IN 1963 Harter, Reddy, and Thorn (1) Pituitary-Adrenal Suppression and Cushing's Syndrome After Intermittent Dexamethasone Therapy

Transcription

1 Pituitary-Adrenal Suppression and Cushing's Syndrome After Intermittent Dexamethasone Therapy NATHAN B. RABHAN, M.D., Baltimore, Maryland Six patients have been treated SUMMARY with high-dosage dexamethasone every 48 hr for 3 to 29 weeks. Pituitary-adrenal function, as measured by the urinary 17-ketosteroid and 17-hydroxysteroid response to intravenous adrenocorticotrophic hormone during therapy, was significantly depressed in all subjects. Significant metabolic side effects occurred in four of the patients, with two instances of pitting edema. Clinical response was excellent in four patients with sarcoidosis, fair in a patient with the nephrotic syndrome, and poor in a patient with reticulum cell sarcoma. The results of this study with dexamethasone differ from recorded experiences with alternateday prednisone, which produces few side effects and minimal pituitary-adrenal suppression. Dexamethasone appears to have more potent and prolonged pituitary-adrenal suppressive properties when compared with a 1:6.6 ratio of prednisone. Although the number of cases treated with alternate-day dexamethasone is small, experience to date indicates that pituitary-adrenal suppression and glucocorticoid side effects should be expected at the dose and duration of dexamethasone therapy administered in the present study. IN 1963 Harter, Reddy, and Thorn (1) described a method of administering corticoids in a single dose every 48 hr that was based on their observation that the therapeutic effect of corticoids persists longer than their metabolic effect. They reported good clinical response, few side effects, and spontaneous adrenal function when 59 patients were tested during therapy with intravenous adrenocorticotrophic hormone (ACTH). Prednisone, cortisone, and triamcinolone were used in 58 patients; dexamethasone was used in only 1 patient. Dexamethasone is one of the most potent corticoid compounds (2), has slight saltretaining properties (2-4), and in current medical practice is used interchangeably in equivalent dosage with prednisone, prednisolone, and triamcinolone (5). We thought it advisable to determine the usefulness of dexamethasone in alternate-day therapy since dexamethasone has not been investigated in this manner. Six patients were treated with dexamethasone every other day for 3 to 29 weeks. All showed manifestations of Cushing's syndrome; five of six showed pituitary-adrenal suppression as measured by a diminished rise of urinary 17 hydroxy corticoids (17 OH) and urinary 17 ketosteroids (17 KS) after intravenous ACTH infusion. This paper examines the difference between dexamethasone and prednisone when used in alternate-day therapy (one single dose of glucocorticoid at 8 AM every 48 hr) and relates these findings to the clinical significance of choice of a specific glucocorticoid compound with this therapeutic schedule. METHODS From December 1964 to June 30, 1965, a prospective study of dexamethasone's effectiveness with intermittent therapy was conducted using both ward and private patients from the General Medical Service, Sinai Hospital, Baltimore, Md. Consecutive hospitalized patients who required steroids for the treatment of their basic disease process were studied if they had Received May 15, 1968; accepted June 3, From the Department of Medicine, The Sinai Hospital of Baltimore, Inc., Baltimore, Md. Request for reprints should be addressed to Nathan B. Rabhan, M.D., 340 E. 34th St., New York, N. Y II4I

