Synthesis of M + 4 Stable Isotopomers of Ergometrine and Ergometrinine.

The priority ergot alkaloids ergometrine and ergometrinine are highly toxic mycotoxins naturally occurring in different types of grains (i.e. rye, wheat, rice), as well as grain-based foods and, therefore, have gained increasing importance for food safety over the last years. The application of HPLC-MS/MS for the analysis of ergot alkaloids in food presupposes the availability of isotopically labelled internal standards. Thus, a multistep synthesis was developed for ergometrine-(N-13CD3) and its epimer ergometrinine-(N-13CD3) with a mass shift of four units compared with the parent compounds. The synthesis is based on the preparation of stable isotope labelled lysergic acid that was coupled with (S)-alaninol. The chemical synthesis of both compounds has been achieved in six steps with an overall yield of 1 % (ergometrine-(N-13CD3)) and 0.6 % (ergometrinine-(N-13CD3)), respectively. Structural identification was performed by MS analysis as well as 1H and 13C NMR.

Long-term outcome of patients with ergonovine induced coronary constriction not associated with ischemic electrocardiographic changes.

OBJECTIVES: This study investigated the long-term outcome of patients with coronary artery constriction induced with ergonovine but not associated with ischemic electrocardiographic changes. METHODS: The ergonovine provocation test was performed in 419 patients with suspected but unproven variant angina. Ergonovine maleate was administered into the coronary arteries at 8 micrograms/min for 5 min during cardiac catheterization. Patients were categorized into three groups according to their response to ergonovine. The positive group contained patients who developed coronary constriction of more than 90% in diameter associated with ischemic electrocardiographic changes and chest pain. The intermediate group contained patients who had coronary constriction of more than 90% but no electrocardiographic changes. The negative group contained patients who had neither significant coronary constriction nor ST segment changes. RESULTS: There were 305 patients, 49, and 65 in the negative, intermediate, and positive groups, respectively. Death occurred in six patients (2%), one (2%), and one (2%) in the negative, intermediate, and positive groups, respectively. Sudden cardiac death occurred in one patient in the negative group. Recurrence of chest pain with effectiveness of sublingual administration of nitroglycerine was observed in 26 patients (9%), 10 (20%), and 11 (17%) in the negative, intermediate, and positive groups, respectively. CONCLUSIONS: Some patients in the intermediate group might show "false negative" response to ergonovine so careful treatment with calcium antagonists should be continued in patients in the intermediate group as well as patients with vasospastic angina.

Decrease of nitric oxide end-products during coronary circulation reflects elevated basal coronary artery tone in patients with vasospastic angina.

The aim of this study was to investigate the role of nitric oxide (NO) in the coronary circulation and its relation to basal coronary artery tone in patients with vasospastic angina (VSA). We evaluated the level of nitric oxide end-products (NOx; nitrite + nitrate) in coronary circulation blood using an HPLC-Griess system for nine patients with VSA and nine control patients. All of the patients with VSA experienced focal spasm in the proximal to middle segments of the left anterior descending coronary artery (LAD) in response to intracoronary injection of ergonovine maleate. The luminal diameter of the coronary artery was measured in each patient by quantitative coronary arteriography. Blood samples for NOx measurement were obtained from the coronary sinus (NOxV) and the ostium of the left coronary artery (NOxA). The NOx difference, calculated from the coronary venous-arterial difference in NOx, was close to zero for the control patients whereas it was clearly negative for the patients with VSA. In addition, the NOx difference in the patients with VSA showed a negative correlation with basal coronary artery tone (r = -0.91, p < 0.01) and a positive correlation with the dose of ergonovine required for spasm provocation (r = 0.77, p < 0.05). These results indicate that increased basal coronary artery tone and higher susceptibility to ergonovine in patients with VSA would be a consequence of coronary endothelial dysfunction as is indicated by NOx.

A novel 5-HT(2) antagonist, sarpogrelate hydrochloride, shows inhibitory effects on both contraction and relaxation mediated by 5-HT receptor subtypes in porcine coronary arteries.

