Cantharidin

Identification

Summary

Cantharidin is a natured product indicated to treat molluscum contagiosum

Brand Names
Cantharone Plus, Ycanth
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.1,2

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 ongoing lack of FDA approval is likely related to certain toxic effects that were observed following oral ingestion, which include ulceration of the gastrointestinal and genitourinary tracts, along with electrolyte and renal function disturbance in humans and animals 1.

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 Nevertheless, it gained its first FDA approval on Jul 21, 2023, under the brand name YCANTH™ by Verrica Pharmaceuticals for the treatment of molluscum contagiosum in adult and pediatric patients.8 The approval was based on positive results from 2 phase III trials, CAMP-1 and CAMP-2, where 46% and 52% of patients treated with cantharidin achieved complete molluscum clearance, respectively.8

Type
Small Molecule
Groups
Approved, Investigational
Structure
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

Cantharidin is approved by the FDA for the topical treatment of molluscum contagiosum in adult and pediatric patients 2 years of age and older.9 It has also been approved by Health Canada for the treatment of common warts (verruca vulgaris), periungual warts, and molluscum contagiosum as a standalone product and resistant and heavily keratinized plantar warts as a combination product with salicylic acid and podophyllin.10

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.1,2,11

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 elucidate any results formally.2

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofMolluscum contagiosum•••••••••••••••••• •••••••••••••••••
Treatment ofMolluscum contagiosum••••••••••••••••••••
Treatment ofMolluscum contagiosum••• •••
Treatment ofPeriungual warts••••••••••••••••••••
Used in combination to treatPlantar wartsCombination Product in combination with: Podophyllin (DB09094), Salicylic acid (DB00936)••••••••••••••••••••
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.11 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. There is consequently no scarring from the topical application of cantharidin.11

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 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 develops within 24 to 48 hours of application and typically resolves 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.

TargetActionsOrganism
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 has 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 were distributed to and exhibited in the bile, kidney, liver, stomach, and tumor cells of ascites hepatoma-bearing mice. Such distribution suggests the agent has an affinity for liver and tumor tissues.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 has been ongoing in 2018.5 There are however some studies regarding such data in animal models like beagle dogs.4

Protein binding

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information has been ongoing in 2018.5 There are however some studies regarding such data in animal models like beagle dogs.4

Metabolism

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information has been ongoing in 2018.5 There are however some studies regarding such data in animal models like beagle dogs.4

Route of elimination

It has been observed that absorbed cantharidin is excreted by the kidney.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 has been ongoing in 2018.5 There are however some studies regarding such data in animal models like beagle dogs.4

Half-life

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information has been ongoing in 2018.5 There are however some studies regarding such data in animal models like beagle dogs.4

Clearance

Little pharmacodynamic and pharmacokinetic data regarding cantharidin in the human body currently exists; recruitment for First-Time-In-Human clinical trials regarding such information has been ongoing in 2018.5 There are however some studies regarding such data in animal models like beagle dogs.4

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

Oral ingestion of cantharidin has resulted in renal failure, blistering and severe damage to the gastrointestinal tract, coagulopathy, seizures, and flaccid paralysis. In the event that YCANTH topical solution is ingested, patients should seek medical attention immediately and contact a Poison Center (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.9

Carcinogenicity studies have not been conducted with cantharidin. Cantharidin was not mutagenic in a bacteria reverse mutation (Ames) assay. An in vitro chromosomal aberration assay in human lymphocytes with cantharidin was inconclusive. Cantharidin was positive in an in vitro micronucleus assay in TK6 cells, primarily through an aneugenic mechanism. The effects of cantharidin on fertility have not been evaluated.9

