[Evaluation of drug concentration in tissues after percutaneous administration of non-steroidal antirheumatics]. / Zur Auswertung von Wirkstoffkonzentrationen in Geweben nach perkutaner Anwendung von nicht-steroidalen Antirheumatika.

For some 10 years it has been usual practice to determine tissue drug concentrations following the application of topical antirheumatic agents. However, testing the measured drug concentrations for their therapeutic relevance continues to be difficult. An appropriate reference parameter is, for example, the IC50 of the inhibition of the prostaglandin synthesis. Moreover, tissue concentrations should be compared with those achieved following oral administration of clinically effective doses. Based upon practical experience with ibuprofen (CAS 15687-27-1) following both topical and oral administrations, it is illustrated how such studies and the tissue concentrations found could be evaluated and interpreted taking into particular consideration the sample size calculation and the therapeutic relevance of the results.

Intrasubject variability in bioequivalence studies illustrated by the example of ibuprofen.

Based upon the results of a bioequivalence study in 18 male and female healthy volunteers receiving each ibuprofen 400 mg at a time interval of 3 days the issue of the intrasubject variation is discussed. It was shown that there was bioequivalence as to the parameters Cmax, AUC0-tlast und AUC0-infinity in the volunteers who repeatedly received the same preparation. The same is true for the secondary target parameters tmax und t1/2. In the present study the intrasubject variability was determined to be 10%. Since ibuprofen does not belong to the drugs with problematic bioavailability it can be expected that in case of repeated application at an interval limited in time equal results are achieved with considerable intra-and intersubject variations.

The importance of pharmacokinetic data on sulpiride: results of a bioequivalence study of two sulpiride 200 mg preparations following oral administration.

In a within-subject comparative trial in 16 healthy volunteers, the bioequivalence of two sulpiride 200 mg preparations was tested using a model-free method of calculation as well as assuming 2- and 3-compartment models. As to AUC act., AUC inf. and Cmax, the test preparation was shown to be significantly superior. Some other differences were found depending on which calculation method was used. The Cmax of the test preparation showed therapeutically relevant plasma concentrations of greater than 400 ng/ml, compared with about 300 ng/ml for the reference preparation. Based upon the raw data obtained, it was the aim of this study to gain further knowledge about other kinetic parameters on which only few data is available. T1/2 beta, clearance, volume of distribution and MRT were calculated using 2- and 3-compartment models. Comparisons with literature data were made and it resulted that a better description of the sulpiride kinetics was obtained when a 3-compartment model was used. Finally, the course of the plasma level was calculated by computer extrapolation assuming a thrice daily administration of sulpiride 200 mg. As a result, steady-state is reached after 3-4 days showing plasma concentrations around 650 ng (reference preparation) and 850 ng (test preparation).

[Percutaneous therapy with non-steroidal anti-inflammatory drugs. Pharmacokinetic criteria of effectiveness]. / Perkutane Therapie mit nichtsteroidalen Antiphlogistika. Pharmakokinetische Kriterien der Effektivität.

As in the case of systemically administered drugs, there is also a requirement for reliable kinetic evidence for the clinical effectiveness of local therapeutic NSAIDs. The conditions required for this are discussed, and compared with provisions already existing in EC countries. On the basis of a comprehensive review of the literature, it is shown that among all the locally employed NSAIDs, kinetically reliable and plausible evidence of therapeutic effectiveness is, at present, available only for indomethacin, diclofenac, salicylic acid salts and ibuprofen.

[Concentrations of ibuprofen and the protein and pH value of synovial fluid and plasma following oral administration of ibuprofen in patients with arthritis]. / Konzentrationen von Ibuprofen und Eiweiss-Gehalt sowie pH-Wert in Kniegelenkserguss und Plasma nach oraler Gabe von Ibuprofen bei Arthritis-Patienten.

Concentrations of Ibuprofen and Protein Concentration and pH-Value in Synovial Fluid and Plasma Following Oral Administration of Ibuprofen in Patients Suffering from Arthritis. In 16 patients suffering from arthritis of the knee the concentration of ibuprofen in the synovial fluid was examined in correlation with the synovial fluid volume, cell count, pH value and protein concentration. The mean ibuprofen concentration in plasma 4 h after oral administration of 400 mg ibuprofen amounted to 15.45 micrograms/ml, the concentration in the synovial fluid was 9.4 micrograms/ml. Due to the inflammatory nature of the effusions the protein concentration in the synovial fluid was evidently increased to an average of 4.46 g/dl and thus was about 65% of the mean plasma protein concentration of 6.88 g/dl. The ibuprofen in the synovial fluid showed a correlation to the protein concentration. On the other hand, there were no significant differences between the pH value in the plasma and in the synovial fluid. There was no tendency to an acid pH. Furthermore, there was no correlation between ibuprofen concentration and cell count. The tests showed that the "accumulation" of the nonsteroidal antiinflammatory drug in the synovial fluid is positively correlated with the high protein concentration but not with the pH value.

