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Laboratory and clinical observations on chlorazanil, a nonmercurial orally effective diuretic agent
Laboratory
and Clinical
Chlorazkil,’
a Nonmercurial
Effective RALPH
V.
FORD,
M.D.,
Diuretic
J. B. ROCHELLE,
CARROLL
an
RUGS to promote edematous
essential
part
practitioner. inator may
all
types
retention
be
by
renal
steroids, multiplicity variety
of agents
normal
the
renal
Attention
excess
Lipschitz
over
substances
possessing
but which
furnished
development
which
compound with
for
salt the
ago’
to a new
an objective has
for
- s - triazine
the least
toxicity
group
by
diuretic
on
and renal
establish-
to a standard as well
following
studies
dogs
subsequent
or Mercuhydrin) have
chronic been
made
with aminophylline.
for this approach
other
and water
agents
and its applicahave
been
pre-
elaborated.*-’
METHODS
These
(A)
toxic, the
OBSERVATIONS
Group I: Thirty-two nonhydrated dogs, which were anesthetized with 30 mg/kg of pentobarbital, were given After suitable single intravenous doses of chlorazanil. control periods, each of four doses was administered
diuretic
furnishes
LABORATORY
Five groups of dogs received chlorazanil and one group (group VI) received chlorazanil in combination with aminophylline. Dogs in group I and IV received chlorazanil as a single intravenous dose. The dogs in groups II, III, and V received chlorazanil orally.
chemical in
AND MATERIALS
of
hydrochloride). and
to
and
relative
responses
Additional
the
curve
of its potency
rationale
influences
includes
response
clinical
the
viously
(N-para-chlorophen-
possesses the strongest
This
of
water. time
were
culminated
its
(meralluride
tion
the ab-
effects.
which
for
as
The
a
SPURR, M.D.,$
in men
excretion
on the drug in combination
it is not
and
and
studied
the
diuretic therapy.
the
explore
first
diuretic
of chlorazanil
yl - 2,4 - diamino
of
of inhibiting
derivatives
development
serum
view
should
of
called 13 years
triazine
In
on
of a dose
calculation
salt-retaining
in pathogenesis,
retention
ment
de-
L.
M.D.,F.A.c.c.~
has been
effect
hemodynamics.
be
factors
failure,
hormone,
investigator capable
was
many
cardiac
etc.
of factors
to
drug
its
electrolytes
denom-
appears
kidney,
antidiuretic
that
subject
the
The for
every
MOYER,
M.D., C.
Texas
in
form
of
common
edema
imbalance,
strange
effect
the
of
of water etiology
equipment
function,
excess
electrolyte
This
the
viz.,
operative;
creased
were
of
of varied
Although
of
sodium
the excretion
states
Orally
C. BULLOCK,
PH.D., and JOHN H.
HANDLEY,
on
Agent+
III, M:D., ALLEN
Houston,
D
Observations
the
for this report.
Supplied as Riker* N-p-chlorophenyl-2,4-diamino-s-triazine, marketed in Europe as Orpidan or Neo-Urofort. 545 (Daquin) and SKF-3195. t From the Departments of Medicine and Pharmacology, BayIor University College of Medicine, and the Medical Service, Veterans Administration Hospital, Houston, Texas. Supported in part by a grant from the Houston Heart Association. 1 Present address : Bowman Gray School of Medicine, Winston-Salem, North Carolina. Zj Present address : Hahnemann Medical College and Hospital, Philadelphia, Pennsylvania. 148
THE AMERICAN JOURNAL OF CARDIOLOGY
Ford et al. to eight and
different
16
periods
Group II:
were
were
each
allowed
given
potassium,
administered
period
and
later.
Urines,
the
were
analyzed
at
other
the
half
collected for
divided
oral
to take
water
10 mgjkg,
and four dogs received
was
ad lzb.
were
beginning
was
the
of a 24-hour
administered
12 hours
24-hour
and
given
Half
40 mg/kg.
as single
sodium
four
doses of
specimens,
potassium,
and
the
Group 111:
Eight
dogs were given
doses of chlorazanil
to determine had
free
The
dietary
as single
access
sodium
to
during
24-hour
water
days in
period
effect.
specimens.
throughout
The
the
study.
for the group
for each dog, being
the control
per day in
of the diuretic
was not standardized
but was kept constant the same
20 mg/kg
for six successive
the persistence
was collected
dogs
dynamics
Observations Methods
previously.ssg
were
hours
dose
of 8 mg/kg.
after
glomerular
drug
as during
used
to determine measured
Concurrent Grou,4 V: made
week
later
were
on renal
have
been
made
before
administration
hemo-
of pento-
renal
plasma
used
Blood
flow.
made
bination
dogs
was pressure
manometry.
on water,
the
on renal
in the
animals
sodium,
hemodynamics
control
had
given
oral
flow, water in the
(10
dogs
mg/kg)
intravenously
glomerular
excretion,
control
in
and
800
state
azanil
on
600
mg
produced
toxicity,
and
filtration
controlled drank
razanil-200 patients tion with
dose-response
ml
24
Urine
hours
* A dose but
(three
in
heart
hours
have
a
male
patients
controlled
been heart
drug.
of variance
The
about
the
was varied
plasma
patients
drank
drug
were
a
a constant was collected two-hour
Each
and,
1959
with
well-
of the patients
This
was
allotted
water
intake
under
oil in six periods
periods
was administered
to be toxic
electrolytes
patients
day.
of chlor-
and
throughthree
six-
to six dogs,
consequently,
diuretic
dose
to
excreted
for
90
patient and
before
breakfast
chloride,
volume,
included
plasma
chest x-ray (III)
of the
this
of
each
hours.
diet
The They
until
of
days by
the
was
Urine (as
collection).
next
allowed
restoration
potassium,
a measure
Other
of
weighed
was collected
for sodium,
creatinine
of their the
were
patient
voiding.
which
to be tested was then
4-6 Each
each
of sodium, hours)
diet of the
of the
routine
studies
electrocardiograms,
and
on each patient. The
Therapy:
This
content
administration
electrolytes,
ap-
g of protein,
meq/24
and analyzed and
contained
requirements
agent
equilibrate
and after
the
ambulatory
meq/24
on
agent, stores.
periods
completeness
single
to
water
be
water every day.
(45
the
diuretic
sodium
in 24-hour
per cent
of the heart
Cal/day.
amount
The diuretic Before
the
the
equilibrate a constant
sodium. of
50
of
diuretic
throughout
100
sodium
3 liters of distilled
allowed
patient
The
of
diet
of 2,800
exactly
in an air-
observation
to
The
ten
of well
of the study for
for control
with the caloric
was
degree
exception
allowed
of this
Briefly,
the
g of carbohydrate,
patient.
technics
continued
ward.
two
without
chlorazanil,
maintained
the
were
somewhat
individual
of
The
under
were
metabolic 300
were
required
patients
and
was made.
were the subjects
With
these
linear,
equivalent
patients
proximately
and the stand-
Since
a roughly
personnel.
excretion.
was performed
estimate
ward
to 10
in combina-
and water
previously.2
metabolic
to these
mg of chlo-
Compared to a Standard
parallel,
patients
in
without
was administered
as “one,”
failure
These
conditioned
excretion
of the drug
potency
mg,
doses of 300 and
described
with
diet
the
effect
of various five
were not done at this dose level.
FEBRUARY,
error,
Sub-
600
vomiting
dose of 600
Bioassay for Potency in Man:
(II)
and
(Mercuhydrin). were
mg.
mg,
with chlorazanil
to meralluride
patient’s
were made899 after
The
failure.
water
of 64 mg/kg
this proved
studies
of
to assure
out the day.
analysis
curves
study
this
oral
curve
was given
was limited
on sodium
obtained
meralluride
ard,
150
sodium
of Chlorazanil
A standard results
with
Since
the effect
aminophylline
Dzuretic:
drug
to 300
mg of aminophylline to determine
administered.
excretion
observed
congestive
fractionally per
urinary
was
3,000
A single
two dose levels.
Ob-
dose.
renal
excretion
for three
a com-
aminophylline
rate,
and sodium and
received
patient
dose-response The
of 10 patients
study.
last
and volume.
the third
nausea
optimum
the bioassay
20 mg/kg
OBSERVATIONS
the
water
it produced
all medications
The
as a single
Electrolyte Excretion Patterns:
and
increased
mg until
dietary
(I)
starting
was
approximated
CLINICAL
A
dose
dose
of these
administration. (B)
a.m.;
the
agents,
administration
solute,
and 6 : 00 p.m. of the same
a single
sequently,
failure
and
dose.
two hours after
anesthetized
given on
6:00
and 100 g of fat with a total
Five
of chlorazanil
servations
at
for
titratable
600 mg of chlorazanil
for chlorazanil.
one
state
been
as a single
were made
mg/kg)
total
received
Relationships:
determined
orally
in a
of the last dose.
(25
Dose-Responsr was
trained
observations
on five
I’I:
dose
analyzed
day.
compared
for
to determine
intra-arterial
were
of chlorazanil
Group
bicarbonate, patients
oral
were phosphate,
600 mg at 6 : 00 a.m.
significant
intravenously
was
direct
Similar
measurements
as a single received
and
excretion.
after
ammonia,
of the three
described
and para-aminohippurate
observations
were
made
technics
rate
by
and potassium
specimens chloride,
Potency Estimate
the period
with 30 mq/kg
Creatinine
filtration
was
per day
and
Observations
three
These
potassium,
on the
in 8 dogs anesthetized
barbital.
periods).
acidity,
approximately
of drug administration. Group II’:
hour sodium,
over 25 per cent of the patients.
were noted.
two divided Urine
8 mg/kg,
in 20-minute
for sodium,
dogs received
They
dogs
volumes
4 mg/kg,
collected
Two
Twelve
20 mg/kg.
order
were
excretion.
chlorazanil.
dose
i.e., 2 mg/kg,
Urines
for six hours and analyzed
and water
Four
dogs,
mg/kg.*
Effect
of
Chlorazanil
daily
oral
doses
Chlorazanil
After
was administered of 300
mg
Chronic
Daily
for five days in
to ten
patients
with
13 3
12.3
P value less than
f
%
8
0.3
0.2
0.2
0 4
-
0.20
300
0.9
0 05
250
0.5
0.01
is0
0.5
0.20
200
0.8
D,
Maximum
response during
Control.
II 05
367
1.1
0.01
350
0.7
0.001
300
0.6
0 lo
250
1.0
Dz
Di
=
0.05
300
0.9
0 01
350
07
0 05
250
0.5
0.10
250
1.0
____-
0.10
267
0.8
0.05
350
0.7
0 10
300
0.6
~~__
0.20
150
0.6
Ds
0 20
233
0.7
0.05
350
0.7
0.10
300
0.6
0.05
150
0.6
Ds
20 min ;tftrr drug.
0 10
267
0.8
0.01
350
0.7
0.05
250
0.5
0.05
225
0.9
D,
(mI/min)
Fiat
flow
D3
Urine
any single ZO-min period.
