Identification and validation of uterine stimulant methylergometrine as a potential inhibitor of caspase-1 activation.

Inflammasomes are intracellular multiprotein complexes of the innate immune system. Upon an inflammatory insult, such as infection or intracellular damage, a nucleotide-binding oligomerization domain-like receptor (NLR) sensor protein and the adaptor protein ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) are assembled to activate protease procaspase-1. This protease processes pro-IL-1ß and pro-IL-18 cytokines, which are released to induce the inflammatory response. De-regulation of inflammasome contributes to the progression of several diseases, such as Alzheimer's disease, diabetes, cancer, inflammatory and autoimmune disorders. We herein describe the identification of methylergometrine (MEM), a drug currently used as a smooth muscle constrictor during postpartum hemorrhage, as an inhibitor of the inflammasome complex in ASC-mediated procaspase-1 activation screening. MEM inhibits the activation of the nucleotide-binding oligomerization domain-like receptor protein 1 (NLRP1) and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasomes in cellular models upon different pro-inflammatory stimuli. Our results suggest that MEM has the potential to reposition in the treatment of inflammatory diseases with the advantages of established safety and clinical data.

Outcome of breastfed infants following post-partum methylergonovine treatment.

OBJECTIVE: To evaluate maternal and breastfed infant's outcome following post-partum maternal use of methylergonovine. METHODS: A prospective, controlled observational study design was used. Mothers who contacted Beilinson Teratology Information Service (BELTIS) were followed by phone interview. Data on lactation, neonatal symptoms and outcomes at the age of 1-3 years were obtained. Mothers' breastfeeding while treated with methylergonovine and their infants were compared to a matched control group of breastfeeding mothers using a drug known to be safe during lactation (amoxicillin). RESULTS: Follow-up was obtained for 38 of 42 women (90.5%). Of whom, six stopped breastfeeding because of concerns regarding drug treatment and three refused to participate. The remaining 29 women and infant pairs were compared to a control group of 58 women and their infants. Comparison showed no effect of methylergonovine on lactation and similarly showed no difference in rate of neonatal complications (p = 1). At time of follow-up there were no differences in growth or in adverse neurodevelopment outcomes (p = 0.26). CONCLUSIONS: No increase in adverse long-term outcomes was found in infants exposed to methylergonovine through breastfeeding. Our data in conjunction with previous estimates of very low drug exposure support continuation of breastfeeding in women requiring treatment with methylergonovine.

Risk factors for obstetric morbidity in patients with uterine atony undergoing caesarean delivery.

BACKGROUND: Uterine atony (UA) is recognized as a leading cause of postpartum haemorrhage. However, knowledge of risk factors of haemorrhage-related morbidity among patients diagnosed with UA is uncertain. We investigated risk factors for haemorrhage-related morbidity among patients undergoing Caesarean delivery with UA. METHODS: We conducted a secondary analysis of data sourced from a 4-yr observational study at 19 US academic centres. Patients with UA were identified based on receiving methylergonovine or carboprost. Our primary outcome (haemorrhage-related morbidity) included a composite of intra- or postpartum transfusion; Caesarean hysterectomy; uterine or hypogastric artery ligation; intensive care admission for: pulmonary oedema, coagulopathy, adult respiratory distress syndrome, postoperative ventilation, or invasive line monitoring. RESULTS: Among 57,182 patients who underwent Caesarean delivery, 2294 (4%) patients developed UA. Haemorrhage-related morbidity occurred in 450 (19.6%) patients with UA. The risk of haemorrhage-related morbidity was increased among African-Americans [adjusted odds ratio (aOR)=2.36; 95% confidence interval (CI)=1.73-3.23], Hispanics (aOR=1.4; 95% CI=1.04-1.9), women with multiple gestations (aOR=1.59; 95% CI=1.06-2.38), placenta praevia (aOR=4.89; 95% CI=3.04-7.87), patients with ASA class III (aOR=1.4; 95 CI=1.03-1.9), or ASA class IV (aOR=5.88; 95% CI=2.48-13.9), exposure to general anaesthesia (GA) (aOR=2.4; 95% CI=1.59-3.62) and combined general and regional anaesthesia (aOR=4.0; 95% CI=2.62-6.09), and ≥2 prior Caesarean deliveries (aOR=1.62; 95% CI=1.1-2.39). CONCLUSIONS: Among patients with UA undergoing Caesarean delivery, the risk of haemorrhage-related morbidity is increased in African-Americans, Hispanics, patients with multiple gestations, placenta praevia, ASA class III or IV, ≥2 prior Caesarean deliveries and those undergoing GA.

