Multi-target mechanism of misoprostol in pregnancy termination based on network pharmacology and molecular docking.

Misoprostol is a prostaglandin analogue that contracts the uterus, prompting the expulsion of the embryo. No systematic evaluation of the mechanisms of misoprostol has previously been performed. In this study, known targets of misoprostol were obtained from the DrugBank database; potential targets of misoprostol were predicted using data from the SwissTargetPrediction and PharmMapper databases; and the main targets of pregnancy termination were obtained from the GeneCards database. The protein-protein interaction (PPI) network of the shared genes between misoprostol and pregnancy termination was constructed using data from the STRING database, and the "misoprostol-pregnancy termination-pathway" network was constructed and potential targets was verified through molecular docking. We analyzed 37 shared target genes and obtained a network diagram of 134 potential targets, which the core therapeutic targets were HSP90AA1, EGFR, and MAPK1. GO functional and KEGG pathway enrichment analyses showed that misoprostol can modulate the VEGF signaling pathway, calcium signaling pathway, and NF-κB signaling pathway in pregnancy termination and mainly interferes with protein phosphorylation, cell localization, and protein hydrolysis regulation processes. This research illustrates the mechanism underlying the pharmacological effect of misoprostol, namely pregnancy termination. However, further experimental verification is warranted for optimal use of misoprostol during clinical practice.

Le misoprostol est un analogue des prostaglandines qui contracte l'utérus, provoquant l'expulsion de l'embryon. Aucune évaluation systématique des mécanismes du misoprostol n'a été réalisée auparavant. Dans cette étude, les cibles connues du misoprostol ont été obtenues à partir de la base de données DrugBank ; Les cibles potentielles du misoprostol ont été prédites à l'aide des données des bases de données SwissTargetPrediction et PharmMapper ; et les principales cibles de l'interruption de grossesse ont été obtenues à partir de la base de données GeneCards. Le réseau d'interaction protéine-protéine (IPP) des gènes partagés entre le misoprostol et l'interruption de grossesse a été construit à l'aide des données de la base de données STRING, et le réseau « voie d'interruption de grossesse-misoprostol ¼ a été construit et les cibles potentielles ont été vérifiées par amarrage moléculaire. Nous avons analysé 37 gènes cibles partagés et obtenu un diagramme de réseau de 134 cibles potentielles, dont les principales cibles thérapeutiques étaient HSP90AA1, EGFR et MAPK1. Les analyses d'enrichissement des voies fonctionnelles GO et KEGG ont montré que le misoprostol peut moduler la voie de signalisation VEGF, la voie de signalisation du calcium et la voie de signalisation NF-κB lors de l'interruption de grossesse et interfère principalement avec les processus de phosphorylation des protéines, de localisation cellulaire et de régulation de l'hydrolyse des protéines. Cette recherche illustre le mécanisme sous-jacent à l'effet pharmacologique du misoprostol, à savoir l'interruption de grossesse. Cependant, une vérification expérimentale plus approfondie est justifiée pour une utilisation optimale du misoprostol au cours de la pratique clinique.

Steroid-Induced Ocular Hypertension in Mice Is Differentially Reduced by Selective EP2, EP3, EP4, and IP Prostanoid Receptor Agonists.