&y to Abbrcviatiorls: L: =
70 of control
P
Mean
C
12 2
P value less than
70 of control
Mean
P value less than
y. of control
MeFin
P value less than
5 !z 3
21
i-
12.7
c
(kg)
y* of control
Mean
_~ __--
__
Body
weight
1 0
DZ =
0 01
467
1.4
c
D1
9
response
6
0 10
950
114
433
52
105 0.05
1750
0.10
1211
109
Da
95 0.05
792
121
149 0 05
1656
102 850
109
I>, =
0 05
1522
137
0 01
1817
558
67
Ds
-
0 01
2600
234
0 01
3150
189
0.05
1650
198
0.05
1242
149
__~
~~~
10
6
4
9
c
11
0.05
200
20
0 20
233
14
0 05
275
6
12 120 0.50
___
0.50
117
7
0 30
150
0.20
144
13
DS
~-~
5
0
9 50
90
_
0.50
117
7
0 50
125
0.30
122
11
Da
122
11
D<
6
6
0 50
100
10
0.40
150
9
0 20
150
ni = 5 111. .*ftzr
0 50
90
9
0 50
133
8
0 40
150
0.50
122
11
Da
(peqlmin)
0 20
potassium
Ds = 4 hr .tfter drug.
~~
156
14
D,
Urine
in Dogs
0 01
___
Excretion
3 hr alter druq
0 05
1311
118
0 05
1517
91
0 10
967
116
0.10
_~~~__
0.10
to eight dogs
0.01
2017
583
70 0 05
to eight dogs
0 05
883
2 hr .~ftrr rlruq.
0.01
1567
141
given
0 05
1833
_~~ 106
to eight dogs
110
given
0 05
575
69
given
0 05
867
104
Ds
to eight dogs
D4
(fieq/min)
on Water and Electrolyte sodium
I
given
l)d =
0 05
2067
186
to 16 mg/kg
0.05
1100
66
to 8 mg/kg
0 01
717
86
to 4 mg/kg
0 01
response
12
592
71 0 20
response
12
Dz
Urine
to 2 mg/kg
30 min .dtcr droq.
The
0.01
550
1.1
The
0 01
500
TABLE Doses of Chlorazanil
The response
The
0.05
325
1.3
Max
The Effect of Single Intravenous
dl-ll$.
0 50
100
10
0 50
167
10
0 10
250
10
0.50
122
=
0 01
220
22
0.05
300
18
0 001
400
16
0.01
211
19
Max
Max
~__ 11
Ds
L’rine was collcctetl in compensated cardiac failure. 24-hour specirnvns and analyzed for sodium and watc’r. The blood of each of these patirnts was analyzed for serum sodium. potassium and chloridr concrntrations, carbon dioxide combining power and for blood urw nitrogrn brfow and after administration of 300 me of chlorazmil a dn\ for five days. 7‘hr E[fcri II,! (.lrlorcizonil on ,Vr~ro,sp Bnlanc~ and (II’1 Hrnal Fu~rctrwrt In anothrr group of 20 hypcrtensiv< nonetlc~mntou5 wctpativnts, trn were givrn 300 rng daily as a slnqIc oral dew and trn werr qivrn 300 my The patients wcw seen at twice. daily for 21 days. wwkly intrrvnls. .lt which rime blood urea nitrogen detrrrninations MVI‘V clone to compare with hascliw studies obtainvtl prior to thr institution of therapy. :\ftcr this study \vas complete, it \vas found advisahlc to study mow prcciscly the effect of chlorazanil on thv I:our patients wcrc blood uwa nitroqrn conwntration. the suhiwts uf Manw studies fur sodium. potassium. chloride, nitro,gvn, phosphate and water with concornitant obscrvatiwb of plasma creatinine and urea nitrogrn. as well as rrieasuwmenls of 24-hour c7xiogcnous crcati( Imsrtl upon singlr plasma creatininr nine clcar,lnr(. dctrrmination I_ Thr patients \xcrc ol)wrvcd for 20 days. the first five* of which constitrltctl a control period, the next ten tlw drug-twarment period and the nrxt live a post-treatment T\vo pdtic*nts wccived 150 mq twice daily and period. two rwrivcd 300 mq twice daily during the drugtrratmrnt periods. Dietary intake was constant fat sodium. nitroqcn. xvatv, and c&rim. I-rim and fc-
‘1‘0 gain hroadcr clinical implications of this problem. another 20 outpatients (from Hypwtrnsivc Clinic i with ~erll-controlled congcstivr failure wcrc givc,n chlorazanil .,‘I II.t 1% VI’
RESULTS (A, I.ABORATORY OBSERVATIOSS GI-o@ I: !%‘hen a single dose of chlorazanil was given intravenously to 32 anesthctizcd, nonhydrated increase
dogs, in
pearing
and
maximum
was
a
in water
no greater
significant
rscretion
after drug
fur fi\x: hours
increase
chlorazanil
\vas \~att’r
bvithin 20 minutes
tion and persisting
mg
thcrc
sodium
ap-
administra-
or more.
excretion with
The due
;I dose
to 16
cJf
kg than with one of 4 mg, kg INIC the diuretic
response
\vas
dosages.
of longer
Potassium
duration excretion
at the was
hiTher
increased
TABLE II THEACUfSWFETOPORN. Bodyltt. KCI.
DOSESOF CHlDRAZANILONWATERAND'ELECTROLYiYE Q(CR?XIMIINMX:
urine VoluJm cc/ndn. c
5 &3&g
glvul
omlly
10.8
0.27 0.42 156 N.S.
sitenoram 9.0
;3
control
P Value 20 &kg
C
D
9.3
twice a
day
0.22 61
23 l$
N.S.
N.S.
C
a3 67
9
D
PD
2E
?!.S.
16 178
N.S.
N.S.
N.S.
N.S.
lbi Ndi.
I.4 N.S.
for one da9 to four doga
0.20 0.34 170 N.S.
0.33 16j N.5.
15
28 16 187 la7 <.l N.S.
0.15 O./d
0.21
S
24
1359
5
293
<.I
N?
C-ho - UC how Controlperiod4(averago) D-Twenty-four hour period durbgdrugadminLt.ntLn PD - Twentg-four hour penod followingdxug administration
FEBRUARY,
PD
9
givenorallytwice a day for one day to four dogs
i?f Control P Value Key:
PD
urine Potmritm m**
twice a day for one day to four doge
?s control P value 10 &kg
D
urin.Sod.l.nm /wa/~.
N.?
5
152
Chlorazanil,
a Nonmercurial
only slightly and this effect was of short duration (Table I). Group II:
Oral
Grou@ V:
When
the chlorazanil
was given
as a single oral dose to five dogs, there was no When
two divided
the drug was given orally in
doses, the diuretic
dramatic
than
istration.
The
following effect
effect
intravenous
on water
effect
was less
four
admin-
excretion
on glomerular hours
plasma
was
four
hours, latter
water excretion
prolonged
being secondary
to the increased
The dose of 5 mg/kg given twice a diuresis,
whereas
a dose
for a period
administration. altered
there
for a period
was a moderate
response
was probably
anesthesia (Table
of
Renal of
but, after reduction. due to the
V).
3?ztterns ofei%c;ret;on in CONTROL STArE (DIET 50 M&l No - 3000 Cc DISr/LLEL’ WATER DAILY) mr * &oT
day did not appear to increase sodium excretion a water
filtration
drug
flow was not
This
sodium loss.
after
two hours after drug administration
just as great as, if not greater than, the increase in sodium excretion rather than the increase in
despite
Diuretic
in
excess of 10 mg/kg given twice a day appeared to increase There
both
water
and sodium
was no consistent
excretion
(Table
effect
excretion.
on potassium
II).
When chlorazanil was given Group IIZ: continuously for six days, the increase in water excretion
persisted
observation.
The
was variable
from
slight
increase
(Table III). Grout IV: eight
throughout effect
the
day to day
above
the
When
anesthetized
period
on sodium
but showed
control
given
dogs,
of
excretion a
observations
intravenously
chlorazanil
to
did
not
have a hypotensive slight increase
effect. In fact, there was a in blood pressure one hour after
drug administration. was
not
altered
dissolved
in 150
slight reduction
Glomerular when
the
ml of saline. in renal
“!
filtration rate
chlorazanil There
plasma
trTh
was was a
flow, but this
was not significant. However, when the drug was administered in a concentrated form in 10 ml of saline, glomerular plasma
filtration
rate and renal
flow were both depressed
one hour or
more following drug administration
(Table
IV). TABXZ
THE QIROKICEFFECT OF ORAL DOSES OF (10 n&kg
D2
c!l 7:
4
xxx
CHLORAZANANIL
ON
WATFB At!DELFsCROJlT!d EXCRETION
given orally twice a day for six days to eight dogs) sodium ticretion /W"/"i".
urine Volume cc/dn.
nt. Kg.
tius
XXUS
Average urinary electrolyte excretion pattern Fig. 1. found in five patients with well-compensated congestive heart failure.
D1, D5
D6
C
%
Dz
Dj
D4
D5
Potassiuuaaxetion /u-d=lll. %
Control 10.8 0.19 0.30 158 0.45 237 0.51 268 0.49 258 0.57 300 0.47 Ur7 16 lbq 27 225 36 U4 23 131 22 163 26 100 16
* p value less thlin
.05 .lO
Key: C - Cmtml
.lO .05
.05
.lO
.05
.lO
.30
.20
.2u
C
%
Dz
D3
D4
*5
9 133 12 133 I.2 Ill XI I.22 xi 133 12 133 12
.50
.P
.M
.50
.40 .lO .30
observations- averageof two 2l+hour urine collectionperiods. 21rham wine collectionperiods.
THE
%
AMERICAN
JOURNAL
OF
CARDIOLOGY
Iby:
volume (ccwn.1
urine
Hemtocrit
Ralal PU8lW FIRN (cc/min.) (CPAN
[&kLe Clearance)
C -
Dh
D3
Dl D2
Glomerular Fxltration Rata
Yean blood prmlsure am. tlg.
GIVBiIhiVRUJSLT
;s 97
35 35 37
.05
:$
.Ol
.50 J&O -50 .50
.lO
.30 .05 .30
-2 .50
.50
.Ol
97
:z
ll2
.50
P valua 1CM than
105 111
98
x or control
z7"
126 128
1U ll2 120
hmn
given in 150 cc saline to eight Qga)
(Average weight- Il.6 kg.1
Control Observations - Observations immediately after adizinistration of Chlorazanil ,I I, II - Observations one hour u " II II - Observations two hours u 1, II " - Observations three hours I'
D3 %
Dl D2
C
%
D3
Period
(8 dkg
THERENAL.RBFCNSETOCHLORAZANIL
TmEIV RESPO~ETO CHUBAUNIL.GI~O~~
Dl D2 D3 DL
crit
37
;: 290
z
;: 98 90
E
72
90 92
96 100
33s
1CC 286
% of contrJ1
.30 .50 .50 .20
.50 .50 .m .lO
.50 .30
.50 .50
.50 .Ol .C5 .05
P value less than
‘.
(Averageweight = 13.2 Kg.)
