The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 82

95. How do you take oral cromolyn?

  • Cromolyn is a mast cell stabilizer. Most mast cell patients are on cromolyn. Currently, it is taken orally for use in the GI tract, or it is taken nebulized for use in the lungs.
  • Cromolyn is an incredibly finicky substance. It sticks to everything. Your body barely uses it: only 2% of cromolyn is actually absorbed in the GI tract and only 5% in the lungs. The cromolyn that is absorbed is actually not the cromolyn that helps stabilize mast cells. The rest basically just sits on top of cells in the GI tract or lungs and stabilizes mast cells that way.
  • In order to maximize benefit from cromolyn, it is important that it not be taken when there is food or medications that cromolyn could stick to. This is mostly an issue for oral cromolyn used in the GI tract. You do not want to take other medications too close to taking cromolyn because the cromolyn may stick to the other med and not be available to stabilize mast cells. You do not want to eat too close to taking cromolyn because the food could stick to cromolyn, making it unavailable to stabilize mast cells, or the food could block the cromolyn from getting to the surface of the mast cells, preventing it from stabilizing them.
  • Oral cromolyn is usually taken 30 minutes before meals and at bedtime for a total of four times daily. Cromolyn should not be taken until two hours or more after eating the previous meal as this is about how long it takes for food to move out of the stomach. It is worth noting that many mast cell patients have gastroparesis or impaired GI motility which can cause food to stay in the stomach longer. There is no particular recommendation on what to do in this instance.
  • Ampules of cromolyn need to be stored at room temperature and protected from light. The ampules should not be taken out of the foil packs until you are using them. They should not be mixed ahead of time.
  • The intended dose for oral cromolyn in mast cell patients is usually 200 mg (two ampules) four times a day. Patients usually do better when they gradually increase the amount of cromolyn they are taking rather than starting at that dose. How slowly they increase varies widely. Patients should speak with their providers about an appropriate dosing schedule. There is lots of information about this in patient groups and forums.

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 79

92. Why is ketotifen not FDA approved? How do I get it?

Ketotifen is a mast cell stabilizer that is also an H1 antihistamine. It is regularly cited by mast cell patients as one of the more effective meds for managing mast cell disease, especially food intolerance. But it can be tricky to get ahold of in the US.

Firstly, ketotifen actually is FDA approved. It is FDA approved in eye drops. However, the formulation typically used by mast cell patients is oral. Oral ketotifen has not been approved in the US, but it’s not because it’s dangerous. It’s because it was never submitted to the FDA for approval. And why was it not submitted? Again, not because it’s dangerous. At the time, the manufacturer did not feel that there was enough of a market to justify the time and expense of an FDA submission when there were so many other H1 antihistamines available both over the counter and with prescription. It’s that simple.

So how do you get ketotifen in the US? You can import it from abroad for personal use as a mast cell patient, but there is an easier way: ketotifen capsules can be bought through compounding pharmacies who order the powder and put it in capsules. The most common strength for capsules is 1mg. Your provider just writes a prescription for it and the compounding pharmacy puts it together for you. As a side note, insurance often does not cover compounded medications so be prepared for that.

Because there wasn’t an FDA submission, there is less safety and dosing information available. In adults, dosing typically starts at 2-3mg a day. Some providers use much higher doses, even going upwards of 20mg per day in some instances. Again, we don’t have study data on this drug in mast cell disease, so conservative dosing is common.

Ketotifen is available as a tablet without a prescription in many countries, including Canada.

