5-Hydroxytryptamine 1F Receptor Agonist Lasmiditan Differentially Regulates Successful Repair and Failed Repair Genes in a Mouse Model of Acute Kidney Injury

Article

作者: Hortareas, John ; Hurtado, Kevin A. ; Janda, Jaroslav ; Santiago Raj, Paul Victor ; Scholpa, Natalie E. ; Schnellmann, Rick G.

Increasing evidence substantiates the role of mitochondrial dysfunction, inflammation, fibrosis, and cell senescence in the onset and progression of acute kidney injury (AKI) to chronic kidney disease . The underlying governing cellular and transcriptional events, however, are not fully understood. Recently, the key factors that regulate successful and failed repair states in the proximal tubule have been identified at a single-cell resolution following bilateral ischemia-reperfusion (I/R) in a mouse model of AKI. Previously, our group showed that treatment with the FDA-approved selective 5-hydroxytryptamine receptor 1F agonist lasmiditan following AKI induces mitochondrial biogenesis , restores renal mitochondrial function, and increases renal and vascular recovery in vivo. Here, we assessed the effect of lasmiditan on transcriptional and translational changes that are responsible for successful repair, injury, and failed repair states in the renal cortex following I/R-induced AKI. Increased levels of successful repair genes such as acyl-coA synthase medium-chain family member 2a, low-density lipoprotein receptor-related protein 2, solute carrier family 5 member 12, and hepatocyte nuclear factor 4 alpha were observed with 6 and 12 days of lasmiditan treatment following AKI compared to vehicle control. While 6 days of lasmiditan treatment had no effect on failed repair genes, the administration of lasmiditan for 12 days decreased the levels of vascular cell adhesion protein 1, tumor necrosis factor α, and interleukin-1β, which drive maladaptive repair. These data reveal that lasmiditan treatment post-AKI differentially regulates successful and failed repair gene expression in the renal cortex, likely contributing to the restoration of renal function and providing a potential targeted therapeutic pathway for the treatment of AKI.

2022-12-01·Archives of Disease in Childhood2区 · 医学

What is new in migraine management in children and young people?

2区 · 医学

Review

作者: Whitehouse, William P ; Howells, Rachel ; Loh, Ne Ron

For this narrative review, we found recent publications on the use and effectiveness of old therapies including nutraceuticals, such as riboflavin, vitamin D, magnesium, melatonin and talking therapies. Recent large trials of established conventional pharmaceuticals such as propranolol, pizotifen, topiramate and amitriptyline for childhood migraine have failed, but the use of a quasi-placebo in future trials could help. We reviewed the evidence for angiotensin antagonists including candesartan in adults, but found a lack of evidence for their use in children. There have been new developments in pharmaceuticals recently, including a more selective 5-HT1F agonist, lasmiditan, an effective acute treatment with no vasoconstrictor activity in adults, currently being tested in children. Also, a number of new calcitonin gene-related peptide (CGRP) antibodies and antagonists, with proven efficacy in acute treatment and/or prevention of migraine in adults, are undergoing trials in children. Peripheral nerve blocks and botulinum toxin are gaining popularity in adult practice, but we really need more good quality evidence for their effectiveness in children. Finally, electroceuticals, that is, therapeutic electric devices, are now marketed for acute and or preventative treatment, including an external trigeminal nerve stimulator (e-TNS), a non-invasive vagal nerve stimulator (nVNS), a single-pulse transcranial magnetic stimulator (sTMS) and a remote electrical neuromodulation device (REN). At the moment, evidence for their effectiveness in children is still lacking. So, there has been much progress, but mostly for adults. We are in urgent need of more migraine trials in children.

2020-11-01·Current Medical Research and Opinion4区 · 医学

Lasmiditan in patients with common migraine comorbidities: apost hocefficacy and safety analysis of two phase 3 randomized clinical trials

4区 · 医学

Article

作者: Hultman, Cory B. ; Hauck, Paula M. ; Clemow, David B. ; Baygani, Simin K.

OBJECTIVEDetermine whether common migraine comorbidities affect the efficacy and safety of lasmiditan, a 5-HT_1F receptor agonist approved in the United States for the acute treatment of migraine.METHODSIn SPARTAN and SAMURAI (double-blind Phase 3 clinical trials), patients with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100mg, 200 mg, or placebo. Lasmiditan increased the proportion of pain-free and most bothersome symptom (MBS)-free patients at 2 h after dose compared with placebo. Most common treatment-emergent adverse events (TEAEs) were dizziness, paraesthesia, somnolence, fatigue, nausea, muscular weakness, and hypoesthesia. Based upon literature review of common migraine comorbidities, Anxiety, Allergy, Bronchial, Cardiac, Depression, Fatigue, Gastrointestinal, Hormonal, Musculoskeletal/Pain, Neurological, Obesity, Sleep, and Vascular Comorbidity Groups were created. Using pooled results, efficacy and TEAEs were assessed to compare patients with or without a given common migraine comorbidity. To compare treatment groups, p-values were calculated for treatment-by-subgroup interaction, based on logistic regression with treatment-by-comorbidity condition status (Yes/No) as the interaction term; study, treatment group, and comorbidity condition status (Yes/No) were covariates. Differential treatment effect based upon comorbidity status was also examined. Trial registration at clinicaltrials.gov: SAMURAI (NCT02439320) and SPARTAN (NCT02605174).RESULTSAcross all the Comorbidity Groups, with the potential exception of fatigue, treatment-by-subgroup interaction analyses did not provide evidence of a lasmiditan-driven lasmiditan versus placebo differential treatment effect dependent on Yes versus No comorbidity subgroup for either efficacy or TEAE assessments.CONCLUSIONSThe efficacy and safety of lasmiditan for treatment of individual migraine attacks appear to be independent of comorbid conditions.

100 项与 5-HT1F receptor agonists( Eli Lilly & Co.) 相关的药物交易

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