D3 - Observationsthree hours after administration of ChlorazanU. D,+- Observationsfour hours after administration of Chlorazanil.
ChlOl%XLanil
C
Hem&~
299 214 297
44
:9 :;
0.7 0.7 2.0 2.1 2.3
man
.,z
Key: C - ControlObservations D, - Observbtions(averageof two lo-minuteperiods)imediately aft-anesthetisation and-twohours after ad&i.str&ion of Chlo&d_J.. D1 - Observationstm hours and 30 minutesafter administration of
C Dl D2 D3 DL
DL D3
pzz; ROW.1 Plasma Flon (cc/~.) (C FAN
D1 D2
Filtration Rats
Dl 9 ?3 D4
C
Period
C
4
RSNAL
giran orallytwo hours before anesthetizingto fire dogs)
ME
GlOmWlllCW
Volwm (cc/min.)
Urine
kan blood prw*ura I. lig.
(2J m&kg
TAELBV
154
Chlorazanil,
Group T’I: to
alter
Aminophylline
the
chlorazanil
renal
did
not
hemodynamic
in five anesthetized
the effect
of chlorazanil
excretion
was not
appear
response
dogs.
on water
affected
a Nonmercurial
to
Likewise, and sodium
by aminophylline.
Oral
acidity total
excretion solutes
CLINICAL
of average
excretions
in five patients
congestive
of urinary
of 600 mg of chlorazanil
single oral dose (Figs. marily
a significant
and chloride increase excretion excretion greatest
constituents
with well-controlled
was sometimes was
in sodium,
There
in bicarbonate decreased
natriuresis.
as a
2 and 3) produced
increase
excretion.
potent
diuretic
pri-
water,
was a moderate
administration
was of a lesser (II) single
of
Patterns of excretion following administration of: 600 mgm CHLORAZANIL P.O. (single)(pt. SA) ,D -
magnitude
oral dose caused
excretion
time
drug
and
lasted
there was a noticeable
Chlorazanil
0.14 l/24 hours.
titratable
of
600 mg was given
than
the
Bioassay for Potency in Man:
relationships:
Ammonia the
of the When
onset
two hours
effect
of
the first dose (Fig. 4).
Potassium
and
The
effect from the second dose which
increased. during
per liter
seen with com-
agents.
twice at 12-hour intervals,
excretion.
Phosphate
but the concentra-
approximately
for 12 to 18 hours. but delayed
heart failure are presented in Figure 1.
Administration
per minute,
The
in terms
tion of solutes in terms of milliosmols
after patterns
also.
increased
was less than the concentration
OBSERVATIONS
determined
depressed
slightly
these effects occurred
Electrolyte Excretion Patterns: The
(I)
were
were
of micro-osmols
parably (B)
Diuretic
of 600 excretion
of 11 meq mg
300
Dose-response
mg
given
an increase and
water
as a
in sodium excretion
of
Following the administration there was an increase in sodium
of 60 meq/24
hours and an increase
Patterns of excretion following administration of: 600 mgm CHLORAZANIL P.O. (single)(pt. JAI
+ ““r
war
500
Fig. 3
Fig. 2
Fig. 2 and 3. Electrolyte excretion pattern in the urine following a single dose of chlorazanil emphasizes a major effect in augmenting the excretion of water, sodium, and chloride with a lesser effect on bicarbonate. THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Ford et al.
155
in water excretion The
increase
paralleled
of 0.39 l/24 hours (Table
in
the
chloride
increase
while potassium
excretion in
excretion
VI).
roughly
sodium
excretion
was not consistently
Chlorazanil 600 mg in combination altered. with 200 mg of aminophylline as a single oral dose produced
an increase
of 57 meq,‘24
hours and an increase
excretion test
of 0.44
showed
in sodium
l/24 hours.
that
the
excretion in water
A Student’s
differences
“t”
in increased
sodium and water excretion
between
chlorazanil
mg of chlorazanil
alone
and
600
with 200 mg of aminophylline cant
(Table
600 mg of
were not signifi-
VII).
Potency estimate of chlorazanil: variance to
meralluride
The
two
the error
not
significant sodium
be 0.49
(Mercuhydrin),
dose-response
and on
An anal!-sis of comparing chlorazanil
was performed
Expressed
standard.
were
in the experimental (Fig.
5).
excretion
was
if meralluride
based
chlorazanil
compared
in another
parallel
trial?
A calculation
showed
in potency,
the standard,
the
curves
to
to meralluride,
is taken
as “one.”
way, 600 mg of chlorazanil
orally is equal to 1 cc (40 mg of Hg) of meralluride
(intramuscularly)
creased
sodium
chlorazanil
in producing
excretion.
based
on
water
compared
to meralluride
to be 2.2,
suggesting
excretion
The
an
excretion
as “one”
a greater
of and
was found
effect
than with comparably
in-
potency
on water
potent
diuretic
agents. (III)
The Effect of Chlorazanil After
Daily Therapy (Table
of 300 mg per day, chlorazanil tinuous
response
patients
(Fig.
in serum
6).
There
days of administration
no significant
concentration
concentration chlorazanil
tion on blood urea nitrogen
or
after five
patients
is
administra-
in 10 nonedematous presented
in
Table
The mean values for blood urea nitrogen
in the group receiving mg%
con-
days in 10
(Fig. 7).
The effect of chronic
IX.
were
electrolyte
in blood urea nitrogen
hypertensive
produced
on five successive
changes
Chronic
As a single dose
VZIZ):
in the control
300 mg daily were 20.4
state,
31.4 after one week,
and 31.9 after three weeks of drug therapy. In the group receiving 600 mg daily, the mean
FEBRUARY,
1959
control
blood
rngyc.
This mean value rose to 45.9 after one
urea
nitrogen
value
was
21.8
156
Chlorazanil.
week and was 43.6 therapy.
Six
of
after three weeks of drug ten
patients
receiving
mg daily and eight, of ten patients mg twice daily demonstrated in blood
urea
nitrogen.
there an alteration
receiving
moderate In
300
Oral Diuretic
Dose response curves: CHLORAZANIL YS MERALLURIDE COMPARATIVE POTENCY
FOR DETERMINATION
OF
300
increases
no instance
of hematocrit
with this elevation
a Nonmercurial
was
contemporary Side
of blood urea nitrogen.
effects seen, more often with the larger dosage, were
anorexia,
occasional
tion of “ganglionic therapy), (IV)
vomiting,
blockade”
and generalized The Effect
weakness.
of Chronic
istration on Nitrogen Balance Studies:
The
significant
studies are presented are the average hypertensive
Chlorazanil
values
results
of the balance These
for two nonedematous each
at
levels, 300 mg and 600 mg daily. administration
there
was a slight
Admin-
and on Renal Function
in Figures 8 and 9.
patients
daily
potentia-
(antihypertensive
two
dosage
During
the
of 300 mg of chlorazanil, increase
in urinary
sodium,
Patterns of excretion following administration of: 600 mgm CHLORAZANIL P.O. (q. 12 hrs&t. SI) UO
50
0
2.5
0
L
kd
Fig. 5. The dose response curves for meralluride and chlorazanil indicate that approximately 600 mg of the latter orally is equivalent to 1 ml of meralluride intramuscularly as a natriuretic agent.
producing volume
a slightly negative
increased
patients
portionately Nitrogen after
small
balance
the
fifth
The endogenous paralleled blood vated.
to a greater
complained
degree
of thirst weight
became day
of
creatinine
the positive
Urinaq
balance.
and the
while
a dispro-
loss was
observed.
progressively drug
positive
administration.
clearance
nitrogen
depression
balance,
while
urea nitrogen concentrations were eleDuring the administration of 600 mg of
chlorazanil
daily, similar changes were observed
but were of greater magnitude became more negative,
: sodium balance
water balance
even more
THE EFFECT OF CHLORAZANIL HYDROCHLORIDE ON SODIUM AND WATER EXCRETION - 300 mgm per day for 5 consecutive days
I D
Following the second dose of the drug in a 12Fig. 4. hour period, there is an additional augmentation of diuresis and natriuresis.
P
are repetitively effecFig. 6. Daily doses of chlorazanil tive in producing water and sodium loss (average of data from 10 patients with compensated congestive failure). THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
157
Ford et al.
negative, positive
while nitrogen and
balance
was accompanied
of creatinine
clearance
urea nitrogen
concentration.
became
and elevation
THE EFFECT OF CHLORAZANIL ON SERUM ELECTROLYTES
more
by depression Changes
of blood in phos-
HYDROCHLORIDE
phate
balance
balance
while
paralleled balance
paralleled changes
those in
in
chloride
those in sodium balance. was not significantly
Among
cardiac
balance Potassium
altered.
the 20 hypertensive
well-controlled
nitrogen
outpatients
failure,
eight
with
showed
a
TABI3 IX
EFFECT OF CHROWICORAL ADMIXISTIWXIONOF CHLORAZANIL ON ElLfYXUREANITRSEZ4 Patient
I Serum
1. L. A. 2. J. B.
CHLuRlOE
3. R. H.
i-/L1
4. 9. c.
S&-LU?C 30 Cd RBON L%OX/DE /T/L/
T
c
;
1 L
25 .
dLOO0
UREA
IVITR~GEN PYm$1
4 30
5. A. L. 6. J. L. 7. J. E. 9. D. T. 9. 0. i. 10. A. G. yean 11. B. w. 12. C. A. 13. D. B.
Blood Urea Nltrqsn C D1 4 28 18 18
17 10 23 27 u 19 20 zQ.4 11
14. R. B.
27 23 23
',5. E". :..
1"4
;;. . "J. . ;.. 19. J. iv. 20. J. R. Mean
::
48
Fig. 7. Serum electrolytes after five days of chlorazanil therapy are not significantly altered except for those directional shifts due to dehydration. FEBRUARY,
1959
Dose (ddq)
2"6 21.8
16 70
600 boo Et
tg.6
c - control 4 - After one reek of therapy D3 - After three weeks of therapy
Chlorazanil,
158 THE EFFECT METABOLIC
OF CHLORAZANIL BALANCE
SOOlUM
60
mEq per 24 hrr
4O
300
mgm
DAILY
a Nonmercurial ON
Oral
IIiuretic
THE EFFECT METABOLIC
OF CHLORAZANIL BALANCE
SODIUM
80
mEq per 24 hrs
600
mgm
DAILY
ON
60
UIillC
20 WATER Lllers pr 24 hrs
1
3
5
10
15
bl: 4
Fecal
I
20
1
1
I
2
WATER
br
L~lers per 24 hrs
4
UIIIK
3
5
15
10
20
J
2
1 13
5
10
15
20
NITROGEN Grams per 24 hrs
12 Ur,ne
NITROGEN
18
Grams per 24 hr
12
UIlW
6 Fecal
Fecal 1
CREATININE CLEARANCE
12
3
5
10
15
20
CREATININE CLEARANCE
(“GFR”1 cc ,lmn
BLOOD UREA NITROGEN mgms %
30 20 1D
CWtrOl
Chlraunil I50 mqm b.i.d.
