Rutin : treatment for arterial hypertension characterized by increased capillary fragility

Historic, archived document

Do not assume content reflects current
scientific knowledge, policies, or practices.

RUTIN: TREATMENT FOR ARTERIAL HYPERTENSION
CHARACTERIZED BY INCREASED
CAP I LLARY FRAGILITY

The contents of this brochure are reproduc-
tions of charts which were exhibited at the
Scientific Assembly of the American Medical
Association, SanFrancisco Session
July 1—5, 1946

LIBRARY

CURRENT SERIAL RECORD

OCT 1 5 1946

U.* DEPARTS? OF WWCtttiuW

This exhibit was awarded a Certificate of
Merit for Original Research by the Committee
on Awards for the Scientific Exhibit of the
American Medical Association

Exh i b i tors

J. 0. Griffith, Jr.
M. A. Lindauer

Hospital of the University of Pennsylvania
Philadelphia, Pa.

R. L. Shanno
Forty Fort, Pa.

J. F. Couch

Eastern Regional Research Laboratory
U.S. Department of Agriculture
Wyndmoor (Philadelphia), Pa.

PETECHIAL
AFTER G T M L I N

INDEX*
TECHNIQUE

1. A circular area, 6 cm. in diameter, is marked off in each
antecubital space.

2. First stage: Inflate a blood pressure cuff about each
upper arm to 35 mm. of mercury for 15 minutes. There-
after, count the petechiae.

3. Second stage: After one hour, repeat, using 50 mm. cuff
pressure.

CALCULATION

Petechiae 1st stage x 2

+ petechiae 2nd stage = P. I.*
Normal = 8 (or less) Increased = 13+

Borderline, probably increased, 9 - 12.

CLINICAL MATERIAL

NUMBER OF CONSECUTIVELY STUDIED
WHITE SKINNED HYPERTENSIVES

NUMBER WITH INCREASED CAPILLARY
FRAGILITY

NUMBER ADEQUATELY FOLLOWED

AVERAGE FOLLOW UP IS 11 MONTHS,
RANGE 3 TO 36 MONTHS.

_ 1600

_ 306
_ 189

100% r

80%

60%

40%

20%

0% L

FRAGILITY NORMAL
FRAGILITY INCREASED

MALE

FEMALE

INCIDENCE

SEX

15%

10%

5%

0%

FRAGILITY NORMAL
FRAGILITY INCREASED

I

I

APOPLEXY RETINAL HEMORRHAGE

HISTORY PRIOR TO FIRST STUDY

60% r

40%

20%

0%

■ FRAGILITY NORMAL
□ FRAGILITY INCREASED

I

Z2

18-20 21-30 31-40 41-50 51-60 61-70 71-

AGE

RELATION BETWEEN BLOOD

PRESSURE LEVEL AND INCREASED
CAPILLARY FRAGILITY'

DIASTOLIC BLOOD PRESSURE

BELOW AND UP

100 100-119120-139140-159 160

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*ALL SUBJECTS CHARTED SHOWED INCREASED
CAPILLARY FRAGILITY.

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RUTIN

[C 27 H30Oi6]

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RUTIN IS A NON-TOXIC FLAVONOL
GLUCOSIDE THAT OCCURS IN THE BUCK-
WHEAT PLANT, PANSY AND FORSYTHIA
FLOWERS , ELDER , EUCALYPTUS , TOBACCO
AND THIRTY OTHER PLANTS. IT WAS
FIRST PREPARED FROM TOBACCO. THE
PRESENT COMMERCIAL SOURCE IS BUCK-
WHEAT LEAVES AND FLOWERS .

RUTIN DOSAGE

Initial dose is 20 mgm. 3 times daily, by mouth, in-
creased until Goth 1 in test becomes normal. Gothlin test
is repeated every 6 weeks so long as previous test is ab-
normal; thereafter, every 3 months.