In isolated porcine coronary arteries, concentrations of 5-HT (10(-8) to 3x10(-5) mol/l), alpha-methylserotonin (alpha-Me-5-HT, 10(-8) to 3x10(-5) mol/l) and ergonovine (10(-9) to 3x10(-4) mol/l) produced contraction, whereas high concentrations (10(-5) to 10(-4) mol/l) of these drugs produced relaxation. Both sarpogrelate and ketanserin produced rightward shifts of contraction concentration-response curves induced by 5-HT and alpha-Me-5-HT at the concentration from 10(-9) to 3x10(-5) mol/l, and only sarpogrelate inhibited the relaxation at high concentrations of 5-HT and displayed 155% of maximal contraction at 10(-4) mol/l 5-HT. On the other hand, sarpogrelate and ketanserin did not show any inhibitory effects on the relaxation induced by high concentrations of ergonovine. These results suggested that sarpogrelate and ketanserin show different inhibitory effects on the relaxation induced by high concentrations of 5-HT, indicating that these two drugs may have different affinities to 5-HT receptor subtypes that may be involved in relaxation.

123I-MIBG myocardial scintigraphy as a noninvasive screen for the diagnosis of coronary artery spasm.

BACKGROUND: It has been suggested that the sympathetic nervous system might play an important role in the development of coronary artery spasm. However, no cardiac imaging modality has been able to demonstrate abnormal sympathetic innervation in patients with coronary artery spasm. The purpose of this study was to assess the presence and location of abnormal sympathetic innervation using iodine 123-metaiodobenzylguanidine (123I-MIBG) single photon emission computed tomography (SPECT) and to evaluate the clinical efficacy of 123I-MIBG SPECT as a noninvasive screening test in patients with coronary artery spasm. METHODS AND RESULTS: Coronary arteriography and a provocative test with intravenous administration of ergonovine maleate were performed in 26 patients (20 men, 6 women, mean age 48.2+/-12.0 years, range 20 to 67 years) who were suspected of having a coronary artery spasm. The subjects were divided into 2 groups: group 1 (n = 18) comprised subjects with a positive provocative test result, and group 2 (n = 8) comprised subjects with negative provocative test results. Ten healthy subjects served as controls. No abnormal MIBG uptake was observed in the control subjects. Abnormal sympathetic nervous innervation using 123I-MIBG SPECT was observed either as a reduced uptake or a defective pattern in the perfused areas in 13 of the 18 regions supplied by vessels of ergonovine-induced vasospasm. Normal sympathetic innervation, as evidenced by normal 123I-MIBG uptake, was noted in all of the 60 segments of normal vessel territories. Reduced uptake of 123I-MIBG was not detected in the perfused areas of 5 vasospasm-induced vessels (perfusion territory of left anterior descending coronary artery [LAD] and the right coronary artery [RCA] in 2 and 3 patients, respectively). The sensitivity and specificity of 123I-MIBG for detection of coronary artery spasm were 72.2% (95% confidence interval [CI] 55% to 89%) and 100%, respectively. The positive predictive and negative predictive values were 100% and 92.3% (95% CI 91% to 93%), respectively. CONCLUSION: 123I-MIBG SPECT is a feasible method to evaluate noninvasively and localize the territories of coronary arteries with spasm. Invasive diagnostic coronary arteriography with ergonovine provocation test may be unnecessary for diagnosis of coronary artery spasm in patients with typical resting pain, negative exercise test or normal thallium perfusion scan results, but showing abnormalities in 123I-MIBG SPECT.

A psychobehavioral factor, alexithymia, is related to coronary spasm.

The aim of this study was to assess whether the psychobehavioral pattern alexithymia is related to coronary artery spasm. Alexithymia, deficient psychological awareness, was examined using the Minnesota Multiphasic Personality Inventory Alexithymia Scale in 100 patients with angina pectoris in whom coronary spasm, defined as > or = 99% coronary narrowing, was documented upon ergonovine provocation, and in 109 patients with chest pain syndrome who were shown to have almost normal coronaries without inducible coronary spasm on coronary angiogram (control group). Alexithymia was approximately twice as prevalent in the coronary spasm group (31%) as in the control group (14%) (p<0.01). Among various conventional risk factors including hyperlipidemia, obesity, diabetes mellitus, hypertension, hyperuricemia, or family history of ischemic heart disease, only male sex and smoking were more prevalent in the coronary spasm group than in the control group (p<0.001). The odds ratios of coronary spasm adjusted for all the other risk parameters including sex and age were 4.14 [95% confidence interval (CI) 1.81-9.47] for alexithymia and 2.38 (95, CI 1.18-4.82) for smoking. A psychobehavioral pattern, alexithymia, relates to coronary spasm. This relationship is independent of the conventional coronary risk factors.

Subacute toxicity of ergometrine maleate in rats.

