230

Reprinted front the Archives of Intertsal Med@ce
   Azlgust 1962, Vol. 110, pp. 230-236
Copyright 1962, by Avnerican Medical AssociatioFc

  Control Study of i    VETERANS ADMINISTRATION
                                            =
                                            I
Antihypertensive Agents I    COOPERATIVE STUDY ON

                                                ANTIHYPERTENSIVE AGENTS=
                                           Es
                                           I
                                          z    WASHINGTOh', D. C.
                                           E
III. Chlorothiazide Alone and in Combination with  I
       Other Agefits; Preliminary Results  8
                                           E
                                           E
                                           E
                                           s

The previous 2 reports of the Veterans

`fbc criteria used for selecting patients and for
classifying severity have been described in a pre-
vious communication.' The Group A patients enter-
ing the study for the first time were treated as
follows :

Administration Cooperative Study on Anti-
hypertensive Agents described the results ob-
tained with reserpine, hydralazine, and 3
ganglion blocking drugs.1*2 The present in-
vestigation is concerned with the evaluation
of chlorothiazide both alone and in combina-
tion with the agents listed above and with
cryptenamine, an alkaloid derived from Ve-
ratrum viride. Although these latter studies
are still in progress, the results seemed of
sufficient interest to warrant a preliminary
report at this time.

Methods

This investigation used 2 separate protocols for
each of 2 different groups of patients. The first
(Group A) were untreated cases entering the study
for the first time. The second (Group B) were
patients who had been under treatment in the co-
operative study for at least 1 year,l*' after which
chlorothiazide was added to the regimens of the
patients taking active medications.

Submitted for publication Feb. 26, 1962.

* Participants : Mark L. Armstrong, M.D. ; Mas-
simo Calabresi, M.D.; Loyal L. Conrad, M.D.;
Harold Dodge, M.D. ; E. E. Eddelman, M.D. ;
Edward D. Freis, M.D. (Chairman) ; Rudolph E.
Fremont, M.D.; Walter M. Kirkendall, M.D.;
David Littman, M.D. ; Clifford G. Pilz, M.D. ; Eli
A. Ramirez, M.D. ; David W. Richardson, M.D.,
and John H. Williams, Jr., B.A.

These included the following Veterans Adminis-
tration Hospitals : Birmingham, Ala. ; Brooklyn ;
Chicago West Side; Iowa City; Oklahoma City;
Richmond, Va. ; San Juan, P.R. ; Seattle; Wash-
ington, D.C.; West Haven, Conn., and West Rox-
bury, Mass.

Mild and moderately severe cases were assigned
one of the following 4 regimens using a double
blind, randomization method : (1) chlorothiazide 500
mg. with reserpine 0.25 mg. combined in a single
tablet twice daily plus hydralazine 25 mg. 4 times
daily for 1 week followed by hydralazine 50 mg.
4 times daily thereafter ; (2) chlorothiazide without
reserpine plus hydralazine, both drugs given as
above ; (3) chlorothiazide without reserpine plus
placebo of hydralazine, given as above ; (4) placebos
of chlorothiazide-reserpine and of hydralazine,
given as above.

Severe cases were assigned one of the following
regimens : ( 1) chlorothiazide 500 mg. combined with
reserpine 0.25 mg. in a single tablet twice daily:
in addition, hydralazine 12.5 mg. (r/i tablet) 3
times daily were given and the doses raised by 12.5
mg. increments to a total dose of 50 mg. 3 times
daily or until the diastolic pressure fell below 100
mg. Hg, or else side-effects supervened ; (2) same as
above except that cryptenamine (an alkaloid de-
rived from Veratrum viride) was substituted for
hydralazine. Each tablet of cryptenamine contained
3 mg., and the initial dose was 1.5 mg. (l/i tablet)
3 times daily.

The tablets of hydralazine and the Veratrum
compound were made up to appear and taste the
same. Chlorothiazide, reserpine, and hydralazine
also were prepared to resemble their respective
placebos. As in the previous study1 3 different
code numbers were assigned to each preparation
including the placebos.

