Trifolium Pratense (Red Clover)

Trifolium Pratense (Red Clover)

Product Name: Клевер луговой, Trifolium pratense, Wiesenklee, Trébol rojo, Trèfle des prés, النفل الأحمر, แดงโคลเวอร์, Qizil yonca, Кызыл беде, Qırmızı yonca, Юнучқаи сурх, Raudonasis dobilas, Sarkanais āboliņš, Конюшина лучна, Qırmızı yonca, תלתן אדום

Synonyms: красный клевер, луговой клевер, клевер обыкновенный, клевер красный, red clover, common clover, purple clover, meadow clover, Wiesenklee, Roter Klee, Trébol rojo, Trébol de los prados, Trèfle rouge, Trèfle des champs, النفل الأحمر, البرسيم الأحمر, โคลเวอร์แดง, แดงโคลเวอร์

Used Parts: flowers, leaves, stems, inflorescences, roots.

Main Indications for the Use of Trifolium pratense (Red Clover): Atherosclerosis, arterial hypertension, climacteric syndrome, premenstrual syndrome, postmenopausal osteoporosis, hyperlipidemia, benign prostatic hyperplasia, trophic skin disorders, acne, eczema, dermatitis, bronchitis, cough, chronic tonsillitis, chronic pharyngitis.

Use of Trifolium pratense in Mixtures and Complexes: Rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, psoriasis, neurodermatosis, chronic gastritis, biliary dyskinesia, migraine, insomnia, anxiety disorder, functional mastalgia, thyroid diseases.

Pharmacological Properties of Trifolium pratense (Red Clover): Estrogen-like, antioxidant, anti-inflammatory, hypolipidemic, sedative, spasmolytic, expectorant, antiseptic, diuretic, blood-purifying, photoprotective, vasodilatory, hepatoprotective, cardioprotective, antitumor, immunomodulatory, antimicrobial, astringent, angioprotective.

Dosage of Pharmaceutical Forms — Trifolium pratense

Powder — Trifolium pratense

Indications (Powder): Atherosclerosis, arterial hypertension, hyperlipidemia, climacteric syndrome, postmenopausal osteoporosis, benign prostatic hyperplasia, acne, eczema, chronic bronchitis.

Standard Dosage (Powder): 1 gram 3 times a day 20 minutes before meals, with warm water.

Enhanced Dosage (Powder): 1.5 grams 3 times a day for pronounced climacteric syndrome, stage II arterial hypertension, and hyperlipidemia with total cholesterol above 6.5 mmol/l.

Maximum Dosage (Powder): Up to 2 grams 3 times a day — allowed short-term for trophic skin disorders, seborrheic dermatitis, and pronounced vasomotor symptoms in postmenopause.

Preventive Dosage (Powder): 0.5 grams 2 times a day, in courses of 30 days with a 14-day break. Recommended for perimenopausal women, men over 50 years of age at risk of prostatic hyperplasia, and patients with a family history of atherosclerosis.

Pediatric Dosage (Powder): Allowed from 12 years of age and body weight of 40 kilograms or more. 0.25 grams 2 times a day. Not recommended for boys before the completion of puberty.

Contraindications (Powder): Estrogen-dependent malignant tumors, pregnancy, lactation, thrombophlebitis, severe hepatic insufficiency. Data on contraindications in children under 12 years of age have not been scientifically registered.

Side Effects (Powder): With overdose, headache, nausea, epigastric pain, and increased menstrual bleeding in women are possible.

Adjustment for Patient Body Weight (Powder): Patients with body weight below 60 kilograms — reduce the dosage by 20%. Patients with body weight over 90 kilograms — increase the dose by 25%, provided there are no contraindications.

Preparation method (Powder): To prepare 100 grams of powder, 120 grams of dried red clover inflorescences are required. The raw material is ground to a powder state using a mill with ceramic blades. Sift through a sieve with a mesh size of 0.5 millimeters. Store in an airtight glass container.

Storage Conditions and Shelf Life (Powder): Store in a dry, dark place at a temperature not exceeding 25 °C. Avoid exposure to direct light and sources of electromagnetic radiation. Shelf life — 12 months. After opening the package, use within 60 days.

Dry Extract — Trifolium pratense

Indications (Dry Extract): Postmenopausal osteoporosis, hyperlipidemia, climacteric syndrome, benign prostatic hyperplasia, seborrheic dermatitis, acne.

Standard Dosage (Dry Extract): 200 milligrams 2 times a day orally 30 minutes before meals.

