Eletriptan

Abstract: The marine environment has been explored in the search for new bioactive compounds over the last 50 years, becoming a highly important and rich source of potent molecules and drug leads reported to possess a wide scope of activities. Alkaloids constitute one of the largest classes of natural products and are synthesized by terrestrial and marine organisms on all evolutionary levels. Alkaloids are usually present in an organism as a mixture consisting of several major and a few minor compounds of the same biosynthetic origin and differing only in functional groups. This group of compounds has apparently evolved as a defense mechanism against predators and as a result alkaloids are often highly potent and toxic molecules.1 Marine invertebrates have proven to be an outstanding source of active molecules, one of the most promising being indole alkaloids. Although many of these marine alkaloids closely resemble the endogenous amines (serotonin, dopamine or histamine), their potential affinity to various neurological targets and consequential impact on animal behavior is virtually unexplored. Indole alkaloids, their activity, synthesis and potential use in medicine have been already reviewed in several articles.2 In this review we provide information on current and potential pharmaceuticals including small molecule natural indole alkaloids, their biological properties, structure-activity relationship studies, and especially their potential for the treatment of neurological disorders. 1.1. The indole moiety in drugs The indole moiety is present in a number of drugs currently on the market. Most of these belong to triptans which are used mainly in the treatment of migraine headaches (Fig. 1). All members of this group are agonists of migraine associated 5HT1B and 5HT1D serotonin receptors. Sumatriptan (Imitrex) was developed by Glaxo for the treatment of migraines and introduced into the market as the first member of the triptan family.3 Relative to the second generation triptans, sumatriptan has lower oral bioavailability and a shorter half-life. Frovatriptan (FROVA®) was developed by Vernalis for the treatment of menstruation associated headaches. Frovatriptan's affinity for migraine specific serotonin receptors 5HT1B is believed to be the highest among all triptans.4 In addition, frovatriptan binds to 5HT1D and 5HT7 receptor subtypes.5 Zolmitriptan marketed by AstraZeneca is used to treat acute migraine attacks and cluster headaches. GlaxoSmithKline's naratriptan (Amerge) is also used in the treatment of migraines and some of its side effects include dizziness, tiredness, tingling of the hands and feet and dry mouth. All available triptans are well tolerated and effective.6 The highest incidence of central nervous system (CNS) related side effects (dizziness, drowsiness) was reported for zolmitriptan (5 mg), rizatriptan (10 mg) and eletriptan (40 mg, 80 mg).7 The differences in side-effect profiles for triptans are not likely caused by their different affinity towards serotonin receptors or other neurological receptors in the CNS. There is a positive correlation between the lipophilicity coefficient and CNS side effects; these undesired effects are also dose-dependent. Figure 1 Currently available drugs from the triptan group. 1.2. Serotonin receptors – possible targets for neurologically active marine indole alkaloids Given that depression affects approximately 18 million Americans annually,8 it is crucial to develop new effective treatments for this disorder. Intensive studies are being conducted in the area of new targets for antidepressant drugs,9,10 but most antidepressant drugs still target the neurotransmitter systems, mainly serotonin, dopamine and noradrenaline. Serotonin is one of the neurotransmitters present in the central and peripheral nervous system which plays an important role in normal brain function and regulates sleep, mood, appetite, sexual function, memory, anxiety and many others.11 Serotonin exerts its effects through seven families of receptors (5-HT1 – 5-HT7) further divided into several subclasses. Except for 5-HT3 receptor which is a ligand-gated ion channel, the serotonin receptors belong to the G-protein coupled receptor family. Due to a lack of selective ligands, there is still little known about several 5-HT receptor subclasses.12 Marine monoindole alkaloids, sharing structure similarities with serotonin, are certain to become useful tools to facilitate the understanding of serotonin receptor function and generate new drug leads for the treatment of depression, anxiety, migraines and other 5HT receptor related disorders.

