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.

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.

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.

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.

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)

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

Oral misoprostol does not hasten oviductal transport of day-5 horse embryos.

In horses, prostaglandin E2 (PGE2) is produced by embryos around Day 5 post-ovulation; PGE2 functions directly at the oviduct promoting embryo transport into the uterus. Non-surgical collection of horse embryos for cryopreservation is recommended at Day 6.5-7 post-ovulation. It was proposed that misoprostol administered orally will hasten oviductal transport of horse embryos. In Experiment 1 (n = 15) there was comparison of time of embryo recovery (Day 6 and 6.5 post-ovulation) from mares administered misoprostol (Day 5 and 5.5) orally to that of untreated mares. On Day 6, embryo collections were attempted; if no embryo was collected, there was a second attempt on Day 6.5. In Experiment 2, (n = 16) misoprostol treatment was initiated on Day 4.5; there was the first embryo collection attempt on Day 5.5, followed by Day 6 and 6.5 if no embryo was collected. Blood samples were collected at 12 h intervals on Day 4.5 or 5, to Day 6.5. In Experiment 1, on days 6 and 6.5, respectively, there was collection of seven and one of a total of eight embryos detected at the time of collection per group (P = 1). In Experiment 2, 12 embryos were collected during 15 cycles with there being a total of three, two, and one collected from mares of both groups on Day 5.5, 6, and 6.5 post-ovulation, respectively (P = 1). Serum progesterone concentrations were not different (P ≥ 0.05). In conclusion, misoprostol, when administered orally, does not hasten oviductal transport of horse embryos.

Caspase-4: A Therapeutic Target for Peptic Ulcer Disease.

Peptic ulcers are caused by the interaction between bacterial and host factors. This study demonstrates enhanced expression of caspase-4 in peptic ulcer patient biopsies, indicating that pyroptosis and noncanonical inflammasome activity may be processes involved in peptic ulcer disease. We show that primary murine macrophages infected with Helicobacter pylori upregulate caspase-11 (the ortholog of human caspase-4), activate caspase-1, and secrete IL-1ß. We demonstrate that misoprostol (a stable PGE1 analogue) decreased IL-1ß secretion and delayed lethality in vivo in a murine peritonitis model. PGE2 was shown to inhibit caspase-11-driven pyroptosis and IL-1ß secretion in macrophages. Overall, we provide evidence for a pathological role of caspase-4/11 in peptic ulcer disease and propose that targeting caspase-4 or inhibiting pyroptosis may have therapeutic potential in the management of peptic ulcers.

Misoprostol ameliorates doxorubicin induced cardiac damage by decreasing oxidative stress and apoptosis in rats.

We investigated the potential cardioprotective effects of misoprostol (MP) on doxorubicin (DOX) induced cardiac damage using histologic and biochemical assessment of rat heart. We used 21 male rats divided randomly into three groups: group 1, control; group 2, DOX; group 3, DOX + MP. The control group was given 0.5 ml 0.9% NaCl intraperitoneally (i.p.) and 1 ml 0.9% NaCl orally for 6 days. DOX was administered as a single dose of 20 mg/kg i.p. on day 3. MP was administered orally for 6 days. We found that treatment with MP decreased significantly serum cardiac troponin-I, brain natriuretic peptide levels, and lactate dehydrogenase, aspartate aminotransferase, alanine transaminase and creatine kinase isoenzyme-MB activities. DOX increased the malondialdehyde level and decreased the catalase, superoxide dismutase activities and glutathione levels; MP prevented these alterations. MP also decreased NADPH oxidase-4 and caspase-3 levels. In the DOX + MP group, oxidative stress was decreased, antioxidant activity was increased and histopathological changes were decreased compared to the DOX group. Cardiac damage caused by DOX was attenuated by MP treatment owing to the antioxidative and anti-apoptotic effects of MP. MP may be useful for reducing the severity of DOX induced damage.

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.

Oral misoprostol, low dose vaginal misoprostol, and vaginal dinoprostone for labor induction: Randomized controlled trial.

