Inhibitory effect of OP-41483.alpha-CD, a prostacyclin analog, on peripheral vascular lesion models in rats.
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The effect of a chemically stable prostacyclin analog, OP-41483 alpha-cyclodextrin clathrate (OP-41483.alpha-CD), on vascular lesions, platelet aggregation and blood pressure were examined and compared with those of prostaglandin E1 alpha-cyclodextrin clathrate (PGE1.CD) in in vivo rat models. 1) In the laurate (1 mg/leg, i.a.)-induced arterial thrombotic model, OP-41483.alpha-CD (1 microgram/kg/min, i.v.) prevented the progression of femoral arterial vascular lesions and enhanced the development of collaterals in the femoral artery. PGE1.CD did not inhibit the progression of vascular damages. 2) In the model of vasoconstriction induced by epinephrine (0.05 mg/tail, s.c.) and ergotamine (2 mg/kg, s.c.), OP-41483.alpha-CD and PGE1.CD, at 1 microgram/kg/min, inhibited the progress of of tail gangrene and lessened the decrease in tail cutaneous blood flow. 3) OP-41483.alpha-CD (1 microgram/kg/min) suppressed the ADP (0.1 mg/kg/min, i.v.)-induced decrease in the number of circulating platelets without affecting the change in blood pressure. In contrast, PGE1.CD (3 micrograms/kg/min) inhibited ADP-induced thrombocytopenia with a decrease in blood pressure. These results indicate that OP-41483.alpha-CD has antiplatelet and cutaneous blood flow improving activities that are greater than its hypotensive effect and may be of therapeutic potential in peripheral vascular diseases. (+info)
Ergotamine-induced upper extremity ischemia: a case report.
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Ergotamine-induced limb ischemia is an extremely rare case. We present a case of a 64-year-old man, who developed ischemia on the right upper extremity due to long-term use of Ergot for migraine headache. Angiography revealed diffused, smooth, and tapered narrowing of the brachial artery. The patient was successfully treated with intravenous nitroprusside. (+info)
Interactions of metoclopramide and ergotamine with human 5-HT(3A) receptors and human 5-HT reuptake carriers.
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The actions of metoclopramide and ergotamine, drugs which are used as a combined migraine medication, on human (h)5-HT3A receptors and 5-HT reuptake carriers, stably expressed in HEK-293 cells, were studied with patch-clamp- and ([3H]5-HT)-uptake techniques. At clinical concentrations, metoclopramide inhibited peak and integrated currents through h5-HT3A receptors concentration-dependently (IC50 = 0.064 and 0.076 microM, respectively) when it was applied in equilibrium (60 s before and during 5-HT (30 microM) exposure). The onset and offset time constants of metoclopramide action were 1.3 and 2.1 s, respectively. The potency of metoclopramide when exclusively applied during the agonist pulse decreased more than 200-fold (IC50 = 19.0 microM, peak current suppression). Metoclopramide (0.10 microM) did not alter the EC50 of 5-HT-induced peak currents. In contrast to the lack of competitive interaction between metoclopramide and 5-HT in this functional assay, metoclopramide inhibited specific [3H]GR65630 binding to human h5-HT3A receptors in a surmountable manner. This seeming discrepancy between functional studies and radioligand binding experiments may be accounted for by (1) the slow kinetics of inhibition of peak currents by metoclopramide compared with the fast onset and offset kinetics of 5-HT-induced currents and (2) the low efficacy of metoclopramide in inhibiting radioligand binding (e.g. only 20% binding inhibition compared to 79% peak current suppression by 200 nM metoclopramide). At low concentrations (1-10 nM), ergotamine had no effect on 5-HT (30 microM)-induced peak currents. Above clinical concentrations, ergotamine (>3 microM) inhibited them. When both drugs were applied together (0.10 microM metoclopramide +0.001 to 0.01 microM ergotamine), an inhibition of both, peak and integrated current responses was observed. Neither metoclopramide (< or =30 microM) nor ergotamine (< or =30 microM) had an effect on the 5-HT reuptake carrier as they did not alter the citalopram-sensitive [3H]5-HT uptake. (+info)
Patients' preference for triptans and other medications as a tool for assessing the efficacy of acute treatments for migraine.
