Apple

Dosage for Apple extract is highly individualized and depends on whether the goal is diagnosis or immunotherapy.

Diagnostic Testing (Skin Prick Method)

• Standard Dose: One drop (approximately 0.05 mL) of the non-standardized extract (e.g., 1:20 w/v) applied to the skin, followed by a skin prick or puncture.
• Observation: The reaction is read 15 to 20 minutes after application. A positive result is typically a wheal diameter 3mm larger than the negative control.

Allergen Immunotherapy (Subcutaneous Injection)

• Build-up Phase: Treatment typically begins with a very dilute solution (e.g., 1:100,000 w/v). Doses are increased weekly or bi-weekly by 0.05 mL to 0.1 mL increments until the 'Maintenance Dose' is reached.
• Maintenance Phase: Once the target dose is reached (e.g., 0.5 mL of a 1:100 w/v solution), injections are spaced out to every 2 to 4 weeks.

Apple allergenic extracts are used in children, but the safety and efficacy have not been established for patients under the age of 5 in some jurisdictions.

• Diagnostic Testing: The procedure is identical to adults, though the number of simultaneous tests may be limited to reduce patient distress.
• Immunotherapy: Dosing is generally the same as adult dosing, as the mechanism is based on immunological threshold rather than body weight. However, pediatric patients must be monitored even more closely for systemic reactions.

Renal Impairment

No specific dosage adjustments are provided in the manufacturer labeling for renal impairment, as the systemic load of protein in diagnostic testing is minimal. However, in high-dose immunotherapy, caution is advised if renal clearance of metabolites is severely compromised.

Hepatic Impairment

No formal studies have been conducted. Since the metabolism of phytoestrogenic components (like phloretin) occurs in the liver, patients with severe hepatic failure should be monitored for unexpected systemic effects if using concentrated oral extracts.

Elderly Patients

Elderly patients may have reduced skin reactivity (reduced histamine response). This can lead to false-negative results in diagnostic testing. Clinicians may consider a positive histamine control to verify skin reactivity.

Apple extracts are medical products and are not 'taken' like standard pills.

• Administration Site: For skin testing, the volar surface of the forearm or the upper back is used. For immunotherapy, injections are given subcutaneously in the outer aspect of the upper arm.
• Food Interactions: For diagnostic testing, there are no specific food restrictions, but patients must avoid antihistamines for 3 to 7 days prior to the test.
• Storage: Extracts must be stored in a refrigerator at 2°C to 8°C (36°F to 46°F). Do not freeze, as freezing can denature the allergenic proteins and render the product ineffective.

In the context of immunotherapy:

• Short Delay (1-3 days): Usually, the scheduled dose can be given without adjustment.
• Long Delay (over 7 days): Your healthcare provider may need to reduce the dose to the previous level or lower to avoid an increased risk of a systemic reaction.
• Never double the dose to catch up on a missed injection.

An 'overdose' of Apple extract typically refers to an accidental administration of a concentration higher than the patient's current tolerance level during immunotherapy.

• Signs of Overdose: Rapid onset of hives (urticaria), swelling of the throat (angioedema), wheezing, drop in blood pressure, or rapid heart rate.
• Emergency Measures: Immediate administration of epinephrine (0.3 mg for adults) and emergency medical transport. In a clinical setting, oxygen, IV fluids, and corticosteroids may be administered.

> Important: Follow your healthcare provider's dosing instructions exactly. Do not adjust your dose or frequency of treatment without direct medical guidance.

Most patients receiving Apple extracts for diagnostic or therapeutic purposes will experience localized reactions. These are generally considered part of the drug's expected pharmacological action.

• Localized Redness (Erythema): A red, warm area at the site of the skin test or injection. This typically appears within minutes and resolves within a few hours.
• Itching (Pruritus): Intense itching at the site of administration is very common. This is caused by the localized release of histamine.
• Wheal Formation: A raised, hive-like bump at the test site. This is the primary indicator of a positive diagnostic test.
• Local Swelling: In immunotherapy, swelling at the injection site (up to the size of a half-dollar) is common and may last for 24 to 48 hours.

• Large Local Reactions (LLR): Swelling that extends beyond the immediate injection site, sometimes involving the entire upper arm. This may require the use of cold compresses or oral antihistamines.
• Oral Allergy Syndrome (OAS): If Apple extract is taken orally or sublingually, patients may experience tingling or itching of the lips, tongue, and throat. This is common in patients who are also allergic to birch pollen.
• Fatigue: Some patients report feeling unusually tired for several hours following an immunotherapy injection.

