Retention of dinoprostone vaginal insert beyond 12 hours for induction of labor.

We evaluate the likelihood of cesarean delivery and identify risks of retaining a sustained-release dinoprostone vaginal insert beyond 12 hours. In a secondary analysis of outcomes, data were collected during a large, randomized trial comparing different sustained-release prostaglandin vaginal inserts for labor induction. Outcomes were compared between cases in whom the dinoprostone insert was removed early (within 12 hours) or late (12 to 24 hours). A total of 431 subjects had the dinoprostone vaginal insert in place for 12 to 24 hours ( N = 226, 52.4%) or within 12 hours ( N = 205, 47.6%). Insert removal for labor complications was less frequent in the late group than in the early group (5.8% versus 21.5%; P ≤ 0.001). Abnormal uterine contractility patterns were less common in the late than early group (25.2% versus 37.6%; P = 0.03). Rates of cesarean delivery during the first hospitalization were similar for late and early groups (25.0% versus 29.2%; P = 0.33). Percentages of infants requiring immediate attention or intensive care were low and similar between groups. Sustained-release intravaginal dinoprostone left in place beyond 12 hours did not increase the risks of intrapartum complications, cesarean delivery, or immediate adverse neonatal events.

Pharmacokinetic profiles of controlled-release hydrogel polymer vaginal inserts containing misoprostol.

Misoprostol, a prostaglandin E1 analogue, is commonly administered intravaginally for cervical ripening and induction of labor. There is uncertainty regarding the correct dose because of the need to divide the tablets, and there is difficulty in removing the product when there is an adverse event. A proprietary hydrogel polymer containing a removable controlled-release reservoir dose of misoprostol is being developed for vaginal administration (misoprostol vaginal insert) to address these drawbacks while maintaining efficacy. This study investigated the pharmacokinetic profiles of these vaginal inserts and orally administered misoprostol. Twelve nonpregnant women received 100-, 200-, and 400-microg misoprostol vaginal inserts and separately received an oral dose of 200 microg of misoprostol. Values for area under the plasma concentration versus time curve, from time 0 to the last measurable concentration, were dose proportional with 481, 1026, and 2191 pg.h/mL for the 100-, 200-, and 400-microg misoprostol vaginal inserts, respectively. Maximum plasma concentrations were 33.1, 73.4, and 144 pg/mL for the 100-, 200-, and 400-microg misoprostol vaginal inserts, compared with 609 pg/mL for the 200 microg of oral misoprostol. After administration of the insert, plasma misoprostol acid levels increased gradually with time of the maximum measured plasma concentration at 5 to 9 hours. Following removal of the insert, misoprostol acid was eliminated rapidly from the systemic circulation with a mean half-life <1 hour.

Pre-ERCP infusion of semapimod, a mitogen-activated protein kinases inhibitor, lowers post-ERCP hyperamylasemia but not pancreatitis incidence.

BACKGROUND: Acute pancreatitis and hyperamylasemia are frequent complications of an ERCP. Semapimod is a synthetic guanylhydrazone that inhibits the mitogen-activated protein kinase (MAPK) pathway, macrophage activation, and the production of several inflammatory cytokines. OBJECTIVE: This study evaluated whether intravenous (IV) administration of semapimod given before an ERCP reduces the incidence of post-ERCP hyperamylasemia and pancreatitis. DESIGN: A single-center, randomized, double-blinded, controlled trial. SETTING: An academic medical center. PATIENTS: Between 2001 and 2005, 242 patients who were undergoing a therapeutic ERCP at our institution were included. INTERVENTION: Patients received a single IV dose of semapimod or a placebo before an ERCP. MAIN OUTCOME MEASUREMENTS: The occurrence of post-ERCP pancreatitis, as well as post-ERCP hyperamylasemia. RESULTS: The incidence of hyperamylasemia was significantly reduced (29.8% vs 18.4%; P = .031). Moreover, semapimod administration significantly lowered the levels of amylase during the first 24 hours after the ERCP. The incidence of clinical pancreatitis was reduced by 40%, without reaching statistical significance (14.9 vs 9.1%; P = .117). LIMITATIONS: A relatively small single-center study. One dose of semapimod was used. CONCLUSIONS: A single dose of IV semapimod 1 hour before an ERCP is safe and exerts a biological effect, demonstrated by a statistically significant reduction of the incidence of hyperamylasemia and the levels of post-ERCP amylase. A protective effect for the development of post-ERCP pancreatitis could not be convincingly demonstrated.

