Concomitant use of calcitonin gene-related peptide (CGRP) antagonists with azole antifungals in patients with hematological malignancies.

OBJECTIVE: Small molecule calcitonin gene-related peptide (CGRP) antagonists such as rimegepant, ubrogepant, and atogepant have been approved for migraine treatment and/or prevention. These molecules are metabolized by cytochrome P-450 3A4 (CYP3A4) enzymes in vivo, hence they are contraindicated or recommended to be avoided in combination with strong/moderate CYP3A4 inhibitors, namely posaconazole (strong) and isavuconazonium (moderate). However, no literature has been published on the impact this interaction has on patient safety and tolerability. In this case series, we report five cases in which CGRP antagonists and azole antifungal therapy were given concurrently, to provide real-world outcomes of this interaction. DATA SOURCES: Electronic medical records at our hospital system were reviewed between January 2021 and December 2023 to find patients who met the criteria of hematological malignancy, taking CGRP-antagonist and azole antifungal therapy. Records were then further investigated to find cases where CGRP antagonists and azole antifungals were used concomitantly. DATA SUMMARY: Concurrent use of CGRP antagonists and azole antifungal therapy was feasible for patients with migraines and hematological malignancies. None of the patients experienced any grade 3 or higher non-hematological toxicity from the proposed over-exposure to CGRP antagonist. The combination was well tolerated without any need for therapy discontinuation or dose modifications. CONCLUSIONS: It is recommended to follow the manufacturers' guidance on drug interactions, however, in the setting where there are no other options, concomitant use of CGRP antagonists with azole antifungals is possible with monitoring and observation for adverse effects.

Migraine inhibitor olcegepant reduces weight loss and IL-6 release in SARS-CoV-2-infected older mice with neurological signs.

COVID-19 can cause neurological symptoms such as fever, dizziness, and nausea. However, such neurological symptoms of SARS-CoV-2 infection have been hardly assessed in mouse models. In this study, we infected two commonly used wild-type mouse lines (C57BL/6J and 129/SvEv) and a 129S calcitonin gene-related peptide (αCGRP) null-line with mouse-adapted SARS-CoV-2 and demonstrated neurological signs including fever, dizziness, and nausea. We then evaluated whether a CGRP receptor antagonist, olcegepant, a "gepant" antagonist used in migraine treatment, could mitigate acute neuroinflammatory and neurological signs of SARS-COV-2 infection. First, we determined whether CGRP receptor antagonism provided protection from permanent weight loss in older (>18 m) C57BL/6J and 129/SvEv mice. We also observed acute fever, dizziness, and nausea in all older mice, regardless of treatment. In both wild-type mouse lines, CGRP antagonism reduced acute interleukin 6 (IL-6) levels with virtually no IL-6 release in mice lacking αCGRP. These findings suggest that migraine inhibitors such as those blocking CGRP receptor signaling protect against acute IL-6 release and subsequent inflammatory events after SARS-CoV-2 infection, which may have repercussions for related pandemic or endemic coronavirus outbreaks.IMPORTANCECoronavirus disease (COVID-19) can cause neurological symptoms such as fever, headache, dizziness, and nausea. However, such neurological symptoms of severe acute respiratory syndrome CoV-2 (SARS-CoV-2) infection have been hardly assessed in mouse models. In this study, we first infected two commonly used wild-type mouse lines (C57BL/6J and 129S) with mouse-adapted SARS-CoV-2 and demonstrated neurological symptoms including fever and nausea. Furthermore, we showed that the migraine treatment drug olcegepant could reduce long-term weight loss and IL-6 release associated with SARS-CoV-2 infection. These findings suggest that a migraine blocker can be protective for at least some acute SARS-CoV-2 infection signs and raise the possibility that it may also impact long-term outcomes.

Pharmacologic characterization of atogepant: A potent and selective calcitonin gene-related peptide receptor antagonist.