Daily dosage Per cent of cases
80 mgm - - 72%

BQ mm - - \b%

100 mgm 3 . 5%

120 mgm ■ 7.0%

150 mgm 2.0%

130 mgm 0,5%

RESULT OF RUTIN THERAPY
I. ON CAPILLARY FRAGILITY

Per cent of cases

Gothlin Test became normal --------- 75%

Gothlin Test became borderline ------- 15%

Gothlin Test became normal but relapsed - - - *\%

Gothlin Test remained positive ------- 6%

EFFECT OF RUTIN THERAPY

II. ON CLINICAL SYMPTOMS

Per cent of cases

Symptoms unchanged

No symptoms initially - - -
Symptoms definitely improved
Symptoms probably improved

30%
\3%
\0%

EFFECT OF RUTIN THERAPY

III. ON THE INCIDENCE OF APOPLEXY

I Patient, while taking rutin and with a normal Gothlin
Index, developed apoplexy and died. He was also in
urem i a.

I Patient whose Gothlin Test remained increased consis-
tently, suffered an attack while taking rutin.

1 Patient failed to report on schedule but died of apo-
plexy 4 months after a normal Gothlin Test, while
allegedly taking rutin.

H Patients suffered apoplexy I to 4- months after discon-
tinuing rutin.

EFFECT OF RUTIN THERAPY
IV. ON THE INCIDENCE OF RETINAL HEMORRHA

2 Patients had subsequent hemorrhages while taking rutin
and with a normal Gothlin Index.

t patients had subsequent hemorrhages while taking rutin
but while the Gothlin Index remained increased.

I Patient had a hemorrhage about 2 months after discon-
tinuing therapy.

EFFECT OF RUTIN

Z. ON SYSTOLIC BLOOD PRESSURE

BEFORE RUTIN
200 - 250 170 - 199 150 - 169 BELOW 150

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170-199

150-169

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WITHIN CD BLOOD PRESSURE UNCHANGED
W& BLOOD PRESSURE HIGHER
BLOOD PRESSURE LOWER

2L ON DIASTOLIC BLOOD PRESSURE

BEFORE RUTIN
OVER 140 120-140 110-119 100-109 BELOW 100

OVER 140

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120-140

110- 119

100-109

BELOW 100

RELATION TO TH I OCYANATE THERAPY

The following items are considered suggestive but not
concl us i ve;

During the past 2 years capillary fragility, which was
initially normal, became increased in 6 patients following
the institution of thiocyanate. This comprises only a
small per cent of the persons given thiocyanate.

In 7 instances the following occurred; A patient with in-
creased fragility was given rutin, and the fragility be-
came normal. After a period of stabilization thiocyanate
was begun and the fragility again became increased. The
dose of rutin was increased, the thiocyanate continued,
and fragility again became normal.

In past years we have noted that the institution of thio-
cyanate therapy is rarely followed by apoplexy or retinal
hemorrhage.

Further direct study along this line appears unjustified,
but it seems reasonable to believe that, in a small number
of cases and perhaps as an i d i osyncracy , thiocyanate may
tend to increase capillary fragility and predispose to
apoplexy or retinal hemorrhage. We do not give thiocya-
nate to patients with increased capillary fragility, but
wait until fragility has become normal following treatment
of at least 3 months. Thereafter, Gothlin test is repeat-
ed every 6 weeks to 3 months, and a return of positive
test usually requires cessation of thiocyanate therapy, or
an increase in rutin dosage.

CONCLUSIONS

1. Increased capillary fragility, measured by the method
of Gothlin, occurs in about 18% of hypertensive

subjects.

2. Hemorrhagic complications, as apoplexy and retinal
hemorrhage, are more common in persons with increased
fragility. Considering the small size of the group
with increased fragility, however, it is to be noted
that the actual figure for persons with apoplexy is
divided about equally between the two groups.

3. Increased capillary fragility can usually be reduced
to normal by rutin, and patients so treated appear to
be protected against apoplexy and retinal hemorrhage
so as to become comparable with the originally normal
group. Unfortunately, separation of an untreated
control group was considered unjustified.

1. Successful rutin therapy may lower blood pressure and
relieve symptoms, but this effect is variable.

5. In persons with increased fragility, rutin therapy
may be a preliminary to and continued along with,
thiocyanate therapy, thus securing a further lowering
of blood pressure.

ADDENDA CONCERNING
INCREASED CUTANEOUS LYMPHATIC FLOW

1. During the past year, it has become apparent that
increased capillary fragility and increased cuta-
neous lymphatic flow bear a relation to each other
and, probably to the same underlying pathologic
process. These observations are preliminary.

