Postgrad Med J: first published as 10.1136/pgmj.33.381.322 on 1 July 1957. Downloaded from 322 ANTITHYROID DRUGS By JAMES CROOKS, M.B., M.R.C.P.(Lond. and Ed.), FR.F.P.S.G. Senior Medical Registrar, University Department of Medicine, Gardiner Institute, Western Infirmary, Glasgow

Antithyroid drugs may be defined as chemical cluded that the perchlorate ion was the most agents which interfere with the synthesis, release potent inhibitor of the iodide-trapping mechanism or peripheral action of the thyroid hormone. of the thyroid. This was followed in 1954 by A large number of chemically unrelated com- successful clinical trials of potassium perchlorate pounds are covered by this definition, but it is in hyperthyroidism (Godley and Stanbury, I954; intended to deal only with those which have a place Morgans and Trotter, I954). in the practical management of hyperthyroidism. Iodide is the oldest of the antithyroid drugs and Such drugs can be divided into three categories: was the only one available for clinical use up to (I) Drugs preventing the synthesis of organic 1943. Although it had been occasionally used in iodine from inorganic iodide. hyperthyroidism during the early part of the 2oth (2) Drugs inhibiting the iodide trap of the century, its use only became popular following thyroid. Plummer's report of a successful clinical trial in (3) The iodide ion. 1923. Thiourea, the parent compound of most of the antithyroid drugs of the first group which are used Group I: Drugs Preventing the Iodination of therapeutically, was shown to be goitrogenic by Tyrosine Griesbach et al. (i941) and Kennedy (1942). The antithyroid drugs to be discussed in this The latter also showed that a derivative of thiourea group are methyl thiouracil, propyl thiouracil,by copyright. was responsible for the goitrogenic properties of methimazole and carbimazole. Brassica seeds. Astwood (I943) further confirmed the antithyroid activity of thiourea and its de- Mechanism of Action rivatives and in I944 published the first clinical While the exact mechanism of action of these report on thiourea and thiouracil in the treatment drugs is controversial, there is general agreement of hyperthyroidism. The toxic effects of these that they interfere with the iodination of the drugs soon diminished the initial enthusiasm for thyroid hormone precursors without affecting the antithyroid drug therapy, but this was revived by ability of the gland to concentrate the iodide ion. the introduction of 4-methyl thiouracil and The three current hypotheses given to explain this http://pmj.bmj.com/ 6-N-propyl thiouracil, which because of their action are: greater potency were effective in smaller doses and (i) They may inhibit the enzyme systems which had fewer side effects. Both drugs had extensive oxidize ionic to elemental iodine. clinical trials and are still widely used. Stanley (2) They may compete with iodide as a sub- and Astwood (I949) then demonstrated that strate for this oxidative enzyme. I - methyl - 2 - mercaptoimidazole (methimazole, (3) Elemental iodine may be reduced to the 'Mercazole,'' had iodide ion the cell of iodine

Tapazole') greater antithyroid depriving thyroid on September 26, 2021 by guest. Protected activity than any other known compound, while necessary for synthesis of the thyroid hormone. Bartels and Sjogren reported a successful clinical Whatever the exact machanism of action, the trial of the drug in 195I. Methimazole is widely level of circulating hormone falls, leading to in- used in the United States, but in this country creased production of thyrotropic hormone by 2 - carbethoxythio - I - methyl - glyoxaline (carbi- the pituitary with consequent thyroid hyperplasia. mazole, ' Neomercazole ') synthesized by Riming- ton and his associates (195I), is the more popular Structure-Activity Relationships of the imidazole derivatives. The antithyroid activity of these drugs has been The history of drugs inhibiting the iodide trap studied using radioiodine techniques (Stanley and of the thyroid began with the demonstration by Astwood, I947; Macgregor and Miller, 1953) Marine and his associates (1932) that acetonitrile and their potencies relative to thiouracil are shown and related compounds