Metagenics
Alergenics
Reduces Allergy Responses
Helps to increase allergic tolerance and reduce allergic reactions by addressing the underlying factors of allergies
- Indicated for asthma and eczema relief
- Supports immune regulation and function
- Reduces sensitivity and improves tolerance to allergens
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BENEFITS
CLINICALLY PROVEN;
Relieves allergy responses
Reduces sensitivity and improves tolerance to environemtal and food indued allergies
Stabilises mast cells
Reduces the occurrence of eczema
Decreases symptoms of asthma and bronchial hyperactivity whilst improving lung function
Optimise GI Epithelial Integrity to lower immune reactivity
Enhance Mucosal Secretions to Neutralise Antigens
Regulates T Helper Cells, lowering allergy responses
Inhibit GI inflammatory mediators to improve tolerance or sensitivity to antigens
Suppress the production of MMPs to prevent tissue remodelling, which increases the susceptability to allergy responses.
Support liver clearance of immunologically active material
OPTIMISES GI EPITHELIAL INTEGRITY
The gut epithelium acts as an important barrier between the ‘inside’ and ‘outside’ world, playing an important role in the absorption of nutrients, ions and water, as well as conveying protection from potentially harmful substances such as toxins, pathogens and allergens. The integrity of the intestinal barrier depends on a complex of proteins that make up different intercellular junctions, including tight junctions (TJs).
A degree of intestinal permeability is certainly required for the efficient passage of nutrients,[8] however disruption of TJs and the resulting increased permeability can lead to the paracellular diffusion pathway allowing increased passage of toxins, pathogens and known allergens; in the case of allergens this can result in an allergic response.[9] A link between increased intestinal permeability and allergy has been made, with numerous studies showing that individuals living with allergic conditions, including asthma, eczema and urticaria, have measurements of intestinal permeability much greater than non-allergic individuals.[10] TJs within the epithelium play a determining factor in the degree of paracellular diffusion, and modulation of TJs can therefore control the degree of permeability via the diffusion pathways[11],[12]and thereby reduce the exposure and response to allergens.
Glutamine is an amino acid that is fundamental to epithelial integrity and the reduction of allergen translocation through the lumen.[13] Low glutamine availability results in atrophy of the intestinal epithelial cells, leading to increased permeability of this important physical barrier.[14] Additionally, glutamine is the precursor molecule for glucosamine, which is essential for mucin synthesis, and has been shown to increase villous height and mucosal thickness,[15] leading to improved barrier function.
Vitamin A is an essential nutrient for optimal epithelial cell growth, differentiation and maintenance.[16] Vitamin A deficiency may result in the cells of mucous membranes failing to regenerate, leading them to flatten and accumulate keratin. Mucin produced by goblet cells forms the main component of the mucus layer that blankets and protects mucous membranes. Production of mucin is vitamin A dependent. A reduction in mucus secretions and cellular integrity reduces the body’s ability to resist pathogens and antigens.[17] Retinoids and retinols, vitamers of vitamin A, also regulate intestinal brush border enzymes involved in the digestive process and are associated with the integrity of TJs and other adherence junction proteins.[18]
Zinc is another essential nutrient for the survival and function of epithelial cells, with deficiency resulting in increased intestinal permeability.[19] Zinc deficiency occurs in both developing countries and throughout the world, and is linked to the severity of the acute-phase response to infection and inflammation, as well as some chronic diseases, such as asthma.[20] Studies show that supplementation of zinc prevents increases in TJ,[21] therefore assisting to reduce the intestinal permeability that may contribute to allergic responses.
Vitamin D receptor (VDR) mediates the majority of the known functions of 1,25-dihydroxyvitamin D [1,25 (OH)2 D3], the active metabolite of vitamin D. Both vitamin D3 and VDR have shown benefits for TJ structure via the increased expression of occludin, ZO-1, ZO-2 and vinculin.[22] Several recent studies suggest that VDR stabilises the TJ structure and modulates intestinal inflammation.[23]
Baical skullcap is also able to up-regulate TJ-related proteins, with in vitro and in vivo studies highlighting baicalein, a flavone from baical skullcap, as being responsible for this action.[24] With research highlighting the importance of maintaining sound epithelial integrity to significantly reduce the impact of allergens, it is imperative to support the TJs and reduce the impact of intestinal permeability in the treatment of allergies.
ENHANCES MUCOSAL SECRETIONS TO NEUTRALISE ANTIGENS
The quantity and quality of mucosal secretions play an important role in the regulation of the gut-immune balance, and in turn, the degree of reactivity to antigens.[25],[26] The secretions are important for the non-immunologic neutralisation of antigens, also referred to as immune exclusion, which is central to the development of protective yet tolerogenic immunity.[27]
Immunoglobulin A (IgA), the predominant immunoglobulin found in all mucus secretions, plays a critical role in the formation of epithelial linings of the skin and mucosal tissues. IgA, and more specifically secretory IgA (sIgA), is considered the first line of defence against the external environment, including antigens and pathogenic microorganisms.[28],[29] In the airways, sIgA in mucosal secretions reduces access of allergens to the lamina propria and, in turn, reduces the resulting inflammatory response.[30] In the intestinal lumen, sIgA:
Directly traps antigens and blocks access to epithelial receptors;
Promotes the uptake and delivery of antigens to dendritic cells (DC) within the gut-associated lymphoid tissues (GALT), to allow for prompt surveillance;
Facilitates antigenic clearance through peristalsis;
Down-regulates inflammatory responses; and
Influences the composition of the gut microbiota.[31]
Shiitake mushroom increases secretory IgA levels and reduces inflammation.
Incorporating substances that increase sIgA is, therefore, considerably beneficial in the management of allergic conditions. These include shiitake mushroom,[32] vitamin A[33] and glutamine,[34]
In a four-week parallel study, 52 males and females ranging in age from 21 to 41, consumed either 5 or 10 grams of whole shiitake mushroom per day. Results showed a significant increase in sIgA levels in saliva, which is regarded as evidence of increased mucosal immunity as a whole. Shiitake mushroom also reduced C-reactive protein levels, indicating a reduced state of inflammation, along with increased levels of key immune regulatory interleukins, interleukin 4 (IL-4) and interleukin 10 (IL-10).[35]
The vitamin A metabolite, all-trans retinoic acid (RA), is responsible for the majority of the physiological effects of vitamin A. This includes the production of gut-tropic B cells and promotion of the differentiation of IgA antibody-secreting cells (IgA-ASC), the sIgA precursors. RA is also important for the modulation of T regulatory cell (Treg) differentiation,[36] a key player in the balance of helper T cells and an important influencer of immune status.[37]
As reduced levels of sIgA within the gut are associated with food allergy,[38] optimising sIgA levels is an important consideration.
Glutamine increases the production of sIgA via a number of mechanisms, including B cell induction of sIgA pathways, sIgA transport and direct impact on the gut microbiota.[39]
Another key immunoglobulin for the modulation, or neutralisation, of a food-induced immune response is IgG4.[40] IgG is present in mucosal secretions,[41] and levels have been considered indicative of an immunological reaction to food-based proteins. It is postulated, however, that the IgG subset, IgG4, along with IgA, both found in tolerant and intolerant individuals, play a protective role in the allergic response by acting as blocking antibodies.[42] Based on this theory, raised levels of IgG and IgA are not considered predictive of food intolerance and may be seen as the immune system supporting the process of oral tolerance.[43],[44]
T HELPER CELL REGULATION
Regardless of the route of entry into the body, the immune system reacts to antigens via the production of a range of immune cells, including antibodies and inflammatory mediators. At the level of the acquired immune system, the end result of an allergic response is an imbalance between the production of the effector T cells, T helper (Th) 1 and Th2.[46]
As the knowledge and understanding of the range and effects of Th cells broadens, novel T helper cell subsets have been identified which are also involved in allergic responses, such as Tregs which produce interleukin IL-10 and transforming growth factor beta (TGFβ), as well as Th17 producing IL-17[47] and Th22[48]producing IL-22, thus beginning to provide further understanding of immune responses beyond the standard Th1/Th2 paradigm.
With regards to the Th1 and Th2 imbalance, which classically defines the immunological imbalance of allergy, the imbalance swings in favour of the production of Th2 cytokines, namely IL-4, IL-13 and IL-15.[49],[50] This imbalance is often referred toas Th2 dominance, or a misdirected Th2 response.[51] Achieving tolerance requires an increase in the production of Tregs and Th1 cells, via immune modulators such as interferon gamma (IFNγ), TGFβ and IL-10.[52],[53],[54] The production of IL-10 and TGFβ by Tregs suppresses mast cells, basophils and eosinophils, as well as IgE production by B cells,[55]and are all key players in the allergic response.
Reishi mushroom is traditionally used in Chinese medicine for immune support, and scientific evidence quantifies its immune modifying properties. Reishi is traditionally indicated for conditions of suppressed or dysregulated immune function, including allergies, and symptoms such as coughing and wheezing.[56],[57],[58] Research indicates that reishi is effective at restoring the Th1/Th2 balance, including a histamine-induced immune response, as seen in allergy.[59],[60] This research is further supported in animal studies where the reishi polysaccharide, PS-G, was shown to induce Th1 cells via the activation of immature dendritic cells.[61]
Perilla’s anti-allergic activities have been studied in clinical trials, in vivo and in vitro. The mechanisms of action are many, including the down-regulation of Th2-type cytokine production, and inhibition of NFkB, TNF-α, IgE and histamine release. In addition, perilla inhibits cyclooxygenase-2 (COX-2) protein expression and caspase-1 activation. These actions all help to down-regulate Th2 dominance.[62] It is important to support both Tregs and Th1/Th2 balance to support an appropriate immune response and decrease the allergic response in an overactive immune system.
INHIBIT GI AND SYSTEMIC INFLAMMATORY MEDIATORS
Continuous exposure to substances that stimulate a hyper-responsive reaction will naturally lead to chronic inflammation. The resulting inflammation will impact the structure and function of the affected organs[93]; therefore reducing the levels of inflammation is paramount.
