CONTRACEPTION
DEVELOPMENT ADMINISTRATION
OF A VAGINAL FOR
SUPPOSITORY
INTERRUPTION
SUITABLE
OF SECOND
FOR
TRIMESTER
SINGLE PREGNANCY
M. Bygdeman, A. Ganguli, K. Kinoshita, V. LundstrGm Department of Obstetrics & Gynecology, Karolinska Hospital & K. Green and S. Bergstriim Department of Chemistry, Karolinska Institutet, Stockholm, Sweden.
ABSTRACT Extra- and intra-amniotic administration of prostaglandins are accepted methods for interruption of second trimester pregnancy. However, an equally effective nonsurgical method would give important advantages especially for large scale programs. Repeated vaginal administration of suppositories containing either 15-methyl PGF methyl ester or 16,16dimethyl PGE2 has been effective in inducing a 2gortion during the first By using different bases for the and second trimesters of pregnancy. suppository and different amounts of 15-methyl PGF methyl ester, a long-acting vaginal suppository has been developed?'Recording of uterine contractility and measurement of plasma concentration showed sufficient release of 15-methyl PGF methyl ester for 12 to 24 hours. One suppository containing 3.0 to 3?? mg 15-methyl PGF methyl ester in 2.2 or 2.5 g of the base Witepsol E-76 was given $" o 25 second trimester patients. Twenty-three patients (92%) aborted within 24 hours following one suppository. The mean induction-abortion interval was 12.4 hours. The abortion process was completed in the remaining two patients by one to three intramuscular injections of 15-methyl PGF20. The incidence of gastrointestinal side effects was low. The mean frequency of vomiting and diarrhea per patient was 1.7 and 0.7, respectively. The results of this single dose vaginal suppository has been encouraging and appears to be an important break-through in the research for an ideal abortifacient.
Accepted
FEBRUARY
for publication
1977 VOL. 15 NO.2
November
23,
1976
129
CONTRACEPTION INTRODUCTION The 15-methyl analogue of PGF2 which is slowly inactivated if administered locally into the uterus (textra-and intra-amniotically) has made possible the development of single injection techniques for the termination of second trimester pregnancies (l,?.). Efforts have then been directed toward development of new methods that are less invasive for midtrimester abortion while maintaining safety with a high success rate and minimum side effects. Therefore, the oral and vaginal routes of administration have been investigated. By the ora route, 16-16-dimethyl PGE2 and its methyl ester have so far not given acceptable clinical results in that the success rate was only 60%. The vaginal administration of 16,16-dimethyl PGE2 or 15-methyl PGF2o methyl ester given every three hours was found to be auseful alternative method for the induction of second trimester abortion (3). Recently, 16,16-dimethyl PGE2 p-benzaldehyde semicarbazone ester given in repeated doses has been reported to be an effective vaginal abortifacient in the second trimester (4). However, the therapy would be further simplified if the necessity of repeated administrations could be reduced by the development of a longer acting vaginal suppository. Repeated administrations of vaginal suppositories containing 1 to 1.5 mg 15-methyl PGF 12tv;;i;; ;z:z; ;noll;laEOf lipid base every three hours up to 24 hours effective method of inducing abortion. Plasma levels of the drug between 500 and 1500 pg/ml are obtained with this therapy (5,6). A suppository that would produce a plasma level of 500 to 1000 pg/ml for 24 hours would be suitable for a single vaginal administration method for termination of pregnancy. The present study describes the development of such a long-acting vagina suppository. Suppositories containing different concentrations of 15methyl PGFza methyl ester in various lipid bases have been prepared and tested by relating the induced uterine activity, success rate and side effects to the plasma level of the drug with the mass spectrometric method. This paper describes part of the work that has led to the development of suppositories that appear suitable for interruption of second trimester pregnancies with a single vaginal administration.
PATIENTS AND METHODS Patients Women admitted to the hospital for therapeutic abortion in the 12th to 20th week of gestation were included in this study. The development of uterine contractility was recorded in five patients by an open-end polyethylene catheter introduced into the amniotic cavity and connected to a Statham transducer and a Grass polygraph. The
130
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CONTRACEPTION
tracings were analyzed with regard to mean uterine activity, intensity and frequency of contractions as well as uterine tonus. The recordings of amniotic pressure were maintained until abortion occurred or rupture of the membranes invalidated accurate recording which in this study was around 12 hours after the start of treatment. The abortion time was defined as the period between insertion of the suppository and expulsion of the fetus or the whole conceptus into the vagina. If the patient had not aborted within 24 hours following the administration, the trial was regarded as a failure. In such cases repeated intramuscular injections of the Tham salt of 15-methyl PGF20 was given (200-300 ug) at two-hour intervals to complete the abortion process. If the placenta was not expelled spontaneously, the trial was regarded as an incomplete abortion. Up to two hours were allowed to pass after expulsion of the fetus before the placenta was removed by surgical evacuation. The clinical course of all patients was observed closely during the treatment by research physicians and nurses. Pelvic examination was refrained from during the induction in order not to interfere with the absorption of the drug. Each patient was treated with suppositories according to the dose schedules given below. Bed rest was required for an hour following the insertion, but thereafter patients who were not undergoing uterine monitoring could ambulate freely. Uterine pain was alleviated by orally administered paracetamol, rectal suppositories of pentazocine, or an intramuscular injection of meperidine hydrochloride. No prophylactic anti-ementic or antidiarrhoeic agents were administered. Preparation of suppositories In this study the results of four different vaginal suppositories will be described (7). The first type contained 2.0 mg of the methyl ester of 15-methyl PGF20 in 2.2 g of a standard Swedish pharmaceutical base ("Adeps Solidus") consisting of mono-, di-and triglycerides of mostly saturated Cl4 and Cl6 straight chain fatty acids. The other types of vaginal suppositories contained 2.5 and 3 mg of the methyl ester of 15-methyl PGF in 2.2 g Witepsol E-76 (Nitro Nobel, Sweden) and 3.5 mg in 2.5 g of i;" rtepsol E-76. This fat melts at about 3'C higher than "Adeps Solidus". Dose schedules Group I. Seven patients received a suppository containing 2 mg 15-methyl PGF2o methyl ester vaginally in 2.2 g "Adeps Solidus". The treatment was repeated every six hours. Group II. Three patients received 2.5 mg 15-methyl PGF20 methyl ester in 2.2 g Witepsol E-76 vaginally every 12 hours. Group III.Twenty-five patients received 3.0 or 3.5 mg 15-methyl PGF20 methyl ester in 2.2 or 2.5 g Witepsol E-76 vaginally as a single administration.