2 1142 NATHAN B. RABHAN Annals of Internal Medicine TABLE 1. Clinical Data on Patients Including Dose i, Duration, and Side Effects of Dexamethasone Therapy Patient, Agt ;, Clinical Dose of Dose Dura Total Side Effects of Therapy Severity and Sex Diagnoses* Dexa- Schedule tion at Dose of Side metha- at 8 AM this Effects sonef Dose mg wk mg R. Q., 41, Focal, local 6 q24hr Nervousness and irritability; Moderate female glomeru 4.5 q24hr 1 soft tissue abcess back; Mild lonephritis 9.0 q48hr 10 paronychia of the toe; Mild 18.0 q48hr 2 hyperglycemia Mild 6.0 q48hr q48hr q48hr 4 J. U-, 21, Sarcoidosis 6.0 q24hr Epigastric distress; Mild male 12.0 q48hr 6 acute duodenal ulcer; Severe 9.0 q48hr 2 cushingoid facies; Mild 7.5 q48hr 1 23-lb weight gain Mild 6.0 q48hr q48hr 6 D. C, 25, Sarcoidosis 6.0 q24hr Nervousness and irritability; Moderate female 12.0 q48hr 3 cushingoid facies; Mild 9.0 q48hr 1 18-lb weight gain Mild 7.5 q48hr 3 J. S., 49, Sarcoidosis 6.0 q24hr Cushingoid facies; Mild female q48hr q48hr q48hr q48hr lb weight gain Mild H. Z., 43, Reticulum 7.5 q24hr H 195 Pitting edema and congestive Severe male cell 12.0 q48hr H heart failure; sarcoma 10-lbf weight gain Moderate L. B., 41, Sarcoidosis 6.0 q24hr U 600 Nervousness; Moderate female 12.0 q48hr 5 hypertension; Moderate 9.0 q48hr 5 pitting pretibial edema; Moderate 7.5 q48hr 2 cushingoid facies; Moderate 6.0 q48hr 2 25-lb weight gain; Moderate 4.5 q48hr 3 hyperglycemia; Mild 3.0 q48hr q48hr 2 * All diagnoses include typical clinical features plus biopsy confirmation. t Patients R. Q., J. D., H. Z., and L. B. received Decadron, courtesy of William E. Worley, M.D., Merck Sharp and Dohme Research Laboratories, West Point, Pa.; Patients D. C. and J. S. received Dexameth, courtesy of Harvey S. Sadow, Ph.D., U. S. Vitam iin Pharmaceutical Corporation, New York, N. Y. not received steroids in the past. The purpose of the investigation was carefully explained to all patients. They were given a single daily dose at 8 AM of dexamethasone, 6 to 7.5 mg for 1 to 2 weeks (Table 1). Once the effective daily dose was established a single dose was given at 8 AM every 48 hr equivalent to double the daily dose (6 to 7.5 mg daily equals 12 to 15 mg every 48 hr). The amount of steroid was increased whenever clinically indicated. When reduction was possible, the rate was based on the patient's response and the presence or absence of side effects. The period of observation varied from 3 to 29 weeks. LABORATORY CONTROL Two consecutive 24-hr urine determinations were obtained from five of the six patients during their initial hospitalization. The first 24-hr specimen was a base-line control, and the

3 Volume 69, No. 6 December 1968 PITUITARY-ADRENAL SUPPRESSION AND CUSHING S SYNDROME I 143 TABLE 2. Urinary Response of 17 Ketosteroid and 17 Hydroxysteroid to Intravenous Adrenocorticotrophic Hormone (ACTH) Before and After Intermittent Dexamethasone Patient Time of Study Dose of 17 Ketosteroid 17 Hydroxysteroid Urinary Steroid* Creat mine at Time Control ACTH Control ACTH of Study Test Test Control ACTH Test R.Q. wuk mg < mg/24 ;, /// g/* / /... / lir Pretreatment control: t J.D. Pretreatment control: t J * J J J D. C. Pretreatment control: J J J.S. Pretreatment control: Lost 6.2 Lost H. Z. Pretreatment control; 0 3.8f $ t 1.50 died on day 21 L. B. No pretreatment control: * All patients on dexamethasone every 48 hr at the time of these studies. Control urine collection on steroid day; ACTH-test urine on nonsteroid day. f Only instance in study when sequence of drug administration altered so that ACTH-test urine on nonsteroid day. t Incomplete urine collections as judged by paired urine creatinine values. These urines were not used in statistical data. Eight-week study on J. D. two separate control collections on consecutive on-steroid day without altering drug sequence. Urine values for both 17 ketosteroid and 17 hydroxysteroid on J. D. and D. C.; average of four determinations of 17 ketosteroid and two determinations of 17 hydroxysteroid. second was collected on the day of an 8-hr intravenous infusion of 25 units of ACTH in 500 ml of Dextrose 5% in water. Twentyfour-hour urine collections were begun at 7 AM, and the intravenous infusions were begun between 8 to 10 AM. The control 24-hr urine collection was taken on the day of steroid administration (Table 2). The ACTH infusion and the ACTH test 24-hr urine collections were on the nonsteroid day. It was necessary to alter the usual schedule of administration only once to achieve the ACTH infusion on the nonsteroid day (Patient R. Q.). Urine was collected in iced containers with 10 ml of toluene as preservative. The accuracy of each collection was checked by urinary ere-

