Biomedical subjects
Publications and source records attributed to O H Kehrhahn.
The position of the artificial lens has an important influence on refractive power calculation. We compared the position of the crystalline lens with that of the artificial lens after cataract surgery by means of Scheimpflug photography. A difference in position of approximately 0.8 mm in the anterior direction could be determined.
According to the accommodation changes in the lens described by Brown, the distance from the cornea vertex was determined in 192 Scheimpflug photos with the aid of a line drawn through the equator of the lens nucleus. The mean value for this section of the total distance was 5.75 mm, the variations being within the range of 5.38-5.9 mm. These results are of importance in the development of refraction and emmetropization of the eye as well as for the determination of the postoperative anterior chamber depth in cataract surgery and a criterion for the different types of glaucoma.
Real lens diameter and real lens volume cannot be measured by Scheimpflug photography, but the apparent lens radii and the lens thickness (anterior and posterior) can. Some stereometric equations allow us to calculate lens volume and lens diameter. Equations for the adaptation of the data points to nonlinear curves are given. There are no linear but sigmoid relationships between the age-dependent parameters. These can be estimated with the aid of equations 2 and 3 presented in this paper. When carrying out further investigations a greater number of parameters should be included in the analysis. It is conceivable that the equations must be expanded in order to be able to take other important parameters into consideration. Preliminary results of the calculations with regard to age are reported.
Seven normal male volunteers each received an injection of 208 mg theophylline anhydride for 4 min, and a 185-mg single oral dose theophylline anhydride (Broncho-Afonilum) on separate occasions. The concentrations of unchanged theophylline was analyzed over a 24-h period in plasma and a 48-h period in urine after both dosage forms. A 2-compartment model was required to describe the intravenous plasma concentration-time course in all seven subjects. A 1-compartment model sufficed to account for the decay of the oral plasma concentrations in all subjects. The mean plasma t1/2 after i.v. dosing was 6.5 h (3.5-9 h), and the mean plasma t1/2 after oral doses was 5.7 h (3-12 h). The calculated total of 23% (11-70%) of the intravenous dose was excreted in urine, and the mean total excretion after the oral dose was 12% (7-19%). The absolute bioavailability of oral theophylline was 94 +/- 20%
Blood pressure, ECG and plasma concentration were determined for up to 12 h following single i.v. (10 mg) and oral (20 mg) doses of amezinium (Regulton) in 8 healthy, male volunteers. The i.v. and oral doses were almost equi-active in significantly increasing systolic blood pressure (SBP) by 14.5 and 15.6 mmHg, respectively. The maximum SBP after the i.v. dose was reached after 45 min, and 105 min after oral administration. The heart rate fell reflexly. The increases in mean and diastolic blood pressures were not significant. Pulse pressure was enhanced after both i.v. and oral administration. The effect on systolic blood pressure lasted for about 4 h. There was a slight shortening of the QTc duration, which could not be explained as a drug effect. Other ECG time intervals were not altered. Multiple regression analysis showed a significant positive correlation between the log plasma concentration and the increase in SBP between 0.5 and 5 h after oral administration (r = 0.78, p less than 0.001) and between 0.75 and 5 h after i.v. administration (r = 0.83, p less than 0.001). 30 min after amezinium p.o. the mean SBP began to rise, when a plasma level of about 30 ng/ml was reached.
The pharmacokinetics of propafenone (Rytmonorm) was studied in 19 healthy volunteers. Propafenone was given intravenously (commercial ampoules of 70 mg) and orally in different doses (150, 300, 450 mg) and forms (solution, commercial film tablets). The results show a dose dependence of bioavailability and maximum plasma concentrations after oral application with over-proportionate increase at higher dose levels yielding bioavailabilities up to 40-50% with single applications of 450 mg. This is interpreted as saturability of a presystemic mechanism during invasion (most probably of the metabolizing enzyme systems of the liver). The mean rate constant of elimination after intravenous application is beta = 0.28 h-1 (95% confidence limits: 0.24-0.33 h-1) corresponding to a half-life of 2.5 h. There are no significant differences in these values after oral application and different dosages. The total plasma clearance of 1.0 1/min (95% confidence limits: 0.9-1.1 1/min) is almost exclusively metabolic. After 12 days of oral dosing (2 tablets of 150 mg propafenone daily) no statistically significant changes of kinetic parameters could be demonstrated although with some volunteers the total clearance decreased. It is considered that in some persons with relatively low clearance the plasma concentrations may reach levels at which a saturation of enzymatic reactions of metabolism may become relevant even after application of such low single doses as 150 mg.