The level of interplay between the antigen presenting cells (APCs), specifically the potent DCs, and foreign substances, plus the continuous cross-talk of the T cells within the GALT, is a key factor in the inflammatory tone of the body as a whole, and the degree of tolerance or sensitivity to antigens.[94]
The reishi mushroom polysaccharide, PS-G, has been shown to support the activation and maturation of DCs, thereby assisting the regulation of immune reactivity. Interestingly, it’s been suggested that PS-G-treated-DC-based immunotherapies may be an option for future research.[95]
Reishi mushroom induces Th1 cells and restores Th1/Th2 balance.
An imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may contribute to the migration of inflammatory cells to the affected tissues, as noted in nasal mucosa specimens from allergic rhinitis patients.[96] MMPs are secreted by inflammatory cells, such as eosinophils, and are responsible for airway remodelling, as seen in those living with asthma.[97]
Vitamin D deficiency has long been linked with allergies and asthma, and 1,25 (OH)2 D3 has been shown to suppress the production of MMPs, whilst also enhancing TIMP-1 levels.[98]
Baical skullcap contains the flavonoids wogonin, baicalein and baicalin, which provide anti-inflammatory effects via the inhibition of various pro-inflammatory mediators, including 5-lipoxygenase, COX and NFκB.[99],[100]Furthermore, baical skullcap also inhibits the release of histamine from mast cells and mitogen activated protein (MAP) kinase expression, which is considered to be a driver of cytokine production.[101] Wogonin is considered a direct COX-2 inhibitor,[102] and animal studies reveal that wogonin increases IgA levels, whilst also decreasing IgE, IL-4, IL-5 and IL-10 secretion, and increasing IFN-γ and IL-2.[103] Traditional use of baical skullcap also supports its use for allergies, red eyes, and eczema.[104]
Shiitake mushroom augments the production of immunomodulating cytokines IL-2 and TNF-α,[105] and as mentioned previously, shiitake significantly increases sIgA levels in saliva, implying improved gut immunity.[106]
SUPPORT LIVER CLEARANCE OF IMMUNE COMPLEXES
The liver is fundamental to the detoxification and removal of environmental toxins and food-based allergens, whilst being an important filter between the gut and the rest of the body.[107] Hepatic DCs have been linked with oral tolerance, T cell anergy, T cell mediated hyporesponsiveness to an antigen,[108] along with the induction of Tregs.[109] A function of the liver’s hepatocytes and Kupffer cells is the sequestering of immunologically active material and, in turn, dampening the intensity of the immune reaction.[110]
Milk thistle has long been used in the support of liver function, and also possesses strong anti-inflammatory and antioxidant properties.[111]
REDUCES SENSITIVTY AND IMPROVE TOLERANCE TO ENVIRONEMENTAL AND FOOD-INDUCED ALLERGIES
Perilla has been shown to be effective in relieving the symptoms of seasonal allergic rhinitis (SAR). This was demonstrated in a study of a Japanese population living with SAR induced by pollen from the Japanese cedar (Cryptomeria aponica). In this RCT, patients with SAR were treated with perilla or placebo. At the end of the trial, those taking perilla noted a significant decrease in itchy nose, watery eyes, itchy eyes, and total symptoms (p<0.05) of SAR when compared to the placebo group. Additionally, the perilla group showed a significant decrease in the numbers of neutrophils and eosinophils in nasal lavage fluid (p<0.05) compared to placebo.[112]
Perilla resulted in a significant decrease in itchy nose, watery eyes, itchy eyes and total symptoms of seasonal allergic rhinitis.
Milk thistle possesses antihistamine effects and has been shown to be beneficial in allergic conditions.[113] In a 2011 randomised clinical trial, 60 patients with the signs and symptoms of allergic rhinitis (AR) and a positive skin prick test completed a one month trial receiving either silymarin (a constituent of milk thistle) and routine antihistamine treatment, or a placebo and the antihistamine treatment. A significant improvement in clinical symptom severity was observed in both groups (9.23 ± 5.14 vs. 2.20 ± 2.69; p<0.001), however it was more statistically significant in the study group (p<0.001), demonstrating a clear benefit to silymarin’s inclusion in the management of AR.[114]
Choline, a component of phosphocholine, is another vitamin-like essential nutrient that has been shown to be low in those living with asthma. Phosphocholine is a constituent of the endothelial cell barrier and a pulmonary surfactant. Based on this, markedly decreased phosphocholine levels in the sera of patients with asthma could indicate a lack of protection in the alveolar region and the conducting airways.[115]
Choline has been studied for its effect on inflammation and lung function in asthma patients. In a randomised study over a six-month period, 56 adult patients of either sex were randomly assigned to receive supplemental oral choline chloride (1500 mg twice daily) and pharmacotherapy (inhaled steroids and long-acting β-agonist), or pharmacotherapy only. Results showed a significant decrease in symptoms and drug scores of patients in the choline group, as well as a decrease in bronchial hyperactivity whilst lung function improved.
The choline treatment group showed reduced Th2 cytokines, including IL-4, IL-5 and TNF-α, and a significant decrease in peripheral blood eosinophil and IgE levels. Blood levels of cysteinyl leukotriene (Cys-LT) and leukotriene B4 (LTB4), inflammatory mediators involved in asthma, reduced significantly compared to baseline, as did levels of the oxidative stress biomarker, 8-isoprostanes.[116]
Choline has an anti-inflammatory action proving beneficial in inflammatory disorders, including asthma and urticaria. A small study of eight patients, aged nine to 78 years of age, living with urticarial, asthma and/or rhinitis reviewed the efficacy of oral choline. The patients had been dependent on long acting antihistamines for a period of two years or more. They were given tricholine citrate (1,000 mg twice a day) along with an antihistamine for 12 weeks. A reduction in the intake of antihistamine was requested after one month.
Results showed that oral choline is effective in the management of urticaria, with no side effects. Additionally, there was also a reduction in antihistamine intake by the patients. The improvements were noticeable in most patients within the first 6 weeks of treatment.[117]
Milk thistle possesses antihistamine effects and has been shown to be beneficial in allergic conditions.
Zinc deficiency may be linked to the occurrence of eczema. This was highlighted in a 2014 study that investigated hair zinc levels in children with eczema. In total there were 101 children, 58 with eczema and 43 controls, all aged between 2 and 14 years. Hair zinc levels were first compared, followed by an evaluation of the clinical efficacy of zinc supplementation.
The atopic patients with low zinc levels were randomly assigned to either group A or B. Group A received supplementation with oral zinc oxide tablets, 12 mg as zinc, for eight weeks, plus oral antihistamines and topical moisturisers. Group B received oral antihistamines and topical moisturisers only, that is, no zinc supplementation. At baseline, the mean zinc level was significantly reduced in eczema patients (113.1 μg/g vs. 130.9 μg/g, p=0.012). After eight weeks, hair zinc levels increased significantly in group A (p<0.001). Eczema area and severity index (EASI) scores, transepidermal water loss (TEWL), and visual analogue scales for pruritus improved more markedly in group A versus B (p=0.044, 0.015 and p<0.001, respectively).
This study clearly shows that oral zinc supplementation may be effective in eczema patients with low hair zinc levels.[118]
Studies suggest nutrient deficiencies may be associated with the development of asthma and allergic conditions including vitamin A and zinc. A systemic review and meta-analysis revealed an inverse relationship between vitamin A and asthma, i.e. higher vitamin A levels were associated with a reduced risk of developing asthma. It also showed that zinc might be effective in relation to asthma prevention.[119]
Vitamin D deficiency increases the likelihood of food allergy, with a lack of direct sun exposure contributing to the risk. Higher rates of childhood food allergy-related hospital admissions, adrenaline auto injector prescriptions, and peanut allergy (up to six times the risk) have been noted in those living further from the equator.[120]
A 2016 systematic review and meta-analysis of observational studies investigating the relationship between vitamin D levels and AR revealed that lower vitamin D levels were associated with a higher AR prevalence in children.[121] Furthermore, a 2016 Cochrane review evaluated the effects of vitamin D in asthma management and included seven trials involving 435 children, and two trials involving 658 adults. The study durations ranged from four to 12 months, and the majority of those taking part presented with mild to moderate asthma. All of the studies compared vitamin D with placebo.
Results revealed that people supplemented with vitamin D experienced fewer asthma attacks requiring treatment with oral steroids. The average number of attacks per person per year reduced from 0.44 to 0.28 with vitamin D supplementation. Supplementation also resulted in a 50% reduced risk of attending hospital with an acute asthma attack, from six per 100 to three per 100.[122]
Choline decreased symptoms of asthma and bronchial hyperactivity whilst improving lung function.
Vitamin D deficiencies are linked to eczema, with the severity of eczema associated with greater vitamin D deficiency. This was highlighted in a study of children, 17 girls and 20 boys, aged between eight months and 12 years presenting with eczema. Results showed that those with mild eczema had significantly higher 25(OH)D3 serum levels compared to those with moderate and severe eczema (p<0.05). The prevalence of patients with sIgE to microbial antigens increased in relation to vitamin D deficiency and atopic dermatitis (AS) severity.[123]
INGREDIENTS
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DIRECTIONS
Children 9-13 years:
Add 1 level metric teaspoon (3.6g) to 100ml water twice daily with food.
Adults and children over 13 years:
Add 2 level metric teaspoons (7.2g) to 200ml water twice daily with food.
EVIDENCE
References
[1] Australian Society of Clinical Immunology and Allergy Inc. Allergy and immune disease in Australia (AIDA) report 2013 [Internet]. Brookvale (AU): Australian Society of Clinical Immunology and Allergy Inc.; 2013 [cited 2017 Sep 15]. Available from: www.allergy.org.au/ascia-reports/allergy-and-immune-diseases-in-australia-2013
[2] Janeway C, Travers P, Walport M, Shlomchik MJ. Immunobiology: the immune system in health and disease. 6th ed. New York (NY): Garland Science Publishing; 2005. p. 517-56.
