Review of nasal therapy: Update

THE JOURNAL

OF

ALLERGY AND

CLtRttCAL VOLUME

NUMBER

72

The John Sheldon Review

Memorial

of nasal therapy:

Philip S. Norman,

LOGY

lMlUt~

5,

PART 1

Lecture

Update

M.D. Baltimore, Md.

The nasal mucosa can react in only one way to a variety of stimuli, i.e., with hyperemia, swelling, and hypersecretion. For that reason, there is little about the appearance of the mucosa in rhinitis to provide a clue as to the cause of the condition. Although we tend to divide rhinitis into allergic and nonallergic rhinitis arbitrarily, in most people it is unlikely to be all one or the other. Many clinicians have observed that patients with undoubted allergy problems affecting the nose react more strongly than normal people to a variety of nonspecific stimuli such as cooking odors, smokes, perfumes, chemicals,. newsprint, and the like. On the other hand, a number of people have chronically malfunctioning noses, with evidence from history, skin tests, or IgE studies of no more than minor specific allergy. At the extreme, the most thorough investigation fails to reveal any evidence of allergic problems. Whether we call such a condition chronic, nonallergic rhinitis or vasomotor rhinitis makes little difference; treatment by specific measures for allergic rhinitis, such as immunotherapy, is unlikely to be helpful. On the other hand, there is a plentiful armamentarium of drugs that may be helpful , although unlikely to be curative. From the Clinical Immunology Division, Department of Medicine, The Johns Hopkins University School of Medicine and The Good Samaritan Hospital, Baltimore, Md. Supported by N.I.H. grants AI-04866 and AI-10304. Presented at the Postgraduate Course in Allergy and Clinical Immunology at the meeting of the American Academy of Allergy and Immunology, Hollywood, Fla., March 1983. Reprint requests: Philip S. Norman, M.D., Clinical Immunology Division, The Good Samaritan Hospital, 5601 Loch Raven Blvd., Baltimore, MD 21239.

Our understanding of the pathophysiology of allergic nasal disease has improved greatly in recent years and warrants a review because it helps our understanding of the goals of therapy. Although there has been extensive indirect evidence to indicate that allergic reactions in the nose initially involve rapid release of mast cell mediators in the mucosa, only recently has there been definitive evidence in humans that mediators actually are released during an allergic reaction. A brief review will help to set the stage for therapeutic discussion. After laboratory challenges with grass and ragweed pollens or extracts in sensitive people, Naclerio et al. 1-s find that clinical symptoms correlate with rapid increases in mediators in nasal secretions, including histamine, PGD,, kinins, leukotrienes, and an enzyme detectable by its ability to hydrolyze the synthetic substrate TAME. These are mast cell mediators except for kinin, which is the product of a mast cell mediator. Fig. 1 shows the result of unilateral nasal challenge with increasing concentrations of grass pollen extract, taking nasal washings within minutes of each challenge. As the strength of the challenge rises, nasal airway conductance on the challenged side declines, symptoms as indicated by the number of sneezes increase, and concentrations of histamine, TAME-esterase activity, and PGDZ all increase. When the challenge is discontinued, mediator concentrations decline rapidly. Fig. 2 compares the responses of eight allergic individuals given challenges sufficient to initiate sneezing and eight nonallergic individuals given similar challenges and shows the rises in mediator concentration that occur in the allergic subjects. When a late reaction occurs 6 hr or more later, preliminary evidence sug421

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J. ALLERGY CLIN. IMMUNOL NOVEMBER 1983

Norman

ADhre~~itrtiorrs

u.wd

Prostaglandin D, Tosyl arginine methyl ester

PGD,:

TAME.:

