0021-972X/78/4705-1137S02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society
Vol. 47, No. 5 Printed in U.S.A.
Comparison of Absorption of Cortisone Acetate and Hydrocortisone Hemisuccinate* BRUCE L. FARISS.f SATOSHI HANE, JEANETTE SHINSAKO, AND PETER H. FORSHAM Clinical Research Service, Madigan General Hospital, Tacoma, Washington 98431; and the Metabolic Research Unit and Department of Medicine, University of California, San Francisco, California 94143 ABSTRACT. In four patients who required maintenance glucocorticoid therapy after bilateral adrenalectomy for Cushing's disease, we compared the effects of im injection and oral ingestion of cortisone acetate and hydrocortisone hemisuccinate. By the former route of administration, cortisone acetate was not effective in elevating plasma cortisol levels or in suppressing plasma adrenocorticotropin, although hydrocortisone was. When given by mouth, no significant difference was
A
CUTE adrenal insufficiency is a lifeL threatening situation that requires the administration of glucocorticoid steroids. In addition, patients on maintenance glucocorticoid therapy must be managed through acute situations precipitated by infections, trauma, stress, or surgical procedures. Treatment programs that recommend cortisone acetate as a parenteral corticosteroid have been outlined (1-3), but other studies have demonstrated that plasma cortisol levels did not rise after im injection of this agent (4, 5). With hydrocortisone hemisuccinate, however, im injection has been shown to be effective (4). In the present study of four patients with chronic adrenal insufficiency after bilateral adrenalectomy for Cushing's disease, im injection of cortisone acetate resulted in only a minimal rise in plasma cortisol levels (or none at all) and an insignificant suppression of plasma ACTH levels. Hydrocortisone, how-
found between the two steroids. Therefore, in the treatment of acute adrenal insufficiency or in the maintenance of patients with chronic adrenal insufficiency and in their preparation for surgery or other stressful situations, we advise against im injection of cortisone acetate. Oral ingestion, however, is appropriate for maintenance. (J Clin Endocrinol Metab 47: 1137, 1978)
ever, caused a significant rise in plasma cortisol and a prompt suppression of the plasma ACTH levels when given by this route. Both agents were equally effective when taken orally. Subjects and Methods Four ambulatory patients participated after their written informed consent had been obtained. Each had undergone bilateral adrenalectomy as the
treatment for Cushing's disease. SB was a 39-yr-old woman who underwent surgery in 1972 after a diagnosis of bilateral adrenal hyperplasia. Her blood pressure was 120/80 mm Hg, with a pulse of 88 beats/min. Her height was 160 cm, with a weight of 61 kg. Her skin pigmentation was normal. She had been maintained on cortisone acetate (25 mg by mouth each morning with 12.5 mg in the afternoon). Fludrocortisone had been taken sporadically. Skull x-ray films had been interpreted as normal on yearly examination. HD was a 66-yr-old woman who underwent surgery in 1971 with a diagnosis of bilateral adenomReceived October 10, 1977. atous hyperplasia. Her blood pressure was 166/90 Address requests for reprints to: Satoshi Hane, Metabolic Research Unit, University of California-San Fran- mm Hg and her pulse was 72 beats/min. Her height was 160 cm, with a weight of 118 kg. She had been cisco, San Francisco, California 94143. * This work was supported by the Clinical Research maintained on cortisone acetate (25 mg twice daily) Service of Madigan General Hospital of Tacoma, WA, with increased salt intake. Since surgery, her skull and by the Levi J. and Mary C. Skaggs Foundation of x-ray examinations had shown some irregularity of Oakland, CA. f Present address: USA Medcomeur, Heidelberg, Ger- the floor of the sella turcica without further changes. She had had increased skin pigmentation. many, APO New York, New York 09403. 1137
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1138
COMMENTS
