Capsaicin

Absorption

Oral: Following oral administration, capsaicin may be absorbed by a nonactive process from the stomach and whole intestine with an extent of absorption ranging between 50 and 90%, depending on the animal . The peak blood concentration can be reached within 1 hour following administration . Capsaicin may undergo minor metabolism in the small intestine epithelial cells post-absorption from the stomach into the small intestines. While oral pharmacokinetics information in humans is limited, ingestion of equipotent dose of 26.6 mg of pure capsaicin, capsaicin was detected in the plasma after 10 minutes and the peak plasma concentration of 2.47 ± 0.13 ng/ml was reached at 47.1 ± 2.0 minutes .
Systemic: Following intravenous or subcutaneous administration in animals, the concentrations in the brain and spinal cord were approximately 5-fold higher than that in blood and the concentration in the liver was approximately 3-fold higher than that in blood .
Topical: Topical capsaicin in humans is rapidly and well absorbed through the skin, however systemic absorption following topical or transdermal administration is unlikely . For patients receiving the topical patch containing 179 mg of capsaicin, a population analysis was performed and plasma concentrations of capsaicin were fitted using a one-compartment model with first-order absorption and linear elimination. The mean peak plasma concentration was 1.86 ng/mL but the maximum value observed in any patient was 17.8 ng/mL .

Toxicity

Acute oral LD50 and dermal LD50 in mouse are 47.2 mg/kg and >512 mg/kg, respectively . Capsaicin is shown to be mutagenic for bacteria and yeast .
Capsaicin can cause serious irritation, conjunctivitis and lacrimation via contact with eyes. It induces a burning sensation and pain in case of contact with eyes and skin. As it is also irritating to the respiratory system, it causes lung irritation and coughing as well as bronchoconstriction. Other respiratory effects include laryngospasm, swelling of the larynx and lungs, chemical pneumonitis,respiratory arrest and central nervous system effects such as convulsions and excitement . In case of ingestion, gastrointestinal tract irritation may be observed along with a sensation of warmth or painful burning . Symptoms of systemic toxicity include disorientation, fear, loss of body motor control including diminished hand-eye coordination, hyperventilation, tachycardia, and pulmonary oedema . Careful early decontamination is recommended and medical intervention should be initiated for any life-threatening symptoms. In case of contact, individual must be removed from the source of exposure and the contacted skin and mucous membranes should be thoroughly washed with copious amounts of water .

Description

Capsaicin has a mild, warm-herbaceous odor and a burning pungent taste (at 10 ppm). It is used in compounded flavors for sauces where the pungent note is desired. This substance is present in several species of Capsicum (Family, Solanaceae). The sensation of pain, accompanied by irritation and inflammation, is due to substance P depletion from sensory (afferent) nerve fibers. These properties are used to study the physiology of pain and the effects as a counterirritant and gastrointestinal stimulant. This substance may be prepared from 3-chloro-2-isopropyltetrahydropyran; biosynthesis from Capsicum frutescens; separation form cis-capsaicin, pelargonic acid vanilamide, and dihydrocapsaicin, reaction of capsaicin.

Description

The aromatic amide capsaicin is the “hot stuff” in chili peppers and paprika. It takes its name from?Capsicum, the genus to which many peppers belong. It was isolated in 1816; its structure was elucidated in 1920; and it was first synthesized in 1930.

Description

Capsaicin is a terpene alkaloid that has been found in Capsicum and has diverse biological activities. It induces inward currents in HEK293 cells expressing rat transient receptor potential vanilloid 1 (TRPV1; EC₅₀ = 0.64 μM at neutral pH), an effect that can be blocked by the TRPV1 inhibitor A-425619. Capsaicin (10 and 50 μM) decreases LPS-induced prostaglandin E₂ (PGE₂; ) production, as well as reduces LPS- and IFN-induced nitric oxide (NO) release in isolated mouse peritoneal macrophages. Capsaicin induces substance P release in rat spinal cord slices with an EC₅₀ value of 2.3 μM. It reduces acetylcholine- or phenylquinone-induced writhing (ED₅₀s = 1.33 and 1.38 mg/kg, respectively, s.c.) but has no effect on the latency to paw withdrawal in the hot plate test in mice (ED₅₀ = >20 mg/kg, s.c.). Formulations containing capsaicin have been used in the treatment of nerve pain associated with shingles.

Chemical properties

Off-White Crystalline Solid

Chemical properties

Crystalline solid, rectangular plates, or scales. Pungent odor and burning taste.

Chemical properties

N-(4-Hydroxy-3-methoxybenzyl)-8-methyl-6-nonenamide has a mild, warm-herbaceous odor and burning, pungent taste (10 ppm). It is used in compounded flavors for sauces where the pungent note is desired.