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 69

83. Are there any supplements that help manage mast cell symptoms?

  • Yes.
  • Mast cell patients are often vitamin or mineral deficient.
  • Iron deficiency is extremely common. This is likely due to anemia of chronic inflammation. Basically, if your body is inflamed long enough, your body hoards the iron and stops moving it from your GI tract into your bloodstream where it can be used. Iron supplements are pretty harsh so patients don’t always tolerate oral supplements. IV iron is an option if your iron is low enough. I personally like the Lucky Iron Fish for increasing iron. It’s pretty neat.
  • Many mast cell patients are magnesium deficient. The exact cause of this is unknown. Lots of us take magnesium supplements.
  • For reasons that aren’t clear, a lot of mast cell patients are vitamin D deficient. Vitamin D acts on mast cells. There is some evidence to suggest that vitamin D can decrease mast cell activation. I personally found that effectively supplementing vitamin D has helped me a lot. A lot of symptoms I blamed on mast cell disease were actually vitamin D deficiency.
  • A number of supplements can decrease mast cell activation or block the action of mast cell mediators. There are a ton of natural mast cell stabilizers. They are sometimes used to help patients manage symptoms, especially in Traditional Chinese Medicine, which in recent years has been studied in clinical trials. Quercetin and resveratrol are commonly used by mast cell patients.
  • I take turmeric daily to reduce inflammation. Turmeric or curcumin can decrease prostaglandin production.
  • Holy Basil is a popular supplement in the mast cell community. It also decreases prostaglandin production. It can also block the histamine H2 receptor. While I often see people say that holy basil is as effective as an H2 blocker as H2 antihistamines like ranitidine or famotidine, I have never been able to find any evidence that this is true. But it does definitely have some ability to block the histamine H2 receptor.
  • Vitamin B12 deficiency sometimes occurs in mast cell patients, especially those with mast cell activation syndrome. This can have some interplay with MTHFR mutations, which can affect the form of vitamin B12 best suited to your body.
  • Vitamin C decreases the amount of histamine released by mast cells. It is recommended by some prominent mast cell researchers and many patients respond well.
  • Alpha lipoic acid is sometimes used, particularly for neurologic symptoms and neurologic pain.
  • I’m not sure if CBD oil is considered a supplement but it is widely used with excellent results. Be aware that the popular notion that marijuana derivatives do not interact with any medications is inaccurate. It especially can interact with tricyclic antidepressants to cause dangerous tachycardia.
  • Keep in mind that all supplements have the potential to interact with medications or to affect a person adversely if they have certain diseases. Exactly how much this happens is hard to pinpoint because over the counter supplements are held to a much lower standard for this type of study than FDA approved medications.
  • Always discuss any supplements you plan to try with your managing provider. Vitamins and minerals can cause toxicity and too much can cause very serious side effects and complications.
  • Do not assume that just because something is derived from nature, or because it is available without a prescription, that something is automatically safer for you than medications.
  • This is not really in my wheelhouse so I would encourage you to ask other patients what has helped them or to consult with a nutritionist.

For additional reading, please visit the following posts:

Effect of vitamin D on mast cells
Naturally occurring mast cell stabilizers: Part 1
Naturally occurring mast cell stabilizers: Part 2
Naturally occurring mast cell stabilizers: Part 3
Naturally occurring mast cell stabilizers: Part 4
The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 19
MTHFR, folate metabolism and methylation

The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 9

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

15. How is mast cell disease treated?
• There are a number of medications to treat mast cell disease. Mast cells release so many chemicals, some in a large quantity. We are not able to totally stop mast cells from releasing the chemicals so we need to use many medications to block their effects on the body.
The baseline regimen for mast cell patients include antihistamines and mast cell stabilizers. Specifically, patients are usually prescribed two antihistamines that work two different ways. These are called H1 antihistamines and H2 antihistamines. The H in these meds stand for histamine. There are many antihistamine options. Antihistamines stop the histamine from working in the body. Even still, many patients experience histamine driven symptoms
Mast cell stabilizers work by making mast cells less likely to release chemicals. There are fewer options for mast cell stabilizers. Cromolyn is a very common mast cell stabilizer. Ketotifen is both a mast cell stabilizer and an antihistamine. Ketotifen that you can take as a pill is not approved in the US because there was not a market for it so it was never submitted to the FDA. However, patients can get ketotifen in pill form through compounding pharmacies in the US.
• Other types of medication commonly used for mast cell disease that block the effect of mast cell chemicals include leukotriene inhibitors and PAF blockers.
Some medications can stop mast cells from making specific chemicals. These include COX inhibitors, lipoxygenase inhibitors, and corticosteroids like prednisone.
Many patients are deficient in some vitamins or minerals because they don’t absorb them well in the GI tract. Vitamin D and iron are commonly low. Patients often take supplements to replace these deficiencies.
• Chemo drugs are sometimes used to treat severe mast cell disease. These drugs can kill mast cells and/or decrease the amount of chemicals released.
• IV fluids are reported by patients to help with symptoms such as fatigue and swelling.
• There are many other medications that can be used to treat other symptoms.

