Pharmacokinetics and ex vivo anti-inflammatory effects of oral misoprostol in horses.

BACKGROUND: Misoprostol is an E prostanoid (EP) 2, 3 and 4 receptor agonist that is anecdotally used to treat and prevent NSAID-induced GI injury in horses. Misoprostol elicits anti-inflammatory effects in vivo in men and rodents, and inhibits TNFα production in equine leucocytes in vitro. OBJECTIVE: Define the pharmacokinetic parameters of oral misoprostol in horses, and determine the inhibitory effect of oral misoprostol administration on equine leucocyte TNFα production in an ex vivo inflammation model. STUDY DESIGN: Pharmacokinetic study, ex vivo experimental study. METHODS: Six healthy adult horses of mixed breeds were used. In phase one, horses were given 5 µg/kg misoprostol orally, and blood was collected at predetermined times for determination of misoprostol free acid (MFA) by UHPLC-MS/MS. Pharmacokinetic parameters were calculated. In phase two, horses were dosed as in phase one, and blood was collected at T0, 0.5, 1 and 4 h following misoprostol administration for leucocyte isolation. Leucocytes were stimulated with 100 ng/mL LPS, and TNFα mRNA concentrations were determined via quantitative real-time PCR. RESULTS: About 5 µg/kg oral misoprostol produced a rapid time to maximum concentration (Tmax ) of 23.4 ± 2.4 min, with a maximum concentration (Cmax ) of 0.29 ± 0.07 ng/mL and area under the curve (AUC0-∞ ) of 0.4 ± 0.12 h ng/mL. LPS stimulation of equine leucocytes ex vivo significantly increased TNFα mRNA concentrations, and there was no significant effect of misoprostol even at the Tmax . MAIN LIMITATIONS: Only a single dose was used, and sample size was small. CONCLUSIONS: Misoprostol is rapidly absorbed following oral administration in horses, and a single 5 µg/kg dose had no significant inhibitory effect on ex vivo LPS-stimulated TNFα mRNA production in leucocytes. Further studies analysing different dosing strategies, including repeat administration or combination with other anti-inflammatory drugs, are warranted.

A crossover pharmacokinetic study of misoprostol by the oral, sublingual and buccal routes.

OBJECTIVES: The aim of the study was to compare the pharmacokinetic parameters of 800 µg oral, sublingual and buccal misoprostol in healthy non-pregnant women. METHODS: This was an open-label, randomised study with a three-way crossover design. Eighteen participants were randomly assigned to treatment sequences of 800 µg oral, sublingual and buccal misoprostol administered under fasting conditions, with a 7-day washout period. Ten participants completed all routes. The primary pharmacokinetic parameters measured were the area under the plasma misoprostol acid concentration-time curve (AUC) from dosing to last quantifiable concentration (AUC0-t), the AUC from 0 to infinity (AUC0-∞) and the maximum plasma concentration (Cmax). Secondary parameters included the plasma elimination rate constant (ke), the half-life and the mean residence time (MRT). RESULTS: There were statistically significant differences in AUC0-∞, AUC0-t and Cmax at the p < 0.05 level for the three routes of administration. The sublingual route achieved the highest bioavailability, and the buccal route achieved the lowest peak concentration. The oral and buccal routes had a similar AUC0-∞ and the buccal route had the highest MRT and ke. There were no differences in half-lives, and no serious adverse events were reported. CONCLUSIONS: This study shows variability in Cmax and AUC by three by-mouth routes of misoprostol administration. The dose in this study was 800 µg, which is among the highest doses seen in current guidelines. These data contribute to the understanding of efficacy and safety of different routes and could provide a basis for deciding whether certain routes are preferable for particular indications.

Effect of bacterial vaginosis on the pharmacokinetics of misoprostol in early pregnancy.

