Harnessing the Therapeutic Potential of Capsaicin and Its Analogues in Pain and Other Diseases

Shaherin Basith, Minghua Cui, Sunhye Hong, Sun Choi, Shaherin Basith, Minghua Cui, Sunhye Hong, Sun Choi

Abstract

Capsaicin is the most predominant and naturally occurring alkamide found in Capsicum fruits. Since its discovery in the 19th century, the therapeutic roles of capsaicin have been well characterized. The potential applications of capsaicin range from food flavorings to therapeutics. Indeed, capsaicin and few of its analogues have featured in clinical research covered by more than a thousand patents. Previous records suggest pleiotropic pharmacological activities of capsaicin such as an analgesic, anti-obesity, anti-pruritic, anti-inflammatory, anti-apoptotic, anti-cancer, anti-oxidant, and neuro-protective functions. Moreover, emerging data indicate its clinical significance in treating vascular-related diseases, metabolic syndrome, and gastro-protective effects. The dearth of potent drugs for management of such disorders necessitates the urge for further research into the pharmacological aspects of capsaicin. This review summarizes the historical background, source, structure and analogues of capsaicin, and capsaicin-triggered TRPV1 signaling and desensitization processes. In particular, we will focus on the therapeutic roles of capsaicin and its analogues in both normal and pathophysiological conditions.

Keywords: analogues; capsaicin; desensitization; neuropathic pain; therapeutic.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of capsaicin, the primary ingredient of chili pepper, and its three important regions, namely A (aromatic head), B (amide linkage) and C (hydrophobic tail) depicted in different colored boxes.
Figure 2
Figure 2
The general chemical structure of capsaicinoid and capsinoid and their related analogues that differ in the R-group are summarized. Capsaicinoids and capsinoids have a common vanillyl moiety and differ in the central linkage (shown in red) and R-group.

References

    1. Nunn N., Qian N. The columbian exchange: A history of disease, food, and ideas. J. Econ. Perspect. 2010;24:163–188. doi: 10.1257/jep.24.2.163.
    1. Mozsik G., Past T., Abdel Salam O.M., Kuzma M., Perjesi P. Interdisciplinary review for correlation between the plant origin capsaicinoids, non-steroidal antiinflammatory drugs, gastrointestinal mucosal damage and prevention in animals and human beings. Inflammopharmacology. 2009;17:113–150. doi: 10.1007/s10787-009-0002-3.
    1. Szolcsanyi J. Capsaicin and sensory neurones: A historical perspective. Prog. Drug Res. 2014;68:1–37.
    1. Bucholz C.F. Chemical investigation of dry, ripe spanish peppers. Alm. Pocket-Book Anal. (Chem.) Apoth. 1816;37:1–30. (In German)
    1. Thresh J.C. Isolation of capsaicin. Pharm. J. Trans. 1876;6:941–947.
    1. Micko K. On our knowledge of capsaicin. J. Inves. Necess. Lux. 1898;1:818–829. (In German)
    1. Nelson E.K. The constitution of capsaicin, the pungent principle of capsicum. J. Am. Chem. Soc. 1919;41:1115–1121. doi: 10.1021/ja02228a011.
    1. Spath S., Darling S.F. Synthese des capsaicins. Chem. Ber. 1930;63B:737–743. doi: 10.1002/cber.19300630331.
    1. Kosuge S., Inagaki Y., Okumura H. Studies on the pungent principles of red pepper. Part VIII. On the chemical constitutions of the pungent principles. Nippon NogeiKagaku Kaishi (J. Agric. Chem. Soc. Jpn.) 1961;35:923–927. doi: 10.1271/nogeikagaku1924.35.10_923. (In Japanese)
    1. Tewksbury J.J., Manchego C., Haak D.C., Levey D.J. Where did the chili get its spice? Biogeography of capsaicinoid production in ancestral wild chili species. J. Chem. Ecol. 2006;32:547–564. doi: 10.1007/s10886-005-9017-4.
    1. Meotti F.C., Lemos de Andrade E., Calixto J.B. TRP modulation by natural compounds. Handb. Exp. Pharmacol. 2014;223:1177–1238.
    1. Buck S.H., Burks T.F. The neuropharmacology of capsaicin: Review of some recent observations. Pharmacol. Rev. 1986;38:179–226.
    1. Lee T.S. Physiological gustatory sweating in a warm climate. J. Physiol. 1954;124:528–542. doi: 10.1113/jphysiol.1954.sp005126.
    1. Szallasi A. Autoradiographic visualization and pharmacological characterization of vanilloid (capsaicin) receptors in several species, including man. Acta Physiol. Scand. Suppl. 1995;629:1–68.
    1. Conway S.J. Trping the switch on pain: An introduction to the chemistry and biology of capsaicin and TRPV1. Chem. Soc. Rev. 2008;37:1530–1545. doi: 10.1039/b610226n.
    1. Rios M.Y., Olivo H.F. Studies in Natural Products Chemistry. Volume 43. Elsevier B.V.; Memphis, TN, USA: 2014. Chapter 3: Natural and synthetic alkamides: Applications in pain therapy; pp. 79–121.
    1. Bode A.M., Dong Z. The two faces of capsaicin. Cancer Res. 2011;71:2809–2814. doi: 10.1158/0008-5472.CAN-10-3756.
    1. Szallasi A., Cortright D.N., Blum C.A., Eid S.R. The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat. Rev. Drug Discov. 2007;6:357–372. doi: 10.1038/nrd2280.
    1. Turnbull A. Tincture of capsaicin as a remedy for chilblains and toothache. Dublin Free Press. 1850;1:95–96.
    1. Buchheim R. Fructus capsici. J. Am. Pharm. Assoc. 1873;22:106.
    1. Cui M., Gosu V., Basith S., Hong S., Choi S. Polymodal transient receptor potential vanilloid type 1 nocisensor: Structure, modulators, and therapeutic applications. Adv. Protein Chem. Struct. Biol. 2016;104:81–125.
    1. Caterina M.J., Schumacher M.A., Tominaga M., Rosen T.A., Levine J.D., Julius D. The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature. 1997;389:816–824.
    1. Nagy I., Friston D., Valente J.S., Torres Perez J.V., Andreou A.P. Pharmacology of the capsaicin receptor, transient receptor potential vanilloid type-1 ion channel. Prog. Drug Res. 2014;68:39–76.
    1. Qutenza. [(accessed on 8 June 2016)]. Available online: .
    1. Haanpaa M., Cruccu G., Nurmikko T.J., McBride W.T., Docu Axelarad A., Bosilkov A., Chambers C., Ernault E., Abdulahad A.K. Capsaicin 8% patch versus oral pregabalin in patients with peripheral neuropathic pain. Eur. J. Pain. 2016;20:316–328. doi: 10.1002/ejp.731.
    1. FDA Center for Drug Evaluation and Research; 2009. [(accessed on 27 November 2015)]. Medical Review. Available online: .
    1. Baranidharan G., Das S., Bhaskar A. A review of the high-concentration capsaicin patch and experience in its use in the management of neuropathic pain. Ther. Adv. Neurol. Disord. 2013;6:287–297. doi: 10.1177/1756285613496862.
    1. De Lille J., Ramirez E. Pharmacodynamic action of the active principles of chillie. Chem. Abstr. 1935;29:4836.
    1. Toh C.C., Lee T.S., Kiang A.K. The pharmacological actions of capsaicin and analogues. Br. J. Pharmacol. Chemother. 1955;10:175–182. doi: 10.1111/j.1476-5381.1955.tb00079.x.
    1. Marini E., Magi G., Mingoia M., Pugnaloni A., Facinelli B. Antimicrobial and anti-virulence activity of capsaicin against erythromycin-resistant, cell-invasive group a streptococci. Front. Microbiol. 2015;6:1281. doi: 10.3389/fmicb.2015.01281.