• Systemic Urticaria: Hives appearing on parts of the body far away from the injection site.
• Gastrointestinal Distress: Nausea, abdominal cramping, or diarrhea, which can be a sign of a systemic allergic progression.
• Hormonal Fluctuations: Due to its Estrogen Receptor Agonist [MoA], very high doses of concentrated apple polyphenols could theoretically cause breast tenderness or changes in menstrual cycle, though this is rarely documented with standard allergenic extracts.

> Warning: Stop using Apple extract products and call your doctor or emergency services immediately if you experience any of the following symptoms of anaphylaxis:

• Difficulty Breathing: Wheezing, chest tightness, or a feeling of 'air hunger.'
• Throat Swelling: A sensation of the throat closing, hoarseness, or difficulty swallowing.
• Cardiovascular Collapse: Dizziness, fainting, rapid or weak pulse, and a sudden drop in blood pressure.
• Angioedema: Significant swelling of the face, lips, tongue, or around the eyes.
• Generalized Cyanosis: A bluish tint to the skin or lips, indicating a lack of oxygen.

Long-term use of Apple extracts in immunotherapy is generally well-tolerated. The primary long-term effect is 'immunological remodeling,' where the body shifts from an IgE-mediated response to an IgG4-mediated response. There is no evidence that long-term use of these extracts increases the risk of malignancy or organ failure. However, patients on long-term therapy should have their skin reactivity re-evaluated periodically.

While 'Apple' specifically may not always carry a unique black box warning, the class of Allergenic Extracts frequently carries a class-wide FDA warning regarding Anaphylaxis:

WARNING: RISK OF SEVERE ALLERGIC REACTIONS

• Allergenic extracts can cause severe life-threatening systemic reactions, including anaphylaxis.
• Do not administer allergenic extracts to patients with severe, unstable, or steroid-dependent asthma.
• Patients must be observed for at least 30 minutes in a medical facility equipped to treat anaphylaxis following administration.
• Patients with certain medical conditions or those taking beta-blockers may be at increased risk and may not respond to epinephrine.

Report any unusual symptoms or persistent side effects to your healthcare provider immediately.

Apple extracts are high-risk biological products. They must only be administered by healthcare professionals who are prepared to manage life-threatening allergic reactions. Patients must remain in the office for a minimum of 30 minutes following any injection or skin test, as most serious reactions occur within this window.

As noted in the side effects section, Apple extracts fall under the FDA class warning for allergenic extracts. The primary risk is anaphylaxis, which can occur even in patients who have previously tolerated the extract without issue. The risk is higher during the 'build-up' phase of immunotherapy or when starting a new vial of extract.

• Anaphylaxis Risk: Patients must be screened for any signs of illness (such as a cold or flu) before receiving an injection, as systemic illness can lower the threshold for a severe allergic reaction.
• Asthma Status: Patients with uncontrolled or severe asthma are at a significantly higher risk for a fatal reaction to allergenic extracts. Asthma must be stable and well-controlled before therapy begins.
• Cross-Reactivity: Patients allergic to Apple are often cross-reactive to other members of the Rosaceae family (pears, peaches, cherries) and to birch pollen (the 'Birch-Apple Syndrome'). This must be considered when interpreting test results.
• Estrogen Sensitivity: Because Apple is an Estrogen Receptor Agonist [MoA], patients with a history of estrogen-dependent cancers (such as certain breast or uterine cancers) should discuss the use of concentrated apple extracts with their oncologist.

• Pre-injection Check: Assessment of current symptoms and vital signs.
• Post-injection Observation: 30-minute mandatory wait time.
• Peak Flow Monitoring: For asthmatic patients, a peak flow meter may be used before and after administration to ensure no bronchospasm has occurred.
• Skin Test Controls: Every Apple skin test must be accompanied by a positive control (histamine) and a negative control (saline) to ensure the validity of the results.

Apple extract itself does not typically cause sedation. However, if a patient experiences a systemic reaction or is given antihistamines to treat a local reaction, their ability to drive or operate machinery may be significantly impaired.

Alcohol consumption should be avoided on the day of an Apple extract injection. Alcohol can cause vasodilation, which may increase the rate of allergen absorption and potentially worsen the severity of an allergic reaction.

If Apple immunotherapy is discontinued, the patient's sensitivity may eventually return to baseline levels. There is no 'withdrawal' syndrome, but the protective immunological benefits will gradually wane over several months to years.

> Important: Discuss all your medical conditions, especially respiratory or heart problems, with your healthcare provider before starting Apple extract therapy.

