Studies on DexamethaHone, A New Synthetic Steroid,

in Rheumatoid A r t h r i t i r A Preliminary Report

Adrenal :Cortical, Metabolic~and~EarlyjClinical~ffecte
By JOSEPH J. BUNIM,ROGERL. BLACK,LEOLUTWAK,
RALPHE. PETEFSON
AND G. DONALDWHED~N

Observations concerning the antirheuma- Es presentate observationes relative a1

tic and physiologic effects of a new syn-
thetic corticosteroid, dexamethasone, are
presented. This preparation, the most po-
tent of any steroid heretofore studied,
did not cause sodium retention or potas-
sium loss in doses sufficient to suppress
rheumatoid disease. Increased nitrogen
and calcium excretion were observed.
Further clinical studies are indicated.
For the present, it is suggested that the
daily dose of dexamethasone should not
exceed 4 mg.
effectos antirheumatic e physiologic del
nove corticosteroide synthetic, dexa-
methasone. Iste preparato, le plus potente
de omne le steroides usque nunc studiate,
non causava retention de natrium o
perdita de kalium quando usate in doses
sufficiente a supprimer morbo rheuma-
toide. Augmentos del excretion de nitro-
geno e de calcium esseva observate.
Studios clinic additional es indicate. Por
le momento, il es suggerite que le dose
diurne de dexamethasone non excede 4
mg*

D EXAMETHASONE' is delta-1,Y-a fluoro,l6a methyl hydrocortisone. In

other words, it is a prednisolone analog to which have been added a
fluorine atom at carbon 9 and a methyl radical at carbon 16. This compound
was synthesized by a team of scientists1 who studied its glucocorticoid,
mineralocorticoid and anti-inflammatory properties in rats and found it to
have the following potencies:
adrenal atrophy, 700 times hydrocortisone
involution of thymus, 400 times hydrocortisone
granuloma inhibition, 190 times hydrocortisone
body weight depression, 100 times hydrocortisone
and glycogen deposition, 17 times hydrocortisone.
In adrenalectomized rats dexamethasone produced neither sodium retention
nor potassium loss.
It will be recalled that prednisone was the first of the synthetic, biologically
active 11,17 oxysteroids that was found to have enhanced anti-inflammatory
potency (compared to hydrocortisone) and yet was free of the objectionable
effects of sodium retention and potassium loss2 It was not, however, free of
~~

From the National Institute of Arthritis and Metabolic Diseases, National Institutes of
Health, Bethesda, Md.
W e wish to acknowledge with gratitude the help of Kurt J . Bloch, M.D., and John A.
D a d , M.D., with the clinical observations und the rrssistance of Bernard Klimun, M.D.,
in the aldosterone studies.
'Dr. Elmer Alpert of Merck Sharp & Dohme Research Laboratories, Division of Merck &
Co., generously provided us with dexamethasone (Decadron).
313
314 BUNIM, BLACK, LVTWAK, PETERSON AND WHEDON

the more serious effects of prolonged corticosteroid administration, such as

rilceration of the stomach or duodenum, osteoporosis leading to skeletal frac-
tures, mental changes and vascular complications.”.i Following prednisone
and prednisolone, other synthetic, antirheumatic steroids, notably triamcino-
lonee and 6-methylprednisolone ( Medrol ) have been introduced, and their
long-term effects are currently being studied.
Efforts at new alterations of the molecular structure of corticosteroids and
clinical trials of such compounds ale directed towards the goal of synthe-
sizing a preparation therapeutically effective and relatively, if not absolutely,
free of serious hazards to the patient.
Initial studies on dexamethasone have revealed that it possesses greater
antirheumatic potency than any steroid thus far synthesized; about six times
that of prednisone or 25 to 30 times that of hydrocortisone. Its capacity to
suppress corticotropin secretion is even more impressive; about 30 times
greater than that of prednisone. Marked suppression of this specific pituitary-
adrenal function is not associated with suppression of aldosterone secretion.
Challenged with sodium deprivation the human subject continues to con-
serve sodium effectively while taking relatively large doses of dexamethasone.
On the other hand, dexamethasone administration is not associated with re-
tention of sodium or loss of potassium when the mineral content of the diet
is unrestricted. Because this compound exhibits these unusual properties
we thought an early report of these studies might be of interest to other
investigators.
EFFECXS
I. HORMONAL
Suppression of corticotropin secretion.-Varying amounts of dexamethasone
in single oral doses were given to a normal subject at midnight, and plasma
concentration of hydrocortisone was measured eight hours later in order to
determine the smallest amount of steroid necessary to suppress plasma level
of hydrocortisone to zero. Dexamethasone was given at 12 midnight rather
than at 8 a.m. so that its effect on plasma hydrocortisone in the early morning
would not coincide with the natural diurnal fall in the late afternoon. It will
be noted in table 1 that a single oral dose of 1.0 mg. was sufficient to reduce
plasma hydrocortisone to zero whereas in the same subject at least 2.0 mg.
of delta-1, 9-a fluorohydrocortisone, which heretofore was the most potent

