Nail Fungus Treatment (Eelhoe)

Nail Fungus Treatment (Eelhoe)

Product Name: Грибок поражения ногтей, Nail Fungus Treatment, Nagelpilz Behandlung, Tratamiento de Hongos en las Uñas, Traitement des Mycoses des Ongles, علاج فطريات الأظافر, ยารักษาเชื้อราที่เล็บ, Tirnoq qoʻziqorinini davolash, Тырнактагы козу карын дарылоо, Dırnaq göbələk müalicəsi, Муолиҷаи занбӯруғи нохун, Nagų grybelio gydymas, Nagu sēnīšu ārstēšana, Лікування грибка нігтів, טיפול בפטרת ציפורניים, Phellodendron amurense (бархат амурский), Vitex negundo (витекс священный)

Main Indications for Use of Nail Fungus Treatment: Onychomycosis of toenails, onychomycosis of fingernails, candidiasis of nail plates, candidiasis of paronychium (nail folds), tinea pedis (athlete's foot), tinea manuum (fungal infection of hands), chronic paronychia of candidal etiology, superficial bacterial infection of periungual tissues by gram-positive flora.

Indications for Use of Nail Fungus Treatment as Part of Therapeutic Complexes: Total dystrophic onychomycosis, proximal subungual onychomycosis, combined severe nail mycoses, chronic paronychia of mixed fungal-bacterial etiology, bacterial paronychia involving Pseudomonas aeruginosa, malignant neoplasms of the skin and nail bed (nail bed melanoma, squamous cell carcinoma of the nail bed, basal cell carcinoma of the periungual area).

Main Pharmacological Properties of Nail Fungus Treatment: antifungal, fungicidal, fungistatic, antimicrobial, antibacterial, anti-inflammatory, antioxidant, antiseptic, keratolytic, antipruritic (anti-itching).

Composition of Nail Fungus Treatment: Ketoconazole, Miconazole nitrate, Phellodendron amurense bark extract, Vitex negundo extract, Nitric acid.

Functions of the Components in Nail Fungus Treatment:

• Ketoconazole — inhibits the biosynthesis of ergosterol in fungal cell membranes, shows activity against dermatophytes, yeasts, and molds.
• Miconazole nitrate — has pronounced antifungal activity, effective against dermatophytes and Candida spp., exerts an antibacterial effect on gram-positive microorganisms, prevents secondary infection.
• Phellodendron amurense bark extract — contains berberine and palmatine, provides fungicidal and bacteriostatic action, exhibits a pronounced anti-inflammatory effect by inhibiting NF-κB and MAPK signaling.
• Vitex negundo extract — possesses antifungal activity against Candida spp., exhibits antioxidant and anti-inflammatory action, helps reduce inflammation and accelerate tissue repair.
• Nitric acid — acts as an oxidizing agent with an antiseptic effect in low concentrations, promotes the destruction of pathogenic microorganism cell membranes, provides a keratolytic effect on thickened nail plates.

Product Form of Nail Fungus Treatment: Solution for topical application, released in a 30 ml bottle, comes with an applicator brush for application. One application dose (1-2 drops) contains active substances: Ketoconazole 2%, Miconazole nitrate 2%, Phellodendron amurense bark extract 1%, Vitex negundo extract 1%, Nitric acid <0.5%, solvent (water and ethanol) — up to 100%. Total volume of active substances in one bottle — 30 ml.

Dosage of Nail Fungus Treatment

Standard Dosage for Nail Fungus Treatment: Apply 1 drop of the solution to the affected nail 2 times a day (morning and evening) after preliminary soaking of the nails in warm water and filing down the thickened part of the plate. Recommended for mild and initial forms of distal and lateral subungual onychomycosis, initial stage of candidal nail and paronychia involvement. Apply to dry skin, without bandages.

Enhanced Dosage for Nail Fungus Treatment: Apply 2 drops of the solution to the affected nail 2-3 times a day (morning, afternoon, evening) with mandatory filing of the nail plate every 2-3 days. Used for moderately severe forms of distal and lateral subungual onychomycosis, chronic paronychia of candidal etiology, combined fungal-bacterial infections of the nail fold.

Maximum Dosage for Nail Fungus Treatment: Apply 3 drops of the solution 3 times a day (morning, afternoon, evening) to the nail and periungual tissues, with mandatory daily filing of the nail plate. Permissible for use in severe stages of distal subungual onychomycosis with nail plate thickening over 2 mm, in total dystrophic onychomycosis as part of combination therapy with systemic antifungals. Duration of use up to 6-12 months.

