TIPS - November 1983

Since the pattern of computerized drug administration simulates that displayed by rats in the self-administration paradigm, the consequences of chronic D-amphetamine use can be examined without resort to the questionable assumption that the effects of a single large injection simulate those of chronic small doses.

While the present program was designed to simulate the self-administration of 0.125 mg kg -1 of D-amphetamine by rats, once the pattern of self-administration of a dose of any drug by any species of experimental animal has been empirically determined,

the program can he easily modified to simu- late the self-administration pattern of inter- est. The pneumatic syringe and the supplies necessary to set up six cages for computer controlled drug administration can be obtained for under $1,000. The Timex Sinclair 1000 ZX 81 microcomputer and the Byte-Back control module are each available for under $100, thus putting com- puterized control of drug-administration within the economic reach of most inves- tigators.

A copy of the computer program appro- priate for the Timex Sinclair 1000 ZX 81

C u r r e n t a w a r e n e s s s e r i e s Key developments in pharmacology

447

microcomputer may he obtained from Dr A. P. Leccese at the address listed below.

A P. LECCESE, W. H. LYNESS

AND J H PIRCH

Pharmacology Department, Texas Tech Univer- say, Health Soences Center, Lubbock, TX 79430 USA

Reading list 1 Lyness0 W. H., Fnedle, N M. and Moore, K E.

(1980) Pharmacol. Bu~chem. Behav. 12, 937--941

2 Weeks, J .R. (1982)Sc/ence 138, 143-144 3 Weeks, J R. (1977) Pharmacol. Biochem

Behav 7, 559-562

0 Colour vision in clinical pharmacology If one may be allowed to open a serious sub- ject with a light-hearted statement: any pharmacologist familiar with the side. effects of digitalis will know that a relation- ship between the eye and the heart is not confined to attraction between the sexes. Patients with digitalis toxicity frequently present with disturbances in their colour vision; they may for example complain of seeing yellow haloes around objects (xanth- opsia) due to a cone dysfunction syndrome. During the last few years the pharmacolo- gist has recognized this digitalis--colour vis- ion phenomenon as a subject worthy of detailed investigation and this has been an important factor leading to the publication of the first symposium proceedings report on colour vision in clinical pharmacology 2.

One of the most useful methods for the measurement of digitalis effects on colour vision has been the Farnsworth-Munsell 100 Hue Test. The patient must arrange in the right order according to hue, 84 col- oured buttons or discs covering the colours of the spectrum. The score for each button depends on it being placed in the correct position and this is plotted on polar co- ordinates. Errors in colour vision discrimi- nation produce projections of the radii of the polar plot and an increase in the patient's 'total error score'.

The Famswotth-Munsell 100 Hue Test is accurate enough to enable a clear correla- tion to be observed between the digitalis serum concentration and the total error score. One important new finding is that a

change in colour vision can be observed even in the absence of clinical signs of in- toxication and when digitalis blood concen- trations are in the therapeutic range. It is fortunate that the impairment of colour vision induced by digitalis glycosides is reversible, and this appears to he the case, not only in mild intoxication when the blue-yellow functions are mainly affected but also in severe cases when both blue-yel- low and red--green functions are involved.

There has been speculation on whether cardiac glycosides produce the same inci- dence of colour vision deficiency, since the members of this class of drugs have marked differences in their physico--chemical prop- erties. The protein binding of digitoxin is very much greater than that for digoxin and thus the therapeutic concentration range for digitoxin is an order of magnitude greater. If we take the difference in the therapeutic range into account when comparing error scores in the Farnswordr-Munsell 100 Hue Test then we fred little difference between the two glycosides in this index of toxicity. For example, total error scores exceed 100 only when digoxin serum concentrations are greater than 1.5 ng ml -~ and digitoxin concentrations are greater than 40 ng ml-L This tells us that effects of digitalis glycosides on the eye are low when the serum concentrations of digoxin and the more highly bound digitoxin are in the therapeutic range and that the effects increase corresponding with the appearance of toxic effects on the heart.

