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300 Postgrad Med J: first published as 10.1136/pgmj.34.392.300 on 1 June 1958. Downloaded from

THE PHARMACOLOGY OF , () AND THEIR NEW ANALOGUES By OLIVER GARROD, M.D., M.R.C.P. Physician, Barnet General Hospital; late Research Fellow, Middlesex Hospital

In man the essential functions of the adrenal (Compound.B). Though it is the cortex stem from at least two , cortisol predominant in a number of (hydrocortisone) and , these differing mammalian species, in man it is of little importance in their quality of action, mode of secretory for only small amounts are secreted (about i mg. regulation, and probable site of production within a day) (Migeon et al., 1956). the gland. The adrenal sex hormones are of re- latively minor physiological importance and will The Secretion and of Cortisol not be considered here. The rate of cortisol secretion is governed by The new synthetic analogues of cortisol are best the level of circulating corticotrophin. Under assessed in relation to the essential duality of quiescent conditions the pituitary corticotrophin function of the as revealed by the output varies inversely with the concentration of actions of its two principal hormones. The first cortisol in the blood, resulting in a fairly steady function is concerned with a number of homoeo- rate of cortisol secretion from day to day. Over-copyright. static processes and with resistance to and riding this basal ' feedback' regulation is the is served by the secretion of cortisol. In the body stress reaction whereby additional corticotrophin cortisol is reversibly interconvertible with corti- is released, probably in response to stimulating sone and is probably the active form of the hor- emanating from the mone. Cortisol and cortisone, with their almost and reaching the adenohypophysis by portal identical actions, are called for venous pathways. Under such extreme stimu- their effects on metabolism. Though lation cortisol secretion may rise to about 250 mg. Ingle (1950) has likened use of the word gluco- a day. corticoid for these to describing an The capacity to suppress corticotrophin secre-' http://pmj.bmj.com/ elephant by the shape of its tail, yet it remains a tion is common to all known glucocorticoids, useful generic term to cover all those diverse natural and synthetic, when given in doses which actions of cortisol and its analogues which seem to 'equal or exceed in equivalence the normal cortisol be inseparably linked with their carbohydrate secretion of about 20 mg. a day. By only partially effects. suppressing corticotrophin secretion smaller doses The second or function of the than these merely replace an equivalent amount of adrenal cortex is concerned with the regulation of endogenous cortisol; hence they are usually in- and balance, and depends effective therapeutically in patients with intact on October 1, 2021 by guest. Protected largely on the secretion of aldosterone. A similar adrenal function. In effective doses they cause but less potent mineralocorticoid is desoxycorti- reversible atrophy of the , whence costerone (DOC) which, though easily synthesized cortisol is mainly derived, which lasts for and used therapeutically as the acetate (DOCA), is many days after treatment has been stopped; secreted only in small amounts by the adrenal hence the importance of slowly tapering off the cortex. Further to their glucocorticoid properties, dose over one to several weeks according to the cortisol and cortisone also have a weak mineralo- duration of the preceeding treatment. If this corticoid activity, which assumes an increasing precaution be neglected the patient is exposed to importance when they are being produced in the risks of an acute when faced excess as in Cushing's syndrome, or administered during this period with severe stress, such as in large doses pneumonia or surgical trauma. Intermediate in quality of action between Likewise, during even moderately intensive cortisolVand aldosterone, but much less potent, is glucocorticoid therapy the patient cannot step up Yune 1958 GARROD: Pharmacology of Cortisone, Cortisol and their New Analogues 301 Postgrad Med J: first published as 10.1136/pgmj.34.392.300 on 1 June 1958. Downloaded from his cortisol secretion in emergency, and must then Biochemically these steroids influence the be protected by raising the dosage, if needs beto metabolism of , , carbohydrate, purines, the equivalent of 200 mg. of cortisone a day. electrolytes and water, and exert a direct calori- Independent of corticotrophic control there are genic action (Evans et al., 1957). In excess