Determining dose and endpoints of a controlled-release misoprostol vaginal insert for a phase III trial.

OBJECTIVE: To determine phase III study design using the phase II data for a proprietary controlled-release misoprostol vaginal insert for cervical ripening and labor induction. METHODS: The reported experiences in 2 phase II trials involving induction of labor in 168 women are discussed. RESULTS: Combining data from 2 phase II studies, we reported a median induction to vaginal delivery interval of <15 hours regardless of parity using the 100-microg insert. This misoprostol vaginal insert was well tolerated with few maternal systemic effects. Uterine hyperstimulation occurred in <5% of cases in the 100-microg and lesser dose groups. Hyperstimulation syndrome attributed to insert led to cesarean delivery in 1 (2.4%) subject in the 200-microg and 2 (33.3%) in the 300-microg dose groups. The lowest cesarean rates were 4.7% (2 of 43) in the 100-microg group and 5.7% (2 of 35) in the 50-microg group. CONCLUSION: Misoprostol vaginal 50-microg and 100-microg inserts had acceptable efficacy and safety profiles, and we agreed to test these doses in a randomized phase III multicenter study using dinoprostone (Cervidil, Forest Pharmaceuticals, St. Louis, Missouri), a dinoprostone vaginal insert, as the blinded comparator.

Racial/Ethnic Differences in Labor Outcomes with Prostaglandin Vaginal Inserts.

OBJECTIVE: The aim of this study is to compare labor outcomes across race/ethnicity in women undergoing prostaglandin labor induction. METHODS: Secondary analysis of misoprostol vaginal insert (MVI) trial, a double-blind, randomized, control trial of 1,308 patients comparing sustained release vaginal inserts containing dinoprostone 10 mg and misoprostol 50 mcg (MVI 50) or 100 mcg (MVI 100). RESULTS: Achievement of active labor and induction failures were similar across race/ethnicity. Cesareans were performed less frequently in whites (29 %) and Hispanics (24.5 %) compared to blacks (32.7 %) (adjusted odds ratio (aOR) 0.87, 95 % confidence interval (CI) 0.47-0.97, p = 0.03 and aOR 0.86, 95 % CI 0.44-0.97, p = 0.03, respectively). When compared to blacks, whites were less likely to undergo cesarean for non-reassuring fetal heart rate tracing (aOR 0.41, 95 % CI 0.25-0.66, p = 0.0003), as were Hispanics (aOR 0.38, 95 % CI 0.22-0.65, p = 0.0004). Postpartum hemorrhage occurred more frequently in Hispanics (8.8 %) versus blacks (4.1 %) and whites (OR 2.27, 95 % CI 0.23-0.82, p = 0.02 and OR 3.69, 95 % CI 0.14-0.51, p < 0.0001, respectively). Birth weights of black infants were lower than whites (p < 0.0001) and Hispanics (p = 0.0003). Neonatal outcomes did not differ between groups. CONCLUSION: Differences in labor induction outcomes with prostaglandin labor induction exist based on race/ethnicity. Blacks delivered smaller babies, were more likely to undergo cesarean, and have cesareans performed for non-reassuring fetal heart tracing compared to other groups. Hispanics were more likely to experience postpartum hemorrhage compared to the other races.

