Gynetox

Dosage for Angelica Archangelica Root varies significantly based on the intended therapeutic indication and the specific formulation used.

• For General Dietary Support (Vitamin C/Nicotinic Acid context): Healthcare providers typically suggest a range of 500 mg to 2,000 mg of the dried root equivalent per day, usually divided into two or three doses.
• For Urological/Calculi Dissolution Support: Clinical studies have utilized standardized extracts at doses of 300-600 mg twice daily.
• For Allergenic Immunotherapy: Dosing is highly individualized and follows a strictly regulated "build-up" phase followed by a "maintenance" phase, administered via subcutaneous injection by a qualified allergist. Doses are measured in Protein Nitrogen Units (PNU) or Bioequivalent Allergy Units (BAU).

Angelica Archangelica Root is generally not recommended for use in children under the age of 12 unless specifically directed by a pediatric specialist. The potential for hormonal interference (due to its classification under Recombinant Human Growth Hormone [EPC] associated pathways) and the risk of severe photosensitivity make it a high-risk agent for pediatric populations. If approved, pediatric dosing is typically calculated based on body weight (e.g., 5-10 mg/kg), but standardized safety data is lacking.

Renal Impairment

Because approximately 70% of the metabolites are excreted renally, patients with a Glomerular Filtration Rate (GFR) below 60 mL/min/1.73m² should use this agent with caution. A 25-50% dose reduction may be necessary for patients with Stage 3 or Stage 4 Chronic Kidney Disease (CKD) to prevent the accumulation of furanocoumarins, which can increase systemic toxicity.

Hepatic Impairment

Since the liver (specifically the CYP450 system) is the primary site of metabolism, patients with Child-Pugh Class B or C hepatic impairment should avoid high doses of Angelica Archangelica Root. Impaired clearance can lead to significantly elevated plasma concentrations and an increased risk of hepatotoxicity.

Elderly Patients

Geriatric patients often have reduced renal and hepatic reserve. Clinical guidelines suggest starting at the lowest possible dose (e.g., 250 mg daily) and titrating upward slowly while monitoring for side effects such as dizziness or skin sensitivity.

• Timing: Oral forms are best taken with food to minimize gastrointestinal irritation and to enhance the absorption of fat-soluble furanocoumarins.
• Administration: Capsules should be swallowed whole with a full glass of water (8 oz). Do not crush or chew standardized capsules, as this may lead to an immediate release of essential oils that can irritate the oral mucosa.
• Storage: Store in a cool, dry place away from direct sunlight. The bioactive furanocoumarins are light-sensitive and can degrade if exposed to UV radiation.
• Sun Protection: Patients taking this medication must use high-SPF sunscreen and wear protective clothing, as the drug increases the skin's sensitivity to ultraviolet light.

If a dose is missed, take it as soon as you remember. However, if it is almost time for your next scheduled dose, skip the missed dose and resume your regular schedule. Do not double the dose to catch up, as this significantly increases the risk of phototoxic reactions.

Signs of an acute overdose of Angelica Archangelica Root include:

• Severe nausea and vomiting
• Extreme skin sensitivity or immediate blistering upon sun exposure
• Dizziness and ataxia (loss of coordination)
• Abnormal bleeding or bruising (due to anticoagulant effects)

In the event of a suspected overdose, contact your local poison control center or seek emergency medical attention immediately. Treatment is primarily supportive, focusing on skin protection and gastrointestinal decontamination if the ingestion was recent.

> Important: Follow your healthcare provider's dosing instructions precisely. Do not adjust your dose or discontinue use without explicit medical guidance, especially if being used for allergenic immunotherapy.

The most frequently reported side effect of Angelica Archangelica Root is Photosensitivity. Patients often report that their skin becomes red, itchy, or painful after even brief exposure to sunlight. This is a direct result of furanocoumarins (like psoralens) binding to DNA in skin cells and reacting with UV light.

Other common effects include:

• Gastrointestinal Distress: Mild nausea, bloating, or flatulence shortly after ingestion.
• Heartburn: An acidic sensation in the chest or throat, likely due to the acidifying activity of the root.
• Increased Menstrual Flow: Women may notice heavier or longer periods, as the herb has traditionally been recognized for its emmenagogue (uterine stimulating) properties.

• Dizziness: A feeling of lightheadedness or vertigo, occurring 1-2 hours after dosing.
• Contact Dermatitis: A localized rash or redness upon handling the raw root or applying topical extracts.
• Headache: Mild to moderate tension-type headaches.
• Polyuria: Increased frequency of urination, attributed to the acidifying and diuretic-like effects of the organic acids.

• Hepatotoxicity: Elevated liver enzymes (ALT/AST) have been noted in rare cases of prolonged, high-dose use.
• Leukopenia: A slight reduction in white blood cell count, requiring monitoring in sensitive individuals.
• Hypoglycemia: In some patients, the root may lower blood sugar levels unexpectedly.

