Synergistic Combinations Of Natural Antifungals In The Management Of Dermatophytosis (Ringworm)

Fungal infections, particularly dermatophytosis, candidiasis, and pityriasis versicolor, affect millions worldwide. Warm climates, humidity, immunosuppression, and poor hygiene increase susceptibility. Conventional antifungal drugs such as azoles and allylamines are effective but may cause resistance, toxicity, or recurrence. Herbal medicine offers a promising alternative due to availability, safety, affordability, and historical therapeutic use^2,4.

Medicinal plants such as Senna alata, neem, and tulsi have long been used in Ayurveda and traditional medicine to treat skin infections, wounds, and inflammatory disorders. Scientific studies increasingly validate their antimicrobial properties. Herbal creams formulated with these plants combine traditional knowledge with modern pharmaceutical technology, providing a safe and effective treatment for fungal infection³.

OVERVIEW OF FUNGAL SKIN INFECTIONS

Superficial fungal infections primarily affect keratinized tissues such as skin, nails, and hair. Common causative organisms include:

• Dermatophytes: Trichophyton, Micros Porum, Epidermophyton
• Yeasts: Candida albicans
• Lipophilic fungi: Malassezia furfur

Symptoms include itching, redness, scaling, and inflammation. These infections are highly contagious and often recurrent. Synthetic drugs are widely used but may lead to resistance or hypersensitivity reactions, highlighting the need for alternative therapies ^3,4.

1. Ringworm

Ringworm (tinea) is a highly contagious fungal skin infection, not a worm, characterized by itchy, red, scaly, ring-shaped patches. Caused by mold-like parasites (dermatophytes), it spreads via direct skin-to-skin contact, pets, or contaminated items⁴.

Symptoms of Ringworm :

• Skin: Red, itchy, scaly patches that may develop raised borders and a clear center (ring-like pattern).
• Scalp (Tinea Capitis): Scaly, bald patches, itching, and sometimes tender, swollen spots.
• Feet (Athlete's Foot): Cracked, flaking, and itchy skin between toes.
• Nails: Thickened, brittle, yellow, or discolored nails¹⁷.

2. Types of Ringworm (Tinea):

• Tinea Corporis (Body Ringworm): Appears anywhere on the skin, often in skin folds, causing a classic ring-shaped rash with raised borders.
• Tinea Pedis (Athlete's Foot): Highly common, causing itching, burning, and cracked skin, particularly between the toes and on the soles.
• Tinea Cruris (Jock Itch): Causes a red, itchy rash in the groin area, inner thighs, and buttocks, more common in men.
• Tinea Capitis (Scalp Ringworm): Affects the scalp, often causing hair loss, scaly patches, and is more common in children.
• Tinea Unguium (Nail Ringworm/Onychomycosis): Affects fingernails and toenails, making them thick, discolored, and brittle.
• Tinea Barbae (Beard Ringworm): Affects the beard/mustache area in men, causing red, inflamed, or crusted patches.
• Tinea Faciei (Face Ringworm): Causes red, itchy, scaly patches on the face.
• Tinea Manuum (Hand Ringworm): Causes dry, scaly rashes or cracked skin on the palms^17,18 .

3. Factor Responsible for Ringworm

I. Causative Organisms (Primary Factors)

Ringworm is mainly caused by three genera of fungi:

• Trichophyton

• Most common cause in humans
• Infects skin, hair, and nails

• Microsporum

• Commonly infects skin and hair
• Often transmitted from animals

• Epidermophyton

• Infects skin and nails only

These fungi feed on keratin, a protein found in skin, hair, and nails^45,26.

II. Environmental Factors

Certain environmental conditions promote fungal growth:

• Warm and humid climate

• Common in tropical regions like India

• Excess sweating (moisture)
• Poor ventilation of skin (tight clothes, shoes)
• Wet skin for long duration ^19,27.

III. Host (Human) Factors

Individual susceptibility plays a major role:

• Poor personal hygiene
• Weakened immune system
• Malnutrition
• Diabetes mellitus
• Skin injuries or cuts
• Excessive sweating (hyperhidrosis) ^29,12.

IV. Source of Infection

Ringworm spreads through different sources:

a) Human-to-human (Anthropophilic)

• Direct skin contact with an infected person
• Sharing clothes, towels, combs

b) Animal-to-human (zoophilic)

• Pets like cats, dogs, cattle

c) Soil-to-human (Geophilic)

• Contact with contaminated soil ^43,37.

