Anti-implantation action of a medicated intrauterine delivery system (MIDS)

CONTRACEPTION

ANTI-IMPLANTATION

ACTION

OF

A MEDICATED

SYSTEM Dean

L.

Robert Israel Section

of Experimental

Obstetrics Southern *This

and

work

Pathology,

supported

** Present Address:

***

WHO

Fellow

Primate

of California

R.G.

Sul 90.000.

Research

California

of

California

from the

University

-

Pathology,

Los Angeles,

by a grant

90033

Ford Foundation Center

95616 Fund&a0

Present Address:

e Fertilidade,

of

County/Univetiity

California Davis,

Endocrinologia

Department

Center,

in part

Ph.D .**

M.D.***

Los Angeles

Medical

DELIVERY

M. D.

Thompson,

Berger,

Gynecology,

California

Moyer,

S.

INTRAUTERINE

(MIDS)*

Independgncia

Univenit&ria

440,

de

Porto Alegre,

Brazil ABSTRACT

Since

emetine

hydrochloride

it was decided ceptive

agent

intrauterine level were

after

recorded

hydrochloride increasingly note

when

that

system the

pronounced the surface

with

area

mining

its overall

ponent

of this parameter.

when effect

emetine

was present

on implantation

Accepted

for

lutea Our

of a medicated

results

with

length

uterine

contmlateml

April

being

found,

that

implantation indicate

effect

is of major

dose On

uterus.

and

in dose level.

synthesis,

as a contm-

of emetine

rabbit

antiimplantation

increases

in the

in the

in the

of corpora

It was also

publication

JULY 1977 VOL. 16 NO. 1

tested

of the device

effectiveness

protein

as a component

analyzed.

a marked

with

of this compound

Six combinations

were

number

and statistically does have

Pocally

(MIDS).

configuration

mating

to interfere

the efficacy

administered

delrvery

and device

10th day

is known

to investigate

and

that

the sites emetine

this becomes

It is of interest importance

the most critical under

to

in detercom-

our conditions,

lumen, it had no observable horn.

8, 1977

39

CONTRACEPTION

INTRODUCTION Utilization ceptive

of the method

associated

nonmedicated

has been

with

their

the

IUD

may be attributed of the

the higher

In addition, amount

IUD

the

lateml

its chance

a suitable

balance

side effects

as evidenced

for clinical

use.

In an effort

to alleviate

maintaining

a high

developed,

known

delivery

system

incorporated

between

on its surface

to rely

on the

(Copper

large

surface

to reduce

an MIDS systemic

is the

factors

combination

is that

in

The second continuous

of

utilized

the uterine

progesterone

has been

on the study of nonsteroidal

40

to their

have

markedly

needed devices

utilized (6).

embryacidal

into

in this type labomtory,

100%

a syn-

varying

release

thempeutic

In our

compounds

a long-tern,

to produce

with the

when

side effects.

is incorpomted

to the minimal

and copper higher

localized

to control

The

agent

system to produce

to produce

been successfully

(4,5)

the

of a medication/

producing

the opportunity

medicants

of

within

contmception.

as an antifertility

without

Different

due

in the selection

of the delivery

cavity

in

advantage

zero.

effective

it is possible

material,

of the MIDS

of medication

for intmuterine

including IUDs

level

If the medication

rates thus affording

nr, therefore

chemotactic

An added

of the lowest dosageLcfmedication

contmception.

within

in the

importance

(MIDS)

low concentration

release

carrier

medication

are

either

a need

the configumtion

approaching

is the capability

intmuterine diffusion

reduction

to that

are

to provide

the side effects.

the drug be highly

administered

thetic

resultant

was intmuterine

(progesterone),

is there

of a device

still

or medicated or metals

and

available

leukocytes (2,3) in order to produce In clinical pmttice it is therefore

and vary

reduce

circulation

Two major carrier first

the size

to significantly

effectiveness currently

while

longer

the

toward

of device

compounds,

pain.

to decrease

a new type

No

area

IUD

directed

of devices

(l),

larger

and

to increasing

has been

IUD

7).

attmction for polymorphonuclear the desired contmceptive result. order

body of an

in some

the

for bleeding

body of the device

the

bleeding.

and

of side effects,

effect,

Chemical

into

effects

uterine rule,

contmceptive

“bioactive”

(MIDS).

directly

as a contm-

size,

contribute

effort

the problem

as the

placed

possible

on the

by the variety

antifertility

and

As a general

may themselves Considerable

(IUD) of side

large

of removal

prongs placed

of bleeding.