A1. 9 n , F, hydrocortisone Dexarnethasone

Plasma F‘ Plasma F
DO%= fig.% Lh1vr fie.%
Control 21 I .O nig. 0
2.5 mg. 0 1.0 mg. 0
Control 18 Control 13
2.0 mg. 0 1.0 mg. 0
Control 23 0.5 mg. 12
1.0 mg. 23 0.25 mg. 13
‘Plasma F = Plasma hydrocortisone concentration.
STUDIFS ON DEXAMETHASONE 315
corticotropin suppressant available, were required to achieve the same cle-
gree of adrenocortical suppression. In previous studies it was found that
the suppression dose of prednisone was 30 mg. and of 9-a fluorohydrocortisone,
5 mg.
The biologic half-time (i.e., the time required for one-half of an intra-
venously administered dose to disappear from the plasma) of dexamethasone
was determined in normal subjects and found to be 170 to 210 minutes. The
half-time for hydrocortisone is 95 to 120 minutesHand for prednisolone about
200 minutes.s
When dexamethasone was given therapeutically to patients with rheumatoid
arthritis in doses of one or two mg. daily (in four divided doses), plasma
concentration of hydrocortisone was reduced to zero within 24 hours, cir-
culating eosinophils were diminished and urinary excretion of corticoids and
17-ketosteroidswere decreased (table 2 and fig. 1) .
Aldosterone respon.siven.ess.-In view of the striking suppression of hydro-
cortisone production that resulted from small doses of dexamethasone it was
of interest to determine whether or not aldosterone secretion was also in-
hibited. Urinary aldosterone excretion in a normal subject on a constant
sodium intake of 2.0 Gm. (87.0 mEq.) and potassium intake of 6.0 Gm. was
measured by the method of Kliman and Petersonlo and found to be 12 rg.
per 24 hours (table 3). When sodium intake was then restricted to 200 mg.
(8.7 mEq. ) daily (potassium intake remaining at 6.0 Gm. ), an initial loss
of sodium occurred, aldosterone excretion increased to 32 Pg., and then posi-
tive balance of sodium was restored (fig. 2 and table 3). At this point dexa-
methasone was given in daily doses of 6 mg. (1.5 mg. every 6 hours) for 12
successive days. On the fourth day of dexamethasone administration a nega-
tive sodium balance developed bnt on the eleventh and twelfth days enough
sodium was conserved to establish a positive balance. Urinary aldosterone
was found to have increased further to 58 rg. per 24 hours. During the
period of dexamethasone administration and salt deprivation, serum sodium
concentration varied from 138 to 142 mEq./l. Five days after dexamethasone
was discontinued but sodium restriction maintained, urinary aldosterone ex-
cretion reached 70 Pg. per day, and serum sodium concentration 145 mEq./l.

TABLE
2.--Effect of Dexamethasone on Adrenal Corti(d Function in Potient toitla
Rheumatoid Arthritis (Case 3 )
Plasma Urinary Excretion
hydroeortisone
Dex. dosage concentration Corticoids 17 ketosteroids
Date (mg./da~) (!-me.%) (mg./24 hrs.) (mg./24 hm.)

3/7 0 26 5.6 2.1

319 0 5.2
3/10 0 22
3/11 1 m0 2.2t 2.lt
3/12 1 0
3/13 1 0
3/15 1 0.4 1.1
‘This blood sample was drawn before the first dose of dexamethasone was given.
fUrine collected during the first 24 hours that patient received dexamethasone.
.iT. CHR!STOPYL?’S HOSPITAL
.-.A- n. ... --.-+..
316 BVNIM, BLACK, LlJTWAK, PETERSON AND WHEDON

DRUG

1-
ESR mm./Hr 50

FOSINOPHILS 2oo
Irnrn.3
0
PLASMA
COMPOUND F: 15
119.%
0

U R I N A R Y 17-KS
m g . 1 2 4 Hrs.
0
0 10 20 30 40 50 60 70 0 10 20 30 40 50
DAYS

FIG.I .--Effect of varying dosages of clexanirthasone ( MK-12.5) and 16-a methyl hydrn-
cortisone ( MK-117) on E.S.R. (Wrstergren 1, eosinophil count, plasma concentration of
hydrocortisone (compound F ) and urinary excretion of 17-ketosteroids, in two patients
with rheumatoid arthritis.
TABLE3.-Changes in Urr'nury Aldosterone Excretion Related to Sodium Intake, Sodium
Excretion and Dexumethmone Administration (6 mg. daily) in a N m l Subject"
Sodium Intake Urinary Urinary No. of days Urinary
sodium potassium dexamethasone aldosterone
Amount No. excretion excretion administered excretion
Date (mEq./day) days (mEa./day) (mErdday) ( 6 mg./day) (&g./day)
4i1415 87.0 6 75.5 132.0 0 12
4/20-21 8.7 6t 0.1 122.2 0 32
4/21-22 8.7 7 6.9 158.3 1 30
4i2425 8.7 10 12.5 110.9 4 32
4/28-29 8.7 14 19.3 122.7 8 38
5/23 8.7 18 9.2 120.8 12 58
5/74 8.7 23 1.4 124.8 5 daysafter 70
stopping
dewmethasone
"Potassium intake remained constant at 6.0 Gm. daily.
t h w sodium diet was started on April 15.

