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Monday, June 2, 2014

The effects of calcitriol treatment in glucocorticoid resistant asthma

The current and most effective treatment for asthma therapy is the use of glucocorticoids by improving the clinical features and airway inflammation associated with asthma. However, a cohort of well-defined asthma patients exists in whom high-dose glucocorticoid treatment is not only clinically ineffective, but potentially detrimental.  Several mechanisms have been proposed to contribute to glucocorticoid resistance, including vitamin D insufficiency. Nanzer et al recently published data that glucocorticoid resistant patients fail to synthesize the anti-inflammatory cytokine interleukin-10 (IL-10) in response to glucocorticoid in vitro compared to glucocorticoid sensitive patients (J Allergy Clin Immunol 2014; 133(6): 1755-1757). When resistant patients ingested a form of vitamin D called calcitriol (1,25-dihydroxyvitamin D3) in combination with glucocorticoid, levels of IL-10 were restored in vivo and ex-vivo. Taken together, these data along with epidemiological evidence linking vitamin D insufficiency/deficiency with poor clinical response to asthma treatment provided the rationale for the authors to perform a proof-of-concept clinical trial.

A small group of glucocorticoid resistant severe asthmatics were chosen and placed on a 2-week course of oral prednisolone and then randomly assigned placebo or 0.25ug calcitriol twice daily for 4 weeks. During the last 2 weeks patients repeated a course of oral prednisolone. The authors hypothesized that the concomitant calcitriol therapy would improve clinical glucocorticoid responsiveness in these patients. They did not expect the short course of calcitriol to restore Vitamin D sufficiency, but to address the short-term effects of calcitriol itself.

A within group comparison showing the change in lung function during the initial screening in response to 2-weeks oral prednisolone versus the response to an identical course of prednisolone plus either placebo or calcitriol, revealed a modest but significant improvement in absolute and predicted FEV₁ within the calcitriol but not the placebo arm. Furthermore, a trend for a positive correlation between baseline serum Vitamin D concentrations and change in predicted lung function following prednisolone was observed in placebo patients. This data suggests that treatment with a short course of calcitriol may improve the clinical glucocorticoid responsiveness in asthma, including patients classified as clinically glucocorticoid resistant. While larger studies with clinically well-defined cohorts are warranted, these results are very encouraging for the treatment of glucocorticoid resistant asthma. 

Mechanisms underlying the neuronal based symptoms of allergy

People with allergies often present with symptoms that are the result of alterations in the nervous system in the organ in which the reaction occurs. Common neuronal symptoms include itchy eyes, sneezing, nasal congestion, rhinorrhea, cough, bronchoconstriction, airway mucus secretion, dysphagia, altered gastrointestinal motility, and itchy swollen skin. Mediators released during an allergic reaction interact with sensory nerves, altering the transmission of signals in the sympathetic and parasympathetic autonomic nerves. Undem and Taylor-Clark describe how the nervous system itself is altered in allergic disease either due to events occurring during critical periods of neuronal development or to persistent nerve stimulation (J Allergy Clin Immunol 2014; 133(6): 1521-1534).

Those that suffer from allergic rhinitis for example, more often react strongly by sneezing when stimulants are applied to the nasal mucosa compared to healthy controls. Considering sneezing is a parasympathetic reflex, it is not surprising that these allergic individuals are often more likely to have nasal allergic symptoms when exposed to smoke, irritants, and cold air.  Similarly, in response to food allergy, immunological activation of mast cells in the gut is associated with alterations in neurotransmission. The authors detail the basic mechanisms of allergen-induced neuromodulation, highlighting the molecular interactions and phenotypic changes that occur. 

The authors emphasize that not only those with allergy produce neuroactive mediators at sites of allergic inflammation, but that the nervous system itself is altered in allergic diseases. Whether this is due to events occurring during critical periods of neuronal development or to persistent nerve activation, the nervous system is rendered hyperactive. As the understanding of basic mechanisms continue to evolve, new therapeutic strategies that target the nervous system will continue to emerge that work synergistically with anti-inflammatory treatments that allow for new, more powerful therapeutic options for allergy sufferers.

Potential food allergens in medications

Excipients are all of the substances found in pharmaceuticals that are added to the active ingredient to provide a benefit in manufacturing, stability, bioavailability, or patient acceptability.  Some excipients are foods or substances derived from foods.  Food allergic patients may rarely have reactions to these products. In his review, John M. Kelso, MD details which food-derived substances are used as pharmaceutical excipients and in which medications. Furthermore, the safety of administration of these medications in food allergic patients is also discussed (J Allergy Clin Immunol 2014; 133(6): 1509-1518). 

Food allergens are proteins that can generate IgE-mediated responses in food-allergic individuals. Since some food-derived excipients in medications are proteins, there is potential for an allergic response.  However, in most cases there is not enough of the food protein present to cause a reaction even in an allergic individual.  For example, most influenza vaccines are grown in eggs,  however there are only trace amounts of the protein in the vaccines and they are considered safe in egg-allergic recipients.  Other vaccines, however, contain substantial quantities of gelatin and do pose a risk of an allergic reaction in those with gelatin allergy.  Other excipients are derived from foods but do not contain protein, thus fish-allergic patients need not avoid fish oil for example.  In some cases, a food-derived excipient such as lactose may be contaminated with milk protein accidentally.

Although food-derived excipients may contain food proteins, reactions are generally quite rare likely because protein amounts are too low to elicit a reaction. If there is a reaction to a medication, it may be from a specific lot that was accidentally contaminated with food protein. However, if a reaction occurs, allergy to the food component should be investigated as a possible cause.