Dose linearity of clonidine after transdermal application.

A prerequisite for optimal antihypertensive treatment is the possibility of individualized dosing. Therefore, three different dosages of the clonidine containing transdermal systems have been developed. The aim of this analysis was to clarify whether a linear enlargement of system size and consequently, a linear increase of the dose coming into contact with the skin will result in a linear increase of bioavailable drug. Data sets were obtained from a study performed in healthy volunteers, who wore these different TTS systems for 7 days each. Every patch was analysed after removal for residual content of clonidine. Plasma levels were measured. The areas under these plasma level curves were calculated by the trapezoidal rule. Apart from the dose of clonidine in the patch, the actual released amount of drug from the patch as well as the area under the plasma level curve were the parameters selected for the data analyses. Plasma levels of clonidine are known to vary within individuals. However, we have shown that within the range 2.5-7.5 mg of clonidine, the area under the plasma level curve as well as the released amounts of drug increase linearly with the dose administered. The regression analysis of released amounts versus the area under the plasma level curve further supports linearity of dosage.

Plasma levels of isosorbide dinitrate and its main metabolites following oral administration of two sustained release formulations in normal man.

The plasma levels of isosorbide dinitrate (ISDN) and the two pharmacologically active metabolites were measured following administration of two oral sustained release formulations containing 40 mg ISDN in nine healthy male volunteers. The new galenic formulation (pellets in a hard gelatin capsule) resulted in generally higher plasma levels for all three assayed substances over the time period of 24 h. The pharmacokinetic interpretation of the plasma levels following administration of the sustained release capsule assuming a one-compartment body model with zero-order invasion and first-order elimination showed a constant liberation over approximately 5 h. The elimination of all three substances was not altered by the new formulation. The plasma levels after administration of the tablet formulaation showed great variations within and between individuals. These data could therefore not be interpreted by the same model.

Finger pulse plethysmographic effects of two oral sustained-release formulations of isosorbide dinitrate in normal man.

Two sustained release formulations of 40 mg isosorbide dinitrate, encapsulated pellets and a tablet, were compared double blind following oral administration of single doses in terms of response on finger pulse plethysmography in nine healthy male volunteers. Following both formulations there was a distinct effect on the depth of b-wave in the first derivative of the finger pulse up to 9 h after administration. This change of the parameter of nitrate action was significantly different from placebo for both formulations. The onset of action was more rapid and the peak response greater for the capsule than for the tablet. The overall effects in terms of area under the effect-time curves was also greater for the capsule than for the tablet, however, not statistically significant. Furthermore, the results show that the method of finger pulse plethysmography can be used to determine onset and duration of action nitrate compounds, after single dose administrations.

Relationship between the pharmacodynamics and pharmacokinetics of two oral sustained-release formulations of isosorbide dinitrate in normal man.

The relationship between the pharmacodynamics and pharmacokinetics of isosorbide dinitrate (ISDN) following oral administration of 40 mg of two different models. A model assuming an additive contribution of all active drug-related substances in plasma to pharmacological effect, i.e., finger pulse plethysmograph, resulted in estimates of relative potencies of ISDN:2-MN:5-MN (2-MN:2-isosorbide mononitrate; 5-MN:5-isosorbide mononitrate) as being 1:0.1:0.025. The data analysis using a receptor model (plasma concentration-effect curves) yielded sigmoid curves yielded sigmoid curves for 2-MN and 5-MN with similar relative potencies in the range of 20-80% of maximum response providing an upper limit for the pharmacodynamic effect due to ISDN, 2-MN or 5-MN in healthy volunteers.

Assay of etozolin and its main metabolite, ozolinone, in plasma by high performance liquid chromatography.

A sensitive and specific method for the determination of the diuretic Ethyl (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetate (etozolin, Elkapin) and its pharmacologically active main metabolite, (Z)-(3-methyl-4-oxo-5-piperidino-thiazolidin-2-ylidene) acetic acid (ozolinone), at therapeutic concentrations in plasma is described. The method is based on high performance liquid chromatography and the use of two structurally similar internal standards. Etozolin and its metabolite are extracted from the plasma into dichloromethane at pH 9 and pH 5, respectively, and the resulting residues are analyzed on a silica gel column. The elution peaks are detected by UV absorption at 281 nm. The sensitivity for both compounds is 20 ng/ml plasma. The precision of the method is about +/- 5%. The applicability to pharmacokinetic studies of etozolin is shown.

GLC determination of tilidine, nortilidine, and bisnortilidine in biological fluids with a nitrogen-sensitive detector.