Enhanced Dosage (Dry Extract): 300 milligrams 2–3 times a day for pronounced climacteric syndrome with vasomotor symptoms and osteoporosis with a T-score below –2.5.

Maximum Dosage (Dry Extract): Up to 400 milligrams 3 times a day — short-term for up to 14 days for severe hyperlipidemia, inflammatory acne resistant to antibiotics.

Preventive Dosage (Dry Extract): 100 milligrams once a day for 60 days with a 30-day break. Recommended for perimenopausal women, men over 50 years of age, and patients with a hereditary risk of atherosclerosis and dyslipidemia.

Pediatric Dosage (Dry Extract): From 12 years of age, with a body weight of 40 kilograms or more: 100 milligrams once a day. For girls — after the onset of menstruation. For boys — not earlier than 15 years of age.

Contraindications (Dry Extract): Estrogen-dependent tumors, pregnancy, lactation, thrombophlebitis. Safety data for use in children under 12 years of age are absent.

Side Effects (Dry Extract): Headache, increased uterine bleeding, skin rashes, dyspepsia. Registered when the dosage is exceeded by 2 or more times.

Adjustment for Patient Body Weight (Dry Extract): Up to 60 kilograms — reduce the dose by 20%. Over 90 kilograms — increase by up to 25% with normal liver function.

Preparation method (Dry Extract): To obtain 100 grams of extract, 500 grams of dry inflorescences are required. The raw material is extracted with 70% ethanol at a temperature of 45 °C for 6 hours. Filter, evaporate the solvent in a water bath to obtain a viscous mass, then dry in a vacuum dryer at a temperature of 40 °C. The resulting extract is ground into powder.

Storage Conditions and Shelf Life (Dry Extract): Store in an airtight dark glass container at a temperature of 15–25 °C, in a dry place, protected from light and EMI. Shelf life — 24 months. After opening the package, use within 3 months.

Alcohol-Based Tincture — Trifolium pratense

Indications (Tincture): Climacteric syndrome, premenstrual syndrome, arterial hypertension, chronic bronchitis, eczema, chronic tonsillitis, seborrheic dermatitis.

Standard Dosage (Tincture): 25 drops (approximately 1.2 milliliters) 3 times a day, diluted in 50 ml of water, 20 minutes before meals.

Enhanced Dosage (Tincture): 40 drops 3 times a day for severe vasomotor manifestations of menopause, pronounced stage I hypertension, and chronic bronchitis with cough and exudate.

Maximum Dosage (Tincture): Up to 60 drops 3 times a day — possible short-term (no more than 5 days) for exacerbation of eczema, prolonged forms of tonsillitis, and resistant dermatitis.

Preventive Dosage (Tincture): 15 drops 2 times a day, in courses of 21 days, with 21-day breaks. Recommended for women aged 45–55 years at the onset of perimenopause and patients with moderate arterial hypertension.

Pediatric Dosage (Tincture): Allowed from 14 years of age with a body weight of 45 kilograms or more: no more than 10 drops 2 times a day, diluted in 50 ml of water. Only under specialist supervision.

Contraindications (Tincture): Alcoholism, pregnancy, lactation, epilepsy, severe hepatic insufficiency, estrogen-dependent tumors. Scientific safety data for children under 14 years of age are absent.

Side Effects (Tincture): Nausea, headache, dizziness, palpitations, allergic rashes when the dose is exceeded by more than 2 times.

Adjustment for Patient Body Weight (Tincture): Up to 60 kilograms — reduce the dose by 25%. Over 90 kilograms — a standard dose is possible, but under blood pressure monitoring.

Preparation method (Tincture): To prepare 100 ml of tincture: pour 20 grams of dry inflorescences with 100 ml of 40% ethanol, infuse in a dark glass container for 14 days at a temperature of 20–25 °C. Shake daily. After infusion, strain, squeeze, store in an airtight dark container.

Storage Conditions and Shelf Life (Tincture): Store in a dark, cool place at a temperature of 8 to 20 °C. Protect from light and sources of EMI. Shelf life — 24 months. After opening, use within 60 days.

Oil Infusion — Trifolium pratense

Indications (Oil Infusion): Atopic dermatitis, eczema, seborrheic dermatitis, acne, psoriasis, chronic folliculitis, trophic ulcers, herpetic rash, varicose eczema.

Standard Dosage (Oil Infusion): Externally — apply 1–2 times a day to affected skin areas. Rub in with light movements.

