- Email: [email protected]
Therapeutic abortion of early human gestation with intramuscular 15-methyl prostaglandin F2α
CONTRACE
THE
TIC A B O
I
OF 15-
N. T
kl, C T, , USN; W.
GES T ..... ~ P
S
ION WITH IN F2 ~
INT
* , U S N; D. T r e ay, C D R , , USN; P. Too rray, LCDR, MC, USN; T. Daane, C T,
SC
ION
R
r, LCDR, , USN
Reproductive Endocrine Division, Department of stetrics & Gynecology and the C l i n i c a l I e s t i g a t l o n Center, N a v a l R e g i o n a l M e d i c a l C e n t e r , Oa a , C a l l f o r n l a 94627
ABSTRACT e e f f e c t i v e n e s s of i n t r a scular !5-methyl prostagla in F 2 ~ ( 1 5 - m e t h y l PGF2~) for t h e r a p e u t i c o r t l o n w a s stud.led in 20 w o m e n d u r i n g the f l r ~ t and s e c o n d t r i m e s t e r s of g e s t a t i o n Intra scular i n j e c t i o n s of 250 ~g re a d m i n i s t e r e d a t i n t e r v a l s of 2 to 3 h o u r s for a t o t a l d o s a g e of up to 4 mE. Serum h an c h o r l o n l c g o n a d o t r o p l n (HCG) and p r o g e s t e r o n e (P) 1 els w e r e a s u r e d by r a d i o l assay p r i o r to s t a r t i n g t h e r a p y and at i n t e r v a l s d u r i n g t h e r a p y for 24 hours. A l l s u b j e c t s had s i d e e f f e c t s , m a i n l y g a s t r o i n t e s t i n a l sy to Of the 20 s u b j e c t s , 15 a b o r t e d c o m p l e t e l y , 3 a b o r t e d i n c o m p l e t e l y , a 2 failed to abort, e five s u b j e c t s o f a i l e d to a b o r t c o ~ l e t e l y also had d i l a t a t i o n and c u r e t t a g e s , ere s an H C G fall in all s u b j e c t s but a m o r e rapid d e c l l n e in t h o s e o ....o r t e d co letely.
Accepted
for p u b l i c a t i o n
* Fe i i o w
MARCH
December
8, 1975
p r o d uc t iv e End o c r ino io gy
1976
V O L . 13 N O . 3
319
CONTRACE
ION
INTRODUCTION Prostagla ins h a v e the p o t e n t i a l to b e a s i g n i f i c a n t a d d i t i o n to the arma n t a r l u m of the o b s t e t r i c l a n - g y n e c o l o g i s t , is b e c a m e a p p a r ent en r and F i l s h e (i) in 1970 I n t r o d u c e d the use of p r o s t a glandln F2~ (PGF~) for s u c c e s s f u l te i n a t i o n of f i r s t and s e c o n d t r i~es t er p r e g n a n c les. A d i s t i n c t d i s a d v a n t a g e in the t h e r a p e u t i c uses of pros t a g l a n d l n s has b e e n t h e i r rapid i n a c t atlon en a d m i n i s t e r e d s y s t e m i c a l l y , n e c e s s i t a t i n g l a r g e r d o s e s of the drug and thus i n c r e a s i n g side effects. ...... e h a l f - l i f e of s y s t e m i c a l l y a d m i n i s t e r e d P G F 2 ~ has b e e n c a l c u l a t e d to b e less ....an o n e m l n u t e (2). M e t h y l a t i o n of P G F 2 ~ at the i S - c a r b o n p o s i t i o n (15 ethyi-PGF2~) has b e e n sho to p r o l o n g the c i r c u l a t i o n t ~ e and i n c r e a s e b i o l o g i c a l a c t i v i t y (3). us it uld se p o s s i b l e to m i n i m i z e the d o s e of pros tag land in n e e d ed t o pro d uc e t he rap eu tic or t ion in the f i r s t t r im e s t e r of p r e g n a n c y a l o n g w i t h a d e c r e a s e in u a n t e d s i d e e f f e c t s -inly n a u s e a , v o m l t l n g , and d l a r r h e a . 15-~ethyl-PGF2~ s u t i l i z e d in this s t u d y for t h e r a p e u t l c a b o r t i o n by intr s c u l a r i n j e c t l o n in f l r s t and s e c o n d t r i m e s t e r p r e ancies. S e r u m c h o r i o n i c go dotropin (HCG)and progesterone (P)were determined p r i o r to and d u r i n g the t r e a t m e n t p e r i o d in a n a t t e t to d e t e r m i n e the effect e ss of the d g o n c o r p u s lute a n d / o r p l a c e n t a l functlon. MATERIALS
tide in
the
AND
METHODS
e p u r p o s e of the s t u d y s to d e t e r m i n e the e f f i c a c y and the ine of s i d e e f f e c t s of 1 5 - m e t h y l - P G F 2 e at t h e r a p e u t i c drug 1 els te
ination
of
first
tr
ester
h
an
pregnancy.
s enty h e a l t h y m e n b e t w e e n the 6th a n d 13th w e e k o f g e s t a t i o n (with the e x c e p t i o n of o n e p a t i e n t at 19 w e e ks, as n o t e d in T ie I) re i n c l u d e d in the study. All subjects had essentially no i findings o n p h y s i c a l ex inatlon a a no I laborato screen. Pregnancy s confi ed by est a t l o n of the s i z e of the u t e s by b nual p e l v i c ex i tion and a p o s i t l v e u r i n a p r e g n a n c y test for H C G a c t i v l t y . *
* Pre
320
os t icon R , Organon
Inc.,
st Orange,
N.
J. 07052.
MARCH
1976
V O L . 13 ~ O . 3
CONTRACE
l e ....
on
ION
i~t e ,
All s J e c t s w e r e v o l u n t e e r s for entry into the study a were l e g a l l y a p p r o v e d for t h e r a p e u t i c t e r m i n a t i o n of pregnancy. Written i formed c o n s e n t for a all n e c e s s a r y d o c u m e n t a t i o n w e r e fully executed. S jeers w i t h k or i d e n t i f i a b l e a r t pts at p r e v i o u s t e r m i n a t i o n of the p r e s t p r e g n a n c y w e r e not i n c l u d e d in the s t u d y group. Also, s u b j e c t s w i t h s proms of t h r e a t e n e d or in it ie abortion, c e r v i c a l dilatation or s p o n t a n e o u s r u p t u r e of r a n e s p r i o r to ~ e d l c a t i o n w e r e excluded. D u e to the s y s t e m i c e f f e c t s of p r o s t a g l a n d i n , s Jeers w i t h n cardiac, pu I (!no !ud ing as t ) h e p a tic or r end I d is ease wet e also e x c l u d e d f r o m the study.
g One of 15 ...m.e t h y l P G F 2 ~ (U-32,921E) ~ s in each 2a ule. This s d i l u t e d w i t h n o r m a l s a l i n e such that 0.5 ml c o n t a i n e d 250 ~g of the drug. ea
ent
utine
Each p a t i e n t s a It ted to the Na 1 R e g i o n a l M e d i c a l Center, Oakland, p r i o r to a b o r t i f a e l e n t therapy. B a s e l i n e c l i n i c a l and i o r a tory s t u d i e s were completed prior to treatment. A n i n i t i a l d o s e of 250 ~g (0.5 ml) 15 ethyl PGF2 ~ was dr up into a s t e r i l e t u b e r c u l i n s y r i n g e and a d m i n i s t e r e d by deep intra scular i n j e c t i o n w i t h the u s u a l s a f e g u a r d s to avoid i n a d v e r t e n t v a s c u l a r inj ec t ion. A d d i t ional int r amus cu far inj ec t ions ( 250 ~ g in 0.5 ml) w e r e a d m i n i s t e r e d at 2- to 3-hour inter Is. Total d o s a g e in this s t u d y did not exceed 4 mg in 48 hours. Side e f f e c t s r e p o r t e d by the s u b j e c t s or ~ s e r v e d by the i e s t l gators w e r e n o t e d and treated as n e c e s s a r y . Compazlne, 5-10 rag, or
t Supplied through Ka la zoo, Mich. * Smith K ! i n e P a. 19 fOX.
