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A specific binding of serotonin (at least 50 fmol/mg protein) was demonstrated in mouse astrocytes in primary cultures. This binding was inhibited by methysergide and by fluoxetine.
15 patients with progressive supranuclear palsy (PSP) are presented with discussion of the value of pneumoencephalography (PEG) and electronystagmography (ENG) in confirming the diagnosis. PEG was performed in 6 patients, and revealed atrophy in the area of the pons and colliculi. ENG, which also was performed in 6 patients, 4 of whom had PEG, confirmed the defects in extraocular movement. Methysergide, which has been suggested as therapy for PSP, was utilized in 6 patients with no evidence of significant improvement.
One hundred and twenty-four migraineurs were treated randomly with 5-hydroxytryptophan (5-HTP) or with methysergide (M). The two groups were homogeneous without significant statistical differences with respect to age, sex, pill use, type of migraine and frequency of attacks before entry. A significant improvement was observed in 75% of the patients treated with M and in 71% of the cases treated with 5-HTP. The most beneficial effect of 5-HTP appears to be felt with regard to the intensity and duration rather than the frequency of the attacks. Side effects were more frequent in the M group than in the 5-HTP group. These results suggest that 5-HTP could be a treatment of choice in the prophylaxis of migraine.
Bromolysergide (BOL 148) and methysergide (UML 491), 2 mg/kg intraperitoneally, and saline were administered to rats 45 min before one-trial passive-avoidance conditioning followed by electroconvulsive shock (ECS) or sham-ECS (ECS). On test session (24 h later), the groups treated with both BOL 148 and UML 491 exhibited a clear-cut retention in comparison to saline-ECS rats. On the other hand, all drugged groups, regardless of their submission to ECS, showed a little less pronounced consolidation than saline-ECS rats. The antiamnestic effect brought about by the two drugs was discussed in terms of receptor antagonism against ECS-released brain serotonin, whereas the lower passive-avoidance level observed in treated animals was considered in relation to a possible antipunishment effect of antiserotoninergic treatment.
Since its first discovery in 1948, serotonin (5-HT) has been the subject of considerable interest. Its potent vasoactivity led to the hypothesis that altered serotonin metabolism was responsible for the pathophysiology of cerebrovascular disease (infarction & hemorrhage) with documentation of elevated levels of serotonin in CSF. If (5-HT) serotonin-mediated release is ultimately responsible for cerebral edema, vasospasm and infarction in experimental and human stroke, then an opportunity exists to pharmacologically block these effects with serotonin-antagonizing agents. This hypothesis has been tested in the laboratory with several agents that inhibit biogenic amines resulting in promising data suggesting a reduction in damage and disability. Since the "natural history of human stroke" results in a 30-40% mortality within the first three weeks, an aggressive new attempt should be directed to increasing the number of survivors in this initial period of high risk. In this regard Sansert (methysergide) was considered worthy of clinical trials.
Using animals with large electrolytic lesions of the median eminence-mediobasal hypothalamus, we confirmed earlier findings that metergoline (ME) and methysergide (MS) inhibit PRL secretion through activation of the dopamine receptors of the pituitary lactotrophs and established, in a quantitative manner, that their dopaminergic potencies are comparable to the potency of the dopamine receptor agonist, piribedil, with ED50 in the order of 0.35 to 0.22 mg/kg. Cyproheptadine (CYP), acting by an unknown mechanism, had only a weak inhibiting effect (ED50 greater than 20.0 mg/kg) in these experimental conditions. In the second part of the study, the PRL-inhibiting actions of ME, MS, CYP, and piribedil, respectively, were tested against the PRL release-stimulating effect of activation of the central serotonergic system that was induced by administration of a large dose of L-5-hydroxytryptophan (5HTP; 100 mg/kg), a small dose of 5HTP (15 mg/kg) in rats pretreated with fluoxetine, or by the serotonin receptor agonist quipazine (10.0 mg/kg, ip). The inhibiting potencies of ME (ED50 0.019, 0.014, and 0.048 mg/kg, respectively) against these three stimuli were much larger than in the lesioned animals or than the corresponding potencies of piribedil (ED50 2.2, 0.24, and 0.41 mg/kg, respectively). It is assumed that in these experimental conditions ME inhibited PRL release by blockade of the central serotonin receptors in addition to its dopaminergic effect and that at low doses (0.1 mg/kg or less) the entire inhibiting effect of ME was probably due to its antiserotonergic activity. With MS, which is a weaker serotonin receptor blocker than ME (ED50 0.178, 0.075, and 0.55 mg/kg, respectively, for the three serotonergic stimuli of PRL release), the antiserotonergic component in its PRL-inhibiting effect was evident but less clearly separable from the dopaminergic component in experiments with 5HTP and with fluoxetine plus 5HTP, whereas in experiments with quipazine the entire action could be accounted for by its dopaminergic activity. CYP was the least potent among the three blockers (ED50 0.6, 0.4, and 1.37 mg/kg, respectively, for the three serotonergic stimuli of PRL release), but appropriate tests indicated that it acted only as a serotonin receptor blocker and not by virtue of its antihistaminic, anticholinergic properties or by a direct action on the pituitary lactotrophs. SQ 10,631, another serotonin receptor blocker that was also tested, had no PRL-inhibiting activity. Because of the dual nature of the PRL-inhibiting mechanism of ME and MS and the low effectiveness of CYP, combined possibly with other actions, the serotonin receptor blockers have limited value in studies concerning the role of the central serotonergic system in the regulation of PRL secretion.