Enhanced Dosage (Oil Infusion): Use 3 times a day, with application under a compress on the affected area for trophic ulcers, psoriatic plaques, and varicose eczema.

Maximum Dosage (Oil Infusion): Up to 4 times a day, in a course of no more than 10 days — for folliculitis and exacerbations of skin herpes.

Preventive Dosage (Oil Infusion): Apply once a day in the evening, in courses of 14 days once a month. Recommended for patients with chronic seborrhea, dry skin, and a tendency to eczematization. Suitable for perimenopausal women and elderly patients.

Pediatric Dosage (Oil Infusion): From 3 years — locally, no more than once a day. Only on limited skin areas. Under dermatologist supervision.

Contraindications (Oil Infusion): Pustular skin lesions in the suppuration stage, active herpes with pronounced exudation, individual sensitivity. Data on contraindications during pregnancy and lactation have not been registered.

Side Effects (Oil Infusion): Contact dermatitis, erythema, itching, burning with hypersensitivity or overdose.

Adjustment for Patient Body Weight (Oil Infusion): Not required — applied externally, adjusted according to the area of affected skin.

Preparation method (Oil Infusion): To obtain 100 grams of oil infusion: take 30 grams of dry red clover inflorescences, pour 100 ml of cold-pressed coconut oil. Infuse for 10 days at a temperature of 35–38 °C in a glass container, shaking daily. After infusion, strain through dense gauze, store in a dark glass bottle.

Storage Conditions and Shelf Life (Oil Infusion): Store in a dark, cool place at a temperature of 10 to 25 °C. Avoid exposure to light and EMI. Shelf life — 6 months. After opening — use within 30 days.

Cream — Trifolium pratense

Indications (Cream): Seborrheic dermatitis, acne, eczema, neurodermatitis, hyperkeratosis, follicular keratosis, atopic dermatitis, psoriasis, age-related dry skin, hyperpigmentation.

Standard Dosage (Cream): Apply a thin layer 1–2 times a day to cleansed skin, preferably in the morning and evening.

Enhanced Dosage (Cream): Apply up to 3 times a day on lesions during exacerbation of psoriasis, atopic dermatitis, and areas with inflammatory acne elements.

Maximum Dosage (Cream): Up to 4 applications per day, in a course of no more than 7 days, with transition to the standard dosage. Used for hyperkeratosis and neurodermatitis with pronounced dry skin.

Preventive Dosage (Cream): Once a day at night, in courses of 10 days with 20-day breaks. Indicated for menopausal women, patients with dry, sensitive skin prone to hyperpigmentation.

Pediatric Dosage (Cream): From 6 years — once a day on limited skin areas. Use under medical supervision, no more than 7 days in a row.

Contraindications (Cream): Allergy to components, weeping dermatoses, active form of rosacea. Scientific data on contraindications during pregnancy and lactation have not been registered.

Side Effects (Cream): Skin irritation, itching, flaking with individual intolerance. Increased acne with prolonged use in large doses.

Adjustment for Patient Body Weight (Cream): Dose adjustment is not required. The area of the affected surface is taken into account.

Preparation method (Cream): For 100 grams of cream: 15 grams of dry red clover extract, 10 grams of coconut oil, 5 grams of jojoba oil, 5 grams of beeswax, 65 grams of chamomile hydrolate. Melt the wax in a water bath, add the oils, then the extract. Pour in the hydrolate at a temperature of 35 °C, whip to a creamy consistency, cool.

Storage Conditions and Shelf Life (Cream): Store in an airtight frosted glass container at a temperature of 5–10 °C. Shelf life — 3 months. After opening — use within 30 days.

Ointment — Trifolium pratense

Indications (Ointment): Trophic ulcers, varicose eczema, psoriasis, infiltrative acne, furunculosis, neurodermatitis, pustular rash, chronic dermatitis.

Standard Dosage (Ointment): Externally — 1–2 times a day in a thin layer on clean skin or with a gauze bandage.

Enhanced Dosage (Ointment): 3 times a day under an occlusive dressing — for exacerbation of trophic ulcers, furunculosis, and resistant forms of dermatitis.

Maximum Dosage (Ointment): Up to 4 applications per day for 5 days — for exacerbation of eczema, infiltrative acne, and varicose ulcers. Transition to the standard dose is mandatory.

Preventive Dosage (Ointment): Once a day before bedtime on areas prone to inflammation. Course 10 days with a 20-day interval. Used for varicose disease, chronic neurodermatitis, and during the season of exacerbations.