A sensitive and specific GLC method is described to determine therapeutic levels of tilidine and its two main metabolites, nortilidine and bisnortilidine, in plasma and urine. The method involves the extraction of the compounds and an internal standard with cyclohexane from alkalinized samples, followed by back-extraction into 1 N HCl. The hydrochloric acid solution is evaporated to dryness. After liberation of the free bases with ammonia, the residue is subjected to GLC analysis with a nitrogen-phosphorus detector and a 1.8-m (6-ft) glass column packed with 1% CRS 101 and 1.5% LAC-4-R-886 on Gas Chrom Q. Sensitivity in plasma and urine is approximately 1 ng/ml for a 5-ml sample.

Gas-chromatographic determination of nanogram amounts of enantiomers of nortilidine, a main metabolite of tilidine, in biological specimens.

We report a specific and sensitive method for determination of the individual optical isomers of nortilidine, a main metabolite of tilidine, with the aid of a nitrogen-sensitive detector. With N-trifluoroacetyl-L-leucyl chloride as chiral reagent, the diastereomeric derivatives of the nortilidine enantiomers could be separated and quantified in the nanogram range. Under these conditions, the enantiomers of bisnortilidine, another main metabolite of tilidine, were also separated. Investigations in rats with the enantiomers of tilidine and nortilidine indicated that no racemization occurs during N-demethylation in the organism. After oral and intravenous administration of 50 mg of tilidine.HCI to a human volunteer, identical concentrations of nortilidine enantiomers were found in the plasma.

[In vitro and in vivo investigations with different nitrofurantoin formulations (author's transl)]. / In-vitro-und In-vivo-Untersuchungen mit verschiedenen galenischen Zubereitungsformen von Nitrofurantoin.

In vitro dissolution tests and biopharmaceutical investigations on healthy test persons were carried out with 4 different galenic tablet formulations. Three of these formulations were prepared by a special galenic process, the fourth corresponded to the usual tablet formulations. It was shown that the dissolution behaviour of the formulations in vitro, in accordance with the specifications of the American Pharmacopoeia (USP XIX), does not correlate with the parameters found in vivo. However, if the formulations in vitro are checked with the Sartorius model according to Stricker, correlations can be found with the in vivo behaviour of nitrofurantoin. A linear relationship was achieved by the special galenic formulation directly regulating the pharmacokinetic behaviour of nitrofurantoin. The known biological scatter of nitrofurantoin was strongly reduced by this process. The amount of the substance still present and circulating in the body creating the side effects could be reduced to a minimum. All facts considered, the therapeutic safety is also ensured.

[TLC-method for quantitative densitometric determination of piprozoline and its main metabolite using internal standards (author's transl)]. / Dünnschichtchromatographische Methode zur quantitativen, densitometrischen Bestimmung von Piprozolin und dessen Hauptmetabolit mit Hilfe interner Standards

A determination method is described for ethyl (Z-3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)acetate (piprozoline, Gö 919, Probilin) and its main metabolite (Gö 3284) extracted from the sample to be analyzed at different pH-values, after the addition of two internal standards to the sample. The extracts are then recombined and applied to TLC plates. After developing twice in a cyclohexane/isopropanol mixture, the substances are determined densitometrically on the plates at 275 nm. By comparing the peak area ratios (substance/internal standard) the peaks were quantitated after plotting a calibration curve. The lower sensitivity limit was approx. 100 ng after extraction of a 1 ml sample.

[Metabolism and pharmacokinetics of piprozoline in rat, dog and man. 3rd communication: Determination of piprozoline and metabolite I in plasma and urine (author's transl)]. / Metabolismus und Pharmakokinetik von Piprozolin bei Ratte, Hund und Mensch. 3. Mitteilung: Bestimmung von Piprozolin und Metabolit I in Plasma und Urin

The new choleretic ethyl (Z)-(3-ethyl-4-oxo-5-piperidino-thiazolidin-2-ylidene)-acetate (piprozoline, Gö 919, Probilin), a monosubstance of the substituted methylthiazolidones, was investigated by thin-layer chromatography with regard to pharmacokinetics in the rat (100 mg/kg i.v.; 20 mg/kg i.v.), dog (100 mg/kg i.g.; 20 mg/kg i.v.) and man (200 mg orally in sugar coated tablets). The substance was absorbed quickly in all species. Because of its rapid metabolisation, unchanged substance could be detected only in the dog after oral administration. In this case and after intravenous administration of piprozoline, the plasma level of the unchanged substance cold be described by two-compartment models with first-order kinetics. After intravenous administration, piprozoline was also rapidly transformed into metabolite I, as metabolite I existed in higher concentrations than the unchanged substance already after 6 min. In all cases, metabolite I was eliminated from the plasma with a half-life of approx. 2 h; 15-30% of the given dose appeared as metabolite I in urine, piprozoline itself could not be detected. After correction to uniform doses of 100 mg/kg, in all species the area under the plasma level curve of the metabolite amounted to approx. 12 mg/ml X h and the apparent volume of distribution to approx. 1-1.5 1/kg body weight. This indicates good availability in animal and man, regardless of the galenic formulation.