939

analgesic drugs continue to be developed, but the problemremains of the patient who demonstrates algic behaviourin the absence of organic disease and in whom analgesicdrugs are ineffective. It may be that psychotropic drugssuch as the dibenzazepine derivatives of the imipraminetype will be useful here, since W. Theobald showedthat they reduce the reaction to pain in animals, particularlyat the higher levels of the integrated response.

If pain is not a specific sensation producing specificresponses it is not surprising, as H. K. Beecher pointedout, that in experimental pain studies in man no simplerelation is found between the stimulus and the subjectiveresponse. This may explain why tests for analgesic drugsin man are difficult to devise. Although differences can bedetected between a narcotic analgesic drug like morphineand a placebo in an ischaemic-type pain, Beecher felt thatthere is at present no satisfactory method for testingnon-narcotic analgesics. Clearly, the treatment of painentails the treatment of the whole man and not simplythe suppression of a simple response to a specific stimulus.

IODIDE GOITRE

NON-TOXic goitre is probably always due to deficientsynthesis of thyroid hormone, low levels of which stimu-late thyroid-stimulating-hormone (T.S.H.) production. Byincreasing the functional activity and tissue mass of thethyroid gland T.s.H. may compensate for a partial failure ofhormone production; if compensation is inadequate myx-cedema develops. The commonest cause of goitre is iodinedeficiency, but inborn errors of hormone synthesis and avariety of goitrogens may also be responsible. Para-

doxically, iodine excess is goitrogenic and even causesmyxoedema in a few individuals 1: it is not clear howiodine produces goitre or why it should do so only in somepeople. Excess thyroidal iodide inhibits synthesis of

thyroid hormone 2 and results in a vicious circle ofincreased T.S.H. secretion and consequent increase iniodine uptake by the gland.4 Most subjects respond to achronic iodide load by a non-T.s.H.-mediated reduction inthyroid trapping, which minimises the inhibition of syn-thesis.5 In those who do get goitre, discharge of inorganiciodide from the gland by thiocyanate or perchlorate can bedemonstrated 7 suggesting that a failure of suchadaptation leads to the thyroid enlargement. Thyroidradioiodine uptake is variable, but often low. Wheniodide is withdrawn the radioiodine uptake reaches

abnormally high levels, and iodide is not discharged bythiocyanate or perchlorate, while the clinical picture ofmyxoedema regresses.l 6 It seems that, as the fallingblood-iodide levels are reflected in those in the

thyroid gland, iodide is again incorporated into thyroidhormone.On p. 922, Dr. Murray and Dr. Stewart report a

study of two patients with iodide goitre, one of whom washypothyroid. Both had low neck uptake of radioiodine.The findings we have mentioned were confirmed. The ex-pected high blood-levels of T.S.H. were demonstrated, and1. Morgans, M. E., Trotter, W. R. Lancet, 1953, ii, 1335.2. Wolff, J., Chaikoff, I. L. Endocrinology. 1948, 43, 174.3. Stanley, M. M. J. clin. Endocr. Metab. 1949, 9, 941.4. Paris, J., McConahey, W. M., Owen, C. A., Woolner, L. B., Bahn, R. C.,

ibid, 1960, 20, 57.5. Braverman, L. E., Ingbar, S. H. J. clin. Invest. 1963, 42, 1216.6. Openheimer, J. H., McPherson, H. T. Am. J. Med. 1961, 30, 218.7. Wayne, E. J., Koutras, D. A., Alexander, W. D. Clinical Aspects of

Iodine Metabolism. Oxford, 1964.

these fell during the recovery phase as thyroid-hormoneoutput increased. In spite of this fall, triiodothyroninesuppressed the high radioiodine uptake in both patients;and Dr. Murray and Dr. Stewart conclude that, since tri-iodothyronine acts by suppression of T.S.H. production,the high thyroid iodine uptake during recovery is T.S.H.-mediated. Previous evidence on this point has beenconflicting,8 9 probably because, to produce the fulleffect, administration of triiodothyronine may have to becontinued for longer than usual.The goitre of iodine excess, therefore, seems to be the

result of inhibition of synthesis of thyroid hormone byhigh levels of intrathyroidal inorganic iodide. Most sub-jects respond to prolonged iodide load by reduction iniodine uptake by the thyroid gland, and only in the com-paratively few in whom this compensation fails does

goitre develop.

