Cantharidin

Identification

Brand Names

Cantharone Plus

Generic Name

Cantharidin

DrugBank Accession Number

DB12328

Background

Cantharidin is a naturally occurring odorless, colorless fatty substance of the terpenoid class that is produced as an oral fluid in the alimentary canal of the male blister beetle ^1,2. For its natural purpose, the male blister beetle secretes and presents the cantharidin to a female beetle as a copulatory gift during mating. Post-copulation, the female beetle places the cantharidin over her eggs as protection against any potential predators.

Available synthetically since the 1950s, topical applications of cantharidin have been used predominantly as a treatment for cutaneous warts since that time ^1,2. In 1962 however, marketers of cantharidin failed to produce sufficient efficacy data, resulting in the FDA revision of approval of cantharidin ².

Today, topical cantharidin products do not necessarily demonstrate any particular better effectiveness at treating topical skin conditions like warts than other commonly available vesicant and/or keratolytics although various studies have also investigated the possibility of using cantharidin as an inflammatory model or in cancer treatment ². Regardless, the onging lack of FDA approval is likely related to certain toxic effects that were observed following oral ingestion, which includes ulceration of the gastrointestinal and genitourinary tracts, along with electrolyte and renal function disturbance in humans and animals ¹.

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 196.202
Monoisotopic: 196.073558866
Chemical Formula: C₁₀H₁₂O₄

Synonyms

1,2-Dimethyl-3,6-epoxyperhydrophthalic anhydride
Cantharidin
Cantharidine
Cantharone
exo-1,2-cis-Dimethyl-3,6-epoxyhexahydrophthalic anhydride
Kantharidin

Pharmacology

Indication

The only therapeutic use for which cantharidin is currently primarily indicated for is as an active ingredient in topical agents for treating common warts (verruca vulgaris), periungual warts, plantar warts, and molluscum contagiosum ^1,2,8.

At the same time, such topical cantharidin applications have also been used for a number of off-label indications like callus removal, cutaneous leishmaniasis, herpes zoster, and acquired perforating dermatosis ². Furthermore, since most topical cantharidin applications are most commonly available in a 0.7% formulation or a more potent 1% mixture, the 0.7% formulation is most commonly indicated for the treatment of common warts, periungual warts, and molluscum contagiosum while the more potent 1% mixture is typically limited only for use by healthcare professionals in a clinical setting for treating plantar warts and other more specialized off-label conditions ^1,2,8.

Moreover, there have also been studies into whether or not cantharidin could be effective at being used as an inflammatory model or in cancer treatment - either of which has yet to formally elucidate any results ².

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Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Cantharidin is a natural toxin produced by the blistering beetle that possesses both vesicant (blistering) and keratolytic effects ^1,2. The substance elicits these effects by inducing acantholysis (loss of intercellular connections) through the targeting of the desmosomal dense plaque, resulting in the detachment of the desmosomes from the tonofilaments ^1,2. Cantharidin's effectiveness against warts is proposed to be a result of the exfoliation of the wart body as a consequence of the compound's acantholytic action ⁸. This acantholytic action generally does not go beyond the epidermal cells so that the basal layer remains intact and minimal effect occurs on the corium ⁸. There is consequently no scarring from the topical application of cantharidin ⁸.

Mechanism of action

Cantharidin is specifically absorbed by lipids in the membrane of epidermal keratinocytes, where it activates the release of neutral serine proteases ^1,2. These enzymes subsequently break the peptide bonds in surrounding proteins, leading to the progressive degeneration of desmosomal dense plaques, which are important cellular structures that participate in cell-to-cell adhesion ^1,2. Such degeneration results in the detachment of the tonofilaments that hold cells together. This process as a whole leads to the selective acantholysis (loss of cellular connections) and blistering of the skin when the cantharidin topical application is applied upon specific topical developments like warts ^1,2. A blister(s) at the application site develop within 24 to 48 hours of application and typically resolve within 4 to 7 days ^1,2. Factors that can modify this proposed time frame include the volume or concentration of cantharidin used, physical contact time of the applied compound (usually between 4 to 24 hours), the presence of any occlusive dressings, or even patient sensitivity to cantharidin ^1,2. The blistered lesions ultimately heal without scarring ^1,2.