could produce thyroid in parentheses below: hyperplasia and that the effect was antagonized by Thiouracil (i), Methyl thiouracil (2), Propyl iodine., In I953, Wyngaarden et al., studied the thiouracil (0.75), Methimazole (Ioo), Carbimazole antithyroid activity of various anions and con- (10o). Postgrad Med J: first published as 10.1136/pgmj.33.381.322 on 1 July 1957. Downloaded from July 1957 CROOKS: Antithyroid Drugs 323 Indications for Use majority of cases treated with methyl thiouracil in In recent years the indications for the use of these this department become euthyroid in four to ten drugs in hyperthyroidism have become more weeks. The rate of control of the disease would clearly defined. Most authorities agree that appear to be related to the dose of each drug and young adults with small or moderately enlarged, not to the drug itself, for example, 30 mg. of diffuse goitres should be given a prolonged trial methimazole daily appears to control hyper- of antithyroid drugs. When the disease occurs thyrodism more rapidly than 300 mg. methyl during pregnancy or puberty this form of therapy thiouracil daily, but no more rapidly than 600 mg. allows more flexible control of thyroid function methyl thiouracil daily. Other factors can in- during a period when the metabolic demands on fluence the rate of control, for example, patients the thyroid are varying. Before partial thyroidec- with nodular glands tend to respond slowly, tomy is carried out toxicity should be controlled though ultimate control is satisfactory. In cases by treatment with one of these drugs. In some responding unexpectedly slowly or incompletely thyrocardiac subjects where rapid control of the cause is usually found to be one of the toxicity is required a short course of one of the following: drugs of this group can begin ten days after (i) Failure of the patient to take the prescribed radioiodine therapy. Finally, in patients where tablets or to space the doses properly. the diagnosis of thyrotoxicosis remains in doubt (ii) A course of iodine has preceded the after full investigation, the patient's reponse to antithyroid drug. antithyroid drug therapy should be observed. (iii) A larger dose of the drug is required. Dosage (iv) The diagnosis of hyperthyroidism is wrong. A large number of dosage schemes have been (2) Changes in Clinical Features. The most used. For example, Iversen (195I) gave 750 mg. persistant symptom is heat intolerance, while the methyl thiouracil daily for one to three months. last physical sign to disappear, excluding the reducing the amount until a dose of 125 mg. was goitre and the eye signs, is the tachycardia. When given daily on alternate days. On the other hand auricular fibrillation is present before treatmentby copyright. Himsworth (1948), in an attempt to avoid myxo- reversion to sinus rhythm is obtained in about edema, used an initial daily dose of 200 mg. one-third of cases within four months, but some methyl thiouracil with maintenance doses of 25 of those continue to have paroxysms of fibrillation to 0oo mg. The scheme of dosage for methyl although euthyroid. Failure and partial success in thiouracil used in this department, 600 mg. daily such cases is doubtless due to coincident coronary for two weeks, then 300 mg. daily until the patient artery disease. Weight increase tends to lag is euthyroid, followed by a maintenance dose of behind the disappearance of most of the other 50 to Ioo mg. daily, has been found to be entirely features. The goitre in most cases is unchanged satisfactory. at first, but occasionally may increase slightly. http://pmj.bmj.com/ In the case of propyl thiouracil approximately The bruit too persists. During maintenance the same dosage scheme may be used as for methyl therapy the gland size usually remains unchanged. thiouracil, though many workers have tended to However, in some cases it diminishes markedly use slightly lower doses. and this is associated with a greater possibility of The variation in schemes of dosage has persisted permanent remission. In this department regular with the newer drugs of this group, methimazole exophthalmometry readings have shown, in 15 and carbimazole. For both substances initial per cent. of subjects, a