1

gests that there is a reappearance of at least some of these mediators. Future work is to be directed toward the possibility that reactions to physical stimuli such as cold air involve the release of mediators. Drug therapy as currently employed is directed toward either prevention of mediator release or counteracting mediators once they are released. Some drugs may do both. The following list shows our current notions. Drugs

thtrt

unmtcrcicl

meditrtor

trcTion

Antihistamines Anticholinergics Sympathomimetics Theophyllines Corticosteroids Cromolyn? Drugs

thut

inhibit

meditrtor

releuse

Some antihistamines Sympathomimetics Theophyllines Corticosteroids Cromolyn The appearance of most drugs on both lists shows that our understanding of drug action is constantly broadening through the collection of new information. Sympathomimetics and theophyllines are listed as drugs that inhibit mediator release as a result of in vitro work which shows that these drugs raise levels of intracellular cyclic AMP and thus inhibit mediator release :’ Cromolyn is incompletely understood. Although it inhibits mediator release, it appears on both lists because it acts in several cellular systems but in others it does not. At the same time, it has effects on phosphodiesterase that may mimic those of theophyllines, raising the possibility of a dual action.,i It may be surprising to find antihistamines and steroids on a list of drugs that inhibit mediator release. Several antihistamines, however, inhibit mediator release in in vitro systems,5 and Naclerio has recently shown that one of them also inhibits mediator release in vivo (personal communication). Fig. 3 shows the result of topical medication with azatadine, a tricyclic antihistamine that inhibits mediator release from basophils and mast cells, in which both symptoms of sneezing and appearance of TAME-esterase are inhibited after the drug is applied. On day 1 with no medication, serial challenges result in similar amounts of sneezing and

TAME-esterase release in secretions. On day 2. the level of reactivity is redetermined and then application of azatadine before the second and final challenge prevents sneezing and mediator release. Similar results have been obtained with cromolyn. The efficacy of steroids in alleviating allergic reactions characterized as immediate has never been explained. At this point, I would like to mention experiments done by Schleimer and associates”* 7 in our laboratory that go a long way toward explaining the effect of steroids in allergic reactions. It is well known that steroids do not alter immediate wheal and erythema skin reactions nor, as usually tested in vitro, the release of histamine from basophils or mast cells. Dr. Schleimer, however, had the clever idea of incubating the steroid with a suspension of basophils for 24 hr to allow the drug to act on the cells before he exposed them to an antigen. By this method, as shown in Fig. 4, he found that a variety of steroids given at concentrations similar to those found in the body effectively inhibited histamine release. In addition, he showed that the potencies of the drugs in vitro were directly related to their potencies in inhibiting inflammatory reactions in vivo6 (Fig. 5). Human lung mast cells, however, continue to release histamine after incubation with steroids.’ As the role of basophils in allergic reactions is still poorly understood, this work may open some ways to elucidate the role of this cell type in allergic reactions more completely. Although I plan to discuss the practical use of steroids in rhinitis, to open a discussion of management, the first consideration when rhinitis is demonstrably allergic is to avoid the allergen either by removing the source or, if that is not possible, by lowering exposure by cleaning the air locally in the home or office. When the condition is not demonstrably allergic or only partly allergic, the pathogenesis of the rhinitis (which is often perennial) is poorly understood but still may be treated by the same drugs that alleviate allergic symptoms. Drug treatment by antihistamines or decongestants is too well known to need discussion in detail, but it is clearly often unsatisfactory to patients because of side effects. The dangers of excessive use of topical decongestants are also well known. The introduction in the fall of 198 1 of two new steroid drugs that can be sprayed into the nose with essentially no systemic side effects has noticeably improved the safe control of allergic nasal symptoms. The currently available nasal steroids, their formulation, and recommended doses are as follows: (Turbinaire; Merck. Sharp & Dohme, Rahway. N.J.): Freon propelled, 100 pgispray, four spraysthree times a day. total dose 1200 pgiday

Dexamethasone

Beclomethasone (Vancenase; Schering Corp.. Kenilworth, N.J.. Beconase; Glaxo Inc., Ft. Lauderdale,

VOLUME 72 NUMBER 5. PART 1

Nasal

ALLERGIC

FIG. 1. Experimental lenges

and

INDIVIDUAL-RIGHT

NOSTRIL

protocol of a nasal washes; NAV. nasal

nasal

CHALLENGED

challenge conductance.