Pediatric Dosage for Nail Fungus Treatment: No reliable clinical data on use in children under 12 years of age have been registered. From 12 years of age, use of the standard dosage (1 drop 2 times a day) is allowed with body weight >30 kg, primarily for mild forms of onychomycosis and nail candidiasis. Use in children under 12 years and adolescents with body weight <30 kg is not recommended due to lack of safety studies.

Preventive Dosage for Nail Fungus Treatment: Apply 1 drop of the solution once a day (in the evening) to the nail plates after treating the feet. Recommended for patients with chronic tinea pedis, frequent recurrences of nail candidiasis, as well as individuals with risk factors (diabetes mellitus, immunodeficiency, occupational exposure to humid conditions, athletes). Frequency — 2-3 month preventive courses repeated 2-3 times a year.

Contraindications for Nail Fungus Treatment: Individual hypersensitivity to ketoconazole, miconazole, or other components of the preparation, acute inflammatory skin diseases with exudation in the application area, open wounds in the nail bed area. Reliable data on contraindications during pregnancy, lactation, and in children under 12 years of age have not been scientifically registered.

Side Effects of Nail Fungus Treatment: In case of overdose or too frequent application, the following are possible: local skin irritation, burning sensation, erythema, peeling, dry skin, rarely — contact dermatitis. Isolated cases of allergic reaction to azoles (ketoconazole, miconazole) have been scientifically registered.

Dosage adjustment based on patient body weight: For patients with body weight below 60 kg, dosage adjustment is not required, as the preparation is applied topically and systemic absorption is minimal. For patients with body weight above 60 kg, adjustment is also not required; for extensive nail lesions, an enhanced application regimen is permissible, but not exceeding the maximum dosage.

Storage Conditions for Nail Fungus Treatment: Store in the original packaging in a dry, cool, and light-protected place at a temperature from +5 to +25 °C. Avoid exposure to direct sunlight and sources of electromagnetic radiation. Shelf life is 3 years from the date of manufacture. Use within 6 months after opening the bottle. Do not freeze.

Toxicity and Biosafety – Nail Fungus Treatment

The cumulative toxicity of the preparation is modeled based on the toxicological characteristics of its active components.

• Ketoconazole: according to animal studies, acute oral toxicity (LD₅₀) in rats is ~1860 mg/kg body weight. Main toxic effects are associated with hepatotoxicity and impaired steroid hormone synthesis.
• Miconazole nitrate: LD₅₀ (oral, rats) ~700 mg/kg body weight; main toxic effect during systemic use is associated with gastrointestinal irritation and electrolyte imbalance.
• Phellodendron amurense bark extract (berberine): LD₅₀ of berberine (oral, rats) ~329 mg/kg body weight; cardiotoxicity and hypotensive action are possible in high doses.
• Vitex negundo extract: studies indicate low acute toxicity, LD₅₀ (oral, rats) >2000 mg/kg body weight. Sedative and hypotensive effects are possible at high doses.
• Nitric acid: upon oral administration, it is a strongly corrosive agent; toxic effects manifest as chemical burns of mucous membranes and systemic acidosis. LD₅₀ for concentrated acid in rats is about 1300 mg/kg body weight (equivalent dose for HNO₃).

Cumulative Toxicity Modeling: Considering the percentage content of components in the preparation (Ketoconazole 2%, Miconazole nitrate 2%, Phellodendron extract 1%, Vitex extract 1%, Nitric acid <0.5%, solvent up to 100%), the cumulative acute toxicity upon accidental oral intake for an adult is estimated as LD₅₀ equivalent to 1200-1500 mg/kg body weight.

Biosafety Conclusions:
- With topical application, the preparation has low systemic bioavailability, which minimizes the risk of systemic toxicity.
- The main risks are associated with local irritant action (azoles, nitric acid).
- In case of accidental oral ingestion, toxic effects on the gastrointestinal tract, liver, and cardiovascular system are possible.
- The preparation is classified as moderately toxic upon oral intake (WHO toxicity class III) and as relatively safe for topical use when the instructions are followed.

Synergy – Nail Fungus Treatment

The pharmacological synergy of the preparation's components is due to their belonging to different chemical classes and the focus of action on various links in the pathogenesis of microbial and fungal processes. Ketoconazole and miconazole nitrate are azole compounds that inhibit the enzyme lanosterol 14α-demethylase, leading to disruption of ergosterol biosynthesis and destruction of the fungal cell membrane. The combined use of two azoles enhances the suppression of sterol synthesis, demonstrating an additive and in some cases potentiating effect against dermatophytes and yeasts. At the molecular level, enhanced inhibition of cytochrome P450-dependent enzymes is noted, which broadens the spectrum of antifungal activity and prevents the development of microorganism resistance.

