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Fingolimod (FTY720) has been approved as the first oral representative of the class of sphingosine-1-phosphate (S1P) receptor modulators for the treatment of relapsing-remitting multiple sclerosis (MS). Besides inducing vaso-relaxation, fingolimod can also influence electrical conduction in the myocardium and vascular endothelium by having a transient negative chronotropic effect on the sinus node.

Introduction:IFNβ products and glatiramer acetate are established treatment first-line options in long-term disease-modifying therapy of multiple sclerosis (MS). These self-injectable medications are used once weekly to once daily. Injection-related issues are common patient-cited reasons for nonadherence. Autoinjectors have been shown to support long-term adherence to injectable medications. The ability to self-inject in MS patients has been associated with a reduced risk of missed injections and drug discontinuation, and a beneficial effect on patient independence.Areas covered:The recently introduced easy-to-use prefilled once-weekly pen is a safe and effective device for intramuscular (IM) IFNβ-1a application and provides a convenient method for self-injection. We reviewed the available published evidence on the characteristics of this device. The once-weekly pen facilitates self-injection and was preferred over prefilled syringes by patients in a prospective open-label, multicenter Phase IIIb trial in MS patients who had been using IM IFNβ-1a in prefilled syringes.Expert opinion:The simple and safe handling, shielded short needle, single-use disposable design and virtually painless injection by the device may contribute to adherence, quality of life and independence in patients using IM IFNβ-1a.

Granulocyte colony–stimulating factor (G-CSF; AX200; Filgrastim) is a stroke drug candidate with excellent preclinical evidence for efficacy. A previous phase IIa dose–escalation study suggested potential efficacy in humans. The present large phase IIb trial was powered to detect clinical efficacy in acute ischemic stroke patients.

Within the last decades significant progress has been made in the understanding of the underlying pathophysiological mechanisms of migraine. There is a general agreement now that migraine is not only a vascular phenomenon but also a genetically determined heterogenic ion-channelopathy resulting in cortical-spreading-depression-like events, the temporary impairment of antinociceptive structures of the brainstem and the activation of the trigeminal-vascular system. The development and use of drugs targeting ion-channels and subsequently reducing cortical excitability appears as a promising avenue for both the acute treatment of migraine and migraine prevention. This review summarizes the current knowledge and evidence for GABAergic drugs in the treatment of migraine.

Migraine headache is a chronic, painful, disabling and potentially progressive, condition primarily occurring in early and middle adulthood. For many patients, daily activities are impaired by the sudden and unpredictable occurrence of migraine attacks. In recent years, significant progress has been made in the field of migraine treatment. For the acute treatment of migraine attacks, 5-hydroxytryptophan1B/Dagonists (so called triptans), were the most innovative development, successfully aborting attacks in less than 1 h. The search for innovative drugs usable for migraine prevention, however, was less successful, mainly due to the lack of reliable and predictive animal models. Recently, neuromodulators such as valproic acid and topiramate, initially developed as anticonvulsants, have been shown in large clinical trials to be effective in the prevention of migraine. As for the acute treatment of migraine attacks more than 10 years ago, large clinical trial programs are now setting new standards for evidence-based medicine in migraine prevention. This review summarizes the current options in migraine prevention with special emphasis on clinical trial design and new developments such as topiramate.

The current literature on medication overuse headache will be reviewed with regard to clinical presentation, pathophysiology, therapy and prognosis in the light of the new headache classification.

Triptane sind Serotonin-Agonisten und die bisher wirksamsten Substanzen in der Akutbehandlung der Migräne. Sie wirken wahrscheinlich über mehrere spezifische Mechanismen, die neben vasokonstriktorischen Effekten meningealer Gefäße, der Inhibition der Neuropeptidfreisetzung auch zentrale Mechanismen umfassen könnten. Durch ein sehr selektives Affinitätsspektrum zeigen sie ein im Vergleich zu Ergotaminen deutlich verbessertes Nebenwirkungsprofil.

Migraine is a paroxysmal disorder with attacks of headache, nausea, vomiting, photo- and phonophobia and malaise. This review summarises new treatment options both for the therapy of the acute attack as well as for migraine prophylaxis. Analgesics like aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) are effective in treating migraine attacks. Few controlled trials were performed for the use of ergotamine or dihydroergotamine. These trials indicate inferior efficacy compared with serotonin (5-HT1B/D) agonists (triptans). The triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan), are highly effective. They improve headache as well as nausea, photo- and phonophobia. The different triptans show only minor differences in efficacy, headache recurrence and adverse effects. The knowledge of their different pharmacological profile allows a more specific treatment of the individual migraine characteristics. Migraine prophylaxis is recommended, when more than three attacks occur per month, if attacks do not respond to acute treatment or if side effects of acute treatment are severe. Substances with proven efficacy include the beta-blockers metoprolol and propranolol, the calcium channel blocker flunarizine, several 5-HT antagonists and amitriptyline. Recently anti-epileptic drugs (valproic acid, gabapentin, topiramate) were evaluated for the prophylaxis of migraine. The use of botulinum toxin is under investigation.