WITH

of an allergic

MIXED

GRASS EXTRACT

individual.

Arrows,

22

-I

20 1

9

I8 .

16

4

423

chal-

. . -

11

67 IO i 6 5

Nasal

update

.. .

IO

6

therapy:

14 20 i

.

I2

.

‘O

.

6

l

7

3

-

6

4

. .

2. 01

A

N NO.Of

SNEEZES

A

N

KININS (dpglml)

- ..

A HISTAMINE ( A pglml)

N

TAME-eskrase (Acpm xIO*~)

A= ALLERGIC N= NON-ALLERGIC FIG. 2. Comparison of sneezing and mediator release in 10 matched allergic (A) and nonallergic (N) subjects. (Only nine values for histamine.) Dots are located at the number of sneezes or the maximum concentration of each mediator in nasal washes after challenge.Lines indicate means. (From Naclerio RM et al: Am Rev Respir Dis, submitted for publication.)

Fla.): Freon propelled, 42 pgispray, two spraystwo to four times a day, total dose 168/336 pglday Flunisolide (Nasalide; Syntex Lab., Inc., Palo Alto, Calif.): metered liquid spray, 25 pg/spray, two times a day, total dose 200 pg/day

four sprays

A comparison of the action of these three drugs and their side effects in treating seasonal and perennial allergic rhinitis should begin with dexamethasone, which appeared for prescription use in 1968. In the middle 1960s (Fig. 6), we studied two matched

424

J. ALLERGY CLIN. IMMUNOL. NOVEMBER 1983

Norman

Effects of Topical Atatadine

n wlthdruQ

I6

Cl withoutdruq

I4

n=7

1

T I23 DayI

I23

I

Day 2

Day2

FIG. 3. Effects of azatadine on nasal challenge. Three serial of 2 days. On the second day, azatadine was administered and responses to the next two challenges were inhibited.

0

I

IO-'0 FIG. 4. Inhibition of IgE-dependent presence of steroid. (From Schleimer

I

10-S

challenges intranasally

1

10-e

basophil histamine release after RP et al: J lmmunol 129:1632,

groups of ragweed hay fever patients who kept symptom diaries during the ragweed hay fever season, rating the severity of their symptoms. We plotted the mean symptom index for each group each day along with that day’s ragweed pollen count. We began treating group I with dexamethasone nasal spray and group II with a placebo. The patients receiving the nasal spray almost immediately did somewhat better

were after

performed the first

1

10-T 24 hr culture 1982.)

on each challenge,

I

10-6 of cells

in the

than the patients on placebo. In the middle of the study, unbeknownst to the patients, we reversed the drugs, so that the formerly treated group I patients began receiving placebo and the former placebo patients in group II began receiving dexamethasone. After 2 more wk; treatment was stopped altogether; the index of symptoms in the two groups began to converge. The difference between the treated and un-

VOLUME 72 NUMBER 5, PART 1

Nasal

Betomethosone

9aFluorocortrsone

FIG. 6. Correlation activity of the same RP et al: J lmmunol

RELATIVE

daily symptom intranasally,

I IO

I 100

TO HYDROCORTISONE

IN VITRQ

steroids as antiinflammatory drugs in vivo and of basophil histamine release. (From Schleimer

PERIOD 2

AugUd FIG. 6. Average sone, 1.2 mglday 36:284, 1965.)

l

Prednisolone

I I

of the activity of several drugs in vitro as inhibitors 129:1632, 1982.)