Physical properties

Appearance: crystalline white powder, with highly volatile and pungent odor. Solubility: freely soluble in alcohol, ether, benzene, and chloroform; slightly soluble in carbon disulfide, petroleum, and hydrochloric acid; insoluble in water. Melting point: 65?°C.

Occurrence

The pungent principle in the fruits of various Capsicum species (Solanaceae)

History

In 1816, Christian Friedrich Bucholz (1770–1818) first carried out the purification of capsaicin. He obtained incompletely purified capsaicin and named it “capsaicin” . In 1876, John Clough Thresh (1850–1932) further purified and got pure capsaicin and named it capsaicin. In 1919, Nelson identified the capsaicin structure. In 1930, E.?Spath and S.?F. Darling used chemical synthesis method for the first time to successfully synthesize capsaicin. In 1961, the Japanese chemists S.? Kosuge and Y.? Inagaki isolated similar substances from capsicum and named them capsaicinoids.
More than 14 capsaicin homologues have been found till now, the structures are similar with capsaicin, and the typical structure is H3CO(HO)-C6H3-CH2-NHCO-R, which is only different from R group. Capsaicin is the highest content in chili pepper. Capsaicin and dihydrocapsaicin are the most potent active substances in capsicum. Capsaicin and its analogues have been synthesized in large quantities in practice and can be used not only in medicine but also in agriculture and industry. Although there is a long history of pharmacological and chemical studies on capsaicin, until November 16, 2009, the US Food and Drug Administration (FDA) approved the first containing high concentration capsaicin prescription Qutenza (8% capsaicin) patch for the treatment of postherpetic neuralgia. At present, most countries have capsaicin prescription drugs on market, but clinical indications are limited in the treatment of pain.

The Uses of Capsaicin

Capsaicin analogue (C175680). It is used as a tool in neurobiological research. Prototype vanilloid receptor agonist. Topical analgesic.

The Uses of Capsaicin

A representative lot is a 5:1 E:Z mixture. It is used as a tool in neurobiological research. Prototype vanilloid receptor agonist. Topical analgesic.

The Uses of Capsaicin

K channel blocker; multiple sclerosis therapy

The Uses of Capsaicin

analgesic (topical), depletes Substance P, neurotoxic

The Uses of Capsaicin

Capsaicin is used in many topical ointments used to relieve the pain of peripheral neuropathy (treatment of pain in the nerve endings near the surface of the skin).

What are the applications of Application

Capsaicin is a TRPV1 receptor agonist that exhibits neuroprotective effects and reversibly inhibits platelet aggregation.

Indications

The capsaicin 8% patch is indicated in the treatment of neuropathic pain associated with post-herpetic neuralgia. There are multiple topical capsaicin formulations available, including creams and solutions, indicated for temporary analgesia in muscle and join pain as well as neuropathic pain.

Background

Capsaicin is most often used as a topical analgesic and exists in many formulations of cream, liquid, and patch preparations of various strengths; however, it may also be found in some dietary supplements. Capsaicin is a naturally-occurring botanical irritant in chili peppers, synthetically derived for pharmaceutical formulations. The most recent capsaicin FDA approval was Qutenza, an 8% capsaicin patch dermal-delivery system, indicated for neuropathic pain associated with post-herpetic neuralgia.

Indications

Capsaicin (Zostrix) is approved for the relief of pain following herpes zoster infection (postherpetic neuralgia). The drug depletes neurons of substance P, an endogenous neuropeptide that may mediate cutaneous pain. It is applied to affected skin after open lesions have healed. Local irritation is common.

Definition

ChEBI: Capsaicin is a capsaicinoid. It has a role as a non-narcotic analgesic, a voltage-gated sodium channel blocker and a TRPV1 agonist.

General Description

Capsaicin occurs as the active ingredient of hot/red pepper and was first obtained by Thresh in 1846. It is a lipophilic vanilloid compound responsible for the acrid taste of hot peppers.

Mechanism of action

Capsaicin is a member of the vanilloid family, a class of compounds with a vanilla moiety. It acts as an agonist binding to vanilloid receptor subtype 1 (TRPV1 - Transient Receptor Potential V1), which is an ion channel-type transmembrane receptor.Activation of the TRPV1 receptor initiates a depolarising cascade, allowing influx of sodium and calcium ions. TRPV1 receptors are present on C- and A-δ fibres of the nociceptive pathway. When the fibres become depolarised, the signal propagates to the spinal cord and into the brain. And capsaicin reduces pain transmission by desensitising sensory afferent axons.

Biological Activity

Prototypic vanilloid receptor agonist (pEC 50 values are 7.97 and 7.10 at rat and human VR1 receptors respectively). Excites a subset of primary afferent sensory neurons, with subsequent antinociceptive and anti-inflammatory effects. Reversibly inhibits aggregation of platelets. Also available as part of the Vanilloid TRPV1 Receptor Tocriset™ .

