INTRAUTERINE

MEDICATION

Effect

WITH

on Rhesus Monkeys

S.

T.

EPSILON

Wearing

Show,

D.

L.

Jr.,

E.

J.

Department 1321

Aoronson Forino

and Gynecology

of Obstetrics

of Southern

North

M.D.

Underwood

R. V.

University

Mission

ACID.

Devices.

M.D.

Moyer,

D.

AMINOCAPROIC

Intrauterine

California

Road,

School

Los Angeles,

of Medicine

California

90033

ABSTRACT Menstrual

blood

and after

intrauterine

loss was quantitated

ethylene

devices

Silicone

rubber

(EACA)

in order

rubber cial

devices

effect

insertions

alone,

to provide

without

sustained

EACA

in monkeys

the nonmedicated

silicone

resulted

values,

in only

insertion. insertion and cone only

over

rubber 44%

devices. resulting circulating degradation

Accepted

(baseline)

the

baseline

blood

in monkeys

wearing

a localized

from intmuterine

VOL.

release

with

EACA alone,

during

the

volume

wearing

11 NO. 4

devices.

medication

1975

A benefi-

plus EACA

over

devices

period

109%

over

after pre-

IUDs alone

plus control

sili-

loss was increased silicone

intmvascular was detectable and

With 96%

rubber

polyethylene blood

hemorrhage

(IUDs).

menstrual

polyethylene

acid

increased

silicone

menstrual

plosminogen,

13,

devices MBL

before poly-

Silicone

on uterine

first

or disseminated

January

rubber

was increased

polyethylene

EACA

alone,

aminocaproic

intmuterine

EACA-releasing

average

levels of fibrinogen, products.

for publication

drug

in those wearing

whereas,

AI’RTL 1975

plus silicone of epsilon

devices

in animals

devices;

Neither

wearing

increase,

menstrual

values

132%

whereas

a 33%

Mean

were

rubber

devices

in utero. _used as control devices.

medication

was demonstrated

of rhesus monkeys

rubber

and polyethylene

was used OS the carrier

of intrauterine

preinsertion

in a group

of silicone

rubber

coagulation by ossay of

fibrin-fibrinogen

CONTRACEPTION

INTRODUCTION The content

of fibrinolytic

(1,2,3,4,5)

suggests a possible

hemorrhage This role vator

associated

devices

systemic

effect

with

beneficial

demonstmted device

(IUD)

possessing capabilities

nolytic

agent

within

the

medication

are

clear

Furthermore,

therapy

release

of an antifibri-

IUD-associated

the

devices

an intrauterine uterine

such hemorrhage

one considers

has been

contmceptive

that

for sustained

of controlling

when

has an ameliorative

intmuterine conclusion

system

as well,

(7,8,9,10,11).

uterus may control

The advantages

orrhage.

to the

acti-

intrauterine

hemorrhage

antifibrinolytic

wearing

lead

to plastic

agents

of systemic

These observations

devices.

or plasminogen-plasmin,

menorrhagia

(12).

system in uterine

of plasminogen

exposed

antifibrinolytic

in human subjects

and endometrium

contraceptive

types of uterine

suffering

effect

blood

fibrinolytic

the activity

The fibrinolytic, in other

on some subjects

a specific

when

in endometrium

(6).

therapy

for the

use of intrauterine

implicated

involved

in menstrual

role

the

increased

in monkeys

is apparently since

with

was further

was found

factors

hem-

by intmuterine

complications

of systemic

treatment. The purpose of this paper is to report experiments performed in rhesus monkeys testing the hypothesis that sustained release of an .antifibrinolytic

agent

from a device

complications

associated

inside with

the

MATERIALS Intrauterine

devices

fashioned

Dow Coming,

Midland,

tubes

(Millipore

were

cylindrical Their

14 mm. steel

releasing

from silicone

suture

METHODS

aminocaproic

(Silastic-TM

Michigan)

encased

Redford,

the bleeding

contraception.

