Determination of bioequivalence of two furosemide preparations; the effect of high doses of furosemide on some pharmacokinetic parameters.

The bioequivalence of two oral preparations of the diuretic furosemide, namely (i) a Croatian pharmaceutical product (test preparation A) and (ii) a reference preparation B, both in a dose of 500 mg was assessed in an open, cross-over, randomized trial in 15 healthy male volunteers, in whom the HPLC method with a fluorescent detector was used to determine its concentrations. The test preparation (A) was found to achieve a considerably higher concentration (17.2 +/- 9.304 mg/l) than the reference preparation (11.1 +/- 6.484 mg/l); the time to peak concentrations was statistically significantly shorter for the test preparation (1.033 +/- 0.743 h) than for the reference preparation (1.656 +/- 0.586), and the areas under the concentration curves were statistically significantly greater for the examined preparation (65.9 mg.h/l) than for the reference preparation (46.845 mg.h/l). The relative bioavailability of the test preparation was 129%, i.e. it was not bioequivalent with the reference preparation. This finding was consistent with the previously performed laboratory quality testing in vitro, where the release of the reference preparation was found to be considerably slower and weaker than that of the test preparation. High doses of furosemide exemplified by 500 mg were found to affect only some of the pharmacokinetic parameters, i.e. they induce an accelerated absorption, an increase in serum concentration, and a prolongation of its half-life.

Bioequivalence of two oral cyclosporine preparations.

A comparison of bioequivalence of two cyclosporine (CAS 59865-13-3) preparations was performed. Ten cyclosporine treated patients with transplanted kidneys were included. Criteria were successful transplantation and minimum period from transplantation of at least 6 months. Two months before the experiment, cyclosporine concentrations had to be in therapeutic range without significant oscillation, and kidney function stabile. There had to be no signs of cyclosporine nephrotoxicity. During the objective biochemical analysis it was not allowed to find malfunction in any of the patient's organ important for cyclosporine pharmacokinetics. Cyclosporine concentrations in whole blood were measured with a specific fluoroimmunoassay. Cyclosporine and metabolites concentrations were measured with radioimmunoassay with non-specific antibody. Mean value and standard deviations and shape of distribution were calculated for all numeric data of patients, measured biochemical and other laboratory parameters. Variance analysis for all measured cyclosporine concentrations according to sampling times (C0 to C12, maximal concentrations C(M), time to maximal concentrations t(M), times of absorption delaying t(Lag) and area under the measured concentration curves (AUC) were statistically checked. According to these data it is concluded that the preparations are bioequivalent; a time to reach maximum concentration was slightly shorter for test preparation (2.5 and 3.2 h, respectively), but not statistically significant. There are no significant differences between the areas under the concentration curves (1667 and 1665 ng.h/ml, respectively). After the calculation of pharmacokinetic parameters of concentration data measured by a non-specific method a significant difference for areas under concentration curves was seen (3709 and 4600 ng.h/ml, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic changes in patients with oedema.