’
Postdrug
Fig. 8. Averages of data from two nonedematous hypertensive patients receiving 300 mg daily of chlorazanil. There is a progressive slightly negative sodium and water balance, and a slightly positive nitrogen balance, contemporary with a small depression of creatinine clearance and elevation of blood urea nitrogen concentration.
rise in blood
urea
nitrogen
concentration
eleven a rise in plasma creatinine after
receiving
three
weeks.
were present
chlorazanil, Increases
in six of the twenty.
creatinine excretions
Depressions
TAESX
and for
The
c
maxi-
orsatinine
Pla_ Creatinine
B.U.U.
Patisnt
measurements
mum blood urea nitrogen concentration was 38 mg%.
C
D
Clearance
detected
of the endogenous
clearances and 15-minute PSP were found in some of the patients.
affected by Daquin therapy; erythrocytes were never found. Decreases in body weight were not statistically significant in these nonpatients
(Table
X).
DISCUSSION The development of triazine derivatives diuretic agents has been somewhat similar that
of
the
carbonic
After sulfanilamide
anhydrase
as to
inhibitors.
was found to have diuretic
17
*“m-age
*
Albuminuria
C = F
.9
22
=
Control. Cells
(never
c
D
c
D
C
D
96 100
66 52
lF w v
: 63 72 82 72 102 76 55 104 59 101 70 92 68 101 85 72
12 10 12 u 12 14 u 15 25 10
N
lrn ;z 105 llo 102 101 82 80 102 101 99 90 Lo2 65 lO2 104 B2
15 25 25 20 22 25 19 25 25 15 :: 25 25 all+ 25 10 25 25 20
2; 22 25
95
78
22
16
D
The results of the urinalysis were not significantly
edematous
Port-drug
Fig. 9. Averages of data from two nonedematous hypertensive patients receiving 600 mg daily of chlorazanil. There is a greater magnitude of change in thr balances described,for Figure 8.
concentration
150 mg b.i.d.,
in both
hl uani 0 8, m b .I.d.
CMtJOl
1.2
(never D
more
than
20 10 25 15 17
l
* + * N N N N * N N N N N N N N N N
l
* P P P F l
N N N P fF N F F N N
1 +)
=
After
three
more
than
10
weeks
WBC/hpf).
therapy. N
Normal. THE
AMERICAN
JOURNAL
OF CARDRXOCY
=
Ford many
properties, development were
of sulfonamide
diuretic
but
serious toxicity and 1944, that
elapsed
years
before
derivatives
relatively
devoid
of the first compound.
Lipschitz
substances
which
In man,
the effective
set of action
within
administration
and
showed
approximately
18
chemically
by
dose range is between Daquin shovvs an on-
300 and 600 mg daily.
of the In 1943
and co-workers’,‘O
characterized
the
et al.
probably tinued
hours.
oral
of action
Thus,
of
it
should
or twice daily
if con-
is desired.
in human
following
duration
be given once diuresis
effect
two hours a
There
beings
on
is a definite
the
excretion
of
sodium, so that it has been calculated to have a potency of 0.5, i.e., it is roughly one-half as
~rallUrlde (Memuhyddn) ~304~ lig (kc) I.M. 1
(Neohydrin)
chlonwrodrin
Fig. 10. the
Structural
presence
in
WmgmHg
formula of chlorazanil.
the
molecule
N=C-N The best
of
Oral
not
4 acetazoleamide 25omppl oral 1
therapeutically because of its severe The exploration of various triazine toxicity. derivatives has culminated in the presentation
apdnometrdine 12oom&Tn oral
groups
possessed
diuretic
effects.
known of these substances triazine
or
is 2,4 diamino-1,3,5-
formoguanamine
but
it
was
(a-)
useful
of chlorazanil
(Daquin)
which is chemically
chloranilino-4-amino-1,3,5-triazine Neo-Urofort)
(Fig.
10)
2-p-
(Orpidan
as an
orally
or
effective
diuretic agent without serious toxicity.” Hungarian workers reported alterations renal tubular
reabsorption
(b&tine)
in
of water with a lesser
and independent effect on sodium and chloride In Germany, studies13 at somewhat excretion.‘? low dosages
(2 mg/kg)
showed
an
chloride,
and
excretion
of
potassium,
ammonia,
and
phosphate,
as well
acidity, were
not
were
not
increased
that the drug
produced
excretion
bicarbonate
markedly
changed.
associated
of sodium,
while
with
the
urinary titratable
as the
These serum
pH,
changes
agreement
with
Hungarian
workers
with
each
other
dogs,
our
results
intravenous
the
German
as well
(who proposed on
basic
indicate
administration
as
mechanisms). that
the
to disagree
following
In the
of chlorazanil
there
is a significant increase in sodium and The percentile increase in excretion
water water
is
greater
natriuretic
FEBRUARY,
potency
potent as meralluride
The results of the present study- are in general
potent
Comparative
1959
than
agents.
with
of various
natriuretic
electrolyte
alterations.
excretion
Fig. 11. agents.
comparably
somewhat
(Mercuhydrin) increase observed
(Mercuhpdrin).
differently,
1
ml
intramuscularly
in sodium excretion following
the
oral
Expressed
of
meralluride produces
equivalent
administration
approximately600 mg of chlorazanil. parison with other orally active diuretic (Fig.
11) indicates
acetazolamide merodrin
that it is more potent
(Diamox),
(Neohydrin),
aminometradinc
(Mictine)
equipotent but
less
an
to that of Com-
agents than
to chloropotent
than
and chlorothiazide
160
Chlorazanil,
(Diuril),
when each
a Nonmercurial
is given orally as a single
dose.
Oral
Diuretic
nonmercurial
diuretic and a moderately
However, patients rapidly develop tolerance to acetazolamide and to aminometradine,
natriuretic agent. The chronic oral administration
the clinical
anil,
limited.
use of which,
If calculation
therefore,
is sharply
of diuretic
based on urine volume changes
potency
(acutely)
is
chlor-
daily,
administered.
aminophylline
and
administered daily
continuously
effective, evidence
and plasma creatinine
of creatinine positive
clearance,
nitrogen
glomerular seen
but
filtration
more
rarely
degree
when
There
appears
patients
in
rate.
and
then
the daily to
the
is associated
excretion,
in
This
decrease
is
only
to a minor
is only
300
variation
of Daquin
upon
with this drug without
tion of any change. Concerning the chlorazanil, illustrate
the
mechanism results
the electrolyte
be helpful.
There
augmentation
mg.
excretion
patterns
excretion paralleled
of bicarbonate
of
monia
excretion
the peak of drug action.
to
those
affected
sodium
chlorothiazide
6.
increased and
depressed
am-
during
it appears
that
7.
carbonic anhydrase However, sim-
inhibitors or organomercurials. ilar patterns of excretion have following
5.
i/i0 to ‘/4 of
slightly
Thus
by
4.
may
multiple mechanisms are affected by this drug or that a sole mechanism affected is different from
3.
by chloride.
phosphate,
are slightly
2.
of
that of chloride and this effect is not consistently is
been observed
administration
for the effect of the latter on potassium
except
8.
excretion
not seen with chlorazanil. 9.
CONCLUSIONS Chlorazanil, doses
of 300
when or 600
filtration
rate.
of this diuretic
as
of electrolyte
excretion
those of mercurials,
carbonic The is its
greater effect on water excretion to sodium excretion.
1. LIPSCHITZ, W. L., HADIDIAN, A., and KERPCSAR,
is also enhanced,
is roughly
pH observed . Urinary while titratable acidity,
300 mg
laboratory
REFERENCES
and extensive
the
excretion
action
experiments
is consistent
the order of magnitude
from
proportionately
the
the producof
of
which is not completely The
of
of action
in its pattern
as compared
among
measurements reflecting the glomerular filtration rate so that some patients can be treated indefinitely
of a fall in glomerular
is different
and
decrease
wide
effect
blood urea
of a
dose
be
patients
with depression
PSP
balance)
some
of chlorazthan
anhydrase inhibitors, and chlorothiazide. most notable characteristic of chlorazanil
is moderately
(elevated
in
mechanism
reflected,
Daquin.
administration
with laboratory nitrogen
Orally administered
had no effect upon the potency of
concurrently Chronic
The
in doses greater
produced
evidence
azanil is more potent orally than is meralluride parenterally
especially
effective
orally mg/day,
administered is an
in
effective
A. : Bioassay of diuretics. J. Pharmacol. G? Exper. Therap. 79: 97,1943. FORD, R. V., SPURR, C. L., and MOYER, J. H.: The problem of bioassay and comparative potency of diuretics: I. Parenteral and oral mercurial diuretics. Antibiotic Med. G’ Clan. Therap. 4: 708, 1957. FORD, R. V., SPURR, C. L., and MOYER, J. H.: The problem of bioassay and comparative potency II. Carbonic anhydrase inhibitors of diuretics: as oral diuretics. Circulation 16: 394, 1957. FORD, R. V., MOYER, J. H., and SPURR, C. L.: Clinical and laboratory observations on chlorothiazide (Diuril) : An orally effective nonmercurial diuretic agent. Arch. Int. Med. 100: 582, 1957. MOYER, J. H., FORD, R. V., HANDLEY, C. A., and SPURR, C. L.: Results of laboratory and clinical studies on three new mercurial diuretics and a comparison with currently available ones. Antibiotic Med. & Clin. Therap. 5: 254, 1958. FORD, R. V., HANDLEY, C. A., MOYER, J. H., and SPURR, C. L.: The problem of biossay and comparative potency of diuretic agents: III. Various oral diuretic agents. Antibiotic Med. & Clin. Therap. 5: 9,1958. FORD, R. V., MOYER, J. H., HANDLEY, C. A., SPURR, C. L., and ROCHELLE, J. B.: Laboratory and clinical observations on three similar diuretic (Micagents : Aminophylline, aminometradine tine), and aminoisometradine (Rolicton). Am. J. M. SC. 234: 640,1957. HANDLEY, C. A., CHAPMAN,D., and MOYER, J. H.: Some pharmacological properties of three new Pm. SOG. Exper. Biol. & mercurial diuretics. Med. 78: 433, 1951. MOYER, J. H. and HANDLEY, C. A.: Renal and cardiovascular hemodynamic response to ganglionic blockade with pendiomide and a comparison with hexamethonium and Arfonad. J. Pharmmol. LY Exper. Thcrap. 113 : 383, 1955. THE AMERICANJOURNAL OF CARDIOLOGY
Ford 10. LIPSCHITZ, W. L. and HADIDIAN, A.: Amides, amines, and related compounds as diuretics. J. Pharmacol. M Exper. Therap. 81 : 84, 1944. Il. SZALDOS, J. : On the diuretic action of 2-parachloranilino-4-amino-1,3,5-triazine (Neo-Urofort). Orvosi H&lap 9: 299, 1953.
FEBRUARY, 1959
161
et al. 12.
G. and CLANCER, 0. : On the diuretic mechanism of action of triazine derivatives. Hungarian Arch. Int. Med. 6: 156, 1953. 13. FRANK, H.: Zum Wirkungs Mechanismus dcs p-chlorphenyldiaminotriazine. Presented at the Karlsruhe Congress, 1956. SZABO,
and Clinical
Chlorazkil,’
a Nonmercurial
Effective RALPH
V.