they wide diurnal variations in the rate of cortisol inhibit tissue and body growth, influence secretion which falls to low levels in the early the local and general response to infection, and morning hours before rising to a sustained peak at raise the body's resistance to stress; they help in around 5 or 6 a.m. Whether this phenomenon maintaining normal functions of the brain, should be allowed to influence the timing and dis- and circulation, and stimulate the gastric tribution of dosage when steroids are being given secretions. in small amounts has yet to be decided. Radioisotope studies have been of great value in Metabolic Effects elucidating the metabolism of cortisol (Migeon et al., 1956; Peterson and Wyngaarden, I955 and Glucocorticoids stimulate protein katabolism, 1956). Within the body the free has a thereby increasing nitrogen output and half life of about I.4 hours, and is reduced to formation (). In excess this leads derivatives such as , tetra- to muscle wasting, weakening of connective and hydrocortisone, and allotetrahydrocortisol (Bush vascular tissue, and the formation of and Willoughby, 1957), which combine in the wide purple striae. Aminoacid, creatine and uric with glycuronic acid to form glucuronides. acid excretion are increased. This last effect may Together these metabolites account for about 36 per be useful when treating acute gout, if not neu- cent. ofthe secreted and are excreted in the tralised by increased uric acid formation. urine where they can be measured as 17-hydroxy- The complex actions of glucocorticoids on car- corticoids (Reddy, I954), or, together with the bohydrate metabolism can be only partly accounted cortol and cortolone derivatives, as I7-ketogenic for by increased gluconeogenesis, for these steroids (Norymberski et al., 1953). Only about steroids also antagonize , promote 4 per cent. of the metabolites of cortisol can be storage, and lower the renal glucose threshold (Fourman et al., 1950). Large doses diminish accounted for as i7-ketosteroids, and about O.I5 copyright. per cent. of the hormone is excreted in the free glucose tolerance and cause mild glycosuria. state (Wade and Kellie, 1957). Impaired liver Frank seldom results (less than i per cent. function and myxoedema retard the conjugation, treated cases), and when it does is usually un- and renal failure the excretion, of these meta- accompanied by ketonuria (Brookman et al., bolites, hyperthyroidism having the opposite effect 1953). Fat mobilization and ketone combustion (Peterson et al., 1955). By means of radio-isotope are accelerated, and starvation ketosis inhibited studies it has been shown that the high plasma (Kinsell et al., 195I). A centripetal redistribution i7-hydroxycorticoid levels of late pregnancy are of body fat contributes towards the Cushingoid due to delayed metabolism, and not increased habitus which is a feature of steroid overdosage. http://pmj.bmj.com/ secretion, of cortisol (Migeon et al., 1957). Water and Electrolytes Physiological and Pharmacological Actions The complicated actions of cortisol and corti- of Cortisol sone on water and electrolyte metabolism, though Despite the protean activities of cortisol, little is mainly located within the , are not confined known about the biochemical processes which to this organ, for these steroids have been shown to mediate these effects within the cells, though there increase the extracellular fluid volume inde- on October 1, 2021 by guest. Protected is evidence that a number of systems are pendently of changes in, external water and involved (Ingle, I950). To quote Ingle (I950): electrolyte balance (Levitt and Bader, 195I). They ' The consequences of cortical hormone action also diminish the sodium : potassium ratio in spread through the organism in a manner re- sweat and saliva (Conn and Fajans, 1952). miniscent of the waves caused by the impact of a Acting as weak , cortisol and stone in a pool of water, but the point of impact of cortisone increase the renal tubular reabsorption the hormone remains unknown for the present.' of sodium, resulting in fluid retention. Often this In most instances cortisol would seem to assist effect is only transient and followed by diuresis; rather than initiate the processes which it affects frank oedema seldom follows unless other factors (Sayers, 1950). Except for the electrolyte effects, are present. Paradoxically, and notably in the actions of cortisol are common to all the Addisonian patients receiving DOCA, these known glucocorticoids, whether natural or syn- steroids may initially increase sodium excretion, thetic, varying in strength