Methysergide

Abstract: Dexfenfluramine was approved in the United States for long-term use as an appetite suppressant until it was reported to be associated with valvular heart disease. The valvular changes (myofibroblast proliferation) are histopathologically indistinguishable from those observed in carcinoid disease or after long-term exposure to 5-hydroxytryptamine (5-HT)(2)-preferring ergot drugs (ergotamine, methysergide). 5-HT(2) receptor stimulation is known to cause fibroblast mitogenesis, which could contribute to this lesion. To elucidate the mechanism of "fen-phen"-associated valvular lesions, we examined the interaction of fenfluramine and its metabolite norfenfluramine with 5-HT(2) receptor subtypes and examined the expression of these receptors in human and porcine heart valves. Fenfluramine binds weakly to 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors. In contrast, norfenfluramine exhibited high affinity for 5-HT(2B) and 5-HT(2C) receptors and more moderate affinity for 5-HT(2A) receptors. In cells expressing recombinant 5-HT(2B) receptors, norfenfluramine potently stimulated the hydrolysis of inositol phosphates, increased intracellular Ca(2+), and activated the mitogen-activated protein kinase cascade, the latter of which has been linked to mitogenic actions of the 5-HT(2B) receptor. The level of 5-HT(2B) and 5-HT(2A) receptor transcripts in heart valves was at least 300-fold higher than the levels of 5-HT(2C) receptor transcript, which were barely detectable. We propose that preferential stimulation of valvular 5-HT(2B) receptors by norfenfluramine, ergot drugs, or 5-HT released from carcinoid tumors (with or without accompanying 5-HT(2A) receptor activation) may contribute to valvular fibroplasia in humans.

Abstract: Intrathecal administration of norepinephrine (NE) and alpha adrenergic agonists in rats with chronic spinal catheters produced a significant elevation of the nociceptive threshold as measured by hot plate and tail flick. The intrathecal NE effect was dose-dependent and antagonized in a competitive fashion by pretreatment with phentolamine (alpha antagonist) but not by propranolol (beta antagonist). Intrathecal administration of isoproterenol (beta agonist) did not alter the nociceptive threshold. Effective doses of intrathecal NE did not produce demonstrable motor effects. Doses 20 times greater than the maximum analgesic dose produced marked weakness of the hindlimbs and tails. The intrathecal NE effect was not antagonized by intrathecal papaverine of bradykinin (vasodilators) or mimicked by angiotensin-II (vasoconstrictor). The intrathecal NE effect was not altered by intrathecal administration of subconvulsant doses of either picrotoxin (gamma-aminobutyric acid antagonist) or strychnine (glycine antagonist) or by i.p. administration of either naloxone (opiate antagonist) or methysergide (serotinin antagonist). The nociceptive threshold was significantly decreased 1 week after intrathecal administration of 6-hydroxydopamine, which depleted spinal cord NE by 85%. Intrathecal administration of tyramine (indirectly acting sympathomimetic amine) produced an elevation of the nociceptive threshold in a control group of animals but was less effective in animals pretreated with intrathecal 6-hydroxydopamine. The tyramine effect was antagonized by intrathecal phentolamine. Intravenous administration of aminophylline (phosphodiesterase inhibitor) did not potentiate the intrathecal NE effect. The relative antinociceptive potencies of alpha adrenergic agonists after intrathecal administration were: l-norepinephrine = dl-epinephrine greater than dl-alpha-methyl norepinephrine greater than clonidine greater than or equal to l-phenylephrine greater than or equal to 3,4-dihydroxytolazoline greater than or equal to oxymetazoline. The relative potencies of intrathecally administered alpha antagonists in antagonizing the intrathecal NE effect were: phentolamine greater than phenoxybenzamine greater than tolazoline greater than or equal to yohimbine.

Abstract: IN 1961, Sicuteri, Testi, and Anselmi 1 demonstrated that the excretion in the urine of 5-hydroxyindoleacetic acid (5HIAA), the principal catabolite of serotonin (5-hydroxytryptamine, 5HT), was increased during some attacks of migraine headache. This was confirmed by Curran, Hinterberger, and Lance 2 in the majority of patients studied whereas Curzon, Theaker, and Phillips 3 were able to find such a correlation in only two out of nine migrainous subjects. Interest in the possible relationship of serotonin to the migraine syndrome had quickened following Sicuteri's preliminary trial of methysergide, a serotonin "antagonist," in the treatment of migraine. 4 The value of methysergide maleate has since been established, although the mechanism of its action is still unexplained. 5 Kimball, Friedman, and Vallejo 6 were unable to produce headache in migrainous subjects by the injection of serotonin or its precursor 5-hydroxytryptophan. Indeed they found that injection of these substances relieved spontaneous migraine headaches. These

Abstract: 1. The effects of intradermally injected prostaglandins (PGs) E1, E2, F1α and F2α have been examined in the rat and in man. 2. PGE1 and PGE2 caused an increase in local vascular permeability in rat skin; their potency was comparable with that of other putative mediators of inflammation (histamine, bradykinin, and 5-hydroxytryptamine), but PGF1α and PGF2α were only slightly active even at a dose of 1 μg. 3. Prior administration of mepyramine and methysergide, or depletion of skin mast cell amines with compound 48/80, indicated that PGE2 exerted its permeability effect in the rat by a release of mast cell amines. 4. Nanogramme doses of PGE1 and PGE2 or microgramme doses of PGF1α and PGF2α injected intradermally into the human forearm induced weal and flare responses. 5. It is concluded that prostaglandins E1 and E2 can act as intermediates in the production of hyperaemia and oedema resulting from cell damage in the rat and man.