AND

epsilon

rubber

Corporation,

uterus may control

intrauterine

382

acid

(EACA)

Medical

Grade

in nylon-backed

Massachusetts).

were Elastomer,

Millipore

These devices

in shape, having diameters of 1.9 mm and lengths of structure was reinforced with a centml core of stainless

which

extended

beyond

one end of the device

to form a

The loop allowed easy removal from the uterine cavity closed loop. The matrix of these devices was mixed the end of each experiment. with acid, TM

EACA before

28 22.5

396

by adding

Calbiochem,

dry epsilon

Los Angeles,

hardening mg of EACA,

with and

aminocaproic California)

stannous in vitro --

octoate.

acid

(6 amino-hexanoic

to liquid, Finished

experiments

monomeric devices

demonstmted

APRIL

at

Silastic-

contained the daily

1975 VOL. 11 NO. 4

CONTRACEPTION

release

pattern

eluted

shown

in a daily

phosphate amount

- 0.075

sions

releosed

reaction

Menstrual (14).

blood

local

aminocaproic

was tested

acid,

by measuring

on the

fifth

day after

fibrinogen

measured

determined

by a previously

protein

method

tion

assayed by a modification

technique

of Menkey,

Initially,

human plasma), Kleiner,

was used to sensitize

the

19 femole

injections

previously

all

regularly

as within,

according manner:

the uterine

At

MBL

into with

A;

assigned

to group

8; and so on. animals,

was nearly

values

had been determined

APRIL

the first

1975

identical

were

VOL.

next

monkey

plasma

this

study.

At

latter

least

bilateral

procedure

result-

(18).

Menstrual

produced

cycles

progesterone mnging

(14),

the

with

in these monkeys

by

on a schedule cycle,

all

from two to seven

blood

loss (MBL)

days.

between,

19 monkeys were

divided

(A and B) in the following

and lowest highest

baseline

and next

values

lowest

were

values

were

In this manner, the two groups coneach having an average baseline MBL

(1.59

and 1.56

ml,

from the previous

then assigned

measured

the

two groups

those with

which

for

ore expressed

had undergone

of menstrual

highest

to group

The two groups

values

the end of each injection

animals

assigned

tion

(a)

ready access from the anterior

or without

in the volume

ten and nine

were

(b) plasminogen

in which

used for

for a period

individual

The two animals

tained

were

with

(18,19).

to baseline

(17)

animals

cavity

endometrium

menstruated

Because of variation as well

tmct

of estmdiol

described

animals

(for which

and Johnson

fistulation,

daily

factors

(15),

degrada-

providing

into

These

inhibition

rhesus monkeys were

normal

in the

red cells.

patent

surface

factors

of the hemagglutination

ing in a chronically histologically

with

thrombosis,

and (c) fibrin-fibrinogen

one year prior to the experiment, oophorectomy and uterocutaneous abdominal

venous

to menses (day 0) and

method

(16)

of pooled

procedure

medication

of uterine

onset of menses (day 5).

as a percent products

that

EACA.

reported

of intrauterine

on the day prior

by a clottable

by o caseinolytic

of

coagulation-fibrinolytic

plasma or serum of test onimals

M

The

made of the same dimen-

the exception

effect

particularly

three

were

with

or systemic

were

(0.033

was measured by a modified

devices

loss was quantitated

devices

saline

days at 37OC.

for seven

the buffer

as drug devices

A possible

epsilon

into

Control

(13).

and materials

In these experiments,

1.

10 ml phosphate-buffered

NaCl , pH 7.0)

N

of EACA

ninhydrin

in Figure

change of

period,

11 NO. 4

either and this

respectively). two menstrual

to control

or drug

was followed

Baseline periods. IUD

inser-

by reversol

of

397

CONTRACEPTION

the assignment

for each

were

made

ously

had been

followed

under

soaked

by washing

In the

first group

of the

19 macaques

menstrual

all

animals

influence

devices

might

animals,

and

three

then

eluted

tern

with

fresh drug and

in vitro

with

for analysis

since

uterine

polyethylene

device

with

drug

IUDs

The remaining same time. cavities

seven

devices

to the

previously

drug

IUDs;

and At

the

sample

control

remaining

data

test of Mann

seven

IUDs

having

all

ossymetrical

Whitney

(21)

A were

inserted

IUDs at the

which

the

had

inserted

inserted

distribution,

At

removed.