> Warning: Stop taking Angelica Archangelica Root and call your doctor immediately if you experience any of the following:

• Anaphylaxis: Symptoms include swelling of the face, lips, or tongue; difficulty breathing; or a rapid drop in blood pressure. This is a risk particularly with the Allergenic Extract [EPC] forms.
• Phototoxicity (Severe): The development of large blisters, skin peeling, or second-degree burns after sun exposure.
• Uncontrolled Bleeding: Blood in the stool, nosebleeds that won't stop, or excessive bruising. This is due to the Anti-coagulant [EPC] properties of the coumarin constituents.
• Jaundice: Yellowing of the eyes or skin, suggesting liver dysfunction.
• Severe Hypotension: Fainting or extreme weakness.

Prolonged use of Angelica Archangelica Root (longer than 6 months) may lead to:

• Chronic Hyperpigmentation: Permanent darkening of skin patches due to repeated sub-clinical phototoxic reactions.
• Vitamin B12 Interference: Some data suggest that chronic use of high-dose Nicotinic Acid [EPC] components may interfere with the absorption or metabolism of other B-vitamins.
• Increased Risk of Cataracts: Due to the accumulation of photosensitizing agents in the lens of the eye, though this is primarily theoretical and based on high-dose animal studies.

No FDA black box warnings are currently issued for Angelica Archangelica Root. However, it is important to note that many products containing this ingredient are not evaluated with the same rigor as synthetic pharmaceuticals. Healthcare providers emphasize that the lack of a black box warning does not imply absolute safety, particularly regarding the risk of severe phototoxicity and potential interactions with anticoagulants.

Report any unusual symptoms to your healthcare provider. Monitoring of skin condition and liver function is recommended for patients on long-term therapy.

Angelica Archangelica Root is a potent pharmacological agent with significant systemic effects. It is not a "simple herb" and must be treated with the same caution as prescription medications. The most critical safety concern is the interaction between the drug and ultraviolet (UV) light. Patients must be educated on the necessity of strict UV avoidance. Furthermore, because it is classified as an Anti-coagulant [EPC], it poses a significant risk for patients undergoing surgery or those with existing bleeding disorders.

No FDA black box warnings for Angelica Archangelica Root.

Allergic Reactions / Anaphylaxis Risk

As a member of the Apiaceae family, Angelica Archangelica Root carries a high risk of cross-reactivity for individuals allergic to celery, carrots, fennel, or coriander. If you have a known allergy to these foods, you are at a significantly higher risk for anaphylaxis. This is particularly relevant when using the Non-Standardized Food Allergenic Extract [EPC] or Plant Allergenic Extract [EPC] versions of the drug.

Phototoxicity and Skin Cancer Risk

The furanocoumarins in Angelica Archangelica Root are DNA-intercalating agents. When activated by UVA light, they form covalent bonds with DNA. This not only causes immediate phototoxic burns but may theoretically increase the long-term risk of skin cancer (squamous cell carcinoma) if the skin is repeatedly exposed to UV light while taking the medication.

Anticoagulation and Bleeding

Because the root contains natural coumarin derivatives, it can thin the blood. This increases the risk of internal bleeding, especially in the gastrointestinal tract. Patients with a history of peptic ulcers or those taking other blood thinners must exercise extreme caution.

Hormonal Effects

Given its classification involving Recombinant Human Growth Hormone [EPC] pathways in certain databases, there is a theoretical risk of interference with the endocrine system. It may mimic or block certain hormonal signals, which could be detrimental to patients with hormone-sensitive conditions (e.g., breast cancer, endometriosis).

Patients taking clinical doses of Angelica Archangelica Root should undergo the following monitoring:

• Skin Examinations: Every 3-6 months to check for signs of phototoxicity or abnormal pigment changes.
• Coagulation Panel: Prothrombin Time (PT) and International Normalized Ratio (INR) should be checked if the patient is also taking anticoagulants.
• Liver Function Tests (LFTs): Baseline and periodic monitoring of AST, ALT, and bilirubin.
• Blood Glucose: Periodic monitoring for patients with diabetes, as the root may cause hypoglycemia.

Angelica Archangelica Root may cause dizziness or mild sedation in some patients. Do not drive or operate heavy machinery until you know how this medication affects you. If you experience vertigo or blurred vision, cease these activities immediately and consult your doctor.

Alcohol should be avoided or strictly limited. Alcohol can increase the risk of gastrointestinal irritation and may exacerbate the dizziness associated with the drug. Furthermore, both alcohol and Angelica Archangelica Root are processed by the liver, and combined use may increase the risk of hepatic strain.