Misoprostol vaginal insert for induction of labor: a delivery system with accurate dosing and rapid discontinuation.

Labor induction and cervical ripening are widely utilized and new methods are constantly being investigated. Prostaglandins have been shown to be effective labor induction agents and, in particular, were compared with other prostaglandin preparations; vaginal misoprostol used off-label was associated with reduced failure to achieve vaginal delivery. The challenge is to provide this medication with the correct dosing for this indication and with the ability to discontinue the medication if needed, all while ensuring essential maternal and neonatal safety. The misoprostol vaginal insert initiates cervical ripening using a delivery system that controls misoprostol release and can be rapidly removed. This article reviews the development, safety and efficacy of the misoprostol vaginal insert for induction of labor and cervical ripening, and will focus on vaginally administered prostaglandins.

Fetal heart rate and cardiotocographic abnormalities with varying dose misoprostol vaginal inserts.

OBJECTIVE: Characterize the incidence and timing of fetal heart rate (FHR) and cardiotocographic abnormalities (CTG) associated with the misoprostol vaginal insert (MVI) during labor induction. METHODS: This secondary analysis of data from the MVI Trial, a multi-site, double-masked, randomized trial of 374 women assigned to MVI 100, 150 or 200 mcg requiring cervical ripening before labor induction evaluated the incidence and clinical outcomes associated with FHR and CTG abnormalities diagnosed using 1997 NICHD definitions. RESULTS: MVI 200 was associated with an increased rate of tachysystole versus MVI 100 (p < 0.001, RR 2.11, 95% CI 1.39, 3.22) but not MVI 150 (p = 0.29, RR 1.31, 95% CI 0.82, 2.11). Tachysystole occurred with the drug in situ in 17 (14.4%) and 50 (38.2%) of MVI 100 and 200 subjects, respectively (p < 0.001). Category II or III FHR patterns after tachysystole occurred in 9 (7.6%) and 26 (19.8%) women in MVI 100 and 200 groups, (p = 0.006). Abnormal FHR patterns were the indication for cesarean in 18 (13.7%) MVI 200 women versus 11 (9.3%) MVI 100 women (p = 0.33). Neonatal outcomes were similar between groups. CONCLUSIONS: While FHR and CTG abnormalities were encountered frequently during all inductions, few were clinically significant.

Misoprostol vaginal insert and time to vaginal delivery: a randomized controlled trial.

OBJECTIVE: To compare the efficacy and safety of a 200-microgram misoprostol vaginal insert with a 10-mg dinoprostone vaginal insert for reducing the time to vaginal delivery. METHODS: In a phase III, double-blind, multicenter study, women being induced with a modified Bishop score of 4 or less were randomly assigned to receive either a 200-microgram misoprostol vaginal insert or a 10-mg dinoprostone vaginal insert. Coprimary end points were time to vaginal delivery and rate of cesarean delivery. Secondary end points included time to any delivery mode, time to onset of active labor, and oxytocin use. RESULTS: A total of 1,358 women were randomized to receive the 200-microgram misoprostol vaginal insert (n=678) or dinoprostone vaginal insert (n=680). Women receiving the misoprostol vaginal insert had a significantly shorter median time to vaginal delivery compared with patients receiving the dinoprostone vaginal insert (21.5 hours compared with 32.8 hours, P<.001). Cesarean delivery occurred in 26.0% and 27.1% of women receiving the misoprostol vaginal insert and dinoprostone vaginal insert, respectively. A significant reduction in time to any delivery (18.3 hours compared with 27.3 hours), time to onset of active labor (12.1 hours compared with 18.6 hours), and proportion of women requiring predelivery oxytocin (48.1% compared with 74.1%) was observed with the misoprostol vaginal insert compared with dinoprostone vaginal insert (P<.001 for each). Uterine tachysystole requiring intervention occurred in 13.3% and 4.0% of participants receiving the misoprostol vaginal insert and dinoprostone vaginal insert, respectively (P<.001). CONCLUSION: Use of a 200-microgram misoprostol vaginal inset significantly reduced times to vaginal delivery and active labor with reduced need for oxytocin compared with the dinoprostone vaginal insert. Cesarean delivery rates were similar with both treatments. Tachysystole was more common in women receiving the 200-microgram misoprostol vaginal insert. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01127581. LEVEL OF EVIDENCE: I.

