Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine

Gomez‐Mancilla, Baltazar; Cutler, N.R.; Leibowitz, MT; Spierings, Elh; Klapper, Jack A.; Diamond, Seymour; Goldstein, Jerome; Smith, Timothy R.; Couch, JR; Fleishaker, Joseph C.; Azie, N; Blunt, DE

doi:10.1046/j.1468-2982.2001.00208.x

Cited by 98 publications

(57 citation statements)

References 26 publications

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“…In addition, a central mechanism of action in blocking the transmission of nociceptive impulses within the trigeminal nucleus caudalis may contribute to the antimigraine effect of LY334370 (Shepheard et al 1999). Nevertheless, PNU-142633 proved to be ineffective in the acute treatment of migraine (Gómez-Mancilla et al 2001), while LY334370 did show some efficacy in high doses that may have interacted with 5-HT 1B receptors (Goldstein et al 2001b;Villalón et al 2002).…”

Section: -Ht 1 Receptor Subtypesmentioning

confidence: 99%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT 1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT 2 receptor antagonists, Ca 2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT 1-7 ), adrenergic (α 1 , α 2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP 2 ), adenosine (A 1 , A 2 , and A 3 ), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.

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Section: -Ht 1 Receptor Subtypesmentioning

confidence: 99%

Current and prospective pharmacological targets in relation to antimigraine action

Mehrotra

Gupta

Chan

et al. 2008

Naunyn-Schmied Arch Pharmacol

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“…Selective agonists of the 5-HT1D receptor, such as PNU-109291 [(s)-3,4-dihydro-1-ethyl]-N-methyl-1H-2-benzopyran-6-carboximide) [73] or 5-HT1F receptors such as LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]-benzamide) [74] have been developed with the idea that they should exert an antimigraine effect by a prejunctional inhibition of neural activity, and should be devoid of any vascular constrictor action. However, PNU-142633 proved to be ineffective in the acute treatment of migraine [75] and LY334370 did show efficacy when used in doses which may interact with 5-HT1B receptors [74,76]. Thus, further investigation is required to establish whether nonvasoconstrictor triptans or other compounds acting at prejunctional levels of terminals of primary sensory neurons are useful in the treatment of migraine and related headaches.…”

Section: Action Of Drugs Effective On Neurogenic Vasodilatationmentioning

confidence: 99%

CGRP and migraine: neurogenic inflammation revisited

Geppetti

Capone²,

Trevisani

et al. 2005

J Headache Pain

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The term 'neurogenic inflammation' refers to a series of proinflammatory responses produced by the stimulation of peripheral terminals of a subset of primary sensory neurons and the subsequent release of the neuropeptides, calcitonin gene-related peptide (CGRP) and the tachykinins, substance P (SP) and neurokinin A (NKA) [1]. The neurons that produce inflammation comprise a heterogeneous cell population with A-delta and C fibres, defined as polymodal nociceptors because they sense thermal, chemical and high-threshold mechanical stimuli. These neurons express on their plasma membrane a large panel of excitatory and inhibitory receptors and channels, and some of these signalling proteins have been successfully used as targets for analgesic or anti-inflammatory drugs. Among the channels expressed on peptidergic primary sensory neurons, transient receptor potential vanilloid-1 (TRPV1) [2], activated by the xenobiotic capsaicin, the pungent ingredient of plants of the genus Capsicum, is of paramount importance. Capsaicin produces burning pain by stimulating TRPV1 and by releasing sensory neuropeptides causes neurogenic inflammation. However, high concentrations/doses of capsaicin have the ability, after an initial excitatory phase, to desensitise the sensory nerve terminals, thus reducing the transmission of sensory/pain signals and abolishing neurogenic inflammation [3, 4]. This specific feature of capsaicin has greatly contributed to define the role of this subset of sensory nerves in pathophysiological models of human diseases and has been Pierangelo Geppetti Jay Guido Capone Marcello Trevisani Paola Nicoletti Giovanni Zagli Maria Rosalia Tola Abstract For more than a century neurogenic inflammation has been proposed to have a role in various human diseases. The present review will cover the conceptual steps of the itinerary that has led to the conclusion that neurogenic inflammation is important in migraine. Of particular relevance for the object of this article is the observation that tachykinindependent neurogenic inflammatory responses are evident in rodents, but much less pronounced or absent in other mammal species, including man, whereas neurogenic vasodilatation, most likely mediated by CGRP, occurs in most mammalian species and also in man. Recent evidence that a CGRP receptor antagonist was effective in the treatment of migraine attack supports the hypothesis that neurogenic vasodilatation is a major underlying mechanism of migraine.