FORD,
M.D.,
Diuretic
J. B. ROCHELLE,
CARROLL
an
RUGS to promote edematous
essential
part
practitioner. inator may
all
types
retention
be
by
renal
steroids, multiplicity variety
of agents
normal
the
renal
Attention
excess
Lipschitz
over
substances
possessing
but which
furnished
development
which
compound with
for
salt the
ago’
to a new
an objective has
for
- s - triazine
the least
toxicity
group
by
diuretic
on
and renal
establish-
to a standard as well
following
studies
dogs
subsequent
or Mercuhydrin) have
chronic been
made
with aminophylline.
for this approach
other
and water
agents
and its applicahave
been
pre-
elaborated.*-’
METHODS
These
(A)
toxic, the
OBSERVATIONS
Group I: Thirty-two nonhydrated dogs, which were anesthetized with 30 mg/kg of pentobarbital, were given After suitable single intravenous doses of chlorazanil. control periods, each of four doses was administered
diuretic
furnishes
LABORATORY
Five groups of dogs received chlorazanil and one group (group VI) received chlorazanil in combination with aminophylline. Dogs in group I and IV received chlorazanil as a single intravenous dose. The dogs in groups II, III, and V received chlorazanil orally.
chemical in
AND MATERIALS
of
hydrochloride). and
to
and
relative
responses
Additional
the
curve
of its potency
rationale
influences
includes
response
clinical
the
viously
(N-para-chlorophen-
possesses the strongest
This
of
water. time
were
culminated
its
(meralluride
tion
the ab-
effects.
which
for
as
The
a
SPURR, M.D.,$
in men
excretion
on the drug in combination
it is not
and
and
studied
the
diuretic therapy.
the
explore
first
diuretic
of chlorazanil
yl - 2,4 - diamino
of
of inhibiting
derivatives
development
serum
view
should
of
called 13 years
triazine
In
on
of a dose
calculation
salt-retaining
in pathogenesis,
retention
ment
de-
L.
M.D.,F.A.c.c.~
has been
effect
hemodynamics.
be
factors
failure,
hormone,
investigator capable
was
many
cardiac
etc.
of factors
to
drug
its
electrolytes
denom-
appears
kidney,
antidiuretic
that
subject
the
The for
every
MOYER,
M.D., C.
Texas
in
form
of
common
edema
imbalance,
strange
effect
the
of
of water etiology
equipment
function,
excess
electrolyte
This
the
viz.,
operative;
creased
were
of
of varied
Although
of
sodium
the excretion
states
Orally
C. BULLOCK,
PH.D., and JOHN H.
HANDLEY,
on
Agent+
III, M:D., ALLEN
Houston,
D
Observations
the
for this report.
Supplied as Riker* N-p-chlorophenyl-2,4-diamino-s-triazine, marketed in Europe as Orpidan or Neo-Urofort. 545 (Daquin) and SKF-3195. t From the Departments of Medicine and Pharmacology, BayIor University College of Medicine, and the Medical Service, Veterans Administration Hospital, Houston, Texas. Supported in part by a grant from the Houston Heart Association. 1 Present address : Bowman Gray School of Medicine, Winston-Salem, North Carolina. Zj Present address : Hahnemann Medical College and Hospital, Philadelphia, Pennsylvania. 148
THE AMERICAN JOURNAL OF CARDIOLOGY
Ford et al. to eight and
different
16
periods
Group II:
were
were
each
allowed
given
potassium,
administered
period
and
later.
Urines,
the
were
analyzed
at
other
the
half
collected for
divided
oral
to take
water
10 mgjkg,
and four dogs received
was
ad lzb.
were
beginning
was
the
of a 24-hour
administered
12 hours
24-hour
and
given
Half
40 mg/kg.
as single
sodium
four
doses of
specimens,
potassium,
and
the
Group 111:
Eight
dogs were given
doses of chlorazanil
to determine had
free
The
dietary
as single
access
sodium
to
during
24-hour
water
days in
period
effect.
specimens.
throughout
The
the
study.
for the group
for each dog, being
the control
per day in
of the diuretic
was not standardized
but was kept constant the same
20 mg/kg
for six successive
the persistence
was collected
dogs
dynamics
Observations Methods
previously.ssg
were
hours
dose
of 8 mg/kg.
after
glomerular
drug
as during
used
to determine measured
Concurrent Grou,4 V: made
week
later
were
on renal
have
been
made
before
administration
hemo-
of pento-
renal
plasma
used
Blood
flow.
made
bination
dogs
was pressure
manometry.
on water,
the
on renal
in the
animals
sodium,
hemodynamics
control
had
given
oral
flow, water in the
(10
dogs
mg/kg)
intravenously
glomerular
excretion,
control
in
and
800
state
azanil
on
600
mg
produced
toxicity,
and
filtration
controlled drank
razanil-200 patients tion with
dose-response
ml
24
Urine
hours
* A dose but
(three
in
heart
hours
have
a
male
patients
controlled
been heart
drug.
of variance
The
about
the
was varied
plasma
patients
drank
drug
were
a
a constant was collected two-hour
Each
and,
1959
with
well-
of the patients
This
was
allotted
water
intake
under
oil in six periods
periods
was administered
to be toxic
electrolytes
patients
day.
of chlor-
and
throughthree
six-
to six dogs,
consequently,
diuretic
dose
to
excreted
for
90
patient and
before
breakfast
chloride,
volume,
included
plasma
chest x-ray (III)
of the
this
of
each
hours.
diet
The They
until
of
days by
the
was
Urine (as
collection).
next
allowed
restoration
potassium,
a measure
Other
of
weighed
was collected
for sodium,
creatinine
of their the
were
patient
voiding.
which
to be tested was then
4-6 Each
each
of sodium, hours)
diet of the
of the
routine
studies
electrocardiograms,
and
on each patient. The
Therapy:
This
content
administration
electrolytes,
ap-
g of protein,
meq/24
and analyzed and
contained
requirements
agent
equilibrate
and after
the
ambulatory
meq/24
on
agent, stores.
periods
completeness
single
to
water
be
water every day.
(45
the
diuretic
sodium
in 24-hour
per cent
of the heart
Cal/day.
amount
The diuretic Before
the
the
equilibrate a constant
sodium. of
50
of
diuretic
throughout
100
sodium
3 liters of distilled
allowed
patient
The
of
diet
of 2,800
exactly
in an air-
observation
to
The
ten
of well
of the study for
for control
with the caloric
was
degree
exception
allowed
of this
Briefly,
the
g of carbohydrate,
patient.
technics
continued
ward.
two
without
chlorazanil,
maintained
the
were
somewhat
individual
of
The
under
were
metabolic 300
were
required
patients
and
was made.
were the subjects
With
these
linear,
equivalent
patients
proximately
and the stand-
Since
a roughly
personnel.
excretion.
was performed
estimate
ward
to 10
in combina-
and water
previously.2
metabolic
to these
mg of chlo-
Compared to a Standard
parallel,
patients
in
without
was administered
as “one,”
failure
These
conditioned
excretion
of the drug
potency
mg,
doses of 300 and
described
with
diet
the
effect
of various five
were not done at this dose level.
FEBRUARY,
error,
Sub-
600
vomiting
dose of 600
Bioassay for Potency in Man:
(II)
and
(Mercuhydrin). were
mg.
mg,
with chlorazanil
to meralluride
patient’s
were made899 after
The
failure.
water
of 64 mg/kg
this proved
studies
of
to assure
out the day.
analysis
curves
study
this
oral
curve
was given
was limited
on sodium
obtained
meralluride
ard,
150
sodium
of Chlorazanil
A standard results
with
Since
the effect
aminophylline
Dzuretic:
drug
to 300
mg of aminophylline to determine
administered.
excretion
observed
congestive
fractionally per
urinary
was
3,000
A single
two dose levels.
Ob-
dose.
renal
excretion
for three
a com-
aminophylline
rate,
and sodium and
received
patient
dose-response The
of 10 patients
study.
last
and volume.
the third
nausea
optimum
the bioassay
20 mg/kg
OBSERVATIONS
the
water
it produced
all medications
The
as a single
Electrolyte Excretion Patterns:
and
increased
mg until
dietary
(I)
starting
was
approximated
CLINICAL
A
dose
dose
of these
administration. (B)
a.m.;
the
agents,
administration
solute,
and 6 : 00 p.m. of the same
a single
sequently,
failure
and
dose.
two hours after
anesthetized
given on
6:00
and 100 g of fat with a total
Five
of chlorazanil
servations
at
for
titratable
600 mg of chlorazanil
for chlorazanil.
one
state
been
as a single
were made
mg/kg)
total
received
Relationships:
determined
orally
in a
of the last dose.
(25
Dose-Responsr was
trained
observations
on five
I’I:
dose
analyzed
day.
compared
for
to determine
intra-arterial
were
of chlorazanil
Group
bicarbonate, patients
oral
were phosphate,
600 mg at 6 : 00 a.m.
significant
intravenously
was
direct
Similar
measurements
as a single received
and
excretion.
after
ammonia,
of the three
described
and para-aminohippurate
observations
were
made
technics
rate
by
and potassium
specimens chloride,
Potency Estimate
the period
with 30 mq/kg
Creatinine
filtration
was
per day
and
Observations
three
These
potassium,
on the
in 8 dogs anesthetized
barbital.
periods).
acidity,
approximately
of drug administration. Group II’:
hour sodium,
over 25 per cent of the patients.
were noted.
two divided Urine
8 mg/kg,
in 20-minute
for sodium,
dogs received
They
dogs
volumes
4 mg/kg,
collected
Two
Twelve
20 mg/kg.
order
were
excretion.
chlorazanil.
dose
i.e., 2 mg/kg,
Urines
for six hours and analyzed
and water
Four
dogs,
mg/kg.*
Effect
of
Chlorazanil
daily
oral
doses
Chlorazanil
After
was administered of 300
mg
Chronic
Daily
for five days in
to ten
patients
with
13 3
12.3
P value less than
f
%
8
0.3
0.2
0.2
0 4
-
0.20
300
0.9
0 05
250
0.5
0.01
is0
0.5
0.20
200
0.8
D,
Maximum
response during
Control.
II 05
367
1.1
0.01
350
0.7
0.001
300
0.6
0 lo
250
1.0
Dz
Di
=
0.05
300
0.9
0 01
350
07
0 05
250
0.5
0.10
250
1.0
____-
0.10
267
0.8
0.05
350
0.7
0 10
300
0.6
~~__
0.20
150
0.6
Ds
0 20
233
0.7
0.05
350
0.7
0.10
300
0.6
0.05
150
0.6
Ds
20 min ;tftrr drug.
0 10
267
0.8
0.01
350
0.7
0.05
250
0.5
0.05
225
0.9
D,
(mI/min)
Fiat
flow
D3
Urine
any single ZO-min period.