Biochem/physiol Actions

Prototype vanilloid receptor agonist. Neurotoxin; activates sensory neurons that give rise to unmyelinated C-fibers, many of which contain substance P. Topical application desensitizes the sensory nerve endings giving a paradoxical antinociceptive effect; systemic administration can be neurotoxic to capsaicin-sensitive cells, especially in newborn animals. Active component of chili peppers.

Pharmacokinetics

Capsaicin is a TRPV1 receptor agonist. TRPV1 is a trans-membrane receptor-ion channel complex activated by temperatures higher than 43 degrees Celsius, pH lower than 6, and endogenous lipids. When activated by a combination of these factors, the channel can transiently open and initiate depolarization due to the influx of calcium and sodium ions. Because TRPV1 is commonly expressed in A-delta and mostly C fibers, depolarization results in action potentials which send impulses to the brain and spinal cord. These impulses result in capsaicin effects of warming, tingling, itching, stinging, or burning. Capsaicin also causes more persistent activation of these receptors compared to the environmental agonists, resulting in a loss of response to many sensory stimuli, described as "defunctionalization". Capsaicin is associated with many enzymatic, cytoskeletal, and osmotic changes, as well as disruption of mitochondrial respiration, impairing nociceptor function for extended periods of time.

Pharmacology

Hbgyes, A. (1878) first reported that capsaicin has a strong stimulating effect, which is the first pharmacological study on capsaicin. And then, a serial of pharmacological effects were discovered. The discovery of capsaicin receptor further explains the mechanism of capsaicin. The capsaicin receptor, also known as transient voltage receptor cation channel V1 (TRPV1), is a nonselective ligand-gated cation channel. TRPV1 is widely distributed in the body, mainly in sensory neurons, and can also be activated by heat and friction damage. Studies on the analgesic effect of capsaicin were carried out earlier and more thoroughly. Capsaicin can act on sensory nerve C primary afferent fibers, bind the end of the neuronal TRPV1 receptor. Capsaicin (1?μM) can result in inward calcium influx, cell depolarization, neuronal excitation, and glutamate release. The sustained neuron excitement and then failure can result in analgesic and antipruritic effects. The mutation of the capsaicin receptor can not only induce obesity but also may be associated with the occurrence of diabetes. Capsaicin can activate and recruit brown fat to prevent obesity. Brown fat can produce non-shivering heat in cold environment and participate in energy consumption. A 10–130?mg daily capsaicin can significantly increase the body’s energy and fat consumption. Capsaicin also has a protective effect on the cardiovascular system. Treatment of capsaicin with rats at a dose of 15?mg/kg can not only promote animal blood circulation and strengthen the cardiovascular function but also reduce the blood pressure , the serum cholesterol, and triglyceride levels. The study result of capsaicin on tumor is still controversial. The epidemiology and basic research have suggested that capsaicin can not only be used as a carcino400 gen but also can prevent cancer. It has been shown that capsaicin can induce cancer cell apoptosis, and animal experiments have shown that prolonged use of capsaicin on the skin can induce skin cancer. Capsaicin is able to scavenge free radicals and inhibit oxidative stress. Capsaicin can promote gastric secretion, increase appetite, relieve flatulence, improve digestive function, and also prevent gastrointestinal infection and diarrhea. Capsaicin can improve the performance of sports and anti-fatigue. Capsaicin is capable of thinning lung mucus, in favor of sputum discharging, enhancing lung tissue perfusion, and preventing and treating emphysema. Capsaicin is also beneficial on psoriasis, frostbite, cold, etc. In addition, capsaicin is also used for the paralysis of peripheral nerve function for hypertension treatment. Capsaicin can be absorbed by the intestine and skin and is able to pass through the blood-brain barrier.

Anticancer Research

Capsaicin is the major pungent ingredient in red and green chili pepper. It is reportedto induce apoptosis selectively in cancer cells and can suppress the activation ofNF-κB through suppression of NF-κB inhibitor IκBα (Aggarwal and Shishodia 2004). It shows anticancer effects in animal models and suppresses carcinogenesisin colon, skin, lung, tongue, and prostate cancers by altering the metabolism ofcarcinogens. It selectively suppresses the human cancer cell growth of prostate,leukemic, glioma, gastric, and hepatic cancers. It inhibited the tumorigenesis linkedand IL-6-induced activation of STAT-3 and STAT3-regulated gene products likecyclin D1, Bcl-2, Bcl-xL, survivin, and VGEF. It arrests cells in G1 phase andinduces apoptosis (Aggarwal et al. 2008; Clark and Lee 2016).

