Allergy Medications Are Nothing to Sneeze At

If you were a kid or a parent in the last 4 decades, you may remember the likes of Mr. Tickle, Mr. Greedy, or Little Miss Bossy. These stumpy characters, created by Roger Hargreaves, were intended to teach children lessons by acting according to their namesakes throughout various challenging situations.

So when Mr. Sneeze, with the help of Little Miss Sunshine, discovered that he had allergies, it appeared that educating children about hay fever was the primary goal of this 2003 children’s book. But it didn’t stop there. British pharmaceutical company GlaxoSmithKline, who commissioned the book, took it one step too far and slipped in a couple pages promoting their allergy medications, Piriton and Piriteze.

In the story told by GSK, Mr. Sneeze may be better known as Mr. Sneak.

 Although never available in stores, the book was sold at GSK roadshows and to Tesco (similar to Costco) Clubcard holders and was available through Allergy UK, a charity that collaborated on the book. How it was approved in the first place remains a mystery, as it violated a law prohibiting the direct advertising of any drug to children. Not surprisingly, GSK came under fire as the British government initiated an investigation and GSK eventually withdrew the book. The story made a splash, with many scientific journals and leading news sources, including Nature, the British Medical Journal, BBC news, and the Guardian covering it.

The BMJ article commented that adding to the controversy, the drugs GSK promoted were no longer the first choice of pediatric antihistamines. As if the real travesty was marketing an outdated product to unsuspecting children and their parents. Nevertheless, the comment highlights a key point:  allergy medications have improved drastically over the years, primarily increasing in safety, efficacy, and ease of use.

The active ingredient in GSK’s Piriton is chlorphenamine, a first generation antihistamine (also found in Advil Allergy and Congestion, for example). Another first-generation antihistamine is the ever-popular diphenhydramine, known by most as Benadryl. These antihistamines are inverse agonists, meaning they work by keeping the H₁ receptor in its inactivated form, precluding the binding of histamine. Although highly effective, first generation antihistamines are plagued with strong sedative effects. This happens because they cross the blood brain barrier (BBB), where they bind 50-90% of H₁ receptors in the central nervous system (CNS) and cause drowsiness. Diphenydramine is such a strong sedative that it is FDA-approved for over-the-counter treatment of insomnia.

Although the drowsiness side effect is undesirable and may impair daily performance, first generation antihistamines are still widely used today, popular because they are fast-acting and relatively safe if used properly. Or, perhaps some people would rather just sleep through allergy season.

The other drug advertised by Mr. Sneeze was Piriteze, which contains cetirizine, a less-drowsy second-generation antihistamine. Second-generation antihistamines, including cetirizine (Zyrtec), fexofenadine (Allegra), and loratidine (Claritin) penetrate the CNS poorly because they are pumped out by P glycoproteins, gatekeepers of the BBB. This greatly reduces the number of CNS H₁ receptors that are occupied, with fexofenadine and loratidine binding negligibly and cetirizine binding up to 30% of the receptors. So, cetirizine may still cause drowsiness at recommended doses, whereas fexofenadine and loratidine should not. Second-generation antihistamines are generally preferred over first-generation for their enhanced safety profile.

P-glycoprotein’s command only works on better-behaved second generation antihistamines; the gatekeeper blind to first-generation antihistamines, which pass through the blood brain barrier.

Antihistamines can also be administered intranasally (azelastine and olopatadine); these medications are as effective as or superior to the second-generation oral antihistamines. However, the most effective treatment for seasonal allergies is actually intranasal corticosteroids. Whereas antihistamines block the early phase allergic response, corticosteroids primarily act during the late phase. These work by inhibiting the recruitment of inflammatory cells, such as eosinophils and basophils, and blocking the secretion of pro-inflammatory mediators such as interleukins, causing a decrease in the levels of circulating leukotriene, histamine, and mast cells. The most potent and effective intranasal corticosteroids are mometasone furoate (Nasonex or Nasacort) and fluticasone propionate (Flonase). The furoate and propionate modifications on the drugs are thought to facilitate their absorption in the nasal mucosa and also reduce their systemic absorption, which means less chance of dangerous side effects.

