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

BACKGROUND: In spite of the substantial therapeutic efficacy of triptans, their site of action is still debated. Subcutaneous sumatriptan is the most efficacious symptomatic treatment for cluster headache (CH) patients, showing therapeutic onset within a few minutes after injection even in migraine patients. However, whether subcutaneous sumatriptan is able to reach the CNS within this short time frame is currently unknown. METHODS: Here, by means of liquid chromatography/mass spectrometry, we investigated peripheral and brain distribution of subcutaneous sumatriptan soon after injection in rats at a dose equivalent to that used in patients. Tissue sumatriptan contents were compared to those of oxazepam, a prototypical lipophilic, neuroactive drug. RESULTS: We report that sumatriptan accumulated within brain regions of relevance to migraine and CH pathogenesis such as the hypothalamus and the brainstem as soon as 1 and 5 minutes after injection. Notably, sumatriptan brain distribution was faster than that of oxazepam, reaching concentrations exceeding its reported binding affinity for 5HT1B/D receptors, and in the range of those able to inhibit neurotransmitter release in vivo. CONCLUSION: Our findings indicate that sumatriptan distributes within the CNS soon after injection, and are in line with prompt pain relief by parenteral sumatriptan in CH patients.

Alcoholic drinks as triggers in primary headaches.

OBJECTIVE: This project aims to investigate the role of alcoholic drinks (ADs) as triggers for primary headaches. METHODS: Patients followed in the Headache Centre and presenting with migraine without aura, migraine with aura (MA), chronic migraine (CM), and tension-type headache (TH) were asked if their headache was precipitated by AD and also about their alcohol habits. Individual characteristics and drink habits were evaluated within two binary logistic models. RESULTS: About one half (49.7%) of patients were abstainers, 17.6% were habitual consumers, and 32.5% were occasional consumers. Out of 448 patients, only 22 (4.9%), all with migraine, reported AD as a trigger factor. None of 44 patients with MA and none of 47 patients with TH reported AD as a trigger factor. Among those patients with migraine who consume AD, only 8% reported that AD can precipitate their headache. Multivariate analyses showed that AD use, both occasional and habitual, is unrelated to TH. Moreover, analysis performed among migraine patients, points out that occasional and habitual drinkers have a lower risk of presenting with CM than abstainers, although statistical significance occurred only among occasional drinkers. Only 3% of migraine patients who abstain from AD reported that they do not consume alcohol because it triggers their headache. CONCLUSION: Our study shows that AD acts as headache triggers in a small percentage of migraine patients. Differing from some prior studies, our data suggest that AD do not trigger MA and TH attacks. Moreover, the percentage of abstainers in our sample is higher compared with that reported in general population surveys.

Information foraging with an oracle.

During ecological decisions, such as when foraging for food or selecting a weekend activity, we often have to balance the costs and benefits of exploiting known options versus exploring novel ones. Here, we ask how individuals address such cost-benefit tradeoffs during tasks in which we can either explore by ourselves or seek external advice from an oracle (e.g., a domain expert or recommendation system). To answer this question, we designed two studies in which participants chose between inquiring (at a cost) for expert advice from an oracle, or to search for options without guidance, under manipulations affecting the optimal choice. We found that participants showed a greater propensity to seek expert advice when it was instrumental to increase payoff (study A), and when it reduced choice uncertainty, above and beyond payoff maximization (study B). This latter result was especially apparent in participants with greater trait-level intolerance of uncertainty. Taken together, these results suggest that we seek expert advice for both economic goals (i.e., payoff maximization) and epistemic goals (i.e., uncertainty minimization) and that our decisions to ask or not ask for advice are sensitive to cost-benefit tradeoffs.

Alcohol and migraine: what should we tell patients?

Alcoholic drinks are a migraine trigger in about one third of patients with migraine in retrospective studies on trigger factors. Many population studies show that patients with migraine consume alcohol in a smaller percentage than the general population. Moreover, research has shown a decreased prevalence of headache with increasing number of alcohol units consumed. The classification criteria of alcohol-related headaches remain problematic. We discuss the role and mechanism of action of alcohol or other components of alcoholic drinks in relation to alcohol-induced headache. In accordance with data from a recent prospective study, we believe that reports overestimate the role of alcohol, as well as other foods, in the triggering of migraine. If a relationship between the intake of alcohol and the migraine attack is not clear, a small dose of alcohol is not contraindicated either for enjoyment or its protective effect on cardiovascular disease.