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CONTRACEPTION Determination of plasma levels of the free acid and methyl ester of 15methyl PGF2u Blood samples (15 ml) were collected at regular intervals during the treatment. Since human plasma contains an esterase which hydrolyzes the methyl ester of 15-methyl PGF2u (8), both the ester and free acid forms have to be quantitated in plasma following administration of the ester. The gas chromatographic - mass spectrometric technique used for these quantitations have been described before (9).
RESULTS 2 mg of 15-methyl PGF2o methyl ester in 2.2 g Adeps Solidus The clinical data and results following vaginal admio&ztration of 2 mg 15-methyl PGF methyl ester at six-hour intervals are given in Table I. In six patienZ" s it was necessary to repeat the treatment one to three times. The success rate following administration at six-hour intervals was 86% with a mean induction-abortion interval of 16.3 hours. The concentration of the drug in plasma was 500-700 pg/ml for up to six hours. The plasma levels in three cases receiving a suppository of this type are shown in Fig. 1 (middle panel). 2.5 mg of 15-methyl PGF2a methyl ester in 2.2 g Witepsol E-76 Three patients received these suppositories at twelve-hour intervals. The clinical data are given in Table I and the plasma levels are shown in Fig. 1 (lower panel). Two of the three cases aborted 15 and 18 hours after the initiation of therapy. The resulting plasma levels were about 200-300 pg/ml. However, the use of the higher melting point fat caused a considerable prolongation of the release of drug from the vagina as illustrated by its presence in the blood stream for at least twelve hours (Fig. 1). 3.0 and 3.5 mg of drug in 2.2 and 2.5 g of Witepsol E-76 Twenty-five patients were treated with one vaginal suppository containing 3.0 or 3.5 mg of 15-methyl PGF2a methyl ester in 2.2 or 2.5 g of the base. Twenty-three of the 25 patients (92%) aborted successfully without additional therapy. The cumulative abortion rate is illustrated in Fig.2. It is of interest to note that in all multiparous patients the pregnancy was terminated within 18 hours. Two nulliparous did not abort within 24 hours. Eventually, both of them aborted completely 34 and 36 hours after the start of treatment following intramuscular injections of 15-methyl The mean induction-abortion interval was 13.4 + 4.8 hours in PGF nulZo' iparous and 10.1 + 3.6 hours in multiparous patiezts. The incidence of complete abortion was 60.8%. Not all women had gastrointestinal side effects. Of the 18 nulliparous patients treated, 72.2% had vomiting and 44.4% diarrhea whereas five out of the seven multiparous patients had no side effects.
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The mean frequency of episodes of vomiting and diarrhea per patient was 1.7 and 0.7, respectively (Fig. 3). Uterine pain was usually described as menstrual-like or as moderate in nature and could be controlled with an average of 1.8 intramuscular injections of 75 mg meperidine hydrochloride per patient (Fig. 3). Vital signs of all patients were stable throughout the therapy. None of the patients was noted to experience a temperature elevation or a flush sensation. Two patients had a bleeding of more than 500 ml. This complication took place coincident with a complete abortion for one case and one hour following an incomplete abortion for the other. The hemorrhage was controlled by oxytocics and curettage. There were no instances of cervical laceration or pelvic infection. The development of uterine contractility in five patients following administration of the long-acting vaginal suppositories is illustrated in Figs. 4 and 5. The rise of uterine activity occurred slowly and gradually after a latent period of approximately one hour. Maximum activity was reached after 7 to 8 hours. Subsequently, the level achieved 350-450 Montevideo Units and was sustained throughout the twelve-hour observation period. The fact that most of the recorded patients aborted at this time or shortly thereafter prohibited a longer recording session. The uterine tonus increasedvery gradually for twelve hours. The frequency of uterine contractions reached a maximum approximately three hours after the administration and was maintained at the same level thereafter up to twelve hours, whereas the intensity continued to increase gradually up to nine hours. Plasma levels of the sum of the ester and acid form from two patients receiving 3.5 mg vaginal suppositories are shown in Fig. 6. In these cases, the maximum concentration was 800 to 900 pg/ml. In the case which did not abort until 15.5 hours following the initiation of therapy, the plasma levels were maintained at this level for more than 14 hours (Fig. 6, lower panel).
