837

HL-A incompatibilities were restoring the antigenicbalance. When the A x cT 0 matings were dividedinto those in which the antecedent child was group A,or group 0, and compared with each other and withall the other matings grouped together, the HL-Aincompatibility scores were found to be comparable ineach of the three mating classes. Therefore, in thiscontext, it would appear that the influences exerted bythe ABO and HL-A systems in trophoblastic neoplasiaare independent of each other.

PrognosisEven though the genetic potential for HL-A in-

compatibility does not prevent the occurrence of atrophoblastic tumour, it might still influence its courseand the patient’s prognosis. Whether or not a chorio-carcinoma is eradicated depends mainly on its sensitivityto chemotherapy. But what we observe as the responseof the tumour to chemotherapy may be profoundlyinfluenced by other factors resulting in tumour-celldeath.10 Immune mechanisms may make an importantcontribution to the killing of tumour cells; for example,it has been shown that choriocarcinomas have a morefavourable prognosis when associated with a well-

developed mononuclear cell reaction.11Theoretically, an immunological response to this

tumour may be provoked by antigens associated withmalignant transformation of the tissue, by trophoblastspecific antigens, and by individual specific antigens orby any combination of these. HL-A incompatibilityrelates only to individual specific antigens, and it is

generally agreed that these antigens are deficientlyexpressed on normal trophoblast, and only the questionwhether these antigens are detected at all remainscontroversial.12, 13 Direct evidence for the presence ofHL-A antigens on choriocarcinoma cells is restrictedto one reported case. 14For the present analysis, we used the simple con-

sideration of the number of antigens that the patientshad in common with their husbands-i.e., 0, 1, or

more. The data presented here suggest that a suc-cessful outcome of treatment is more likely for in-compatibly mated patients. There was 1 death

amongst 16 patients with 0 antigens in common withtheir husbands and 5 in 29 when they had one ormore antigens in common. The difference is not

statistically significant. We could not find any obviouscorrelation between the duration of therapy necessaryto achieve remission in the survivors, or the extent ofmetastases, and the degree of HL-A incompatibility.It seems likely that other factors influence prognosismore profoundly than the degree of HL-A incom-patibility.Many of the patients formed potent HL-A anti-

bodies, but others, who also had been adequatelystimulated, showed no evidence of circulating cytotoxicantibodies. There was no simple correlation betweenclinical outcome and the presence or absence ofantibodies. Nevertheless, it is possible that in somepatients the antibodies collaborated in tumour rejectionwhilst in other cases they may have played an enhancingrole. We are now making a detailed study of the be-haviour of HL-A antibodies in trophoblastic neoplasia.We thank Dr. P. R. Golding and other clinicians who have

cooperated in the collection of these data; Prof. J. R. Batchelor,

Dr. J. Murray, and the National Institutes of Health for some ofthe antisera; and Mrs. 1. Mrazek for technical assistance.

Requests for reprints should be addressed to S. D. L., RoyalMarsden Hospital, London S.W.3.

REFERENCES

1. Bagshawe, K. D., Rawlins, G., Pike, M. C., Lawler, S. D. Lancet,1971, i, 553.

2. Allen, F., Amos, D. B., Batchelor, R., Bodmer, W., Ceppellini,R., Dausset, J., Engelfriet, C., Jeannet, M., Kissmeyer-Nielsen,F., Morris, P., Payne, R., Terasaki, P., van Rood, J. J., Walford,R., Zmijewski, C., Albert, E., Mattiuz, P., Mickey, M. R., Piazza,A. Joint Report of Fourth International HistocompatibilityWorkshop: Histocompatibility Testing, p. 17. Copenhagen, 1970.

3. Rapaport, F., Dausset, J. Science, 1970, 167, 1260.4. Lawler, S. D., Klouda, P. T., Hardisty, R. M., Till, M. M. Br. J.