V. Lifestyle and Behavioral Factors

• Wearing tight or synthetic clothes
• Walking barefoot in public places (gyms, bathrooms)
• Sharing personal items
• Poor drying of body after bathing ³².

VI. Other Contributing Factors

• Use of steroid creams (can worsen infection)
• Hot and sweaty occupations (laborers, athletes)
• Crowded living conditions⁴².

MEDICINAL PLANTS USED IN HERBAL ANTIFUNGAL CREAM

1. Senna alata

Senna alata (syn. Cassia alata), commonly known as ringworm bush, is a tropical medicinal plant traditionally used to treat fungal skin diseases. Leaves contain anthraquinones, flavonoids, saponins, and tannins responsible for antimicrobial activity³¹.

Taxonomical Identification :

Kingdom: Plantae (Plants)

Phylum/Division: Tracheophyta (vascular plants)

Class: Magnoliopsida (Dicotyledons)

Order: Fabales

Family: Fabaceae (Leguminosae)

Subfamily: Caesalpinioideae

Genus: Senna

Species: Senna alata (L.) Roxb³².

Botanical identification :

Scientific name: Cassia alata L.

Family : Leguminosae

Common Names: Candle Bush, Candle Cassia, Ringworm Bush, Empress Candle Plant²⁶.

Appearance:

Colour:  Senna alata : bright yellow  vibrant green leaves

Taste : spicy, warm, and slightly bitter

Texture :  thinly leathery texture²⁶.

Native Habitat: Originally from South America, now widely distributed throughout the tropics (pantropical) . Native to the Amazon Rainforest, it is now found in tropical regions worldwide, including Africa, Asia, Australia, and the Caribbean.

Growth Environment: It thrives in sunlit and humid environments and is often used as an ornamental plant^37,22.

Medicinal Uses: Known for antifungal properties, particularly in treating ringworm, eczema, and skin infections³⁷.

Safety and Toxicity :

1. Acute Toxicity: Studies in rats and mice show high safety levels, with lethality (LD50) often observed only at extremely high doses (e.g., >2000 mg/kg), classifying it as practically non-toxic at therapeutic levels.
2. Sub-acute/Sub-chronic Toxicity: Oral administration of leaf extract at doses (e.g., 250–1000 mg/kg) for 14-15 days did not show significant toxicity to liver or kidney functions, with no significant alterations in hematological parameters.
3. Adverse Effects: Known adverse effects in humans and animals, typically from excessive intake, include diarrhea. Some studies reported high-dose concerns such as elevated creatinine levels or mild behavioral changes in animals.
4. Use Warnings: S. alata acts as a potent laxative and, according to, can cause severe diarrhea. Some studies also suggest it may have abortifacient properties, making it unsuitable for use during pregnancy^37,38.

Fig.1: Senna alata.

2. Neem (Azadirachta indica)

Neem is widely used in traditional medicine for its antimicrobial, anti-inflammatory, and wound-healing properties. Leaves, bark, seeds, and oil contain bioactive compounds such as azadirachtin, nimbin, quercetin, and limonoids²⁴.

Taxonomic Identifucation :

Kingdom: Plantae

Order: Sapindales

Family: Meliaceae (Mahogany family)

Subfamily: Melioideae

Genus: Azadirachta

Species: A. indica

Botanical Identification:

Scientific name: Azadirachta Indica A.Juss.

Family : Meliaceae

Common name: Nimtree , Neem , Margose , Indian lilac ¹⁹.

Appearance:

Colour : dark green                                    

Taste : extremely bitter                             

Texture: smooth & glossy ¹⁹.  

Native Habitat and Characteristics :

Origin: Native to the Indian subcontinent, including India, Pakistan, Bangladesh, Sri Lanka, and Nepal.

Climate: Thrives in tropical and semi-tropical climates, known for being drought-resistant, long-lived (150–200 years), and able to grow in arid conditions with minimal water.

Habit: A fast-growing, large, evergreen tree with a thick, rounded canopy that provides significant shade^20,29.

Medicinal Uses : Every part of the neem tree—leaves, bark, flowers, fruits, seeds, and oil—is used for therapeutic purposes¹⁵.

