Periorbital Nociception in a Progressive Multiple Sclerosis Mouse Model Is Dependent on TRPA1 Channel Activation.

Headaches are frequently described in progressive multiple sclerosis (PMS) patients, but their mechanism remains unknown. Transient receptor potential ankyrin 1 (TRPA1) was involved in neuropathic nociception in a model of PMS induced by experimental autoimmune encephalomyelitis (PMS-EAE), and TRPA1 activation causes periorbital and facial nociception. Thus, our purpose was to observe the development of periorbital mechanical allodynia (PMA) in a PMS-EAE model and evaluate the role of TRPA1 in periorbital nociception. Female PMS-EAE mice elicited PMA from day 7 to 14 days after induction. The antimigraine agents olcegepant and sumatriptan were able to reduce PMA. The PMA was diminished by the TRPA1 antagonists HC-030031, A-967079, metamizole and propyphenazone and was absent in TRPA1-deficient mice. Enhanced levels of TRPA1 endogenous agonists and NADPH oxidase activity were detected in the trigeminal ganglion of PMS-EAE mice. The administration of the anti-oxidants apocynin (an NADPH oxidase inhibitor) or alpha-lipoic acid (a sequestrant of reactive oxygen species), resulted in PMA reduction. These results suggest that generation of TRPA1 endogenous agonists in the PMS-EAE mouse model may sensitise TRPA1 in trigeminal nociceptors to elicit PMA. Thus, this ion channel could be a potential therapeutic target for the treatment of headache in PMS patients.

Functional Hybrid Nanoemulsions for Sumatriptan Intranasal Delivery.

In recent years, advanced nanohybrid materials processed as pharmaceuticals have proved to be very advantageous. Triptans, such as the commercially available intranasal sumatriptan (SMT), are drugs employed in the treatment of painful migraine symptoms. However, SMT effectiveness by the intranasal route is limited by its high hydrophilicity and poor mucoadhesion. Therefore, we designed hybrid nanoemulsions (NE) composed of copaiba oil as the organic component plus biopolymers (xanthan, pectin, alginate) solubilized in the continuous aqueous phase, aiming at the intranasal release of SMT (2% w/v). Firstly, drug-biopolymer complexes were optimized in order to decrease the hydrophilicity of SMT. The resultant complexes were further encapsulated in copaiba oil-based nanoparticles, forming NE formulations. Characterization by FTIR-ATR, DSC, and TEM techniques exposed details of the molecular arrangement of the hybrid systems. Long-term stability of the hybrid NE at 25°C was confirmed over a year, regarding size (~ 120 nm), polydispersity (~ 0.2), zeta potential (~ -25 mV), and nanoparticle concentration (~ 2.1014 particles/mL). SMT encapsulation efficiency in the formulations ranged between 41-69%, extending the in vitro release time of SMT from 5 h (free drug) to more than 24 h. The alginate-based NE was selected as the most desirable system and its in vivo nanotoxicity was evaluated in a zebrafish model. Hybrid NE treatment did not affect spontaneous movement or induce morphological changes in zebrafish larvae, and there was no evidence of mortality or cardiotoxicity after 48 h of treatment. With these results, we propose alginate-based nanoemulsions as a potential treatment for migraine pain.

Migraine Treatment in Emergency Departments of Brazil: A Retrospective Study of 2 Regions.

OBJECTIVE: This study describes the approaches, medications used, and time of care for migraineurs, who have been in emergency departments (ED) from 2 different regions of Brazil. METHODS: Retrospective, cross-sectional, observational, non-randomized study of migraine patients seen at 2 headache centers in Brazil. RESULTS: Eighty-four migraine patients (15 men and 69 women) were divided into 2 groups: chronic (19%, n = 16) and episodic migraineurs (81%, n = 68). In the ED, medications were used in the following order of frequency: dipyrone or metamizole (89.3%, 75/84), nonsteroidal anti-inflammatory drugs (57.1%; 48/84) opioids (51.1%; 43/84), metoclopramide (29.8%; 25/84), dexamethasone (28.6%; 24/84), chlorpromazine (13.1%; 11/84), and subcutaneous sumatriptan (7.1%; 6/84). The average time in the care center was 8.2 hours, but only 23 patients (27.4%) left the hospital with greater than 50% relief in headache severity. CONCLUSIONS: Dipyrone and nonsteroidal anti-inflammatories were the most used drugs, but nearly half received opioids. More efficient drugs were poorly used. Considering the number of patients leaving the hospital with headache relief, a changing treatment paradigm should be carried out in Brazil.

A sumatriptan coarse-grained model to explore different environments: interplay with experimental techniques.

In this work, we developed a coarse-grained model of sumatriptan suitable for extensive molecular dynamics simulations. First, we confirmed the interfacial distribution of this drug in bilayers through cryogenic transmission electron microscopy and small-angle X-ray scattering techniques, as was predicted by our previous atomistic simulations. Based on these simulations, we developed a coarse-grained model for sumatriptan able to reproduce its overall molecular behavior, captured by atomistic simulations and experiments. We then tested the sumatriptan model in a micellar environment along with experimental characterization of sumatriptan-loaded micelles. The simulation results showed good agreement with photon correlation spectroscopy and electrophoretic mobility experiments performed in this work. The particle size of the obtained micelles was comparable with the simulated ones; meanwhile, zeta-potential results suggest adsorption of the drug on the micellar surface. This model is a step forward in the search for a suitable drug-delivery system for sumatriptan.

