MAR 2 3 1999
`
`J5/120 CllNiC,~L ,C,Cif:.,CES CENTER
`G~O HIGt&At.a t-'H-!A!HSON, W: 53792
`
`

`

`Supplement to
`THE JOURNAL OF
`
`AllergyA o Clinical
`Immunology
`A\\¥1
`
`UMBER 3, PART 2
`
`VOLUME 103
`
`PATHOPHVSIOLOGV AND PHA RMACOTHERAPY
`OF ALLERGIC RHINITIS
`
`Guest Editor
`Sheldon Spector, MD
`
`1/ESTON LIBRARY
`HAR 2 3 1999
`
`Supported by an educational grant from
`Wallace Laboratories, Division of Carter-Wallace, Inc.
`
`

`

`Supplement to
`THE JOURNAL OF
`
`Allergy AND Clinical
`Immunology
`~I
`
`NUMBER 3, PART 2
`
`VOLUME 103
`
`OFFICIAL JOURNAL OF THE AMERICAN ACADEMY OF ALLERGY, ASTHMA AND IMMUNOLOGY
`
`Pathophysiology and pharmacotherapy of allergic rhinitis
`
`Foreword
`Sheu/011 Specta1; MD Las Angeles, Calif
`
`Mediators of inflammation and the inflammatory process
`Martha White, MD V?irshingta11, D. C.
`
`Clinical manifestations of the release of histamine and other
`inflammatory mediators
`Robert Naclerio, MD Chicago, Ill.
`
`Ideal pharmacotherapy for allergic rhinitis
`Sheldon Spectm; MD Las A11geles, Calif
`
`Use of nasal steroids in managing allergic rhinitis
`Craig LaForce, MD Raleigh, N. C.
`
`Pros and cons of the use of antihistamines in managing
`allergic rhinitis
`James Day, MD Kingsto11, Ontario, Ct111ndt1
`
`Management of allergic rhinitis with a combination antihistamine/
`anti-inflammatory agent
`Phil Lieberma11, MD K,,oxville, Te1111.
`
`S377
`
`S378
`
`S382
`
`S386
`
`S388
`
`S395
`
`S400
`
`~'Y~ Mosby Copyright© 1999 by Mosby, Inc.
`
`Vol 103, No. 3, Pt. 2, March 1999. The Journal of Allergy and Clinical Immunology (ISSN 0091 -6749) is published monthly, except semimonthly in Janu(cid:173)
`ary (thirteen issues per year), by Mosby, Inc., 11830 Westline Industrial Dr., St. Louis, MO 63146-3318; phone I (800) 453-435 I or (314) 453-4351. Peri(cid:173)
`odicals postage paid at St. Louis, Mo., and additional mailing offices. Postmaster: Send change of address to The Journal of Allergy and Clinical Immunol(cid:173)
`ogy, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318. Annual subscription rates effective through September 30, 1999: domestic, $146.00 for indi(cid:173)
`viduals and $280.00 for institutions. Printed in the U.S.A. Copyright© 1999 by Mosby, Inc.
`
`J ALLERGY CLIN IMMUNOL
`
`March 1999 3A
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Ideal pharm acotherapy for allergic
`rhinitis
`
`Sheldon Spector, MD Los Angeles, Cal(f
`
`The chnracteristics of the "ideal" pharmacotherapeutic agent
`for managing the symptoms of seasonal allergic rhinitis and
`the advantages and disadvantages of the pharmacotherapeutic
`agents that are currently available arc reviewed. Deconges(cid:173)
`tants, mast cell stabilizers, anticholincrgics, intranasal steroids,
`and oral antihistamines and their place in the therapeutic
`armamentarium of the clinician are discussed. (J Allergy
`Clin Immunol 1999;103:S386-7)
`
`The ideal therapeutic agent for managing the symp(cid:173)
`toms of seasonal allergic rhinitis (SAR) would be one
`that effectively addresses the pathophysiology of both the
`early-phase reaction (EPR) and the late-phase reaction
`(LPR). This drug would antagonize histamine at the HI(cid:173)
`receptor sites of effector cells, managing the cardinal
`symptoms of SAR including nasal pruritus, sneezing, rhi(cid:173)
`noffhea, and nasal congestion. Because other chemical
`mediators are also released with mast cell degranulation,
`the ideal drug would have to counter these effects as well.