We tested five chemically and metabolically stable prostaglandin (PG) receptor agonists in a mouse model of dexamethasone-induced ocular hypertension (OHT). Whilst all compounds significantly (p < 0.05, ANOVA) lowered intraocular pressure (IOP) after twice-daily bilateral topical ocular dosing (5 µg/dose) over three weeks, the time course and magnitude of the responses varied. The onset of action of NS-304 (IP-PG receptor agonist) and rivenprost (EP4-PG receptor agonist) was slower than that of misoprostol (mixed EP2/EP3/EP4-PG receptor agonist), PF-04217329 (EP2-PG receptor agonist), and butaprost (EP2-PG receptor agonist). The rank order of IOP-lowering efficacies aligned with the onset of actions of these compounds. Peak IOP reductions relative to vehicle controls were as follows: misoprostol (74.52%) = PF-04217329 (74.32%) > butaprost (65.2%) > rivenprost (58.4%) > NS-304 (55.3%). A literature survey indicated that few previously evaluated compounds (e.g., latanoprost, timolol, pilocarpine, brimonidine, dorzolamide, cromakalim analog (CKLP1), losartan, tissue plasminogen activator, trans-resveratrol, sodium 4-phenyl acetic acid, etc.) in various animal models of steroid-induced OHT were able to match the effectiveness of misoprostol, PF-04217329 or butaprost. Since a common feature of the latter compounds is their relatively high affinity and potency at the EP2-PG receptor sub-type, which activates the production of intracellular cAMP in target cells, our studies suggest that drugs selective for the EP2-PG receptor may be suited to treat corticosteroid-induced OHT.

Desmopressin, Misoprostol, nor Carboprost Affect Platelet Aggregability Following Traumatic Brain Injury and Aspirin.

INTRODUCTION: Desmopressin (DDAVP) has been utilized clinically in patients taking aspirin (ASA) to improve drug-induced platelet dysfunction. Misoprostol and carboprost, prostaglandin analogs commonly used for postpartum hemorrhage, may also induce platelet aggregation. The aim of this study was to determine the effects of DDAVP, misoprostol, and carboprost administration on platelet aggregability following traumatic brain injury (TBI) in mice treated with ASA. METHODS: Male C57BL/6 mice were randomized into seven groups (n = 5 each): untouched, ASA only, Saline/TBI, ASA/TBI, ASA/TBI/DDAVP 0.4 µg/kg, ASA/TBI/misoprostol 1 mg/kg, and ASA/TBI/carboprost 100 µg/kg. TBI was induced via a weight drop model 4-h after ASA (50 mg/kg) gavage. Mice were given an intraperitoneal injection of DDAVP, misoprostol, or carboprost 10 minutes after TBI. In vivo testing was completed utilizing tail vein bleed. Mice were sacrificed 30-min posttreatment and blood was collected via cardiac puncture. Whole blood was analyzed via Multiplate impedance aggregometry, rotational thromboelastometry, and TEG6s. RESULTS: Mice receiving misoprostol after ASA/TBI demonstrated decreased tail vein bleeding times compared to ASA only treated mice. However, mice treated with misoprostol following ASA and TBI demonstrated decreased platelet aggregability compared to untouched mice and TBI only mice within the arachidonic acid agonist pathway. By contrast, DDAVP and carboprost did not significantly change platelet aggregability via adenosine diphosphate or arachidonic acid following ASA and TBI. However, DDAVP did decrease the platelet contribution to clot via rotational thromboelastometry. CONCLUSIONS: Reversal of medication-induced platelet inhibition has become increasingly controversial after TBI. Based on these results, DDAVP, misoprostol, nor carboprost consistently improve platelet aggregability following TBI in those also treated with ASA.

Protective effect of misoprostol against paclitaxel-induced cardiac damage in rats.

OBJECTIVE: One of the most critical reasons for limiting cancer treatment is the toxic effects of anti-cancer drugs on healthy tissues and organs. This study aims to investigate the possible protective effects of misoprostol (MS) against the damage that arises from paclitaxel (PT), an anti-cancer pharmacological agent, in the rat heart using histopathological and biochemical analyses. METHODS: In this study, four groups, each containing seven animals, were formed by random selection from 28 Sprague Dawley female rats. Control group rats were administered 1 ml of normal saline orally and intraperitoneally (i.p.) for six days. While the PT group rats were administered PT at a dose of 2 mg/kg intraperitoneally (i.p.) on days 0, 2, 4, and 6, the MS group was administered MS at a dose of 0.2 mg/kg in 1 ml normal saline by oral gavage for six days. PT and MS were administered to the PT + MS group rats in the same dose and route as the previous groups. RESULTS: Administration of PT increased serum lactate dehydrogenase (LDH), cardiac troponin I (cTn-I), creatine kinase isoenzyme MB (CK-MB), and brain natriuretic peptide (BNP) levels. PT administration also decreased the levels of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) in the heart tissue while increasing the level of malondialdehyde (MDA) (p < 0.05). In histopathological examinations, pathological changes, such as edema, congestion, hemorrhage, apoptosis, and degeneration, occurred in the heart tissue of PT-treated rats. The negative changes in histopathological and biochemical parameters that occurred in the PT group were almost not observed in the PT + MS group (p < 0.005). CONCLUSION: When the findings were evaluated, it was concluded that MS protects the heart tissue from the harmful effects of PT, probably due to its antioxidant, anti-apoptotic and TNF-alpha suppressive effects.

