Metagenics
Alergeze
Symptomatic Relief of Allergies
Modulates histamine release and inflammation associated with allergic reactions
- Reduces effector cell activation to lower histamine production
- Reduces Inflammatory Mediators
- Reduces Swelling and Oedema
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BENEFITS
CLINICALLY PROVEN;
Reduces Activation of Mast Cells, Basophils and Eosinophils to lower Histamine production
Attenuates Respiratory Histamine production
Reduces the severity and duration of allergic reactions
Reduces Swelling and Oedema
Attentuates Food Allergies, Intolerances and Sensitivities
Reduces Skin Allergies and Reactions
Asthma Treatement
Allergic Rhinitis (Hay Fever) Treatment
LOWERS HISTAMINE PRODUCTION
The classic allergic reaction begins when the allergen complex (e.g. IgE antibodies) binds to the mast cell, resulting in mast cell degranulation and the release of histamine and other inflammatory mediators.[18],[19] Therefore, in order to reduce the reaction, potent mast cell stabilisation is required. Mast cells release a variety of inflammatory mediators including cytokines, chemokines, prostaglandins, leukotrienes, enzymes and platelet activating factor (PAF).[20],[21] Mast cells reside in the tissues that are involved in the allergic reaction.[22] They form part of the mucosal immune system and can commonly be found in the mucosa of the respiratory and gastrointestinal tract and submucosa of skin cells,[28] making these organs key areas for the expression of allergy symptoms (Table 1).
Interestingly the “skin seems to have its own equivalent of the hypothalamic-pituitary-adrenal (HPA) axis”,[23] the main regulator is cortisol releasing hormone.[24] Acute stress releases CRH in the skin, which activates mast cells and inducing a local response, one of the mechanisms by which stress may worsen the allergic reaction.[25]
ATTENTUATES RESPIRATORY HISTAMINE PRODUCTION
Allergic rhinitis involves mast cell activation in the nasal cavity. In fact, mast cell degranulation accounts for approximately one-half the symptoms of allergic rhinitis and is a key therapeutic target.
Interestingly, viral infections have been shown to exacerbate asthma. For example, 80% of childhood asthma exacerbations are associated with viral airway infections. The mechanism may be due to activation of viral toll-like receptors (TLR-9) on human mast cells triggering an inflammatory response.[26]
Gastrointestinal mast cells play a role in many of the symptoms associated with food hypersensitivity.
Food allergies involve activation of the mucosal and connective tissue mast cells in the gastrointestinal tract and dermis.[27]
Histamine, the principal inflammatory mediator in many allergies, is released by mast cells in the immediate-response phase, and by basophils in the delayed-response phase.[29] Histamine binds to Histamine (H1) receptors and this has several consequences: it increases vasodilation, capillary permeability, and smooth muscle contraction.[30] A number of nutraceuticals have been shown to stabilise and deactivate mast cells and reduce histamine levels, playing a critical role in reducing the allergic reaction. Quercetin and NRA2™ provide a strong combination with potent mast cell stabilising activity.
NRA2™
NRA2™ has antihistamine, antioxidant and anti-inflammatory activity. It works via mast cell stabilisation, thereby down-regulating histamine. In animal studies, NRA2™ has been shown to down-regulate histamine in a concentration dependent manner.[31] The ability of NRA2™ to reduce histamine suggests its benefit in improving early symptoms. It has been postulated that NRA2™’s effective control over sneezing, rhinorrhoea and nasal pruritus is due to antihistamine activity.[32]
Quercetin
Quercetin is known to assist with membrane stabilisation of mast cells and basophils, resulting in reduced degranulation and reduced histamine release.[33],[34],[35]Quercetin assists with the stabilisation of mast cells and gastrointestinal cytoprotection via lactone stimulating mucus production, and also inhibits the release of histamine and serotonin from intestinal mast cells.[36]
Eosinophils are cells that circulate in the blood. They attack tissue at the site of an allergic reaction, causing damage.[37] In cutaneous allergic reactions, hypersensitivity states and bronchial asthma, eosinophils are often present in more than 500/µl of blood, with eosinophilia commonly associated with hay fever, eczema and allergic disease.[38],[39],[40]
NRA2™ has been shown to reduce absolute eosinophil count. In an open label study of 174 patients, compared with baseline count, absolute eosinophil count at week 12 was significantly reduced following treatment with NRA2™.[42] After 12 weeks of treatment, mean absolute eosinophil count reduced from 516 to 373 cells per µl; close to normal readings (see Figure 2).[43]