B) were

was employed

the

uterine

present.

were

devices

APRIL

devices

following

the animals were

de-

menses (day 0).

already

(group

of this menses,

and

periods

devices

pat-

suitable

polyethylene

into

(group A)

elution

14 were

control

devices

re-

were

19 macaques

with

menses (day 0),

with

removed.

days.

inserted

rubber

into groups

as previously

of group

were

polyethylene

the conclusion

the

the from

0 and

their

only

two or three

inserted

all’silicone

following

inserted

inserted,

onset of the next

B were

of this menses,

For nonpaired

398

before

intm-

were

of the original

seven animals

insertion,

that

on day

design

in

IUD

before

inserted

for seven

expelled

After

an

These devices

of Y-T

were

either

infections.

dose during

removed

devices

to compare

in vitro -each

19 animals monkeys

were all

menses).

devices

of group

Prior to onset of the

sample-mnk

IUDs,

Drug and control

been

devices.

without

immediately

in addition

conclusion

entirely

five

or developed

devices

were

rapidly

inserted

the day

devices

for four days in order

Although

(20).

On

IUDs were inserted

eluted

were

a

men-

in group

the

maximum

devices

this period,

(during

polyethylene

by drug devices

to test the hypothesis

inserted

drug

onset of the next

test menses to produce

control

insertion

two periods

inserted

scribed

monkeys,

days after

into each

had discontinued

In this way,

influence.

Following

drug mes

Following

this

was inserted

to provide

in order

previously

respectively.

In four additional

were

the

B.

Control

to the first

previ-

1:12,000

animals

replaced

1).

insertions

which

hydrochloride

expected

expected

counteract

test menses,

B and A,

moved

were

IUD all

in group

(see Figure

20 days prior

EACA

second all

period

after

were

devices

on the endometrium

uterine

a control day

All

devices

saline.

the day before

drug devices

the menstrual

physiologic

on the first

the control

with

benzolkonium

of experiments, On

of measurement.

conditions

in aqueous

A and by fresh control exhaustible

period

sterile

in sterile

bleeding.

ses (day 0),

subsequent

surgically

with

were

with control

removed.

the

two

in testing

for

1975 VOL. 11 NO. 4.

CONTRACEPTION

differences

between

Otherwise,

samples.

a two-tailed

paired

WAS

t-test

used.

RESULTS Figure vices

1 shows the mean selected

monkey

at

random

elution

pattern

from the total

The majority

experiments.

determined number

of contained

from eight

manufactured EACA

drug defor the

was eluted

during

IO-

8-

t

Figure

1.

Amount

of epsilon

aminocaproic

acid

released

each

day

from

drug devices line

in vitro (for in vitro conditions see text). Solid -represents mean release fromeight devices eluted for

seven

consecutive

days in vitro.

release

from four deviceye-

uterine

cavities

of monkeys

vitro.

APRIL

1975 VOL. 11 NO. 4

and

Broken line represents mean for the first three days in for the

following

four days in -

399

CONTRACEPTION

first

three

monkeys.

the

At

days,

corresponding

the end of seven

ods of menstruation, vitro.

87%

The dotted

devices vitro

eluted

line

to the period

days,

of the drug

thatfor

the

findings

indicate

The latter

elution

in utero

drug elution

to the

in utero --

in the periin

pattern

in vitro of I&r -days and then in

was nearly

eluted

flow longest

from the devices

for three

elzionpattern

last four days of devices that

had eluted

shows the mean

in rhesus monkeys

for four days.

of heaviest

corresponding

the same-as

entirely

in vitro. -was similar to that

These measured

in vitro. -The results of the first in Table the

I.

first

crease

Silicone

menses after

over

devices

baseline

was 96%

releasing

devices

experiment rubber

insertion, MBL

on menstrual

devices

produced

in the

first

period

whereas

was only

(p> 0.10).

33%

TABLE MENSTRUAL

BLOOD

INSERTION

AFTER

loss are

increased

but not in the second.

(p = 0.0516),

AND

blood an

LOSS

(ml)

WITH

IN

The mean

in animals

that

summarized

MBL only

wearing

in animals

wearing

in

in-

control EACA-

I RHESUS MONKEYS

CONTROL

AND

DRUG

BEFORE DEVICES

Baseline

Group (10

1.59

A

monkeys)

Group

1.56

B

(9 monkeys)

After serted During mean

400

two menstrual two to three the menstrual MBL

in

periods

without

menses prior period

14 macaques

2.12

1.55

Drug

Control

3.06

1.43

Control

Drug

devices,

to insertion

before

insertion

was 3.31

ml.

polyethylene

IUDs were

in-

of control

and

drug devices.

of control

and

drug devices,

Average

APRIL

MBL

1975

for these same

VOL. 11 NO. 4

CONTRACEPTION

animals

wearing

a control

device

period

was 3.67,

for one menstrual animals 2.27 of

wearing

109%

for an drug

a drug device

Thus,

ml.

over

in Table

of

accounted

the polyethylene by the

blood

alone

accounted

IUD

for the same

and

baseline

was significant (p~O.02).

