Twelve healthy volunteers were treated with two different sustained‐ release formulations of theophylline (Nuelin Depot 350 mg and Theo‐Dur 300 mg) twice daily in an open cross‐over study. The serum levels in steady state without and with concomitant administration of antacid were studied. Antacid did not influence the serum theophylline levels in the Theo‐Dur treatment period, while in the Nuelin Depot treatment period antacids caused a significantly larger increase in serum levels of theophylline after drug intake. The difference between morning and peak concentrations were also much higher with the combination Nuelin Depot/antacid. This implies that physicochemical factors such as gastrointestinal fluid pH might influence the degradation and/or absorption of some slow‐release theophylline formulations as reflected in serum concentrations, and thereby contribute to the therapeutic and side effects of such drugs.
Cefcanel daloxate hydrochloride is a new oral cephalosporin prodrug. It is a double cephem ester of cefcanel, which is the active principle released in the body after uptake of an intermediate cephem mono ester. The present study investigated the pharmacokinetics of cefcanel following a single oral dose of cefcanel daloxate hydrochloride 300 mg to healthy volunteers and to patients with various degrees of stable renal insufficiency. Twenty individuals from 21 to 74 years of age received a single oral dose of cefcanel daloxate hydrochloride together with an i.v. bolus injection of iohexol for a simultaneous assessment of glomerular filtration rate (GFR). The concentrations of cefcanel and iohexol in plasma and urine were measured using high performance liquid chromatography. Cefcanel renal clearance and fraction excreted in the urine were linearly correlated with renal function and thus, logarithmic increases in plasma area under the concentration versus time curve and plasma elimination half-life were seen with decreasing GFR. Although steady state kinetics were not performed our findings suggest that a dosage reduction is not necessary even in pre-uraemic patients.
The pharmacokinetics of piretanide, a new loop diuretic, were studied in four patients with GFR 4.7‐14.8 ml/min. An oral dose of piretanide 18 mg was given at 08.00 h in two patients and at 08.00 h and 14.00 h in two. Blood samples were drawn after 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. Serum concentrations of piretanide were estimated by radioimmunoassay. The peak serum concentration of piretanide (1‐2 h after drug administration) was 510‐880 ng/ml, independent of renal function. Elimination half life (t1/2) was 1.2‐4.1 h, area under the curves (AUC(0,24)) 1.63‐2.44 micrograms ml‐1 h, volume of distribution (Vz) 0.30–0.741#kg, total plasma clearance (CL) 122.8‐184.0 ml/min and renal clearance (CLR) 1.5‐5.2 ml/min. The clinical effects of oral treatment with piretanide 18 mg twice daily were compared with bumetanide 3 mg twice daily in eight patients with renal failure (GFR 2.2‐24.5 ml/min). Both drugs equally increased the 24 h output of urine (delta V), sodium (delta UNaV), chloride (delta UC1V), potassium (delta UKV) and calcium (delta UCaV). Fractional excretion of sodium (ENa%) was doubled by piretanide in patients with GFR less than 8 ml/min while a five fold increase was found in patients with GFR greater than 8 ml/min. The onset of effect was the same for both drugs, but the duration exceeded 6 h only for piretanide. Both drugs were most effective on the first of two consecutive treatment days. Delta UC1V was always greater than delta UNaV and urinary phosphate excretion was unchanged, as expected of a loop diuretic without significant proximal effects. Metabolic or clinical side effects were not noticed.
The serum concentrations of theophylline, total free fatty acids (FFA) and subgroups were studied in ten healthy volunteers treated with sustained release theophylline twice daily during 9 days. Analyses were performed before and on day 1, 4 and 9 of treatment. Mean theophylline serum levels within the therapeutic range were obtained during the study, ranging from 62 ± 7 to 82 ± 10 umol/1. The mean serum concentrations of total FFA and subgroups increased significantly during treatment, showing the highest levels on day 4. Comparing fasting total FFA concentrations, an increase of 123% and 48% from pretreatment levels were found on day 4 and 9, respectively. The subgroups were influenced to a different degree by theophylline intake. Arachidonic acid (20:4) was not increased, while among the others, saturated FFA increased less than the unsaturated.
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