BIOAVAILABILITY OF 4 PHARMACEUTICAL FORMULATIONS OF METRONIDAZOLE TESTED ON NORMAL HEALTHY-VOLUNTEERS

1. Single doses of four metronidazole formulations (the unmarketed Trichomol, 200 mg, 400 mg, 500 mg, and the commercially available Flagyl, 400 mg) were administered to 14 healthy adult male volunteers in order to determine their pharmacokinetic profiles. 2. Plasma metronidazole concentrations were measured by high pressure liquid chromatography. The results were plotted against time and the curves obtained were used to calculate pharmacokinetic parameters (area under the curves, maximum achieved concentration and time at which it occurred, elimination constant, and half-life). 3. Trichomol formulations of 200 mg and 500 mg significantly differed from the 400 mg formulation with respect to area under the curve and maximum concentration. Trichomol 400 mg and Flagyl 400 mg showed no significant differences in maximum concentration or area under the curve. No differences were observed in half-life or time of appearance of maximum concentration among formulations. 4. Good correlations occurred between maximum concentration, area under the curve and amount of metronidazole ingested, indicating a linear pharmacokinetic profile. 5. We conclude that Trichomol 400 mg proved to be bioequivalent to the commercially available reference Flagyl 400 mg according to U.S. Food and Drug Administration requirements.24121251126

COMPARATIVE BIOAVAILABILITY OF SINGLE DOSES OF TABLET FORMULATIONS OF CETIRIZINE DIHYDROCHLORIDE IN HEALTHY MALE-VOLUNTEERS

The bioavailability of two tablet formulations of cetirizine (Zetir from Abbott and Zyrtek from UCB) were compared in 14 healthy male volunteers who received a single dose of 10 mg of cetirizine dihydrochloride in an open randomized two-period crossover design with a 7-day washout period between doses. Plasma samples were obtained over a 24 h interval and cetirizine concentrations were determined by HPLC with ultraviolet detection. From the plasma cetirizine concentration vs, time curves, AUC((0 - 24)) (area under the concentration vs. time curves from 0 to 24 h), C-max (maximum achieved concentration), T-max (time to achieve C-max), K-e (terminal first order elimination constant), elimination half-life (t(1/2)) and AUC((0-infinity)) (area under the concentration vs. time curves extrapolated to infinity) were obtained. The two cetirizine dihydrochloride tablet brands did not show statistically significant differences in bioavailability as assessed by analysis of AUC((0 - 24)), AUC((0-infinity)), C-max, T-max, K-e and t(1/2) values. Based on these results and on the U.S. Food and Drug Administration requirements [1985, 1993], we conclude that both formulations are bioequivalent.331273

Simultaneous determination of nitrite and nitrate anions in plasma, urine and cell culture supernatants by high-performance liquid chromatography with post-column reactions

A high-performance liquid chromatographic method for the determination of nitrite and nitrate anions derived from nitric oxide in biological fluids is presented. After separation on a strong anion-exchange column (Spherisorb SAX, 250x4.6 mm I.D., 5 mu m), two on-line post-column reactions occur. The first involves nitrate reduction to nitrite on a copper-plated cadmium-filled column. In the second, the diazotization-coupling reaction between nitrite and the Griess reagent (0.05% naphtylethylendiamine dihydrochloride plus 0.5% sulphanilamide in 5% phosphoric acid) takes place, and the absorbance of the chromophore is read at 540 nm. This methodology was applied to biological fluids. Before injection into the chromatographic system, the samples were diluted and submitted to suitable clean-up procedures (urine and cell culture supernatant samples are passed through C-18 cartridges, and serum samples were deproteinized by ultrafiltration through membranes with a molecular mass cut-off of 3000). The method has a sensitivity of 30 pmol for both anions, as little as 0.05-0.1 ml sample volume is required and linearity is observed up to 60 nmol for each anion.686215716