&y to Abbrcviatiorls: L: =
70 of control
P
Mean
C
12 2
P value less than
70 of control
Mean
P value less than
y. of control
MeFin
P value less than
5 !z 3
21
i-
12.7
c
(kg)
y* of control
Mean
_~ __--
__
Body
weight
1 0
DZ =
0 01
467
1.4
c
D1
9
response
6
0 10
950
114
433
52
105 0.05
1750
0.10
1211
109
Da
95 0.05
792
121
149 0 05
1656
102 850
109
I>, =
0 05
1522
137
0 01
1817
558
67
Ds
-
0 01
2600
234
0 01
3150
189
0.05
1650
198
0.05
1242
149
__~
~~~
10
6
4
9
c
11
0.05
200
20
0 20
233
14
0 05
275
6
12 120 0.50
___
0.50
117
7
0 30
150
0.20
144
13
DS
~-~
5
0
9 50
90
_
0.50
117
7
0 50
125
0.30
122
11
Da
122
11
D<
6
6
0 50
100
10
0.40
150
9
0 20
150
ni = 5 111. .*ftzr
0 50
90
9
0 50
133
8
0 40
150
0.50
122
11
Da
(peqlmin)
0 20
potassium
Ds = 4 hr .tfter drug.
~~
156
14
D,
Urine
in Dogs
0 01
___
Excretion
3 hr alter druq
0 05
1311
118
0 05
1517
91
0 10
967
116
0.10
_~~~__
0.10
to eight dogs
0.01
2017
583
70 0 05
to eight dogs
0 05
883
2 hr .~ftrr rlruq.
0.01
1567
141
given
0 05
1833
_~~ 106
to eight dogs
110
given
0 05
575
69
given
0 05
867
104
Ds
to eight dogs
D4
(fieq/min)
on Water and Electrolyte sodium
I
given
l)d =
0 05
2067
186
to 16 mg/kg
0.05
1100
66
to 8 mg/kg
0 01
717
86
to 4 mg/kg
0 01
response
12
592
71 0 20
response
12
Dz
Urine
to 2 mg/kg
30 min .dtcr droq.
The
0.01
550
1.1
The
0 01
500
TABLE Doses of Chlorazanil
The response
The
0.05
325
1.3
Max
The Effect of Single Intravenous
dl-ll$.
0 50
100
10
0 50
167
10
0 10
250
10
0.50
122
=
0 01
220
22
0.05
300
18
0 001
400
16
0.01
211
19
Max
Max
~__ 11
Ds
L’rine was collcctetl in compensated cardiac failure. 24-hour specirnvns and analyzed for sodium and watc’r. The blood of each of these patirnts was analyzed for serum sodium. potassium and chloridr concrntrations, carbon dioxide combining power and for blood urw nitrogrn brfow and after administration of 300 me of chlorazmil a dn\ for five days. 7‘hr E[fcri II,! (.lrlorcizonil on ,Vr~ro,sp Bnlanc~ and (II’1 Hrnal Fu~rctrwrt In anothrr group of 20 hypcrtensiv< nonetlc~mntou5 wctpativnts, trn were givrn 300 rng daily as a slnqIc oral dew and trn werr qivrn 300 my The patients wcw seen at twice. daily for 21 days. wwkly intrrvnls. .lt which rime blood urea nitrogen detrrrninations MVI‘V clone to compare with hascliw studies obtainvtl prior to thr institution of therapy. :\ftcr this study \vas complete, it \vas found advisahlc to study mow prcciscly the effect of chlorazanil on thv I:our patients wcrc blood uwa nitroqrn conwntration. the suhiwts uf Manw studies fur sodium. potassium. chloride, nitro,gvn, phosphate and water with concornitant obscrvatiwb of plasma creatinine and urea nitrogrn. as well as rrieasuwmenls of 24-hour c7xiogcnous crcati( Imsrtl upon singlr plasma creatininr nine clcar,lnr(. dctrrmination I_ Thr patients \xcrc ol)wrvcd for 20 days. the first five* of which constitrltctl a control period, the next ten tlw drug-twarment period and the nrxt live a post-treatment T\vo pdtic*nts wccived 150 mq twice daily and period. two rwrivcd 300 mq twice daily during the drugtrratmrnt periods. Dietary intake was constant fat sodium. nitroqcn. xvatv, and c&rim. I-rim and fc-
‘1‘0 gain hroadcr clinical implications of this problem. another 20 outpatients (from Hypwtrnsivc Clinic i with ~erll-controlled congcstivr failure wcrc givc,n chlorazanil .,‘I II.t 1% VI’
RESULTS (A, I.ABORATORY OBSERVATIOSS GI-o@ I: !%‘hen a single dose of chlorazanil was given intravenously to 32 anesthctizcd, nonhydrated increase
dogs, in
pearing
and
maximum
was
a
in water
no greater
significant
rscretion
after drug
fur fi\x: hours
increase
chlorazanil
\vas \~att’r
bvithin 20 minutes
tion and persisting
mg
thcrc
sodium
ap-
administra-
or more.
excretion with
The due
;I dose
to 16
cJf
kg than with one of 4 mg, kg INIC the diuretic
response
\vas
dosages.
of longer
Potassium
duration excretion
at the was
hiTher
increased
TABLE II THEACUfSWFETOPORN. Bodyltt. KCI.
DOSESOF CHlDRAZANILONWATERAND'ELECTROLYiYE Q(CR?XIMIINMX:
urine VoluJm cc/ndn. c
5 &3&g
glvul
omlly
10.8
0.27 0.42 156 N.S.
sitenoram 9.0
;3
control
P Value 20 &kg
C
D
9.3
twice a
day
0.22 61
23 l$
N.S.
N.S.
C
a3 67
9
D
PD
2E
?!.S.
16 178
N.S.
N.S.
N.S.
N.S.
lbi Ndi.
I.4 N.S.
for one da9 to four doga
0.20 0.34 170 N.S.
0.33 16j N.5.
15
28 16 187 la7 <.l N.S.
0.15 O./d
0.21
S
24
1359
5
293
<.I
N?
C-ho - UC how Controlperiod4(averago) D-Twenty-four hour period durbgdrugadminLt.ntLn PD - Twentg-four hour penod followingdxug administration
FEBRUARY,
PD
9
givenorallytwice a day for one day to four dogs
i?f Control P Value Key:
PD
urine Potmritm m**
twice a day for one day to four doge
?s control P value 10 &kg
D
urin.Sod.l.nm /wa/~.
N.?
5
152
Chlorazanil,
a Nonmercurial
only slightly and this effect was of short duration (Table I). Group II:
Oral
Grou@ V:
When
the chlorazanil
was given
as a single oral dose to five dogs, there was no When
two divided
the drug was given orally in
doses, the diuretic
dramatic
than
istration.
The
following effect
effect
intravenous
on water
effect
was less
four
admin-
excretion
on glomerular hours
plasma
was
four
hours, latter
water excretion
prolonged
being secondary
to the increased
The dose of 5 mg/kg given twice a diuresis,
whereas
a dose
for a period
administration. altered
there
for a period
was a moderate
response
was probably
anesthesia (Table
of
Renal of
but, after reduction. due to the
V).
3?ztterns ofei%c;ret;on in CONTROL STArE (DIET 50 M&l No - 3000 Cc DISr/LLEL’ WATER DAILY) mr * &oT
day did not appear to increase sodium excretion a water
filtration
drug
flow was not
This
sodium loss.
after
two hours after drug administration
just as great as, if not greater than, the increase in sodium excretion rather than the increase in
despite
Diuretic
in
excess of 10 mg/kg given twice a day appeared to increase There
both
water
and sodium
was no consistent
excretion
(Table
effect
excretion.
on potassium
II).
When chlorazanil was given Group IIZ: continuously for six days, the increase in water excretion
persisted
observation.
The
was variable
from
slight
increase
(Table III). Grout IV: eight
throughout effect
the
day to day
above
the
When
anesthetized
period
on sodium
but showed
control
given
dogs,
of
excretion a
observations
intravenously
chlorazanil
to
did
not
have a hypotensive slight increase
effect. In fact, there was a in blood pressure one hour after
drug administration. was
not
altered
dissolved
in 150
slight reduction
Glomerular when
the
ml of saline. in renal
“!
filtration rate
chlorazanil There
plasma
trTh
was was a
flow, but this
was not significant. However, when the drug was administered in a concentrated form in 10 ml of saline, glomerular plasma
filtration
rate and renal
flow were both depressed
one hour or
more following drug administration
(Table
IV). TABXZ
THE QIROKICEFFECT OF ORAL DOSES OF (10 n&kg
D2
c!l 7:
4
xxx
CHLORAZANANIL
ON
WATFB At!DELFsCROJlT!d EXCRETION
given orally twice a day for six days to eight dogs) sodium ticretion /W"/"i".
urine Volume cc/dn.
nt. Kg.
tius
XXUS
Average urinary electrolyte excretion pattern Fig. 1. found in five patients with well-compensated congestive heart failure.
D1, D5
D6
C
%
Dz
Dj
D4
D5
Potassiuuaaxetion /u-d=lll. %
Control 10.8 0.19 0.30 158 0.45 237 0.51 268 0.49 258 0.57 300 0.47 Ur7 16 lbq 27 225 36 U4 23 131 22 163 26 100 16
* p value less thlin
.05 .lO
Key: C - Cmtml
.lO .05
.05
.lO
.05
.lO
.30
.20
.2u
C
%
Dz
D3
D4
*5
9 133 12 133 I.2 Ill XI I.22 xi 133 12 133 12
.50
.P
.M
.50
.40 .lO .30
observations- averageof two 2l+hour urine collectionperiods. 21rham wine collectionperiods.
THE
%
AMERICAN
JOURNAL
OF
CARDIOLOGY
Iby:
volume (ccwn.1
urine
Hemtocrit
Ralal PU8lW FIRN (cc/min.) (CPAN
[&kLe Clearance)
C -
Dh
D3
Dl D2
Glomerular Fxltration Rata
Yean blood prmlsure am. tlg.
GIVBiIhiVRUJSLT
;s 97
35 35 37
.05
:$
.Ol
.50 J&O -50 .50
.lO
.30 .05 .30
-2 .50
.50
.Ol
97
:z
ll2
.50
P valua 1CM than
105 111
98
x or control
z7"
126 128
1U ll2 120
hmn
given in 150 cc saline to eight Qga)
(Average weight- Il.6 kg.1
Control Observations - Observations immediately after adizinistration of Chlorazanil ,I I, II - Observations one hour u " II II - Observations two hours u 1, II " - Observations three hours I'
D3 %
Dl D2
C
%
D3
Period
(8 dkg
THERENAL.RBFCNSETOCHLORAZANIL
TmEIV RESPO~ETO CHUBAUNIL.GI~O~~
Dl D2 D3 DL
crit
37
;: 290
z
;: 98 90
E
72
90 92
96 100
33s
1CC 286
% of contrJ1
.30 .50 .50 .20
.50 .50 .m .lO
.50 .30
.50 .50
.50 .Ol .C5 .05
P value less than
‘.
(Averageweight = 13.2 Kg.)
D3 - Observationsthree hours after administration of ChlorazanU. D,+- Observationsfour hours after administration of Chlorazanil.