Ergot alkaloids, produced by the fungus Claviceps purpurea, are found in small amounts in foodstuffs. The human disease ergotism, caused by high intake of ergot alkaloids, is well known; however, little is known about the toxicity of these compounds. The subacute toxicity of an ergot alkaloid, ergometrine maleate, was therefore studied. Sprague-Dawley rats were treated with 0, 2, 10, 50 and 250 mg ergometrine maleate/kg diet for 4 wk. Plasma glucose levels were decreased in females at 50 and 250 mg/kg. Thyroxin levels were decreased at 50 (males only) and 250 mg/kg. At the high dose level, organ weights of heart, liver, ovaries and kidneys were increased. In male rats a slight dose-related increase in the incidence of enlarged mediastinal lymph nodes and, to some extent, of enlarged parathymal lymph nodes, was seen. Histopathological examination revealed evidence of increased glycogen storage in the liver of animals treated with 250 mg/kg. The no-observed-effect level in this study was 10 mg/kg.

Ergonovine-echo test to assess the significance of chest pain at rest without ECG changes.

The aim of this study was to assess the feasibility and diagnostic role of ergonovine maleate infusion under continuous two-dimensional echocardiographic monitoring for the identification of vasospastic myocardial ischaemia in patients with chest pain at rest not associated with diagnostic ECG changes. One hundred and twenty-eight consecutive patients, selected on the basis of absence of ischaemic ECG changes during angina at rest before or during hospitalization, were enrolled in the study. Ergonovine maleate was i.v. administered in scaled doses (from 0.025 to 0.2 mg at 10 min intervals) under echocardiographic, electrocardiographic and systemic blood pressure monitoring. Wall motion asynergies were observed in 33 patients, accompanied by typical chest pain in 24 patients and by ECG changes in 25 (ST elevation in 13 patients, ST depression in seven, T wave changes in five). All patients were able to complete the test. Non life-threatening ventricular arrhythmias were observed in four patients exclusively in association with ischaemia. In seven patients with a positive test, coronary artery spasm was documented at angiography. In 16 patients with a positive test, the vasospastic event was reproduced by a hyperventilation-echo test or a second ergonovine maleate-echo test performed within 3 days of the first examination. In none of the patients with a negative test was documentation of myocardial ischaemia due to a primary reduction in coronary blood flow. Thus, in patients who do not show ECG changes during chest pain at rest, the ergonovine maleate-echo test is feasible and safe; it permits the recognition of ischaemic episodes on the basis of wall motion abnormalities when conventional 12-lead ECG-recorded chest pain is non-diagnostic.

[Clinical significance of diffuse vasoconstriction of coronary arteries--a study using hyperventilation thallium-201 myocardial imaging].

Hyperventilation Thallium-201 imaging was evaluated for the examination of the existence of ischemia in the cases of diffuse vasoconstriction under the ergonovine maleate provocative test for coronary artery. Transient myocardial perfusion defect (PD) was demonstrated in 14 patients with ergonovine induced vasospasm (group S), and 13 of these patients also demonstrated redistribution (RD) (92.4%). In 14 patients with diffuse vasoconstriction (group D), nine demonstrated PD, and all of them revealed RD. On the other hand, only one of ten (10%) patients demonstrated PD and RD in a group of patients without spasm or diffuse vasoconstriction (group N). In addition, the left ventricular myocardium was divided into nine segments on a SPECT image, and the mean minimum washout rate (WOR) of each segment was evaluated. These values were compared with the percent change of the lung/heart ratio between early and delayed images (delta L/H%). Both the mean minimum WOR mean and delta L/H% of group D were significantly smaller than that of group N (p < 0.001), and only approximated to group S. Thus, the possibility of myocardial ischemia of diffuse vasoconstrictive coronary artery is implicated and such patients are supposed to be treated medically as vasospastic angina.

Intraumbilical oxytocin for management of retained placenta.

OBJECTIVE: The purpose of the study was to investigate the removal of a retained placenta. METHOD: Oxytocin was injected into the vein of the umbilical cord. A total of 109 patients with retention of the placenta were randomized into two groups. Active management of the third stage of labor was carried out by giving oxytocin 5 IU intravenously and ergometrine maleate 0.2 mg intramuscularly after delivery of the fetus. Group 1, which comprised 68 patients, was allocated to receive 50 IU oxytocin diluted in 10 ml 0.9% sodium chloride solution, and the 41 patients in group 2 were given 20 ml plasma expander (dextran 70) into the umbilical vein. RESULTS: Forty-nine cases (72%) in the oxytocin group and 22 cases (54%) in the dextran 70 group required manual removal of the retained placenta. No significant differences were found between group 1 (oxytocin) and group 2 (dextran 70). CONCLUSION: Our results indicate that intraumbilical vein injection of oxytocin is not effective for removal of a retained placenta.