PERIOD 1

425

Hydrocortisone

l

POTENCY

update

l

l

0.1 c 0.1

therapy:

PERIOD 3

September scores of ragweed-sensitive or placebo. (From Norman

treated groups was highly significant and demonstmted that dexamethasone could inhibit the symptoms of seasonal hay fever.8 The drawback with inhaling dexamethasone was that in most patients it partially inhibited adrenal

patients while PS, Winkenwerder

using dexamethaWL: J ALLERGV

function while it was being used. Excretion of endogenous steroid in the urine was reduced in our study (Fig. 7), and this has led to care in the use of dexamethasone for more than several months at a time.” Our studies indicated that about one third of a nasally

426

J. ALLERGY CLIN. IMMUNOL. NOVEMBER 1983

Norman

+3 +2 +I

0 0 A 0 . * .

0 -I -2 -3

D.B. H.F. D.H. D.W. P.M. EM. RR.

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, , , , , ,, , , ,, ,I (( 21

SEPTEMBER

31

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20

OCTOBER

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17-hydroxycorticoids aerosols intranasally. 40:57,

1968.)

applied dexamethasone dose is absorbed systemically and is active metabolically. This represents about one half the usual 0.75 mg oral tablet. Systemic absorption seems to be insufficient to account for the local therapeutic effect. Although dexamethasone is quite safe to use for brief seasonal periods, it never caught on for treatment of chronic rhinitis. Beclomethasone, first used to treat asthma, was tested extensively in Europe for rhinitis also. An early study by Chatterjee et al.‘” indicated that both intranasal beclomethasone and intranasal cromolyn were effective in suppressing grass hay fever symptoms as the pollen count rose. Beclomethasone, however, appeared to be somewhat the better (Fig. 8). The finding that beclomethasone could successfully treat seasonal rhinitis led to studies to explore safety by determining the lowest dose that would cause adrenal suppression. Assessment of morning plasma cortisol concentrations shows that a total daily dose of 1 mg shows no evidence of suppression of adrenal function (Fig. 9). Morning cortisols are depressed only after doses of 4 mg or greater-10 to 12 times the recommended dose of 300 to 400 pg-and even then suppression is less than complete.” Such findings led to an interest in the use of beclomethasone for chronic rhinitis. A study by Tar10 et a1.12 was conducted similarly to our early dexamethasone trial but with measurement of nasal airway resistance (Fig. 10). Before treatment began, mean baseline values were about 5 for one group and 6 for the other. Then one group was placed on beclomethasone therapy and the other group on placebo. After 3 wk there was a crossover: the placebo group switched to beclomethasone, and the treated group received placebo. Within about 5 days, the nasal airway resistance crossed over as well-the former treated group

was getting worse, and the former placebo group was improving. Beclomethasone may also be used in patients who have chronic rhinitis with nasal polyposis. In a study by Mygind et al. “’ in Denmark (Fig. 11). within a few days after starting treatment with beclomethasone, the patients have a rather dramatic decline in their symptoms. The other drug first offered in 1981 is flunisolide. Like beclomethasone, it can be recommended for both seasonal and chronic rhinitis. It may also be useful in patients with nasal polyps. Flunisolide is not dispensed in the Freon-propelled canisters we are accustomed to for respiratory tract drugs. which spray a micronized powder into the nose. Rather. it comes in a propylene glycol solution, which is sprayed into the nose by a mechanical pump. Presumably, this liquid vehicle allows the drug to spread through the nasal mucosa successfully and is useful in patients whose rhinitis includes complaints of dryness and crusting of the nasal mucosa. In 1974, Turkeltaub”’ carried out a controlled trial of flunisolide in our clinic in two matched groups of patients with seasonal rhinitis (Fig. 12). In the group that received flunisolide, symptoms were markedly reduced and stayed low for as long as the drug was administered, whereas in matched patients receiving the propylene glycol vehicle, symptoms rose and fell with the ragweed pollen count. Complaints of adverse effects were actually higher in the vehicle-treated group (Table I). Occasional side effects of flunisolide were nasal dryness and unpleasant residual taste. sore throat, and sneezing. In terms of the major adverse effect of adrenal suppression, there was no evidence that morning plasma cortisol levels dropped in patients who were receiving the recommended doses of topical flunisolide for seasonal rhinitis’* (Fig. 13). This drug is also effective in chronic rhinitis. Again, a study of two matched groups of patients in our clinic showed that flunisolide treatment for 12 wk caused greater improvement in symptoms than vehicle treatment (Fig. 14), and treatment for this period did not suppress adrenal function. In our study and others, results are better in patients who have evidence of allergy, as indicated by positive skin tests’;’ (Fig. 15). Continuing treatment with flunisolide in an open trial was offered to those patients who considered it beneficial. These patients were allowed to vary the dose of flunisolide according to their perception of need (Table II). Only six of 22 patients felt the need to continue the originally recommended daily dose of 300 pg. One of these occasionally would increase to