MARCH
1976
the c o u r t e s y 4 9001.
of Dr. Paul Sc
& French Laboratories,
VOL.
13 N O ....3
ille,
The U p j o h n Co.,
1500 S p r i n g G a r d e n St., P h i l a d e l p h i a ,
3 21
CONTRACE
I
T o r e c a n , + i 0 rag, s administered intramuscularly c r y 3 h o u r s as n e e d e d f o r n a u s e a .... o t a b l e t s of L o m o t l l were given orally every 3 hours for diarrhea. For analgesla, D e r o l , 75 rag, w a s ...a. d m l n l s t e r e d in t r a m u s c u l a r ly e ry 3 h o u r s a s r e q u ir ed. During therapy the subjects were carefully monitored. Frequent v i t a l s l g n s a n d s l d e e f f e c t s t o g e t h e r w i t h t h e o n s e t of v a g l n a l b l e e d l n g w e r e r e e o rd e d d u r i n g d r u g a d m In i s t r a t io n. V l ta i s i g n s w e r e m o n i t o r e d for
bo
6
hours
to
post
A
therapy.
lysi8
The foll i n g t e s t s w e r e d o n e o n e a c h s t u d y s u b j e c t (a) b e f o r e o n s e t o f t h e r a p y , (b) at 8 h o u r s a f t e r t h e s t a r t of t h e r a p y , a n d (c) 24 h o u r s a f t er i n i t ia t i o n o f t h e r a p y : H e m a t oc r i t, it e c e i! c o u n t , differential and platelet count, urine analyses, billrubin (direct and total), SGOT, SGPT, alkaline phosphatase, serum creatlnine, N, s e r u m electrolytes, and blood glucose. Ten cc blood were also dr n f r o m t h e a n t i c u b i t a l v e i n , a l l o w e d to c l o t a n d t h e n c e n t r i f u g e d at 2 5 0 0 R P M . Serum was stored at-20°C for later HCG and P analysis The blood samples were dra at b a s e l i n e a n d repeated c r y 2 h o u r s u p to 12 h o u r s a n d t h e n a g a i n at 24 h o u r s . T H C G w a s .... d.e t e r m i n e d b y a d o u b l e a n t l b o d y r a d i o i u n o a s s a y (R~A) as described by ~ee and co-workers (3). Serum P was determined by RIA by a modification of the procedure described by Abraham and co-workers (4,5). A 0.i0 M phosphate buffer adjusted t pH 7.0 and containing 0.1% gelatin s used. E a c h a s s a y t u b e c o n t a i n e d a 0 . 5 m l a l i q u o t of b u f f e r c o n t a l n l n g t h e e x t r a c t e d f r a c t i o n , °0.I m i of d i i u t e d a n t ody, a n d 0 . i i of b u f f e r c o n t a i n i n g a p p r o x i m a t e l y 5 0 0 0 c p m of t r i t l a t e d s t e r o i d . A f t e r 12 h o u r s of i n c u b a t i o n at 4oC, u o und radioactivity was separated u s in g a c ha r c o a i s u sp ens ion. Th e an tib o d i e s we r e ob t a in ed f r om D r. G u y E. rah o f H a rb o r G e n e r a i H o sp i t a I n r r a n t e, C a i i for n £ a. A n t i b o d y S - 4 9 # 6 w a s u s e d f o r P at a f i n a l dilu~tion of i : 1 2 0 , 0 0 0 . Inter-
and
we re
intraassay
i0.7%
~Sandoz tSearle
322
variation
at
0.154
ng/mi
expressed
and
as
7.7i% at
coefficient
0.141
of
v
iation
for
P
ng/~l.
Pharmaceuticals, R o u t e i0, st H a n o v e r , N. J. L a b o r a for i e s B o x 51 i0, C h i c a g o , I l i .... 6 0 6 8 0 .
MARCH
1976
07936.
V O L . 13 NO. 3
CONTRACE
ION
RES ULT S Of the 20 s Jeers, 15 orted c pletei7 5 f a i l e d to ort (Table I). e f e failures included three s jeers aborted inco letely d O did t . r e s p o n d .... S u r g i c a l i n t e e n t l o n (D&C) s n e c e s s a r y in all f e s jeers. Statistical a lysis using square test r e a l e d no d i f f e r e n c e in s u c c e s s r a t e of t p ou~ g r o u p of s jeers v sus at of the n u i l l p a r o u s gro . er, a l u a t l o n of the o e t o f ortlon terval using the Student t test r led e i n t e r v a l for t h e lllparous s J e e r s to b e s l g n l f l e a n t l y l o n g e r t h a n t h a t of e p a r o u s s j e e r s (0.02 < p < 0.05).
All
s
Syst ic s e e f f e c t s ~ e r e ted a Jeers d onstrated gastrolntest
a r e l i s t e d in T les I a 1 e f f e c t s of the a E n.
iI.
e progesterone i els d o t correlate with t e after initiation of t h e r a p y in the f a i l u r e g r o u p b u t do c o r r e l a t e in the lete group (r = 0.447, df = 217, p < 0 . 0 1 for r a 8 # 0 w i t h p < 0.01). s the p r e g r e s s i o n l i n e s for t h e o g r o u p s a r e not s i g n i f i c a n t l y d i f f e r ent. e G 1 els do c o r r e l a t e w i t h t e a f t e r i n i t i a t i o n of erapy in b o t h groups. In the f a i l u r e group: r = 0.507, df = 481 p < 0 . 0 1 for r and ~ # 0 th p < 0.01. In the co i e t e group: r = -0.4257~ df = 99, p < 0 . 0 1 for r and B # 0 w i t h p < 0.01. e HCG regression lines for the o gro s a r e ai st p a r a l l e l (slope for f a i l u r e ~ -693; s l o p e for co iete, -642) b u t a r e s i g n i f i c a n t l y d i f f e r e n t a s id t by S t u d e n t t test a n a l y s i s ich r is p < 0.01. is is esp ialiy true en t h e h a l f - l l f e of H C G is c o n s i d e r e d , e n the ~ e d l a n l u e s of 12 a 24 h o u r s of t h e t groups are evaluat b y t h e c h l - s q u a r e test, t h e r e is a dlffere e (p < 0.001). us, t re is a m o r e r Id d e c l l of H C G l e v e l s d u r i n g t h e f i r s t 24 h o u r s a f t e r i n i t i a t i o n of t h e r a p y in the co i e t e v e r s u s the f a i l u r e group. DISCUSS
ION
....