[3] Australian Society of Clinical Immunology and Allergy Inc. Allergy and immune disease in Australia (AIDA) report 2013 [Internet]. Brookvale (AU): Australian Society of Clinical Immunology and Allergy Inc.; 2013 [cited 2017 Sep 15]. Available from: https://www.allergy.org.au/ascia-reports/allergy-and-immune-diseases-in-australia-2013.
[4] Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nature Reviews. Immunology. 2016 May 27;16(6):341.
[5] Sirisinha S. The pleiotropic role of vitamin A in regulating mucosal immunity. Asian Pacific journal of allergy and immunology. 2015 Jun;33(2):71-89.
[6] Clark JA, Coopersmith CM. Intestinal crosstalk–a new paradigm for understanding the gut as the “motor” of critical illness. Shock (Augusta, Ga.). 2007 Oct;28(4):384.
[7] Gourbeyre P, Denery S, Bodinier M. Probiotics, prebiotics, and synbiotics: impact on the gut immune system and allergic reactions. Journal of Leukocyte Biology. 2011 May 1;89(5):685-95
[8] Perrier C, Corthesy B. Gut permeability and food allergies. Clinical & Experimental Allergy. 2011 Jan 1;41(1):20-8.
[9] Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC. Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr. 2011 May;141(5):769-76.
[10] Miller A. The pathogenesis, clinical implications and treatment of intestinal hyperpermeability. Alt Med Rev [Internet]. 1997 [cited 2017 Jul 13]. Available at: http://static1.1.sqspcdn.com/static/f/290061/15262306/1322064750827/Intestinal_Hyperpermeability.pdf?token=0vEeWSqCFTx9k6wiH6hvN17fXc8%3D.
[11] Shin HS, Bae MJ, Jung SY, Shon DH. Inhibitory effect of skullcap (Scutellaria baicalensis) extract on ovalbumin permeation in vitro and in vivo. Food Chem. 2013 Sep 1;140(1-2):22-30.
[12] Ulluwishewa D, Anderson RC, McNabb WC, Moughan PJ, Wells JM, Roy NC. Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr. 2011 May;141(5):769-76.
[13] Miller A. The pathogenesis, clinical implications and treatment of intestinal hyperpermeability. Alt Med Rev [Internet]. 1997 [cited 2017 Jul 13]. Available at: http://static1.1.sqspcdn.com/static/f/290061/15262306/1322064750827/Intestinal_Hyperpermeability.pdf?token=0vEeWSqCFTx9k6wiH6hvN17fXc8%3D.
[14] Camilleri M, Madsen K, Spiller R, Van Meerveld BG, Verne GN. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterology & Motility. 2012 Jun 1;24(6):503-12.
[15] Miller A. The pathogenesis, clinical implications and treatment of intestinal hyperpermeability. Alt Med Rev [Internet]. 1997 [cited 2017 Jul 13]. Available at: http://static1.1.sqspcdn.com/static/f/290061/15262306/1322064750827/Intestinal_Hyperpermeability.pdf?token=0vEeWSqCFTx9k6wiH6hvN17fXc8%3D.
[16] Sirisinha S. The pleiotropic role of vitamin A in regulating mucosal immunity. Asian Pac J Allergy Immunol. 2015 Jun;33(2):71-89. PMID: 26141028.
[17] Vitamin and mineral requirements in human nutrition. 2nd ed.; Vitamin A [Internet]. 2004. [Citied 24/08/2016] Available from: http://apps.who.int/iris/bitstream/10665/42716/1/9241546123.pdf. p. 19-33.
[18] Vieira MM, Paik J, Blaner WS, Soares AM, Mota RM, Guerrant RL, Lima AA. Carotenoids, retinol, and intestinal barrier function in children from northeastern Brazil. J Pediatr Gastroenterol Nutr. 2008 Nov;47(5):652-9.
[19] Wang X, Valenzano MC, Mercado JM, Zurbach EP, Mullin JM. Zinc supplementation modifies tight junctions and alters barrier function of CACO-2 human intestinal epithelial layers. Dig Dis Sci. 2013 Jan;58(1):77-87. doi: 10.1007/s10620-012-2328-8. PMID: 22903217.
[20] Yousef AM, Elmorsy E. Serum zinc level in bronchial asthma. Egyptian Journal of Chest Diseases and Tuberculosis. 2017 Jan 31;66(1):1-4.
[21] Finamore A, Massimi M, Conti Devirgiliis L, Mengheri E. Zinc deficiency induces membrane barrier damage and increases neutrophil transmigration in Caco-2 cells. J Nutr. 2008;138:1664-1670.
[22] Zhang YG, Wu S, Sun J. Vitamin D, vitamin D receptor, and tissue barriers. Tissue Barriers. 2013 Jan 1;1(1).
[23] Zhang YG, Wu S, Sun J. Vitamin D, vitamin D receptor, and tissue barriers. Tissue Barriers. 2013 Jan 1;1(1).
[24] Shin HS, Bae MJ, Jung SY, Shon DH. Inhibitory effect of skullcap (Scutellaria baicalensis) extract on ovalbumin permeation in vitro and in vivo. Food Chem. 2013 Sep 1;140(1-2):22-30.
[25] Colombo BM, Scalvenzi T, Benlamara S, Pollet N. Microbiota and mucosal immunity in amphibians. Frontiers in Immunology. 2015;6.
[26] Mantis NJ, Rol N, Corthésy B. Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunology. 2011 Nov;4(6):603.
[27] Corthësy B. Secretory immunoglobulin A: well beyond immune exclusion at mucosal surfaces. Immunopharmacol immunotoxicol. 2009 Jun 1;31(2):174-9.
[28] Mantis NJ, Rol N, Corthésy B. Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 2011 Nov 1;4(6):603-11.
[29] Corthësy B. Secretory immunoglobulin A: well beyond immune exclusion at mucosal surfaces. Immunopharmacol immunotoxicol. 2009 Jun 1;31(2):174-9.
[30] Mantis NJ, Rol N, Corthésy B. Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 2011 Nov;4(6):603-11.
[31] Mantis NJ, Rol N, Corthésy B. Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 2011 Nov;4(6):603-11.
[32] Dai X, Stanilka JM, Rowe CA, Esteves EA, Nieves C Jr, Spaiser SJ, et al. Consuming Lentinula edodes (Shiitake) mushrooms daily improves human immunity: a randomized dietary intervention in healthy young adults. J Am Coll Nutr. 2015;34(6):478-87.
[33] Cassani B, Villablanca EJ, De Calisto J, Wang S, Mora JR. Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol Aspects Med. 2012 Feb;33(1):63-76.
[34] Miller A. The pathogenesis, clinical implications and treatment of intestinal hyperpermeability. Alt Med Rev [Internet]. 1997 [cited 2017 Jul 13]. Available at: http://static1.1.sqspcdn.com/static/f/290061/15262306/1322064750827/Intestinal_Hyperpermeability.pdf?token=0vEeWSqCFTx9k6wiH6hvN17fXc8%3D.
[35] Dai X, Stanilka JM, Rowe CA, Esteves EA, Nieves C Jr, Spaiser SJ, et al. Consuming Lentinula edodes (Shiitake) mushrooms daily improves human immunity: a randomized dietary intervention in healthy young adults. J Am Coll Nutr. 2015;34(6):478-87.
[36] Cassani B, Villablanca EJ, De Calisto J, Wang S, Mora JR. Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol Aspects Med. 2012 Feb;33(1):63-76.
[37] Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nature Immunol. 2008 Mar;9(3):239.
[38] Ren W, Wang K, Yin J, Chen S, Liu G, Tan B, et al. Glutamine-induced secretion of intestinal secretory immunoglobulin A: a mechanistic perspective. Frontiers in Immunology. 2016;7.
[39] Ren W, Wang K, Yin J, Chen S, Liu G, Tan B, et al. Glutamine-induced secretion of intestinal secretory immunoglobulin A: a mechanistic perspective. Frontiers in Immunology. 2016;7.
[40] Berin MC, Sampson HA. Food allergy: an enigmatic epidemic. Trends in Immunology. 2013 Aug 31;34(8):390-7.
[41] Baker K, Lencer WI, Blumberg RS. Beyond IgA: the mucosal immunoglobulin alphabet. Mucosal Immunology. 2010 Jul 1;3(4):324.
[42] Berin MC, Sampson HA. Food allergy: an enigmatic epidemic. Trends in Immunology. 2013 Aug 31;34(8):390-7.
[43] Berin MC, Sampson HA. Food allergy: an enigmatic epidemic. Trends in Immunology. 2013 Aug 31;34(8):390-7.
[44] Albin S, Nowak- A. Potential treatments for food allergy. Immunology and allergy clinics of North America. 2015 Feb 28;35(1):77-100.
[45] Berin MC, Sampson HA. Food allergy: an enigmatic epidemic. Trends in Immunology. 2013 Aug 31;34(8):390-7.
[46] Chapoval S, Dasgupta P, Dorsey NJ, Keegan AD. Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6. Journal of leukocyte biology. 2010 Jun 1;87(6):1011-8.
[47] Oboki K, Ohno T, Saito H, Nakae S. Th17 and allergy. Allergo J Int. 2008 Jan 1;57(2):121-34.
[48] Eyerich K, Eyerich S. Th22 cells in allergic disease. Allergo J Int. 2015 Feb 1;24(1):1-7.
[49] Du Toit G, Foong RM, Lack G. Prevention of food allergy - Early dietary interventions. Allergol Int. 2016 Oct;65(4):370-377.
[50] Lack G. Update on risk factors for food allergy. J Allergy Clin Immunol. 2012 May;129(5):1187-97.
[51] Palm NW, Rosenstein RK, Medzhitov R. Allergic host defences. Nature. 2012 Apr 25;484(7395):465-72.
[52] Du Toit G, Foong RM, Lack G. Prevention of food allergy - Early dietary interventions. Allergol Int. 2016 Oct;65(4):370-377.
[53] Lack G. Update on risk factors for food allergy. J Allergy Clin Immunol. 2012 May;129(5):1187-97.
[54] Akdis CA, Akdis M. Mechanisms of immune tolerance to allergens: role of IL-10 and Tregs. J Clin Invest. 2014 Nov;124(11):4678-80.