VOLUME72 NUMBER 5,PARTl

Nasal

‘191

20I

21I

22I

23II

24

25I

26II

27

28II

29

30I

2p

pollen count beclomethasone

III

update

427

2

July

Jllllt? FIG. 8. Grass open circles,

therapy:

and

mean nasal dipropionate.

symptom scores. (From Chatterjee

Triangles, Sodium cromoglycate; SS et al: Clin Allergy4:343, 1974.)

~,l,~,11~11~1,,,,,,,1,,1111111111111111111111l111~

-6-4-2 0 2 4 6 6 IO 12 14 6 16 202224262630323436364042 -5 -3 -I I 3 5 7 9 II I3 15 I7 I9 21 23 25 27 29 31 33 % 37

39

41 43

Time (days)

Ooee of beclomethaeone FIG. 9. The administration

9:00

A.M. plasma cotiisol concentration of beclomethasone dipropionate.

400 @g/day when more than usually symptomatic. The most frequently employed dose was 200 pg/day, but several patients thought their symptoms were relieved with less, and one patient used only 50 pg (i.e., one spray in each nostril) two or three times a

diwo0ionate

6~

-

in four healthy male subjects after (From Harris DM et al: Clin Allergy4:291,

6 ma intranasal 1974.)

week. Plasma cortisols tested every 6 mo over 2 yr remained normal in all 22 patients.‘” At the final examination in 15 patients who continued flunisolide therapy for 5 yr, the nasal mucosa was considered normal in 10. There were nasal

428

J. ALLERGY CLIN. IMMUNOL. NOVEMBER 1983

Norman

CONTROL

FIG. 10. Mean weekly patients. (From Tarlo

PERIOD 1

PERIOD 2

value for nasal airway resistance NAIR ,,.&cm H,O/L/sec) SM et al: J ALLERGY CLIN IMMUNOL 59:232, 1977.)

in two

groups

of

I-

I-

a-

l Period

of treatment

#

i

I

I

I

I

L

I

5

IO

I5

20

1

25

Days FIG. 11. Average daily symptom polyposis. Open circle, Beclomethasone Clin Allergy 5: 159, 1975.)

scores

from 31 dipropionate:

mucosal edema and slight redness in four. One other patient had only mucosal redness. No evidence of mucosal atrophy was found in any of the patients.16 Although some of topically applied flunisolide and beclomethasone is absorbed systemically, in recommended doses they induce no adrenal suppression, presumably because of rapid metabolism. Although

patients triangle,

with moderate placebo. (From

to severe nasal Mygind N et al:

adrenal suppression can be observed if the dose is raised high enough, in individuals who do not respond to recommended doses, it is appropriate to use a larger dose because any adrenal suppression will still be less than that occasioned by an equally effective dose of systemic steroid. Side effects are mainly transient nasal burning and