Teratogenicity and Reactive Oxygen Species after transient embryonic hypoxia: Experimental and clinical evidence with focus on drugs causing failed abortion in humans.

Teratogenicity and Reactive Oxygen Species after transient embryonic hypoxia: Experimental and clinical evidence with focus on drugs with human abortive potential. Reactive Oxygen Species (ROS) can be harmful to embryonic tissues. The adverse embryonic effects are dependent on the severity and duration of the hypoxic event and when during organongenesis hypoxia occurs. The vascular endothelium of recently formed arteries in the embryo is highly susceptible to ROS damage. Endothelial damage results in vascular disruption, hemorrhage and maldevelopment of organs, which normally should have been supplied by the artery. ROS can also induce irregular heart rhythm in the embryo resulting in alterations in blood flow and pressure from when the tubular heart starts beating. Such alterations in blood flow and pressure during cardiogenesis can result in a variety of cardiovascular defects, for example transpositions and ventricular septal defects. One aim of this article is to review and compare the pattern of malformations produced by transient embryonic hypoxia of various origins in animal studies with malformations associated with transient embryonic hypoxia in human pregnancy due to a failed abortion process. The results show that transient hypoxia and compounds with potential to cause failed abortion in humans, such as misoprostol and hormone pregnancy tests (HPTs) like Primodos, have been associated with a similar spectrum of teratogenicity. The spectrum includes limb reduction-, cardiovascular- and central nervous system defects. The hypoxia-ROS related teratogenicity of misoprostol and HPTs, is likely to be secondary to uterine contractions and compression of uterinoplacental/embryonic vessels during organogenesis.

Integrative transcriptomics and proteomics analyses to reveal the therapeutic effect and mechanism of Buxue Yimu Pills in medical-induced incomplete abortion rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Medical abortions using mifepristone and misoprostol have been approved in many countries for early pregnancy loss. Despite its high success rate, this medication regimen can result in incomplete abortion, which is responsible for endometrial damage, prolonged uterine bleeding, abdominal pain, etc. Buxue Yimu Pills (BYP) is a famous Chinese medicine prescription that is widely used in the field of gynecology and obstetrics for treating patients with postpartum complications. However, the therapeutic effect and mechanism of BYP remain to be explored. AIM OF THE STUDY: This study aimed to clarify the therapeutic effect and mechanism of action of BYP in postpartum complications using mifepristone and misoprostol-induced incomplete abortion in rats. MATERIALS AND METHODS: Experimental medical-induced incomplete abortion model rats were constructed using mifepristone and misoprostol, and further treated with saline or BYP by intragastric administration. Detailed information regarding the changes in mRNA and protein levels in the uterine tissues of rats regulated by BYP was illustrated by RNA sequencing (RNA-seq) analysis and quantitative proteomics analysis. The differentially expressed genes and proteins were further subjected to Gene Ontology (GO) and pathway enrichment analyses and further verified using quantitative Real-time PCR (qRT-PCR) analysis and western blot assay. RESULTS: BYP administration markedly alleviated the increase in serum prostaglandin F2α (PGF2α) and expression of PGF2α receptor (PGF2αR) in uterine tissues and inhibited the decrease in serum chorionic gonadotrophin (CG). Compared with the model group, 674 genes were upregulated and 344 genes were downregulated by BYP administration; 108 proteins were upregulated and 48 proteins were downregulated by BYP administration. qRT-PCR analysis of the uterine tissues showed that BYP treatment reversed the variation tendency of genes, including Mmp7, Mmp14, Timp2, Col6a4, Jak2, Wnt7a, and Mylk compared with the model group. Western blot analysis showed that BYP administration affected PKCδ, Collagen VI, MMP7, TIMP2, MLCK, and p-MLC protein levels. CONCLUSION: BYP administration facilitated uterine recovery in medical-induced incomplete abortion rats, and this therapeutic effect involved various targets and biological processes, including the TIMP2/MMP7 and MLCK/p-MLC signaling pathways, etc.

