Nabih M. Ramadan

Efficacy and Safety of Topiramate for the Treatment of Chronic Migraine: A Randomized, Double-Blind, Placebo-Controlled Trial

Objective.—To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine.

Optimizing the dose of zolmitriptan (Zomig,* 311C90) for the acute treatment of migraine A multicenter, double-blind, placebo-controlled, dose range-finding study

This study investigated the efficacy of zolmitriptan (Zomig, formerly 311C90) in acute migraine therapy. Patients with a history of migraine were randomized in a double-blind, multicenter, placebo-controlled, dose range-finding study of oral zolmitriptan 1, 2.5, 5, or 10 mg versus placebo for the treatment of a severe or moderate migraine headache. Patients with persistent or recurrent headache 4 to 24 hours after the initial dose, who did not take escape medication, were eligible to receive a second blinded dose of either zolmitriptan or placebo. Of 1,144 patients treated, 999 evaluable patients completed the study. The headache response rates with zolmitriptan doses ≥ 2.5 mg were 44 to 51% at 1 hour, 65 to 67% at 2 hours, and 75 to 78% at 4 hours (all significantly superior to placebo). Also, zolmitriptan effectively relieved migraine-associated symptoms such as nausea, photophobia and phonophobia, and reduced activity impairment. Rates of headache recurrence, headache persistence, and use of escape medication were lower with zolmitriptan doses ≥ 2.5 mg than with placebo. In patients with persistent or recurrent headache, a second zolmitriptan dose effectively treated both headache and nonheadache symptoms. Zolmitriptan was well tolerated, with a lower incidence of adverse events being reported with doses≤ 2.5 mg than with those ≥5 mg. Zolmitriptan is a well tolerated and effective acute migraine therapy providing rapid relief of migraine headache within 1 hour. A clear dose-response relationship between efficacy and tolerability suggests that 2.5 mg is the optimal initial dose for the acute treatment of a migraine attack.

Clinical efficacy and tolerability of 2.5 mg zolmitriptan for the acute treatment of migraine

Previous studies demonstrated that zolmitriptan at doses of 1 to 25 mg was highly effective in treating acute migraine attacks. The 2.5-mg dose had a favorable therapeutic effect with high efficacy and good tolerability. The objective of this study was to further evaluate the efficacy of a single 2.5-mg dose of zolmitriptan (Zomig, formerly known as 311C90) for acute treatment of a single moderate or severe migraine attack. The study was a randomized, double-blind, placebo-controlled clinical trial. Female and male patients, 12 to 65 years old, with migraine (with or without aura) for ≥1 year, one to six migraines per month, and age at onset < 50 years were included; 327 patients were screened and randomized to receive either zolmitriptan (n = 219) or placebo (n = 108). Patients treated a single moderate or severe migraine headache with 2.5 mg zolmitriptan or placebo and recorded clinical efficacy and adverse events on a diary form. Headache response at 2 hours was 62% for zolmitripan compared with 36% for placebo(p < 0.001); at 4 hours, headche response was 70% with zolmitriptan and 37% with placebo (p < 0.001). Headache recurrence in patients treated with 2.5 mg zolmitriptan was 22% (versus placebo 30%). The headache response at 4 hours, pain-free rate, and response rate of nonheadache symptoms favored zolmitriptan over placebo. No serious adverse events were associated with zolmitriptan treatment. A 2.5-mg dose of zolmitriptan is clinically effective and well tolerated for the acute treatment of migraine.

Defining the Relationship Between Ovarian Hormones and Migraine Headache

Objective.—(1) To determine whether the attack characteristics of migraine differ between different intervals of the menstrual cycle; (2) To ascertain whether the “rate of change,”“magnitude of change,” or “total burden” of urinary hormone metabolites correlates with headaches outcome measures during different intervals of the menstrual cycle.

Medical Oophorectomy With and Without Estrogen Add‐Back Therapy in the Prevention of Migraine Headache

Objectives.—To determine the preventive benefit of “medical oophorectomy” and transdermal estradiol in women with migraine.

Safety and Pharmacokinetics of Dihydroergotamine Mesylate Administered Via a Novel (Tempo™) Inhaler

Objective.— We investigated the pulmonary absorption of dihydroergotamine (DHE) mesylate and compared the safety, pharmacokinetic, and metabolic profile of 4 different doses of orally inhaled DHE delivered by the Tempo™ Inhaler (MAP Pharmaceuticals Inc., Mountain View, CA, USA) with 1.0 mg intravenously (IV) administered DHE in 18 healthy subjects.

Symptoms of premenstrual syndrome and their association with migraine headache

Objectives.—To determine the association between the severity of premenstrual (PMS) symptoms and headache outcome measures during natural menstrual cycles and after medical oophorectomy.

Reduced Adverse Event Profile of Orally Inhaled DHE (MAP0004) vs IV DHE: Potential Mechanism

Background.— MAP0004 is a novel orally inhaled formulation of dihydroergotamine mesylate (DHE) currently in development that has been clinically observed to provide rapid (∼10 minutes) therapeutic levels of DHE but with lower rates of adverse effects (dizziness, nausea, and paresthesia) compared with intravenous (IV) dosing. Receptor‐based mechanistic studies were conducted to determine if differences between IV DHE and inhaled DHE (MAP0004) binding and functional activity were responsible for the improved adverse event profile.

Aerosol delivery of ergotamine tartrate via a breath-synchronized plume-control inhaler in humans

ABSTRACT Objective: To compare systemic delivery of ergotamine tartrate (ET) via a breath-synchronized, plume-control inhaler (BSPCI) (Tempo ET*) with a sublingual ergot preparation and a commercial inhaler. Methods: Study 1 determined plasma ET concentrations in seven healthy subjects after administration of ET by a 2 mg tablet (Lingraine†) and a BSPCI delivering 258 μg of ET. Study 2 determined plasma ET concentrations in 16 healthy subjects after administration via an ET metered dose inhaler (ME) (Medihaler‡) delivering 2052 μg of ET and a BSPCI delivering 129 μg of ET. Gamma scintigraphy with 99mTc validation was used to quantify lung deposition. Results: For both studies, ET Cmax was higher with the BSPCI (study 1: sublingual ET 134 pg/mL at 37 min; BSPCI 3743 pg/mL at 3 min; study 2: metered-dose inhaler 1109 pg/mL at 4 min; BSPCI 1210 pg/mL at 2.5 min). Mean dose normalized AUC was several-fold higher with the BSPCI compared with sublingual ET and ME dosing. Lung deposition of ET with the BSPCI was 33.5, 8.9, 11.4, and 13.2% for whole, central, intermediate, and peripheral lung, respectively, with a 1.5 peripheral : central ratio. Conclusion: Based on these open-label studies, the BSPCI allows rapid delivery of potentially therapeutic plasma concentrations of ET at approximately 1/15th the dose of comparators.

Acute Treatments: Some Blind Alleys

SUMMARY The introduction of sumatriptan, a selective 5-HT1B/1D agonist, for the treatment of migraine sparked a new era of drug research in this field. Many novel targets have since been developed, and tested in the clinic. The promise of these approaches is to deliver an anti-migraine compound with the optimal efficacy and safety profile. In this chapter, blind alleys in anti-migraine development are discussed. The falling soldiers have included the NK-1 antagonists, some second-generation 5-HT1B/1D agonists, CP-122,288, 4991W93, the neurosteroid ganaxolone, selective 5-HT1F (LY334370) and 5-HT1D agonists (PNU-142,633), and the endothelin-1 antagonist bosentan. Some of these promising targets failed to demonstrate clinical efficacy, while others were stopped for preclinical toxicity.