The Group B patients were those who had been
under treatment for more than 1 year with either
reserpine, reserpine plus hydralazine, placebos, or
reserpine plus ganglion blocking agents.`va The

134


.s'TUDY OF ANTIHYPLRTENSlVk AGENTS                               231

TABLE I.--Croup A: Cllange in Blood Pressure from Pretreatment Hospital
Averaac to Third-Muntlt Hnnle Pressure by Regimen and Severity

Severity :XKI RegimeD

Mild and modwltely SeTwe
Cl~lorotbi:~zide+resergine+
  hydr:&lazine
Chlon,thi;lzide+hydralazine
Chlorothiazide
rlcitcetm
Severe
ClllorotIliilzide+resergine+
  cryptenxmine
Chlorotlii;lzide+reserpine+
  hydr:rlazine

No. of
Cases

23

37
34
32

15

25

Systolic                   Dinstolic

rretre:lt.
Level

  DifTel-enw xt 3 MO.
_---
       0 90 Confidence
  AV       Limit

163

Ii9

186

-17.2   -10.4 to -24.0

-11.2    - 5.7 to -16 7
- 3.2    + 0.8 to - 7.2
- 0.9   + 5.2 to - 7.0

-17.9   - 6.2 to -29.6

-22.7   -14.2 to -31.2

cases had been divided so that all patients with   All of the patients with severe hypertension in
mild and half of those with moderately severe hy-  prior treatment Group B and half of those with
pertension received the rescrpine, hytlralazine, and  moderately severe hypertension had been treated
placebo regimens. The addition of chlorothiazide  with reserpine 0.25 mg. twice daily plus 1 of 3
was accomplished in these cases by substituting for  ganglion blocking agents : mecamylamine, chlori-
the 0.25 mg. reserpine tablet a specially prepared  sondamine, or pentolinium tartrate."' Chlorothiazide
tablet containing reserpine 0.25 mg. pius chloro-  was added to their regimens by substituting a tab-
thiazide 500 mg. A similar-appearing placebo also  let containiq 500 mg. of chlorothiazide and 0.25
was manufacturetl. These tablets were given the  mg. of reserpine for the prior 0.25 mg. of reserpine.
same code number identifications as used in the  This tablet was administered twice daily. At the
prior study except that the letter "C" preceded  same time the dose of the ganglion blocking agent
the series of digits. By substituting the "C" series  was decreased to half the prechlorothiazide level
medication for the prior "A" series those patients  because of the well-known enhancement of the
taking either reserpine plus hydralazine or reserpine  antihypertensive effect of blocking drug induced by
plus placebo of hydralazine had chlorothiazide 500  chlorothiazide. Further adjustments of the doses
mg. twice daily added to their regimens, while those  of the ganglion blocking agent were then made from
patients who were not treated with active prepara-  this reduced level as seemed indicated fpr control
tions had only placebo of chlorothiazide added.    of the blood pressure.

CHLOROTHIAZIDE + RESERPINE + HYDRALAZINE

PERCENT OF CASES

        CHLOROTHIAZIDE + HYDRALAZINE
30 r

Difference nt 3 MO.

Pretrent.         0.90 Confidence
Level     AV.      Limit

108     -14.3   - 9.8 to -18.8

105     -11.X   - 7.9 to -15.7
103     - 1.9   + 1.2 to - 5.0
105       0.0   + 3.7 to - 3.7

119     -16.4   - 9.3 to -23.5

118     -20.9   -15.8 to -26.0

PERCENT OF CASES     CHLOROTHIAZIDE

             PLACEBO
30 r               f

Fig. l.-Percentage distribution curves of changes in systolic blood pressure at the end of
3 months of treatment in patients with mild and moderate hypertension. Changes in systolic
l,ressure from pretreatment values are listed on the abscissae and percentage of patients on
the ordinates.

135

Veterans Administration


232                                ARCN1I'E.C OF INTERNAL MEDICINE

    CHIDROTHIAZIDE + RESERPINE + HYDRALAZINE                     C!iLOROTHIAZIDE
PERCENT or CASES                               PERCEHT OF CASES

??

CHLOROTHlAZlDE o

PLACEBO

Fig. Z.-Percentage tlistriblltion curves of changes in diastolic blood pressure. Other notations

. are as-in Figure 1.

