Do Mast Cell Stabilizers Affect Driving?

What Are Mast Cell Stabilizers and How do They Work?

Mast cell stabilizers are the name given to a cluster of medicines that inhibit the release of

histamine and other potent chemical mediators from mast cells.

Mast cells are a category of white blood cell that are part of our immune system and play a

key role in our body's response to antigens (a toxic or foreign substance that is perceived as

a danger to our body and which induces an immune response).

They are implicated in anaphylaxis, allergic rhinitis, allergic conjunctivitis, asthma,

autoimmune diseases, eczema, itch, and reproductive disorders.

The mast cell stabilizers nedocromil and cromolyn work by blocking a calcium channel that

is essential for mast cell degranulation (the release of chemical mediator-containing

secretory granules which happens after contact with a specific antigen).

Mast cell stabilizers can be used to prevent asthma and symptoms of seasonal or chronic

allergic rhinitis. (1)

Mast cells play a very important role in the occurrence of allergic diseases because of their

hypersensitive response to otherwise harmless substances that cause an allergic reaction.

Mast cells are therefore vital players in both the development and maintenance of allergic

diseases and are subsequently considered an attractive therapeutic target in the treatment of

allergic diseases such as allergic rhinitis, asthma, and allergic conjunctivitis.

Mast cells play a major role in the immunopathology of the immediate-hypersensitivity

reaction, which happens in response to contact with certain allergens.

Mature mast cells are categorised into 2 subtypes depending on their location; connective

tissue mast cells (CTMCs), which exist in tissues such as the small bowel submucosa, skin

and peritoneal cavity, or mucosal mast cells (MMCs), which mature in mucosal tissues like

the intestinal lamina propria and in the airways.

Sources of Mast Cell Stabilizers

Mast cell stabilizing agents from natural sources

• Flavonoids
• Coumarins
• Phenols
• Terpenoids
• Alkaloids
• Biologics

Semi-synthetic inhibitors of mast cell degranulation

Synthetic inhibitors of mast cell degranulation

• Syk inhibitors
• JAK3 inhibitors
• KIT TK inhibitors
• Ceramide Kinase (CerK) inhibition
• Phosphodiesterases ( PDEs) inhibition
• Miscellaneous inhibitors
• Old drugs with new uses as mast cell stabilizers

All the above sources of mast cell stabilizers are outlined in depth in the review by D F.Finn

and JJ Walsh (2)

New Therapeutic Areas for Mast Cell Stabilizers

Endometriosis is a chronic estrogen-dependent inflammatory disease of unclear Etiology

that affects 15-20% of women of reproductive age.

Targeting Mast Cells might offer new options to treat this disease. (3)

Because endometriosis is a multifactorial disease, and considering that numbers of Mast

Cells and activated Mast Cells were clearly increased in endometriotic lesions in both

animals and humans, use of Mast Cell (MC) stabilizers and inhibitors might prove to be

effective to treat endometriosis and its associated pain.

However, more research from preclinical studies and clinical trials will help to better define

the status of MCs in the treatment of this pathology.

According to K Matsuda and fellow investigators ,Mast cells may also play an important

role in protection against helminth infections and in the induction of allergic diseases;

however, new studies indicate that these cells also contribute to neovascularization,

which is essential for tissue remodelling, chronic inflammation, and carcinogenesis.(4)

They demonstrated that mast cells are essential for sprouting angiogenesis in a murine

model of oxygen-induced retinopathy (OIR).

Furthermore, although mouse strains lacking mast cells did not demonstrate retinal

neovascularization following hypoxia, mice developed OIR following infusion of mast

cells or after injection of mast cell tryptase (MCT).

Relative hypoxia stimulated mast cell degranulation via transient receptor potential

ankyrin 1.

Subsequent surges in MCT stimulated retinal endothelial cells to produce monocyte

chemotactic protein-1 (MCP 1) and angiogenic factors, lead to sprouting angiogenesis. 

Mast cell stabilizers as well as specific tryptase and MCP1 inhibitors stopped the

development of OIR in WT mice.

Preterm infants with early retinopathy of prematurity had substantially higher plasma MCT

levels than age-matched infants without disease, suggesting mast cells contribute to human

disease.

Together, these results suggest therapies that suppress mast cell activity should be further

explored as a potential option to preventing eye diseases and subsequent blindness induced

by neovascularization. 

Abdominal aortic aneurysm (AAA), is a progressive segmental abdominal aortic dilation

that is associated with high mortality.

It is characterized by inflammation, smooth muscle cell (SMC) depletion and extracellular

matrix (ECM) degradation.

Surgical intervention and endovascular therapy are indicated to prevent rupture of large

AAAs.

Unfortunately, there is no reliable pharmacological agent available to limit AAA expansion.

Previously, extensive investigations and a body of ongoing clinical trials aimed at defining

potent treatments to inhibit and even revert AAA growth.

Y D Wang and fellow authors summarized recent progress of potential strategies,

particularly macrolides, tetracyclines, statins, angiotensin converting enzyme inhibitors,

angiotensin receptor blocker, corticosteroid, anti-platelet drugs and mast cell stabilizers. (5)

Furthermore, they considered recently identified novel molecular targets, which have

potential to be translated into clinical practice in the future.

Suppression of Wheal and Flare in Histamine Test by the Main H1 Antihistamines

Commercialized in Brazil

It has been 40 years ago since we commenced studying the effects of antihistamines on

wheals and flares (6)

Most recently, Helena Maciel-Guerra and colleagues wished to compare the potency of

antihistamines currently available in Brazil (7).

Their goal was to appraise the tolerability and efficacy of the major commercial brand and

generic H1 antihistamines with regard to the suppression of the wheal and flare to the

histamine test.