e s t h e s i s of 15 or 16 s u b s t i t u t e d a n a l o g u e s of P G F 2 ~ a PGE 2 has led to the d elop nt of p r o s t a g i a der t es ich are effective en g en o r a l l y (6) or i n t r a s c u l a r l y (7). e prostagla In~ 15 e t h y l P G F 2 ~ P is an a l o g u e of turaily Occurring PGF2~ Ich has been dlfled by substituting a methyl group on carbo 15. is s s t l t u t i o n pr e n t s enz tic d e g r a d a t i o n by the enz e 15-d ydroge se a m a k e s this p a r t i c u l a r s u b s t a n c e 4 0 - 1 0 0 t s re potent than PGF2~ (8). it w a s a n t l c l p a t e d at this i n c r e a s e in p o t e n c y w o u l d ..a ..l l I n d u c t i o n of a b o r t ion w i t h a ch 1 er t o t a l d o s e of p r o s t a g l a d s uently decreased inc e n c e of s i d e e f f e c t s . e s u c c e s s f u l te i n a t l o n of e a r l y p r e g n a n c y th r e t ely s II d o s e s of 1 5 - m e t h y l P G F 2 ~ s achl ed in 1 5 / 2 0 s u b J e c t s ~ i t h the 24ur s t u d y p e r i o d d at the d o s e d e t e ined for t h ~ s p r o t o c o l . The
MARCH
1976
V O L . 13 N O . 3
323
0
-4
>
@.
b~
18 19 20
17
1 2 3 4 5 6 7 8 9 I0 II 12 13 14 15 16
..........
Pt. No.
20 22 24 18 21 15 19 21 20 18 18 20 19 21 21 19 30 21 20 21
Age (yrs)
3 1 i I 2 i 2 2 1 2 2 2 1 3 2 i 5 1 1 1
Orava
1 0 0 0 0 0 0 1 0 1 1 1 0 2 1 0 4 0 0 0
Para
1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
11 11 7 i0 i0 8 9 9 9 12 Ii 8 6 8 12 19 7 13 I0 Ii
Oestation (wks)
13 14 14 8 15 15 12 4 13 9 12 9 9 4 13 12 4 4 o 12
(250
Total injections
3250 3500 3500 2000 4000 4000 3000 1000 3250 2250 3000 2250 2250 1000 3250 3000 i000 i000 2250 3000
Total dose PGF2~
complete failure complete " incomplete complete " " " " " " incomplete complete incomplete failure complete " " ,1
Results/ abortion
of I n ~ s ~
PGFga
13 hr 15 h/15 15 h/47 15 h/30 18 h/45 12 h 6 h/30 14 h/15 9 h/35 12 hi05 I0 h 25 h/12 6 h/35 25 h/08 6 h/55 5 h/50 12 h/15 12 h
m m m
m m m
m
m m m
m m m m
x x x x x x x x x x
x x x x x x x x x
x x x x x x x x x x
x
x x x x x x x x x x
x x x x x x x x x
x
x x x x x x x x x
Induction- ............~S!de ..... eff.ects .......... abortion Vomiting Nausea Diarrhea interval
Dosage Schedule, Hesults, and Side Effects
Abortions
Charac'~eri s~cs, ""
Table I
>
CONTR
.E
ION
le II
of
cts er
Pa
19
Fever
(> lO0°F)
Chills is Diarrhea
Blood !oss
MARCH
9t6
(< 150 co)
V O L . 13 N O . 3
% of
tal
95%
none
0%
"
OZ
20
i00%
19
95%
20
10o%
325
CONTRACE
ION
drug s a d m i n i s t e r e d in a d o s e of 250 ~g e 2-3 h o u r s w i t h a m e a n onsetortlon inte 1 i n s u c c e s s f u l c a s e s of 1 1 . 4 h o u r s . Parous s u b j e c t s (8/20) h a d e l t h e r a co lete o r t l o n (7/8) or an co lete o r t l o n (1/8) th o n s e t - a b o r t l o n i n t e r v a l of 9.2 hours, lliparous subjects c l e t e i y a b o r t e d in 8/12 c a s e s , co leteiy orted in 2/12 a f a i l e d in 2/12 w i t h ~ e a n o n s e t .... o r t l o n i n t e ai 13.2 hours, is s u g g e s t s t t lliparous s jeers are ~ore reslstant a n d a p p e a r e d to r e q u i r e a l a r g e r o n s e t - a b o r t i o n i n t e a l (p < 0.05) tO a c h i e v e co lete u l s l o n of the p r o d u c t s of c o n c e p t i o n w i t h t h e u s e of p r o s t a g l d s. is s a l s o the e erl ce of r (9) o fo a shorter Inductio .... ortion t e r v a l in p a r o u s as co a r e d to l l i p a r o u s subJ ects. In s u c c e s s f u l cases co fete ortion was achi ed w i t h a t o t a l d o s e of 1 5 - m e t h y ! P 2~ b e een 1.0 mg a 4 . 0 ~g. is t o t a l d o s e is d e c i d e d l y l e s s an the t o t a l d o s e of P G F 2 ~ a d m i n i s t e r e d by v a r i o u s routes by other i e s t l g a t o r s (I, i0). H er, wl this d e e r sed d o s a g e , the d e s i r e d r e s u l t of 1 0 0 % co lete ortion with a mln of side effects was not achl ed. e s jeers all had either diarrhea, nausea and/or vomiting (Tables I a II). hyperpyr ia s noted. By a l y s i s of s e r i a l H C G a P 1 els, a s i g n i f i c a n t d i f f e r e n c e S ted in t h e r e d u c t i o n of s e r G d u r i n g t h e f i r s t 24 h o u r s a f t e r t h e r a p y (p < 0 . 0 1 ) i n the g r o u p a c h i e v i n g co f e t e a b o r t i o n (Fig. la). e G r e s p o n s e i n the co fete group was significantly different from the r e s p o n s e of the f a i l u r e g r o u p (p < 0.01). How er, t h e r e is a s i g n i f i c a n t r e d u c t i o n in ser HCG levels t h e inc fete-failed g r o u p (p < 0 . O f ) . e f a c t t h a t in ch c a s e o f e failed-lnco fete o r t i o n g r o u p , set HCG s n o t e d to d e c l i n e m signify these pregn c i e s w e r e t o t a l l y or p a r t i a l l y i n t e r r u p t e d b y the 15 ethyl PGF2~ i n j e c t i o n s b u t t h a t co f e t e p l a c e n t a l s e p a r a t i o n or u l s i o n d u e to t r a p p i n g w a s ~ o t p o s s i b l e d u e to a r i g i d c e r v i x . Treatment wl 1 i rla or d e l e t a r i a p r i o r to o n s e t of 15thyl PGF2~ injection probably would shorten the onset injectlo abortion interval, is could result in a higher success rate a possibly all a reduction in the d o s e n e e d e d to p r o d u c e a b o r t i o n . S ce the n P p r o b a b l y a c t s as a u t e r o t r o p i n a n d t a l u t e o l y t i c a g e n t (I0), significant decli in t h e p r o g e s t e r o n e i els w e r e o b s e ed in e i t h e r g r o u p (Figs. 1 a 2). Blood loss all cases s mini This prob ly r e s u l t s f r o ~ t h e t e t a n i c d o s e s of 15 ethyl PGF2~ used
1 (less uterine
t h a n 150 cc, l e II). c o n t r a c t i o n w i t h the
H o p efu I ly, fu r th er s t u d y p r o to c o I s c a n b e u ert a k to i e s tiga t e the a d m i n i s t r a t i o n of I er d o s e s of 1 5 - m e t i P G F 2 ~ a f t e r ce lea/ preco i t i o n i n g of l a m a r i a i n s e r t i o n .... By d e c r e a s i the o n s e t of j ection to o r t i o n time and u a n t e d s i d e e f f e c t s , this uld pe it the e f f i c a c i o u s u s e of an intr uscular prostagia i n as a n a b o r t i f a c i e n t in the f i r s t t r e s t e r of p r e g n a n c y ther y obviat g the n e c e s s i of a D & C in a j o r i t y of the s jeers. ....