4 1144 NATHAN B. RABHAN Annals of Internal Medicine TABLE 3. Normal Values for Mean Increase in Urinary 17 Ketosteroid and 17 Hydroxysteroid After an 8-hr Intravenous Infusion of 25 Units Adrenocortocotrophic Hormone Study 17 Keterosteroid 17 Hydroxysteroid mg/24 hr 1. In 151 normal subjects (9) 5.2 (range 0-19) In 52 normal subjects (9) 15.2 (range, ) 2. In normal subjects (10) 3 to 5 times the control; less than 100% increase indicative of adrenal suppression 3. In patients R. Q., J. D., and D. C. Before dexamethasone 9.1 (range, ) 15.9 (range, ) After dexamethasone 3.2 (range, ) 4.0 (range, ) atinine values. Four of 37 urine samples were judged as inaccurate collections and were excluded from statistical analysis (Table 2). Aliquots of the 24-hr urine samples were frozen and airmailed to Biochemical Procedures.* Analysis of 17 KS was done according to the method of Drektor as modified by Wilson and Lipset (6). For analysis of 17 OH, the Porter- Silber Reagent method (7) was used. Dexamethasone does not contribute significantly to the urinary 17 OH levels with the Porter-Silber method even in doses of 8 mg/24 hr (8). The usual mean increase for urinary 17 KS and 17 OH during a single 8-hr infusion of 25 units of ACTH is depicted in Table 3 (9, 10). During therapy, urine collections for 17 KS and 17 OH before and during ACTH stimulation were obtained in five of six patients. Eighteen ACTH infusions were performed during the study. Blood hematocrit, peripheral white count and differential, fasting blood sugar, urea, and serum potassium were obtained initially and at 2- and 6-month intervals. Standard posterioanterior and lateral X rays of the chest were obtained initially in all patients; at 1-month intervals in three patients (J. D., D. C, and J. S.), and at the end of the study in all patients. Slit-lamp examination of the cornea and lens were obtained in five of six patients before, during, and at the end of the study. Color photographs of the face to judge "cushingoid features" were obtained initially, at 1- and 2- month intervals, and at the end of the study in five of six patients. Stool analysis for blood and barium gastrointestinal studies were done only in symptomatic patients (J. D.). Supplemental therapy in the form of antacids, antituberculous drugs, diuretics, and androgenic hormones were not used prophylactically because of Harter, Reddy, and Thorn's experience (1) with alternate-day therapy. All patients were asked to follow a 1- to 2-g sodium diet without specific caloric or fluid restrictions. In each patient the weight and blood pressure were recorded at the onset of the study. PITUITARY-ADRENAL RESULTS RESPONSIVENESS ACTH stimulation before treatment in three patients (R. Q., J. D., and D. C.) increased the mean milligram value of urinary 17 KS by 9.1 mg (range, 5.1 to 14.2). During therapy the mean increase for 17 KS after ACTH stimulation decreased to 3.1 mg (range, 1.2 to 5.8) for these three patients. The P value for this change is 0.10 > 0.05 * (Figure 1). In these same three patients before treatment an 8-hr ACTH test increased the 17 OH urinary values by a mean of 15.9 mg (range, 9.1 to 29.0). During therapy the mean increase for urinary 17 OH after ACTH stimulation diminished to 4 mg (range, 1.8 to 7.7). This decrease is statistically significant (P = 0.02)* (Figure 1). A similar analysis cannot be made for J. S. or L. B. (Table 2). However, after alternate-day dexamethasone was begun, the mean increase in urinary 17 OH during ACTH stimulation was less than the pretreatment increase in the above three control patients. * Marvin B. Rodney, M.D., Medical Director, Biochemical Procedures, North Hollywood, Calif. *The Wilcoxon Rank Sum Test (11).

