Prostaglandin E1 Analogue Misoprostol Research Articles

Methotrexate: Use in the Post Dobbs v. Jackson Era.

Methotrexate is one of the most frequently used medications for the treatment of rheumatic diseases. Although initially developed for use as chemotherapy for both solid and hematologic malignancies, it was used as early as the 1960s with success for rheumatoid arthritis (RA) and psoriatic arthritis, ultimately being approved by the US Food and Drug Administration for the treatment of RA in 1988. Beyond RA and psoriatic arthritis, methotrexate is used in the treatment of systemic lupus erythematosus, idiopathic inflammatory myopathies, and other inflammatory conditions. Methotrexate is cytotoxic to the trophoblast and has been used to treat both ectopic pregnancy and gestational trophoblastic neoplasia, leading to studies in the early 1990s that showed it was effective and safe for early abortion in combination with prostaglandin E1 analog misoprostol. Methotrexate is also a teratogen, causing serious birth defects in 6%-10% of patients taking it while pregnant. Additionally, women are more likely to be affected by both RA at SLE, as compared with males, thus worsening the burden of these adverse effects. Both methotrexate's history of use as an abortifacient and its teratogenic properties make its use more complicated in the current era of abortion policy in the United States following the Dobbs v. Jackson Women's Health Organization ruling. Recently published data suggest that this ruling has affected both provider perspectives and patient experiences as it relates to methotrexate use. In the post-Dobbs era, the role of the rheumatologist as it relates to patients' sexual and reproductive health is likely to expand.

Interaction of endocannabinoid system and cyclooxygenase metabolites with fatty acid amide hydrolase and cyclooxygenase enzyme activities on contractile responses in rat vas deferens tissue.

The endocannabinoid system and prostaglandins are important modulators in the genitourinary system. This study aimed to investigate the possible interactions between the endocannabinoid system and the cyclooxygenase (COX) pathway on rat vas deferens. For this purpose, the concentration responses of the endocannabinoid anandamide, prostaglandin F2α analog latanoprost, and prostaglandin E1 analog misoprostol on the electrical field stimulation (EFS)-induced contractile responses were obtained. The concentration responses to anandamide were obtained again in the presence of nonselective COX inhibitor flurbiprofen and prostaglandin analogs, while the concentration responses of latanoprost and misoprostol were obtained in the presence of cannabinoid receptor antagonists and fatty acid amide hydrolase (FAAH) enzyme inhibitor URB597. FAAH, COX-1, and COX-2 enzyme levels in vas deferens tissue samples were also determined. The cumulative addition of anandamide was not different from the vehicle; however, the EFS-induced contractile responses were significantly increased with the incubation of latanoprost or flurbiprofen in the prostatic portion. Flurbiprofen and misoprostol decreased FAAH enzyme levels in both portions of the vas deferens, while latanoprost induced the inhibition in the prostatic portion. The cumulative administration of latanoprost and misoprostol significantly enhanced the contractile responses in the prostatic portion. This effect of latanoprost was significantly antagonized by URB597 and AM251. The enhancing effect of misoprostol was antagonized by anandamide, URB597, AM251, and AM630. Anandamide, AM251, AM630, and URB597 decreased enzyme levels of COX-1 and COX-2 in both portions of the vas deferens. These results demonstrate an intricate crosstalk between endocannabinoids and prostaglandins in modulation of the vas deferens contractility.