16. Do I have to take medication if I feel okay?
Mast cell patients are usually recommended to take baseline medications like antihistamines and mast cell stabilizers even if they feel okay. This is for two main reasons: mast cells can damage your body even if you don’t feel it; and if you do not take baseline medications, you will have less protection from a severe reaction and anaphylaxis.
• Many patients have other medications prescribed to be taken as needed. These medications are given when symptoms are bad and do not necessarily have to be taken daily.
• Please speak with your provider to clarify what meds are taken as needed and what meds are taken every day.
For more detailed reading, please visit these posts:

The Provider Primer Series: Management of mast cell mediator symptoms and release

The Provider Primer Series: Mast cell activation syndrome (MCAS)

The Provider Primer Series: Cutaneous Mastocytosis/ Mastocytosis in the Skin

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (ISM, SSM, ASM)

The Provider Primer Series: Diagnosis and natural history of systemic mastocytosis (SM-AHD, MCL, MCS)

Take home points: September 2015

Naturally occurring mast cell stabilizers: Part 1

Naturally occurring mast cell stabilizers: Part 2

Naturally occurring mast cell stabilizers: Part 3

Naturally occurring mast cell stabilizers: Part 4

Amentoflavone Ginkgo biloba, St. John’s Wort Decreases histamine release
Artekeiskeanol A Artemisa keiskeana May treat arthritis

Decreases mast cell degranulation

Decreases production of IL-13 and TNF

Curcimin Turmeric Decreases degranulation

Decreases production of IL-4 and TNF

Ellagic acid Strawberries, raspberries, pomegranate, walnuts Suppresses IgE activation

Decreases release of histamine, TNF, IL-6

Emodin Rhubarb, frangula bark Decreases IgE degranulation

Decreases IgE triggered production of TNF, PGD2, LTC4

Decreases secretion of TNF and IL-6

Epigallocatechin gallate White and green teas, apples, onions, hazelnuts Decreases degranulation

Decreases LTC4 secretion

Fisetin Apples, onions, persimmon, strawberries, cucumber Decreases IgE degranulation

Decreased IgE triggered histamine release

Decreases production of IL-1b, IL-6, IL-8 and TNF

Decreased action of NF-kB, decreased mediator production

Furanocoumarin from Angelica dahurica Angelica dahurica Inhibits COX-2 and 5-LO, decreasing production of prostaglandins and LTC4
Genistein Genista tinctoria Decreases IgE degranulation

Decreases histamine release

Nature tyrosine kinase inhibitor

Ginkgetin Gingko biloba Inhibits COX-2 and 5-LO, inhibiting production of prostaglandins and leukotrienes
Gnetin H Paeonia aneomala Resveratrol derived polymer

Decreases mast cell degranulation

Effective at lower dose than reservatrol

Decreases histamine secretion

Decreases production of TNF, IL-4, COX-2 and PGE2

Homoisoflavonone Cremastra appendiculata Inhibits COX-2 and 5-LO, inhibiting production of prostaglandins and leukotrienes

Decreases IgE triggered production of TNF and IL-6

Honokiol Magnolia obovata Suppresses allergic response and basophil activation
Hydroxytyrosol Olive oil, olive leaves Inhibited activation of mast cells at high concentration
Hypothemycin Hypomyces mushrooms Interfere with activation of CKIT and IgE receptors, inhibiting mast cell activation

 

Decreases production of IL-4

Kaempferol Potatoes, squash, cucumbers, peaches, Aloe versa Decreases IgE degranulation

Decreased IgE triggered histamine release

Affects estrogen signaling

Luteolin Celery, carrots, chamomile tea Prophylactic use of luteolin suppresses activation of mast cells and T cells

Decreases IgE degranulation

Decreases production of mediators

Magnolol Magnolia obovata Suppresses allergic response and basophil activation
Morin Osage orange, guava Decreases mast cell degranulation

Decreases IgE activation

Myricetin Walnuts, onions, red grapes Decreases IgE degranulation

Decreased IgE triggered histamine release

Decreases production of IL-6 and TNF

Decreased action of NF-kB, decreased mediator production

Polydatin Resveratrol precursor

Makes small intestine mucosa less “leaky” and inhibited allergic reaction in intestines

Decreases degranulation by up to 65%

Decreases histamine in intestinal mucosa and serum

Decreases production of IL-4

Quercetin Red onion, sweet potato, kale Inhibits production of histamine, prostaglandins, leukotrienes, IL-1b, IL-6, IL-8 and TNF
Resveratrol Grapes, raspberries, blueberries, peanuts Directly interferes with degranulation