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Oral triptans are effective and well tolerated acute treatments for migraine, but clinical differences between them are small and difficult to measure in conventional clinical trials. Patient preference assesses a global measure of efficacy and tolerability, and may be a more sensitive means of distinguishing between these drugs. In a series of studies, patients consistently expressed a clear preference for triptans over their usual non-triptan acute medications, e.g., analgesics and ergotamine. Direct comparator studies of patient preference with oral triptans showed that patients could distinguish between different triptans, and between different formulations of the same triptan. Patients could even distinguish between the three oral doses of sumatriptan. The most frequently provided reasons for preference were speed of response and overall effectiveness. Patient preference is a sensitive clinical trial endpoint and physicians should consider using it when reviewing the efficacy of acute migraine medications. (+info)
Carotid vascular effects of ergotamine and dihydroergotamine in the pig: no exclusive mediation via 5-HT1-like receptors.
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1. Though it is well known that the antimigraine drugs ergotamine and dihydroergotamine reduce carotid arteriovenous anastomotic shunting, it is uncertain whether a 5-HT1-like receptor is responsible for this effect. Using a high dose of methiothepin (3 mg kg-1), which completely blocks the carotid vascular effects of sumatriptan, we have attempted to study the role of 5-HT1-like receptors in the carotid vascular effects of ergotamine as well as dihydroergotamine in anaesthetized pigs. 2. Both ergotamine and dihydroergotamine increased arterial blood pressure and decreased heart rate. 3. The ergot alkaloids reduced dose-dependently total carotid blood flow and conductance as a result of a selective decrease in the arteriovenous anastomotic fraction. The nutrient fraction increased, particularly to bones, tongue and salivary glands with ergotamine and to ears, head skin, bones and salivary glands with dihydroergotamine. In contrast, dural vascular conductance tended to decrease. 4. Methiothepin (3 mg kg-1) partially antagonized the decrease in total carotid and arteriovenous anastomotic blood flow and conductance by the ergot alkaloids; the ED30 for ergotamine and dihydroergotamine (agonist dose eliciting a 30% decrease in arteriovenous anastomotic conductance) was raised by 3.1 and 5.2 fold respectively. 5. These results indicate that the effects of ergotamine and dihydroergotamine are partly mediated by methiothepin-sensitive receptors, which may probably belong to either 5-HT1-like or alpha 2-adrenoceptor category. However, an important part of the effect of ergot alkaloids is left after methiothepin and this could be mediated by other, perhaps novel, receptors. (+info)
Contractile responses to ergotamine and dihydroergotamine in the perfused middle cerebral artery of rat.
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The vasomotor effects of ergotamine and dihydroergotamine (DHE) on the middle cerebral artery (MCA) of rats were studied using the pressurised arteriography method and in vitro myographs. MCAs from Sprague-Dawley rats were mounted on two glass micropipettes using the arteriograph, pressurised to 85 mmHg and luminally perfused. All vessels used attained spontaneous contractile tone (34.9+/-1.8% of resting tone) and responded to luminal adenosine triphosphate (ATP) with dilatation (24.1+/-4.0%), which showed functioning endothelium. Luminally added ergotamine or DHE induced maximal contractions of 16.8+8% and 22.4+/-0.9%, respectively, compared to the resting diameter, with a pEC(50) of 8.7+/-0.1 for ergotamine and 9.0+/-0.1 for DHE. Abluminal application of ergotamine and DHE also caused concentration-dependent contractions of the perfused MCA by 21.4+/-2.1% and 23.1+/-7.0%, respectively, with pEC(50) values of 7.6+/-0.2 for ergotamine and 8.4+/-0.5 for DHE. The responses were blocked by the 5-HT(2A) receptor antagonist ketanserin (concentration 10(-12) to 10(-5) M) and partially with the 5-HT(1B) receptor antagonist BRL-11557PM-B. The 5-HT(1D) receptor antagonist SB-224289-A had no significant effect. Using a myograph technique, isolated ring segments of the MCA with intact endothelium were mounted on two metal wires. Neither agonist caused relaxation of resting vessels, however, they both responded by weak contractile responses (26+/-3% of submaximal contractile capacity relative to 60 mM potassium). The contractions were typically slow in on and off set (about 30-60 min). The long duration of ergots should be investigated further in an attempt to design drugs with less recurrence. (+info)
Ergovaline-induced vasoconstriction in an isolated bovine lateral saphenous vein bioassay.