Results

Group A (Previously Untreated) Patients.
Chlorothiazide Regimens in Mild and Mod-

erate Hypertension: The results in the mild
and moderately severe groups suggested that
the various agents have additive effects. The
average reduction from the hospital basal
pretreatment, systolic/diastolic blood pres-
sure l to the average home blood pressure was
7.9/3.8 mm. Hg in the chlorothiazide-treated
patients and 0.9,`O.O in the placebo-treated
group (Figs. 1 and 2). The patients receiving
chlorothiazide plus hydralazine exhibited an
average reduction of 10.2/11.8 mm. Hg, and

  CHLOROTHIAZIDE + RESERPINE + CRYPTENAMINE

PERCENT OF CASES

3o I-                     c   DECREASE

those taking chlorothiazide, hydralazine, and
reserpine showed an average fall of 17.2i14.3
mm. Hg. None of the 23 patients receiving
the 3-drug regimen (chlorothiazide, hydrala-
zine, and reserpine) exhibited an increase in
tliastolic blood pressure (Fig. 2).

Chlorothiazide and Reserpine with Hy-
clralazine or Veratrum in Severe Hyperten-
sion: In the Group A patients with severe
hypertension, the 25 patients receiving re-
serpine and chlorothiazide plus a titrated dose
of hydralazine exhibited a reduction of blood
pressure averaging 22.7120.9 mm. Hg (Figs.
3 and 4). These values are not significantly
different from those which had been previ-

   CHLOROTHIAZIDE + RESERPINE + CRYPTENAMINE

PERCENT OF CASES
30 1                    i
      INCREASE                 DECREASE

20     INCREASE                            20 t
IO                                      IO
n                                      0    ,

CHLOROTHIAZIDE + RESERPINE + HYDRALAZINE       CHLOROTHIAZIDE + RESERPINE + HYDRALAZINE

44  36  28  20  12  404  12  20  28  36  44

IO                                      81

0     ?3 I
                                      L
    I I I I I I I I I I I              I I I I I , I I I   I
   44  36  28  20  12  404  12  20  28  36 4:          a4  36  28  20  I2  4 04   12  20  28  36  44

Fig. 3.-Percentage distribution curves of changes
in systolic blood pressure at the end of 3 months of
treatment in patients with severe hypertension.

Fig 4.-Percentage distribution curves of changes
in diastolic blood pressure in patients with severe
hypertension.
         Vol. 110, Aug., 1962     136


STUDY OF ANTIHYPERTENSIVE AGENTS.

   T.?BLE 2.-Grouj B: Effect of Addition of Chlorothiaside After One Year of Treatment
   mtlz ReseTpine, Reserpine plus Hydralazine or Reserpinc plus Ganglion Blocking Age&

233

  Antihyp. Regimen

Chlorothiazide added to
Reserpine
Reserpine dr hydrnlazinr
Reswpine & gang. block. n&mts
"A" plncebo to "C" placebo

          Av. Blood Pressure, Mm. Hg
    p-w--        -
No of     Prior to    T.nst MO. Refore   3 Ma. After
Casea    Any Treat    ~l~lo~ot~~i~zi~le C~~lorothia~ide

Xl       l59/102       154196       145/N
il      158/102       153/92       14?/P6
68       I80/116      IA1 19;       151 I93
36       m/101       164/104       lfi4/105
    I_-

ously obtained with reserpine and ganglion  thiazide was 5/10 mm. Hg. During the 3
blocking agents without clliorothiazide in  months after addition of chlorothiazide there
severe hypertension.2 The somewhat greater  was a further reduction of 1116 mm. Hg or a
reduction of blood pressure in the severe as  total average fall of 16/16 mm. Hg from the
compared to the mild and moderate groups  mean pretreatment value. The post-treatment
probably is related to the fact that the pre-  average diastolic pressure was 86 mm. Hg.
treatment levels of blood pressure were In 70 patients receiving reserpine 0.25 mg.
higher in the severe cases.`" The distribution  twice daily without hydralazine, a mean re-
curve in this reserpine-, ~lorothiazide-, and  duction of S/6 mm. IIg from pretreatment
hydralazine-treated group showed no patients  basal values before chlorothiazide decreased
with a rise in diastolic blood pressure (Fig.  further to 14/l 1 after the addition of chloro-
4). The average reduction of blood pressure  thiazide, an additional reduction of 9/5 mm.
in the severe patients treated with chlorothia-  Hg. The average pressure of the 36 placebo-
zide, reserpine, and cryptenamine was 17.9,'  treated patients was unaffected by the addi-
16.4 mm. Hg.               tion of chlorothiazide placebo.
Group B ~P~e~.ou~l~ Twoted) Patients.-   The reduction of diastolic blood pressure
Addition of Chlorothiazide to Mild and  after the administration of ChIorothiaz~de was
Moderate Cases Previously Treated with  correlated with the degree of elevation of
Reserpine, Hydralazine : Chlorothiazide or  these readings prior to chlorothiazide. The
its placebo was added to the regimens of 177  patients with elevations of diastolic above 90
mild and moderately severe Group B patients  mm. Hg exhibited the greatest response;
who had been treated with reserpine, hydrala-  those between 80 and 90, a lesser response,
zine, or placebo regimens for one year or  and the few below 80 mm. Hg showed essen-
longer. I>2 In 71 patients receiving reserpine  tially no change in average diastolic pressure
0.25 mg. twice daily and hydralazine 50 mg.  after chlorothiazide was added.
4 times daily, the average reduction from   Addition of Chlorothiazide to Moderate
pretreatment "basal" levels prior to chloro-  and Severe Cases Previously Treated with