Decreases production of TNF, IL-6 and IL-8

Rottlerin Mallotus philippensis Decreases degranulation of airway mast cells

Decreases histamine release

Suppresses IgE activation

Rutin Decreases IgE degranulation

Decreased IgE triggered histamine release

Decreases production of IL-1b, IL-6, IL-8 and TNF

Decreased action of NF-kB, decreased mediator production

Scopoletin Stinging nettle, Japanese belladonna, chicory, passion flower Decreases production of TNF, IL-6, IL-8

Inhibits NF-kB, affecting mediator production

Selinidin Angelia keiskei Inhibits IgE degranulation

Decreases production of LTC4 and TNF

Substance Source Function
Thunberginol A Hydrangeae macrophylla Decreases histamine release

Decreases production of TNF and IL-4

Thunberginol B Hydrangeae macrophylla Decreases degranulation from IgE or other sources

Decreases IgE triggered production of IL-2, IL-3, IL-4, IL-13, TNF and GM-CSF

Xanthones from purple mangosteen Garcinia mangostana Decreases release of histamine, PGD2, LTC4 and IL-6

 

Role of sex hormones in hereditary angioedema

Gastroparesis: Autonomic nervous system and vagus nerve (Part Six)

  • ANS controls many involuntary functions including digestion and therefore gastric emptying
  • The vagus nerve coordinates gastric motility
  • ANS dysfunction inhibits digestion and motility
  • GP is common in patients with ANS conditions, like POTS
  • Treatment of autonomic dysfunction (as in POTS) can sometimes improve GP
  • Damage to the vagus nerve can cause liquids to move rapidly out of the stomach while solids are retained
  • Surgery and high blood sugar can damage the vagus nerve
  • In GP patients, nerve cells are not shaped correctly
  • 83% of GP patients have abnormalities in their stomach biopsies

Gastroparesis: Idiopathic gastroparesis (Part Seven)

  • 35-67% of GP cases are idiopathic (IGP)
  • IGP affects three times more women than men, especially young and middle-aged women
  • IGP is more likely in young women who are overweight or obese
  • Moderate to severe abdominal pain was more frequent in IGP than other types
  • Nausea, abdominal pain, vomiting, bloating and feeling full are common in IGP
  • Medications that may be helpful but need investigation include sildenafil, paroxetine, cisapride, tegaserod, clonidine and buspirone

Naturally occurring mast cell stabilizers: Part 4

I mentioned resveratrol in the previous post under its broad classification as a phenol.  Looking more narrowly, resveratrol is a derivative of stilbene.  It is found in several foods, including grapes and berries like blueberries and raspberries.  Resveratrol can form oligomers, in which several of the same molecule are connected together.  One such oligomer is Gnetin H.  This product is isolated from Paeonia anomala and is used in Mongolian Chinese medicine.  It has been found to significantly impair mast cell degranulation and is effective at lower doses than resveratrol.  Gnetin H also decreased histamine secretion and production of TNF and IL-4, as well as COX-2 and PGE2 (not a typo, prostaglandin E2).

Polydatin is a precursor to resveratrol.  In a rat model, administration of polydatin was found to make the small intestine mucosa much less “leaky”.  It also inhibited hypersensitivity in the small intestine.  Importantly, it decreased degranulation by as much as 65% (determined by examining tissue with toluidine blue staining), and decreased histamine in both serum and intestinal mucosa.  Degranulation involves changes in calcium inside the mast cell and treatment with polydatin interfered with this process.  It also interrupted production of IgE by suppressing IL-4 secretion.  In another paper, polydatin was also found to suppress anaphylaxis in the mouse model of passive cutaneous anaphylaxis.

Hydroxytyrosol is a phenol derived from olive oil and olive leaves.  In nature, it occurs in the form of oleuropein, which can be broken down to hydroxytyrosol.  In a study that used β-hexosaminidase as a  marker for mast cell degranulation, both hydroxytyrosol and oleuropein inhibited activation in cells at high concentrations. This is promising but future research is needed.

In mouse and human mast cells, hypothemycin was found to interfere with activation of the CKIT receptor and the IgE receptor (FceRI).  This resulted in suppression of degranulation and production of cytokines, including IL-4.  This product was originally extracted from a mushroom of the Hypomyces genus.

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Finn, DF, Walsh, JJ. Twenty-first century mast cell stabilizers. J Pharmacol 2013 Sep; 170(1): 23-37.