Prevention of nephrotoxicity induced by amikacin: The role of misoprostol, A prostaglandin E1 analogue.

Amikacin (AK) is an aminoglycoside that is widely used to treat life-threatening Gram-negative infections, especially in intensive care units. Despite its wide clinical indications, AK causes serious side effects such as kidney toxicity. AK was found to lead to tissue damage primarily through apoptosis and oxidative stress. Therefore, it was investigated whether misoprostol (MP), which has antioxidant and antiapoptotic properties, had a beneficial effect on kidney damage caused by AK. It was observed that kidney injury molecule-1 (KIM-1) mRNA, blood urea nitrogen (BUN), creatinine (Cr), NADPH oxidase-4 (NOX-4) and Caspase-3 (CAS-3) levels increased in the AK-treated group in comparison with the control group, while uric acid, albumin, and total protein levels were decreased. In rats that were treated with AK+MP, the levels of KIM-1 mRNA, BUN, Cr, NOX-4 and CAS-3 were significantly decreased in comparison with the AK group, while uric acid, albumin and total protein levels increased. According to the obtained results, MP was found to be quite effective in the protection of kidneys from the toxic effects of AK.

Protective potential of misoprostol against kidney alteration via alleviating oxidative stress in rat following exposure to paclitaxel.

The present study investigated the protective effect of misoprostol (MSP) (0.2 mg/kg, oral) against kidney injury caused by paclitaxel (PLX) (2 mg/kg, intraperitoneal) in female Sprague Dawley rats. Twenty-eight 8-week-old rats were used and divided randomly into four equal groups (n = 7): control, MSP, PLX, and PLX+MSP. Malondialdehyde (MDA) level, serum creatinine (Cr), and blood urea nitrogen (BUN) were significantly increased in the PLX group compared to the control group (p < 0.05), while superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) were decreased (p < 0.05). In the PLX+MSP group, levels of serum Cr, and BUN were significantly decreased than the MSP group (p < 0.05). Further, lower level of MDA, and higher activity of GSH, SOD, and CAT was detected in the PLX+MSP than the PLX group (p < 0.05). In the PLX group, we also found a significant decrease in the total number of glomeruli and the mean volumes of cortex, medulla, and kidney compared to the control group (p < 0.05). Besides, these stereological parameters were improved in the PLX+MSP group than the PLX group (p < 0.05). We speculated that administration of MSP attenuated the toxic effect of PLX on kidney tissue due to its antioxidative and anti-apoptotic efficacy of MSP.

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

AIMS: Heat 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 METHODS: Heat 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 FINDINGS: Heat 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. SIGNIFICANCE: This study indicates that misoprostol could alleviate intestinal damage and organ injury caused by heat stress and be a potential therapy for heat-related illnesses.

The effects of mifepristone on the structure of human decidua and chorion and Bax and Bcl-2 expression at early stage of pregnancy.

