[Concentration of cefadroxil in kidney tissue and serum after oral administration in patients with normal and impaired renal function]. / Konzentration von Cefadroxil im Nierengewebe und Serum nach oraler Applikation bei Patienten mit normaler und eingeschränkter Nierenfunktion.

In 17 patients (7 with normal renal function, 10 with impaired renal function) who underwent renal surgery, renal tissue samples and blood samples were taken 3-4 h following the administration of a single oral dose of 1000 mg cefadroxil. It was demonstrated that the concentrations in renal tissue were within the range from 14.2 to 115 micrograms/g tissue, while the serum levels varied from 11.6 to 63.3 micrograms/ml serum. A statistically significant correlation between serum levels and renal tissue levels can be demonstrated. The correlation of the distribution ratio: serum level/tissue level to serum creatinine level proved to be a linear regression, i.e. the distribution quotient decreased if the serum creatinine level increased. This means that the renal tissue level of cefadroxil in comparison to serum level will be lower in patients with renal impairment. However, even with much impaired renal function the renal tissue level exceeded the minimum inhibitory concentration for the most relevant pathogens.

[A comparative pharmacokinetic study for tablet and suppository formulations of a combination product of caffeine, ethaverine, propyphenazone, paracetamol and phenobarbital (author's transl)]. / Vergleichende Pharmakokinetik der Wirkstoffkombination Coffein, Ethaverin, Propyphenazon, Paracetamol und Phenobarbital aus einer Tabletten- und Suppositoriumzubereitung.

After the single-dose application of Migräne-Kranit, a combination of caffeine, ethaverine, propyphenazone, paracetamol and phenobarbital, tablets and suppositories in six healthy male volunteers aged from 24 to 28 years, serum concentrations were determined. The estimated relative bioavailabilities of the single substances in the suppository formulation vary between 120% for propyphenazone and 83% for phenobarbital in comparison to the tablets. The lag-times and the absorption rates for the substances in both formulations differ significantly. The absorption rates for the substances in the tablet are faster than for those in the suppository. The estimates for the elimination rates show only small differences between the two formulations.

Estimation of Rate constant from measurement during free dosage regimen.

The estimation procedure for pharmakokinetic rate constants of blood and/or urine levels which have been taken during a free dosage regimen is described under the assumption of a classical open two-compartment model of first order. In an example phenylbutazone concentration measurements are used to demonstrate the iteration estimation procedure and to discuss the specific problems in order to receive unbiased and best estimates. Advantages and disadvantages of multiple-dose studies in free dosage regimen are itemised, and model functions for the free dosage regimen are suggested.

[Pharmacokinetics and bioavailability of the myotonolytic N-(hydroxy-2-ethyl)-cinnamide (author's transl)]. / Zur Pharmakokinetik und Bioverfügbarkeit des Myotonolytikums N-(Hydroxy-2-äthyl)-cinnamid.

The bioavailability, the absorption and elimination rate (biological half-life) as well as the volume of distribution for different routes of application were tested for the myotonolytic N-(hydroxy-2-ethyl)-cinnamide (LCB-29). 60 mg were administered i.v., 400 mg p.o. and 400 mg or 7 X 200 mg as ointment. For the i.v. and oral application the serum levels as well as the urine levels were determined. The amount of LCB-20 which may have been present in the urine after the ointment application was below the limit of detection. Serum concentrations were determined 10 times within 24 h after each application. Based on these values an absolute bioavailabiltiy for the LCB-29-ointment could be estimated at 1% in an application on 200 cm2 skin. This proved that the absorption of LCN-29 as ointment is very low compared to that in the oral application (absolute bioavailability 30%). The half-life was determined to be quite similar for all 3 routes of application: approximately 1 h. The absorption rate decreased by the factor 1.7 when LCB-29 was administered cutaneously instead of orally.

[Testing the effectiveness of cerebrally active drugs. Preliminary communication on a test model for cerebrally active drugs in humans]. / Zur Frage der Wirksamkeitsprüfung von zerebralaktiven Arzneimitteln. Vorläufige Mitteilung über ein Modell zur Erprobung Erprobung zerebralaktiver Arzneimittel an Probanden.

