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Investigative Report

A Novel Topical Formulation Containing Strontium Chloride Significantly Reduces the Intensity and Duration of Cowhage-Induced Itch

doi: 10.2340/00015555-1564


The aim of this double-blinded, vehicle-controlled study was to test the antipruritic efficacy of topical strontium to relieve a nonhistaminergic form of itch that would be clinically relevant for chronic pruritic diseases. Itch induced with cowhage is mediated by PAR2 receptors which are considered to play a major role in itch of atopic dermatitis and possibly other acute and chronic pruritic conditions. The topical strontium hydrogel formulation (TriCalm®) was tested in a head-to-head comparison with 2 common topical formulations marketed as antipruritics: hydrocortisone and diphenhydramine, for their ability to relieve cowhage-induced itch. Topically-applied strontium salts were previously found to be effective for reducing histamine-induced and IgE-mediated itch in humans. However, histamine is not considered the critical mediator in the majority of skin diseases presenting with chronic pruritus. The current study enrolled 32 healthy subjects in which itch was induced with cowhage before and after skin treatment with a gel containing 4% SrCl2, control vehicle, topical 1% hydrocortisone and topical 2% diphenhydramine. Strontium significantly reduced the peak intensity and duration of cowhage-induced itch when compared to the control itch curve, and was significantly superior to the other two over-the-counter antipruritic agents and its own vehicle in antipruritic effect. We hereby show that a 4% topical strontium formulation has a robust antipruritic effect, not only against histamine-mediated itch, but also for non-histaminergic pruritus induced via the PAR2 pathway, using cowhage.


Alexandru D.P. Papoiu, Rodrigo Valdes-Rodriguez, Leigh A. Nattkemper, Yiong-Huak Chan, Gary S. Hahn, Gil Yosipovitch
Department of Dermatology , Wake Forest University Health Sciences, Winston-Salem, NC, USA


1. Papoiu ADP, Tey HL, Coghill RC, Wang H, Yosipovitch G. Cowhage-induced itch as an experimental model for pruritus. A comparative study with histamine-induced itch. PLoS One 2011; 6: e17786.

2. Shelley WB, Arthur RP. Studies on cowhage (Mucuna pruriens) and its pruritogenic proteinase, mucunain. AMA Arch Derm 1955; 72: 399–406.

3. Johanek LM, Meyer RA, Hartke T, Hobelmann JG, Maine DN, LaMotte RH et al. Psychophysical and physiological evidence for parallel afferent pathways mediating the sensation of itch. J Neurosci 2007; 27: 7490–7497.

4. Steinhoff M, Stander S, Seeliger S, Ansel JC, Schmelz M, Luger T. Modern aspects of cutaneous neurogenic inflammation. Arch Dermatol 2003; 139: 1479–1488.

5. Lee SE, Jeong SK, Lee SH. Protease and protease-activated receptor-2 signaling in the pathogenesis of atopic dermatitis. Yonsei Med J 2010; 51: 808–822.

6. Bin Saif GA, Ericson ME, Yosipovitch G. The itchy scalp – scratching for an explanation. Exp Dermatol 2011; 20: 959–968.

7. Ikoma A, Cevikbas F, Kempkes C, Steinhoff M. Anatomy and neurophysiology of pruritus. Semin Cutan Med Surg 2011; 30: 64–70.

8. Elmariah SB, Lerner EA. Topical therapies for pruritus. Semin Cutan Med Surg 2011; 30: 118–126.

9. Hahn GS. Strontium is a potent and selective inhibitor of sensory irritation. Dermatol Surg 1999; 25: 689–694.

10. Zhai H, Hannon W, Hahn GS, Pelosi A, Harper RA, Maibach HI. Strontium nitrate suppresses chemically-induced sensory irritation in humans. Contact Dermatitis 2000; 42: 98–100.

11. Zhai H, Hannon W, Hahn GS, Harper RA, Pelosi A, Maibach HI. Strontium nitrate decreased histamine-induced itch magnitude and duration in man. Dermatology 2000; 200: 244–246.

12. Williams EJ. Experimental designs balanced for the estimation of residual effect of treatments. Aust J Sci Res 1949; 2: 149–168.