`The primary effect of these mediators is to recruit inflam(cid:173)
`matory cells from the nasal vasculature to the nasal
`mucosa, setting up the potential for an inflammatory
`reaction. These recruited inflammatory cells also release
`chemical mediators that contribute to non-HJ-mediated
`symptoms in LPR, particularly nasal congestion. The
`ideal drug would therefore inhibit mediator release from
`the mast cells with the subsequent effect of minimizing
`inflammatory cell recruitment, thereby reducing the
`potential for inflammation. So the ideal drug would not
`only treat the acute EPR symptoms of SAR but also
`affect the LPR by reducing inflammatory cell migration
`and the underlying process of inflammation.
`To manage the acute symptoms of SAR, the ideal drug
`would have to be fast-acting with first-dose effectiveness.
`To ensure patient compliance, the drug should only have
`to be taken when the patient has symptoms with a dosing
`schedule of once or twice daily. The ideal drug would
`effectively manage the specific symptom(s) that a patient
`is having, with few or no side effects. For patients with
`multiple symptoms the ideal drug would effectively man(cid:173)
`age all of the symptoms, eliminating the need for con(cid:173)
`comitant medication. The drug would have a favorable
`side effect profile, which would also assist patient com(cid:173)
`pliance. Delivering the drug directly to the nasal mucosa
`could minimize systemic effects and concentrate the drug
`where it could produce an optimal effect.
`
`From the UCLA School of Medicine.
`Reprint requests: Sheldon Srcctor, MD , California Allergy and Asthma.
`11645 Wil shire Blvd. Suite I 090, Los Angeles, CA 90025.
`Copyright <D 1999 by Mosby, Inc,
`0091-6749/99/$8,00 + 0 1/0/96502
`
`5386
`
`Abbn:l'iatio11s 11setl
`EPR: Early-phase reaction
`LPR: Late-phase reaction
`SAR: Seasonal allergic rhinitis
`
`CURRENTLY AVAILABLE AGENTS
`Decongestants (both the oral and topical formulations)
`constrict blood vessels and reduce blood supply to the
`nasal mucosa through a direct effect on a-adrenergic
`receptors. 1 Decongestants provide effective relief of
`nasal congestion but have minimal effects on the other
`symptoms of allergic rhinitis :rnd therefore would be
`effective therapy for a patient whose only symptom was
`nasal congestion . Topical decongestants have the disad(cid:173)
`vantage of predisposing the patient to rebound conges(cid:173)
`tion or rhinitis medicamentosa.2 Oral decongestants are
`associated with dose-related central nervous system
`stimulating and pressor effects that may not be appropri(cid:173)
`ate in some patients. 3
`Although the precise mechanism of action of mast cell
`stabilizers has yet to be determined, it is believed that cro(cid:173)
`molyn sodium inhibits the release of histamine and other
`mediators of inflammation by stabilizing mast cells.4 Cro(cid:173)
`molyn sodium is most effective when used in prophylac(cid:173)
`tic form for symptoms of allergic rhinitis; hence it must
`be started before the allergy season begins. Therefore the
`biggest disadvantage of cromolyn sodium is that the prod(cid:173)
`uct must be administered for several weeks before opti(cid:173)
`mal relief of symptoms is realized, and patients must use
`it regularly, usually 4 times daily, to obtain maximal ben(cid:173)
`efit.5 These '.2 requirements frequently present compliance
`challenges to patients and may result in missed doses and
`less-than-optimal clinical results. Also, the response to
`intranasal cromolyn sodium varies, and it is generally less
`effective in severe cases of allergic rhinitis.6 After 3
`weeks of treatment in patients with SAR7 and after 4
`weeks of treatment in patients with perennial allergic
`rhinitis, 8 intranasal corticosteroids demonstrated a superi(cid:173)
`or therapeutic effect compared with crornolyn sodium.