BACKGROUND: Misoprostol has been shown to be an effective agent for cervical ripening and termination of early pregnancy especially when administered vaginally. Our objective was to evaluate whether bacterial vaginosis (BV) affected the pharmacokinetics of vaginally administered misoprostol during early pregnancy. METHODS: Ten women with BV and 10 healthy women requesting medical abortion up to 9 weeks of pregnancy were administered 200 mg mifepristone followed 24-48 h later by a single dose of 800 µg misoprostol vaginally. Blood samples were taken before (0 h) and 0.5, 1, 2, 3 and 4 h after misoprostol administration. Misoprostol acid was determined in serum samples using liquid chromatography/tandem mass spectrometry. RESULTS: All women with BV had a vaginal pH > 4.7. The mean bioavailability measured as the area under the curve (AUC) and maximum concentration (C(max)) appeared higher in the control than in the BV group (1458.7 versus 878.1 pg h/ml) and (630.7 versus 342.5 pg/ml), respectively, but did not achieve statistical significance and there was no other significant difference in the pharmacokinetics between the two groups. However, if two women with vaginal pH > 4.7 were excluded from the control group the difference in AUC240 (1359 versus 878.1 pgh/ml) reached statistical significance (P = 0.048). CONCLUSIONS: BV had an effect on pharmacokinetics of vaginally administered misoprostol in early pregnancy. However, the results should be interpreted with caution due to the small sample size and marked individual variations.

[Developmental toxicity of misoprostol: an update]. / Toxicidad del misoprostol sobre la gestación: Revisión de la literatura.

Misoprostol, a synthetic analog of prostaglandin E1, is currently used in Chile and other countries as an antiulcer medication, mainly for the prevention of non-steroidal anti-inflammatory-induced gastric ulcers. Due to its uterotonic properties, it is also indicated in obstetrics for induction of labor and termination of pregnancy. In this last case, misoprostol is either used alone or in combination with other oxytocic drugs such as methotrexate or mifepristone. The use of misoprostol as an abortifacient agent is considered to be safe since it rarely causes serious side effects. However up to 15 % of misoprostol-induced-abortions may not be successful, even under medical supervision, leading to in utero exposure to the drug and to the induction of a series of birth defects including limb and joints defects and Moebius syndrome. Reports from the nineties failed to show a strong epidemiological association between in utero drug exposure and induction of defects, a situation that has changed now that the number of cases reported has increased. Since the practice of abortion is illegal in Chile, many women turn to off-medical procedures to interrupt their pregnancy and use misoprostol as an easy and cheap alternative, readily available in the INTERNET. The lack of medical supervision in these cases may lead to situations that favor the induction of congenital defects. Here, we present an updated review of scientific data, to evaluate the risk of birth defects in babies exposed to the drug during pregnancy termination failed attempts.

A randomized comparison of pharmacokinetics of a single vaginal dose of dry misoprostol or misoprostol moistened with normal saline or with acetic acid.

BACKGROUND: The pharmacokinetics of vaginal misoprostol as a dry tablet or as a tablet moistened with normal saline or with acetic acid were studied. METHODS: For this study, 42 women requesting termination of pregnancy at gestational age of <12 weeks were recruited and received 400 µg vaginal misoprostol tablets. They were randomized into three groups: (i) dry tablets, (ii) tablets moistened with 3 ml of normal saline and (iii) tablets moistened with 3 ml of 5% acetic acid. Venous blood samples were taken at 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330 and 360 min after misoprostol administration. Misoprostol acid (MPA) was determined in serum samples using gas chromatography/tandem mass spectrometry. RESULTS: The serum peak MPA concentration (C(max)) was significantly higher and the time-to-peak concentration (T(max)) was significantly shorter in the normal saline and acetic acid groups, when compared with the dry tablet group. Both areas under the curve at 240 and 360 min (AUC(240) and AUC(360)) of the normal saline and acetic acid groups were also significantly greater than that of the dry tablet group. The coefficients of variation in C(max) and T(max) were highest in the normal saline group, while that of AUC(240) and AUC(360) were highest in the dry tablet group. The C(max) was significantly higher in subjects in the dry tablet group with vaginal pH < 5 than in those with pH 5. There were no significant differences in other pharmacokinetic parameters between subjects with vaginal pH < 5 and those with vaginal pH 5 in all three groups. CONCLUSIONS: Vaginal misoprostol tablets moistened with normal saline or 5% acetic acid achieved better absorption than the dry tablet. The use of vaginal misoprostol tablets moistened with normal saline or 5% acetic acid would potentially improve the clinical efficacy of misoprostol. HKClinicalTrials.com registration: HKCTR-821.