Pediatric Dosage (Ointment): From 6 years, once a day locally. Do not apply to open wounds and purulent processes. Mandatory under medical supervision.

Contraindications (Ointment): Open wounds with purulent discharge, active herpetic infection, allergic reaction to components. Data on contraindications during pregnancy and lactation have not been scientifically registered.

Side Effects (Ointment): Itching, erythema, increased inflammation with hypersensitivity to ointment components.

Adjustment for Patient Body Weight (Ointment): Not required — only according to the area of application.

Preparation method (Ointment): For 100 grams: 10 grams of thick alcoholic clover extract, 70 grams of petroleum jelly (or coconut oil), 10 grams of lanolin, 10 grams of beeswax. All components are mixed at a temperature of 60 °C in a water bath, cooled to 35 °C with constant stirring. Transfer to a sterile jar.

Storage Conditions and Shelf Life (Ointment): Store in a tightly closed container in the refrigerator at a temperature of 5 to 10 °C. Protect from light and heat. Shelf life — 90 days. After opening — no more than 30 days.

Serum — Trifolium pratense

Indications (Serum): Androgenic alopecia, age-related skin dryness, hyperpigmentation, wrinkles, seborrheic dermatitis, acne, post-acne, couperose, impaired skin microcirculation.

Standard Dosage (Serum): Apply 1–2 drops 2 times a day to cleansed facial skin or scalp.

Enhanced Dosage (Serum): 3 times a day on problem areas — for intense hair loss, hyperpigmentation, and pronounced couperose.

Maximum Dosage (Serum): Up to 5 applications per day (pointwise) for androgenic alopecia and pronounced photoaging of facial skin, no more than 7 days in a row.

Preventive Dosage (Serum): Once a day in the evening, in courses of 20 days with a 10-day break. Recommended for women aged 40+, at the first signs of skin aging, and patients with seasonal hair loss.

Pediatric Dosage (Serum): From 12 years — pointwise once a day for acne or focal seborrhea. Under cosmetologist supervision.

Contraindications (Serum): Allergy to components, weeping forms of dermatitis, herpetic eruptions. Scientific safety data during pregnancy, lactation, and in children under 12 years of age are absent.

Side Effects (Serum): Burning, redness, flaking, increased rashes — with individual intolerance or overdose.

Adjustment for Patient Body Weight (Serum): Not required — the dosage is determined by the area of application.

Preparation method (Serum): For 100 ml: 10 ml of aqueous glycerin clover extract, 2 ml of peptide solution (optional), 1 ml of natural preservative (rosemary extract), 20 ml of witch hazel hydrolate, 67 ml of purified water. Mix at a temperature of 25 °C. Pour into a bottle with a dispenser. Shake before use.

Storage Conditions and Shelf Life (Serum): Store at a temperature of 4 to 8 °C in a tightly closed bottle. Avoid exposure to direct light. Shelf life — 30 days. After opening — use within 20 days.

Lotion — Trifolium pratense

Indications (Lotion): Oily skin, acne, seborrheic dermatitis, enlarged pores, post-acne, initial signs of photoaging, tendency to hyperpigmentation.

Standard Dosage (Lotion): Wipe the skin with a cotton pad 2 times a day — morning and evening. Can be used under cream or serum.

Enhanced Dosage (Lotion): Up to 3–4 times a day on areas with active inflammation or oiliness. Use in courses of 5–7 days.

Maximum Dosage (Lotion): 5 applications per day pointwise or on the T-zone for active acne. Course — no more than 3 days in a row.

Preventive Dosage (Lotion): Once a day at night. Course 14 days monthly. Indicated for adolescents with oily skin, adults with seasonal acne exacerbations, and patients with impaired skin barrier.

Pediatric Dosage (Lotion): From 10 years — once a day for oily skin and initial manifestations of acne. Use under adult supervision.

Contraindications (Lotion): Skin damage, active herpes, hypersensitivity to components. Data on use during pregnancy and lactation are absent.

Side Effects (Lotion): Dry skin, irritation, redness with frequent use on sensitive skin.

Adjustment for Patient Body Weight (Lotion): Not required — applied externally, the dosage depends on the coverage area.

Preparation method (Lotion): For 100 ml: 15 ml of alcoholic clover extract, 10 ml of lavender hydrolate, 5 ml of natural apple cider vinegar, 70 ml of distilled water. Mix the components in a glass container, infuse in the shade for 12 hours, pour into a sterile bottle with a dispenser.