[The percutaneous kinetics of ibuprofen from a cream formulation]. / Zur perkutanen Kinetik von Ibuprofen aus einer Cremezubereitung.

The percutaneous penetration of an ibuprofen cream at 5% (Dolgit Creme) was tested in guinea pigs. Already 20 min after application of the cream on the shaved skin high ibuprofen concentrations of about 10 micrograms/g were found in the subcutaneous and in the muscular tissue. The plasma concentrations reached only one tenth of the values ascertained in the tissues. 2 h after application the concentrations in the tissue increased by 50%, whereas the increase of the plasma concentrations was more significant. The results confirm in agreement with kinetic studies in man that ibuprofen penetrates from the tested formulation directly and very quickly in deeper tissues. The deviation of the active ingredient over the systemic circulation is improbable.

[Bioavailability of metoclopramide in a sustained-release preparation]. / Zur Bioverfügbarkeit von Metoclopramid aus einer retardierten Darreichungsform.

The aim of this study was to examine the pharmacokinetical behaviour of metoclopramide of Gastronetron retard capsules after a single administration to 8 healthy male volunteers. Determinations of the concentration of metoclopramide in the serum were made up to 24 h p.a. The calculation of the serum concentration curves was based on an open 2-compartment model. It has been proved that already 30 min after oral administration effective serum concentrations could be reached, which are maintained over about 24 h. An approximate value of 71% was obtained for the bioavailability of metoclopramide of Gastronerton retard capsules. The action achieved by the administration of 1 capsule Gastronerton retard per day can be considered equal to that of 3 single administrations of the conventional oral pharmaceutical form.

[Pharmacologic-toxicologic study of an ibuprofen-containing creme]. / Pharmakologisch-toxikologische Untersuchung einer Ibuprofen-haltigen Creme.

The antiphlogistic action, the percutaneous penetrability as well as the systemic and local tolerance of cremes with a different ibuprofen content after epicutaneous administration were examined in the rat, the guinea-pig and the rabbit. The antiphlogistic action was dose-dependently assessed on the carrageenin-induced edema of the rat paw and on UV-erythema in the guinea pig. The cotton-pellet test carried out on the rat evidenced only modest efficacy. The percutaneous penetration of ibuprofen after single epicutaneous application was obtained through the assessment of the active principle in the tissues and in the serum. The tests carried out for ascertaining the systemic and cutaneous tolerance did not evidence even after 3 to 4 weeks treatment with the ibuprofen creme any signs of intolerance due to the substance. In the investigation of the mucosal tolerance, the instillation of ibuprofen creme into the conjunctival sac of the rabbit led to strong yet reversible intolerance reactions in the conjunctiva and in the eyelid. Bearing on the results obtained on the whole, ibuprofen creme at 5% can be envisaged for clinical examination for the treatment of circumscribed rheumatic and traumatic diseases.

[Bioavailability of metoclopramide with special reference to relevant literature data]. / Zur Bioverfügbarkeit von Metoclopramid unter besonderer Berücksichtigung einschlägiger Literaturdaten.

An intraindividual comparative study of the pharmacokinetic properties of metoclopramide, the active principle of Gastronerton, and metoclopramide of a reference drug after one single administration was carried out on 6 male healthy volunteers. Gastronerton was available as ampoules, tablets, solution and capsules; the reference drug as ampoules, tablets and solution (all of them as commercial products). The concentrations of metoclopramide in the serum were determined until 24 h after administration. As one of the persons dropped out another volunteer was included. There were 6 cases for the intraindividual comparison of the parenteral/enteral form except for the comparison of the tablets/ampoules of the reference drug. An open 2-compartment model was taken as a basis for the calculation of the serum concentration curves and the pharmacokinetic parameters. With regard to the maximum serum concentrations, the preparations differed only insignificantly. The bioavailability results were as follows: metoclopramide of Gastronerton tablets 80.3%, metoclopramide of the tablets of the reference drug 57.6%, Gastronerton solution 76.7%, solution of the reference drug 49.7%. The bioavailability of metoclopramide of Gastronerton capsules was 54.8%. The half-life values were between 2.8 and 8.3 h with a mean value of 5 h.

Characteristics of lofexidine in pharmacological screening.

Pharmacological and limited toxicological screening tests have been performed in order to provide an initial assessment of a new hypotensive substance, 2-[1-(2,6-dichlorphenoxy)-ethyl-2-imidazoline hydrochloride (lofexidine, Lofetensin and Loxacor). After intravenous and intraduodenal administration, this new delta 2-imidazoline compound caused a dose-related, long-lasting reduction of blood pressure. This effect was demonstrable with doses of only 1-10 microgram/kg (i.v.) and 6-60 microgram/kg (intraduodenally). The results suggest a clonidine-like mechanism of action and provided justification for more detailed pharmacological and toxicological studies.