Toxicidad del misoprostol sobre la gestación: Revisión de la literatura / Developmental toxicity of misoprostol: An update

Misoprostol, a synthetic analog of prostaglandin E1, is currently used in Chile and other countries as an antiulcer medication, mainly for the prevention of non-steroidal anti-infammatory-induced gastric ulcers. Due to its uterotonic properties, it is also indicated in obstetrics for induction of labor and termination of pregnancy. In this last case, misoprostol is either used alone or in combination with other oxytocic drugs such as methotrexate or mifepristone. The use of misoprostol as an abortifacient agent is considered to be safe since it rarely causes serious side effects. However up to 15 percent of misoprostol-induced-abortions may not be successful, even under medical supervision, leading to in utero exposure to the drug and to the induction of a series of birth defects including limb and joints defects and Moebius syndrome. Reports from the nineties failed to show a strong epidemiological association between in utero drug exposure and induction of defects, a situation that has changed now that the number of cases reported has increased. Since the practice of abortion is illegal in Chile, many women turn to off-medical procedures to interrupt their pregnancy and use misoprostol as an easy and cheap alternative, readily available in the INTERNET. The lack of medical supervision in these cases may lead to situations that favor the induction of congenital defects. Here, we present an updated review of scientifc data, to evaluate the risk of birth defects in babies exposed to the drug during pregnancy termination failed attempts.

Pharmacokinetics of repeated doses of misoprostol.

BACKGROUND: Misoprostol is widely used in obstetrics and gynaecology for medical abortion, cervical priming and induction of labour. To aid the design of effective and safe regimens, we have investigated the pharmacokinetic parameters after the vaginal or sublingual administration of repeated doses of 400 microg of misoprostol. METHODS: Women undergoing termination of pregnancy by suction evacuation were randomized to receive 400 microg of sublingual or vaginal misoprostol every 3 h for five doses. Venous blood was taken at 180, 200, 240, 360, 380, 420, 540, 560, 600, 720, 740, 780 and 900 min after the first dose of misoprostol for determination of the plasma level of misoprostol acid (MPA). RESULTS: The peak plasma levels of MPA decreased with successive doses of vaginal misoprostol, whereas the peak plasma levels were similar with successive doses of sublingual misoprostol. After the third dose, the peak plasma levels of MPA after sublingual misoprostol were significantly higher than those after vaginal administration. After the final dose, the area under the MPA concentration-time curve after sublingual administration was significantly higher than that after vaginal misoprostol (P < 0.031). However, subgroup analysis in the vaginal administration group showed that the progressive decline in the peak plasma levels of MPA occurred only in women with significant vaginal bleeding. CONCLUSIONS: The peak plasma level of MPA after each dose of misoprostol is higher and the bioavailability is also greater after sublingual administration, compared with that after vaginal administration, of repeated doses of misoprostol. The difference was probably due to the reduction in absorption of vaginal misoprostol in the presence of significant vaginal bleeding.

Misoprostol: pharmacokinetic profiles, effects on the uterus and side-effects.

Misoprostol, a synthetic prostaglandin E1 analogue, is commonly used for medical abortion, cervical priming, the management of miscarriage, induction of labor and the management of postpartum hemorrhage. It can be given orally, vaginally, sublingually, buccally or rectally. Studies of misoprostol's pharmacokinetics and effects on uterine activity have demonstrated the properties of the drug after various routes of administration. These studies can help to discover the optimal dose and route of administration of misoprostol for individual clinical applications. Misoprostol is a safe drug but serious complications and teratogenicity can occur with unsupervised use.

Misoprostol for the treatment of early pregnancy failure.

Nearly 20% of all pregnancies end in early pregnancy failure, and surgical evacuation of retained products of conception is often used to manage this failure. Misoprostol is an inexpensive, stable analog of prostaglandin E(1), and is powerful at contracting the uterus. With intravaginal misoprostol, the peak plasma levels are lower, but the levels after 4 hours are higher, than after oral or sublingual administration. With oral misoprostol, the evacuation rates in early pregnancy varied from about 50% up to 96%. Similar variation in evacuation rates were obtained from small trials with intravaginal misoprostol. To date, only small studies have used sublingual misoprostol, and there has been no direct comparison to oral or intravaginal misoprostol. A recent large clinical trial has shown, that with intravaginal misoprostol 800 microg, an expulsion rate of 84% can be achieved by 8 days. This large trial also established that women prefer misoprostol to surgical evacuation. Two economic evaluations have shown that misoprostol treatment is less costly than surgical intervention. On the basis of recent findings, it seems likely that misoprostol treatment will become a standard or preferred treatment for early pregnancy failure.