MEASUREMENT OF PLASMA VERAPAMIL LEVELS BY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY

1. We have developed an alternative procedure for the measurement of verapamil levels in human plasma by reverse-phase high performance liquid chromatography with fluorimetric detection. 2. Prior to assay, plasma is submitted to a double extraction procedure, using first n-heptane in alkaline medium and then an acid phosphate buffer. Flecainide, a compound not related to verapamil, is used as internal standard. Mean recoveries of 70 and 63 % were obtained for verapamil and flecainide, respectively. 3. The sensitivity (5 ng/ml), reproducibility (inter-assay % CV = 1.7-8.7; intra-assay % CV = 2-4) and high recovery during sample clean-up make this method useful for the quantitation of verapamil in therapeutic monitoring and pharmacokinetic studies. 4. The method is illustrated with the pharmacokinetic results obtained for 14 healthy male volunteers who received a single 240 mg dose of the commercially available tablets of Dilacoron Retard(R) 240 mg. The mean values for the area under the curve from 0 to 24 h (AUC[0-24]), maximum achieved concentration (C(max)) and time to achieve the maximum concentration (T(max)) were 863 ng h-1 ml-1, 112 ng/ml and 4 h, respectively.26775376

PHARMACOKINETIC PROFILE OF 2 DIFFERENT PHARMACEUTICAL FORMS OF THEOPHYLLINE (A SLOW-RELEASE TABLET AND A SYRUP) AFTER MULTIPLE-DOSE ADMINISTRATION TO HEALTHY-HUMAN VOLUNTEERS

Due to the narrow therapeutic range of theophylline, plasma concentrations of this drug are monitored in patients undergoing chronic therapy. Slow-release preparations avoid the fluctuations in plasma levels and improve patient compliance. In this study, we have compared the pharmacokinetic profiles of a theophylline slow-release tablet and a syrup form, when administered in multiple doses to healthy adult volunteers. The classification based upon releasing patterns is confirmed.88115515

NEUTROPHILS AND MONONUCLEAR-CELLS FROM PATIENTS WITH CHRONIC GRANULOMATOUS-DISEASE RELEASE NITRIC-OXIDE

1 Chronic granulomatous disease (CGD) is a group of genetic disorders characterised by recurrent severe suppurative infections due to impaired microbial killing. The principal biochemical defect is an impairment in the production of reactive oxygen intermediates by phagocytes. 2 Nitric oxide (NO) is synthesised from the guanidino nitrogen atom(S) Of L-arginine and has recently been proposed to be involved in defence mechanisms. The aim of this study was to investigate the involvement of the oxidative burst in the biosynthesis of NO by neutrophils and mononuclear cells from patients with CGD. 3 NO synthesis was assayed by the ability of neutrophils and mononuclear cells to inhibit thrombin-induced washed platelet aggregation while superoxide anion (O2-) production was measured spectrophotometrically by the superoxide dismutase inhibitable reduction of cytochrome c. 4 Neutrophils and mononuclear cells from patients with CGD released NO. This release was inhibited by nitro-L-arginine methyl ester but could be reversed by L-arginine. Zymosan- and PMA-induced O2- production was less than 10% as compared with healthy controls. 5 These results indicate that O2- production is not essential for NO synthesis in human leucocytes.35548549

The effect of a 1-week administration of cetirizine on the chemotaxis and superoxide anion production of neutrophils from healthy volunteers

The aim of the present investigation was to examine the effect of a I-week oral administration of the anti-allergic drug cetirizine on healthy volunteer neutrophil chemotaxis and superoxide anion (O-2-) production. Eight male volunteers were selected after clinical examination and laboratory tests. Neutrophils were isolated from peripheral blood using a discontinuous density gradient. Spontaneous migration and platelet activating factor(PAF, 10(-6) and 10(-8) M) or zymosan-activated plasma (ZAP)-induced chemotaxis were studied in a 48-well microchemotaxis chamber. Basal and phorbol 12-myristate 13-acetate (PMA, 30 nM) stimulated O-2- production were measured spectrophotometrically. Cetirizine (10 mg per day) was given orally during 1 week. Both neutrophil chemotaxis and O-2- production were assessed before and 2 h, 24 h, and 1 week after orally administered cetirizine. Plasma cetirizine levels were monitored by high performance liquid chromatography (HPLC) with ultraviolet detection. Spontaneous neutrophil migration and PAF- or ZAP-induced chemotaxis showed no significant variation before or at various intervals after the initiation of treatment with cetirizine. Basal and PMA-stimulated neutrophil O-2- production was also not affected by cetirizine. The maximum concentration attained by cetirizine (C-max) was 293 +/- 38 ng/ml and generally peaked (T-max) within 1.9 +/- 0.7 h. We conclude that the administration of cetirizine for 1 week does not alter human neutrophil chemotaxis and O-2- production.3439610

Nitric oxide synthase inhibitor influences prostaglandin and interleukin-1 production in experimental arthritic joints