Visual fields were normal, and no neurological symptoms were present. HH was a 46-yr-old woman who underwent surgery in 1960 with a diagnosis of bilateral adrenal hyperplasia. Her blood pressure was 122/80 mm Hg and her pulse was 80 beats/min. Her height was 178 cm, with a weight of 82 kg. She had been maintained on cortisone acetate (25 mg in the morning with 12.5 mg in the afternoon). She had also taken fludrocortisone (0.1 mg daily). She had been noted to have increased pigmentation beginning approximately 6 months after surgery. Slight enlargement of the sella turcica, which had not changed, had been seen on skull x-ray films. There had been no neurological symptoms, and visual fields were normal. JT was a 42-yr-old woman who had a subtotal adrenalectomy in 1957. Cushing's disease recurred, and the adrenal remnant was excised in 1970. Her blood pressure was 114/80 mm Hg and her pulse was 84 beats/min and regular. Her height was 160 cm, with a weight of 58 kg. She had been maintained on cortisone acetate (25 mg twice daily) and fludrocortisone (0.05 mg every other day). There had been no change in her skull x-ray examinations or her skin pigmentation. Each patient's glucocorticoid steroid treatment was withheld after the afternoon before each study. At 0800 h, in a fasting state, each received a single im injection of 50 mg either cortisone acetate or hydrocortisone hemisuccinate. During the 4-h test, blood was withdrawn at 0, 1, 2, 3, and 4 h through a butterfly needle placed in an antecubital vein for plasma cortisol and ACTH determinations. The zero time value was obtained before injection. In an attempt to determine if delayed absorption of either agent occurred, individual samples were drawn for plasma cortisol and ACTH measurement at 4-h intervals for 48 h, during which time the patients were hospitalized. Each was given 50 mg cortisone acetate im as a single injection at the start of the 48 h; 24 h into the study, hydrocortisone hemisuccinate (50 mg) was given as a single im injection. The cortisone acetate used for the im studies was sterile cortisone acetate suspension (U.S.P.; 25 mg/ml),1 which was obtained from The Upjohn Co.; the hydrocortisone hemisuccinate preparation used was Solu-Cortef (mix-o-vial) from The Upjohn Co. The plasma cortisol level was measured by the
.JCK&M • 1978 Vol 47 • No 5
fluorimetric method of Mattingly (7), for which normal values in our laboratory ranged from 5-25 jtig/dl. Plasma ACTH levels were determined by the method of Rees et al. (8) with slight modifications, and normal values ranged from 10-100 pg/ml. Patients SB, HD, and HH were also given 50 mg cortisone acetate (Cortisone Acetate tablets, U.S.P., The Upjohn Co.) or hydrocortisone (Cortef tablets, U.S.P., The Upjohn Co.) by mouth on separate study days. Blood samples were obtained at 0, 1, 2, 3, and 4 h for plasma cortisol and ACTH levels. Results
Intramuscular injection of cortisone acetate caused neither a significant rise in plasma cortisol levels nor a noteworthy suppression of ACTH values during the 4-h study. Indeed, plasma cortisol levels remained essentially unchanged: from a mean basal value of 6.6 ±1.1 /ig/dl (±SEM), the highest level achieved was 7.8 ± 1 . 6 /tg/dl at 1 h, with the 4-h value returning to 6.7 ± 1.4 jug/dl. ACTH levels never fell below 300 pg/ml (from a mean basal value of 357 ± 85 pg/ml to a low of 312 ± 42 at 3 h). In contrast, hydrocortisone hemisuccinate, similarly administered, caused a prompt rise in plasma cortisol from a mean basal level of 9.0 ± 1.2 jug/dl to 64.2 ± 11.1, 59.4 ± 10.6,48.6 ± 10.6, and 39.8 ± 7.4 jug/dl at 1, 2, 3, and 4 h, respectively. ACTH levels were suppressed from a baseline value of 286 ± 70 pg/ml to 137 ± 29, 75 ± 21, 53 ± 12, and 40 ± 12 pg/ml at 1, 2, 3, and 4 h, respectively. Similar results were obtained during the 48h study, as can be seen in Table 1. During the 24 h after im injection of cortisone acetate, blood samples every 4 h revealed no significant change, indicating that there is no delayed absorption of this agent. Again, the response to hydrocortisone administration was prompt. Mean levels of plasma cortisol rose from a basal value of 6.5 ± 1.6 jug/dl at 0800 h of the second day to 40.8 ± 6.9 /xg/dl after 4 h; and ACTH levels fell from 306 ± 105 pg/ml at 0800 h to 39 ± 23 and 60 ± 49 pg/ml at 4 and 8 h, respectively {i.e. 1200 and 1600 h of the second study day). 1 This was measured spectrophotometrically as PorterOral administration of cortisone acetate efSilber chromogens (6) against a known standard of cortifected a response that mimicked that caused sone and was found to contain the exact specified amount by hydrocortisone, although neither the eleof cortisone acetate.