326
MARCH
1976
V O L . 13 N O . 3
r~
>
CO
b,,,
E o
I
E
0
4
........ t
Fig. la
2
o,,,,,~ ........... w
Z~O0-
4,o00-
so~oo~
I0
I4
i. . . . . . . . . . l
12 Time (hours)
i............ i...........
B
~
16
'a
IB
I 20
Serum human chorionic gonadotropin (HCG) levels prior to, during, and following treatment with intramuscular 15methyl-PGF2~ in subjects who completely aborted.
6
i ......
I "". . . . . . . I 22 2
Z
0
C~
0
< 0
=
>
O3
2
E
0
ffl
c 0
C
E
2
0
I
4
Fig. ib
I ........ i
I
"I
"]
8 I0
12
14
I ..................I...
"" Time (hours)
I ........ i.....
I .......
16
I
18
I
20
24
i ...... I
22
Serum progesterone levels prior to, during, and after treatment with intramuscular 15-methyl_PGF2 ~ in subjects who completely aborted.
6
...........I.....
O Z
>
0 Z
f'l
i
¢
o~
>
Go
E
O I
|~-'"
J-~--...__ j
Fig. 2a
~m----
'.......... ~ - - " ~ e - - ~
Time
(hours)
I
20
| .......
18
incomplete
i
i................. I............. i . . . . . . . . 1 ............... ~ . . . . . . 8 10 12 14 16
- - ~ - - " -. . . .
"~'---'~'~i
foilure
•
22
1. . . . .
24
I
- I1 -.-.--__... B
Serum human chorionic gonadotropin (HCG) levels prior to, during, and following treatment with intramuscular 15methyl-PGF2~ in subjects who incompletely aborted or who failed to abort.
0 ............. i................ i........ i 0 2 4 6
2,000-
I0,000 m
_!
20,000~ ~-"~+~- ..~_~,+..~
30,o00-
40,000 I = , .
50,0007
0 Z
>
0
Z
<
=
>
n
E
D
70
D = D
C
0
I
16-
E 20-_
m
24-
2
•
~io. 2b 0
4
8
I
I0
Time
!
I2
(hours}
M,
.............~......
16
I'
in~nmn
18
I
I......
20
~erum progesterone !ev ~ p~. . . . ~uring, and following treatment with intramusc ~..,~thyl-PGF: ~ ~- subjects ~ho incompletely aborted or who failed to ~ ,
6
I
I
P failure
24
i..........- 7
22
Z
o
>
z
3
CONTRACEPTION
A CK NOW L ED GM ENT S This i estigation s support r e a u of ~ e d i c e a Surgery, by a gr t f r o m the Up~ n Co a
in part Depart
by
fu s provided by e for CIP 5-48-584 a
e op ions a'~d a s s e r t i o n s c o n t a i n e d h e r e i n a r e t h o s e of t h e a u thors a a r e n o t to b e c o n s tru as o f f i c i a l or as r e f l e c t l n E the vl s of t h e D e p a r t m e n t or t h e n 1 s e r v i c e at large. T h e a u t h o r s w i s h to a c erson, Sa y tse augh, G a p rogestero ass s.
ledge Jane
the t e c h n i c a l a s s l s t a er, a eodore
e of L da k l s for t h e
REFER ENC ES I.
r
gla
,
S.M.M.
in F2a.
a
Filshle,
Lancet
1:
G.M. :
157-159,
Therapeutic 1970.
2.
Sa e i s s o n, B. : Bro o k ~o d ge s Reprod. d. 91 376, 1972.
3.
Lee, P . A . , dgiey, A . R . , Jr., a Jaffe, R.B.: hu n go dotroplns. VIII. Ser cone tratlo ho one d f o l l i c l e st iatlng hor ne in a d u l t exogenous testosterone administration, g. Clin. 35: 6 3 6 - 6 4 1 , !972.
4.
5.
os i
abortion
on pro s tag I
using prosta-
ins
J.
l a t l o n of of l u t e l n l z l n g les f o l l ing doerlnol, t
.
rah , G.E., H o p p e r , K., T u l c h l n s k y , D., S w e r d l o f f , R.S., a Odeli, W.D. : S ultaneous measurement of p l a s m a p r o g e s t e r o n e , i7-hydro p r o g e s t e r o n e a n d e s t r a d l o l 1 7 - ~ by r a d i o ass . A lye. L e t t e r s 4: 3 2 5 - 3 3 5 , 1971. r a h a m , G.E., S ~ e r d l o f f , R., T u l c h l n s k y , dlo a s s a y of p l a s progesterone. t . 32: 6 1 9 - 6 2 4 , 1 9 7 1 ....
D. d Odell, W.D.: J. Clln. E ocrlnol.
6.
rim, S.S., Sivas oo, R., and tn , S.S. ortifacl t a c t i o n of o r a l l y a d m i n i s t e r 16,16-d ethyl prostagla in E 2 and its m e t h y l e s t e r . P r o s t a g l a n d i n s 6.- 3 4 9 - 3 5 4 , 1 9 7 4 ....
7.
B i e n l a r z , J., nter, G., a Sco gna, A. : E f f l c a c y a accepta b i l l t y of 15 ( S ) - i S - m e t h y l - p r o s t a g l a n d i n E 2 - m e = h y l e s t e r f o r m i d t r i m e s t e r p r e g n a n c y t e r m i n a t i o n . ....... J. stet. G y n e c o l . !20: 8 4 0 - 8 4 3 , 1974.
MARCH
1976
V O L . 13 N O . 3
331
CONTRACE
ION
8.
rim, S.M.M., Shar , S.D. and F i l s h i e , G.M. : Te i n a t i o n of pregn cy w i t h 15 m e t h y l a i o g u e s of p r o s t a g l a i E2 a F2~, in S o u t h e r n , E.M. (ed): gZa , Cl Ical A p p l i c a t i o n s in ~ n R roductlon. N York, F u t u r a P u b l i s h i n g Co a , inc., 1972, p p 307--32i.
9.
r , S.M.M. and Shar , S.D. : T h e r a p e u tic ort ion a i n d u e t ion of l a b o u r by the i n t r a v a g l n a l a i n l s t r a t l o n of p r o s t a g l a n d l n s E 2 a F2~. J. s tet. G y n a e e o l . Br. Co o . 781 294-300, 1971.
lO.
332
Tred y, D.R. and M i s c h e l ! , D.R., Jr.: Ther eutic o r t i o n of early hu n g e s t a t i o n w i t h v a g i n a l s u p p o s i t o r i e s of p r o s t a g l a n d (F 2). . J. Obstet. G y n e c o l . 116: 7 9 5 - 7 9 8 , 1973.