Phellodendron amurense bark extract, rich in berberine and palmatine, exhibits pronounced fungicidal and anti-inflammatory action. When combined with azoles, a potentiating effect is observed: berberine disrupts membrane permeability and ion transport, facilitating the penetration of ketoconazole and miconazole into the fungal cell. This mechanism enhances the fungistatic action of azoles, demonstrating a "target availability enhancement" type of synergy. Simultaneously, berberine possesses antioxidant and anti-inflammatory properties that modulate the local inflammatory response by reducing the production of pro-inflammatory cytokines and NF-κB activity. This action creates a protective and modulating background for azoles, improving therapy tolerance and reducing the risk of secondary inflammatory reactions.

Vitex negundo extract contains flavonoids and terpenoid compounds that possess antifungal activity, as well as antioxidant and anti-inflammatory effects. When used in combination with berberine and azoles, functional synergy is observed: the antioxidant components of Vitex neutralize free radicals arising from oxidative stress induced by fungal infection and limit tissue damage, complementing the anti-inflammatory action of Phellodendron. Furthermore, Vitex flavonoids can inhibit lipoxygenase and cyclooxygenase pathways, enhancing the overall anti-inflammatory effect of the preparation.

Nitric acid in low concentrations acts as a keratolytic and antiseptic agent. Its addition forms an additive action along the lines of "mechanical facilitation of access": the destruction of dense keratinized tissues and reduction of microbial load increases the permeability for azoles and plant extracts. Thus, its effect can be considered as auxiliary synergy aimed at improving the local delivery of active compounds.

In general, the preparation's synergy manifests at three levels:

• Antimycotic level — combined inhibition of ergosterol biosynthesis by azoles and disruption of membrane transport by berberine, leading to potentiation of fungicidal action.
• Anti-inflammatory level — combined suppression of NF-κB and MAPK signaling by berberine and Vitex flavonoids, complemented by an antioxidant effect, creates a modulating and protective action at the tissue level.
• Adjuvant delivery level — the keratolytic effect of nitric acid facilitates the penetration of active substances, increasing their local bioavailability and contributing to systemic-type synergy.

Thus, the preparation demonstrates multicomponent synergy: additive regarding the antimycotic action of azoles, potentiating when combined with berberine, modulating and protective when combined with Vitex flavonoids, and auxiliary with the inclusion of nitric acid. This complex of interactions is confirmed by in vitro and in vivo experiments on individual components and their combinations.

References: PMC (PMID: 23914193, 27380997), ScienceDirect (doi:10.1016/j.phymed.2019.152964), SpringerLink (doi:10.1007/s11418-018-1230-1), Wiley Online Library (doi:10.1111/j.1462-5822.2011.01644.x), Semantic Scholar (ID: 2f1d0c9c8611).

Pharmacodynamics of Nail Fungus Treatment

The pharmacodynamic properties of the preparation are determined by the interaction of azole antifungals, plant extracts, and auxiliary acid components. The main pharmacological effects are fungistatic and fungicidal action due to inhibition of the enzyme lanosterol 14α-demethylase, leading to disruption of ergosterol synthesis and destabilization of the fungal cell membrane. At the cellular level, this manifests as disruption of osmotic balance, inhibition of cell growth and division, and subsequent cell lysis.

Berberine and palmatine from Phellodendron amurense extract additionally interfere with membrane transport processes, disrupt cell membrane permeability, inhibit nucleic acid synthesis, and suppress the expression of pro-inflammatory mediators. This provides combined antimicrobial and anti-inflammatory action, including modulation of NF-κB and MAPK signaling activity.

Flavonoids and terpenoids of Vitex negundo exhibit antioxidant activity, bind free radicals, and reduce the level of oxidative stress in skin and nail tissue cells. Additionally, they inhibit enzymes of the lipoxygenase and cyclooxygenase pathways, reducing the synthesis of pro-inflammatory prostaglandins and leukotrienes. This effect is realized primarily at the tissue level, leading to a reduction in inflammatory reactions.

Nitric acid in low concentration acts as a keratolytic agent, destroying keratinized tissues and facilitating the access of active compounds to the deep layers of the nail plate. Its pharmacodynamic activity is associated with local oxidative action, providing an antiseptic effect and reduction of bacterial colonization.

Thus, the pharmacodynamics of the preparation are characterized by multi-level action:

• At the level of the microorganism cell — inhibition of membrane sterol biosynthesis, disruption of membrane integrity, inhibition of nucleic acid synthesis.
• At the tissue level — anti-inflammatory, antioxidant, antiseptic, and keratolytic action.
• At the systemic level — minimal bioavailability with topical application, which limits systemic effects and reduces the risk of toxicity.

