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By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville. Dr. Kuritzky is a consultant for GlaxoSmithKline and is on the speaker's bureau of GlaxoSmithKline, 3M, Wyeth-Ayerst, Pfizer, Novartis, Bristol-Myers Squibb, AstraZeneca, Jones Pharma, and Boehringer Ingelheim.
Allergic rhinitis is often treated successfully with antihistamines and local corticosteroids, but because of inadequate symptom control, patient preference, or both, sometimes allergen desensitization becomes preferable. Most of our knowledge about desensitization comes from studies using parenteral allergens, but other routes for desensitization have been suggested. Sublingual immunotherapy (SIT) has been recently demonstrated in large double-blind, placebo controlled trials to be effective in reducing allergic rhinitis symptoms and need for rescue medication.
The exact mechanism by which parenteral immunotherapy produces its beneficial effects is still controversial, since treatment induces T regulatory cells that blunt the late-phase reaction, generates IgG "blocking" antibodies to offending antigens, and decreases the IgE response to antigens. Because SIT provides antigen in sufficient magnitude that some is absorbed through the oral vasculature, stimulation of regional lymph nodes to produce allergen-specific IgG has been demonstrated.
Advantages of SIT include that desensitization may be initiated at a full maintenance dose (as compared to injections, which must be very gradually titrated), the very low likelihood of anaphylaxis (as demonstrated by trial data to date), and lack of necessity for injections, which may be preferred by some patients, especially children.
Disadvantages of SIT include limitations of approved antigens (thus far, grass allergens are the only ones commercially available, and none are yet FDA approved), limited data-base compared with injection immunotherapy, and especially the uncertainty surrounding durability of SIT, since long term trials of SIT (beyond 2 years) are lacking.
For patients with compelling reasons to seek SIT instead of injection, SIT is available in England.
Frew, AJ. N Engl J Med. 2008;358:2259-2264.
Methylnaltrexone for Opioid-Induced Constipation
Of the adverse effects induced by opioid therapy, constipation is singular in its persistence. Opioid-induced bowel dysfunction (OBD) is felt to result primarily from action of opioids upon the mu receptor in the colonic myenteric plexus, resulting in lack of contractility of the longitudinal muscle fibers, and hence a loss of peristalsis. Traditional laxative tools for constipation are generally employed with some success. Bulk forming laxatives (eg, fiber), should be avoided in OBD, since they may actually worsen symptoms or even lead to full obstruction in a non-motile colon.
Methylnaltrexone (MTX) is a mu-receptor antagonist which, because it is a quaternary amine compound, does not induce withdrawal symptoms in persons on chronic opioid therapy. Small pilot trials have supported the utility of both oral and parenteral MTX for prompt relief of constipation.
Thomas, et al studied a population of subjects on opioid therapy (n=133) who had not achieved relief of constipation with "traditional" laxatives. MTX subcutaneous was administered every other day for two weeks. Within 4 hours of the first dose, almost half of subjects had a spontaneous bowel movement (ie, without the use of a "rescue" laxative). Pain scores were not adversely affected, and there were no signs of opioid withdrawal. No serious adverse events attributable to MTX were seen.
Thomas J, et al. N Engl J Med. 2008;358:2332-2343.
Prucalopride for Severe Constipation
Chronic constipation sufferers have few FDA-approved therapeutic choices since the removal of tegaserod from the market due to CV toxicity. Mechanistically similar to tegaserod, prucalopride (PRU) is a 5-HT4 receptor agonist; dissimilar to tegaserod, PRU does NOT interact with receptors putatively associated with cardiovascular risk.
A double-blind trial of PRU in severe constipation randomized patients to 2-4 mg/d of oral PRU x 12 weeks or placebo (n=620). Entry criteria included having < 2 spontaneous bowel movements (SBM) per week; indeed, 75% of study subjects had < 1 bowel movement per week.
Thirty-one percent of PRU-treated subjects (2 mg dose) reported three or more SBM per week, vs 12% of the placebo group. Other problematic attributes of constipation (eg, straining at stool, consistency of SBM) were statistically improved also. Treatment was rated as quite-extremely effective in 33.3% of PRU 2 mg subjects (vs 17% placebo).
No serious adverse effects were seen. Diarrhea was seen in 13.5% of patients at the 2 mg dose (vs 5.3% placebo). PRU shows promise as a treatment for chronic severe constipation.
Camilleri M, et al. N Engl J Med. 2008;358:2344-2354.