Using Cyclosporin A (CsA) as an unconditioned stimulus has previously demonstrated that behaviorally conditioned inhibition of splenocyte proliferation and cytokine production is mediated via the splenic nerve. Therefore, we currently examined the adrenergic modulation of conditioned suppression of splenocyte function. Chemical sympathectomy via 6-OHDA completely blocked the conditioned suppression of splenocyte proliferation to mitogens and cytokine (IL-2, IFN-γ) production. Furthermore, administration of β-adrenoceptor antagonist propranolol abrogated the conditioned effect on splenocyte proliferation. Supporting the position that conditioning is β-adrenergic-dependent, addition of β-adrenoceptor agonist, but not α-adrenoceptor agonists, to splenocytes in vitro mimicked the conditioned suppression of splenocyte functions, with these effects blocked by propranolol. Therefore, these data indicate that behavioral conditioning of splenocyte function in the rat is regulated by the sympathetic nervous system, predominantly via β-adrenergic mechanisms.

Migraine is a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia and phonophobia, and malaise. This review summarizes new treatment options for the therapy of acute attacks. Sumatriptan was the first specific serotonin-1BD agonist for the treatment of acute migraine attacks. Apart from the oral and subcutaneous formulation, it is also available as nasal spray and suppository. The other new migraine drugs zolmitriptan, naratriptan, rizatriptan and eletriptan differ in their pharmacological profiles, which translates into minor differences in efficacy, headache recurrence and side-effects. Importantly, in clinical practice individual patients may show a preference for one treatment over another. New drugs in migraine treatment include substance-P antagonists, nitric oxide synthetase inhibitors and calcitonin gene-related peptide antagonists.

Neuropeptide Y (NPY) is a unique modulator of renal function that enhances urine flow and sodium excretion despite marked reductions in renal blood flow. We investigated whether the cyclooxygenase inhibitor indomethacin alters the renal NPY effects in anesthetized rats. Treatment with 5 mg/kg indomethacin i.p. lowered urinary prostaglandin excretion by ≈85%. Systemic infusion of NPY elevated mean arterial pressure by ≈15 mm Hg and renovascular resistance by ≈8.0 mm Hg/ml/min, whereas the related peptide YY3–36(PYY3–36) did not. Nevertheless, both peptides enhanced urine flow rate by ≈250 and ≈100 μl/15 min, respectively, and sodium excretion by ≈15 μmol/15 min. Treatment with indomethacin did not affect NPY- and PYY3–36-induced alterations of systemic and renovascular hemodynamics but completely abolished NPY- and PYY3–36-induced diuresis and natriuresis. Endogenous creatinine clearance was not affected by any treatment. We conclude that cyclooxygenase-derived arachidonic acid metabolites are not involved in the systemic or renal hemodynamic effects of NPY and PYY3–36but mediate NPY- and PYY3–36-induced diuresis and natriuresis.

We examined whether 7-nitroindazole (7-NI), a putative inhibitor of neuronal nitric oxide synthase (nNOS), decreases cerebral infarction 24 h after proximal middle cerebral artery (MCA) occlusion. In preliminary experiments, we determined that 7-NI (25, 50, and 100 mg/kg i.p.) decreased nitric oxide synthase (NOS) activity within cerebral cortex by 40–60% when measured up to 120 min, but not 240 min after administration. At 25 or 50 mg/kg, 7-NI did not alter the systemic arterial blood pressure or the dilation of pial arterioles after topical acetylcholine (10 and 100 μM). To examine the effect of 7-NI on infarct size, 55 Sprague–Dawley halothaneanesthetized rats were subjected to proximal MCA occlusion (modified Tamura method). Five minutes after occlusion, 7-NI (25 or 50 mg/kg i.p.) or vehicle was injected. Animals treated with 25 or 50 mg/kg showed 25 and 27% reductions in infarct volume, respectively. Coadministration of l-arginine (300 mg/kg i.p.) plus 7-NI (25 mg/kg i.p.) reversed the effect. If, indeed, the effects of 7-NI are mediated by inhibition of nNOS activity, these results suggest that enzymatic products of the neuronal isoform promote ischemic injury and that they do so at least within the first few hours after permanent occlusion. The results also emphasize the importance of developing strategies to selectively inhibit the neuronal isoform inasmuch as we observed previously that administering the less selective NOS inhibitor, Nω-nitro-l-arginine (L-NA), in the same model either caused no change or increased the volume of ischemic injury.