5 Volume 69, No. 6 December 1968 PITUITARY-ADRENAL SUPPRESSION AND CUSHING'S SYNDROME I H5 COMPLICATIONS OF THERAPY All side effects of therapy are listed in Table 1. Weight gain occurred in all patients except R. Q., who was edematous at the onset of the study. Mean weight gain for all patients was 16 lb; two patients gained more than 20 lb. Pitting pretibial and pedal edema developed in two patients. This occurrence is significant since several short-term metabolic studies (2-4) reported negligible salt-retaining properties after administration of dexamethasone. Liddle (12) has suggested that dexamethasone will probably cause salt retention at doses in excess of 6 mg daily. One of the patients with edema (L. B.) developed systolic and diastolic hypertension. The other patient (H. Z.), who had compensated heart failure while on digoxin before the study, developed severe congestive heart failure with ascites and bilateral pleural effusions. In the remaining four patients the weight gain reflected both an increased appetite and a gradual return to preillness weight. In the nephrotic patient (R. Q.) who had hypogammaglobulinemia there were two separate episodes of staphylococcal pyoderma. Epigastric distress which was due to an active duodenal ulcer developed in only one patient (J. D.). Hyperglycemia developed in two patients, but glycosuria and clinical diabetes were not observed. Three female patients developed irritability and nervousness at higher doses of dexamethasone and responded to modest reduction in steroid dose. Five patients had slit-lamp examinations of the cornea and lens before, during, and at the end of the study. Posterior subcapsular cataracts did not develop in any of these patients; however, increased diffuse punctuate specks were noted in the posterior capsule in two patients after 4 and 6 months of steroid administration. Gastrointestinal hemorrhage, electrolyte imbalance, and osteoporosis did not occur. It is of interest that ecchymoses and thinning FIGURE 1. Mean milligram increase in 17 hydroxycorticoids (17 OH) and 17 ketosteroids (17 KS) after intravenous infusion of adrenocorticotrophic hormone (ACTH) (see Methods). Each dot represents individual values; the line represents the mean of these values. The difference in mean increase between control and posttreatment observations in Patients R. Q., J. D., and D. C. is P = 0.02 for 17 OH and P = 0.1 > 0.05 for 17 KS. The mean increase for all patients after dexamethasone is similar to the posttreatment mean increases for these patients. of the skin were not observed, although Boland (13) lists these as common side effects of four-times-a-day dexamethasone therapy. CLINICAL RESPONSE The four patients with sarcoidosis responded well to both daily and every-otherday administration of dexamethasone. The nephrotic patient (R. Q.) responded only to large doses of dexamethasone. The patient with reticulum cell sarcoma (H. Z.) worsened