FEBRUARY 1977 VOL. 15 NO.2
133
Adeps Solidus 2.2 g
2 mg
3.0or 3.5 mg once
Witepsol E-76 2.2 or 2.5 g
2.5 mg Witepsol E-76 every12 hrs 2.2 g
every6 hrs
Type and amount of base
Dose schedule
25
3
7
No. of patients
15.0
14.3
17.8
Mean gestational age (weeks)
3.0 or 3.5
3.7
5.6
Mean total dose (mg)
23
2
6
(92)
(66)
(86)
Success rate No. %
14
1
5
Complete abortion No.
Table I. Clinical outcome of vaginal administration of U-methyl PGF2o methyl ester for induction of second trimester abortion.
9
1
1
Incomplete abortion No.
12.4
16.5
16.3
Mean induction abortion interval (hours)
3
b
CONTRACEPTION
1Omg
I
llgbasr
1000
/
\
/
/
.i.,
_,,
5
2.0 mg/2.2g
base
2.5 rng12.29
h.m
base
10 Hours
Fig. 1. Plasma levels of 15-methyl and methyl ester following vaginal of 15-methyl PGF2o methyl ester. Upper Curve - 1.0 mg of 15-methyl in 1.1 g base (Adeps Solidus) Middle Curve - 2.0 mg of 15-methyl in 2.2 g base (Adeps Solidus) Lower Curve - 2.5 mg of 15-methyl in 2.2 g base with higher melting
FEBRUARY 1977 VOL. 15 NO.2
PGF2cl free acid admrnistration
PGF2o
methyl
PGF2cl methyl
ester
ester
PGF methyl ester '2% (Witep sol E-76). porn
135
Hours
10
Fig. 2. Cumulative abortion rate in relation to -following a single vaginal administration of 3.0 or 3.5 mg 15-methyl PCF2M methyl ester to 25 second trimester patients. l - - -e nulliparas multiparas ._._.-a o-----9 all cases.
5
DIARRHEA
I
r
0.76
ANALGESIC INJECTION
I
11.8
Fig. 3. Mean frequency of gastrointestinal side effects and analgesic injections following vaginal administration of 3.0 or 3.5 mg 15-methyl PGF2a methyl ester to 25 second trimester patients.
VOMITING
-72
CONTRACEPTION
-
Uterine activity
- - -0 Tonus
-Fig. 4. Development of uterine activity and tonus following -1 administration of a single suppository containing 3.5 mg of 15-methyl PGF2cL methyl ester in five second trimester patients.
-Intensity + - -Contractions/lOmin 10
5 5
Hours
10
Fig. 5. Patterns of frequency and intensity of contraction following vaginal administration of a single suppository containing 3.5 mg of 15-methyl PGF methyl ester in five zn second trimester patients.
FEBRUARY 1977 VOL. 15 NO.2
137
CONTRACEPTION
vv
Ab
I
Ab
1
1
2
4
6
8
10
I
12
14
16
Hours Fig. 6. Plasma levels of 15-methyl PGF2cl methyl ester in 2 patients following administration of single vaginal suppository containing . . 3.5 mg of 15-methyl PGFza methyl ester. (V = vomltlng)
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DISCUSSION The primary prostaglandins (PGE2 and PGF ) have been used by the vaginal route to induce second trimester abor2V ion. The treatment is associated with a high frequency of gastrointestinal side effects which in some patients is unacceptable (10). However, the vaginal route offers advantages over the extra- or intra-amniotic route especially with regard More satisfactory results have been to simplicity of administration. obtained with PGE2 if the suppository was inserted in a diaphragm supplemented by infusion of oxytocin (11). Recent results indicate that some of the new prostaglandin analogues, especially 15-methyl PGF 2ct. methyl ester and 16,16-dimethyl PGE2, are more suitable than the primary compounds if efficacy and frequency of side effects are considered. Due to the stability problem with 16,16-dimethyl PGE2, 15-methyl PGF2u methyl ester was preferred in this study. Repeated vaginal administration of 1.0 to 1.5 mg 15-methyl PGFza methyl ester every third hour is an effective and safe method in terminating both first and second trimester pregnancies (12,13). However, a longer acting vaginal suppository would be even more satisfactory. The design of such a suppository was based on the experience collected with the repeated vaginal administration of 15-methyl PGFza methyl ester. The results from these studies indicated that the desired and effective plasma level of 15-methyl PGF free acid and methyl ester is 500 to 1000 pg/ml maintained for up to 22% ours. Even if considerable individual variations are observed, several factors, e.g. the amount of the compound and the base and the physical characteristics of the base, turned out to be of importance for the rate and duration of the absorption of the drug. If the amount of the original base, Adeps Solidus, was increased from 1.1 to 2.2 g, a significant prolongation of the release was achieved (Fig. 1, upper panel). The plasma concentration remained at a high level for up to six hours with the 2.2 g suppository, compared to three to four hours following administration of the 1.1 g suppository. Abortion could also be induced if the treatment was repeated at six-hour intervals. A further prolongation of the release could be achieved by using a similar base, Witepsol E-76, with a slightly higher melting point (36OC compared to 33'C for Adeps Solidus). If the amount of 15-methyl PGFza methyl ester was increased to 3.0 or 3.5 mg, the plasma concentration reached the desired level of 800-900 pg/ml after 4 to 6 hours and remained at this level until the last hours prior to abortion. The decline in plasma concentration observed prior to abortion may be due to a decreased absorption of the compound from the vagina since it coincides with vaginal bleeding and rupture of the membranes. The development of uterine contractility followed similar patterns as that of the plasma levels. Both the intensity and frequency of the contraction as well as uterine tonus increased very gradually, even more slowly than following intra-amniotic administration of 2.5 mg 15-methyl PGF2o. The successful outcome of the therapy indicates that an initial
FEBRUARY 1977 VOL. 15 NO.2
