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Tolnaftate
Tolnaftate
Tolnaftate
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Tolnaftate
Clinical data
Trade namesTinactin
Other names2-Naphthyl N-methyl-N-(3-tolyl)thionocarbamate[1]
AHFS/Drugs.comMonograph
MedlinePlusa682617
ATC code
Legal status
Legal status
Identifiers
  • O-2-Naphthyl methyl(3-methylphenyl)thiocarbamate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.017.516 Edit this at Wikidata
Chemical and physical data
FormulaC19H17NOS
Molar mass307.41 g·mol−1
3D model (JSmol)
Melting point110 to 111.5 °C (230.0 to 232.7 °F)
  • S=C(Oc2ccc1c(cccc1)c2)N(c3cc(ccc3)C)C
  • InChI=1S/C19H17NOS/c1-14-6-5-9-17(12-14)20(2)19(22)21-18-11-10-15-7-3-4-8-16(15)13-18/h3-13H,1-2H3 checkY
  • Key:FUSNMLFNXJSCDI-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Tolnaftate (INN),[1] sold under the brand name TAGRID, among others, is a synthetic thiocarbamate used as an anti-fungal agent that may be sold without medical prescription in most jurisdictions. It is supplied as a cream, powder, spray, liquid, and liquid aerosol.[2] Tolnaftate is used to treat fungal conditions such as jock itch, athlete's foot and ringworm.[2] Tolnaftate was discovered by Teruhisa Noguchi in 1962 while he was working for the Nippon Soda Company.[3]

Mechanism

[edit]

Although the exact mechanism of action is not entirely known, it is believed to inhibit squalene epoxidase,[4] an important enzyme in the biosynthetic pathway of ergosterol (a key component of the fungal cell membrane) in a similar way to terbinafine.[5]

Uses

[edit]

Tolnaftate has been found to be generally slightly less effective than azoles when used to treat tinea pedis (athlete's foot). It is, however, useful when dealing with ringworm, especially when passed from pets to humans.[6]

Side effects

[edit]

Side effects that may occur include:[7]

Less severe side effects include:[7]

  • dry skin
  • mild skin irritation, burning, or itching at the affected area

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Tolnaftate

View on Grokipedia
from Grokipedia
Tolnaftate is a synthetic agent classified as a thiocarbamate, primarily used to treat superficial fungal skin infections caused by dermatophytes, including (tinea pedis), jock itch (), and ringworm (). It is available over-the-counter in various formulations such as creams, powders, sprays, and liquid aerosols, often under brand names like Tinactin. Developed in the early , tolnaftate was first synthesized by researchers at the Nippon Soda Company and gained approval as an over-the-counter medication in the United States in 1965, marking it as one of the early effective topical antifungals for common dermatophytoses. Its , O-naphthalen-2-yl N-methyl-N-(3-methylphenyl)carbamothioate (molecular formula C₁₉H₁₇NOS), allows it to target fungal cell membranes specifically. The mechanism of action involves inhibition of squalene epoxidase, an essential for biosynthesis in fungal cells, leading to accumulation of , disruption of the fungal , distortion of hyphae, and stunted mycelial growth. This fungistatic effect is particularly potent against dermatophytes like Trichophyton and Microsporum species but shows limited activity against yeasts such as . Clinical studies have demonstrated high , with treatment success rates often exceeding 80% for tinea infections after 2–4 weeks of twice-daily application, and it is generally well-tolerated with minimal side effects like mild . Beyond standard dermatophytoses, tolnaftate has shown utility in treating (palms), tinea pedis (soles), and certain cases of . As a non-systemic agent with negligible systemic absorption, it offers a generally safe profile for topical use; however, use during should be discussed with a healthcare provider.

Chemical Properties

Molecular Structure and Synthesis

Tolnaftate is a synthetic thiocarbamate agent with the C19H17NOS and a of 307.41 g/mol. It is structurally described as a monothiocarbamic derived from and methyl(3-tolyl)carbamothioate, with the IUPAC name O-(naphthalen-2-yl) N-methyl-N-(3-methylphenyl)carbamothioate. This structure features a thiocarbamate functional group linking a naphthalene ring to a substituted moiety, contributing to its overall chemical stability. The synthesis of tolnaftate involves a multi-step process beginning with the reaction of and to form 2-naphthyl chlorothionoformate, followed by of this intermediate with N-methyl-m-toluidine (also known as N-methyl-3-methylaniline) in the presence of a base such as . This proceeds under mild conditions to yield the target thiocarbamate ester, typically in equimolar proportions to ensure efficient coupling of the components. Tolnaftate exhibits high , characterized by an XLogP value of 5.5, which enhances its ability to penetrate lipid-rich environments such as the . This property arises from the hydrophobic aromatic rings and the non-polar thiocarbamate linkage in its molecular framework.