PROPRANOLOL

SEVERAL drugs have lately been introduced which

specifically block j3-adrenergic receptors.10 Dichloroiso-

prenaline 11 had too much intrinsic adrenergic stimu-

lating ability to be of clinical value, and the use of

pronethalol was restricted because it was found to pro-duce tumours in mice after long administration. 12 Pro-

pranolol, however, has little, if any, intrinsic adrenergicactivity, and it has not been shown to be carcinogenic.It is a potent blocker of (3-adrenergic receptors whichhas already proved of great interest, not only in thetreatment of several conditions but also as a valuable

pharmacological tool in the study of autonomic activityin animals and man; and at least two international

symposia 13 14 have been devoted to this drug.Propranolol reduces the rate and force of contraction

of the heart by blocking its sympathetic drive, and whenthis drive has already been removed, propranolol has noeffect. 15 16 This action may be the basis for its effect in

angina pectoris,17-21 in which propranolol improves theexercise tolerance of most patients. Although it reducescoronary blood-flow, it also reduces myocardial oxygenrequirements during exercise, and this is probably respon-sible for its therapeutic effect. Nevertheless, propranololmust be used with caution in patients with anginabecause of the risk of cardiac failure caused by depressionof the myocardium. In a letter on p. 955, Dr. Parratt,referring to other possible mechanisms of anti-anginaldrugs, mentions the possibility that propranolol induceslocal anxsthesia of cardiac and coronary pain receptors.

In conjunction with an x-receptor-blocking drug, suchas phenoxybenzamine, propranolol has been used inthe preoperative and operative management of patients8. Harrison, M. T., Alexander, W. D., Harden, R.McG. Lancet, 1963, i,

1238.9. Dimitriadou, A., Fraser, R. Proc. R. Soc. Med. 1961, 54, 345.

10. Lancet, 1966, ii, 1309.11. Powell, C. E., Slater, I. H. J. Pharmac. exp. Therap. 1958, 122, 480.12. Alcock, S. J., Bond, P. A. Proc. Eur. Soc. Study Drug Toxicity, 1964,

4, 30.13. Am. J. Cardiol. 1966, 18, 303-487.14. Cardiologia, 1966, 49, suppl. 2.15. Shanks, R. G. Am. J. Cardiol. 1966, 18, 308.16. Shanks, R. G. Cardiologia, 1966, 49, suppl. 2, 1.17. Wolfson, S., Heinle, R. A., Herman, M. V., Kemp, H. G., Sullivan,

J. M., Gorlin, R. Am. J. Cardiol. 1966, 18, 345.18. Hamer, J., Sowton, E. ibid. p. 354.19. Grant, R. H. E., Keelan, P., Kernohan, R. J., Leonard, J. C., Nance-

kievill, L., Sinclair, K. ibid. p. 361.20. Gillam, P. M. S., Prichard, B. N. C. ibid. p. 366.21. Rabkin, R., Stables, D. P., Levin, N. W., Suzman, M. M. ibid. p. 370.

940

with phaeochromocytoma.22 23 They prevent overstimu-lation of P-receptors in the heart by circulating cate-

cholamines, which might otherwise produce arrhythmias,and of a-receptors in the arteriolar bed, which might leadto hypertension. The role of propranolol in the treatmentof essential hypertension is not yet decided. WhileRichards 24 found only a modest decrease in arterial

pressure, others 25 have noted more impressive hypo-tensive action. Paterson and Dollery 21 found that theeffects of 240 mg. of propranolol in mild hypertensionwere indistinguishable from those of hydrochlorothiazide.The mechanism of this action is uncertain, but it is

probably secondary to its cardiac effects.Cardiac arrhythmias, both atrial and ventricular, have

been successfully treated with propranolol 27-33 ; and it isparticularly valuable in the treatment of digitalis-inducedarrhythmias-an action which may be due to its quinidine-like properties rather than to P-adrenergic blockade. Thedextro-isomer of pronethalol is effective against arrhyth-mias, but it has very little &bgr;-blocking activity comparedwith the racemic mixture. In a similar way, the dextro-isomer of propranolol is at least ten times less active as a&bgr;-blocking agent than racemic propranolol (the com-mercially available form),34 and it will be of interest tolearn whether it too has considerable anti-arrhythmicactivity. The action of propranolol in arrhythmia sug-gested a possible application in the prophylactic treat-ment of patients with myocardial infarction, but con-trolled trials have failed to confirm this.35

P-adrenergic activity seems to be important in the

hyperkinetic cardiac manifestations of thyrotoxicosis andanxiety, and in these conditions too propranolol may beuseful. 36-3 9 But it is important to remember, sinceasthma may be triggered by anxiety, that propranolol iscontraindicated in asthmatic patients,40 because broncho-dilatation is mediated by &bgr;-receptors and their blockadeproduces bronchoconstriction.The properties of propranolol extend further than the

heart and bronchi. Marsden and Owen 41 have shownthat it reduces spontaneous parkinsonian tremor andprevents the increase in tremor produced by an injec-tion of adrenaline. These observations raise importantquestions on the role of adrenergic activity in mainten-ance of normal control of skeletal muscle.