pain

to the

involved.

incidence

of expulsion,

achieving

device

by a variety

use such as abdominal

These complications cases the shape,

intrauterine

accompanied

of

dose

level.

of IUD emphasis

for use in medicated or spermididal

effects

JULY 1977 VOL. 16 NO. 1

CONTRACEPTION

compared Emetine

to compounds hydrochloride

that

are

currently

is an example

was shown to be a highly

in use.

of this class of compound

effective

antifertility

agent

as the

which result

of an

in vivo and in vitro drug screening program conducted in our --It has been used as an amebicide laboratory over the past seveml years.

since

1912

(9) in the effect size

(7) and more treatment

by interfering of the golgi

lation

(12)

fertility Emetine methyl

circulation, levels

investigate as emetine)

protein and

other

substances

has a pharmacologic

synthesis

interfering

(lo),

reducing

in oxidative

the

phosphory-

An emetine

in the mitochondria. rats has been

alkaloid

Emetine

is highly in high

Ipecac (Fig.

soluble

dimer

shown to produce

an anti-

and

cephaeline

are

would

within

the contmceptive as an

a polymer

delivery

known Since

lumen,

known

For these efficacy

of the parent side effects the

the administmtion

the uterine

intrauterine

a salt

doses (7).

involve

no side effects

of this compound.

is chemically

l),

and produces

pharmacological

daily

there

of

hydrochloride

water

hydrochloride

gram quantities

into

to female

is the principle

of emetine

(ll),

(8) or with Emetine

(13).

ether.

compound,

used alone cancer.

cellular

occurring

orally

effect

administered

low

with

complex

normally

administered

recently

of advanced

and not into

of emetine

antiimplantation

of only

to be associated

reasons,

hydrochloride when

use

micro-

the systemic with

it was decided

agent

when

proposed

such to

(referred

to

incorpomted

system.

OCH

2CI'*xH,O

Figure

1

EMEllNE

JULY 1977 VOL. 16 NO. 1

HYDROCHLORIDE

41

CONTRACEPTION

MATERIALS IUD

AND

METHODS

MANUFACTURE

It is known

that

the

IUD

not

it is firmly

not only

important

(usually

are

the size,

to ifs effectiveness

fixed

in position

configuration (14,15,16),

(15,

and

location

of

but also whether

17) or free

in the

uterine

or

lumen

more effective).

The MIDS

in this study were

urations:

2.7

X 5.0

of these devices and were

mm,

were

manufactured

2.7

X 20.0

capable

of such size

in the following

mm,

of carrying

as to have

and

1.0

the various

minimal

three

X 20.0

config-

mm.

All

dosages of emetine

contraceptive

activity

of their

own. The devices Corning

were

manufactured

Elastomer

382)

(18,19)

and designed

chloride

per device

devices

(IDS)

1,

2,

Burroughs

manufactured

medication.

Prior to surgical

by immersion

for 20 minutes

grade

to the method

to contain (USP,

were

from medical

according

3,

silicone

of Fu, & Co,

in a 1:750

MIDS

dilution

hydro-

Lot 13840).

in the same manner both

(Dow

and Moyer

and 4 mg of emetine

Wellcome

insertion,

rubber

Kale,

and

Control

contained

and IDS were

no

sterilized

of benzalkonium

chloride

in water. INSERTION Sexually 3.5

OF

to 3.6

caged

virgin

kg were

IDS were sodium

rabbit

under

inserted

laparotomy

under

of each

Since lumen,

needled

6-O

sterile

conditions

wall

to which

silk

in place

suture

to have

only

under

Labs).

upper

group

by a single

was passed through

1 mm from one end and the device

intravenous

A blunt or middle

the animal

the devices

remain

MIDS

placed

and

into

the

puncture third

was

free

loose attachment,

each

and

and

A midventral

horns exposed. in the

Water

The MIDS

the animal

Diamond

either

weighing individually

per day.

libitum.

with

uterine

rabbits

They were

ad

experimental

it was decided held

White

and dark

(Diabutal,

and the

uterine

horn according

assigned. uterine

the

Zealand this study.

both provided

anesthesia

was performed through

New

12 hours light

chow were

pentabarbital

was made

female,

used throughout

and maintained

commercial

mately

IUDs

mature,

in the a twin-

IDS approxiuterine

cavity

through the puncture. The suture was passed through the uterine wall on either side of the device and the two ends joined on the other surface of the horn.