Bromocriptine, a dopamine D(2) receptor agonist with the structure of the amino acid ergot alkaloids, induces neurite outgrowth in PC12 cells.

To investigate whether dopamine agonists induce neurite outgrowth, we examined the effects of dopamine D(2) receptor agonists such as bromocriptine, talipexole, and pramipexole in PC12 cells, a well-studied model of neurite outgrowth. Bromocriptine significantly induced neurite outgrowth in a concentration-dependent manner. Neither talipexole nor pramipexole induced neurite outgrowth. Domperidone and sulpiride, dopamine D(2) receptor antagonists, did not have any effect on the bromocriptine-induced neurite outgrowth. These results suggest that the stimulation of dopamine D(2) receptors would not affect neurite outgrowth in nerve regeneration. Next, we investigated how bromocriptine-induced neurite outgrowth. Bromocriptine is not only a dopamine D(2) receptor agonist but also an ergot alkaloid. We examined the involvement of the structure of ergot alkaloids in the effect of bromocriptine. Ergot alkaloids have been divided into two groups: amino acid ergot alkaloids, including bromocriptine, and amine ergot alkaloids. Amino acid ergot alkaloids, such as ergocornine and ergotamine, induced neurite outgrowth, but amine ergot alkaloids, including ergometrine and methylergometrine, did not. These results indicate that the structure of amino acid ergot alkaloids is important for the effect of bromocriptine. Moreover, the effect of bromocriptine was inhibited by a src inhibitor and a mitogen-activated protein kinase kinase (MEK) inhibitor. Taken together, bromocriptine-induced neurite outgrowth via src and the MEK/extracellular signal-regulated kinase 1/2 signaling pathway in PC12 cells.

[Two cases of congenital airway obstruction managed with ex utero intrapartum treatment procedures: anesthetic implications]. / Dos casos de obstrucción congénita de la vía aérea sometidos a E.X.I.T. ("ex-utero intrapartum treatment"): implicaciones anestésicas.

An ex utero intrapartum treatment (EXIT) procedure provides sufficient time to gain control of the potentially obstructed fetal upper airway while uterine placental circulation is maintained during cesarean section. We report 2 cases in which fetal congenital upper airway obstruction was managed without complications during EXIT procedures. We also discuss general considerations concerning the obstetric patient and the performance of intramuscular fetal anesthesia. Before the hysterotomy, sevoflurane at 1.5 minimum alveolar concentration was administered to assure sufficient uterine relaxation during EXIT. The 2 parturients remained hemodynamically stable during the procedure and uterine and placental perfusion was adequate. Nasotracheal intubation was possible in 1 fetus after a cervical mass was dissected. In the other, a tracheostomy was created. After the umbilical cord was clamped, the concentration of sevoflurane anesthetic gas was reduced and oxytocin and methylergometrine were administered to induce adequate uterine contractions within a few minutes. Both neonates survived the EXIT procedure with no complications.

[Effects of methylergometrine and oxytocin on blood loss and uterine contraction during cesarean section].

BACKGROUND: The effects of intravenous oxytocics on blood loss and uterine contraction during cesarean section were studied in 136 parturients. METHODS: The subjects were randomized to receive either methylergometrine 0.2 mg bolus (MEM group; n = 34), oxytocin 10 IU over 30 seconds (OX 30 s group; n = 34), oxytocin 10 IU over 5 minutes (OX 5 m group; n = 34) or oxytocin 10 IU over 15 minutes (OX 15 m group; n = 34). The subjects received spinal anesthesia with 11-12 mg of intrathecal isobaric bupivacaine (0.5%). Additional intramyometrial prostaglandin F2alpha (PGF2alpha) was administered when obstetrician diagnosed uterine atony. We analyzed total amount of blood loss including amniotic fluid and number of parturients that received additional intramyometrial PGF2alpha to evaluate uterine contraction. RESULTS: The amounts of blood loss in the OX 30 s and OX 5 m groups were significantly lower than in the MEM group, and the numbers of parturients received additional PGF2alpha in all the oxytocin treat ment groups were significantly lower than in the MEM group (P < 0.05). There were no significant differences in blood loss and uterine contractior among the oxytocin treatment groups. CONCLUSIONS: Intravenous oxytocin 10 IU over 30 seconds to 15 minutes was effective to decrease blood loss and uterine contraction than intravenous methylergometrine 0.2 mg bolus.

Reinforcement in an in vitro analog of appetitive classical conditioning of feeding behavior in Aplysia: blockade by a dopamine antagonist.