    1. Dorantes L., Colmenero R., Hernandez H., Mota L., Jaramillo M.E., Fernandez E., Solano C. Inhibition of growth of some foodborne pathogenic bacteria by capsicum annum extracts. Int. J. Food Microbiol. 2000;57:125–128. doi: 10.1016/S0168-1605(00)00216-6.
    1. Walpole C.S., Wrigglesworth R., Bevan S., Campbell E.A., Dray A., James I.F., Perkins M.N., Reid D.J., Winter J. Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 1. The aromatic “a-region”. J. Med. Chem. 1993;36:2362–2372. doi: 10.1021/jm00068a014.
    1. Walpole C.S., Bevan S., Bloomfield G., Breckenridge R., James I.F., Ritchie T., Szallasi A., Winter J., Wrigglesworth R. Similarities and differences in the structure-activity relationships of capsaicin and resiniferatoxin analogues. J. Med. Chem. 1996;39:2939–2952. doi: 10.1021/jm960139d.
    1. Yoshioka M., St-Pierre S., Suzuki M., Tremblay A. Effects of red pepper added to high-fat and high-carbohydrate meals on energy metabolism and substrate utilization in Japanese women. Br. J. Nutr. 1998;80:503–510.
    1. Arabaci B., Gulcin I., Alwasel S. Capsaicin: A potent inhibitor of carbonic anhydrase isoenzymes. Molecules. 2014;19:10103–10114. doi: 10.3390/molecules190710103.
    1. O’Neill J., Brock C., Olesen A.E., Andresen T., Nilsson M., Dickenson A.H. Unravelling the mystery of capsaicin: A tool to understand and treat pain. Pharmacol. Rev. 2012;64:939–971. doi: 10.1124/pr.112.006163.
    1. Al Othman Z.A., Ahmed Y.B., Habila M.A., Ghafar A.A. Determination of capsaicin and dihydrocapsaicin in capsicum fruit samples using high performance liquid chromatography. Molecules. 2011;16:8919–8929. doi: 10.3390/molecules16108919.
    1. Thomas B.V., Schreiber A.A., Weisskopf C.P. Simple method for quantitation of capsaicinoids in peppers using capillary gas chromatography. J. Agric. Food Chem. 1998;46:2655–2663. doi: 10.1021/jf970695w.
    1. Cordell G.A., Araujo O.E. Capsaicin: Identification, nomenclature, and pharmacotherapy. Ann. Pharmacother. 1993;27:330–336.
    1. Luo X.J., Peng J., Li Y.J. Recent advances in the study on capsaicinoids and capsinoids. Eur. J. Pharmacol. 2011;650:1–7. doi: 10.1016/j.ejphar.2010.09.074.
    1. Shintaku K., Uchida K., Suzuki Y., Zhou Y., Fushiki T., Watanabe T., Yazawa S., Tominaga M. Activation of transient receptor potential a1 by a non-pungent capsaicin-like compound, capsiate. Br. J. Pharmacol. 2012;165:1476–1486. doi: 10.1111/j.1476-5381.2011.01634.x.
    1. Kobayashi K., Fukuoka T., Obata K., Yamanaka H., Dai Y., Tokunaga A., Noguchi K. Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with aδ/c-fibers and colocalization with trk receptors. J. Comp. Neurol. 2005;493:596–606. doi: 10.1002/cne.20794.
    1. Salas M.M., Hargreaves K.M., Akopian A.N. TRPA1-mediated responses in trigeminal sensory neurons: Interaction between TRPA1 and TRPV1. Eur. J. Neurosci. 2009;29:1568–1578. doi: 10.1111/j.1460-9568.2009.06702.x.
    1. Guimaraes M.Z.P., Jordt S.E. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. CRC Press; Boca Raton, FL, USA: 2007. TRPA1: A sensory channel of many talents.
    1. Ho K.W., Ward N.J., Calkins D.J. TRPV1: A stress response protein in the central nervous system. Am. J. Neurodegener. Dis. 2012;1:1–14.
    1. Liao M., Cao E., Julius D., Cheng Y. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature. 2013;504:107–112. doi: 10.1038/nature12822.
    1. Tominaga M., Caterina M.J., Malmberg A.B., Rosen T.A., Gilbert H., Skinner K., Raumann B.E., Basbaum A.I., Julius D. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron. 1998;21:531–543. doi: 10.1016/S0896-6273(00)80564-4.
    1. Cao E., Liao M., Cheng Y., Julius D. TRPV1 structures in distinct conformations reveal activation mechanisms. Nature. 2013;504:113–118. doi: 10.1038/nature12823.
    1. Yang F., Xiao X., Cheng W., Yang W., Yu P., Song Z., Yarov-Yarovoy V., Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. Nat. Chem. Biol. 2015;11:518–524. doi: 10.1038/nchembio.1835.
    1. Swain J., Kumar Mishra A. Location, partitioning behavior, and interaction of capsaicin with lipid bilayer membrane: Study using its intrinsic fluorescence. J. Phys. Chem. B. 2015;119:12086–12093. doi: 10.1021/acs.jpcb.5b05351.
    1. Kweon H.J., Yu S.Y., Kim D.I., Suh B.C. Differential regulation of proton-sensitive ion channels by phospholipids: A comparative study between asics and TRPV1. PLoS ONE. 2015;10:e0122014. doi: 10.1371/journal.pone.0122014.
    1. Aneiros E., Cao L., Papakosta M., Stevens E.B., Phillips S., Grimm C. The biophysical and molecular basis of TRPV1 proton gating. EMBO J. 2011;30:994–1002. doi: 10.1038/emboj.2011.19.
    1. Jordt S.E., Tominaga M., Julius D. Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc. Natl Acad. Sci. USA. 2000;97:8134–8139. doi: 10.1073/pnas.100129497.
    1. Devesa I., Planells-Cases R., Fernandez-Ballester G., Gonzalez-Ros J.M., Ferrer-Montiel A., Fernandez-Carvajal A. Role of the transient receptor potential vanilloid 1 in inflammation and sepsis. J. Inflamm. Res. 2011;4:67–81.
    1. Jancso N., Jancso-Gabor A., Szolcsanyi J. The role of sensory nerve endings in neurogenic inflammation induced in human skin and in the eye and paw of the rat. Br. J. Pharmacol. Chemother. 1968;33:32–41. doi: 10.1111/j.1476-5381.1968.tb00471.x.
    1. Smutzer G., Devassy R.K. Integrating TRPV1 receptor function with capsaicin psychophysics. Adv. Pharmacol. Sci. 2016;2016:1512457. doi: 10.1155/2016/1512457.
    1. Donnerer J., Amann R. The inhibition of neurogenic inflammation. Gen. Pharmacol. 1993;24:519–529. doi: 10.1016/0306-3623(93)90208-F.
    1. Shimomura Y., Kawada T., Suzuki M. Capsaicin and its analogs inhibit the activity of nadh-coenzyme q oxidoreductase of the mitochondrial respiratory chain. Arch. Biochem. Biophys. 1989;270:573–577. doi: 10.1016/0003-9861(89)90539-0.
    1. Anand P., Bley K. Topical capsaicin for pain management: Therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br. J. Anaesth. 2011;107:490–502. doi: 10.1093/bja/aer260.
    1. Szallasi A., Blumberg P.M. Vanilloid (capsaicin) receptors and mechanisms. Pharmacol. Rev. 1999;51:159–212.
    1. Docherty R.J., Yeats J.C., Bevan S., Boddeke H.W. Inhibition of calcineurin inhibits the desensitization of capsaicin-evoked currents in cultured dorsal root ganglion neurones from adult rats. Pflug. Arch. 1996;431:828–837. doi: 10.1007/s004240050074.