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y
COMMENTS
vation of cortisol nor the suppression of ACTH was as marked with the former (Table 2). With cortisone acetate, plasma cortisol rose from 12.1 ± 1.2 to 43.1 ± 8.3 jug/dl at 2 h and plasma ACTH fell from 257 ± 153 to 61 ± 28, 35 ± 14, and 28 ± 11 pg/ml at 2, 3, and 4 h, respectively. With hydrocortisone, plasma cortisol rose from 10.1 ± 3.2 to 64.5 ±11.3 jug/dl after 2 h and plasma ACTH levels fell from 275 ± 123 to 42 ± 9, 26 ± 11, and 18 ± 6 pg/ml at 2, 3, and 4 h, respectively. Discussion Previous investigations have shown that
1139
cortisone acetate when given im failed to cause a significant elevation of the plasma cortisol level (4, 5). In contrast, similar administration of hydrocortisone hemisuccinate effected a prompt and significant rise (4). When given by mouth, however, cortisone acetate did cause a prompt rise in the plasma cortisol level (9), and no significant difference was found between this response and that caused by oral hydrocortisone. The present study of four patients with chronic adrenal insufficiency after bilateral adrenalectomy for Cushing's disease corroborates these findings. Blood samples for determination of plasma cortisol and ACTH levels
TABLE I. Comparison of im injections of cortisone acetate and hydrocortisone hemisuccinate on plasma 11-hydroxycorticosteroids and ACTH 11-Hydroxycorticosteroids (/xg/dl) 1 ime (h)
Cortisone acetate
Hydrocortisone hemisuccinate
Mean ±
Patient
SB
HD
HH
0800 1200 1600 2000 2400 0400
9.0 12.0 12.9 13.0 10.6 8.3
8.5 9.4 9.9 8.3 7.5 8.8
9.1 8.0 6.0 7.7 5.9 5.7
0800 1200 1600 2000 2400 0400 0800
9.4 61.3 20.4 12.5 9.1 6.5 7.4
8.6 36.3 12.9 5.0 3.9 7.9 9.4
2.6 33.2
ACTH (pg/ml)
SB
HD
HH
JT"
1.2 0.9 1.5 1.2 1.0 1.0
813 571 852 534 256 288
229 217 358
8.8 10.2
± ± ± ± ± ±
149
61 139 160 75 28 82
(12) (12) (14) (18) (15) (26)
368 ± 309 ± 457 ± 257 ± 129 ± 173 ±
232 135 209 141 67 61
5.4 32.4 17.9 7.3 5.8 4.5 5.1
6.5 40.8 15.2 7.1 5.6 5.6 6.0
± ± ± ± ± ± ±
1.6 6.9 2.4 1.9 1.4 1.2 1.6
489 82
296 28
133 8
157
12
808 371 409 315
7 36 100 122
11 41
(12) (16) (12) (15) (18) (17) (10)
306 ± 39 ± 60 ± 285 ± 143 ± 205 ± 169 ±
105 23 49 262 114 102 74
4.1
8.6 10.9 9.1
2.7 2.7 2.2
SEM
7.7 9.5 9.9 9.5 8.2 8.3
JT
9.6 4.1
Mean ±
Patient
SEM
161 104
23 105 71
Cortisone acetate was given as a single 50-mg im injection at 0800 h on day 1; hydrocortisone hemisuccinate was giyen similarly 24 h later (at 0800 h on day 2). " ACTH values in patient J T were not included in the mean value, since they were at the lower limit of the assay. TABLE 2. Comparison of oral ingestion of cortisone acetate and hydrocortisone on plasma 11-hydroxycorticosteroids and ACTH Steroid Cortisone acetate
(fig/dl)
ACTH (pg/ml)
1h
2h
SB HD HH
14.6 11.3 10.4 12.1 ± 1.2
46.3 25.8 39.3 37.1 ± 6.0
53.4 27.0 48.8 43.1 ± 8.3
SB HD HH
16.2 88.0 115.6 61.8 46.6 512 292 20.7 144 8.1 40.8 34.5 29.8 192 41.9 68 64.8 54.5 120 85.5 5.9 10.1 ± 3.2 78.5 ± 15.5 64.5 ± 11.3 48.4 ± 9.7 36.4 ± 8.0 275 ± 123 168 ± 66
3h
4h
Oh
1h
Oh
Mean ± SEM Hydrocortisone hemisuccinate Mean ± SEM
11-Hydroxycorticosteroids
Pn
2h
3h
4h
94 57 49 221 43.9 555 47.3 24 77 39 131 17.3 144 22.7 12 12 9 61 35.4 72 42.3 37.4 ± 7.5 32.2 ± 7.9 257 ± 153 138 ± 46 61 ± 28 35 ± 14 28 ± 11 56 45 26 42 ± 9
48 16 13 26 ± 11
30 10 15
18 ± 6
Each steroid was given as a single 50-mg oral dose, and blood samples were collected at 0, 1, 2, 3, and 4 h.