The pharmacokinetics of furosemide (frusemide) in patients with oedema have been relatively well studied, but in many studies it is unclear whether the disease or the oedema per se has the major effect. The rate of absorption of oral furosemide in patients with oedema was decreased, but total bioavailability was almost unchanged. The peak serum concentration (Cmax) and time taken to achieve Cmax were either decreased or unchanged. Binding of furosemide to plasma proteins is lower in patients with congestive heart failure (CHF), decompensated liver cirrhosis (DLC) and nephrotic syndrome, probably as a result of hypoalbuminaemia. The elimination half-life (t1/2) can be unchanged (CHF, DLC) or prolonged (chronic renal failure: CRF). Plasma and renal clearance are reduced in patients with CRF and nephrotic syndrome, but are almost unchanged in CHF and DLC. Disease-induced disorders are mainly responsible for the alterations of furosemide pharmacokinetics in oedematous conditions, while the influence of oedema per se is probably not clinically relevant. The pharmacokinetics of digoxin have been studied in a small number of studies only. In patients with CHF, considerable interindividual differences have been found. Because digoxin has a narrow therapeutic window, this drug should be administered cautiously to oedematous patients. Theophylline has higher bioavailability in patients with oedema, with a significantly higher Cmax in patients with hepatic cirrhosis and CHF than in healthy volunteers (29 and 22%, respectively). Furthermore, clearance decreases and t1/2 increases in these patients. Angiotensin converting enzyme (ACE) inhibitors are often administered as prodrugs, and their pharmacokinetic profile could be influenced by the diseases that accompany oedematous states. However, the effect of oedema is difficult to discriminate from that of the disease. Individual ACE inhibitors are affected differently, but importantly the dosage of perindopril should be reduced in patients with CHF, while for most other ACE inhibitors the changes in pharmacokinetic parameters are clinically irrelevant. In conclusion, studies on pharmacokinetic changes in oedema are limited. Besides affecting absorption (after oral administration) and conversion of the prodrug to the active form, probably as a result of the associated disease, oedema has not been proven to cause any clinically relevant changes in pharmacokinetic parameters for individual drugs. However, further studies of this aspect of pharmacokinetics are needed.

[The chemical war in Croatia]. / Kemijski rat protiv Hrvatske.

During the present war against the Republic of Croatia, chemical weapons have been used by the Yugoslav Federal Army (YFA) against both civilians and Croatian Army soldiers. The use of irritants was suspected (Vukovar, Bogdanovci and Vinkovci, October-November, 1991; Solin in the Split area, September, 1991) and proved (Velika Gorica in the Zagreb area, September, 1991; Cakovec, November, 1991) in many cases. The use of psychochemical incapacitating agents (Bilje near Osijek, July, 1991), as well as of psychostimulants in YFA own soldiers (Zadar, August, 1991) has been suspected on clinical findings or laboratory tests. The use of acetylcholnesterase inhibitors was proved in one aggressor's diversion (Zadar, Krusevo, July, 1991). Phosphorus from projectiles and fuming boxes caused poisoning and skin burns due to incineration (Vukovar, November, 1991). YFA used the civilian's fear of chemical and biological weapons, throwing untoxic substances all over the Croatian territory. Great ecocide problems have occurred with massive industry devastation (Sisak, Osijek, October, 1991-January, 1992), with enumerous amounts of toxic substances released into the soil and river aquatoria.

Determination of serum atenolol using HPLC with fluorescence detection following isolation with activated charcoal.

In order to determine the bio-availability and pharmacokinetics of two oral 100 mg atenolol preparations, a simple analytical method was developed. Atenolol was determined in serum submitted to an extraction procedure consisting of: (a) adsorption of atenolol to activated charcoal at pH 11, (b) washing the charcoal with water to remove co-extracts and (c) elution of atenolol from the charcoal with organic solvent. The extracts were then analysed by high-performance liquid chromatography (HPLC) with fluorescence detection. The pharmacokinetic parameters obtained from eight healthy humans involved in a clinical bioavailability trial are also presented.

Determination of biological equivalence of two atenolol preparations.

In healthy volunteers (n = 8), the biological equivalence of the two oral atenolol preparations was investigated. Atenolol concentration was assessed by HPLC. Drug and internal standard were isolated by adsorption with active charcoal. Chromatography was performed on RP-18 column (10 mu) with mobile phase of 0.015 mol/l KH2PO4/acetonitrile 70:30. The flow rate of the mobile phase was 1.5 ml/min. UV detector operated at the wave length of 225 nm. The sensitivity of the method was 25 micrograms/l and variation coefficients within the assay were less than 10% in the therapeutic concentration range. Biological half-life was on the average 3.8 h, absorption half-life 0.8 h, and the peak concentration time 2.5 h. Both preparations have been found bioequivalent.