    1. Mohapatra D.P., Nau C. Desensitization of capsaicin-activated currents in the vanilloid receptor TRPV1 is decreased by the cyclic amp-dependent protein kinase pathway. J. Biol. Chem. 2003;278:50080–50090. doi: 10.1074/jbc.M306619200.
    1. Szolcsanyi J., Jancso-Gabor A. Sensory effects of capsaicin congeners I. Relationship between chemical structure and pain-producing potency of pungent agents. Arzneimittelforschung. 1975;25:1877–1881.
    1. Szolcsanyi J. A pharmacological approach to elucidation of the role of different nerve fibres and receptor endings in mediation of pain. J. Physiol. (Paris) 1977;73:251–259.
    1. Nolano M., Simone D.A., Wendelschafer-Crabb G., Johnson T., Hazen E., Kennedy W.R. Topical capsaicin in humans: Parallel loss of epidermal nerve fibers and pain sensation. Pain. 1999;81:135–145. doi: 10.1016/S0304-3959(99)00007-X.
    1. Simone D.A., Nolano M., Johnson T., Wendelschafer-Crabb G., Kennedy W.R. Intradermal injection of capsaicin in humans produces degeneration and subsequent reinnervation of epidermal nerve fibers: Correlation with sensory function. J. Neurosci. 1998;18:8947–8959.
    1. Szolcsanyi J. Forty years in capsaicin research for sensory pharmacology and physiology. Neuropeptides. 2004;38:377–384. doi: 10.1016/j.npep.2004.07.005.
    1. Hail N., Jr. Mechanisms of vanilloid-induced apoptosis. Apoptosis. 2003;8:251–262. doi: 10.1023/A:1023620821878.
    1. Santha P., Jancso G. Transganglionic transport of choleragenoid by capsaicin-sensitive c-fibre afferents to the substantia gelatinosa of the spinal dorsal horn after peripheral nerve section. Neuroscience. 2003;116:621–627. doi: 10.1016/S0306-4522(02)00701-7.
    1. Jancso G., Dux M., Oszlacs O., Santha P. Activation of the transient receptor potential vanilloid-1 (TRPV1) channel opens the gate for pain relief. Br. J. Pharmacol. 2008;155:1139–1141. doi: 10.1038/bjp.2008.375.
    1. Tewksbury J.J., Nabhan G.P. Seed dispersal. Directed deterrence by capsaicin in chilies. Nature. 2001;412:403–404. doi: 10.1038/35086653.
    1. Tewksbury J.J., Reagan K.M., Machnicki N.J., Carlo T.A., Haak D.C., Penaloza A.L., Levey D.J. Evolutionary ecology of pungency in wild chilies. Proc. Natl. Acad. Sci. USA. 2008;105:11808–11811. doi: 10.1073/pnas.0802691105.
    1. Levey D.J., Tewksbury J.J., Cipollini M.L., Carlo T.A. A field test of the directed deterrence hypothesis in two species of wild chili. Oecologia. 2006;150:61–68. doi: 10.1007/s00442-006-0496-y.
    1. Szolcsányi J., Barthó L. Impaired defense mechanisms to peptic ulcer in the capsaicin desensitized rat. In: Mózsik G.Y., Hänninen O., Jávor T., editors. Advances in Physiological Sciences, Gastrointestinal Defense Mechanisms. Volume 29. Ergamon Press; Budapest, Hungary: 1981. pp. 39–51.
    1. Jessell T.M., Iversen L.L., Cuello A.C. Capsaicin-induced depletion of substance p from primary sensory neurones. Brain Res. 1978;152:183–188. doi: 10.1016/0006-8993(78)90146-4.
    1. Jancso G., Kiraly E., Jancso-Gabor A. Pharmacologically induced selective degeneration of chemosensitive primary sensory neurones. Nature. 1977;270:741–743. doi: 10.1038/270741a0.
    1. Nagy J.I., Iversen L.L., Goedert M., Chapman D., Hunt S.P. Dose-dependent effects of capsaicin on primary sensory neurons in the neonatal rat. J. Neurosci. 1983;3:399–406.
    1. Kissin I., Szallasi A. Therapeutic targeting of TRPV1 by resiniferatoxin, from preclinical studies to clinical trials. Curr. Top. Med. Chem. 2011;11:2159–2170. doi: 10.2174/156802611796904924.
    1. Salat K., Jakubowska A., Kulig K. Zucapsaicin for the treatment of neuropathic pain. Expert Opin. Investig. Drugs. 2014;23:1433–1440. doi: 10.1517/13543784.2014.956079.
    1. Bevan S., Hothi S., Hughes G., James I.F., Rang H.P., Shah K., Walpole C.S., Yeats J.C. Capsazepine: A competitive antagonist of the sensory neurone excitant capsaicin. Br. J. Pharmacol. 1992;107:544–552. doi: 10.1111/j.1476-5381.1992.tb12781.x.
    1. Trbovich M., Yang H. Capsaicin 8% patch for central and peripheral neuropathic pain of persons with incomplete spinal cord injury: Two case reports. Am. J. Phys. Med. Rehabil. 2015;94:e66–e72. doi: 10.1097/PHM.0000000000000301.
    1. Remadevi R., Szallisi A. Adlea (ALGRX-4975), an injectable capsaicin (TRPV1 receptor agonist) formulation for longlasting pain relief. IDrugs. 2008;11:120–132.
    1. Iadarola M.J., Gonnella G.L. Resiniferatoxin for pain treatment: An interventional approach to personalized pain medicine. Open Pain J. 2013;6:95–107. doi: 10.2174/1876386301306010095.
    1. Gaubitz M., Schiffer T., Holm C., Richter E., Pisternick-Ruf W., Weiser T. Efficacy and safety of nicoboxil/nonivamide ointment for the treatment of acute pain in the low back—A randomized, controlled trial. Eur. J. Pain. 2016;20:263–273. doi: 10.1002/ejp.719.
    1. Snitker S., Fujishima Y., Shen H., Ott S., Pi-Sunyer X., Furuhata Y., Sato H., Takahashi M. Effects of novel capsinoid treatment on fatness and energy metabolism in humans: Possible pharmacogenetic implications. Am. J. Clin. Nutr. 2009;89:45–50. doi: 10.3945/ajcn.2008.26561.
    1. Walker K.M., Urban L., Medhurst S.J., Patel S., Panesar M., Fox A.J., McIntyre P. The VR1 antagonist capsazepine reverses mechanical hyperalgesia in models of inflammatory and neuropathic pain. J. Pharmacol. Exp. Ther. 2003;304:56–62. doi: 10.1124/jpet.102.042010.
    1. El Kouhen R., Surowy C.S., Bianchi B.R., Neelands T.R., McDonald H.A., Niforatos W., Gomtsyan A., Lee C.H., Honore P., Sullivan J.P., et al. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel and selective transient receptor potential type V1 receptor antagonist, blocks channel activation by vanilloids, heat, and acid. J. Pharmacol. Exp. Ther. 2005;314:400–409. doi: 10.1124/jpet.105.084103.
    1. Wong G.Y., Gavva N.R. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks. Brain Res. Rev. 2009;60:267–277. doi: 10.1016/j.brainresrev.2008.12.006.
    1. Othman A.A., Nothaft W., Awni W.M., Dutta S. Effects of the TRPV1 antagonist ABT-102 on body temperature in healthy volunteers: Pharmacokinetic/pharmacodynamic analysis of three phase 1 trials. Br. J. Clin. Pharmacol. 2013;75:1029–1040. doi: 10.1111/j.1365-2125.2012.04405.x.
    1. Jts 653. [(accessed on 7 March 2016)]. Available online: .
    1. Japic Clinical Trials Information. [(accessed on 7 March 2016)]. Available online: .
    1. Smith H., Brooks J.R. Capsaicin-based therapies for pain control. Prog. Drug Res. 2014;68:129–146.
    1. Sharma S.K., Vij A.S., Sharma M. Mechanisms and clinical uses of capsaicin. Eur. J. Pharmacol. 2013;720:55–62. doi: 10.1016/j.ejphar.2013.10.053.