MARCH
1976
V O L . 13 N O . 3
THE
TIC A B O
I
OF 15-
N. T
kl, C T, , USN; W.
GES T ..... ~ P
S
ION WITH IN F2 ~
INT
* , U S N; D. T r e ay, C D R , , USN; P. Too rray, LCDR, MC, USN; T. Daane, C T,
SC
ION
R
r, LCDR, , USN
Reproductive Endocrine Division, Department of stetrics & Gynecology and the C l i n i c a l I e s t i g a t l o n Center, N a v a l R e g i o n a l M e d i c a l C e n t e r , Oa a , C a l l f o r n l a 94627
ABSTRACT e e f f e c t i v e n e s s of i n t r a scular !5-methyl prostagla in F 2 ~ ( 1 5 - m e t h y l PGF2~) for t h e r a p e u t i c o r t l o n w a s stud.led in 20 w o m e n d u r i n g the f l r ~ t and s e c o n d t r i m e s t e r s of g e s t a t i o n Intra scular i n j e c t i o n s of 250 ~g re a d m i n i s t e r e d a t i n t e r v a l s of 2 to 3 h o u r s for a t o t a l d o s a g e of up to 4 mE. Serum h an c h o r l o n l c g o n a d o t r o p l n (HCG) and p r o g e s t e r o n e (P) 1 els w e r e a s u r e d by r a d i o l assay p r i o r to s t a r t i n g t h e r a p y and at i n t e r v a l s d u r i n g t h e r a p y for 24 hours. A l l s u b j e c t s had s i d e e f f e c t s , m a i n l y g a s t r o i n t e s t i n a l sy to Of the 20 s u b j e c t s , 15 a b o r t e d c o m p l e t e l y , 3 a b o r t e d i n c o m p l e t e l y , a 2 failed to abort, e five s u b j e c t s o f a i l e d to a b o r t c o ~ l e t e l y also had d i l a t a t i o n and c u r e t t a g e s , ere s an H C G fall in all s u b j e c t s but a m o r e rapid d e c l l n e in t h o s e o ....o r t e d co letely.
Accepted
for p u b l i c a t i o n
* Fe i i o w
MARCH
December
8, 1975
p r o d uc t iv e End o c r ino io gy
1976
V O L . 13 N O . 3
319
CONTRACE
ION
INTRODUCTION Prostagla ins h a v e the p o t e n t i a l to b e a s i g n i f i c a n t a d d i t i o n to the arma n t a r l u m of the o b s t e t r i c l a n - g y n e c o l o g i s t , is b e c a m e a p p a r ent en r and F i l s h e (i) in 1970 I n t r o d u c e d the use of p r o s t a glandln F2~ (PGF~) for s u c c e s s f u l te i n a t i o n of f i r s t and s e c o n d t r i~es t er p r e g n a n c les. A d i s t i n c t d i s a d v a n t a g e in the t h e r a p e u t i c uses of pros t a g l a n d l n s has b e e n t h e i r rapid i n a c t atlon en a d m i n i s t e r e d s y s t e m i c a l l y , n e c e s s i t a t i n g l a r g e r d o s e s of the drug and thus i n c r e a s i n g side effects. ...... e h a l f - l i f e of s y s t e m i c a l l y a d m i n i s t e r e d P G F 2 ~ has b e e n c a l c u l a t e d to b e less ....an o n e m l n u t e (2). M e t h y l a t i o n of P G F 2 ~ at the i S - c a r b o n p o s i t i o n (15 ethyi-PGF2~) has b e e n sho to p r o l o n g the c i r c u l a t i o n t ~ e and i n c r e a s e b i o l o g i c a l a c t i v i t y (3). us it uld se p o s s i b l e to m i n i m i z e the d o s e of pros tag land in n e e d ed t o pro d uc e t he rap eu tic or t ion in the f i r s t t r im e s t e r of p r e g n a n c y a l o n g w i t h a d e c r e a s e in u a n t e d s i d e e f f e c t s -inly n a u s e a , v o m l t l n g , and d l a r r h e a . 15-~ethyl-PGF2~ s u t i l i z e d in this s t u d y for t h e r a p e u t l c a b o r t i o n by intr s c u l a r i n j e c t l o n in f l r s t and s e c o n d t r i m e s t e r p r e ancies. S e r u m c h o r i o n i c go dotropin (HCG)and progesterone (P)were determined p r i o r to and d u r i n g the t r e a t m e n t p e r i o d in a n a t t e t to d e t e r m i n e the effect e ss of the d g o n c o r p u s lute a n d / o r p l a c e n t a l functlon. MATERIALS
tide in
the
AND
METHODS
e p u r p o s e of the s t u d y s to d e t e r m i n e the e f f i c a c y and the ine of s i d e e f f e c t s of 1 5 - m e t h y l - P G F 2 e at t h e r a p e u t i c drug 1 els te
ination
of
first
tr
ester
h
an
pregnancy.
s enty h e a l t h y m e n b e t w e e n the 6th a n d 13th w e e k o f g e s t a t i o n (with the e x c e p t i o n of o n e p a t i e n t at 19 w e e ks, as n o t e d in T ie I) re i n c l u d e d in the study. All subjects had essentially no i findings o n p h y s i c a l ex inatlon a a no I laborato screen. Pregnancy s confi ed by est a t l o n of the s i z e of the u t e s by b nual p e l v i c ex i tion and a p o s i t l v e u r i n a p r e g n a n c y test for H C G a c t i v l t y . *
* Pre
320
os t icon R , Organon
Inc.,
st Orange,
N.
J. 07052.
MARCH
1976
V O L . 13 ~ O . 3
CONTRACE
l e ....
on
ION
i~t e ,
All s J e c t s w e r e v o l u n t e e r s for entry into the study a were l e g a l l y a p p r o v e d for t h e r a p e u t i c t e r m i n a t i o n of pregnancy. Written i formed c o n s e n t for a all n e c e s s a r y d o c u m e n t a t i o n w e r e fully executed. S jeers w i t h k or i d e n t i f i a b l e a r t pts at p r e v i o u s t e r m i n a t i o n of the p r e s t p r e g n a n c y w e r e not i n c l u d e d in the s t u d y group. Also, s u b j e c t s w i t h s proms of t h r e a t e n e d or in it ie abortion, c e r v i c a l dilatation or s p o n t a n e o u s r u p t u r e of r a n e s p r i o r to ~ e d l c a t i o n w e r e excluded. D u e to the s y s t e m i c e f f e c t s of p r o s t a g l a n d i n , s Jeers w i t h n cardiac, pu I (!no !ud ing as t ) h e p a tic or r end I d is ease wet e also e x c l u d e d f r o m the study.
g One of 15 ...m.e t h y l P G F 2 ~ (U-32,921E) ~ s in each 2a ule. This s d i l u t e d w i t h n o r m a l s a l i n e such that 0.5 ml c o n t a i n e d 250 ~g of the drug. ea
ent
utine
Each p a t i e n t s a It ted to the Na 1 R e g i o n a l M e d i c a l Center, Oakland, p r i o r to a b o r t i f a e l e n t therapy. B a s e l i n e c l i n i c a l and i o r a tory s t u d i e s were completed prior to treatment. A n i n i t i a l d o s e of 250 ~g (0.5 ml) 15 ethyl PGF2 ~ was dr up into a s t e r i l e t u b e r c u l i n s y r i n g e and a d m i n i s t e r e d by deep intra scular i n j e c t i o n w i t h the u s u a l s a f e g u a r d s to avoid i n a d v e r t e n t v a s c u l a r inj ec t ion. A d d i t ional int r amus cu far inj ec t ions ( 250 ~ g in 0.5 ml) w e r e a d m i n i s t e r e d at 2- to 3-hour inter Is. Total d o s a g e in this s t u d y did not exceed 4 mg in 48 hours. Side e f f e c t s r e p o r t e d by the s u b j e c t s or ~ s e r v e d by the i e s t l gators w e r e n o t e d and treated as n e c e s s a r y . Compazlne, 5-10 rag, or
t Supplied through Ka la zoo, Mich. * Smith K ! i n e P a. 19 fOX.