Objective: To assess involvement of nitric oxide (NO) in the increase in eicosanoid and interleukin-1 (IL-1) levels in the synovial fluid during antigen-induced arthritis (AIA) in rabbits treated with a competitive inhibitor of NO synthesis. Subjects: Thirteen New Zealand White rabbits were sensitized with 5 mg of methylated bovine serum albumin (mBSA). Arthritis was induced in the knee joint by injecting 0.5 ml of a sterile solution of mBSA (2 mg/ml) into the intra-articular cavity. Treatment: Prior to the induction of arthritis, the animals received N-Omega-Nitro-L-Arginine Methyl Ester (LNAME) or N-Omega-Nitro-D-Arginine Methyl Ester (DNAME) for 2 weeks, both at a dose of 20 mg/kg/day mixed with drinking water. Methods: Leukocyte efflux (total and differential white cell count), vascular permeability (Evans's blue method), synovial PMN cell infiltrate, and total nitrite (NO2.)/nitrate (NO3.) (HPLC), PGE(2), TxB(2), LTB(4) (radioimmunoassay), and IL-1 beta (ELISA) levels were quantified in the synovial fluid. Results: LNAME but not DNAME significantly suppressed leukocyte efflux and protein leakage into the articular cavity as well as synovial PMN cell infiltrate. Total NO2./NO3., PGE(2) and IL-1 beta levels were significantly reduced in the synovial fluid of LNAME treated animals. TxB(2) and LTB(4) were not affected by LNAME treatment. Conclusion: These data clearly show NO involvement in the IL-1-induced PGE(2) production in the synovial fluid of antigen-induced arthritis in rabbits.462727

Short-term sucralfate administration alters potassium diclofenac absorption in healthy male volunteers

Aims Since patients who regularly take NSAIDS may use sucralfate because of its cytoprotective properties, we examined the influence of this compound on the pharmacokinetics of diclofenac. Methods Potassium diclofenac (105 mg) was administered orally to eighteen healthy male volunteers with or without a 5-day pre-treatment with sucralfate (2000 mg twice daily). Blood samples were collected at intervals post-dose and serum concentrations of diclofenac were determined by reverse-phase h.p.l.c. Results Pre-treatment with sucralfate significantly decreased both the AUC(0,8 h) [2265ng h ml(-1) (geometric mean) (range 1815-2827) vs 1821ng h ml(-1) (1295-2562)] and the C-max [1135 ng ml(-1) (geometric mean) (range 898-1436) vs 701 ng ml(-1) (501-981)] with no significant delay in absorption [t(max) 1.0 h (median) (range 0.5-2.0) vs 1.0 h (0.5-4.0)]. Conclusions The short-term treatment of healthy male volunteers with sucralfate decreases potassium diclofenac bioavailability,; These findings suggest that either an appropriate increase in the diclofenac intake or the use of another gastric mucosa protector must be adopted.43110410

Bioequivalence study of two enalapril maleate tablet formulations in healthy male volunteers - Pharmacokinetic versus pharmacodynamic approach

Objective: Two different conventional release enalapril maleate tablet formulations were evaluated for their relative bioavailability (Eupressin tablets 10 mg, Biosintetica as the test formulation vs Renitec tablets 10 mg Merck Sharp & Dhome, as the reference formulation). A single 20 mg oral dose of each preparation was administered to 18 healthy male adult volunteers and their bioequivalence was assessed by comparing the serum enalaprilat and total enalapril (enalaprilat plus enalapril maleate) concentration-time curves. Angiotensin converting enzyme (ACE) activity was also quantified in each serum sample. Results. The pharmacokinetic parameters obtained for each formulation were the area under the time-concentration curve from 0 to 24 h (AUC([0-24])), maximum concentration C-max and the time at which it occurred (t(max)). When serum enalaprilat concentration-time curves were employed to assess bioequivalence, the formulations were bioequivalent in the extent but not in the rate of absorption. However no difference in either the extent or the rate of absorption were observed when serum total enalapril vs time curves were analysed. ACE activity-time curves were similar for both formulations and showed that ACE was 90% inhibited 3-5 h after enalapril administration, and till approximately 50% after 24 h. At that time, circulating enalaprilat and total enalapril levels were less than the tenth of C-max. Conclusion: The results show that complete bioequivalence of the two formulations can be concluded from serum total enalapril concentration data, and that serum ACE activity is not a suitable pharmacodynamic variable for assessing bioequivalence.50539940