    1. Nilius B. Trp channels in disease. Biochim. Biophys. Acta. 2007;1772:805–812. doi: 10.1016/j.bbadis.2007.02.002.
    1. Immke D.C., Gavva N.R. The TRPV1 receptor and nociception. Semin. Cell Dev. Biol. 2006;17:582–591. doi: 10.1016/j.semcdb.2006.09.004.
    1. Evangelista S. Novel therapeutics in the field of capsaicin and pain. Expert Rev. Clin. Pharmacol. 2015;8:373–375. doi: 10.1586/17512433.2015.1044438.
    1. Dworkin R.H., O’Connor A.B., Audette J., Baron R., Gourlay G.K., Haanpaa M.L., Kent J.L., Krane E.J., Lebel A.A., Levy R.M., et al. Recommendations for the pharmacological management of neuropathic pain: An overview and literature update. Mayo Clin. Proc. 2010;85:S3–S14. doi: 10.4065/mcp.2009.0649.
    1. Derry S., Moore R.A. Topical capsaicin (low concentration) for chronic neuropathic pain in adults. Cochrane Database Syst. Rev. 2012;12 doi: 10.1002/14651858.CD010111.
    1. Casanueva B., Rodero B., Quintial C., Llorca J., Gonzalez-Gay M.A. Short-term efficacy of topical capsaicin therapy in severely affected fibromyalgia patients. Rheumatol. Int. 2013;33:2665–2670. doi: 10.1007/s00296-012-2490-5.
    1. Robbins W.R., Staats P.S., Levine J., Fields H.L., Allen R.W., Campbell J.N., Pappagallo M. Treatment of intractable pain with topical large-dose capsaicin: Preliminary report. Anesth. Analg. 1998;86:579–583. doi: 10.1213/00000539-199803000-00027.
    1. Derry S., Sven-Rice A., Cole P., Tan T., Moore R.A. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst. Rev. 2013;2:CD007393.
    1. Treede R.D., Wagner T., Kern K.U., Husstedt I.W., Arendt G., Birklein F., Cegla T., Freynhagen R., Gockel H.H., Heskamp M.L., et al. Mechanism- and experience-based strategies to optimize treatment response to the capsaicin 8% cutaneous patch in patients with localized neuropathic pain. Curr. Med. Res. Opin. 2013;29:527–538. doi: 10.1185/03007995.2013.781019.
    1. Kennedy W.R., Vanhove G.F., Lu S.P., Tobias J., Bley K.R., Walk D., Wendelschafer-Crabb G., Simone D.A., Selim M.M. A randomized, controlled, open-label study of the long-term effects of ngx-4010, a high-concentration capsaicin patch, on epidermal nerve fiber density and sensory function in healthy volunteers. J. Pain. 2010;11:579–587. doi: 10.1016/j.jpain.2009.09.019.
    1. Backonja M., Wallace M.S., Blonsky E.R., Cutler B.J., Malan P., Jr., Rauck R., Tobias J. Ngx-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomised, double-blind study. Lancet Neurol. 2008;7:1106–1112. doi: 10.1016/S1474-4422(08)70228-X.
    1. Irving G.A., Backonja M.M., Dunteman E., Blonsky E.R., Vanhove G.F., Lu S.P., Tobias J. A multicenter, randomized, double-blind, controlled study of ngx-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia. Pain Med. 2011;12:99–109. doi: 10.1111/j.1526-4637.2010.01004.x.
    1. Webster L.R., Peppin J.F., Murphy F.T., Tobias J.K., Vanhove G.F. Tolerability of ngx-4010, a capsaicin 8% patch, in conjunction with three topical anesthetic formulations for the treatment of neuropathic pain. J. Pain Res. 2012;5:7–13. doi: 10.2147/JPR.S25272.
    1. Webster L.R., Nunez M., Tark M.D., Dunteman E.D., Lu B., Tobias J.K., Vanhove G.F. Tolerability of ngx-4010, a capsaicin 8% dermal patch, following pretreatment with lidocaine 2.5%/prilocaine 2.5% cream in patients with post-herpetic neuralgia. BMC Anesthesiol. 2011;11:25. doi: 10.1186/1471-2253-11-25.
    1. Mason L., Moore R.A., Derry S., Edwards J.E., McQuay H.J. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004;328:991. doi: 10.1136/.
    1. Laslett L.L., Jones G. Capsaicin for osteoarthritis pain. Prog. Drug Res. 2014;68:277–291.
    1. Deal C.L., Schnitzer T.J., Lipstein E., Seibold J.R., Stevens R.M., Levy M.D., Albert D., Renold F. Treatment of arthritis with topical capsaicin: A double-blind trial. Clin. Ther. 1991;13:383–395.
    1. McCarthy G.M., McCarty D.J. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J. Rheumatol. 1992;19:604–607.
    1. Altman R.D., Aven A., Holmburg C.E., Pfeifer L.M., Sack M., Young G.T. Capsaicin cream 0.025% as monotherapy for osteoarthritis: A double-blind study. Semin. Arthritis Rheum. 1994;23:25–33. doi: 10.1016/S0049-0172(10)80023-X.
    1. McCleane G. The analgesic efficacy of topical capsaicin is enhanced by glyceryl trinitrate in painful osteoarthritis: A randomized, double blind, placebo controlled study. Eur. J. Pain. 2000;4:355–360. doi: 10.1053/eujp.2000.0200.
    1. Schnitzer T.J., Pelletier J.P., Haselwood D.M., Ellison W.T., Ervin J.E., Gordon R.D., Lisse J.R., Archambault W.T., Sampson A.R., Fezatte H.B., et al. Civamide cream 0.075% in patients with osteoarthritis of the knee: A 12-week randomized controlled clinical trial with a longterm extension. J. Rheumatol. 2012;39:610–620. doi: 10.3899/jrheum.110192.
    1. Kosuwon W., Sirichatiwapee W., Wisanuyotin T., Jeeravipoolvarn P., Laupattarakasem W. Efficacy of symptomatic control of knee osteoarthritis with 0.0125% of capsaicin versus placebo. J. Med. Assoc. Thail. 2010;93:1188–1195.
    1. Schnitzer T.J., Posner M., Lawrence I.D. High strength capsaicin cream for osteoarthritis pain: Rapid onset of action and improved efficacy with twice daily dosing. J. Clin. Rheumatol. 1995;1:268–273. doi: 10.1097/00124743-199510000-00003.
    1. Hochberg M.C., Altman R.D., April K.T., Benkhalti M., Guyatt G., McGowan J., Towheed T., Welch V., Wells G., Tugwell P. American college of rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthrits Care Res. 2012;64:465–474. doi: 10.1002/acr.21596.
    1. Mathew N.T., Reuveni U., Perez F. Transformed or evolutive migraine. Headache. 1987;27:102–106. doi: 10.1111/j.1526-4610.1987.hed2702102.x.
    1. Fusco B.M., Barzoi G., Agro F. Repeated intranasal capsaicin applications to treat chronic migraine. Br. J. Anaesth. 2003;90:812. doi: 10.1093/bja/aeg572.
    1. Marks D.R., Rapoport A., Padla D., Weeks R., Rosum R., Sheftell F., Arrowsmith F. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia. 1993;13:114–116. doi: 10.1046/j.1468-2982.1993.1302114.x.
    1. Fusco B.M., Marabini S., Maggi C.A., Fiore G., Geppetti P. Preventative effect of repeated nasal applications of capsaicin in cluster headache. Pain. 1994;59:321–325. doi: 10.1016/0304-3959(94)90017-5.