IUD

however,

plus

summarized

produced

(pO.lO).

TABLE MENSTRUAL

BLOOD

LOSS

POLYETHYLENE

IUDs

OF

CONTROL

Polyethylene IUD

Group

IN

RHESUS MONKEYS

BEFORE AND AND

First

Table

III

on day

results

1975

Second

Devices

Rubber

2.25

There

5 from monkeys was no significant

VOL. 11 NO. 4

inserted

Period

Polyethylene

+

+

Devices

3.71 Control

for the coagulation-fibrinalytic

0 and day

IUDs on day 0.

APRIL

DEVICES

Drug

gives

WEARING

INSERTION

Period

Polyethylene

(7 monkeys)

drawn

AFTER

DRUG

Rubber

3.35

A

(ml)

II

assays on samples with

difference

control between

and drug values

for

401

CONTRACEPTION

day

0 and day

drug

IUD

5 for any

groups

of the three

assays in either

TABLE VALUES* IN

OF

the

control

or the

(p>O.lO).

CIRCULATING

MONKEYS

ON

III

COAGULATION-FIBRINOLYTIC

DAYS

RELATED

TO

FACTORS

THE MENSTRUAL

PERIOD**

Day 0

Fibrinogen

(mg/dl )

(19 monkeys) Plasminogen

(%)

(19 monkeys) FDP-FgDPt

(pg/ml)

(9 monkeys)

366 2 13.8

Control

377

- 13.5 +

Control

365

Drug

340

2 16.9

Drug

183 + 12.6

Control

187 2 13.9

Control

171 f7.02

Drug

187 t

Drug

2 14.6

14.3

0.97

*0.04

Control

1.81

t 0.46

Control

0.90

f0.08

Drug

1.26

+ 0.23

Drug

c *

Mean

**

Day

t

(-Standard

+S.E.M. 0 = Day

Day 5 = Fifth FDP-FgDP

-I

prior

Error of the Mean).

to onset of menses.

day after

onset of menses.

= Fibrin-Fibrinogen

Degradation

Products.

DISCUSSION Previous key

work

intmuterine women ranging

devices

the oophorectomized-fistulated

model

for human

polyethylene

IUDs have

with

In comparison, between

70 and

uterine

For instance,

(14,18,20,22).

from 83 to 106%

was increased

402

research

devices

wearing

bows (12,23). lene

has shown that

is o useful

mean 92%

blood

Lippes

response

quantitative

shown average

Saf-T-Coils,

rhesus mon-

bleeding

increases

loops,

loss from

and

of

of MBL

Birnberg

rhesus monkey

in response to two types

to

studies

models

of polyethy-

(20).

APRIL

1975 VOL. 11 NO. 4

CONTRACEPTION

In the study tion

with

reported

epsilon

demonstrated blood

in monkeys

rubber

and

132%

devices;

wearing

MBL

i.e.

the effects

of EACA

be similar

hemostatic

In any

intrauterine

case,

intmuterine

ing organ

therapy

with

acid)

oml

over

menstrual

intrauterine

dose,

each

menstrual period, Future studies dosage. rote

t&

in an effort

for a year

-ility

that

ontifibrinolytic

uterine

or future

medication

bleeding

associated

may with

the weight

1975

i.e. and

menses may have

or localized

effects

intravenous achieving

resulting

animals

Samples

were

with high.

in the uterine

assays were

performed

bleeding

for assay on day 0 were

VOL. 11 NO. 4

at day

achieved In an attempt

taken

medica-

or pelvic

on monkey 5,

levels

intmuterine

from intmuterine

coagulation

still

doses of

in monkeys

the concentmtion very

advan-

of necessity

plasma

shown here

been

an

practical

the absence

was associated

However,

drugs (e.g.

to maintain

to the onset of menses (day 0) and again

Many so.

of humans)

day

a bleed-

In addition,

a major,

18 to 30 gm daily,

coagulation-fibrinolytic prior

with

The effect

thrombosis

of treating

antifibrinolytic

doses each

oml

vomiting,

vascular

are obvious.

as related

oral

25 mg per week.