2. Increased cutaneous lymphatic flow indicates pas-
sage of fluid through the capillary wall, which
may be due to either increased capillary pressure
or increased capillary permeability.

3. Increased capillary pressure is apt to be associa-
ted with either pituitary or kidney disease.

4. It is probable that increased capillary permeabil-
ity is often associated with increased capillary
fragility. In the present series, 36% of the sub-
jects with increased fragility showed increased
cutaneous lymphatic flow.

5. When increased capillary fragility and increased
cutaneous lymphatic flow are associated, both be-
come normal after rutin therapy.

6. Increased cutaneous lymphatic flow not associated
with increased fragility, pituitary or kidney dis-
ease, also usually becomes normal after rutin

therapy (12 out of 17 cases).

7. Thiocyanate is ineffective in lowering blood pres-
sure in persons with increased cutaneous lymphatic
flow, and its use may be followed by actual edema.
It is effective after the condition has been cor-
rected by rutin.

8. In 105 persons with increased capillary fragility
and increased cutaneous lymphatic flow, apoplexy
occurred 13 times and retinal hemorrhage 9 times.
In 4-2 persons with increased cutaneous lymphatic
flow and normal capillary fragility, apoplexy and
retinal hemorrhage occurred, each, 5 times.

9. The above patients with increased cutaneous lym-
phatic flow only have been on rutin therapy for a
short period, up to 10 months. No further apo-
plexy has occurred, but one has had another reti-
nal hemorrhage, coming on 3 weeks after cutaneous
lymphatic flow had again become increased.

TECHNIQUE FOR MEASURING CUTANEOUS
LYMPHATIC FLOW

The blue colloidal dye, patent blue, is used, pur-
ified according to the method of McMaster.

One injects intracutaneously 0.04 c.c. of the dye
in the antecubital space and follows the spread of
streamers for 15 minutes. Spread during the first
minute is due to the force of the injection. From
the first to the 15th minute, the spread should be
no more than 3/Uths of an inch. A greater spread
indicates an increased flow.

The color disappears, always within 2 days, often
in 18 hours. In some 5000 tests no reaction has
occurred and no permanent discoloration resulted.
Rarely, a transient redness is seen about the area
of injection, lasting one hour.

Reprinted from American heart journal. St. Louis. Vol. 28. No. 6, Pages
758-762. December. 1944

RELATION BETWEEN RUTIN AND CRUDE HESPER ID IN

INCREASED CAPILLARY FRAGILITY IN HYPERTENSION:
INCIDENCE, COMPLICATIONS, AND TREATMENT

J. Q. Griffith, Jr.,* M. D. , and M. A. Lindauer, M. D.

Philadelphia, Pa.

In 1940, Peterson 1 stated: "capillary rupture with intimal hemorrhage in
relation to the precipitation of coronary thrombi has been described...."
by Paterson, 2 Wartman, 3 and Vdnternit z and his coworkers. 4 He goes on to
state: "capillary rupture with intimal hemorrhage is intimately con-
cerned with the mechanism of cerebral arterial thrombosis and possibly,
in certain cases, with the causation of cerebral arter iospasm and rup-
ture. It is suggested that the factors responsible for the rupture of
intimal capillaries in the cerebral arteries are high int racapillary
pressure from hypertension, progressive atheromatous degeneration of the
supporting tissue and increased capillary fragility from a variety of
causes. "

It seemed possible, therefore, that an abnormal condition of the capil-
laries might be e factor in the production of certain of the vascular
accidents which sometimes occur in cases of hypertension. "We were es-
pecially interested in the relation of such complications to thiocyanate
therapy, for we had noted cutaneous ecchymoses rather commonly, retinal
hemorrhages less commonly, and apoplexy and coronary occlusion very rare-
ly after the initiation of such therapy. The more serious complications
were rare enough to suggest that they were merely coincidental, yet were
regarded as alarming nevertheless.

Method and Material

For a period of eighteen months all persons with hypertension who were
routinely studied in our laboratory had, in addition, a measurement of
capillary fragility by the Petechial Index of Gothlin, 5 with certain mi-
nor modifications.

