Biomedical subjects
Publications and source records attributed to H Jaeger.
A single-centre, open, Phase I-study comparison of the pharmacokinetics of a single dose of metaclazepam 10 mg, a new 1,4-benzodiazepine has been done in 10 older and 20 younger volunteers. No important age-related effect was found on the kinetics of metaclazepam or its N-desmethyl derivative, the principal metabolite in man.
The utilization of psychotropic drugs in patients with advanced neoplastic disease was studied over a 14-month period. Eight hundred twenty-four (82.4%) of one thousand consecutively admitted patients were prescribed at least one psychotropic agent. Antipsychotic agents were prescribed for 61.3% and hypnotics for 55.8% of the total patient sample. Only one out of ten patients received an antidepressant medication. Significantly more psychotropic drugs were prescribed for the relatively younger patients (less than 50 years). Diphenhydramine, prochlorperazine, and haloperidol were the most frequently prescribed psychopharmacologic agents. The most common reasons for prescribing psychotropic medications were for psychologic distress, sleep disorders, and nausea and vomiting. Clinical consequences are discussed.
The aim of the study was to determine the relative bioavailability and the pharmacokinetic parameters following administration of a slow-release formulation of isosorbide dinitrate (ISDN, Isdin) capsules (20, 40 and 60 mg). A gas chromatographic method was used to determine the plasma concentrations of ISDN and isosorbide-5-mononitrate (IS-5-MN). All of the required pharmacokinetic parameters were ascertained. The study was performed on 12 healthy volunteers in a steady-state crossover design. A comparison of the areas under the plasma concentration/time curves of the test preparations and the commercial preparations showed higher values for the test preparations in all of the investigations. However, these values were only statistically significant for the 40 and 60 mg formulations ISDN and the 60 mg formulation IS-5-MN.
The relative bioavailabilities and pharmacokinetic profiles of 2 carbocisteine preparations (capsules, granulate) were evaluated in a single dose and a steady state study. 10 healthy volunteers took in a randomized, 2fold cross over design 750 mg 3-(carboxymethylthio)alanine (carbocisteine, Transbronchin) (1 portion of the granulate or 2 capsules) as a single dose or for 4 days 3 times a day (every 8 h) 1 portion of the granulate or 2 capsules, respectively. During the saturation phase the pre-dose serum levels in the morning were determined and on day 5 - after a last dosing the elimination kinetics were evaluated. The same time frame of blood withdrawals was used for the evaluation of serum kinetics after single dosing. The new developed gaschromatographic method for the rapid, sensitive and reliable quantitative determination of carbocisteine in serum saves not only a lot of time but also improves the detection limit and selectivity by a factor of approx. 10. The studies revealed bioequivalency of the carbocisteine granulate and capsule preparations. After multiple dosing, no cumulation of the carbocisteine serum levels occurred. A comparison of the AUCo-infinity and AUC tau (single/multiple dosing, respectively) showed linear pharmacokinetics without enzyme induction or saturation phenomena in man.
In a comparative tolerance study with two different intravenous methylxanthine preparations, a theophylline-ethylendiamine preparation (TE-reference preparation) was tested against a combination of theophylline, proxyphylline (7-(2-hydroxypropyl)-theophylline) and diprophylline (7-(2,3-dihydroxypropyl)-theophylline) (Neobiphyllin; TPD = test preparation) in 10 healthy volunteers by a single blind cross-over design. Both preparations were infused under continuous control of vital parameters (blood pressure, pulse, respiration frequency, heart rhythm) as infusions (1 ampoule with 800 mg TPD or 1 short-infusion with 480 mg of TE for 20 min, each) up to the individual tolerance limit or the pre-defined limit of 3 ampoules/short infusions, respectively. The maximum tolerated infusion time and the serum levels at which the first side-effects appeared, were compared. These maximum doses could be administered to 6 volunteers under TPD, but only to two under medication with the reference preparation. Side-effects under TPD occurred in 5, after infusion of the reference preparation in 9 volunteers. Serum levels of theophylline at the end of the infusion period reached (14.6 +/- 4.21 (TPD) and 23.01 +/- 6.02 mg/l (TE), respectively. The average infusion time for the test preparation was 54.8, for the reference preparation 46.2 min. The average serum theophylline levels of the 5 volunteers with side-effects under TPD reached--when these side-effects occurred --11.26 +/- 4.52 mg/l; the same volunteers showed after administration of TE levels of 14.94 +/- 7.49 mg/l. Our results showed an approx. additive effect of the side-effects together with an--according to literature--over-additive pharmacological effect of the single components of TPD.(ABSTRACT TRUNCATED AT 250 WORDS)
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Following a single dose of a 20 mg nifedipine retard-tablet (Pidilat retard or a marketed formulation) to 12 healthy volunteers in a randomized, two-fold cross-over trial the nifedipine plasma levels were quantitatively determined by gas chromatography up to 24 h p.a. The relative bioavailabilities and important pharmacokinetic parameters were calculated and then statistically evaluated for significant differences between the preparations. Approx. 2 h after dosing, peak concentrations of 13 to 74 ng/ml were reached, the minimal therapeutic plasma level of 10-15 ng/ml was - in general - upheld for 10 respectively 8 h. Terminal elimination half-lives were calculated to be 5 and 8 h, respectively. An extrapolation with the obtained data for the expected steady state plasma levels after a twice-a-day dosing showed that the above mentioned therapeutically relevant plasma levels of the unchanged drug are in general achieved for most of the dosage interval. The strong inter- and intraindividual variations of blood levels after nifedipine application, which have already been described by numerous other authors, could also be observed in this study.