Cardiotocographic abnormalities associated with misoprostol and dinoprostone cervical ripening and labor induction.

OBJECTIVE: To characterize the incidence and timing of cardiotocographic (CTG) abnormalities associated with misoprostol and dinoprostone vaginal inserts during labor induction. STUDY DESIGN: This was a secondary analysis of data collected during the misoprostol vaginal insert (MVI) trial, a multi-site, double-masked, randomized trial of women requiring cervical ripening before induction of labor. The timing, incidence and clinical outcomes associated with CTG abnormalities were analyzed among three study groups. RESULTS: 1308 subjects were randomized to receive dinoprostone pessary, misoprostol 50 mcg (MVI 50) or 100 mcg (MVI 100) vaginal insert. 6.8% of MVI 50-treated women had a uterine contractile abnormality (hyperstimulation, hypertonus and/or tachysystole) while the study drug was in situ, compared to 17.4% with dinoprostone insert (p<0.001) and 17.3% with MVI 100 (p<0.001). There was no significant difference in incidence of fetal heart rate (FHR) abnormalities that occurred with the study drug-11.2% with dinoprostone, compared to 9.9% with MVI 50 and 10.7% with MVI 100. Cardiotocographic (CTG) abnormalities while the study drug was in situ occurred later in women treated with MVI 50 (7.5h [6.2-9.8]) compared to dinoprostone (5.5h [4.2-6.6], p=0.003) and MVI 100 (7.0 h [5.7-7.9], p=0.13). Eight participants in MVI 50 group underwent cesarean section secondary to a CTG event that was initially noted with the study drug in situ, compared to eight dinoprostone-treated participants and 16 in the MVI 100 group, but these differences were not statistically significant. CONCLUSION: Cardiotocographic abnormalities were less frequent and occurred after longer exposure with MVI 50 than MVI 100 or dinoprostone. Clinical outcomes were similar among the groups.

Misoprostol vaginal insert for successful labor induction: a randomized controlled trial.

OBJECTIVE: To compare three doses of misoprostol vaginal insert for successful labor induction measured by the proportion of vaginal deliveries within 24 hours. METHODS: A total of 374 women with modified Bishop scores of 4 or lower before induction of labor were randomly assigned to receive misoprostol vaginal insert (MVI) 100 (n=118), MVI 150 (n=125), or MVI 200 (n=131) micrograms. The insert was removed for onset of active labor or adverse event. The primary outcome was proportion of vaginal deliveries within 24 hours. The comparison group was MVI 100. Safety was assessed by comparing rates of cesarean deliveries and adverse events. RESULTS: Twenty-four percent of women receiving MVI 200 failed to achieve vaginal delivery within 24 hours compared with 36.3% of those receiving MVI 100 (P=.057, relative risk [RR] 0.66, 95% confidence interval [CI] 0.42-1.04). Compared with MVI 100, MVI 200 reduced median time to vaginal delivery (1,181 compared with 1,744 minutes, P=.02) and need for oxytocin (48.9% compared with 70.9%, P<.001, RR 0.70, 95% CI 0.56-0.85). The cesarean rates for women assigned to MVI 200 and 100 were 22.9% (30/131) and 31.4% (37/118) (P=.15, RR 0.73, 95% CI 0.48-1.10). Misoprostol vaginal insert 200 was associated with an increased rate of tachysystole (41.2%) compared with MVI 100 (19.5%) (P<.001, RR 2.11, 95% CI 1.39-3.22). CONCLUSION: Compared with MVI 100, MVI 200 was associated with a significant reduction in time to vaginal delivery, but did not improve proportion with vaginal delivery by 24 hours. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00828711.