TECHNIQUE OF THE TEST.--(l) Mark off a circular area, 6 cm. in diameter,
in each antecubital area. Mark off all blemishes and marks in this area
that might later be confused with petechiae. (2) Place a standard blood
pressure cuff about each arm, and maintain in each a pressure of -35 mm.
of mercury for fifteen minutes. Lower the pressure, and count and mark
all petechiae within the two circular areas, using a good light and a
magnifying lens of 5 D or its equivalent. (-3) One hour or more later,
repeat, using a cuff pressure of 50 mm. of mercury.

From the Robinette Foundation and the medical Clinic of the Hospital Of

the university of pennsylvania
Received for publication Jan. 22. 1944

Atwater Kent Fellow in Medicine

The Petechial Index is calculated as follows: To the number of petechiae
occurring at 35 mm. of mercury multiplied by 2, add the additional number
occurring at 50 millimeters. Based upon the Petechial Index, capillary-
fragility is considered to be: (a) normal, if the Index is 8 or less,
(b) increased (abnormal) if the Index is 13 or more, and (c) borderline,
but probably abnormal, if the Index is 9 to 12.

In order to save time, the second stage can be omitted under the follow-
ing conditions: (l) The number of petechiae after the first stage is 2
or less. Such persons may be considered normal. Usually, but not in-
variably, the person is normal who has 3 petechiae after the first stage.
(2) If 6 or more petechiae appear after the first stage, the subject may
be considered abnormal. {z) The test is a repetition, and may be com-
pared with the corresponding first stage of an earlier test. Repetition
in less than three weeks, however, is unreliable in any case.

The second stage should always be done if the fragility is being tested
in a subject for the first time and there are 4 or 5 petechiae after the
first stage. It should also be dene in most cases when the number after
the first stage is 3.

The patients, 265 in all, had history and physical examination by various
members of our hospital staff and referring physicians. Special atten-
tion was paid to the following: (l) history suggesting apoplexy, (2)
history of spontaneous cutaneous ecchymoses, (3) presence of retinal hem-
orrhages, as ascertained by ophthalmoscopic examinat ion, and (4-) simul-
taneous medication with thiocyanate.

Ophthalmoscopic examination was carried out by physicians with varying
degrees of skill, so that the occurrence of retinal hemorrhages as a pos-
itive sign iray be accepted, whereas their absence did not necessarily
entirely exclude them.

The period of study was never less than six months nor more than twenty
months.

Thirty-three patients with increased fragility were treated, with Eesperi-
din* by mouth in a dose of 250 to 500 nig. three times a day, and nine
more were given hesperidin Methyl Chalcone* by mouth in a dose of 10 mg.
three times a day. In addition, fourteen such patients were treated with
Putin, the result of which has already been reported. 6

Resul ts

1. INCIDENCE OF INCREASED CAPILLARY FRAGILITY: As shown in Fig. 1,
illary fragility was found to be normal in 218 of the series, or 82 per
cent (approximately). It was definitely increased in 44 subjects, where-
as, in three, it was borderline, making a total of 47 persons, or 18 per
cent (approximately) , whose capillary fragility was, at least, not nor-
mal. Judging from the occurrence of con-plications, it appears that the
borderline group should be classed as definitely abnormal.

Supplied by Abbott Laboratories, North Chicago, 111.

2. RELATION OF CAPILLARY FRAGILITY TO SEX AND AGE: As shorn in Fig. 1,
there was no significant relationship between capillary fragility and
either sex or age.

3. RELATION OF CAPILLARY FRAGILITY TO BLOOD PRESSURE LEVEL: Fig. 2

shows the systolic and diastolic blood pressure of 54 patients with in
creased capillary fragility. There was obviously no relationship between
the occurrence of increased capillary fragility and blood pressure level.
This series of 54 patients was obtained by adding to the original series
of 47, seven subjects from an earlier group who were called back for
study because they had developed one or more of the "complications" of
increased fragility.