ChlOl%XLanil
C
Hem&~
299 214 297
44
:9 :;
0.7 0.7 2.0 2.1 2.3
man
.,z
Key: C - ControlObservations D, - Observbtions(averageof two lo-minuteperiods)imediately aft-anesthetisation and-twohours after ad&i.str&ion of Chlo&d_J.. D1 - Observationstm hours and 30 minutesafter administration of
C Dl D2 D3 DL
DL D3
pzz; ROW.1 Plasma Flon (cc/~.) (C FAN
D1 D2
Filtration Rats
Dl 9 ?3 D4
C
Period
C
4
RSNAL
giran orallytwo hours before anesthetizingto fire dogs)
ME
GlOmWlllCW
Volwm (cc/min.)
Urine
kan blood prw*ura I. lig.
(2J m&kg
TAELBV
154
Chlorazanil,
Group T’I: to
alter
Aminophylline
the
chlorazanil
renal
did
not
hemodynamic
in five anesthetized
the effect
of chlorazanil
excretion
was not
appear
response
dogs.
on water
affected
a Nonmercurial
to
Likewise, and sodium
by aminophylline.
Oral
acidity total
excretion solutes
CLINICAL
of average
excretions
in five patients
congestive
of urinary
of 600 mg of chlorazanil
single oral dose (Figs. marily
a significant
and chloride increase excretion excretion greatest
constituents
with well-controlled
was sometimes was
in sodium,
There
in bicarbonate decreased
natriuresis.
as a
2 and 3) produced
increase
excretion.
potent
diuretic
pri-
water,
was a moderate
administration
was of a lesser (II) single
of
Patterns of excretion following administration of: 600 mgm CHLORAZANIL P.O. (single)(pt. SA) ,D -
magnitude
oral dose caused
excretion
time
drug
and
lasted
there was a noticeable
Chlorazanil
0.14 l/24 hours.
titratable
of
600 mg was given
than
the
Bioassay for Potency in Man:
relationships:
Ammonia the
of the When
onset
two hours
effect
of
the first dose (Fig. 4).
Potassium
and
The
effect from the second dose which
increased. during
per liter
seen with com-
agents.
twice at 12-hour intervals,
excretion.
Phosphate
but the concentra-
approximately
for 12 to 18 hours. but delayed
heart failure are presented in Figure 1.
Administration
per minute,
The
in terms
tion of solutes in terms of milliosmols
after patterns
also.
increased
was less than the concentration
OBSERVATIONS
determined
depressed
slightly
these effects occurred
Electrolyte Excretion Patterns: The
(I)
were
were
of micro-osmols
parably (B)
Diuretic
of 600 excretion
of 11 meq mg
300
Dose-response
mg
given
an increase and
water
as a
in sodium excretion
of
Following the administration there was an increase in sodium
of 60 meq/24
hours and an increase
Patterns of excretion following administration of: 600 mgm CHLORAZANIL P.O. (single)(pt. JAI
+ ““r
war
500
Fig. 3
Fig. 2
Fig. 2 and 3. Electrolyte excretion pattern in the urine following a single dose of chlorazanil emphasizes a major effect in augmenting the excretion of water, sodium, and chloride with a lesser effect on bicarbonate. THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
Ford et al.
155
in water excretion The
increase
paralleled
of 0.39 l/24 hours (Table
in
the
chloride
increase
while potassium
excretion in
excretion
VI).
roughly
sodium
excretion
was not consistently
Chlorazanil 600 mg in combination altered. with 200 mg of aminophylline as a single oral dose produced
an increase
of 57 meq,‘24
hours and an increase
excretion test
of 0.44
showed
in sodium
l/24 hours.
that
the
excretion in water
A Student’s
differences
“t”
in increased
sodium and water excretion
between
chlorazanil
mg of chlorazanil
alone
and
600
with 200 mg of aminophylline cant
(Table
600 mg of
were not signifi-
VII).
Potency estimate of chlorazanil: variance to
meralluride
The
two
the error
not
significant sodium
be 0.49
(Mercuhydrin),
dose-response
and on
An anal!-sis of comparing chlorazanil
was performed
Expressed
standard.
were
in the experimental (Fig.
5).
excretion
was
if meralluride
based
chlorazanil
compared
in another
parallel
trial?
A calculation
showed
in potency,
the standard,
the
curves
to
to meralluride,
is taken
as “one.”
way, 600 mg of chlorazanil
orally is equal to 1 cc (40 mg of Hg) of meralluride
(intramuscularly)
creased
sodium
chlorazanil
in producing
excretion.
based
on
water
compared
to meralluride
to be 2.2,
suggesting
excretion
The
an
excretion
as “one”
a greater
of and
was found
effect
than with comparably
in-
potency
on water
potent
diuretic
agents. (III)
The Effect of Chlorazanil After
Daily Therapy (Table
of 300 mg per day, chlorazanil tinuous
response
patients
(Fig.
in serum
6).
There
days of administration
no significant
concentration
concentration chlorazanil
tion on blood urea nitrogen
or
after five
patients
is
administra-
in 10 nonedematous presented
in
Table
The mean values for blood urea nitrogen
in the group receiving mg%
con-
days in 10
(Fig. 7).
The effect of chronic
IX.
were
electrolyte
in blood urea nitrogen
hypertensive
produced
on five successive
changes
Chronic
As a single dose
VZIZ):
in the control
300 mg daily were 20.4
state,
31.4 after one week,
and 31.9 after three weeks of drug therapy. In the group receiving 600 mg daily, the mean
FEBRUARY,
1959
control
blood
rngyc.
This mean value rose to 45.9 after one
urea
nitrogen
value
was
21.8
156
Chlorazanil.
week and was 43.6 therapy.
Six
of
after three weeks of drug ten
patients
receiving
mg daily and eight, of ten patients mg twice daily demonstrated in blood
urea
nitrogen.
there an alteration
receiving
moderate In
300
Oral Diuretic
Dose response curves: CHLORAZANIL YS MERALLURIDE COMPARATIVE POTENCY
FOR DETERMINATION
OF
300
increases
no instance
of hematocrit
with this elevation
a Nonmercurial
was
contemporary Side
of blood urea nitrogen.
effects seen, more often with the larger dosage, were
anorexia,
occasional
tion of “ganglionic therapy), (IV)
vomiting,
blockade”
and generalized The Effect
weakness.
of Chronic
istration on Nitrogen Balance Studies:
The
significant
studies are presented are the average hypertensive
Chlorazanil
values
results
of the balance These
for two nonedematous each
at
levels, 300 mg and 600 mg daily. administration
there
was a slight
Admin-
and on Renal Function
in Figures 8 and 9.
patients
daily
potentia-
(antihypertensive
two
dosage
During
the
of 300 mg of chlorazanil, increase
in urinary
sodium,
Patterns of excretion following administration of: 600 mgm CHLORAZANIL P.O. (q. 12 hrs&t. SI) UO
50
0
2.5
0
L
kd
Fig. 5. The dose response curves for meralluride and chlorazanil indicate that approximately 600 mg of the latter orally is equivalent to 1 ml of meralluride intramuscularly as a natriuretic agent.
producing volume
a slightly negative
increased
patients
portionately Nitrogen after
small
balance
the
fifth
The endogenous paralleled blood vated.
to a greater
complained
degree
of thirst weight
became day
of
creatinine
the positive
Urinaq
balance.
and the
while
a dispro-
loss was
observed.
progressively drug
positive
administration.
clearance
nitrogen
depression
balance,
while
urea nitrogen concentrations were eleDuring the administration of 600 mg of
chlorazanil
daily, similar changes were observed
but were of greater magnitude became more negative,
: sodium balance
water balance
even more
THE EFFECT OF CHLORAZANIL HYDROCHLORIDE ON SODIUM AND WATER EXCRETION - 300 mgm per day for 5 consecutive days
I D
Following the second dose of the drug in a 12Fig. 4. hour period, there is an additional augmentation of diuresis and natriuresis.
P
are repetitively effecFig. 6. Daily doses of chlorazanil tive in producing water and sodium loss (average of data from 10 patients with compensated congestive failure). THE
AMERICAN
JOURNAL
OF
CARDIOLOGY
157
Ford et al.
negative, positive
while nitrogen and
balance
was accompanied
of creatinine
clearance
urea nitrogen
concentration.
became
and elevation
THE EFFECT OF CHLORAZANIL ON SERUM ELECTROLYTES
more
by depression Changes
of blood in phos-
HYDROCHLORIDE
phate
balance
balance
while
paralleled balance
paralleled changes
those in
in
chloride
those in sodium balance. was not significantly
Among
cardiac
balance Potassium
altered.
the 20 hypertensive
well-controlled
nitrogen
outpatients
failure,
eight
with
showed
a
TABI3 IX
EFFECT OF CHROWICORAL ADMIXISTIWXIONOF CHLORAZANIL ON ElLfYXUREANITRSEZ4 Patient
I Serum
1. L. A. 2. J. B.
CHLuRlOE
3. R. H.
i-/L1
4. 9. c.
S&-LU?C 30 Cd RBON L%OX/DE /T/L/
T
c
;
1 L
25 .
dLOO0
UREA
IVITR~GEN PYm$1
4 30
5. A. L. 6. J. L. 7. J. E. 9. D. T. 9. 0. i. 10. A. G. yean 11. B. w. 12. C. A. 13. D. B.
Blood Urea Nltrqsn C D1 4 28 18 18
17 10 23 27 u 19 20 zQ.4 11
14. R. B.
27 23 23
',5. E". :..
1"4
;;. . "J. . ;.. 19. J. iv. 20. J. R. Mean
::
48
Fig. 7. Serum electrolytes after five days of chlorazanil therapy are not significantly altered except for those directional shifts due to dehydration. FEBRUARY,
1959
Dose (ddq)
2"6 21.8
16 70
600 boo Et
tg.6
c - control 4 - After one reek of therapy D3 - After three weeks of therapy
Chlorazanil,
158 THE EFFECT METABOLIC
OF CHLORAZANIL BALANCE
SOOlUM
60
mEq per 24 hrr
4O
300
mgm
DAILY
a Nonmercurial ON
Oral
IIiuretic
THE EFFECT METABOLIC
OF CHLORAZANIL BALANCE
SODIUM
80
mEq per 24 hrs
600
mgm
DAILY
ON
60
UIillC
20 WATER Lllers pr 24 hrs
1
3
5
10
15
bl: 4
Fecal
I
20
1
1
I
2
WATER
br
L~lers per 24 hrs
4
UIIIK
3
5
15
10
20
J
2
1 13
5
10
15
20
NITROGEN Grams per 24 hrs
12 Ur,ne
NITROGEN
18
Grams per 24 hr
12
UIlW
6 Fecal
Fecal 1
CREATININE CLEARANCE
12
3
5
10
15
20
CREATININE CLEARANCE
(“GFR”1 cc ,lmn
BLOOD UREA NITROGEN mgms %
30 20 1D
CWtrOl
Chlraunil I50 mqm b.i.d.