Nasal

VOLUME 72 NUMBER 5, PART 1

PRE-TREATMENT

TREATMENT

PERKID

PERIOD

POST-TREATMENT

therapy:

update

429

PERIOD

Flunisolrde Study 1974

! .,_- --\,,,---\ I2

16

20’ 24 AUGUST

FIG. 12. Average daily count. (From Turkeltaub

I1 28

l

’

5

IT 8

I

I

I

I

IO

15

20

25

During Parid

Control Vehicle king Traatmnt Period

Plasma Cortisol Level Post Treatment Average (ug/ml) RG. 13. Average plasma cortisol levels obtained before and after 3 wk of aerosol treatment. (From Turkeltaub PC et al: J ALLERGY CLIN IMMUNOL 58:597, 1976.)

occasionally drying of the mucosa to the point where crusting and bleeding may occur. The liquid vehicle of flunisolide may be better in the latter regard. Long-term local side effects are rare, and mucosal atrophy has not been observed in patients who have used topical steriod for up to 5 yr. Cromolyn sodium, as a 4% solution for nasal use, has been extensively tried for allergic rhinitis and inhibits the physiologic effects of nasal allergen challengel and the symptoms of seasonal rhinitis.@ It has only recently been licensed for use in the United States, although it has been in use in Europe and Canada for some time. Although it has been described as extremely effective in inhibiting both the early and

----

Pollen Count

, 24

I 28

VI

I 8 4 OCTOBER

group and the 58:597, 1976.)

daily

ragweed

\__\

1 1 I2 I6 20 SEPTEMBER

symptom scores of each treatment PC et al: J ALLERGY CLIN IMMUNOL

A Flursahdr Treatment

G 0 1”

I 4

Flunrsolrde

:

6-

E

420

PRE TREATMENT

1

l-2

I 3-4

pollen

I 1 I 7-8 s-to 5-6 WEEKS OF THERAW

1 II-12

FIG. 14. Average daily symptom score for patients receiving treatment for perennial rhinitis. (From Turkeltaub PC et al: Allergy 37:303, 1982.)

late physiologic responses to nasal challenge (more so than topical steroid),“, I9 one clinical trial has suggested that cromolyn is less effective than beclomethasone in seasonal rhinitis10 (Fig. 8). Although topical steroids are useful in only some cases of perennial rhinitis and nasal polyposis, it is not possible to predict accurately which patients will improve. When there are several positive skin tests to common allergens, a successful result is more likely than when skin tests show no response. Nevertheless, topical steroids are worth a trial in cases of perennial rhinitis without positive skin tests. It is important to tell patients given these agents for the first time that they will not experience immediate

430

J. ALLERGY CLIN. IMMUNOL. NOVEMBER 1983

Norman SKIN TEST NEGATIVE PATIENTS

FLUNISOLIDE . a VEHICLE 0 6

FIG. 15. Average daily symptoms scores for each perennial reactivity during the 2 wk pretreatment and end of treatment bars, Mean score of the group of patients in each vertical Allergy 37:303, 1982.)

TABLE and

I. Adverse

effects

of

intranasal

TABLE

flunisolide

placebo

on Flunisolide

Nasal irritation Nasal dryness Sore throat Sneezing Unpleasant residual taste Dry mouth Stomatitis Total From

Turkeltaub

IMMUNOL

PC,

Norman

2 2 I 1 2

8 PS, Crepea

rhinitis patient, based on skin test (wk 11 and 12) period. Horizontal column. (From Turkeltaub PC et al:

II. Perennial

Patients

10 1

Dose b.4

2

50 100 200 300 >300

S: .I ALLERGY

2 to

5 yr follow-up

flunisolide

Placebo

a0

1 1 10

rhinitis,

receiving

each

dose

No. of patients

1 2 1 10 5 1

CLIN

58:597. 1976.