but not in quality from probably by raising the glomerular filtration rate one such compound to another. (Garrod et al., I955a). The basis for their '302 POSTGRADUATE MEDICAL JOURNAL 3fune 1.958 Postgrad Med J: first published as 10.1136/pgmj.34.392.300 on 1 June 1958. Downloaded from sodium-diuretic action in cardiac, scirrhotic and Anti-inflammatory and Anti-allergic Actions nephrotic oedema, is not yet understood. Glucocorticoids modify both general and local Potassium excretion is increased by a direct responses to inflammatory agents. Under. their renal tubular action, augmented by potassium re- suppressive influence fever abates and there, is a lease from''protein breakdown. As opposed to fall in the erythrocyte sedimentation rate which pure mineralocorticoids such as aldosterone and can be correlated with a decrease in -plasma DOC, glucoco'rticoids act specifically and per- fibrinogen and gamma-globulin concentrations missively on water diuresis and so protect against (Fletcher et al., 1952); the plasma tends Water intoxication. Without them there is great to rise. delay in excreting a water load, and when they are The local anti-inflammatory effects of these given in excess water diuresis is accelerated. The steroids are related to several actions:-a lessening underlying osmotic mechanisms are only partly of fibroblast-response and cellular reaction, a di- understood but seem to involve a direct action on minution: in the number of mast cells and con- the renal tubules. sequently in the amount of tissue hyaluronic acid, and an inhibition of specific antibody synthesis. Bone and Metabolism Whilst these actions may be desirable in the treat- ment of ' diseases and of excessive con- Here, again, the effects of glucocorticoids are nective tissue proliferation in other ,disorders, they complex and obscure. Prolonged treatment re- predispose to the spread of tuberculosis and other sults in negative calcium, phosphorus and bacterial infections unless appropriate antibiotic nitrogen balances and eventually osteoporosis. cover is provided. These steroids also antagonize the action' of vita- The remarkable. antiallergic properties of the min D and its analogues (Dickel, ig i) and so glucocorticoids are probably related to their neutralize the effects of antitetanic treatment in modifying action on antigen-antibody reactions hypoparathyroidism (Moehlig and Steinbach, and on histamine release, and may be lifesaving in I954). By inhibiting excessive calcium absorp- such conditions as status asthmaticus and bene- tion from the gut, they correct the defect'Which ficial in many other disorders. causes hypercalcaemia in some cases of (Hellman et al., 1956). Central Nervous System copyright. Glucocorticoids increase cerebral excitability, The Circulation predisposing to fits arid, psychoses in susceptible The actions of glucocorticoids on the circulation subjects. Euphoria and are common are largely permissive. Without them the blood accompaniments of steroid therapy and less often pressure and glomerular filtration rate. fall sharply. agitated . The electroencephalograph Similarly can be corrected by bit shows characteristic changes in Addison's disease lateral followed by minimal corti- (Forsham et al., 1949) and in patients on large sone maintenance (Harrison et al., 1952); yet, doses of cortisone (Bolandd and Headley, .I949). http://pmj.bmj.com/ provided renal function is good, hypertension The pain-relieving properties of these steroids seldom follows the use of these steroids in man, seem to be related to their local anti-inflammatory despite their potentiating the pressor a'ction of action rather -thanr to any' direct effects on the noradrenaline (Kurland and Freedberg, I95 I). sensory nervous system. Large doses can raise the glomerular filtration rate Gastric Secretions to supernormal levels. Cerebral blood flow in- Glucocorticoids increase the concentrattons,of creases, but cerebral oxygen and glucose utilization on October 1, 2021 by guest. Protected are not affected (Schieve et al., pepsin.and hydrochloric acid in the ,; as 195I). reflected in a rise of uropepsin excretion (Eastcott et al., 1953). This action, which is independent Blood and Blood Vessels of the route of steroid administration, predisposes Glucocorticoids in excess cause e3sinopenia and to peptic ulceration in those susceptible and is one regression of lymphoid tissue, this last action ex- of the major risks of steroid therapy. plaining their usefulness in the treatment' of lymphosarcoma and lymphatic leukaemia. They Secondary Endocrie Effects stimulate neutrophil and red cell production.and