Quercetin has also been shown to reduce eosinophil count. Animal studies have found quercetin at 10 mg/kg, reduced eosinophils in blood and lung fluid.[44]
REDUCES INFLAMMATORY MEDIATORS
Allergic reactions involve the release of a variety of inflammatory mediators including prostaglandins, inflammatory cytokines, chemokines, and leukotrienes.[45],[46] Inflammation is an important aspect of immediate and late phase allergic reactions.[47] Down-regulation of these mediators may have a significant impact on reducing the severity and duration of the allergic reaction, especially the late phase, where many of these markers are elevated.[48]
NRA2™
NRA2™ has anti-inflammatory activity. NRA2™.’s ability to reduce histamine suggests a promising role for early phase relief, although it also has the ability to modulate inflammatory mediators such as lipoxygenase for improving late phase effects.[49]
Quercetin
Quercetin has been shown to play a modulating, biphasic and regulatory action on inflammation and immunity.[50] It modulates inflammatory pathways by down-regulating the production of cytokines, chemokines, leukotrienes (inhibits lipoxygenase) and prostaglandins (inhibits cyclooxygenase). Furthermore, quercetin has been shown to down-regulate inducible nitric oxide synthase (iNOS), nuclear factor kappa beta (NFkB) and decrease tumor necrosis factor alpha (TNF-α) overproduction.[51],[52],[53] Interestingly, a recent randomised, double blind, placebo-controlled trial in 50 women with rheumatoid arthritis found that eight weeks of supplemental quercetin at 500 mg/day significantly reduced plasma inflammatory marker highly sensitive-TNF-α levels, providing symptomatic improvement, highlighting the anti-inflammatory action of quercetin.[54]
Bromelains
Bromelains’ anti-inflammatory activity involves specific inhibition of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE-2) and substance P.[55] It may also act by down-regulating NFkB, thromboxane B2 (TXB2)and inhibition of interleukin-8 induced neutrophil migration and adhesion.[56] Bromelains appear to have an immunomodulatory effect and have been shown to reduce TNF-α secretion when immune cells are already stimulated, for example in inflammation induced cytokine production.[57] Furthermore, quercetin's efficacy may be enhanced when bromelains are taken concomitantly.[58]
REDUCES SWELLING AND OEDEMA
Vasodilation and vascular permeability are components of the inflammatory and allergic cascade that contribute to signs and symptoms of inflammation. Injury to blood vessels triggers the kinin system, which produces several inflammatory mediators and causes a further increase in vascular permeability. Increased levels of kinins are present in the airways of asthmatic patients within minutes after challenge with an allergen.[59] It has been proposed that kinins are released at the very early phase of allergies, and may increase plasma extravasation and cause bronchoconstriction.[60]
Bromelains
Bromelains act through the induction of proteolytic activity at the inflammatory site. They reduce the production of plasmakinins,[61] thus reducing vasodilation and vascular permeability. Bromelains also work through the activation of plasmin which breaks down fibrin (Figure 3).[62],[63] Bromelains are used internationally by physicians as a preventative measure for inflammation-associated sequelae that may occur secondary to cosmetic, laser and surgical skin procedures. A systematic review found that clinical trials on bromelains for prevention of post procedure ecchymosis and oedema were mostly positive (5/7 trials), suggesting bromelains are a promising treatment option.[64]
ATTENTUATES FOOD ALLERGIES, INTOLERANCES AND SENSITIVITIES
A food allergy develops when a person comes into contact with an allergen that triggers the production of antibodies, which circulate and attach to immune cells. It is important to note that other parts of the immune system may also react to certain foods (i.e. eosinophilic or T cell driven inflammation).[125] Food allergies often involve activation of the mucosal and connective tissue mast cells in the gastrointestinal tract and dermis. Mediators such as histamine and platelet activating factor (PAF) are also released.[126],[127]
Quercetin has been shown to improve T helper 1 (Th1)/T helper 2 (Th2) balance and restrain antigen specific IgE antibody formation.[128],[129] In one study, for example, rats sensitised to peanut extract were treated with quercetin at doses of 50 mg/kg/mL one week post sensitisation, for four weeks. After the four week treatment period, quercetin completely abrogated peanut-induced anaphylactic reactions. These findings suggest quercetin is potent enough to suppress ongoing IgE response.[130]
In animal studies, Quercetin quells peanut induced anaphylactic reaction in peanut sensitised rats.... findings suggest quercetin is potent enough to suppress ongoing IgE response.