Finally, there are some studies that suggest cantharidin's chemical profile as a potent and selective inhibitor of protein phosphatase 2A confers upon it an oxidative stress-independent growth inhibition of pancreatic cancer cells through cancer cell-cycle arrest and apoptosis ³.

Nevertheless, the fact that little data regarding the pharmacodynamics and pharmacokinetics of cantharidin in the human body exists ⁵ and certain toxic effects of cantharidin that have been observed following oral ingestion in humans like ulceration of the gastrointestinal and genitourinary tracts, along with electrolyte and renal function disturbance ¹ are strong reasons as to why the compound currently lacks FDA approval is used fairly limitedly for formal therapeutic indications.

Target	Actions	Organism
UAryl hydrocarbon receptor	agonist	Humans

Absorption

Cantharidin is absorbed from the gastrointestinal tract, and, to a limited extent from the skin as well ⁶.

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information have been ongoing in 2018 ⁵. There are however some studies regarding such data in animal models like beagle dogs ⁴.

Volume of distribution

After oral or IP injection of (3)H-labeled cantharidin, high levels of radioactivity distributed to and were exhibited in the bile, kidney, liver, stomach, and tumor cells of ascites hepatoma-bearing mice ⁶. Such distribution suggests the agent has an affinity for liver and tumor tissues ⁶.

Protein binding

Metabolism

Route of elimination

It has been observed that absorbed cantharidin is excreted by the kidney ⁶.

Half-life

Clearance

Adverse Effects

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Toxicity

Side effects observed from the topical application of cantharidin include blistering, erythema, pain, bleeding, ring warts, post-inflammatory hyperpigmentation, lymphangitis, secondary bacterial cellulitis, scarring, and varicelliform vesicular dermatitis ².

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions: This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Not Available
Food Interactions: No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Cantharidin 0.7%	Liquid	0.7 g/100g	Topical	Sincerus Florida, LLC	2019-05-17	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End
CANTHACUR PS %1,%5,%30 TOPIKAL SOLUSYON 7,5 ML	Cantharidin (10.2 mg/ml) + Podophyllin (51 mg/ml) + Salicylic acid (306 mg/ml)	Solution	Topical	ASSOS İLAÇ KİMYA GIDA ÜRÜNLERİ ÜRETİM VE TİC. A.Ş.	2020-08-14	Not applicable
Canthacur-PS	Cantharidin (1 %) + Podophyllin (5 %) + Salicylic acid (30 %)	Liquid	Topical	Paladin Labs Inc	1983-12-31	2017-05-30
Cantharone Plus	Cantharidin (1 %) + Podophyllin (2 %) + Salicylic acid (30 %)	Liquid	Topical	Dormer Laboratories Inc.	1984-12-31	Not applicable

Unapproved/Other Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
Cantharidin 0.7%	Cantharidin (0.7 g/100g)	Liquid	Topical	Sincerus Florida, LLC	2019-05-17	Not applicable
Cantharidin 1% / Podophyllum Resin 5% / Salicylic Acid 30%	Cantharidin (1 g/100g) + Podophyllin (5 g/100g) + Salicylic acid (30 g/100g)	Liquid	Topical	Sincerus Florida, LLC	2019-05-17	Not applicable

Chemical Identifiers

UNII: IGL471WQ8P
CAS number: 56-25-7
InChI Key: DHZBEENLJMYSHQ-XCVPVQRUSA-N
InChI: InChI=1S/C10H12O4/c1-9-5-3-4-6(13-5)10(9,2)8(12)14-7(9)11/h5-6H,3-4H2,1-2H3/t5-,6+,9+,10-
IUPAC Name: (1R,2S,6R,7S)-2,6-dimethyl-4,10-dioxatricyclo[5.2.1.0²,⁶]decane-3,5-dione
SMILES: [H][C@]12CC[C@]([H])(O1)[C@]1(C)C(=O)OC(=O)[C@]21C