6 1146 NATHAN B. RABHAN Annals of Internal Medicine and died after 3 weeks of therapy with dexamethasone. Five patients were transferred to everyother-day therapy after 7 to 10 days; the sixth patient was switched at 2 weeks. There were no difficulties during or after the change over period, and there was no difference in clinical response. DISCUSSION Pituitary-adrenal suppression and manifestations of Cushing's syndrome appeared in all patients in the present study after alternate-day dexamethasone therapy. These results are different from recorded experiences with prednisone administered every 48 hr (1, 14-16). ALTERNATE-DAY PREDNISONE Some measure of pituitary-adrenal function has been assessed in four separate studies of alternate-day prednisone therapy (1, 14-16). These investigations indicate that, although the basal steroid output can be normal (16), at larger prednisone doses it is often suppressed (1, 14, 15). However, after intravenous ACTH (1) and insulininduced hypoglycemia (15), pituitary-adrenal responses were comparable to normal controls. Most of these patients received only alternate-day prednisone. In Harter, Reddy, and Thorn's study (1) the patients were initially given 40 mg of prednisone in four divided daily doses for 8 to 20 days TABLE 4. Clinical Equivalent Milligram Dose of Corticoid Compounds Compared with Their Plasma Half Life and Proposed Pituitary- Adrenal Suppressive Properties Compound 1. Cortisone 2. Hydrocortisone 3. Prednisone 4. Prednisolone 5. Triamcinolone 6. Dexamethasone 7. Betamethasone Clinical Equivalent Dose (5) mg Plasma Half Life* Pituitary- Adrenal Suppressive Ratios (17) tnin 30 Short-acting 110 Short-acting 60 Short-acting 200 Short-acting 300f Moderate-acting 200 Long-acting unknown^ Long-acting * For half life of cortisone, hydrocortisone, prednisone, prednisolone, and dexamethasone (25). t For half life of triamcinolone (26). i For half life of betamethasone (27). (in some intances the dose was decreased to 5 to 7.5 mg, four times a day) before converting to alternate-day therapy. This short period of daily therapy did not interfere with pituitary-adrenal responsiveness to intravenous ACTH, a point worth emphasizing since one possible explanation for the pituitary-adrenal suppression noted in the present study was the once-daily administration of 6 to 7.5 mg of dexamethasone for 1 to 2 weeks before alternateday therapy. Symptoms and signs of Cushing's syndrome were either mild or absent in most of the patients in these studies (1, 14, 15). Actual improvement in cushingoid side effects (moon facies, seizures, and diminished growth) induced by four divided daily doses of prednisone occurred when nephrotic children were placed on equivalent milligram doses of prednisone every other day (14). That this freedom from severe glucocorticoid side effects is not dose-dependent is illustrated in two adult males who received 100 and 120 mg of prednisone every other day for 6 and 8 months, respectively, without developing moon facies (15). This dose of prednisone exceeds the equivalent of dexamethasone (Table 4) used in all patients in the present study. ALTERNATE-DAY DEXAMETHASONE Recently there have been reports of the use of alternate-day dexamethasone therapy (17-19). Harter and associates described two patients taking alternate-day dexamethasone with diminished responses to intravenous ACTH. One of these patients took 4.5 mg every other day for 3 months; the other took 1 mg on alternate days for 5 months (17). In a crossover drug study in the same group of patients Heimlich and co-workers (18) demonstrated significant pituitary-adrenal suppression with dexamethasone 4.5 mg every other day. Prednisone, in a dose 6.6 times as great (30 mg), was associated with normal pituitary-adrenal function.