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1140
COMMENTS
revealed that administration by im injection was effective only for hydrocortisone even when values were measured every 4 h for 24 h after each agent was given. Therefore, cortisone acetate seems not to be absorbed sufficiently, either promptly or by delayed response, to effect the desired therapeutic change. It should not be given im in the treatment of acute adrenal insufficiency or as coverage for patients undergoing surgical procedures. Such patients should be treated with a hydrocortisone preparation. When cortisone acetate and hydrocortisone were given by mouth to three of the four patients in this study, the response to each agent was similar. Therefore, for those patients requiring chronic glucocorticoid therapy, oral administration of cortisone acetate is sufficient and appropriate.
JCK & M Vol 47
197H No 5
References 1. BONDY, P. K., The adrenal cortex, In Bondy, P. K., and L. E. Rosenberg (eds.), Duncan's Diseases of Metabolism, ed. 7, Philadelphia, W. B. Saunders Co., 1974, p. 1155. 2. PARENTERAL CORTICOSTEROIDS IN EMERGENCY, Drug Ther
Bull 5: 6, 1967. 3. HlMATHONOKAM, T., S. R. NEWMARK, M. GREENFIELD, AND
R. G. DLUHY, Acute adrenal insufficiency, JAMA 230: 1317, 1974. 4. KEHLET, H., S. NISTRUP MADSEN, AND C. BINDER, Cortisol
and cortisone acetate in parenteral glucocorticoid therapy, Acta Med Scand 195: 421, 1974. 5. PLUMPTON, F. S., G. M. BESSER, AND P. V. COLE, Corticoste-
roid treatment and surgery, Anaesthesia 24: 12, 1969. 6. SILBER, R. H., AND C. C. PORTER, Determination of 17, 21-
dihydroxy-20-ketosteroids in urine and plasma, J Biol Chem 210: 923, 1954. 7. MATTINGLY, D., A simple fluorimetric method for the estimation of free 11-hydroxycorticoids in human plasma, J Clin Pathol 15: 374, 1962. 8. REES, L. H., D. M. COOK, J. W. KENDALL, C. F. ALLEN, R. M. KRAMER, J. G. RATCLIFFE, AND R. A. KNIGHT, A radioim-
munoassay for rat plasma ACTH, Endocrinology 89: 254, 1971. 9. KEHLET, H., CHR. BINDER, AND M. BLICHERT-TOFT, Gluco-
corticoid maintenance therapy following adrenalectomy: assessment of dosage and preparation, Clin Endocrinol 5: 37, 1976.
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Vol. 47, No. 5 Printed in U.S.A.