In a randomized, two-fold cross-over design 12 healthy volunteers received a normal-release 10 mg nifedipine soft gelatine capsule (Pidilat or a marketed product, respectively). The quantitative determination of the drug in plasma was achieved by gas chromatography up to 24 h p.a. Some important pharmacokinetic parameters and the relative bioavailabilities of the preparations were calculated and subsequently compared statistically: statistically significant differences between the preparations could not be found. Mean peak plasma concentrations of 121.2 +/- 47.3 and 104.5 +/- 32.9 ng/ml were reached approximately 0.5 h p.a. Both plasma level curves were practically identical, with the exception of the obtained absolute peak plasma concentrations. The known strong inter- and intraindividual variations of the plasma levels were found to be less pronounced in this study.
Imidazole 2-hydroxybenzoate is a new antiphlogistic compound with analgesic and antipyretic properties undergoing clinical investigations. The purpose of this pilot study was to evaluate new methods for the quantitation of imidazole, salicylic acid and salicyluric acid in plasma and urine. Imidazole metabolites caused considerable methodologic difficulties in plasma and urine. They were below the detectable limit. Salicylic acid metabolites were present in plasma also under the limit of detection (0.5 microgram/ml). In urine the metabolite salicyluric acid was measured in considerable quantities, whereas gentisinic acid was under the limit of detection. Three healthy volunteers were given a single p.o. dose of 750 mg imidazole 2-hydroxybenzoate in order to examine the practicability of these new methods a well as to evaluate the pharmacokinetics. The data are presented and interpreted. Further studies in this respect are advised.
Since 10 years there is a phenomenal increase in the use of mass spectrometry, combined with (capillary-) gas chromatography and dedicated data systems for the rapid, reliable, sensitive and selective determination of xenobiotics (drugs, their degradation/biotransformation products etc.) in biological fluids. This applies especially since the introduction of newer developments in ionization techniques (CI, DCI, FAB) and gas chromatographic column technology (fused silica, bonded phase columns). We employed such a sophisticated method for the quantitative determination of N-[3-(1-benzyl-cycloheptyl-oxy)-propoxy]-N,N'- dimethylammoniumhydrogen fumarate (bencyclane) in human plasma after oral application of a therapeutic doses. Our results clearly show that this approach is the best method available; furthermore the detected plasma levels will lead to discussions with respect to the pharmacokinetic properties of the drug.
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Diphenhydramine has been in medical use for 35 years as an antihistamine and hypnotic. We evaluated the pharmacokinetic parameters, which are not only important for disposition studies, in the serum of 10 volunteers who received a single dose of 31 mg diphenhydramine. For this purpose a suitable capillary GC-method was developed, which has a detection limit of 2 micrograms/l (serum); the calibration curve is linear between 2.5 and 120 micrograms/l, the reproducibility is always better than 3.6% and the average recovery is about 100.1%. The combination of a relatively non-polar extraction solvent, a selective detector (N-FID) and a fused silica, bonded-phase capillary column led to a more rapid sample clean-up procedure (no back-extraction needed) and is sensitive and specific enough for the quantitative determination of diphenhydramine, orphenadrine or other ethanolamines in human serum.
