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.

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.

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.

[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.

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.

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.

Complete denervation of the heart (autotransplantation) for treatment of severe, refractory coronary spasm.

A 49 year old man had severe refractory Prinzmetal's variant angina and angiographically documented coronary arterial spasm of a dominant circumflex artery. The spasm was provoked by methergine (an ergot alkaloid) and seemed resistant to various forms of medical therapy including administration of nitrates, nifedipine, verapamil, diltiazem and amiodarone. The attacks of angina at rest persisted at the rate of 7 to 15/day and were frequently associated with atrioventricular (A-V) block. After unsuccessful plexectomy performed in another institution, the patient underwent complete cardiac denervation (produced by autotransplantation). The follow-up data have interesting implications in relation to treatment of refractory variant angina, as well as possible mechanisms of coronary arterial spasm.

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.

Effect of methylergonovine on puerperal prolactin secretion.

Serum prolactin concentration was measured by radioimmunoassay in 29 women, in the first 1 1/2 hours postpartum. Fourteen women received 0.2 mg methylergonovine maleate (Methergine) intramuscularly after the delivery of the placenta. Fifteen women who served as controls received only saline. The rise in serum prolactin concentration seen in the control women (266.4 ng/ml +/- 40.8 SE) was significantly greater than that seen in methylergonovine-treated patients (141.0 ng/ml +/- 29.0. SE).

13,14-Dihydro-15-keto-PGF2 alpha (PGFM) and sulprostone serum levels after application of sulprostone to postpartum women.

13 ,14 -Dihydro-15-keto-PGF2 alpha (PGFM) serum levels were determined by radioimmunoassay in 101 postpartum women who were treated with 200 micrograms methergin, 5 I.U. oxytocin and 500 micrograms sulprostone, respectively, 30 min after expulsion of placenta. All patients had normal deliveries. The present radioimmunoassay system did not show cross-reactivity with sulprostone. In addition, radioimmunoassayable sulprostone serum levels were monitored. Covariance analysis of area under PGFM serum levels between time zero and 180 min after application of oxytocics was performed. A higher but statistically not significantly PGFM serum level was maintained in subjects treated with sulprostone. Sulprostone serum levels are rapidly attained after application. Decrease of radioimmunoassayable sulprostone indicates a half-life of 75 min. These data corroborate clinical findings of an accompanying paper and combine to suggest that sulprostone may be a useful alternative therapy in high-risk patients with severe postpartum atony and hemorrhage in whom prior preventive measures have failed.

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.

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.

[Response of coronary arteries to the intracoronary injection of isosorbide dinitrate. Dose-response curve]. / Réponse des artères coronaires à l'injection intracoronaire de dinitrate d'isosorbide. Etablissement d'une courbe dose-réponse.

The coronary vasodilator properties of isosorbide dinitrate (ISDN) are well known but the dosage remains empirical. The aim of this study was to construct a dose-response curve to ISDN with respect to vasoconstriction induced by ergometrine. The heart rate, aortic pressure and coronary angiography were analysed before and 3 and 5 minutes after I.V. injection of 0.4 mg of methylergometrine and 3 minutes after intracoronary injection of 5, 15, 60, 240 and 1,000 micrograms of ISDN in 10 patients with an average age of 53.2 +/- 10.8 years (ISDN group). Six other patients with an average age of 56.5 +/- 12.8 years comprised the control group and only received ergometrine. The coronary diameters were measured by quantitative coronary angiography using the CAESAR system of automatic contour detection. Three coronary segments with angiographically normal appearances and a resting diameter greater than or equal to 1.85 mm were analysed in each patient. With respect to the maximal constriction observed 5 minutes after the injection of methylergometrine, the percentage increase in coronary diameter was 9 +/- 7%, 26 +/- 12%, 33 +/- 15%, 38 +/- 14% and 39 +/- 16% after 5, 15, 60, 240 and 1,000 micrograms of ISDN respectively (p less than 0.005 vs control). A plateau effect was observed after a cumulative dose of 80 micrograms and administration of higher doses of 240 and 1,000 micrograms only caused mild nonsignificant additional increase in vessel diameter. In comparison with the control group, the systolic blood pressure only fell significantly with doses greater than 240 micrograms of ISDN (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

[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.

[Hemodynamic and coronary effects of methylergometrin]. / Effets hémodynamiques et coronaires de la méthylergométrine.

The methylergometrine test (ME) was performed during coronary angiography in 43 patients either by a single injection of 0,4 mg (34 cases) or by fractioned doses every 5 minutes of 0,1 mg, 0,2 mg, 0,3 mg, 0,4 mg (total 1 mg) (9 cases). Opacification of the coronary arteries was performed 1, 3 and 5 minutes after each injection; left ventricular pressures were recorded with a Millar catheter-tip transducer. The heart rate and first derivative of left ventricular pressure did not vary significantly after the 0,4 mg single dose ME. Left ventricular end systolic pressure rose by 11 p. 100 (p less than 0,001) and left ventricular end diastolic pressure from 18,3 to 23,1 mmHg (p less than 0,001). Myocardial oxygen consumption assessed by the TTI rose from 2873 +/- 896 to 3083 +/- 788 mmHg.s-1 .min (p less than 0,01), but myocardial contractility as assessed by the V max fell from 1,68 +/- 0,40 to 1,58 +/- 0,35 s-1 (p less than 0,001). The reduction in the calibre of the coronary lumen was identical after the single 0,4 mg dose and the 1 mg fractioned doses. In the later case, 50 p. 100 of the maximal response was observed after the first injection of 0,1 mg. After the single dose of 0,4 g ME the reduction in coronary lumen was very rapid over the first 3 minutes. Prolonged observation up to the 10th minute (7 patients) showed slight aggravation of the vasoconstriction between the 5th and 10th minutes, justifying an injection of a nitrate derivative before discontinuing surveillance. The vasoconstriction induced by ME seems to be within the physiological limits of vasoconstriction. The maximal overall decrease of the coronary diameter was 12,3 +/- 7,8 p. 100 and never exceeded 20 p. 100. There was a significant difference in the response of atheromatous patients in whom the vasoconstriction was greater in the presence of resting angina than in the absence of resting angina (16,4 +/- 8,7 p. 100 compared to 9,7 +/- 6,4 p. 100, p less than 0,01).

[Effect of ergot alkaloid derivatives on milk secretion in the immediate postpartum period]. / Effet de dérivés des alcaloïdes de l'ergot de seigle sur la sécrétion lactée dans le post-partum immédiat.

30 women received an intramuscular injection of 0.2 mg of methylergobasine immediately after delivery and then 3 tablets of 1 mg of ergotamine tartrate per mouth daily for 6 days post-partum. 28 women received no treatment after delivery. The selection of the two groups was random. The treatment with rye ergot derivatives did not have a significant effect on the quantity of milk that the infant took, nor on the infant's weight gain in the 6 first days of life.