Use of prostaglandin E1 analog (misoprostol) to aid cervical dilation in birth induction (a case report)

The cervix is a barrier between the environment and the uterus, composed of longitudinal folds that continue along the uterine folds. Cervical dilation is associated with increased synthesis of prostaglandin E2 (PGE2). Dilatation may fail due to congenital malformations or adhesions of the cervix caused, for example, by previous dystocia or by failure of any mechanisms that regulate cervical relaxation including a reduction in collagen and glycosaminoglycans and an increase in water content and metalloproteinases. Labor induction often requires the ripening of the cervix mechanically or pharmacologically. Oxytocin success may be reduced if the cervix is not favorable or responsive. Misoprostol, a synthetic prostaglandin E1 analog, is widely used in reproduction in cases of oviduct obstruction. It also promotes cervical softening by the dissolution of extracellular collagen. A 17-year-old mixed-breed mare from a private farm in the Middle East presented with abdominal discomfort and signs of imminent delivery, 10th months after embryo transfer. A slight thickening of the uterus-placental junction (7.12mm) was observed during transrectal ultrasound evaluation, but there was no placental detachment. On transabdominal imaging, the absence of a fetal heartbeat, fetal movements, and torsion of the umbilical cord were observed. Imaging evaluations were performed with an ultrasound machine DCS - MyLab™25 GOLD, 5Hzfrequency. Hematological analysis of the mare showed results within normal ranges. Flunixin Meglumine (10mL i.v., Finadyne, 50mg/mL, MSD) was administered before the abortion procedure. After confirmation of fetal death and dystocia in the mare, the cervix dilation process began with a local application of 1mg of misoprostol 200mcg diluted in lubricating gel and mechanical massage. Then, intravenous oxytocin (Syntocin, 10UI/mL, Illium) was started gradually every 5 minutes (5IU, 5IU, 10IU, 10IU). Mild sedation and analgesia was achieved with detomidine (0.6mL i.v., Dormiun V, 10mg/mL, Agener Uniao) and butorphanol (1mL i.v., Torbugesic, 14,58mg/mL, Zoetis). The mare showed signs of delivery before the mechanical rupture of the allantochorion. The position of the fetus (head back and right shoulder flexion) was corrected transvaginally by mechanical maneuver. After removing the fetus, 5 mg of dinoprost (i.m., Lutalyse, 6.71mg/mL, Zoetis) was administered to aid uterine contractility and clearance. The placenta did not have macroscopic changes. The fetus showed an absence of the right posterior limb's first, second, and third phalanges. During fetal necropsy, no other changes were observed. Uterine lavage was performed 24h and 48h after the procedure, using Ringer Lactate Solution (LRS), with 10% iodine (20mL/5L LRS) followed by 20IU oxytocin every eight hours for two consecutive days.

Improvement in heat stress-induced multiple organ dysfunction and intestinal damage through protection of intestinal goblet cells from prostaglandin E1 analogue misoprostol

AimsHeat stroke is a life-threatening disorder triggered by thermoregulatory failure. Hyperthermia-induced splanchnic hypoperfusion has been reported to induce intestinal barrier dysfunction and systemic immune response that ultimately cause multiple-organ failure and death. Intestinal goblet cells contribute greatly to the formation of mucus barrier, which hinders translocation of gut microorganisms. Studies have reported that misoprostol can not only alleviate ischemic injury but also protect GI mucosal layer. Therefore, we evaluated the effects of misoprostol on intestinal goblet cells after heat stress and on multiple-organ dysfunction in heat stroke rats. Main methodsHeat stress was established in the heating chamber and followed by misoprostol treatment. Changes in hemodynamics, organ function indices, inflammation, oxidative stress, and survival rate were analyzed. Furthermore, ilea and LS174T cells were used to examine intestinal functions. Key findingsHeat stress caused dysfunction of intestinal goblet cells and damage to ilea by increasing oxidative stress and apoptosis. Increased nitrosative stress and inflammation accompanied by hypotension, hypoperfusion, tachycardia, multiple-organ dysfunction, and death were observed in the heat stroke rat model. Treatment of LS174T cells with misoprostol not only decreased oxidative stress and apoptosis but also reduced cytotoxicity caused by heat stress. Moreover, misoprostol prevented disruption of the enteric barrier, multiple-organ injury, and death in rats with heat stroke. SignificanceThis study indicates that misoprostol could alleviate intestinal damage and organ injury caused by heat stress and be a potential therapy for heat-related illnesses.