SUNCT syndrome or first division trigeminal neuralgia associated with cerebellar hypoplasia.

Short-lasting unilateral neuralgiform headache (SUNCT) and first division trigeminal neuralgia (TN) are rare and very similar periorbital unilateral pain syndromes. Few cases of SUNCT are associated with posterior skull lesions. We describe a 54-year-old man with symptoms compatible with both the previous painful syndromes, associated with a small posterior skull and a cerebellar hypoplasia. The short height and the reported bone fractures could be compatible with a mild form of osteogenesis imperfecta, previously described in one case associated with SUNCT. However, a hypoplastic posterior cranial fossa characterizes also Chiari I malformation. The difficult differential diagnosis between SUNCT and TN and their relation with posterior skull malformations is debated.

Migraine pain: reflections against vasodilatation.

The original Wolff's vascular theory of migraine was supported by the discovery of a class of drugs, the triptans, developed as a selective cephalic vasoconstrictor agents. Even in the neurovascular hypothesis of Moskowitz, that is the neurogenic inflammation of meningeal vessels provoked by peptides released from trigeminal sensory neurons, the vasodilatation provoked by calcitonin gene-related peptide (CGRP) is considered today much more important than oedema. The role of cephalic vasodilatation as a cause of migraine pain was recently sustained by studies showing the therapeutic effect of CGRP receptor antagonists. We discuss the evidence against vasodilatation as migraine pain generator and some findings which we suggest in support of a central (brain) origin of pain.

Alcohol-induced headaches: Evidence for a central mechanism?

Alcoholic drinks (ADs) have been reported as a migraine trigger in about one-third of the migraine patients in retrospective studies. Some studies found that ADs trigger also other primary headaches. The studies concerning the role of ADs in triggering various types of primary headaches published after the International Headache Society classification criteria of 1988 were reviewed, and the pathophysiological mechanisms were discussed. Many studies show that ADs are a trigger of migraine without aura (MO), migraine with aura (MA), cluster headache (CH), and tension-type headache (TH). While data on MO and CH are well delineated, those in MA and TH are discordant. There are sparse reports that ADs are also triggers of less frequent types of primary headache such as familial hemiplegic migraine, hemicrania continua, and paroxysmal hemicrania. However, in some countries, the occurrence of alcohol as headache trigger is negligible, perhaps determined by alcohol habits. The frequency estimates vary widely based on the study approach and population. In fact, prospective studies report a limited importance of ADs as migraine trigger. If ADs are capable of triggering practically all primary headaches, they should act at a common pathogenetic level. The mechanisms of alcohol-provoking headache were discussed in relationship to the principal pathogenetic theories of primary headaches. The conclusion was that vasodilatation is hardly compatible with ADs trigger activity of all primary headaches and a common pathogenetic mechanism at cortical, or more likely at subcortical/brainstem, level is more plausible.

Transcriptional response of human umbilical vein endothelial cells to low doses of ionizing radiation.

We used cDNA microarray hybridization technology to monitor the transcriptional response of Human Umbilical Vein Endothelial (HUVEC) cells to x-rays doses ranging from 2 to 200 cGy. An early time window from irradiation (4h) was selected in order to minimize the effects of the cell cycle blockage eventually induced at high doses of irradiation. Three different gene-clustering algorithms have been used to group the 4134 monitored ORF based on their transcriptional response in function of the irradiation dose. The results show that while few genes exhibit a typical dose-dependent modulation with a variable threshold, most of them have a different modulation pattern, peaking at the two intermediate doses. Strikingly even the lowest dose used (2 cGy) seems to be very effective in transcriptional modulation. These results confirm the physiological relevance of sublethal-dose exposures of endothelial cells and strengthens the hypothesis that alternative dose-specific pathways of radioadaptive response exist in the mammalian cells. 111 genes were found to be modulated at all doses of irradiation. These genes were functionally classified by cellular process or by molecular function. Genes involved in coagulation and peroxidase activity and structural constituent of ribosomes were over-represented among the up-regulated genes as compared with their expected statistical occurrence. Three genes coding for regulatory kinase activities (CDK6; PRCKB1 and TIE) are found down-regulated at all doses of irradiation.

Ancestral maximum likelihood of evolutionary trees is hard.

