The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects.

First-generation histamine H1-receptor antagonists, such as diphenhydramine, triprolidine, hydroxyzine or chlorpheniramine (chlorphenamine), frequently cause somnolence or other CNS adverse effects. Second-generation H1-antagonists, such as terfenadine, astemizole, loratadine and cetirizine, represent a true advance in therapeutics. In manufacturers' recommended doses, they have a more favourable benefit/risk ratio than their predecessors with regard to lack of CNS effects, and do not exacerbate the adverse CNS effects of alcohol or other CNS-active chemicals. Rarely, some of the newer H1-antagonists may cause cardiac dysrhythmias after overdose or under other specific conditions. The concept of a risk-free H1-antagonist is proving to be an oversimplification. An H1-antagonist absolutely free from adverse effects under all circumstances is not yet available for use. The magnitude of the beneficial effects of each H1-antagonist should be related to the magnitude of the unwanted effects, especially in the CNS and cardiovascular system, and a benefit-risk ratio or therapeutic index should be developed for each medication in this class.

H1-receptor antagonists. Comparative tolerability and safety.

Asymmetric neural control systems in human self-regulation

During the past 20 years, research in the behavioral sciences has become increasingly sophisticated. New findings concerning the brain and behavior have forced upon us the unpleasant necessity of reexamining our models. Concepts once useful, such as "the unconscious," "regression," and "motivation," no longer serve to adequately encompass the data. Ashby is a representative of this new order of sophistication in research, as he proceeds to investigate the problem of the brain's orderliness. He accepts, as fact, that the nervous system behaves adaptively and assumes that it is, in its essentials, mechanistic. These two data are approached as not irreconcilable. From this point, he proceeds to examine dynamic systems from the standpoint of rigorous scientific —dominantly mathematical—logic until he has evolved a theoretical counterpart of brain functioning. He then builds and experiments with a prototype electronic model, which he names the "Homeostat," and tests various aspects of his theories of

Design for a Brain

Changes in interhemispheric amplitude relationships in the EEG during sleep

Analysis of the quantified electroencephalogram of the left occipital lead (Drohocki's integrative method) of 21 normal male subjects revealed an average coefficient of variation in electrical energy of 15.4 per cent. In 25 male chronic schizophrenic patients, the mean coefficient of variation was 8 per cent. Placebo administration did not produce any significant change in either group. In the normal men, oral dosage with 0.3 p.g per kilogram of D-N, N diethyllysergamide (lysergic acid diethylamide, LSD-25) produced a 33 per cent decrease in variability without significant change in the mean energy content of the electroencephalogram. When the dose of lysergic acid diethylamide was increased to 1 p.g per kilogram, a 25 per cent decrease in variability and 23 per cent reduction of the energy content of the electroencephalogram followed. In schizophrenic patients, lysergic acid diethylamide at 1 μg per kilogram orally did not affect the mean energy content but produced a 47 per cent increase in variability. The findings indicate that the electroencephalogram of male institutionalized chronic schizophrenics tends to be hyperregulated. Similar hyperregulation is produced in normal volunteers by threshold and larger doses of lysergic acid diethylamide.

Quantitative electroencephalographic analysis of naturally occurring (schizophrenic) and drug-induced psychotic states in human males

Publisher Summary The data obtained from the quantitative integration of the Electroencephalogram (EEG) under varied experimental conditions reveal a difference in the level of brain wave variability in normal subjects as compared to male chronic schizophrenic patients. A correlation was found between the level of EEG amplitude variability and psychological behavioral ratings of chronic schizophrenics. Based on these observations and many others mentioned in the chapter it is concluded that the integrative method of EEG analysis provides both, more information and a different kind of information than that derived from visual inspection of EEG records alone. Integrated EEG data reflects the action of physiological mechanisms of the brain to a reasonable extent and proposes a model of brain function derived from such data. The model of brain function at the cortical levels, is essentially characterized by the regulating mechanisms maintaining a state of equilibrium in a constantly changing environment. Stimulation, hyperexcitation, and hallucinatory states (spontaneous or drug induced) correspond to different degrees of hyper-regulations.

Amplitude Analysis of The Electroencephalogram: Review of the Information Obtained with the Integrative Method

Electro-cerebral activity in schizophrenics and non-psychotic subjects: Quantitative EEG amplitude analysis

A recent development in characterization and measurement of drug actions on the brain has been the use of quantitative electroencephalographic methods.’ Although quantitation was undertaken by means of laborious manual methods at the time of the earliest EEG recordings2 and somewhat later,9.4 it was not until 1948 that a fairly simple and reliable automatic device was designed which made possible large scale longitudinal studies of the amounts and quantitative variations of the electical activity of the brain.5 This device, the electronic integrator of Drohocki, performs a continuous, cumulative measurement of the area under the successive waves, irrespective of their f requen~y.~ .~ A convenient way to visualize the kind of measurement performed by Drohocki‘s device is to consider it as summating the total energy content of the EEG within any given time period. Due to difliculties with time constants and calibration, these energy content measurements cannot be readily expressed in standard units. Instead, the results are expressed in terms of baseline settings and control measurements. From qualitative EEG studies, it has been known for a long time that drugs which are stimulants produce a characteristic EEG change defined as “alerting” or “activation.” In relation to the pattern observed before treatment this effect consists most often of a decrease in wave amplitude with a concomittant increase in wave frequency (“desynchronization”) . In the quantified EEG the overall effect appears as a decrease in energy content. On the other hand, sedative drugs produce what is loosely called “synchronization,” and this is manifested by an increase in EEG energy content. The first question concerns the sensitivity and reliability of the integrative EEG method. As is well known, the spontaneous EEG is quite variable. It is not uncommon to find during periods preceding drug administration strips of the record of various lengths in which the pattern resembles closely the one brought about by the treatment. Obviously such a situation calls for the use of statistical analysis since the problem of the signrficance of changes is of prime importance. This is where the advantage of the integrative approach becomes apparent since it permits a straightforward statistical appraisal of the changes, if any, brought about by drugs. The way in which this is achieved is the following: The integrator is

Leonide Goldstein

Papers

Changes in interhemispheric amplitude relationships in the EEG during sleep

Quantitative electroencephalographic analysis of naturally occurring (schizophrenic) and drug-induced psychotic states in human males

Amplitude Analysis of The Electroencephalogram: Review of the Information Obtained with the Integrative Method

Electro-cerebral activity in schizophrenics and non-psychotic subjects: Quantitative EEG amplitude analysis

Quantitative electroencephalography in man as a measure of CNS stimulation.