title: Measuring niacin-associated skin toxicity (NASTy) stigmata along with symptoms to aid development of niacin mimetics.
abstract: Though cardioprotective, niacin monotherapy is limited by unpleasant cutaneous symptoms mimicking dermatitis: niacin-associated skin toxicity (NASTy). Niacin is prototypical of several emerging drugs suffering off-target rubefacient properties whereby agonizing the GPR109A receptor on cutaneous immune cells provokes vasodilation, prompting skin plethora andrubor, as well asdolor,tumor, andcalor, and systemically, heat loss,frigor, chills, and rigors. Typically, NASTy effects are described by subjective patient-reported perception, at best semi-quantitative and bias-prone. Conversely, objective, quantitative, and unbiased methods measuring NASTy stigmata would facilitate research to abolish them, motivating development of several objective methods. In early drug development, such methods might better predict clinical tolerability in larger clinical trials. Measuring cutaneous stigmata may also aid investigations of vasospastic, ischemic, and inflammatory skin conditions. We present methods to measure NASTy physical stigmata to facilitate research into novel niacin mimetics/analogs, detailing characteristics of each technique following niacin, and how NASTy stigmata relate to symptom perception. We gave niacin orally and measuredruborby colorimetry and white-light spectroscopy, plethora by laser Doppler flowmetry, andcalor/frigorby thermometry. Surprisingly, each stigma's abruptness predicted symptom perception, whereas peak intensity did not. These methods are adaptable to study other rubefacient drugs or dermatologic and vascular disorders.
authors.affiliation: University of Pennsylvania Institute for Translational Medicine and Therapeutics, Philadelphia PA; Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania Medical Center, Philadelphia, PA; Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania Medical Center, Philadelphia, PA. Electronic address: richard.dunbar@uphs.upenn.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Dunbar
authors.affiliation: Department Medicine, York Hospital, York, PA.
authors.forename: Harsh
authors.initials: H
authors.lastname: Goel
authors.affiliation: Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania Medical Center, Philadelphia, PA.
authors.forename: Sony
authors.initials: S
authors.lastname: Tuteja
authors.affiliation: Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN.
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Song
authors.affiliation: University of Pennsylvania Institute for Translational Medicine and Therapeutics, Philadelphia PA.
authors.forename: Grace
authors.initials: G
authors.lastname: Nathanson
authors.affiliation: HUMC Mountainside Hospital, Montclair, NJ.
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Babar
authors.affiliation: University of Pennsylvania Institute for Translational Medicine and Therapeutics, Philadelphia PA; Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania Medical Center, Philadelphia, PA.
authors.forename: Dusanka
authors.initials: D
authors.lastname: Lalic
authors.affiliation: University of Pennsylvania Institute for Translational Medicine and Therapeutics, Philadelphia PA; Departments of Dermatology and Biostatistics and Epidemiology, and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gelfand
authors.affiliation: University of Pennsylvania Institute for Translational Medicine and Therapeutics, Philadelphia PA; Department of Medicine, Division of Cardiovascular Medicine, University of Pennsylvania Medical Center, Philadelphia, PA; Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA; Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania Medical Center, Philadelphia, PA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: cyberDERM, Inc., Broomall, PA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Grove
mesh_terms: D032701:Biomimetics; D003124:Colorimetry; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D050171:Dyslipidemias / Q000150:complications / Q000188:drug therapy; D005483:Flushing / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use; D007509:Irritants / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use; D017078:Laser-Doppler Flowmetry; D009525:Niacin / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000503:physiopathology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: C530636:HCAR2 protein, human; D000960:Hypolipidemic Agents; D007509:Irritants; D043562:Receptors, G-Protein-Coupled; D011978:Receptors, Nicotinic; D009525:Niacin
keywords: dyslipidemia; flushing; hypolipidemic drugs; laser Doppler flowmetry; niacin-associated skin toxicity; quantitation; white-light spectroscopy