REDUCES SKIN ALLERGIES AND REACTIONS
Food allergens are often characteristically resistant to digestion by pepsin in the stomach, allowing them to reach the mucosal surface of the small intestine intact. Bromelains have broad-spectrum enzyme activity over an optimum pH range of 5.5-8.0, providing proteolytic activity in the stomach as well as small intestine,[131] meaning bromelains may assist in breaking down potential allergens before a reaction is evoked.
Exposure of the epidermis or dermis to allergens causes a localised allergic reaction. Endemic mast cell activation in the skin leads immediately to a local increase in vascular permeability, which causes extravasation of fluid and swelling.[132] Several recent clinical and preclinical findings suggest quercetin shows promise as a natural treatment for inflammatory skin disease.[133] Atopic skin lesions are characterised by increased infiltration of inflammatory cells, such as monocytes, eosinophils, macrophages, mast cells and activated T helper cells (Th1 and Th2).[134] Quercetin has been shown to reduce eosinophil count, stabilise mast cells, regulate T cells and reduce IgE antibodies making it an ideal candidate for the amelioration of atopic skin disorders.[135],[136],[137] Furthermore, studies have shown that treatment with quercetin suppressed levels of inflammatory cytokines through peroxisome proliferator-activated receptor alpha (PPAR-α) up-regulation, which may improve skin barrier dysfunction in atopic disease.[138]
Bromelains have the potential to support a variety of skin reactions, due to their ability to reduce inflammatory oedema and markers. A small study in eight patients with Pityriasis lichenoides chronica (an uncommon, idiopathic dermatosis characterised by waves of erythematous, scaly papules) found that treatment with only 40 mg of bromelains per day for one month led to clinical recovery in these patients. In a 12 month follow up, two patients experienced relapse five to six months post treatment, but responded to another cycle of therapy.[139]
ASTHMA TREATMENT
Asthma is a respiratory condition charactised by inflammation of the airways which produces swelling, narrowing of the airways, and the build-up of mucus. Due to its mast cell stabilising activity, quercetin may be used for the treatment of mast cell-derived allergic inflammatory diseases, such as asthma.[140]
Animal models have shown that quercetin suppresses eosinophilic inflammation associated with asthma. Animal studies have shown that more than 25% of absorbed quercetin is localised in lung tissue, suggesting direct benefit to the airways given its anti-inflammatory properties.[141] Quercetin may be useful in the treatment of the varying phases of the asthma response, due to its ability to inhibit histamine and protein release, limit phospholipase A2 activity, and reduce the recruitment of neutrophils and eosinophils in the lungs.[142] In animal studies, bromelains have been shown to limit airway inflammation, allergic sensitisation and allergic airway disease via modulation of dendritic cells, with subsequent reduction in T cell activation and IgE levels.[143],[144]
Mediators released from mast cells in the respiratory tract lead to constriction of the bronchioles, bronchi and upper airways and produce symptoms of asthma. The anti-spasmodic activity of NRA2™ has been compared with antihistamines against carbachol and barium chloride–induced spasmodic activity, with NRA2™ providing comparable protection in animal models.[145]
ALLERGIC RHINITIS (HAY FEVER) TREATMENT
Allergic rhinitis, commonly known as hay fever, often presents with mast cell and basophil activation, triggering inflammation and swelling. Nutrients that address these mechanisms are showing clinical benefit in a variety of studies.
NRA2™
NRA2™ has been clinically trialled in over 500 patients and demonstrates the effectiveness of NRA2™ in allergy relief.[146],[147]In a randomised, double blind, placebo-controlled study with 48 patients over three months the major symptoms of AR were significantly reduced (Figure 4), while the assessment on the quality of life revealed an improvement in 70% of the patients in the NRA2™ supplemented group.[148]
In a multicentre clinical trial involving 545 patients (171 RCT and 374 open label), NRA2™ reduced the three major symptoms of allergic rhinitis, namely sneezing, rhinorrhoea (runny nose) and nasal congestion (blocked nose).