Glucocorticoids are an anti-inflammatory subclass of corticosteroids that include the natural steroid cortisol. Cortisol, and its synthetic analogues, mometasone and fluticasone, work by activating the glucocorticoid receptor, which down-regulates the production of pro-inflammatory molecules. The furoate and propionate side chains are shown in red and blue, respectively.

Yet another treatment, allergen immunotherapy (allergy shots), may be appropriate for allergy patients who have detectable specific IgE antibodies to relevant trigger allergens. Specific immunotherapy (SIT) involves exposure to increasing doses of specific allergen(s). The dose-increase phase usually lasts 14-28 weeks during which desensitization occurs, meaning cells become less reactive or non-reactive to IgE-mediated immune responses. As discussed previously, Type I hypersensitivity reactions are mediated by T-helper 2 cells and allergy-prone infants have diminished T-helper 1 reactions. Perhaps not surprisingly, successful immunotherapy is associated with a shift towards a Th1-type reaction.

So, whereas antihistamines and glucocorticoids treat allergy symptoms, SIT can actually modify the disease and provide lasting protection against allergies. Furthermore, it has been shown to prevent subsequent sensitization to new allergens. In one study, 3 years of immunotherapy provided protection in some patients for up to 12 years and reduced the occurrence of additional allergies in almost half the patients.

Traditionally, SIT is administered subcutaneously (under the skin) by injection. However, last year three sublingual (under the tongue) allergen immunotherapy drugs were approved by the FDA in rapid succession. Oralair, which contains 5 grass pollen extracts (timothy, Kentucky blue, perennial rye, orchard and sweet vernal), became the first FDA-approved sublingual allergen extract. Eight days later, the FDA announced approval of Grastek, which contains only timothy grass extracts. Another 6 days later, Ragwitek was approved for the treatment of short ragweed pollen allergies. Whereas Oralair and Grastek are approved for pediatric use (10+ and 5+ years, respectively), Ragwitek is for adults (18+) only. All drugs showed moderate efficacy in clinical trials, with approximately 20-25% reduction in symptoms and need for symptom-management medication during one allergy season, compared to patients in the placebo group.

If needles aren’t your cup of tea, sublingual immunotherapy may provide a more palatable option.

Interestingly, the allergen extracts given by injection are not tested in clinical trials, but are FDA-approved based on purity, safety, and potency. Nonetheless, subcutaneous immunotherapy (SCIT) has been used safely and successfully worldwide for decades. And although it is new in the US, sublingual immunotherapy (SLIT) has been used successfully in Europe for years. From a cost perspective, immunotherapies compare favorably to pharmacotherapies (drugs like antihistamines and glucocorticoids).

Some people want a spoonful of sugar to help the medicine go down…or perhaps a spoonful of honey in place of medication entirely. Anecdotal evidence suggests that eating local, unfiltered raw honey can have similar effects to SIT by desensitizing the immune system. The idea is logical:  bees incorporate pollen into honey; therefore, eating local, unprocessed honey will expose you to the pollen prevalent in your area. Only a few studies have addressed the efficacy of honey for allergy treatments; one lasted only 10 days (no reduction in allergies observed) or used birch pollen-spiked honey for 5 months (effective at reducing allergies). Unfortunately, neither of these studies properly evaluated honey as an allergy treatment. The first had the right idea, but desensitization requires months (not days) to be effective, and while the second study demonstrates the feasibility of the idea, artificially-spiked honey does not address the real question.

Despite the shortcomings of these studies, the reason honey will never be recommended for allergy treatment is also logical:  the types of pollen bees primarily use are from fragrant flowers, not the wind-carried pollen from grasses like timothy and ragweed or trees like birch, which are responsible for the majority of allergies. Furthermore, the dose of any allergenic pollen in honey is very low and not controlled, making it virtually impossible to achieve desensitization analogous to that observed with SIT.

Searching for an allergy cure in a “hunny” jar will only get you sticky…you’d be better off sticking your head in it to reduce your exposure to wind-carried pollen.

While honey may help clear the bitter aftertaste from intranasal or sublingual medications, it will do little to alleviate your allergies. Better to stick to the tried-and-true methods for real allergy relief - while we may not yet know how best to prevent allergies, certainly many effective options exist to treat them.