[55]Akdis CA, Akdis M. Mechanisms of immune tolerance to allergens: role of IL-10 and Tregs. J Clin Invest. 2014 Nov;124(11):4678-80.
[56] Hempen CH, Fischer T. A materia medica for Chinese medicine plants, minerals and animal products. Edinburgh (UK): Elsevier/Churchill Livingstone; 2009. p. 436-437.
[57] Holmes P. Jade remedies, a Chinese herbal reference for the West. Vol 2. Boulder: Snow Lotus Press; 1997. p. 554-556.
[58] Bensky D, Clavey S, Stoger E, Gamble A. Substances that Calm the Spirit. Chinese herbal material medica. 3rd ed. Eastland Press. 2004. p. 935-937.
[59] Powell M. The use of Ganoderma lucidum (Reishi) in the management of histamine-mediated allergic responses. Townsend Letter: The Examiner of Alternative Medicine. 2006 May 1(274):78-82.
[60] Chang H-M, But P P-H. Pharmacology and applications of Chinese materia medica. Vol 1. Singapore: World Scientific Publishing Co. Pte. Ltd; 2001. p. 598.
[61] Lin YL, Lee SS, Hou SM, Chiang BL. Polysaccharide purified from Ganoderma lucidum induces gene expression changes in human dendritic cells and promotes T helper 1 immune response in BALB/c mice. Mol Pharmacol. 2006 Aug;70(2):637-44.
[62] Ishihara T, Okamoto I, Masaki N, Kohno K, Tanimoto T, Ikegami H, et al. [Inhibition of antigen-specific T helper type 2 responses by Perilla frutescens extract]. Arerugi. 1999 Apr;48(4):443-50.
[63] Miller A. The pathogenesis, clinical implications and treatment of intestinal hyperpermeability. Alt Med Rev [Internet]. 1997 [cited 2017 Jul 13]. Available at: http://static1.1.sqspcdn.com/static/f/290061/15262306/1322064750827/Intestinal_Hyperpermeability.pdf?token=0vEeWSqCFTx9k6wiH6hvN17fXc8%3D.
[64] Miller A. The pathogenesis, clinical implications and treatment of intestinal hyperpermeability. Alt Med Rev [Internet]. 1997 [cited 2017 Jul 13]. Available at: http://static1.1.sqspcdn.com/static/f/290061/15262306/1322064750827/Intestinal_Hyperpermeability.pdf?token=0vEeWSqCFTx9k6wiH6hvN17fXc8%3D.
[65] Camilleri M, Madsen K, Spiller R, Van Meerveld BG, Verne GN. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterology & Motility. 2012 Jun 1;24(6):503-12.
[66] Sirisinha S. The pleiotropic role of vitamin A in regulating mucosal immunity. Asian Pac J Allergy Immunol. 2015 Jun;33(2):71-89. PMID: 26141028.
[67] Vieira MM, Paik J, Blaner WS, Soares AM, Mota RM, Guerrant RL, et al. Carotenoids, retinol, and intestinal barrier function in children from northeastern Brazil. J Pediatr Gastroenterol Nutr. 2008 Nov;47(5):652-9.
[68] Finamore A, Massimi M, Conti Devirgiliis L, Mengheri E. Zinc deficiency induces membrane barrier damage and increases neutrophil transmigration in Caco-2 cells.
[69] Wang X, Valenzano MC, Mercado JM, Zurbach EP, Mullin JM. Zinc supplementation modifies tight junctions and alters barrier function of CACO-2 human intestinal epithelial layers. Dig Dis Sci. 2013 Jan;58(1):77-87. doi: 10.1007/s10620-012-2328-8. PMID: 22903217.
[70] Zhang YG, Wu S, Sun J. Vitamin D, vitamin D receptor, and tissue barriers. Tissue Barriers. 2013 Jan 1;1(1).
[71] Shin HS, Bae MJ, Jung SY, Shon DH. Inhibitory effect of skullcap (Scutellaria baicalensis) extract on ovalbumin permeation in vitro and in vivo. Food Chem. 2013 Sep 1;140(1-2):22-30.
[72] Colombo BM, Scalvenzi T, Benlamara S, Pollet N. Microbiota and mucosal immunity in amphibians. Frontiers in Immunology. 2015;6.
[73] Mantis NJ, Rol N, Corthésy B. Secretory IgA's complex roles in immunity and mucosal homeostasis in the gut. Mucosal Immunol. 2011 Nov;4(6):603-11.
[74] Dai X, Stanilka JM, Rowe CA, Esteves EA, Nieves C Jr, Spaiser SJ, et al. Consuming Lentinula edodes (Shiitake) mushrooms daily improves human immunity: a randomized dietary intervention in healthy young adults. J Am Coll Nutr. 2015;34(6):478-87.
[75] Cassani B, Villablanca EJ, De Calisto J, Wang S, Mora JR. Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol Aspects Med. 2012 Feb;33(1):63-76.
[76] Miller A. The pathogenesis, clinical implications and treatment of intestinal hyperpermeability. Alt Med Rev [Internet]. 1997 [cited 2017 Jul 13]. Available at: http://static1.1.sqspcdn.com/static/f/290061/15262306/1322064750827/Intestinal_Hyperpermeability.pdf?token=0vEeWSqCFTx9k6wiH6hvN17fXc8%3D.
[77] Horst AK, Neumann K, Diehl L, Tiegs G. Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell Mol Immunol. 2016 May;13(3):277-92.
[78] Mills S, Bone K. Herbal approaches to system dysfunctions. Principles and practice of phytotherapy. 2nd ed. Edinburgh: Elsevier/Churchill Livingstone; 2013. p. 198-199.
[79] Du Toit G, Foong RM, Lack G. Prevention of food allergy - Early dietary interventions. Allergol Int. 2016 Oct;65(4):370-377.
[80] Lack G. Update on risk factors for food allergy. J Allergy Clin Immunol. 2012 May;129(5):1187-97.
[81] Akdis CA, Akdis M. Mechanisms of immune tolerance to allergens: role of IL-10 and Tregs. J Clin Invest. 2014 Nov;124(11):4678-80.
[82] Powell M. The use of Ganoderma lucidum (Reishi) in the management of histamine-mediated allergic responses. Townsend Letter: The Examiner of Alternative Medicine. 2006 May 1(274):78-82.
[83] Chang H-M, But P P-H. Lingzhi. Pharmacology and Applications of Chinese Materia Medica Vol 1. Singapore; World Scienfitic Publishing Co. Pte. Ltd. 2001. 1986. p. 598.
[84] Ishihara T, Okamoto I, Masaki N, Kohno K, Tanimoto T, Ikegami H, et al. [Inhibition of antigen-specific T helper type 2 responses by Perilla frutescens extract]. Arerugi. 1999 Apr;48(4):443-50.
[85] Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature. 2008 Jul 24;454(7203):445-54. PMC3573758.
[86] Berraies A, Hamzaoui K, Hamzaoui A. Link between vitamin D and airway remodeling. J Asthma Allergy. 2014 Apr 1;7:23-30.
[87] Berraies A, Hamzaoui K, Hamzaoui A. Link between vitamin D and airway remodeling. J Asthma Allergy. 2014 Apr 1;7:23-30.
[88] Butenko IG, Gladtchenko SV, Galushko SV. Anti-inflammatory properties and inhibition of leukotriene C4 biosynthesis in vitro by flavonoid baicalein from Scutellaria baicalensis georgy roots. Agents Actions. 1993;39 Spec No:C49-51.
[89] Li-Weber M. New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat Rev. 2009 Feb;35(1):57-68.
[90] Lim BO. Efficacy of wogonin in the production of immunoglobulins and cytokines by mesenteric lymph node lymphocytes in mouse colitis induced with dextran sulfate sodium. Biosci Biotechnol Biochem. 2004 Dec;68(12):2505-11.
[91] Liu M, Li J, Kong F, Lin J, Gao Y. Induction of immunomodulating cytokines by a new polysaccharide-peptide complex from culture mycelia of Lentinus edodes. Immunopharmacol. 1998 Nov;40(3):187-98.
[92] Dai X, Stanilka JM, Rowe CA, Esteves EA, Nieves C Jr, Spaiser SJ, et al. Consuming Lentinula edodes (Shiitake) mushrooms daily improves human immunity: a randomized dietary intervention in healthy young adults. J Am Coll Nutr. 2015; 34(6). p.478-87.
[93] Galli SJ, Tsai M, Piliponsky AM. The development of allergic inflammation. Nature. 2008 Jul 24;454(7203):445-54. PMC3573758.
[94] Vighi G, Marcucci F, Sensi L, Di Cara G, Frati F. Allergy and the gastrointestinal system. Clinical & Experimental Immunology. 2008 Sep 1;153(s1):3-6.
[95] Lin YL, Lee SS, Hou SM, Chiang BL. Polysaccharide purified from Ganoderma lucidum induces gene expression changes in human dendritic cells and promotes T helper 1 immune response in BALB/c mice. Molecular Pharmacology. 2006 Aug 1;70(2):637-44.
[96] Mori S, Pawankar R, Ozu C, Nonaka M, Yagi T, Okubo K. Expression and roles of MMP-2, MMP-9, MMP-13, TIMP-1, and TIMP-2 in allergic nasal mucosa. Allergy, asthma & immunology research. 2012 Jul 1;4(4):231-9.
[97] Berraies A, Hamzaoui K, Hamzaoui A. Link between vitamin D and airway remodeling. J Asthma Allergy. 2014 Apr 1;7:23-30.
[98] Berraies A, Hamzaoui K, Hamzaoui A. Link between vitamin D and airway remodeling. J Asthma Allergy. 2014 Apr 1;7:23-30.
[99] Butenko IG, Gladtchenko SV, Galushko SV. Anti-inflammatory properties and inhibition of leukotriene C4 biosynthesis in vitro by flavonoid baicalein from Scutellaria baicalensis georgy roots. Agents Actions. 1993;39 Spec No:C49-51.
[100] Li-Weber M. New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat Rev. 2009 Feb;35(1):57-68.
