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Pharmacoepidemiology of triptans in a headache centre
No full textThe efficacy and safety of triptans in the absence of contraindications have been proved. Nevertheless, these drugs are not much used in clinical practice [1], while they are the most commonly used class of medication in the specialty care [2].
The aims of our study were: (i) examining the pharmacoepidemiology of triptans in the population of migraine patients treated at a specialist centre; (ii) analysing if there were any differences among patients continuing to use triptans and patients that, after having tried these drugs, discontinued them.
Methods. We examined all migraine patients, according to International Classification of Headache Disorders 2nd edition criteria [3], older than 18, consecutively examined for a follow-up visit at the ambulatories of the Headache Centre of the University Hospital of Modena from October 2008 to March 2009. Only patients who had used/used triptans as abortive treatments were included.
A questionnaire with closed and open questions about the use and tolerability of triptans was prepared for the study. The questionnaire was administered in the waiting room by a trained a postgraduated student of the School of Clinical Pharmacology, who had never examined the patients before.
Results. 343 migraine patients (F: 75%, M: 25%; mean age 40.4+10.3 years) reported to have used/use triptans. Migraine without aura (n=247, 72%) was the most common diagnosis, followed by chronic migraine (n=90, 26%) and migraine with aura (n=6, 2%). Globally, 60% (n=206) of the sample had tried at least two triptans and 72 % (n=246) continued to use them habitually.
The patients who had discontinued triptans (97/343, 28%) were significantly younger (mean age 36.8+6 years), had been suffering from migraine for less years (7.6+4), and had less migraine days/month (7.7+6) than those who instead continued to use them (mean age 41.8+1 years; years of migraine 15.5+9; migraine days/month: 13.4+1; P <0.0001, Student's t-test for unpaired data).
Much more patients among those who had discontinued triptans (89/97, 92%) than among those who continued to use them (139/246, 57%) reported triptan-associated side effects (P <0.0001, Fisher’s exact test). Most patients who had discontinued triptans (57/97, 59%) had taken this decision precisely because of side effects. The decision to continue to use triptans had instead been taken by most patients because of their efficacy (210/246, 85%).
The most used triptans had been sumatriptan (66%), almotriptan (54%), and rizatriptan (47%). The triptan discontinued by the highest percentage of the patients who had used it (31/37, 84%) had been sumatriptan 6 mg subcutaneous injection. Rizatriptan 10 mg had been significantly more discontinued (85/113, 75%) than sumatriptan 50 mg (28/71, 39%), almotriptan (84/146, 45%), zolmitriptan (44/78, 56%), and rizatriptan 5 mg (23/49, 47%) (P<0.05, Chi-square test). Significantly more patients reported side effects with sumatriptan 6 mg subcutaneous injection (33/37, 89%) and 100 mg tablet (50/75, 67%) than with any other triptan.
No patient reported serious or unexpected adverse triptan-associated effects. The most common side effects were the so-called “triptan sensations”, i.e., a feeling of drowsiness (47%) and of neck or chest tightness (36%).
Conclusions. In general, the patient decides to take a given drug depending on the balance between awaited benefits and potential risks. Most migraine patients going to a specialist centre continue to use triptans, after having tried them, above all for their efficacy. The minority discontinuing them are younger patients, who have been suffering from less severe migraine and for less time. These younger migraine patients seem inclined to consider the cost to pay in terms of worrisome, but non-serious side effects, unacceptable if compared to the benefits of the use of triptans.
References
[1] MacGregor E.A., Brandes J., Eikermann A. (2003). Migraine prevalence and treatment patterns: the global migraine and zolimitriptan evaluation survey. Headache 243: 19-26
[2] Bigal M., Rapoport A., Aurora S. et al. (2007). Satisfaction with current migraine therapy: experience from 3 centers in US and Sweden. Headache 47: 475-479
[3] Headache Classification Subcommittee of the International Headache Society (2004). The International Classification of Headache Disorders, 2nd edn. Cephalalgia 24.(Suppl 1):1-16
Lessons from triptans in migraine treatment
No full textResearch for a new antimigraine compound started at Glaxo in 1972 and led to the discovery of the first triptan drug, sumatriptan, a 5-HT1-like receptor agonist with an indolic structure identical to neurotransmitter 5-HT.
On November 14th, 1991, SISC organised in some Italian Headache Centres the “Migraine Day”, officially starting the sumatriptan “revolution”, followed by the “age of triptans”. The availability of sumatriptan, a specific analgesic for migraine pain, had opened new prospects of migraine treatment, which up to then had only used non-specific analgesics, such as FANS, paracetamol, and ergotamine, an agonist drug of various receptors, with important side effects and contraindications. Research was immediately directed towards the synthesis of triptans with better pharmacokinetic and pharmacodynamic characteristics and less side effects. Six triptans were synthesized, 5 of which had the same indolic structure as sumatriptan and were therefore defined as “me-too”, while one had a carbazolic structure.