A double-blind cross-over study was carried out in ten healthy volunteers to investigate whether there was possible propafenone (Rytmonorm) interaction with alcohol and whether series propafenone produced EEG changes. For this a series of performance variables and two rating scales describing subjective condition (EWL, Bf-S) were used. In addition the volunteers described spontaneously the undesired effects with their own verbal concepts. Under all conditions of the trial no systematic EEG changes were found. The propafenone-alcohol combination effect was not different from the placebo-alcohol effects. Only the flicker fusion frequency (CFF) measurements yielded systematic changes. The CFF was decreased at the termination of the investigation compared with the beginning. However, these effects were similar under both propafenone and placebo and did not differ statistically significantly from each other. Thus, these effects could not be caused by propafenone.
Seven normal male volunteers received an injection of 208 mg theophylline-anhydride (Solosin) each for 4 min, and a 225-mg single oral dose (Afonilum) on separate occasions. The concentration of unchanged theophylline was analyzed over a 24-h period in plasma and over a 48-h period in urine, after both dosage forms. A two-compartment model was required to describe the i.v. plasma concentration-time course in all seven subjects. A one-compartment model sufficed to account for the decay of the oral plasma concentrations in five of the subjects. The mean plasma t 1/2 after i.v. dosing was 6.5 h (3.5-9 h), and the mean plasma t 1/2 after oral doses was 5.9 h (3-8.3 h). The calculated mean total of 23% (11-70%) of the i.v. dose was excreted in the urine, and the mean total excretion after the oral dose was 15% (7-44%). The absolute bioavailability of Afonilum was 108 +/- 11%.
The absolute bioavailability and pharmacokinetics of 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (amesiniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, were examined following i.v. injection (10 mg) and single p.o. doses administered to eight healthy male volunteers. After i.v. injection plasma levels of amezinium were described by a tri-exponential function and the mean half-lives of the three phases were 0.08, 1.5 and 14 h, respectively. The volume of distribution at steady state ranged between 201 and 476 1. After p.o. doses of tablets, absorption of the drug obviously commenced immediately after dosing. After 0.5 h the absorption took place more rapidly and peak plasma levels between 31 and 61 ng/ml were reached after 1.2 to 2.4 h. The mean terminal half-life in plasma was 13 h after p.o. doses. 77% of the i.v. dose was excreted unchanged in the urine over 48 h; the mean excretion after the p.o. dose was 32%. Within the first 7 h the renal clearance of amezinium was considerably higher than afterwards. The mean absolute bioavailability determined by means of the area under the plasma concentration-time curve (AUC) was 53% and ranged between 40% and 74%.
The bilinear model, log 1/C = a log P--b log (betaP + 1) + c, is a new model for the qunatitative description of non-linear relationships between hydrophobic character and biological activity. In contrast to the parabolic Hansch model the bilinear model considers the particular effect that a linear relationship exists between lipophilicity and biological activity up to a point where this linear relationship breaks down to a non-linear relationship. Two different calculation procedures for the bilinear mode, a stepwise iteration method and the Taylor series iteration method, are explained and demonstrated with examples. The bilinear model and the parabolic Hansch model are compared by means of the statistical parameters r, s and F, by a partial F test and by an analysis of the residuals obtained with both models.
The relationships between the linear free energy related Hansch model and the mathematical models of Free-Wilson and Bocek-Kopecký are reviewed and discuss. Some examples are given to illustrate the theoretically derived relationships and to demonstrate scope and limitations of each mathematical model. The modified Free-Wilson approach is shown to be completely equivalent to a nonparabolic Hansch approach; it can be used to study additivity or nonadditivity of group contributions and to control and improve the fitting of Hansch equations. The Bocek-Kopecký approach is related to the parabolic form of the Hansch approach; its practial use is limited by the great number of variables involved.
The Fujita-Ban model and the classical Free-Wilson model are shown to be linearly related: the de novo group contributions obtained by one model are linear transformations of those obtained by the other model. An example is given to illustrate this linear dependence. The Fujita-Ban model is characterized by a number of advantages as compared with the classical Free-Wilson model: no transformation of the structural matrix and no symmetry equations are necessary; all group contributions are based on an arbitrarily chosen reference compound, preferably the unsubstituted compound; the constant term, which is the theoretically predicted activity value of the reference compound, and the values of the group contributions are not markedly influenced by addition or elimination of a compound; the problem of linear dependence (the singularity problem) sometimes can be circumvented by preparation of a contracted matrix; if the unsubstituted compound is chosen as reference compound, the group contributions are numerically equivalent to Hansch-derived group contributions; therefore, the Hansch approach and the Fujita-Ban model can be combined to a mixed approach. Taking all these facts into consideration, the Frujita-Ban model is recommended as the most suitable approach for the calculation of de novo group contributions.
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