MARCH
1976
the c o u r t e s y 4 9001.
of Dr. Paul Sc
& French Laboratories,
VOL.
13 N O ....3
ille,
The U p j o h n Co.,
1500 S p r i n g G a r d e n St., P h i l a d e l p h i a ,
3 21
CONTRACE
I
T o r e c a n , + i 0 rag, s administered intramuscularly c r y 3 h o u r s as n e e d e d f o r n a u s e a .... o t a b l e t s of L o m o t l l were given orally every 3 hours for diarrhea. For analgesla, D e r o l , 75 rag, w a s ...a. d m l n l s t e r e d in t r a m u s c u l a r ly e ry 3 h o u r s a s r e q u ir ed. During therapy the subjects were carefully monitored. Frequent v i t a l s l g n s a n d s l d e e f f e c t s t o g e t h e r w i t h t h e o n s e t of v a g l n a l b l e e d l n g w e r e r e e o rd e d d u r i n g d r u g a d m In i s t r a t io n. V l ta i s i g n s w e r e m o n i t o r e d for
bo
6
hours
to
post
A
therapy.
lysi8
The foll i n g t e s t s w e r e d o n e o n e a c h s t u d y s u b j e c t (a) b e f o r e o n s e t o f t h e r a p y , (b) at 8 h o u r s a f t e r t h e s t a r t of t h e r a p y , a n d (c) 24 h o u r s a f t er i n i t ia t i o n o f t h e r a p y : H e m a t oc r i t, it e c e i! c o u n t , differential and platelet count, urine analyses, billrubin (direct and total), SGOT, SGPT, alkaline phosphatase, serum creatlnine, N, s e r u m electrolytes, and blood glucose. Ten cc blood were also dr n f r o m t h e a n t i c u b i t a l v e i n , a l l o w e d to c l o t a n d t h e n c e n t r i f u g e d at 2 5 0 0 R P M . Serum was stored at-20°C for later HCG and P analysis The blood samples were dra at b a s e l i n e a n d repeated c r y 2 h o u r s u p to 12 h o u r s a n d t h e n a g a i n at 24 h o u r s . T H C G w a s .... d.e t e r m i n e d b y a d o u b l e a n t l b o d y r a d i o i u n o a s s a y (R~A) as described by ~ee and co-workers (3). Serum P was determined by RIA by a modification of the procedure described by Abraham and co-workers (4,5). A 0.i0 M phosphate buffer adjusted t pH 7.0 and containing 0.1% gelatin s used. E a c h a s s a y t u b e c o n t a i n e d a 0 . 5 m l a l i q u o t of b u f f e r c o n t a l n l n g t h e e x t r a c t e d f r a c t i o n , °0.I m i of d i i u t e d a n t ody, a n d 0 . i i of b u f f e r c o n t a i n i n g a p p r o x i m a t e l y 5 0 0 0 c p m of t r i t l a t e d s t e r o i d . A f t e r 12 h o u r s of i n c u b a t i o n at 4oC, u o und radioactivity was separated u s in g a c ha r c o a i s u sp ens ion. Th e an tib o d i e s we r e ob t a in ed f r om D r. G u y E. rah o f H a rb o r G e n e r a i H o sp i t a I n r r a n t e, C a i i for n £ a. A n t i b o d y S - 4 9 # 6 w a s u s e d f o r P at a f i n a l dilu~tion of i : 1 2 0 , 0 0 0 . Inter-
and
we re
intraassay
i0.7%
~Sandoz tSearle
322
variation
at
0.154
ng/mi
expressed
and
as
7.7i% at
coefficient
0.141
of
v
iation
for
P
ng/~l.
Pharmaceuticals, R o u t e i0, st H a n o v e r , N. J. L a b o r a for i e s B o x 51 i0, C h i c a g o , I l i .... 6 0 6 8 0 .
MARCH
1976
07936.
V O L . 13 NO. 3
CONTRACE
ION
RES ULT S Of the 20 s Jeers, 15 orted c pletei7 5 f a i l e d to ort (Table I). e f e failures included three s jeers aborted inco letely d O did t . r e s p o n d .... S u r g i c a l i n t e e n t l o n (D&C) s n e c e s s a r y in all f e s jeers. Statistical a lysis using square test r e a l e d no d i f f e r e n c e in s u c c e s s r a t e of t p ou~ g r o u p of s jeers v sus at of the n u i l l p a r o u s gro . er, a l u a t l o n of the o e t o f ortlon terval using the Student t test r led e i n t e r v a l for t h e lllparous s J e e r s to b e s l g n l f l e a n t l y l o n g e r t h a n t h a t of e p a r o u s s j e e r s (0.02 < p < 0.05).
All
s
Syst ic s e e f f e c t s ~ e r e ted a Jeers d onstrated gastrolntest
a r e l i s t e d in T les I a 1 e f f e c t s of the a E n.
iI.
e progesterone i els d o t correlate with t e after initiation of t h e r a p y in the f a i l u r e g r o u p b u t do c o r r e l a t e in the lete group (r = 0.447, df = 217, p < 0 . 0 1 for r a 8 # 0 w i t h p < 0.01). s the p r e g r e s s i o n l i n e s for t h e o g r o u p s a r e not s i g n i f i c a n t l y d i f f e r ent. e G 1 els do c o r r e l a t e w i t h t e a f t e r i n i t i a t i o n of erapy in b o t h groups. In the f a i l u r e group: r = 0.507, df = 481 p < 0 . 0 1 for r and ~ # 0 th p < 0.01. In the co i e t e group: r = -0.4257~ df = 99, p < 0 . 0 1 for r and B # 0 w i t h p < 0.01. e HCG regression lines for the o gro s a r e ai st p a r a l l e l (slope for f a i l u r e ~ -693; s l o p e for co iete, -642) b u t a r e s i g n i f i c a n t l y d i f f e r e n t a s id t by S t u d e n t t test a n a l y s i s ich r is p < 0.01. is is esp ialiy true en t h e h a l f - l l f e of H C G is c o n s i d e r e d , e n the ~ e d l a n l u e s of 12 a 24 h o u r s of t h e t groups are evaluat b y t h e c h l - s q u a r e test, t h e r e is a dlffere e (p < 0.001). us, t re is a m o r e r Id d e c l l of H C G l e v e l s d u r i n g t h e f i r s t 24 h o u r s a f t e r i n i t i a t i o n of t h e r a p y in the co i e t e v e r s u s the f a i l u r e group. DISCUSS
ION
....