significant increase in doses of 20 to 40 mg. daily followed by main- exophthalmos, which tends to regress when on September 26, 2021 by guest. Protected tenance doses of 5 to I5 mg. daily usually produce treatment is stopped. This compares favourably satisfactory results, though in some cases a larger with the 75 per cent. increase after partial thyroid- initial dose is necessary. ectomy reported by Soley (1942). In arriving at the optimum dose, a balance has (3) Assessment of Response. The only satis- to be struck between the rate of control of symp- factory method of ascertaining response to toms and the incidence of toxic effects, the higher treatment is by clinical assessment, changes in the dose the more rapid being the rate of control objective signs being particularly valuable. The and the higher the incidence of toxic effects. basal metabolic rate, using Robertson and Reid's standards, usually falls within the normal range Response to Treatment one to three weeks before the patient is clinically (i) Rate of Control. The therapeutic response euthyroid. The serum cholesterol tends to rise to treatment as measured by the disappearance rapidly after two to three weeks of treatment, but of the symptoms and most of the signs of hyper- is not of value in deciding when the patient is thyroidism is uniformly satisfactory, and the euthyroid. Postgrad Med J: first published as 10.1136/pgmj.33.381.322 on 1 July 1957. Downloaded from 324 POSTGRADUATE MEDICAL JOURNAL July I957 Duration of Treatment, Remissions and Relapses living children showing no evidence of thyroid Those authorities who advocate long periods of disturbances. In most instances where a goitre continuous antithyroid drug therapy have theore- has been reported in an infant there is evidence of tical support for their view in that these drugs are overdosage and it is the practice in this department unlikely to shorten the course of the disease and to under-treat pregnant subjects since pregnancy that when prolonged remissions are obtained the itself is a hypermetabolic state. In three cases disease has spontaneously run its course. Iversen treated in this way during the past year, none of (I95I) for example, believes that treatment should the children had a goitre. The infants in such be carried on for six months or longer, while cases should not be breast fed in order to avoid the Dunlop and Rolland (I950) found a relapse rate of transmission of the antithyroid drug in the milk. 69 per cent. after treatment of under one year, The importance of the flexible control of thyro- compared with 33 per cent. over one year. On toxicosis in pregnancy made possible by the use of the other hand, Bartels (I950) and Goodwin et al. antithyroid drugs is underlined by the high (1954) maintain that the duration of treatment incidence of miscarriages and stillbirths in bears no relation to the length of the subsequent untreated cases. period of remission. Eight of twenty patients treated here with methyl thiouracil and kept on a Complications of Treatment maintenance dose for three months only, relapsed The first two drugs used, thiourea and thiouracil, within six months. Higher relapse rates have were extremely toxic and no drug of this group has been found in cases with post-operative recur- proved to be totally free from side-effects. The rences and nodular goitres (McCullagh et al., more recently introduced compounds are, however, 195 ) and one of the reasons for the great variation relatively safe therapeutic agents. of results obtained by different workers is likely There is a group of toxic effects which are very to be found in the type of cases treated. uncommon and which include nausea, vomiting, On the basis of the available evidence it would diarrhoea, jaundice and headache. Only the appear that at least a year's continuous therapy major toxic effects will be considered in detail and with an antithyroid drug is desirable except in they can be conveniently divided into sensitivityby copyright. patients with mild thyrotoxicosis and small diffuse reactions and depression of bone marrow elements. goitre, who might be given shorter courses, particularly if there is a diminution in the size-of Sensitivity Reactions the