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Challenges and Opportunities in Migraine

Challenges and Opportunities in Migraine

Aynur Ozge, MD, PhD
Department of Neurology, Mersin University School of Medicine, Mersin, Türkiye

Reza Ghouri
Department of Neurology, Brain 360 Integrative Center, İstanbul, Türkiye

Derya Uludüz
Department of Neurology, Brain 360 Integrative Center, İstanbul, Türkiye; Department of Neurology, Cerrahpaşa University Medical Faculty, İstanbul, Türkiye


This comprehensive review examines the impact of vascular risk factors on the phenotypic expression of migraine in the elderly population. Migraine, particularly migraine with aura, has been established as a risk factor for ischemic lesions of the brain, stroke, and other cardiovascular diseases. The association between migraine and specific vascular events, such as stroke, myocardial infarction, and angina pectoris, underscores the need for a comprehensive understanding of the interplay between migraine and cardiovascular diseases. The challenges in differentiating migraine from vascular insults, especially in the elderly population, highlight the need for improved diagnostic and treatment strategies to address the complexities of managing migraine in this demographic. Patient education and treatment of modifiable risk factors may decrease future vascular events, emphasizing the importance of addressing vascular risk factors in migraine management. The potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes underscores the broader implications of addressing vascular risk factors in migraine management. The clinical and public health relevance of understanding the modifiability of vascular risk factors in elderly migraine patients extends to addressing challenges in cancer survivorship, radiological emergency response, and rational person behavior, emphasizing the diverse applications of addressing vascular risk factors in healthcare and public health. Ultimately, the clinical and public health relevance of understanding the impact of vascular risk factors on the phenotypic expression of elderly migraine underscores the need for continued research and clinical vigilance in addressing the complex interplay between migraine and vascular risk factors in the elderly population.

Parisa Gazerani


Developing drugs for brain disorders poses significant hurdles. These challenges stem from the scarcity of optimal models for preclinical drug testing and the often observed lack of translation from preclinical to human clinical trials. Further complexity arises from the specific targeting required in many brain disorders, with drug delivery often impeded by the necessity to cross the blood-brain barrier (BBB). As such, the search for novel and efficient platforms for preclinical drug development is a vibrant area of research. In acknowledgment of the limitations of animal tests – such as the lack of translation owing to species differences – and in alignment with the principles of reduction, refinement, and replacement (3Rs), the scientific community is moving towards promoting animal-free drug development plans. In this context, human brain organoids are rapidly emerging as potential alternatives to traditional methods. These early-stage in vitro models, mirroring in vivo complexities, hold great promise for preclinical drug testing for brain disorders. Stable organoid phenotypes and the uncovering of disease-specific features could soon elevate them to a valuable strategy in pharmaceutical testing for a range of brain disorders. Recent advancements in assay-ready organoid platforms and microfluidic chips present considerable potential for the application of human brain organoids in drug development. This commentary briefly discusses the generation of human brain organoids and their application in drug development with existing examples, focusing on their potential use in preclinical drug development for migraine, a prevalent, complex, and disabling brain disorder. The associated challenges and opportunities will also be outlined.

Russ Best


Mint and to a lesser extent menthol have been used since antiquity for medicinal purposes. Key components of mint and menthol use such as composition and intake, safety and traditional uses are discussed prior to a review of clinical and human performance outcomes in the areas of digestive and respiratory health; antibacterial and anti-fungal properties, nocioception, migraine and headache and emerging evidence regarding COVID 19. Evidence suggests benefit for patients with irritable bowel syndrome and related digestive issues, with analgesic and respiratory effects also noted. Perceptual characteristics relating to thermal comfort and sensation, taste sensitivity and alertness are also considered; these effects are predominantly driven by stimulation of transient receptor potential melastatin 8 (TRPM8) activity resulting in sensations of cooling and freshness, with lesser influence on thirst. Finally, sport performance is considered as a domain that may further elucidate some of the aforementioned underpinning outcomes due to its systemic and dynamic nature, especially when performed in hot environmental conditions.