The dopamine receptor agonist, apomorphine HCl (0.75 mg sc) increased serum growth hormone (GH) concentrations in each of 6 subjects. This increase was not inhibited by pretreatment with the serotonin antagonist, methysergide, but was completely abolished in the 4 individuals pretreated with pimozide, a selective dopamine receptor blocking agent. These results provide further evidence that apomorphine-induced GH secretion is mediated by a dopaminergic mechanism and is independent of a serotonergic mechanism.
The effect of methysergide (MES), a serotoninergic antagonist on prolactin (PRL) blood levels was studied in five hyperprolactinemic amenorrheic women. The drug was administered for five days at a daily dosage of 11.2 mg. MES decreased significantly the PRL blood levels in all subjects (p less than 0.01). Since the MES has been shown to have antiserotoninergic effects and since serotonin has been thought to be involved in the control of PRL release, the effects of MES in lowering PRL might be due to a decrease of serotonin tone.
The Neodymium (Nd):YAG laser is commonly used in ophthalmology mainly for the posterior capsulotomy in patients with secondary cataract after extracapsular cataract extraction. A frequent side-effect following different kinds of YAG laser treatments is an acute increase in the intraocular pressure (IOP). The present study addresses the role of calcitonin gene-related peptide (CGRP) in the ocular irritative response following YAG laser anterior capsulotomy in rabbits. The YAG laser anterior capsulotomy caused an irritative response in the eye, which consisted of an increase in the IOP, miosis and breakdown of the blood-aqueous barrier. Following YAG laser capsulotomy, CGRP-immunoreactivity was found in the aqueous humour in different molecular weight forms as revealed by gel-permeation chromatography. One of the peaks coeluted with synthetic human CGRP. Methysergide attenuated the increase in the IOP and disruption of the blood-aqueous barrier, but not the miosis, following YAG laser anterior capsulotomy. The present study demonstrates the release of CGRP into the aqueous humour following YAG laser capsulotomy, and suggests that CGRP is partly causing the increase in IOP and disruption of the blood-aqueous barrier in this irritative response.
A case of acute arterial spasm of the lower extremities, after the ingestion of methysergide, is presented. Arterial spasm was documented by arteriography, and return to normality followed discontinuation of the drug.
Chronic foot pain developed in a 43-year-old woman after taking methysergide, a potent vasoconstrictor. The etiology was believed to be ischemic monomelic neuropathy, which results from the compromise of blood flow to an extremity. The patient eventually required a surgical sympathectomy after lumbar sympathetic blocks failed to provide permanent relief.
The pharmacokinetics of methysergide (MS) and its metabolite methylergometrine (MEM) was studied in male Sprague-Dawley rats. MS was administered iv in doses of 0.71 (0.25 mg/kg) or 2.8 mumol/kg (1.0 mg/kg). The metabolite MEM was administered as iv doses of 0.74 (0.25 mg/kg) or 2.9 mumol/kg (1.0 mg/kg). The steady state characteristics of these compounds were also studied after constant rate iv infusion of MS at two different rates, 0.70 and 14.0 nmol/min per kg. Plasma protein binding and blood/plasma partitioning for MS were determined over a range of concentrations. Plasma and blood concentrations of MS and MEM were measured by HPLC with fluorescence detection. The plasma clearance of MS was high and ranged from 74.2-102 ml/min per kg. The two iv doses of MS were not equivalent after dose correction; clearance, volume of distribution at steady-state and terminal half-life were significantly greater for the higher dose. Plasma clearance from the two iv infusions of MS were in accordance with that from the lower iv dose. Protein binding as well as the plasma/blood partitioning, of MS was constant over the range of concentrations observed in the disposition studies, averaging 84.2% and 1.67%, respectively. The metabolite MEM had a plasma clearance five to six times lower than that of the parent drug but a similar volume of distribution at steady state. The formation of MEM after MS administration was relatively low and appeared to be saturable since the formation clearance of MEM decreased significantly from 3.5 to 1.9 ml/min per kg for the low and the high rate of iv infusion of MS, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
One case of isolate stenosis of the popliteal artery in a young woman is reported in this article. Since acid Methysergide maleate had been taken over a longer period, this lesion was placed into the nosological context of toxic arterial fibrodysplasia. Although such lesions usually recede at the end of treatment, the severity and abruptness of ischemia in this case led to operating the patient. This allowed an anatomopathological examination, which showed the diffusion of fibrosis into all layers of the arterial wall.
