Zucapsaicin

Zucapsaicin mediates an antinociceptive action via acting as an agonist at TRPV1. TRPV1 play an important physiological role of transducing chemical, mechanical and thermal stimuli as well as pain transduction, and participate in pain modulation and perception. They are mainly distributed in C sensory nerve fibers as well as Aẟ fibers to transmit sensory information involving inflammatory and neuropathic pain, and activation of these channels releases somatostatin, calcitonin gene-related peptide (CGRP) and other neuropeptides (neurokinin A, kassinin), leading to neurogenic inflammation [A19720]. Zucapsaicin is also reported to affect the peptidergic afferent neurons via a desensitization mechanism to decrease the levels of dorsal root ganglia and sciatic calcitonin gene-related peptide (CGRP) and substance P (SP) [L877].

Zucapsaicin mediates an antinociceptive action via acting as an agonist at TRPV1. TRPV1 play an important physiological role of transducing chemical, mechanical and thermal stimuli as well as pain transduction, and participate in pain modulation and perception. They are mainly distributed in C sensory nerve fibers as well as Aẟ fibers to transmit sensory information involving inflammatory and neuropathic pain, and activation of these channels releases somatostatin, calcitonin gene-related peptide (CGRP) and other neuropeptides (neurokinin A, kassinin), leading to neurogenic inflammation. Zucapsaicin is also reported to affect the peptidergic afferent neurons via a desensitization mechanism to decrease the levels of dorsal root ganglia and sciatic calcitonin gene-related peptide (CGRP) and substance P (SP).

Zucapsaicin excites and desensitizes C-fibers via agonist at TRPV1 on nociceptive neurons. It binds to intracellular sites and initially stimulates the channels, causing burning sensation. The mechanism of pharmacological action of zucapsaicin has not been fully understood yet. It is suggested that this compound, similarly to its trans isomer, is an agonist of the vanilloid receptor VR1 (TRPV1) and a neuronal calcium channel blocker.{{cite book | vauthors = Bevan SJ, Docherty RJ | chapter = Cellular mechanisms of the action of capsaicin. | veditors = Wood J | title = Capsaicin in the study of pain. | publisher = Academic Press | location = London, England | date = 1993 | pages = 27–44 }}{{cite journal | vauthors = Anand P, Bley K | title = Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch | journal = British Journal of Anaesthesia | volume = 107 | issue = 4 | pages = 490–502 | date = October 2011 | pmid = 21852280 | pmc = 3169333 | doi = 10.1093/bja/aer260 }} Capsaicin is able to excite and desensitize C-fibers. As such, it is not only able to cause pain, but also exhibit analgesic properties. Initially, it stimulates TRPV1, which is responsible for a burning sensation. This effect is followed by a longlasting refractory state – ‘desensitization’ – during which the previously excited sensory neurons become unresponsive to capsaicin and other stimuli. It was shown that desensitization and tachyphylaxis of TRPV1 channels contribute to capsaicin-induced pain relief.{{cite journal | vauthors = St Pierre M, Reeh PW, Zimmermann K | title = Differential effects of TRPV channel block on polymodal activation of rat cutaneous nociceptors in vitro | journal = Experimental Brain Research | volume = 196 | issue = 1 | pages = 31–44 | date = June 2009 | pmid = 19404626 | doi = 10.1007/s00221-009-1808-3 | s2cid = 25823889 }} Desensitization of TRPV1 represents the main mechanism of its inhibitory function.

Three distinct pathways of capsaicin-induced desensitization have been described: i) activation of calcineurin, which results in dephosphorylation of TRPV1; ii) activation of phospholipase C with the subsequent phosphatidylinositol 4,5-biphosphate hydrolysis (rather controversial) and iii) activation of calcium-dependent protein kinase C isoforms and subsequent channel phosphorylation.Stucky CL, Dubin AE, Jeske NA, et al. Roles of transient receptor potential channels in pain. Brain Res Rev 2009;60(1):2-23{{cite encyclopedia | vauthors = Nilius B, Owsianik G |title=Encyclopedia of Pain |entry=Transient Receptor Potential Family of Ion Channels |date=2013 |publisher=Springer Berlin Heidelberg |journal=Genome Biology |volume=12 |issue=3 |isbn=978-3-642-28752-7 |doi=10.1007/978-3-642-28753-4_202324 |pmid=21401968 |pmc=3129667 |pages=4037}} Desensitization involves both tachyphylaxis (short-term desensitization) and long-term, persistent, desensitization.{{cite journal | vauthors = Szallasi A, Sheta M | title = Targeting TRPV1 for pain relief: limits, losers and laurels | journal = Expert Opinion on Investigational Drugs | volume = 21 | issue = 9 | pages = 1351–69 | date = September 2012 | pmid = 22780443 | doi = 10.1517/13543784.2012.704021 | s2cid = 32934502 }}{{Cite journal |last=Trevisani |first=Marcello |date=26 July 2010 |title=Targeting TRPV1: Challenges and Issues in Pain Management |url=https://benthamopen.com/contents/pdf/TODDISJ/TODDISJ-2-37.pdf |journal=The Open Drug Discovery Journal |volume=2 |issue=3 |pages=37–49 |doi= 10.2174/1877381801002030037 |doi-broken-date=1 November 2024 |doi-access=free|issn=1877-3818}}{{cite journal | vauthors = Khairatkar-Joshi N, Szallasi A | title = TRPV1 antagonists: the challenges for therapeutic targeting | journal = Trends in Molecular Medicine | volume = 15 | issue = 1 | pages = 14–22 | date = January 2009 | pmid = 19097938 | doi = 10.1016/j.molmed.2008.11.004 }} It is suggested that the downregulation of proalgesic substances (such as SP) and upregulation of analgesic peptides are implicated in desensitization.Brederson JD, Kym PR, Szallasi A. Targeting TRP channels for pain relief. Eur J Pharmacol 2013;716:61-76 The exhaustion of SP reserves renders neurons desensitized and refractory. These mechanisms of desensitization are not fully understood. It is thought that the short-term desensitization is related to capsaicin's ability to block the intra-axonal transport of NGF, SP and somatostatin.{{cite journal | vauthors = Papoiu AD, Yosipovitch G | title = Topical capsaicin. The fire of a 'hot' medicine is reignited | journal = Expert Opinion on Pharmacotherapy | volume = 11 | issue = 8 | pages = 1359–71 | date = June 2010 | pmid = 20446852 | doi = 10.1517/14656566.2010.481670 | doi-access = free }}