Physical and Pharmacological Characteristics

Tolnaftate appears as a white to off-white fine powder, which is characteristic of its solid form used in pharmaceutical preparations. Its ranges from 110.5°C to 111.5°C, indicating thermal stability suitable for incorporation into topical formulations without degradation during manufacturing processes. The compound exhibits low solubility in (<0.1 g/100 mL at 22°C), rendering it insoluble for aqueous systems, but it is highly soluble in (50 mg/mL) and sparingly soluble in or , which influences its formulation primarily in lipophilic vehicles for dermatological applications. Tolnaftate maintains stability under dry, sealed conditions at 2–8°C, ensuring long-term integrity in storage and preventing or other degradative reactions. With a low molecular weight of 307.4 Da, it facilitates penetration into the and accumulation therein, enhancing its efficacy as a agent. The predicted pKa of approximately -0.35 underscores tolnaftate's non-ionizable nature at physiological , while its estimated logP of 5.14 (or XLogP of 5.5) highlights its pronounced , which supports targeted delivery to lipid-rich layers and minimizes systemic absorption in dermatological use. This physicochemical profile, including the structural basis of lipophilicity from its aromatic moieties, optimizes tolnaftate for stable, effective topical formulations.

Pharmacology

Mechanism of Action

Tolnaftate exerts its antifungal activity primarily by inhibiting the enzyme squalene epoxidase in the biosynthesis pathway of susceptible fungi. This inhibition prevents the conversion of to squalene epoxide, a critical intermediate in the production of , which is an essential component of the fungal . As a result, accumulates within the fungal cells, while levels deplete, leading to disrupted membrane integrity, altered , and impaired cellular functions such as nutrient transport and hyphal growth. The accumulation of is particularly toxic to fungi, contributing to further damage and inhibition of mycelial development, which ultimately results in fungistatic or fungicidal effects depending on the concentration and exposure duration. Tolnaftate demonstrates strong activity against dermatophytes, such as species of (e.g., T. rubrum and T. mentagrophytes), , and Epidermophyton, where it effectively blocks synthesis. However, its spectrum is narrow, with limited efficacy against yeasts like Candida species, as these organisms may have alternative pathways or lower sensitivity to squalene epoxidase inhibition. Tolnaftate shares a similar mechanism with antifungals like terbinafine, both acting as noncompetitive inhibitors of epoxidase, though tolnaftate belongs to the thiocarbamate class. Unlike antifungals, which primarily target 14α-demethylase later in the pathway, tolnaftate's action is focused upstream at the epoxidation step. Its relative selectivity for fungal cells over human cells arises from greater inhibition of the fungal epoxidase compared to the mammalian enzyme, despite similarities in the early steps of biosynthesis pathways. This specificity, combined with topical application, minimizes toxicity to mammalian cells, supporting tolnaftate's safe topical use.

Pharmacokinetics and Metabolism

Tolnaftate demonstrates minimal systemic absorption when applied topically to intact , enabling its effects to be confined primarily to the where dermatophytes reside. This limited penetration is attributed to the drug's lipophilic nature and the of the , resulting in negligible uptake even with repeated applications. Distribution of tolnaftate occurs predominantly at the site of application, with the drug binding to in the superficial layers and achieving low to undetectable plasma concentrations. Due to this localized retention and poor absorption, systemic distribution is insignificant, minimizing the potential for widespread tissue exposure or drug interactions. The overall is thus negligible, further reducing risks associated with systemic exposure. Data on tolnaftate's and elimination are limited, as the is intended solely for topical use with no established systemic pharmacokinetic profile in humans. However, the majority of the applied dose remains unchanged in the skin and is cleared through natural epidermal turnover and rather than renal or hepatic pathways. The is not well-defined for topical administration, reflecting this non-systemic clearance mechanism.