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“…Surprisingly PNU-142633 was also associated with cardiac adverse events, such as chest pain, mild atrioventricular block and QTc prolongation. 24 The findings of this study suggest that the anti-migraine effects of triptans are mediated through a 5-HT receptor other than the 1D subtype.…”

mentioning

confidence: 67%

“…43 It is noteworthy to mention that antagonists of the neurokinin-1 receptor and agonists of the 5-HT 1D receptor block neurogenic inflammation, but they do not abort migraine attacks. 24,47 Lately, Peroutka postulated that the ability of drugs to selectively inhibit neuronal plasma extravasation in rodents has no predictive value for the efficacy in the acute treatment of migraine. 48 Activity of the 5-HT 1F receptor can also be measured by assessing the binding of the stable analogue [35S] GTP␥S.…”

Section: -Ht 1f Receptor Agonists Inhibit Neurogenic Inflammationmentioning

confidence: 99%

5-HT1F Receptor Agonists: A New Treatment Option for Migraine Attacks?

2010

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Summary:Migraine is a debilitating disorder of the CNS. Although therapeutic options for migraine attacks have tremendously advanced with the development of triptans more than a decade ago, several conditions (such as vascular disease) restrict their use. Moreover, some patients do not respond to triptans and other currently available medications. Therefore, treatment alternatives are needed. Study data show that 5-HT 1F receptor agonists successfully abort migraine attacks. These data also suggest a favorable vascular side-effect profile of these substances, which could be beneficial for migraine treatment in subjects with cardiac or vascular disease. We discuss the current knowledge of 5-HT 1F receptor-mediated effects, in part by comparing them to triptans, and we also summarize data from basic research and clinical trials. Key Words: 5-HT 1F , serotonin receptor, migraine, treatment, triptans. CURRENT TREATMENT OPTIONSMigraine attacks can be treated effectively with nonsteroidal anti-inflammatory drugs, pain killers, the first generation triptan (sumatriptan), and newer triptans such as rizatriptan or almotriptan. To date, these 5-HT 1B/1D agonists represent the gold standard for the treatment of migraine attacks. A meta-analysis showed that 59% of all patients achieve a headache response with 100 mg sumatriptan orally. Approximately 29% of subjects are pain-free after 2 h, and 20% of subjects show sustained pain freedom (pain-free by 2 h after dosing and no headache recurrence or use of rescue medication through 24 h). With some of the newer triptans, higher success rates of as much as 40% for the 2 h pain-free endpoint can be seen.1 Despite the good efficacy of triptans, it has been estimated that approximately 25% of all migraine patients do not respond to triptan treatment, even when the drug is used correctly (i.e, according to prescribed dose, time, and route of administration).2 The reasons for treatment failure remain obscure.Triptans are supposed to have three important mechanisms of action: 1) vasoconstriction, 2) inhibition of neuropeptide release, and 3) inhibition of signal transmission to second order neurons within the trigeminal nucleus complex. 3 The inhibition of calcitonin generelated peptide and substance P release attenuates peripheral consequences of trigeminal stimulation (e.g., neurogenic inflammation) and also central pain transmission. However, it is still an unsolved question as to whether neuronal or vascular or both mechanisms are responsible for the anti-migraine effect of these compounds. 5-HT 1 RECEPTORS AND MIGRAINETriptans exert their function mainly through binding at the 5-HT 1B and 5-HT 1D receptor. The 5-HT 1B receptor can be found on smooth muscle cells in cerebral and coronary vessels, and this receptor mediates triptan induced vasoconstriction.4 -8 Experimentally, various isolated blood vessels from several species contract in response to triptans. The vascular effects of 5-HT 1B/1D agonists are more pronounced in cranial vessels than in peripheral arteries, probably ...

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Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine

Cited by 98 publications

References 26 publications

Current and prospective pharmacological targets in relation to antimigraine action

Current and prospective pharmacological targets in relation to antimigraine action

CGRP and migraine: neurogenic inflammation revisited

5-HT1F Receptor Agonists: A New Treatment Option for Migraine Attacks?

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