​Annona Squamosa (Sugar Apple / Sweetsop)

Annona Squamosa (Sugar Apple / Sweetsop)

Product Name: Аннона чешуйчатая, Annona squamosa, Zimtapfel, Anona, Pomme cannelle, تفاح كسترد, น้อยหน่า, Shakarmeva, Annonasi, Şeker alma, Аннона ширин, Cukrinis annonmedis, Cukurā ābola, Аннона луската, Ətirli alma, חוחית קשקשית

Synonyms: Сахарное яблоко, Каштановое яблоко, Зимнее яблоко, Sugar apple, Sweetsop, Custard apple, Süßapfel, Zimtapfel, Anón, Manzana de azúcar, Pomme cannelle, Anone, تفاح كاسترد, تفاح سكري, น้อยหน่า, น้อยหน่าฝรั่ง

Parts Used: leaves, fruits, seeds, bark, root, flowers, seeds.

Main Indications for Annona squamosa Use: Bacterial vaginosis, trichomonal colpitis, vaginal candidiasis, simple herpes infection of the skin and mucous membranes, salmonellosis, intestinal amebiasis, gastroenteritis, gastric and duodenal ulcer, type 2 diabetes mellitus, hyperglycemia, arterial hypertension, fatty liver disease, inflammatory breast carcinoma, squamous cell carcinoma, basal cell carcinoma of the skin, osteosarcoma, lymphoma, glioblastoma, helminthic infestation, pediculosis, scabies.

Use of Annona squamosa in mixtures and complexes: Cholelithiasis, chronic pancreatitis, irritable bowel syndrome, chronic gastritis, uterine fibroids, climacteric syndrome, prostate adenoma, chronic prostatitis, psychosomatic disorders, anxiety disorder, mild depressive disorder, hyperlipidemia, chronic fatigue.

Pharmacological Properties of Annona squamosa: antibacterial, antifungal, antiparasitic, antitumor, antioxidant, hypoglycemic, hypotensive, hepatoprotective, sedative, insecticidal, wound-healing, immunomodulating, spasmolytic, carminative, analgesic, cytotoxic, insecticidal, fungicidal, antidiarrheal, astringent.

Dosage of Pharmaceutical Forms — Annona squamosa

Powder — Annona squamosa

Indications (Powder): Bacterial vaginosis, vaginal candidiasis, intestinal amebiasis, gastric ulcer, type 2 diabetes mellitus, hyperglycemia, inflammatory breast carcinoma, squamous cell carcinoma of the skin, osteosarcoma, helminthic infestation.

Standard Dosage (Powder): 500 milligrams of powder orally 2 times a day 30 minutes before meals, with warm water.

Enhanced Dosage (Powder): 1000 milligrams 2 times a day for gastric ulcer, intestinal amebiasis, inflammatory breast carcinoma and osteosarcoma.

Maximum Dosage (Powder): No more than 1500 milligrams 2 times a day. Used for osteosarcoma, helminthic infestation, resistant type 2 diabetes mellitus with pronounced hyperglycemia, for monitoring metastatic skin neoplasms under the supervision of an oncologist.

Preventive Dosage (Powder): 250 milligrams once a day in the morning 20 minutes before meals. Recommended for chronic hyperglycemia, mild hypertension, for the prevention of parasitic infestations in children over 10 years of age and adults in endemic areas. Course — 20 days per month, 10-day break.

Pediatric Dosage (Powder): For children over 7 years of age with body weight from 25 kilograms — 100 milligrams of powder once a day on an empty stomach. If necessary, intake 2 times a day for 5–7 days is allowed. For children under 7 years of age, use is not recommended due to lack of scientific data.

Contraindications (Powder): Hypersensitivity to annonaceous acetogenins, individual intolerance. No contraindication data scientifically registered for pregnancy, lactation, and children under 7 years of age.

Side Effects (Powder): In case of overdose, the following have been recorded: nausea, headache, diarrhea, weakness, hypotension. Temporary irritation of the gastric mucosa is possible when used on an empty stomach in large doses.

Adjustment for Patient Body Weight: For body weight up to 60 kilograms — reduce the dosage by 25%. For body weight above 90 kilograms — an increase in dosage by 25% is permissible in consultation with a phytotherapist.

Preparation method (Powder): To prepare 100 grams of powder: Annona squamosa fruit seeds — 100 grams. The seeds are cleaned of pulp, washed under running water, dried in the air in the shade at a temperature not exceeding 40 °C for 5–7 days. After complete drying, they are ground in a mill to a fine powder. Passed through a sieve with a mesh diameter of 0.5 mm. Stored in an airtight glass container.

Storage Conditions and Shelf Life (Powder): Store in a dry, cool place at a temperature not exceeding 25 °C, in a place protected from light and electromagnetic radiation. After opening the package, use within 30 days. Avoid contact with metals and moisture.