goitre during treatment. A skin rash is the most common manifestation and is usually urticarial although a variety of other Pre-operative Treatment types of rashes do occur. Another common It is generally agreed that antithyroid drugs of sensitivity reaction is drug fever. Much less this group should be used to prepare a thyrotoxic commonly lymph and salivary gland enlargement, patient for partial thyroidectomy. Some autho- arthralgia and conjunctivitis have been reported.http://pmj.bmj.com/ rities, however, believe that such pre-operative These reactions tend to occur between the tenth preparation is not always necessary and would and eighteenth days of treatment or within the confine it to severe cases (McCullagh and first 14 days after treatment has been resumed. Surridge, 1948; Pemberton et al., 1949). How- The reactions usually last two to three days and the ever, there has been a definite decrease in skin rashes generally respond to treatment with an operative mortality since the use of these drugs antihistaminic drug such as promethazine hydro- pre-operatively became general. In the two weeks chloride. The less severe reactions of this type do preceding operation iodine in the form of potas- not require the cessation of therapy, but since the on September 26, 2021 by guest. Protected sium iodide 30 mg. daily should be substituted incidence of subsequent bone-marrow depression in order to diminish the vascularity of the gland. is increased in such cases, it is probably advisable to change to an alternative therapeutic agent, such Treatment During Pregnancy as potassium perchlorate. There would seem to Goitre and hypothyroidism have been reported be little to choose between methyl thiouracil, to occur in the infants of mothers receiving anti- prophyl thiouracil and methimazole with respect thyroid drug therapy (Eaton, 1945; Ball and to the incidence of those reactions but with Morrison, 1948), but this is an uncommon event. carbimazole the incidence would appear to be less Astwood (I951) points out that if the dose of the (Burrell et al., I956). antithyroid drug has been adjusted to ensure a normal output of hormone by the maternal thyroid Agranulocytosis it is unlikely that the function of the foetal gland This is the only potentially lethal complication would be significantly depressed. He reported of treatment with this group of drugs. The 22 completed pregnancies in I9 patients, the 22 agranulocytosis may be of two types, the com- Postgrad Med J: first published as 10.1136/pgmj.33.381.322 on 1 July 1957. Downloaded from July 1957 CROOKS: Antithyroid Drugs 325 moner being impairment of white cell maturation Mechanism of Action at the pre-myelocyte or myelocyte level and, since The goitrogenic action of these anions can be the availability of penicillin, carrying a good overcome by the administration of iodide and this prognosis. The other, and graver type where the suggests they interfere with the uptake of inorganic maturation defect is at myeloblast level, can be iodide by the thyroid (Franklin et al., I944; differentiated by a marrow biopsy which should Wyngaarden et al., 1953). Furthermore, in- always be carried out in cases suspected of organic iodide already trapped by the thyroid is agranulocytosis. There seems to be little doubt discharged by the administration of the anions. that thiouracil produced this complication more The exact mechanism by which the anions act is often than any of the others and Moore (1946) unknown, but presumably if the circulating blood found an incidence of 2 per cent. in 9,281 cases. iodide level is high enough, the block can be Reviewing the results of other workers using overcome. methyl thiouracil, Barfred (I947) found that 9 of 604 cases developed agranulocytosis, an Potassium Perchlorate in the Treatment of incidence of 1.49 per cent. Bartels (1948) Thyrotoxicosis reporting 486 cases treated with propyl thiouracil The therapeutic value of perchlorate as an found two cases of agranulocytosis (0.4 per cent.), antithyroid drug has not been fully evaluated. but the initial dosage used for propyl thiouracil Weight for weight it is a less potent agent than had a less potent antithyroid action than methyl methyl thiouracil