Involvement of calcitonin gene-related peptide in migraine: regional cerebral blood flow and blood flow velocity in migraine patients

Calcitonin gene-related peptide (CGRP)-containing nerves are closely associated with cranial blood vessels. CGRP is the most potent vasodilator known in isolated cerebral blood vessels. CGRP can induce migraine attacks, and two selective CGRP receptor antagonists are effective in the treatment of migraine attacks. It is therefore important to investigate its mechanism of action in patients with migraine. We here investigate the effects of intravenous human alpha-CGRP (hαCGRP) on intracranial hemodynamics. In a double-blind, cross-over study, the effect of intravenous infusion of hαCGRP (2 μg/min) or placebo for 20 min was studied in 12 patients with migraine without aura outside attacks. Xenon-133 inhalation SPECT-determined regional cerebral blood flow (rCBF) and transcranial Doppler (TCD)-determined blood velocity (Vmean) in the middle cerebral artery (MCA), as well as the heart rate and blood pressure, were the outcome parameters. No change of rCBF was observed at the end of infusion [1.2% ± 1.7 with hαCGRP, vs. −1.6% ± 3.1 with placebo (mean ± SD)] (P = 0.43). Vmean in MCA decreased to 13.5% ± 3.6 with hαCGRP versus 0.6% ± 1.8 with placebo (P < 0.005). Since rCBF was unchanged, this indicates a dilation of the MCA. hαCGRP induced a decrease in MAP (12%) (P < 0.005) and an increase in heart rate (58%) (P < 0.0001). CGRP dilates cerebral arteries, but the effect is so small that it is unlikely to be the only mechanism of CGRP-induced migraine

The 5-HT1F receptor agonist lasmiditan as a potential treatment of migraine attacks: a review of two placebo-controlled phase II trials

Lasmiditan is a novel selective 5-HT1F receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT1F receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo-controlled RCT, lasmiditan doses of 2.5–45 mg were used, and there was a linear association between headache relief (HR) rates and dose levels (P < 0.02). For lasmiditan 20 mg, HR was 64 % and for placebo it was 45 % (NS). In the oral placebo-controlled RCT, lasmiditan doses of 50, 100, 200 and 400 mg were used. For HR, all doses of lasmiditan were superior to placebo (P < 0.05). For lasmiditan 400 mg, HR was 64 % and it was 25 % for placebo. Adverse events (AEs) emerging from the treatment were reported by 22 % of the patients receiving placebo and by 65, 73, 87 and 87 % of patients receiving 50, 100, 200 and 400 mg, respectively. The majority of AEs after lasmiditan 100 and 400 mg were moderate or severe. For the understanding of migraine pathophysiology, it is very important to note that a selective 5-HT1F receptor agonist like lasmiditan is effective in the acute treatment of migraine. Thus, migraine can be treated with a drug that has no vasoconstrictor ability. While lasmiditan most likely is effective in the treatment of migraine attacks it had, unfortunately, a high incidence of CNS related AEs in the oral RCT. If confirmed in larger studies in phase III, this might adversely limit the use of this highly specific non-vascular acute treatment of migraine. Larger studies including the parameters of patients’ preferences are necessary to accurately position this new treatment principle in relation to the triptans

New acute treatments for headache

Although we have several acute care medications for the treatment of migraine, we are always looking for new medications to treat our patients. Patients often say that their headaches are not under optimal control and would be happy to try another medication. Patients look for faster onset of relief, more complete relief, no recurrent headache and no adverse events. This article will cover some new and some anticipated acute care products, CGRP antagonists, sumatriptan by iontophoretic patch, sumatriptan by needle-free injections, DHE by oral inhalation and diclofenac potassium in a sachet. Botulinum toxin therapy, although a preventive measure, will be mentioned at the end

Optimal Homogenization of Perfusion Flows in Microfluidic Bio-Reactors: A Numerical Study