Misoprostol administered by epithelial routes: Drug absorption and uterine response.

OBJECTIVE: To quantify and compare serum levels and uterine effects following vaginal (dry), vaginal (moistened), buccal, and rectal misoprostol administration. METHODS: Forty women seeking elective abortion between 6 and 12 6/7 weeks were randomly assigned to receive 400 mug of misoprostol by one of four routes. A 2.5-mm pressure monitoring catheter was placed through the cervix to the uterine fundus to record uterine tone and activity during the 5-hour observation period. Serum levels of misoprostol acid were measured at 15 and 30 minutes, then every 30 minutes. RESULTS: The four groups were similar in age, race or ethnicity, body mass index, parity, and gestation. Serum levels after vaginal, vaginal moistened and buccal administration rose gradually, peaked between 15 and 120 minutes and fell slowly. Vaginal and vaginal moistened routes produced higher peak serum levels than buccal and rectal (445.9 and 427.1 compared with 264.8 and 202.2 pg/mL; P = .03) and higher serum concentration area under the curve at 5 hours (1,025.0 and 1279.4 compared with 519.6 and 312.5 pg-hr/mL; P < .001). Uterine tone and activity, however, were similar for buccal and the two vaginal routes. After rectal administration, serum levels peaked earlier (P < .001) then dropped more abruptly, and peak uterine tone (P < .001) and total activity (P = .04) were lower than after the other routes. CONCLUSION: Although serum levels were lower for buccal compared with the vaginal routes, the three routes produced similar uterine tone and activity. Rectal administration produced lower uterine tone and activity. Vaginal serum levels were two to three and a half times higher than those observed in prior misoprostol pharmacokinetic studies.

The pharmacokinetics and different regimens of misoprostol in early first-trimester medical abortion.

Misoprostol is a synthetic prostaglandin E(1) analogue that is commonly used for medical abortion. It can be given orally, vaginally and sublingually. A pharmacokinetic study has shown that sublingual misoprostol has the shortest onset of action, the highest peak concentration and the greatest bioavailability among the three routes of administration. Earlier clinical trials have shown that vaginal misoprostol is superior to oral misoprostol when combined with mifepristone for early first-trimester medical abortion. Recent studies on the clinical efficacy of sublingual misoprostol have demonstrated that it is as effective as vaginal misoprostol. Further studies are required to determine the optimal dose and route of administration of misoprostol that can give the highest complete abortion rate, lowest ongoing pregnancy rate and least side effects.

Pharmacokinetics of a novel oral slow-release form of misoprostol.

BACKGROUND: The pharmacokinetics of a novel slow-release (SR) misoprostol was studied and compared to conventional misoprostol. METHODS: Thirty-one women, pregnant between 8 and 12 weeks, requesting surgical abortion were randomly allocated to receive orally 400 microg conventional misoprostol, 400 microg SR misoprostol or 800 microg SR misoprostol. Venous blood samples were taken at 0, 30, 60, 120, 240 and 360 min after the administration of misoprostol. Misoprostol acid (MPA) was determined in serum samples using liquid chromatography/tandem mass spectrometry. RESULTS: Serum peak concentration (Cmax) was highest for conventional oral misoprostol. The time to peak concentration (Tmax) was similar for all groups. The area under the curve up to 360 min was similar for conventional and for 800 microg SR misoprostol and significantly greater for these groups compared to 400 microg SR misoprostol (P = 0.013). CONCLUSION: The new SR form of misoprostol demonstrated lower peak levels but longer-lasting elevation in plasma levels compared to conventional oral misoprostol. The AUC for 800 microg SR misoprostol was similar to that of 400 microg of conventional oral misoprostol. SR misoprostol may offer an alternative to repeated administration of oral misoprostol or to vaginal administration.

Comparison of misoprostol plasma concentrations following buccal and sublingual administration.