Contributed by: Julia van Rensburg, PhD

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Ariano R, Berto P, Tracci D, Incorvaia C, & Frati F (2006). Pharmacoeconomics of allergen immunotherapy compared with symptomatic drug treatment in patients with allergic rhinitis and asthma. Allergy and asthma proceedings : the official journal of regional and state allergy societies, 27 (2), 159-63 PMID: 16724637

Nasser S, Vestenbaek U, Beriot-Mathiot A, & Poulsen PB (2008). Cost-effectiveness of specific immunotherapy with Grazax in allergic rhinitis co-existing with asthma. Allergy, 63 (12), 1624-9 PMID: 19032235

Wallace DV, Dykewicz MS, Bernstein DI, Blessing-Moore J, Cox L, Khan DA, Lang DM, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CC, Schuller D, Spector SL, Tilles SA, Joint Task Force on Practice, American Academy of Allergy, Asthma & Immunology, American College of Allergy, Asthma and Immunology, & Joint Council of Allergy, Asthma and Immunology (2008). The diagnosis and management of rhinitis: an updated practice parameter. The Journal of allergy and clinical immunology, 122 (2 Suppl) PMID: 18662584

Derendorf H, & Meltzer EO (2008). Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications. Allergy, 63 (10), 1292-300 PMID: 18782107

Sur DK, & Scandale S (2010). Treatment of allergic rhinitis. American family physician, 81 (12), 1440-6 PMID: 20540482

Allergies! Type I Hypersensitivity: When More Isn’t Better

Our last article discussed various hay fever inducing allergens encountered throughout the year. We learned that even for some of the most allergenic pollens, like birch and ragweed, only certain antigens derived from the pollen actually induce an allergic response. While the differences in the structure of these primary antigens can partially explain why some are allergenic and others are not, it really boils down to how the antigen interacts with an individual’s immune system. Some molecules make better allergens than others because they interact with the major player in Type I hypersensitivity, immunoglobulin E (IgE).

Interestingly, IgE earned its name based on the fact that it reacted with the ragweed pollen antigen E, now known as the primary ragweed antigen “Amb a 1”. In 1921, scientists K. Prausnitz and H. Kustner identified a serum component that was responsible for allergic reaction. It wasn’t until 1966 that T. and K. Ishikawa identified IgE as the serum component. Everyone has a small amount of this potent antibody circulating the blood; IgE accounts for less than 0.05-0.2% (0.1-0.4 μg/mL) of the circulating antibodies in non-atopic individuals. Some, but not all, atopic individuals have higher levels of circulating IgE, up to 0.79%.

Even Sabrina Fairchild knew that “More isn’t always better…sometimes it’s just more.”

In individuals without allergies, an IgE-mediated immune response occurs as a defense against parasitic infections. In this case, the resulting physiological changes clear the parasite and protect the body against further damage caused by the parasite. However, in individuals with allergies, the IgE-mediated response is classified as a Type I hypersensitivity.

Let’s follow a pollen grain on its first journey in an allergic individual. The first encounter of an allergen sensitizes the individual to that specific allergen, but symptoms are not experienced. Initially, the pollen particle encounters the peripheral defenses, nasal hairs, eyelids, and beating cilia in the throat. These hairs prevent most particles from entering the airway or sinuses. Pollen particles must be extremely tiny (about 1x10^-6 meters) to pass through this initial barrier. Upon reaching the nasal mucosa, enzymes in mucous secretions break down the tough outer shell of the pollen (the exine), releasing the allergenic substance.

 

Antigen presenting cells engulf the allergenic substance, process it with enzymes, and display the antigen on the cell surface within a cradle-like protein called the class II major histocompatibility complex (MHC). Another type of immune cell, called T-helper, or Th, cells bind the presented antigen. Th2 cells release molecules called cytokines, which communicate to naive B cells to begin dividing and maturing. Some B cells differentiate into plasma cells, which produce and secrete a specific class of antibodies, or immunoglobulin (Ig). Humans produce 5 circulating antibody isotypes:  IgG, IgM, IgA, IgD and IgE. Particularly, Th2 cells produce the cytokines interleukin (IL)-4 and IL-13, which stimulate B cells to produce IgE. The allergic response appears to be localized, as plasma cells secreting IgE are 1000 times greater in nasal mucosa than in circulation.

