The bioavailability of 3 different commercial available isosorbide mononitrate (IS-5-MN; CAS 16051-77-7) 40 mg slow-release preparations (A, B and reference formulation C) was determined after oral application to 18 healthy volunteers in a randomized cross-over study. The AUC after C (26.9 mumol/l x h) was not significantly different from that for A (25.1 mumol/l x h) and B (26.0 mumol/l x h). The corresponding 95% confidence intervals were within the limits of 80-120%. Maximal plasma concentrations (Cmax) for C (1.90 mumol/l), A (1.91 mumol/l), and B (2.05 mumol/l) were obtained at (tmax) 5.72 h, 4.94 h and 4.72 h, respectively. The 95% confidence intervals for Cmax and tmax were within the prescribed limits of 70-130%. Mean residence times (MRT) 10.5 h (C), 10.3 h (A), and 10.1 h (B) and plateau-times (duration over which the plasma concentration greater than 0.524 mumol/l) 17.8 h (C), 17.1 h (A), and 17.0 h (B) were not significantly different. It is concluded that the test preparations A and B are bioequivalent to reference C. Systolic blood pressure and heart rate, easily measurable indeces of the pharmacodynamic effects, showed no significant differences between the 3 preparations. In agreement with recently published data, plasma concentrations above 1.5 mumol/l did not result in a further reduction of systolic blood pressure, but were associated with a further marked elevation in heart rate.

Adult↗

PubMed1991

Prescription of drugs not listed in a clinic's pharmacopoeia: supervision by clinical pharmacologists.

The pharmaceutical market in the FRG offers about 11,000 different preparations and formulations. A restricted list (pharmacopoeia) containing approximately 1,000 drugs has been proved to cover the routine requirements of a university clinic and most of the additional drugs demanded by the physicians as 'exceptis excipiendis'. Restrictive control of requests for drugs not included in the internal pharmacopoeia by clinical pharmacologists has reduced the absolute number of requests by half, and about 60% of the remaining requests could be replaced by drugs listed in the pharmacopoeia. The majority of the special requests arose from the continuation of drugs presented to out-patients by the resident physicians after admission of the patient to the hospital. The supervision may lead to more critical revision of out-patient medication, but a substantial reduction of drug expenditure was not attained, as the drugs requested amounted only to a minor fraction of the overall drug expenditure by the hospital.

Drug Prescriptions↗

PubMed1991

Pharmacodynamic profile of verapamil in relation to absolute bioavailability: investigations with a conventional and a controlled-release formulation.

The absolute bioavailability F and response (prolongation of the PR interval) of verapamil after single doses of the same oral formulation administered on two different days were investigated in 16 male subjects with an 80 mg fast dissolving and a 240 mg controlled-release preparation and compared with a bolus injection of 5 mg of verapamil. The absolute bioavailability was 23% in both investigations for the 80 mg preparation and 32% in both investigations for the 240 mg dosage form. The individual values obtained for tmax, cmax, F, and AUC0-alpha showed a wide intersubject variability; therefore, no significant differences could be observed between the two trials for each dosage, but significant differences existed between the investigations of the two preparations. After intravenous administration, concentration-effect curves were about twofold left shifted when compared with the 80 mg tablet and about threefold left shifted when compared with the 240 mg tablet. Estimation of the drug input rate showed significantly (p less than 0.05) smaller values when the controlled-release tablet was given (80 mg tablet: 95.1 and 107.7 mg/h; 240 mg tablet; 55.8 and 46.3 mg/h). Thus, the effect and bioavailability of verapamil show sufficient intersubject reproducibility if the same formulation is given. The differences between the responses and the bioavailability after administration of different preparations may be related as well to the drug absorption rate and the stereoselective first pass of verapamil as to saturation of first-pass metabolism.

Administration, Oral↗

PubMed1991

[Biologic availability and hemodynamic actions following administration of sublingual glycerol trinitrate. A new delivery system].