In a pilot study the feasibility of a new model in clinical pharmacology was investigated for testing cerebro-active drugs on healthy volunteers. For this study 6 volunteers were examined under room-air conditions (pO2 = 155 mmHg) and under a reduced oxygen mixture (12% O2, 88% N2, pO2 = 89 mmHg). Using the "Wiener Determinationsgeraet" (WDG) the subjects were tested as to their receptivity for complex information, their capacity for assimilating information, their reaction capacity, their reaction speed and reaction reliability. The results showed a stochastic connection between measured values on the WDG and the arterial oxygen partial pressure of the volunteers. These results justify additional studies with the described "hypoxia model" in order to test whether this reduction in capability in the healthy volunteers can be counteracted by application of cerebro-active drugs. This model could be used as a screening test for posology and pharmacodynamic effects in view of the further drug development in phase II studies on a larger number of patients.

[Pharmacokinetics and relative bioavailability of a nitroglycerin ointment formulation (author's transl)]. / Pharmakokinetik und relative Bioverfügbarkeit einer Nitroglycerin-Salbenzubereitung.

A comparative pharmacokinetic study was performed for three different nitroglycerin application forms. Serum concentrations were determined in six healthy male volunteers aged from 25 to 29 years. The serum concentrations of nitroglycerin after application of nitroglycerin ointment (Neos-nitro-ointment), of a sustained-release capsule and a sublingual capsule demonstrated that the ointment shows a similar absorption rate (Kr = 0.957 h-1) as the sustained-release capsule (Kr = 1.244 h-1) and furthermore results in a twice as high serum concentration when given in a 30.4 mg nitroglycerin dose as compared to one sustained-release capsule. Since the elimination rate of nitroglycerin was determined similar in all three application forms with a half-life of t1/2 approximately equal to 5 min it can be stated that the duration of effect after the application of ointment is longer than that of the sustained-release form based on the higher serum concentration.

Comparative pharmacokinetics and relative bioavailability for different preparations of nitrofurantoin.

In a single-dose study three different dosage forms of nitrofurantoin tablets are compared in order to attain a longer duration of efficacy by means of sustained-release dosage forms. In particular, bioavailability and the rate constants are estimated and show for one dosage form significant advantages. The measured serum and urine concentration levels are evaluated with a two-compartment model of first order which assumed the sustained release of the drug in an exponential manner.

[Estimation of pharmacokinetic constants in irregular repeated drug administration (author's transl)]. / Die Schätzung pharmakokinetischer Konstanten bei wiederholter, unregelmässiger Arzneimittelverabreichung.

Least squares estimations for the fraction of the dose absorbed, volume of distribution, absorption and elimination rate based on drug measurements in blood and urine after aperiodical administration are described for a one-compartment model with first-order absorption. The non-linear regression analysis is carried out by means of a modified Gauss-Newton iteration procedure by Hartley. BASIC and FORTRAN functions are developed and applied in an example. The advantages of unbiased and consistent least-squares estimations in pharmacokinetics are pointed out.

[Analog computer analysis of radioactivity kinetics in man following oral administration of tilidine HCl-14C]. / Analogrechneranalyse der Radioaktivitätskinetik beim Menschen nach oraler Gabe von Tilidin HCl-14-C

Models for studying the absorption and elimination kinetics of 14-C labelled DL-Ethyl-trans-2-dimethylamino-1-phenyl-cyclohex-3-ene-trans-1-carboxylate-hydrochloride (Tilidine - HCl, Valoron) are developed, based on the concentration vs. time of radioactivity in the plasma following a single oral administration in man. For this purpose, the average concentration values in the plasma of 3 healthy adults, as given by Vollmer and Poisson [12] were employed. 1. Two three-compartment-models were developed which simulate with sufficient accuracy the 14-C-Valoron concentration curve in the plasma. 2. Computer analysis enables one to determine the distribution of 14-C-Valoron among the intra- and extravasal compartments and the half life for absorption t1/2 equals 0.57 h, for transport from plasma into the extravasal compartment t1/2 equals 3.31 h, for resorption t1/2 equals 4.11 h, for elimination with feces t1/2 equals 29.5 h and for elimination in urine t1/2 equals 8.75 h. 3. The use of two different models allows one to draw conclusions concerning the participation of parenchymatous organs in storage and elimination. 4. The probable radioactivity curve is calculated for repeated oral application of 14-C-Valoron in 8 hours intervals.