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
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Cantharidin 0.7%Liquid0.7 g/100gTopicalSincerus Florida, LLC2019-05-17Not applicableUS flag
YcanthSolution3.20 mg/0.45mLTopicalVerrica Pharmaceuticals Inc.2023-07-21Not applicableUS flag
YcanthSolution3.20 mg/0.45mLTopicalVerrica Pharmaceuticals Inc.2023-07-21Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
CANTHACUR PS %1,%5,%30 TOPIKAL SOLUSYON 7,5 MLCantharidin (10.2 mg/ml) + Podophyllin (51 mg/ml) + Salicylic acid (306 mg/ml)SolutionTopicalASSOS İLAÇ KİMYA GIDA ÜRÜNLERİ ÜRETİM VE TİC. A.Ş.2005-06-10Not applicableTurkey flag
Canthacur-PSCantharidin (1 %) + Podophyllin (5 %) + Salicylic acid (30 %)LiquidTopicalPaladin Labs Inc1983-12-312017-05-30Canada flag
Cantharone PlusCantharidin (1 %) + Podophyllin (2 %) + Salicylic acid (30 %)LiquidTopicalDormer Laboratories Inc.1984-12-31Not applicableCanada flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Cantharidin 0.7%Cantharidin (0.7 g/100g)LiquidTopicalSincerus Florida, LLC2019-05-17Not applicableUS flag
Cantharidin 1% / Podophyllum Resin 5% / Salicylic Acid 30%Cantharidin (1 g/100g) + Podophyllin (5 g/100g) + Salicylic acid (30 g/100g)LiquidTopicalSincerus Florida, LLC2019-05-17Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as furofurans. These are organic compounds containing a two furan rings fused to each other. Furan is a five-membered aromatic ring with four carbon atoms and one oxygen atom.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Furofurans
Sub Class
Not Available
Direct Parent
Furofurans
Alternative Parents
Dicarboxylic acids and derivatives / Tetrahydrofurans / Carboxylic acid anhydrides / Lactones / Oxacyclic compounds / Dialkyl ethers / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Aliphatic heteropolycyclic compound / Carbonyl group / Carboxylic acid anhydride / Carboxylic acid derivative / Dialkyl ether / Dicarboxylic acid or derivatives / Ether / Furofuran / Hydrocarbon derivative / Lactone
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
monoterpenoid, cyclic dicarboxylic anhydride (CHEBI:64213)
Affected organisms
  • Humans and other mammals

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
  1. Al-Dawsari NA, Masterpol KS: Cantharidin in Dermatology. Skinmed. 2016 Apr 1;14(2):111-4. eCollection 2016. [Article]
  2. 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]
  3. 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]
  4. Dang Y, Zhu C: [Pharmacokinetics and bioavailability of cantharidin in beagle dogs]. Zhongguo Zhong Yao Za Zhi. 2009 Aug;34(16):2088-91. [Article]
  5. 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]
  6. NLM Toxnet: Catharidine [Link]
  7. TITCK Product Information: Canthacur (cantharidin) topical solution [Link]
  8. Approval of YCANTH™ (cantharidin) topical solution as the First FDA approved Treatment of Pediatric and Adult Patients with Molluscum Contagiosum [Link]
  9. FDA Approved Drug Product: YCANTHTM (cantharidin) topical solution [Link]
  10. Health Canada Approved Drug Proucts: CANTHARONE (Cantharidin) and CANTHARONE PLUS (Cantharidin + salicylic acid + podophyllin) topical solution [Link]
  11. Canthacur (cantharidin 0.7%) Solution for Topical Use Package Insert [File]
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

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SolutionTopical0.7 %
SolutionTopical
LiquidTopical0.7 g/100g
LiquidTopical
SolutionTopical3.20 mg/0.45mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US11147790No2021-10-192038-08-22US flag
US11052064No2021-07-062035-05-28US flag

Properties

State
Not Available
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility16.6 mg/mLALOGPS
logP1.1ALOGPS
logP1.06Chemaxon
logS-1.1ALOGPS
pKa (Strongest Basic)-4.2Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count3Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area52.6 Å2Chemaxon
Rotatable Bond Count0Chemaxon
Refractivity45.4 m3·mol-1Chemaxon
Polarizability18.54 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-0900000000-5d18c0d738f16ee2fef6
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-00di-0900000000-9c1327f4990426b67cd7
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-3900000000-d254d7abb3ad3ba19da5
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-00di-0900000000-d0cdac726fbcbc5b1446
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-01b9-4900000000-de68b7e43d4c795c5680
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-00di-2900000000-d7bb09c895754c598054
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-140.03691
predicted
DeepCCS 1.0 (2019)
[M+H]+142.4325
predicted
DeepCCS 1.0 (2019)
[M+Na]+148.70927
predicted
DeepCCS 1.0 (2019)

Targets

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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
  1. 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 August 01, 2023 19:26