    1. Diamond S., Freitag F., Phillips S.B., Bernstein J.E., Saper J.R. Intranasal civamide for the acute treatment of migraine headache. Cephalalgia. 2000;20:597–602. doi: 10.1046/j.1468-2982.2000.00088.x.
    1. Saper J.R., Klapper J., Mathew N.T., Rapoport A., Phillips S.B., Bernstein J.E. Intranasal civamide for the treatment of episodic cluster headaches. Arch. Neurol. 2002;59:990–994. doi: 10.1001/archneur.59.6.990.
    1. Cianchetti C. Capsaicin jelly against migraine pain. Int. J. Clin. Pract. 2010;64:457–459. doi: 10.1111/j.1742-1241.2009.02294.x.
    1. Diaz-Laviada I., Rodriguez-Henche N. The potential antitumor effects of capsaicin. Prog. Drug Res. 2014;68:181–208.
    1. Lin C.H., Lu W.C., Wang C.W., Chan Y.C., Chen M.K. Capsaicin induces cell cycle arrest and apoptosis in human kb cancer cells. BMC Complement. Altern. Med. 2013;13:46. doi: 10.1186/1472-6882-13-46.
    1. Macho A., Calzado M.A., Munoz-Blanco J., Gomez-Diaz C., Gajate C., Mollinedo F., Navas P., Munoz E. Selective induction of apoptosis by capsaicin in transformed cells: The role of reactive oxygen species and calcium. Cell Death Differ. 1999;6:155–165. doi: 10.1038/sj.cdd.4400465.
    1. Zhang R., Humphreys I., Sahu R.P., Shi Y., Srivastava S.K. In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ros generation and mitochondrial death pathway. Apoptosis. 2008;13:1465–1478. doi: 10.1007/s10495-008-0278-6.
    1. Pramanik K.C., Boreddy S.R., Srivastava S.K. Role of mitochondrial electron transport chain complexes in capsaicin mediated oxidative stress leading to apoptosis in pancreatic cancer cells. PLoS ONE. 2011;6:e20151. doi: 10.1371/journal.pone.0020151.
    1. Mori A., Lehmann S., O’Kelly J., Kumagai T., Desmond J.C., Pervan M., McBride W.H., Kizaki M., Koeffler H.P. Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer Res. 2006;66:3222–3229. doi: 10.1158/0008-5472.CAN-05-0087.
    1. Ferreira A.K., Tavares M.T., Pasqualoto K.F., de Azevedo R.A., Teixeira S.F., Ferreira-Junior W.A., Bertin A.M., de-Sa-Junior P.L., Barbuto J.A., Figueiredo C.R., et al. Rpf151, a novel capsaicin-like analogue: In vitro studies and in vivo preclinical antitumor evaluation in a breast cancer model. Tumour Biol. 2015;36:7251–7267. doi: 10.1007/s13277-015-3441-z.
    1. Clark R., Lee J., Lee S.H. Synergistic anticancer activity of capsaicin and 3,3’-diindolylmethane in human colorectal cancer. J. Agric. Food Chem. 2015;63:4297–4304. doi: 10.1021/jf506098s.
    1. Sarkar A., Bhattacharjee S., Mandal D.P. Induction of apoptosis by eugenol and capsaicin in human gastric cancer ags cells—Elucidating the role of p53. Asian Pac. J. Cancer Prev. 2015;16:6753–6759. doi: 10.7314/APJCP.2015.16.15.6753.
    1. Bu H.Q., Cai K., Shen F., Bao X.D., Xu Y., Yu F., Pan H.Q., Chen C.H., Du Z.J., Cui J.H. Induction of apoptosis by capsaicin in hepatocellular cancer cell line smmc-7721 is mediated through ros generation and activation of jnk and p38 mapk pathways. Neoplasma. 2015;62:582–591. doi: 10.4149/neo_2015_070.
    1. Chang H.C., Chen S.T., Chien S.Y., Kuo S.J., Tsai H.T., Chen D.R. Capsaicin may induce breast cancer cell death through apoptosis-inducing factor involving mitochondrial dysfunction. Hum. Exp. Toxicol. 2011;30:1657–1665. doi: 10.1177/0960327110396530.
    1. Chou C.C., Wu Y.C., Wang Y.F., Chou M.J., Kuo S.J., Chen D.R. Capsaicin-induced apoptosis in human breast cancer mcf-7 cells through caspase-independent pathway. Oncol. Rep. 2009;21:665–671.
    1. Thoennissen N.H., O’Kelly J., Lu D., Iwanski G.B., La D.T., Abbassi S., Leiter A., Karlan B., Mehta R., Koeffler H.P. Capsaicin causes cell-cycle arrest and apoptosis in er-positive and -negative breast cancer cells by modulating the EGFR/HER-2 pathway. Oncogene. 2010;29:285–296. doi: 10.1038/onc.2009.335.
    1. Choi C.H., Jung Y.K., Oh S.H. Autophagy induction by capsaicin in malignant human breast cells is modulated by p38 and extracellular signal-regulated mitogen-activated protein kinases and retards cell death by suppressing endoplasmic reticulum stress-mediated apoptosis. Mol. Pharmacol. 2010;78:114–125. doi: 10.1124/mol.110.063495.
    1. De-Sa-Junior P.L., Pasqualoto K.F., Ferreira A.K., Tavares M.T., Damiao M.C., de Azevedo R.A., Camara D.A., Pereira A., de Souza D.M., Parise Filho R. Rpf101, a new capsaicin-like analogue, disrupts the microtubule network accompanied by arrest in the G2/M phase, inducing apoptosis and mitotic catastrophe in the mcf-7 breast cancer cells. Toxicol. Appl. Pharmacol. 2013;266:385–398. doi: 10.1016/j.taap.2012.11.029.
    1. Wutka A., Palagani V., Barat S., Chen X., El Khatib M., Gotze J., Belahmer H., Zender S., Bozko P., Malek N.P., et al. Capsaicin treatment attenuates cholangiocarcinoma carcinogenesis. PLoS ONE. 2014;9:e95605. doi: 10.1371/journal.pone.0095605.
    1. Lee S.H., Richardson R.L., Dashwood R.H., Baek S.J. Capsaicin represses transcriptional activity of beta-catenin in human colorectal cancer cells. J. Nutr. Biochem. 2012;23:646–655. doi: 10.1016/j.jnutbio.2011.03.009.
    1. Yang J., Li T.Z., Xu G.H., Luo B.B., Chen Y.X., Zhang T. Low-concentration capsaicin promotes colorectal cancer metastasis by triggering ros production and modulating AKT/mTOR and stat-3 pathways. Neoplasma. 2013;60:364–372. doi: 10.4149/neo_2013_048.
    1. Oh S.H., Lim S.C. Endoplasmic reticulum stress-mediated autophagy/apoptosis induced by capsaicin (8-methyl-n-vanillyl-6-nonenamide) and dihydrocapsaicin is regulated by the extent of c-Jun NH2-terminal kinase/extracellular signal-regulated kinase activation in wi38 lung epithelial fibroblast cells. J. Pharmacol. Exp. Ther. 2009;329:112–122.
    1. Kim Y.M., Hwang J.T., Kwak D.W., Lee Y.K., Park O.J. Involvement of ampk signaling cascade in capsaicin-induced apoptosis of HT-29 colon cancer cells. Ann. N. Y. Acad. Sci. 2007;1095:496–503. doi: 10.1196/annals.1397.053.
    1. Lu H.F., Chen Y.L., Yang J.S., Yang Y.Y., Liu J.Y., Hsu S.C., Lai K.C., Chung J.G. Antitumor activity of capsaicin on human colon cancer cells in vitro and colo 205 tumor xenografts in vivo. J. Agric. Food Chem. 2010;58:12999–13005. doi: 10.1021/jf103335w.