BACKGROUND: As a progesterone receptor antagonist, mifepristone combined with misoprostol is widely used to terminate early pregnancy in clinical practice. It has also been reported that mifepristone may cause cell death in decidual cells and result in hemorrhage of the decidua and insufficient blood supply. However, little is known about the histological effects of mifepristone on human decidua and chorion. METHODS: Histological and subcellular structural changes of decidua and chorionic villi from women taking mifepristone at early pregnancy times were examined by Hematoxylin and eosin (H&E) staining and transmission Electron microscope. The expression of apoptosis-related proteins Bax/Bcl-2 was examined by immunohistochemistry. RESULTS: After 48 h of mifepristone administration, the decidua tissue and chorionic villus structures were altered in women within 39-49 days of gestation and displayed varying degrees of degeneration and necrosis-like features. Apoptotic events were observed in the decidua and chorionic villi of early pregnancy, and mifepristone treatment significantly increases the number of apoptotic cells. The increased apoptotic events were concomitant with the increased expression of Bax and decreased expression of Bcl-2. CONCLUSION: This study provides evidence that mifepristone induces histological and subcellular changes in decidua and chorionic villi. Mifepristone modulates the relative ratio of Bax/Bcl-2 and the increased apoptosis contributes to the pregnancy termination at early stage of pregnancy.

A synthetic prostaglandin E1 analogue, misoprostol, ameliorates paclitaxel-induced oxidative damage in rat brain.

The main objective of our study was to examine the protection of misoprostol (MP) on paclitaxel (PAX) side effects in rat brains. Twenty-eight female Sprague-Dawley rats were provided to form 4 groups, each containing seven rats: the control group was given 1 mL of 0.9% NaCl intraperitoneally (i.p.) and 1 mL of 0.9% NaCl orally for six days. In treatment groups, each rat was injected with 2 mg/kg PAX i.p. on days 0, 2, 4, and 6 of the study, and 0.2 mg/kg/day MP was given by oral gavage for six days. Levels of malondialdehyde (MDA) and glutathione (GSH), activities of superoxide dismutase (SOD), and catalase (CAT) of tissue samples were measured. In immunohistochemical analyzes, it was observed that tumor necrosis factor-alpha (TNF-α) and cleaved caspase-3 expression in the cerebellum hippocampus and cerebral cortex were increased in the PAX group compared to the other groups. The increase in TNF-α and cleaved caspase-3 expression detected in PAX group rats were significantly decreased in the PAX + MP group. The results obtained in this study confirm the hypotheses that PAX can increase apoptosis in brain tissue both directly and through cytokines such as TNF-α. It also shows that MP can be used as a protective and therapeutic pharmacological agent against the harmful effects of PAX on brain tissue. In addition, it seems that the use of MP can improve PAX-induced brain damage by preventing oxidative damage.

Protective Effects of Melatonin and Misoprostol against Experimentally Induced Increases in Intestinal Permeability in Rats.

Intestinal mucosal barrier dysfunction caused by disease and/or chemotherapy lacks an effective treatment, which highlights a strong medical need. Our group has previously demonstrated the potential of melatonin and misoprostol to treat increases in intestinal mucosal permeability induced by 15-min luminal exposure to a surfactant, sodium dodecyl sulfate (SDS). However, it is not known which luminal melatonin and misoprostol concentrations are effective, and whether they are effective for a longer SDS exposure time. The objective of this single-pass intestinal perfusion study in rats was to investigate the concentration-dependent effect of melatonin and misoprostol on an increase in intestinal permeability induced by 60-min luminal SDS exposure. The cytoprotective effect was investigated by evaluating the intestinal clearance of 51Cr-labeled EDTA in response to luminal SDS as well as a histological evaluation of the exposed tissue. Melatonin at both 10 and 100 µM reduced SDS-induced increase in permeability by 50%. Misoprostol at 1 and 10 µM reduced the permeability by 50 and 75%, respectively. Combination of the two drugs at their respective highest concentrations had no additive protective effect. These in vivo results support further investigations of melatonin and misoprostol for oral treatments of a dysfunctional intestinal barrier.