Like all revolutions, the triptans’ was a complete one. The congresses, courses, and conferences were practically all about the research of the triptan with the highest therapeutic index.
However, the physiopathology of migraine pain implies, besides 5-HT, noradrenaline, the formation of NO, GABA, enkephalins, and the release of neurotransmitters (SP and CGRP) and neuropeptides.
The proof that an agonist of receptor CGRP is effective in migraine pain treatment when taken by mouth opens new prospects. If there are available different types of antimigraine drugs and their associations, subtypes of patients shall be identified, according to the different treatments or associations they need.
The methodological elements which can be deduced from research on the clinical efficacy of triptans, opening new prospects of research about the physiopathology and clinical aspects of migraine, are the following:
1°) detecting premonitory symptoms that may increase the awareness of migraine;
2°) detecting the onset time of migraine aura and its signs and symptoms;
3°) deciding when the drug must be administered in clinical trials;
4°) detecting pain intensity (light, moderate, or severe) and the possible autonomic symptoms when administering the drug and afterwards, after established periods of time, and assessing the following primary end points:
- pain relief and pain free after 30 and 60 minutes
- pain free after 2 hours (not pain relief)
- sustained pain free after 24 hours
- sustained pain free and no side effects after 24 hours
and the following secondary end points:
- presence and intensity of possible other symptoms (osmophobia, phonophobia, photophobia, nausea, vomiting)
- recurrence after 24 hours
- disability time per treated attack
- consistency across multiple attacks.
The criteria of inclusion of migraine patients in clinical trials must consider the severity of migraine, assessing the progress and characteristics of the last 5-10 attacks, in order to divide into groups the subjects included in the studies. The efficacy of a drug is different in episodic migraine patients with attacks lasting 3-4 hours and in patients with attacks lasting 4-8 hours or previously treated with drugs causing pain relief for a few hours, with the reappearance of pain, for example, after 4-6 hours.
Patients’ selection contributes to the disparity between clinical trials and clinical practice; it is fundamental that patients in clinical trials are as similar as possible to the patients who are then going to take the drugs in clinical practice.
Drugs should be used as research tools and clinical records should be created on these bases, in order to know more about the mechanism of pain generation subsequent to the activation of the trigeminal vascular system and about the role played by vasodilatation and plasma protein extravasation
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Plasma concentrations of glutamate in patients suffering from chronic migraine overusing acute medication, before and after withdrawal treatment
No full textA dysfunction of the glutamatergic system would have an essential role in the pathogenetic mechanism of the migraine. Glutamate is implicated in cortical spreading depression, trigeminovascular activation, and central sensitization [1]. Higher glutamate levels than those of healthy controls have been reported in migraine patients’ plasma and platelets [2] and in chronic migraine patients’ cerebrospinal fluid [3].
Our aim was verifying if there were differences in the plasma levels of glutamate between patients with chronic migraine overusing acute medications and control subjects, and if plasma levels of glutamate in chronic migraine patients modified after withdrawal from the overused medication.
Methods. We studied 12 patients (F=10, M=2; mean age 50.3±9.8 years) with diagnosis of chronic migraine, according to ICHD-II criteria, overusing acute medications, and 15 healthy subjects as controls (F=2, M=3; mean age 48.2±7.3 years). Patients were studied twice, before and after 15 days of standardized inpatient withdrawal treatment. Venous blood samples for the assay of glutamate concentrations were taken in the morning, after overnight fasting. Glutamate concentrations were measured by means of a fluorimetric detector high pressure liquid chromatographic (HPLC/FD) method.
Results. Plasma concentrations of glutamate were significantly higher in chronic migraine patients either before (62.5±5.1 μmol/L) or after treatment (27.7±11.3 μmol/L) than in control subjects (7.3±2.9 μmol/L) (P<0.05, ANOVA followed by Student-Newman-Keuls’ test). However, after 15 days of inpatient withdrawal treatment, once overuse was interrupted, and the frequency of headache reduced, plasma glutamate concentrations were significantly lower in the same patient with respect to the prior level (P<0.0001, Student’s t-test for paired data), without any differences depending on the kind of medication overused.
Conclusions. Elevated plasma levels of glutamate in chronic migraine sufferers could support the role of this excitatory aminoacid in the process of central sensitization. The decline in glutamate plasma concentrations is associated with medication-overuse discontinuation and reduced headache frequency; thus, plasma glutamate levels monitoring in chronic migraine might serve as a biomarker of clinical improvement.