e s t h e s i s of 15 or 16 s u b s t i t u t e d a n a l o g u e s of P G F 2 ~ a PGE 2 has led to the d elop nt of p r o s t a g i a der t es ich are effective en g en o r a l l y (6) or i n t r a s c u l a r l y (7). e prostagla In~ 15 e t h y l P G F 2 ~ P is an a l o g u e of turaily Occurring PGF2~ Ich has been dlfled by substituting a methyl group on carbo 15. is s s t l t u t i o n pr e n t s enz tic d e g r a d a t i o n by the enz e 15-d ydroge se a m a k e s this p a r t i c u l a r s u b s t a n c e 4 0 - 1 0 0 t s re potent than PGF2~ (8). it w a s a n t l c l p a t e d at this i n c r e a s e in p o t e n c y w o u l d ..a ..l l I n d u c t i o n of a b o r t ion w i t h a ch 1 er t o t a l d o s e of p r o s t a g l a d s uently decreased inc e n c e of s i d e e f f e c t s . e s u c c e s s f u l te i n a t l o n of e a r l y p r e g n a n c y th r e t ely s II d o s e s of 1 5 - m e t h y l P G F 2 ~ s achl ed in 1 5 / 2 0 s u b J e c t s ~ i t h the 24ur s t u d y p e r i o d d at the d o s e d e t e ined for t h ~ s p r o t o c o l . The
MARCH
1976
V O L . 13 N O . 3
323
0
-4
>
@.
b~
18 19 20
17
1 2 3 4 5 6 7 8 9 I0 II 12 13 14 15 16
..........
Pt. No.
20 22 24 18 21 15 19 21 20 18 18 20 19 21 21 19 30 21 20 21
Age (yrs)
3 1 i I 2 i 2 2 1 2 2 2 1 3 2 i 5 1 1 1
Orava
1 0 0 0 0 0 0 1 0 1 1 1 0 2 1 0 4 0 0 0
Para
1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
11 11 7 i0 i0 8 9 9 9 12 Ii 8 6 8 12 19 7 13 I0 Ii
Oestation (wks)
13 14 14 8 15 15 12 4 13 9 12 9 9 4 13 12 4 4 o 12
(250
Total injections
3250 3500 3500 2000 4000 4000 3000 1000 3250 2250 3000 2250 2250 1000 3250 3000 i000 i000 2250 3000
Total dose PGF2~
complete failure complete " incomplete complete " " " " " " incomplete complete incomplete failure complete " " ,1
Results/ abortion
of I n ~ s ~
PGFga
13 hr 15 h/15 15 h/47 15 h/30 18 h/45 12 h 6 h/30 14 h/15 9 h/35 12 hi05 I0 h 25 h/12 6 h/35 25 h/08 6 h/55 5 h/50 12 h/15 12 h
m m m
m m m
m
m m m
m m m m
x x x x x x x x x x
x x x x x x x x x
x x x x x x x x x x
x
x x x x x x x x x x
x x x x x x x x x
x
x x x x x x x x x
Induction- ............~S!de ..... eff.ects .......... abortion Vomiting Nausea Diarrhea interval
Dosage Schedule, Hesults, and Side Effects
Abortions
Charac'~eri s~cs, ""
Table I
>
CONTR
.E
ION
le II
of
cts er
Pa
19
Fever
(> lO0°F)
Chills is Diarrhea
Blood !oss
MARCH
9t6
(< 150 co)
V O L . 13 N O . 3
% of
tal
95%
none
0%
"
OZ
20
i00%
19
95%
20
10o%
325
CONTRACE
ION
drug s a d m i n i s t e r e d in a d o s e of 250 ~g e 2-3 h o u r s w i t h a m e a n onsetortlon inte 1 i n s u c c e s s f u l c a s e s of 1 1 . 4 h o u r s . Parous s u b j e c t s (8/20) h a d e l t h e r a co lete o r t l o n (7/8) or an co lete o r t l o n (1/8) th o n s e t - a b o r t l o n i n t e r v a l of 9.2 hours, lliparous subjects c l e t e i y a b o r t e d in 8/12 c a s e s , co leteiy orted in 2/12 a f a i l e d in 2/12 w i t h ~ e a n o n s e t .... o r t l o n i n t e ai 13.2 hours, is s u g g e s t s t t lliparous s jeers are ~ore reslstant a n d a p p e a r e d to r e q u i r e a l a r g e r o n s e t - a b o r t i o n i n t e a l (p < 0.05) tO a c h i e v e co lete u l s l o n of the p r o d u c t s of c o n c e p t i o n w i t h t h e u s e of p r o s t a g l d s. is s a l s o the e erl ce of r (9) o fo a shorter Inductio .... ortion t e r v a l in p a r o u s as co a r e d to l l i p a r o u s subJ ects. In s u c c e s s f u l cases co fete ortion was achi ed w i t h a t o t a l d o s e of 1 5 - m e t h y ! P 2~ b e een 1.0 mg a 4 . 0 ~g. is t o t a l d o s e is d e c i d e d l y l e s s an the t o t a l d o s e of P G F 2 ~ a d m i n i s t e r e d by v a r i o u s routes by other i e s t l g a t o r s (I, i0). H er, wl this d e e r sed d o s a g e , the d e s i r e d r e s u l t of 1 0 0 % co lete ortion with a mln of side effects was not achl ed. e s jeers all had either diarrhea, nausea and/or vomiting (Tables I a II). hyperpyr ia s noted. By a l y s i s of s e r i a l H C G a P 1 els, a s i g n i f i c a n t d i f f e r e n c e S ted in t h e r e d u c t i o n of s e r G d u r i n g t h e f i r s t 24 h o u r s a f t e r t h e r a p y (p < 0 . 0 1 ) i n the g r o u p a c h i e v i n g co f e t e a b o r t i o n (Fig. la). e G r e s p o n s e i n the co fete group was significantly different from the r e s p o n s e of the f a i l u r e g r o u p (p < 0.01). How er, t h e r e is a s i g n i f i c a n t r e d u c t i o n in ser HCG levels t h e inc fete-failed g r o u p (p < 0 . O f ) . e f a c t t h a t in ch c a s e o f e failed-lnco fete o r t i o n g r o u p , set HCG s n o t e d to d e c l i n e m signify these pregn c i e s w e r e t o t a l l y or p a r t i a l l y i n t e r r u p t e d b y the 15 ethyl PGF2~ i n j e c t i o n s b u t t h a t co f e t e p l a c e n t a l s e p a r a t i o n or u l s i o n d u e to t r a p p i n g w a s ~ o t p o s s i b l e d u e to a r i g i d c e r v i x . Treatment wl 1 i rla or d e l e t a r i a p r i o r to o n s e t of 15thyl PGF2~ injection probably would shorten the onset injectlo abortion interval, is could result in a higher success rate a possibly all a reduction in the d o s e n e e d e d to p r o d u c e a b o r t i o n . S ce the n P p r o b a b l y a c t s as a u t e r o t r o p i n a n d t a l u t e o l y t i c a g e n t (I0), significant decli in t h e p r o g e s t e r o n e i els w e r e o b s e ed in e i t h e r g r o u p (Figs. 1 a 2). Blood loss all cases s mini This prob ly r e s u l t s f r o ~ t h e t e t a n i c d o s e s of 15 ethyl PGF2~ used
1 (less uterine
t h a n 150 cc, l e II). c o n t r a c t i o n w i t h the
H o p efu I ly, fu r th er s t u d y p r o to c o I s c a n b e u ert a k to i e s tiga t e the a d m i n i s t r a t i o n of I er d o s e s of 1 5 - m e t i P G F 2 ~ a f t e r ce lea/ preco i t i o n i n g of l a m a r i a i n s e r t i o n .... By d e c r e a s i the o n s e t of j ection to o r t i o n time and u a n t e d s i d e e f f e c t s , this uld pe it the e f f i c a c i o u s u s e of an intr uscular prostagia i n as a n a b o r t i f a c i e n t in the f i r s t t r e s t e r of p r e g n a n c y ther y obviat g the n e c e s s i of a D & C in a j o r i t y of the s jeers. ....