Colour vision deficiency is therefore a common sign of digitalis toxicity. It has a higher incidence than any other single symptom of intoxication, including those detectable using the electrocardiogram, and is as frequently encountered as all cardiac symptoms taken together. The parallelism of cardiac symptoms of toxicity and effects on the eye could occur because the retinal cone system is rich in (Na + + K ÷ )-ATPase activity and this is the probable receptor enzyme for digitalis in the heart. It has been suggested that this enzyme is important in normal coiour vision since the impinge` mcnt of light on rhodopsin results in sodium influx and potassium efflux, cation move. ments which are assisted by the activity of (Na + 4- K+)-ATPase. It can therefore be concluded that the toxic effects of digitalis on the eye are related in some way to (Na + + K+)-ATPase inhibition in the retinal cones l.s. If this is true then colour vision measurement could he a useful phar- macodynamic test of digitalis toxicity.

Clinical pharmacology today focuses predominantly on drug monitoring. Pharmacokinetic principles have, to a large extent, already been worked out for us, but our mastery of pharmacodynamic problems is not so well advanced. There is, for exam- ple, an urgent need for new methods of assessing neural and sensory effects of drugs. Colour vision changes induced by digitalis have shown that colour vision is a quantifiable, pharmacodynamic response, suitable for investigating drug action. The retina is anatomically, biochemically and physiologically one of the most thoroughly investigated regions of the nervous system. It contains a variety of receptors, can he

448

studied as an isolated organ and has an intermediate complexity between peri- pherai nerves and the CNS. Phar- macologists have much to do in the field of retina studies before they can stand on a par with these other disciplines. Our under- standing of the events relevant to the effects of drugs on the retina and their significance with regard to the CNS and drug action at the molecular level is very limited. The

studies which have begun with an analysis of digitalis effects on colour vision can thus be considered as the earliest steps into this new research field.

BARRY G. WOODCOCK

AND NORBERT RIETBROCK

Department of Clinical Pharmacology, University Chmc, Frankfurt Am Main, FRG.

TIPS - November 1983

Reading list 1 Aronson, J. K. (1979) in Methods in Clinical

Pharmacology (Rietbrock, N., Woodcock, B. G and Neuhans, G., eds), pp. 17-25, Vieweg Vedag, Braunschweig- Wiesbaden, Germany

2 Rietbrock, N. and Woodcock, B, G (eds) (1983) Color Viszon in Clinical Pharmacology, Vieweg Veflag, Braunschweig-Wlesbaden, Germany

3 Robertson, D M., Hollenhorst, R. W. and Cal- lahan, J. A. (1966)Arch. Ophthalmol (Chicago) 76, 852-857

Chiral antidepressants: a potential help in antidepressant and behavioural research In the field of neuro|eptics, optical anti- podes have been used as pharmacological tools for a considerable time. Examples include (+)- and (-)-butaclamol and (+)- and (-)-sulpiride. In antidepressant research, little use has been made so far of the potential offered by chiral drugs. This may partly be attributed to the fact that of the 'first generation' antidepressants (or, in other words, the tricyclics) which have dominated research for many years, only those which do not exhibit 'typical tricyclic pharmacology', such as butriptyline and trimipramine, contain a chiral centre. However, an impressive number of the newer, 'second generation' drugs, many of them with a more or less established clinical antidepressant activity, do possess this property (e.g. azamianserin, citalopram, diclofensine, femoxetine, fluotracene, flu- oxetine, metapramine, mianserin, nisoxe- fine, nomifensine, oxaflozane, oxaproti- line, paroxetine, quinupramine, tanda- mine, and viloxazine). Nevertheless, the literature is remarkably poor with respect to data on the pharmacological properties of the individual enantiomers.