Storage Conditions and Shelf Life (Lotion): Store at a temperature of 5 to 15 °C, away from light and heating appliances. Shelf life — 60 days. After opening — use within 30 days.

Mask — Trifolium pratense

Indications (Mask): Androgenic alopecia, hyperkeratosis, skin photoaging, acne, post-acne, seborrheic dermatitis, psoriasis, age-related skin dryness, hyperpigmentation.

Standard Dosage (Mask): Apply to the skin of the face or scalp 2 times a week for 15–20 minutes, then rinse thoroughly with warm water.

Enhanced Dosage (Mask): 3 times a week for pronounced inflammation, exacerbation of acne, initial alopecia, and hyperpigmentation.

Maximum Dosage (Mask): Daily use for 5 days — for acute inflammatory rashes, dermatitis, and skin flaking. After 5 days, transition to the standard regimen.

Preventive Dosage (Mask): Once a week, in a course of 30 days every 3 months. Recommended for adolescents with oily skin, patients during hormonal fluctuations, and perimenopausal women.

Pediatric Dosage (Mask): From 12 years — once a week. Only if indicated (acne, seborrhea) and under adult supervision.

Contraindications (Mask): Open wounds, weeping forms of dermatitis, acute herpes, allergy to components. Data on contraindications during pregnancy and lactation have not been scientifically registered.

Side Effects (Mask): Burning, redness, skin tightness, contact allergy with individual intolerance.

Adjustment for Patient Body Weight (Mask): Not required — applied locally.

Preparation method (Mask): For 100 grams: 15 grams of clover inflorescence powder, 20 grams of white clay, 10 ml of coconut oil, 2 ml of lavender essential oil, 53 ml of sage hydrolate. Mix until a homogeneous paste is obtained. Store in the refrigerator.

Storage Conditions and Shelf Life (Mask): In a glass jar with a tightly closing lid, at a temperature of 4–8 °C. Shelf life — 14 days. After opening — use within 5 days.

Shampoo — Trifolium pratense

Indications (Shampoo): Androgenic alopecia, seborrheic dermatitis of the scalp, scalp itching, dandruff, hair loss, post-stress alopecia, oily seborrhea.

Standard Dosage (Shampoo): Apply to wet hair 2–3 times a week. Lather, leave on the scalp for 2–3 minutes, then rinse with warm water.

Enhanced Dosage (Shampoo): Up to 4 times a week for exacerbation of seborrheic dermatitis or pronounced hair loss.

Maximum Dosage (Shampoo): Daily use is allowed short-term (up to 7 days) for active dandruff and intense scalp itching.

Preventive Dosage (Shampoo): Once a week — in a course of 2 months with a subsequent break. Suitable for patients with seasonal hair loss and adolescents with oily seborrhea.

Pediatric Dosage (Shampoo): From 5 years — once a week. Only with a natural formula without SLS. The volume of use depends on hair length.

Contraindications (Shampoo): Allergy to components, inflamed areas of the scalp, pustular lesions. Safety during pregnancy and lactation has not been studied.

Side Effects (Shampoo): Dry hair, scalp irritation, contact allergy. Occur rarely.

Adjustment for Patient Body Weight (Shampoo): Not required — depends on hair length and thickness.

Preparation method (Shampoo): For 100 ml: 60 ml of soap base (without sulfates), 10 ml of aqueous clover extract, 10 ml of sage hydrolate, 10 ml of coconut oil, 5 ml of glycerin, 5 ml of tea tree oil. Mix the components at 35 °C, leave for 24 hours. Pour into a bottle with a dispenser.

Storage Conditions and Shelf Life (Shampoo): Store at a temperature of 10 to 20 °C in a dark place. Shelf life — 90 days. After opening — use within 30 days.

Toner — Trifolium pratense

Indications (Toner): Oily skin, enlarged pores, acne, post-acne, couperose, seborrheic dermatitis, hyperpigmentation, photoaging, vascular network on the face.

Standard Dosage (Toner): Wipe the skin 2 times a day — morning and evening after washing, before applying serum or cream.

Enhanced Dosage (Toner): Up to 3 times a day — for pronounced inflammation, skin oiliness, and couperose. Apply locally with a cotton pad on problem areas.

Maximum Dosage (Toner): Up to 4 applications per day — allowed short-term (3–5 days) for exacerbation of acne and pronounced post-acne with an inflammatory component.