[101] Jung HS, Kim MH, Gwak NG, Im YS, Lee KY, Sohn Y, et al. Antiallergic effects of Scutellaria baicalensis on inflammation in vivo and in vitro. J Ethnopharmacol. 2012 May 7;141(1):345-9.
[102] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015:48-58.
[103] Lim BO. Efficacy of wogonin in the production of immunoglobulins and cytokines by mesenteric lymph node lymphocytes in mouse colitis induced with dextran sulfate sodium. Biosci Biotechnol Biochem. 2004 Dec;68(12):2505-11.
[104] Hempen CH, Fischer T. A materia medica for Chinese medicine plants, minerals and animal products. Edinburgh (UK): Elsevier/Churchill Livingstone; 2009. p. 436-437.
[105] Liu M, Li J, Kong F, Lin J, Gao Y. Induction of immunomodulating cytokines by a new polysaccharide-peptide complex from culture mycelia of Lentinus edodes. Immunopharmacol. 1998 Nov;40(3):187-98.
[106] Dai X, Stanilka JM, Rowe CA, Esteves EA, Nieves C Jr, Spaiser SJ, et al. Consuming Lentinula edodes (Shiitake) mushrooms daily improves human immunity: a randomized dietary intervention in healthy young adults. J Am Coll Nutr. 2015;34(6):478-87.
[107] Gao B, Jeong WI, Tian Z. Liver: an organ with predominant innate immunity. Hepatology. 2008 Feb 1;47(2):729-36.
[108] Vickery BP, Scurlock AM, Jones SM, Burks AW. Mechanisms of immune tolerance relevant to food allergy. Journal of Allergy and Clinical Immunology. 2011 Mar 31;127(3):576-84.
[109] Horst AK, Neumann K, Diehl L, Tiegs G. Modulation of liver tolerance by conventional and nonconventional antigen-presenting cells and regulatory immune cells. Cell Mol Immunol. 2016 May;13(3):277-92.
[110] Mills S, Bone K. Herbal approaches to system dysfunctions. Principles and Practice of Phytotherapy. 2nd edition.Edinburgh: Churchill Livingstone. 2013. p. 198-199
[111] Bahmani M, Shirzad H, Rafieian S, Rafieian-Kopaei M. Silybum marianum: beyond hepatoprotection. Journal of Evidence-Based Complementary & Alternative Medicine. 2015 Oct;20(4):292-301.
[112] Takano H, Osakabe N, Sanbongi C, Yanagisawa R, Inoue K, Yasuda A, et al. Extract of Perilla frutescens enriched for rosmarinic acid, a polyphenolic phytochemical, inhibits seasonal allergic rhinoconjunctivitis in humans. Exp Biol Med (Maywood). 2004 Mar; 229(3):247-54.
[113] Choi YH, Yan GH. Silibinin attenuates mast cell-mediated anaphylaxis-like reactions. Biological and Pharmaceutical Bulletin. 2009 May 1;32(5):868-75.
[114] Bakhshaee M, Jabbari F, Hoseini S, Farid R, Sadeghian MH, Rajati M, et al. Effect of silymarin in the treatment of allergic rhinitis. Otolaryngol Head Neck Surg. 2011 Dec;145(6):904-9.
[115] Jung J, Kim SH, Lee HS, Choi GS, Jung YS, Ryu DH, et al. Serum metabolomics reveals pathways and biomarkers associated with asthma pathogenesis. Clin Exp Allergy. 2013 Apr;43(4):425-33.
[116] Mehta AK, Singh BP, Arora N, Gaur SN. Choline attenuates immune inflammation and suppresses oxidative stress in patients with asthma. Immunobiol. 2010 Jul;215(7):527-34.
[117] Gaur S N, Mehta A K, Singh B P and Arora N. Clinical response to choline in patients of allergic Urticaria: A preliminary report. Indian J Allergy Asthma Immunol. 2005; 19(2):93-96.
[118] Kim JE, Yoo SR, Jeong MG, Ko JY, Ro YS. Hair zinc levels and the efficacy of oral zinc supplementation in patients with atopic dermatitis. Acta Derm Venereol. 2014 Sep;94(5):558-62.
[119] Nurmatov U, Devereux G, Sheikh A. Nutrients and foods for the primary prevention of asthma and allergy: systematic review and meta-analysis. J Allergy Clin Immunol. 2011 Mar;127(3):724-33:1-30.
[120] American Academy of Allergy, Asthma & Immunology. Vitamin D and Food Allergy. [Internet]. 2017 [cited 2017 Jul 7]. Available from: https://www.aaaai.org/conditions-and-treatments/library/allergy-library/vitamin-d-food-allergy.
[121] Kim YH, Kim KW, Kim MJ, Sol IS, Yoon SH, Ahn HS, et al. Vitamin D levels in allergic rhinitis: a systematic review and meta-analysis. Pediatr Allergy Immunol. 2016 Sep;27(6):580-90.
[122] Martineau A, Takeda A, Nurmatov U, Sheikh A, Griffiths CJ. Vitamin D for the management of asthma (Protocol). Cochrane Database of Systematic Reviews. 2015 Mar 3:1-0.
[123] Peroni DG, Piacentini GL, Cametti E, Chinellato I, Boner AL. Correlation between serum 25-hydroxyvitamin D levels and severity of atopic dermatitis in children. Br J Dermatol. 2011 May;164(5):1078-82.
[124] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 753.
[125] Natural Medicines. Glutamine [Internet]. 2017 [cited 2017 Jan 18]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=878.
[126] Natural Medicines. Milk Thistle [Internet]. 2017 [cited 2017 May 4]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=138.
[127] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 951-65.
[128] Skidmore-Roth L. Mosby’s handbook of herbs & natural supplements. 4th ed. Missouri: Mosby Elsevier; 2010. p. 497-9.
[129] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 753.
[130] Skidmore-Roth L. Mosby’s handbook of herbs & natural supplements. 4th ed. Missouri: Mosby Elsevier; 2010. p. 567-9.
[131] Bensky D. Chinese herbal medicine materia medica. 3rd ed. Seattle, USA: Eastland Press Inc; 2004. p. 131.
[132] Health Canada. Monograph Reishi – Ganoderma lucidum [Internet]. 2016 [cited 2016 Sep 30]. Available from: http://webprod.hc-sc.gc.ca/nhpid-bdipsn/atReq.do?atid=reishi.
[133] Hempen CH, Fischer T. A materia medica for Chinese medicine plants, minerals and animal products. Edinburgh (UK): Elsevier/ Churchill Livingstone; 2009. p. 436-437.
[134] Skidmore-Roth L. Lentinan. In: Mosby’s handbook of herbs & natural supplements 4th ed. Missouri: Mosby Elsevier. 2010:393-5.
[135] Health Canada. Monograph Mushrooms. [Online]. 2016. Available from: http://webprod.hc-sc.gc.ca/nhpid-bdipsn/atReq.do?atid=mushrooms.champignons&lang=eng#rsk4. . [Cited 29/09/2016].
[136] Gardner Z, McGuffin M, editors. Lentinula edodes. In: American herbal products association’s botanical safety handbook. 2nded. Boca Raton (FL): CRC Press. 2013:509-11.[137] Levy AM, Kita H, Phillips SF, Schkade PA, Dyer PD, Gleich GJ, Dubravec VA. Eosinophilia and gastrointestinal symptoms after ingestion of shiitake mushrooms. J Allergy Clin Immunol. 1998 May;101(5):613-20. PubMed PMID: 9600497.
[138] Holmes P. Jade remedies – a Chinese herbal reference for the West. Vol 2. Colorado, US: Snow Lotus Press; 1997. p. 579-80.
[139] Bensky D. Chinese herbal medicine materia medica. 3rd ed. Seattle, USA: Eastland Press Inc; 2004. p. 131.
[140] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 753.
[141] Bensky D. Chinese herbal medicine materia medica. 3rd ed. Seattle, USA: Eastland Press Inc; 2004. p. 444.
[142] Michalak KP, Maćkowska-Kędziora A, Sobolewski B. Key roles of glutamine pathways in reprogramming the cancer metabolism. Oxidative Medicine and Cellular Longevity. 2015 Oct 25;2015.
[143] Braun L, Cohen M. L-Glutamine. In: Herbs and natural supplements: an evidence-based guide. 3rd ed. Sydney: Elsevier/Churchill Livingstone. 2010. p. 543-552.
[144] Natural Medicines. Vitamin A. [Internet]. 2015 [Cited 6/04/2017]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=964#scientificName.
[145] American Herbal Products Association. Ganoderma lucidum. In: Gardner Z, McGuffin M, editors. American Herbal Products Association’s Botanical Safety Handbook. 2nded. Boca Raton (FL): CRC Press; 2013. p. 387-90.
[146] Harkness R, Bratman S. Mosby’s handbook of drug-herb and drug-supplement interactions. Missouri: Mosby Inc; 2003. p. 70-1.
[147] Natural Medicines. Shiitake Mushroom [Internet]. 2015 [cited 2017 May 4]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=680#scientificName.
[148] American Herbal Products Association. Lentinula edodes. In: Gardner Z, McGuffin M, editors. American herbal products association’s botanical safety handbook. 2nded. Boca Raton (FL): CRC Press; 2013. p. 509-11.
[149] Skidmore-Roth L. Mosby’s handbook of herbs & natural supplements. 4th ed. Missouri: Mosby Elsevier; 2010. p. 567-9.
[150] Fetrow CH, Avila JR. Professionals handbook of complementary and alternative medicines. 3rd ed. Philadelphia: Lippincott Williams & Wilkins. 2004. p. 754
[151] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 578.
[152] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone. 2015. p. 57-8.
[153] Natural Medicines. Vitamin A [Internet]. 2015 [cited 2017 Apr 6]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=964#scientificName.
[154] Braun L, Cohen M. Vitamin A. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 1. Sydney: Elsevier/Churchill Livingstone; 2015. p. 1049.
[155] Natural Medicines. Vitamin A [Internet]. 2015 [cited 2017 Apr 6]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=964#scientificName.