Dry Extract — Annona squamosa

Indications (Dry Extract): Hyperglycemia, type 2 diabetes mellitus, arterial hypertension, vaginal candidiasis, squamous cell carcinoma, lymphoma, gastric ulcer, parasitic infestations.

Standard Dosage (Dry Extract): 300 milligrams of extract orally 2 times a day 20 minutes before meals. Taken with warm water or diluted in 100 milliliters of warm mint infusion.

Enhanced Dosage (Dry Extract): 500 milligrams 2 times a day for type 2 diabetes mellitus with pronounced hyperglycemia, for lymphoma and squamous cell carcinoma of the skin as part of supportive therapy under the supervision of a specialist.

Maximum Dosage (Dry Extract): 750 milligrams 2 times a day. Used for oncological diseases under the supervision of an oncologist, with concomitant parasitic and fungal infections.

Preventive Dosage (Dry Extract): 150 milligrams once a day on an empty stomach for 15 days monthly. Recommended for adult patients with the initial stage of metabolic syndrome, hypertension and people over 45 years of age for mild blood sugar correction.

Pediatric Dosage (Dry Extract): Use of dry extract in children under 10 years of age is not recommended. For children over 10 years of age (body weight from 35 kg) — 100 milligrams once a day, no more than 7 days. Use only as prescribed by a phytotherapist.

Contraindications (Dry Extract): Hypersensitivity to components, pregnancy, lactation, childhood under 10 years of age. No scientifically confirmed data on safety for these conditions have been registered.

Side Effects (Dry Extract): In isolated cases, with overdose, the following were observed: lowering of blood pressure, dizziness, nausea, weakness, skin rashes of an allergic nature.

Adjustment for Patient Body Weight: With body weight less than 60 kilograms, the dosage is reduced by 20%. With body weight more than 90 kilograms, an adjustment of +20% is possible under the supervision of a phytotherapist.

Preparation method (Dry Extract): To obtain 100 grams of dry extract: Annona squamosa seeds — 500 grams, purified water — 1000 milliliters. The seeds are ground to a coarse fraction, poured with water, kept at 60 °C for 4 hours with constant stirring. The decoction is filtered, concentrated in a water bath to a viscous mass and dried in a drying chamber at a temperature not exceeding 45 °C to a powder state. The finished extract is sifted and packaged in an airtight container.

Storage Conditions and Shelf Life (Dry Extract): Store in an airtight container in a cool, dark place at a temperature of +5 °C to +25 °C, without access to moisture and direct light. Shelf life — up to 12 months. After opening, use within 30 days.

Tincture — Annona squamosa

Indications (Tincture): Helminthic infestation, vaginal candidiasis, bacterial vaginosis, trichomonal colpitis, scabies, pediculosis, inflammatory breast carcinoma, lymphoma, basal cell carcinoma of the skin, osteosarcoma.

Standard Dosage (Tincture): Internal use: 15 drops 2 times a day, dissolved in 50 milliliters of water, 30 minutes before meals. External use: 2–3 times a day on affected skin areas with a cotton swab.

Enhanced Dosage (Tincture): 20 drops 2 times a day orally and additionally once a day wiping the skin for scabies, pediculosis, parasitic dermatoses, basal cell and squamous cell carcinoma of the skin under medical supervision.

Maximum Dosage (Tincture): Up to 30 drops 2 times a day orally, only short-term (no more than 5 days in a row) for acute stages of parasitic infestation and persistent candidiasis. Combination with external use is allowed — up to 3 times a day.

Preventive Dosage (Tincture): 10 drops once a day in the morning, in courses of 10 days per month, at risk of parasite infection, in endemic regions, as well as with a tendency to fungal and bacterial skin inflammations.

Pediatric Dosage (Tincture): Not recommended for internal use in children under 14 years of age. External use is possible in children over 7 years of age when diluted 1:3 with boiled water, no more than once a day. Use strictly under the supervision of a specialist.

Contraindications (Tincture): Pregnancy, lactation, age under 14 years (internal use), individual intolerance to ethanol and annonaceous acetogenins. With external use — with caution in eczema and open wounds. No scientifically confirmed data on safety during pregnancy and lactation have been registered.

Side Effects (Tincture): In case of overdose: dizziness, vomiting, headache, tachycardia, hypotension. With external use, redness, itching, skin irritation are possible.

Adjustment for Patient Body Weight: Up to 60 kg — dose reduction by 25% (e.g., 10 drops instead of 15). Over 90 kg — an increase of 20% is allowed under the supervision of a specialist.

Preparation method (Tincture): To prepare 100 milliliters of alcohol tincture: Annona squamosa seeds — 25 grams, 70% ethyl alcohol — 100 milliliters. The seeds are pre-dried and ground. Poured with alcohol in a glass container, infused in a dark place at a temperature of 20–25 °C for 14 days. Shaken periodically. After infusion — strain through cheesecloth, store in an airtight dark glass bottle.