After application of an ointment of glycerol trinitrate (nitroglycerin, Nitrofortin; in the following briefly called GTN) the bioavailability of the unchanged GTN was evaluated. For that purpose a gas chromatographic/mass spectrometric method was employed, the only method which guarantees the selectivity and sensitivity necessary for this kind of studies. In this respect selectivity means that only the unchanged drug is determined and degradation and/or biotransformation products are measured only if needed. Considering the well-known tremendous inter-individual variations, which are quite common in studies with this compound, and the associated problems of getting statistically relevant data the study was performed on 12 volunteers. Detectable GTN-levels were obtained up to 48 h after application, maximum plasma levels (836.1 +/- 124.2 pg/ml) were reached after 1.37 +/- 1.55 h. 12 h after application plasma concentrations of 154 +/- 20 pg/ml were observed which decreased to 65 +/- 13 pg/ml after 24 h.
For five different brands of acetylsalicylic acid (ASA) preparations the in vitro/in vivo data were determined and tested for comparability. The in vitro dissolution rates were determined by two different methods (Paddle, rotating basket) whereas the in vivo data were obtained from 15 volunteers in a 5-fold cross-over trial. The markedly worse in vitro dissolution (rotating basket) of one preparation is in contrast to the in vivo data which showed bioequivalency of all five preparations. It is doubled that in vitro measurements alone reveal sufficient informations for any predictions of the in vivo characteristics (e.g. bioavailability) of a preparation. It was possible to determine separately ASA and salicylic acid using a highly selective HPLC-method developed by us.
For 4 different brands of indomethacin preparations the in vitro dissolution data as well as their relative bioavailabilities were determined. The in vitro tests were performed by the rotating basket method; the quantitative determinations of the serum-levels were determined by an gas chromatographic/mass spectrometric assay employing registration of the characteristic selected ion current profiles of the compound. Furthermore a special method for synthesis of the needed internal standard was also developed. The in-vivo-studies - with 15 volunteers in a 4 fold crossover-showed - in contrast to the worse in-vitro-dissolution of one preparation - bioequivalency of all four preparations. Our results clearly show that statements on in-vitro/in-vivo correlations have to be cautious.
The relative bioavailability and pharmacokinetic profile of two oxazepam preparations were evaluated in 12 normal volunteers by a newly developed HPLC-method. After oral application of one tablet of the test (Noctazepam) and reference preparation, respectively, no statistically significant differences of the AUC, Cmax Tmax and t1/2 were found. As compared to the reference preparation the relative bioavailability of the test preparation as 110%; both preparations are therefore bioequivalent.
The aim of this study was to investigate the effect of an analgesic-antirheumatic fixed combination drug containing dexamethasone (Ambene) on this endocrine system. 10 healthy volunteers received an intramuscular injection of Ambene as either single dose once, single dose on three consecutive days or on three alternating days. Early morning ACTH plasma concentrations, endogenous cortisol profiles and dexamethasone kinetics were determined and insulin-hypoglycemia tests stimulated stress conditions before, during and after Ambene-application. In all cases treatment led to short-term suppression of the reactability of the Hypothalamus-Anteropituitary Corticoadrenal System. Three days after single dose or alternating day administration for three days reactions of this endocrine system were completely restored, while after administration on three consecutive days there still was a slight decrease in basal and insulin-stimulated cortisol values. The short half-life of water soluble dexamethasone in Ambene appears to be the reason for the rapid restitution of this endocrine system.
The aim of this study was to determine the relative bioavailability of five oral allopurinol preparations and evaluation of the pharmacodynamic effect. Included were two slow-release formulations. The study was performed as complete five-way randomized steady-state cross-over trial in 10 healthy volunteers. Each day 300 mg of 1H-pyrazolo-(3,4-d) pyrimidin-4-ol (allopurinol) were orally administered for 7 days, followed by a wash-out phase of 14 days. The minimal serum levels of allopurinol and its major metabolite oxypurinol were determined by HPLC. In parallel the concentrations of uric acid in blood and in 24-h urine were measured. The two slow-release formulations had a significantly lower relative bioavailability compared to the normal formulations and, moreover, a slow-release effect could not be demonstrated. In all cases the clinical effect of the test preparations could be demonstrated, and a correlation between bioavailability and pharmacodynamic effect could be calculated. A correlation between published in vitro data and the present in vivo data could not be found.