[Asta von Mallinckrodt-Haupt, 1896-1960. In memory of the 50th anniversary of her death]. / Asta von Mallinckrodt-Haupt, 1896-1960: Zum Gedenken anlässlich ihres 50. Todestages.

A retrospective on the remarkable life of the female Professor of Dermatology in Germany. She was best known for her studies of fungal diseases of the skin. The article is based on personal recollections of her daughter and a comprehensive study of her scientific work.

Enzyme visualization with partially dehydrated agarose substrate layers: detection of paraoxonase after thin-layer isoelectric focusing in agarose.

A new approach is described for studying the polymorphism of paraoxon hydrolyzing serum esterases after isoelectric focusing of native sera. Enzyme visualization is performed by a modified sandwich procedure which is faster and also affords higher resolution and considerably improved sensitivity. Up to seven paraoxon splitting isoenzymes can be visualized and clearly distinguished from arylesterases and phosphatases by using 3-naphtyl acetate, paraoxon, 5-bromo-4-chloro-3-indolyl acetate and 5-bromo-4-chloro-3-indolyl phosphate as substrates. The new technique is also able to differentiate between paraoxonase isoenzymes sensitive to EDTA and those which are EDTA-stable. Immunofixation with anti-human serum albumin-antibodies revealed similar isoelectric points for these isoenzymes, although they are not assumed to be identical. The new technique may prove useful in other applications of enzyme visualization where diffusion of enzymes and/or cleavage products is the major problem.

[Antibiotic pharmacokinetics in patients with mucoviscidosis]. / Antibiotika-Pharmakokinetik bei Patienten mit Mukoviszidose.

In this review we summarize the available literature on the pharmacokinetics of antibacterials in cystic fibrosis. A special impact is given on the results of our group which will be put in perspective with the results of other authors. The homogeneity of our patient population allows a valid comparison between patient and volunteer data. We do not confirm the previously suggested strongly enhanced elimination of antibacterials in CF. Our findings have recently been confirmed by other investigators. However, since in the clinical situation a more heterogeneous group of patients is treated it seems rational to increase the dose of the antibacterials by about 20-30%.

Determination of sotalol in human body fluids for pharmacokinetic and toxicokinetic studies using high-performance liquid chromatography.

A sensitive, reliable and discriminating assay method is reported for the determination of sotalol (4-(1-hydroxy-2-isopropylaminoethyl)methanesulfonanilide) in human plasma and urine. The assay procedure has been successfully used during pharmacokinetic studies in healthy volunteers and patients as well as during toxicokinetic analysis. For sample preparation the internal standard atenolol was added to the specimen which was then extracted with n-pentanol-chloroform (1/3) at pH 9.0 followed by re-extraction into 0.05 mol/l sulfuric acid. Chromatography with fluorimetric detection was performed on Hypersil ODS 5 micron including the addition of heptanesulfonic acid and sodium dodecyl sulfate to the mobile phase of acetonitrile-water-acetic acid (20/79/1). Calibration was linear over the ranges of 0.1 to 5.0 micrograms/ml and 0.2 to 100 micrograms/ml for plasma and urine, respectively. Over these ranges coefficients of variation were below 10%. Recovery was between 82 and 98% from plasma and between 92 and 99% from urine.

High dose treatment with antibiotics in cystic fibrosis--a reappraisal with special reference to the pharmacokinetics of beta-lactams and new fluoroquinolones in adult CF-patients.

In this review we analyzed the pharmacokinetic basis for high dose treatment with antibiotics of patients with cystic fibrosis. Both our results and those from other well designed pharmacokinetic studies do not support the view that low blood levels of antibacterials are a common feature of CF. We were unable to detect a decrease in absorption, nor could we find evidence for enhanced elimination of antibacterials in CF. Both these factors have been considered responsible for reducing the plasma (and tissue) levels of antibiotics. Most recent studies on kidney function are in agreement with these findings, since neither inulin nor creatinine clearance differ between CF-patients and healthy volunteers. In contrast to previous discussion, the volume of distribution (Vdss) was not elevated for any compound. The rational of weight correction of volume terms like Vdss or total clearance has never been clearly demonstrated and should therefore not be used without prior proof of relevance. Since the variability of pharmacokinetic parameters of antibiotics in CF-patients may be considerable, we suggest that a dose increase of 20-30% may be justified, but cannot agree with two to fourfold increases in dosage as previously proposed and applied in many CF-centers. Until more findings become available for non-adult CF-patients, these conclusions are only valid for adult CF-patients.