Less than

in both MIDS plain

and

gut suture

both medicated horns (medicated 3-O

42

chromic

1 mm of suture

through and

suture

exposed

in the

uterine

was closed

with

a single

the serosa and outer

non-medicated

on the

remained

The puncture

IDS horns.

right),

and 2-O

silk

devices

were

the peritoneum suture

uterine

musculature.

inserted and

5-O

After

in opposite

muscles were

lumen

uterine

closed

with

used for the skin.

JULY 1977 VOL. 16 NO. 1

CONTRACEPTION

EXPERIMENTAL Each of the

DESIGN four emetine

further

subdivided

utilized

so that

horn with

which

were

inserted

inserted

days after

New

White

Zealand

designated these On

as Day

Day

At

t4is

surgery

were

a count

size

female

of the

mm) MIDS

uterine

horn.

was presented

to mate other

were

Control horns.

to two different

with

both.

time

intervals

sacrificed tract

of the corpora

and

third

in the contralateral

reproductive

was made

as the number,

to be

of the devices

This data utilized

was in

on this fact.

the animals and the

All

X 20.0

of each

and all

predictited

anesthetic

time

as well

each

2).

(oviductal)

inserted

bucks and allowed

10 post-mating,

pentabarbital

(Figure

third

were

and 4 mg) were

of the device

1 mg (2.7

of the

0 of pregnancy

experiments

(1,2,3

in the proximal

in the middle

Fi’ve to seven

groups

resulted

the exception

of the same dimensions,

IDS,

level

to the dimensions

six basic groups

in these groups were uterine

dosage

according

location

by an overdose removed

lutea

of the

of

for examination.

present

in each

fetuses within

the

ovary uterine

lumen. RESULTS AND Of

the

90 rabbits

because

initially

significant

lbe

lumen

mnging

from

even -

The antiimplantation various

seveml

dosage

reduced

the

the dosage showed

number

implant

were

number that

the surface

on thei.r ovemll

levels with

the

(SA)

effectiveness.

(169.6

a primary that

alteration

it required

only

in length

mther

however, uterine

treated

length

of the in size

than

in combination

MIDS

size,

measuring

regardless

of

horns consistently

exerted 2.7

2). a maior

by the fact X 5.0

as 1 mg in a 2.7

diameter

a

progressively

ones (Fig.

MIDS

phenomenon

1 or 2 mg of emetine

JULY 1977 VOL. 16 NO. 1

the

In those groups where a single

of the

IUD

area

with

constant

This was evidenced

it re uired 3 mg of emetine in a device Y the same result mm SA) to accomplish The surface

no

(5,14,20,21,22).

doses of emetine

(42.4

mm2 SA).

well

of emetine

2.

groups,

than

area

showed

sides (Wilcoxon

the entire

the control

of implants

present

remarkably

tested

In all

involved,

not used

length).

increasing

of implants.

were

from the anesthetic

studies

along

shown in Figure

that

(26%)

This correlates

of the different

of emetine

size

(CL’s)

reported

distribution

are

showed

and MIDS

It was apparent that

levels effect

a greater

influence

of MIDS

23

or death

and control

horns and were

cm (total

effects

sizes

dose/response

uterine

1.9

lutea

treated

in previously

in their

in both 1.4

the

test ~~0.01).

investigators

The fetuses were uterine

infections

of corpora

between

signed-ranks

results of other

to this study,

uterine

number

differences

matched-pairs

with

committed

of pseudopregnancy,

administered.

DISCUSSION

mm

X 20.0

may be attributed as evidenced

in a device

measuring

mm to

by the 1.0

fact X

43

9120

-

Figure 2

EFFECT

~

OF DOSE AND

DEVICE DIMENSION:2.7x20.0mm

USED/ TOTAL

LEVE:

ANIMALS:

DOSE

_L._

:_.:

I

MIDS

9/10

DIMENSIONS

2.7x5.0mm

2mg

.C.....C.. ::::::::::: ..::.._.. ::::::::::: _..._._..... _. ,.... .._. ::....,... . . . . . . .._

c......... ::::::::::: .~::::_ :::::: j::: ::::::::::: ::::::::::: .?...._..._ ::::::::::: :::::: j::: ::::::::::: _~.~_~.~_~_ ::::::::::: .._.. _.,..