Effects of maternal obesity on duration and outcomes of prostaglandin cervical ripening and labor induction.

OBJECTIVE: To estimate the effect of maternal body mass index (BMI) on progress and outcomes of prostaglandin labor induction. METHODS: This study was a secondary analysis of data collected during the Misoprostol Vaginal Insert Trial, a multisite, double-blind, randomized trial of women requiring cervical ripening before induction of labor. The duration, characteristics, and outcomes of labor were analyzed after stratification by BMI categories. Multivariable regression analysis was performed on all outcomes of interest, adjusting for race, parity, and treatment group allocation. RESULTS: One thousand two hundred seventy-three patients were stratified according to BMI categories, with 418 study participants classified as lean (BMI less than 30), 644 as obese (BMI 30-39.9), and 211 as extremely obese (BMI 40 or higher). The incidence of cesarean delivery increased from 21.3% in the BMI less than 30 group to 29.8% in the BMI 30-39.9 group (odds ratio [OR] 1.57, 95% confidence interval [CI] 1.18-2.1, P=.002) and 36.5% in the BMI 40 or higher group (OR 2.12, 95% CI 1.47-3.06, P<.001). Median dose and duration of predelivery oxytocin in the lean group (2.6 units and 6.5 hours) was significantly lower than for women in either the obese (3.5 units and 7.7 hours) or the extremely obese (5.0 units and 8.5 hours) group. Median time to delivery was significantly longer in the BMI 40 or higher (27.0 hours) and BMI 30-39.9 (24.9 hours) groups compared with the BMI less than 30 (22.7 hours) group (P<.001). The relationship between maternal obesity and adverse labor and delivery outcomes persisted in a multivariable analysis that adjusted for race, parity, and treatment group allocation. CONCLUSION: Duration of labor, oxytocin requirements, and cesarean delivery rates are significantly higher with increasing maternal obesity in prostaglandin-induced women. LEVEL OF EVIDENCE: II.

Pharmacokinetics of a controlled-release misoprostol vaginal insert at term.

OBJECTIVE: The objective of this investigation was to report the pharmacokinetic properties of misoprostol administered intravaginally to women at term via a controlled-release hydrogel polymer insert. METHODS: This open-label, dose escalation trial consisted of 31 nulliparous women at term who were treated intravaginally in cohorts of six with inserts containing reservoirs from 25 through 300 microg (7 at 200 microg) of misoprostol. Inserts remained intravaginally until the patient went into labor, developed adverse events, or completed 24 hours of treatment. Complete data about residual drug in the inserts and plasma concentrations of misoprostol acid were gathered for 27 and 25 patients, respectively. RESULTS: Misoprostol was released at a constant rate (5.1% total dose per hour) with the amount absorbed being directly proportional to the dose reservoir. For the 25-, 50-, 100-, 200-, and 300-microg reservoir doses, the maximum median plasma concentrations were 6.4, 11.3, 21.7, 40.8, and 74.2 pg/mL, respectively, and the area under the curve until drug removal was 39, 117, 223, 269, and 477 pg x h/mL. Regardless of dose, the peak plasma concentration occurred at approximately 7 hours after insertion and the elimination half-life of the misoprostol acid was 0.55 hours (95% confidence interval, 0.36 to 1.32 hours). CONCLUSIONS: Misoprostol is released from the vaginal insert in a controlled manner and is eliminated rapidly after removal. Pharmacokinetic parameters are proportional to the reservoir dose.

Ventriculo-lumbar perfusion in acute ischemic stroke.