Although exerting a direct calorigenic action can induce a mild reversible polycythaemia. They glucocorticoids in high dosage also. suppress have no consistent effects on platelet formation, functior, as shown by diminished radio- purpura being'suppressed because of their action iodine uptake (Berson and Yalow, 1952) and a fall in depressing capillary fragility (Zweichach et, al., in the plasma protein-bound iodine (Hill et ial., r953). I950). Gonadal function may also be; depressed. June I 958 GARROD: Pharmacology of Cortisone, Cortisol and their New Analogues 303 Postgrad Med J: first published as 10.1136/pgmj.34.392.300 on 1 June 1958. Downloaded from The androgenici side-effects of large doses, such as cortisol and cortisone respectively, were dis- acne and hirsutism, may be due to i7-ketosteroid covered in the laboratories of the Schering Cor- metabolites of cortisone. poration (Herzog et al., I955). The introduction of a double bond between the first two carbon Aldosterone atoms of the steroid ring increases the glucocorti- Aldosterone, the other major adrenocortical coid potencies of cortisol and cortisone by at least hormone, is the principal regulator of sodium and 4 to 5 times, yet without enhancing their mineralo- potassium balance, and is secreted mainly by the corticoid activities. Thus, and zona glomerulosa (Ayres et al., I957). Although can be given in therapeutic dosage cortisol also contributes towards sodium retention without of causing excessive sodium re- and in excess may even become the predominant tention or potassium depletion. In all other ways mineralocorticoid, yet its rate of secretion is un- their actions resemble those of the parent steroids, related to the changing requirements of sodium but with 4 to 5 times the potency. Except when and potassium balance. treating adrenal failure, sodium retention and potassium depletion are undesirable side-effects of By contrast with cortisol,-the secretion of aldo- steroid therapy, and especially in debilitated, sterone is geared to the needs of the extracellular hypertensive, oedematous or cardiac patients, or fluid volume, or more precisely probably of the when the aim of treatment is to promote sodium arterial side of the vascular compartment (Bartter, diuresis. These new compounds are therefore I956). The mechanisms which regulate this rapidly replacing cortisone and cortisol in general secretion are unknown but seem to be largely in- use, thereby obviating the need for sodium re- dependent of pituitary control since they remain striction and supplementary potassium unless intact after hypophysectomy. The physiological heroic doses are being used as in the treatment of stimuli for increased aldosterone secretion are a certain blood dyscrasias. loss or deprivation from the body of sodium, Recent studies have shown that prednisone and water, or blood, and a high potassium intake. prednisolone are largely excreted in unmetabolized Conversely, a high sodium intake, pitressin- form, giving rise to fewer tetrahydro-derivitives induced water intoxication, and potassium de- (Slaunwhite and Sandberg, 1957; Vermeulen, copyright. privation all inhibit the secretion (Bartter, 1956). 1956). As with the natural steroids, prednisolone Prolonged oversecretion of aldosterone, as in and prednisone are freely interconvertible within Primary , leads to severe the body (Gray et al., 1956). potassium deficiency, alkalosis, and excessive sodium retention which, being mainly intracellular, 9-alpha-fluorohydrocortisone seldom gives rise to oedema. Similar effects occur with overdosage of DOCA or fluorohydrocortisone The remarkable effects of adding a halogen atom (vide infra), and can likewise be corrected by in the 9-alpha position to the cortisol molecule were discovered by Fried and Sabo (I Of http://pmj.bmj.com/ severely restricting the sodium intake. these derivatives only the chlorinated and fluori- nated compounds were found to exceed the natural Synthetic Analogues of Cortisol and Cortisone steroid in potency. Whereas the glucocorticoid By effecting minor adjustments to the steroid activity of 9-alpha-fluorohydrocortisone (FHC) is ring or its attachments the chemist has been able about io times that of cortisone, the mineralocori- to a remarkable degree to enhance and modify the coid activity exceeds that of the parent compound actions of these steroid hormones. Qualitatively, by at least ioo times (Garrod et al., 1955b) and is however, these changes have only brought about a slightly greater than that of aldosterone. on October 1, 2021 by guest. Protected shift of balance between their glucocorticoid and Despite its enhanced glucocorticoid potency the mineralocorticoid potencies. So far only three of extreme electrolyte activities of FHC preclude its the many new compounds have found their way systemic use as a substitute for cortisone (Ward et into general use: the two delta- i steroids, pred- al., 1954). However, since it can be given by nisolone and prednisone, and 9-alpha-fluorohydro- mouth, it is an ideal substitute for DOCA in treat- cortisone (). Two other compounds ing at doses of about O.1-0.2 have recently been made available.