CONTRACEPTION
strong stimulation of uterine contractility is not a necessary prerequisite for the induction of second trimester abortion with prostaglandin. The gradual onset of uterine activity may be of significance in that uterine discomfort and subjective side effects do not develop acutely. Patient discomfort in the present study usually occurred in the hours immediately preceding abortion and could be controlled with analgesic medication. The efficacy and safety of vaginal administration of one long-acting suppository was evaluated in 25 second trimester patients. Twenty-three patients or 92% aborted within 24 hours following the initiation of therapy. In the remaining two patients, the abortion process was completed by one to three intramuscular injections of 15-methyl PGF The success rate is comparable to that following repeated vaginaIcladministration of 15-methyl PGF2a methyl ester (1.5 mg every third hour). The short mean induction-abortion interval of 12.4 +4.7 hours is a notable feature especially since the initial absorption of the compound from the vagina is slow. The interpretation of this observation is unclear. It might indicate that the suppository also has a local effect. The frequency of complete abortion is not only/dependent on the abortion method used but also on the stage of gestation and on the management of the third stage. If the placenta was not expelled spontaneously during the first two hours following the abortion, surgical evacuation was performed. In this study 60.8% of the patients aborted completely. This is comparable to the rate obtained at our department with other abortion methods in the midtrimester when the third stage was managed in the same way. The frequency of gastrointestinal side effects (mean no. of episodes of vomiting 1.7 and diarrhea 0.7) was acceptable and comparable to that found following repeated vaginal administration of 15-methyl PGF methyl ester or following intra-amniotic injections of 2.5 mg 15-methy12pGF2a. No serious complications were encountered. The results of the present investigation which showed a high success rate and an acceptable frequency of minor side effects suggest that the administration of one vaginal suppository containing 3.0 to 3.5 mg 15methyl PGF20 methyl ester offers a primary therapeutic alternative in patients in the second trimester where a technically simple method is desired and necessary for the treatment of a large number of patients.
ACKNOWLEDGEMENT This work has been supported by the Expanded Progranunefor Research and Training in Human Reproduction of the World Health Organization. The prostaglandin used was generously supplied by The Upjohn Co., Canada.
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CONTRACEPTION REFERENCES 1.
Wiqvist, N., Bygdeman, M., Papageorgiou, C. and Toppozada, M. Intra-uterine administration of prostaglandin by the extra-amniotic route. Prostaglandins 6:193-205 (1974).
2. Wiqvist, N., Bygdeman, M. and Toppozada, M. Intra-amniotic prostaglandin administration - a challenge to the currently used methods for induction of midtrimester abortion. Contraception 8:113-131 (1973). 3. Bygdeman, M. and Bergstriim,S., in Obstetric and Gynecological Uses of Prostaglandins (Sultan M.M. Karim, Editor) Eurasia Press, Singapore,1976, p.67-81. 4. Karim, S.M.M., in Obstetric and Gynecological Uses of Prostaglandins. (Sultan M.M. Karim, Editor) Eurasia Press, Singapore,l976, p. 127154. 5. Green, K., Bygdeman, M., Leader, A. and Martin, J.N., in Advances in Prostaglandin and Thromboxane Research (B. Samuelsson and R. Paoletti, Editors) Raven Press, N.Y.,1976, Vol. 2, p. 719-725. 6. Grzen, K. and Bygdeman, M. Plasma levels of the methyl ester of 15methyl PGF in connection with intravenous and vaginal administration. Prostaglan$?ns 11:879-892 (1976). 7. Bygdeman, M., Martin, J.N., Wiqvist, N. Gre'en,K. and Bergstrom, S. Reassessment of systemic administration of prostaglandins for induction of midtrimester abortion.Prostaglandins 8:157-169 (1974). 8. Miller, O.V. and Magee, W.E. In vitro hydrolysis of prostaglandin F2o esters by serum or plasma of different animal species. Prostaglandins 7:29-38 (1974). 9. Lincoln, F.J., Ax&, U., GrBen, K., Ohlsson, H. and Samuelsson, B. Gas liquid chromatographic - mass spectrometric methods for quantitation of prostaglandin analogues. Analytical Letters 9:187- 201, (1976). 10. Beguin, F., Bygdeman, M., Toppozada, M. and Wiqvist, N. The response of the midpregnant human uterus to vaginal administration of prostaglandin suppositories. Prostaglandins 1:397-405 (1972). 11. Schulman, J., Saklana, L., Tsai, T., Leibman, T., Cunningham, M. and Randolph, S. Prostaglandin E2 induced abortion with vaginal suppositories in a contraceptive diaphragm. Prostaglandins 7:195205 (1974). 12. Martin, J.N., Jr., Bygdeman, M., Ramadan, M., Green, K., Leader, A., Lundstrom, V. and Wiqvist, N. Vaginally administered 16,16-dimethyl PGE2 for the induction of midtrimester abortion. Prostaglandins 11: 123-132 (1976). 13. Bygdeman, M., Borell, U., Leader, A., Lundstram, V., Martin, J.N.,Jr., Eneroth, P. and G&en, K. in Advances in Prostaglandin and Thromboxane Research (B. Samuelsson and R. Paoletti, Editors) Raven Press, N.Y., 1976, Vol. 2, p. 693-704. FEBRUARY
1977
VOL. 15 NO.2
141
DEVELOPMENT ADMINISTRATION
OF A VAGINAL FOR
SUPPOSITORY
INTERRUPTION
SUITABLE
OF SECOND
FOR
TRIMESTER
SINGLE PREGNANCY
M. Bygdeman, A. Ganguli, K. Kinoshita, V. LundstrGm Department of Obstetrics & Gynecology, Karolinska Hospital & K. Green and S. Bergstriim Department of Chemistry, Karolinska Institutet, Stockholm, Sweden.
