Article

Effects of the calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS on alpha-CGRP-induced regional haemodynamic changes in anaesthetised rats.

Department of Pharmacology, Cardiovascular Research Institute COEUR, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
Basic &amp Clinical Pharmacology &amp Toxicology (Impact Factor: 2.29). 07/2004; 94(6):291-7. DOI: 10.1111/j.1742-7843.2004.pto940606.x
Source: PubMed

ABSTRACT Several studies suggest that a calcitonin gene-related peptide (CGRP) receptor antagonist may have antimigraine properties, most probably via the inhibition of CGRP-induced cranial vasodilatation. We recently showed that the novel selective CGRP receptor antagonist, BIBN4096BS (1-piperidinecarboxamide, -N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl] carbonyl] pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl) methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-, [[R-(R,(R*,S*)]), attenuated the CGRP-induced porcine carotid vasodilatation in a model predictive of antimigraine activity. In order to evaluate the potential safety of BIBN4096BS in migraine therapy, this study was designed to investigate the effects of intravenous BIBN4096BS on alpha-CGRP-induced systemic and regional haemodynamic changes in anaesthetised rats, using radioactive microspheres. In vehicle-pretreated animals, consecutive intravenous infusions of alpha-CGRP (0.25, 0.5 and 1 microg kg(-1) min.(-1)) dose-dependently decreased mean arterial blood pressure with an accompanying increase in heart rate and systemic vascular conductance whereas cardiac output remained unchanged. Alpha-CGRP also increased the vascular conductance to the heart, brain, gastrointestinal tract, adrenals, skeletal muscles and skin, whilst that to the kidneys, spleen, mesentery/pancreas and liver remained unaltered. The above systemic and regional haemodynamic responses to alpha-CGRP were clearly attenuated in BIBN4096BS (3 mg kg(-1) intravenously)-pretreated animals. These results indicate that exogenously administered alpha-CGRP dilates regional vascular beds via CGRP receptors on the basis of the antagonism produced by BIBN4096BS. Moreover, the fact that BIBN4096BS did not alter baseline haemodynamics suggests that endogenously produced CGRP does not play an important role in regulating the systemic and regional haemodynamics under resting conditions.

0 Bookmarks
 · 
85 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: Migraine afflicts approximately 11% of the population worldwide producing substantial disability, resulting in loss of productivity both at home and at the workplace. Calcitonin gene-related peptide (CGRP) is closely involved in the cascade of molecular events leading to migraine painful crisis. AREAS COVERED: Acute treatment of migraine is actually based on the use of triptans, class drug which presents a clear limitation due to its cardiovascular side effects. Gepants, a CGRP antagonist class, might offer a new non-vasoconstrictive approach in the acute treatment of migraine. Four chemically unrelated CGRP receptor (CGRP-R) antagonists (olcegepant, telcagepant, MK-3207 and BI 44370 TA) have displayed efficacy in the treatment of migraine. EXPERT OPINION: When compared with triptans, gepants class showed a similar efficacy, moreover corresponding to the best published results for oral triptans. CGRP antagonists are in different phases of their development, and the treatment of migraine could be based on the use of gepants, as class of acute medications. However, CGRP-R antagonists clinical trials seem to be discouraging for their forthcoming use in clinical practice. New CGRP-R antagonists, such as BMS-927711 and BI 44370 TA, are in the pipeline and their developments will outline the future of this drug class.
    Expert Opinion on Investigational Drugs 04/2012; 21(6):807-18. · 4.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Migraine is a highly prevalent neurovascular disorder that can be provoked by infusion of calcitonin gene-related peptide (CGRP). CGRP, a neuropeptide released from activated trigeminal sensory nerves, dilates intracranial and extracranial blood vessels and centrally modulates vascular nociception. On this basis, it has been proposed that: (i) CGRP may play an important role in the pathophysiology of migraine; and (ii) blockade of CGRP receptors may abort migraine.With the advent of potent and selective CGRP receptor antagonists, the importance of CGRP in the pathophysiology of migraine and the therapeutic principle of CGRP receptor antagonism were clearly established. Indeed, both olcegepant (BIBN4096BS, given intravenously) and telcagepant (MK-0974, given orally) have been shown to be safe, well tolerated and effective acute antimigraine agents in phase I, phase II, and for telcagepant phase III, studies. However, recent data reported elevated liver transaminases when telcagepant was dosed twice daily for three months for the prevention of migraine rather than acutely.The potential for a specific acute antimigraine drug, without producing vasoconstriction or vascular side effects and with an efficacy comparable to triptans, is enormous. The present review will discuss the role of CGRP in the pathophysiology of migraine and the various treatment modalities that are currently available to target this neuropeptide.
    Pharmacology [?] Therapeutics 12/2009; · 7.75 Impact Factor
  • Headache The Journal of Head and Face Pain 06/2013; 53(6):1004-6. · 2.94 Impact Factor

Full-text (2 Sources)

Download
2 Downloads
Available from
Oct 6, 2014