relief of nasal obstruction such as they may be accustomed to with local decongestants. Symptomatic relief may require as long as 2 wk, and continuing trial for that long is indicated before the drug is abandoned. The early side effect of transient nasal burning may be unpleasant when the drug is first applied to an inflamed nasal mucosa. This effect often lessens as the mucosa normalizes with continued use. Although thesedrugs will often help symptoms of nasal obstruction in patients with nasal polyps and make the polyps shrink, sometimes even disappear, the polyps tend to recur when the steroid is discon-

tinued. At times the nasal obstruction is so severe as to compromise the penetration of the drug. It may be possible to treat with oral steroid in sufficient dose to shrink the polyps and then change over to local steroid while tapering the systemic dose. Even though the patient may eventually require a polypectomy, any reduction in size makes the operation easier, and continued local steroid after a polypectomy may prevent or slow recurrence of the polyps. It is often asked how to manage the many patients who simultaneously have asthma and nasal disease. If we give orally inhaled beclomethasone to treat the

VOLUME 72 NUMBER 5. PART 1

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431

Odminisrrotion

concentration in five dipropionate daily doses of beclomethasone

asthma, can we add intranasal beclomethasone or flunisolide to treat the nasal symptoms? Won’t the two drugs have additive effects on adrenal function? Fig. 16 shows study patients given 1 mg/day orally inhaled beclomethasone. When 1 mg/day nasal beclomethasone (three times the recommended dose) was given, plasma cortisols were not suppressed, and only when the total dose of topical steroid was raised to 3 mg/day was a mild reduction in morning cortisol observed. ” A similar study by Toogood et al. ,20 in which nasal flunisolide and orally inhaled beclomethasone were given together, again showed no adrenal suppression. Furthermore, during pregnancy, beclomethasone or flunisolide is probably the safest drug that can be used to treat rhinitis. They appear to have a greater margin of safety in terms of fetal health than antihistamines or decongestant drugs. The question most frequently raised by nonallergists is: Will these drugs replace desensitization treatment? In patients with simple seasonal rhinitis, they allow adequate treatment of many people who have not sought professional help because of the fear of the inconvenience and expense of multiple injections. In patients who have multiple allergies with prolonged symptoms, desensitization still has an important place, since many patients eventually get tired of medicating themselves daily and want to consider injections. Actually, the actions of intranasal steroids

update

(days)

Doily dase by mm-nosol FIG. 16. The 9:00 A.M. plasma cortisol inhalation of 1 mg of beclomethasone tranasal administration of increasing et al: Clin Allergy 4:291, 1974.)

therapy:

healthy male subjects after the oral together with the simultaneous indipropionate. (From Harris DM

and desensitization injections may well be additive, and it appears appropriate, particularly in severely affected patients, to use both.

REFERENCES 1. Naclerio RM, Meier HL, Adkinson NF Jr, Kagey-Sobotka A, Meyers DA, Norman PS, Lichtenstein LM: In vivo demonstration of inflammatory mediator release following nasal challenge with antigen. Eur J Respir Dis 64r26, 1983. 2. Naclerio RM, Meier HL, Kagey-Sobotka A, Adkinson NF Jr, Meyers DA, Norman PS, Lichtenstein LM: Mediator release after nasal airway challenge with allergen. Am Rev Respir Dis (in press). 3. Proud D, Togias A, Naclerio RM, Crush SA, Norman PS, Lichtenstein LM: Kinins are generated in vivo following nasal airway challenge of allergic individuals with allergen. J Clin Invest (in press). 4. Lichtenstein LM, DeBemardo R: The immediate allergic response: in vitro action of cyclic AMP-active and other drugs on the two stages of histamine release. J Immunol lCn:ll31, 1971. 5. Johansson AG: Specific inhibitors of mediator release and their modes of action. In Bach MK, editor: Immediate hypersensitivity: modem concepts and developments. New York, 1978, Marcel Dekker, Inc., pp. 533560. 6. Schleimer RP, Ma&la&an DW Jr, Gillespie E, Lichtenstein LM: Inhibition of basophil histamine release by antiinflammatory steroids. II. Studies on the mechanism of action. J Immuno1 129:1632, 1982. 7. Schleimer RP, Schuhnan ES, MacClashan DW Jr, Peters SP, Adams GK III, Lichtenstein LM, Adkinson NF Jr: Effects of dexamethasone on mediator release from human lung frag-

432

J. ALLERGY CLIN. IMMUNOL. NOVEMBER 1983

Norman

ments

and purified

human

lung mast cells.