[156] Braun L, Cohen M. Vitamin A. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 1. Sydney: Elsevier/Churchill Livingstone; 2015. p. 1049.
[157] Stargrove MB, Treasure J, McKee DL. Herb, nutrient and drug interactions. St Louis, USA; Mosby Elsevier; 2010. p. 235-252.
[158] Harkness R, Bratman S. Mosby’s handbook of drug-herb and drug-supplement interactions. Missouri: Mosby Inc; 2003. p. 160.
[159] Healthnotes. A-Z Interactions by herb or vitamin. In: Gaby AR, Healthnotes Medical Team, editors. A-Z guide to drug-herb-vitamin interactions. 2nd ed. New York: Three Rivers Press; 2006. p. 312.
[160] Natural Medicines. Vitamin A [Internet]. 2015 [cited 2017 Apr 6]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=964#scientificName.
[161] Braun L, Cohen M. Vitamin A. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 1. Sydney: Elsevier/Churchill Livingstone; 2015. p. 1049.
[162] Stargrove MB, Treasure J, McKee DL. Herb, nutrient and drug interactions. St Louis, USA: Mosby Elsevier; 2010. p. 235-252.
[163] Harkness R, Bratman S. Mosby’s handbook of drug-herb and drug-supplement interactions. Missouri. Mosby Inc; 2003. p. 335.
[164] Natural Medicines. Vitamin A [Internet]. 2015 [cited 2017 Apr 6]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=964#scientificName.
[165] MIMs Online [Internet]. St Leonards (NSW): MIMs Australia Pty Ltd.; 2017. CYP450 Drug Interactions. [2017; cited 2017 Apr 19]. Available from: http://www.emims.com.au/Australia/pub/latestIssue/Clinical%20Resources/CYP450%20Drug%20Interactions.
[166] Blix HS, Viktil KK, Moger TA, et al. Drugs with narrow therapeutic index as indicators in the risk management of hospitalised patients. Pharm Pract (Granada). 2010 Jan;8(1). p. 50-5.
[167] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 57-8.
[168] Natural Medicines. Vitamin D. [Internet]. 2017 [cited 18/01/2017]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=929.
[169] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 1125-1146.
[170] Simone CB 2nd, Simone NL, Simone V, et al. Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 1. Altern Ther Health Med. 2007 Jan-Feb;13(1). p. 22-28.
[171] Simone CB 2nd, Simone NL, Simone V, et al. Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 2. Altern Ther Health Med. 2007 Jan-Feb;13(1). p. 28-39.
[172] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 3rd ed. Sydney: Elsevier/Churchill Livingstone; 2010. p. 543-552.
[173] Ehrlich SD. Glutamine [Internet]. 2017 [cited 2017 Mar 17]. University of Maryland Medical Centre. Available from:http://umm.edu/health/medical/altmed/supplement/glutamine.
[174] Natural Medicines. Baikal skullcap. [Internet]. 2015 [Cited 2017 Apr 19]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=903.
[175] Skidmore-Roth L. Mosby’s handbook of herbs and natural supplements. 4th ed. Missouri: Mosby Elsevier; 2010. p. 567-9.
[176] Natural Medicines. Vitamin D. [Internet]. 2017 [cited 18/01/2017]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=929.
[177] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 1125-1146.
[178] Natural Medicines. Milk Thistle. [Internet]. 2017 [cited 2017 May 4]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=138.
[179] MIMs Online [Internet]. St Leonards (NSW): MIMs Australia Pty Ltd.; 2014. Amizide – Full PI [2013 Aug; cited 2017 May 4]. Available from: http://www.emims.com.au/Australia/drug/info/Amizide/Amizide?type=full.
[180]Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 1. Sydney: Elsevier/Churchill Livingstone; 2015. p. 1049.
[181] Stargrove MB, Treasure J, McKee DL. Herb, nutrient and drug interactions. St Louis, USA: Mosby Elsevier; 2010. p. 235-252.
[182] Natural Medicines. Vitamin D [Internet]. 2017 [cited 18/01/2017]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=929.
[183] Natural Medicines. Vitamin D [Internet]. 2017 [cited 18/01/2017]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=929.
[184] Natural Medicines. Vitamin D [Internet]. 2017 [cited 18/01/2017]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=929.
[185] Natural Medicines. Vitamin D [Internet]. 2017 [cited 18/01/2017]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=929.
[186] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 1. Sydney: Elsevier/Churchill Livingstone; 2015. p. 1049.
[187] Stargrove MB, Treasure J, McKee DL. Herb, nutrient and drug interactions. St Louis, USA: Mosby Elsevier; 2010. p. 235-252.
[188] Healthnotes. A-Z Interactions by herb or vitamin. In: Gaby AR, Healthnotes Medical Team, editors. A-Z guide to drug-herb-vitamin interactions. 2nd ed. New York: Three Rivers Press; 2006. p. 312.
[189] Natural Medicines. Milk Thistle [Internet]. 2017 [cited 2017 May 4]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=138.
[190] Natural Medicines. Vitamin D [Internet]. 2017 [cited 18/01/2017]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=929.
[191] Burke RR, Rybicki BA, Rao DS. Calcium and vitamin D in sarcoidosis: how to assess and manage. In: Seminars in respiratory and critical care medicine. Thieme Medical Publishers. 2010;31(4):474-484.
[192] Natural Medicines. Vitamin D [Internet]. 2017 [cited 18/01/2017]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=929.
[193] Natural Medicines. Zinc [Internet]. 2017 [cited 2017 Jan 18]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=878.
[194] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 3rd ed. Sydney: Elsevier/Churchill Livingstone; 2015. p. 1197-1223.
[195] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 3rd ed. Sydney: Elsevier/Churchill Livingstone; 2015. p. 1197-1223.
[196] Natural Medicines. Zinc [Internet]. 2017 [cited 2017 Jan 18]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=878. [197] Bisen PS, Baghel RK, Sanodiya BS, et al. Lentinus edodes: a macrofungus with pharmacological activities. Curr Med Chem. 2010;17(22):2419-30.[198] Shimada S, Komamura K, Kumagai H, et al. Inhibitory activity of shiitake flavor against platelet aggregation. Biofactors. 2004;22(1-4): 177-9.
[199] Odani S, Tominaga K, Kondou S, et al. The inhibitory properties and primary structure of a novel serine proteinase inhibitor from the fruiting body of the basidiomycete, Lentinus edodes. Eur J Biochem. 1999 Jun;262(3). p. 915-23
[200] Natural Medicines. Reishi Mushroom [Internet]. 2013 [cited 2017 May 4]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=905#scientificName.
[201] American Herbal Products Association. Ganoderma lucidum. In: Gardner Z, McGuffin M, editors. American Herbal Products Association’s Botanical Safety Handbook. 2nded. Boca Raton (FL): CRC Press; 2013. p. 387-90.
[202] Healthnotes. Interaction by Herb or Vitamin. In: Gaby AR, Healthnotes Medical Team, editors. A-Z Guide to Drug-Herb-Vitamin Interactions. 2nded. New York: Three Rivers Press; 2006. p. 298.
[203] Natural Medicines. Glutamine. [Internet]. 2017 [cited 2017 Jan 18]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=878.
[204] Natural Medicines. Reishi Mushroom [Internet]. 2013 [cited 2017 May 4]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=905#scientificName.
[205] American Herbal Products Association. Ganoderma lucidum. In: Gardner Z, McGuffin M, editors. American Herbal Products Association’s Botanical Safety Handbook. 2nded. Boca Raton (FL): CRC Press; 2013. p. 387-90.
[206] Stargrove MB, Treasure J, McKee DL. Herb, nutrient and drug interactions. St Louis, USA: Mosby Elsevier.;2010. p. 133-6.
[207] Natural Medicines. Shiitake Mushroom [Internet]. 2015 [cited 2017 May 4]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=680#scientificName.
[208] Skidmore-Roth L. Mosby’s handbook of herbs and natural supplements. 4th ed. Missouri: Mosby Elsevier; 2010. p. 567-9.
[209] Fetrow CH, Avila JR. Professionals handbook of complementary and alternative medicines. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2004. p. 754.
[210] Root-Bernstein R, Fairweather D. Complexities in the relationship between Infection and autoimmunity. Curr Allergy Asthma Rep. 2014 Jan;14(1):407.[211] Lull C, Wichers HJ, Savelkoul HF. Antiinflammatory and immunomodulating properties of fungal metabolites. Mediators Inflamm. 2005 Jun 9;2005(2):63-80. [212] Dai X, Stanilka JM, Rowe CA, Esteves EA, Nieves C Jr, Spaiser SJ, et al. Consuming Lentinula edodes (Shiitake) mushrooms daily improves human immunity: a randomized dietary intervention in healthy young adults. J Am Coll Nutr. 2015; 34(6). p.478-87.
[213] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 57-8.
[214] Natural Medicines. Glutamine. [Internet]. 2017 [cited 2017 Jan 18]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=878.
[215] Natural Medicines. Reishi Mushroom [Internet]. 2013 [cited 2017 May 4]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=905#scientificName.
[216] Homma M, Oka K, et al. A novel 11-beta-hydroxysteroid dehydrogenase inhibitor contained in Saiboku-To, a herbal remedy for steroid-dependent bronchial asthma. J Pharm Pharmacol. 1994;46(4):305-9.
[217] Harkness R, Bratman S. Mosby’s handbook of drug-herb and drug-supplement interactions. Missouri: Mosby Inc.; 2003. p. 219-21.
[218] Skidmore-Roth L. Mosby’s handbook of herbs and natural supplements. 4th ed. Missouri: Mosby Elsevier; 2010. p. 497-9.
[219] Harkness R, Bratman S. Mosby’s handbook of drug-herb and drug-supplement interactions. Missouri: Mosby Inc.; 2003. p. 219-21.
[220] Natural Medicines. Milk Thistle [Internet]. 2017 [cited 2017 May 4]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=138.
[221] MIMs Online [Internet]. St Leonards (NSW): MIMs Australia Pty Ltd.; 2014. Amizide – Full PI [2013 Aug; cited 2017 May 4]. Available from: http://www.emims.com.au/Australia/drug/info/Amizide/Amizide?type=full.