Safety and Toxicity :

1. Topical Use (Skin/Hair): Generally safe to use on skin or hair in creams or oils for up to 2 weeks.
2. Short-term: Low doses (e.g., 60 mg bark extract) for up to 10 weeks are likely safe for adults.
3. Long-term/High doses: Unsafe; can cause serious liver and kidney damage.
4. Toxicity in Children: Very high risk. Small amounts (5–30 mL) of neem oil have caused severe, sometimes fatal, poisoning in infants and children (vomiting, seizures, brain damage).
5. Reproductive Safety: Likely unsafe during pregnancy, as it can cause miscarriages. It may also decrease fertility in both men and women.
6. Environmental Toxicity: Neem oil is a broad-spectrum pesticide that can harm beneficial insects like butterflies and ladybugs, though it is often considered safe for bees if not sprayed directly on them.
7. Contamination Risk: Improperly stored neem seeds can produce highly toxic aflatoxins¹⁶¹⁵.

Fig .2: Azadirachta indica.

3. Tulsi (Ocimum sanctum)

Tulsi is an aromatic medicinal herb belonging to the Lamiaceae family. It contains essential oils rich in eugenol, methyl chavicol, linalool, and other terpenoids^22,23.

Taxonomic Identification of Tulsi:

Kingdom: Plantae

Division: Angiosperms (Magnoliophyta)

Class: Magnoliopsida

Order: Lamiales

Genus: Ocimum

Species: O. tenuiflorum L. (commonly O. sanctum)³⁸.

Botanical Identification:

Scientific name: Ocimum basilicum L.

Family:  Lamiaceae

Common name : Tulsi , Basil ⁴.

Appearance:

Colour:  green, but some varieties are purple

Taste: a combination of sweet, peppery, and slightly minty

Texture: slightly glossy ³.

Native Habitat and Characteristics :

Region: Indigenous to India, Malaysia, Australia, West Africa, and some Arab countries.

Environment: Prefers warm, humid environments; commonly found in wastelands and as an undershrub in forests.

Adaptability: It is highly adaptable, often cultivated in home gardens and near temples.

Growing Conditions: Thrives in full sun within moist, well-drained soil, though it can tolerate varied soil types^26,45.

Medicinal Uses : anti-inflammatory , treat respitatory tract infection lower stress and antioxidant properties³³.

Safety and Toxicity :

Pregnancy & Fertility: Avoid high doses, as it may cause miscarriage or affect fertility.

Bleeding Disorders/ Surgery: Because it may slow blood clotting, avoid usage two weeks before surgery.

Diabetes: It can lower blood sugar; monitor glucose levels closely if taking medication.

Hypothyroidism: It may lower thyroid hormone levels, potentially worsening hypothyroidism.

"Pitta" Imbalance: Excessive consumption may cause a burning sensation, acidity, or skin irritation^33,16.

Fig. 4 : Ocimum sanctum.

4. Phytochemical Constituents Responsible for Antifungal Activity

The antifungal properties of herbal extracts are attributed to diverse phytochemicals:

Terpenoids in plants are known to possess antimicrobial activity against pathogenic fungi, including Candida and dermatophytes^9,10.

5. Synergistic Combinations: Rationale and Mechanism

Synergy occurs when combined agents produce a greater therapeutic effect than either alone. Combining herbal extracts with conventional antifungals offers several advantages .

- Enhanced antifungal potency

- Reduced dosage requirements

- Lower toxicity and improved safety

- Slower development of drug resistance

- Faster symptom recovery and lower relapse rate ¹⁸ .

I. Mechanism of action  Antifungal Agent:

A. Ergosterol Inhibition / Cell Membrane Disruption

Drug enters fungal cell

↓

Inhibits ergosterol synthesis (e.g., azoles block the 14-α demethylase enzyme).

↓

Decreased ergosterol content in the cell membrane

↓

Alteration of membrane structure and fluidity

↓

Increased membrane permeability

↓

Leakage of essential intracellular components (ions, proteins)

↓

Fungal cell death^33,2

B. Cell Wall Synthesis Inhibition

Antifungal drugs target fungal cell walls.

↓

Inhibition of β-(1,3)-glucan synthesis (by echinocandins)

↓

Weakening of cell wall structure

↓

Loss of cell integrity

↓

Osmotic imbalance

↓

Cell lysis

↓

Fungal cell death^46,12.

C. Nucleic Acid Synthesis Inhibition (Optional third mechanism)

Drug enters fungal cell

↓

Converted into active metabolite (e.g., flucytosine → 5-FU)

↓

Inhibits DNA/RNA synthesis

↓

Blocks protein synthesis

↓

Cell death³⁹.