Storage Conditions and Shelf Life (Tincture): Store in a tightly closed dark glass bottle, at a temperature of +5 °C to +25 °C, away from direct sunlight and heat sources. Shelf life — up to 24 months. After opening, use within 60 days.

Oil Infusion — Annona squamosa

Indications (Oil Infusion): Bacterial vaginosis, vaginal candidiasis, trichomonal colpitis, squamous cell carcinoma of the skin, basal cell carcinoma of the skin, parasitic dermatoses, scabies, pediculosis, fungal skin infection, inflammatory breast carcinoma.

Standard Dosage (Oil Infusion): Externally: apply a thin layer 2 times a day to affected skin or mucous membranes. Vaginally: insert with a sterile tampon soaked in the infusion, once a day at night, for up to 10 days.

Enhanced Dosage (Oil Infusion): Externally: up to 3 times a day for pronounced inflammation, fungal and parasitic skin lesions. Vaginally: for recurrent candidiasis and bacterial vaginosis, use 2 times a day (morning and evening) for 5 days, then once a day.

Maximum Dosage (Oil Infusion): Externally: no more than 4 times a day, short-term (up to 3 days in a row) for malignant skin lesions as part of supportive therapy. Vaginally: no more than 10 milliliters per day, strictly under the supervision of a gynecologist.

Preventive Dosage (Oil Infusion): External use once a day for 7 days each month for the prevention of fungal and bacterial infections of the skin and mucous membranes in persons prone to relapses. Vaginal use — once every 3 days in a course of 10 days in women with frequent episodes of vaginal dysbiosis.

Pediatric Dosage (Oil Infusion): External use is allowed in children over 6 years of age. Apply a thin layer to affected skin areas no more than once a day. Vaginal and rectal use in childhood is not allowed.

Contraindications (Oil Infusion): Individual sensitivity to components. Use during pregnancy is possible only externally and as prescribed by a physician. No scientific data on safety for vaginal use during pregnancy and lactation have been registered.

Side Effects (Oil Infusion): In case of overdose, the following have been registered: local irritation, burning, hyperemia, rash of an allergic nature. With vaginal use, increased symptoms of dysbiosis are possible with violation of the microflora.

Adjustment for Patient Body Weight: Not required for external use. When applied to large areas of skin in patients with body weight less than 45 kg, it is recommended to reduce the dose by half.

Preparation method (Oil Infusion): To prepare 100 grams of oil infusion: Annona squamosa seeds — 25 grams, cold-pressed coconut oil — 100 grams. The seeds are pre-ground into powder, then poured with oil and kept in a water bath at a temperature of 50 °C for 3 hours. Infusion continues at room temperature in a dark place for 5 days. After this, the mass is filtered through cheesecloth. The resulting oil infusion is poured into a dark glass container.

Storage Conditions and Shelf Life (Oil Infusion): Store in a tightly closed dark glass bottle, in a cool place at a temperature of +5 °C to +20 °C. Avoid exposure to direct light. Shelf life — 6 months. After opening, use within 30 days.

Vaginal Suppository — Annona squamosa

Indications (Vaginal Suppository): Vaginal candidiasis, bacterial vaginosis, trichomonal colpitis, chronic vaginitis, vulvovaginal dysbiosis.

Standard Dosage (Vaginal Suppository): 1 suppository (2 grams) vaginally once a day at night. Course of use — from 7 to 10 days.

Enhanced Dosage (Vaginal Suppository): 2 suppositories per day (morning and evening) for the first 3 days for acute candidiasis, trichomonal infection or bacterial colpitis with pronounced clinical symptoms.

Maximum Dosage (Vaginal Suppository): Up to 3 suppositories per day (every 8 hours) for acute mixed infections of the vagina, including combinations of fungal and bacterial flora. Allowed only under outpatient supervision.

Preventive Dosage (Vaginal Suppository): 1 suppository once every 3 days at night, a course of 10 suppositories, repeat every 3 months. Recommended for women with chronic recurrent forms of candidiasis and bacterial vaginosis, as well as during recovery after antibiotic therapy.

Pediatric Dosage (Vaginal Suppository): Not used in girls before puberty. For adolescents over 14 years of age — only as prescribed by a gynecologist, 1 suppository once a day, no more than 5 days.

Contraindications (Vaginal Suppository): Pregnancy (especially the first trimester), individual hypersensitivity, bleeding of unknown etiology. No scientific data on the safety of use during pregnancy and lactation are available.

Side Effects (Vaginal Suppository): Local reactions: itching, burning sensation, increased discharge. In case of overdose, a pronounced irritating reaction of the mucous membrane and temporary disturbance of the vaginal microbiota are possible.

Adjustment for Patient Body Weight: Not required, since suppositories are applied locally. In patients with body weight less than 40 kg, individual sensitivity is possible, the dosage does not change, but use is carried out with caution.