Comparison of Absorption of Cortisone Acetate and Hydrocortisone Hemisuccinate* BRUCE L. FARISS.f SATOSHI HANE, JEANETTE SHINSAKO, AND PETER H. FORSHAM Clinical Research Service, Madigan General Hospital, Tacoma, Washington 98431; and the Metabolic Research Unit and Department of Medicine, University of California, San Francisco, California 94143 ABSTRACT. In four patients who required maintenance glucocorticoid therapy after bilateral adrenalectomy for Cushing's disease, we compared the effects of im injection and oral ingestion of cortisone acetate and hydrocortisone hemisuccinate. By the former route of administration, cortisone acetate was not effective in elevating plasma cortisol levels or in suppressing plasma adrenocorticotropin, although hydrocortisone was. When given by mouth, no significant difference was
A
CUTE adrenal insufficiency is a lifeL threatening situation that requires the administration of glucocorticoid steroids. In addition, patients on maintenance glucocorticoid therapy must be managed through acute situations precipitated by infections, trauma, stress, or surgical procedures. Treatment programs that recommend cortisone acetate as a parenteral corticosteroid have been outlined (1-3), but other studies have demonstrated that plasma cortisol levels did not rise after im injection of this agent (4, 5). With hydrocortisone hemisuccinate, however, im injection has been shown to be effective (4). In the present study of four patients with chronic adrenal insufficiency after bilateral adrenalectomy for Cushing's disease, im injection of cortisone acetate resulted in only a minimal rise in plasma cortisol levels (or none at all) and an insignificant suppression of plasma ACTH levels. Hydrocortisone, how-
found between the two steroids. Therefore, in the treatment of acute adrenal insufficiency or in the maintenance of patients with chronic adrenal insufficiency and in their preparation for surgery or other stressful situations, we advise against im injection of cortisone acetate. Oral ingestion, however, is appropriate for maintenance. (J Clin Endocrinol Metab 47: 1137, 1978)
ever, caused a significant rise in plasma cortisol and a prompt suppression of the plasma ACTH levels when given by this route. Both agents were equally effective when taken orally. Subjects and Methods Four ambulatory patients participated after their written informed consent had been obtained. Each had undergone bilateral adrenalectomy as the
treatment for Cushing's disease. SB was a 39-yr-old woman who underwent surgery in 1972 after a diagnosis of bilateral adrenal hyperplasia. Her blood pressure was 120/80 mm Hg, with a pulse of 88 beats/min. Her height was 160 cm, with a weight of 61 kg. Her skin pigmentation was normal. She had been maintained on cortisone acetate (25 mg by mouth each morning with 12.5 mg in the afternoon). Fludrocortisone had been taken sporadically. Skull x-ray films had been interpreted as normal on yearly examination. HD was a 66-yr-old woman who underwent surgery in 1971 with a diagnosis of bilateral adenomReceived October 10, 1977. atous hyperplasia. Her blood pressure was 166/90 Address requests for reprints to: Satoshi Hane, Metabolic Research Unit, University of California-San Fran- mm Hg and her pulse was 72 beats/min. Her height was 160 cm, with a weight of 118 kg. She had been cisco, San Francisco, California 94143. * This work was supported by the Clinical Research maintained on cortisone acetate (25 mg twice daily) Service of Madigan General Hospital of Tacoma, WA, with increased salt intake. Since surgery, her skull and by the Levi J. and Mary C. Skaggs Foundation of x-ray examinations had shown some irregularity of Oakland, CA. f Present address: USA Medcomeur, Heidelberg, Ger- the floor of the sella turcica without further changes. She had had increased skin pigmentation. many, APO New York, New York 09403. 1137
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 11:25 For personal use only. No other uses without permission. . All rights reserved.
1138
COMMENTS