ABSTRACT Extra- and intra-amniotic administration of prostaglandins are accepted methods for interruption of second trimester pregnancy. However, an equally effective nonsurgical method would give important advantages especially for large scale programs. Repeated vaginal administration of suppositories containing either 15-methyl PGF methyl ester or 16,16dimethyl PGE2 has been effective in inducing a 2gortion during the first By using different bases for the and second trimesters of pregnancy. suppository and different amounts of 15-methyl PGF methyl ester, a long-acting vaginal suppository has been developed?'Recording of uterine contractility and measurement of plasma concentration showed sufficient release of 15-methyl PGF methyl ester for 12 to 24 hours. One suppository containing 3.0 to 3?? mg 15-methyl PGF methyl ester in 2.2 or 2.5 g of the base Witepsol E-76 was given $" o 25 second trimester patients. Twenty-three patients (92%) aborted within 24 hours following one suppository. The mean induction-abortion interval was 12.4 hours. The abortion process was completed in the remaining two patients by one to three intramuscular injections of 15-methyl PGF20. The incidence of gastrointestinal side effects was low. The mean frequency of vomiting and diarrhea per patient was 1.7 and 0.7, respectively. The results of this single dose vaginal suppository has been encouraging and appears to be an important break-through in the research for an ideal abortifacient.
Accepted
FEBRUARY
for publication
1977 VOL. 15 NO.2
November
23,
1976
129
CONTRACEPTION INTRODUCTION The 15-methyl analogue of PGF2 which is slowly inactivated if administered locally into the uterus (textra-and intra-amniotically) has made possible the development of single injection techniques for the termination of second trimester pregnancies (l,?.). Efforts have then been directed toward development of new methods that are less invasive for midtrimester abortion while maintaining safety with a high success rate and minimum side effects. Therefore, the oral and vaginal routes of administration have been investigated. By the ora route, 16-16-dimethyl PGE2 and its methyl ester have so far not given acceptable clinical results in that the success rate was only 60%. The vaginal administration of 16,16-dimethyl PGE2 or 15-methyl PGF2o methyl ester given every three hours was found to be auseful alternative method for the induction of second trimester abortion (3). Recently, 16,16-dimethyl PGE2 p-benzaldehyde semicarbazone ester given in repeated doses has been reported to be an effective vaginal abortifacient in the second trimester (4). However, the therapy would be further simplified if the necessity of repeated administrations could be reduced by the development of a longer acting vaginal suppository. Repeated administrations of vaginal suppositories containing 1 to 1.5 mg 15-methyl PGF 12tv;;i;; ;z:z; ;noll;laEOf lipid base every three hours up to 24 hours effective method of inducing abortion. Plasma levels of the drug between 500 and 1500 pg/ml are obtained with this therapy (5,6). A suppository that would produce a plasma level of 500 to 1000 pg/ml for 24 hours would be suitable for a single vaginal administration method for termination of pregnancy. The present study describes the development of such a long-acting vagina suppository. Suppositories containing different concentrations of 15methyl PGFza methyl ester in various lipid bases have been prepared and tested by relating the induced uterine activity, success rate and side effects to the plasma level of the drug with the mass spectrometric method. This paper describes part of the work that has led to the development of suppositories that appear suitable for interruption of second trimester pregnancies with a single vaginal administration.
PATIENTS AND METHODS Patients Women admitted to the hospital for therapeutic abortion in the 12th to 20th week of gestation were included in this study. The development of uterine contractility was recorded in five patients by an open-end polyethylene catheter introduced into the amniotic cavity and connected to a Statham transducer and a Grass polygraph. The
130
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CONTRACEPTION
tracings were analyzed with regard to mean uterine activity, intensity and frequency of contractions as well as uterine tonus. The recordings of amniotic pressure were maintained until abortion occurred or rupture of the membranes invalidated accurate recording which in this study was around 12 hours after the start of treatment. The abortion time was defined as the period between insertion of the suppository and expulsion of the fetus or the whole conceptus into the vagina. If the patient had not aborted within 24 hours following the administration, the trial was regarded as a failure. In such cases repeated intramuscular injections of the Tham salt of 15-methyl PGF20 was given (200-300 ug) at two-hour intervals to complete the abortion process. If the placenta was not expelled spontaneously, the trial was regarded as an incomplete abortion. Up to two hours were allowed to pass after expulsion of the fetus before the placenta was removed by surgical evacuation. The clinical course of all patients was observed closely during the treatment by research physicians and nurses. Pelvic examination was refrained from during the induction in order not to interfere with the absorption of the drug. Each patient was treated with suppositories according to the dose schedules given below. Bed rest was required for an hour following the insertion, but thereafter patients who were not undergoing uterine monitoring could ambulate freely. Uterine pain was alleviated by orally administered paracetamol, rectal suppositories of pentazocine, or an intramuscular injection of meperidine hydrochloride. No prophylactic anti-ementic or antidiarrhoeic agents were administered. Preparation of suppositories In this study the results of four different vaginal suppositories will be described (7). The first type contained 2.0 mg of the methyl ester of 15-methyl PGF20 in 2.2 g of a standard Swedish pharmaceutical base ("Adeps Solidus") consisting of mono-, di-and triglycerides of mostly saturated Cl4 and Cl6 straight chain fatty acids. The other types of vaginal suppositories contained 2.5 and 3 mg of the methyl ester of 15-methyl PGF in 2.2 g Witepsol E-76 (Nitro Nobel, Sweden) and 3.5 mg in 2.5 g of i;" rtepsol E-76. This fat melts at about 3'C higher than "Adeps Solidus". Dose schedules Group I. Seven patients received a suppository containing 2 mg 15-methyl PGF2o methyl ester vaginally in 2.2 g "Adeps Solidus". The treatment was repeated every six hours. Group II. Three patients received 2.5 mg 15-methyl PGF20 methyl ester in 2.2 g Witepsol E-76 vaginally every 12 hours. Group III.Twenty-five patients received 3.0 or 3.5 mg 15-methyl PGF20 methyl ester in 2.2 or 2.5 g Witepsol E-76 vaginally as a single administration.