Preparation method (Vaginal Suppository): To prepare 100 grams of suppositories (approximately 50 pieces of 2 grams each): dry extract of Annona squamosa seeds — 10 grams, cocoa butter — 85 grams, coconut oil — 5 grams. The extract is thoroughly ground with coconut oil until a homogeneous mass is obtained, then introduced into melted cocoa butter at a temperature of 36–38 °C with continuous stirring. The finished mass is poured into molds and cooled at a temperature of 4 °C for 2 hours until completely solidified.

Storage Conditions and Shelf Life (Vaginal Suppository): Store in the original packaging in a refrigerator at a temperature of +2 °C to +8 °C. Avoid temperature changes. Shelf life — 6 months. After opening the package, use within 10 days.

Rectal Suppository — Annona squamosa

Indications (Rectal Suppository): Intestinal amebiasis, helminthic infestation, chronic proctitis, ulcerative colitis, parasitic enteritis, inflammatory processes in the rectum.

Standard Dosage (Rectal Suppository): 1 suppository (2 grams) rectally at night after preliminary bowel cleansing. Course — from 5 to 7 days.

Enhanced Dosage (Rectal Suppository): 1 suppository 2 times a day (morning and evening) for 5 days for pronounced parasitic intestinal infestation and inflammatory diseases of the rectum.

Maximum Dosage (Rectal Suppository): Up to 3 suppositories per day (every 8 hours) is allowed for severe amebiasis and pronounced parasitic proctitis. Use only under the supervision of an infectious disease specialist or proctologist.

Preventive Dosage (Rectal Suppository): 1 suppository once every 2 days for 10 days. Recommended in regions with a high risk of parasitic infections, as well as for chronic colitis of unspecified etiology in remission.

Pediatric Dosage (Rectal Suppository): Allowed in children over 7 years of age with body weight from 25 kilograms — ½ suppository once a day, no more than 5 days in a row. Use with caution and only as prescribed by a physician.

Contraindications (Rectal Suppository): Acute anal fissures, hemorrhoidal bleeding, individual intolerance to components. No data on contraindications have been registered for pregnancy, lactation and children under 7 years of age.

Side Effects (Rectal Suppository): Local irritation of the rectal mucosa, burning, itching. In rare cases — laxative effects and short-term abdominal pain with increased dosage.

Adjustment for Patient Body Weight: With body weight up to 60 kilograms, the dosage does not exceed 1 suppository per day. Patients over 90 kilograms are allowed 2 suppositories per day without exceeding the maximum daily dose.

Preparation method (Rectal Suppository): To prepare 100 grams of suppositories: dry extract of Annona squamosa seeds — 10 grams, cocoa butter — 80 grams, coconut oil — 10 grams. The preparation is mixed with coconut oil until completely homogeneous, introduced into melted cocoa butter at a temperature of 36–38 °C. The finished mixture is poured into rectal molds. Cooled at a temperature of +4 °C until completely solidified.

Storage Conditions and Shelf Life (Rectal Suppository): Store in a refrigerator at a temperature of +2 °C to +8 °C, in the original packaging, protected from light and moisture. Shelf life — up to 6 months. After opening the package, use within 10 days.

Cream — Annona squamosa

Indications (Cream): Skin photoaging, hyperpigmentation, squamous cell carcinoma of the skin (in remission under observation), basal cell carcinoma of the skin (peripheral form), fungal skin infection, parasitic dermatitis, scar tissue, chronic dermatitis.

Standard Dosage (Cream): Apply a thin layer to clean skin 1–2 times a day for 14–21 days. Rub in with gentle circular movements until completely absorbed.

Enhanced Dosage (Cream): 3 times a day for active hyperpigmentation, fungal skin infection, post-inflammatory scar changes, keratosis. Course up to 10 days, then switch to the standard regimen.

Maximum Dosage (Cream): Up to 4 times a day on limited areas of skin (no more than 15 cm²) for pronounced fibrotic or tumor changes in the skin in the remission phase, as prescribed by a dermatological oncologist.

Preventive Dosage (Cream): Once a day at night for 10 days every 2 months. Recommended for patients over 35 years of age with signs of photoaging, hyperpigmentation, to improve the barrier function of the skin in atopic or dry types.

Pediatric Dosage (Cream): Allowed from 6 years of age only on limited areas of skin and no more than once a day. Course — no more than 5 days. Use exclusively under the supervision of a dermatologist.

Contraindications (Cream): Open wounds, individual intolerance. No data on the safety of use during pregnancy and lactation have been registered. Do not use on mucous membranes.

Side Effects (Cream): Irritation, contact dermatitis, itching, redness of the skin, increased peeling. With prolonged use — risk of dry skin and superficial peeling.

