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Migraine causes more years of life lived with disability than almost any other condition in the world and can significantly impact the lives of individuals with migraine, their families, and society. The use of medication for the prevention of migraine is an integral component to reducing disability caused by migraine. There are many different drug classes that have been investigated and shown efficacy in migraine prophylaxis. This article examines several of the classes of medications that are used for migraine preventive treatment, specifically, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, serotonin antagonists, alpha-adrenergic agonists, and N-methyl-D-aspartic acid receptor antagonists.
Learn More >Migraine is a chronic paroxysmal neurological disorder characterized by multiphase attacks of head pain and a myriad of neurological symptoms. Chronic migraine causes a great personal and societal burden. Many patients are poorly responsive to, or non-compliant with, conventional migraine preventive therapies. For this reason, physicians are constantly looking for effective migraine prevention strategies. The recent introduction of an innovative pharmacological class useful for migraine prevention, namely monoclonal antibodies towards calcitonin gene-related peptide or its receptors, opens a new, immense therapeutic scenario. In this commentary, the development and efficacy of this novel class of preventive anti-migraine therapy have been discussed and compared with the conventional therapies of migraine prevention.
Learn More >The presence and growth of endometrial tissue outside the uterine cavity in endometriosis patients is primarily driven by hormone-dependent and inflammatory processes – the latter being frequently associated with severe, acute and chronic pelvic pain. The EP4 subtype of prostaglandin E2 (PGE2) receptors (EP4-R) is a particularly promising anti-inflammatory and anti-nociceptive target as both this receptor subtype and the pathways forming PGE2 are highly expressed in endometriotic lesions. High-throughput screening resulted in the identification of benzimidazole derivatives as novel hEP4-R antagonists. Careful SAR investigation guided by rational design identified a methyl substitution adjacent to the carboxylic acid as an appropriate means to accomplish favorable pharmacokinetic properties by reduction of glucuronidation. Further optimization led to the identification of benzimidazolecarboxylic acid BAY 1316957, a highly potent, specific and selective hEP4-R antagonist with excellent DMPK properties. Notably, treatment with BAY 1316957 can be expected to lead to prominent and rapid pain relief and significant improvement of the patients` quality of life.
Learn More >Inhibitors that target the glycine transporter 2, GlyT2, show promise as analgesics but may be limited by their toxicity through complete or irreversible binding. Acyl-glycine inhibitors, however, are selective for GlyT2 and have been shown to provide analgesia in animal models of pain with minimal side effects, but are comparatively weak GlyT2 inhibitors. Here, we modify the simple acyl-glycine by synthesising lipid analogues with a range of amino acid head groups in both L- and D- configurations, to produce nanomolar affinity, selective GlyT2 inhibitors. The potent inhibitor oleoyl- D-lysine (33) is also resistant to degradation in both human and rat plasma and liver microsomes, and is rapidly absorbed following an intraperitoneal injection to rats and readily crosses the blood brain barrier. We demonstrate that 33 provides greater analgesia at lower doses, and does not possess the severe side effects of the very slowly reversible GlyT2 inhibitor, ORG25543 (2).
Learn More >The purpose of the following review is to summarize the most recent understanding of migraine pathophysiology, as well as of basic and clinical science pharmacologic literature regarding the development of calcitonin gene receptor peptide (CGRP) antagonists as a novel therapeutic modality for the treatment of migraine headaches. A review is provided of erenumab, the first of its class FDA approved CGRP antagonist.
Learn More >Calcitonin gene-related peptide (CGRP) is a neuropeptide with a pivotal role in the pathophysiology of migraine. Blockade of CGRP is a new therapeutic target for patients with migraine. CGRP and its receptors are distributed not only in the central and peripheral nervous system but also in the cardiovascular system, both in blood vessels and in the heart. We reviewed the current evidence on the role of CGRP in the cardiovascular system in order to understand the possible short- and long-term effect of CGRP blockade with monoclonal antibodies in migraineurs.In physiological conditions, CGRP has important vasodilating effects and is thought to protect organs from ischemia. Despite the aforementioned cardiovascular implication, preventive treatment with CGRP antibodies has shown no relevant cardiovascular side effects. Results from long-term trials and from real life are now needed.
Learn More >Peripheral inflammation produces a long-lasting latent sensitization of spinal nociceptive neurons that is masked by tonic inhibitory controls. We explored mechanisms of latent sensitization with an established four-step approach: 1) induction of inflammation; 2) allow pain hypersensitivity to resolve; 3) interrogate latent sensitization with a channel blocker, mutant mouse, or receptor antagonist; 4) disrupt compensatory inhibition with a receptor antagonist so as to reinstate pain hypersensitivity. We found that the neuropeptide Y Y1 receptor antagonist BIBO3304 reinstated pain hypersensitivity, indicative of an unmasking of latent sensitization. BIBO3304-evoked reinstatement was not observed in AC1 knockout mice and was prevented with intrathecal co-administration of a pharmacological blocker to either: the N-methyl-D-aspartate receptor (NMDAR); adenylyl cyclase type 1 (AC1); protein kinase A (PKA); transient receptor potential cation channel A1 (TRPA1); channel V1 (TRPV1); or exchange protein activated by cAMP (Epac1 or Epac2). A PKA activator evoked both pain reinstatement and touch-evoked pERK expression in dorsal horn; the former was prevented with intrathecal co-administration of a TRPA1 or TRPV1 blocker. An Epac activator also evoked pain reinstatement and pERK expression. We conclude that PKA and Epac are sufficient to maintain long-lasting latent sensitization of dorsal horn neurons that is kept in remission by the NPY-Y1 receptor system. Furthermore, we have identified and characterized two novel molecular signaling pathways in the dorsal horn that drive latent sensitization in the setting of chronic inflammatory pain: NMDAR→AC1→PKA→TRPA1/V1 and NMDAR→AC1→Epac1/2. New treatments for chronic inflammatory pain might either increase endogenous NPY analgesia or inhibit AC1, PKA or Epac.
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