and using a dose of 200 mg. thiouracil and it is likely that the toxicity of the three times daily the rate of control is more two drugs are comparable. Using methimazole, variable than with methyl thiouracil, the euthyroid Bartels and Sjogren (195i) had one case of severe state being achieved in from 7 to 20 weeks. Some granulocytopenia in Ioo treated cases, and patients prove resistant to the drug, but in all but Doniach (I953) using carbimazole in 120 patients one of 52 cases adequate control was finally found no toxic effects and attributed this to a more achieved. It is possible that larger doses should release of the active ' thiol ' be used and our scheme is 200 gradual by hydrolysis present dosage mg. by copyright. group which it has in common with methimazole. five times daily. Patients are advised to avoid In this last series it is of interest that three patients eating fish, taking cough mixtures and other who had had toxic effects with methyl thiouracil medicines containing iodine, and to use uniodised had no complications on carbimazole. Burrell salt. The clinical response to treatment, apart et al. (1956) concluded that carbimazole was the from the rate of control, is similar to that produced least toxic of this group of drugs in a survey of by methyl thiouracil. 1,046 patients and a review of the literature, but As might be expected from the relatively simple eight cases of agranulocytosis have already been the is the least toxic in the United States and this perchlorate molecule, drug reported country of the antithyroid drugs with therapeutic appli- http://pmj.bmj.com/ during the use of this drug. cations. Of the 52 cases only one complained of In the practical management of the patient most dyspepsia while taking the drug and this disap- authorities now agree that there is little yalue in peared although therapy was continued. Godley carrying out serial white blood counts at weekly and Stanbury (1954) reported one case of dyspepsia or longer intervals because agranulocytosis can and one case in whom a duodenal ulcer perforated, occur so rapidly. Close, but not obsessive watch in a series of 24 patients treated with perchlorate. should be kept over the patient under treatment, Morgans and Trotter (I954) treated I08 cases with especially during the first eight weeks, when the this drug and the only side effects observed were on September 26, 2021 by guest. Protected incidence of toxic effects is highest. gastro-intestinal symptoms in two patients, one of whom had a diaphragmatic hernia and the other Group II: Drugs Inhibiting the Iodide Trap a peptic ulcer. There is no evidence that perch- of the Thyroid lorate causes hypersensitivity reactions, or has any The anions which possess a significant goitro- depressant effect on the bone marrow. It is, genic, action are, in order of decreasing activity, therefore, a valuable alternative in cases who have perchlorate, thiocyanate and nitrate. Thiocyanate had toxic effects caused by the drugs of Group I. and nitrate have no therapeutic importance as Potassium perchlorate is probably unsuitable antithyroid drugs because of their toxicity. for the treatment of patients preceding partial Potassium perchlorate has, however, been used thyroidectomy since Godley and Stanbury (I954) successfully in the treatment of thyrotoxicosis and found that the glands were more vascular than much of the description which follows is based on would be expected with thiourea derivatives and personal experience in over 50 cases treated during iodide. The effect of perchlorate in the pregnant the past i8 months. thyrotoxic subject has not so far been reported, but Postgrad Med J: first published as 10.1136/pgmj.33.381.322 on 1 July 1957. Downloaded from 326 POSTGRADUATE MEDICAL JOURNAL July I957 in one case treated here, the infant showed no the flexibility of control of thyroid function which thyroid abnormality at birth. can be achieved by careful prescribing. This is of particular value in those states where the metabolic Group III: The Iodide Ion demands on the thyroid are fluctuating, for It is intended to discuss iodothiouracil along example, in pregnancy and at puberty. This with the iodide ion, as they behave similarly. room