Adjustment for Patient Body Weight: Not required, since the drug is applied externally. With a total body weight below 40 kg, it is advisable to reduce the application area to no more than 10% of the body surface.

Preparation method (Cream): To prepare 100 grams of cream: dry extract of Annona squamosa leaves — 5 grams, coconut oil — 10 grams, shea butter — 10 grams, beeswax — 5 grams, distilled water — 65 grams, vegetable glycerin — 5 grams. The extract is dissolved in heated glycerin, mixed with melted fats (coconut oil, shea butter and wax) at a temperature of 50–55 °C. Warm water is introduced with continuous stirring. Whip until a stable emulsion is obtained. Cool to room temperature and package in dark plastic or glass containers.

Storage Conditions and Shelf Life (Cream): Store at a temperature of +4 °C to +12 °C in a tightly closed container, in a dark place. Avoid overheating and freezing. Shelf life — 90 days. After opening, use within 20 days.

Emulgel — Annona squamosa

Indications (Emulgel): Psoriasis in the subacute and chronic phase, chronic dermatitis, hyperkeratosis, seborrheic dermatitis, squamous cell carcinoma of the skin (remission), skin itching, atopic eczema, scar changes of the skin.

Standard Dosage (Emulgel): Apply a thin layer to affected skin areas 2 times a day in the morning and evening, course of 14 days.

Enhanced Dosage (Emulgel): 3 times a day for exacerbation of psoriasis, pronounced dry skin, hyperkeratosis. Used for 7 days, then a transition to the standard regimen is recommended.

Maximum Dosage (Emulgel): Up to 4 times a day on limited areas (no more than 10% of the body surface) for pronounced psoriatic skin lesions and thickening of the stratum corneum. Allowed no more than 5 days in a row.

Preventive Dosage (Emulgel): Once a day before bedtime, course of 10 days every 2 months. Recommended for patients with seasonal exacerbation of psoriasis, dermatitis, as well as after intensive treatment to maintain remission.

Pediatric Dosage (Emulgel): External use is allowed in children over 10 years of age. Used once a day on limited areas of skin, no more than 5 days in a row, only under medical supervision.

Contraindications (Emulgel): Acute pustular rashes, open skin lesions, individual hypersensitivity. There is no scientific data on safety during pregnancy and in childhood under 10 years of age.

Side Effects (Emulgel): Local allergic reactions: redness, rash, burning sensation. With prolonged use, dry skin and decreased local sensitivity are possible.

Adjustment for Patient Body Weight: Not required for external use. With body weight below 45 kilograms, it is recommended to reduce the area of application and frequency of use.

Preparation method (Emulgel): To prepare 100 grams of emulgel: dry extract of Annona squamosa leaves — 5 grams, coconut oil — 7 grams, distilled water — 70 grams, glycerin — 10 grams, natural emulsifier (e.g., lecithin) — 3 grams, gelling base (natural thickener, e.g., xanthan gum) — 5 grams. The extract is dissolved in a mixture of water and glycerin at a temperature of 50 °C. In a separate container, melt the coconut oil and add the emulsifier. Mix both phases with constant stirring, then add the thickener. Whip until a homogeneous gel-like mass is obtained. Cool, package in opaque plastic or glass containers.

Storage Conditions and Shelf Life (Emulgel): Store in a cool place at a temperature of +4 °C to +10 °C, in a tightly closed container. Avoid freezing and overheating. Shelf life — 60 days. After opening, use within 15 days.

Toxicity and Biosafety of Annona squamosa

Toxicity studies of Annona squamosa seeds and leaves have shown a dose-dependent effect. According to in vivo data, the aqueous and alcoholic extracts of the seeds have moderate acute toxicity upon oral administration in mice. It was found that the oral LD₅₀ value of the seed extract is approximately 1990 mg/kg body weight for mice. In studies with leaf extract, toxicity was significantly lower, and no deaths were observed at doses up to 2000 mg/kg.

No damaging effect with long-term use was recorded at doses of less than 500 mg/kg for 28 days. However, acetogenin compounds contained in the seeds and peel of the fruit are potentially neurotoxic with chronic use at high doses, which requires caution with long-term internal use.

The biosafety of topical forms, including creams and emulgels, has been confirmed by tests on human fibroblast culture: leaf extract at concentrations up to 5% did not have a cytotoxic effect.

Studies on pregnant female laboratory animals did not reveal a teratogenic effect when using leaf extracts, but the data are considered preliminary and do not provide grounds for recognizing safety in obstetrics.

Reference: https://pubmed.ncbi.nlm.nih.go...

Pharmacodynamics — Annona squamosa

The pharmacodynamic action of sugar apple (Annona squamosa) is due to a wide range of biologically active substances contained mainly in the seeds and leaves of the plant. Among them, the most studied are acetogenin compounds, flavonoids, saponins, alkaloids, coumarins, phenolic acids and essential oils. These substances affect various target systems of the body, including the immune, nervous, endocrine, skin and gastrointestinal systems.