From this experiment it was evident that aldosterone prodnction, unlike

hydrocortisone production, was not inhibited bv dexamethasone. Indeed dexa-
methasone failed to suppress normal aldosterone responsiveness to dietary
sodium restriction or sodium loss.
11. METABOLICBALANCESTUDIES
A full report of the methods employed and results obtained in these meta-
bolic balance studies will be published separately at a later date. A brief
summary of the findings follows.
STUDIES ON DEXAMETHASONE 317

U R I N A R Y A LDOSTERON E
I /
P9J
24 hrs.

mEq./ I ,404
I35
-
SERUM SODIUM

I I

mEq./
24 hrs.

100’
I I
n . POTASSIU~ I
m E q./
24 hrs.

50

0
pgJ100 10
0
0 5 10 15 20 25 30 35
DAYS
FIG.2.-Aldosterone responsiveness to restriction of dietary sodirmi ( reduced from 87
mEq. to 8.7 mEq. per 24 hours) and again to sodium loss temporarily inducrd by dexa-
methasone (formerly known as hexadecadrol) administration (6.0 mg. daily). Effects of
dexamethasone on urinary potassirmi excretion ( note first day of drug sdministration and
withdrawal); on serum sodinm ( during sodium deprivation and loss ) ; on circulating eosino-
phils and on concentration of plasma hydroccrtisone are also demonstrated.
318 BUNIhf, BLACK, LUTWAK, PETERSON AND \\WEDON

Two female patients, 28 and 31 years old, both having active rheumatoid
arthritis of moderate severity and slight impairment of functional capacity
(class 2 ) were the subjects in this study. Measured daily dietary intake was
kept constant. The amounts of minerals and nitrogen ingested are shown in
figures 3 and 4. Complete urinary and fecal collections were made and
analyzed for sodium, potassium, nitrogen, calcium and phosphorus content.
The balance charts in figures 3 and 4 are so arranged that intake of dietary
constituents is plotted down from the upper “base” line and excretion, urinary
and fecal, is then plotted up from the intake line. Consequently, net reten-
tion, or positive balance, is represented by values below the ‘%base” line and
net loss, or negative balance, by values above the “base” line.
In addition to dexamethasone (MK-125) a related steroid, MK-117,’ was
administered for another period. Both new synthetic steroids have in common
a methyl radical at carbon 16 but unlike MK-125, MK-117 has no double
bond between carbons 1 and 2 and no halogen at carbon 9. MK-117, then,
is 16-a methyl hydrocortisone.
As indicated in the charts, in one case (02-01-98) three dosage schedules
of MK-125 were followed (2, 6 and 10 mg. daily) and 2 schedules of
MK-117 (50 and 100 mg. daily). In the second case (01-83-93) MK-117 was
given first in a daily dosage of 50 mg. only, and MK-125 given later in two
dosage schedules: 6 and 10 mg. daily. In both cases each period of steroid
administration was preceded and followed by a drug-free period.
Sodium balance.--.4dministration of dexamethasone produced a noticeable
diuresis of sodium in both patients and, as will be recalled, also in the normal
subject (fig. 2 ) on whom aldosterone studies were done. In case 02-01-98
diuresis occurred when daily dosages of 6 and 10 mg. were given; in the
normal subject when 6 mg. and in case 01-83-93 only when 10 mg. daily
were administered. Withdrawal of the drug produced a significant reten-
tion of sodium for a brief period. Administration of 50 mg. MK-117 produced
a more marked sodium loss in both patients than 10 mg. of dexamethasone.
Potassium.-Dexamethasone produced little if any change in potassium bal-
ances at any dosage level of the drug in case 09-01-98 or 01-83-93. In the
normal subject (fig. 2 ) given 6 mg. daily, potassium loss occurred during
the first day of drug administration and retention during the first day after
it was discontinued. With MK-117 nci changes in potassium excretion were
noted in either of the two patients.
Nitrogen-Administration of dexamethasone produced a definite increase in
nitrogen excretion in case 02-01-98. This became more marked as the daily
dose of the drug was increased until, on the 10 mg. dosage and on daily
intake of 115 Gm. of nitrogen, slightly negative balance was reached. Upon
withdrawal of the drug, increased retention of nitrogen followed. In case
01-83-93, on the other hand, only slight, if any, change occurred in nitrogen
excretion, even at the 10 mg. dosage. MK-117 produced similar changes in

‘Supplied by Dr. Elmer Alpert, Merck Sharp & I h h m e Research Laboratories, Division
of Merck & Co.
STUDIES ON DEXAMETHASONE 319

t t + + t t

K G.

. . .

G M.
PER
24
2.0 I I I 1
HRS.
n
" .
I
POTASSIUM I I I I l l
2.0- I
4.0- I
6.0 I I I I l l
0

.400

-800 1 11
0

.600

I .200

I 7 13 19 25 31 37 43 49 55 el 67 73 79
3 DAY PERIODS

FIG. 3.-Metabolic balance studies in a 28 year old female patient (ambulatory) with
rheumatoid arthritis before, during :md after aclministration of dexamethasone ( MK-125)
and 16-a methyl hydrocortisone (MK-117) in varying dosages.
320 BUNJM, BL4CK, LLTVAK, PETERSON Ah'D WHEWN