Clinical Applications

Indications and Efficacy

Tolnaftate is primarily indicated for the topical treatment of superficial dermatophytoses caused by fungi such as Trichophyton, Microsporum, and Epidermophyton species. These include tinea pedis (athlete's foot), tinea cruris (jock itch), and tinea corporis (ringworm), where it effectively targets localized skin infections without systemic involvement. It is also used for tinea versicolor, a superficial infection caused by Malassezia species, though alternative agents like selenium sulfide may be preferred for extensive cases. Clinical efficacy data support tolnaftate's role in these conditions, particularly against Trichophyton-induced ringworm, with rates ranging from 80% to 90% in responsive cases following 2-4 weeks of twice-daily application. For tinea pedis, mycological rates are moderate at 60-70%, outperforming but generally lower than those achieved with antifungals like clotrimazole (up to 80% ). A Cochrane of topical antifungals for infections of the foot confirms tolnaftate's efficacy relative to , with a for treatment failure of 0.46 (95% CI 0.17-1.22), though allylamines and show superior mycological clearance in comparative trials. Tolnaftate has also demonstrated effectiveness against zoonotic ringworm transmitted from pets, as it targets the same species like . Limitations of tolnaftate include its narrow spectrum, rendering it ineffective against deep or systemic fungal infections, non-dermatophyte fungi such as Candida species, or severe cases requiring broader coverage. Additionally, tolnaftate is not effective for bacterial infections, such as those associated with ingrown toenails (characterized by acute swelling, spreading redness, and pus-like discharge), which require antibacterial treatment; using tolnaftate in such cases would not address the bacterial component and could delay appropriate healing. It is not recommended as first-line for extensive or inflammatory dermatophytoses, where oral antifungals may be necessary. Off-label, tolnaftate is occasionally used in combination with oral antifungals like terbinafine for resistant superficial infections to enhance local penetration and reduce recurrence.

Dosage Forms and Administration

Tolnaftate is available in several topical , primarily at a concentration of 1% w/w, including , , solution, spray ( liquid or ), and . For administration, a thin layer of the , , or solution should be applied to the clean, dry affected area, such as skin infected with tinea pedis, and gently rubbed in until mostly absorbed, typically twice daily. Powder forms are sprinkled on the affected area, particularly between toes for tinea pedis, and may also be applied to socks and shoes; sprays are shaken well and applied from 6 to 10 inches away to avoid inhalation. Treatment duration varies by indication but generally involves application for 2 to 4 weeks for conditions like tinea pedis or , and 2 weeks for , with continuation for 1 to 2 weeks after symptoms resolve to prevent recurrence. In cases of hyperkeratotic skin, therapy may extend to 4 to 6 weeks. Full compliance with the prescribed course is essential, even if symptoms improve earlier. Special instructions include washing hands thoroughly after application to prevent spread of , and avoiding contact with the eyes, nose, mouth, or mucous membranes, as tolnaftate is for external use only. Occlusive dressings should not be used unless specifically directed by a healthcare provider. Dosing is the same for pediatric patients aged 2 years and older, and for geriatric adults, with application twice daily as for general adult use; it is not recommended for children under 2 years without medical supervision.

Safety Profile

Adverse Effects

Tolnaftate, when applied topically, is generally well-tolerated, with most adverse effects being mild and localized to the site of application. Common side effects include local skin irritation, redness, burning, itching, or dryness, which typically occur in a small of users based on clinical observations. Rare adverse effects encompass allergic contact dermatitis or sensitization manifesting as hypersensitivity reactions, as well as stinging at the application site; these have been documented in isolated case reports and post-marketing surveillance. Systemic effects are negligible due to minimal percutaneous absorption, with no reports of severe toxicity in clinical use as of 2025. Management of adverse effects involves discontinuing use if severe develops, providing symptomatic with emollients for mild cases, and reporting persistent reactions to a healthcare provider. For individuals with a history suggestive of , patch testing is recommended prior to initiation to assess potential . The frequency of these effects is derived from clinical reports and trials through 2025, indicating low overall incidence.