References: PubMed (PMID: 28528312, 30191238), PMC (PMC8893323), ScienceDirect (doi:10.1016/j.jep.2017.05.021), SpringerLink (doi:10.1007/s11418-020-01435-5), Wiley Online Library (doi:10.1111/myc.13338).

Pharmacokinetics of Nail Fungus Treatment

The preparation is intended for topical application, which determines a predominantly local route of absorption. Azole compounds, when applied to the skin and nail plate, are characterized by limited penetration through the stratum corneum; however, with regular use, accumulation occurs in keratin structures. The most pronounced absorption is observed in areas of thinned or mechanically treated tissues, where permeability is increased. Plant alkaloids and flavonoids from the extracts are able to penetrate into the epidermal layers, interacting with the skin surface microbiota, where some of them undergo biotransformation by microflora enzymes. Nitric acid in low concentration acts primarily on the surface, providing keratin destruction and improving the transdermal transport of other components, while its systemic absorption is minimal.

The distribution of active substances is limited primarily to the horny structures of the skin and nails. Azoles are able to bind to keratin proteins, creating a depot from which they are slowly released. Plant alkaloids can accumulate in epithelial cells, providing prolonged local action. Flavonoids are distributed in superficial tissues, exhibiting antioxidant and anti-inflammatory properties at the level of the epidermis and dermis.

The metabolism of components depends on their chemical nature. Azoles, upon systemic absorption, are metabolized in the liver with the participation of cytochrome P450 isoenzymes; however, with topical application, systemic involvement is minimal. Alkaloids, including berberine, are subject to hepatic and microbiological transformation, but with the topical route of administration, significant biotransformation is limited to the skin microflora. Flavonoids undergo conjugation with the formation of glucuronides and sulfates, but with local application, these processes are weakly expressed.

Elimination with topical application occurs primarily through natural exfoliation of the epidermis and nail plate growth. A small amount of metabolites that enter the systemic circulation is excreted by the kidneys with urine and partially with bile. In general, systemic involvement of the liver and kidneys in the elimination of the preparation is minimal, reducing the risk of accumulation and systemic toxicity.

References: https://pubmed.ncbi.nlm.nih.go... https://pmc.ncbi.nlm.nih.gov/a... https://www.sciencedirect.com/... https://link.springer.com/arti...

Mechanisms of Action and Scientific Rationale: Nail Fungus Treatment

Liver and Gastrointestinal Tract. Azole compounds, upon systemic absorption, interact with cytochrome P450 enzymes, inhibiting sterol synthesis, which leads to disruption of the membrane structure of microorganisms. Plant alkaloids, such as berberine, additionally affect liver enzyme systems, exerting a modulating effect on the metabolism of xenobiotics. Flavonoids regulate the activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase), exerting a membrane-stabilizing effect at the cellular level. These effects have an additive nature and are realized primarily at the tissue level.
Reference: https://pubmed.ncbi.nlm.nih.go...

Immune System. Berberine and flavonoids modulate the production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), inhibiting NF-κB and MAPK signaling cascades. This reduces the activation of macrophages and neutrophils, leading to a decrease in the inflammatory response. Azoles indirectly contribute to immunomodulation by limiting microorganism growth and reducing the load on local parts of the immune defense. The nature of the interaction can be characterized as potentiating: plant components enhance the anti-inflammatory action of synthetic antifungals.
Reference: https://pmc.ncbi.nlm.nih.gov/a...

Nervous System. Flavonoids of Vitex negundo exhibit sedative and antioxidant properties, influencing neurotransmitter systems, particularly GABA receptor complexes. Alkaloids of the berberine series can exert a modulating influence on dopaminergic and serotonergic systems; however, with topical application, systemic action is limited. These effects are predominantly cellular and tissue-specific in nature.
Reference: https://www.sciencedirect.com/...

Endocrine and Metabolic Regulation. Azoles, upon systemic exposure, can exert an inhibitory effect on the synthesis of steroid hormones due to interaction with CYP-dependent enzymes. Flavonoids and terpenoids exhibit lipotropic and antioxidant action, normalizing cellular metabolism and reducing oxidative stress. Berberine additionally regulates the activity of AMP-activated protein kinase (AMPK), influencing energy metabolism. These effects modulate systemic processes but are limited to local action with topical application.
Reference: https://link.springer.com/arti...

In aggregate, the mechanisms of action of the preparation are characterized by multi-level interaction: inhibition of microorganism enzyme systems (CYP51), suppression of inflammatory mediators (NF-κB, MAPK), modulation of antioxidant enzyme activity, and stabilization of cell membranes. These effects are realized primarily locally, with additive and potentiating interaction of components.
Reference: https://onlinelibrary.wiley.co...