01 -83-93
'-1 MK-117 I
I I
t
"BUFFERIN': 5.0 Gm.
t t- +1 I 1
59.0,
KG.
I I 1-
0
SODIUM 1 n I I I I
d -lJL-L_r -- I

GM.
I .o- " I
PER
24 2.0
I I l l
HRS. POTASSIUM I I I

4 0

60

NITROGEN I I I

I 7 13 19 25 31 37 43 49 55
3 DAY P E R I O D S

FIG. 4.-Metabolic balance studies in a 31 year old female patient (ainbiilatory) with
rheumatoid arthritis while taking salicylatt-s ( 3 . 0 Gm. daily) and before. during and after
atlministrritioii of 16-a methyl liydrocortiwnc ( hlK-117 ) SO mg. daily, :ind d~,~;inicth:isoii~
(MK-125) in dosages of 6 and 10 mg. daily.

nitrogen metabolism. In case 02-01-98 negative nitrogen balance occurred

at 100 mg. dosage, whereas in case 01-83-93 nitrogen excretion increasecl
but negative balance did not occur on 50 mg. dosage and on a diet contain-
ing 12.8 Gm. of nitrogen.
Pho~hori~~.-Administrationof dexamethasone resulted in an increasingly
negative balance of phosphorus, due to an increase in both urinary and fecal
phosphorus excretion. Withdrawal of the drug was followed by retention
of phosphorus. In case 01-83-93 this effect was apparent only at the higher
dosage level. A similar pattern was observed with MK-117.
CnZciicm.--In case 02-01-98 dexamethasone produced a marked increase in
STUDIES ON DEXAMETHASONE 321

TABLEI.-Results of Glucose Tderunce leats on Patients Treated with Dexumethasone

Patients who received no steroid therapy for inany months prior to dexamethasone
Duration of
Dex. dose therapy at Type Previous
Cave mg./day time of test test used Result steroid therapy

1 4.0 10 wks. Intravenous Nonnal Prctdnisone

(3.0) * stopped 5 mos. prev.
3 1.o 9 wks. Intravenous Nonnal Prcdnisone
( 3.41 stopped 12 mos. prev.
5 2.0t 18 days Oral Normal Prdnisone
stopped 30 mos. prev.
~~ ~~~ ~ ~ ~ ~ ~ _ _ _ _

Patients who received MK-1094 prior to dexamethasone

Q 2.4 2 wks. Intravenous Normal MK 109 for 9 mos.
(4.3) prior to dex.
10 4.0 18 days Oral Normal M K 109 for 10 mos.
prior to dex.
~ ~ ~~~

Patients who reccivecl pwdnisone prior to drxarnethasone

2 2.4 9 wks. Intravenous Diabetic Pred. for 15 mos.
( 1.7) prior to dex.
4 3.8 9 wks. Intravenous Nonnal Pred. for 8 mos.
( 3.41 prior to dex.
6 1.2 4 wks. Intravenous Diabetic Pred. for 21 mos.
(1.3) prior to dex.
7 2.0 4 wks. Intravenous Diabetic Pred. for 12 mos.
( 2.2 ) prior to dex.
11 3.6 1 wk. Oral Borderline Pred. for 36 mos.
prior to dex.
~ ~~ ____

*Results of intravenous tests given in parenthesis are the K values calculated according
to method of Amatuzio et al." K is the rate of disappearawe of glucose (excess above
fasting level) expressed as percentage of increment disappearing per minute. The normal
range is 2.97 to 4.85.Values obtained in dkbetics range from 0.93 to 2.48. Values between
2.48 and 2.97 are borderline.
tFor 9 days immediately prior to test patient received 8.0 mg. daily for research purposes.
1MK-109 is 18-methylprednisone made by Merck Sharp flr Dohme.

calcium excretion and a negative balance when 6 mg. dosage was reached.
At this dosage 1.05 Gm. of calcium was excreted daily. Negative calcium
balance persisted for six days after the drug was discontinued. The increased
losses of calcium were accounted for, almost entirely, by increased fecal
excretion, and were apparent only to a slight extent in urinary excretion.
Again, in case 01-83-93 this effect was less marked; a negative calcium
balance was not reached until 10 mg. of dexamethasone was given daily. MK-
117 at 50 mg. dosage produced little change in calcium balance but at 100
mg. a negative balance occurred, again mainly as a result of increased fecal
excretion. With MK-117, however, the loss of calcium was reversed almost
as soon as the drug was discontinued.
322 BUNIM, BLACK, LUTWAK, PETERSON AND WHEDON

GLUCOSE TOLERANCE TESTS

--
7- 1
150

9( 100
c
E

a t
0 1
3 50 !-
rF-4 BEFORE THERAPY
m i
I- t--.I 8 M D A Y OF HEXADECADROL
2mg FOR 12 DAYS
{ 6mg FOR 6 DAYS
1.
~
I
~

1-
I I i .. ~ ~~~~ .. . ..I
~~. . . ~
i
_1
I I 2 3
'2
TIME-HOURS
FIG.5.--Glucose tolerance tests (oral) lwfore and on 18th day of dexaniethasonr ( fornierly
known as hexaclecadrol) administration. This patient (case Fi, table 4 ) hut1 received no
steroids for 30 months prior to dexamethasone administration.