BACKGROUND: The trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) is identified as an essential element in migraine pathogenesis. METHODS: In vitro and in vivo studies evaluated pharmacologic properties of the CGRP receptor antagonist atogepant. Radioligand binding using 125I-CGRP and cyclic adenosine monophosphate (cAMP) accumulation assays were conducted in human embryonic kidney 293 cells to assess affinity, functional potency and selectivity. Atogepant in vivo potency was assessed in the rat nitroglycerine model of facial allodynia and primate capsaicin-induced dermal vasodilation (CIDV) pharmacodynamic model. Cerebrospinal fluid/brain penetration and behavioral effects of chronic dosing and upon withdrawal were evaluated in rats. RESULTS: Atogepant exhibited high human CGRP receptor-binding affinity and potently inhibited human α-CGRP-stimulated cAMP responses. Atogepant exhibited significant affinity for the amylin1 receptor but lacked appreciable affinities for adrenomedullin, calcitonin and other known neurotransmitter receptor targets. Atogepant dose-dependently inhibited facial allodynia in the rat nitroglycerine model and produced significant CIDV inhibition in primates. Brain penetration and behavioral/physical signs during chronic dosing and abrupt withdrawal were minimal in rats. CONCLUSIONS: Atogepant is a competitive antagonist with high affinity, potency and selectivity for the human CGRP receptor. Atogepant demonstrated a potent, concentration-dependent exposure/efficacy relationship between atogepant plasma concentrations and inhibition of CGRP-dependent effects.

Antinociceptive effect of the calcitonin gene-related peptide receptor antagonist BIBN4096BS in mice with bacterial cystitis.

Patients with urinary tract infections (UTIs) suffer from urinary frequency, urgency, dysuria, and suprapubic pain, but the mechanisms by which bladder afferents sense the presence of uropathogens and encode this information is not well understood. Calcitonin gene-related peptide (CGRP) is a 37-mer neuropeptide found in a subset of bladder afferents that terminate primarily in the lamina propria. Here, we report that the CGRP receptor antagonist BIBN4096BS lessens lower urinary tract symptoms and prevents the development of pelvic allodynia in mice inoculated with uropathogenic Escherichia coli (UPEC) without altering urine bacterial loads or the host immune response to the infection. These findings indicate that CGRP facilitates the processing of noxious/inflammatory stimuli during UPEC infection. Using fluorescent in situ hybridization, we identified a population of suburothelial fibroblasts in the lamina propria, a region where afferent fibers containing CGRP terminate, that expresses the canonical CGRP receptor components Calcrl and Ramp1. We propose that these fibroblasts, in conjunction with CGRP+ afferents, form a circuit that senses substances released during the infection and transmit this noxious information to the central nervous system.NEW & NOTEWORTHY Afferent C fibers release neuropeptides including calcitonin gene-related peptide (CGRP). Here, we show that the specific CGRP receptor antagonist, BIBN409BS, ameliorates lower urinary tract symptoms and pelvic allodynia in mice inoculated with uropathogenic E. coli. Using fluorescent in situ hybridization, we identified a population of suburothelial fibroblasts in the lamina propria that expresses the canonical CGRP receptor. Our findings indicate that CGRP contributes to the transmission of nociceptive information arising from the bladder.

Gestational exposure to erenumab-The outcome of three pregnancies.

Erenumab is a monoclonal antibody (mAb) approved for the preventive treatment of migraine. While preclinical studies on calcitonin gene-related peptide mAbs did not identify any reproductive toxicity, pregnant and breastfeeding women were excluded from the pivotal human studies, and therefore the safety of calcitonin gene-related peptide medications in this population must be studied. So far, postmarketing data of accidental exposures have not brought to light any specific toxicities. Three women treated with erenumab in our series conceived while exposed to the drug. All had previous successful pregnancies, were on erenumab for more than 6 months, and had ≥80% reduction in headache frequency. The one who stopped erenumab only 1 month before conceiving had a spontaneous abortion during the first trimester due to a gestational trophoblastic neoplasia and has since conceived with an uneventful gestation. The other two women stopped treatment during the first trimester, and both pregnancies went to term with no complications. All babies have shown normal development. No plausible explanation relates the mechanism of action of erenumab and the serious complication that occurred in one patient. Continuous follow-up and reporting of all exposures are encouraged to gather safety data on pregnant and nursing women and on the development of the newborns. So far, immediately stopping the drug is advised and may contribute to decreasing the potential risks.