    1. Lo Y.C., Yang Y.C., Wu I.C., Kuo F.C., Liu C.M., Wang H.W., Kuo C.H., Wu J.Y., Wu D.C. Capsaicin-induced cell death in a human gastric adenocarcinoma cell line. World J. Gastroenterol. 2005;11:6254–6257. doi: 10.3748/wjg.v11.i40.6254.
    1. Park S.Y., Kim J.Y., Lee S.M., Jun C.H., Cho S.B., Park C.H., Joo Y.E., Kim H.S., Choi S.K., Rew J.S. Capsaicin induces apoptosis and modulates mapk signaling in human gastric cancer cells. Mol. Med. Rep. 2014;9:499–502.
    1. Huh H.C., Lee S.Y., Lee S.K., Park N.H., Han I.S. Capsaicin induces apoptosis of cisplatin-resistant stomach cancer cells by causing degradation of cisplatin-inducible aurora-a protein. Nutr. Cancer. 2011;63:1095–1103. doi: 10.1080/01635581.2011.607548.
    1. Meral O., Alpay M., Kismali G., Kosova F., Cakir D.U., Pekcan M., Yigit S., Sel T. Capsaicin inhibits cell proliferation by cytochrome C release in gastric cancer cells. Tumour Biol. 2014;35:6485–6492. doi: 10.1007/s13277-014-1864-6.
    1. Huang S.P., Chen J.C., Wu C.C., Chen C.T., Tang N.Y., Ho Y.T., Lo C., Lin J.P., Chung J.G., Lin J.G. Capsaicin-induced apoptosis in human hepatoma hepg2 cells. Anticancer Res. 2009;29:165–174.
    1. Moon D.O., Kang C.H., Kang S.H., Choi Y.H., Hyun J.W., Chang W.Y., Kang H.K., Koh Y.S., Maeng Y.H., Kim Y.R., et al. Capsaicin sensitizes trail-induced apoptosis through sp1-mediated DR5 up-regulation: Involvement of Ca2+ influx. Toxicol. Appl. Pharmacol. 2012;259:87–95. doi: 10.1016/j.taap.2011.12.010.
    1. Zhang J.H., Lai F.J., Chen H., Luo J., Zhang R.Y., Bu H.Q., Wang Z.H., Lin H.H., Lin S.Z. Involvement of the phosphoinositide 3-kinase/AKT pathway in apoptosis induced by capsaicin in the human pancreatic cancer cell line panc-1. Oncol. Lett. 2013;5:43–48.
    1. Sanchez A.M., Sanchez M.G., Malagarie-Cazenave S., Olea N., Diaz-Laviada I. Induction of apoptosis in prostate tumor pc-3 cells and inhibition of xenograft prostate tumor growth by the vanilloid capsaicin. Apoptosis. 2006;11:89–99. doi: 10.1007/s10495-005-3275-z.
    1. Sanchez A.M., Malagarie-Cazenave S., Olea N., Vara D., Chiloeches A., Diaz-Laviada I. Apoptosis induced by capsaicin in prostate pc-3 cells involves ceramide accumulation, neutral sphingomyelinase, and jnk activation. Apoptosis. 2007;12:2013–2024. doi: 10.1007/s10495-007-0119-z.
    1. Wang P., Sun Y.C., Lu W.H., Huang P., Hu Y. Selective killing of k-ras-transformed pancreatic cancer cells by targeting NAD(P)H oxidase. Chin. J. Cancer. 2015;34:166–176. doi: 10.1186/s40880-015-0012-z.
    1. Pramanik K.C., Fofaria N.M., Gupta P., Ranjan A., Kim S.H., Srivastava S.K. Inhibition of beta-catenin signaling suppresses pancreatic tumor growth by disrupting nuclear β-catenin/tcf-1 complex: Critical role of stat-3. Oncotarget. 2015;6:11561–11574. doi: 10.18632/oncotarget.3427.
    1. Venier N.A., Colquhoun A.J., Sasaki H., Kiss A., Sugar L., Adomat H., Fleshner N.E., Klotz L.H., Venkateswaran V. Capsaicin: A novel radio-sensitizing agent for prostate cancer. Prostate. 2015;75:113–125. doi: 10.1002/pros.22896.
    1. Venier N.A., Yamamoto T., Sugar L.M., Adomat H., Fleshner N.E., Klotz L.H., Venkateswaran V. Capsaicin reduces the metastatic burden in the transgenic adenocarcinoma of the mouse prostate model. Prostate. 2015;75:1300–1311. doi: 10.1002/pros.23013.
    1. Zheng L., Chen J., Ma Z., Liu W., Yang F., Yang Z., Wang K., Wang X., He D., Li L. Capsaicin causes inactivation and degradation of the androgen receptor by inducing the restoration of mir-449a in prostate cancer. Oncol. Rep. 2015;34:1027–1034. doi: 10.3892/or.2015.4055.
    1. Haslam D.W., James W.P. Obesity. Lancet. 2005;366:1197–1209. doi: 10.1016/S0140-6736(05)67483-1.
    1. Whiting S., Derbyshire E., Tiwari B.K. Capsaicinoids and capsinoids. A potential role for weight management? A systematic review of the evidence. Appetite. 2012;59:341–348. doi: 10.1016/j.appet.2012.05.015.
    1. Whiting S., Derbyshire E.J., Tiwari B. Could capsaicinoids help to support weight management? A systematic review and meta-analysis of energy intake data. Appetite. 2014;73:183–188. doi: 10.1016/j.appet.2013.11.005.
    1. Belza A., Frandsen E., Kondrup J. Body fat loss achieved by stimulation of thermogenesis by a combination of bioactive food ingredients: A placebo-controlled, double-blind 8-week intervention in obese subjects. Int. J. Obes. (Lond.) 2007;31:121–130. doi: 10.1038/sj.ijo.0803351.
    1. Zhang L.L., Yan Liu D., Ma L.Q., Luo Z.D., Cao T.B., Zhong J., Yan Z.C., Wang L.J., Zhao Z.G., Zhu S.J., et al. Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ. Res. 2007;100:1063–1070. doi: 10.1161/01.RES.0000262653.84850.8b.
    1. Kang J.H., Tsuyoshi G., Le Ngoc H., Kim H.M., Tu T.H., Noh H.J., Kim C.S., Choe S.Y., Kawada T., Yoo H., et al. Dietary capsaicin attenuates metabolic dysregulation in genetically obese diabetic mice. J. Med. Food. 2011;14:310–315. doi: 10.1089/jmf.2010.1367.
    1. Kang J.H., Goto T., Han I.S., Kawada T., Kim Y.M., Yu R. Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet. Obesity (Silver Spring) 2010;18:780–787. doi: 10.1038/oby.2009.301.
    1. Garami A., Balasko M., Szekely M., Solymar M., Petervari E. Fasting hypometabolism and refeeding hyperphagia in rats: Effects of capsaicin desensitization of the abdominal vagus. Eur. J. Pharmacol. 2010;644:61–66. doi: 10.1016/j.ejphar.2010.07.002.
    1. Joo J.I., Kim D.H., Choi J.W., Yun J.W. Proteomic analysis for antiobesity potential of capsaicin on white adipose tissue in rats fed with a high fat diet. J. Proteome Res. 2010;9:2977–2987. doi: 10.1021/pr901175w.
    1. Stearns A.T., Balakrishnan A., Radmanesh A., Ashley S.W., Rhoads D.B., Tavakkolizadeh A. Relative contributions of afferent vagal fibers to resistance to diet-induced obesity. Dig. Dis. Sci. 2012;57:1281–1290. doi: 10.1007/s10620-011-1968-4.
    1. Saito M., Yoneshiro T. Capsinoids and related food ingredients activating brown fat thermogenesis and reducing body fat in humans. Curr. Opin. Lipidol. 2013;24:71–77. doi: 10.1097/MOL.0b013e32835a4f40.
    1. Hsu C.L., Yen G.C. Effects of capsaicin on induction of apoptosis and inhibition of adipogenesis in 3T3-L1 cells. J. Agric. Food Chem. 2007;55:1730–1736. doi: 10.1021/jf062912b.
    1. Yoshioka M., Lim K., Kikuzato S., Kiyonaga A., Tanaka H., Shindo M., Suzuki M. Effects of red-pepper diet on the energy metabolism in men. J. Nutr. Sci. Vitaminol. (Tokyo) 1995;41:647–656. doi: 10.3177/jnsv.41.647.
    1. Yoshioka M., St-Pierre S., Drapeau V., Dionne I., Doucet E., Suzuki M., Tremblay A. Effects of red pepper on appetite and energy intake. Br. J. Nutr. 1999;82:115–123.
    1. Yoshioka M., Doucet E., Drapeau V., Dionne I., Tremblay A. Combined effects of red pepper and caffeine consumption on 24 h energy balance in subjects given free access to foods. Br. J. Nutr. 2001;85:203–211. doi: 10.1079/BJN2000224.
    1. Westerterp-Plantenga M.S., Smeets A., Lejeune M.P. Sensory and gastrointestinal satiety effects of capsaicin on food intake. Int J. Obes. (Lond.) 2005;29:682–688. doi: 10.1038/sj.ijo.0802862.
    1. Leung F.W. Capsaicin as an anti-obesity drug. Prog. Drug Res. 2014;68:171–179.
    1. Mozsik G. Capsaicin as new orally applicable gastroprotective and therapeutic drug alone or in combination with nonsteroidal anti-inflammatory drugs in healthy human subjects and in patients. Prog. Drug Res. 2014;68:209–258.
    1. Mózsik G., Past T., Habon T., Keszthelyi Z., Perjési P., Kuzma M., Sándor B., Szolcsányi J., Abdel-Salam Omar M.E., Szalai M. Chapter 11: Capsaicin is a new gastrointestinal mucosal protecting drug candidate in humans—Pharmaceutical development and production based on clinical pharmacology. In: Mozsik G., Abdel-Salam Omar M.E., Takeuchi K., editors. Capsaicin—Sensitive Neural Afferentation and the Gastrointestinal Tract: From Bench to Bedside. InTech; Rijeka, Croatia: 2014. pp. 265–364.
    1. Bortolotti M., Coccia G., Grossi G., Miglioli M. The treatment of functional dyspepsia with red pepper. Aliment. Pharmacol. Ther. 2002;16:1075–1082. doi: 10.1046/j.1365-2036.2002.01280.x.
    1. Fuhrer M., Hammer J. Effect of repeated, long term capsaicin ingestion on intestinal chemo- and mechanosensation in healthy volunteers. Neurogastroenterol. Motil. 2009;21:521–527. doi: 10.1111/j.1365-2982.2008.01227.x.
    1. Yeoh K.G., Kang J.Y., Yap I., Guan R., Tan C.C., Wee A., Teng C.H. Chili protects against aspirin-induced gastroduodenal mucosal injury in humans. Dig. Dis. Sci. 1995;40:580–583. doi: 10.1007/BF02064374.
    1. Bortolotti M., Porta S. Effect of red pepper on symptoms of irritable bowel syndrome: Preliminary study. Dig. Dis. Sci. 2011;56:3288–3295. doi: 10.1007/s10620-011-1740-9.
    1. Li Q., Li L., Wang F., Chen J., Zhao Y., Wang P., Nilius B., Liu D., Zhu Z. Dietary capsaicin prevents nonalcoholic fatty liver disease through transient receptor potential vanilloid 1-mediated peroxisome proliferator-activated receptor delta activation. Pflug. Arch. 2013;465:1303–1316. doi: 10.1007/s00424-013-1274-4.
    1. Mozsik G., Szolcsanyi J., Racz I. Gastroprotection induced by capsaicin in healthy human subjects. World J. Gastroenterol. 2005;11:5180–5184.
    1. Prakash U.N., Srinivasan K. Beneficial influence of dietary spices on the ultrastructure and fluidity of the intestinal brush border in rats. Br. J. Nutr. 2010;104:31–39. doi: 10.1017/S0007114510000334.
    1. Prakash U.N., Srinivasan K. Enhanced intestinal uptake of iron, zinc and calcium in rats fed pungent spice principles—Piperine, capsaicin and ginger (zingiber officinale) J. Trace Elem. Med. Biol. 2013;27:184–190. doi: 10.1016/j.jtemb.2012.11.003.
    1. McCarty M.F., DiNicolantonio J.J., O’Keefe J.H. Capsaicin may have important potential for promoting vascular and metabolic health. Open Heart. 2015;2:e000262. doi: 10.1136/openhrt-2015-000262.
    1. Ahuja K.D., Ball M.J. Effects of daily ingestion of chilli on serum lipoprotein oxidation in adult men and women. Br. J. Nutr. 2006;96:239–242. doi: 10.1079/BJN20061788.
    1. Sylvester D.M., LaHann T.R. Effects of capsaicinoids on platelet aggregation. Proc. West. Pharmacol. Soc. 1989;32:95–100.
    1. Meddings J.B., Hogaboam C.M., Tran K., Reynolds J.D., Wallace J.L. Capsaicin effects on non-neuronal plasma membranes. Biochim. Biophys. Acta. 1991;1070:43–50. doi: 10.1016/0005-2736(91)90144-W.
    1. Mittelstadt S.W., Nelson R.A., Daanen J.F., King A.J., Kort M.E., Kym P.R., Lubbers N.L., Cox B.F., Lynch J.J., III Capsaicin-induced inhibition of platelet aggregation is not mediated by transient receptor potential vanilloid type 1. Blood Coagul. Fibrinolysis. 2012;23:94–97. doi: 10.1097/MBC.0b013e32834ddf18.
    1. Harper A.G., Brownlow S.L., Sage S.O. A role for TRPV1 in agonist-evoked activation of human platelets. J. Thromb. Haemost. 2009;7:330–338. doi: 10.1111/j.1538-7836.2008.03231.x.
    1. Ma L., Zhong J., Zhao Z., Luo Z., Ma S., Sun J., He H., Zhu T., Liu D., Zhu Z., et al. Activation of TRPV1 reduces vascular lipid accumulation and attenuates atherosclerosis. Cardiovasc. Res. 2011;92:504–513. doi: 10.1093/cvr/cvr245.
    1. Zvara A., Bencsik P., Fodor G., Csont T., Hackler L., Jr., Dux M., Furst S., Jancso G., Puskas L.G., Ferdinandy P. Capsaicin-sensitive sensory neurons regulate myocardial function and gene expression pattern of rat hearts: A DNA microarray study. FASEB J. 2006;20:160–162. doi: 10.1096/fj.05-4060fje.
    1. Peng J., Li Y.J. The vanilloid receptor TRPV1: Role in cardiovascular and gastrointestinal protection. Eur. J. Pharmacol. 2010;627:1–7. doi: 10.1016/j.ejphar.2009.10.053.
    1. Lo Y.C., Hsiao H.C., Wu D.C., Lin R.J., Liang J.C., Yeh J.L., Chen I.J. A novel capsaicin derivative voa induced relaxation in rat mesenteric and aortic arteries: Involvement of cgrp, no, cgmp, and endothelium-dependent activities. J. Cardiovasc. Pharmacol. 2003;42:511–520. doi: 10.1097/00005344-200310000-00009.
    1. Bratz I.N., Dick G.M., Tune J.D., Edwards J.M., Neeb Z.P., Dincer U.D., Sturek M. Impaired capsaicin-induced relaxation of coronary arteries in a porcine model of the metabolic syndrome. Am. J. Physiol. Heart Circ. Physiol. 2008;294:H2489–H2496. doi: 10.1152/ajpheart.01191.2007.