Hœmat. 1971, 21, 595.5. Mogensen, B., Kissmeyer-Nielsen, F. Transpl. Proc. 1969, 1, 76.6. McDevitt, H. O., Benacerraf, B. Adv. Immun. 1969, p. 31.7. Ellman, L., Green, I., Benacerraf, B. Nature, 1970, 227, 1140.8. Kissmeyer-Nielsen, F., Jensen, K. B., Ferrara, G. B., Kjerbye,

K. E., Svejgaard, A. Transpl. Proc. (in the press).9. Kissmeyer-Nielsen, F., et al. ibid. 1971, 3, 1019.

10. Bagshawe, K. D. Lect. scient. Basis Med. 1970, p. 89.11. Elston, C. E. J. Path. 1969, 97, 261.12. Currie, G. A., van Doorninck, W., Bagshawe, K. D. Nature, 1968,

219, 191.13. Simmons, R. L., Lipschultz, M. L., Rios, A., Ray, P. K. Nature New

Biol. 1971, 231, 111.14. Van Rood, J. J. Personal communication.

MYDRIATIC DRUGS FOR ROUTINE

FUNDAL INSPECTION

A Reappraisal

S. E. SMITH

Department of Pharmacology,St. Thomas’s Hospital Medical School, London S.E.1

Summary The intensity and duration of mydria-

sis and cycloplegia induced by local

application to the eye of several drug preparationshave been studied in 5 healthy volunteer subjects. Theuse of 0·5% tropicamide, a powerful mydriatic andcycloplegic with rapid onset of action, is advocated forroutine fundal inspection. Cyclopentolate and hom-atropine are unsuitable because of their long durationof action and eucatropine because of its slight activity.A combination of eucatropine and phenylephrine is

effective, safe, and short-acting, provided that theaction of phenylephrine is reversed with thymoxamine.

Introduction

ROUTINE mydriasis for inspection of the fundus isoften unsatisfactory for several reasons. Firstly, it

exposes the patient to the risk of an attack of glaucomabecause of angle closure and/or pupil block. Secondly,the most effective mydriatics are also cycloplegic andthus paralyse accommodation for near vision, makingboth reading and binocular vision difficult. Thirdly,the drugs in common use are long-acting and theinconvenience to the patient caused by mydriasis andcycloplegia seems excessive. Fourthly, patients withdarkly pigmented irides usually respond poorly to anyof the drugs used.Though several drugs have been introduced over the

years, comparisons of their effectiveness and durationof action have been based largely on clinical impressions,with the result that most reference texts offer onlyloose descriptions of their action .2-5

838

The object of the present experiments was to com-pare the various available mydriatics by means of

objective measurements of mydriasis and cycloplegiaand to identify the most satisfactory one for routineclinical use.

Methods

Five subjects, healthy males and females aged 20-42years, voluntarily took part in the investigation. Pupildiameters were recorded photographically in duplicate, 6

using a Nikkormat reflex camera with 210 mm. lens at1-5 m. distance with flash illumination. General lightingin the room was artificial only and gave a constant readingof 4-8 on a Weston Master’ meter. The near-point ofaccommodation was measured in quadruplicate with a

sliding rule and converted into dioptres.7Three resting control measurements were taken at 5-

minute intervals, following which one drop (mean volume0-032 ml.) of mydriatic solution was placed in one conjunc-tival sac without pressure on the inner canthus. Furthermeasurements were taken at 5, 10, 20, and 40 minutes andat 1, 2, 4, 8, 24, and, if necessary, 48 hours after druginstillation. Mydriasis was expressed as the increment in

Time course of mydriasis and cycloplegia in five subjects (ver-tical lines indicate S.E. of mean) induced by:

a, cyclopentolate hydrochloride 0-5%.b, eucatropine hydrochloride 5 %.c, homatropine hydrobromide 0-5%.

pupil diameter in millimetres, and cycloplegia as thedecrement in accommodation power in dioptres. A meandecrement of 10-4 dioptres in the five subjects representedcomplete paralysis of accommodation.

All drugs were made up in physiological saline solution,adjusted to pH 6-5, and sterilised by filtration. Each of thefive subjects received every drug preparation.

Results

The mydriatic and cycloplegic effects of cyclo-pentolate hydrochloride, eucatropine hydrochloride,homatropine hydrobromide, tropicamide, phenyl-ephrine hydrochloride, and a mixture of eucatropinehydrochloride and phenylephrine hydrochloride are

shown in the accompanying figure. Important featuresof intensity of effect and recovery at 8 and 24 hoursafter instillation are indicated in the table. Cyclo-pentolate 0-5% was found to be the most powerfulmydriatic and cycloplegic agent, but its duration ofaction was long and neither pupil diameter nor

accommodation returned to normal until 48 hours afteradministration. Homatropine 0-5% had an action

d, phenylephrine hydrochloride 3%.e, tropicamide 0-5%.f, eucatropine hydrochloride 2% and phenylephrine hydro-

chloride 3%. At second arrow thymoxamine hydrochloride 0.5%administered.