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131
CONTRACEPTION Determination of plasma levels of the free acid and methyl ester of 15methyl PGF2u Blood samples (15 ml) were collected at regular intervals during the treatment. Since human plasma contains an esterase which hydrolyzes the methyl ester of 15-methyl PGF2u (8), both the ester and free acid forms have to be quantitated in plasma following administration of the ester. The gas chromatographic - mass spectrometric technique used for these quantitations have been described before (9).
RESULTS 2 mg of 15-methyl PGF2o methyl ester in 2.2 g Adeps Solidus The clinical data and results following vaginal admio&ztration of 2 mg 15-methyl PGF methyl ester at six-hour intervals are given in Table I. In six patienZ" s it was necessary to repeat the treatment one to three times. The success rate following administration at six-hour intervals was 86% with a mean induction-abortion interval of 16.3 hours. The concentration of the drug in plasma was 500-700 pg/ml for up to six hours. The plasma levels in three cases receiving a suppository of this type are shown in Fig. 1 (middle panel). 2.5 mg of 15-methyl PGF2a methyl ester in 2.2 g Witepsol E-76 Three patients received these suppositories at twelve-hour intervals. The clinical data are given in Table I and the plasma levels are shown in Fig. 1 (lower panel). Two of the three cases aborted 15 and 18 hours after the initiation of therapy. The resulting plasma levels were about 200-300 pg/ml. However, the use of the higher melting point fat caused a considerable prolongation of the release of drug from the vagina as illustrated by its presence in the blood stream for at least twelve hours (Fig. 1). 3.0 and 3.5 mg of drug in 2.2 and 2.5 g of Witepsol E-76 Twenty-five patients were treated with one vaginal suppository containing 3.0 or 3.5 mg of 15-methyl PGF2a methyl ester in 2.2 or 2.5 g of the base. Twenty-three of the 25 patients (92%) aborted successfully without additional therapy. The cumulative abortion rate is illustrated in Fig.2. It is of interest to note that in all multiparous patients the pregnancy was terminated within 18 hours. Two nulliparous did not abort within 24 hours. Eventually, both of them aborted completely 34 and 36 hours after the start of treatment following intramuscular injections of 15-methyl The mean induction-abortion interval was 13.4 + 4.8 hours in PGF nulZo' iparous and 10.1 + 3.6 hours in multiparous patiezts. The incidence of complete abortion was 60.8%. Not all women had gastrointestinal side effects. Of the 18 nulliparous patients treated, 72.2% had vomiting and 44.4% diarrhea whereas five out of the seven multiparous patients had no side effects.
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CONTRACEPTION
The mean frequency of episodes of vomiting and diarrhea per patient was 1.7 and 0.7, respectively (Fig. 3). Uterine pain was usually described as menstrual-like or as moderate in nature and could be controlled with an average of 1.8 intramuscular injections of 75 mg meperidine hydrochloride per patient (Fig. 3). Vital signs of all patients were stable throughout the therapy. None of the patients was noted to experience a temperature elevation or a flush sensation. Two patients had a bleeding of more than 500 ml. This complication took place coincident with a complete abortion for one case and one hour following an incomplete abortion for the other. The hemorrhage was controlled by oxytocics and curettage. There were no instances of cervical laceration or pelvic infection. The development of uterine contractility in five patients following administration of the long-acting vaginal suppositories is illustrated in Figs. 4 and 5. The rise of uterine activity occurred slowly and gradually after a latent period of approximately one hour. Maximum activity was reached after 7 to 8 hours. Subsequently, the level achieved 350-450 Montevideo Units and was sustained throughout the twelve-hour observation period. The fact that most of the recorded patients aborted at this time or shortly thereafter prohibited a longer recording session. The uterine tonus increasedvery gradually for twelve hours. The frequency of uterine contractions reached a maximum approximately three hours after the administration and was maintained at the same level thereafter up to twelve hours, whereas the intensity continued to increase gradually up to nine hours. Plasma levels of the sum of the ester and acid form from two patients receiving 3.5 mg vaginal suppositories are shown in Fig. 6. In these cases, the maximum concentration was 800 to 900 pg/ml. In the case which did not abort until 15.5 hours following the initiation of therapy, the plasma levels were maintained at this level for more than 14 hours (Fig. 6, lower panel).