More recently, evidence had been accumulating thatpropranolol may interfere with the response of plasmaglucose and free fatty acids during insulin-tolerancetests. It may, therefore, potentiate the action of insulin22. Prichard, B. N. C., Ross, E. J. ibid. p. 394.23. Ross, E. J., Prichard, B. N. C., Kaufman, L., Robertson, A. I. G.,

Harries, B. J. Br. med. J. 1967, 1, 191.24. Richards, F. A. Am. J. Cardiol. 1966, 18, 384.25. Prichard, B. N. C., Gillam, P. M. S. ibid. p. 387.26. Paterson, J. W., Dollery, C. T. Lancet, 1966, ii, 1148.27. Bath, J. C. J. L. Am. J. Cardiol. 1966, 18, 415.28. Szekely, P., Jackson, F., Wynne, N. A., Vohra, J. K., Batson, G. A.,

Dow, W. I. M. ibid. p. 426.29. Harris, A. ibid. p. 431.30. Schamroth, L. ibid. p. 438.31. Stock, J. P. P. ibid. p. 444.32. Turner, J. R. B. ibid. p. 450.33. Reutter, F. Cardiologia, 49, suppl. 2, 83.34. Shanks, R. G. Br. J. Pharmac. Chemother. 1967, 29, 204.35. Lancet, 1966, ii, 950.36. Turner, P., Granville-Grossman, K. L., Smart, J. V. ibid. 1965, ii,

1316.37. Howitt, G., Rowlands, D. ibid. 1966, i, 628.38. Granville-Grossman, K. L., Turner, P. ibid. p. 788.39. Bollinger, A., Gander, M., Pylkkanen, P. O., Forster, G. Cardiologia,

1966, 49, suppl. 2, 68.40. McNeill, R. S. Lancet, 1964, ii, 1101.41. Marsden, C. D., Owen, D. A. L. ibid. 1965, ii, 1259.

and oral hypoglycaemic agents 42 43 and may be all themore dangerous because the usual hypoglycaemic signsassociated with catecholamine liberation, such as sweat-ing and tachycardia, may be abolished. Nevertheless,such an action may open the way to a better understand-

ing of the receptor sites which are concerned in glyco-genolysis and free-fatty-acid mobilisation. Indeed,though its therapeutic role may not be great, propranololhas already provided much information on the role of(3-adrenergic activity in many diseases. Further lines ofresearch are already indicated in its use in the eye toelucidate the place of a and receptors in lid-retractionand pupil responses 44; in its inhibition of the decreasein eosinophil-count produced by adrenaline 45; and inthe changes in psychological testing induced by adrena-line alone and with propranolol.46 There is also littledoubt that the drug will help in the more detailedevaluation of the factors concerned in the control ofcardiovascular function both at rest and in response toexercise.

WOUND REPAIR: SUTURES OR STRIPS?

IN animals, response to injury has two components.First there is an alteration in metabolism (perhapsmediated hormonally), in which the chief changes are

loss of nitrogen and potassium and retention of sodiumand water. This systemic response was first observed bySir David Cuthbertson 47 in Glasgow in 1930 and hassince been investigated by Moore 48 in the U.S.A. and byWilkinson 49 and Lequesne 50 in Great Britain. Thoughthe significance of these metabolic changes is not under-stood, presumably they are concerned with repair. Thesecond element in the response is the repair of the wounditself, which in many respects resembles neoplasia, withactive cell-division and the laying down of new tissue.The local process has been extensively studied both inthe United States 51 52 and in Great Britain.53-56 Ordmanand Gillman 57 have reviewed in great detail the eventswhich occur in and around incisional wounds in the skinof pigs (which is believed to resemble human skin moreclosely than does that of other mammals). They empha-sise the very rapid migration of epithelium over thenarrow incision so that epithelial cover is achieved oftenwithin 24 hours. The epithelium creeps below the scaband often moves down into the wound itself, forming akind of spur. Once the epithelial sheets from eitherside have united, they develop the structural features ofadult epidermis, with keratinisation and differentiation.Rapid epithelial cover is, of course, valuable as an

effective means of preventing infection, for most patho-42. Abramson, E. A., Arky, R. A., Woeber, K. A. ibid. 1966, ii, 1386.43. Kotler, M. N., Berman, L., Rubenstein, A. H. ibid. p. 1389.44. Sneddon, J. M., Turner, P. ibid. p. 525.45. Braunsteiner, H., Dienstl, F. Klin. Wschr. 1967, 45, 274.46. Fejér, A. G. Lancet, 1966, ii, 750.47. Cuthbertson, D. P. Biochem. J. 1930, 24, 1244.48. Moore, F. D. The Metabolic Care of Surgical Patients. Philadelphia,

1959.49. Wilkinson, A. W. Body Fluids in Surgery. Edinburgh, 1955.50. Lequesne, L. Fluid Balance and Surgical Practice. London, 1954.51. Dunphy, J. E. Ann. R. Coll. Surg. 1960, 26, 69.52. Grillo, H. S., Watts, G. H., Gross, J. Ann. Surg. 1958, 148, 145.53. Abercrombie, M., James, D. W. J. Embryol. exp. Morph. 1957, 5, 171.54. Slome, D. Wound Healing. London, 1961.55. Bullough, W. S. in Wound Healing (edited by Sir Charles Illingworth).

London, 1966.56. Douglas, D. M. Wound Healing and Management. Edinburgh, 1963.57. Ordman, L. J., Gillman, T. Archs Surg., Chicago, 1966, 93, 857, 883,

911.