Bioavailability and Hemodynamic Properties of Sublingually Applied Glyceryl Trinitrate/A new delivery system Bioavailability of glyceryl trinitrate (GTN, CAS 55-63-0) was investigated in 16 healthy subjects after sublingual application of 0.8 mg GTN from either a reference product (B) where GTN release is effected by fluorochlorohydrocarbon (FCH) or a test product (A) (Corangin Nitrospay) where GTN release is effected FCH-independently by a pumping system. Plasma concentrations of GTN and hemodynamic effects (digital plethysmography) were measured until 30 min after application. There was no significant difference (Wilcoxon's matched pairs signed rank test) in AUCo-t (A: 8.9 +/- 7.3 ng x h/ml; B: 8.3 +/- 7.6 ng x h/ml) and Cmax (A: 1.43 +/- 1.26 ng/ml; B: 1.13 +/- 1.06 ng/ml), but tmax was significantly shorter after application of the test product (A: 4.6 +/- 1.0 min; B: 6.7 +/- 2.7 min, p less than 0.01). Nonparametric confidence limits (90%) were 0.80-1.89 for AUCo-t (point estimator of the median 1.14), 0.92-2.78 for Cmax (point estimator 1.06) and 0.61-0.90 for tmax (point estimator 0.75). EC50-values obtained from the individual concentration/effect-curves were linked with the concentration/time-curves to establish the time of reaching EC50 (tEC50). GTN response did not differ for both preparations (EC50A: 0.25 +/- 0.24 ng/ml; EC50 B: 0.34 +/- 0.36 ng/ml), coincident with tmax, tEC50 was significantly shorter after administration of (A) (A: 1.8 +/- 0.3 min, B: 2.7 +/- 1.0 min). With respect to the variability of GTN pharmacokinetics, the test preparation shows superior bioavailability and a faster onset of hemodynamic action.

Administration, Sublingual↗

PubMed1990

Oxidant-induced changes in the cellular energy homeostasis. A study with 3,5-dimethyl N-acetyl-p-benzoquinone imine and isolated hepatocytes.

Exposure of isolated hepatocytes to 400 microM 3,5-dimethyl N-acetyl-p-benzoquinone imine (3,5-diMe NAPQI), rapidly induced the formation of plasma membrane blebs. More than 50% of the viable cells were affected after 1 min incubation with 3,5-diMe NAPQI. Rapid loss of mitochondrial ATP, and sequential increases in ADP and AMP accompanied hepatocyte blebbing. 3,5-diMe NAPQI also induced a pronounced elevation of mitochondrial NADP level, whereas the NAD concentration was unaffected. Similar alterations in the adenine and pyridine nucleotide pools were found to occur in the cytosol, although at slower rates. During the initial phase of ATP loss and NADP production, there was also a concomitant decrease in the oxygen uptake of the hepatocytes. The decreases in energy substrates occurred in parallel to an increased uptake of trypan blue into the cells. Treatment of the hepatocytes with dithiothreitol, following 4 min exposure of the cells to 3,5-diMe NAPQI, reversed the quinone imine-induced changes in nucleotide levels and reduced the cytotoxicity. It is concluded that alteration of mitochondrial function, which results in changes in the cellular energy homeostasis, is an important event in the development of cytotoxicity caused by 3,5-diMe NAPQI.

Adenosine Triphosphate↗

PubMed1990

[Gyrase inhibitors. Central nervous side effects and inhibition of methylxanthine elimination].

Explore the source record for details and available documents.

4-Quinolones↗

PubMed1990

N-acetyl-p-benzoquinone imine-induced changes in the energy metabolism in hepatocytes.

The effect of N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite of acetaminophen, on the energy metabolism in isolated hepatocytes was investigated. Incubation of cells with NAPQI (400 microM) resulted in an immediate uptake into the mitochondria, followed by both reduction and glutathione conjugation of the quinone imine. These reactions were extremely rapid and were associated with depletion of the mitochondrial ATP content (greater than 80% depletion after 1 min exposure). The loss of ATP was accompanied by increases in ADP and AMP, as well as NADP. No effect on mitochondrial NAD was observed during this initial phase. Similar alterations were produced by NAPQI in the cytosolic compartment. Furthermore, incubation of hepatocytes with NAPQI inhibited oxygen consumption by nearly 90% within 10 s. In parallel to these biochemical changes, there was marked bleb formation on the surface of the hepatocytes, which was found to precede cell death (trypan blue uptake). In conclusion, our results demonstrate that during exposure of hepatocytes to NAPQI, dramatic changes in cellular energy metabolism occur. These biochemical alterations may be caused by a rapid decrease in mitochondrial function, and they may play an important role in the initiation of NAPQI-induced cytotoxicity.

Adenosine Diphosphate↗

PubMed1990

Ciprofloxacin absorption in different regions of the human gastrointestinal tract. Investigations with the hf-capsule.