Do not stop taking this medication abruptly if you are using it as part of an Allergenic Extract [EPC] immunotherapy program, as this can disrupt the desensitization process. For other uses, tapering is generally not required, but you should always consult your healthcare provider before stopping to ensure your underlying condition is managed.

> Important: Discuss all your medical conditions, including any history of skin cancer or bleeding disorders, with your healthcare provider before starting Angelica Archangelica Root.

• Psoralens (e.g., Methoxsalen): Using Angelica Archangelica Root with other psoralens used for psoriasis (PUVA therapy) can lead to catastrophic, full-body phototoxic reactions. This combination is strictly contraindicated.
• Warfarin (Coumadin): Because the root contains natural coumarins, it can significantly potentiate the effects of Warfarin, leading to a dangerously high INR and life-threatening hemorrhage.

• Fluoroquinolones (e.g., Ciprofloxacin, Levofloxacin): These antibiotics are also known to cause photosensitivity. Combining them with Angelica Archangelica Root creates an additive effect, greatly increasing the risk of severe burns.
• Tetracyclines (e.g., Doxycycline): Similar to fluoroquinolones, these increase UV sensitivity and should be used with extreme caution.
• NSAIDs (e.g., Ibuprofen, Naproxen): Both NSAIDs and Angelica can irritate the stomach lining and increase bleeding risk. Close monitoring for signs of GI bleeding is required.

• CYP3A4 Substrates (e.g., Simvastatin, Cyclosporine): Angelica Archangelica Root can inhibit the CYP3A4 enzyme. This leads to increased plasma concentrations of these drugs, potentially increasing their toxicity (e.g., rhabdomyolysis risk with statins).
• Antidiabetic Medications (e.g., Metformin, Insulin): The root may have additive blood-sugar-lowering effects. Patients should monitor their glucose levels more frequently to avoid hypoglycemia.

• Grapefruit Juice: Grapefruit is a potent inhibitor of CYP3A4. Since Angelica is also metabolized by and inhibits this enzyme, consuming grapefruit juice can lead to unpredictably high levels of the root's bioactive compounds in the blood.
• High-Fat Meals: Dietary fats increase the absorption of lipophilic furanocoumarins, which may increase the risk of side effects.
• Celery and Parsley: These foods also contain furanocoumarins. High consumption while taking the medication can increase the total systemic "psoralen load."

• St. John's Wort: This herb also causes photosensitivity. Combining it with Angelica is not recommended.
• Ginkgo Biloba / Garlic / Ginger: These supplements have antiplatelet effects. Combining them with the Anti-coagulant [EPC] properties of Angelica increases the risk of bruising and bleeding.
• Kava Kava: Both Kava and Angelica can affect the liver; combined use should be avoided to prevent hepatotoxicity.

• Prothrombin Time (PT/INR): May be falsely or truly elevated.
• Urine pH: The Acidifying Activity [MoA] of the root will lower urine pH, which may affect the results of urinalysis or the solubility of other excreted drugs.
• Liver Enzyme Tests: May show elevations in ALT, AST, or Alkaline Phosphatase.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking. A complete medication reconciliation is essential to prevent dangerous interactions.

Angelica Archangelica Root must NEVER be used in the following circumstances:

1. 1Pregnancy: The root is a known emmenagogue and uterine stimulant. It can induce uterine contractions and has been historically associated with miscarriage. Its use during pregnancy poses a significant risk to the fetus.
2. 2Hypersensitivity to Apiaceae: If you have had a severe allergic reaction (anaphylaxis) to celery, fennel, anise, or coriander, you must not use this drug. The risk of cross-reactivity is nearly 100% in sensitive individuals.
3. 3Active Peptic Ulcer Disease: Due to its Anti-coagulant [EPC] properties and potential for GI irritation, it can cause life-threatening bleeding in patients with open ulcers.
4. 4Porphyria: This is a group of rare genetic disorders that affect the skin and nervous system. Angelica can exacerbate the photosensitivity associated with porphyria, leading to severe skin damage.

In these cases, a careful risk-benefit analysis by a healthcare provider is required:

• Diabetes Mellitus: Because the root can lower blood sugar, it may complicate the management of diabetes. Close monitoring is essential.
• Scheduled Surgery: Patients should stop taking Angelica Archangelica Root at least 14 days prior to any surgical procedure to prevent excessive intraoperative or postoperative bleeding.
• History of Skin Cancer: Individuals with a history of melanoma or non-melanoma skin cancer should avoid this agent due to its DNA-intercalating and photosensitizing properties.
• Bleeding Disorders: Patients with hemophilia or von Willebrand disease should only use this agent under strict hematological supervision.

Patients should be aware of potential cross-sensitivity with:

• Other Angelica species (e.g., Angelica sinensis or Dong Quai).
• Psoralen-containing plants (e.g., Giant Hogweed, Lime, Bergamot).
• Chemical Allergens: Individuals sensitive to certain chemical fragrances may react to the essential oils in the root.