7 Volume 69, No. 6 December 1968 PITUITARY-ADRENAL SUPPRESSION AND CUSHING'S SYNDROME I 147 Fleisher (19) reported less severe metabolic side effects and more normal pituitaryadrenal function when 10 nephrotic children were given dexamethasone every other day instead of daily in four divided doses. It is difficult to compare these findings with the results of Heimlich and associates and the present study since the majority of the patients in Fleisher's report (19) were on corticoids before the onset of his investigation, and the initial metapyrone test was normal (20) only in four of nine patients. Betamethasone, a flourinated prednisolone derivative similar to dexamethasone, produced significant pituitary-adrenal suppression in 10 asthmatic children receiving 3 mg every 48 hr (21). THERAPEUTIC IMPLICATIONS Corticoid compounds have been compared, in equivalent dose (Table 4), in reference to anti-inflammatory potency, type and degree of cushingoid side effects, and the amount necessary to produce pituitary-adrenal suppression. It is generally stated that there are no real differences between dexamethasone and an amount of prednisone 6.6 times as large in anti-inflammatory properties (2, 5, 13) and in the total prevalence of cushingoid side effects (2, 5, 13, 22, 23), although the type and degree of side effect varies between compounds. Although this same ratio of 0.75 mg dexamethasone equals 5 mg of prednisone is claimed for pituitary-adrenal suppression (22), others have reported that dexamethasone is at least 30 times as potent as prednisone (2). Recent studies by Harter (17) and Harter, Hall, and Bayles (24) have demonstrated prolonged suppression of the urinary 17- ketogenic response to metapyrone after a single dose of dexamethasone and betamethasone. This prolonged suppression was not observed after similar administration of cortisone, hydrocortisone, prednisone, and prednisolone (Table 4). It is unlikely that dexamethasone's prolonged pituitaryadrenal suppressive properties are due to its plasma half life (Table 4), since [1] prednisolone has a similar half life (25) and was not associated with prolonged suppression; and [2] triamcinolone, which has the longest plasma half-life (26), was associated only with moderate suppression (17, 24). Even though corticoid compounds may be equal in their anti-inflammatory and metabolic side-effect potentials, evidence has accumulated that there are differences between compounds when an alternate-day therapeutic schedule is used. As stated above,, the reason for dexamethasone's failure to work in this type of treatment schedule is, in all probability, a more potent, or prolonged pituitary-adrenal suppressive effect, or both. Prednisone, which has less pituitary-adrenal suppressive properties when compared with the clinically effective dose of dexamethasone, appears to be the drug of choice in alternate-day therapy. ACKNOWLEDGMENTS I acknowledge with thanks the assistance of Dr. David Rabinowitz in reviewing the manuscript. I am indebted to Dr. Albert I. Mendeloff for providing funds, equipment, and advice and criticism; to Dr. R. I. Levy for assistance in the mangement of patient R. Q.; to Dr. J. Gross for permission to report patient H. Z.; to Dr. M. B. Blum and P. Berson for assistance with Patient L. B. and for performing slit-lamp examinations of the cornea and lens in all patients. Dr. E. F. Wamsteker of the Research Laboratories, Parke, Davis & Co., Ann Arbor, Mich., kindly provided the adrenocorticotrophic hormone used in this sutdy (ACTH-Corticotropin Injection 25 units [SV 97] Lot No. DJ 205). Ralph A. Knight, Ph.D., Assistant Professor of Microbiology, Women's Medical College, Philadelphia, Pa., performed the statistical analysis of the study. Mr. George Thompson and Mrs. Aurora Trigg, of the Biochemistry Laboratories, Sinai Hospital, Baltimore, provided laboratory and bookkeeping assistance.