[1] Ramadan NM. The link between glutamate and migraine. CNS Spectr 2003; 8(6):446-9
[2] Alam Z, Coombes N, Waring RH, Williams AC, Steventon GB. Plasma levels of neuroexcitatory amino acids in patients with migraine or tension headache. J Neurol Sci 1998; 156(1):102-6
[3] Peres MF, Zukerman E, Senne Soares CA, Alonso EO, Santos BF, Faulhaber MH. Cerebrospinal fluid glutamate levels in chronic migraine. Cephalalgia 2004; 24(9):735-
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
The GHB analogue n-(4-trifluoromethyl)-4-methoxybutanamide prevents the behavioral and neurodegenerative consequences of repeated episodes of alcohol withdrawal, in rats.
No full textAbrupt cessation of chronic consumption of alcohol produces a severe withdrawal syndrome, characterized by behavioral signs (increased anxiety, tremor, hyperactivity and seizures, conspicuous memory deficits) associated with neurodegeneration, particularly in the hippocampus and in the hippocampal cholinergic fiber network. The mechanism appears to be a classical excitotoxic cascade, with overactivation of the glutamatergic/NMDA neurotransmission associated with concurrently diminished GABAergic neurotransmission.
Gamma-hydroxybutyric acid (GHB) functions as a neurotransmitter in the CNS, with specific high affinity binding sites in defined brain structures, including the hippocampus, and with affinity also for GABA B receptors, alike present in the hippocampus. GHB has long been used for the treatment of alcohol dependence, where it effectively decreases ethanol craving and consumption as well as withdrawal symptoms, likely by a substitution mechanism. Moreover, it exerts a protective effect against brain damage produced by traumatic, excitotoxic or ischemic injuries.
N-(4-trifluoromethylbenzyl)-4-methoxybutanamide (GET73) is a GHB analogue with more potent and longer-lasting activity than the parent compound. Aim of the present research was to study the possible protective effect of GET73 against the consequences of repeated episodes of alcohol withdrawal in chronically alcohol-consuming rats.
METHODS and TREATMENT. After 1 week of adaptation to our housing conditions, adult male rats of a Wistar Kyoto strain had tap water substituted with an alcohol aqueous solution (6% by volume) as ad libitum
beverage. Control rats received tap water containing sucrose of same caloric content. At the end of the 3rd, 4th and 5th week, alcohol solution -and sucrose solution in controls- were withdrawn for 24 hr and replaced
with tap water. At the end of the last withdrawal period, rats were observed for gross behavior and open-field behavior. After the behavioral observation, rats were killed under ether anesthesia, and brains were
removed for histological examination. Alcohol-consuming rats were randomly assigned to i.p. treatment either with GET73 (1, 5 or 10 mgkg-1, at the beginning of each withdrawal episode, and again 12 hr later and 30 min
before behavioral testing) or with the vehicle. The research protocol had been approved by the Animal Experimentation Ethical Committee of the University of Modena and Reggio Emilia.
RESULTS. At the end of the 3rd alcohol-withdrawal episode, vehicle-treated rats were excited, hyperactive, squeaking, aggressive and attemping to bite when handled; in the open-field, grooming and ambulation were
increased, compared with non-alcohol-consuming rats. GET73 produced a reduction of ambulation (inner ond outer crossing), rearing and grooming (vehicle-treated: inner cross. 14.8 +/- 6.5; outer cross. 53.0 +/- 25.7;
rearings 7.8 +/- 4.2; grooming 10.5 +/-5.2 (m +/- S.D.). GET73 10 mg/kg: inner cross. 3.6 +/- 2.3 (F = 16.77; P = 0.000); outer cross. 13.4 +/-11.0 (F = 9.26; P = 0.000); rearings 3.8 +/- 2.2 (F = 11.1; P= 0.000); grooming 0.0 (F= 16.80; P= 0.000)(ANOVA followed by S.N.K. test)). The histological picture in abstinent rats treated with the vehicle was characterized by a severe damage of the hippocampal CA1 subfield, with almost complete absence of vital neurons, demyelinization, marked reduction of the number of synapses, and astrogliosis. The treatment with GET73 produced a dose-dependent protection: with the highest dose (10
mg/kg) the number of vital neurons and synapses was minimally reduced and astrogliosis was quite limited.
CONCLUSIONS. These results show that in chronically alcohol-consuming rats, the behavioral and neurodegenerative consequences of repeated episodes of alcohol withdrawal are prevented by the GHB analogue N-(4-trifluoromethyl)-4-methoxybutanamide (GET73). The possible mechanisms may likely involve
(i) reduced release of excitatory amino acids as a consequence of the activation of both GHB and GABAB receptors, (ii) hyperpolarisation of hippocampal neurons by activating GABAB receptors and by increasing K+ conductance
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