Improvement was also observed in absolute eosinophil count, mucociliary clearance time, peak expiratory flow rate and peak nasal flow rate. No serious adverse events that warranted cessation of treatment were observed. In the open label component, the total nasal symptom score reduced by 78% at week 12. In the randomised controlled trial, the total nasal symptoms significantly improved in the treatment group (68% at six weeks and 75% at 12 weeks) compared to the placebo (54% at 6 weeks and 56% at 12 weeks, an overall improvement of 19%).
Quercetin
A study was conducted in 123 patients sensitised to house dust mites and displaying nasal symptoms of allergic rhinitis. The study used nasal scrapings from patients to measure the histamine response to quercetin and sodium cromoglycate, a mast cell stabilising prescription drug. Quercetin inhibited histamine release from nasal scrapings by 46% to 96%, compared to 58% to 72% for the prescription drug.[150]
Bromelains
Bromelains have been found to be an effective mucolytic agent in respiratory tract disease.[151] For example, the therapeutic efficacy of bromelains was evaluated in 116 children under the age of 11 years, diagnosed with acute sinusitis. The duration of symptoms in patients treated with bromelains was 16% shorter (6.66 days) than the use of standard therapy (7.95 days), a statistically significant difference. Standard therapy consisted generally of mainstream drugs and physical therapies.[152] Furthermore, three randomised controlled trials in acute rhino-sinusitis showed significant reduction in nasal mucosa inflammation.[153]
INGREDIENTS
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DIRECTIONS
Adults:
Take 2 tablets twice daily with food.
EVIDENCE
References
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WARNINGS
Contraindications
Allergy: Hypersensitivity to quercetin,[167] ginger,[168],[169] pineapple or other members of the Bromeliaceae family.[170] Avoid use.
Moderate Level Cautions
Anticoagulant/antiplatelet drugs: Bromelains[171],[172] and ginger[173],[174],[175] are thought to have antiplatelet activity. Research suggests that Phyllanthus emblica is an anticoagulant[176] and can inhibit platelet aggregation by 36%.[177] Theoretically, combining ginger, bromelains or Phyllanthus emblica with other drugs that have this activity might increase the risk of bruising and bleeding. Use with caution and monitor patients INR levels.
Bleeding disorders: Due to the anticoagulant properties of ginger, there have been safety concerns in regards to the risk of increased bleeding tendency in patients with bleeding disorders. Although this theoretical possibility is not reflected functionally in human studies, it would still warrant caution in situations which carry a high risk of bleeding, such as haemorrhagic stroke and postoperative events. To minimise the risk of exacerbation of these bleeding events it is recommended to discontinue the use of ginger during acute bleeding episodes, such as during and immediately after a haemorrhagic stroke, or in patients who are at high risk for haemorrhagic stroke.[178],[179],[180]
Surgery: Due to the anticoagulant properties of ginger, there have been safety concerns in regards to the risk of increased postoperative bleeding. Although this theoretical possibility is not reflected functionally in human studies, it still warrants caution in postoperative events. To minimise the risk of exacerbation of these bleeding events, it is recommended to discontinue the use of ginger 4-7 days before elective procedures which have a high risk for bleeding complications.[181],[182],[183]
Low Level Cautions
Amiodarone: This anti-arrhythmic drug is metabolised by cytochromes P450 2C8 and 3A4, and has a narrow therapeutic range. Quercetin[184],[185] and piperine, a constituent of black and long pepper,[186] inhibits the activity of these enzymes which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.[187],[188]
Antibiotics (Amoxicillin,[189] Penicillin,[190] Erythromycin[191] and Tetracycline antibiotics[192]): Some evidence suggests that bromelains might increase levels of amoxicillin,[193],[194] penicillin, erythromycin and tetracycline antibiotics. However a study using 80 mg of bromelains and 500 mg of tetracycline found no difference in plasma levels when it was taken with or without bromelains. [195] Use with caution and monitor patient.