A c-Fos activation map in nitroglycerin/levcromakalim-induced models of migraine.

BACKGROUND: Chronic migraine is a common and highly disabling disorder. Functional MRI has indicated that abnormal brain region activation is linked with chronic migraine. Drugs targeting the calcitonin gene-related peptide (CGRP) or its receptor have been reported to be efficient for treating chronic migraine. The CGRP signaling was also shared in two types of chronic migraine models (CMMs). However, it remains unclear whether the activation of specific brain regions could contribute to persistent behavioral sensitization, and CGRP receptor antagonists relieve migraine-like pain in CMMs by altering specific brain region activation. Therefore, it's of great interest to investigate brain activation pattern and the effect of olcegepant (a CGRP receptor-specific antagonist) treatment on alleviating hyperalgesia by altering brain activation in two CMMs, and provide a reference for future research on neural circuits. METHODS: Repeated administration of nitroglycerin (NTG) or levcromakalim (LEV) was conducted to stimulate human migraine-like pain and establish two types of CMMs in mice. Mechanical hypersensitivity was evaluated by using the von Frey filament test. Then, we evaluated the activation of different brain regions with c-Fos and NeuN staining. Olcegepant was administered to explore its effect on mechanical hyperalgesia and brain region activation. RESULTS: In two CMMs, acute and basal mechanical hyperalgesia was observed, and olcegepant alleviated mechanical hyperalgesia. In the NTG-induced CMM, the medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and the caudal part of the spinal trigeminal nucleus (Sp5c) showed a significant increase of c-Fos expression in the NTG group (p < 0.05), while pre-treatment with olcegepant reduced c-Fos expression compared with NTG group (p < 0.05). No significant difference of c-Fos expression was found in the paraventricular thalamic nucleus (PVT) and ventrolateral periaqueductal gray (vlPAG) between the vehicle control and NTG group (p > 0.05). In the LEV-induced CMM, mPFC, PVT, and Sp5c showed a significant increase of c-Fos expression between vehicle control and LEV group, and olcegepant reduced c-Fos expression (p < 0.05). No significant difference in c-Fos expression was found in vlPAG and ACC (p > 0.05). CONCLUSIONS: Our study demonstrated the activation of mPFC and Sp5c in two CMMs. Olcegepant may alleviate hyperalgesia of the hind paw and periorbital area by attenuating brain activation in CMMs.

Recently approved and emerging drug options for migraine prophylaxis.

INTRODUCTION: Migraine occupies the first position regarding the disability caused in female working population (15-49 years). Research in the field of prophylaxis in this pathology has made enormous strides in recent years. AREAS COVERED: In this narrative review, we retrace the most important scientific evidence regarding recently approved and emerging drugs for the prophylactic treatment of migraine. The purpose of this article is in fact to evaluate currently approved or emerging pharmacological agents for migraine prophylaxis. This review is based on the literature published in the peer review journal obtained through PubMed, Cochrane library, Clinicaltrials.gov, and US FDA. EXPERT OPINION: Monoclonal antibodies (mAbs) that target the calcitonin gene-related peptide signaling pathway (CGRP) have marked an innovation in prophylactic migraine therapy. The combination of Onabotulinumtoxin-A (OBTA) and mAbs appears to be an effective, but costly, therapeutic option for resistant cases. New classes of molecules like gepants and ditans seem to give exceptional results. In addition, new prophylactic drugs are emerging with several targets: the pituitary adenylate cyclase-activating polypeptide (PACAP), ion channels, several receptors coupled to G proteins, orexin, and glutamate. All these therapies will implement and improve migraine management, as well as personalized medicine for each patient.