Abstract: The triptans, selective serotonin 5-HT1B/1D agonists, are very effective acute migraine drugs. Soon, seven different triptans will be clinically available at 13 different oral doses, making evidence-based selection guidelines necessary. Triptan trials have similar designs, facilitating meta-analysis. We wished to provide an evidence-based foundation for using triptans in clinical practice, and to review the methodological issues surrounding triptan trials. We asked pharmaceutical companies and the principal investigators of company-independent trials for the 'raw patient data' of all double-blind, randomized, controlled, clinical trials with oral triptans in migraine. All data were cross-checked with published or presented data. We calculated summary estimates across studies for important efficacy and tolerability parameters, and compared these with those from direct, head-to-head, comparator trials. Out of 76 eligible clinical trials, 53 (12 not yet published) involving 24089 patients met the criteria for inclusion. Mean results (and 95% confidence intervals) for sumatriptan 100 mg, the first available and most widely prescribed oral triptan, are 59% (57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free (pain free by 2 h and no headache recurrence or use of rescue medication 2-24 h post-dose), and 67% (63-70) for consistency (response in at least two out of three treated attacks); placebo-subtracted proportions for patients with at least one adverse event (AE) are 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7). Compared with these data: rizatriptan 10 mg shows better efficacy and consistency, and similar tolerability; eletriptan 80 mg shows better efficacy, similar consistency, but lower tolerability; almotriptan 12.5 mg shows similar efficacy at 2 h but better sustained pain-free response, consistency, and tolerability; sumatriptan 25 mg, naratriptan 2.5 mg and eletriptan 20 mg show lower efficacy and better tolerability; zolmitriptan 2.5 mg and 5 mg, eletriptan 40 mg, and rizatriptan 5 mg show very similar results. The results of the 22 trials that directly compared triptans show the same overall pattern. We received no data on frovatriptan, but publicly available data suggest substantially lower efficacy. The major methodological issues involve the choice of the primary endpoint, consistency over multiple attacks, how to evaluate headache recurrence, use of placebo-subtracted proportions to control for across-study differences, and the difference between tolerability and safety. In addition, there are a number of methodological issues specific for direct comparator trials, including encapsulation and patient selection. At marketed doses, all oral triptans are effective and well tolerated. Differences among them are in general relatively small, but clinically relevant for individual patients. Rizatriptan 10 mg, eletriptan 80 mg and almotriptan 12.5 mg provide the highest likelihood of consistent success. Sumatriptan features the longest clinical experience and the widest range of formulations. All triptans are contra-indicated in the presence of cardiovascular disease.

Abstract: The study aims to provide an updated assessment of the evidence for individual pharmacological therapies for acute migraine treatment. Pharmacological therapy is frequently required for acutely treating migraine attacks. The American Academy of Neurology Guidelines published in 2000 summarized the available evidence relating to the efficacy of acute migraine medications. This review, conducted by the members of the Guidelines Section of the American Headache Society, is an updated assessment of evidence for the migraine acute medications. A standardized literature search was performed to identify articles related to acute migraine treatment that were published between 1998 and 2013. The American Academy of Neurology Guidelines Development procedures were followed. Two authors reviewed each abstract resulting from the search and determined whether the full manuscript qualified for review. Two reviewers studied each qualifying full manuscript for its level of evidence. Level A evidence requires at least 2 Class I studies, and Level B evidence requires 1 Class I or 2 Class II studies. The specific medications - triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan [oral, nasal spray, injectable, transcutaneous patch], zolmitriptan [oral and nasal spray]) and dihydroergotamine (nasal spray, inhaler) are effective (Level A). Ergotamine and other forms of dihydroergotamine are probably effective (Level B). Effective nonspecific medications include acetaminophen, nonsteroidal anti-inflammatory drugs (aspirin, diclofenac, ibuprofen, and naproxen), opioids (butorphanol nasal spray), sumatriptan/naproxen, and the combination of acetaminophen/aspirin/caffeine (Level A). Ketoprofen, intravenous and intramuscular ketorolac, flurbiprofen, intravenous magnesium (in migraine with aura), and the combination of isometheptene compounds, codeine/acetaminophen and tramadol/acetaminophen are probably effective (Level B). The antiemetics prochlorperazine, droperidol, chlorpromazine, and metoclopramide are probably effective (Level B). There is inadequate evidence for butalbital and butalbital combinations, phenazone, intravenous tramadol, methadone, butorphanol or meperidine injections, intranasal lidocaine, and corticosteroids, including dexamethasone (Level C). Octreotide is probably not effective (Level B). There is inadequate evidence to refute the efficacy of ketorolac nasal spray, intravenous acetaminophen, chlorpromazine injection, and intravenous granisetron (Level C). There are many acute migraine treatments for which evidence supports efficacy. Clinicians must consider medication efficacy, potential side effects, and potential medication-related adverse events when prescribing acute medications for migraine. Although opioids, such as butorphanol, codeine/acetaminophen, and tramadol/acetaminophen, are probably effective, they are not recommended for regular use.