Antidiabetic drugs: Evidence from animal studies (100, 200 and 300 mg/kg) suggests that Terminalia fruit and seed extracts have hypoglycemic effects. Theoretically, concomitant use of Terminalia with antidiabetic drugs could affect blood sugar control and increase the risk of hypoglycaemia in some patients. Use cautiously and adjust dosing if required.[196],[197]
Carbamazepine: This anti-epileptic, neurotropic and psychotropic drug is metabolised by cytochromes P450 and 3A4, and has a narrow therapeutic range. Quercetin[198],[199] and piperine, a constituent of black and long pepper,[200] inhibits the activity of these enzymes which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.[201],[202]
Cyclosporine: This potent immunosuppressant drug is metabolised by cytochrome P450 3A4 and P glycoprotein and has a narrow therapeutic range. Quercetin[203],[204] and piperine, a constituent of black and long pepper [205] inhibits the activity of these substances which theoretically may alter the drug’s therapeutic effect. A small study in healthy volunteers shows that pretreatment with quercetin increases plasma levels and prolongs the half-life of a single dose of cyclosporine.[206],[207],[208] Use cautiously in patients on this medication, monitor for symptom changes and consult the patient’s specialist if cyclosporine is prescribed for organ transplant.[209],[210]
CNS Depressants (e.g. Barbiturates): In animal research, certain constituents from Albizia flowers have been shown to potentiate pentobarbital-induced sleeping time in mice. Theoretically, Albizia might enhance the therapeutic and adverse effects of CNS depressants.[211],[212] Use with caution and adjust dosing if required.
Diazepam: This anxiolytic and sedative drug is metabolised by cytochromes P450 3A4, 1A1, 1A2 and has a narrow therapeutic range. Quercetin[213],[214] and piperine, a constituent of black and long pepper,[215] inhibits the activity of these enzymes which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for increased drowsiness or other adverse effects.[216],[217]
Digoxin: This cardiac glycoside drug is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range. Quercetin[218],[219] and piperine, a constituent of black and long pepper,[220] inhibits the activity of this enzyme, which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and only under medical supervision.[221],[222]
Disopyramide: This antiarrhythmic drug is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range. Quercetin[223],[224] and piperine, a constituent of black and long pepper,[225] inhibits the activity of this enzyme which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.[226],[227]
Ethosuximide: This anticonvulsant drug is metabolised by cytochrome P450 3A4 and has a narrow therapeutic range. Quercetin[228],[229] and piperine, a constituent of black and long pepper,[230] inhibits the activity of this enzyme which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.[231],[232]
Flecainide: This antiarrhythmic drug is metabolised by cytochrome P450 2D6, and has a narrow therapeutic range. Quercetin[233],[234] and piperine, a constituent of black and long pepper[235] inhibits the activity of this enzyme which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.[236],[237]
Gallstones or gallbladder disease: Ginger may cause gallbladder contractions. Use with caution in patients with a history of gallbladder disease.[238],[239],[240]
Gastric ulcers: Use with caution in people with active stomach (peptic) or duodenal ulcers. Ginger may cause gastric irritation. Discontinue use if there is an increase in pain.[241],[242],[243]
Hepatotoxic drugs: In clinical research, Ayurvedic formulations containing Phyllanthus emblica, Zingiber officinale, Tinospora cordifolia and Boswellia serrata (total combined input 400mg) were associated with elevated serum glutamic pyruvic transaminase (SGPT) levels with otherwise normal liver function. Blood levels normalised after stopping the treatment. While it is unclear if the hepatic effects were associated with Phyllanthus emblica or other ingredients of the Ayurvedic formulations, theoretically, Phyllanthus emblica might have additive adverse effects on the liver when used with hepatotoxic drugs.[244],[245] Use with caution.