,:;:;:I:;::: :_:.:_:.:_: ::j::::::: _~.~_~_~_~_ ::::::::::: ...._._..._

53

ON

1a/20

3mc

THE

-

8/10 l.Ox20.0mm

ANTI-IMPLANTATION

9/10

lrns

RATE

14/20

E)(p.m

CON. 17

CONTRACEPTION

20.0

mm (62.8

number

the same relative

of CL) whi1.e it

factors

appear

total

amount

rapidity

of diffusion

The total

amount

(longer

The first

within

the

Emetine, tion

uterine

action toxic

fluid

norma I ly

occur

.

It has been

documented

metabolic

Day

were

incubated uptake

of the

with pool

is the

greater

surface

of emetine

in preventing

the exact as well

emetine

as to the

fluids,

glandular that

implanta-

mechanism

that

it is likely

possible could

non-medicated

uterine

secretions

effect

of this

could

be tissues.

or blasto-

implantation

would

emetine

might

devices

can

and uterus

from rabbits

nu terial

there

by these

This reduced

may be reflected

mechanism

intrauterine

embryo

thymidine,

(24).

which

emetine

not

have

with

with

emetine

blastocysts

uptake

blastocyst

laboratory,

containing

in

by auto’

an inhibition

protein

devices,

decrease

as measured

indicated

‘by an altered

interfere

In our

was a demonstrable

for the demonstrated

be an interference

(23).

metabolic

contraceptive

activity

steroidogenic

activity.

of system. of

et al. (25) in a recent paper demonstrated the presence of wo 5t --5sterordogenic pathways in preimplantation mbbit embryos; A -3B-

hydroxysteroid ductase.

but,

is not knownwhat

obtained

labeled

analysis

Another Dickmann

it

and surrounding

area.

is effective

embryo

of both

in tritiated

synthesis

important

that

activity

6 blastocysts,

radiographic DNA

present

fluids

not only

tissues themselves.

when the

At

the

bearing

from the surfose of the device.

It is possible

altered,

between

The second

in those MIDS

uterus,

unknown.

sufficiently

on the uterine

the

rabbit

remains

uterine

those of lesser surface

if the pH of the uterine

were

the

(42.4

the antiimpfan-

of time

a larger continuous

to the preimplantation

For example, coel

released

in this study,

in the

mm long

this has a direct

into

mm2

(fetuses/

(3 mg) to

X 5.0

of this exposure.

provide

than

as administered

antifertility

with

lumen

length

of the medicant

would

from occurring

directly

duration

as much

2.7

(169.6

mte

in determining

is the

implantation:

of medication

length)

times

a device

of drug diffusing

the total

areas

three

with

mm IUD

in implantation

to be of importance

tissues but also or rate

almost

rate

tation effect of an MIDS. insertion of the device and on the

X 20.0

reduction

required

rea h the same implantation 5 mm SA). Two other

1 mg in o 2.7

or

mm2 SA),

SA) to achieve

dehydrogenase

The authors

developmental

potential

were

adversely

then

implantation

and

associated

affected would

3 or 17B_hydroxysteroid:NAD(P) these

of the embryo. such that

they

two pathways They were

felt

with that

no longer

oxidore-

the metabolic

if the fully

and

two pathways functional

not occur.

JULY 1977 VOL. 16 NO. 1

45

CONTRACEPTION

In summary

1.

our findings Emetine

in this study, 2. concurrent

indicate

hydrochloride,

is capable

There

that: when

of blocking

is a progressive

increases

in emetine

administered

implantation

decrease

in the in the

levels

rabbit

in the implantation

concentration

when

utilized

uterus.

rate

utilizing

with

a given

size

MIDS. 3.

The surface

its effectiveness. surface

area 4.

on the of the

46

There

of an MIDS

increase

is placed

in

leading

is no effect of implants

device

uterine

area

modifications

number

medicated

An

length

a major

the

in determining

upper

horli

factor

antiimplantation

in the dosages

contralateral

in either

role

is the most critical

to an increased

of emetine, in the

plays

used

in activity.

in this study,

of the uterus when

(proximal)

or middle

the

third

length.

JULY

1977

VOL. 16 NO. 1

CONTRACEPTION

REFERENCES 1.

Moyer, D.L. Overview of bioactive IUDs to date. Chapter in: Intrauterine Devices (R.G. Wheeler, G.W. Duncan and J.J. Speidel, Editors), Academic Press Co., New York, 1974, p. 191.

2.

El Sahwi, S. and Moyer, D.L. Antifertility effects of the intrauterine foreign body. Contraception,2:1-28, 1970.

3.

El Sahwi, S. and Moyer, D.L. The leukocytic response to an intrauterine foreign body in the rabbit. Fertil. Steril., 22:398-408, 1971.

4.