Visual fields were normal, and no neurological symptoms were present. HH was a 46-yr-old woman who underwent surgery in 1960 with a diagnosis of bilateral adrenal hyperplasia. Her blood pressure was 122/80 mm Hg and her pulse was 80 beats/min. Her height was 178 cm, with a weight of 82 kg. She had been maintained on cortisone acetate (25 mg in the morning with 12.5 mg in the afternoon). She had also taken fludrocortisone (0.1 mg daily). She had been noted to have increased pigmentation beginning approximately 6 months after surgery. Slight enlargement of the sella turcica, which had not changed, had been seen on skull x-ray films. There had been no neurological symptoms, and visual fields were normal. JT was a 42-yr-old woman who had a subtotal adrenalectomy in 1957. Cushing's disease recurred, and the adrenal remnant was excised in 1970. Her blood pressure was 114/80 mm Hg and her pulse was 84 beats/min and regular. Her height was 160 cm, with a weight of 58 kg. She had been maintained on cortisone acetate (25 mg twice daily) and fludrocortisone (0.05 mg every other day). There had been no change in her skull x-ray examinations or her skin pigmentation. Each patient's glucocorticoid steroid treatment was withheld after the afternoon before each study. At 0800 h, in a fasting state, each received a single im injection of 50 mg either cortisone acetate or hydrocortisone hemisuccinate. During the 4-h test, blood was withdrawn at 0, 1, 2, 3, and 4 h through a butterfly needle placed in an antecubital vein for plasma cortisol and ACTH determinations. The zero time value was obtained before injection. In an attempt to determine if delayed absorption of either agent occurred, individual samples were drawn for plasma cortisol and ACTH measurement at 4-h intervals for 48 h, during which time the patients were hospitalized. Each was given 50 mg cortisone acetate im as a single injection at the start of the 48 h; 24 h into the study, hydrocortisone hemisuccinate (50 mg) was given as a single im injection. The cortisone acetate used for the im studies was sterile cortisone acetate suspension (U.S.P.; 25 mg/ml),1 which was obtained from The Upjohn Co.; the hydrocortisone hemisuccinate preparation used was Solu-Cortef (mix-o-vial) from The Upjohn Co. The plasma cortisol level was measured by the
.JCK&M • 1978 Vol 47 • No 5
fluorimetric method of Mattingly (7), for which normal values in our laboratory ranged from 5-25 jtig/dl. Plasma ACTH levels were determined by the method of Rees et al. (8) with slight modifications, and normal values ranged from 10-100 pg/ml. Patients SB, HD, and HH were also given 50 mg cortisone acetate (Cortisone Acetate tablets, U.S.P., The Upjohn Co.) or hydrocortisone (Cortef tablets, U.S.P., The Upjohn Co.) by mouth on separate study days. Blood samples were obtained at 0, 1, 2, 3, and 4 h for plasma cortisol and ACTH levels. Results
Intramuscular injection of cortisone acetate caused neither a significant rise in plasma cortisol levels nor a noteworthy suppression of ACTH values during the 4-h study. Indeed, plasma cortisol levels remained essentially unchanged: from a mean basal value of 6.6 ±1.1 /ig/dl (±SEM), the highest level achieved was 7.8 ± 1 . 6 /tg/dl at 1 h, with the 4-h value returning to 6.7 ± 1.4 jug/dl. ACTH levels never fell below 300 pg/ml (from a mean basal value of 357 ± 85 pg/ml to a low of 312 ± 42 at 3 h). In contrast, hydrocortisone hemisuccinate, similarly administered, caused a prompt rise in plasma cortisol from a mean basal level of 9.0 ± 1.2 jug/dl to 64.2 ± 11.1, 59.4 ± 10.6,48.6 ± 10.6, and 39.8 ± 7.4 jug/dl at 1, 2, 3, and 4 h, respectively. ACTH levels were suppressed from a baseline value of 286 ± 70 pg/ml to 137 ± 29, 75 ± 21, 53 ± 12, and 40 ± 12 pg/ml at 1, 2, 3, and 4 h, respectively. Similar results were obtained during the 48h study, as can be seen in Table 1. During the 24 h after im injection of cortisone acetate, blood samples every 4 h revealed no significant change, indicating that there is no delayed absorption of this agent. Again, the response to hydrocortisone administration was prompt. Mean levels of plasma cortisol rose from a basal value of 6.5 ± 1.6 jug/dl at 0800 h of the second day to 40.8 ± 6.9 /xg/dl after 4 h; and ACTH levels fell from 306 ± 105 pg/ml at 0800 h to 39 ± 23 and 60 ± 49 pg/ml at 4 and 8 h, respectively {i.e. 1200 and 1600 h of the second study day). 1 This was measured spectrophotometrically as PorterOral administration of cortisone acetate efSilber chromogens (6) against a known standard of cortifected a response that mimicked that caused sone and was found to contain the exact specified amount by hydrocortisone, although neither the eleof cortisone acetate.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 11:25 For personal use only. No other uses without permission. . All rights reserved.