TABLE 3.-Group B: Average Change in Diastolic Blood Pressure, According
       to Average Diustolic Presmre Prior to Change

Chlorothiazid~ Added to

Diastolic Pressure Prior
to Change, Mm. Hg

   90 or higher
   80 to QO
   Less than 80
   AIX cases

   Reserpine

No. of    AP. cmnge.
cvm?s     Mm. Hg

47        -7.4
15        -5.4
8        +3.7
70        -5.7

Re~rpine~~~d~~tzi~e

h-0. of    Av. Change,
CCLSCAS     Mm Hg

36        -9.1
27        -2.3
  8        t-1.0
71        -5.5

137    Veterans Adnzinistratiora


234                                ARCHIVES OF INTERNAL MEDICINE

TABLE 4.-Azrerage Laboratory Values Before Therapy and at 3 and 12 Months,
    for Patients Receiving Chlorothiazide and Control Patients

Weight,    Na,     K     CL     co 1,    BUN,  Uric Acid,   FBS,
Lb.    MEq/L   MEq/L   MEq/L   MEq/L   Mg. Yo   Mg. %   -clg. %

Patients on chlorothiazide
No. of patients tested
Pretrwtment levels
Three-month levels
-No. of patients tested
Pretreetment levels
Twelve-month levels
Patients on placebo
No. of patients tested
Pretreatment levels
Three-month levels
No. of patients tested
Pretreatment levels
Twelve-month levels

(203)     (216)     (209)     (217)     (211)     (214)     (65)     (41)
172      139     4.5      104      27      16     5.5      100
172      139     4.2      103      2i      17     5.6      103
(95)     (101)     (101)     (100)     (95!     (102)     (22)     (8)
168      139     45      104      27      16     5.6      102
170      139     4.2      103      27      18     6.2      103

(51)     (52)     (521     (50)     (49)     (53)     (11)     (11)
175      139     45      104      27      15     5.2      108
174      140     4.6      103      27            5.4      95
(23)     (24)     (24)     (23)     (23)  (2::     (9)      (6)
176      138     4.6      105      26      14     5.3      I14
174      140     4.5      103      27      13     5.8      9i

Reserpine and Ganglion Blocking Drugs:
Data were available on the addition of chloro-
thiazide to the regimens of 68 patients taking
reserpine 0.25 mg. twice daily plus 1 of 3
ganglion blocking agents-mecamylamine,
chlorisondamine, or pentolinium tartrate.
Since the previous study failed to reveal sig-
nificant differences in the antihypertensive
effectiveness of the 3 blocking drugs, the 68
patients are reported as a single group. The
average blood pressure in these patients was
reduced from a basal pretreatment value of
180/116 to 161/97 after 1 year of treatment
with reserpine and ganglion blocking drugs.
The addition of chlorothiazide resulted in a
further average reduction of 11 mm. systolic
and 5 mm. diastolic, to 151/93 mm. Hg. In
addition, doses of the blocking drug were
reduced to one-half or less of the prechloro-
thiazide levels in approximately 45% of these
patients.