In a recently developed in vitro analog of appetitive classical conditioning of feeding in Aplysia, the unconditioned stimulus (US) was electrical stimulation of the esophageal nerve (En). This nerve is rich in dopamine (DA)-containing processes, which suggests that DA mediates reinforcement during appetitive conditioning. To test this possibility, methylergonovine was used to antagonize DA receptors. Methylergonovine (1 nM) blocked the pairing-specific increase in fictive feeding that is usually induced by in vitro classical conditioning. The present results and previous observation that methylergonovine also blocks the effects of contingent reinforcement in an in vitro analog of appetitive operant conditioning suggest that DA mediates reinforcement for appetitive associative conditioning of feeding in Aplysia.

Modulation of contractions to ergonovine and methylergonovine by nitric oxide and thromboxane A2 in the human coronary artery.

This study explored the modulatory effects of nitric oxide and thromboxane A2 on contractions to ergonovine and methylergonovine in human coronary arteries. To elucidate the different role of nitric oxide synthase in the response to the ergot alkaloids, the serotonin (5-HT) receptors involved in nitric oxide synthase in the response to the ergot alkaloids, the 5-HT receptors involved in nitric oxide release and the contraction of the vascular smooth muscle were characterized with more selective 5-HT-receptor agonists and antagonists. Rings of human coronary arteries from explanted hearts were suspended in organ chambers for isometric tension recording. After testing for contractile (potassium chloride, 60 mM) and endothelial function (substance P, 10(-8) M), respectively, they were exposed to ergot alkaloids or other agonists in the absence or presence of U 46619 (10(-9) M), or nitro-L-arginine (10(-4) M), or both. Ergonovine and methylergonovine were comparable, weak vasoconstrictors in untreated preparations. Contractions to ergonovine were augmented by U 46619, but not by nitro-L-arginine. Contractions to methylergonovine were augmented only by combining U 46619 and nitro-L-arginine. Serotonin and methylergonovine, but not ergonovine, elicited endothelium-dependent, nitric oxide-mediated relaxations. Nonselective 5-HT(1B/1D)-receptor stimulation caused both contractions and relaxations; selective 5-HT1B stimulation caused relaxations only. In the human coronary artery, contractions to ergonovine are not dependent on NO release but are synergistically augmented by thromboxane. Methylergonovine causes similar effects on the vascular smooth muscle, but contractions are inhibited by the release of NO from the endothelium. The 5-HT receptor on the endothelium appears to be different from the receptor on the vascular smooth muscle, which mediates the contractile response to the ergot alkaloids.

Use of methergine for the prevention of postoperative endometritis in non-elective cesarean section patients.

OBJECTIVE: Methergine increases constriction of uterine musculature which may facilitate sloughing of endometrial debris, close uterine vessels, and prevent post-cesarean endometritis. The objective of this study was to evaluate the efficacy of methergine in preventing endometritis in patients undergoing non-elective cesarean section delivery. METHODS: Eighty patients undergoing non-elective cesarean section were enrolled in a prospective randomized clinical trial of methergine (41) versus no methergine (39) administration during the postpartum period. The hospital records were abstracted after discharge to compare the postpartum course. RESULTS: There were no significant demographic differences between the two groups. The women receiving methergine had a significant reduction in the rate of postoperative endometritis (10% vs. 36%, P < 0.005). In addition, the mean postoperative hemoglobin was significantly higher in the methergine treated group (P < 0.001). CONCLUSIONS: The use of methergine postpartum in women undergoing non-elective cesarean sections significantly reduces the incidence of postoperative endometritis and blood loss.

Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications.

BACKGROUND: Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis. METHODS AND RESULTS: Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (+/-)-fenfluramine; (+)-fenfluramine; (-)-fenfluramine; its metabolites (+/-)-norfenfluramine, (+)-norfenfluramine, and (-)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (+/-)-, (+)-, and (-)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT(2B) receptor and were partial to full agonists at the 5-HT(2B) receptor. CONCLUSIONS: Our data imply that activation of 5-HT(2B) receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT(2B) receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT(2B) receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT(2B) receptors.

Drugs and uterine motility.

Nurses who care for pregnant and laboring women are faced with an increasingly frequent use of pharmaceutical agents that facilitate initiation of labor (uterotropins), augment labor (uterotonics), or potentially stop labor (tocolytics). The choice of the drug, administration, side effects, and complications varies. Knowledge about uterine physiology helps the clinician understand the action of these agents. Knowledge of the differences and similarities among oxytoxics, ergots, prostaglandins, and the various drugs used as tocolytics is essential for safe and effective care of women and their fetuses who may be exposed to these agents.