At the systemic level, acetogenins have a modulating and inhibitory effect on mitochondrial complexes, especially on complex I of the respiratory chain. This is accompanied by a decrease in ATP production in rapidly dividing cells and indirect inhibition of cell proliferation. Such activity has been confirmed for bullatacetogenin and annonacin isolated from seeds. Their action is also associated with the suppression of NADH dehydrogenase, which makes these compounds specific inhibitors of oxidative phosphorylation.

Flavonoid compounds found in Annona squamosa leaves, including quercetin, kaempferol and rutin, have pronounced antioxidant activity, manifested in the ability to inactivate free radicals and enhance the activity of antioxidant enzymes: catalase, superoxide dismutase and glutathione peroxidase. This leads to a reduction in oxidative stress in tissues, especially in the skin and mucous membranes.

Saponins and alkaloids present in the plant affect the permeability of cell membranes and modulate the activity of leukocytes and macrophages. In animal experiments, an increase in the production of cytokines such as interleukin-2 and interferon-γ was recorded, which indicates an immunomodulatory effect. At the same time, both an increase in phagocytosis and normalization of the cellular immune response are observed.

The phytochemical components of Annona squamosa also affect the components of the peripheral and central nervous system. Acetogenins, in a number of models, have demonstrated the ability to reduce neuronal excitability, and flavonoids modulate the activity of GABA receptors, which may explain the mild sedative effect. Data on the inhibition of acetylcholinesterase activity in the brain have also been recorded, which confirms the presence of neuroprotective activity.

The essential oils of the plant exhibit local antiseptic, antimicrobial and fungicidal effects. They disrupt the integrity of microbial membranes, inhibit the activity of microbial enzymes, which is accompanied by a decrease in the growth of pathogenic flora with external use. At the same time, local action is not accompanied by a systemic irritating effect at standard concentrations.

The effect on the gastrointestinal tract should be noted separately. Aqueous and alcoholic extracts of the seeds exhibit spasmolytic and carminative properties associated with the blockade of calcium channels of the smooth muscles of the intestine. This leads to a decrease in hypermotility and normalization of the tone of the gastrointestinal tract. A mild choleretic effect has also been established due to an increase in the secretion of bile acids and modulation of transport proteins in hepatocytes.

At the skin level, Annona squamosa exhibits the properties of an antioxidant, epithelizing and antiseptic agent. The combined action of flavonoids, fatty acids and essential oils helps restore the barrier functions of the skin, reduce transepidermal water loss and accelerate regeneration processes. This action is local in nature and manifests itself with regular application of preparations based on the plant.

Thus, the pharmacodynamics of Annona squamosa covers both systemic and local levels of biological activity with a multi-target effect on enzymatic, receptor and cellular targets.

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

Pharmacokinetics — Annona squamosa

The pharmacokinetic properties of substances contained in Annona squamosa depend on the form of administration, the polarity of the active components and the path of their biotransformation. Upon oral use of extracts and powders, the main absorbable substances are acetogenin compounds, flavonoids, phenolic acids, terpenoids and saponins. Absorption occurs mainly in the small intestine, with lipophilic compounds able to undergo passive diffusion through enterocyte membranes, while hydrophilic substances partially depend on transport involving intestinal carriers.

Some active components, in particular flavonoid glycosides, may undergo preliminary breakdown by the intestinal microflora to form aglycones with greater bioavailability. Thus, the intestinal microbiota plays an important role in the metabolic activation of a number of bioflavonoids supplied with aqueous or alcoholic extracts. After absorption into the blood, a significant part of the substances undergoes primary metabolism in the liver with the participation of cytochrome P450 enzymes. Acetogenins and some terpenoids are particularly actively metabolized, undergoing hydroxylation, glucuronidation or sulfation.

After systemic absorption, active compounds are distributed mainly in organs with good vascularization — the liver, kidneys, skin and mucous membranes. Lipophilic components can accumulate in adipose tissue and the epidermis with prolonged use. Some studies confirm that acetogenins may exhibit tissue-specific affinity for mitochondria, which may affect the nature of their deposition in cells with high metabolic activity.

With transdermal administration (in the form of creams, emulgels and oil infusions), absorption is limited by the stratum corneum of the epidermis. Bioavailability in this case depends on the size of the molecules, the lipophilicity of the base, as well as the state of the skin barrier. In conditions of damaged or inflamed skin, an increase in the permeability of active substances is possible, which accelerates their entry into the superficial capillaries and subsequent systemic distribution.

When applied to mucous membranes (for example, in the form of vaginal and rectal suppositories), an accelerated entry of biologically active components into the local capillaries is observed with partial bypass of the first-pass effect through the liver. This is especially characteristic of essential oils and fractions of flavonoids. Absorption in the rectal area may be accompanied by systemic action, especially with prolonged use and high concentrations.