Long-term follow-up of coronary narrowing with spasm.

In order to clarify the fate of coronary narrowing with spasm, repeat angiograms of coronary narrowing with and without spasm were compared. The mean interval between the first and second angiograms was 3.6 years (range, 1.1-8.5 years). Improvement of narrowing was more frequent in the vasospastic group (23%) than in the group without spasm (3%, P < 0.005). The cause of this improvement in the vasospastic group may have been the resolution of the spasm in the first angiogram, but the presence of intravascular thrombus or bleeding or edema of the coronary arterial wall may have resolved in the second angiogram.

Values of intravenous ergonovine test with two-dimensional echocardiography for diagnosis of coronary artery spasm.

The purpose of this study was to evaluate the clinical validity of the bedside ergonovine test with digital echocardiography and the side-by-side continuous cineloop display method (ergonovine echocardiography) as a noninvasive diagnostic tool for coronary artery spasm. Bedside ergonovine test was performed in 66 patients who showed coronary vasospasm during coronary angiography including provocation testing (group with variant angina) and 39 patients with normal angiograms and no evidence of coronary artery spasm (group with nonanginal pain). A bolus of ergonovine maleate (0.025 or 0.05 mg) was injected at 5-minute intervals up to total cumulative dosage of 0.35 mg, and 12-lead electrocardiography and two-dimensional echocardiography were recorded every 3 minutes after each injection. Left ventricular wall motion was analyzed with a commercially available quad system. The positive criteria of bedside ergonovine test included reversible ST segment elevation or depression on electrocardiograms (ECG criteria) and reversible regional wall motion abnormalities by echocardiography (Echo criteria). The overall sensitivity and specificity of ECG criteria were 53% (35/66; 95% confidence interval 41% to 65%) and 100%, respectively. By Echo criteria the sensitivity increased to 89% (59/66; 95% confidence interval 81% to 97%), with a specificity of 95% (37/39).(ABSTRACT TRUNCATED AT 250 WORDS)

Intravascular ultrasound detection of atherosclerosis at the site of focal vasospasm in angiographically normal or minimally narrowed coronary segments.

OBJECTIVES: The purpose of this study was to use intravascular ultrasound imaging to examine the presence of occult atherosclerosis at the site of focal vasospasm in angiographically normal or minimally narrowed segments, testing the role of atherosclerosis in the development of vasospasm. BACKGROUND: Previous clinical and experimental studies have suggested that early atherosclerosis is present at the site of focal vasospasm. However, no clinical data exist demonstrating occult disease at the site of vasospasm at angiographically insignificant stenoses. METHODS: Twenty-two patients with chest pain at rest or during exertion, or both, were studied. Vasospasm was provoked by intracoronary administration of ergonovine maleate (0.01 to 0.04 mg). After relief of vasospasm by nitroglycerin administration, intravascular ultrasound imaging was performed with a 32- or 64-element, 20-MHz, synthetic aperture array ultrasound device. RESULTS: Focal vasospasm (arterial diameter reduction > or = 90%) with ST-T segment elevation was provoked in 15 patients: in the left anterior descending coronary artery in 8 patients and in the right coronary artery in 7. The remaining seven patients (control group) showed diffuse narrowing, averaging 22 +/- 12% (mean +/- SD) in diameter from the baseline angiograms after ergonovine administration. Atherosclerosis, defined as a significantly thickened intimal leading edge (0.42 +/- 0.07 mm) associated with an increased sonolucent zone (0.57 +/- 0.30 mm), was detected by ultrasound at all 15 sites with focal vasospasm, although these sites were normal or minimally narrowed by angiography. In contrast, seven segments from the control group exhibited a thin intimal leading edge (0.14 +/- 0.04 mm, p < 0.01) and sonolucent zone (0.10 +/- 0.07 mm, p < 0.01), indicating the absence of localized atherosclerotic lesions. CONCLUSIONS: These results indicate that atherosclerosis is present at the site of focal vasospasm, even in the absence of angiographically significant coronary disease. We suggest that the existence of such atherosclerotic lesions is related to the occurrence of focal vasospasm in the clinical settings.