In addition to producing the correct isotype, the plasma cells also produce highly specific antibodies that will bind the antigen tightly. Through the process of clonal selection and clonal expansion, a specific IgE molecule with high affinity for the antigen is produced en masse, creating an army like the clone troopers.

Although the army of IgE clones may not be as large as the clone troopers, it's every bit as powerful in wreaking immune havoc.

The circulating IgE has a specific receptor that allows it to bind tissue mast cells and blood basophils. At this point, the body is considered “sensitized” to the allergen. Additionally, memory B cells are formed in preparation for the second encounter of the antigen.

Nothing happens yet, but the body essentially lays in wait to encounter the allergen again. Upon second exposure, the allergenic antigen binds two IgE molecules that are already situated on the mast cells and basophils. These crosslinked IgE molecules are much more stable and can continue sending signal for weeks. The signal, as allergy sufferers know all too well, is a massive inflammatory response mediated by various pharmacologically active molecules contained within and produced by mast cells and basophils. These cells store the inflammatory molecules, like histamine, in granules or inner pockets. When the antigen binds IgE, mast cells and basophils undergo degranulation, releasing large amounts of chemical mediators like the histamine targeted by most antihistamine allergy medications.

The antigen acts like Wile E. Coyote, detonating the IgE fuse, causing the mast cell bomb to explode and release clouds of histamine. Histamine, in turn, damages only our tissues, never touching the elusive (and harmless) Roadrunner allergen.

Mast cells quickly synthesize additional mediators, including leukotriene and prostaglandin. These mediators signal certain physiological changes, including vasodilation (nasal blockage), smooth muscle contraction (coughing), increased mucus secretion (runny nose), and increased vascular permeability (inflammation). Sensory nerves are stimulated, resulting in sneezing and itching. This early phase, or immediate hypersensitivity reaction, happens so rapidly that symptoms are noticed within minutes of exposure to the allergen.

Although histamine is probably the most well-known pharmacologically active molecule, it is actually not the most potent or the longest acting player. Rather, it is the first molecule released in the allergic reaction. Following degranulation, mast cells and basophils produce and release other mediators called prostaglandins and leukotrienes. Initially, contraction of bronchial and tracheal muscles is mediated by histamine, but shortly after, further contraction occurs as a result of prostaglandin and leukotrienes. Leukotrienes are 10 times more potent than histamine at causing bronchoconstriction than histamine.

How an antigen, say pollen, triggers an allergic response.

About 50% of the time, 4 to 8 hours after the early phase reaction, the late phase begins. Other cytokines, particularly IL-5, attract other inflammatory cells, including eosinophils. The symptoms of the late phase reaction resemble those of the early phase, but tend to be characterized by less sneezing and itching and more congestion and mucus production. The inflammatory response from the late phase can damage tissues and last for days.

So why do some people endure the suffering of hay fever and others do not? Tune in next time to find out the genetic and environmental factors that contribute to allergic rhinitis.

 

 

Contributed by Julia van Rensburg, PhD
Follow Julia on Twitter.

Ishizaka K, Ishizaka T, & Hornbrook MM (1966). Physico-chemical properties of human reaginic antibody. IV. Presence of a unique immunoglobulin as a carrier of reaginic activity. Journal of immunology (Baltimore, Md. : 1950), 97 (1), 75-85 PMID: 4162440

Kasaian MT, Meyer CH, Nault AK, & Bond JF (1995). An increased frequency of IgE-producing B cell precursors contributes to the elevated levels of plasma IgE in atopic subjects. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 25 (8), 749-55 PMID: 7584687

Verstraelen, S., Bloemen, K., Nelissen, I., Witters, H., Schoeters, G., & Heuvel, R. (2008). Cell types involved in allergic asthma and their use in in vitro models to assess respiratory sensitization Toxicology in Vitro, 22 (6), 1419-1431 DOI: 10.1016/j.tiv.2008.05.008

Takhar P, Smurthwaite L, Coker HA, Fear DJ, Banfield GK, Carr VA, Durham SR, & Gould HJ (2005). Allergen drives class switching to IgE in the nasal mucosa in allergic rhinitis. Journal of immunology (Baltimore, Md. : 1950), 174 (8), 5024-32 PMID: 15814733