839

MEAN INTENSITY AND DURATION OF MYDRIASIS AND CYCLOPLEGIA INDUCED BY DIFFERENT DRUG PREPARATIONS

about equal to that of cyclopentolate 0-1%, and fullrecovery took about 24 hours. Tropicamide 05%induced maximal mydriasis intermediate between

cyclopentolate 01% and 05%, but both onset andoffset of action were much faster; full recovery tookonly 8 hours. By comparison with cyclopentolate,tropicamide produced marginally less cycloplegia.Eucatropine at concentrations of 1%, 2%, and 5%

and phenylephrine 3% alone produced only moderatemydriasis of rather slow onset and offset, but a com-bined solution of the two drugs (eucatropine 2% plusphenylephrine 3%) produced a more marked effectthough the time-course of action was similar. Theoffset of action was accelerated by reversal with 1 dropof thymoxamine hydrochloride 0-5% administered1 hour after the first drug instillation.

Discussion

This investigation involved a study on only five

subjects and the results therefore provide little indi-cation of the likely variation in response in a largerpopulation of patients, particularly if it included somewith darkly pigmented irides. Nevertheless, the experi-ments reveal considerable differences between thedifferent mydriatics studied, and these differences arevalid because each drug preparation was applied tothe same subjects.

All the mydriatics studied here are weak bases, whoseionisation and thus lipid solubility and ability to crossthe conjunctiva are strongly pH-dependent. It there-fore seems likely that commercial preparations, for thestability of which a rather low pH is required, wouldbe somewhat less effective than those of pH 65 usedhere.

Clearly the use of cyclopentolate in particular, andprobably of homatropine, for fundal inspection aloneis quite unjustifiable. Their long duration of action, atleast in subjects with only moderate degrees of irispigmentation, imposes too much discomfort on the

use (

)mat

ifiahl

patient. Tropicamide, which does not seem to be usedso commonly, has been found to be just as effective amydriatic but, by contrast with the other drugs, itsrates of onset and offset of action were faster. Onlycyclopentolate 0-5% and tropicamide 0-5% inducedmydriasis quickly enough to allow fundal inspectionwithin 20 minutes of drug instillation-a reasonablerequirement in busy ophthalmic and other depart-ments. The advantage to the patient in using tropica-mide because of its rapid offset of action is obvious.The subjects in this study in fact complained of severediscomfort after cyclopentolate but hardly at all aftertropicamide. The routine use of tropicamide for fundalinspection is strongly advocated.A reasonable alternative has been found in the

combination of eucatropine and phenylephrine, thoughthe increased risk of glaucoma from pupil block duringrecovery from the effects of the phenylephrine makesreversal of its action with thymoxamine necessary. 8This combination was found to produce little or nodiscomfort in the subjects tested.

I thank the staff and postgraduate students of the PharmacyDepartment, St. Thomas’s Hospital, who made up the drugsolutions and acted as subjects; Mr. P. M. Dear for technicalassistance; and the donors of the drugs-Dr. J. M. Mc-Gilchrist, William R. Warner & Co. Ltd. (eucatropine andthymoxamine); Dr. J. M. Simister, W.B. Pharmaceuticals Ltd.(cyclopentolate); and Mr. D. J. Drain, Smith & NephewResearch Ltd. (tropicamide).

REFERENCES

1. Mapstone, R. Br. J. Ophthal. 1968, 52, 19.2. Innes, I. R., Nickerson, M. in The Pharmacological Basis of Thera-

peutics (edited by L. S. Goodman and A. Gilman). New York,1970.

3. Extra Pharmacopoeia: Martindale (edited by R. G. Todd). London,1967.

4. Lowenstein, O., Loewenfeld, I. E. in The Eye (edited by H. Davson).London, 1969.

5. Leopold, I. H. in Drugs of Choice 1970-71 (edited by W. Modell).St. Louis, 1970.

6. Sneddon, J. M., Turner, P. J. Physiol., Lond. 1967, 189, 20P.7. Herxheimer, A. Br. J. Pharmac. Chemother. 1958, 13, 184.8. Mapstone, R. Br. J. Ophthal. 1970, 54, 690.