Changes in Body Weight and
Certain Blood Constituents

The average values for body weight, serum
sodium and chloride, blood COz, and BUN
in approximately 210 patients were essen-
tially unchanged from pretreatment values
when tested at the end of 3 months of therapy
with chlorothiazide. There also were no sig-
nificant changes in these parameters after 1
year of continuous treatment as determined
in approximately 100 patients. The group
treated with placebos also showed no signifi-
cant changes. The average values of serum
potassium were unchanged in the placebo
group, but in the chlorothiazide-treated pa-
tients, the average serum potassium level fell
from 4.5 pretreatment to 4.2 mEq. per liter
both at 3 months and at 1 year after begin-
ning administration of chlorothiazide. Serum
potassium levels also were determined after

   TABLE S.-Percentage of Patients Showing Abnormal Laboratory Values Before and
          Afer 3 Months of Treatment with Chlorothiazide or Placebo

                          Serum Potassium,
                             MEq/L
                Serum Sodium, -            Serum Chloride, Serum Uric Acid, F&sting Blood Sugar,
                <135 MEq/L  <3.5  <3.0   <2.5   <QO MEqiL    >i.Q Mg %     > 120 Mg %

Patients on chlorothiazide
Number of patients tested     (216)     (209) (209) (209)     (211)         (65)          (41)
`% of patients with ab-       14 2       2.6   0.5   0.0      0.9          12.3          ti.6
normal levels pretreatment
% at 3 months           10.6       8.7   0.5   0.0      0.5          12.6         17 0
Patients 011 plncebo
Number of patients tested     (52)      (53)
           1.9 (j3)   (53)      (53)          (14)          (14)
% of p:ttients with ab-       15.3           0.0   0.0      0.0          7.2         21.4
  normal levels pretreatment
70 at 3 months           13.5       0.0   0.0   0.0      1.9          7.2         23.1

Vol. 110, Aug., 1962    138


STUDY 0); ANTlHYPEKTENSlVE AGENTS                              235

1 week of chlorothiazide treatment in 97 pa-
tients. The serum potassium in these 97
patients averaged 4.50 pretreatment, 4.06 at
one week, and 4.06 mEq. per liter at 3
months, indicating that the reduction oc-
curred during the first week of treatment.

The laboratory data also were analyzed for
the percentage of patients exhibiting abnor-
mal serum concentrations of sodium, chlo-
ride, and potassium. There was no significant
difference between the number of patients
exhibiting serum sodium levels below 13.5
mEq. per liter and serum chloride values
below 90 mEq. per liter at 3 months after
chlorothiazide as compared to before treat-
ment. The incidence of serum potassium
values below 3.5 mEq. per liter increased
from 2.6% at pretreatment to 8.7% at 3
months, whereas in the placebo group the
incidence decreased from 1.9% to 0.0%.
There was no increase in the number of pa-
tients exhibiting potassium levels below 3.0
mEq. per liter, and there were no patients
with levels below 2.5 mEq. either before or
after treatment.

Changes in serum uric acid and in fasting
blood sugar were determined in a smaller
number of patients. The results obtained to
date must be regarded as being preliminary.
The average values for serum uric acid were
essentially unchanged in 65 patients at the
end of 3 months of treatment. At 1 year, the
mean values increased in 22 patients from
5.6 to 6.2 mg. %. The average values for
the fasting blood sugar in 41 patients were
not significantly altered either at 3 months or
at 1 year. The incidence of patients with
levels above 120 mg. $%, however, increased
from 6.6% in the pretreatment period to
17.0% at 3 months. Data on a larger series
of cases will be required to determine the
significance of these trends.

Comment

Although the numbers of patients in some
of the treatment groups are still too small to
provide a final estimate of the comparative
effectiveness of certain of the treatment
regimens, particularly chlorothiazide alone

130     Veterans Administratio+a

and the combination of chlorothiazide and
hydralazine, certain features seemed worthy
of reporting at this time. There was a distinct
trend indicating the additive effects of com-
bining various drugs. Chlorothiazide plus
reserpine resulted in a greater reduction of
arterial pressure than either chlorothiazide or
reserpine alone. The chlorothiazide, reser-
pine, and hydralazine combination was quite
effective and, in fact, resulted in as great a
reduction of blood pressure in the severe
cases as reserpine plus ganglion blocking
agents.2 In the less severe groups this combi-
nation reduced the average diastolic blood
pressure to normal. The chlorothiazide, re-
serpine, and hydralazine regimen did not
require the careful dosage regulation needed
with blocking agents, nor did it produce as
high an incidence of disturbing side-effects.