8 1148 NATHAN B. RABHAN Annals of Internal Medicine REFERENCES 1. HARTER, J. G., REDDY, W. J., THORN, G. W.: Studies on an intermittent corticosteroid dosage regimen. New Eng. J. Med. 269: 591, BUNIM, J. J., BLACK, R. L., LUTWAK, L., PETFR- SON, R. E., WHEDON, G. D.: Studies on dexamethasone, a new synthetic steroid in rheumatoid arthritis a preliminary report. Arthritis Rheum. 1: 313, MILLS, L. C., CHAYES, Z., NEWMAN, B.: Comparative effects of steroids on water and electrolyte balance, in Inflammation and Diseases of Connective Tissue, edited by MILLS, L. C., MOYER, J. H., W. B. Saunders Co., Philadelphia, 1961, p LIDDLE, G. W.: Effects of anti-inflammatory steroids on electrolyte metabolism. Ann. NY Acad. Sci. 82: 854, LAULER, D. P., THORN, G. W.: Nonspecific use of ACTH and adrenal steroids in clinical practice, in Principals of Internal Medicine, edited by HARRISON, T. R., ADAMS, R. D., BENNETT, I. L., RESNICK, W. H., THORN, G. W., WINTROBE, M. M., McGraw-Hill Book Co., Inc., New York, 1966, p WILSON, H., LIPSETT, M. B.: Use of periodate oxidation in the clinical anlysis of urine corticoids. Anal. Biochem. 5: 217, SILBER, R. H.: Free and conjugated 17 hydroxycorticoids in urine, in Standard Methods of Clinical Chemistry, edited by SELIGSON, D., Academic Press, Inc., Publishers, New York, 1963, p LIDDLE, G. W.: Tests of pituitary-adrenal suppressibility in the diagnosis of cushing's syndrome. J. Clin. Endocr. 20: 1539, JENKINS, D., FORSHAM, P. H.., LAIDLOW, J. L., REDDY, W. J., THORN, G. W.: Use of ACTH in the diagnosis of adrenalcortical insufficiency. Amer. J. Med. 18: 3, FORSHAM, P.: The adrenals, in Textbook of Endocrinology, edited by WILLIAMS, R. H., W. B. Saunders Co., Philadelphia, 1968, p WILCOXON, F., WILCOX, R.: Methods for determining the significance of differences between two treatments, in Some Rapid Approximate Statistical Procedures, Lederle Laboratories, New York, 1964, p LIDDLE, G. W., Fox, M.: Structure-function relationships of anti-inflammatory steroids, in Inflammation and Diseases of Connective Tissue, edited by MILLS, L. C, MOYER, J. H., W. B. Saunders, Philadelphia, 1961, p BOLAND, E. W.: The treatment of rheumatoid arthritis with adrenocorticoids and their synthetic analogues. Ann. NY Acad. Sci. 84: 887, SOYKA, L. F.: Treatment of the nephrotic syndrome in childhood. Use of an alternate-day prednisone regimen. Amer. J. Dis. Child. 113: 693, ACKERMAN, G. L., NOLAN, C. M.: Adrenocortical responsiveness after alternate-day corticoid therapy. New Eng. J. Med. 278: 405, Cocco, A. E., MENDELOFF, A. I.: An evaluation of intermittent corticosteroid therapy in the management of ulcerative colitis. Johns Hopkins Med. J. 120: 162, HARTER, J. G.: Corticosteroids: their physiologic use in allergic disease. New York J. Med. 66: 827, HEIMLICH, E. M., EASTON, J. E., BRUSSER, R. J., WHITE, J., AARON, B.: Effect of drug and dose on adrenal responsiveness in alternate-day steroid therapy (abstract). /. Allerg. 39: 111, FLEISHER, D. S.: Pituitary-adrenal responsiveness after corticosteroid therapy in children with nephrosis. /. Pediat. 70: 54, RICHMOND, L., CHAPPELL, J., CLEVELAND, W. W.: Response of children to methopyrapone (metopirone). /. Pediat. 64: 381, SIEGEL, S. C, HEIMLICH, E. M., RICHARDS, W., TAYLOR, W. F., KELLY, V. C: Effects of alternate-day steroid therapy in asthmatic children (abstract). J. Allerg. 36: 209, WEST, K. M., JOHNSON, P. C, KYRIAKOPOULOS, A. A., BAHR, W. J., BLOEDOW, C. E.: The physiologic effect of dexamethasone. Arthritis Rheum. 3: 129, FRAWLEY, T. F., SHELLEY, T., KISTLER, H.: Effects of anti-inflammatory steroids on carbohydrate metabolism, with emphasis on hypoglycemia and diabetic states. Ann. NY Acad. Sci. 82: 868, HARTER, J. G., HALL, A. P., BAYLES, T. B.: Physiological studies with single doses of steroid analogs and the implications for longterm alternate day steroid therapy (abstract). Arthritis Rheum. 8: 445, PETERSON, R. E.: Metabolism of adrenocorticoids in man. Ann. NY Acad. Sci. 82: 846, MELBY, J. C, SILBER, R. H.: Clinical pharmacology of water-soluble corticosteroid esters. Amer. Practit. 12: 155, HAIN, K. H.: Personal communication.