Curbohydrute metabolism.-Glucose tolerance tests were done on 10

patients receiving dexamethasone for varying periods ( table 4 ) . The curves
were normal in the three patients who had received no steroids for months
prior to dexamethasone administration (see figure 5 ) and in the two patients
who had received MK-109,* for nine and ten months prior to dexamethasone.
Glucose tolerance was impaired, however, in 4 of the S patients who had taken
prednisone for long periods prior to dexamethasone therapy.
111. CLINICAL
STUDIES
Materials and Methods
Putkr~ts.-Twelve patients with rheumatoid arthritis were given dexamethasone and ob-
served daily while they were hospitalized at the Clinical Center. Data concerning age and
sex distribution and functional classification of the patients, duration and stage of the
arthritis, antirheumatic medications received in the past, and patients' objections to these
drugs are given in table 5.
Method of administration.-Soon after each patient was admitted to the study, antirheu-
inatic drug therapy was limited to a single compound; aspirin alone in cases 1, 3 and 5,

"MK-109is a new steroid closely related to dexamethasone. It is 16-a niethylprednisone.

Supplied by Dr. Ehiier Alpert, Merrk Sharp & llohnie Research Laboratories, Llivision of
Merck & Co.
STUDIES ON DFXAMETHASONE 323
TABLE
5.-Composition of Series
Duration
Case, of Arth. Stage of Functional Previous Objections
Age & Sex (yrs. 1 Arth. ClW Therapy. prev. ther.
1,41,F ?h 11 2 Aspirin Inadequate
Prednisone control
2,39,M 1% I 2 Aspirin In adequate
Cortisone control
Prednisolone
3,17, F 2 I 2 Aspirin Inadequate
Prednisone control
4,43,F 10 I11 3 Aspirin Inadequate
Codeine control
Prednisone
5,28, F 6 111 2 Aspirin Inadequate
Chloroquine control
Cortisone
6,45, M 8 111 4 Aspirin Inad. cont.
Gold Gastric
Cortisone ulcer on
Prednisone prednisone
7,33,M 2 I 2 Chloroquine Inadequate
Phenylbutazone control
Prednisone
8,54,F 17 111 1 Aspirin, Gold None
Phenylbutazone
Cortisone
Prednisone
Triamcinolone
9,36, F IV Aspirin Inadequate
Cortisone control
Prednisone
10,38, F IV Aspirin Rash from
Phenylbutazone phenylbut.
Cortisone Inadequate
Prednisone control
1 I , 57, M 6 111 3 Aspirin Inadequate
Prednisone control
12,46,M 9 111 3 Aspirin, Codeine Inadequate
Gold, Cortisone control
Prednisone
‘Not arranged in chronologic sequence.
and prednisone alone in all other cases except case 8, in which triamcinolone alone was
used. One and the same observer’ examined the patients twice weekly and determined
the clinical status according to specified indexes’ which will be enumerated later. In the
nine patients receiving steroids on admission, the daily dose of the drug was gradually re-
duced at intervals of several days until a flare of arthritis occurred. At this point the dosage
immediately preceding the flare was established as the minimal “hospital” d0se.f The flare

‘Results of repeated determinations of these indexes in any one patient in a constant

state showed very close agreement when made by one observer, whereas those made by
inultiple observers showed different but parallel values.
t h v i d e d the disease activity remained relatively constant, we have found repeatedly
that the steroid dosage employed immediately prior to admission may be apppredably re-
duced during the first few weeks of hospitalization, before a flare occurs.
324 BUNIM, BlAACK, LUTWAK, PETERSON AND WHEDON

was quickly overcome by promptly restoring the niinimal satisfactory dosage, and niedica-
tion was then abruptly changed to dexsniethasone given in four evenly divided doses every
six hours. The first seven patients were iinaware of the time when dexaniethasone was first
administered to them. A placebo capsule of identical appearance had been given for many
days prior to institution of dexaniethasone therapy. Again, by our use of placebos the pa-
tients who had been getting prednisone or trianicinolone did not know when these steroids
were discontinued. Since the physician who made the clinical observations knew the na-
ture and dosage of the prescribed medications, the blindfold test was single and not
double.
Zndexes used-In each case the same observer estimated pain on motion, tenderness and
swelling of each affected joint. The circumference of each proximal interphalangeal joint
was measured by jewelers’ rings. Grip strength was measured by a standard grip meter.’
Duration of morning stiffness was detennined by questioning the patient. Range of motion
was measured by a physical therapist. The erythrocyte sedimentation rate (E.S.R.) and
C-reactive protein (C-R.P.) were determined twice weekly and the hematocrit once each
week.
Dosage.-In the first few cases we deterniined by trial and error that the dosage of dexa-
inethasone required for satisfactory control varied from 1 to 4 nig. daily. In two cases ( 8 and
12) of unusual severity, 6 mg. daily were used for four and two weeks respectively. When
it became apparent that the antirheumatic potency ratio of dexamethasone compared to
prednisone was about 6 : l we decided not to exceec! it dosage of 4 mg. daily. In three
cases ( I , 3 and 4 ) aspirin wiis added in an at-tempt to keep steroid dosnge at lowest pos-
sible levels. The effectiveness of this principle is well illustrated in figure 6. This chart
indicates that the antirheiimatic potency of one mg. dexaiiiethasone is greater than 3.6 C h i .
of aspirin and that addition of aspirin to steroid therapy rcstores control of “escaping”
symptoms, thereby obviating need for increasing dexamethasone dosage. It will be noted iu
table 7 that the lowest dose in the series was 0.8 nig. daily (case 6). For 20 months prior
to hospitalization the patient had been taking 30 ing. of prednisone and 2.4 Gm. of aspirin
daily.
Relutiue crntirhcccrnc/tic potency.-Eight of the 12 patients wcre taking prednisone to-
gether with some other preparation a t the time of admission. The dexainethasonc,‘prednisonc
ratio of antirheumatic potency was calculated in these cases ( table 6 ) . The calculatioii
was based on the dosage ratio required to achieve equivalent clinical control of the arthritis
crt the time the c h n g e f r ~ r r pretlnisone
i to clexornetlicrsorie wos first mutle. In sonic instiinces,
a s in case 6, it was found subseqncntly that dexainethiisone dosage could IJK lowered froin
1.5 to 0.8 mg. daily without diminishing the ckgrce of iinprovenient. The lower dosage
was not used to calculate relative potency, however, since the activity of the disease might
have subsided in the interim. l’tiis variable coiild have been estimated by reversing the
change from dexamethasone to prednisone, hut such :I procedure had not been carried out
in each case. Under the circumstances of this trial, then, the range of dosage ratio wiis
found to vary from 2.5 to 10, and averaged 6.0.
Puttern of response.-Subjective and objective i~nproveiiic.nt,when it occurred, was noted
within 12 to 24 hours after beginning dcsanieth;isone atlniinistmtion ant1 iisually rcaclied
inaximuni degree in 3 weeks (fig. 6).When the drug was discontinued, severe relapse
followed within 12 hours.