BACKGROUND: New indications for misoprostol include medical abortion, cervical softening, induction of labor and treatment of postpartum hemorrhage. Various routes of misoprostol administration under study include oral, vaginal, buccal, sublingual and rectal. MATERIALS AND METHODS: This was an open-label, randomized, cross-over study of the pharmacokinetic differences of buccal vs. sublingual misoprostol 800 mug in 10 healthy women. RESULTS: Of the 10 women enrolled, 2 withdrew after experiencing excessive cramping from the sublingual route of misoprostol. The mean misoprostol plasma concentration-time curves at 4 h [area under the curve (AUC)0-4)] and the maximum concentration (C(max)) showed that levels were significantly higher for sublingual administration than the buccal route. Buccal misoprostol administration resulted in fewer symptoms and was found to be more acceptable. CONCLUSIONS: Sublingual administration of misoprostol had a higher AUC and C(max) compared with buccal administration. The pharmacokinetics may help to determine the best application of misoprostol depending on the indication.

Pharmacokinetics of prostaglandins.

Naturally occurring prostaglandins (PGs) are rapidly metabolized in the human circulation. For clinical use a number of PG analogues have therefore been developed which are resistant to rapid inactivation. Among these are carboprost, gemeprost and misoprostol. Following intramuscular injection of carboprost, plasma levels peaked after 20 minutes and declined slowly thereafter. In amniotic fluid the half-life was between 31 and 37 hours. Gemeprost is administered vaginally, and maximum plasma levels were reached after 2-3 hours, with detectable levels for at least 6-8 hours. Pharmacokinetic data on misoprostol are available following oral, vaginal and sublingual administration. Following oral treatment, plasma levels peaked at about 30 minutes, while after vaginal administration of the tablets the levels increased gradually and reached maximum levels after 70-80 minutes, but remained detectable for a significantly longer time. After sublingual administration the peak concentration was the same as for oral treatment but declined significantly more slowly. Endocervical administration of PGE(2) might be regarded as a local therapy, while following vaginal administration increased plasma levels of metabolites can generally be found. The plasma profile varies with the vehicle used.

Pharmacokinetics of different routes of administration of misoprostol.

BACKGROUND: The pharmacokinetic parameters of four different routes of administration of a single dose of 400 microg of misoprostol were studied. METHODS: A total of 40 women undergoing termination of pregnancy by suction evacuation was randomized by computer model to receive 400 microg of misoprostol by one of four routes: (i) sublingual (ii) oral (iii) vaginal and (iv) vaginal with addition of water. Venous blood samples were taken at 0, 1, 2, 5, 10, 20, 30, 45, 60, 120, 240 and 360 min after the administration of misoprostol. Misoprostol acid (MPA) was determined in serum samples using gas chromatography/tandem mass spectrometry. RESULTS: Sublingual misoprostol achieved the highest serum peak concentration (Cmax) (574.8 +/- 250.7 pg/ml) of MPA and this was significantly higher than those in the other groups [Oral: 287.6 +/- 144.3 pg/ml (P < 0.01), vaginal: 125.2 +/- 53.8 pg/ml (P < 0.001) and vaginal with water: 162.8 +/- 57.1 pg/ml (P < 0.001)]. The time to peak concentration (Tmax) was similar in both the sublingual (26.0 +/- 11.5 min) and oral groups (27.5 +/- 14.8 min) and was significantly shorter than those in both vaginal groups. The area under the MPA concentration versus time curve up to 360 min in the sublingual group (743.7 +/- 291.2 pg.h/ml) was significantly greater than those in oral (402.8 +/- 151.6 pg.h/ml, P < 0.05) and vaginal (433.7 +/- 182.6 pg.h/ml, P < 0.05) groups, but no significant difference was found between sublingual and vaginal administration if water (649.3 +/- 333.8 pg.h/ml) was added. CONCLUSION: The new sublingual route of administration of misoprostol demonstrated a great potential to be developed into a method of medical abortion.

Does an acidic medium enhance the efficacy of vaginal misoprostol for pre-abortion cervical priming?