Dopaminergic synapses mediate neuronal changes in an analogue of operant conditioning.

Feeding behavior in Aplysia can be modified by operant conditioning in which contingent reinforcement is conveyed by the esophageal nerve (E n.). A neuronal analogue of this conditioning in the isolated buccal ganglia was developed by using stimulation of E n. as an analogue of contingent reinforcement. Previous studies indicated that E n. may release dopamine. We used a dopamine antagonist (methylergonovine) to investigate whether dopamine mediated the enhancement of motor patterns in the analogue of operant conditioning. Methylergonovine blocked synaptic connections from the reinforcement pathway and the contingent-dependent enhancement of the reinforced pattern. These results suggest that dopamine mediates at least part of the neuronal modifications induced by contingent reinforcement.

[Immediate collateral coronary circulation after a methylergometrin test]. / Apparition immédiate d'une circulation collatérale coronaire après test à la méthylergométrine.

The development of a collateral coronary circulation has been well studied by angiography in two main clinical situations: myocardial infarction (by durable coronary occlusion) and angina (due to significant coronary artery stenosis), but only rarely in spastic angina. The authors report the case of severe spasm at the site of non-significant stenosis after a methylergometrine test, with immediate contro-lateral collateral circulation in a patient with a short history of spastic angina without myocardial infarction. This observation demonstrates that collateral circulation may develop very rapidly in spastic angina (without basal ischaemia in the absence of significant coronary stenosis), because this patient only had seven ten-minute episodes of clinical ischaemia. As collateral circulation may mask clinical and electrical signs in spastic angina, this case suggests that angiographic control should be systematic during the methylergometrine test.

Ergot alkaloids. Current status and review of clinical pharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology.

Ergot alkaloids are well known preparations. Ergot alkaloids used in obstetrics and gynaecology are ergometrine (ergonovine; EM), methylergometrine (methergine; ME) and bromocriptine. The pharmaceutical properties of ME EM) are critical. To guarantee stability, ME and EM ampoules should be stored in a cool, dark place. ME and EM tablets are unstable in all conditions and they show an unpredictable bioavailability, which prevents oral use of the drugs for any purpose. ME and EM are known for their strong uterotonic effect and, compared with other ergot alkaloids, for their relatively slight vasoconstrictive abilities. ME and EM do have a place in the management of the third stage of labour as they are strong uterotonics. They act differently from oxytocin and prostaglandins, and have different adverse effects. Oxytocin should be used as prophylaxis or a the drug of first choice; next, ME or EM should be used, and if none of these drugs produce the desired effects, prostaglandins should be used to control bleeding. Ergot alkaloid use in gynaecology has been limited and today is discouraged even in essential menorrhagia. It is suggested that EM and ME be used (parenterally) only in first trimester abortion curettage, to reduce blood loss. Bromocriptine has been used for lactation suppression. However, alternatives such as cabergoline, which possess fewer adverse effects, are now available and therefore preferred for this indication. In sum, there is no place for the prophylactic use of ME and EM in obstetrics or gynaecology. They can be used for therapeutic purposes in the third stage of labour. During use, the practitioner must be alert for adverse effects.

The angiotensin II type 1 receptor gene polymorphism is associated with coronary artery vasoconstriction.

OBJECTIVES: This study sought to assess the potential association of the angiotensin-converting enzyme (ACE) and angiotensin II type 1 (AT1) receptor gene polymorphisms on coronary vasomotion in humans. BACKGROUND: Abnormal coronary vasomotion plays a role in the clinical expression of coronary atherosclerosis. The components of the renin-angiotensin system are important determinants of vasomotor tone. Furthermore, epidemiologic evidence suggests that these components are involved in the pathogenesis of coronary artery disease. Indeed, two genetic polymorphisms of the ACE and AT1 receptor genes were synergistically associated with the occurrence of myocardial infarction. The influence of these genetic polymorphisms on the risk of myocardial infarction may be related, at least in part, to a deleterious effect on coronary vasomotion. METHODS: We studied the response of angiographically normal human coronary arteries after intravenous injection of methylergonovine maleate, a potent vasoconstrictor whose effects have been previously explored in various aspects of coronary artery disease. We characterized the ACE and AT1 receptor genotypes in a consecutive series of 140 patients with normal coronary arteries. Coronary vasomotion was assessed with quantitative coronary angiography. RESULTS: No effect of the ACE gene polymorphism was detected. Conversely, the patients carrying the AT1 receptor CC genotype (n = 13) had significantly greater vasoconstriction in distal coronary vessels (p < 0.009). CONCLUSIONS: The AT1 receptor gene polymorphism is associated with coronary vasomotion in humans.