OBJECTIVE: To compare effectiveness and safety of oral misoprostol (50 µg every four hours as needed), low dose vaginal misoprostol (25 to 50 µg every six hours as needed), and our established dinoprostone vaginal gel (one to two mg every six hours as needed) induction. MATERIALS AND METHODS: Consenting women with a live term single cephalic fetus for indicated labor induction were randomized (3N = 511). Prior uterine surgery or non-reassuring fetal surveillance were exclusions. Concealed computer generated randomization was stratified and blocked. Newborns were assessed by a team unaware of group assignment. The primary outcome was time from induction at randomization to vaginal birth for initial parametric analysis. Sample size was based on mean difference of 240 minutes with α2 = 0.05 and power 95%. Non-parametric analysis was also pre-specified ranking cesareans as longest vaginal births. RESULTS: Enrollment was from April 1999 to December 2000. Demographics were similar across groups. Analysis was by intent to treat, with no loss to follow up. Mean time (±SD) to vaginal birth was 1356 (±1033) minutes for oral misoprostol, 1530 (±3249) minutes for vaginal misoprostol, and 1208 (±613) minutes for vaginal dinoprostone (P = 0.46, ANOVA). Median times to vaginal birth were 1571, 1339, and 1451 minutes respectively (P = 0.46, Kruskal-Wallis). Vaginal births occurred within 24 hours in 44.9, 53.5 and 47.7% respectively (P = 0.27, χ2). There were no significant differences in Kaplan Meier survival analyses, cesareans, adverse effects, or maternal satisfaction. The newborn who met birth asphyxia criteria received vaginal misoprostol, as did. all three other newborns with cord artery pH<7.0 (P = 0.04, Fisher Exact). CONCLUSION: There was no significant difference in effectiveness of the three groups. Profound newborn acidemia, though infrequent, occurred only with low dose vaginal misoprostol.

Effects of misoprostol treatment on doxorubicin induced renal injury in rats.

We investigated the potential nephroprotective effects of misoprostol (MP) on doxorubicin (DOX) induced renal injury using histologic and biochemical assessment of rat kidneys. We used 21 male rats divided into three groups: group 1, control; group 2, DOX; group 3, DOX + MP. The control group was given 0.5 ml 0.9% NaCl and 1 ml 0.9% NaCl orally for 6 days. DOX was administered as a single dose of 20 mg/kg on day 3. MP was administered orally for 6 days. We found that treatment with MP decreased serum creatinine and blood urea nitrogen levels significantly. DOX increased the malondialdehyde level and decreased catalase, superoxide dismutase activities and glutathione level. These alterations were prevented in renal tissues by MP. MP also decreased NADPH oxidase-4 and caspase-3 levels. In the DOX + MP group, oxidative stress was decreased, antioxidant activity was increased and histopathological changes were reduced compared to the DOX group. Renal injury caused by DOX was attenuated by MP treatment owing to the antioxidative and anti-apoptotic effects of MP.

The protective effect of misoprostol against doxorubicin induced liver injury.

We investigated the potential hepatoprotective effects of misoprostol (MP) on doxorubicin (DOX) induced liver injury in rats using histology and biochemistry. We used 21 male Sprague-Dawley rats divided randomly into three groups: group 1, control; group 2, DOX; group 3, DOX + MP. The control group was injected intraperitoneally (i.p.) with 0.5 ml 0.9% w/v NaCl and given 1 ml 0.9% NaCl orally for 6 days. DOX was administered i.p. as a single dose of 20 mg/kg. MP, 0.2 mg/kg, was given orally for 6 days. Treatment with MP increased high density lipoprotein cholesterol levels and decreased serum alanine aminotransferase, aspartate aminotransferase, low density lipoprotein cholesterol, triglycerides and total cholesterol levels significantly in serum. Increased malondialdehyde level and decreased catalase, glutathione and superoxide dismutase levels caused by DOX were suppressed significantly in liver tissue by MP. DOX + MP reduced loss of body weight. Oxidative stress was decreased, antioxidant activity was increased and histopathological changes were reduced in the DOX + MP group compared to the DOX group. Liver injury caused by DOX was attenuated by MP treatment owing to the antioxidative and anti-apoptotic effects of MP, which might be useful for reducing the severity of DOX induced liver injury.

Rectal vs. sublingual misoprostol before cesarean section: double-blind, three-arm, randomized clinical trial.

PURPOSE: The commonest surgical procedure for women is cesarean delivery. Postpartum hemorrhage and intra-operative blood during cesarean delivery is a major concern to all obstetricians. This study was conducted to assess the efficacy of the adjuvant use of misoprostol and oxytocin in decreasing intra-operative blood loss in cesarean delivery. METHODS: This was a double-blinded randomized clinical trial including 636 term pregnant woman scheduled for cesarean section at Ain Shams University Maternity Hospital, Cairo, Egypt, between February 2013 and February 2014. Participants received either 400-µg misoprostol rectally or sublingually or placebo before cesarean section together with 5-IU oxytocin IV. The main outcome measure was intra-operative blood loss. Difference between the three groups was analyzed using one-way ANOVA test (for numeric variables) and Chi-square test (for categorical variables). P < 0.05 was considered statistically significant. RESULTS: Intra-operative blood loss was higher in patients who did not receive misoprostol (Placebo Group) (295-1075 ml, 641.7 ± 135.7) than those who received it, regardless the route of administration, rectal (135-830 ml, 457.5 ± 140.7; P < 0.001), and sublingual (135-680 ml, 357.8 ± 129.7; P < 0.001). In addition, sublingual route was associated with significantly lower estimated intra-operative blood loss compared to rectal administration (P < 0.001). CONCLUSIONS: Misoprostol with oxytocin is an effective drug-combination for decreasing intra-operative blood loss during cesarian section with clinical superiority to sublingual over rectal route.