Stephen Bevan Shrewsbury, MBChB
Impel Pharmaceuticals Inc., Seattle, WA, USA

Greg Davies, BSc (Hons)
Impel Pharmaceuticals Inc, Seattle, WA, USA

Lisa McConnachie, PhD
Impel Pharmaceuticals Inc, Seattle, WA, USA

John Hoekman, PhD
Impel Pharmaceuticals Inc, Seattle, WA, USA


Nasal drug delivery presents a potential opportunity for achieving rapid, extensive drug absorption via a nonoral route by 1) avoiding degradation within the gastrointestinal tract and first-pass metabolism in the liver and 2) facilitating faster onset via rapid absorption into the bloodstream. However, the site of drug deposition within the nasal cavity may impact drug pharmacokinetics. Precision Olfactory Delivery (POD®) by Impel Pharmaceuticals Inc. is a new technology that provides handheld, manually actuated, propellant-powered drug delivery to the upper nasal space for rapid and efficient absorption. Rapid onset of effect can be a major advantage in many clinical applications where quick and effective administration is needed (eg, alleviating agitation in emergency settings or reducing debilitating migraine symptoms). Here, we review the pharmacokinetic profile of INP105, which is being developed to deliver olanzapine (OLZ) by POD to treat agitation in patients with autism. Because formulation can play a large role in the pharmacokinetic profile of a nasally administered drug, we provide a comprehensive review of both published and previously unpublished preclinical data outlining how the INP105 formulation was developed and optimized for study in humans. Multiple formulation carriers and excipients were tested to find a stable INP105 formulation with a desirable nasal absorption profile. Because the nasal architecture in nonhuman primates (NHPs) is similar to humans, the pharmacokinetics and tolerability of an INP105 combination product (NHP-INP105) using a clinical formulation combined with a device specifically designed for NHPs has been investigated in preclinical NHP studies, providing translational data for human studies and the pathway for testing novel products and formulations. The pharmacokinetics and tolerability of INP105 were then evaluated in an early clinical study in humans, demonstrating favorable pharmacokinetic and pharmacodynamic profiles. In this review, we aim to illustrate how delivery of therapeutics to the upper nasal space using POD, such as with agents like INP105, has the potential to optimize nasal delivery and unlock the potential of delivery-limited drugs to provide patients with rapid onset of effect, ease of use, and convenience.

Sherri Mendelson


Objective: To determine what adverse effects of neonatal phototherapy have been identified and the general breadth of the research.

Data Sources: A search for relevant sources was conducted using PubMed, The Cochrane Database, Ovid, and Clinical Key via EBSCO Discovery Search from January 2013-January 2023.

Study Selection: Sources were included if participants had undergone phototherapy for hyperbilirubinemia during their first weeks of life, including term and preterm infants.  Twenty-three sources met the inclusion criteria.

Data Extraction: Extraction included citation, design, context, aim, participants, outcomes, and main results.

Data Synthesis: General concepts leading the synthesis included adverse effects of neonatal phototherapy.  In addition, specific subgroups of adverse effects explored included childhood allergies, childhood cancers, patent ductus arteriosus (PDA), migraine headaches, attention deficit hyperactivity disorder, autism spectrum disorder, eye disorders and acoustic disorders.

Conclusion: While the quality of studies varies, more rigorous research on adverse effects of neonatal phototherapy would benefit from careful selection of methods and reference standards, direct measures of each adverse outcome identified in adults and children, and prospective cohort studies linking early neonatal exposure with each adverse outcome outcomes throughout childhood and adolescence.

Elucidating the effects of hyperbilirubinemia versus neonatal phototherapy on each potential adverse outcome will help to determine if new treatment methods for infants with hyperbilirubinemia need to be developed.

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