Resit its
Initial objective and subjective improvement following desamethasone ad-
ministration was marked in five patients, moderate in four, slight in two and
failed to occur in one (table 7). Of the three patients who had been taking
aspirin alone prior to dexamethasone (cases 1, 3 and 5 ) two exhibited marked

*Manufactured by Misdoln-Frank Company, New York, N.Y.

STUDIES ON DEXAMETHASONE 325

TABLEB.-Uexarneth~sone/Prednisone Ratio of Antirheumtic Potency

Minimal Satisfactory Equivalent*
Maintenance “hospital” dose of dexamethasone
Druga given daily dose predniaone ( d o n e ) dose (without Dexamethasone
prior to prior to prior to switch aspirin) /Prednisone
Case ndmission admission ( mg./rlay ) (mg./dny) Ratio
-
I) Prednisone + 10 mg.
Aspirin 3.6 Gm. 10 2 5
4 Prednisone + 25 mg.
Aspirin + 8.0Gm.
Codeine 240 mg. 15 6 2.5
6 Prednisone + 30 mg.
Aspirin 2.4 Gm. 16 1.5 10
7 Prednisone + 15 mg.
Phenylbutazone 300 mg.
+ Chloroquine 250 mg. 10 1.5 0.6
9 Prednisone + 18 mg.
Aspirin 2.4 Gin. 18 2 Q
10 Prednisone + 10 mg.
Aspirin 4.5 Gm. 20 4 5
11 Prednisone + 15 mg.
Aspirin 2.4 Gm. 24 4 0
12 Prednisone + 30 mg.
Aspirin + 3.6 Gm.
Codeine “large doses” 24 6 4
Average 6.0
*Dose required to achieve equivslent, clinical control of arthritis.

and one moderate improvement. Morning stiffness, which was present in ten
patients who were taking either aspirin or prednisone, disappeared completely
in nine and was reduced from a duration of two hours to 30 minutes in the
remaining patient. The C-R.P. (determined at end of 24 hours) disappeared in
six patients, diminished appreciably in two and failed to change in two. (In
one patient this test was not done and in another only a trace of the protein
was present before the new steroid was given.) The E.S.R. (Westergren) de-
creased by 30 mm. or more per hour in seven patients and by 20 mm. or less
in four. In the one patient who failed to improve on dexamethasone, the E.S.R.
rose. In five cases, however, the E.S.R. rose again from suppressed levels, even
though clinical improvement was maintained. Significant increase in hematocrit
was noted in only one case. (Approximately 30 to 50 ml. of blood per week
were drawn from each patient for various laboratory tests.)
Undesirable side eflects.-No major toxic reactions occurred during this
brief period of trial (table 7.) One patient (case 6 ) had developed a duodenal
ulcer two years prior to admission while taking 40 mg. of prednisone daily. A
symptomless gastric ulcer was discovered when he was admitted to the Clinical
Center, at which time he was taking 30 mg. prednisone daily. There was radio-
graphic evidence of healing, however, when the patient was examined one
month later, when he was taking 10 mg. of prednisone daily. Roentgenographic
examination of the stomach and duodenum done during the eleventh week of
dexamethasone therapy revealed no evidence of an ulcer (table 8 ) . Six other
patients were x-rayed at various intervals during dexamethasone administration,
326 BUNIM, BLACK, LUTWAK, PETERSON AND WHEDON

%DEFICIT oL
RING
SIZE 54

46
40
SWELLING 2o

0
TENDER- 40
NESS 20
0
8
PAIN ON
MOTION 4

43
BODY Wt
(Kg 1 39
0 4 8 12 16 20 24 28 I 5 9 13 17 21 25 29 3 7 II
March April May
FIG. 6.-( Case 3 ) . Effect of tle.cirinetliusoii(. ( fomierly known as hexatlecadrol) and of
coiirbined tlexamethasone and aspirin ther,ipy on indexes of joint symptoinb and signs. The
yatient was given ti high c.iloric dirzt in an effort t o help her reg'iin nonnal weight.