y
COMMENTS
vation of cortisol nor the suppression of ACTH was as marked with the former (Table 2). With cortisone acetate, plasma cortisol rose from 12.1 ± 1.2 to 43.1 ± 8.3 jug/dl at 2 h and plasma ACTH fell from 257 ± 153 to 61 ± 28, 35 ± 14, and 28 ± 11 pg/ml at 2, 3, and 4 h, respectively. With hydrocortisone, plasma cortisol rose from 10.1 ± 3.2 to 64.5 ±11.3 jug/dl after 2 h and plasma ACTH levels fell from 275 ± 123 to 42 ± 9, 26 ± 11, and 18 ± 6 pg/ml at 2, 3, and 4 h, respectively. Discussion Previous investigations have shown that
1139
cortisone acetate when given im failed to cause a significant elevation of the plasma cortisol level (4, 5). In contrast, similar administration of hydrocortisone hemisuccinate effected a prompt and significant rise (4). When given by mouth, however, cortisone acetate did cause a prompt rise in the plasma cortisol level (9), and no significant difference was found between this response and that caused by oral hydrocortisone. The present study of four patients with chronic adrenal insufficiency after bilateral adrenalectomy for Cushing's disease corroborates these findings. Blood samples for determination of plasma cortisol and ACTH levels
TABLE I. Comparison of im injections of cortisone acetate and hydrocortisone hemisuccinate on plasma 11-hydroxycorticosteroids and ACTH 11-Hydroxycorticosteroids (/xg/dl) 1 ime (h)
Cortisone acetate
Hydrocortisone hemisuccinate
Mean ±
Patient
SB
HD
HH
0800 1200 1600 2000 2400 0400
9.0 12.0 12.9 13.0 10.6 8.3
8.5 9.4 9.9 8.3 7.5 8.8
9.1 8.0 6.0 7.7 5.9 5.7
0800 1200 1600 2000 2400 0400 0800
9.4 61.3 20.4 12.5 9.1 6.5 7.4
8.6 36.3 12.9 5.0 3.9 7.9 9.4
2.6 33.2
ACTH (pg/ml)
SB
HD
HH
JT"
1.2 0.9 1.5 1.2 1.0 1.0
813 571 852 534 256 288
229 217 358
8.8 10.2
± ± ± ± ± ±
149
61 139 160 75 28 82
(12) (12) (14) (18) (15) (26)
368 ± 309 ± 457 ± 257 ± 129 ± 173 ±
232 135 209 141 67 61
5.4 32.4 17.9 7.3 5.8 4.5 5.1
6.5 40.8 15.2 7.1 5.6 5.6 6.0
± ± ± ± ± ± ±
1.6 6.9 2.4 1.9 1.4 1.2 1.6
489 82
296 28
133 8
157
12
808 371 409 315
7 36 100 122
11 41
(12) (16) (12) (15) (18) (17) (10)
306 ± 39 ± 60 ± 285 ± 143 ± 205 ± 169 ±
105 23 49 262 114 102 74
4.1
8.6 10.9 9.1
2.7 2.7 2.2
SEM
7.7 9.5 9.9 9.5 8.2 8.3
JT
9.6 4.1
Mean ±
Patient
SEM
161 104
23 105 71
Cortisone acetate was given as a single 50-mg im injection at 0800 h on day 1; hydrocortisone hemisuccinate was giyen similarly 24 h later (at 0800 h on day 2). " ACTH values in patient J T were not included in the mean value, since they were at the lower limit of the assay. TABLE 2. Comparison of oral ingestion of cortisone acetate and hydrocortisone on plasma 11-hydroxycorticosteroids and ACTH Steroid Cortisone acetate
(fig/dl)
ACTH (pg/ml)
1h
2h
SB HD HH
14.6 11.3 10.4 12.1 ± 1.2
46.3 25.8 39.3 37.1 ± 6.0
53.4 27.0 48.8 43.1 ± 8.3
SB HD HH
16.2 88.0 115.6 61.8 46.6 512 292 20.7 144 8.1 40.8 34.5 29.8 192 41.9 68 64.8 54.5 120 85.5 5.9 10.1 ± 3.2 78.5 ± 15.5 64.5 ± 11.3 48.4 ± 9.7 36.4 ± 8.0 275 ± 123 168 ± 66
3h
4h
Oh
1h
Oh
Mean ± SEM Hydrocortisone hemisuccinate Mean ± SEM
11-Hydroxycorticosteroids
Pn
2h
3h
4h
94 57 49 221 43.9 555 47.3 24 77 39 131 17.3 144 22.7 12 12 9 61 35.4 72 42.3 37.4 ± 7.5 32.2 ± 7.9 257 ± 153 138 ± 46 61 ± 28 35 ± 14 28 ± 11 56 45 26 42 ± 9
48 16 13 26 ± 11
30 10 15
18 ± 6
Each steroid was given as a single 50-mg oral dose, and blood samples were collected at 0, 1, 2, 3, and 4 h.
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1140
COMMENTS
revealed that administration by im injection was effective only for hydrocortisone even when values were measured every 4 h for 24 h after each agent was given. Therefore, cortisone acetate seems not to be absorbed sufficiently, either promptly or by delayed response, to effect the desired therapeutic change. It should not be given im in the treatment of acute adrenal insufficiency or as coverage for patients undergoing surgical procedures. Such patients should be treated with a hydrocortisone preparation. When cortisone acetate and hydrocortisone were given by mouth to three of the four patients in this study, the response to each agent was similar. Therefore, for those patients requiring chronic glucocorticoid therapy, oral administration of cortisone acetate is sufficient and appropriate.
JCK & M Vol 47
197H No 5
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