• Beta-Blockers (e.g., Propranolol, Atenolol): These medications are strictly contraindicated or used with extreme caution during Apple extract therapy. Beta-blockers can block the effects of epinephrine, the primary treatment for anaphylaxis. If a patient on a beta-blocker has a severe reaction to Apple extract, the reaction may be refractory (unresponsive) to standard emergency treatment.
• MAO Inhibitors (e.g., Phenelzine): These can potentiate the effects of sympathomimetic amines used to treat reactions, leading to hypertensive crises.

• ACE Inhibitors (e.g., Lisinopril): Some evidence suggests that ACE inhibitors may increase the risk of systemic reactions to allergenic extracts and may interfere with the body's natural compensatory mechanisms during an allergic event.
• Tricyclic Antidepressants (TCAs): Like MAOIs, TCAs can interfere with the management of an allergic reaction if epinephrine is required.

• Antihistamines (e.g., Cetirizine, Loratadine, Diphenhydramine): These medications will suppress the skin's response to Apple extract. Patients must stop taking first-generation antihistamines 3 days prior and second-generation antihistamines at least 7 days prior to diagnostic testing to avoid false-negative results.
• H2 Blockers (e.g., Famotidine): These may also mildly suppress skin test reactivity and should be discontinued before testing.
• Systemic Corticosteroids: Long-term use of high-dose steroids can suppress immune responses and may alter the results of allergy testing or the efficacy of immunotherapy.

• Birch Pollen-Related Foods: Patients with Birch-Apple syndrome may have increased sensitivity if they consume raw hazelnuts, carrots, or celery around the time of their Apple extract treatment.
• Caffeine: High doses of caffeine may increase heart rate and jitteriness, which can be confused with the early signs of a systemic allergic reaction.

• St. John's Wort: May induce CYP enzymes involved in the metabolism of the phytoestrogenic components of Apple, potentially reducing their estrogenic effect.
• Soy Isoflavones: Since both Apple and Soy contain phytoestrogens, taking them together may have an additive effect on estrogen receptors. This should be monitored in patients sensitive to hormonal changes.

• Skin Prick Tests: As mentioned, Apple extract is itself a diagnostic tool. Its use will interfere with any other skin tests being performed simultaneously if the reactions overlap.
• Serum IgE Tests: Treatment with Apple extracts for immunotherapy will eventually lead to changes in serum-specific IgE and IgG4 levels, which is the intended clinical outcome but must be interpreted correctly by a lab specialist.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, especially those for blood pressure or heart rhythm.

Apple extracts must NEVER be used in the following circumstances:

• Previous Severe Anaphylaxis: If a patient has had a life-threatening reaction to Apple extract in the past, the risk of re-administration usually outweighs any diagnostic or therapeutic benefit.
• Severe/Unstable Asthma: Patients whose asthma is not well-controlled (e.g., FEV1 consistently below 70% of predicted) are at an unacceptably high risk of fatal bronchospasm during Apple extract administration.
• Acute Infection or Fever: Administration during an active infection can increase the risk of a systemic allergic reaction.
• Malignancies of the Immune System: Patients with active leukemia or lymphoma should not undergo immunotherapy as their immune system cannot respond predictably to the treatment.

• Beta-Blocker Therapy: As discussed, the inability to respond to epinephrine makes Apple extract therapy significantly more dangerous.
• Pregnancy (Initiation): Immunotherapy should generally not be started during pregnancy due to the risk of anaphylaxis-induced fetal hypoxia. However, if a patient is already on a stable maintenance dose, it may sometimes be continued.
• Autoimmune Diseases: Patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis may experience a flare-up of their condition if the immune system is stimulated by allergenic extracts.
• Estrogen-Dependent Tumors: Due to the Estrogen Receptor Agonist [MoA], patients with active or recent history of estrogen-sensitive cancers should use Apple extracts only after a thorough risk-benefit analysis.

Patients should be aware of cross-sensitivity with:

• Birch Pollen (Betula): Due to the similarity between Mal d 1 and Bet v 1 proteins.
• Other Rosaceae Fruits: Including Pear, Peach, Plum, Apricot, and Strawberry.
• Latex: Some patients with 'Latex-Fruit Syndrome' may show sensitivity to Apple extracts.

> Important: Your healthcare provider will evaluate your complete medical history and current medications before prescribing or administering Apple extract.

FDA Pregnancy Category: C

There are no adequate and well-controlled studies of Apple allergenic extracts in pregnant women.

• Teratogenicity: It is unknown whether Apple extract can cause fetal harm when administered to a pregnant woman. Animal reproduction studies have not been conducted.
• Clinical Risks: The primary risk during pregnancy is maternal anaphylaxis. A severe allergic reaction can lead to maternal hypotension (low blood pressure) and uterine hypoperfusion, resulting in fetal hypoxia (lack of oxygen) and potential fetal death or premature labor.
• Recommendation: Healthcare providers typically do not start Apple immunotherapy during pregnancy. If a patient becomes pregnant while on maintenance therapy, the dose is usually not increased, and many clinicians choose to suspend treatment until after delivery.