EXCIPIENT & METHODOLOGY:

1. Excipient :

• Borax

Borax acts as an essential emulsifier and stabilizer in vitiligo cream formulations, enabling the blending of oily herbal extracts with water-based components to create a smooth, consistent texture³⁸.

• Stearic acid

Stearic acid acts as a crucial emulsifier and thickener in vitiligo cream, creating a stable, smooth, and luxurious texture that ensures uniform application of active ingredients⁴¹.

• Liquid paraffin

Liquid paraffin acts as an occlusive emollient in vitiligo creams, forming a protective, non-greasy barrier that seals in moisture to alleviate dryness in depigmented patches^37,14.

• Glycerin (Glycerol):

Glycerin acts as a humectant, providing moisturizing properties to the skin by retaining water³⁹.

• Xanthan gum :

Xanthan gum is a common food additive made from sugar fermented by bacteria. It acts as a binder, thickener, and stabilizer to improve texture and keep ingredients from separating. As an emulsifier, it helps things such as oil and water mix¹⁸.

• Triethanolamine (TEA):

Is often acts as a pH adjuster or neutralizer, commonly used to neutralize carbomer resin (a thickener) to create a clear, stable gel. It can also behave as an emulsifier²⁰.

• Methylparaben:

A popular preservative used to prevent the growth of bacteria and mold in personal care products, ensuring safety and extending shelf life^28,40.

• Distilled water

Distilled water acts as a high-purity, contaminant-free solvent that ensures stability and prevents unwanted chemical reactions in vitiligo cream formulations³³.

2. Methedology:

2.1. Drying and Powdering

Fresh leaves of Senna alata, Neem (Azadirachta indica), and Tulsi (Ocimum sanctum) are  collected.

The leaves are thoroughly washed with distilled water to remove dust and impurities. They are then shade-dried at room temperature until completely moisture-free. The dried leaves are ground into coarse powder using a grinder and stored in airtight containers for further extraction⁴³.

2.2. Extraction of Plant Materials (Hot Water Extraction / Decoction)

The powdered plant materials are taken in a beaker and mixed with distilled water in a ratio of 1:10 (w/v).

The mixture is heated  at 60–70°C for about 1 hour to extract the active phytochemicals^7,19.

Figure 5 : Decoction method

Decoction method : A decoction is a method of herbal extraction, and sometimes coffee brewing, that involves boiling tough plant materials—such as roots, bark, seeds, and twigs—in water for 15-45 minutes to extract active ingredients such as Senna alata , Ocimum basilicum , Azadirachta indica etc⁷.

After heating, the extract is filtered through muslin cloth to remove plant residues.

Figure 6 : Filtration of extract

2.3. Formulation Procedure

A. Preparation of Oil Phase

Stearic acid, Xanthan gum, liquid paraffin, and Borax are taken in a beaker.

The mixture is heated in a water bath at 70–75°C until all components melt and form a homogeneous oil phase³⁹.

Figure 7: oil phase preparation

B. Preparation of Aqueous Phase

In another beaker, distilled water, glycerin, and preservative are taken.

The mixture is heated up to 70–75°C

Triethanolamine (TEA) is then added slowly with gentle stirring to maintain proper emulsification^27,36.

Figure 8: aqueous phase preparation

2.4. Incorporation of Herbal Extracts

The prepared Senna alata extract, neem extract/oil, and extract tract are added to the hot aqueous phase.

The mixture is stirred properly to ensure uniform dispersion of the herbal components¹³.

Figure 9 : Mixing of cream with Homogenizer

2.5. Emulsification

The aqueous phase is slowly added to the oil phase with continuous stirring⁴¹.

The mixture is stirred using a magnetic stirrer or mechanical stirrer for about 20–30 minutes until a smooth cream emulsion is formed³³.

2.6. Cooling

The cream is allowed to cool gradually to room temperature while stirring continuously to prevent phase separation and ensure a stable formulation³¹.

2.7. Addition of Fragrance

A few drops of essential oil (such as lavender or eucalyptus) are added to the cooled cream and mixed gently to provide a pleasant fragrance¹².

2.8. Packaging

The final herbal cream is transferred into sterilized airtight containers or collapsible tubes and stored for further evaluation and use⁴⁸.

EVALUATION:

 1: Evaluation of Bioactive compounds :