Ultra-rapid brain uptake of subcutaneous sumatriptan in the rat: Implication for cluster headache treatment

Muzzi, Mirko; Zecchi, Riccardo; Ranieri, Giuseppe; Urru, Matteo; Tofani, Lorenzo; Cesaris, Francesco De; Panconesi, Alessandro; Chiarugi, Alberto

doi:10.1177/0333102419896370

Cited by 14 publications

(11 citation statements)

References 35 publications

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“…Data suggests that overall, the triptans seem to remain largely restricted to peripheral nervous system (PNS) sites of action [6]. However, recent evidence in rats suggests that subcutaneous sumatriptan can accumulate rapidly in the central nervous system (CNS) [7,8]. The development and clinical efficacy of non-vasoconstriction drugs for the treatment of migraine led to the conclusion and current predominate theory that vasoconstriction is not the triptan's therapeutic mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

et al. 2020

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Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second-and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT 1B/1D receptors. The discovery that the serotonin 1F (5-HT 1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT 1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT 1B receptors, the activation of 5-HT 1F receptors does not cause vasoconstriction. The potency of different serotonergic agonists towards 5-HT 1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT 1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites. Lasmiditan activation of CNS-located 5-HT 1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT 1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT 1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT 1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT 1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.

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Section: Introductionmentioning

confidence: 99%

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

et al. 2020

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“…A recent animal study showed that the highest sumatriptan concentration in the CNS was reached in the hypothalamus after 1 and 5 min of a subcutaneous injection of the drug (10). It is noteworthy that the hypothalamic concentration of the drug was higher compared to the trigeminal ganglion and the meninges (10), both peripheral sites where sumatriptan is commonly thought to exert its action in CH. The administration of 6 mg subcutaneous sumatriptan in humans was associated with a decrease in 5-HT 1B receptor binding in the brain, particularly in pain-modulating regions (11).…”

Section: Discussionmentioning

confidence: 99%

“…In an animal model of TAC, sumatriptan reduced the activity in the trigeminocervical complex (TCC) after parasympathetic activation more than the CGRP-receptor antagonist olcegepant (9). A recent animal study showed that the highest sumatriptan concentration in the CNS was reached in the hypothalamus after 1 and 5 min of a subcutaneous injection of the drug (10). It is noteworthy that the hypothalamic concentration of the drug was higher compared to the trigeminal ganglion and the meninges (10), both peripheral sites where sumatriptan is commonly thought to exert its action in CH.…”

Section: Discussionmentioning

confidence: 99%

Cluster headache not responsive to sumatriptan: A retrospective study

et al. 2020

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Introduction Subcutaneous sumatriptan, a 5HT1B/1D agonist, is the most effective drug in cluster headache acute treatment. About 25% of the patients do not respond to subcutaneous sumatriptan; the reasons for this are unknown. In this study, we compare clinical characteristics of cluster headache patients responding and non-responding to subcutaneous sumatriptan. Methods We retrospectively investigated the clinical records of 277 cluster headache patients. Patients reporting repeated satisfactory response to subcutaneous sumatriptan within 15 minutes were considered responders. Results Of 206 cluster headache patients who had used subcutaneous sumatriptan (mean age 45.6, 16% females, 48% chronic), 91% were responders, and 9% non-responders. Compared to responders, non-responders had longer and more frequent attacks: 60 (median; IQR 38–90) vs. 100 (60–120) minutes ( p = 0.028), 4 (2.5–5) vs. 3 (2–4) attacks/day ( p = 0.024). No other difference was found. Conclusions In cluster headache attacks with long duration and high frequency, pain mechanisms not involving 5HT1B/1D receptors may play a more relevant role.

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“…In the late 1980s, some serotonin agonists, known as triptans, were developed for the treatment of migraine. Intranasal sumatriptan (SMT) is the gold standard treatment for severe migraines (Muzzi et al, 2020). However, SMT is a hydrophilic molecule, which limits its permeation through the nasal mucosa and makes it difficult to cross the blood-brain barrier (BBB), despite SMT action on the central nervous system (Pascual and Muñoz, 2005;Tfelt-Hansen, 2010).…”

Section: Introductionmentioning

confidence: 99%