`Therefore supplemental therapy with other pharmacolog(cid:173)
`ic agents is usually necessary for an acceptable response
`to be achieved,3 especially in a patient in whom conges(cid:173)
`tion is a troublesome symptom.
`Anticholinergic drugs (eg, ipratropium) are drugs that
`competitively inhibit the effects of acetylcholine by
`blocking its binding to receptors at neuroeffector sites on
`glandular tissue, 9 resulting in a reduction in the volume
`of secretions from the nose.3 Ipratropium is not effective
`for the management of symptoms of rhinitis other than
`
`

`

`J ALLERGY CLIN IMMUNOL
`VOLUME 103, NUMBER 3, PART 2
`
`Spector S387
`
`rhinorrhea. 10 Therefore when a patient has rhinorrhea in
`the absence of other symptoms, ipratropium monothera(cid:173)
`PY is considered appropriate therapy. Likewise, ipratropi(cid:173)
`um is also effective in the management of the rhinorrhea
`component of the common cold_ I I
`Although intranasal steroids are considered effec(cid:173)
`tive drugs for managing allergic rhinitis, symptomatic
`response to intranasal steroids may not be evident for
`several days after therapy is initiated, and some patients
`may require a therapeutic trial of 2 to 3 weeks to deter(cid:173)
`mine whether the treatment is satisfactory. For treatment
`with intranasal steroids to be effective, they must be used
`on a regular basis to maintain optimal therapeutic effica(cid:173)
`cy.12 Despite the general consensus among clinicians that
`topically administered steroids are only minimally
`bioavailable, the safety of these drugs remains a concern,
`particularly in children and adolescents. Studies 13,l4
`demonstrated that serum and urinary cortisol levels were
`statistically significantly decreased by the short-term use
`(up to 14 days) of several intranasal steroids (fluticasone,
`beclomethasone, budesonide, and triamcinolone) in ther(cid:173)
`apeutit: dosages. In a recent 12-month, placebo-con(cid:173)
`trolled, double-blind study 15 of 100 children (aged 6 to 9
`years) who were receiving 168 µg beclomethasone twice
`daily, bone growth as measured by standing height was
`evaluated at 1-, 2-, 4-, 6-, 8-, I 0-, and 12-munth intervals.
`A significant (P < .05) decrease in bone growth was
`observed at the 1-, 6-, 8- and 12-month visits; however,
`the authors suggested that the clinical importance of
`these findings should be determined. Based on these and
`other findings, the Food and Drug Administration's Pul(cid:173)
`monary and Allergy Drugs and Endocrine and Metabolic
`Drugs Advisory Committees has recently considered the
`use of class labeling for inhaled and intranasal steroids
`regarding the issue of pediatric growth suppression.
`Oral antihistamines manage sneezing, nasal itching,
`and rhinorrhea associated with allergic rhinitis but are
`not as effective in relieving nasal obstruction. 6. I 6 It is
`estimated that only 33% to 50% of patients with SAR
`have no symptoms with antihistamine therapy, 17 suggest(cid:173)
`ing that mediators other than histamine contribute to
`symptom development. Leukotricnes, prostaglandins,
`and kinins are known to contribute to the development of
`nasal congestion, which may explain the lack of effec(cid:173)
`tiveness of antihistamines in managing congestion. 18
`Although antihistamines effectively manage the H 1-
`receptor-mediated symptoms of the EPR in patients with
`SAR, they have not been as effective in managing the
`symptoms of the LPR, particularly congestion, and the
`underlying inflammatory process of SAR. Therefore
`leukotriene antagonists (cg, zafirlukast, montelukast)
`used in combination with antihistamines may be appro(cid:173)
`priate therapy for patients with allergic rhinitis.
`
`CONCLUSION
`Optimal treatment of patients with SAR can be
`achieved only by managing both the EPR and LPR. The
`symptoms observed in EPR are most effectively man(cid:173)
`aged by an H 1-receptor antagonist, whereas the effects of
`LPR are best managed with a corticosteroid. Therefore
`the ideal pharmacologic therapy would be a drug that
`possessed not only H 1-receptor antagonist activity but
`also anti-inflammatory activity. In addition, this drug
`would have a favorable safety profile, would not have to
`be taken in prophylat:tic form, and would be fast-acting
`and convenient to administer.