References

General References

Al-Dawsari NA, Masterpol KS: Cantharidin in Dermatology. Skinmed. 2016 Apr 1;14(2):111-4. eCollection 2016. [Article]
Torbeck R, Pan M, DeMoll E, Levitt J: Cantharidin: a comprehensive review of the clinical literature. Dermatol Online J. 2014 Jun 15;20(6). [Article]
Li W, Xie L, Chen Z, Zhu Y, Sun Y, Miao Y, Xu Z, Han X: Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis. Cancer Sci. 2010 May;101(5):1226-33. doi: 10.1111/j.1349-7006.2010.01523.x. Epub 2010 Feb 5. [Article]
Dang Y, Zhu C: [Pharmacokinetics and bioavailability of cantharidin in beagle dogs]. Zhongguo Zhong Yao Za Zhi. 2009 Aug;34(16):2088-91. [Article]
NIH ClinicalTrials.gov: First-time-in-Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699 [Link]
NLM Toxnet: Catharidine [Link]
TITCK Product Information: Canthacur (cantharidin) topical solution [Link]
Canthacur (cantharidin 0.7%) Solution for Topical Use Package Insert [File]

External Links

KEGG Compound: C16778
PubChem Compound: 5944
PubChem Substance: 347828590
ChemSpider: 5731
BindingDB: 50090505
RxNav: 1984
ChEBI: 64213
ChEMBL: CHEMBL48449
ZINC: ZINC000017611186
Wikipedia: Cantharidin

MSDS

Download (26.4 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Warts, Genital	1
4	Not Yet Recruiting	Treatment	Molluscum Contagiosum Skin Infection / Verruca Vulgaris	1
3	Completed	Treatment	Molluscum Contagiosum	2
2	Completed	Treatment	Condylomata Acuminata / Papillomavirus Infections / Sexually Transmitted Disease (STD) / Sexually Transmitted Diseases, Viral / Skin Diseases / Skin Diseases, Infectious / Skin Diseases, Viral / Verruca (Warts)	1
2	Completed	Treatment	DNA Virus Infections / Papillomavirus Infections / Skin Diseases / Skin Diseases, Infectious / Skin Diseases, Viral / Tumor Virus Infections / Verruca (Warts) / Verruca Vulgaris / Virus Diseases / Warts Hand	1
2	Completed	Treatment	Molluscum Contagiosum	2
1	Completed	Diagnostic	Rheumatoid Arthritis	1
1	Completed	Other	Inflammation	1
0	Completed	Basic Science	Cardiovascular Function	1
Not Available	Completed	Treatment	Molluscum Contagiosum, Skin Disease	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Solution	Topical
Solution	Topical
Liquid	Topical	0.7 g/100g
Liquid	Topical

Prices

Not Available

Patents

Not Available

Properties

State

Not Available

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	16.6 mg/mL	ALOGPS
logP	1.1	ALOGPS
logP	1.06	ChemAxon
logS	-1.1	ALOGPS
pKa (Strongest Basic)	-4.2	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	0	ChemAxon
Polar Surface Area	52.6 Å²	ChemAxon
Rotatable Bond Count	0	ChemAxon
Refractivity	45.4 m³·mol^-1	ChemAxon
Polarizability	18.54 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Details1. Aryl hydrocarbon receptor

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Agonist

General Function: Transcription regulatory region dna binding
Specific Function: Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes...
Gene Name: AHR
Uniprot ID: P35869
Uniprot Name: Aryl hydrocarbon receptor
Molecular Weight: 96146.705 Da

References

Zhang S, Qin C, Safe SH: Flavonoids as aryl hydrocarbon receptor agonists/antagonists: effects of structure and cell context. Environ Health Perspect. 2003 Dec;111(16):1877-82. [Article]

Drug created at October 20, 2016 21:57 / Updated at October 21, 2021 04:40

Cantharidin

Identification

Structure for Cantharidin (DB12328)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

References