Comparison of efficacy and safety of erenumab between over and under 65-year-old refractory migraine patients: a pivotal study.

Previous studies reported a positive effect of anti-CGRP monoclonal antibodies (mAbs) in migraine prevention, either in over (O65) and under (U65) 65-year-aged patients. The aim of our study was to evaluate and compare real-life efficacy and safety of mAbs between young and elder migraine patients. Fifteen O65 and fifteen U65 patients, treated with monthly mAbs for 6 months, were enrolled and matched for sex, monthly headache days (MHD), and monthly migraine days (MMD) at baseline. Between-group differences in MHD and MMD, number of pills and days of acute medication intake, HIT-6, MIDAS, Numeric Rating Scale (NRS), and Allodynia Symptom Checklist (ASC-12) were assessed after 3 (M3) and 6 (M6) months of treatment. Adverse events (AEs) were also investigated. In each group, thirteen patients (87%) were women and nine (60%) had chronic migraine. Baseline mean MHD and MMD of both groups were 20 (SD 9.6). Mean age was 70 (65-76) and 45 (19-55) in the O65 and U65 group, respectively. Before starting mAbs, patients have tried an average of 4 preventives in both groups. After 3 and 6 months of treatment, both groups had a reduction of all clinical features under examination, without statistically significant differences between groups. A similar proportion of patients in each group complained of AEs (M3 and M6, p = 1.0). Our real-life data showed that treatment with mAbs is as effective and safe in O65 as U65 migraine patients. Further studies are needed to confirm these findings.

Migraine monoclonal antibodies against CGRP change brain activity depending on ligand or receptor target - an fMRI study.

Background: Monoclonal antibodies (mAbs) against calcitonin gene-related peptides (CGRP) are novel treatments for migraine prevention. Based on a previous functional imaging study which investigated the CGRP receptor mAb (erenumab), we hypothesized that (i) the CGRP ligand mAb galcanezumab would alter central trigeminal pain processing; (ii) responders to galcanezumab treatment would show specific hypothalamic modulation in contrast to non-responders; and (iii) the ligand and the receptor antibody differ in brain responses. Methods: Using an established trigeminal nociceptive functional magnetic imaging paradigm, 26 migraine patients were subsequently scanned twice: before and 2-3 weeks after administration of galcanezumab. Results: We found that galcanezumab decreases hypothalamic activation in all patients and that the reduction was stronger in responders than in non-responders. Contrasting erenumab and galcanezumab showed that both antibodies activate a distinct network. We also found that pre-treatment activity of the spinal trigeminal nucleus (STN) and coupling between the STN and the hypothalamus covariates with the response to galcanezumab. Conclusions: These data suggest that despite relative impermeability of the blood-brain barrier for CGRP mAb, mAb treatment induces certain and highly specific brain effects which may be part of the mechanism of their efficacy in migraine treatment. Funding: This work was supported by the German Ministry of Education and Research (BMBF) of ERA-Net Neuron under the project code BIOMIGA (01EW2002 to AM) and by the German Research Foundation (SFB936-178316478-A5 to AM). The funding sources did not influence study conduction in any way. Clinical trial number: The basic science study was preregistered in the Open Science Framework (https://osf.io/m2rc6).

Brazilian descriptive study of 104 consecutive real-world migraine patients treated with monoclonal antibodies.