Lignocaine: Commonly known as a local anaesthetic, lignocaine is sometimes used intravenously to treat cardiac arrhythmia. This drug is metabolised by cytochromes P450 2D6, 1A1, 1A2 and 3A4, and has a narrow therapeutic range. Quercetin[246],[247],[248] and piperine, a constituent of black and long pepper,[249] inhibits the activity of these enzymes which theoretically may alter the drug’s therapeutic effect. Typically, use of lignocaine for arrhythmia is very short term and an interaction is unlikely, however it may be prudent to monitor the patient for possible symptom changes.[250],[251]
Olanzapine: This antipsychotic medication is used for the treatment of schizophrenia and bipolar disorder. It is metabolised by cytochromes P450 2D6, 1A1 and 1A2 and has a narrow therapeutic range. Quercetin[252],[253] and piperine, a constituent of black and long pepper,[254] inhibits the activity of these enzymes which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and only under medical supervision.[255],[256]
Phenobarbitone: This barbiturate is a widely used anti-seizure medication that is metabolised by cytochromes P450 3A4, 1A1 and 1A2 and has a narrow therapeutic range. Quercetin[257],[258] and piperine, a constituent of black and long pepper,[259] inhibits the activity of these enzymes which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.[260],[261]
Phenytoin: This anti-epileptic, anticonvulsant and anti-seizure drug is metabolised by cytochromes P450 2C9 and 3A4 and has a narrow therapeutic range. Quercetin[262],[263] and piperine, a constituent of black and long pepper[264] inhibits the activity of these enzymes which theoretically may alter the drug’s therapeutic effect. At 20 mg per day, piperine has been shown to increase Phenytoin Cmax from 4.08 to 5.2 mg/ml.[265] Use cautiously in patients on this medication and monitor for symptom changes.[266],[267]
Propranolol: This beta blocker is used to treat conditions such as angina, hypertension and irregular heartbeat, and is metabolised by cytochrome P450 2D6. Piperine, a constituent of black pepper, inhibits the activity of this enzyme which theoretically may alter the drug’s therapeutic effect. Furthermore, in a crossover study, six subjects received a single dose of 50 mg propranolol in combination with piperine 20 mg a day for 7 days. Cmax increased from 45 (propranolol alone) to 92 ng/ml (with 20 mg piperine) with a similar increase in bioavailability, with the area under the curve increasing from 561 to 1140 ng/ml/hr.[268] Use cautiously and monitor for any adverse side effects.
Quinolone antibiotics: Theoretically, quercetin might competitively inhibit quinolone antibiotics by binding to the DNA gyrase site on bacteria. Quinolones include ciprofloxacin (Cipro), levofloxacin (Levaquin), ofloxacin (Floxin), moxifloxacin (Avelox), gatifloxacin (Tequin), and others.[269],[270] Separate dose and use with caution.
Rifampicin: This antibiotic is used to treat several types of bacterial infections. Piperine, a constituent of black pepper, may inhibit the metabolism and perhaps increase the absorption of rifampicin when taken in relatively high doses or in formulations that deliberately concentrate the alkaloid piperine. The bioavailability of rifampicin has been enhanced at 50 mg/kg and 80 mg/kg of piperine in rats.[271] Although this can be used as a therapeutic advantage, it can also predispose the patient to increased risk of side effects.[272] Use cautiously and monitor for any adverse side effects.
Theophylline: This methylxanthine drug is used for acute relief in respiratory diseases such as COPD and asthma. This drug is metabolised by cytochromes P450 3A4, 1A1 and 1A2 and has a narrow therapeutic range. Quercetin[273],[274] and piperine, a constituent of black and long pepper,[275] inhibits the activity of these enzymes which theoretically may alter the drug’s therapeutic effect. At 20 mg per day Piperine has been shown to increase theophylline from 4.55 to 7.36 µg/ml, increasing its bioavailability.[276] Use cautiously in patients on this medication and monitor for any adverse effects.[277],[278]
Tramadol: Tramadol is a narcotic-like pain reliever used to treat moderate to severe pain. This drug is metabolised by cytochromes P450 2D6 and 3A4 and has a narrow therapeutic range. Quercetin[279],[280] and piperine, a constituent of black and long pepper,[281] inhibits the activity of these enzymes which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for any changes in pain management.[282],[283]
Valproate: This anti-epileptic, anticonvulsant and anti-seizure drug is metabolised by cytochrome P450 3A4, and has a narrow therapeutic range. Quercetin[284],[285] and piperine, a constituent of black and long pepper,[286] inhibits the activity of this enzyme which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor for symptom changes.[287],[288]
Warfarin: This anticoagulant medication is metabolised by cytochromes P450 2C9, 1A1, 1A2 and 3A4 and has a narrow therapeutic range. Quercetin[289],[290] and piperine, a constituent of black and long pepper,[291] inhibits the activity of these enzymes which theoretically may alter the drug’s therapeutic effect. Use cautiously in patients on this medication and monitor INR levels.[292],[293]
Pregnancy and Breastfeeding
Avoid in Pregnancy.
NRA2™ includes a combination of herbs used in the traditional Ayurvedic blend Triphala. There is limited information available from reputable sources regarding Triphala’s (Terminalia chebula, Terminalia bellerica and Phyllanthus emblic) use in pregnancy. However, based on traditional use and information from Ayurvedic Medicine by Sebastian Pole, it’s been decided that the use of Triphala should be avoided during pregnancy.[294] Of note, safety studies in animals on NRA2™ have shown no maternal changes or teratogenic effect.[295],[296]
MGXALER