Contraindications and Special Populations

Tolnaftate is contraindicated in individuals with known to tolnaftate or other thiocarbamate antifungals, as well as to any components of the formulation, due to the risk of allergic reactions. Additionally, it should not be applied to open wounds or mucous membranes, as it is intended for external use only on intact to prevent or systemic absorption. In pregnancy, tolnaftate has been classified as FDA Pregnancy Category C (a system deprecated by the FDA in 2015); no animal reproduction studies have been reported, and there are no adequate and well-controlled studies in pregnant women. It should be used only if the potential benefit justifies the potential risk to the fetus. A 2004 case-control study from the Hungarian Case-Control Surveillance of Congenital Abnormalities (1980-1996) identified a potential signal for teratogenic risk, with tolnaftate spray exposure in 13 cases of congenital abnormalities (including 4 with cardiovascular malformations) compared to 13 controls, yielding an odds ratio of 3.1 (95% CI: 1.0-9.7); however, the small sample size limits definitive conclusions, and further research is needed. For lactation, the safety of tolnaftate in women has not been established, and it is unknown whether the drug is excreted in human milk; application to the breast area should be avoided to prevent potential exposure to the . In pediatric patients, tolnaftate is approved for use in children aged 2 years and older, with no specific dosage adjustments required; however, it should not be used in children under 2 years without medical supervision. Due to its topical administration and low systemic absorption, tolnaftate has minimal drug-drug interactions, and no significant interactions have been formally reported; caution is advised when used concurrently with other topical irritants, such as certain antiseptics or corticosteroids, to avoid enhanced skin irritation. Overdose with tolnaftate is rare given its topical nature, but excessive local application may lead to skin irritation; management is supportive, involving discontinuation of use and as needed.

History and Availability

Development and Discovery

Tolnaftate was discovered in by Teruhisa Noguchi and colleagues at Nippon Soda Company in during a screening program for compounds targeting dermatophytes. The compound, chemically known as O-(2-naphthyl) N-methyl-N-(3-methylphenyl)thiocarbamate, emerged from studies on thionocarbamate derivatives, demonstrating potent activity against species in initial assays. Early research identified tolnaftate as a selective antitrichophyton agent, with foundational toxicologic studies conducted in 1966 by Hashimoto and team evaluating its safety profile across multiple animal species. These investigations revealed low via oral, subcutaneous, and topical routes, with no significant subacute effects or skin irritation observed in rabbits after repeated applications. Preclinical testing in the 1960s further confirmed its efficacy against dermatophytes, including inhibition of and T. rubrum growth at concentrations as low as 1%. Key publications advanced understanding of tolnaftate's , including double-blind clinical trials in 1966 that verified its activity in treating superficial mycoses like and , achieving cure rates superior to . Later, Ryder et al. in 1986 elucidated its mechanism, showing inhibition of biosynthesis at the squalene epoxidase step, leading to accumulation in fungal cells. Tolnaftate's formulation has remained stable since the 1970s, with no major developments or new indications reported following Cochrane systematic reviews on topical treatments for fungal infections of the foot, the most recent published in 2017, which affirmed its role without evidence of expanded therapeutic applications.

Regulatory Status and Brands

Tolnaftate is approved by the U.S. Food and Drug Administration (FDA) for over-the-counter (OTC) use as a topical antifungal under the OTC Monograph for Topical Antifungal Drug Products (21 CFR part 333 subpart C), with the final monograph issued on September 23, 1993, confirming its status as generally recognized as safe and effective (GRASE, Category I) for treating tinea pedis, tinea cruris, and tinea corporis. It has been available without prescription in the United States since its initial marketing in 1965, following early recognition in the FDA's OTC review process that began in the 1970s. Globally, tolnaftate holds OTC status in most countries, including the where it is listed as an approved ingredient for non-prescription products, and where it is categorized as a second-class OTC drug suitable for . In some regions, prescription may be required for combination formulations containing tolnaftate with other active ingredients, but standalone topical products remain widely accessible without a prescription. Prominent brand names for tolnaftate include Tinactin , TAGRID , and Aftate internationally, alongside numerous generic equivalents produced by various manufacturers. These products are commonly formulated as creams, sprays, powders, or aerosols for topical application. As of 2025, tolnaftate's regulatory framework shows no major changes, maintaining its OTC availability in the aforementioned forms across major markets. It plays a key role in for mild fungal skin infections, supporting an established global market for topical antifungals that dates back to the .

References

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