No increase in pregnancy rate of mares after preovulatory deep uterine horn application of misoprostol.

A potential source of fertility loss in mares is oviductal dysfunction, potentially caused by masses or debris in the lumen, that may prevent either sperm from reaching the fertilization site or the embryo from reaching the uterus. Recently a novel therapeutic method leading to increased pregnancy results was described by infusing misoprostol, a synthetic prostaglandin E1, in the uterus of mares with unexplained fertility problems. In this study, we aimed, after examining the compatibility of misoprostol with semen, to evaluate the pregnancy rate after routine preovulatory deep uterine horn application of misoprostol in clinically normal oestrous mares, which were inseminated in the same cycle. In experiment 1, ejaculates of 10 stallions diluted with INRA 96™ were mixed with different concentrations of misoprostol (0.01 mg/mL, 0.001 mg/mL, 0.0001 mg/mL, and 0.00001 mg/mL) and total semen motility was evaluated immediately, 12, 24, 48, and 72 h later, and compared with a control sample (mixed with NaCl 0.9%). In experiments 2 and 3, 33 privately-owned clinically normal oestrous mares were each allocated to a treatment or control group. Ovulation was then induced with intramuscularly 2.25 mg deslorelin acetate. At the moment of ovulation induction (experiment 2) and 24 h earlier (experiment 3), 0.2 mg misoprostol diluted in 2 mL NaCl 0.9% were applied deep in the uterine horn (treatment groups) and pure 2 mL NaCl 0.9% in the mares of the control groups. Mares were then inseminated 24 h after deslorelin administration and prior to ovulation with commercial chilled-warmed or frozen-thawed semen, as well as immediately after ovulation detection (both types of semen) maximally 48 h after ovulation induction. In experiment 1, regardless of time and compared with the control groups, all solutions with different concentrations of misoprostol had a negative effect on total motility of semen, which was significant for the highest concentrations (0.01 mg/mL: 18.0% reduction, CI = 22-13%, p = < 0.01). We found no beneficial effect of preovulatory uterine treatment with misoprostol on pregnancy rate (OR = 0.45, CI = 0.15-1.31, p = 0.14): in experiment 2, 2/11 (18.2%) mares of the treatment group became pregnant vs. 12/22 (54.5%) mares in the control group (OR = 0.19, CI = 0.03-1.06, p = 0.07), in experiment 3, 5/14 (35.7%) mares in the treatment group vs. 7/19 (36.8%) mares in the control group (OR = 0.95, CI = 0.23-4.02, p = 0.95), respectively. In conclusion, pregnancy rate was not increased in reproductively normal mares with routine preovulatory deep uterine horn application of misoprostol.

Translational profiling of mouse dopaminoceptive neurons reveals region-specific gene expression, exon usage, and striatal prostaglandin E2 modulatory effects.

Forebrain dopamine-sensitive (dopaminoceptive) neurons play a key role in movement, action selection, motivation, and working memory. Their activity is altered in Parkinson's disease, addiction, schizophrenia, and other conditions, and drugs that stimulate or antagonize dopamine receptors have major therapeutic applications. Yet, similarities and differences between the various neuronal populations sensitive to dopamine have not been systematically explored. To characterize them, we compared translating mRNAs in the dorsal striatum and nucleus accumbens neurons expressing D1 or D2 dopamine receptor and prefrontal cortex neurons expressing D1 receptor. We identified genome-wide cortico-striatal, striatal D1/D2 and dorso/ventral differences in the translating mRNA and isoform landscapes, which characterize dopaminoceptive neuronal populations. Expression patterns and network analyses identified novel transcription factors with presumptive roles in these differences. Prostaglandin E2 (PGE2) was a candidate upstream regulator in the dorsal striatum. We pharmacologically explored this hypothesis and showed that misoprostol, a PGE2 receptor agonist, decreased the excitability of D2 striatal projection neurons in slices, and diminished their activity in vivo during novel environment exploration. We found that misoprostol also modulates mouse behavior including by facilitating reversal learning. Our study provides powerful resources for characterizing dopamine target neurons, new information about striatal gene expression patterns and regulation. It also reveals the unforeseen role of PGE2 in the striatum as a potential neuromodulator and an attractive therapeutic target.

