Migraine is associated with cardiovascular disorders but the underlying mechanisms are unknown. Arterial structure and function are important determinants of cardiovascular morbidity and mortality. The aim of the present study was to assess arterial properties in patients with migraine of recent onset.In a cross-sectional study, structural and functional arterial properties were assessed using ultrasound and applanation tonometry in 50 patients with a history of migraine >1 and <6 years during a headache-free interval and 50 age- and gender-matched subjects without a history of migraine.Brachial artery diameter (4.82 +/- 0.93 mm vs 5.39 +/- 0.89 mm, p = 0.01) and compliance (0.30 +/- 0.17 mm(2)/kPa vs 0.37 +/- 0.19 mm(2)/kPa, p = 0.02) were decreased in migraine patients compared with controls. Femoral artery compliance was decreased in migraine patients (1.19 +/- 0.55 mm(2)/kPa vs 1.42 +/- 0.59 mm(2)/kPa, p = 0.04). Carotid arterial wall properties were similar between groups. Aortic augmentation index was increased in migraine patients (4 +/- 10% vs -1 +/- 10%, adjusted p = 0.04). Flow-mediated vasodilation of the brachial artery (normalized to peak shear rate) was decreased in patients with migraine (29 +/- 15 vs 37 +/- 15 10(-3)%. sec, p = 0.006).Functional arterial properties are altered in patients with migraine of recent onset.
Monoclonal antibodies (mAbs) targeting calcitonin gene‐related peptide (CGRP) signaling are being explored as prophylactic treatments for migraine. Erenumab (AMG 334) is the first potent, selective, and competitive human mAb antagonist of the CGRP receptor. We report the data from two phase I studies assessing the safety, pharmacokinetics (PK), and pharmacodynamics of single and multiple administrations of erenumab in healthy subjects and patients with migraine. The results indicate that the PK profile of erenumab is nonlinear from 1 mg to 70 mg and the linear portion of the clearance from 70 mg to 210 mg is consistent with other human immunoglobulin G2 antibodies. Single doses of erenumab resulted in >75% inhibition of capsaicin‐induced dermal blood flow, with no apparent dose‐dependency for erenumab ≥21 mg. Erenumab was generally well tolerated, with an acceptable safety profile, supporting further clinical development of erenumab for migraine prevention.
Transient receptor potential Ankyrin 1 (TRPA1) is an ion channel expressed by sensory neurons, where it mediates pain signaling. Consequently, it has emerged as a promising target for novel analgesics, yet, to date, no TRPA1 antagonists have been approved for clinical use. In the present translational study, we utilized dermal blood flow changes evoked by TRPA1 agonist cinnamaldehyde as a target engagement biomarker to investigate the in vivo pharmacology of LY3526318, a novel TRPA1 antagonist. In rats, LY3526318 (1, 3, and 10 mg/kg, p.o.) dose-dependently reduced the cutaneous vasodilation typically observed following topical application of 10% v/v cinnamaldehyde. The inhibition was significant at the site of cinnamaldehyde application and also when including an adjacent area of skin. Similarly, in a cohort of 16 healthy human volunteers, LY3526318 administration (10, 30, and 100 mg, p.o.) dose-dependently reduced the elevated blood flow surrounding the site of 10% v/v cinnamaldehyde application, with a trend toward inhibition at the site of application. Comparisons between both species reveal that the effects of LY3526318 on the cinnamaldehyde-induced dermal blood flow are greater in rats relative to humans, even when adjusting for cross-species differences in potency of the compound at TRPA1. Exposure-response relationships suggest that a greater magnitude response may be observed in humans if higher antagonist concentrations could be achieved. Taken together, these results demonstrate that cinnamaldehyde-evoked changes in dermal blood flow can be utilized as a target engagement biomarker for TRPA1 activity and that LY3526318 antagonizes the ion channel both in rats and humans.
Currently available drugs for the acute treatment of migraine, i.e. ergot alkaloids and triptans, are cranial vasoconstrictors. Although cranial vasoconstriction is likely to mediate-at least a part of-their therapeutic effects, this property also causes vascular side-effects. Indeed, the ergot alkaloids and the triptans have been reported to induce myocardial ischemia and stroke, albeit in extremely rare cases, and are contraindicated in patients with known cardiovascular risk factors. In view of these limitations, novel antimigraine drugs devoid of vascular (side) effects are being explored. Currently, calcitonin gene-related peptide (CGRP) receptor antagonists, which do not have direct vasoconstrictor effects, are under clinical development. Other classes of drugs, such as 5-HT(1F) receptor agonists, glutamate receptor antagonists, nitric oxide synthase inhibitors, VPAC/PAC receptor antagonists and gap junction modulators, have also been proposed as potential targets for acute antimigraine drugs. Although these prospective drugs do not directly induce vasoconstriction, they may well induce indirect vascular effects by inhibiting or otherwise modulating the responses to endogenous vasoactive substances. These indirect vascular effects might contribute to the therapeutic efficacy of the previously mentioned compounds, but may alternatively also lead to vascular side-effects. As described in the current review, some of the prospective antimigraine drugs with a proposed non-vascular mechanism of action may still have direct or indirect vascular effects.
We describe the case of a 71-years-old man in chronic hospital hemodialysis who was admitted to the hospital because of symptomatic hypoglycemia. We discovered that this was due to a documented intoxication with cibenzoline, an antiarrhythmic drug , used to treat (supra-)ventricular tachyarrhythmia. In addition we made a short review of the literature concerning cibenzoline intoxication.