Absorption pharmacokinetics reveal a relationship between plasma concentrations of misoprostol and its therapeutic effect. To achieve a constant plasma profile and optimal efficacy, it is important to develop a medium that ensures complete dissolution of vaginal misoprostol tablets. Vaginal misoprostol is said to liquefy better in an acidic medium; thus, the aim of this study was to determine whether a 200 microg misoprostol tablet dissolved in acetic acid would be more efficacious than 200 microg misoprostol dissolved in water for pre-abortion cervical priming. A total of 120 healthy nulliparous women requesting legal termination of pregnancy between 6-12 weeks gestation were allocated randomly to either of the study groups. Vacuum aspiration was performed 3-4 h after insertion of the misoprostol tablet. Using Hegar's dilator, the degree of cervical dilatation before operation was measured. Of 60 women, 14 (23%) achieved a cervical dilatation of >/=8 mm when the misoprostol dose was dissolved in acetic acid; 12 (20%) achieved a similar cervical dilatation when the dose was dissolved in water. The mean cervical dilatation for the acid and water media used was 6.3 mm and 6.2 mm respectively; these differences were not statistically significant, neither were pre-operative and intra-operative blood losses statistically different between the two groups. Twenty-four (40%) and four (7%) respectively of women in whom a water medium was used experienced vaginal bleeding and abdominal pain; 20 (33%) and 0 women respectively among those in whom an acetic acid medium was used experienced vaginal bleeding and abdominal pain. These differences in side effects were not statistically significant. Our study shows that the use of acetic acid to dissolve vaginal misoprostol does not improve the efficacy in achieving successful cervical dilatation for pre-abortion cervical priming.

PIP: This study determines whether an acetic medium can enhance the efficacy of vaginal misoprostol, in comparison with a water medium, for pre-abortion cervical priming. A total of 120 nulliparous women requesting legal termination of pregnancy between 6-12 weeks gestation were allocated randomly to either of the study groups. Vacuum aspiration was performed 3-4 hours after insertion of the misoprostol tablet. Using Hegar's dilator, the degree of cervical dilatation before operation was measured. Results demonstrate that of the 60 women, 14 (23%) achieved a cervical dilatation of 8 mm or more when the misoprostol dose was dissolved in acetic acid; 12 (20%) achieved a similar cervical dilatation when the dose was dissolved in water. The mean cervical dilatation for the acid and water media used was 6.3 mm and 6.2 mm, respectively. The differences in both of these parameters were not statistically significant. Similarly, there was no statistically significant difference between groups in terms of pre-operative and intra-operative blood loss. About 24 (40%) and 4 (7%), respectively, of women in the group in which a water medium was used experienced vaginal bleeding and abdominal pain, compared with 20 (33%) and 0 women, respectively, who used acetic acid. These differences in side effects were not statistically significant. The study showed that the use of acetic acid to dissolve vaginal misoprostol does not improve the efficacy in achieving successful cervical dilatation for pre-abortion cervical priming.

Comparison between oral and vaginal administration of misoprostol on uterine contractility.

OBJECTIVE: To compare the degree of absorption and the effect on uterine contractility of the prostaglandin E1 analogue misoprostol after vaginal and oral administration. METHODS: Thirty women with a normal intrauterine pregnancy between 8 and 11 weeks' gestation who requested termination of pregnancy were given either 0.2 mg (orally n = 5; vaginally n = 6) or 0.4 mg (orally n = 10; vaginally n = 9) of misoprostol. Intrauterine pressure was recorded using a Grass polygraph connected to a pressure transducer 30 minutes before misoprostol was given and for 4 hours thereafter. At the end of the recording, suction curettage was performed. Blood samples were obtained at 0, 0.5, 1, 2, 4, and 6 hours for measurement of misoprostol, which was assayed by high-pressure liquid chromatography-mass spectrometry. RESULTS: In all patients, the first effect was an increase in uterine tonus. After 0.4 mg of misoprostol administered orally, uterine tonus started to increase after a mean (+/- standard deviation) time of 7.8+/-3.0 minutes and reached its maximum after 25.5+/-5.0 minutes. The corresponding times after vaginal administration were 20.9+/-5.3 minutes and 46.3+/-20.7 minutes, respectively. The initial increase in tonus was also more pronounced after oral than after vaginal administration. After vaginal administration, all patients developed uterine contractions; the activity, measured in Montevideo units, increased continuously during the observation period. This was not the case after oral administration. Plasma levels of misoprostol were measured in 18 patients. The highest levels were found 30 minutes after oral treatment and 1-2 hours after vaginal administration. CONCLUSION: The long-lasting and continuously increasing uterine contractility after vaginal administration can be explained only in part by a direct effect of misoprostol. The longer period of elevated plasma levels of misoprostol may also have initiated the prolonged events leading to increased uterine contractility.