Development and validation of an LC-ESI-MS/MS method for the simultaneous quantification of naproxen and sumatriptan in human plasma: application to a pharmacokinetic study.

A sensitive and fast liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for the simultaneous quantification of naproxen and sumatriptan in human plasma. A simple liquid-liquid extraction procedure, with a mixture of ethyl acetate, methyl tert-butyl ether, and dichloromethane (4:3:3, v/v), was used for the cleanup of plasma. Naratriptan and aceclofenac were employed as internal standards. The analyses were carried out using an ACE C18 column (50 × 4.6 mm i.d.; particle size 5 µm) and a mobile phase consisting of 2 mM aqueous ammonium acetate with 0.025 % formic acid and methanol (38:62, v/v). A triple-quadrupole mass spectrometer equipped with an electrospray source in the positive mode was set up in the selective reaction monitoring mode to detect the ion transitions m/z 231.67 → m/z 185.07, m/z 296.70 → m/z 157.30, m/z 354.80 → m/z 215.00, and m/z 336.80 → m/z 97.94 for naproxen, sumatriptan, aceclofenac, and naratriptan, respectively. The method was validated and proved to be linear, accurate, precise, and selective over the ranges of 2.5-130 µg mL(-1) for naproxen and 1-50 ng mL(-1) for sumatriptan. The validated method was successfully applied to a pharmacokinetic study with simultaneous administration of naproxen sodium and sumatriptan succinate tablet formulations in healthy volunteers.

The 5-HT1D/1B receptor agonist sumatriptan enhances fear of simulated speaking and reduces plasma levels of prolactin.

This study measured the effects of the preferential 5-HT1D/1B receptor agonist sumatriptan in healthy volunteers who performed the Simulated Public Speaking Test (SPST), which recruits the neural network involved in panic disorder and social anxiety disorder. In a double-blind, randomised experiment, 36 males received placebo (12), 50 mg (12) or 100 mg (12) of sumatriptan 2 h before the SPST. Subjective, physiological and hormonal measures were taken before, during and after the test. The dose of 100 mg of sumatriptan increased speech-induced fear more than either a 50mg dose of the drug or placebo. The largest dose of sumatriptan also enhanced vigilance more than placebo, without any change in blood pressure, heart rate or electrical skin conductance. Sumatriptan decreased plasma levels of prolactin. A significant but moderate increase in plasma cortisol after SPST occurred, independent of treatment. Because sumatriptan decreases 5-HT release into the extracellular space, the potentiation of SPST-induced fear caused by the drug supports the hypothesis that 5-HT attenuates this emotional state. As acute administration of antidepressants has also been shown to enhance speaking fear and increase plasma prolactin, in contrast to sumatriptan, the 5-HT regulation of stress-hormone release is likely to be different from that of emotion.

The use of combination therapies in the acute management of migraine.

BACKGROUND AND OBJECTIVES: Migraine is a highly prevalent neurological disorder with multiple peripheral and central mechanisms. Targeting a single mechanism for treating individual attacks as well as for performing the prophylaxis has been shown to be only partially effective. Recently, the role of combining agents for acute migraine treatment has gained attention and the combination of a triptan plus a non-steroidal anti-inflammatory drug (NSAID) has demonstrated better efficacy. This review focuses on the fundamentals of treating migraine attacks with two or more agents, and emphasizes the characteristics of the recently approved fixed combination sumatriptan-naproxen. METHODS: A PubMed search using the terms "migraine", "treatment", "acute", "triptans", "non-steroidal anti-inflammatory drugs", "sumatriptan", "naproxen", and "combination" was used. In addition, abstracts presented in the major meetings of the American Headache and the International Headache Societies along with the American Academy of Neurology were also evaluated. RESULTS: Although most of the few studies encountered were not controlled, there is a clear trend for better efficacy in combining triptans with NSAID. Additionally, the results of two recent large and controlled studies using fixed combinations of sumatriptan (50 mg and 85 mg) with 500 mg naproxen sodium confirm the initial observations of the clear superiority of this combination over the use of each agent alone. The differences in the endpoints 24-hour pain-relief response as well as pain-free and pain-relief parameters at 2-hour time-point are the most noticeable efficacy measures. Tolerability was not different between studied drugs. CONCLUSIONS: Combining triptans with NSAID and other agents for the acute treatment of migraine suggests better outcome efficacy measures than the use of single agents. The fixed combination of sumatriptan and naproxen sodium offers improved 2-hour and 24-hour benefits over monotherapy with each one these options. Recently issued FDA approval for marketing the combination (sumatriptan 50 mg-naproxen 500 mg) emphasizes the usefulness and safety of this new treatment for migraine attacks.