TRPV1 receptor
TRPV1 (Transient Receptor Potential Vanilloid 1): Zucapsaicin is an agonist of the TRPV1 receptor (vanilloid receptor VR1). [1]
- Neuronal Calcium Channel Blocker: It is suggested that zucapsaicin acts as a neuronal calcium channel blocker. [1]

As a TRPV1 agonist, (Z)-capsaicin is the cis isomer of capsaicin. Moreover, (Z)-capsaicin may inhibit calcium channels in neurons [1].

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After oral administration, (Z)-Capsaicin (also known as Zucapsaicin) can significantly reduce nociceptive behavior in rats. In guinea pigs with primary or recurrent experimental genital herpes simplex virus infection, (Z)-capsaicin is also tolerant [1].

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Antinociceptive Effects (Oral Administration in Rats): Zucapsaicin, administered orally, significantly attenuated nociceptive behavior in both phases of the formalin test in adult rats. This effect was observed for a long duration (4-7 days). In the thermal paw withdrawal test, zucapsaicin at tolerable doses produced a protracted and statistically significant increase in thermal response latency, with the effect evolving within more than an hour and less than 24 hours, and lasting for 2-3 days. [1]
- Antinociceptive Effects (Spinal Nerve Ligation Model in Rats): In the Chung model (spinal nerve ligation) of neuropathic pain, the observed inhibitory effect of zucapsaicin was moderate but statistically significant. [1]
- Effects on Genital Herpes Infection (Topical Application in Guinea Pigs): Topical application of zucapsaicin was tested for the treatment of primary or recurrent experimental genital herpes simplex virus infection in guinea pigs. Animals displayed mild discomfort following initial treatment but became rapidly desensitized. Animals treated during the primary infection experienced a long-lasting reduction in recurrent disease. Furthermore, treatment during the latent infection significantly reduced recurrent disease. [1]
- Cardiovascular Effects (Dermal and Oral Studies): In a 9-month chronic dermal toxicity study in minipigs using zucapsaicin cream (concentrations of 0.075%, 0.75%, and 3.75%), electrocardiographic examinations were normal. In a 4-week oral toxicity study in dogs at doses of 0, 3, 10, and 30 mg/kg, electrocardiographic recordings were also normal. [1]

The mechanism of action and clinical indications of zucapsaicin are similar to that of its naturally occurring isomer, capsaicin. However, in contrast to capsaicin, zucapsaicin is better tolerated. In the future, zucapsaicin could become a valuable drug for treating pain relief. Indeed, it is possible, in addition to providing NP relief, that it may have a use in treating osteoarthritic pain, headaches and pain that accompany intestinal diseases.[1]

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Antinociceptive Studies in Rats:** Antinociceptive effects were evaluated in adult rats using the formalin test and thermal paw withdrawal test after oral administration of zucapsaicin. The specific doses used were not detailed in the text. [1]
- **Genital Herpes Study in Guinea Pigs:** Topical treatment with zucapsaicin was administered to guinea pigs to evaluate its effect on primary and recurrent experimental genital herpes simplex virus infection. The specific formulation and dosing regimen were not detailed in the text. [1]
- **Cardiovascular Safety Studies:**
- **Minipig Dermal Study:** A 9-month chronic dermal toxicity study was conducted in minipigs using zucapsaicin cream at concentrations of 0.075%, 0.75%, and 3.75%. Electrocardiographic examinations were performed prior to treatment, at week 1, at 4.5 months, and at 9 months. [1]
- **Dog Oral Study:** A 4-week oral toxicity study was performed in dogs at zucapsaicin doses of 0, 3, 10, and 30 mg/kg. [1]

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Antinociceptive Studies in Rats: Antinociceptive effects were evaluated in adult rats using the formalin test and thermal paw withdrawal test after oral administration of zucapsaicin. The specific doses used were not detailed in the text. [1]
- Genital Herpes Study in Guinea Pigs: Topical treatment with zucapsaicin was administered to guinea pigs to evaluate its effect on primary and recurrent experimental genital herpes simplex virus infection. The specific formulation and dosing regimen were not detailed in the text. [1]
- Cardiovascular Safety Studies:
- Minipig Dermal Study: A 9-month chronic dermal toxicity study was conducted in minipigs using zucapsaicin cream at concentrations of 0.075%, 0.75%, and 3.75%. Electrocardiographic examinations were performed prior to treatment, at week 1, at 4.5 months, and at 9 months. [1]
- Dog Oral Study: A 4-week oral toxicity study was performed in dogs at zucapsaicin doses of 0, 3, 10, and 30 mg/kg. [1]

Absorption, Distribution and Excretion
Capsaicin has a low systemic absorption rate and is mainly distributed at the administration site. Animal studies show a systemic absorption rate of 0.075%. Rat studies indicate that capsaicin and its metabolites, after transdermal administration, are primarily excreted slowly through urine and feces (up to 2/3), with very little exhaled. Metabolism/Metabolites In vitro studies show that capsaicin has a weak to moderate inhibitory effect on various cytochrome P450 enzymes, but due to the low systemic absorption rate, its clinical significance is limited. Biological Half-Life In rats, the elimination half-life of capsaicin and its metabolites is approximately 7 to 11 hours.