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Adeps Solidus 2.2 g
2 mg
3.0or 3.5 mg once
Witepsol E-76 2.2 or 2.5 g
2.5 mg Witepsol E-76 every12 hrs 2.2 g
every6 hrs
Type and amount of base
Dose schedule
25
3
7
No. of patients
15.0
14.3
17.8
Mean gestational age (weeks)
3.0 or 3.5
3.7
5.6
Mean total dose (mg)
23
2
6
(92)
(66)
(86)
Success rate No. %
14
1
5
Complete abortion No.
Table I. Clinical outcome of vaginal administration of U-methyl PGF2o methyl ester for induction of second trimester abortion.
9
1
1
Incomplete abortion No.
12.4
16.5
16.3
Mean induction abortion interval (hours)
3
b
CONTRACEPTION
1Omg
I
llgbasr
1000
/
\
/
/
.i.,
_,,
5
2.0 mg/2.2g
base
2.5 rng12.29
h.m
base
10 Hours
Fig. 1. Plasma levels of 15-methyl and methyl ester following vaginal of 15-methyl PGF2o methyl ester. Upper Curve - 1.0 mg of 15-methyl in 1.1 g base (Adeps Solidus) Middle Curve - 2.0 mg of 15-methyl in 2.2 g base (Adeps Solidus) Lower Curve - 2.5 mg of 15-methyl in 2.2 g base with higher melting
FEBRUARY 1977 VOL. 15 NO.2
PGF2cl free acid admrnistration
PGF2o
methyl
PGF2cl methyl
ester
ester
PGF methyl ester '2% (Witep sol E-76). porn
135
Hours
10
Fig. 2. Cumulative abortion rate in relation to -following a single vaginal administration of 3.0 or 3.5 mg 15-methyl PCF2M methyl ester to 25 second trimester patients. l - - -e nulliparas multiparas ._._.-a o-----9 all cases.
5
DIARRHEA
I
r
0.76
ANALGESIC INJECTION
I
11.8
Fig. 3. Mean frequency of gastrointestinal side effects and analgesic injections following vaginal administration of 3.0 or 3.5 mg 15-methyl PGF2a methyl ester to 25 second trimester patients.
VOMITING
-72
CONTRACEPTION
-
Uterine activity
- - -0 Tonus
-Fig. 4. Development of uterine activity and tonus following -1 administration of a single suppository containing 3.5 mg of 15-methyl PGF2cL methyl ester in five second trimester patients.
-Intensity + - -Contractions/lOmin 10
5 5
Hours
10
Fig. 5. Patterns of frequency and intensity of contraction following vaginal administration of a single suppository containing 3.5 mg of 15-methyl PGF methyl ester in five zn second trimester patients.
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CONTRACEPTION
vv
Ab
I
Ab
1
1
2
4
6
8
10
I
12
14
16
Hours Fig. 6. Plasma levels of 15-methyl PGF2cl methyl ester in 2 patients following administration of single vaginal suppository containing . . 3.5 mg of 15-methyl PGFza methyl ester. (V = vomltlng)
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DISCUSSION The primary prostaglandins (PGE2 and PGF ) have been used by the vaginal route to induce second trimester abor2V ion. The treatment is associated with a high frequency of gastrointestinal side effects which in some patients is unacceptable (10). However, the vaginal route offers advantages over the extra- or intra-amniotic route especially with regard More satisfactory results have been to simplicity of administration. obtained with PGE2 if the suppository was inserted in a diaphragm supplemented by infusion of oxytocin (11). Recent results indicate that some of the new prostaglandin analogues, especially 15-methyl PGF 2ct. methyl ester and 16,16-dimethyl PGE2, are more suitable than the primary compounds if efficacy and frequency of side effects are considered. Due to the stability problem with 16,16-dimethyl PGE2, 15-methyl PGF2u methyl ester was preferred in this study. Repeated vaginal administration of 1.0 to 1.5 mg 15-methyl PGFza methyl ester every third hour is an effective and safe method in terminating both first and second trimester pregnancies (12,13). However, a longer acting vaginal suppository would be even more satisfactory. The design of such a suppository was based on the experience collected with the repeated vaginal administration of 15-methyl PGFza methyl ester. The results from these studies indicated that the desired and effective plasma level of 15-methyl PGF free acid and methyl ester is 500 to 1000 pg/ml maintained for up to 22% ours. Even if considerable individual variations are observed, several factors, e.g. the amount of the compound and the base and the physical characteristics of the base, turned out to be of importance for the rate and duration of the absorption of the drug. If the amount of the original base, Adeps Solidus, was increased from 1.1 to 2.2 g, a significant prolongation of the release was achieved (Fig. 1, upper panel). The plasma concentration remained at a high level for up to six hours with the 2.2 g suppository, compared to three to four hours following administration of the 1.1 g suppository. Abortion could also be induced if the treatment was repeated at six-hour intervals. A further prolongation of the release could be achieved by using a similar base, Witepsol E-76, with a slightly higher melting point (36OC compared to 33'C for Adeps Solidus). If the amount of 15-methyl PGFza methyl ester was increased to 3.0 or 3.5 mg, the plasma concentration reached the desired level of 800-900 pg/ml after 4 to 6 hours and remained at this level until the last hours prior to abortion. The decline in plasma concentration observed prior to abortion may be due to a decreased absorption of the compound from the vagina since it coincides with vaginal bleeding and rupture of the membranes. The development of uterine contractility followed similar patterns as that of the plasma levels. Both the intensity and frequency of the contraction as well as uterine tonus increased very gradually, even more slowly than following intra-amniotic administration of 2.5 mg 15-methyl PGF2o. The successful outcome of the therapy indicates that an initial