Seshadri, B., Gibor, Y. and Scommegna, A. Antifertility effects of intrauterine progesterone in the rabbit. Am. J. Obstet. Gynec., 109:536-541, 1971.

5.

Vickery, B.H., Erickson, G.I., Bennett, J.P., Mueller, N.S. and Haleblian, J.K. Antifertility effects in the rabbit by continuous low release of progestin from an intrauterine device. Biol. Reprod., 3:154-162, 1970.

6.

Polidoro, J.P., Culver, R.M., Thomas, 5. and Hahn, D.W. Mechanism of anti-implantation by copper IUD in the rabbit: transport and recovery of ova. Contraception, 10:481-490, 1974.

7.

Goodman, L.S. and Gilman, A. The Pharmacolgical Basis of Therapeutics. Third Edition. MacMillan Co., N.Y., 1965.

8.

Israel, L., Depierre, A., Boutillier, J. and Chahinian, P. Activite anticanereuse de I'Cmeltine.La Nouvelle Presse Medicale, 2:720, 1973.

9.

Street, E.W. Cyclophosphamide plus emetine in lung cancer. The Lancet, 19:381, 1972.

10.

Chakrabarti, S., Dube, U.K. and Roy, S.C. Effects of emetine and cyclohexamide on mitochondrial protein synthesis in different systems. Biochem. J., 128:461-462, 1972.

11.

Flickinger, C.J. Decreased formation of Golgi bodies in amebae in the presence of RNA and protein synthesis inhibitors. 3. Cell. Biol., 49:221-226, 1971.

12.

Lietman, P.S. Mitochondrial protein synthesis: inhibition by emetine hydrochloride. Molecular Pharmacology, 7:122128, 1970.

JULY 1977 VOL. 16 NO. 1

47

CONTRACEPTION

13.

R.N, Kar, B. and Mundle, M. Antifertilitv Khanna, N.M., Iyer, effect of emetine dimer. J. Sci. Industr. Res., 21:84-90, 1962.

14.

Adams, C.E. and Eckstein, P. The effect of intrauterine foreiqn bodies on pregnancy in the rabbit. Fertil. qteril., 16:508-521, 1965.

15.

Adams, C.E. and Eckstein, P. Effect of intrauterine silk threads on location and survival of conceptuses in the rabbit. J. Reprod. Fertil., 9:351-354, 1965.

16.

Ledger, W.J., Virkar, K.D. and Irvin, L.A. Effect of plastic intrauterine device upon implantation in the rabbit. Obstet. Gynec., 28:521-525, 1966.

17.

Brown, E. and Foote, R.H. The effect of plastic devices in the uterine lumen on preqnancy and parturition in the rabbit. J. Reprod. Fertil., 12:373-375, 1966.

18.

Fu, J.C., Kale, A.K. and Moyer, D.L. Drug-incoroorated silicone discs as sustained release capsules. I. Chloroquine diphosphate. J. Biomed. Mater. Res., 7~71-78, 1973.

19.

Fu, J.C., Kale, A. and Moyer, D.L. Diffusion of p.yrimeJthanG;nedfrom silicone rubber and flexible epoxy druq capsules. . Mater. Res., 7:193-200, 1973.

20.

Dukelow, W.R., Perry, H.A. and Williams, W.L. Intrauterine deviceinduced embryonic mortality in rabbits. Fertil. Steril., 18:557-564, 1967.

21.

Hussein, M. and Ledqer, W.J. Preimplantation effect of an intrauterine device in the rabbit. Am. J. nbstet. Gynec., 103:221223, 1969.

22.

Ledger, W.J. and Rickley, J.E. Effect of a plastic foreign body on the genital tract of the female rabbit. qbstet. Gynecol., 27:658-664, 1966.

23.

Eckstein, P. Mechanisms of action of intrauterine contraceptive devices in women and other mammals. Brit. Med. Bull., 26:52-59, 1970.

24.

Mizumoto, H., Hohman, W.R. and Moyer, D.L. Effects of medicated IUDs (Histamine, Chloroquine, Daraprim, Emetine) on DNA metabolism in rabbit blastocysts - an autoradioqraphic study. Submitted for publication.

48

JULY 1977 VOL. 16 NO. 1

CONTRACEPTION

25.

Dickmann, .Z.,Dey, S.K. and Gupta, J.S. Steroidogenesis in rabbit preim lantation embryos. Proc. Nat. Acad. Sci., 72~238-243, e 975.

JULY 1977 VOL. 16 NO. 1

49