Although not quite as effective as the chlo-
rothiazide, reserpine, hydralazine regimen, it
is of interest that the Veratrum compound
plus the first 2 agents resulted in a significant
reduction of both systolic and diastolic blood
pressure. Since patients of comparable se-
verity were not given chlorothiazide and
reserpine without other agents, it is not possi-
ble to state how much of the antihypertensive
effect was contributed by cryptenamine. The
results obtained with this regimen will be
reported in more detail, including incidence
of nausea and vomiting and treatment fail-
ures, as more data become available.

The blood chemistry values indicated that
the induction of hyponatremia or hypo-
chloremia by chlorothiazide was rarely en-
countered in hypertensive patients. Mild to
moderate hypokalemia was common, but
serum potassium levels below 3.0 mEq. per
liter were unusual. Potassium supplements
were prescribed in only a few cases in this
series, although many patients were advised
to drink 1 glass of orange juice daily.

Individual patients often react differently
from the average, the blood pressures of
some being controlled on a regimen contain-
ing 1 or 2 antihypertensive drugs. Consider-
ing the extra cost and increased incidence of
toxic effects as additional agents are pre-
scribed, it would seem desirable in clinical


236

ARCHIVES OF INTERhrAL MEDICINE

practice, in managing mild and moderate
forms of hypertension requiring treatment,
to begin with a single agent and add other
drugs one at a time until the desired level of
blood pressure is obtained.

Summary

Preliminary results of the effects on ele-
vated blood pressure of chlorothiazide alone
and in combination with various other agents
are the subject of this report.

Mild to Moderate Hypertension.-Chloro-
thiazide in a dose of 500 mg. twice daily
resulted in a reduction of blood pressure
averaging 7.9/3.8 mm. Hg (systolic/diastolic)
as compared to no change in the placebo-
treated group.

The average reduction of blood pressure
in previously untreated patients given chloro-
thiazide plus hydralazine 50 mg. 4 times daily
was 1 l/12 mm. Hg, and in those taking chlo-
rothiazide, hydralazine, and reserpine in a
maintenance dose of 0.25 mg. twice daily, it
was 17/11 mm. Hg.

Chlorothiazide also was added to the regi-
mens of patients who had been treated previ-
ously with reserpine alone or in combination
with hydralazine for 1 year. The reduction
from average pretreatment levels of blood
pressure was 14/l 1 mm. in the chlorothiazide
plus reserpine group and 16/16 mm. in the
patients receiving these 2 agents plus hy-
dralazine.

Moderate and Severe Hypertension.-
Chlorothiazide, reserpine, and hydralazine

resulted in an average fall of 23/21 mm. Hg.
This was not significantly different from the
results previously obtained with reserpine
and ganglion blocking agents in patients of
similar severity.

Treatment with chlorothiazide, reserpine,
and cryptenamine (an alkaloid of Veratrum
viride) was associated with an average fall
of B/16 mm. Hg.

The addition of chlorothiazide after 1 year
to the regimens containing reserpine plus
ganglion blocking drugs resulted in an addi-
tional average reduction of 10/4 mm. Hg. In
45% of these patients, the doses of the block-
ing agents were reduced to half or less of
the prechlorothiazide levels.

We wish to thank the representatives of Merck,
Ciba, Irwin Neisler & Co., and Wyeth Laboratories
who collaborated in the manufacture, labeling, an(l
distribution of the special preparations of antihyper-
tensive drugs and placebos used in this study.

Edward D. Freis, M.D., Chairman, Antihyperten-
sive Drug Study, Veterans Administration Hospital,
2650 Wisconsin Ave., N.W., Washington 7, D.C.

REFERENCES

I. Veterans Administration Cooperative Study on
Antihypertensive Agents : A Double Blind Control
Study of Antihypertensive Agents : I. Compara-
tive Effectiveness of Reserpine, Reserpine and Hy-
dralazine,  and 3 Ganglionic Blocking Agents.
Chlorisondamine, Mecamylamine, and Pentoliniun-
Tartrate, Arch. Tntern. Med. 106 :81, 1960.
2. Veterans Administration Cooperative Study on
Antihypertensive Agents : A Double Blind Control
Study of Antihypertensive Agents, Arch. Intern.
Med. this issue, page 222.

Printed and Published in the United States of America

140