In recent years, the interest in small-scale bio-reactors has increased dramatically. To ensure homogeneous conditions within the complete area of perfused microfluidic bio-reactors, we develop a general design of a continually feed bio-reactor with uniform perfusion flow. This is achieved by introducing a specific type of perfusion inlet to the reaction area. The geometry of these inlets are found using the methods of topology optimization and shape optimization. The results are compared with two different analytic models, from which a general parametric description of the design is obtained and tested numerically. Such a parametric description will generally be beneficial for the design of a broad range of microfluidic bioreactors used for, e.g., cell culturing and analysis and in feeding bio-arrays

Treatment of migraine attacks based on the interaction with the trigemino-cerebrovascular system

Primary headaches such as migraine are among the most prevalent neurological disorders, affecting up to one-fifth of the adult population. The scientific work in the last decade has unraveled much of the pathophysiological background of migraine, which is now considered to be a neurovascular disorder. It has been discovered that the trigemino-cerebrovascular system plays a key role in migraine headache pathophysiology by releasing the potent vasodilator calcitonin gene-related peptide (CGRP). This neuropeptide is released in parallel with the pain and its concentration correlates well with the intensity of the headache. The development of drugs of the triptan class has provided relief for the acute attacks but at the cost of, mainly cardiovascular, side effects. Thus, the intention to improve treatment led to the development of small CGRP receptor antagonists such as olcegepant (BIBN4096BS) and MK-0974 that alleviate the acute migraine attack without acute side events. The purpose of this review is to give a short overview of the pathological background of migraine headache and to illustrate the mechanisms behind the actions of triptans and the promising CGRP receptor blockers

Genotype–phenotype correlation in migraine without aura focusing on the rs1835740 variant on 8q22.1

A large two-stage GWAS by Antilla et al. reported the minor allele of rs1835740 on 8q22.1 to be associated with common types of migraine. The objective of the present study was to determine the clinical correlate of the variant in migraine without aura (MO). Clinical data on 339 successfully genotyped MO patients (patients with attacks of migraine without aura and no attacks of migraine with aura) were obtained by an extensive validated semi-structured telephone interview performed by a physician or a trained senior medical student. Reliable, systematic and extensive data on symptoms, age of onset, attack frequencies and duration, relevant comorbidity, specific provoking factors including different hormonal factors in females, and effect and use of medication, both abortive and prophylactic, were thereby obtained. A comparison of carriers and non-carriers were performed. Comparison of homozygotes with heterozygotes was not performed as the number of homozygotes was too small for statistical purposes. Data from other MO populations in the GWAS by Antilla et al. were not included as phenotype and clinical data were obtained differently. While thousands of patients are needed to detect a genetic variant like rs1835740, 339 are sufficient to detect meaningful clinical differences. 136 of 339 patients were carriers of the variant, 15 were homozygous. Comparison of carriers with non-carriers showed no significant difference in any of the parameters studied. In conclusion, the rs1835740 variant has no significant influence on the clinical expression of MO

Effects of gestational age at birth on cognitive performance : a function of cognitive workload demands

Objective: Cognitive deficits have been inconsistently described for late or moderately preterm children but are consistently found in very preterm children. This study investigates the association between cognitive workload demands of tasks and cognitive performance in relation to gestational age at birth. Methods: Data were collected as part of a prospective geographically defined whole-population study of neonatal at-risk children in Southern Bavaria. At 8;5 years, n = 1326 children (gestation range: 23–41 weeks) were assessed with the K-ABC and a Mathematics Test. Results: Cognitive scores of preterm children decreased as cognitive workload demands of tasks increased. The relationship between gestation and task workload was curvilinear and more pronounced the higher the cognitive workload: GA2 (quadratic term) on low cognitive workload: R2 = .02, p<0.001; moderate cognitive workload: R2 = .09, p<0.001; and high cognitive workload tasks: R2 = .14, p<0.001. Specifically, disproportionally lower scores were found for very (<32 weeks gestation) and moderately (32–33 weeks gestation) preterm children the higher the cognitive workload of the tasks. Early biological factors such as gestation and neonatal complications explained more of the variance in high (12.5%) compared with moderate (8.1%) and low cognitive workload tasks (1.7%). Conclusions: The cognitive workload model may help to explain variations of findings on the relationship of gestational age with cognitive performance in the literature. The findings have implications for routine cognitive follow-up, educational intervention, and basic research into neuro-plasticity and brain reorganization after preterm birth