Effect of cervical priming with misoprostol on cervical entry in women undergoing vaginoscopic hysteroscopy for evaluation of abnormal uterine bleeding: a randomized controlled trial.

OBJECTIVE: To study the effect of cervical priming with misoprostol on cervical entry in women undergoing diagnostic hysteroscopy for evaluation of abnormal uterine bleeding. METHODS: Randomized controlled trial conducted in teaching hospital and tertiary referral center on 122 women requiring diagnostic hysteroscopy for evaluation of abnormal uterine bleeding. Women were randomized into two equal groups (n = 122). Study group received 200-µg vaginal misoprostol, 3 h prior to vaginoscopic hysteroscopy. No drug was used in control group. No analgesia or anesthesia was used in either group. Outcome measure included (i) ease of cervical entry (Likert scale), and (ii) pain scoring (Visual Analog Scale) and procedural entry time. RESULTS: Forty-six (75.41%) patients in the study group and 17 (27.87%) in control group had easy or very easy entry (Likert scale-4 and 5) (p < 0.001). Median pain scoring by VAS and the median procedural entry time was significantly lower in the study group compared to the control group (p < 0.001). CONCLUSION: Use of 200-µg vaginal misoprostol, administered vaginally 3 h before diagnostic vaginoscopic hysteroscopy, was found to be simple and effective method of cervical priming in facilitating cervical entry with minimal side effects. Clinical Trial registry of India (CTRI): (CTRI/2015/04/005666) (website: http://ctri.nic.in ).

Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1.

Effective treatment of chronic myelogenous leukemia (CML) largely depends on the eradication of CML leukemic stem cells (LSCs). We recently showed that CML LSCs depend on Tcf1 and Lef1 factors for self-renewal. Using a connectivity map, we identified prostaglandin E1 (PGE1) as a small molecule that partly elicited the gene expression changes in LSCs caused by Tcf1/Lef1 deficiency. Although it has little impact on normal hematopoiesis, we found that PGE1 treatment impaired the persistence and activity of LSCs in a pre-clinical murine CML model and a xenograft model of transplanted CML patient CD34+ stem/progenitor cells. Mechanistically, PGE1 acted on the EP4 receptor and repressed Fosb and Fos AP-1 factors in a ß-catenin-independent manner. Misoprostol, an FDA-approved EP4 agonist, conferred similar protection against CML. These findings suggest that activation of this PGE1-EP4 pathway specifically targets CML LSCs and that the combination of PGE1/misoprostol with conventional tyrosine-kinase inhibitors could provide effective therapy for CML.

Factors related to completeness of medical abortion with mifepristone and misoprostol.

BACKGROUND: Medical abortion that occurs in early pregnancy is generally safe and successful, but incomplete medical abortion can result in complications. This study aimed to examine factors related to completeness of medical abortion with mifepristone and misoprostol, and then to provide a new direction for research into establishing complete abortion with mifepristone and misoprostol. METHODS: Sixty-three patients with early pregnancy requesting medical abortion with mifepristone and misoprostol were selected. Immunohistochemistry was used to detect the expression and location of progesterone receptor, estrogen receptor, insulin-like growth factor-1, and vascular endothelial growth factor in chorionic villi among these women. Reverse transcriptase polymerase chain reaction was then used to determine the expression of insulin-like growth factor-1 and vascular endothelial growth factor mRNA. RESULTS: According to the outcome of medical abortion, the women were divided into either the incomplete medical abortion group (n=34) or the complete medical abortion group (n=29). Immunohistochemical analysis showed that progesterone receptor and estrogen receptor protein expression was not detected in chorionic villi in the two groups. However, compared with the complete abortion group, there was a marked decrease in the expression of insulin-like growth factor-1 and a significant increase in the expression of vascular endothelial growth factor (p<0.05) in the incomplete abortion group. There was no significant difference in mRNA expression between the incomplete and complete abortion groups. CONCLUSION: The expression of insulin-like growth factor 1 protein and vascular endothelial growth factor protein in chorionic villi may be related to the outcome of medical abortion with mifepristone and misoprostol.