1The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA‐agonist muscimol on dural plasma protein ([125I]‐bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (SP) administration (1 nmol kg−1, i.v.) in anaesthetized Sprague‐Dawley rats.2Intraperitoneal (i.p.) injection of sodium valproate or muscimol, but not baclofen (≤10 mg kg−1, i.p.) dose‐dependently reduced dural plasma protein extravasation caused either by electrical trigeminal stimulation (ED50: 6.6±1.4 mg kg−1, i.p., and 58 + 18 μg kg−1, i.p. for valproate or muscimol, respectively) or by intravenous substance P administration (ED50: 3.2±1.4 mg kg−1, i.p. and 385±190 μg kg−1, i.p. for valproate or muscimol, respectively).3Valproate (6.6 mg kg−1, i.p.) or muscimol (58 μ kg−1, i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration.4The GABAA‐antagonist bicuculline (0.01 mg kg−1, i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the GABAB‐receptor antagonist, phaclofen (0.01‐1 mg kg−1, i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP administration.5Valproate decreased plasma extravasation following substance P administration in adult animals, neonatally treated with capsaicin by a bicuculline‐reversible mechanism. This suggests that GABAA‐receptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats.6We conclude that sodium valproate blocks plasma extravasation in the meninges through GABAA‐mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABAAreceptor may become useful for the development of selective therapeutic agents for migraine and cluster headache. The GABA transaminase inhibitor and activator of glutamic acid decarboxylase, valproic acid is being used for the treatment of migraine. Its mechanism of action is unknown. We tested the effects of sodium valproate and GABAA‐agonist muscimol on dural plasma protein ([125I]‐bovine serum albumin) extravasation evoked by either unilateral trigeminal ganglion stimulation (0.6 mA, 5 ms, 5 Hz, 5 min) or substance P (SP) administration (1 nmol kg−1, i.v.) in anaesthetized Sprague‐Dawley rats. Intraperitoneal (i.p.) injection of sodium valproate or muscimol, but not baclofen (≤10 mg kg−1, i.p.) dose‐dependently reduced dural plasma protein extravasation caused either by electrical trigeminal stimulation (ED50: 6.6±1.4 mg kg−1, i.p., and 58 + 18 μg kg−1, i.p. for valproate or muscimol, respectively) or by intravenous substance P administration (ED50: 3.2±1.4 mg kg−1, i.p. and 385±190 μg kg−1, i.p. for valproate or muscimol, respectively). Valproate (6.6 mg kg−1, i.p.) or muscimol (58 μ kg−1, i.p.) had no effect on mean arterial blood pressure or heart rate when measured for 30 min after i.p. administration. The GABAA‐antagonist bicuculline (0.01 mg kg−1, i.p.) completely reversed the effect of valproate and muscimol on plasma extravasation following electrical stimulation or substance P administration, whereas the GABAB‐receptor antagonist, phaclofen (0.01‐1 mg kg−1, i.p.) did not. Bicuculline or phaclofen, given alone, did not alter the plasma extravasation response after either electrical stimulation or SP administration. Valproate decreased plasma extravasation following substance P administration in adult animals, neonatally treated with capsaicin by a bicuculline‐reversible mechanism. This suggests that GABAA‐receptors are not found primarily on those afferent neurones or fibres which are sensitive to capsaicin treatment in neonatal rats. We conclude that sodium valproate blocks plasma extravasation in the meninges through GABAA‐mediated postjunctional receptors probably within the meninges. The dosages required are comparable to those used clinically. Agonists and modulators at the GABAAreceptor may become useful for the development of selective therapeutic agents for migraine and cluster headache.

For many decades, headache and migraine were thought to evolve from dilated cranial blood vessels. Vasoconstrictors such as ergotamine and, more recently, sumatriptan were considered appropiate treatments. With the introduction of animal models and the emergence of molecular pharmacology, this traditional concept has been challenged, and an important role for neuropeptides, neuronal receptors and neurogenic inflammation is emerging. Neurogenic inflammation develops within the meninges as a consequence of neuropeptide release from primary afferent fibers and has been hypothesized to be of importance in migraine. Neurogenic inflammation provides protection for many organs, contributes to tissue repair and serves as a useful model to define the receptor population and peptide mechanisms of relevance to drug discovery in migraine. The possible role played by neurotransmitters and neuropeptides in migraine and their receptors as potential targets for treatment will be discussed.

•Across age groups, alemtuzumab efficacy was greater than SC IFNB-1a over 2 years.•Alemtuzumab maintained clinical and MRI efficacy over 8 years in all age groups.•Age-related increases in serious infections, malignancies, and deaths were observed.

Chronic migraine affects approximately 1% of the adult population and is defined as headache on ≥15 d/mo with ≥8 days of migraine-type headache. Since treatment often remains frustrating for both the patient and physician, new treatment strategies are highly welcome.