and were found to exhibit no lesions in the gastrointestinal tract. Epigastric

pain, suggestive of peptic ulcer, occurred in one patient (case S) during the
fourth day of excessive dosage (10 ing. daily), administered for research pur-
poses during metabolic balance studies. Anticholinergic therapy was instituted,
the pain disappeared promptly and the steroid was discontinued at the end
of the sixth day. X-ray examination of the upper gastrointestinal tract one week
after onset of symptoms was negative. In all patients, stools were tested for
occult blood frequently. In the seven patients listed in table 8, a positive test
was found with increasing frequency in three. In two of these three aspirin was
combined with steroid therapy. One patient (case 1) developed recurrent,
transverse upper abdominal pain while taking dexamethasone. The basis for this
symptom is as yet undetermined.
All patients reported increased appetites, hut only two gained weight. One
of these made a determined effort to regain the weight she had lost during a
recent, severe exacerbation of the disease (case 3). It should be borne in mind
that although the diet at the Clinical Center was not restricted, food was
served in customary hospital portions, and free access to the kitchen was not
STUDIES ON DEXAMETHASONE 327

available. Two patients who were permitted “leave” from the hospital gained
much weight while at home.
Minor side effects occurred in eight patients: insomnia in four, increased
sweating in three, mild hirsutism in two, cutaneous purpura in two, and slight
facial rounding in one. Three patients, two males and one female, experi-
enced no unwanted effects. None of the patients developed hypertension,
edema, hyperglycemia or glycosuria.

DISCUSSION
The capacity of a new steroid to suppress inflammation and corticotropin
secretion has been estimated by methods which are admittedly crude but
nevertheless quite useful. There seems to be a general parallelism, though no
exact mathematical correlation, between the potencies of these two types of
biologic activity. It has been found in this laboratory0 that the amounts of
steroids required to suppress plasma levels of hydrocortisone to zero in normal
subjects are approximately 30 mg. of prednisone, 5 mg. of 9-a fluorohydrocorti-
sone, 2 mg. of delta-1, 9-a fluorohydrocortisone and 1 mg. of dexamethasone.
The anti-inflammatory potency of these four synthetic steroids increases in the
same order but not in the same ratio; for example, dexamethasone has about
six rather than 30 times the antirheumatic potency of prednisone.
Development of reliable methods for quantitative analysis of daily aldo-
sterone excretion in urine and availability of a very potent corticotropin sup-
pressant has now made it possible to demonstrate that aldosterone production
by the adrenal cortex in man is independent of anterior pituitary control. More-
over, some insight into the mechanism of sodium excretion and retention under
the influence of natural and synthetic corticosteroids may be derived from the
aldosterone study. Administration of dexamethasone resulted in loss of sodium
which was probably secondary to direct effect on renal function. Aldosterone
responsiveness remained unimpaired despite marked or complete suppression
of corticotropin production by the adenohypophysis. A few days after nega-
tive sodium balance developed aldosterone production increased sufficiently
to restore a positive balance of sodium, even in the presence of marked restric-
tion of dietary sodium. Potassium loss during the first day of dexamethasone ad-
ministration and immediate retention during the first day following discontinu-
ance of the drug may have resulted from an effect of the steroid on renal
function.
The tissue-wasting effects of adrenal cortical steroids as reflected in in-
creased excretion of nitrogen and phosphorus-principally urinary-are well
known, However, the demonstration that dexamethasone produces a significant
and sustained negative balance in calcium-chiefly as a result of increased
fecal excretion-is virtually unique. Although prolonged corticosteroid ad-
ministration in rheumatoid arthritis has been associated with a high incidence
of pathologic fractures, data from studies on adult animals,” from histopatho-
logic sections from patients with Cushing’s syndrome,** and from metabolic
studies in patients with various disease^'^-'^ have failed to account thus far
i2c
3
m
STUDIES ON DEXAMETHASONE 329
TABLE8.Pastrointestinal Studies Befnrc and During Deramethasone Therapy

X-ray exam. Occult blood

after adm. Main- Duration of SUDPIP- in stools Results
and prior tenance dexamethasone ment?, (benzidine) f of
Case, to dexa- dose of dexa- therapy at aspinn latest
Age methasone nietbasone time of latest adniin. Digestive Prior During x-ray
dr Sex therapy (mg./day) x-yay exam. (Om./day) symptoms to Rx Rx exam.
1, 41, F Neg. 4.0 9 wks. 3.G Upper 2 2 Nea.
abdom. pain
2. 46, M Neg. 2.4 11 wka. 0 None 0 0 Nea.
3. 17. F 1.9 8 wks. 2.4 None 1 2 NW.
4, 43. F Neg.
NW. 3.6 D mks. 3.6 None 1 2 NeS.
Epig. pain
6, 28, F Nee. 2.0 4 wke. 0 during 10 mg. 1 a NeS.
dosage
(research)
6*.39. M Healed ulcer 1.2 6 wks. 0 None 0 1 NeS.
7, 33. M Neg. 2.0 4 wks. 0 None 0 0 Neg.
+A duodenal ulcer had been found by x-ray examination of this patient prior to admisaion and a
symptomless gastric ulcer during prednisone therapy after admission (see text).
t o = negative t a t . 1 = occasionally positive test. 2 = frequently positive lest.