1. The absorption of ciprofloxacin from different regions of the human gastrointestinal tract was investigated in four healthy males using a remote-controlled drug delivery device (hf-capsule). 2. Significant differences in AUC were observed in the control study (oral administration of ciprofloxacin solution without the hf-capsule = 100%) and after release of ciprofloxacin in the jejunum (geometric mean: 37%), the ileum (mean: 23%), the ascending colon (mean: 7%) and the descending colon (mean: 5%), whereas tmax showed no difference for any of the absorption sites. Ciprofloxacin release in the stomach resulted in the greatest AUC (mean: 140%). Thus, it is concluded that the main absorption site of ciprofloxacin is the upper gastrointestinal tract, up to the jejunum. 3. Differences in presystemic metabolism of known drug metabolites along the gut could be excluded, as the pattern of urinary recovery of desethylene-, sulpho-, and oxo-ciprofloxacin and the parent compound was similar for all drug release sites.

Administration, Oral↗

PubMed1990

Bioaequivalence of sublingual glycerol trinitrate. Bioavailability and haemodynamic effects after application of a fluorochlorohydrocarbons-dependent spray and a new pumping system.

Bioaequivalence of glycerol trinitrate (GTN, CAS 55630) was investigated in 16 healthy volunteers after sublingual application of 2 x 0.41 mg GTN from two different spray-formulations (A: fluorochlorohydrocarbons (FHC)-dependent formulation; B: FHC-free pumping system). Plasma concentrations of GTN (measured by a gas chromatographic method) and haemodynamic effects (measured by digital plethysmography) were monitored 30 min after application. EC50 of the individual concentration-effect curves were calculated and linked to the individual concentration-time curves to establish the time of reaching EC50 (tEC50). AUC0-infinity, Cmax, tmax and the haemodynamic parameters were compared intraindividually (Wilcoxons matched pairs sign rank test), bioequivalence of B to A was tested on the basis of nonparametric 95%-confidence intervals (Tukey). There was no significant difference in the AUC0-infinity (A: 14.2 ng min/ml, B: 16.3 ng min/ml), but significant differences were obtained in Cmax (A: 1.41 ng/ml, B: 2.77 ng/ml, p less than 0.01) and tmax (A: 6.8 min, B: 3.9 min, p less than 0.01). The confidence intervals of the ratio B/A were 0.81-1.56 for AUC0-infinity, 1.3-3.13 for Cmax and 0.50-0.58 for tmax. The GTN-response did not differ after both formulations (EC50 A: 0.441 ng/ml, EC50 B: 0.421 ng/ml), but significant differences were observed for tEC50 (A: 2.82 min, B: 1.05 min, p less than 0.01). Preparation B exhibits a superior bioavailability and a more rapid onset of haemodynamic efficacy.

Administration, Sublingual↗

PubMed1989

Absorption differences of ciprofloxacin along the human gastrointestinal tract determined using a remote-control drug delivery device (HF-capsule).

The single-dose absorption kinetics of ciprofloxacin in different regions of the human gastrointestinal tract were investigated using a remote-control drug delivery device (HF-capsule). Doses of 180 to 200 mg ciprofloxacin (as a lactic acid solution) were placed in the HF-capsule and administered to four healthy male adults. The position of the HF-capsule in the gastrointestinal tract was checked via radiographic examination. The release of the solution from the HF-capsule was induced by a radio signal. In each volunteer, the solution was released into five different regions of the gastrointestinal tract: the stomach (B), jejunum (C1), ileum (C2), ascending colon (D1), and descending colon (D2). Two control runs (A1, A2), involving oral administration of the solution, were used as a reference for calculation of area under the curve. The oral administration of a conventional 250-mg tablet (A3) was also studied. The plasma concentration of ciprofloxacin and urine concentrations of ciprofloxacin, desethylene- (M1), sulfo- (M2), and oxociprofloxacin (M3) were determined fluorimetrically by high-performance liquid chromatography. Intraindividual comparisons indicated a progressive decrease in the amount of ciprofloxacin absorbed (100 percent = mean of AUCA1 and AUCA2) from the jejunum (-61 percent, median), ileum (-75 percent), colon ascendens (-90 percent), and colon descendens (-95 percent). Absolute amounts of renally excreted ciprofloxacin and metabolites decreased due to the reduced absorption of ciprofloxacin, but the metabolite pattern was unchanged. It is concluded that the main absorption site for ciprofloxacin is the upper part of the intestinal tract (duodenum, jejunum).

