Apiol

Because Apiole (parsley) is primarily used as an allergenic extract or found within botanical supplements, there is no single 'standard' oral dose established by the FDA for therapeutic use. However, clinical patterns include:

• Allergenic Testing: For skin prick testing, a single drop of a non-standardized extract (often 1:10 or 1:20 w/v) is applied to the forearm or back. Results are interpreted by an allergist after 15-20 minutes.
• Historical Oral Use: In older pharmacopeias, doses of 0.12 to 0.3 mL of liquid apiole were sometimes cited for menstrual stimulation. Warning: Modern clinical guidelines strongly advise against these doses due to the high risk of organ failure.
• Dietary Intake: Normal culinary consumption of parsley provides negligible amounts of apiole (typically less than 10mg per serving), which is generally considered safe for healthy adults.

Apiole (parsley) is not approved for internal use in pediatric populations. The risk of nephrotoxicity (kidney damage) and hepatotoxicity (liver damage) is significantly higher in children due to their smaller body mass and developing metabolic pathways. In allergenic testing, pediatric use must be strictly supervised by a board-certified allergist, using highly diluted extracts to minimize the risk of systemic absorption or anaphylaxis.

Renal Impairment

Apiole is known to be nephrotoxic. Patients with a glomerular filtration rate (GFR) below 60 mL/min/1.73m² should avoid any supplemental or concentrated form of apiole. Even in diagnostic testing, caution is advised if the patient has a history of acute kidney injury.

Hepatic Impairment

As the liver is responsible for the oxidative metabolism of apiole, patients with Child-Pugh Class B or C hepatic impairment are at an increased risk of 'apiolism' (apiole poisoning). Dose-related liver stress can exacerbate existing cirrhosis or hepatitis.

Elderly Patients

Geriatric patients often have reduced renal clearance and may be more sensitive to the estrogenic effects of apiole. Use in this population should be limited to essential diagnostic testing under close monitoring of vital signs and kidney function.

If you are undergoing diagnostic testing with Apiole:

• Preparation: Ensure you have not taken antihistamines (like loratadine or cetirizine) for at least 3-7 days prior, as these can mask the results of the allergenic extract.
• Administration: The extract is applied to the skin by a healthcare professional. Do not ingest the diagnostic solution.
• Observation: You must remain in the clinic for at least 30 minutes following administration to monitor for signs of a systemic allergic reaction (anaphylaxis).

If using botanical parsley extracts:

• With Food: Always take with a meal to reduce gastrointestinal irritation.
• Storage: Store concentrated oils or extracts in amber glass bottles away from direct sunlight and heat to prevent chemical degradation of the phenylpropenes.

For allergenic testing, a missed appointment should be rescheduled. For supplemental use, if a dose is missed, skip the missed dose and return to your regular schedule. Never double the dose to catch up, as the toxicity of apiole is strictly dose-dependent.

Apiole overdose is a medical emergency. Symptoms include:

• Neurological: Vertigo, tinnitus (ringing in ears), ataxia (loss of coordination), and seizures.
• Hematological: Hemolytic anemia (destruction of red blood cells).
• Organ Failure: Jaundice (yellowing of skin/eyes indicating liver failure) and oliguria (reduced urine output indicating kidney failure).

Emergency Measures: If ingestion of concentrated apiole is suspected, contact a poison control center immediately. Treatment involves gastric lavage, activated charcoal, and intensive supportive care to manage renal and hepatic function.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose without medical guidance.

When exposed to Apiole, particularly through culinary or diagnostic means, the following side effects may occur:

• Contact Dermatitis: Redness, itching, or small bumps at the site of skin contact. This is common during allergenic testing as the body reacts to the extract.
• Gastrointestinal Upset: Mild nausea or abdominal cramping, especially if parsley extracts are taken on an empty stomach.
• Photosensitivity: Apiole and related compounds in parsley can make the skin more sensitive to ultraviolet (UV) light, potentially leading to faster sunburns.

• Dizziness and Vertigo: A feeling of spinning or lightheadedness, often occurring shortly after the ingestion of concentrated extracts.
• Headache: Persistent dull aching in the cranial region.
• Tinnitus: A high-pitched ringing in the ears, which is often an early warning sign of phenylpropene toxicity.

• Abnormal Uterine Bleeding: Due to its Estrogen Receptor Agonist [MoA], apiole can cause spotting between periods or unusually heavy menstrual flow.
• Urticaria: Widespread hives or skin rashes that appear far from the site of initial contact.
• Hypotension: A sudden drop in blood pressure, which may lead to fainting (syncope).