Misoprostol plus isosorbide mononitrate versus misoprostol alone for cervical ripening during labor induction: A systematic review and meta-analysis of randomized controlled trials.

AIM: To conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) that examined the maternal and neonatal outcomes of misoprostol+isosorbide mononitrate (ISMN) versus misoprostol alone (control) in promoting cervical ripening during labor induction. METHODS: We searched five databases from inception until 05-May-2021. We assessed risk of bias of RCTs, meta-analyzed 23 endpoints, and pooled them as mean difference or risk ratio with 95% confidence interval. RESULTS: Overall, five RCTs met the inclusion criteria, comprising 850 patients (426 and 424 patients were allocated to misoprostol+ISMN and misoprostol group, respectively). Overall, the RCTs had a low risk of bias. Pertaining to maternal delivery-related outcomes, there was no significant difference between both groups regarding the mean interval from drug administration to delivery, rate of vaginal delivery, rate of cesarean section delivery, and rate of need for oxytocin augmentation. Pertaining to maternal drug-related side effects, the rate of maternal headache was significantly higher in disfavor of the misoprostol+ISMN compared with misoprostol alone. However, the rates of maternal nausea, hypotension, flushing, palpitation, dizziness, postpartum hemorrhage, and uterine tachysystole did not differ between both groups. Pertaining to neonatal outcomes, there was no significant difference between both groups regarding rates of NICU admission, meconium-stained amniotic fluid, and Apgar score <7 at five minutes. CONCLUSION: Compared with misoprostol alone, co-administration of misoprostol+ISMN did not correlate with superior maternal delivery-related outcomes. The rate of maternal headache was significantly higher in disfavor of the misoprostol+ISMN group. There was no significant difference between both groups regarding neonatal endpoints.

Comparing the efficacy of dilapan with extra-amniotic saline infusion and oral misoprostol for cervical ripening in term pregnancies.

INTRODUCTION: Labor induction is an important issue in modern obstetrics. One of the important factors for the success of induction of labor is the Bishop score of cervix. OBJECTIVE: The purpose of the present study was to evaluate and compare the efficacy of dilapan with extra-amniotic saline infusion and oral misoprostol for cervical ripening in term pregnancies. METHODS: This clinical trial study was performed on 120 nulliparous pregnant women with the Bishop score of less than 5. Group one, group two and group three received dilapan, extra amniotic saline infusion (EASI) and misoprostol respectively. All three groups were compared for duration from beginning of the intervention up to cervical ripening and Bishop Score of ≥7, duration of active phase and the second stage of labor, number of deliveries in the first 24 h, duration from beginning of the intervention up to delivery, rout of delivery as well as neonatal weight, neonatal Apgar score; hyper- stimulation, and need for oxytocin and oxytocin doses administered after 12 h of intervention. RESULTS: The number of deliveries in the first 24 h after intervention were not significantly different between the three groups. There was no significant difference between the three groups according to duration from beginning of the intervention up to cervical ripening and Bishop Score of ≥7, duration of active phase and the second stage of labor, duration from beginning of the intervention up to delivery, rout of delivery as well as neonatal weight, neonatal Apgar score; and hyperstimulation. The Bishop Score was higher in the misoprostol group 6 h after intervention [dilapan: 4.32 ± 1.38, EASI: 5.47 ± 1.28, and misoprostol: 6.72 ± 1.61 (p = .000)], Oxytocin requirement [dilapan: 38 (95%) women, EASI: 37 (92.50%) and misoprostol: 30 (75%) women, p = .013], and required dose [dilapan: 7543 ± 2465 miu/ml, EASI: 5758 ± 1615miu/ml and misoprostol: 4930 ± 2589miu/ml, p = .000] were lower in misoprostol group. CONCLUSION: Dilapan is an effective and safe method for cervical ripening in full term gestations. In cases where misoprostol and EASI cannot be used or are not desirable, dilapan can be used as an alternative.Trial registration number and registry website: IRCT20091023002624N25.