Maximum likelihood (ML) (Neyman, 1971) is an increasingly popular optimality criterion for selecting evolutionary trees. Finding optimal ML trees appears to be a very hard computational task--in particular, algorithms and heuristics for ML take longer to run than algorithms and heuristics for maximum parsimony (MP). However, while MP has been known to be NP-complete for over 20 years, no such hardness result has been obtained so far for ML. In this work we make a first step in this direction by proving that ancestral maximum likelihood (AML) is NP-complete. The input to this problem is a set of aligned sequences of equal length and the goal is to find a tree and an assignment of ancestral sequences for all of that tree's internal vertices such that the likelihood of generating both the ancestral and contemporary sequences is maximized. Our NP-hardness proof follows that for MP given in (Day, Johnson and Sankoff, 1986) in that we use the same reduction from Vertex Cover; however, the proof of correctness for this reduction relative to AML is different and substantially more involved.

Alcohol and migraine: trigger factor, consumption, mechanisms. A review.

This study investigates the importance of alcohol as a migraine trigger factor, the prevalence of alcohol consumers and the mechanism of headache provocation. A MEDLINE search from 1988 to October 2007 was performed for "headache and alcohol", "headache and wine", "migraine and alcohol" and "migraine and wine". In retrospective studies, about one-third of the migraine patients reported alcohol as a migraine trigger, at least occasionally, but only 10% of the migraine patients reported alcohol as a migraine trigger frequently. Regional differences were reported, perhaps depending in part on alcohol habits. No differences were found between migraine and tension headache and different genders. However, prospective studies limit considerably the importance of alcohol as a trigger. Recent studies show that migraine patients consume less alcohol than controls. Red wine was reported to be the principal trigger of migraine, but other studies show that white wine or other drinks are more involved. Then, the discussion based on the different composition of the various alcoholic beverages, in order to discover the content of alcoholic drinks responsible for migraine attack, reflects this uncertainty. Biogenic amines, sulphites, flavonoid phenols, 5-hydroxytryptamine mechanisms and vasodilating effects are discussed. The fact that few headache patients cannot tolerate some alcoholic drinks does not justify the consideration that alcohol is a major trigger and the suggestion of abstinence. In fact, low doses of alcohol can have a beneficial effect on patients such as migraineurs, who were reported to have an increased risk of cardiovascular disease.

Serotonin and migraine: a reconsideration of the central theory.

The 5-hydroxytryptamine (5-HT) has been implicated in migraine pathophysiology for the past 50 years. A low central 5-HT disposition associated with an increase in 5-HT release during attack is the most convincing change of 5-HT metabolism implicated in migraine. Peripheral studies on plasma/platelet have not generally shown low 5-HT levels. Studies on 5-HT reactivity showed hypersensitivity, also expressed as reduced tachyphylaxis (habituation), which successively was evidenced as the most characteristic marker of an altered sensory neurotransmission. Even the gender and seasonal variations of 5-HT parameters seem to agree with a low 5-HT turnover with receptoral hypersensitivity. The interpretation of the effects of some serotonergic drugs and recent neuroimaging studies give major evidence for this cascade of events. Although the exact mechanism that links abnormal 5-HT neurotransmission to the manifestation of head pain has yet to be fully understood, a deficit on 5-HT descending pain inhibitory system is still probably today the most implicated in migraine pathophysiology. This short review focuses and discusses the alteration of peripheral and central 5-HT parameters in migraine patients.

Triptans in the Italian population: a drug utilization study and a literature review.

Previous studies performed in selected populations show a poor utilization of triptans for migraine. The objectives of our study were to establish patterns of triptans utilization in a large sample, covering 1/10 of Italian population (5.57 millions), and to perform a review of published studies on this topic. We investigated drug prescription database collected during 2006 from 33 health authorities distributed in 8 different regions. About 0.6% of the subjects received at least one prescription of triptans in 1 year: 77.7% were females and 22.3% males. Age distribution shows that 9.5% of patients were aged above 65, and received prescriptions for 8.2% of packages. The review of the literature suggests that these percentages of utilization are common to several countries, and shows that occasional triptan users who received only one prescription in 1 year are a large percentage (40-60%); moreover, a minor population of triptan users utilize a large amount of total triptans. Finally triptans are frequently prescribed in people aged above 65 years, a population in which triptans are contraindicated or not recommended. Our study and the analyzed ones indicate suboptimal treatment of migraine patients with triptans and also an incorrect use in some patients (triptan abusers, elderly).