Uterine evacuation by vaginal misoprostol after second trimester pregnancy interruption.

BACKGROUND: The purpose was to study the capacity of vaginal misoprostol in combination with methylergometrine to achieve complete evacuation of the uterus without ensuing surgical evacuation of the uterine cavity. METHODS: We performed this trial on 228 women seeking pregnancy interruption. Vaginal misoprostol was given in a dosage of 800 micrograms in early second trimester. All women received concomitant treatment with peroral methlyergometrine from the moment of misoprostol application every 8 hours until uterine evacuation. Follow-up was continued until the first menstruation after interruption. RESULTS: Complete uterine evacuation was achieved in 173/228 cases (76%) [group 1]. The remaining 55 women [group 2] underwent manual evacuation of placental remnants trapped in the cervix. In seven of these women a conventional curettage was carried out due either to ultrasound evidence of placental remnants or due to uterine bleeding. The interval between misoprostol application and fetal expulsion averaged 14.9 hours (s.d. 9.6) in group 1 and 21.0 hours (s.d. 14.5) in group 2 (p=0.006). CONCLUSIONS: Misoprostol, in combination with methylergometrine, is a remarkably efficient drug in achieving uterine evacuation also in the absence of surgical evacuation of the uterine cavity. The present study provides justification for a more expectant attitude after vaginal misoprostol treatment for pregnancy interruption. The avoidance of close to 80% of otherwise conventional curettages would seem to represent a major advantage, particularly in settings where manpower and material resources are scarce.

Oral administration of methylergometrine shows a late and unpredictable effect on the non-pregnant human menstruating uterus.

OBJECTIVE: To study the pharmacodynamic and pharmacokinetic properties of oral and intravenous methylergometrine upon uterine motility during menstruation. STUDY-DESIGN: Intra-uterine pressure was measured in six volunteers with a fluid-filled sponge-tipped catheter during menstruation. Methylergometrine was given orally (0.5 mg) or intravenously (0.2 mg) in a cross-over design. RESULTS: After intravenous administration, a fast increase of the frequency of uterine contractions and basal tone occurred with a decrease of amplitude, lasting at least 30 min. Oral administration had a late and less marked effect on uterine motility. An intravenous dose administered 24 h after an oral dose had no effect on uterine motility. Pharmacokinetic data, such as the maximum plasma concentration (Cmax), the time at which Cmax is reached (tmax) and the half-life of absorption (t1/2abs) also demonstrated large individual variations after oral administration. CONCLUSIONS: Oral administration of methylergometrine had an unpredictable and late effect on uterine motility on the menstruating uterus, probably due to an unpredictable bioavailability, in contrast with the fast and predictable effect after intravenous administration.

Dose-response curve of angiographically smooth human epicardial vessel segments to intracoronary injections of isosorbide dinitrate.

The coronary vasodilator properties of isosorbide dinitrate are well established but the doses generally used (1,000-2,000 micrograms) are still empirical. We studied, with the use of quantitative coronary arteriography (CAESAR System), the response of smooth vessel segments (greater than 1.85 mm diameter), preconstricted with methylergometrine (400 micrograms i.v.), to intracoronary injections of graded doses (5-100 micrograms) of isosorbide dinitrate and the effects of these injections on systemic hemodynamic parameters in 10 patients undergoing diagnostic coronary angiography. Six further patients, in whom the injections of isosorbide dinitrate were replaced by equivalent volumes of normal saline, served as controls. Relative to the diameter 5 min after injection of methylergometrine, the diameter increased by a mean +/- SD of 9 +/- 7, 26 +/- 12, 33 +/- 15, 38 +/- 14, and 39 +/- 16% after injections of 5, 15, 60, 240, and 1,000 micrograms, respectively, of isosorbide dinitrate. After a cumulative dose of 80 micrograms, subsequent doses did not cause further significant increases in diameter. Injection of saline in the control group did not alter the coronary diameter. A significant fall in systolic arterial pressure, compared to the control group, occurred at a cumulative dose of 320 micrograms. The mean arterial pressure and heart rate were unchanged. Significant coronary vasodilation occurs with intracoronary doses of isosorbide much smaller than those currently employed. Cumulative doses of 320 micrograms or more cause systemic hemodynamic changes without producing additional coronary vasodilation. During interventional cardiac procedures, where systemic hypotension is undesirable, the use of smaller doses of intracoronary isosorbide dinitrate than currently employed may be feasible and should be investigated further.