[Comparative pharmacokinetics of paracetamol in humans following single oral and rectal administration (author's transl)]. / Vergleichende Humanpharmakokinetik von Paracetamol nach oraler und rektaler Einmalapplikation.

The pharmacokinetic behaviour of N-acetyl-p-aminophenol (paracetamol) after single dose applications of 500 mg and 1000 mg dosages in the form of liquids, tablets and suppositories was compared. The estimation of the pharmacokinetic constants by a simultaneous curve fitting with a direct search procedure, based on an open two-compartment model, showed for the liquid as well as for the tablet formulation a good conformable and dosage proportional behaviour of the relative bioavailability. In opposite to the oral application, the suppositories had a significantly reduced invasion kinetics with a comparable elimination kinetics characterized by a lowering of Cmax and an increase of Tmax-values with comparable AUCs. The calculation of collapse-coefficients showed, with the exception of one suppository formulation, for all administrations a pharmacokinetic behaviour deviating from an open one-compartment model. The clinical consequences resulting from the pharmacokinetic behaviour of the different galenic formulations and routes of administrations are discussed.

[A novel method for measurement of cerebral blood flow in the animal experiment]. / Eine methodische Alternative zur Messung der Gehirndurchlutung im Tierexperiment

A method is described for the measurement of cerebral blood flow by coutinuous registration of the venous out-flow from the temporal sinus of anaesthetized dogs. This method can be used advantageously for the screening of unknown compounds because samples of "cerebral" venous blood are obtained by a less complicated and reliable technique. Changes in cerebral blood flow induced with well defined substances, were registered with our method. The results are discussed.

[Pharmacology of "essential" phospholipids (author's transl)]. / Pharmakologie "essentieller" Phospholipide (EPL)

In an extensive pharmacological screening of "essential" phospholipids (EPL) antilipemic, hepatoprotective, broncholytic, as well as slight choleretic effects were found and the substance decreased capillary permeability. There was practically no influence on other functions or systems including the vegetative system (heart, circulation, respiration).

[The anti-hyperlipemic and anti-atherogenic effect of "essential" phospholipids: a pharmacologic trial]. / Die antihyperlipämische und antiatherogene Wirksamkeit der "essentiellen" Phospholipide (EPL) im pharmakologischen Versuch

To prove antilipemic and antiatherogenic effectiveness several animal species were given "essential" phospholipids (EPL) during different experimental procedures. The following actions were studied: 1. Effect of EPL-substance after prophylactic and therapeutic oral administration (dosage: 50, 150, 450 mg/kg bodyweight daily) in rats with acute and subacute hypelipemia induced by triton. 2. Effect of EPL-substance after prophylactic and therapeutic oral administration (dosage: 50, 150, 450, 1800 mg/kg bodyweight daily) in rats with dietetic hypercholesterolemia. 3. Effect of EPL-substance after daily oral administration (dosage: 50, 150, 450 mg/kg bodyweight) on the development of coronary and aortic atherosclerosis and various biochemical parameters in cholesterol-fed cockerels. 4. Effect of EPL-substance after dialy oral administration (dosage: 50, 150, 450 mg/kg bodyweight) on subacute triton-hyperlipemia in mini pigs. Triton-administration causes a greater or smaller increase in all parameters of the lipid metabolism measured. EPL treatment decreases these parameters during therapeutic and prophylactic administration in some cases even reaching normal values. The effect was clearly dose-dependent. EPL inhibit the increase in total lipids in dietetic hypercholesterolemia during therapeutic as well as during prophylactic administration. The effect was clearly dose-dependent in all doses, being statistically significant at the highest dosage level. In cockerels EPL were effective at all dose levels in counteracting the development of coronary atherosclerosis while the effect in atherosclerosis of aorta was less distinct. Except for non-esterified fatty acids, EPL reduced all biochemical parameters measured.

[Further investigational results with the dermatometer according to bingmer (author's transl)]. / Weitere Experimentalbefunde mit dem Dermatometer nach Bingmer

Further results of investigations using the dermatometer according to Bingmer for the determination of the actual moisture content of superficial skin layers are presented. The investigations are divided into in-vitro tests, tests on excised skin and tests on humans. Results indicate that the Bingmer apparatus used in these trials shows considerable specific sensitivity to changes in the moisture content of the media examined. Different results obtained by other workers might be due to the use of Bingmer apparatus with a different carrier frequency. The advantage of apparatus based on 9 Kc carrier frequency is stressed. As a whole, the use of the Bingmer apparatus may be considered a step forward in dermatological and cosmetic examination techniques.