Other Central Nervous System Diseases and Disorders
Divya Vohora in The Third Histamine Receptor, 2008
Current drug treatment for migraine headaches includes nonsteroidal antiinflammatory drugs (NSAIDs) such as ibuprofen, the ergot dihydroergotamine (DHE) and the 5-HT1D agonist, sumatriptan. NSAIDs inhibit prostaglandin synthesis and attenuate neurogenic inflammation in the trigeminovascular system. However, NSAIDs are ineffective for many migraine patients and are associated with the risk of dyspepsia and gastrointestinal hemorrhage. DHE is associated with nausea, vomiting, abdominal pain, diarrhea, and cerebral vasoconstriction. Side effects associated with sumatriptan are coronary vasospasm and chest heaviness (reviewed in Ref. 40). Furthermore, both DHE and sumatriptan are significantly less active in humans after oral administration. Newer 5-HT1D agonists are available (e.g., Eletriptan and Almotriptan). These drugs are orally active and are more potent than sumatriptan; however, the pharmacology of these second-generation sumatriptanlike drugs does not exclude potential cardiovascular effects. In light of these therapeutic limitations, an antimigraine drug that demonstrates oral efficacy without the cardiovascular liability of current therapies is still required.
Medications
R. Andrew Chambers in The 2 × 4 Model, 2017
Topiramate is an anticonvulsant/antimigraine drug that in parallel to bupropion, may also represent a bonafide, PDDA, given the reasonably strong evidence that it has efficacy as both a mood stabilizer and an anti-addiction medication. However, the drug still lacks FDA indications for psychiatric or addiction indications. The mechanism of action of the drug is quite complex and incompletely understood but seems to modulate both glutamatergic and GABAergic neurotransmission with activities involving calcium channels (transmitter release) and sodium channels (action potential propagation). The anti-addiction properties of the drug may extend to alcohol and psychostimulant addiction, and possibly behavioral addictions such as compulsive eating, where it does have FDA approved efficacy, as a component of weight loss medication.
Research Planning and Development Perspectives
Gary M. Matoren in The Clinical Research Process in the Pharmaceutical Industry, 2020
At the second critical stage of the R&D cycle, the movement of compounds into man, we need skilled and observant clinical pharmacologists. At this stage and also as compounds move into broader Phase III trials the phenomenon of "clinical serendipity," which is the accidental or unexpected discovery of various clinical effects, can be an important factor in the generation of new therapies. Many historical examples of such drug usage may be noted. Recently, however, we have seen propranolol broaden its approved use from an antiarrhythmic in 1967 to an antianginal in 1973, to an antihypertensive agent in 1976, and to an antimigraine agent in 1979. It is now also being used to prevent second heart attacks. Since such utility, sometimes discovered through unexpected clinical observations, has been the method by which an impressive array of new drugs and drug uses have been generated in the past, one can conclude that drug "discovery" is not restricted to the early phases of the R&D process but extends to all stages including postmarketing. Figure 2 illustrates the role of clinical observation and investigation in the evolution of new drugs [2]. Observations in the clinic may generate impetus for specific clinical programs aimed at providing new therpeutic applications. Clinical observations and studies may also stimulate fundamental knowledge about the behavior of drug substances and related pharmacological phenomena which results in new or revised hypotheses that trigger preclinical research or entirely new clinical investigations. In these ways the astute and observing clinical pharmacologist can be a prime factor in the discovery of utility in novel drug moieties and in designing new drug substances.
Pharmacological strategies to treat attacks of episodic migraine in adults
Published in Expert Opinion on Pharmacotherapy, 2021
The Atlas of Headache Disorders, prepared by WHO in collaboration with Lifting The Burden: the Global Campaign against Headache, presents data collected in a questionnaire from a survey in 101 countries [6]. ‘For treatment of acute episodic migraine, other NSAID s (than aspirin) are, as a class, the most widely preferred drugs (86% of countries that responded). Paracetamol (69%) and aspirin (52%) follow.’ [6] ‘Globally, the equally-preferred specific anti-migraine drugs are ergotamine (34% of countries that responded) and sumatriptan (33%).’ [6] Ergotamine was preferred in all regions but Europe and the Western Pacific, where sumatriptan leads (with four-fold preference in Europe) [6]. Even in region in which sumatriptan is the preferred specific antimigraine drug triptans are only used by a minority of patients with episodic migraine. In the United States, it is 18% of these patients who actually use a triptan [7], and in 10 European countries, 3% to 11% of migraine patients actually use a triptan (an outlier is Spain with 22% of patients using a triptan) [8].
A critical review of the neurovascular nature of migraine and the main mechanisms of action of prophylactic antimigraine medications
Published in Expert Review of Neurotherapeutics, 2021
Bruno A. Marichal-Cancino, Abimael González-Hernández, Raquel Guerrero-Alba, Roberto Medina-Santillán, Carlos M. Villalón
Other cranial neurovascular mechanisms that may be relevant in migraine prophylaxis are those related with pharmacological actions in the CNS. Indeed, central mechanisms may also inhibit the cranial vasodilatation produced by endogenous (trigeminal) release of CGRP. For example, in a migraine model in anaesthetized dogs, the external carotid (cranial) vasodilatation produced by intracarotid artery infusions of capsaicin is dose-dependently inhibited by intrathecal (spinal C1-C3) administration of: (i) the selective α2-adrenoceptor agonist B-HT 933, with activation of spinal α2A/2C-adrenoceptors [132]; (ii) the antimigraine agent sumatriptan, with activation of spinal 5-HT1B receptors [133]; and (iii) the antimigraine agent dihydroergotamine, with activation of spinal 5-HT1B and α2A/2C-adrenoceptors [127]. Likewise, this cranial vasodilator response to capsaicin is also inhibited by oral chronic treatment with the selective serotonin reuptake inhibitor fluoxetine [134]. Taken together, these findings suggest that cranial neurovascular mechanisms that may be relevant in migraine prophylaxis are exerted at the peripheral and central levels. Depending on the specific prophylactic agent, each these four mechanisms may be induced to a varying degree (see below).
Almotriptan: a review of 20 years’ clinical experience
Published in Expert Review of Neurotherapeutics, 2019
The genetic determinants of drug response in migraine are complex; however, several polymorphisms associated with antimigraine drug metabolizing enzymes have been identified [94]. It is possible that in the future, pharmacogenetic considerations could help guide the selection of triptans for a number of individual patients. The variety of pathways involved in the metabolism of ALT may make it less susceptible to genomic variations between patients [95].
Related Knowledge Centers
- Ergot
- Ergotamine
- Sumatriptan
- Triptan
- Zolmitriptan
- Trigeminal Nerve
- Headache
- Migraine
- NONsteroidal Anti-Inflammatory Drug
- Vasoconstriction