Published data are available on the opti- cal antipodes of tandamine, viloxazine, mianserin and its aza analogue, and of oxaprotiline. The inhibiting properties of tandamine on the neuronal uptake of nor- adrenaline (NA) and its related psychophar- macological properties seem to be confined largely, if not exclusively, to the ( - ) - enantiomer ~. The s(-)-enantiomer of viloxazine, the configuration of which is related to that of the naturally occurring R(--)-enantiomer of NA, inhibits the uptake of i.v. injected [SH]-NA into the mouse heart at about 50 times lower doses, and that into rat hypothalamic sy- naptosomes in vitro at about 30 times lower concentrations than R ( + )-viloxazinC. Simi- larly, s(-)-viloxazine was reported to be about 10-30 times more active than the R (+)-enantiomer in antagonizing reserpine

hypothermia, in reducing locomotor activity 3 and in enhancing the acquisition of passive avoidance behaviour in bulbectom- ized rats'.. It is of interest in view of the behaviourally, neurochemically and electrophysiologically established, enhanc- ing effects of viloxazine on 5-HT transmis- sion (see Ref. 2), that its enantiomers do not differ in their 5-HT releasing proper- ties".

As far as mianserin is concerned, it is the s(+)-enantiomer which possesses the c~2-antagonistic and NA uptake-inhibiting properties, and which inhibits rat muricide behaviour (a test for potential antidepress- ant activity); the R(--)-enantiomer is vir- tually devoid of any activity in this respect 5. Similarly, the c~2-antagonistic properties of azamianserin (which, in contrast with mianserin, is devoid of NA uptake- inhibiting effects) also seem to reside in the (+)-enantiomer 6'7. Thus, according to the current hypotheses, the pharmacological data would be interpreted to suggest that clinical antidepressant efficacy of mianse- fin, and possibly also of its aza analogue, would be confined to the (+)-enantiomers. On the other hand, the results of pharrnaco-EEG studies of human volun- teers suggest antidepressant properties of both enantiomers in each casC '8.

A similar situation is encountered with oxaprotiline, a compound with potent NA uptake-inhibiting properties and well- documented clinical antidepressant activ- ity. s (+)-oxaprotiline, the configuration of which is related to that of the unnatural s (+)-NA, possesses the NA uptake inhibit- ing and related psychopharmacological properties, whereas the antihistaminic effects are common to both enantiomers. On the other hand, the a(--)-enantiomer is somewhat more potently al- noradrenolyticL It is of interest that, in this case, In'st clinical results, although very preliminary and with a limited number of patients, seem to indicate an antidepressant

© 1983 Elsevier Science Publishers B V . Amsterdam 0165 - 6147/83/$01 00

effect of the R(-)-enantiomer (Mueller et al., Abstract VII. World Congress Psychiatry, Vienna, 11-16 July 1983).

Those who find it logical that uptake sites and receptors for an optically active trans- mitter also display stereoselectivity towards chiral drugs, will be deceived by the fact that the enantiomers of the bicyclo-octene derivative, LR 5182, do not differ in their ability to inhibit the uptake of NA, but rather in that to block the uptake of 5-HT, which is a nonchiral molecule TM. This emphasizes a conclusion already reached from the fact that the NA uptake inhibiting enantiomer of oxaprotiline, in contrast with that of viloxazine, has the opposite absolute configuration than the naturally occurring ( - ) -NA; absolute configuration is only of importance inasmuch as one or other of the enantiomers may better fulfil the steric requirements of a recognition site.

As evidenced by the few examples quoted above, enantiomers of chiral anti- depressants may differ in some but share other properties. The resolution and indi- vidual pharmacological characterization of a few more would provide valuable tools to explore the significance of each of these properties for their behavioural and phar- macological effects. Finally, this might also help in defining which properties of antidepressant agents are related to their clinical action and which are not, provided some of the chiral pairs are also tested clinically.

It can be inferred from this that resolution and characterization of chiral anti- depressants is not a waste of resources for academic frivolity, but can provide a serious contribution towards an improvement of antidepressant drugs and an understanding of their action in the future. In particular, they can help either to prove the validity of the monoamine hypotheses or to find a way out!

P C. WALDMEIER

Research Department, Pharmaceuticals Division, Ciba-Geigy Ltd, CH-4002 Basel, Switzerland

Reading list 1 Lippmann, W. and Pugsley, T. A. (1976)

Biochern. Pharmaeol. 25, 1179-1186