Intestinal handling of water and electrolytes and motility were monitored in conscious dogs with chronic 25-cm Thiry-Vella loops of proximal jejunum. Absorption/secretion was quantitated using a neutral isosmotic perfusate containing [14C]polyethylene glycol as a recovery marker. Under basal conditions the animals absorbed water, Na+ and Cl-, while there was no net action on K+. Intravenous serotonin infusion (30 micrograms/kg/min) increased circulating levels of serotonin to a mean of 1556 +/- 191 ng/ml within 15 min of the commencement of the infusion. The infusion induced a significant secretion of water (mean -73 +/- 7 microliters/min) and electrolytes (sodium -10.4 +/- 0.7 muEq/min; potassium -0.8 +/- 0.05 muEq/min; chloride -12.4 +/- 1.0 muEq/min) in the dogs and all showed signs of hyperserotoninemia (salivation, loose bowel movements, tachypnea). After administration of ketanserin (33 micrograms/kg/min), a significant reduction in secretion was demonstrated (water +20.8 +/- 16.1 microliters/min; sodium 7.2 +/- 3.0 muEq/min; potassium -0.02 +/- 0.1 muEq/min; and chloride -1.9 +/- 2.8 muEq/min) as well as reduced motor activity. A similar antisecretory effect was demonstrated with atropine infusion (20 micrograms/kg/min), although this drug had a far more significant effect on the gastrointestinal motility recorded in the loop. Infusion of methysergide (33 micrograms/kg/min) did not significantly affect secretion (water -111.4 +/- 59.0 microliter/min; sodium -17.4 +/- 9 muEq/min; potassium -0.9 +/- 0.4 muEq/min; chloride -20.3 +/- 7.0 muEq/min). These results suggest possible actions which may make ketanserin useful in the treatment of symptoms of the carcinoid syndrome.
The annular gap junctions in the cuboidal ependymocytes of the median eminence of rats were studied after intraventricular administration (3rd ventricle) of methysergide and thyrotropin releasing hormone. Isolated annular gap junctions were found in the ependymocytes of normal animals. In experimental rats an increase was observed in the number of annular gap junctions at 5 min after administration of the drugs; the increase was more apparent at 10 min postadministration. Likewise, the ependymocytes showed a clear development of the Golgi complex and an increase in the number of vesicles close to the lateral membranes. Accordingly, the increase observed in annular gap junctions could be interpreted as a sign of cellular activity indicative of a greater exchange of substances through the ependymocytes.
The clinical pharmacokinetics of ergotamine, dihydroergotamine, ergotoxine, bromocriptine, methysergide, and lergotrile are reviewed. Generally the new radioimmunoassay methods have partially resolved the problems involved in determining some of these ergot derivatives in biologic fluids after the low doses used clinically. However, our present knowledge of their pharmacokinetics is limited and much work remains to be done in this area. Many cases show a great difference between results produced with a radioactive drug and with radioimmunoassay. The longer half-lives measured by using a radioactive derivative are apparently due to the many metabolites of ergot alkaloids. However, we still do not know the clinical importance of these metabolites. For instance, the amount of dihydroergotamine reaching the systemic circulation remains below 1% (radioimmunoassay), but according to studies performed with a radioactive derivative the absorption quotient is about 30%. Further studies are needed to resolve the problem of an apparently high "first-pas" metabolism of this and other ergot alkaloids in the liver or gastrointestinal mucosa.
A 39-year-old woman who suffered from migraine is described. She developed analgesic nephropathy due to phenacetin, and constrictive pericarditis, probably due to methysergide treatment.
The ability of various drugs to prevent the lethal effects of 4-methoxyamphetamine (PMA) and 3, 4-methylenedioxyamphetamine (MDA) were reduced by pretreatment with phentolamine and 6-hydroxydopamine suggesting that release of norepinephrine from peripheral adrenergic nerves contributed to their toxicity. Pretreatment with methysergide reduced the lethal effects of (+)- and (-)-amphetamine, MDA, PMA and 2, 5-dimethoxy-4-methylamphetamine (STP) suggesting that an action on serotonergic receptors contributed to their toxicity. Pretreatment with 4-chloroamphetamine, practolol and haloperidol did not alter the lethal effects of the agents studied.