Sublingual misoprostol vs. oral misoprostol solution for induction of labor: A retrospective study.

IntroductionInduction of labor (IOL) is one of the most common obstetrical procedures, with an increasing rate. The prostaglandin E1 analogue misoprostol is frequently used as a primary method of labor induction. The optimal dose and route of administration is yet to be ascertained.AimTo compare efficiacy and safety between a regimen of sublingually administered misoprostol and a regimen of orally administered misoprostol, with cesarean delivery as primary outcome.MethodsA retrospective study was conducted including women carrying a live, singleton fetus in a cephalic position with labor induced at >37 + 0 gestational weeks at Skåne University hospital, Lund, between January 1st 2013 to December 31st 2017. Data was obtained from computerized obstetrical charts.ResultsTotally 2,404 women were included; 974 induced with sublingual misoprostol and 1,430 with oral solution. In primiparous women the cesarean delivery rate was lower in primiparous women induced with oral compared to sublingual misoprostol (20.5% vs. 28.6%, p < 0.001), whereas in parous women the rates did not differ significantly 4.9% vs. 7.5%; NS). The increased risk of caesarean remained after controlling for potential confounding factors (adjusted odds ratio 1.49 (1.14–1.95). Women induced with sublingual misoprostol had a shorter time to vaginal delivery when compared to oral solution (primiparous median 16.7 h vs. 21.7 h; p < 0.001, parous median 9.9 h vs. 13.3 h; p = 0.01), and a higher rate of vaginal delivery within 24 h (primiparas 77.7% vs. 63.3%, p < 0.001, parous 93.2% vs. 84.2%; p = 0.01).ConclusionIOL with oral misoprostol solution was associated with a significantly higher vaginal delivery rate when compared to sublingual misoprostol, whereas sublingual misoprostol was associated with a significantly shorter time from induction to vaginal delivery. Oral administration is considered the most safe and efficient administration of misoprostol, although more studies are needed to find the optimal route and dosage of misoprostol for IOL.

Efficacy of 50 µg Versus 25 µg Vaginal Misoprostol for Cervical Ripening and Labor Induction: A Randomized Trial

Background: Cervical ripening is the process of initiating labor in women with an unripe cervix. Vaginally administered prostaglandin E1 analog (misoprostol) has been promising in cervical ripening and labor induction. However, optimal dosage and dose-dependent adverse effects in this administration route need further clarification. Objectives: This trial aimed to compare the efficacy and adverse effects of 50 mcg vs. 25 mcg of vaginal misoprostol in low-risk term pregnant women. Methods: This double-blind, single-center, randomized clinical trial included 200 low-risk term pregnancies undergoing labor induction with a Bishop score of 2 or less. Patients were assigned randomly to receive 25 mcg or 50 mcg of vaginal misoprostol every six hours up to four times until the active phase of labor was reached. The primary outcome included time to vaginal delivery (latent and active phase of labor), and secondary outcomes included the total dosage of prescribed misoprostol, the need for oxytocin for labor augmentation, and the cesarean section rate. Results: Misoprostol 50 micrograms resulted in a significantly shorter time in the first phase of labor (P-value = 0.002), the second phase of labor (P-value = 0.030), and the third phase of labor (P-value = 0.020). The number of administered misoprostol, the need for additional oxytocin, uterine hyperstimulation, cesarean delivery rate, Apgar score, umbilical artery pH, and neonatal intensive care unit (NICU) administration were statistically similar between the two groups. Conclusions: This study showed that 50 mcg of vaginal misoprostol (vs. 25 mcg) for cervical ripening could reduce labor phase duration without significantly increasing adverse maternal and neonatal outcomes.

Improvement in Heat Stress-Induced Multiple Organ Dysfunction Through Protection of Intestinal Goblet Cells from Prostaglandin E1 Analogue Misoprostol

Improvement in Heat Stress-Induced Multiple Organ Dysfunction Through Protection of Intestinal Goblet Cells from Prostaglandin E1 Analogue Misoprostol

Misoprostol treatment prevents hypoxia-induced cardiac dysfunction through a 14-3-3 and PKA regulatory motif on Bnip3

Systemic hypoxia is a common element in most perinatal emergencies and is a known driver of Bnip3 expression in the neonatal heart. Bnip3 plays a prominent role in the evolution of necrotic cell death, disrupting ER calcium homeostasis and initiating mitochondrial permeability transition (MPT). Emerging evidence suggests a cardioprotective role for the prostaglandin E1 analog misoprostol during periods of hypoxia, but the mechanisms for this protection are not completely understood. Using a combination of mouse and cell models, we tested if misoprostol is cardioprotective during neonatal hypoxic injury by altering Bnip3 function. Here we report that hypoxia elicits mitochondrial-fragmentation, MPT, reduced ejection fraction, and evidence of necroinflammation, which were abrogated with misoprostol treatment or Bnip3 knockout. Through molecular studies we show that misoprostol leads to PKA-dependent Bnip3 phosphorylation at threonine-181, and subsequent redistribution of Bnip3 from mitochondrial Opa1 and the ER through an interaction with 14-3-3 proteins. Taken together, our results demonstrate a role for Bnip3 phosphorylation in the regulation of cardiomyocyte contractile/metabolic dysfunction, and necroinflammation. Furthermore, we identify a potential pharmacological mechanism to prevent neonatal hypoxic injury.

Labour Induction with Misoprostol in German Obstetric Clinics: What Are the Facts on Such Use?

Subject While the synthetic prostaglandin E1 analogue misoprostol is the most effect labour induction agent, its use is off-label for the most part. For this reason, and in view of its potential adverse effects and varying approaches to its administration, the drug has recently once again become a focus of critical attention. The objective of this survey was thus to establish a record of labour induction with misoprostol in German clinics and determine the impact of the negative reporting on everyday obstetric practice. Material and Methods In this cross-sectional study, 635 obstetrics and gynaecology departments in Germany were requested by email to participate in our survey in February/March 2020. Online responses to 19 questions were requested regarding the clinic, use of misoprostol before and after the critical reporting, use of misoprostol (sourcing, method of administration, dosage, monitoring) and other labour induction methods. Results A total of 262 (41.3%) of the clinics solicited for the survey completed the questionnaire. There were no differences regarding the care level (Perinatal Centre Level I, Perinatal Centre Level II, Clinic with Perinatal Focus or Obstetric/Private Clinic; p = 0.2104) or birth counts (p = 0.1845). In most cases, misoprostol was prepared in the clinicʼs own pharmacy (54%) or imported from another country (46%) and administered orally in tablet form (95%). Misoprostol dosage levels varied (25 µg [48%], 50 µg [83%], 75 µg [6%], 100 µg [47%] and > 100 µg [5%]). Most of the clinics used premanufactured tablets/capsules (59%), although Cytotec tablets were also divided (35%) or dissolved in water (5%). Misoprostol administration intervals were mainly every 4 hours (64%) or every 6 hours (30%). CTG checks were run in most cases before and after administration of a dose of misoprostol (78% and 76%) and before and after administration of a dose of prostaglandin E2 (both 88%). Presence of contractions led to no misoprostol (59%) or no prostaglandin E2 (64%) being administered in most cases. The critical reporting resulted in discontinuation of use of misoprostol in 17% of the clinics – mainly smaller obstetric/private clinics with fewer than 1000 births. Labour cocktails were used mainly in obstetric and private clinics (61%). Conclusion Misoprostol is an established agent for labour induction in German clinics. The dosing schemes used vary. Improvements of currently common management practices are required, especially in the area of labour induction (CTG checks before and after administration of labour-inducing medication, no administration of prostaglandin if contractions are ongoing). The discussion of use of misoprostol in the media resulted in stoppage of its use mainly in smaller clinics.

Caspase-11 promotes allergic airway inflammation

Activated caspase-1 and caspase-11 induce inflammatory cell death in a process termed pyroptosis. Here we show that Prostaglandin E2 (PGE2) inhibits caspase-11-dependent pyroptosis in murine and human macrophages. PGE2 suppreses caspase-11 expression in murine and human macrophages and in the airways of mice with allergic inflammation. Remarkably, caspase-11-deficient mice are strongly resistant to developing experimental allergic airway inflammation, where PGE2 is known to be protective. Expression of caspase-11 is elevated in the lung of wild type mice with allergic airway inflammation. Blocking PGE2 production with indomethacin enhances, whereas the prostaglandin E1 analog misoprostol inhibits lung caspase-11 expression. Finally, alveolar macrophages from asthma patients exhibit increased expression of caspase-4, a human homologue of caspase-11. Our findings identify PGE2 as a negative regulator of caspase-11-driven pyroptosis and implicate caspase-4/11 as a critical contributor to allergic airway inflammation, with implications for pathophysiology of asthma.

Potency and acceptability of oral misoprostol compared with vaginal misoprostol prior to first trimester abortions

Present study was done to assess the effectiveness and acceptability of oral misoprostol compared with vaginal misoprostol for cervical priming before termination of first trimester pregnancy. Recently, prostaglandin E1 analogue misoprostol has caught much attention as cervical priming agent. Prostaglandins are used in different doses and different routes considering the different available results. Misoprostol was originally marketed for prevention of peptic ulcers caused by Prostaglandin synthetase inhibitor (NSAIDS) but now it has a widespread role in obstetric practice specially as a cervical priming agent. The aim of present study is to compare oral misoprostol versus vaginal misoprostol for cervical ripening and to assess its acceptability among women.

Misoprostol-Induced Modification of the Notch Signaling Pathway in the Human Cervix.

The complex and multifactorial mechanisms that initiate and sustain the early labor process in the human uterus and cervix are still not well defined. Cervical maturation or ripening is likely to play a key role in preparing for birth. Prostaglandins have many different functions, including the regulation of uterine contractility and structure during pregnancy. The prostaglandin E1 analogue misoprostol is frequently used as a uterotonic and cervical ripening agent. Notch is a transmembrane receptor family responsible for basic functions such as cell survival, cell-cell communication, and differentiation and decidualization in pregnancy. However, our understanding of the effect of Notch signaling on the cervical ripening process is limited. This study was conducted in 20 pregnant women aged at 12 to 20 weeks of gestation undergoing medical abortion for fetal or maternal indications. True-Cut needle biopsies were taken from the anterior cervix 4 hours after oral ingestion of 200-μg misoprostol or before the ingestion of misoprostol in the control group. Cervical expression of Notch receptors and ligands changed during the early phase of prostaglandin-induced preterm labor. Four hours after the administration of misoprostol, it was seen that N1 expression increased in muscle, while DLL1 and J2 expression increased in blood vessels, and N4 expression increased in macrophages. Knowing the mechanisms that initiate preterm birth is the most important step in planning the treatments and actions to prevent premature birth. As a signal that affects and perhaps directs preterm labor, Notch is prone to be an important actor in this process.

Misoprostol regulates Bnip3 repression and alternative splicing to control cellular calcium homeostasis during hypoxic stress

The cellular response to hypoxia involves the activation of a conserved pathway for gene expression regulated by the transcription factor complex called hypoxia-inducible factor (HIF). This pathway has been implicated in both the adaptive response to hypoxia and in several hypoxic-ischemic-related pathologies. Perinatal hypoxic injury, often associated with prematurity, leads to multi-organ dysfunction resulting in significant morbidity and mortality. Using a rodent model of neonatal hypoxia and several representative cell lines, we observed HIF1α activation and down-stream induction of the cell death gene Bnip3 in brain, large intestine, and heart which was mitigated by administration of the prostaglandin E1 analog misoprostol. Mechanistically, we determined that misoprostol inhibits full-length Bnip3 (Bnip3-FL) expression through PKA-mediated NF-κB (P65) nuclear retention, and the induction of pro-survival splice variants. We observed that the dominant small pro-survival variant of Bnip3 in mouse cells lacks the third exon (Bnip3ΔExon3), whereas human cells produce a pro-survival BNIP3 variant lacking exon 2 (BNIP3ΔExon2). In addition, these small Bnip3 splice variants prevent mitochondrial dysfunction, permeability transition, and necrosis triggered by Bnip3-FL by blocking calcium transfer from the sarco/endoplasmic reticulum to the mitochondria. Furthermore, misoprostol and Bnip3ΔExon3 promote nuclear calcium accumulation, resulting in HDAC5 nuclear export, NFAT activation, and adaptive changes in cell morphology and gene expression. Collectively, our data suggests that misoprostol can mitigate the potential damaging effects of hypoxia on multiple cell types by activating adaptive cell survival pathways through Bnip3 repression and alternative splicing.

Neuroprotection by misoprostol against rotenone-induced neurotoxicity in rat brain

Objective: To investigate the effect of the prostaglandin E1 analogue misoprostol on oxidative stress and neurodegeration caused by subcutaneous rotenone administration in rats. Methods: Rotenone was administered in a dose of 1.5 mg/kg every other day for 2 weeks. Starting from the 1st day of rotenone injection, rats were subcutaneously treated with misoprostol at doses of 10, 100 or 1 000 μ g/kg. Rats were evaluated for brain lipid peroxidation (malondialdehyde: MDA), reduced glutathione (GSH), nitric oxide (NO) levels, and paraoxonase-1 (PON-1) activity. The concentrations of the anti-apoptotic protein B cell/lymphoma-2 (Bcl-2) were determined in the striatum. Histopathologic examination and the expression of inducible nitric oxide synthase (iNOS) in the cerebral cortex and striatum were also performed. Results: Compared with the vehicle-treated group, rotenone caused a significant increase in brain lipid proxidation (MDA) by 61% (P

La prescription hors AMM en gynécologie-obstétrique : du pragmatisme médico-économique au potentiel risque médico-légal

The scandal of the Mediator® case led the legislature to take measures in order to regulate off-label drugs prescriptions. Indeed the law issued in December 29th, 2011 on strengthening the safety of drugs and all derivative health products came to pave the way for an “over-cautious” practice of medicine in line with the precautionary principle erected as a constitutional principle. The supervision of off-label prescribing has had a direct impact on the exercise of the medical profession and has resurrected the issues related to the freedom of prescription, the obligation to provide information to patients and in general their whole responsibility. It is important to mention that the prescribing act is part of the freedom and the strict prerogative of those skilled in the art: the physician in this case. The off-label prescription is commonly accepted in certain specialties, such as anesthesia and intensive care, oncology or pediatrics where it is even subject of a memorandum of use because of concerns regarding the availability of forms adapted to children. However, the physician must ensure that no appropriate therapeutic alternative is available and inform the patient, fundamental principle of the right to respect for the will of the person. Off-label use of the prostaglandin-E1 analogue misoprostol in obstetrics and gynecology is a good example. In fact, this drug obtained a marketing authorization for the treatment or prevention of peptic ulcers and other stomach disorders, is commonly used off-label when inducing labour or intrauterine device insertion. These are the issues that need to be clarify and carefully assessed in order to help physicians to understand the impact of the law and the state of the jurisprudence on the exercise of their profession.

Ulcerating and stenosing enteropathy treated with misoprostol

A case of a 40-year-old man with chronic anaemia because of nonspecific ulcerating and stenosing enteropathy is presented. The diagnosis was made on the basis of capsule endoscopy, histology of resected ileum and no use of NSAIDs. He showed a clinical response to treatment with misoprostol, and therefore, he was investigated for a possible impairment in eicosanoid biosynthesis compared with healthy controls. No deficient synthesis of prostacyclin, prostaglandin E2 and thromboxane was found on examination of metabolites in blood and urine. This suggests a normal release of arachidonic acid from phospholipids. Ex-vivo cyclooxygenase (COX) assays showed normal COX-1 and COX-2 activities. The clinical response to treatment with the prostaglandin E1 analogue misoprostol suggests a defective prostaglandin E synthesis in the intestinal mucosa.

Prostaglandin-induced cervical remodelling in humans in the first trimester is associated with increased expression of specific tight junction, but not gap junction proteins

BackgroundProstaglandins (PG) are widely employed to induce cervical remodelling (CR) in pregnancy. However, the underlying molecular mechanisms are not fully elucidated. Tight junctions (TJ) and gap junctions (GJ) regulate paracellular and intercellular solute transport respectively but their role in the process of CR remains unexplored. We hypothesized that the synthetic prostaglandin E1 analogue Misoprostol (M), widely used in clinical practice to induce CR, may alter TJ and GJ expression as part of the changes in the extracellular matrix (ECM) associated with remodelling. We investigated the effects of Misoprostol exposure on the expression of cervical TJ (claudins 1, 2, 4, 5, 7 and occludin) and GJ (connexins 43, 30 and 26) in the 1st trimester.MethodsCervical biopsies were obtained from pregnant women and comparisons of TJ and GJ protein expression (by western blotting) and immunolocalisation (laser scanning confocal microscopy) made between those who were administered vaginal Misoprostol (n = 10) and those who were not (n = 5).ResultsWe found that Misoprostol-treated tissue (M+) had higher expression of Claudins 1,2,4,7 and occludin (p < 0.05) than untreated (M-) tissue. Expression levels of Claudins 1, 2 and 4 were positively correlated to interval from Misoprostol treatment to biopsy, whilst occludin was negatively correlated. Misoprostol-treated cervical tissue demonstrated more endothelial claudin-5 and occludin, whilst expression of GJs were unchanged.ConclusionOur observations suggest, for the first time, that increased expression of tight junction proteins may be one of the mechanisms by which Misoprostol induces CR in humans. Further studies are needed to explore if TJ proteins may be therapeutic targets to alter timing of CR in clinical practice.

The Effects of Enprostil and RS-86505-007 on In-vitro Intestinal Permeability of Rabbit and Monkey

Enprostil is a prostaglandin E2 analogue characterized as a racemic mixture of four stereoisomers. Enprostil and a single isomer, RS-86505-007, were evaluated for their effects on the permeability of actively and passively transported compounds in segments of small intestine from rabbits and monkeys. Consistent with human in-vivo studies, which have demonstrated decreases in absorption of D-xylose, both compounds inhibited D-glucose transport. The passively transported compounds mannitol and progesterone were also less permeable in this model in the presence of enprostil or RS-86505-007. In contrast to the concentration-dependent inhibition displayed by ouabain, RS-86505-007 had no effect on purified Na+K(+)-ATPase. It is suggested that an effect of a general nature, possibly an increase in the barrier properties at the intestinal surface, may explain the transport inhibition. Of two other enprostil isomers, RS-86812-007 inhibited D-glucose transport in rabbit small intestine, while RS-86505-008 had no effect. The prostaglandin E1 analogue misoprostol was ineffective in monkey and poorly effective in rabbit. This suggests that the inhibition of D-glucose transport by enprostil and its active stereoisomers is mediated through some structurally specific receptor interaction.

A comparative study between isosorbide mononitrate (IMN) versus misoprostol prior to hysteroscopy

Abstract Objective To compare the efficacy of a nitric oxide donor (isosorbide mononitrate) and a prostaglandin E1 analogue (misoprostol) for cervical priming before hysteroscopy. Design Comparative clinical trial. Methods A total of 162 patients with diagnosed intrauterine lesions scheduled for hysteroscopy were allocated to two groups: in group A patients ( n =81) IMN 40mg was inserted into the posterior fornix of the vagina while misoprostol 200μg was inserted into the posterior fornix of the vagina in group B patients ( n =81). Results There was no significant difference between IMN and misoprostol with regard to the duration of application or difficult dilatation. In contrast, there was a significant difference between IMN and misoprostol with regard to baseline cervical dilatation (5mm for IMN and 8mm for misoprostol) and duration of dilatation (73s for IMN and 49s for misoprostol). There was no significant difference between IMN and misoprostol with regard to nausea, vomiting and hot flushes. In contrast, there was a significant difference between IMN and misoprostol with regard to abdominal pain (17 cases for IMN and 55 cases for misoprostol) and headache (65 cases for IMN and 9 cases for misoprostol). Conclusion Misoprostol is superior to isosorbide mononitrate regarding better baseline cervical dilatation, less duration of dilatation, less incidence cervical injury and finally better feasibility of the procedure.

Prostaglandin E1 and misoprostol increase epidermal growth factor production in 3D-cultured human annulus cells

Background context Epidermal growth factor (EGF) is a peptide known to modulate a number of cellular responses including embryogenesis, cell proliferation, and cell survival. Little is known about EGF and its regulation in human annulus cells. Previous work has identified EGF and its receptor in control outer annulus disc tissue, but not in herniated tissue. Purpose To determine if human annulus cells express EGF in vitro, to determine if the epidermal growth factor-receptor (EGF-r) was expressed in vivo and in vitro in disc cells, to test the effect of EGF on annulus cell proliferation and proteoglycan production in vitro, and to test the effect of prostaglandin E1 (PGE1) and misoprostol on disc cell production of EGF in vitro. Study design/setting Studies were approved by the authors' Human Subjects Institutional review Board. Human disc tissue was used for immunocytochemistry, and human annulus cells were tested in vitro. Patient sample Thirty-four disc specimens were used for studies of proteoglycan production, cell proliferation, and EGF production in vitro. An additional nine discs were used for EGF-r immunolocalization. Methods Disc tissue was used for immunocytochemical studies for the localization of EGF-r and as a source for cultured annulus cells. Monolayer culture was used to test proliferation responses to 0, 25, 50, or 75 ng/mL EGF over a 2-day culture period. Three-dimensional (3D) culture in a collagen sponge was used to test 100,000 cells cultured in a paired experimental design over 14 days for production of EGF and proteoglycans. Cells were exposed to control conditions, or to either misoprostol at 8 ng/mL or PGE1 at 10 −7 M. Conditioned media was harvested and assayed using an enzyme-linked immunosorbent assay (ELISA) assay with the Human Protein Cytokine Antibody Array I kit. Replicate EGF relative intensity values were averaged and normalized to controls assayed on the same membrane. 3D-cultured cells were also used to confirm EGF gene expression using microarray analysis. Standard statistical methods were used to analyze results. Results Microarray analysis of mRNA from annulus cells in 3D culture confirmed expression of EGF, and immunocytochemistry verified the presence of EGF-r in vitro and in vivo. PGE1, at a dose of 10 −7 M, and misoprostol (a synthetic PGE1 analog) at a dose of 8 ng/mL, both significantly increased EGF levels in annulus cells cultured in 3D compared with control levels (p=.031 and .034, respectively). No significant difference, however, was seen in cell proliferation or in total sulfated proteoglycan production in EGF-exposed annulus cells. Conclusions Data showed that EGF is expressed and produced by annulus cells in vivo and in 3D culture, with significantly greater in vitro EGF produced in the presence of PGE1 or the PGE1 analog misoprostol. Misoprostol, developed for prevention/treatment of nonsteroidal anti-inflammatory-induced gastropathy, has now been reported to have some interesting anabolic effects stimulating osteoblasts during fracture healing and during ovariectomy in animal models. Exogenous EGF did not increase cell proliferation in monolayer, or total production of proteoglycans in 3D culture. Additional work is needed to further delineate the role of EGF in the human disc.