* mg. a day. The cortisone-like action of such The Delta-I Compounds: Prednisolone and amounts is very small, so cortisone must also be Prednisone given to achieve adequate replacement. These compound', which are analogues of This contraindication applies less when the steroid is used topically, as in disease, for it These are (i6 hydroxy-9-alpha-fluoro- is little absorbed into the circulation. Excessive prednisolone) and 6-methyl prednisolone. sodium retention has, however, been reported 304 POSTGRADUATE MEDICAL JOURNAL June I958Postgrad Med J: first published as 10.1136/pgmj.34.392.300 on 1 June 1958. Downloaded from following liberal use of FHC ointments in patients solved in 500 ml. of 5 per cent. dextrose, and act with extensive ulcerated skin lesions. maximally when infused at a rate of io to I2 mg. A third use of FHC, which takes advantage of an hour. The sodium succinate ester is very its enhanced glucocorticoid activity, is in tests to soluble in water; IOO mg. given intravenously, differentiate adrenocortical tumours from adreno- dissolved in 2 ml. of distilled water or saline, cortical hyperplasia (Renold et al., 1955). Using begins to act within about half an hour (Orr this compound the metabolic end-products are et al., 1955). Prednisolone-2i-phosphate has the small enough rot to disguise the falls in I7- advantage of being stable in solution and very ketosteroid and 17-hydroxysteroid excretion which soluble. follow the steroid-induced suppression of endo- For topical and intraarticular use, only cortisol genous corticotrophin in patients with adrenal or its analogues, prednisolone and FHC are effec- hyperplasia. tive, their effective concentrations in suspension or as ointments being roughly inversely propor- Some More Recent Cortisol Derivatives tional to their glucocorticoid potencies (vide By the addition of a 6-methyl group to cortisol supra). Cortisol and FHC are used in acetate or prednisolone or a i6-OH group to FHC or form, prednisolone as the free compound or 9-alpha fluoroprednisolone compounds can be acetate. obtained with even greater glucocorticoid potency than prednisolone, and without excessive mineralo- BIBLIOGRAPHY AYRES, P. J., GARROD, O., PEARLMAN, W. H., TAIT, corticoid activity (Spero et al., 1956; Bernstein S. A. S., TAIT, J. F., and WALKER, G. (I957), Ciba Found. et al., I956). These compounds, which have not Colloq. Endocrin., 'Hormones in Blood,' Churchill, London. yet been subjected to full clinical trial, are un- BARTTER, F. C. (I956), Metab., 5, 369. BERNSTEIN, S., et al. (1956), J. Amer. chem. Soc., 78, 5693. likely to offer advantages over prednisolone as BERSON, S. A., and YALOW, R. S. (I952), J. clin. Endocr., 12, 407. they seem to have no important qualitative dif- BOLAND, E. W., and HEADLEY, N. E. (0949),J. Amer. med. Ass., 141, 301. ferences in their glucocorticoid actions. BROOKMAN, J. J., DRACKMAN, S. R., SCHAEFER, L. E., Then, there are the 2-methyl derivatives of and ADLERSBURG, D. (I953), Diab., 2, I00. cortisol and FHC, which are the most potent BUSH, I. E., and WILLOUGHBY, M. (19S7), Biochem.Y.., in press. CONN, J. W., and FAJANS, S. S. (I952), Ann. Rev. Physiol., x4, mineralocorticoids yet discovered (Liddle et al., 453- copyright. 1956). The second of these two compounds is DICKEL, H. (i5si), Minch. med. Wschr., 93, I. EASTCOTT, H. H. G., FAWCETT, J. K., and ROB, C. G. (1953), several thousand times as active as cortisol on Lancet, i, io68. electrolyte metabolism, and a single oral dose is EVANS, E. S., CONTROPOULOS, A. N., and SIMPSON, N. E. (1957), Endocrin., 60, 403. effective for about 48 hours. Many more ana- FLETCHER, A. A., DAUPHINEE, J. A., and OGRYZLO, XI. A. logues of cortisol are being prepared and sub- (1952), 7. clin. Invest., 3I, 56I. FORSHAM, P. H., BENNETT, L. L., ROCHE, M., REISS, jected to biological assay. R. S., SLESSOR, A., FLINCK, E. B., and THORN, G. W. (I9495, . clin. Endocr., 9, 66o. FOURMAN, P., BARTTER, F. C., ALBRIGHT, F., DEMPSEY, Modes of Administration of Steroid Hormones E., CARROLL, E., and ALEXANDER, J. A. (I950), Y. clin.