Kim M, et al. Gnetin H isolated from Paeonia anomala inhibits FceRI-mediated mast cell signaling and degranulation. J Ethnopharmacol 2014 Jul 3; 154(3): 798-806.

Yang B, et al. Polydatin attenuated food allergy via store-operated calcium channels in mast cell. World J Gastroenterol 2013 Jul 7; 19(25): 3980-3989.

Yuan M, et al. Polydatin (PD) inhibits IgE-mediated passive cutaneous anaphylaxis in mice by stabilizing mast cells through modulating Ca2+ mobilization. Toxicol Appl Pharmacol 2012 Nov 1; 264(3): 462-469.

Persia FA, et al. Hydroxytyrosol and oleuropein of olive oil inhibit mast cell degranulation induced by immune and non-immune pathways.  Phytomedicine. 2014 Sept 25; 21(11): 1400-1405.

Naturally occurring mast cell stabilizers: Part 3

Coumarins are compounds that occur naturally in a number of plant species.  Several medications are derived from coumarins, including several anticoagulants, such as warfarin. They are notable for being fragrant.  Coumarin increases resorption of edema fluids.

Scopoletin is a coumarin present in the root structures of several species, including Urtica dioica (stinging nettle), Scopolia japonica (Japanese belladonna), chicory and passion flower.  In human mast cells, scopoletin interferes with production of TNF, IL-6 and IL-8.  It was found to inhibit NF-kB, which participates in the inflammatory response.

Artekeiskeanol A is a coumarin extracted from Artemisa keiskeana.  In traditional medicine systems, it is sometimes used to treat rheumatoid arthritis.  It suppressed degranulation, decreased production of TNF and IL-13.  Selinidin, a coumarin found in Angelica keiskei, suppresses IgE-initiated degranulation and decreases production of LTC4 and TNF. Rottlerin from the tree Mallotus philippensis attenuates IgE activation, degranulation of at least airway mast cells, and histamine release.

Cinnamic acid is a coumarin that decreased antigen stimulated degranulation in basophils, but similar action has not been recorded in mast cells.  It is most commonly extracted from cinnamon oil. A furanocoumarin found in Angelica dahurica inhibits action of COX-2 and 5-LO, decreasing production of PGD2 and LTC4, in addition to preventing degranulation.

Thunberginol A and B from Hydrangeae macrophylla inhibits histamine release from activated mast cells.  Thunberginol A prevents release of TNF and IL-4. In particular, thunberginol B is a potent mast cell stabilizer, suppressing degranulation from IgE or other causes.  It can also suppress production of IL-2, IL-3, IL-4, IL-13, TNF and GM-CSF when triggered by IgE.

Ellagic acid is found in nuts and fruit, such as strawberries, raspberries, pomegranate and walnuts. It interferes with IgE activation of mast cells and decreases release of histamine, TNF and IL-6.

Plant phenols have been reported to have medicinal effects for many years.  Magnolol and honokiol, two substance found in the bark of Magnolia obovata, can interfere with basophil degranulation as well as allergic response more generally.  Resveratrol is a phenol derivative present in berries, peanuts and grapes.  It is a potent supporessor of inflammatory mast cell products, including TNF, IL-6 and IL-8.  It also interferes with the structures required for degranulation and can also interfere with basophil degranulation.

Curcumin is another phenol derivative and is already quite popular in the mast cell community. (Disclaimer: I take turmeric, which contains curcumin.)  Curcumin has well described anti-inflammatory and anti-allergic benefits.  It inhibits mast cell and basophil degranulation and decreases release of IL-4 and TNF.  It also suppresses a popular lab model of allergy, passive cutaneous anaphylaxis.

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Finn, DF, Walsh, JJ. Twenty-first century mast cell stabilizers. J Pharmacol 2013 Sep; 170(1): 23-37.

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Moon PD, et al. Use of scopoletin to inhibit the production of inflammatory cytokines through inhibition of the IkappaB/NF-kappaB signal cascade in the human mast cell line HMC-1. Eur J Pharmacol 2007 Jan 26; 555(2-3): 218-225.

Kishiro S, et al. Selinidin suppresses IgE-mediated mast cell activation by inhibiting multiple steps of Fc epsilonRI signaling. Biol Pharm Bull 2008 Mar; 31(3): 442-448.