for therapeutic manoeuvre is also of value in cases with marked exophthalmos where exacerba- Mechanism of Action tion following surgery may be feared and where The iodide ion when given in therapeutic doses the indications for radioiodine therapy may not be results in involution of the gland and an increase in fulfilled. .The absence of the risk of permanent colloid storage even in the presence of a goitrogen. myxoedema is another advantage not shared by It also leads to a reduction in the release of thyroid surgery and radioiodine therapy. That this form hormone (Ansell and Miller, I952). However, of treatment can be given without admission to suppression of thyroxine synthesis and release hospital may be of considerable economic ad- would appear to be evanescent (Wolff et al., 1949). vantage to the patient and its general availability It is not clear whether iodide acts directly on the is of special value in areas where there is no thyroid or by the inhibition of the pituitary skilled thyroid surgeon or centre equipped to secretion of thyrotropic hormone. carry out radioiodine therapy. The main disadvantage of these drugs is the long Iodide and Iodothiouracil in the Treatment of duration of therapy. Adequate and safe control Thyrotoxicosis can, however, be achieved by clinical assessment The symptomatic response of thyrotoxicosis to alone, fairly frequently in the first two months, the administration of iodide as potassium iodide and at much longer intervals subsequently. or Lugol's iodine, is rapid and has been used as However, even if this is done and the incon- a therapeutic test. The maximum effect is venience of long term therapy minimised, the obtained in o1 to 15 days but following this escape personality of some patients makes them unsuitable from control is common and there may even be an for this form of treatment. With the introductionby copyright. exacerbation of symptoms. It is mainly used in of carbimazole and perchlorate, the hazards of the preparation of patients for partial thyroid- therapy are comparable to that of the best surgery ectomy and it should be given for two weeks and certainly less than that of inferior surgery. before operation either with or following one of the The overall relapse rate of 50 per cent. even after drugs of Group I. When rapid control of toxicity long term therapy with antithyroid drugs has been is required after radioiodine therapy a course of a great disappointment, especially since the iodide lasting three weeks can be started ten days possibility of permanent remission cannot be after the radioiodine has been given. predicted before treatment is begun. Opinions are divided concerning the place of In conclusion, the effective use of antithyroid-http://pmj.bmj.com/ 5-iodo-2-thiouracil (iodothiouracil) in therapy, drugs demands the selection of suitable patients, but Williams et al. (I949) came to the conclusion careful clinical assessment of progress and ad- that the response to this drug was more like that justment of dosage, and above all, patience. observed with iodide than with thiouracil. The recommended initial dose of I50 mg. daily only Acknowledgement contains 75 mg. of thiouracil. It is favoured by I wish to thank Professor E. J. Wayne for some for but criticism and advice the

surgeons pre-operative preparation, helpful regarding on September 26, 2021 by guest. Protected like iodide, has no place in the long-term treatment preparation of this paper. of hyperthyroidism. BIBLIOGRAPHY an Action as a ANSELL, G., and MILLER, H. (1952), Lancet, ii, 5. Drugs having Antithyroid Side-effect ASTWOOD, E. B. (1943), J. Pharmacol., 78, 79. A number of with ASTWOOD, E. B. (I944), J. clin. Endocr., 4, 229. drugs therapeutic applications ASTWOOD, E. B. (I95I), Ibid., II, 1045. in other fields have also an antithyroid action. BALL, K. P., and MORRISON, B. (1948), Proc. roy. Soc. Med., 41, I95. Important examples of such goitrogens are para- BARFRED, A. (1947), Amer. J. med. Sci., 214, 349. acid and BARTELS, E. C. (1950), 'Progress in Clinical Endocrinology,' aminosalicylic (Macgregor Somner, p. 87, Heinemann, London. 