Invest., 29, I462. http://pmj.bmj.com/ For pharmacological use, cortisone and FHC FRIED, J., and SABO, E. F. (1954), Y. Amer. chem. Soc., 76, I455. are prescribed as the acetate esters, prednisone GARROD, O., DAVIES, S. A., and CAHILL, G., Jr. (x955a), and prednisolone usually as the free compounds, -7. clin. Invest., 34, 76I. GARROD, 0., NABARRO, J. D. N., PAWAN, G. L. S., and and cortisol in either form. Orally, they act within WALKER, G. (I955b), Lancet, 2, 367. 2 to 3 hours and are effective for about I2 GRAY, C. H., GREEN, M. A. S., HOLNESS, N. J., and hours, LUNNON, J. B. (I956), Y. Rndocr., 4,146. depending on the dose. To maintain adequate GRAY, S. J., BENSON, J. A., REIFENSTEIN, R. W., and blood levels with oral therapy large doses should SPIRO, H. M. (i9sI),.y. Amer. med. Ass., 147, I529. be given I2-hourly and small doses HARRISON, J. H., THORN, G. W., and CRISCITIELLO, M. G. 8-hourly, (I952), Y. Urol., 67, 405. on October 1, 2021 by guest. Protected though FHC can be given once a day. HELLMAN, L., BRADLOW, H. L., FRAZELL, E. L., and GALLAGHER, T. F. (I956),.7. clin. Invest., 35, 033. With intramuscular injection the rate of HENNEMAN, P. H., DEMPSEY, E. F., CARROLL, E. L., and absorption is far slower and the effects of a single ALBRIGHT, F. (I956), Ibid., 35, 1229. dose HERZOG, H. L., NOBILE, A., TOLKSDORF, S., CHARNEY, may last, though feebly, for several days. In W., HERSHBERG, E. B., PERLMAN, P. L., and PECHET, the case of cortisol the free compound is more M. M. (i955), Seience, 122, 176. rapidly absorbed than the less soluble acetate. HILL, S. R., REISS, R. S., FORSHAM, P. H., and THORN, This route of G. W. (I950), Y. clin. Endocr., I0, 1375. administration offers no real advan- INGLE, D. J. (I950), Ibid., to, 1312. tages over the oral route, and is rarely indicated. KINSELL, L. W., MARGEN, S., MICHAELS, G. D., and To obtain a rapid effect, as in the treatment of PARTRIDGE, J. (Ig5I), Proc. 2nd Clin. ACTH Conf., x, 308. acute adrenal crisis and status KURLAND, G. S., and FREEDBERG, A. S. (I95I), Proc. Soc. asthmaticus it is exp. Biol. (N. Y.), 78, 28. necessary to use intravenous cortisol, either as the LEVITT, M. F., and BADER, M. E. (9si),J. clin. Invest., 30, 655. free compound (alcohol) or preferably as 'the LIDDLE, G. W., RICHARDS, J. E., and TOMKINS, G. 1M. sodium succinate ester or intravenous predniso- (I956),J. cdn. Endocr., I6, 917. lone-21i-phosphate. ioO mg. of cortisol are dis- Bibliography continued on page 309 June 1958 BAYLISS: Cortisone and its Analogues in 309 Postgrad Med J: first published as 10.1136/pgmj.34.392.300 on 1 June 1958. Downloaded from A also GURLING, K. J., GORE, M. B. R., and BARON, D. N. (1958), cretion. similar effect may be observed Y. Endocr. 