrotoxicity and the thiazide diuretic's hepatotoxicity.

Relative bioavailability of different oral sustained release oxprenolol tablets.

The bioequivalence of oral dosage forms of oxprenolol was assessed in a triple crossover study on two groups of 12 volunteers each. Single 160 mg doses of oxprenolol hydrochloride were given after an overnight fast of either oxprenolol sustained-release tablets in a megaloporous system, a hydrophil matrix and Slow-Trasicor (Ciba-Geigy) in the first group, or floating slow-release tablets administered with food or in absence of food, and rapid release Oxprenolol (Terapia, Cluj-Napoca) tablets, in the second group. Serum oxprenolol concentrations were measured by a gas chromatographic method. Pharmacokinetic parameters which describe bioavailability and general kinetic behavior of the drug were calculated from individual serum profiles. They were subjected to statistical analysis (paired Student's t test, p < 0.05). The customary bioequivalence criterion was used: 0.8 < parameter ratio(tested/standard) < 1.2. Megaloporous tablets showed bioequivalence with the reference sustained release product Slow-Trasicor. Hydrophil tablets showed moderate sustained-release characteristics. Floating tablets showed significantly greater oxprenolol absorption when taken with food and were non-bioequivalent with floating tablets without food, as well as with the reference rapid release tablets, of oxprenolol. However, fasting tablets were bioequivalent to the Slow-Trasicor product, when taken with food.

Optimization of propranolol hydrochloride sustained-release pellets using box-behnken design and desirability function.

The objective of the present study was to evaluate three process parameters for the application of ethylcellulose films from organic solutions to obtain multi-particulate controlled drug delivery of propranolol hydrochloride. The coating process was developed in a classical coating pan. A Box-Behnken central composite design was used to evaluate the effect of the film thickness (expressed as the amount of lacquer applied on pellets' surface unit), concentration of lacquer in the coating dispersion, and the plasticizer concentration on the independent variables. Those were t85, the degree of sticking in the coating pan, and the duration of the coating process. Contour and response surface plots were depicted based on the equation given by the model. Because the results were competitive, i.e., improving one response had an opposite effect on another one, an overall desirability function was described to ameliorate the interpretation of the results. The optimization procedure generated the maximum overall desirability value. A formulation was prepared under the optimized conditions yielding response values which were close to the predicted values. To understand the mechanism of drug release from the optimized pellets various models were used to fit the dissolution data. The Higuchi model appears to provide the best correlation.

Oxprenolol release from bioadhesive gelatin/poly(acrylic acid) microspheres.

Drug release from gelatin/poly(acrylic acid) oxprenolol-loaded microspheres has been evaluated using an in situ sink immersion method and a wetting method. The kinetics of drug release were analysed by applying the empirical exponential equation and by the calculation of the approximate contribution of the diffusional and relaxational mechanism to the anomalous release process by fitting the data to the coupled Fickian/Case II equation. The influence of glutaraldehyde cross-linking agent concentration, the poly(acrylic acid) content, the pH of the release medium and the particle size of the beads on the drug release kinetics were evaluated and discussed.

Dynamic swelling behaviour of gelatin/poly(acrylic acid) bioadhesive microspheres loaded with oxprenolol.

The dynamic swelling of gelatin/poly(acrylic acid) microspheres loaded with oxprenolol has been evaluated. The movement of two distinct and characteristic swelling boundaries was measured directly using an optical microscope. Swelling rate constants associated with the inner moving front and the outer swelling boundary were determined. A polynomial equation incorporating both Fickian diffusion and case II relaxational models was used to fit the kinetics of liquid uptake. The influence of the concentration of the cross-linking agent, the poly(acrylic acid) load, the pH of the swelling medium and the particle size of the microspheres, on the swelling kinetics, was evaluated and discussed.

"In vivo" effects of lithium sulphate on the turnover of rat tissue nucleotides.

The effects of lithium sulphate following acute administration to Wistar rats - in therapeutic and toxic doses - were investigated, using as markers the levels and turnover of brain, kidney and liver nucleotides. Adenine- and guanine-dependent nucleotides were assayed concomitantly, using a high- performance liquid chromatographic method. Following acute administration, lithium's effects on 3',5'- cAMP levels were more significant at hepatic and cerebral level, in a dose-dependant manner. The effect on 3',5'-cGMP had tissue specificity and was not dose-dependant. It might be possible that 3',5'-cGMP is a better indicator of lithium toxicity than 3',5'-cAMP.

Controlled release of nifedipine from gelatin microspheres and microcapsules: in vitro kinetics and pharmacokinetics in man.

Nifedipine was embedded in a gelatin matrix to develop a prolonged release dosage form. The effects of polymer/drug ratio, size of the beads, cross-linking with formaldehyde and ethylcellulose coating of the gelatin microspheres on the in vitro release rate of the drug were investigated. The data were analysed according to different laws that can govern the release mechanism: first-order, Higuchi square root of time, spherical matrix and zero-order. The in vitro release kinetics of nifedipine from gelatin microspheres were mainly first-order; from formaldehyde hardened gelatin microspheres, complied with the diffusion model for a spherical matrix, and from ethylcellulose-coated gelatin microspheres, obeyed zero-order kinetics. These findings suggest the possibility of modifying the formulation in order to obtain the desired controlled release of the drug for a convenient oral sustained delivery system. The pharmacokinetic parameters of nifedipine, after administration of a single oral dose of nifedipine-loaded hardened gelatin microspheres to volunteers, suggest that the preparation can be considered as a sustained release delivery system for nifedipine.