> Warning: Stop taking Apiole (parsley) and call your doctor immediately if you experience any of these.

• Nephrotoxicity (Kidney Damage): Symptoms include swelling in the ankles or feet (edema), sudden weight gain, and changes in urine color or frequency. Apiole can cause acute tubular necrosis, a serious condition where the kidney's filtering tubes are damaged.
• Hepatotoxicity (Liver Injury): Characterized by dark urine, clay-colored stools, severe upper abdominal pain, and jaundice. Clinical studies have shown that high doses of apiole lead to centrilobular necrosis in the liver.
• Hemolytic Anemia: This occurs when apiole causes red blood cells to break down faster than the body can replace them. Symptoms include extreme fatigue, pale skin, and shortness of breath.
• Anaphylaxis: A life-threatening allergic reaction. Signs include swelling of the throat, difficulty breathing, a rapid pulse, and a feeling of impending doom.
• Seizures: High concentrations of apiole can lower the seizure threshold, leading to involuntary muscle contractions and loss of consciousness.

Prolonged exposure to Apiole, even at sub-toxic doses, can lead to chronic organ stress. Long-term effects include:

• Chronic Kidney Disease: Repeated minor insults to the renal tubules can lead to permanent scarring and reduced kidney function over years.
• Hormonal Dysregulation: Continuous stimulation of estrogen and androgen receptors may interfere with the body's natural feedback loops, potentially affecting fertility or bone density.
• Pigmentation Changes: Chronic photosensitivity can lead to permanent 'patchy' skin discoloration (hyperpigmentation).

No FDA black box warnings currently exist for Apiole (parsley) as a non-standardized allergenic extract. However, historical medical literature and toxicology reports serve as a 'de facto' warning regarding its use as an abortifacient. In many jurisdictions, the sale of concentrated apiole is restricted due to its high toxicity and risk of death when used in attempts to terminate pregnancy.

Report any unusual symptoms to your healthcare provider immediately. Monitoring of blood counts and organ function is recommended for anyone using concentrated parsley derivatives.

Apiole (parsley) is a potent bioactive compound that should never be treated as a 'harmless' herbal supplement. Its classification as an Estrogen and Androgen [EPC] means it can significantly alter hormonal balance. Patients must be aware that the line between a 'therapeutic' dose and a 'toxic' dose of Apiole is exceptionally narrow. This compound is primarily intended for diagnostic use by trained immunologists and is not recommended for self-administration.

No FDA black box warnings for Apiole (parsley). However, the medical community recognizes a severe risk of fatal organ failure associated with the ingestion of parsley essential oils or purified apiole for the purpose of inducing menstruation or abortion. This use is strictly contraindicated and medically dangerous.

• Allergic Reactions / Anaphylaxis Risk: As a 'Standardized Chemical Allergen,' Apiole is a known trigger for severe hypersensitivity. Patients with known allergies to carrots, celery, or fennel (the Apiaceae family) are at a significantly higher risk of cross-reactivity and anaphylaxis.
• Hepatotoxicity and Nephrotoxicity: Apiole is a direct toxin to the liver and kidneys. It can cause acute organ failure even in individuals with no prior history of disease. Regular monitoring of BUN, Creatinine, and LFTs (Liver Function Tests) is required if exposure is significant.
• Neurotoxicity: Apiole can cause 'apiolism,' a syndrome characterized by significant neurological impairment, including permanent damage to the auditory nerve (tinnitus/deafness) and motor coordination centers.
• Hormonal Sensitivity: Individuals with hormone-sensitive conditions (e.g., breast cancer, uterine fibroids, endometriosis) should avoid Apiole due to its Estrogen Receptor Agonist [MoA] activity, which could theoretically stimulate the growth of sensitive tissues.

If a patient is exposed to significant amounts of Apiole or is using it within a clinical trial, the following monitoring is essential:

1. 1Complete Blood Count (CBC): To check for signs of hemolytic anemia (low hemoglobin and haptoglobin, high bilirubin).
2. 2Renal Function Tests: Serum creatinine and GFR should be checked at baseline and periodically.
3. 3Liver Enzyme Panels: Monitoring for elevations in AST and ALT which indicate hepatic stress.
4. 4Urinalysis: To detect hematuria (blood in urine) or proteinuria, which are early signs of renal tubular damage.

Apiole can cause sudden dizziness, vertigo, and ataxia. Patients should not drive or operate heavy machinery for at least 24 hours after a diagnostic test involving apiole or if they are experiencing any neurological side effects from parsley-based products.