[222] MIMs Online [Internet]. St Leonards (NSW): MIMs Australia Pty Ltd.; 2017. CYP450 Drug Interactions. [2017; cited 2017 Apr 19]. Available from: http://www.emims.com.au/Australia/pub/latestIssue/Clinical%20Resources/CYP450%20Drug%20Interactions.
[223] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 57-8.
[224] MIMs Online [Internet]. St Leonards (NSW): MIMs Australia Pty Ltd.; 2017. CYP450 Drug Interactions. [2017; cited 2017 Apr 19]. Available from: http://www.emims.com.au/Australia/pub/latestIssue/Clinical%20Resources/CYP450%20Drug%20Interactions.
[225] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 57-8.
[226] American Herbal Products Association. Ganoderma lucidum. In: Gardner Z, McGuffin M, editors. American Herbal Products Association’s Botanical Safety Handbook. 2nded. Boca Raton (FL): CRC Press; 2013. p. 387-90.
[227] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 3rd ed. Sydney: Elsevier/Churchill Livingstone; 2015 p. 1197-1223.
[228] MIMs Online [Internet]. St Leonards (NSW): MIMs Australia Pty Ltd.; 2017. CYP450 Drug Interactions. [2017; cited 2017 Apr 19]. Available from: http://www.emims.com.au/Australia/pub/latestIssue/Clinical%20Resources/CYP450%20Drug%20Interactions.
[229] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 57-8.
[230] Natural Medicines. Milk Thistle [Internet]. 2017 [cited 2017 May 4]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=138.
[231] MIMs Online [Internet]. St Leonards (NSW): MIMs Australia Pty Ltd.; 2014. Amizide – Full PI [2013 Aug; cited 2017 May 4]. Available from: http://www.emims.com.au/Australia/drug/info/Amizide/Amizide?type=full.
[232] MIMs Online [Internet]. St Leonards (NSW): MIMs Australia Pty Ltd.; 2017. CYP450 Drug Interactions. [2017; cited 2017 Apr 19]. Available from: http://www.emims.com.au/Australia/pub/latestIssue/Clinical%20Resources/CYP450%20Drug%20Interactions.
[233] Blix HS, Viktil KK, Moger TA, et al. Drugs with narrow therapeutic index as indicators in the risk management of hospitalised patients. Pharm Pract (Granada). 2010 Jan;8(1):50-5.
[234] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 57-8.
[235] Natural Medicines. Reishi Mushroom [Internet]. 2013 [Cited 04/05/2017]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=905#scientificName.
[236] MIMs Online [Internet]. St Leonards (NSW): MIMs Australia Pty Ltd.; 2017. CYP450 Drug Interactions. [2017; cited 2017 Apr 19]. Available from: http://www.emims.com.au/Australia/pub/latestIssue/Clinical%20Resources/CYP450%20Drug%20Interactions.
[237] Blix HS, Viktil KK, Moger TA, et al. Drugs with narrow therapeutic index as indicators in the risk management of hospitalised patients. Pharm Pract (Granada). 2010 Jan;8(1):50-5.
[238] Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide. 4th ed. Vol 2. Sydney: Elsevier/Churchill Livingstone; 2015. p. 57-8.
[239]Mills S, Bone K. The essential guide to herbal safety. Philadelphia, USA: Elsevier/Churchill Livingstone; 2005. p. 594-6.
[240l] Natural Medicines. Choline [Internet]. 2015 [Cited 2017 May 4]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs supplements/professional.aspx?productid=1017.
[241] Nutrient Reference Values for Australia and New Zealand. Australian Government Department of Health and Ageing [Internet]. 2017 [cited 2017 May 4]. Available from: https://www.nhmrc.gov.au/_files_nhmrc/file/publications/17122_nhmrc_nrv_update-dietary_intakes-web.pdf.
[242] Natural Medicines. Vitamin A [Internet]. 2015 [cited 2017 Apr 6]. Available from: https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=964#scientificName.
[243] Australian Government Press. Vitamin A. Nutrient Reference Values for Australia and New Zealand including recommended dietary intakes. 2005. p. 59-66.
WARNINGS
Contraindications
Avoid this product if you have allergies or sensitivities to:
Glutamine: Use with caution in patients with known allergy/hypersensitivity to monosodium glutamate (MSG). Glutamine may be metabolised to glutamate in the body and in theory may precipitate symptoms of MSG sensitivity. Use with caution and monitor patient symptoms.[125]
Milk thistle: Avoid in individuals with known allergy or hypersensitivity to members of the Asteraceae/Compositae family.[126],[127]
Perilla[128],[129] and skullcap.[130],[131]
Reishi mushroom: Avoid with known allergy or hypersensitivity to reishi mushrooms or derivatives thereof.[132],[133]
Shiitake: Most allergic reactions occur after ingestion of raw or partially cooked shiitakes, or after physically handling them. Avoid with known allergy or hypersensitivity to mushrooms or derivatives thereof.[134],[135],[136],[137] Note that this product uses shiitake mushrooms that have been boiled, which reduces the risk of reactions.
Diarrhoea: Traditional Chinese herbal medicine states that baical skullcap and perilla should not be used in diarrhoea, therefore avoid in this condition.[138],[139], [140],[141]
Glioblastoma multiforme (GM): As GM shows normal activity of the Krebs cycle and only partially deteriorated ability to produce the ATP from fatty acids in the oxidative phosphorylation chain, supplementation with glutamine may lead to increased cellular energy production in GM cells potentiating their growth and development. Avoid use.[142]
Hepatic disease; including liver cirrhosis, hepatic encephalopathy and other severe hepatic disorders: Glutamine, which is metabolised to ammonia, may lead to accumulation of nitrogen/ammonia waste in the blood increasing the risk of ammonia-based encephalopathy and coma. Avoid use.[143]
Hepatotoxic drugs: Excessive doses of vitamin A can cause hepatotoxic effects, ranging from elevated liver enzymes to liver failure. Taking high doses of vitamin A in combination with other potentially hepatotoxic drugs might increase the risk of liver disease. Advise patients against combining high doses of vitamin A with other hepatotoxic drugs. Some drugs that can adversely affect the liver include acetaminophen/paracetamol (Tylenol/Panadol), amiodarone (Cordarone), carbamazepine (Tegretol), isoniazid (INH), methotrexate (Rheumatrex), methyldopa (Aldomet), and many others.[144]
Immunosuppressants:Reishi and shiitake mushroom extracts have immunomodulation effects, which could reduce the effectiveness of immunosuppressive therapy.[145],[146],[147],[148]
Baical skullcap may also decrease the effects of immunosuppressant medicine.[149],[150],[151] Use with caution and under medical supervision in patients on these medications post-organ transplant etc.
Interferon therapy: Sho-saiko-to is a Japanese kampo medicine containing baical skullcap, which may interact with interferon therapy causing acute pneumonitis (extrinsic allergic alveolitis). It seems to be due to an allergic-immunological mechanism. Therefore, baical skullcap is contraindicated in interferon therapy.[152]
Osteoporosis: Chronic high intakes of vitamin A, 10,000 IU or more per day, seems to increase the risk for osteoporosis. Studies in middle-aged men and postmenopausal women show that those with high serum retinol levels are more prone to osteoporosis and bone fracture. Therefore avoid vitamin A in patients with osteoporosis.[153],[154]
Retinoids: Retinoids, which are vitamin A derivatives, could have additive toxic effects when taken with vitamin A supplements. Although concomitant use of supplemental vitamin A and pharmaceutical retinoids has not been formally investigated, and evidence of clinical significance is lacking, "consensus" considers additive effect inevitable and inherently risky. Therefore advise patients taking retinoids to avoid vitamin A supplements. Some of these retinoids include acitretin (Soriatane), bexarotene (Targretin), etretinate (Tegison), and isotretinoin (Accutane), tretinoin (Retin-A, Renova), and tazarotene (Avage).[155],[156],[157],[158],[159]
Tetracycline antibiotics: Adjunct therapy with vitamin A may increase side effects such as headaches and benign intracranial hypertension (pseudotumour cerebri). This can occur with either an acute overdose of vitamin A, or chronic accumulation from doses of 40,000 units/day or more. Case reports suggest that taking tetracyclines and vitamin A concurrently can increase the risk of this condition. Avoid concomitant retinoids, including vitamin A at doses above 10,000 IU/day, during antibiotic therapy employing tetracyclines. Discontinue use immediately if symptoms appear.[160],[161],[162]
Warfarin:
Vitamin A toxicity is associated with haemorrhage and hypoprothrombinaemia, possibly due to vitamin K antagonism. This is supported by animal studies. High doses of vitamin A could increase the risk of bleeding with warfarin. Advise patients taking warfarin to avoid doses of vitamin A above the Tolerable Upper Intake Level of 10,000 units/day for adults or consider monitoring coagulation parameters more frequently in patients taking vitamin A with warfarin, and adjust the warfarin dose if necessary.[163],[164]
This anticoagulant medication is metabolised by cytochrome P450 1A2,[165] and has a narrow therapeutic range.[166] Baical skullcap inhibits the activity of this enzyme which theoretically may alter warfarin’s therapeutic effect.[167] Use cautiously in patients on this medication and monitor INR levels.
Moderate Level Cautions
Calcium channel blockers: Use with caution in patients on calcium channel blockers. Hypercalcaemia due to high doses of vitamin D can reduce the effectiveness of such medications in atrial fibrillation. Avoid vitamin D doses above 2,000 IU (50 µg) daily and monitor.[168], [169]
Chemotherapy/Radiotherapy: Milk thistle has antioxidant activity, and it has generally been thought that antioxidants may interfere with chemotherapy and/or radiotherapy by decreasing the efficacy of the treatment, although recent studies have found that antioxidants are safe to use in conjunction with these treatments. However, it is still advisable to check with a patient’s oncologist before recommending a formula containing antioxidants.[170],[171]
Chronic renal failure: Glutamine should be used with caution in people with chronic renal failure or kidney disease,[172],[173] possibly due to its high percentage of nitrogen and its action on ammonia. Use with medical supervision.