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Ergovaline has been proposed as a toxic component of endophyte-infected tall fescue. As many of the symptoms of fescue toxicosis are a result of compromised circulation, the objective of this study was to examine the vasoconstrictive potentials of ergovaline and a more documented ergopeptine, ergotamine, using a bovine, lateral (cranial branch) saphenous vein bioassay. Segments of the cranial branch of the lateral saphenous vein (2 to 3 cm) were collected from healthy, mixed breed cattle (n = 12 and n = 5 for the ergovaline and ergotamine experiments, respectively) at local abattoirs. The veins were trimmed of excess fat and connective tissue, sliced into 2- to 3-mm cross sections, and suspended in a myograph chamber containing 5 mL of a modified Krebs-Henseleit, oxygenated buffer (95% O2 + 5% CO2; pH = 7.4; 37 degrees C). The tissue was allowed to equilibrate at 1 g of tension for 90 min before of the addition of treatments. Increasing doses of ergovaline (1x10(-11) to 1 x10(-4) M) or ergotamine (1 x10(-11) to 1 x 10(-5) M) were administered every 15 min after buffer replacement. Contractile response data were normalized to a percentage induced by a reference dose of norepinephrine (1 x10(-4) M). Contractile responses of saphenous veins were similar for ergovaline and ergotamine. Initial contractile responses began at 1 x10(-8) M for both ergovaline and ergotamine (4.4 +/- 0.8% and 5.6 +/-1.1%, respectively). Vascular tension continued to increase as the alkaloid concentrations increased (maximums: 43.7 +/-7.1% at 1 x10(-5) M ergotamine; 69.6 +/- 5.3% at 1 x10(-4) M ergovaline). Interestingly, ergovaline-induced contractions (1 x10(-4) M) were not reversed by repeated buffer replacement over a 105-min period. As previously shown with ergotamine, these results confirm that ergovaline is a potent vasoconstrictor. The resistance of an ergovaline-induced contraction to relaxation over an extended period of time suggests a potential for bioaccumulation of this ergopeptine alkaloid and may aid in understanding its toxicity within the animal. (+info)
Ergotamine treatment during pregnancy and a higher rate of low birthweight and preterm birth.
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AIMS: Previously the association between oral ergotamine treatment during pregnancy and gestational age at delivery, birthweight, the rate of preterm birth and low birthweight has not been studied. METHODS: Newborn infants without congenital abnormalities born to mothers with or without ergotamine treatment during pregnancy were evaluated in the population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996. RESULTS: Of 38,151 newborn infants with medically recorded gestational age and birth weight, 77 were born to mothers who had received ergotamine treatment during pregnancy. A statistically significant decrease was found in the mean gestational age (0.7 weeks) and birth weight (196 g) among exposed relative to unexposed infants, though these differences were not obstetrically significant. However, there was a significant increase in the proportion of low birthweight newborns (16.4% vs. 5.7%) and preterm births (16.4% vs. 9.2%) after the use of ergotamine during pregnancy. The effect of ergotamine was more obvious in male newborn infants, particularly after treatment in the third trimester. CONCLUSIONS: The association between low birthweight and/or preterm birth and ergotamine treatment may be connected with the effect of ergotamine on the placenta of pregnant women. (+info)