`
`REFERENCES
`I, Philip G, Togias A . .\llergie rhinitis: today's approach tu treatment, J
`Respir· Di., 1995; 16:367-72.
`2. Dusha)' ME, Johnson CE. Management of allergic rhinitis: focus on
`intranasal agents. Pharmacotherapy I 989;9:338-50.
`.1 . Meltzer EO, Schatz M. Pharn1acothcrapy of rhinitis-1987 and beyond.
`lmmunol ,\llergy Clin Nor·th Am I 987;7:57-91 .
`4. Drucc HM. Kalincr MA. Allergic rhiniti,. JAMr\ 1988:259:260-3.
`5. Lieberman P. Rhiniti,: allergic and nonallergic. Ho,p Pract 1988;23: I 17-
`45.
`6. Nathan R,\. Changing ~lralcgic~ in the treatment of allergic rhinili:,,, Ann
`Allergy Asthma lmmunol 19%;77:255-9.
`7. Bjcrrum P, Jllum P. Treatment of seasonal allergic rhinitis with budes(cid:173)
`onide and disodium cromogi)'Cate, Allergy 1985;.Jll:65-9.
`8. Hillas J. Boolh RJ , Somcrlield S, Morton R, A\'ery J, Wilson JO. A com(cid:173)
`paratil'c trial of intranasal bcclomcthasonc dipropionatc and sodium cro(cid:173)
`moglycatc in patient:-. with chronic perennial rhinitis. Clin Allergy
`I 980; IU:253-8.
`9. Brown JH, TaylorP. Muscarinic Receptors. In: Hardman JG, Limbird LE.
`editors. Goodman and Gilman's The pharmacological ba.sis of therapeu(cid:173)
`tics. 9th ed. New York: McGraw-Hill: 1996. p. 141-60.
`I 0. Borum P. Intranasal ipratropium: inhibilion of mcthacholine induced
`hypcrsecrelion. Rhinology I 978: I 6:225-33.
`11 . Spector· RL. The common cold: current therapy and natural hi,lory. J
`Allergy Clin lmmunul 1995;95: 1133-8,
`12. Mygind N, Hansen I. Pedersen CB , Prytz S, Sorensen H. Intranasal
`beclomctha:-.onc dip10piu11atc aerosol in allergic na~al di:-.casc:-.. Postgrad
`Med J 1975;5 I (Suppl 4): I 07-10.
`13. Wilson AM. Mcfarlane LC, Lipworth BJ. Effects of repeated once daily
`dosing of three intrana~;,il corlicosteroitls on basal :ind dynamic mcasun.::)
`of hypothalamic-pituitary-adrenal a,is activity. J Allergy Clin lmmunol
`1998; IO I :4 70--1.
`14. Knutsson U, Sticrna P, Marcus C. Carbtedt-Duke J, Carlslrom K. Bron(cid:173)
`ncgard i\1. Effect~ of intranasal glucucrnticoid~ on endogenous glucocor(cid:173)
`ticoid peripheral and central funcLion. J Endocrinol I 995; 144:301-10.
`15. Rachelefsky GS. Chcrl'insky P, Meltzer EO. Morris RM. Seltzer JM.
`Skoncr DP, ct al. ,\n c1•aluation of the effects of beclomethasonc dipropi(cid:173)
`onalc aqueous na, al spray [VanccnasL, AQ (\INS)] on long-tcr1n g1owth
`in children [abstract]. J Allergy Clin lmmunol 1998; I Ill :S236.
`16 Naclerio R, Solomon W. Rhinitis and inhalant allergens. Ji\MA 1997;
`278: 1842-8.
`17. Bousquet J, Chanez P. Michel FB. Pathophysiology and treatment of sea(cid:173)
`sonal allergic rhiniti,. Rcspir Med I 990;84(Suppl A): 11 -7.
`18. Naclerio R~I. Allergic rhinitis. N Engl J Mcd 1991 ;325:860-9.
`
`