Preventive Dosage (Toner): Once a day, in courses of 14 days each month. Recommended for patients with skin microbiome disorders, menopausal women, and adolescents with oily skin.

Pediatric Dosage (Toner): From 10 years — once a day if indicated (acne, inflammation, oily skin). Only in the absence of irritation and under adult supervision.

Contraindications (Toner): Skin damage, allergic reaction to components, rosacea in the acute stage. Data on contraindications during pregnancy and lactation have not been registered.

Side Effects (Toner): Redness, feeling of skin tightness, mild burning with increased sensitivity or frequent use.

Adjustment for Patient Body Weight (Toner): Not required — the dosage is determined by skin type and area.

Preparation method (Toner): For 100 ml: 15 ml of aqueous clover extract, 10 ml of witch hazel hydrolate, 5 ml of apple cider vinegar, 5 ml of aloe vera extract, 65 ml of distilled water. Mix in a glass container at a temperature of 20 °C. Infuse for 8 hours in the refrigerator. Store in a spray bottle.

Storage Conditions and Shelf Life (Toner): Store in the refrigerator at a temperature of 4 to 8 °C. Avoid exposure to sunlight. Shelf life — 30 days. After opening — use within 14 days.

Toxicity and Biosafety of Trifolium pratense

Trifolium pratense is considered a non-toxic plant with a high biosafety profile when used in standard pharmacological dosages. Experimental studies on animals show that acute oral administration of clover extract does not cause lethal outcomes even at doses significantly exceeding therapeutic ones.

The established LD₅₀ value for ethanolic extract of Trifolium pratense upon oral administration to rats is more than 5000 mg/kg body weight, which indicates very low acute toxicity. At the same time, clinically significant side effects were not observed either with short-term or long-term use of the extract in animals.

The results of subchronic toxicological studies also confirm the absence of hepato- and nephrotoxicity with repeated administration of the extract for 90 days.

Reference: https://www.ncbi.nlm.nih.gov/p...

Pharmacodynamics — Trifolium pratense

The pharmacodynamic activity of Trifolium pratense is determined by a wide range of biologically active substances, including isoflavones, flavonoids, phenolic acids, triterpenes, coumarins, and phytosterols. The main pharmacological effects are realized through interaction with hormone-sensitive receptors, antioxidant and anti-inflammatory activity, as well as the ability to modulate key signaling pathways.

One of the key pharmacodynamic mechanisms is the selective affinity of isoflavones for estrogen receptors α and β, especially the β-subtype, expressed in the tissues of blood vessels, bone tissue, skin, and the central nervous system. These compounds act as phytoestrogens — natural ligands with modulating action, capable of activating or inhibiting estrogen signaling pathways depending on tissue specificity and the concentration of endogenous hormones.

The antioxidant action of Trifolium pratense is realized through the ability of flavonoids and phenolic acids to neutralize reactive oxygen species, suppress lipid peroxidation, and stabilize cell membranes. Studies have shown the inhibitory effect of extracts on the activity of NADPH-oxidase and lipoxygenase enzymes, as well as on the production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in macrophages and epithelial cells.

Anti-inflammatory activity is realized through suppression of COX-2 and iNOS expression, a decrease in the level of prostaglandins and nitric oxide, as well as through stabilization of mast cell membranes and reduction of degranulation. These effects are especially pronounced with local application of preparations containing concentrated fractions of isoflavones and phenolic compounds.

With respect to the nervous system, Trifolium pratense extracts have a mild sedative and anxiolytic effect. This is associated with modulation of GABA receptor activity and an effect on the level of neurotransmitters, including serotonin and dopamine, which is demonstrated in studies on animal models.

At the level of the immune system, modulating effects have been established: moderate enhancement of phagocytic activity of neutrophils and stimulation of the production of interleukins regulating the innate immune response. A positive effect on fibroblast proliferation and activation of TGF-β-dependent pathways has also been shown, which may contribute to reparative processes.

For the skin, preparations based on Trifolium pratense demonstrate antiseptic, soothing, and capillary-protective effects. These properties are explained by the content of tannins and triterpenes, which strengthen the vascular wall and reduce capillary permeability. The endocrine system is also a target system, since regular exposure to phytoestrogens can have a modulating effect on the hypothalamic-pituitary-ovarian axis, without causing proliferative changes in hormone-dependent tissues. This is confirmed by in vitro and in vivo studies. Depending on the pharmacological form and route of administration, the effect can be systemic (with oral intake or alcoholic tincture) or local (with the use of ointments, creams, oil infusions).