BACKGROUND: Migraine is a highly disabling and prevalent neurological disorder. A peptide, calcitonin gene-related peptide, was identified as involved in migraine pathophysiology and monoclonal anti-CGRP antibodies have been developed. AIM: To describe the clinical characteristics and therapeutic response of migraine patients treated with monoclonal antibodies. METHOD: An observational, prospective, uncontrolled, and descriptive study was carried out with a sample of 112 consecutive patients with episodic or chronic migraine treated with monoclonal antibodies. Eight patients did not return for the following medical consultation. They were excluded from the study. RESULTS: A total of 104 patients were described. There was a predominance of episodic migraine. Before treatment, the average frequency of headache was 15.3 ± 8.5 days per month, during the previous three months. Monoclonal antibodies were prescribed at the following frequency: erenumab (49%), galcanezumab (45.2%), and fremanezumab (5.8%). After the third month, the reduction in headache attacks was greater than 50% in 57.7% of patients. Adverse events were referred by 18.3% of patients, in this order of frequency: constipation (7.7%), insomnia (2.9%), vertigo (1.9%), erythema at the injection site (1.9%), arthralgia (1%), nasopharyngitis (1%), facial and hand edema (1%), irritation at the injection site (1%), and paresthesia at the injection site (1%). CONCLUSIONS: This described analysis of migraine patients who used monoclonal antibodies presented one of the first Brazilian experiences with real-world patients. Our results may enlighten clinicians on the outcomes and ways of prescribing anti-CGRP antibodies.

Treatment of migraine with monoclonal antibodies.

INTRODUCTION: In the few last years, a new family of drugs, anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs), has been developed for migraine therapy. Anti-CGRP mAbs are highly effective, but the current limited experience with their use and their high-cost warrant establishing certain rules of use. AREAS COVERED: The present review provides an overview of the management of migraine patients, especially those who are undergoing treatment with anti-CGRP mAbs. EXPERT OPINION: Thanks to new research focused on the pathophysiology of migraine, and the discovery that CGRP plays a key role in its etiopathogenesis, new drugs targeting CGRP have been developed. These drugs have led to a paradigm shift, anticipating new and stimulating possibilities in migraine treatment. While physicians and patients are full of expectation about the advantages of this new family of drugs, there are still obstacles to overcome in order to make the best use of them. It is essential to form multidisciplinary teams that can identify patients who will benefit from these therapies, conducting cost-effective treatments. The follow-up of these therapies in the coming years is paramount due to the lack of experience in the management of these drugs and the peculiarity of disease evolution in migraine patients.

Calcitonin Gene-Related Peptide (CGRP)-Targeted Monoclonal Antibodies and Antagonists in Migraine: Current Evidence and Rationale.

Calcitonin gene-related peptide (CGRP), a 37 amino-acid neuropeptide found mostly in peptidergic sensory C-fibers, has been suggested to be implicated in the pathogenesis of migraine, which is one of the most common neurological disorders seen in medical practice, affecting almost 16% of the US population. While previously thought to be a vascular condition, migraine attacks are the result of neurogenic inflammation and peripheral/central sensitization through dysfunctional activation of the trigeminovascular system. To date, two classes of therapeutic agents have been developed to interrupt the function of CGRP: CGRP-targeted monoclonal antibodies (mAbs) and small-molecule antagonists (gepants). There are currently four CGRP-targeted mAbs and three gepants that are US Food and Drug Administration (FDA) approved for the treatment of migraine. Multiple phase II and III studies have established the efficacies and tolerability of these treatments. Previously, we reviewed the fundamental role of CGRP in migraine pathogenesis. Here, we discuss in depth the clinical evidence (randomized controlled trials and real-world studies), safety, and tolerability of CGRP-targeted mAbs and gepants for treating migraine.

The Arrival of Anti-CGRP Monoclonal Antibodies in Migraine.

Remarkable advancements have been made in the field of migraine pathophysiology and pharmacotherapy over the past decade. Understanding the molecular mechanism of calcitonin gene-related peptide (CGRP) has led to the discovery of a novel class of drugs, CGRP functional blocking monoclonal antibodies (mAbs), for migraine prevention. CGRP is a neuropeptide inherently involved in migraine physiology where its receptors are found dispersed throughout the central and peripheral nervous systems. CGRP-targeted mAbs are effective in the preventive treatment of both chronic and episodic migraine. The advantages of mAbs over oral migraine preventives are numerous. Favorable attributes of the mAbs include high affinity and selectivity for CGRP molecular targets, long-circulating plasma half-lives, and limited risk for nonspecific hepatic and renal toxicity. This pharmacological profile leads to fewer off-target (side) effects and drug-drug interactions rendering mAbs an attractive alternative to traditional small molecule therapies, especially for the preventive treatment of migraine. MAbs display minimal drug interaction thus are excellent for patients prescribed with multiple medications. However, the long-term safety of CGRP blockade is incompletely known, and CGRP mAbs use should be avoided during pregnancy. CGRP mAbs represent a radical shift in preventing chronic and episodic migraine.

Extreme ecchymoses in a migraine patient using concomitant treatment with calcitonin gene-related peptide receptor antibodies and fish oil supplements: a case report.

BACKGROUND: Erenumab, a monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor, is registered for migraine prevention. Compared to other conventional migraine prevention medicines (i.e. topiramate, betablockers and amitriptyline) erenumab has better tolerability. Impaired hemostasis has not been reported previously. Here, we report the first case of an increased tendency to bruise in a migraine patient treated with erenumab. CASE PRESENTATION: A 41-year old female migraine patient was treated with erenumab for 12 months, which led to a significant reduction of headache and migraine days. Three months after treatment start, she experienced increased tendency to bruise leading to extreme ecchymosis after 4 months treatment. Platelet counts and aggregation, thromboelastography, activated partial thromboplastin time (APTT) and international normalized ratio (INR) were all normal. Thorough interview revealed intake of fish oil supplements for many years prior to treatment. The increased tendency to bruise subsided after discontinuation of fish oil supplements. CONCLUSION: The combination of fish oil supplements and erenumab may cause increased tendency to bruise. Erenumab has no effect on the platelets per se but may cause impaired wound healing by suppression of CGRP. Thus, small and unnoticeable bruises may be aggravated instead in patients with tendency to bruise caused by for instance fish oil supplements.

[Migraine preventive treatment: monoclonal antibodies against calcitonine gene related peptide]. / Tratamiento preventivo en migraña: anticuerpos monoclonales contra la vía del péptido relacionado con el gen de la calcitonina.

Migraine is a very prevalent disorder that is estimated to affect about 10-15% of adult subjects. According to the World Health Organization migraine is one of the first causes of disability. Traditional preventive treatments discovered by serendipity include Beta blockers, antinconvulsants drugs, calcium channel blockers, tricyclic antidepressants and onabotulinum A and offer about 50% efficacy after controlled placebo trials and real life use. Because of lack of adherence and adverse events, there is a loss of beneficial sustain on these treatments. Recently, the efficacy and safety of monoclonal antibodies (MA) that act on the peptide pathway related to the calcitonin gene (CGRP) has been evaluated in migraine, being the first specific tailored treatment on one of the multiple targets on migraine. This family of drugs: erenumab, galcanezumab, fremanezumab, eptinezumab, finished Fase III, extensions trials and many of them are in the market approved since 2018.Since 2019 are available in Argentina. We will describe the rationale for the prescription of this family of new drugs for migraine.

La migraña es un trastorno muy prevalente que afecta a alrededor del 15% de los sujetos adultos. Es clasificada por la Organización Mundial de la Saludentre los primeros puestos como causa de discapacidad. Los tratamientos preventivos habituales hasta ahora derivan de otras indicaciones y por serendipia se utilizan en prevención de migraña: betabloqueantes, drogas antiepilépticas, antidepresivos tricíclicos, bloqueantes de canales de calcio, toxina botulínica. Todas ellas han mostrado eficacia similar al 50% en reducir el número de episodios migrañosos pese a efectos secundarios indeseados. Durante los últimos años, se ha evaluado la eficacia y seguridad de los anticuerpos monoclonales (AM) que actúan sobre la vía del péptido relacionado con el gen de la calcitonina (CGRP) en migraña. Dicho péptido es relevante en la activación del dolor en territorio meníngeoy es mediado por terminales nerviosas trigeminales una vez activado el proceso migrañoso. Su dosaje en crisis migrañosas ha sido elevado en diversos estudios y su neutralización/bloqueo, redunda en alivio del dolor. Los anticuerpos monoclonales erenumab, galcanezumab, fremanezumab, eptinezumab aprobados en el mercado EE.UU./Europa desde 2018 y tras varios trabajos de Fase III y abiertos de extensión, mostraron clara seguridad yeficacia y están presentes en nuestro medio desde mediados de 2019. Desarrollamos la racionalidad e indicaciones de uso de los mismos.

Tratamiento preventivo en migraña: anticuerpos monoclonales contra la vía del péptido relacionado con el gen de la calcitonina / Migraine preventive treatment: monoclonal antibodies against calcitonine gene related peptide

Resumen La migraña es un trastorno muy prevalente que afecta a alrededor del 15% de los sujetos adultos. Es clasificada por la Organización Mundial de la Saludentre los primeros puestos como causa de discapacidad. Los tratamientos preventivos habituales hasta ahora derivan de otras indicaciones y por serendipia se utilizan en prevención de migraña: betabloqueantes, drogas antiepilépticas, antidepresivos tricíclicos, bloquean tes de canales de calcio, toxina botulínica. Todas ellas han mostrado eficacia similar al 50% en reducir el número de episodios migrañosos pese a efectos secundarios indeseados. Durante los últimos años, se ha evaluado la eficacia y seguridad de los anticuerpos monoclonales (AM) que actúan sobre la vía del péptido relacionado con el gen de la calcitonina (CGRP) en migraña. Dicho péptido es relevante en la activación del dolor en territorio meníngeoy es mediado por terminales nerviosas trigeminales una vez activado el proceso migrañoso. Su dosaje en crisis migrañosas ha sido elevado en diversos estudios y su neutralización/bloqueo, redunda en alivio del dolor. Los anticuerpos monoclonales erenumab, galcanezumab, fremanezumab, eptinezumab aprobados en el mercado EE.UU./Europa desde 2018 y tras varios trabajos de Fase III y abiertos de extensión, mostraron clara seguridad yeficacia y están presentes en nuestro medio desde mediados de 2019. Desarrollamos la racionalidad e indicaciones de uso de los mismos.

Abstract Migraine is a very prevalent disorder that is estimated to affect about 10-15% of adult subjects. Ac cording to the World Health Organization migraine is one of the first causes of disability. Traditional preventive treatments discovered by serendipity include Beta blockers, antinconvulsants drugs, calcium channel blockers, tricyclic antidepressants and onabotulinum A and offer about 50% efficacy after controlled placebo trials and real life use. Because of lack of adherence and adverse events, there is a loss of beneficial sustain on these treat ments. Recently, the efficacy and safety of monoclonal antibodies (MA) that act on the peptide pathway related to the calcitonin gene (CGRP) has been evaluated in migraine, being the first specific tailored treatment on one of the multiple targets on migraine. This family of drugs: erenumab, galcanezumab, fremanezumab, eptinezumab, finished Fase III, extensions trials and many of them are in the market approved since 2018.Since 2019 are available in Argentina. We will describe the rationale for the prescription of this family of new drugs for migraine.

Diagnosis and Management of Headache: A Review.