Interethnic differences in the detoxification of organophosphates: the human serum paraoxonase polymorphism.

Paraoxon, 0,0-diethyl-0-p-nitrophenylphosphate is the highly toxic metabolite of parathion. The activity of paraoxonase, the enzyme which hydrolyses paraoxon in human serum shows a genetically influenced polymorphism with strong interethnic differences. The serum paraoxonase genotype has a significant influence on the paraoxon clearance and consequently on the toxic action of paraoxon and some related organophosphates and definitively protects the serum cholinesterase. Persons with low paraoxonase activity seem to be more endangered when handling parathion and related insecticides. More than 50% of all Europeans can be included in this group. The distribution of paraoxonase activity in human serum will be shown for samples which were collected from all over the world. As one moves from Europe in the direction of Africa and Asia the percentage of the low activity group decreases and was not even demonstrable in some tribes.

Interlaboratory survey on thallium in urine.

Quality assurance of analytic results was legalized in the Federal Republic of Germany by the law regulating the calibration of measuring devices of July 11, 1969, and the ordinance concerning the exception from compulsory calibration dated June 29, 1970. Accordingly, in the field of health care the Guidelines of the Medical Society of West Germany for the realization of quality assurance activities have to be followed. Since January 1, 1974, the law regulating the calibration of measuring devices has been fully effective. In the field of legal medicine the clinico-toxicologic analysis is considered to be a part of health care. As far as quantitative determinations are considered, these analyses have to follow the regulations mentioned above. To fulfil the basic program, adequate control samples are necessary. For toxicologic analysis there have been no control samples so far. Therefore, a control sample for thallium has been developed which can be used for long- and short-term interlaboratory surveys. The results are reported.

A study of the polymorphism and ethnic distribution differences of human serum paraoxonase.

The enzyme serum paraoxonase shows a polymorphism in Europeans which is governed by two alleles. The first allele has a gene frequency plow of 0.716-0.777, and is manifested as a low activity group in homozygotes. More than 50% of all European test subjects can be included in this group. A second allele with a gene frequency qhigh of 0.223-0.284 was found in typical European distributions and is manifested in both the form of a second heterozygotic and a third homozygotic group with high activities. The Hardy-Weinberg rule for a two-allele model is valid for the distribution. The gene frequency plow of the first allele decreases as one moves from Europe in the direction of Africa and Asia. In typical Mongoloid and Negroid collectives, less than 10% of the population can be included in the low-activity group, a group which is not even demonstrable in the Aborigines of Australia. The serum paraoxonase of the Aborigine population shows unimodal distribution. The validity of the Hardy-Weinberg rule for a three-allele model must be rejected in all examined collectives. Human serum paraoxonase shows neither age-related changes in activity nor sex-dependent activity differences.

[On kinetics of the paraoxon hydrolysing enzyme in human serum (EC 3.1.1.2) (author's transl)]. / Zur Kinetik des Paraoxon-spaltenden Enzyms im menschlichen Serum (EC 3.1.1.2).

Human serum contains an enzyme which hydrolyses Paraoxon (E-600, an organic ester of phosphoric acid) by splitting of p-nitrophenol. This enzyme is very specific and shows a statistically significant polymorphism: I.e. in a normal population there are three groups with high, middle and low enzyme activity. The results presented in this paper confirm this polymorphism by showing a differing kinetic behaviour of the enzyme in the three groups. Paraoxon, methyl-paraoxon and chlor-methyl-paraoxon are most likely hydrolysed by the same enzyme and in the same way. On the other hand hydrolysation of n-propyl-paraoxon seems to be dependent on a different enzyme. A kompetitive inhibition of paraoxon-hydrolysation is exerted by S-substituted analogues of paraoxon. Paraoxon-hydrolysation is not influenzed by the addition of singly or doubly desalcylized derivatives of Paraoxon or compounds in which the nitro group is not in the p-position.

[Acute fatal copper intoxication. Casuistic and considerations on differential diagnosis (author's transl)]. / Akute tödliche Kupfervergiftung. Kasuistik und Uberlegungen zur Differentialdiagnose.

If the diagnosis of copper-intoxication cannot be made by determination of copper in the collected specimen of the intestine, there may be problems in the differential diagnosis. In Wilson's disease and other cases of symptomatical hypercupriaemia copper content of brain tissues is elevated, while it is normal in acute copper intoxication.