Bheekha-Escura, Roy, et al. Pharmacologic regulation of histamine release by the human recombinant histamine-releasing factor. May 1999; 103(5): 937-943.

Hong J, et al. Suppression of the antigen-stimulated RBL-2H3 mast cell activation by Artekeiskeanol A. Planta Med 2009 Nov; 75(14): 1494-1498.

Naturally occurring mast cell stabilizers: Part 2

As discussed in the previous post, many flavonoids can modulate mast cell responses.  Luteolin, a flavone, has been studied for its powerful effects on inflammatory cells.  With prophylactic administration of this molecule, activation of mast cells and T cells can be prevented in a disease model for multiple sclerosis. Luteolin can also inhibit IgE-triggered degranulation as well as production of various mediators.  It is found in many foods, including celery, carrots, and chamomile tea.

Genistein, an isoflavone, prevents IgE-induced degranulation and histamine release.  It is a natural tyrosine kinase inhibitor, mostly activate against EGFR. It can be extracted from Genista tinctoria, also called dyer’s broom.  Several structurally related molecules also have mast cell modulating effects. Amentoflavone, from Ginkgo biloba and St. John’s Wort, decreases histamine release by mast cells. Ginkgetin, derived from Ginkgo biloba leaves, inhibits phospholipase A2, a mast cell mediator, and inhibits production of PGD2 by interfering with the COX-2 enzyme and of LTC4 by interfering with 5-lipoxygenase.

Emodin is an anthraquinone with a long history of use in herbal medicine traditions.  It boasts an array of anti-allergic activity and can inhibit the following IgE induced effects: mast cell degranulation; production of TNF, PGD2 and LTC4; and secretion of TNF and IL-6. It is under investigation for use in type II diabetes, where it can decrease the activity of glucocorticoids in obese animals and may treat insulin resistance.  Emodin can be found in rhubarb, frangula bark and other plants.

A number of other natural molecules also have mast cell stabilizing effects. Epigallocatechin gallate, found in higher quantities in white and green teas, as well as apples, onions and hazelnuts, can inhibit mast cell degranulation and LTC4 secretion.  Xanthones found in the juice and fruit of the purple mangosteen, Garcinia mangostana, decreased histamine release as well as PGD2, LTC4 and IL-6 from mast cells.

 

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Kritas SK, et al. Luteolin inhibits mast cell-mediated allergic inflammation. J Biol Regul Homeost Agents 2013 Oct-Dec; 27(4): 955-959.

Theoharides TC, Kempuraj D, Iliopoulou BP. Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis. Adv Exp Med Biol 2007; 601: 423-30.

Son JK, et al. Ginkgetin, a biflavone from Ginkgo biloba leaves, inhibits cyclooxygenases-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells. Biol Pharm Bull 2005 Dec; 28(12): 2181-4.

Lu Y, et al. Emodin, a naturally occurring anthraquinone derivative, suppresses IgE-mediated anaphylactic reaction and mast cell activation. Biochem Pharmacol 2011 Dec 1; 82(11): 1700-1708.

Kim DY, et al. Emodin attenuates A23187-induced mast cell degranulation and tumor necrosis factor-a secretion through protein kinase C and IkB kinase 2 signaling. Eur J Pharmacol 2014 Jan 15; 723: 501-506.

Naturally occurring mast cell stabilizers: Part 1

Warning: Naturally occurring molecules can interfere with medications or adversely affect disease state.  Please consult with your managing provider before adding supplements or drastically changing diet.

Flavonoid is a broad term used to describe certain plant derived metabolites. It can be used to refer to a variety of molecules, including isoflavonoids, neoflavonoids and anthoxanthins, which are categorized based on structure.  A number of flavonoids have been shown experimentally to modulate mast cell behavior and function as mast cell stabilizers.

Homoisoflavonone decreases production of PGD2 and leukotrienes B4 and C4 by downregulating COX-2 and 5-LO, the enzymes that make these molecules from arachidonic acid. It also interferes directly with the manufacture of IL-6 and TNF in mast cells stimulated by IgE (the traditional allergy pathway).  Homoisoflavonone can be isolated from bulbs of Cremastra appendiculata, which is commonly called Chinese tulip despite being an orchid.  Chinese tulip is commonly used in Chinese medicine.  Related homoisoflavonoids, extracted from the tuber of Ophiopogon japonicas, mondograss, are anti-inflammatories, possibly by interfering with COX-2 and 5-LO.