Abordaje integral de la Interrupción Voluntaria del Embarazo: (segunda entrega) / Comprehensive approach to the voluntary interruption of pregnancy: (second issue)

La legalización de la interrupción voluntaria del embarazo ha transformado la práctica médica con respecto a la atención de las pacientes que desean interrumpir la gestación hasta la semana 14 en Argentina. En la primera entrega, el equipo PROFAM compartió su punto de vista a través de una adaptación de su material educativo destinado, sobre todo, a aclarar los aspectos legales que hacen a la práctica cotidiana. En esta entrega se desarrolla en detalle el procedimiento para realizar un aborto farmacológico con misoprostol y mifepristona, así como las generalidades del aspirado manual endouterino. (AU)

The legalization of voluntary termination of pregnancy has transformed medical practice regarding the care of patients who wish to terminate a pregnancy up to 14 weeks in Argentina. In the first issue, the PROFAM team shared its point of view through an adaptation of its educational material aimed, above all, at clarifying the legal aspects of daily practice. In this issue, the procedure to perform a pharmacological abortion with misoprostol and mifepristone is developed in detail, as well as the generalities of manual uterine aspiration technique. (AU)

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.

Hematometra y hematocervix en paciente postmenopáusica: reporte de caso / Hematometry and hematocervix in postmenopausal patient: case repor

El hematometra es la retención de sangre en el útero y comúnmente se presenta en mujeres jóvenes con anomalías mullerianas pero puede aparecer también en mujeres postmenopausicas por causas secundarias como traumas, tumores, terapia de remplazo hormonal, estenosis cervical, entre otras. En esta presentación de caso interesante se describe una mujer postmenopáusica bajo terapia de remplazo hormonal. Dicha mujer inicia con hemorragia uterina anormal por lo que se le realiza ultrasonido evidenciando hematómetra y hematocervix. Como método diagnóstico y terapéutico de la hemorragia postmenopáusica se le realiza histerectomía abdominal en la cual la patología evidencia leiomiomatosis uterina con endometrio secretor

Hematometra is the retention of blood in the uterus and commonly occurs in young women with Mullerian abnormalities but can also appear in postmenopausal women due to secondary causes such as trauma, tumors, hormone replacement therapy, cervical stenosis, among others. In this presentation an interesting case is described a postmenopausal woman under hormone replacement therapy. She said woman began with abnormal uterine bleeding, so an ultrasound was performed showing hematometer and hematocervix. As a method diagnosis and treatment of postmenopausal hemorrhage, abdominal hysterectomy is performed in which the pathology shows uterine leiomyomatosis with secretory endometrium

Misoprostol-augmented induction of labour for third trimester fetal demise in a patient with prior hysterotomies.

A 31-year-old G3P2002 with history of two prior caesarean sections presented with influenza-like illness, requiring intubation secondary to acute respiratory distress syndrome. Investigations revealed intrauterine fetal demise at 30-week gestation.She soon deteriorated with sepsis and multiple organs impacted. Risks of the gravid uterus impairing cardiopulmonary function appeared greater than risks of delivery, including that of uterine rupture. Vaginal birth after caesarean was achieved with misoprostol and critical care status rapidly improved.Current guidelines for management of fetal demise in patients with prior hysterotomies are mixed: although the American College of Obstetricians and Gynecologists recommends standard obstetric protocols rather than misoprostol administration for labour augmentation, there is limited published data citing severe maternal morbidity associated with misoprostol use. This case report argues misoprostol-augmented induction of labour can be a reasonable option in a medically complex patient with fetal demise and prior hysterotomies.