16, 304. when cortisone is given to a hypercalcaemic patient JAILER, J. W.-, GOLD, J. J., and WALLACE, E. Z. (I954), with multiple bony metastases if the steroid in- Amer. Y. Med., I6, 340. KUPPERMAN, H. S., BLATT, M. H. G., VESELL, M., hibits the growth of the neoplastic tissue. In GAGLIANI, J., WEISBADER, H., and VOSBURGH, L. hyperparathyroidism, on the other hand, cortisone (I955), Y. clin. Endocr., x5, 9I I . LANCET (I9S5), i, 6. does not influence the hypercalcaemia. LEITH, W., and BECK, J. C. (I957), Y. clin. Endocr., 17, 28o. LIDDLE, G. W., and RICHARDS, J. E. (I956), Science, 123, 324. BIBLIOGRAPHY NABARRO, J. D. N., and WALKER, G. (I957), Brit. med. J., ii, 17. ANDERSON, J., DENT, C. E., HARPER, C., and PHILPOT, OWEN, J. A., ENGEL, F. L., and WEBSTER, T. B. (1957), G. R. (I9S4), Lancet, ii, 720. Y. clin. Endocr., 17, 272. BARTTER, F. (x956), Metabolism, 5, 369. PRADER, A. (1953), Helv. paediat. Acta, 8, 386. BAYLISS, R. I. S. (1957a), Proc. roy. Soc. Med. 50, 76I. SEGALOFF, A., GORDON, D., and HORWITT, B. N. (1955), BAYLISS, R. I. S. (1957b), in 'Moder Trends in Endocrinology,' Y. Amer. med. Ass., x57, I479. London, Butterworth. SPENCE, A. W., JENKINS, J. S., and ROBINSON, A. M. (I956), Brit. med. Y., ii, 1348. BECK, R. N., and MONTGOMERY, D. A. D. (I956), Brit. med.J., WERNER, S. C. (I9S3), Y. clin. Endocr., 13, 1332. ii, 921. WILKINS, L., LEWIS, R. A., KLEIN, R., GARDNER, L. I., COPE, C. L. (I956), Ibid., ii, I93. CRIGLER, J. F., ROSENBERG, E., and MIGEON, C. J. FOURMAN, P., and HORLER, A. R. (1954), Lancet, i, 334. (1951), Ibid., xII, I. ANAESTHETICS (Postgraduate Medical Journal) Price: 3s. lld. post free

THE MODERN VIEW OF ANAESTHESIA CHLORPROMAZINE AND ALLIED G. S. W. Organe, M.D., D.A., F.F.A.R.C.S. SUBSTANCES

E PRODUCTION OF John Beard, M.D., D.A., F.F.A.R.C.S., copyright. UNCONSCIOUSNES D.C.H. B. G. B. Lucas, D.A., F.F.A.R.C.S. CONTROLLED HYPOTHERMIA ANALGESIA E. J. Delorme, M.D., F.R.C.S.(C.) J. B. Wyman, M.B.E., D.A., F.F.A.R.C.S. MANAGEMENT OF T APNOEIC MUSCLE RELAXATION IN SURGERY PATIENT Angus Smith, F.F.A.R.C.S. Ronald Woolmer, D.A., F.F.A.R.C.S. CONTROL OF THE BLOOD PRESSURE THE USE OF ANTIDOTES IN AND CONTROLLED HYPOTENSION ANAESTHESIA C. F. Scurr, M.V.O., D.A., F.F.A.R.C.S. B. A. Sellick, D.A., F.F.A.R.C.S. http://pmj.bmj.com/ Published by THE FELLOWSHIP OF POSTGRADUATE MEDICINE 60, Portland Place, London, W.1 on October 1, 2021 by guest. Protected

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