References:
https://pubmed.ncbi.nlm.nih.go...
https://www.sciencedirect.com/...
https://www.ncbi.nlm.nih.gov/p...
https://onlinelibrary.wiley.co...

Pharmacokinetics — Trifolium pratense

The pharmacokinetic properties of Trifolium pratense have been studied to a limited extent; however, generalized patterns characteristic of the classes of compounds contained in it, especially isoflavones and flavonoids, can be identified. The most typical routes of administration are oral (most often — powder, dry extract, alcoholic tincture) and transdermal (ointment, cream, oil infusion, serum).

Upon oral administration, isoflavones undergo primary hydrolysis in the gastrointestinal tract under the action of intestinal microflora, transforming into aglycones with higher bioavailability. The absorption process occurs in the small intestine through passive diffusion. The participation of intestinal microbes in the transformation of some isoflavones into biologically active metabolites has been identified, which may vary depending on the individual composition of the microflora.

After absorption, active substances undergo phase I and II metabolism in the liver. The main processes include hydroxylation, methylation, and conjugation with glucuronic acid or sulfates. These processes ensure further excretion of compounds with bile and urine. Partial enterohepatic recirculation may contribute to the prolongation of the action of some metabolites.

The distribution of active components occurs mainly in well-perfused organs and tissues — the liver, kidneys, skin, and mucous membranes. Lipophilic components, including triterpenes and lipophilic fractions, are able to partially accumulate in cell membranes and adipose tissue with prolonged use.

With transdermal application (ointment, cream, infusion), the main substances penetrate the epidermal barrier within the stratum corneum and superficial layers of the dermis. The action in this case is realized predominantly locally. The depth of penetration may increase with the use of fat-based carriers (for example, coconut oil) and in the presence of irritant components (for example, essential oils).

Metabolism of substances with external use occurs in the skin (with the participation of CYP450 enzymes and estrogen sulfotransferase), as well as partially in the liver after systemic absorption of insignificant amounts. Excretion occurs mainly with urine and bile, depending on the degree of systemic intake. Thus, Trifolium pratense is characterized by moderate systemic absorption, active hepatic biotransformation, limited cumulative potential, and a predominance of local action with external use.

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

Mechanisms of Action and Scientific Rationale — Trifolium pratense

The pharmacological action of Trifolium pratense is realized mainly through active metabolites of the isoflavone class, such as formononetin, daidzein, genistein, and biochanin A. These compounds are able to bind to nuclear estrogen receptors (ERα and ERβ), while selectively activating the β-subtype. Such interaction modulates the expression of genes regulating proliferation, apoptosis, angiogenesis, and extracellular matrix synthesis, especially in the endothelium, bone, and nervous tissues.

From the point of view of the anti-inflammatory mechanism, clover extracts inhibit the activation of the transcription factor NF-κB, which leads to a decrease in the production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and chemokines, as well as suppression of COX-2 and iNOS expression. Additionally, a decrease in the production of prostaglandins of the E series and nitric oxide is observed, which stabilizes the local inflammatory reaction.

The antioxidant properties of Trifolium pratense are due to the high content of flavonoids and phenolic acids, which have the ability to neutralize free radicals, inhibit lipid peroxidation, and restore the activity of antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase). The ability to suppress the formation of hydroxyl and superoxide radicals in vitro has also been established.

The modulating effect on the immune system is realized through an effect on phagocyte activity and the cytokine profile. In vivo studies demonstrate that the aqueous-alcoholic extract of Trifolium pratense is able to increase the expression of IL-10 and reduce the level of IL-17, as well as potentiate the differentiation of regulatory T-cells, which indicates immunoregulatory activity at the level of adaptive immunity.

In the central nervous system, interaction of Trifolium pratense components with GABA-A and dopamine receptors has been identified. These interactions mediate a moderate anxiolytic and sedative effect, which is realized through a decrease in neuronal excitability. Effects of modulation of monoaminergic neurotransmitters, including serotonin and norepinephrine, have also been established, which is confirmed by neurobiochemical studies.

Cellular targets of Trifolium pratense include macrophages, keratinocytes, osteoblasts, and fibroblasts. When exposed to fibroblasts, active fractions stimulate the expression of type I and III collagen, accelerate cell migration, and the synthesis of growth factors (including VEGF and TGF-β), which determines the reparative effect with local use.

Additionally, inhibitory effects on lipoxygenase and acetylcholinesterase enzymes have been established. These properties indicate the possibility of neuroprotective and anti-exudative activity, especially under conditions of oxidative stress.