It is not known whether Apple allergenic proteins or their phytoestrogenic metabolites are excreted in human milk.

• Risk-Benefit: Because many proteins are digested in the infant's gastrointestinal tract, the risk to the nursing infant is generally considered low. However, the effect of Apple's 'Estrogen Receptor Agonist' activity on a nursing infant's developing endocrine system has not been studied.
• Recommendation: Use with caution. Discuss the timing of injections and breastfeeding with your doctor.

• Approval: Apple extracts are used in children for diagnosis. However, the safety of immunotherapy in children under age 5 is not well-established because young children may be unable to communicate the early symptoms of a systemic reaction.
• Growth Effects: There is no evidence that Apple extracts affect growth or development in children.
• Special Considerations: In children with both Apple allergy and asthma, the risk of a severe reaction is significantly higher.

• Pharmacokinetics: Older patients may have reduced renal function, which could theoretically slow the clearance of Apple metabolites, though this is rarely clinically significant for allergenic extracts.
• Comorbidities: The presence of cardiovascular disease in the elderly makes the use of epinephrine (required for treating reactions) more risky, as it can trigger arrhythmias or myocardial infarction (heart attack).
• Skin Reactivity: Reduced skin turgor and mast cell density in the elderly can lead to smaller wheal sizes during testing.

Specific guidelines for Apple extract in renal impairment are lacking. Since the proteins are primarily processed by the immune system and small metabolites are excreted renally, clinicians should monitor for any signs of systemic accumulation if high doses are used in patients with Stage 4 or 5 Chronic Kidney Disease (CKD).

In patients with significant hepatic impairment (Child-Pugh Class B or C), the metabolism of Apple's phytoestrogenic components (like phloretin) may be reduced. While not a contraindication for skin testing, it warrants caution for long-term, high-dose immunotherapy.

> Important: Special populations require individualized medical assessment and close monitoring by an allergy specialist.

Apple extracts operate via two distinct pharmacological pathways:

1. 1Immunological Pathway: The extract contains specific allergenic proteins (Mal d 1, 2, 3, and 4). Upon exposure, these proteins cross-link IgE antibodies on the surface of mast cells. This triggers the release of histamine and other mediators. In immunotherapy, repeated exposure at increasing doses induces the production of IgG4 'blocking antibodies' and regulatory T-cells (Tregs), which suppress the IgE-mediated allergic response.

1. 1Endocrine Pathway (Estrogen Receptor Agonist): Apple contains phloretin, a dihydrochalcone. Phloretin acts as a ligand for Estrogen Receptors (ERα and ERβ). It mimics the structure of 17β-estradiol, allowing it to bind to the receptor's ligand-binding domain. This triggers the recruitment of co-activators and the transcription of estrogen-responsive genes. This activity is classified as 'Estrogen Receptor Agonist [MoA].'

• Dose-Response: In skin testing, there is a clear dose-response relationship between the concentration of the Apple extract and the diameter of the wheal.
• Time to Onset: Skin reactions occur within 15–20 minutes. Systemic immunological changes from immunotherapy take 3–6 months to become apparent.
• Duration of Effect: A single skin test reaction lasts 2–4 hours. The desensitization effect of a full course of immunotherapy can last for several years after discontinuation.

| Parameter | Value |

|---|---|

| Bioavailability | <5% (Skin Prick); Variable (Oral) |

| Protein Binding | 80-90% (Phloretin component) |

| Half-life | 2-4 hours (Small molecule polyphenols) |

| Tmax | 1-2 hours (Oral ingestion of extracts) |

| Metabolism | Hepatic (Glucuronidation/Sulfation) |

| Excretion | Renal (>70%), Fecal (<20%) |

• Molecular Components: A complex mixture of proteins (Mal d 1-4) and polyphenols (Phloretin, Quercetin, Catechin).
• Phloretin Formula: C15H14O5
• Molecular Weight: 274.27 g/mol (Phloretin)
• Solubility: Proteins are soluble in aqueous saline; polyphenols are poorly soluble in water but soluble in ethanol or glycerin.

Apple belongs to the Non-Standardized Food Allergenic Extract class. It is grouped with other Rosaceae extracts like Peach and Cherry. Due to its phytoestrogen content, it also shares properties with the Estrogen drug class, similar to other plant-derived SERMs (Selective Estrogen Receptor Modulators).