Clinical Use

In clinical practice, capsaicin is mainly used for topical administration, such as in the treatment of osteoarthritis and rheumatoid arthritis pain, diabetic nerve pain, pain after surgery, chemotherapy- or radiotherapy-induced oral pain, psoriasis, etc. Capsaicin irritates the mucous membrane to cause sneezing, nose bleeding, coughing, mucus secretion, tears, bronchoconstriction, breathing difficulties, and other symptoms. The main adverse effects of capsaicin preparations are contact dermatitis, skin inflammation or blisters, and in severe situation burn-like lesion.

Synthesis

From 3-chloro-2-isopropyltetrahydropyran; biosynthesis from Capsicum frutescens; separation from cis-capsaicin, pelargonic acid vanillamide and dihydrocapsaicin; reaction of capsaicin

Potential Exposure

Botanical animal and insect repellent used to repel birds, voles, deer, rabbits, squirrels, insects, and attacking dogs. Capsaicin, which is made from the Capsicum red chili pepper can be used indoors to protect carpets and upholstered furniture, and outdoors to protect fruit and vegetable crops, flowers, ornamental plants, shrubbery, trees, and lawns. It is also used in pepper sprays such as MACE, and as an analgesic in creams, lotions and solid sticks to reduce arthritic, postoperative and neuopathic pain, such as shingles. Capsaicin is obtained by grinding dried, ripe Capsicum frutescens L. chili peppers into a fine powder. The oleoresin is derived by distilling the powder in a solvent and evaporating the solvent. The resulting highly concentrated liquid has little odor but has an extremely pungent taste

Side Effects

Common adverse reactions to Capsaicin topical patch administration include localised symptoms of erythema, pain, itching, oedema, swelling and dryness, as well as hypertension, papules, nausea, vomiting, nasopharyngitis, sinusitis and bronchitis. Rare complications include: abnormal skin odour, cough, dizziness, dysgeusia, headache, sensory dullness, peripheral oedema, peripheral sensory neuropathy and throat irritation.

Metabolism

Capsaicin metabolism after oral administration is unclear, however it is expected to undergo metabolism in the liver with minimal metabolism in the gut lumen. In vitro studies with human hepatic microsomes and S9 fragments indicate that capsaicin is rapidly metabolized, producing three major metabolites, 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin, whereas vanillin was a minor metabolite . It is proposed that cytochrome P450 (P450) enzymes may play some role in hepatic drug metabolism . In vitro studies of capsaicin in human skin suggest slow biotransformation with most capsaicin remaining unchanged.

storage

Room temperature

Shipping

UN2811 Toxic solids, organic, n.o.s., Hazard Class: 6.1; Labels: 6.1-Poisonous materials, Technical Name Required.

Purification Methods

Recrystallise capcaicin from pet ether (b 40-60o), or pet ether/Et2O (9:1). Also purify it by chromatography on neutral Al2O3 (grade V) and elute successively with *C6H6, *C6H6/EtOAc (17:3) then *C6H6/EtOAc (7:3), and distil it at 120o/10-5mm, then repeatedly recrystallise the needles from isopropanol (charcoal). [Crombie et al. J Chem Soc 11025 1955, Bennett & Kirby J Chem Soc(C) 442 1968.] It causes pain and is neurotoxic [Bevan & Szolcsanyi Trends in Pharmacol Sci 11 330 1990, Beilstein 13 IV 2588].

Incompatibilities

Slowly hydrolyzes in water, releasing ammonia and forming acetate salts.

Waste Disposal

Do not discharge into drains or sewers. Dispose of waste material as hazardous waste using a licensed disposal contractor to an approved landfill. Consult with environmental regulatory agencies for guidance on acceptable disposal practices. Incineration with effluent gas scrubbing is recommended. In accordance with 40CFR165, follow recommendations for the disposal of pesticides and pesticide containers. Noncombustible containers should be crushed and buried under more than 40 cm of soil. Must be disposed properly by following package label directions or by contacting your local or federal environmental control agency, or by contacting your regional EPA office

References

1) Gunthorpe et al. (2002) The diversity in the vanilloid (TRPV) receptor family of ion channels; Trends Pharmacol. Sci. 23 183 2) Van Der Stelt and Di Marzo (2004) Endovanilloids. Putative endogenous ligands of transient receptor potential vanilloid 1 channels; Eur. J. Biochem. 271 1827 3) Perkins and Campbell (1992) Capsazepine reversal of the antinociceptive action of capsaicin in vivo; Br. J. Pharmacol. 107 329 4) Kim et al..(2003) Capsaicin exhibits anti-inflammatory property by inhibiting IkB-a degradation in LPS-stimulated peritoneal macrophages; Cell. Signal., 15 299 5) Di Marzo et al. (2001) Hypolocomotor effects in rats of capsaicin and two long chain capsaicin homologues; Eur. J. Pharmacol., 420 123