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Topical Administration: Minimal systemic absorption of 0.075% zucapsaicin after topical administration was confirmed in rats and minipigs. In minipigs, circulation levels of zucapsaicin were generally below the limit of quantitation (2.5 ng/L). In rats, dose-dependent increases in exposure were observed for creams containing concentrations higher than 0.075%. [1]
- Oral Administration: In rats, a possible first-pass metabolism after oral administration was observed. [1]
- Intravenous Administration (Rats): Rat studies of intravenously administered [14C]-zucapsaicin showed that the half-life for clearance of zucapsaicin and its metabolites is 7-11 hours. [1]
- Distribution (Rats): Tissue distribution profiles of zucapsaicin were similar after dermal and intravenous administration, but differed after oral administration, possibly due to the first-pass effect. [1]
- Elimination (Rats): In rats, the majority of zucapsaicin and its metabolites were eliminated within 72 hours. The metabolism of zucapsaicin in rats was extensive and depended on both sex and route of administration. Zucapsaicin and its metabolites are mainly excreted in urine and feces. [1]
- Human Oral Pharmacokinetics: When administered orally to healthy human volunteers, zucapsaicin was not absorbed (serum levels < 0.01 ng/mL). To avoid gastrointestinal discomfort, an enteric-coated soft gel capsule formulation was developed, which prevented systemic absorption and essentially eliminated abdominal discomfort. [1]

Topical Tolerability: In clinical studies, zucapsaicin (0.075% cream) was better tolerated than capsaicin, with a lower incidence of burning/stinging sensations (statistically significant on the first day of treatment). The incidence of erythema was also lower, though not statistically significant. No serious photoallergic or phototoxic potential was shown for zucapsaicin in healthy adults. [1]
- Gastrointestinal Tolerability: Oral administration of non-enteric-coated zucapsaicin produced more local burning and discomfort in the gastrointestinal tract than comparable dosages of capsaicin. This effect was essentially eliminated when the drug was formulated with an enteric coating. [1]
- Clinical Adverse Events: The most common adverse events observed for topical zucapsaicin 0.075% in clinical trials were application site reactions, such as transient burning or warming sensations after application. This was the most common adverse drug reaction leading to withdrawal and was strongly concentration-dependent. However, the percentage of patients reporting burning sensations decreased over time during a 12-week controlled study. [1]

[1]. Civamide (cis-capsaicin) for treatment of primary or recurrent experimental genital herpes. Antimicrob Agents Chemother. 1999 Nov;43(11):2685-8.

Zucapsaicin belongs to the phenolic and methoxybenzene class of compounds. It is the cis isomer of capsaicin and is a local analgesic used to treat knee osteoarthritis and other neuropathic pain. Capsaicin is a modulator of transient receptor potential cation channel subfamily V member 1 (TRPV-1) (also known as the vanillin receptor or capsaicin receptor 1), which can reduce pain and improve joint function. Capsaicin has also been evaluated for the treatment of a variety of conditions presenting as chronic neuropathic pain, including herpes simplex virus (HSV) infection, cluster headaches, migraines, and knee osteoarthritis. In 2010, Health Canada approved Zucapsaicin as a topical cream under the brand name Zuacta, but it has not yet received approval from the U.S. Food and Drug Administration (FDA). Drug Indications Zucapsaicin is indicated for use in combination with oral COX-2 inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs) to relieve severe pain in adult patients with knee osteoarthritis that is not controlled by oral COX-2 inhibitors or NSAIDs alone, for a duration not exceeding three months. Mechanism of Action Zucapsaicin excites and desensitizes C-fibers by activating TRPV1 receptors on nociceptive neurons. It binds to intracellular sites, initially stimulating TRPV1 channels and causing a burning sensation. Activation of TRPV1 leads to influx of calcium and sodium ions, resulting in cellular depolarization. Following capsaicin-induced hypersensitivity, channel sensitivity is reduced and persistent desensitization (rapid-acting tolerance) occurs through multiple pathways. Desensitization is thought to be dependent on intracellular calcium ion levels. Reduced TRPV1 channel activity and the release of inflammatory neuropeptides produce analgesic effects, thereby relieving pain. Capsaicin activates calcineurin and calcium-dependent protein kinase C isoforms, leading to TRPV1 phosphorylation. TRPV1 phosphorylation enhances responsiveness to capsaicin, strengthens capsaicin- or proton-induced responses, and lowers the temperature threshold for TRPV1 activation. Studies have shown that capsaicin is involved in the activation of phospholipase C, followed by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), leading to TRPV1 inactivation. Rapid tolerance or persistent desensitization is reversible, involving the downregulation of analgesic substances (such as substance P) and the upregulation of analgesic peptides.