Temporal variability and correlation with geometric parameters in vasospastic angina: a quantitative angiographic study.

Long-term changes in vasocontractility were examined in 23 coronary segments from 20 patients with variant angina using computer-based quantitative coronary angiography and ergonovine provocation tests repeated at an interval of 42 +/- 14 months. Measurements of vasospasticity at the sites of fixed stenoses were compared with values predicted by an elementary geometric theory based on the assumption that the cross-sectional area of a vessel wall is constant regardless of its state of vasoconstriction. While all patients were symptomatic initially, only 11 remained symptomatic at follow-up. At the initial provocation test, the response was correctly predicted in four segments, was lower than expected in one, and was stronger in 18. At follow-up, only one of the four segments in which the response had been initially predicted correctly again showed the predicted response and the remaining three showed a response weaker than expected; the one segment which was initially hypocontractile remained hypocontractile at follow-up; and of the 18 segments which were initially hypercontractile, 12 exhibited hypercontractility again, four had the predicted value and the remaining two showed hypocontractility. In only one of 23 segments did the geometric theory predict the behaviour of vasospasticity at the site of fixed stenosis on both tests. Vasospastic responsiveness is a dynamic process demonstrating temporal variability and is not directly predicted by geometric theory.

Role of coronary vasospasm in the pathogenesis of myocardial infarction: study in patients with no significant coronary stenosis.

The role of coronary vasospasm in the pathogenesis of myocardial infarction is unclarified. Among 212 patients with myocardial infarction in whom percutaneous transluminal coronary angioplasty (PTCA) or coronary thrombolysis was not performed at the acute stage, 21 patients (10%) showed no significant coronary stenosis (the degree of stenosis was less than 50% of the luminal diameter) by coronary angiography 4 weeks after myocardial infarction. Among them, 11 (52%) had preinfarction angina at rest, including two with variant angina, and nine (43%) had postinfarction angina at rest. Intracoronary ergonovine maleate induced coronary vasospasm in 12 (75%) of 16 patients examined. Coronary vasospasm occurred in the infarct-related coronary arteries in all patients, and importantly, multivessel coronary vasospasm occurred in 11 patients (69%). The infarct size was relatively small in these patients: (1) seven patients (33%) had Q wave myocardial infarction while 14 patients (67%) had non-Q wave myocardial infarction; (2) peak creatine phosphokinase (CPK) was lower than 1000 IU/ml in all patients; and (3) thallium-201 (Tl-201) scintigraphic study showed no perfusion defect in 8 of 18 patients. There was only one patient with congestive heart failure and no patient died. These results suggest that coronary vasospasm may play an important role in the pathogenesis of myocardial infarction in patients without significant coronary stenosis. The relatively small infarct size suggests that coronary reperfusion occurred in the early stages of myocardial infarction.

Hyperventilation-echocardiography test for the diagnosis of myocardial ischaemia at rest.

The purpose of this study was to assess the feasibility, safety, specificity and sensitivity of the hyperventilation test performed under echocardiographic monitoring for the provocation of vasospastic ischaemia. Hyperventilation (approximately 30 cycles.min-1 for 5 min) was performed in 104 hospitalized patients, referred for pain typical of angina at rest, under 2-D echocardiographic and 12-lead electrocardiographic monitoring. All the tests were completed and no significant side effect was observed. In-hospital documentation of spontaneous myocardial ischaemia and/or ergonovine-induced ischaemia was achieved in 38 patients (group I). A positive hyperventilation-echocardiography test (occurrence of new transient asynergies or worsening of basal ones) was obtained in 32/38 patients. Among the group I patients, only 23 had diagnostic ST-T changes and only 16 experienced chest pain during the hyperventilation-echo test. Of the 66 patients without evidence of myocardial ischaemia at rest (negative ECG monitoring during hospitalization and/or negative ergonovine maleate-echo test)--Group II, none showed echocardiographic changes, seven presented ST-T changes and six complained of typical chest pain during the test. Thus, in relation to in-hospital documentation of myocardial ischaemia at rest, both spontaneous and/or ergonovine-induced episodes, the hyperventilation-echo test showed a specificity of 100%, a sensitivity of 84%, a positive predictive value of 100% and a negative predictive value of 92%. In conclusion, hyperventilation performed under echocardiographic monitoring is feasible and safe; it can be proposed as a screening test to unmask vasospastic myocardial ischaemia in patients with angina at rest, in whom documentation of spontaneous episodes is not available.