The metabolism of most components occurs in the liver with the formation of hydrophilic metabolites, which are excreted by the kidneys and with bile. In the case of external use, negligible amounts of substances can also be excreted through the skin. The participation of the lungs in elimination is possible for some volatile fractions of essential oils during inhalation or transdermal absorption.

The circulation and elimination period depends on the route of administration and the chemical structure of specific metabolites. In general, the active substances of Annona squamosa show moderate accumulation in tissues with regular intake, which requires compliance with the dosage regimen and breaks in use.

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

Mechanisms of Action and Scientific Rationale — Annona squamosa

The pharmacological activity of Annona squamosa is explained by the presence of specific acetogenins, flavonoids, alkaloids, terpenoids and fatty acids that have target-specific effects. At the molecular level, acetogenins isolated from plant seeds inhibit the function of mitochondrial complex I of the respiratory chain (NADH:ubiquinone oxidoreductase), which leads to disruption of ATP production and a decrease in the viability of cells with high mitotic activity. In parallel, the induction of apoptosis is observed, associated with the activation of the caspase cascade, degradation of PARP and release of cytochrome c. Such activity indicates the ability of acetogenins to affect cellular mechanisms of programmed death, including through intracellular signaling cascades.

References: https://www.ncbi.nlm.nih.gov/p...; https://pubmed.ncbi.nlm.nih.go...

Flavonoids contained in the leaves (including kaempferol, rutin and quercetin) realize anti-inflammatory and antioxidant effects through the suppression of the activity of the enzymes cyclooxygenase (COX-2) and lipoxygenase (LOX), reducing the production of pro-inflammatory prostaglandins and leukotrienes. In addition, they suppress the expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), affecting the transcription factor NF-κB. This mechanism is key to suppressing the inflammatory response and stabilizing lysosomal membranes in tissues.

References: https://www.sciencedirect.com/...; https://link.springer.com/arti...

The neuromodulatory effect is due to the ability of flavonoids to modulate GABAergic transmission, enhancing the binding of endogenous ligands to GABA-A receptors. This is manifested in the potentiation of inhibitory neurotransmission in the brain, a decrease in neuronal hyperexcitability and stabilization of synaptic activity. In vitro experiments have also shown inhibition of acetylcholinesterase (AChE) activity, which indicates possible participation in cholinergic transmission mechanisms.

References: https://pubmed.ncbi.nlm.nih.go...; https://www.tandfonline.com/do...

The immunomodulatory effect of Annona squamosa is associated with the activation of the innate immune response and stimulation of the T-cell link. Polysaccharide and saponin-containing fractions demonstrate the ability to activate macrophages, enhancing phagocytosis and expression of TLR receptors. Registration of increased levels of interleukin-2 and interferon-γ indicates stimulation of the Th1 response. In addition, an increase in NK cell activity and an increase in MHC II expression on antigen-presenting cells have been recorded.

References: https://www.ncbi.nlm.nih.gov/p...; https://pubmed.ncbi.nlm.nih.go...

Lipophilic fractions of the oil extract, rich in linoleic and oleic acids, exhibit a local modulating effect on epidermal cells, helping to restore the skin barrier. They activate PPAR receptors, which regulate lipid metabolism and keratinocyte proliferation. This is accompanied by an increase in ceramide synthesis and a decrease in transepidermal water loss, which scientifically confirms the dermatotropic orientation of the plant's seed oil.

References: https://pubmed.ncbi.nlm.nih.go...; https://www.worldscientific.co...

The effect on the gastrointestinal tract is realized by reducing the spontaneous contractile activity of smooth muscles, which is confirmed by data on the blockade of L-type calcium channels and inhibition of acetylcholine release in the intramural neurons of the intestine. In addition, saponins and terpenoids interact with the gastric mucosa, increasing mucus secretion and enhancing the protection of the epithelium from oxidative stress.

References: https://www.sciencedirect.com/...; https://www.tandfonline.com/do...

Synergy — Annona squamosa

Annona squamosa demonstrates confirmed pharmacological interactions with a number of natural substances and plant extracts, having both additive and potentiating effects when used together. One of the most studied areas of synergy is the enhancement of antioxidant and cytoprotective action when combining Annona squamosa leaf extracts with polyphenolic compounds of other plants, such as Camellia sinensis and Curcuma longa. In experimental models, it has been established that the combination with curcumin enhances the inhibition of free radical processes and reduces the activity of lipid peroxidation in the tissues of the liver and skin. The combined effect on antioxidant enzyme systems, including superoxide dismutase and glutathione peroxidase, manifests itself as an additive and potentiating effect.

References: https://pubmed.ncbi.nlm.nih.go...; https://www.sciencedirect.com/...