CNS depressants: CNS depressants, including relaxant herbs, have sedative effects on the nervous system. Animal research and clinical evidence suggests that baical skullcap may cause sedation and cognitive impairment. Theoretically, concomitant use of baical skullcap and drugs with sedative properties may cause additive therapeutic and adverse effects.[174],[175] Therefore, use cautiously in patients on this medication and monitor for increased drowsiness or other adverse effects.
Digoxin:
Hypercalcaemia induced by high doses of vitamin D (i.e. doses >2,000 IU/day or 50 µg/day) can increase the risk of fatal cardiac arrhythmias with cardiac glycosides. Avoid high doses of vitamin D and use under medical supervision only.[176],[177]
This cardiac glycoside is metabolised via glucoronidation, and has a narrow therapeutic range. Milk thistle has the potential to affect the clearance of drugs that undergo glucuronidation and theoretically may alter the drug’s therapeutic effect.[178] Use cautiously in patients on this medication and only under medical supervision.[179]
HMG-CoA reductase inhibitor drugs (statins): These drugs block the body’s production of cholesterol, and are used to lower elevated cholesterol. Statin use is associated with an increase in vitamin A blood levels, as seen in a human trial. Therefore, if taking concomitantly, observe patients for side effects.[180],[181]
Hypercalcaemia: Vitamin D doses above 2,000 IU (50 µg) daily should be avoided due to the risk of increased calcium accumulation.[182] Use with caution and only under medical supervision.[183]
Hyperparathyroidism: Vitamin D doses above 2,000 IU (50 µg) daily should be avoided due to the risk of increased calcium accumulation.[184] Use with caution and only under medical supervision.[185]
Oral contraceptives and HRT: Oral contraceptives and HRT are associated with increased serum levels of vitamin A, at least in part due to increased hepatic synthesis of retinol binding protein (RBP) and elevated export of RBP-retinol complex. Taking oral contraceptives and vitamin A concomitantly may result in increased levels of serum vitamin A, therefore avoid vitamin A daily doses above 10,000 IU if taking this combination.[186],[187],[188] In addition, animal model research shows that silymarin, a constituent of milk thistle, binds to oestrogen receptor beta. Theoretically, milk thistle might interfere with oestrogen therapy, due to competition for oestrogen receptors.[189]
Renal failure and/or chronic kidney disease: Vitamin D doses above 2,000 IU (50 µg) daily should be avoided due to the risk of increased calcium accumulation. Use with caution and only under medical supervision.[190]
Sarcoidosis or other granulomatous disease: The synthesis of vitamin D is altered by granulomatous inflammation, resulting in increased production of 1, 25-dihydroxyvitamin D.[191] Vitamin D doses above 2,000 IU (50 µg) daily should be avoided due to the risk of increased calcium accumulation. Use with caution and only under medical supervision.[192]
Low Level Cautions
Amiloride: Conflicting information exists regarding the potential interactions between amiloride and zinc. Amiloride has been reported to both reduce zinc excretion (leading to zinc accumulation), and lead to zinc deficiency. Monitor zinc status.[193],[194]
Antibiotics: Zinc may form insoluble complexes with certain antibiotic medications. Separate doses by at least 2 hours before[195] or 4-6 hours after zinc supplementation.[196]
Anticoagulant/Antiplatelet drugs: Shiitake and reishi mushrooms may inhibit platelet aggregation,[197],[198],[199],[200],[201],[202] which could have additive effects if the patient is taking anticoagulants concomitantly. Use cautiously in patients taking antiplatelet and/or anticoagulant medications (e.g. aspirin or warfarin) and monitor international normalised ratio (INR) as well as potential adverse bleeding.
Anticonvulsant medications: Theoretically, glutamine may reduce seizure threshold in those taking anticonvulsant medication. Glutamine may be converted to glutamate, an excitatory neurotransmitter. Medications include Carbamazepine, Phenobarbital, Phenytoin, Primidone, and Valproate. Use with caution and monitor patient symptoms.[203]
Antidiabetic drugs: Reishi mushroom may theoretically decrease blood sugar, which could have additive effects when used with antidiabetic drugs in some diabetes patients. Monitor blood glucose levels closely and adjust dose as necessary.[204],[205],[206]
Autoimmune disease:
It has been suggested that reishi, shiitake,[207] and baical skullcap[208],[209] should be avoided in individuals where immune suppression is desired. However, due to the emerging role of infection in the pathogenesis of autoimmune disease,[210] and therapeutic actions of reishi,[211] shiitake,[212] and baical skullcap,[213] they may in fact be useful in the management of certain cases of autoimmune disease. Practitioners are advised to use their discretion when treating patients with autoimmune conditions.
Bipolar disorder: Theoretically, glutamine may affect behaviour in people with bipolar disorder. Glutamine may be converted to glutamate, an excitatory neurotransmitter. Use with caution and monitor patient symptoms.[214]
Bleeding disorders: Theoretically, high doses of reishi mushroom might increase the risk of bleeding in people with certain bleeding disorders. While a daily dose of 1.5 grams does not seem to decrease platelet aggregation, a higher daily dose of 3 grams seems to decrease platelet aggregation. To minimise the risk of exacerbation of bleeding events, it is recommended to discontinue use of reishi in bleeding disorders.[215]
Corticosteroids:
Baical skullcap and perilla may augment the effects of corticosteroids through their ability to inhibit enzymatic metabolism of these drugs. This could result in unintentionally high levels of prednisolone or related drugs. This could prolong the drug's activity and possibly increase its side effects. Individuals using steroidal anti-inflammatory drugs should consult with their prescribing physician and/or a qualified practitioner of herbal medicine about the potential risks.[216],[217],[218],[219]
Diazepam:
This anxiolytic and sedative drug is metabolised via glucoronidation, and has a narrow therapeutic range. Milk thistle has the potential to affect the clearance of drugs that undergo glucuronidation and theoretically may alter the drug’s therapeutic effect.[220] Use cautiously in patients on this medication and monitor for increased drowsiness or other adverse effects.[221]
This anxiolytic and sedative drug is metabolised by cytochrome P450 1A2,[222] and has a narrow therapeutic range. Baical skullcap inhibits the activity of this enzyme which theoretically may alter the drug’s therapeutic effect.[223] Use cautiously in patients on this medication and monitor for increased drowsiness or other adverse effects.
Lignocaine: Commonly known as a local anaesthetic, lignocaine is sometimes used intravenously to treat arrhythmia. This drug is metabolised by cytochrome P450 1A2,[224] and has a narrow therapeutic range. Baical skullcap inhibits the activity of this enzyme which theoretically may alter the drug’s therapeutic effect.[225] 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.
Long-term use: Reishi appears to have low toxicity and good tolerability. However, various side effects that are generally mild in nature and rare cases of toxicity have been documented, but these generally lack consistency and are often complicated by concomitant disease and other medicines.[226] Monitor in long term use.
NSAIDs: Zinc may form insoluble complexes with certain NSAIDs. Separate doses by at least 2 hours.[227]
Olanzapine: This antipsychotic medication is used for the treatment of schizophrenia and bipolar disorder. It is metabolised by cytochrome P450 1A2,[228] and has a narrow therapeutic range. Baical skullcap inhibits the activity of this enzyme which theoretically may alter the drug’s therapeutic effect.[229] Use cautiously in patients on this medication and only under medical supervision.
Oxazepam: This anxiolytic and sedative drug is metabolised via glucoronidation, and has a narrow therapeutic range. Milk thistle has the potential to affect the clearance of drugs that undergo glucuronidation and theoretically may alter the drug’s therapeutic effect.[230] Use cautiously in patients on this medication and monitor for increased drowsiness or other adverse effects.[231]
Phenobarbitone: This barbiturate is a widely used anti-seizure medication that is metabolised by cytochrome P450 1A2,[232] and has a narrow therapeutic range.[233] Baical skullcap inhibits the activity of this enzyme which theoretically may alter the drug’s therapeutic effect.[234] Use cautiously in patients on this medication and monitor for symptom changes.
Surgery: Theoretically, high doses of reishi mushroom might increase the risk of bleeding if used perioperatively. While a daily dose of 1.5 grams does not seem to decrease platelet aggregation, a higher daily dose of 3 grams seems to decrease platelet aggregation. It is recommended to discontinue using high doses of reishi mushrooms for 2 weeks prior to surgery.[235]
Theophylline: This methylxanthine drug is used for acute relief in respiratory diseases such as COPD and asthma. This drug is metabolised by cytochromes P450 1A2 and 2E1,[236] and has a narrow therapeutic range.[237] Baical skullcap inhibits the activity of these enzymes, which theoretically may alter the drug’s therapeutic effect.[238] Use cautiously in patients on this medication and monitor for any adverse effects.
Pregnancy and Breastfeeding
Safety has not been conclusively established in humans, Practitioner discretion is advised when prescribing for use in pregnancy due to the following cautions:
Please note: Although no adverse effects from milk thistle have been seen in pregnancy,[239] if physiological changes occur that mobilize toxins stored in maternal tissues, these toxins may be harmful to the foetus. Therefore, the use of herbal detoxification products during pregnancy is not recommended. Use practitioner discretion.
Choline: Doses up to 3 grams daily for pregnant and lactating women up to 18 years of age, and 3.5 grams daily for women 19 years and older are not likely to cause adverse effects.[240],[241]
Vitamin A: Doses of less than 10,000 IU per day are not likely to cause adverse effects. Daily intake of greater than 10,000 IU can cause foetal malformations. Excessive dietary intake of vitamin A has also been associated with teratogenicity. The first trimester of pregnancy seems to be the critical period for susceptibility to vitamin A-associated birth defects such as craniofacial abnormalities and abnormalities of the central nervous system. Pregnant women should monitor vitamin A intake from all sources.[242] The recommended daily intake of vitamin A in pregnancy is 2,666 IU (800 μg) and the upper limit is 10,000 IU (3,000 μg).[243]
MGXALEP
