Fragments of ACTH affect electrophysiological signs of controlled stimulus processing in humans.

It has been proposed that the systemic administration of the 4-10 fragment of ACTH in humans affects primarily attention. In the present study, influences of ACTH 4-10 on event-related potential (ERP) indicators of attention were evaluated in healthy men. The influences were compared with those of an analog of the ACTH 4-9 sequence (HOE 427) which was expected to have an increased potency. Following an adaptation session, each of 20 healthy men was tested on four occasions in a double-blind study designed according to a latin-square. On each occasion, subjects received (iv) one of the following treatments: placebo, ACTH 4-10 (1 mg), HOE 427 (60 micrograms) and HOE 427 (200 micrograms). Treatments were administered 40 min prior to recordings of ERPs. ERPs were recorded while the subjects performed on a dichotic listening task paradigm. The various tone pips presented in this task elicit ERPs providing measures of controlled stimulus processing (Nd reflecting selectivity of attention, and P3) and automatic processing of stimulus deviance (mismatch negativity). ACTH 4-10 as well as 200 micrograms HOE 427 reduced Nd and also P3 amplitudes following attended stimuli. Smaller (non-significant) changes in the same direction were observed following 60 micrograms HOE 427. The results suggest an impairing influence of ACTH 4-10 and of HOE 427 on signs of controlled stimulus processing, particularly on the Nd. The analog appeared to be more potent than the endogenous 4-10 fragment.

[Galenic and clinico-pharmacologic studies of prednicarbate (Hoe 777)]. / Galenische und klinisch-pharmakologische Untersuchungen zu Prednicarbat (Hoe 777).

The corticoid prednicarbate (test name: Hoe 777) is derived from prednisolone having no halogenic groups (chemical name: prednisolone-17-ethyl carbonate-21-propionate). Because of the specific physical and chemical properties of prednicarbate, galenic research strove to optimize the vehicle. Further development was only performed on those drug-containing bases showing especially good drug release (granting the most favorable action) in a) the vasoconstriction test and b) the UV erythema test practiced on volunteers with healthy skin. Exemplarily dealing with the special preparations predicarbate cream, ointment, and greasy ointment, we give some details of studies on drug dosage, vehicle selection, and the optimum water/lipid ratio.

Kinetics of UV-erythema in normal subjects.

In the expanding field of clinical dermatopharmacology we standardized an erythema model for testing drugs with effects on UV-induced inflammation in normal male Caucasian subjects. Using a light source with fibre-optic transmission and precise radiation characteristics, some of the shortcomings of conventional UV-application could be overcome. The radiation geometry during the various experiments was kept constant by a tube, permitting a defined area of exposure. Up to eight skin areas of the backs of normal volunteers were radiated with 86.2% UV-A and 13.8% UV-B. After exclusion of hyporeactive and hyperreactive subjects a good intrasubject reproducibility was obtained repeatedly over at least 3 months. According to the definition of bioavailability, our method allows the measurement of the rate and extent of UV-induced erythema. This model has been used for testing topical steroids, non-steroidal antiphlogistics in a variety of pharmaceutical formulations.

[Adequate and inadequate trials in "clinical" pharmacology]. / Adäquate und nicht adäquate Verfahren in der "Klinischen" Pharmakologie.

Our definition, based on 14 years of practical experience, is as follows: In clinical pharmacology, a procedure is adequate if it can be used in normal subjects in a non-invasive way and if it generates relevant information concerning pharmacotherapy in patients. Six examples are discussed in detail; the variable body weight may cause wide variations, for example, in absorption characteristics; unhomogeneous groups of subjects are likely to lead to poorly reproducible results. Body position and food intake (individual eating habits) may disguise drug effects by creating additional "noise". By titrating the heart rate during work load on the ergometer in order to achieve and maintain a target rate, individual differences in physical fitness and skill can be eliminated. Orthostatic regulation of cardiovascular variables may be impaired without concomitant psychic lability. The latter indicates predisposition to placebo responses, e.g. in studies using the standardized tourniquet pain model and mild analgesics. In normal subjects computer analysis of cerebral biosignals in combination with psychometric and behavioural tests usually gives more reliable information as compared to the patient pretreated with different drugs.

Standardized mental stress in healthy volunteers induced by delayed auditory feedback (DAF).

Using delayed auditory feedback (delay 0.175 s) a standardized form of mental stress was investigated in 8 healthy male volunteers. After a resting period and a period of undelayed reading, the volunteers were exposed for 5 min to the DAF stress. During the DAF period heart rate increased by 10% and systolic and diastolic blood pressure increased by 9% and 18%, respectively. As a measure of acute sympathetic activation, plasma concentrations of norepinephrine and epinephrine rose by 68% and 49%, respectively. The activity od dopamine-beta-hydroxylase in plasma was increased by 25%. From these results it can be concluded that the DAF procedure provides a suitable method for inducing a standardized mental stress in normal subjects, which can be measured as changes in biochemical and cardiovascular variables.