EACA , particularly

5).

of EACA

(24).

nausea,

possibly

the advantages

Therapeutic

1 x 10B3 M

include

and

contraception,

from

systemic

APRIL

In

apparently

first

in utero

indicate

thempy

as well

oml

tion

with

EACA

several

to detect

lightly

the

dosage

useful

is not consistent

the uterus during

(day

are

appropriate

EACA

requires

one-tenth

doses of only

one day

which

effective

hypotension,

medication.

approximating

beds,

devices.

high

lower

administration

in humans mnge

within

silicone

in monkeys

EACA

during

at a rather

minimum

these side effects,

of intmuterine

(about

baseline

of excessive

This requirement

EACA

rubber

at a considerably

releasing

by local

tmnexamic

for daily

44%

intrauterine

during

devices

postural

Considering

tage

above

polyethylene

plus control

only

released

to systemic

vertigo,

effect.

wearing

silicone

alone,

occurred

the

control

reactions

systemic

in animals

was

menstrual

contmception.

diarrhea, (24).

Average

polyethylene

these experiments

devices

effective

Adverse

to 33%

to determine

to fabricate

provide

devices

25 mg of EACA

could

designed

more.

IUDs.

MBL was increased

medica-

hemorrhage

insertion.

approximately

the effect are

109%

of intrauterine

on uterine

polyethylene

plus EACA-releasing rubber

from 96%

after

Although

mean

effect

(EACA)

in those wearing

polyethylene

reduced

wearing

whereas

response to silicone period

acid

was increased

loss (MBL)

lUDs alone

an ameliorative

here,

aminocaproic

five

days

although

before

vascular

samples later

only

drug device

403

CONTRACEPTION

insertion;

therefore,

attributed

to the effects

significant

difference

fibrin-fibrinogen drug

with

conclusive

serious and

were

Although

investigation

the

control

vascular

and or

or pelvis

by demonstrating

is not

directly

that

fibrin-fibrinogen

the menstrual IUDs found

higher

A possible

cavity

cycle

where

degradation

(25), levels

source

another during

lysis of fibrinogen

or (b) increased

menses,

bed during

menses,

However,

products

in our animals

and/or

fibrinolysis

EACA

(day 5 versus day

men-

for such products

did

in

not inhibit

since

levels

0) in monkeys

were

with

either

or drug devices.

preventing inhibition

in the

uterine

uterus at the

maintain

e.g.

fluidity

cavity

thrombosis

of this activity,

therefore,

effects

on the

dosage

of heparin

function

may inhibit

be designed

so that

oblitemtion

presence

uterine

causing

hemorrhage IUD

Complete

have

itself

is prevented fibrous

may help

harmful systemic

serious

of fibrinolytic

by thrombus and of an

fibrosis.

a

thereby

just as proper

without dosage

may play

discha ye, could

However,

intrauterine

serious

of menstruation

theoretically

coagulation

of the cavity

the physical

fibrinolytic

that

time

of menstrual

and subsequent

of this organ.

we anticipate

such oblitemtion. with

uterus

interpretation

during

menstruation

activity

addition,

control

not to be asso-

bed of the latter

be

no

plasminogen, either

appeared

the

circulating

during

of degradation

during

role,

can

that

from the uterine to occur

Fibrinolytic

causing

indicates

menses (26).

physiologic

orrhage,

be made so only

between

increase

unchanged

EACA

However,

not wearing

is known

such an

with

5 could

Since

of fibrinogen,

in animals

with

0 and day

or both.

in the vascular

of women

than

uterine

medication

do not change

is (a) absorption fibrin

day

not deposited.

levels

struation

in levels

circulation.

could

between menstruation,

products

coagulation

one study

product

was found

degradation

or in the systemic thrombi

of EACA,

intmuterine

IUDs,

ciated

assay differences

hem-

inhibitors without

reaction.

In

to obviate

We conclude that the effects of intmuterine medication inhibitors merits further study in animal models.

ACKNOWLEDGEMENTS This study was supported

404

by a gmnt

from the

Ford Foundation.

APRIL

1975

VOL. 11 NO. 4

CONTRACEPTION

REFERENCES 1.

Albrechtsen,

0.

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