[Nifedipine pharmacokinetics in liver cirrhosis patients after the administration of a single oral dose]. / Farmacocinetica nifedipinei la bolnavi cu ciroza hepatica dupa administarea unei doze unice oral.

The niphedipine pharmacokinetics was investigated in the patients with hepatic cirrhosis, in comparison with a group of healthy subjects, after administering unique doses of 10 mg per os. The niphedipine concentrations in serum were determined by a gas chromatography method. The niphedipine pharmacokinetics may be described in correspondence with the open pharmacokinetic model. The values of pharmacokinetic parameters of niphedipine in the patients with hepatic cirrhosis are significantly modified in comparison with those noticed in the healthy subjects. An increase in the level of the maximum concentrations (158 ng/ml versus 68 ng/ml), of the biological half time (11.9 hours versus 2.5 hours) and of the area under the curve of the drug concentrations in time (450 ng.ml-1.hour versus 205 ng.ml-1.hour) were found. The relative bioavailability [correction of biodisponibility] of niphedipine was double in the patients with hepatic cirrhosis versus the healthy subjects. The modified pharmacokinetics of niphedipine in the patients with hepatic cirrhosis and the great individual variations found, require a decrease of the dose in this category of patients and a surveillance of the clinical effect.

[The bioavailability of nifedipine in different solid pharmaceutical preparations for oral use]. / Biodisponibilitatea nifedipinei din diferite preparate farmaceutice solide pentru uz oral.

The paper reports on the bioavailability of niphedipine in various pharmaceutic preparations administered in a single dose of 10 mg, per os, to volunteer subjects: Niphedipine dragees (Terapia, Cluj-Napoca), Adalat capsules (Bayer); Adalat coated tablets (Bayer and Birlasik Alman Ilac Fabricalari, Istanbul) and Corinfar dragées (VEB Arzneimittelwerk, Dresden). In the blood samples collected, niphedipine was determined by a gas-chromatographic procedure. Pharmacokinetic analysis of the experimental data was made by a digital computer. Bioavailability of niphedipine was the best with Adalat capsules. The relative bioavailability of the other products was: tablets (Adalat); 93%; dragées (Niphedipine): 92%; dragées (Corinfar 86%). Absorption speed of Niphedipine decreases in the order: capsules, tablets, indigenous and imported dragées. Statistical analysis (Student test) shows that the differences in bioavailability among the preparations are not important. Efficiently therapeutic plasmatic concentrations are maintained for about 6 hours after a single dose of 10 mg administered as tablets and dragées and for 8 hours in the case of capsules. Important differences exist between the maximum concentration of niphedipine in blood, following some differences in the absorption speed, achieved after administration of capsules, on the one hand, and of tablets and dragées on the other hand. Choosing the type of tablet depends, therefore, on the nature of the affection treated. Niphedipine (Terapia) has corresponding biopharmaceutic properties and is useful in treating hypertension and for preventing and treating anginal attacks.

Bioavailability of nifedipine from different oral dosage forms in healthy volunteers.

The absolute and relative bioavailability of nifedipine (1) from different formulations administered as single oral doses in healthy volunteers was determined. Serum concentrations of 1 were measured by GC. The absolute bioavailability of 1 was 53% because of presystemic metabolism. The bioavailability of Adalat (Bayer) tablets, Nifedipina (Terapia) and Corinfar (VEB Arzneimittelwerk Dresden) sugar-coated tablets was 93%, 92% and 86% (respectively) as compared with Adalat capsules. The AUC were not significantly different. The Cmax and tmax values were different, indicating that the absorption of 1 showed differences in first-order rate constants of dissolution in the above mentioned order. Despite the differences among the formulations studied, each preparation may have its merits. In a multiple dose regimen of 20 mg 1 (Nifedipina, Terapia) t.i.d., minimal therapeutic drug levels were achieved and maintained during steady state, from the 1st d of treatment.

The kinetics of nifedipine release from porous hydrophilic matrices and the pharmacokinetics in man.

Porous hydrophilic tablets of nifedipine were prepared with hydroxypropyl methylcellulose as swellable polymer, as well as with the addition of a solid dispersion of the drug in polyethylene glycol, a water soluble system. The kinetic data conformed with the Higuchi square root equation and first order release for in vitro release from a single planar surface of the tablet, as well as release from the whole tablet. The addition of a soluble fraction to the porous swellable release system increased the nifedipine release rate constant. This shows that the dosage form may be formulated as a drug-polymer system which exhibits constant release at a desired rate. In the bioequivalence study with five volunteers, the pharmacokinetic parameters of a sustained release hydrophilic tablet of nifedipine and of immediate release capsules were determined. Although the bioavailability of the two preparations is similar, the therapeutic effects may differ. The rate of absorption, the maximum concentration levels, the time of the peak and the period of maintenance of the therapeutic serum levels after single oral doses are different after the administration of the two tested formulations. The hydrophilic tablets of nifedipine may be useful as a sustained release formulation for long term treatment of hypertension.