Adult↗

PubMed1989

Ciprofloxacin-caffeine: a drug interaction established using in vivo and in vitro investigations.

The inhibitory effects of ciprofloxacin and other quinolone derivatives on the hepatic cytochrome P450-dependent metabolism of caffeine have been investigated in humans. In vivo studies involved an intraindividual comparison of the single-dose kinetics of caffeine before and during quinolone administration in 12 healthy men. Changes of enzymatic caffeine degradation by the quinolones were studied in vitro using human liver microsomes from three donors. Enoxacin and pipemidic acid markedly prolonged caffeine elimination in vivo. A positive correlation exists between the doses of enoxacin or ciprofloxacin and the prolongation (increases) in the caffeine elimination half-life. Decreases in caffeine elimination, using doses of ciprofloxacin in the upper part of the recommended dose range, were approximately 1.5-fold in comparison with untreated control subjects, whereas in the case of enoxacin there was a sixfold change. In vitro results with enoxacin, ofloxacin, ciprofloxacin, and pipemidic acid show a competitive inhibition (Dixon plots) of caffeine 3-demethylation. Ciprofloxacin and enoxacin showed the strongest inhibitory effects in vitro, whereas ofloxacin had the lowest inhibitory effect. These results are qualitatively reflected in the in vivo results; however, the clinical effects may be dependent on pharmacokinetic disposition of the quinolone and this could explain the weak inhibitory action of ciprofloxacin in vivo.

Adult↗

PubMed1989

Study of potential kinetic interactions of picumast dihydrochloride and theophylline in vitro and after oral administration in man.

The kinetic interaction of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) and theophylline has been studied in vitro (displacement from protein binding) and in vivo in healthy male non-smokers after oral administration. In a randomized, three-way cross-over study, 12 subjects received at weekly intervals either separated or combined single doses of picumast dihydrochloride (10 mg) and theophylline (7 mg/kg b.w.) Picumast and its metabolites were analysed in plasma and urine up to 24 h and theophylline was assayed in plasma during the same time. Theophylline pharmacokinetic parameters like time to peak concentration, peak concentration, elimination half-life, area under the plasma concentration-time curve and oral clearance were not changed after a concomitant dose of picumast dihydrochloride. The combination of theophylline and picumast dihydrochloride revealed no significant changes in the picumast pharmacokinetic parameters t1/2, tmax and CLR. However, Cmax and AUC0-24 decreased significantly by 11% and 7%, resp. Additional theophylline administration significantly increased peak concentration of the intermediate active metabolite M2 by 23% from 7 to 8.6 ng/ml. The absorptive parameters, i.e. time to peak and peak concentration of M1 as well as the AUC calculated from 0-24 h and the renal clearance did not differ in single or combined picumast dihydrochloride administration. A supplementary in vitro study showed no change in plasma protein binding of picumast (100 ng/ml) in the presence of theophylline (20 micrograms/ml) and vice versa. In all volunteers picumast dihydrochloride proved to be safe and well tolerated and treatment was not negatively influenced by theophylline co-administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Interaction of quinolones with the theophylline metabolism in man: investigations with lomefloxacin and pipemidic acid.

The single-dose pharmacokinetics of theophylline alone and at the end of a five-day treatment period with a new difluorinated quinolone antibacterial, lomefloxacin (400 mg/d) and pipemidic acid (400 mg b.i.d.) were investigated in 12 healthy male volunteers. Concentration of theophylline and its metabolites 1-methylxanthine, 1-methyluric acid, 1.3-dimethyluric acid and 3-methylxanthine were determined in plasma, and (except 1-methyluric acid) in urine by HPLC separation. The elimination half-life of theophylline before quinolone treatment was 5.7 +/- 2.0 h and did not change significantly under coadministration of lomefloxacin (6.2 +/- 2.0 h), whereas with pipemidic acid a marked prolongation (10.8 +/- 2.3 h) occurred. Results without and during coadministration of lomefloxacin showed no detectable 1-methylxanthine in plasma. With pipemidic acid, 1-methylxanthine was observed in the plasma and 1-methyluric acid and 3-methylxanthine were not detected. Lomefloxacin showed only a slight alteration in the metabolite formation of theophylline, whereas pipemidic acid induced marked changes. In contrast to pipemidic acid, no metabolic interaction would be expected under concomitant use of lomefloxacin and theophylline within the recommended dose range for both drugs.

4-Quinolones↗