1954), resorcinol (Bull and Fraser, 1951), and BARTELS, E. C. (1948), J din. Endocr., 8, 766. BARTELS, E. C., and SJOGREN, R. W. (I95I), Ibid., II, 1057, cobalt (Kriss et al., I955). BULL, G. M., and FRASER, R. (I95I), Lancet, i, 851. BURRELL, C. D., FRASER, R., and DONIACH, D. (1956), Brit. med. J., i, 1453. The Advantages and Disadvantages of Antithyroid DONIACH, D. (I953), Lancet, i, 873. DUNLOP, D. M., and ROLLAND, C. F. (1950), Proc. roy. Soc. Drugs Med., 43, 937. The most important advantage possessed by EATON, J. C. (1945), Lancet, i, I7I. these drugs in the treatment of thyrotoxicosis, is Continued on page 332 Postgrad Med J: first published as 10.1136/pgmj.33.381.322 on 1 July 1957. Downloaded from 332 POSTGRADUATE MEDICAL JOURNAL July 1957 that liver changes usually accompanied the con- Surgical Progress 1955 for the blocks which appear dition (Cooke and Luxton, 1955) and a larger in this article. confirmatory series appeared from the Cleveland Clinic (Skillern, I956) last year. The raised y globulin levels, their delayed return to normal BIBLIOGRAPHY after thyroidectomy and the infiltration of the CLARK, D. E., and NELSEN, T. S. (I953), Jour. Amer. med. Ass., with cells and COOKE,R. T., and WILDER, E. (I954), Lancet i, 984. thyroid lymphocytes, plasma lym- COOKE, R. T., and LUXTON, R. W. (955), Ibd., i, 968. phoid tissue prompted Roitt et al. (1956) to look CRILE, G., Jr. (I948), Ann. Surg., 127, 640. CRILE G., Jr., and FISHER, E. R. (I953), Cancer, 6, 57. - for an immune response. They have reported a CRILE, G., Jr., and HAZARD, J. B. (i95I), J. clin. Endocr., precipitin reaction of serum with extract of human 1, 1123. thyroid gland and they postulate that it parallels CRILE, G., Jr., and RUMSEY, E. W. (950o), J. Amer. med. Ass., DE QUERAIN F. (1904), Mitt. Grenzgeb. Med. Chir., 2, Supp., the destruction of the patient's own thyroid, and DE QUERVAI, F., and GIORDANENGO, G. (I93S), bid., the an 44 538 especially colloid, by auto-antibody. FRASER R., and HARRISON, R.J. (I952), Lancet, i, 382. It might well be expected that in subacute HAMLIN, E., Jr., and VICKERY, A L. (956), New Eng. J. a Med., 24, 742. thyroiditis similar positive flocculation test would HAZARD, J. B. (955) Amer. din. Path., 25, 399. be obtained and W. R. Trotter and D. Doniach in- HEPTINSTALL, R. I., and..EASTCOTT, H. H. G. (i953). Brit. j. Surg., 41, 471. form me that they have obtained a positive reaction KAHN, J., SPRITZLER, R. J., and SHECTOR, W. E. (g193), in the Ann. intern. Med., 39, I29. serum of two patients with this disease. KING, B. T., and ROSELLINI, L. J. (x94s), J. Amer. med. Ass., For those who are interested in recent advances 12, , 267. LASSER, R. P. (93), Ibid., 152, 133. in problems of immunology and thyroid disease LINDSAY, S., DAILEY, M. E., FRIEDLANDER, J., YEE, G., is and SOLEY, M. H. (1952) .. din. Endocr., 12, 1578; also there an excellent leading article in the Lancet, Trans. Amer. Ass. Goiter (1952), pp. 384-411. Vol. I, p. which reviews the LINDSAY, S., and DAILEY, M. E. (I954), Surg. Gynec. Obstet., May 25, 1957, 1075, 98, 197 whole subject up to the present time. This has PERLOFF, W. H. (x9S6), . clin. Endocr., x6, 542. now become one of the frontiers ROBBINS J., RALL, J. E., TRUNNELL, J. B., and RAWSON, rapidly expanding R.W. (i95x) Ibid.,Ix,txo6. of ROITT, I. M., bONIACH, D., CAMPBELL, P. N., and HUD- thyroid investigation. SON, R.V. (I956) Lancet, ii, 820. SKILLERN, P. G., ChILE, G., McCULLAGH, P., HAZARD,

J. B., LEWIS, L. A., and BROWN, H. (i956), J. din. Endoer.,by copyright. Acknowledgment 6, 35. We are indebted to the publishers of British TAYLOR,T S. (t955), 'Brit. Surg. Progress,' pp. 148-x60, London. RUTHIN CASTLE, NORTH WALES A Clinic for the diagnosis and treatment of Internal Diseases Mental or Infectious Diseases). The (except http://pmj.bmj.com/ Clinic is provided with a staff of doctors, technicians and nurses. The surroundings are beautiful. The climate is mild. There is central heating throughout. The annual rainfall is 30.5 inches, that is, less than the average for England. The Fees are inclusive and vary according to the room occupied. For particulars apply to THE SECRETARY. Ruthin Castle, North Wales. Telegrams: Caetle. Ruthi. Telpomes: Ruchi 66 on September 26, 2021 by guest. Protected

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