INTRODUCTION: Effective treatment for severe ischemic stroke continues to be largely an unmet medical need. Using a nonvascular (paravascular cerebrospinal fluid) pathway to provide oxygen and nutrients to ischemic tissues may be a means of treating this disease. The primary objective of this study was to evaluate the safety and technical feasibility of ventriculo-lumbar perfusion with the oxygenated fluorocarbon nutrient emulsion (OFNE) perfusion system in the treatment of patients with severe hemispheric cerebral ischemia. RESULTS: Four patients were enrolled in this pilot study. At admission, patients' National Institutes of Health Stroke Scale scores ranged from 16 to 24. The perfusion pathway was successfully established in all four patients. Maximum perfusion rates varied from 25 to 40 mL/minute; total volume perfused over the 24-hour period ranged from 30.6 to 45.8 L. ICP ranged from -3 to 16 mmHg during the perfusion. The 24-hour perfusion was successfully completed in all four patients with no serious adverse events during the perfusion. CONCLUSION: It is technically feasible and safe to establish a ventriculo-lumbar perfusion pathway using a specially designed lumbar drainage catheter and to control intracranial pressure while perfusing large volumes of OFNE.

Misoprostol dose selection in a controlled-release vaginal insert for induction of labor in nulliparous women.

OBJECTIVE: The purpose of this study was to identify the maximum tolerable dose and to determine the efficacy of different misoprostol dose reservoirs in an intravaginal controlled-release hydrogel polymer. STUDY DESIGN: Nulliparous women at > or = 37 weeks' gestation requiring cervical ripening and induction of labor were treated with misoprostol in a controlled-release, retrievable hydrogel polymer vaginal insert. Sequential cohorts of 6 patients were to be treated with escalating dose reservoirs of 25, 50, 100, 200, and 300 mug. The insert was to be removed upon onset of active labor, at 24 hours, or earlier if treatment-related adverse events occurred. The safety end point was determination of the maximum tolerable dose (MTD) based on occurrence of hyperstimulation syndrome. Our primary efficacy end point was time to vaginal delivery. RESULTS: Increasing reservoir doses of misoprostol up to 100 microg produced more rapid increases in modified Bishop scores, less need for oxytocin, and a shorter time to vaginal delivery. Doses above 100 microg did not further enhance cervical ripening or shorten time to vaginal delivery. The median time to vaginal delivery was 14.2 hours using the 100 microg dose. Uterine hyperstimulation and adverse fetal heart rate effects occurred with the 200 and 300 microg inserts. CONCLUSION: The 100 microg vaginal insert resulted in successful cervical ripening and rapid vaginal delivery with an acceptable safety profile for future randomized clinical trials.

Reduction of cerebral infarction using the third circulation.

OBJECTIVE: To ascertain whether ventriculosubarachnoid perfusion of the brain with an oxygen-carrying nutrient emulsion affects the volume of infarction in animals with permanent middle cerebral artery occlusion. DESIGN: Prospective, randomized, controlled trial. SETTING: An animal laboratory in a university setting. SUBJECTS: Twenty-eight closed colony adult cats weighing between 3.5 and 4.5 kg. INTERVENTIONS: Cats were assigned randomly into one of three groups: untreated surgical controls, artificial cerebrospinal fluid (ACSF) perfused, or oxygenated fluorochemical (t-bis perfluorobutylethylene; F44E) nutrient emulsion (OFNE) perfused. The formulation used in this study was developed for clinical use and is currently being used in a phase 1 clinical trial in patients with severe ischemic stroke. Focal cerebral ischemia was induced by permanently clipping the middle cerebral artery via the retro-orbital approach. Treatment was initiated 90 mins postocclusion and continued for 18 hrs. Animals were killed 1 hr after the termination of perfusion, the brains were sectioned and stained with 2,3,5-triphenyltetrazolium chloride, and the infarct area was determined with a computer digitizer. MEASUREMENTS AND MAIN RESULTS: There was a significant difference in cerebral infarct volume in the OFNE-perfused animals compared with the other groups ( p