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CONTRACEPTION
strong stimulation of uterine contractility is not a necessary prerequisite for the induction of second trimester abortion with prostaglandin. The gradual onset of uterine activity may be of significance in that uterine discomfort and subjective side effects do not develop acutely. Patient discomfort in the present study usually occurred in the hours immediately preceding abortion and could be controlled with analgesic medication. The efficacy and safety of vaginal administration of one long-acting suppository was evaluated in 25 second trimester patients. Twenty-three patients or 92% aborted within 24 hours following the initiation of therapy. In the remaining two patients, the abortion process was completed by one to three intramuscular injections of 15-methyl PGF The success rate is comparable to that following repeated vaginaIcladministration of 15-methyl PGF2a methyl ester (1.5 mg every third hour). The short mean induction-abortion interval of 12.4 +4.7 hours is a notable feature especially since the initial absorption of the compound from the vagina is slow. The interpretation of this observation is unclear. It might indicate that the suppository also has a local effect. The frequency of complete abortion is not only/dependent on the abortion method used but also on the stage of gestation and on the management of the third stage. If the placenta was not expelled spontaneously during the first two hours following the abortion, surgical evacuation was performed. In this study 60.8% of the patients aborted completely. This is comparable to the rate obtained at our department with other abortion methods in the midtrimester when the third stage was managed in the same way. The frequency of gastrointestinal side effects (mean no. of episodes of vomiting 1.7 and diarrhea 0.7) was acceptable and comparable to that found following repeated vaginal administration of 15-methyl PGF methyl ester or following intra-amniotic injections of 2.5 mg 15-methy12pGF2a. No serious complications were encountered. The results of the present investigation which showed a high success rate and an acceptable frequency of minor side effects suggest that the administration of one vaginal suppository containing 3.0 to 3.5 mg 15methyl PGF20 methyl ester offers a primary therapeutic alternative in patients in the second trimester where a technically simple method is desired and necessary for the treatment of a large number of patients.
ACKNOWLEDGEMENT This work has been supported by the Expanded Progranunefor Research and Training in Human Reproduction of the World Health Organization. The prostaglandin used was generously supplied by The Upjohn Co., Canada.
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1977 VOL. 15 NO. 2
CONTRACEPTION REFERENCES 1.
Wiqvist, N., Bygdeman, M., Papageorgiou, C. and Toppozada, M. Intra-uterine administration of prostaglandin by the extra-amniotic route. Prostaglandins 6:193-205 (1974).
2. Wiqvist, N., Bygdeman, M. and Toppozada, M. Intra-amniotic prostaglandin administration - a challenge to the currently used methods for induction of midtrimester abortion. Contraception 8:113-131 (1973). 3. Bygdeman, M. and Bergstriim,S., in Obstetric and Gynecological Uses of Prostaglandins (Sultan M.M. Karim, Editor) Eurasia Press, Singapore,1976, p.67-81. 4. Karim, S.M.M., in Obstetric and Gynecological Uses of Prostaglandins. (Sultan M.M. Karim, Editor) Eurasia Press, Singapore,l976, p. 127154. 5. Green, K., Bygdeman, M., Leader, A. and Martin, J.N., in Advances in Prostaglandin and Thromboxane Research (B. Samuelsson and R. Paoletti, Editors) Raven Press, N.Y.,1976, Vol. 2, p. 719-725. 6. Grzen, K. and Bygdeman, M. Plasma levels of the methyl ester of 15methyl PGF in connection with intravenous and vaginal administration. Prostaglan$?ns 11:879-892 (1976). 7. Bygdeman, M., Martin, J.N., Wiqvist, N. Gre'en,K. and Bergstrom, S. Reassessment of systemic administration of prostaglandins for induction of midtrimester abortion.Prostaglandins 8:157-169 (1974). 8. Miller, O.V. and Magee, W.E. In vitro hydrolysis of prostaglandin F2o esters by serum or plasma of different animal species. Prostaglandins 7:29-38 (1974). 9. Lincoln, F.J., Ax&, U., GrBen, K., Ohlsson, H. and Samuelsson, B. Gas liquid chromatographic - mass spectrometric methods for quantitation of prostaglandin analogues. Analytical Letters 9:187- 201, (1976). 10. Beguin, F., Bygdeman, M., Toppozada, M. and Wiqvist, N. The response of the midpregnant human uterus to vaginal administration of prostaglandin suppositories. Prostaglandins 1:397-405 (1972). 11. Schulman, J., Saklana, L., Tsai, T., Leibman, T., Cunningham, M. and Randolph, S. Prostaglandin E2 induced abortion with vaginal suppositories in a contraceptive diaphragm. Prostaglandins 7:195205 (1974). 12. Martin, J.N., Jr., Bygdeman, M., Ramadan, M., Green, K., Leader, A., Lundstrom, V. and Wiqvist, N. Vaginally administered 16,16-dimethyl PGE2 for the induction of midtrimester abortion. Prostaglandins 11: 123-132 (1976). 13. Bygdeman, M., Borell, U., Leader, A., Lundstram, V., Martin, J.N.,Jr., Eneroth, P. and G&en, K. in Advances in Prostaglandin and Thromboxane Research (B. Samuelsson and R. Paoletti, Editors) Raven Press, N.Y., 1976, Vol. 2, p. 693-704. FEBRUARY
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