Contractile responses to ergotamine and dihydroergotamine in the perfused middle cerebral artery of rat

Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access to the central nervous system by diffusion, whereas other substances can cross the BBB by carrier-mediated influx transport, receptor-mediated transcytosis and absorptive-mediated transcytosis. Studies of drugs relevant to migraine pathophysiology and treatment have been examined with the pressurized arteriography method. The drugs, given both luminally and abluminally, provide important notions regarding antimigraine site of action, probably abluminal to the BBB. The problems with the BBB in animal models designed to study the pathophysiology, acute treatment models and preventive treatments are discussed with special emphasize on the triptans and calcitonin gene-related peptide (CGRP). The human experimental headache model, especially the use of glycerol trinitrate (the nitric oxide model), and experiences with CGRP administrations utilize the systemic administration of the agonists with effects on other vascular beds also. We discuss how this can be related to genuine migraine attacks. Our view is that there exists no clear proof of breakdown or leakage of the BBB during migraine attacks, and that antimigraine drugs need to pass the BBB for efficacy.

Section: Consequences Of Preserved Bbb For Migraine Treatmentmentioning

confidence: 96%

The Blood-Brain Barrier in Migraine Treatment

Edvinsson

Tfelt‐Hansen

2008

“…In a second series of experiments, canine femoral veins incubated for 10 min with DHE (2 × 10 −7 M) elicited a slow, concentration-dependent increase in tension, which could not be eliminated by changing the bathing solution every 7.5 min for two h (Figure 5) (34). In an in vitro study using the middle cerebral artery of rats, DHE caused a slow onset of a contractile response with a time to maximum of 25–32 min (35). Repeated flushing of the bath caused a return to baseline 13–48 min after initiating the washing (35).…”

Section: Pharmacological Investigations Of Time-effect Curves Of Dhementioning

confidence: 99%

Relatively slow and long-lasting antimigraine effect of dihydroergotamine is most likely due to basic pharmacological attributes of the drug: A review

Tfelt‐Hansen

2013

“…The problem of recurrence (after an initial response the migraine pain recurs) after subcutaneous sumatriptan treatment was first observed by Iversen in Denmark in 1989 (104); and in RCTs it has been found that oral and rectal ergotamine (51) and subcutaneous dihydroergotamine (105) caused less, in most cases 50% less, recurrence than the triptans (51, 52). This is most likely due to tight binding of ergot alkaloids to the vascular receptor (106).…”

Section: Bioavailability and Working Mechanism Of Ergotaminementioning

confidence: 99%

History of the Use of Ergotamine and Dihydroergotamine in Migraine From 1906 and Onward

Tfelt-Hansen

Koehler

2008

Dale showed in 1906 in a seminal work that ergot inhibits the pressor effect of adrenaline. Stoll at Sandoz isolated ergotamine from ergot in 1918. Based on the belief that migraine was due to increased sympathetic activity, ergotamine was first used in the acute treatment of migraine by Maier in Switzerland in 1925. In 1938 Graham and Wolff demonstrated the parallel decrease of temporal pulsations and headache after ergotamine i.v. This inspired the vascular theory of Wolff: an initial cerebral vasoconstriction followed by an extracranial vasodilation. Dihydroergotamine (DHE) was introduced as an adrenolytic agent in 1943. It is still in use parenterally and by the nasal route. Before the triptan era ergotamine and DHE had widespread use as the only specific antimigraine drugs. From 1950 the world literature on ergotamine was dominated by two adverse events: ergotamine overuse headache and the relatively rare overt ergotism. Recently, oral ergotamine, which has an oral bioavailability of < 1%, has been inferior to oral triptans in randomized clinical trials. A European Consensus in 2000 concluded that ergotamine is not a drug of first choice. In an American review of 2003 it was suggested that ergotamine may be considered in the treatment of selected patients with moderate to severe migraine.