Measuring niacin-associated skin toxicity (NASTy) stigmata along with symptoms to aid development of niacin mimetics

J Lipid Res. 2017 Apr;58(4):783-797. doi: 10.1194/jlr.D071696. Epub 2017 Jan 23.

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 and rubor, as well as dolor, tumor, and calor, 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 measured rubor by colorimetry and white-light spectroscopy, plethora by laser Doppler flowmetry, and calor/frigor by 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.

Keywords: dyslipidemia; flushing; hypolipidemic drugs; laser Doppler flowmetry; niacin-associated skin toxicity; quantitation; white-light spectroscopy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomimetics
  • Colorimetry
  • Dose-Response Relationship, Drug
  • Drug-Related Side Effects and Adverse Reactions / classification
  • Drug-Related Side Effects and Adverse Reactions / pathology*
  • Dyslipidemias / complications
  • Dyslipidemias / drug therapy
  • Flushing / chemically induced
  • Flushing / pathology
  • Humans
  • Hypolipidemic Agents / adverse effects*
  • Hypolipidemic Agents / chemistry
  • Hypolipidemic Agents / therapeutic use
  • Irritants / adverse effects*
  • Irritants / chemistry
  • Irritants / therapeutic use
  • Laser-Doppler Flowmetry
  • Niacin / adverse effects*
  • Niacin / chemistry
  • Niacin / therapeutic use
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, Nicotinic / metabolism
  • Skin / drug effects
  • Skin / physiopathology*
  • Vasodilation / drug effects

Substances

  • HCAR2 protein, human
  • Hypolipidemic Agents
  • Irritants
  • Receptors, G-Protein-Coupled
  • Receptors, Nicotinic
  • Niacin