4. RELATION OF CAPILLARY FRAGILITY TO THE OCCURRENCE OF APOPLEXY: A

history of apoplexy, followed by paralysis, was obtained in four cases,
or '2 percent (approximately) of the patients whose capillary fragility
was normal. Four more subjects in this group gave an atypical history,
namely, that a diagnosis of apoplexy had at one time been made (usually
severe headache was described as a '''slight stroke") , but there never was
any paralysis, nor were there any neurological sequelae at the time the
patient was studied. If these were included, it would raise the inci-
dence of apoplexy in the group with normal fragility to 4 per cent. On
the other band, seven of the patients with increased fragility gave a
definite history of apoplexy followed by paralysis, and five more had
strokes during the period of observation, making a total incidence in the
group of twelve, or 25 per cent (approximately) . It would appear, there-
fore, that apoplexy occurred, with greater frequency in persons with hy-
pertension associated with increased fragility than in those with norn;al
capillary fragility.

5- RELATION OF CAPILLARY FRAGILITY TO THE OCCURRENCE OF RETINAL HEMOR-
RHAGES: Retinal hemorrhages were recognized in five persons with normal
capillary fragility, or 2 per cent (approximately) , and in ten persons,
or 21 per cent (approximately), whose capillary fragility was increased
It seems likely, therefore, that retinal hemorrhages occur more commonly
in those persons with hypertension whose capillary fragility is increased.

6. RELATION OF CAPILLARY FRAGILITY TO THIOCYANATE MEDICATION: Ten per-
sons were studied who were attending our dispensary and receiving thio-
cyanate prior to the beginning of this investigation. These persons were
chosen because all of them showed either cutaneous ecchymoses (nine
cases) or retinal hemorrhages (one case) beginning soon after the onset
of thiocyanate medication. All ten persons showed an increase .in capil-
lary fragility. Three other patients with increased capillary fragility
were given thiocyanate without other treatment. One patient developed
cutaneous ecchymoses, one developed, retinal hemorrhages, and the third
died of a stroke. We have not felt justified in continuing this phase of
the study, but have made it a rule never to give thiocyanate to a patient
with increased capillary fragility until, or unless, that fragility has
become normal as the result of treatment. . Thiocyanate therapy has been
used in twelve such cases without incident.

7- RELATION OF CAPILLARY FRAGILITY TO MORTALITY: During the twenty

months' period of study there were three deaths in the group with normal

fragility, or 1 per cent (approximately), and five deaths, or 10 per cent
(approximately) , in the group with increased fragility. It seems prob-
able that the mortality is greater among persons with hypertension and
increased capillary fragility than among those with hypertension and nor-
mal fragility.

8. EFFECT OF TREATMENT: Hesperidin was given to 33 persons with in-
creased capillary fragility, only 23 of whom were adequately followed.
In 20 of these, capillary fragility, as measured by Gothlin's test, be-
came normal within one or two months after starting treatment, and re-
mained so thereafter except in two instances, in which the patient
discontinued treatment without permission, when the test became abnormal,
to become normal again when treatment was resumed. In three subjects
the capillary fragility was not affected by treatment and remained ab-
normal; two of these developed apoplexy and died. One of the 20 patients
whose fragility returned to normal after therapy also died of apoplexy.
This patient had a high degree of papilledema when first seen.

Hesperidin methyl chalcone was given to nine persons' with increased cap-
illary fragility. In seven of these the fragility became normal, while
two were unaffected. This group has been followed only six to nine
months, and no complications have occurred in any of the nine sub-
j ects.

We have not felt justified in discontinuing medication at intervals to
secure adequate controls for its effectiveness. Also, one cannot say
with the evidence at hand that reversion of Gothlin's test to normal in-
dicates that the subject is less likely to suffer one of the hemorrhagic
complications of hypertension, but it seems likely that such is the case.

Summary

1. Capillary fragility was increased in about 18 per cent of 265 cases
of hypertension. This incidence was not related to sex, age, or degree
of hypertension.

■2. Persons with increased capillary fragility are especially predisposed
to apoplexy, retinal hemorrhage, and death.

3- Thiocyanate tends to make worse a previously abnormal fragility, or
perhaps in certain cases may even change fragility from normal to in-
creased. Ihen this occurs, thiocyanate may be a factor in the causation
of apoplexy and other hemorrhagic phenomena.

4. Hesperidin and hesperidin methyl chalcone restored fragility to nor-
mal in about 84 per cent of cases of increased capillary fragility. It
is hoped, but not yet proved, that this may also lessen the frequency of
the complications of increased capillary fragility.