for the apparent detrimental effects of these steroids on calcium storage. Com-
plete balance studies done in this laboratory'0 on the metabolic effects of
prednisolone over 24 to 36 days revealed a calcium-losing effect in only one of
three patients and even that was not repeatable with prednisone. Balance
studies of similar length with delta-1, 9-alpha fluorohydrocortisone in 3 other
patients showed increases in urinary calcium but the decreases in fecal calcium
were of equivalent degree so that no net change occurred in calcium balance.16
The decided shift in calcium balance resulting from dexamethasone administra-
tion, therefore, is of considerable interest. The failure to obtain a consistent
effect on calcium metabolism by diverse corticosteroids is quite puzzling and
suggests to one of us (G. D. W. ) that interference with osteoid formation may
be an oversimplified explanation for the clinically observed effects of these
steroids on bone. Some of the effects of dexamethasone and MK-117 on mineral
metabolism, particularly calcium, indicate that the kidney and intestine may
be important sites of action.
As a therapeutic agent, what advantages does dexamethasone possess com-
pared with the antecedent corticosteroids? Increased antirheumatic potency per
se is no real advantage. What is needed is an agent that possesses a higher thera-
peutic ratio. Whether prolonged dexamethasone administration will continue to
suppress effectively disease activity and yet not give rise to serious toxic effects
is the primary question. At least one year, and more likely several years, of
careful observation will be necessary to answer this question. Early, short-term
observations may be misleading, and certainly do not permit sound evaluation
of a new therapeutic agent. It may be of some interest, however, that at this
preliminary period, in a small group of patients, short-term administration of
dexamethasone has not yet been associated with edema, hypertension, impair-
ment of carbohydrate tolerance, peptic ulcer or pathologic fracture.
SUMMARY

Physiologic, metabolic and early clinical effects of dexamethasone, a new syn-

thetic corticosteroid, have been described. On a weight basis (mg. for mg.) the
ranacitv of dexamethasone to SuDDress corticotronin secretion of the adeno-
330 BUNIM, BLACK, LUTWAK, PETERSON AND WHEDON

hypophysis in man is about 30 tiines greater than prednisone and it5 antirheii-
matic potency approximately six times that of prednisone. In both types of bio-
logic activity dexamethasone is the most potent steroid thus far synthesized; yet
it does not inhibit adrenal cortical elaboration of aldosterone or impair aldos-
terone responsiveness to sodium loss or deprivation. In dosages which are ade-
quate to suppress symptoms of disease activity in rheumatoid arthritis, i.e.,
fractions of one mg. to 4 mg. daily, or even in larger, experimental dosages ( 10
mg. daily) there is no retention of sodium or loss of potassium. In dosages of
6 or 10 mg. daily, increased excretion of nitrogen and appreciably negative
calcium and phosphorus balances we produced. Carbohydrate tolerance is
iinimpaired when dexamethasone is given to patients with rheumatoid arthritis
in therapeutic dosages for as long as ten weeks.
Dexamethasone was siibjected to clinical trial, for periods up to 12 weeks, in
18 patients with rheumatoid arthritis whose diseuse had not been adequately
controlled by therapeutic measures in current use. In 16 patients with active
rheumatoid arthritis dexamethasone administration in dosages varying from 0.8
to 4.0 mg. daily was followed by marked subjective and objective improvement
in five, moderate improvement in seven and slight improvement in four. In two
additional cases of unusual severity, a daily dosage of 6.0 mg. was explored
briefly with unsatisfactory results. In three of the cases that responded satis-
factorily aspirin was added to dexamethasone therapy in order to reduce the
need for higher steroid dosage. Minor undesirable side effects were noted in
14 of the 18 patients studied. N o major toxic effects occurred during the
brief period of trial.
CONCLUSION
Preliminary results of clinical and laboratory investigations on the effect of
dexamethasone in rheumatoid arthritis are encouraging enough to warrant fur-
ther trial. Results obtained from metabolic balance studies and from determi-
nations of dexamethasone/prednisone ratio of antirheumatic potency indicate
that for the present it would be prudent not to exceed daily dosage of 4 mg.
of dexamethasone in long-term therapy of most cases of active rheumatoid
arthritis.
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Joseph 1. Bunim, M.D., Clinical Director, National Institute

of Arthritis and Metabolic Diseases, Bethesda, Md.; Associate
Professor of Medicine, Johns Hopkim University, Baltimore,
Md.

Roger L. Black, M.D., Senior Znuestigator, National Znstitute

of Arthritis and Metabolic Diseases, Bethesdu, Md.; Clinical
Assistant Professor of Medicine, Georgetown Uniuersity,
Washington, D. C .

Leo Lutwak, Ph.D., M.D., Notional Institute of Arthritis and

Metabolic Diseases, Bethesdu, Ald.

Ralph E . Peterson, M.D., Senior Investigator, National Zmti-

tute of Arthritis and Metabolic Diseases, Bethestla, Md.

G . Donald Whedon, M.D., Chief, Metabolic Diseases Branch,

National Zmtitute of Arthritis and Metabolic Diseases,
Bethesdu, Md.