326
MARCH
1976
V O L . 13 N O . 3
r~
>
CO
b,,,
E o
I
E
0
4
........ t
Fig. la
2
o,,,,,~ ........... w
Z~O0-
4,o00-
so~oo~
I0
I4
i. . . . . . . . . . l
12 Time (hours)
i............ i...........
B
~
16
'a
IB
I 20
Serum human chorionic gonadotropin (HCG) levels prior to, during, and following treatment with intramuscular 15methyl-PGF2~ in subjects who completely aborted.
6
i ......
I "". . . . . . . I 22 2
Z
0
C~
0
< 0
=
>
O3
2
E
0
ffl
c 0
C
E
2
0
I
4
Fig. ib
I ........ i
I
"I
"]
8 I0
12
14
I ..................I...
"" Time (hours)
I ........ i.....
I .......
16
I
18
I
20
24
i ...... I
22
Serum progesterone levels prior to, during, and after treatment with intramuscular 15-methyl_PGF2 ~ in subjects who completely aborted.
6
...........I.....
O Z
>
0 Z
f'l
i
¢
o~
>
Go
E
O I
|~-'"
J-~--...__ j
Fig. 2a
~m----
'.......... ~ - - " ~ e - - ~
Time
(hours)
I
20
| .......
18
incomplete
i
i................. I............. i . . . . . . . . 1 ............... ~ . . . . . . 8 10 12 14 16
- - ~ - - " -. . . .
"~'---'~'~i
foilure
•
22
1. . . . .
24
I
- I1 -.-.--__... B
Serum human chorionic gonadotropin (HCG) levels prior to, during, and following treatment with intramuscular 15methyl-PGF2~ in subjects who incompletely aborted or who failed to abort.
0 ............. i................ i........ i 0 2 4 6
2,000-
I0,000 m
_!
20,000~ ~-"~+~- ..~_~,+..~
30,o00-
40,000 I = , .
50,0007
0 Z
>
0
Z
<
=
>
n
E
D
70
D = D
C
0
I
16-
E 20-_
m
24-
2
•
~io. 2b 0
4
8
I
I0
Time
!
I2
(hours}
M,
.............~......
16
I'
in~nmn
18
I
I......
20
~erum progesterone !ev ~ p~. . . . ~uring, and following treatment with intramusc ~..,~thyl-PGF: ~ ~- subjects ~ho incompletely aborted or who failed to ~ ,
6
I
I
P failure
24
i..........- 7
22
Z
o
>
z
3
CONTRACEPTION
A CK NOW L ED GM ENT S This i estigation s support r e a u of ~ e d i c e a Surgery, by a gr t f r o m the Up~ n Co a
in part Depart
by
fu s provided by e for CIP 5-48-584 a
e op ions a'~d a s s e r t i o n s c o n t a i n e d h e r e i n a r e t h o s e of t h e a u thors a a r e n o t to b e c o n s tru as o f f i c i a l or as r e f l e c t l n E the vl s of t h e D e p a r t m e n t or t h e n 1 s e r v i c e at large. T h e a u t h o r s w i s h to a c erson, Sa y tse augh, G a p rogestero ass s.
ledge Jane
the t e c h n i c a l a s s l s t a er, a eodore
e of L da k l s for t h e
REFER ENC ES I.
r
gla
,
S.M.M.
in F2a.
a
Filshle,
Lancet
1:
G.M. :
157-159,
Therapeutic 1970.
2.
Sa e i s s o n, B. : Bro o k ~o d ge s Reprod. d. 91 376, 1972.
3.
Lee, P . A . , dgiey, A . R . , Jr., a Jaffe, R.B.: hu n go dotroplns. VIII. Ser cone tratlo ho one d f o l l i c l e st iatlng hor ne in a d u l t exogenous testosterone administration, g. Clin. 35: 6 3 6 - 6 4 1 , !972.
4.
5.
os i
abortion
on pro s tag I
using prosta-
ins
J.
l a t l o n of of l u t e l n l z l n g les f o l l ing doerlnol, t
.
rah , G.E., H o p p e r , K., T u l c h l n s k y , D., S w e r d l o f f , R.S., a Odeli, W.D. : S ultaneous measurement of p l a s m a p r o g e s t e r o n e , i7-hydro p r o g e s t e r o n e a n d e s t r a d l o l 1 7 - ~ by r a d i o ass . A lye. L e t t e r s 4: 3 2 5 - 3 3 5 , 1971. r a h a m , G.E., S ~ e r d l o f f , R., T u l c h l n s k y , dlo a s s a y of p l a s progesterone. t . 32: 6 1 9 - 6 2 4 , 1 9 7 1 ....
D. d Odell, W.D.: J. Clln. E ocrlnol.
6.
rim, S.S., Sivas oo, R., and tn , S.S. ortifacl t a c t i o n of o r a l l y a d m i n i s t e r 16,16-d ethyl prostagla in E 2 and its m e t h y l e s t e r . P r o s t a g l a n d i n s 6.- 3 4 9 - 3 5 4 , 1 9 7 4 ....
7.
B i e n l a r z , J., nter, G., a Sco gna, A. : E f f l c a c y a accepta b i l l t y of 15 ( S ) - i S - m e t h y l - p r o s t a g l a n d i n E 2 - m e = h y l e s t e r f o r m i d t r i m e s t e r p r e g n a n c y t e r m i n a t i o n . ....... J. stet. G y n e c o l . !20: 8 4 0 - 8 4 3 , 1974.
MARCH
1976
V O L . 13 N O . 3
331
CONTRACE
ION
8.
rim, S.M.M., Shar , S.D. and F i l s h i e , G.M. : Te i n a t i o n of pregn cy w i t h 15 m e t h y l a i o g u e s of p r o s t a g l a i E2 a F2~, in S o u t h e r n , E.M. (ed): gZa , Cl Ical A p p l i c a t i o n s in ~ n R roductlon. N York, F u t u r a P u b l i s h i n g Co a , inc., 1972, p p 307--32i.
9.
r , S.M.M. and Shar , S.D. : T h e r a p e u tic ort ion a i n d u e t ion of l a b o u r by the i n t r a v a g l n a l a i n l s t r a t l o n of p r o s t a g l a n d l n s E 2 a F2~. J. s tet. G y n a e e o l . Br. Co o . 781 294-300, 1971.
lO.
332
Tred y, D.R. and M i s c h e l ! , D.R., Jr.: Ther eutic o r t i o n of early hu n g e s t a t i o n w i t h v a g i n a l s u p p o s i t o r i e s of p r o s t a g l a n d (F 2). . J. Obstet. G y n e c o l . 116: 7 9 5 - 7 9 8 , 1973.
MARCH
1976
V O L . 13 N O . 3