The desensitization is a reversible phenomenon. It begins a few hours after capsaicin application and may last even several weeks. The reversible desensitization was found useful in the treatment of pain, whereas the site-specific ablation of sensory nerves transmitting pain stimuli is a promising approach (‘molecular scalpel’) to achieve a permanent pain relief in patients suffering from bone cancer pain or HIV-induced neuropathies. Desensitization and depletion of pronociceptive neurotransmitters induce chemical denervation with a loss of function, which is clinically used in osteoarthritis, diabetic neuropathy, psoriasis and others.{{cite journal | vauthors = Palazzo E, Luongo L, de Novellis V, Berrino L, Rossi F, Maione S | title = Moving towards supraspinal TRPV1 receptors for chronic pain relief | journal = Molecular Pain | volume = 6 | pages = 1744-8069-6-66 | date = October 2010 | pmid = 20937102 | pmc = 2959024 | doi = 10.1186/1744-8069-6-66 | doi-access = free }}{{cite journal | vauthors = Lambert DG | title = Capsaicin receptor antagonists: a promising new addition to the pain clinic | journal = British Journal of Anaesthesia | volume = 102 | issue = 2 | pages = 153–5 | date = February 2009 | pmid = 19151045 | doi = 10.1093/bja/aen354 | doi-access = free }}{{cite journal | vauthors = Lambert GA, Davis JB, Appleby JM, Chizh BA, Hoskin KL, Zagami AS | title = The effects of the TRPV1 receptor antagonist SB-705498 on trigeminovascular sensitisation and neurotransmission | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 380 | issue = 4 | pages = 311–25 | date = October 2009 | pmid = 19690836 | doi = 10.1007/s00210-009-0437-5 | s2cid = 11113986 }} In dorsal root ganglia and the sciatic nerve, zucapsaicin decreases levels of SP and CGRP, indicating that it influences peptidergic afferent neurons via a desensitization mechanism{{cite journal | vauthors = Holzer P | title = Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides | journal = Neuroscience | volume = 24 | issue = 3 | pages = 739–68 | date = March 1988 | pmid = 3288903 | doi = 10.1016/0306-4522(88)90064-4 | s2cid = 35325223 }}[41]. When administered topically, the intended targets for zucapsaicin are the neurons that innervate the local area of application. These neurons transmit pain toward the CNS.

Zucapsaicin displays low systemic absorption and localizes at the area of application. In animal studies, systemic absorption is 0.075%.{{cite web | title = Zuacta (zucapsaicin cream) product monograph | url = https://s3-us-west-2.amazonaws.com/drugbank/cite_this/attachments/files/000/001/639/original/zuacta.pdf?1537810886 | publisher = Sanofi Canada }}{{Unreliable medical source|date=March 2024}}{{cite patent | inventor = Bernstein JE | title = Method and compositions of civamide to treat disease of the intestines. | country = WO | number = 2011100668 | pubdate = 2011 }}{{cite journal | vauthors = Schnitzer TJ, Pelletier JP, Haselwood DM, Ellison WT, Ervin JE, Gordon RD, Lisse JR, Archambault WT, Sampson AR, Fezatte HB, Phillips SB, Bernstein JE | title = Civamide cream 0.075% in patients with osteoarthritis of the knee: a 12-week randomized controlled clinical trial with a longterm extension | journal = The Journal of Rheumatology | volume = 39 | issue = 3 | pages = 610–20 | date = March 2012 | pmid = 22089461 | doi = 10.3899/jrheum.110192 | doi-access = free }}

In vitro studies demonstrates weak to moderate inhibitory effects on various cytochrome P450 enzymes, although not clinically significant due to low systemic absorption.

In rat studies, zucapsaicin and its metabolites are slowly excreted into urine and feces (up to 2/3), with minimal elimination via exhalation following dermal administration.

In rats, the elimination half life of zucapsaicin and its metabolites is approximately 7 to 11 hours.

Most common adverse effects involved application site reactions such as transient burning and warm sensation. Other adverse effects observed in clinical trials are eye irritation, arthralgia, aggravated osteoarthritis, burning sensation, headache, cough and sneezing. Oral LD50 in mouse is >87.5 mg/kg in male and <60 mg/kg in females. Oral LD50 in rats is >90 mg/kg in males and >60 mg/kg in females.

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Category:Drugs acting on the musculoskeletal system

Category:Capsaicinoids

Category:Transient receptor potential channel modulators