Alcohol should be strictly avoided when taking Apiole. Alcohol induces certain CYP450 enzymes in the liver which may accelerate the formation of toxic metabolites from apiole, significantly increasing the risk of hepatotoxicity.

There is no known withdrawal syndrome associated with Apiole. However, if using it for its nitrogen-binding or hormonal properties, discontinuation should be discussed with a doctor to ensure that the underlying condition (such as amenorrhea) is managed through safer, more standardized pharmaceutical means.

> Important: Discuss all your medical conditions with your healthcare provider before starting Apiole (parsley).

• Oral Contraceptives and Hormone Replacement Therapy (HRT): Because Apiole acts as an Estrogen and Progesterone [EPC], it can compete with or amplify the effects of synthetic hormones. This may lead to an increased risk of blood clots (thromboembolism) or render birth control less effective by disrupting the precise hormonal balance required for contraception.
• Warfarin (Coumadin): Parsley extracts are rich in Vitamin K, which directly antagonizes the anticoagulant effects of warfarin. Furthermore, Apiole's potential to cause hemolytic anemia can complicate the management of blood disorders and anticoagulation therapy.
• Nephrotoxic Drugs (e.g., Aminoglycosides, NSAIDs): Combining Apiole with other drugs that stress the kidneys (like high-dose ibuprofen or gentamicin) significantly increases the risk of acute renal failure.

• Tamoxifen: As an estrogen receptor agonist, Apiole may interfere with the estrogen-blocking action of Tamoxifen used in breast cancer treatment, potentially reducing the efficacy of the cancer therapy.
• Diuretics (e.g., Furosemide, Hydrochlorothiazide): Apiole has mild diuretic properties. Combining it with prescription diuretics can lead to severe dehydration and electrolyte imbalances (hypokalemia).
• Androgen Deprivation Therapy (ADT): For patients being treated for prostate cancer, Apiole's Androgen Receptor Agonist [MoA] activity may counteract the goals of therapy.

• Cytochrome P450 Inducers (e.g., Rifampin, Phenytoin): These drugs may speed up the metabolism of Apiole, potentially leading to a higher concentration of toxic metabolites.
• Antidiabetic Medications: Apiole may influence blood glucose levels; patients should monitor their blood sugar closely if using parsley extracts.

• Grapefruit Juice: Grapefruit inhibits CYP3A4, the enzyme partly responsible for breaking down Apiole. This can lead to dangerously high systemic levels of Apiole, increasing the risk of toxicity.
• High-Fat Meals: Since Apiole is lipophilic, consuming it with high-fat foods may significantly increase its absorption rate and peak plasma concentration (Cmax).

• St. John’s Wort: This herb induces CYP3A4 and may alter the metabolic clearance of Apiole.
• Other Phytoestrogens (e.g., Soy, Red Clover): Using Apiole alongside other herbal estrogens can lead to an additive effect, causing symptoms of estrogen dominance (breast tenderness, mood swings).
• Ginkgo Biloba: May increase the risk of bleeding when combined with the potential hematological side effects of Apiole.

• Liver Function Tests (LFTs): Apiole can cause false elevations in AST/ALT.
• Urine Glucose: High doses of parsley extracts may interfere with certain urine glucose dipstick tests.
• Creatinine Clearance: Apiole-induced nephrotoxicity will result in a measured decrease in creatinine clearance.

For each major interaction, the mechanism typically involves either pharmacodynamic competition at the hormone receptor site or pharmacokinetic interference through the CYP450 enzyme system. The clinical consequence is usually either increased organ toxicity or the failure of a primary medication to treat its intended condition.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking.

Apiole (parsley) must NEVER be used in the following circumstances:

• Pregnancy: Apiole is a known abortifacient and uterine stimulant. It can cause uterine contractions, placental hemorrhage, and fetal death. Its use during pregnancy is associated with high maternal mortality due to renal and hepatic failure.
• Active Kidney Disease: Because Apiole is directly nephrotoxic, any existing renal impairment (such as glomerulonephritis or interstitial nephritis) makes the use of this compound extremely dangerous.
• Severe Hepatic Impairment: Patients with liver failure or cirrhosis cannot safely metabolize Apiole, leading to rapid systemic poisoning.
• Hypersensitivity: Anyone with a documented severe allergy to parsley or other members of the Apiaceae family (celery, coriander, cumin, dill) must avoid Apiole extracts.

Conditions requiring careful risk-benefit analysis by a physician:

• Hormone-Sensitive Cancers: Patients with a history of breast, ovarian, or uterine cancer should avoid Apiole due to its estrogenic activity.
• Bleeding Disorders: Due to potential effects on red blood cells and interactions with Vitamin K pathways, those with hemophilia or thrombocytopenia should use caution.
• Epilepsy: Because apiole may lower the seizure threshold, individuals with seizure disorders require close monitoring.