They utilised a quasi-experimental, open study with 10 healthy adults submitted to the

histamine test on the ventral aspect of the forearms.

After 20 minutes, flares and wheal were examined.

The tests were performed after 2 hours of intake of dexchlorpheniramine, hydroxyzine,

levocetirizine, fexofenadine, loratadine, cetirizine, ebastine, desloratadine, rupatadine and

epinastine, as well as generics of loratadine, fexofenadine and cetirizine.

RESULTS

Every antihistamines showed a reduction in the wheal compared to the control (p <0.02),

and also in the flare, except for rupatadine (p = 0.70).

In the internal comparison, cetirizine, fexofenadine, epinastine, levocetirizine,

dexchlorpheniramine and hydroxyzine were the most potent, with no difference between

them (p > 0.1).

As for halo, cetirizine, epinastine, hydroxyzine and fexofenadine were the most potent, with

no difference between them (p > 0.1).

The most frequent adverse effect was drowsiness, which was more prevalent among first-

generation drugs (p <0.01).

Generic loratadine, fexofenadine and cetirizine halos were higher than their controls (p

<0.03).

The authors stated that a limitation of this study was that it was a single-centre study

evaluating only aspects related to histamine.

CONCLUSIONS

Brazilian commercial antihistamines presented diverse profiles of inhibition of wheal and

flares in the histamine test, as well as adverse effects.

Interestingly generic loratadine, fexofenadine and cetirizine presented greater flares than

brand drugs.

The investigators raised the possibility that this could be due to intrinsic properties of a

specific generic preparation.

How Do Mast Cell Inhibitors Affect Driving?

A Leroy and MM Morse have published the most definitive report on the effects of drugs on

driving vehicles. (8)

The authors found that Mast Cell Stabilizers with an Odds Ratio of 3.00 (P<0.04) were the

second largest class of drugs that impaired driving after barbiturates (Odds Ratio 7.5;

P=0.00)

This data pertaining to the increased risk of a motor vehicle accident that includes odds ratio

along with confidence intervals for all statistically significant diseases, therapeutic drug

classes and drug interactions that impair driving are also provided on my website:

www.internationalclinicaltrials.com

Implications for Drivers Taking Mast Cell Inhibitors

According to the Mayo Clinic (9) antihistamines that tend to cause drowsiness are:

• Diphenhydramine
• Chlorpheniramine

Those that are much less likely to cause drowsiness include:

• Cetirizine (Zyrtec Allergy)
• Desloratadine (Clarinex)
• Fexofenadine (Allegra Allergy)
• Levocetirizine (Xyzal)
• Loratadine (Alavert, Claritin)

Wherever possible, drivers should take less sedating drugs especially those over 60 years of

age who have impaired reaction times due to their age. (10)

References

(1)Drugs.com. [ https://www.drug.com/drug-class/mast-cell-stabilizers.html.] Mast Cell Information from Drugs.com; c2000-18 [Updated:2018 May 1;Cited May 23] Available from https://www.drug.com/drug-class/mast-cell-stabilizers.html

(2)D.F. Finn and J. J. Walsh. Twenty-first century mast cell stabilizers Br. J. Pharmacol 2013 Sep; 170(1):23-37.Published online 2013 Aug 15. doi:  10.1111/bph.12138

(3) Binda MM, Donnez J, Dolmans MM. Targeting mast cells: a new way to treat

endometriosis. Expert Opin Ther Targets. 2017 Jan; 21(1):67-75. Epub 2016 Nov 28.

(4) Matsuda K, Okamoto N, Kondo M, Arkwright PD, Karasawa K, Ishizaka S, Yokota

S, Matsuda A, Jung K, Oida K, Amagai Y, Jang H, Noda E, Kakinuma R, Yasui

K, Kaku U, Mori Y, Onai N, Ohteki T, Tanaka A, Matsuda H. Mast cell hyperactivity

underpins the development of oxygen-induced retinopathy. J Clin Invest. 2017 Nov1;

127(11):3987-4000. doi: 10.1172/JCI89893. Epub 2017 Oct 9.

(5) Wang YD, Liu ZJ, Ren J, Xiang MX. Pharmacological Therapy of Abdominal Aortic

Aneurysm: An Update. Curr 2017 Apr 1 3. doi:

10.2174/1570161115666170413145705. [Epub ahead of print]

(6)  Franks, H M, Lawrie, M, Schabinsky, V V, Starmer, G A and Teo, R K C The

Interaction between Ethanol and Antihistamines 3 Mebhydrolin Med. J. Aust.

,(1981) 2:477-479. 

(7)Maciel-GuerraH, Penha Má, Jorge MFS, Libório RDS, Carrijo ACNDA, Parise-

Fortes MR, Miot HA.Suppression of wheal and flare in histamine test by the main H1

antihistamines commercialized in Brazil. An Bras Dermatol. 2018 Mar; 93(2):233-

237. doi: 10.1590/abd1806-4841.20186807.

(8)Leroy A, Morse MM, for the US Department of Transportation/National Highway

Traffic Safety Administration. Exploratory study of the relationship between multiple

medications and vehicle crashes: analysis of databases. Washington, DC:

U.S.DOT/NHTSA; 2008: Publication DTNH22-02-C-05075.

(9)Allergy Medications. Know your options. https://www.mayoclinic.org/diseases-

conditions/allergies/in-depth/allergy-medications/art-20047403.? 1998-2018 Mayo

Foundation for Medical Education and Research (MFMER). All rights reserved.

(10)Doroudgar S, Chuang HM, Perry PJ, Thomas K, Bohnert K, Canedo J.Driving

Performance Comparing Older versus Younger Drivers. Traffic Inj Prev. 2016 Jun

21:0. [Epub ahead of print]