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Pharmacodynamics
Zucapsaicin exerts its analgesic effect as a TRPV1 agonist. TRPV1 plays an important physiological role in transmitting chemical, mechanical, and thermal stimuli, as well as pain signals, and is involved in pain modulation and perception. They are mainly distributed in class C sensory nerve fibers and class Aẟ fibers, transmitting sensory information associated with inflammatory and neuropathic pain. Activation of these channels releases somatostatin, calcitonin gene-related peptide (CGRP), and other neuropeptides (neurokine A, carcinin), leading to neurogenic inflammation. Zucapsaicin has also been reported to affect peptidergic neurons through a desensitization mechanism, thereby reducing the levels of calcitonin gene-related peptide (CGRP) and substance P (SP) in the dorsal root ganglion and sciatic nerve.

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Background: Zucapsaicin (civamide) is the synthetic cis isomer of naturally occurring capsaicin. It is an agonist of the TRPV1 receptor. [1]
- Mechanism of Action: The mechanism involves initial activation (causing a burning sensation) followed by a long-lasting refractory state called desensitization, where sensory neurons become unresponsive. This desensitization is thought to result from the depletion of proalgesic substances like substance P and calcitonin gene-related peptide (CGRP) and is the basis for its analgesic effect. [1]
- Clinical Indications (Investigational): Zucapsaicin is under investigation for the relief of neuropathic pain, including postherpetic neuralgia. It has also shown therapeutic efficacy in pain accompanying osteoarthritis of the knee. Other potential uses being explored include the treatment of headaches (migraine, cluster), Crohn's disease, ulcerative colitis, and pain associated with intestinal diseases. [1]
- Clinical Formulations: Various formulations have been developed and tested, including:
- Topical Cream (0.075%): Used for osteoarthritis pain. [1]
- Dermal Patch: Containing 0.210 mg of zucapsaicin per patch, studied for postherpetic neuralgia and post-incisional neuralgia. [1]
- Intranasal Spray (0.01%): Studied for cluster headaches and postherpetic neuralgia of the trigeminal nerve. [1]
- Enteric Capsules: Studied for Crohn's disease and ulcerative colitis. [1]
- Clinical Trial Outcomes: A 12-week randomized controlled trial showed that 0.075% zucapsaicin cream was an effective analgesic for knee osteoarthritis, with efficacy demonstrated for up to 1 year of continuous use. It was effective as monotherapy or as an adjunct to oral COX-2 inhibitors or NSAIDs. [1]

C18H27NO3

305.4119

305.199

C, 70.79; H, 8.91; N, 4.59; O, 15.72

25775-90-0

Capsaicin;404-86-4

1548942

Typically exists as white to off-whit solids at room temperature

1.0±0.1 g/cm3

511.5±50.0 °C at 760 mmHg

71.5-74.5

263.1±30.1 °C

0.0±1.4 mmHg at 25°C

1.524

3.33

2

3

9

22

341

0

O=C(C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C(/[H])=C(/[H])\C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([H])([H])C1C([H])=C([H])C(=C(C=1[H])OC([H])([H])[H])O[H]

YKPUWZUDDOIDPM-VURMDHGXSA-N

InChI=1S/C18H27NO3/c1-14(2)8-6-4-5-7-9-18(21)19-13-15-10-11-16(20)17(12-15)22-3/h6,8,10-12,14,20H,4-5,7,9,13H2,1-3H3,(H,19,21)/b8-6-

(Z)-N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide

Civamide; (Z)-Capsaicin; BRN 4261852; cis-Capsaicin; Zucapsaicin, trade name Civanex.Zucapsaicin; 25775-90-0; cis-Capsaicin; Civamide; Civanex; (Z)-N-(4-Hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide; (Z)-8-Methyl-N-vanillyl-6-nonenamide;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 125 mg/mL (~409.29 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.81 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (6.81 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (6.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)