A review of the current and potential oxygen delivery systems and techniques utilized in cluster headache attacks.

BACKGROUND: Despite oxygen therapy being one of the foremost acute treatments for cluster headache (CH) attacks, little is known about the different techniques and systems. OBJECTIVES: In this review we will examine the efficacy of the standard non-rebreather mask (NRM) with room temperature oxygen in relieving pain in CH, and try to compare it with the diversity of other oxygen gas conditions and interfaces like partial rebreathers, simple masks, nasal cannulas, tusk masks, demand valve oxygen, hyperbaric and cooled oxygen. METHOD: We searched non-structured Pubmed, Medline, the Cochrane online database and instruction protocols from various oxygen delivery devices. CONCLUSIONS AND IMPLICATIONS: Interfaces like demand valves and tusk masks are already proving to be superior or at least similar to the standard NRM in terms of fraction of inspired oxygen (FiO2), though the demand valve only showed better results than the NRM in a single study in only four participants. Furthermore, new research shows how lower temperatures of the gas may be an essential part of effective pain relief and hyperbaric treatments show potential in preventing night time attacks.

Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients.

RIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases. SAR443060 (previously DNL747) is a selective, orally bioavailable, central nervous system (CNS)-penetrant, small-molecule, reversible inhibitor of RIPK1. In three early-stage clinical trials in healthy subjects and patients with AD or ALS (NCT03757325 and NCT03757351), SAR443060 distributed into the cerebrospinal fluid (CSF) after oral administration and demonstrated robust peripheral target engagement as measured by a reduction in phosphorylation of RIPK1 at serine 166 (pRIPK1) in human peripheral blood mononuclear cells compared to baseline. RIPK1 inhibition was generally safe and well-tolerated in healthy volunteers and patients with AD or ALS. Taken together, the distribution into the CSF after oral administration, the peripheral proof-of-mechanism, and the safety profile of RIPK1 inhibition to date, suggest that therapeutic modulation of RIPK1 in the CNS is possible, conferring potential therapeutic promise for AD and ALS, as well as other neurodegenerative conditions. However, SAR443060 development was discontinued due to long-term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early-stage clinical trials. The dose-limiting toxicities observed for SAR443060 preclinically have not been reported for other RIPK1-inhibitors, suggesting that these toxicities are compound-specific (related to SAR443060) rather than RIPK1 pathway-specific.