’
Postdrug
Fig. 8. Averages of data from two nonedematous hypertensive patients receiving 300 mg daily of chlorazanil. There is a progressive slightly negative sodium and water balance, and a slightly positive nitrogen balance, contemporary with a small depression of creatinine clearance and elevation of blood urea nitrogen concentration.
rise in blood
urea
nitrogen
concentration
eleven a rise in plasma creatinine after
receiving
three
weeks.
were present
chlorazanil, Increases
in six of the twenty.
creatinine excretions
Depressions
TAESX
and for
The
c
maxi-
orsatinine
Pla_ Creatinine
B.U.U.
Patisnt
measurements
mum blood urea nitrogen concentration was 38 mg%.
C
D
Clearance
detected
of the endogenous
clearances and 15-minute PSP were found in some of the patients.
affected by Daquin therapy; erythrocytes were never found. Decreases in body weight were not statistically significant in these nonpatients
(Table
X).
DISCUSSION The development of triazine derivatives diuretic agents has been somewhat similar that
of
the
carbonic
After sulfanilamide
anhydrase
as to
inhibitors.
was found to have diuretic
17
*“m-age
*
Albuminuria
C = F
.9
22
=
Control. Cells
(never
c
D
c
D
C
D
96 100
66 52
lF w v
: 63 72 82 72 102 76 55 104 59 101 70 92 68 101 85 72
12 10 12 u 12 14 u 15 25 10
N
lrn ;z 105 llo 102 101 82 80 102 101 99 90 Lo2 65 lO2 104 B2
15 25 25 20 22 25 19 25 25 15 :: 25 25 all+ 25 10 25 25 20
2; 22 25
95
78
22
16
D
The results of the urinalysis were not significantly
edematous
Port-drug
Fig. 9. Averages of data from two nonedematous hypertensive patients receiving 600 mg daily of chlorazanil. There is a greater magnitude of change in thr balances described,for Figure 8.
concentration
150 mg b.i.d.,
in both
hl uani 0 8, m b .I.d.
CMtJOl
1.2
(never D
more
than
20 10 25 15 17
l
* + * N N N N * N N N N N N N N N N
l
* P P P F l
N N N P fF N F F N N
1 +)
=
After
three
more
than
10
weeks
WBC/hpf).
therapy. N
Normal. THE
AMERICAN
JOURNAL
OF CARDRXOCY
=
Ford many
properties, development were
of sulfonamide
diuretic
but
serious toxicity and 1944, that
elapsed
years
before
derivatives
relatively
devoid
of the first compound.
Lipschitz
substances
which
In man,
the effective
set of action
within
administration
and
showed
approximately
18
chemically
by
dose range is between Daquin shovvs an on-
300 and 600 mg daily.
of the In 1943
and co-workers’,‘O
characterized
the
et al.
probably tinued
hours.
oral
of action
Thus,
of
it
should
or twice daily
if con-
is desired.
in human
following
duration
be given once diuresis
effect
two hours a
There
beings
on
is a definite
the
excretion
of
sodium, so that it has been calculated to have a potency of 0.5, i.e., it is roughly one-half as
~rallUrlde (Memuhyddn) ~304~ lig (kc) I.M. 1
(Neohydrin)
chlonwrodrin
Fig. 10. the
Structural
presence
in
WmgmHg
formula of chlorazanil.
the
molecule
N=C-N The best
of
Oral
not
4 acetazoleamide 25omppl oral 1
therapeutically because of its severe The exploration of various triazine toxicity. derivatives has culminated in the presentation
apdnometrdine 12oom&Tn oral
groups
possessed
diuretic
effects.
known of these substances triazine
or
is 2,4 diamino-1,3,5-
formoguanamine
but
it
was
(a-)
useful
of chlorazanil
(Daquin)
which is chemically
chloranilino-4-amino-1,3,5-triazine Neo-Urofort)
(Fig.
10)
2-p-
(Orpidan
as an
orally
or
effective
diuretic agent without serious toxicity.” Hungarian workers reported alterations renal tubular
reabsorption
(b&tine)
in
of water with a lesser
and independent effect on sodium and chloride In Germany, studies13 at somewhat excretion.‘? low dosages
(2 mg/kg)
showed
an
chloride,
and
excretion
of
potassium,
ammonia,
and
phosphate,
as well
acidity, were
not
were
not
increased
that the drug
produced
excretion
bicarbonate
markedly
changed.
associated
of sodium,
while
with
the
urinary titratable
as the
These serum
pH,
changes
agreement
with
Hungarian
workers
with
each
other
dogs,
our
results
intravenous
the
German
as well
(who proposed on
basic
indicate
administration
as
mechanisms). that
the
to disagree
following
In the
of chlorazanil
there
is a significant increase in sodium and The percentile increase in excretion
water water
is
greater
natriuretic
FEBRUARY,
potency
potent as meralluride
The results of the present study- are in general
potent
Comparative
1959
than
agents.
with
of various
natriuretic
electrolyte
alterations.
excretion
Fig. 11. agents.
comparably
somewhat
(Mercuhydrin) increase observed
(Mercuhpdrin).
differently,
1
ml
intramuscularly
in sodium excretion following
the
oral
Expressed
of
meralluride produces
equivalent
administration
approximately600 mg of chlorazanil. parison with other orally active diuretic (Fig.
11) indicates
acetazolamide merodrin
that it is more potent
(Diamox),
(Neohydrin),
aminometradinc
(Mictine)
equipotent but
less
an
to that of Com-
agents than
to chloropotent
than
and chlorothiazide
160
Chlorazanil,
(Diuril),
when each
a Nonmercurial
is given orally as a single
dose.
Oral
Diuretic
nonmercurial
diuretic and a moderately
However, patients rapidly develop tolerance to acetazolamide and to aminometradine,
natriuretic agent. The chronic oral administration
the clinical
anil,
limited.
use of which,
If calculation
therefore,
is sharply
of diuretic
based on urine volume changes
potency
(acutely)
is
chlor-
daily,
administered.
aminophylline
and
administered daily
continuously
effective, evidence
and plasma creatinine
of creatinine positive
clearance,
nitrogen
glomerular seen
but
filtration
more
rarely
degree
when
There
appears
patients
in
rate.
and
then
the daily to
the
is associated
excretion,
in
This
decrease
is
only
to a minor
is only
300
variation
of Daquin
upon
with this drug without
tion of any change. Concerning the chlorazanil, illustrate
the
mechanism results
the electrolyte
be helpful.
There
augmentation
mg.
excretion
patterns
excretion paralleled
of bicarbonate
of
monia
excretion
the peak of drug action.
to
those
affected
sodium
chlorothiazide
6.
increased and
depressed
am-
during
it appears
that
7.
carbonic anhydrase However, sim-
inhibitors or organomercurials. ilar patterns of excretion have following
5.
i/i0 to ‘/4 of
slightly
Thus
by
4.
may
multiple mechanisms are affected by this drug or that a sole mechanism affected is different from
3.
by chloride.
phosphate,
are slightly
2.
of
that of chloride and this effect is not consistently is
been observed
administration
for the effect of the latter on potassium
except
8.
excretion
not seen with chlorazanil. 9.
CONCLUSIONS Chlorazanil, doses
of 300
when or 600
filtration
rate.
of this diuretic
as
of electrolyte
excretion
those of mercurials,
carbonic The is its
greater effect on water excretion to sodium excretion.
1. LIPSCHITZ, W. L., HADIDIAN, A., and KERPCSAR,
is also enhanced,
is roughly
pH observed . Urinary while titratable acidity,
300 mg
laboratory
REFERENCES
and extensive
the
excretion
action
experiments
is consistent
the order of magnitude
from
proportionately
the
the producof
of
which is not completely The
of
of action
in its pattern
as compared
among
measurements reflecting the glomerular filtration rate so that some patients can be treated indefinitely
of a fall in glomerular
is different
and
decrease
wide
effect
blood urea
of a
dose
be
patients
with depression
PSP
balance)
some
of chlorazthan
anhydrase inhibitors, and chlorothiazide. most notable characteristic of chlorazanil
is moderately
(elevated
in
mechanism
reflected,
Daquin.
administration
with laboratory nitrogen
Orally administered
had no effect upon the potency of
concurrently Chronic
The
in doses greater
produced
evidence
azanil is more potent orally than is meralluride parenterally
especially
effective
orally mg/day,
administered is an
in
effective
A. : Bioassay of diuretics. J. Pharmacol. G? Exper. Therap. 79: 97,1943. FORD, R. V., SPURR, C. L., and MOYER, J. H.: The problem of bioassay and comparative potency of diuretics: I. Parenteral and oral mercurial diuretics. Antibiotic Med. G’ Clan. Therap. 4: 708, 1957. FORD, R. V., SPURR, C. L., and MOYER, J. H.: The problem of bioassay and comparative potency II. Carbonic anhydrase inhibitors of diuretics: as oral diuretics. Circulation 16: 394, 1957. FORD, R. V., MOYER, J. H., and SPURR, C. L.: Clinical and laboratory observations on chlorothiazide (Diuril) : An orally effective nonmercurial diuretic agent. Arch. Int. Med. 100: 582, 1957. MOYER, J. H., FORD, R. V., HANDLEY, C. A., and SPURR, C. L.: Results of laboratory and clinical studies on three new mercurial diuretics and a comparison with currently available ones. Antibiotic Med. & Clin. Therap. 5: 254, 1958. FORD, R. V., HANDLEY, C. A., MOYER, J. H., and SPURR, C. L.: The problem of biossay and comparative potency of diuretic agents: III. Various oral diuretic agents. Antibiotic Med. & Clin. Therap. 5: 9,1958. FORD, R. V., MOYER, J. H., HANDLEY, C. A., SPURR, C. L., and ROCHELLE, J. B.: Laboratory and clinical observations on three similar diuretic (Micagents : Aminophylline, aminometradine tine), and aminoisometradine (Rolicton). Am. J. M. SC. 234: 640,1957. HANDLEY, C. A., CHAPMAN,D., and MOYER, J. H.: Some pharmacological properties of three new Pm. SOG. Exper. Biol. & mercurial diuretics. Med. 78: 433, 1951. MOYER, J. H. and HANDLEY, C. A.: Renal and cardiovascular hemodynamic response to ganglionic blockade with pendiomide and a comparison with hexamethonium and Arfonad. J. Pharmmol. LY Exper. Thcrap. 113 : 383, 1955. THE AMERICANJOURNAL OF CARDIOLOGY
Ford 10. LIPSCHITZ, W. L. and HADIDIAN, A.: Amides, amines, and related compounds as diuretics. J. Pharmacol. M Exper. Therap. 81 : 84, 1944. Il. SZALDOS, J. : On the diuretic action of 2-parachloranilino-4-amino-1,3,5-triazine (Neo-Urofort). Orvosi H&lap 9: 299, 1953.
FEBRUARY, 1959
161
et al. 12.
G. and CLANCER, 0. : On the diuretic mechanism of action of triazine derivatives. Hungarian Arch. Int. Med. 6: 156, 1953. 13. FRANK, H.: Zum Wirkungs Mechanismus dcs p-chlorphenyldiaminotriazine. Presented at the Karlsruhe Congress, 1956. SZABO,