Acute Migraine Therapy: New Drugs and New Approaches

The conceptual shift of our understanding of migraine from a vascular disorder to a brain disorder has dramatically altered the approach to the development of new medicines in the field. Current pharmacologic treatments of acute migraine consist of nonspecific and relatively specific agents. Migraine-specific drugs comprise two classes, the ergot alkaloid derivatives and the triptans, serotonin 5-HT1B/1D receptor agonists. The ergots, consisting of ergotamine and dihydroergotamine (DHE), are the oldest specific antimigraine drugs available and are considered relatively safe and effective. Ergotamine has been used less extensively because of its adverse effects; DHE is better tolerated. The triptan era, beginning in the 1990s, was a period of considerable change, although these medicines retained vasoconstrictor actions. New methods of delivering older drugs include orally inhaled DHE and the transdermal formulation of sumatriptan, both currently under study. Novel medicines being developed are targeted at neural sites of action. Serotonin 5-HT1F receptor agonists have proven effective in phase II studies and have no vascular actions. Calcitonin gene-related peptide (CGRP) receptor antagonists are another promising nonvasoconstrictor approach to treating acute migraine. Olcegepant (BIBN4096BS) and telcagepant (MK-0974) have been shown to be safe and effective in phase I, II, and (for telcagepant) phase III clinical trials. Other targets under investigation include glutamate (AMPA/kainate), TRPV1, prostanoid EP4, and nitric oxide synthase. With new neural targets and the potential for therapeutic advances, the next era of antimigraine medications is near

Patient satisfaction with out-of-hours primary care in the Netherlands

BACKGROUND: In recent years out-of-hours primary care in the Netherlands has changed from practice-based to large-scale cooperatives. The purpose of this study is to determine patient satisfaction with current out-of-hours care organised in general practitioner (GP) cooperatives, and gain insight in factors associated with this satisfaction. METHODS: From March to June 2003, 2805 questionnaires were sent to patients within three weeks after they had contacted the GP cooperative in their region. The study was conducted in the province of Limburg in the South of the Netherlands. One-third of these questionnaires was sent to patients who had only received telephone advice, one-third to patients who attended the GP cooperative for consultation, and one-third to patients who received a home visit. Four weeks after the first reminder, a non-respondents telephone interview was performed among a random sample of 100 patients. Analyses were performed with respect to the type of consultation. RESULTS: The total response was 42.4% (1160/2733). Sixty-seven percent of patients who received telephone advice only reported to be satisfied with out-of-hours care. About 80% of patients who went to the GP cooperative for consultation or those receiving a home visit, reported to be satisfied. Factors that were strongly associated with overall satisfaction included, the doctor's assistant's attitude on the phone, opinion on GP's treatment, and waiting time. CONCLUSION: Patients seem generally satisfied with out-of-hours primary care as organised in GP cooperatives. However, patients who received telephone advice only are less satisfied compared to those who attended the GP cooperative or those who received a home visit

Effect of CGRP and sumatriptan on the BOLD response in visual cortex

To test the hypothesis that calcitonin gene-related peptide (CGRP) modulates brain activity, we investigated the effect of intravenous CGRP on brain activity in response to a visual stimulus. In addition, we examined if possible alteration in brain activity was reversed by the anti-migraine drug sumatriptan. Eighteen healthy volunteers were randomly allocated to receive CGRP infusion (1.5 μg/min for 20 min) or placebo. In vivo activity in the visual cortex was recorded before, during and after infusion and after 6 mg subcutaneous sumatriptan by functional magnetic resonance imaging (3 T). 77% of the participants reported headache after CGRP. We found no changes in brain activity after CGRP (P = 0.12) or after placebo (P = 0.41). Sumatriptan did not affect brain activity after CGRP (P = 0.71) or after placebo (P = 0.98). Systemic CGRP or sumatriptan has no direct effects on the BOLD activity in visual cortex. This suggests that in healthy volunteers both CGRP and sumatriptan may exert their actions outside of the blood–brain barrier