IMPORTANCE: Approximately 90% of people in the US experience headache during their lifetime. Migraine is the second leading cause of years lived with disability worldwide. OBSERVATIONS: Primary headache disorders are defined as headaches that are unrelated to an underlying medical condition and are categorized into 4 groups: migraine, tension-type headache, trigeminal autonomic cephalalgias, and other primary headache disorders. Studies evaluating prevalence in more than 100 000 people reported that tension-type headache affected 38% of the population, while migraine affected 12% and was the most disabling. Secondary headache disorders are defined as headaches due to an underlying medical condition and are classified according to whether they are due to vascular, neoplastic, infectious, or intracranial pressure/volume causes. Patients presenting with headache should be evaluated to determine whether their headache is most likely a primary or a secondary headache disorder. They should be evaluated for symptoms or signs that suggest an urgent medical problem such as an abrupt onset, neurologic signs, age 50 years and older, presence of cancer or immunosuppression, and provocation by physical activities or postural changes. Acute migraine treatment includes acetaminophen, nonsteroidal anti-inflammatory drugs, and combination products that include caffeine. Patients not responsive to these treatments may require migraine-specific treatments including triptans (5-HT1B/D agonists), which eliminate pain in 20% to 30% of patients by 2 hours, but are accompanied by adverse effects such as transient flushing, tightness, or tingling in the upper body in 25% of patients. Patients with or at high risk for cardiovascular disease should avoid triptans because of vasoconstrictive properties. Acute treatments with gepants, antagonists to receptors for the inflammatory neuropeptide calcitonin gene-related peptide, such as rimegepant or ubrogepant, can eliminate headache symptoms for 2 hours in 20% of patients but have adverse effects of nausea and dry mouth in 1% to 4% of patients. A 5-HT1F agonist, lasmiditan, is also available for acute migraine treatment and appears safe in patients with cardiovascular risk factors. Preventive treatments include antihypertensives, antiepileptics, antidepressants, calcitonin gene-related peptide monoclonal antibodies, and onabotulinumtoxinA, which reduce migraine by 1 to 3 days per month relative to placebo. CONCLUSIONS AND RELEVANCE: Headache disorders affect approximately 90% of people during their lifetime. Among primary headache disorders, migraine is most debilitating and can be treated acutely with analgesics, nonsteroidal anti-inflammatory drugs, triptans, gepants, and lasmiditan.

Migraine therapeutics differentially modulate the CGRP pathway.

BACKGROUND: The clinical efficacy of migraine therapeutic agents directed towards the calcitonin-gene related peptide (CGRP) pathway has confirmed the key role of this axis in migraine pathogenesis. Three antibodies against CGRP - fremanezumab, galcanezumab and eptinezumab - and one antibody against the CGRP receptor, erenumab, are clinically approved therapeutics for the prevention of migraine. In addition, two small molecule CGRP receptor antagonists, ubrogepant and rimegepant, are approved for acute migraine treatment. Targeting either the CGRP ligand or receptor is efficacious for migraine treatment; however, a comparison of the mechanism of action of these therapeutic agents is lacking in the literature. METHODS: To gain insights into the potential differences between these CGRP pathway therapeutics, we compared the effect of a CGRP ligand antibody (fremanezumab), a CGRP receptor antibody (erenumab) and a CGRP receptor small molecule antagonist (telcagepant) using a combination of binding, functional and imaging assays. RESULTS: Erenumab and telcagepant antagonized CGRP, adrenomedullin and intermedin cAMP signaling at the canonical human CGRP receptor. In contrast, fremanezumab only antagonized CGRP-induced cAMP signaling at the human CGRP receptor. In addition, erenumab, but not fremanezumab, bound and internalized at the canonical human CGRP receptor. Interestingly, erenumab also bound and internalized at the human AMY1 receptor, a CGRP receptor family member. Both erenumab and telcagepant antagonized amylin-induced cAMP signaling at the AMY1 receptor while fremanezumab did not affect amylin responses. CONCLUSION: The therapeutic effect of agents targeting the CGRP ligand versus receptor for migraine prevention (antibodies) or acute treatment (gepants) may involve distinct mechanisms of action. These findings suggest that differing mechanisms could affect efficacy, safety, and/or tolerability in migraine patients.