    1. Yang D., Luo Z., Ma S., Wong W.T., Ma L., Zhong J., He H., Zhao Z., Cao T., Yan Z., et al. Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension. Cell Metab. 2010;12:130–141. doi: 10.1016/j.cmet.2010.05.015.
    1. Chen Q., Zhu H., Zhang Y., Wang L., Zheng L. Vasodilating effect of capsaicin on rat mesenteric artery and its mechanism. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2013;42:177–183. (In Chinese)
    1. Xu X., Wang P., Zhao Z., Cao T., He H., Luo Z., Zhong J., Gao F., Zhu Z., Li L., et al. Activation of transient receptor potential vanilloid 1 by dietary capsaicin delays the onset of stroke in stroke-prone spontaneously hypertensive rats. Stroke. 2011;42:3245–3251. doi: 10.1161/STROKEAHA.111.618306.
    1. Fragasso G., Palloshi A., Piatti P.M., Monti L., Rossetti E., Setola E., Montano C., Bassanelli G., Calori G., Margonato A. Nitric-oxide mediated effects of transdermal capsaicin patches on the ischemic threshold in patients with stable coronary disease. J. Cardiovasc. Pharmacol. 2004;44:340–347. doi: 10.1097/01.fjc.0000137161.76616.85.
    1. Shim W.S., Tak M.H., Lee M.H., Kim M., Koo J.Y., Lee C.H., Oh U. TRPV1 mediates histamine-induced itching via the activation of phospholipase a2 and 12-lipoxygenase. J. Neurosci. 2007;27:2331–2337. doi: 10.1523/JNEUROSCI.4643-06.2007.
    1. Imamachi N., Park G.H., Lee H., Anderson D.J., Simon M.I., Basbaum A.I., Han S.K. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc. Natl. Acad. Sci. USA. 2009;106:11330–11335. doi: 10.1073/pnas.0905605106.
    1. Boyd K., Shea S.M., Patterson J.W. The role of capsaicin in dermatology. Prog. Drug Res. 2014;68:293–306.
    1. Wilson S.R., Bautista D.M. Itch Mechanisms and Treatment. Taylor & Francis Group, LLC.; Oxfordshire, UK: 2014. Role of transient receptor potential channels in acute and chronic itch.
    1. Polydefkis M., Hauer P., Sheth S., Sirdofsky M., Griffin J.W., McArthur J.C. The time course of epidermal nerve fibre regeneration: Studies in normal controls and in people with diabetes, with and without neuropathy. Brain. 2004;127:1606–1615. doi: 10.1093/brain/awh175.
    1. Yu C.S. Study on hif-1alpha gene translation in psoriatic epidermis with the topical treatment of capsaicin ointment. ISRN Pharm. 2011;2011:821874.
    1. Tarng D.C., Cho Y.L., Liu H.N., Huang T.P. Hemodialysis-related pruritus: A double-blind, placebo-controlled, crossover study of capsaicin 0.025% cream. Nephron. 1996;72:617–622. doi: 10.1159/000188949.
    1. Weisshaar E., Dunker N., Gollnick H. Topical capsaicin therapy in humans with hemodialysis-related pruritus. Neurosci Lett. 2003;345:192–194. doi: 10.1016/S0304-3940(03)00511-1.
    1. Sekine R., Satoh T., Takaoka A., Saeki K., Yokozeki H. Anti pruritic effects of topical crotamiton, capsaicin, and a corticosteroid on pruritogen-induced scratching behavior. Exp. Dermatol. 2012;21:201–204. doi: 10.1111/j.1600-0625.2011.01433.x.
    1. Lysy J., Sistiery-Ittah M., Israelit Y., Shmueli A., Strauss-Liviatan N., Mindrul V., Keret D., Goldin E. Topical capsaicin—A novel and effective treatment for idiopathic intractable pruritus ani: A randomised, placebo controlled, crossover study. Gut. 2003;52:1323–1326. doi: 10.1136/gut.52.9.1323.
    1. Lotti T., Teofoli P., Tsampau D. Treatment of aquagenic pruritus with topical capsaicin cream. J. Am. Acad. Dermatol. 1994;30:232–235. doi: 10.1016/S0190-9622(94)70022-2.
    1. Williams S.R., Clark R.F., Dunford J.V. Contact dermatitis associated with capsaicin: Hunan hand syndrome. Ann. Emerg. Med. 1995;25:713–715. doi: 10.1016/S0196-0644(95)70188-5.
    1. Kim-Katz S.Y., Anderson I.B., Kearney T.E., MacDougall C., Hudmon K.S., Blanc P.D. Topical antacid therapy for capsaicin-induced dermal pain: A poison center telephone-directed study. Am. J. Emerg. Med. 2010;28:596–602. doi: 10.1016/j.ajem.2009.02.007.
    1. Peppin J.F., Majors K., Webster L.R., Simpson D.M., Tobias J.K., Vanhove G.F. Tolerability of ngx-4010, a capsaicin 8% patch for peripheral neuropathic pain. J. Pain Res. 2011;4:385–392. doi: 10.2147/JPR.S22954.
    1. Akcay A.B., Ozcan T., Seyis S., Acele A. Coronary vasospasm and acute myocardial infarction induced by a topical capsaicin patch. Turk. Kardiyol. Dern. Ars. 2009;37:497–500.
    1. Papoiu A.D., Yosipovitch G. Topical capsaicin. The fire of a ‘hot’ medicine is reignited. Expert Opin. Pharmacother. 2010;11:1359–1371. doi: 10.1517/14656566.2010.481670.
    1. Harding L.M., Murphy A., Kinnman E., Baranowski A.P. Characterization of secondary hyperalgesia produced by topical capsaicin jelly—A new experimental tool for pain research. Eur. J. Pain. 2001;5:363–371. doi: 10.1053/eujp.2001.0253.
    1. Bode A.M., Cho Y.Y., Zheng D., Zhu F., Ericson M.E., Ma W.Y., Yao K., Dong Z. Transient receptor potential type vanilloid 1 suppresses skin carcinogenesis. Cancer Res. 2009;69:905–913. doi: 10.1158/0008-5472.CAN-08-3263.
    1. Bley K., Boorman G., Mohammad B., McKenzie D., Babbar S. A comprehensive review of the carcinogenic and anticarcinogenic potential of capsaicin. Toxicol. Pathol. 2012;40:847–873. doi: 10.1177/0192623312444471.
    1. Huang X.F., Xue J.Y., Jiang A.Q., Zhu H.L. Capsaicin and its analogues: Structure-activity relationship study. Curr. Med. Chem. 2013;20:2661–2672. doi: 10.2174/0929867311320210004.
    1. Teixeira M.J., Menezes L.M., Silva V., Galhardoni R., Sasson J., Okada M., Duarte K.P., Yeng L.T., Andrade D.C. Liposomal topical capsaicin in post-herpetic neuralgia: A safety pilot study. Arq. Neuropsiquiatr. 2015;73:237–240. doi: 10.1590/0004-282X20140232.
    1. Huang Y.B., Lin Y.H., Lu T.M., Wang R.J., Tsai Y.H., Wu P.C. Transdermal delivery of capsaicin derivative-sodium nonivamide acetate using microemulsions as vehicles. Int. J. Pharm. 2008;349:206–211. doi: 10.1016/j.ijpharm.2007.07.022.
    1. Tavano L., Alfano P., Muzzalupo R., de Cindio B. Niosomes vs microemulsions: New carriers for topical delivery of capsaicin. Colloids Surf. B Biointerfaces. 2011;87:333–339. doi: 10.1016/j.colsurfb.2011.05.041.
    1. Muzzalupo R., Tavano L., Cassano R., Trombino S., Ferrarelli T., Picci N. A new approach for the evaluation of niosomes as effective transdermal drug delivery systems. Eur. J. Pharm. Biopharm. 2011;79:28–35. doi: 10.1016/j.ejpb.2011.01.020.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi