Synthetic Prostaglandin E1 Analogue Research Articles

CLINICAL AND PHARMACOLOGICAL CHARACTERISTICS OF THE USE OF REBAMIPIDE IN DISEASES OF THE GASTROINTESTINAL TRACT LITERATURE REVIEW

NSAID-induced lesions of the gastrointestinal tract gained wide spread in the recent decade. Their range includes lesion of the esophagus, syndrome of dyspepsia, gastropathy and enteropathy. Diagnosis establishment of enteropathy is complicated and became possible after introduction of the capsule endoscopy. PPI are used for treatment of gastropathy, but they are not effective for treating enteropathy. Cytoprotective prostaglandins play the key role in the development of NSAID lesions of the gastrointestinal tract. Synthetic analogues of prostaglandins of misoprostol type possess cytoprotective action, but cause a significant number of adverse events. Rebamipide, a new gastroprotective agent in Russia stimulates production of endogenous prostaglandins. This drug proved its efficacy during the clinical trials performed according to the standards of the evidence-based medicine.

A critical appraisal of the misoprostol removable, controlled-release vaginal delivery system of labor induction.

BackgroundInduction of labor is a major issue in pregnancy management. Finding strategies to increase rate and decrease time to vaginal delivery is an important goal, but maternal or neonatal safety must remain the primary objective. Misoprostol is a synthetic analogue of prostaglandin used off label to ripen the cervix and induce labor. The misoprostol vaginal insert (MVI) was designed to allow a controlled-release delivery of misoprostol (from 50 to 200 μg) with a removal tape. The objective of this review was to make a critical appraisal of this device referring to the literature.MethodsA literature search was performed in the PubMed and Cochrane databases using the keywords “vaginal misoprostol insert”.ResultsSeveral studies compared different doses of MVI (50, 100, 150, and 200 μg) with the 10 mg dinoprostone insert. The 100 μg MVI compared with the dinoprostone vaginal insert (DVI) showed similar efficacy and no significant differences in cesarean delivery rate. MVI 200 μg compared with DVI showed a reduced time to vaginal delivery and oxytocin need but had an increased risk of uterine hyperstimulation. The rate of hyperstimulation syndrome was two to three times more frequent with the 200 μg MVI than the 100 μg.ConclusionCurrent data suggest that the 100 μg MVI would provide the best balance between efficacy and safety. Further studies should be performed to evaluate this dose, especially in high-risk situations needing induction of labor.

Development and validation of LC methods for the separation of misoprostol related substances and diastereoisomers

Misoprostol is a synthetic prostaglandin E1 analogue which is mainly used for prevention and treatment of gastric ulcers, but also for abortion due to its labour inducing effect. Misoprostol exists as a mixture of diastereoisomers (1:1) and has several related impurities owing to its instability at higher temperatures and moisture. A simple and robust reversed phase liquid chromatographic (RPLC) method is described for the separation of the related substances and a normal phase (NP) LC method for the separation of misoprostol diastereoisomers. The RPLC method was performed using an Ascentis Express C18 (150mm×4.6mm, 5μm) column kept at 35°C. The mobile phase was a gradient mixture of mobile phase A (ACN–H2O–MeOH, 28:69:3 v/v/v) and mobile phase B (ACN–H2O–MeOH, 47:50:3 v/v/v) eluted at a flow rate of 1.5mL/min. UV detection was performed at 200nm. The NPLC method was undertaken by using an XBridge bare silica (150mm×2.1mm, 3.5μm) column at 35°C. The mobile phase contained 1-propanol–heptane–TFA (4:96:0.1%, v/v/v), pumped at a flow rate of 0.5mL/min. UV detection was performed at 205nm. This LC method can properly separate the two diastereoisomers (Rs>2) within an analysis time of less than 20min. Both methods were validated according to the ICH guidelines. Furthermore, these new LC methods have been successfully applied for purity control and diastereoisomers ratio determination of misoprostol bulk drug, tablets and dispersion.

PGE2 receptor agonist misoprostol protects brain against intracerebral hemorrhage in mice

Intracerebral hemorrhage (ICH) is a devastating form of stroke. Misoprostol, a synthetic prostaglandin E1 (PGE1) analog and PGE2 receptor agonist, has shown protection against cerebral ischemia. In this study, we tested the efficacy of misoprostol in the 12-month-old mice subjected to 1 of 2 complementary ICH models, the collagenase model (primary study) and blood model (secondary study, performed in an independent laboratory). We also investigated its potential mechanism of action. Misoprostol posttreatment decreased brain lesion volume, edema, and brain atrophy and improved long-term functional outcomes. In the collagenase-induced ICH model, misoprostol decreased cellular inflammatory response; attenuated oxidative brain damage and gelatinolytic activity; and decreased high-mobility group box 1 (HMGB1) expression, Src kinase activity, and interleukin-1β expression without affecting cyclooxygenase-2 expression. Furthermore, HMGB1 inhibition with glycyrrhizin decreased Src kinase activity, gelatinolytic activity, neuronal death, and brain lesion volume. Src kinase inhibition with 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) decreased gelatinolytic activity and brain edema and improved neurologic function but did not decrease HMGB1 protein level. These results indicate that misoprostol protects brain against ICH injury through mechanisms that may involve the HMGB1, Src kinase, and matrix metalloproteinase-2/9 pathways.

Effects of topical application of misoprostol on cervical relaxation in mares.

Mares who have not delivered a foal early in life may experience limitations in cervical relaxation, primarily during oestrus. A closed cervix prevents intrauterine deposition of semen during natural breeding, may delay uterine clearance after insemination leading to intrauterine fluid accumulation in, and subsequent infertility. Therefore, a reliable pharmacological method of dilating the equine cervix would have practical application in veterinary medicine. The goal of this study was to investigate the effectiveness of topically applied, synthetic prostaglandin E1 analogue (PGE1 ) for stimulating dilation of the equine cervix. Ten mares in dioestrus were randomly assigned to one of two treatments in a single-blind crossover study: (treatment) PGE1 gel (1000mcg compounded misoprostol cream) applied topically to the external cervical os (n=5), and (control) a vehicle cream applied topically to the external cervical os (n=5). Transrectal palpation and ultrasonographic measurements of the cervix were performed prior to, six and 24h post-treatment. Digital measurements were taken, per vagina, at six and 24h post-treatment. Mares were monitored through the subsequent oestrous cycle for ovulation. Mares were assigned to the opposite treatment group such that each mare served as her own control (crossover). Data were analysed using parametric (split-plot anova), as well as nonparametric (Kruskal-Wallis anova, Wilcoxon's rank-sum test) methods. At six and 24h there were no significant differences for tone, length, height, degree of relaxation or echotexture between control and PGE1 treated groups at the measured time points (p>0.05). Topical cervical application of PGE1 did not induce a measurable degree of cervical relaxation under the conditions of this experiment.

The impact of non-steroidal anti-inflammatory drugs on the small intestinal epithelium

The small intestine has been called as a dark continent of digestive tract and it had been very difficult to diagnose or treat the disease of small intestine. However recent technological development including video capsule endoscopy or balloon-assisted endoscopy has made us to aware the various diseases of small intestine. By using capsule endoscopy, many researchers reported that more than 70% of patients treated continuously with non-steroidal anti-inflammatory drugs (NSAID) exhibit the mucosal damage of small intestine. In some cases, NSAID not only causes mucosal damage but also results in life threatening bleeding from small intestine, which had not been prevented or cured by gastro-protective drug or anti-gastric acid secretion drug administration. Therefore to investigate and identify the effective drug that protects small intestine from mucosal damage is urgently expected. In spite of extensive investigation in clinical field, only a few drugs such as misoprostol, a synthetic prostaglandin E1 analogue, has been reported as an effective one but is not satisfactory enough to fulfill the requirement of patients who suffer from NSAID-induced mucosal damage of small intestine. And now, extensive study is being performed using several gastro-mucoprotective drugs by many researchers. In this review, we introduce the current clinical situation in small intestinal injury of patients under NSAID treatment, and to summarize the molecular mechanism by which NSAID, including acetyl salicylic acid, cause small intestinal damage. In addition, we present results of clinical trials performed so far, and refer the possible preventive method or treatment in the near future.

The effectiveness of vaginal misoprostol in achieving cervical ripening before operative hysteroscopy (OHYS)

OHYS has gained popularity in management of intrauterine abnormalities. Cervical dilatation (CD) represents a real challenge during the procedure. Misoprostol, a synthetic prostaglandin E1 analogue has a cervical ripening effect, being more effective when it is administered vaginally than orally. Aim of this work is to evaluate the effectiveness of vaginal Misoprostol in facilitating CD prior to OHYS.

Intestinal absorption of lysozyme, an egg-white allergen, in rats: Kinetics and effect of NSAIDs

The absorption pathway(s) of a representative food allergen, lysozyme, and the mechanisms of lysozyme absorption facilitated by non-steroidal anti-inflammatory drugs were examined by intestinal closed-loop and re-circulating perfusion methods in rats. The absorption rate of fluorescein isothiocyanate (FITC)-labeled lysozyme in the proximal intestine was higher than that for a marker of non-specific absorption, FD-10, and was suppressed by colchicine (endocytosis inhibitor). Aspirin increased the absorption of FITC-lysozyme in the proximal intestine with no effects on tissue accumulation. Diclofenac facilitated FITC-lysozyme absorption, but meloxicam and loxoprofen exerted no effects on absorption. Co-administration of misoprostol (synthetic prostaglandin-E1 analog) with aspirin significantly ameliorated the aspirin-facilitated absorption of FITC-lysozyme to the same level as that seen with controls. Thus, lysozyme absorption was mediated by endocytic and paracellular pathways in the proximal intestine, and was facilitated by aspirin and diclofenac after impairment of the paracellular pathway. Misoprostol may suppress the allergen absorption facilitated by aspirin.

An Ongoing Epidemic of Birth Defects

In the 1990s, misoprostol (synthetic prostaglandin E1 analogue) was found to be an effective abortive agent when taken orally and became widely used in Latin America as a means to terminate unwanted pregnancies. A variety of congenital anomalies have been observed among the children of women who ingested misoprostol, but failed to terminate their pregnancy. We report here eight years of experience in Panama with the detection and follow-up of the malformations seen in infants associated with the use of misoprostol prostaglandin during the first trimester of pregnancy. During the period between April 1995 and March 2003, we identified 63 infants at the Panama’s Children’s Hospital who were exposed to misoprostol while in the womb and who were born with malformations. These infants were evaluated by a team of neonatologists, geneticists, cardiologists, ophthalmologists, and radiologists.

Misoprostol decreases oxidative stress and liver injury in bacterial lipopolysaccharide-induced endotoxemia in mice

The effect of misoprostol, a synthetic prostaglandin E1 analog, on the development of oxidative stress induced in mice with lipopolysaccharide (LPS) endotoxin was investigated. Misoprostol was administered by intraperitoneal route (i.p.) at doses of 10, 100, or 1,000 μg/kg at the time of LPS injection (200 μg/kg, i.p.). Mice were euthanized 4 h later. Lipid peroxidation (malondialdehyde; MDA), reduced glutathione (GSH), nitric oxide (nitrite/nitrate) levels as well as paraoxonase activity were measured in brain and liver. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities as well as DNA fragmentation were determined in the liver. The administration of LPS increased oxidative stress both in the brain and liver tissue. There were significantly increased MDA and nitrite and decreased GSH and PON1 activity in the brain and liver, respectively. In addition, LPS was associated with markedly elevated plasma ALT and AST level as well as increased liver DNA fragmentation. The administration of misoprostol at 100 or 1,000 μg/kg decreased brain MDA by 17.6 and 30 %, increased GSH by 29.8 and 33.3 %, and decreased nitric oxide by 21.74 and 42.5 %, respectively, compared with the lipopolysaccharide control group. Liver MDA decreased by 27 %, GSH increased by 47.7 %, and nitric oxide decreased by 37.2 % with misoprostol at 1,000 μg/kg. Paraoxonase activity increased in both the brain and liver by misoprostol administration. The increase in liver AST and ALT and DNA fragmentation after endotoxin administration was normalized by misoprostol. These results indicate that misoprostol can alleviate oxidative stress in the presence of a mild systemic inflammatory illness, indicating a new and potentially important therapeutic application for the drug.

EFFECTS OF SESAMUM RADIATUM AQUEOUS LEAF EXTRACT ON RHYTHMIC CONTRACTIONS OF UTERINE SMOOTH MUSCLE BUNDLES FROM PREGNANT RATS

Sesamum radiatum is employed in traditional medicine for parturient women to facilitate deliveries. In this study, the effects of the aqueous leaf extract were examined on the contractile activity of uterine smooth muscle isolated from pregnant Wistar rats (19-21 days). The isometric contractile force of the uterine smooth muscle bundles was recorded by using a strain gauge. S. radiatum aqueous leaf extracts (ESera, 1×10 -4 µg/ml - 100µg/ml) showed uterotonic properties. These uterotonic effects were characterized by the increase of the amplitude, the frequency and the basal tone of the uterine smooth muscle strips in normal Mac Ewen solution and by the development of contracture in depolarizing solution and in solution without calcium. Similar effects were observed with Oxytocin (OT, 2.5×10 -14 µg/ml - 2.5×10 -9 µg/ml) and misoprostol (Miso, 1×10 -3 µg/ml - 0.08µg/ml). In Ca 2+ -free solution, the addition of the ESera (10 µg / ml) elicited the development of contracture in the presence of EGTA (0.1 mM). This result suggests that ESera could act on the double calcium flux (intracellular and extracellular) like misoprostol, a synthetic analogue of prostaglandin E1. In conclusion, the aqueous leaf extract of S. radiatum (ESera) had uterotonic effects (prostaglandin-like activity) on uterine contraction in pregnant rats.

Cervical Priming and Scar Rupture

Misoprostol, a synthetic prostaglandin E1 analog, is being increasingly used for cervical priming to facilitate first trimester surgical termination and has been shown to be safe in women with previous uterine surgery [1, 2]. We report a case of uterine rupture with oral misoprostol for cervical priming before surgical evacuation in a woman with previous cesarean section.

Cardiac arrest during sulprostone administration – a case report

Sulprostone, a synthetic prostaglandin analogue with potent uterotonic action, has been shown to have a low complication rate in a large series. We present a case of cardiac arrest in a parturient after Caesarean section during continuous infusion of intravenous sulprostone administered for atonic post-partum haemorrhage. She had cardiopulmonary resuscitation for 25 min before spontaneous circulation returned. The sequence of events, the results of investigations carried out during the intensive care unit stay, and the presence of multiple cardiovascular risk factors, suggest that sulprostone caused coronary spasm, bradycardia, and subsequent asystole, similar to other cases described in the literature.

Use of Misoprostol in Pregnancy- A Review Article

Prostaglandins are the pharmacological agents used for induction of labour and augmentation of labour. Prostaglandin E2 gel is used for cervical ripening and induction of labour. These are however, costly and need to be stored in a refrigerator at a temperature of 2 - 8°C, half life 18 months. The Tablet form of prostaglandin E2 is not available in Bangladesh. Misoprostol, a synthetic prostaglandin (PG) E1 analogue is used orally for the treatment of gastric and duodenal ulcer and used as a cytoprotective agent. It was first used for labour induction in 1987. Prostaglandin can be used in several gynaecological and obstetric conditions. It can be given through several routes. This article will elaborately delinate the role of misoprostol, a prostaglandin in obstetrics and gynaecological conditions. Medicine Today 2010 Volume 22 Number 02 Page 94-98 DOI: http://dx.doi.org/10.3329/medtoday.v22i2.12443

Dose–response relationship of locally applied nimodipine in an ex vivo model of cerebral vasospasm

Cerebral vasospasm is a severe complication of subarachnoid hemorrhage (SAH). The calcium channel inhibitor nimodipine has been used for treatment of cerebral vasospasm. No evidence-based recommendations for local nimodipine administration at the site of vasospasm exist. The purpose of this study was to quantify nimodipine's local vasodilatory effect in an ex vivo model of SAH-induced vasospasm. SAH-induced vasospasm was modeled by contracting isolated segments of rat superior cerebellar arteries with a combination of serotonin and a synthetic analog of prostaglandin A(2). A pressure myograph system was used to determine vessel reactivity of spastic as well as non-spastic arteries. Compared to the initial vessel diameter, a combination of serotonin and prostaglandin induced considerable vasospasm (55 ± 2.5 % contraction; n = 12; p < 0.001). Locally applied nimodipine dilated the arteries in a concentration-dependent manner starting at concentrations as low as 1 nM (n = 12; p < 0.05). Concentrations higher than 100 nM did not relevantly increase the vasodilatory effect. Nimodipine's vasodilatory effect was smaller in spastic than in non-spastic vessels (n = 12; p < 0.05), which we assume to be due to structural changes in the vessel wall. The described ex vivo model allows to investigate the dose-dependent efficacy of spasmolytic drugs prior to in vivo experiments. Low concentrations of locally applied nimodipine have a strong vasodilatory effect, which is of relevance when considering the local application of nimodipine in cerebral vasospasm.

A prospective survey of cases of complications of induced abortion presenting to Goroka hospital, Papua New Guinea, 2011

Induced abortion on demand or for socio-economic indications is illegal in Papua New Guinea under the 1974 Criminal Code. Nevertheless, the procedure is known to be widely practised. This prospective study examines the demographic and medical features of women presenting with complications of induced abortion to Goroka Hospital in a 6-month period. It was noted that abortion was most commonly induced using the synthetic prostaglandin analogue misoprostol. Although illegal induced abortion cannot be condoned, it appears that misoprostol, much safer in this context than mechanical or traditional herbal methods, is now being widely used for the purpose of induced abortion in Papua New Guinea, as it is in other developing countries.

Lack of Evidence for Neonatal Misoprostol Neurodevelopmental Toxicity in C57BL6/J Mice

Misoprostol is a synthetic analogue of prostaglandin E1 that is administered to women at high doses to induce uterine contractions for early pregnancy termination and at low doses to aid in cervical priming during labor. Because of the known teratogenic effects of misoprostol when given during gestation and its effects on axonal growth in vitro, we examined misoprostol for its potential as a neurodevelopmental toxicant when administered to neonatal C57BL6/J mice. Mice were injected subcutaneously (s.c.) with 0.4, 4 or 40 µg/kg misoprostol on postnatal day 7, the approximate developmental stage in mice of human birth, after which neonatal somatic growth, and sensory and motor system development were assessed. These doses were selected to span the range of human exposure used to induce labor. In addition, adult mice underwent a battery of behavioral tests relevant to neurodevelopmental disorders such as autism including tests for anxiety, stereotyped behaviors, social communication and interactions, and learning and memory. No significant effects of exposure were found for any measure of development or behavioral endpoints. In conclusion, the results of the present study in C57BL/6J mice do not provide support for neurodevelopmental toxicity after misoprostol administration approximating human doses and timed to coincide with the developmental stage of human birth.

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.

Efficacy and safety of vaginal misoprostol in second trimester medical termination of pregnancy

Search for safe and effective method for second trimester termination of pregnancy continue from the time, when pregnancy termination was legalized through MTP act in India. With the knowledge about the potent uterotonic potential of misoprostol ,a synthetic prostaglandin analog , it is being (off label) used for second trimester termination of pregnancy with satisfactory results .Various dosage schedules and routes have been tried for this purpose .Present study was carried out to know the efficacy and safety of vaginal administration of misoprostol for second trimester of pregnancy .One hundred forty eight women seeking termination of pregnancy in second trimester, for various indications as per MTP act, over three years period at government approved MTP center, attached to Medical college hospital, were included in the study .Initial dose of 400 microgram of misoprostol by per vaginal route ,followed by 200 microgram was used for induction of abortion. Overall success rate was 92 percent and average induction abortion interval was 14 hours .There were no serious side effects or complications related to misoprostol .Average dose required for complete abortion was 1200 micrograms .Misoprostol was found to be safe and effective for second trimester medical termination of pregnancy.

A randomized, double-blind, placebo-controlled trial of misoprostol for oral mucositis secondary to high-dose chemotherapy

Misoprostol, a synthetic analog of prostaglandin E1, has anti-inflammatory and mucosa-protecting properties. The objective of this study was to evaluate the efficacy of misoprostol oral rinse in reducing the severity of oral mucosal injury caused by high-dose chemotherapy. The study used a randomized, double-blind, placebo-controlled, parallel-group design. Oncology patients receiving myeloablative high-dose chemotherapy, in preparation for a hematopoietic stem cell transplant, were randomized to misoprostol or placebo rinse. The primary outcome measure was the severity of oral mucositis, measured using the modified Oral Mucositis Index. Additional outcome measures included the severity of mouth pain (measured using a Visual Analog Scale and the Pain Affect Faces Scale), duration of hospital stay, and days on total parenteral nutrition. This study was originally planned to accrue 160 subjects but was terminated early due to revised sponsor research priorities. The intent-to-treat population consisted of 22 subjects randomized to misoprostol rinse and 26 subjects randomized to placebo rinse. There was no significant difference between the two groups in mucositis or pain severity. In both groups, duration of hospital stay was approximately 19 days, and number of days on total parenteral nutrition was 17-18 days. There were no serious adverse events attributable to misoprostol rinse. Although this study did not find a beneficial effect of a misoprostol rinse in mucositis secondary to high-dose chemotherapy, the small sample size limits the strength of this conclusion. Given the proposed importance of the prostaglandin pathway in the pathogenesis of oral mucositis, additional studies are warranted.