Patients allergic to Apiole may also react to:

• Myristicin: Another phenylpropene found in nutmeg and parsley.
• Anethole: Found in anise and fennel.
• Celery: There is a high rate of cross-reactivity between parsley allergenic extracts and celery extracts (Celery-Mugwort-Birch syndrome).

> Important: Your healthcare provider will evaluate your complete medical history before prescribing or administering Apiole (parsley).

FDA Category: Not Assigned (Historically Contraindicated).

Apiole is strictly contraindicated during pregnancy. It has been used illicitly to induce abortion, a practice that frequently results in the death of both the fetus and the mother. The mechanism of teratogenicity and toxicity involves severe oxidative stress to the placenta and maternal organs. There is no safe level of supplemental Apiole during any trimester of pregnancy.

It is unknown if Apiole is excreted in human breast milk. However, due to its low molecular weight and lipophilic nature, passage into milk is highly likely. Because of the risk of neonatal nephrotoxicity and the infant's immature liver function, breastfeeding is not recommended if the mother is using concentrated parsley extracts or undergoing intensive allergenic testing.

Safety and effectiveness in children under the age of 18 have not been established. The use of Apiole in children is generally restricted to diagnostic allergy testing under the care of a specialist. Pediatric patients are at a higher risk for systemic absorption and subsequent organ toxicity from topical or oral exposure.

Clinical data on the use of Apiole in the elderly are limited. However, older adults typically have a natural decline in renal function (GFR). Since Apiole is eliminated renally and is a known nephrotoxin, the risk of accumulation and 'apiolism' is significantly higher in this population. Geriatric patients are also more likely to be on multiple medications (polypharmacy), increasing the risk of drug-drug interactions, particularly with anticoagulants and blood pressure medications.

In patients with renal impairment, the half-life of Apiole is significantly prolonged. Dose-dependent damage to the renal tubules can lead to a rapid transition from chronic kidney disease to acute renal failure. Use is generally avoided in any patient with a baseline creatinine clearance of less than 60 mL/min.

Apiole requires hepatic oxidation for clearance. In patients with significant liver dysfunction (Child-Pugh Class B or C), the risk of centrilobular necrosis is elevated. These patients should avoid parsley seed oils and concentrated extracts entirely.

> Important: Special populations require individualized medical assessment to avoid life-threatening toxicity.

Apiole (2,5-dimethoxy-3,4-methylenedioxy-1-allylbenzene) is a phenylpropene that functions as a multi-receptor ligand. Its primary molecular targets include:

1. 1Nuclear Estrogen Receptors (ER): Apiole acts as a weak agonist, binding to the ligand-binding domain of ER-alpha and ER-beta, which modulates the transcription of estrogen-responsive genes.
2. 2Androgen Receptors (AR): It exhibits agonistic activity at the AR, which may contribute to its metabolic effects.
3. 3Ammonium Binding: Apiole interacts with ammonium ions in the blood, though the exact molecular transporter involved is still under investigation.
4. 4Prostaglandin Modulation: At high doses, it may stimulate the release of prostaglandins in uterine tissue, leading to its emmenagogue effects.

The onset of action for Apiole's allergenic response is rapid (15-30 minutes), while its hormonal and toxicological effects have a slower onset (4-12 hours post-ingestion). The duration of effect is prolonged due to its sequestration in adipose tissue. Tolerance to its hormonal effects has not been clinically documented, but its toxic effects are cumulative.

| Parameter | Value |

|---|---|

| Bioavailability | ~60-70% (Oral) |

| Protein Binding | ~85% (Primarily Albumin) |

| Half-life | 12-24 hours (Estimated) |

| Tmax | 1-2 hours |

| Metabolism | Hepatic (CYP3A4, CYP2E1) |

| Excretion | Renal (70%), Fecal (25%), Pulmonary (5%) |

• Molecular Formula: C12H14O4
• Molecular Weight: 222.24 g/mol
• Solubility: Insoluble in water; highly soluble in ethanol, ether, and oils.
• Structure: A benzene ring with two methoxy groups, one methylenedioxy group, and an allyl side chain. It exists as 'parsley apiole' (found in P. crispum) and 'dill apiole' (an isomer found in dill).

Apiole is classified as a Non-Standardized Food Allergenic Extract [EPC]. It is chemically related to other phenylpropenes like safrole and myristicin, which also exhibit similar neurotoxic and hepatotoxic profiles at high concentrations.