13. Wang BS, Wang XJ, Gong LK. The construction of a Williams design and randomization in cross-over clinical trials using SAS. J Stat Softw 2009, 29, Code Snippet 1.

14. Deng C, Graz J. Generating randomization schedules using SAS programming, SUGI-27 Conference Proceedings 2002, Paper 267, SAS Institute Inc., Cary, NC, USA. ISBN 1-59047-061-3.

15. Patel T, Yosipovitch G. The management of chronic pruritus in the elderly. Skin Therapy Lett 2010; 15: 5–9.

16. Tey HL, Yosipovitch G. Targeted treatment of pruritus: a look into the future. Br J Dermatol 2011; 165: 5–17.

17. Brown EM. The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics. Subcell Biochem 2007; 45: 139–167.

18. Saidak Z, Brazier M, Kamel S, Mentaverri R. Agonists and allosteric modulators of the calcium-sensing receptor and their therapeutic applications. Mol Pharmacol 2009; 76: 1131–1144.

19. Phillips CG, et al. Calcium-sensing receptor activation depresses synaptic transmission. J Neuroscience 2008; 28: 12062–12070.

20. Xu-Friedman MA, Regehr WG. Presynaptic strontium dynamics and synaptic transmission. Biophys J 1999; 76: 2029–2042.

21. Sugihara I. Activation and two modes of blockade by strontium of Ca2+-activated K+ channels in goldfish saccular hair cells. J Gen Physiol 1998; 111: 363–379.

22. Rodriguez-Contreras A, Lv P, Zhu J, Kim HJ, Yamoah EN. Effects of strontium on the permeation and gating phenotype of calcium channels in hair cells. J Neurophysiol 2008; 100: 2115–2124.

23. Goda Y, Stevens CF. Two components of transmitter release at a central synapse. Proc Natl Acad Sci USA 1994; 91: 12942–12946.

24. Augustine GJ, Eckert R. Divalent cations differentially support transmitter release at the squid giant synapse. J Physiol 1984; 346: 257–271.

25. Miledi R. Strontium as a substitute for calcium in the process of transmitter release at the neuromuscular junction. Nature 1966; 212: 1233–1234.

26. Dodge FA Jr, Miledi R, Rahamimoff R. Strontium and quantal release of transmitter at the neuromuscular junction. J Physiol 1969; 200: 267–283.

27. Meiri U, Rahamimoff R. Activation of transmitter release by strontium and calcium ions at the neuromuscular junction. J Physiol 1971; 215: 709–726.

28. Mellow AM, Perry BD, Silinsky EM. Effects of calcium and strontium in the process of acetylcholine release from motor nerve endings. J Physiol 1982; 328: 547–562.

29. Bain AI, Quastel DM. Quantal transmitter release mediated by strontium at the mouse motor nerve terminal. J Physiol 1992; 450: 63–87.

30. Abdul-Ghani MA, Valiante TA, Pennefather PS. Sr2+ and quantal events at excitatory synapses between mouse hippocampal neurons in culture. J Physiol 1996; 495: 113–125.

31. Tokunaga T, Miyazaki K, Koseki M, Mobarakeh JI, Ishizuka T, Yawo H. Pharmacological dissection of calcium channel subtype-related components of strontium inflow in large mossy fiber boutons of mouse hippocampus. Hippocampus 2004; 14: 570–585.

32. Falke J, Drake S, Hazard AL, Peersen OB. Molecular tuning of ion calcium signaling protein. Q Rev Biophys 1994; 27: 219–290.

33. Zefirov AL, Grigoriev PN. Sensitivity of intracellular calcium-binding sites for exo- and endocytosis of synaptic vesicles to Sr, Ba, and Mg ions. Neurosci Behav Physiol 2010; 40: 389–396.

34. Li C, Davletov BA, Südhof TC. Distinct Ca2+ and Sr2+ binding properties of synaptotagmins. Definition of candidate Ca2+ sensors for the fast and slow components of neurotransmitter release. J Biol Chem 1995; 270: 24898–24902.

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Volume 93, Issue 5

DOI: 10.2340/00015555-1564

Pages: 520-526

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