> Important: Your healthcare provider will evaluate your complete medical history, including any rare genetic conditions, before prescribing Angelica Archangelica Root.

FDA Category: Not Formally Assigned (Generally considered Contraindicated).

Angelica Archangelica Root is strictly avoided during pregnancy. Clinical data and traditional evidence indicate that the root possesses potent emmenagogue (menstrual-inducing) and abortifacient (abortion-inducing) properties. It can stimulate uterine smooth muscle contractions, leading to preterm labor or spontaneous abortion. Furthermore, the furanocoumarins can cross the placental barrier, and their effects on fetal development are not well-characterized, posing a risk of teratogenicity.

It is unknown whether the bioactive constituents of Angelica Archangelica Root pass into human breast milk. However, many of the essential oils and coumarins are small, lipophilic molecules that are likely to be excreted in milk. Due to the risk of photosensitivity and potential hormonal effects in the nursing infant, the use of this agent is not recommended while breastfeeding. If use is deemed medically necessary, breastfeeding should be discontinued.

Safety and effectiveness in pediatric populations have not been established. The Recombinant Human Growth Hormone [EPC] association suggests that the root could theoretically interfere with normal growth and development in children. Additionally, children have thinner skin and are at a much higher risk for severe, scarring phototoxic reactions. Most clinical guidelines suggest avoiding this agent in children under 12 years of age.

Clinical trials involving older adults have shown that this population is more susceptible to the side effects of Angelica Archangelica Root.

• Renal Clearance: Age-related decline in GFR can lead to toxic accumulation.
• Polypharmacy: Elderly patients are more likely to be on anticoagulants or CYP3A4-metabolized drugs, increasing the risk of dangerous interactions.
• Fall Risk: The potential for dizziness and orthostatic hypotension increases the risk of falls and subsequent fractures.

In patients with moderate to severe renal impairment (CrCl < 30 mL/min), the excretion of glucuronide conjugates is significantly delayed. This can lead to a prolonged half-life of furanocoumarins. Dosing should be reduced by at least 50%, and patients must be monitored closely for signs of systemic toxicity.

Patients with hepatic cirrhosis or significant liver dysfunction (Child-Pugh Class B or C) should avoid this medication. The liver's inability to process the essential oils and furanocoumarins can lead to acute-on-chronic liver failure or severe systemic phototoxicity due to extremely high plasma levels.

> Important: Special populations require individualized medical assessment. Always inform your specialist about your age, pregnancy status, or any organ impairment.

Angelica Archangelica Root exerts its effects through several distinct molecular pathways:

1. 1DNA Intercalation: The furanocoumarins (e.g., xanthotoxin) intercalate into the double helix of DNA. Upon exposure to UVA radiation (320–400 nm), these molecules form monoadducts and cross-links with pyrimidine bases (primarily thymine). This inhibits DNA synthesis and cell proliferation, which is the basis for its use in certain hyperproliferative skin conditions but also the cause of its phototoxicity.
2. 2Calcium Chelation: Organic acids within the root have a high affinity for divalent cations. In the renal tubule, they bind to Ca2+, reducing the concentration of free calcium ions available to form insoluble salts with oxalate or phosphate.
3. 3Enzyme Inhibition: The agent acts as a competitive inhibitor of CYP3A4, the most common enzyme involved in drug metabolism in the human liver.

• Onset of Action: For gastrointestinal or acidifying effects, onset is typically 30-60 minutes. For allergenic desensitization, effects may take weeks or months to manifest.
• Duration of Effect: The photosensitizing effects can last for up to 24-48 hours after a single dose, as the furanocoumarins remain bound to skin tissues.
• Tolerance: There is no evidence of physiological tolerance to the acidifying or chelating effects, though immunological tolerance is the goal of allergenic therapy.

| Parameter | Value |

|---|---|

| Bioavailability | 40% - 60% |

| Protein Binding | 85% - 92% |

| Half-life | 4 - 12 hours |

| Tmax | 1.5 - 3 hours |

| Metabolism | Hepatic (CYP3A4, CYP2A6) |

| Excretion | Renal (70%), Fecal (30%) |

• Molecular Components: Includes α-pinene, limonene, β-phellandrene (essential oils); imperatorin, xanthotoxin, bergapten (furanocoumarins); and angelic acid.
• Solubility: Bioactive constituents are primarily lipophilic (fat-soluble), though the organic acids are water-soluble.
• Drug Class: Classified as a botanical therapeutic within the Vitamin C [EPC] and Anti-coagulant [EPC] categories.

Angelica Archangelica Root is unique in that it bridges the gap between traditional herbal medicine and standardized pharmaceutical extracts. It is related to other Apiaceae-derived agents but is distinguished by its specific concentration of macrocyclic lactones and furanocoumarins.