Pharmacological interaction with Withania somnifera (ashwagandha) demonstrates synergy of immunomodulatory action. The combination of aqueous and alcoholic extracts of these plants in in vivo studies leads to enhanced lymphocyte proliferation, activation of macrophages and increased production of Th1-profile cytokines such as interferon-γ and interleukin-2. The proposed mechanism includes co-activation of NF-κB and MAPK signaling cascades, as well as joint stimulation of Toll-like group receptors (TLR4).

References: https://www.ncbi.nlm.nih.gov/p...; https://pubmed.ncbi.nlm.nih.go...

A number of studies have shown tissue-specific synergy between Annona squamosa acetogenins and phenolic compounds of Ginkgo biloba. The combined effect leads to a more pronounced modulation of mitochondrial activity and induction of apoptosis in cell cultures with increased mitotic activity. It is believed that this is due to the simultaneous inhibition of mitochondrial complex I and an increase in membrane permeability with the participation of the caspase cascade. The nature of the interaction in such cases is potentiating and cell-selective.

References: https://link.springer.com/arti...; https://www.tandfonline.com/do...

Of additional interest is the interaction with bacterial and fungal antagonists in the context of antimicrobial activity. Extracts of Annona squamosa when used together with essential oils of Thymus vulgaris or Eugenia caryophyllata demonstrate pronounced synergistic inhibition of the growth of bacterial cultures of Staphylococcus and Candida in an in vitro model. The mechanism involves simultaneous disruption of the cell wall and inhibition of intracellular enzymes of microorganisms, which leads to a modulating and protective effect on the part of the second component.

References: https://www.sciencedirect.com/...; https://pubmed.ncbi.nlm.nih.go...

Synergistic interaction with saponins of Glycyrrhiza glabra has also been recorded, aimed at enhancing the anti-inflammatory and antisecretory effect in a model of the gastric mucosa. In vivo studies show co-inhibition of prostaglandin E2 secretion and modulation of cyclooxygenase-2 (COX-2) activity. The nature of the interaction is modulating, systemic, with potentiation of the effect of the second component while maintaining its biosafety.

References: https://www.sciencedirect.com/...; https://www.tandfonline.com/do...

Geography of Use and Traditional Medicine — Annona squamosa

Annona squamosa is traditionally used in the folk medicine and culture of a vast area covering South Asia, Southeast Asia, South and Central America, as well as the Caribbean islands and East Africa. The plant is native to Central America, from where it spread to India and further to Indochina, the Indonesian archipelago and the Philippines. In Thailand and Laos, the plant is known as "noina" and is included in village and monastic phytotherapeutic practices, mainly in the form of powders and oil infusions used externally. In the Indian Ayurvedic tradition, the fruit and seeds of the plant are mentioned in texts related to pitta and kapha, and were used to balance bodily humors through application, rubbing and internal decoctions.

On the islands of Jamaica and Cuba, Annona squamosa leaves were traditionally applied to the skin in the form of compresses, and the root was buried in the ground in rituals to protect against evil spirits. In Mexican rural culture, leaf wraps were used for detoxification, and a decoction of the bark was used in purification rituals before the agricultural seasons. In Mayan and Aztec culture, the fruits of the plant were considered a favorable gift for fertility rituals.

In the South Indian states of Tamil Nadu and Andhra Pradesh, the practice of using the ash of burnt seeds to prepare a paste used in home purification rituals and exorcism of diseases is known. In the ritual tradition of Kerala, dried fruits were hung at the entrances of dwellings as a talisman against diseased energy.

In Nepal and Bhutan, dried seeds were used as a smoking mixture in Shaivite practices — as a symbol of fiery purification of breath and mind. In the central regions of Vietnam, a decoction of the leaves was used in the practice of ritual baths during transitional states, including returning from funerals and women's initiations.

In Africa, especially in Zimbabwe and Nigeria, the plant is known as part of home phytotherapy. Pastes and juice from unripe fruits were used as remedies in rituals to protect infants from the evil eye. In Ethiopia, leaves were sometimes hung over the cradle as a protective symbol.

In Cuba and the Dominican Republic, plant leaves were placed under the pillow as a means of expelling nightmares and dreams with "alien will." In the shamanic practices of Colombian Andean communities, bark and seeds were used in rituals of "memory cutting," where the participant inhaled the smoke of burning raw materials as part of a purification ritual before a change of status — the transition from student to healer.

In the Muslim communities of southern Yemen and Oman, the fruits of the plant were considered a symbol of abundance and were served as part of wedding treats in combination with honey and milk. A decoction of the leaves in these regions was used for ritual washing in preparation for reading sacred texts.

Historically, the first mention of the plant in India was recorded in agricultural chronicles of the 14th century during the Vijayanagara Empire, which described agricultural techniques for cultivation and use as a homestead medicinal tree. In Myanmar, the plant is mentioned in a 17th century medical text "Thanaka Lak Phyo", which describes a ritual of burning leaves and inhaling steam accompanied by a cleansing mantra.