References:
https://pubmed.ncbi.nlm.nih.go...
https://www.sciencedirect.com/...
https://www.ncbi.nlm.nih.gov/p...
https://www.tandfonline.com/do...
https://link.springer.com/arti...

Synergy — Trifolium pratense

Pharmacological synergy of Trifolium pratense with other plant and natural substances has been confirmed in several areas. Particularly pronounced potentiating effects are observed in combination with other sources of phytoestrogens — such as Glycine max and Cimicifuga racemosa. The combined effect of these plants enhances affinity for β-estrogen receptors, modulates hormone-dependent signaling pathways without pronounced proliferative action on tissues sensitive to estrogens.

In models of oxidative stress, additive and potentiating enhancement of antioxidant activity is observed with the combined use of Trifolium pratense with Camellia sinensis, Curcuma longa, and Vitis vinifera. The mechanism is based on synergistic suppression of ROS and enhancement of the activity of endogenous antioxidant enzymes.

The anti-inflammatory effect of Trifolium pratense is enhanced in combination with Salix alba and Zingiber officinale. Combined inhibition of COX-2, iNOS, and NF-κB expression has been established, as well as a decrease in the levels of inflammation mediators. This effect is predominantly tissue-specific, especially in skin and joint structures.

The immunomodulatory effect of Trifolium pratense can be complemented in combination with Echinacea purpurea and Panax ginseng. In this case, an increase in phagocytic activity, enhanced lymphocyte proliferation, and an increase in IL-10 production are observed with a simultaneous decrease in IL-1β and TNF-α. Together, this provides systemic modulation of innate and adaptive immune responses.

Also, an enhancement of the reparative activity of Trifolium pratense with local use together with Centella asiatica and Aloe vera has been demonstrated. The effect is due to combined stimulation of collagen production, acceleration of fibroblast and keratinocyte migration, and activation of the TGF-β signaling cascade.

References:
https://www.sciencedirect.com/science/article/abs/pii/S2225411015000983
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053092/
https://pubmed.ncbi.nlm.nih.gov/18053932/
https://link.springer.com/article/10.1007/s11418-012-0621-5
https://www.tandfonline.com/do...

Geography of Use and Traditional Medicine — Trifolium pratense

Trifolium pratense has a long history of use in the folk medicine of Europe, Asia, and North Africa. One of the earliest records of the use of clover are the notes of European herbalists of the 16th century, where it is mentioned in the context of blood purification and maintenance of women's health. In Slavic countries, clover was traditionally collected during the flowering period; its inflorescences were used for the preparation of decoctions and infusions used internally and externally. It was also part of mixtures used for washes, mouth rinses, and poultices.

In Irish and Scottish traditions, clover was revered as a symbol of purification and fertility. In some regions, it was used in health rituals, where a clover wreath was placed on the head of a sick person or used in smoke purification ceremonies. Similar ritual meanings were attributed to clover in the Balkan region, especially in Macedonia and Serbia, where it was considered a "herb against the evil eye" and a protective plant. In these regions, clover was dried and stored at the head of the bed or under the pillow.

In the territory of China and Tibet, Trifolium pratense was not included in the classical canons of traditional medicine; however, in some Tibetan and Uyghur sources, it is mentioned as a component of phytocompositions used externally in the form of compresses. In North Africa, clover was used in Berber medicine — as part of formulations for poultices, washes, and skin applications.

In Germany and Austria, clover was known as Wiesenklee and was used in folk medicine in the form of warm infusions and wraps. Its role in women's mixtures — "Frauenkräuter" — used during transitional periods of life, was particularly noted. In Swiss and French alpine villages, clover was dried and added to straw pillows, believing that it promotes restful sleep.

In the territory of India, clover is not considered a classic plant of Ayurveda; however, in some local practices, it was used as an herbal powder for the skin, especially for newborns, and in the form of juice mixed with other herbs.

In a number of cultures, clover also had non-medical significance. In Slavic and Finnish folklore, it was considered a plant of luck and integrity; the three-leaf symbol was used as a sign of the three worlds — underground, earthly, and heavenly. In Christian Europe, clover was associated with the Trinity, and its image was present on some medieval coats of arms and amulets. Smoking forms or forms as part of incense for Trifolium pratense have not been recorded. Nevertheless, hay with a predominance of clover was traditionally used to create a relaxing atmosphere in baths, healing steam rooms, and hay therapy in Central Europe.