J Clin

Invest

71:

1830, 1983. 8. Norman PS, Winkenwerder WL: Suppression of hay fever symptoms with intranasal dexamethasone aerosol. J ALLERGY

36:284. 1965. 9. Norman PS. Winkenwerder

WL. Agbayani BF, Migeon CJ: Adrenal function during the use of dexamethasone aerosols in the treatment of ragweed hay fever. J ALLERGY 40~57, 1967. 10. Chatteqee SS, Nassar WY, Wilson 0. Butler AC: Intra-nasal beclomethasone dipropionate and intra-nasal sodium cromoglycate: a comparative trial. Clin Allergy 4:343, 1974. Il. Harris DM. Martin LE. Harrison C, Jack D: The effect of intra-nasal heclomethasone dipropionate on adrenal function. Clin Allergy 4:291. 1974. 12. Tarlo SM. Cockcroft DW. Dolovich J, Hargreave FE: Beclomethasone dipropionate aerosol in perennial rhinitis. J ALLERGY CLIN

IMMUNOL

59:232. 1977.

13. Mygind

N. Brahe Pedersen C. Prytz S, Sdrensen H: Treatment of nasal polyps with intranasal heclomethasone dipropionate aerosol. Clin Allergy 5:159. 1975. 14. Turkeltaub PC. Norman PS, Crepea S: Treatment of ragweed hay fever with an intranasal spray containing flunisolide: a new synthetic corticosteroid. J ALLERGY CLIN IMMUNOL S&597. 1976.

Bound

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15. Turkehaub PC, Norman PS. Johnson JD. Crepea S: Treatment of seasonal and perennial rhinitis with intranasal flunisolidc. Allergy 37:303, 1982. 16. Norman P.S. Turkeltaub PC: Long-term treatment of perennial rhinitis with intranasal flunisolide spray. In Rhinitis-topical pharmacotherapy. Oxford. 1983. The Medicine Publishing Foundation, pp. 35-40. 17. Pelikan Z, Peiikan-Filipek M: The effects of disodium cromoglycate and heclomethasone dipropionate on the immediate response of the nasal mucosa to allergen challenge. Ann Allergy 49:283. 1982. 18. Cohan RH. Bloom FL, Rhoades RB. Wittig HJ, Haugh LD: Treatment of perennial allergic rhinitis with cromolyn sodium. J ALLERGY CLIN IMMUNOL 58:121, 1976. 19. Pelikan Z: The effects of disodium cromoglycate and beclomethasone dipropionate on the late nasal mucosa response to allergen challenge. Ann Allergy 49200. 1982. 20. Toogood JH. Jennings B. Crepea SB, Johnson JD: Efficacy and safety of concurrent use of intranasal flunisolide and oral beclomethasone aerosols in treatment of asthmatics with rhinitis. Clin Allergy 12:95. 1982.

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IMMUNOLOGY

are available

to subscribers (only) for the 1983 issues from the Publisher, at a cost of $47.50 ($57.10 international) for Vol. 71 (January-June) and Vol. 72 (July-December). Shipping charges are included. Each bound volume contains a subject and author index, and all advertising is removed. Copies are shipped within 30 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact Mr. Deans Lynch at The

C. V. Mosby Co., 11830 Westline Industrial Dr., St. Louis. MO. 63146. Subscriptions must be in force to qualify. a regular journal subscription.

Bound volumes are not available

in place of