5. It is probable that thiocyanate should not be given to persons with
increased capillary fragility, unless or until that fragility has become
normal as the result of therapy. After this has been done, thiocyanate
apparently can be given with impunity.

100%
80%
60%
40%
20%

CAPILLARY FRAGILITY

■ NORMAL
□INCREASED

. i. In

INCIDENCE MALE FEMALE
SEX

18-20 2\-30 31-40 41-50 51-60 61-70 70+

AGE

Fig. 1. — Chart comparing- the incidence of normal and increased capillary fragility
in the general hypertensive group (on the left) and in groups selected on the basis
of sex and age. The figures for the two columns on the left are expressed as per-
centage of the entire group of 265 cases. The percentage figures for sex and age,
however, refer only to the total group with normal fragility (filled-in rectangle) or
increased fragility (open rectangle). The age is expressed in years.

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SYSTOLIC BLOOD PRESSURE

260

Fig. 2. — Chart showing the systolic and diastolic blood pressure of 54 persons with in-
creased capillary fragility. Each dot represents one subject.

References

1 paterson, J. C. : Capillary Rupture With intimal Hemorrhage in Causation of Cerebral

Vascular Lesions, Arch. path. 29: 345, 1940

2 Paterson, J. C. : Vascularization and Hemorrhage of intima of Arteriosclerotic Coro-

nary Areteries, Arch. Path. 22: 313, 1936.

3 Wartman, W. B. : Occlusion of Coronary Arteries by Hemorrhage into Their Walls, Am

Heart J. 15: 459, 1938

4 Winternitz, M. C. , Thomas, R. M. , and LeCompte, P. M. : The Biology of Arterioscle-

rosis, Springfield, 1938, Charles C. Thomas

5 Ahlborg, If. G. , and Brante, G. : Parallel Investigations into Ascorbic Acid (Vitamin

C) Content in Blood Plasma and into Strength of Cutaneous Capillaries in Healthy
Children, Acta med. Scandinav. 104: 527, 1940

6 Griffith, J. Q. , jr., Couch, J. F., and Lindauer, M. A.: Effect of Rutin on In-

creased Capillary Fragility, Proc. Soc. Exper. Biol. 4 Med. 55; 228, 1944

Crude Hesperidin in most instances has a therapeutic effect identical
with rutin. An occasional supply of crude Hesperidin, however, is inac-
tive. Rutin has the advantage of be in? a chemically pure substance and
hence of uniform activity, and is effective in much smaller doses than
crude Hesperidin.

CASE 1

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1 2345 6 78 9 10 11 12
MONTH OF TREATMENT

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U

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CASE 2

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SYSTOLIC
DIASTOLIC

1 2

YEAR OF TREATMENT

3

CASE 3

12 3 4
MONTH

5 6 7 8 9 10 11 12
OF TREATMENT

% 55 WITH THIOCYANATE THERAPY, SATISFACTORY
DROP IN PRESSURE OCCURS , BUT CAPILLARY
FRAGILITY BECOMES INCREASED AND ECCHYMOTIC
SKIN RASH APPEARS . AFTER INTERVAL OF RUTIN
THERAPY ALONE , RASH DISAPPEARS AND THEN
THIOCYANATE IS RESUMED .

CASE 4

[+++ +NNNNN =CLF~1

K\\\\\\ rutin WWWWN

1 2 3 4 5 6 7 8 9 10 ' i2 14 ' 16 '
MONTH OF TREATMENT

CASE 5

N N N N

N

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N GOTHLIN

HESPERIDIN,

RUTIN

160r

• SYSTOLIC
° DIASTOLIC

1

J,

12 3 4

YEAR OF TREATMENT

EFFECT OF RUTIN ON
FROM IRRADIATION

RECOVERY
IN RATS

ALL RATS GIVEN 2385 R TO ONE
FOOT, IN ONE TREATMENT.

FOOT
ABNORMAL

FOOT
NORMAL

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ONSET 0-5 6-iO 11-15 16-20 21-25 26-30 31-35 END

DAYS

o NORMAL CONTROL

• GIVEN RUTIN BY PELLET

IMPLANTATION / 20 MGM .

EVERY THIRD 'DAY