Flavonols have been noted for their anti-allergic activity for a number of years.  Morin is a flavonol found in natural sources like Maclura pomifera (Osage orange) and Psidium guajava (guava).  Morin prevents mast cell degranulation and manufacture of cytokines like TNF and IL-4, as well as suppressing IgE activation almost completely at higher doses (please note the study on this used mice so it’s not clear what those dose would be in humans).  Other mast cell active flavonols include quercetin, myricetin, rutin, fisein and kaempferol.

Quercetin downregulates the expression of histidine decarboxylase, the enzyme that modifies histidine, an amino acid, to histamine.  Quercetin also inhibits release of histamine, prostaglandins and leukotrienes.  Additionally, it decreases production and release of IL-1b, IL-6, IL-8 and TNF.  Quercetin was reported to be stronger and more effective at inhibiting mediator release than cromolyn when taken prophylactically, although this has not yet been judged as true by any regulatory body.  Quercetin is found naturally in a number of foods, such as red onion, sweet potato, kale, and many others.  It is also found in small quantities in teas made with Camellia sinensis.  Rutin is a derivative of quercetin, found in citrus fruits, apples, cranberries and others.

Fisetin, kaempferol, myricetin, quercetin and rutin inhibited IgE mediated histamine release and prevented increased concentration of calcium inside mast cells, which is necessary for degranulation.  Fisetin, quercetin and rutin all decreased production of IL-1b, IL-6, IL-8 and TNF. Fisetin, myricetin and rutin all decreased action of NF-kB, which controls the pathway regulating production of cytokines. Myricetin is a particularly effective mast cell stabilizer.  It decreased degranulation and release of TNF and IL-6, but not IL-1b or IL-8.

Flavonols have been evaluated for other medicinal properties aside from mast cell modulation.  Myricetin has been suggested as a treatment for many diseases, including diabetes, while kaempferol affects many molecular pathways, including estrogen signaling.  These molecules occur naturally in a number of plants, including walnuts, onions and red grapes for myricetin; apples, onions, persimmons, strawberries and cucumbers for fisetin; and potatoes, squash, cucumbers, peaches and Aloe vera for kaempferol.

 

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Weng Z., et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity inhumans. PLoS One. 2012; 7(3): e33805.

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Lee, YS, et al. Homoisoflavonone prevents mast cell activation and allergic responses by inhibition of Syk signaling pathway. Allergy 2014; 69: 453-462.

 

 

 

 

Mast cell medications: Everything but antihistamines

The following medications listed are available in oral, intramuscular or intravenous formulation. Not all medications are available in the US or Europe. Topical and inhaled medications are not included in these lists.

Mast cell stabilizers interfere structures on the cell membrane required for degranulation and thus prevent the release of granule contents, including histamine.

Mast cell stabilizers
Cromolyn sodium/ Cromoglicic acid/ Nedocromil
Ketotifen
Omalizumab*
Quercetin
*mechanism unclear

 

Beta-2 adrenergic agonists cause smooth muscles to relax, which allow airways to open. These are used almost exclusively in asthma and pulmonary disease, which a secondary use in controlling uterine contractions in labor.

Beta-2 adrenergic agonists
Albuterol
Terbutaline

 

Leukotriene receptor antagonists work by interfering with the function of leukotrienes by blocking the CysLT1 receptor. Leukotrienes are heavily involved in airway reactivity and inflammation.

Leukotriene receptor antagonists
Montelukast
Pranlukast
Zafirlukast

 

5-lipoxygenase inhibitors prevent leukotrienes from being made.

5-lipoxygenase inhibitor
Curcumin
St. John’s Wort
Zileuton

 

Corticosteroids interfere with the activity of mast cells and production of mast cell mediators.

Mast cell stabilizers
Budesonide*
Dexamethasone
Hydrocortisone
Prednisone
Prednisolone
*taken orally, with effects local to the GI tract

 

Proton pump inhibitors reduce the production of gastric acid and treat heartburn, nausea and reflux. This can also be achieved by H2 antihistamines and for this reason, the two classes are often confused. The following medications, which are taken often by mast cell patients, have no known antihistamine effect. They can safely be taken with H2 antihistamines and help many mast cell patients, but it is important to clarify that they are NOT antihistamines.

Proton pump inhibitors
Dexlansoprazole
Esomeprazole
Ilaprazole
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole