VOLUME 8 1 NUMBER 4 Allergic bronchopulnlonary ;+spe:gillosis I C, Peters MS, Schrolter AL, Kephart GM, Gleich GJ. Localiza- tion of eosinophil major basic protein in chronic urticaria. J invest Dermatol 1983;81:39-43. 16. Kurup VP, Ting EY. Fink IN. Immunochemical characteriza- tion of Aspergillus antigens. Infect Immun 1983;41:698-701. 17. Husu SM, Raine L. The use of avidin-biotin-peroxidase com- plex (ABC) in diagnosis and research pathology. In: De Lellis RA. ed. Advances in immunohistochemistry. New York: Mas- son Publishing, 1984:31-42. 18. Knutsen AL, Tsai CC. Graft-versus-host like illness in a child with phenobarbital hypersensitivity. Pediatrics 1986;78:4. 19. Bedrossian CWM, Greenberg SD, Singer D, Jensen J, Ro- senberg H. The lung in cystic fibrosis of the pancreas. Hum Pathol 1976;7: 195-204. 20. Frigas E, Loegering DA, Solley GO, Farrow FM, Gleich GJ. Elevated levels of eosinophil granule major basic protein in the sputum of patients with bronchial ahlhm;i \4:.vo c’hrr Proc 1981;56:345-53. 21. Davis WB, Fells GA. Sun X-H, Gadek JE, ;\‘i?:er A. (:lystal RG. Eosinophil-mediated injury to lung parenchymal ceils and interstitial matrix: a possible role for eobinoph:ls in chronic inflammatory disorders of the lower respirac!)r: ITI~‘I 1 i‘lin Invest 1984:74:269. 22. Slavin RG, Hutcheson PS, Knutsen AP. Participation oi cell- mediated immunity in allergic bronchopulmonarb aspergll- losis. Int Arch Allergy Appl lmmunol 1987;tii ,137~11 23. Leatherman VW. Michael AF, Schwartz BA. Helldai JR Lung T cells in hypersensitivity pneumot&L, ;\:t:. Intern Mcd 1984; 100:390-92. 24. Hunninghake GW, Crystal RG. Pulmonary sarco~oos;s.a dis- order mediated by excess helper T-lymphocyte xtivtty II sites of disease activity. N Engl J Med 19X1:30’;:4;:+-7~~ Double-blind placebo-contrakd study of loratadine, mequitazine, and placebo in the symptomatic treatment of seasonal allergic rhinitis W. Skassa-Brociek, MD,* J. Bousquet, MD,* F. Mantes,* M. Verdier,* D. Schwab,** M . Lherminier,** and F.-B * Michel, MD * I Montpellier and Levallois-Perret, France Loratadine is a long-acting H, antagonist devoid of anticholinergic and sedative effects. A double-blind, placebo-controlled, parallel-group study was performed in 69 patients to compure efJicacy and safety of loratadine and mequitazine. Patients allergic to grass pollens were randomly assigned to one of the three treatment groups and followed up to 2 weeks during the peak of the pollen season. Symptoms of allergic rhinitis were evaluated at baseline and after 3, 7, and 14 days of treatment by the physician with patients rating their response daily on diaq cards. Both loratadine and mequitazine induced a significant relief of nasal symptoms when these were compared to placebo. Loratadine was found to be signijicantly superior to placebo qfter 3 days of treatment, whereas a significant improvement was only observed after 7 days in patients treated with mequitazine. For nonnasal symptoms, none of the two anti-H, antagonist induced a significant improvement, and this lack of effect may be related to low symptoms at baseline. Loratadine did not induce more side effects than placebo. Loratadine can be considered to be an effective and safe anti H, histamine with a rapid onset of action. (J AUEKW CLIN IMMUNOL 1988;81:725-30.) From the *Clinique des Maladies Respiratires, Hopital l’Algue- longue, Montpellier, and **Laboratoires Unicet, Levallois Per- ret, France. Received for publication April 13, 1987. Accepted for publication Oct. 24, 1987. Reprint requests: J. Bousquet, MD, Clinique des Maladies Res- piratires, Hopital 1’Aiguelongue, 34059 Montpellier Cedex, France. Pollen-induced allergic rhinitis is a very common disease. Anti-H, -receptor antagonists relieve nasal and ocular symptoms, but most available drugs induce side effects, such as drowsiness and seda- tion, and have variable anticholinergic activities. I’ ’ Newer compounds, such as astemizole,” terfenadine,4 and mequitazine, ‘. ’ have been found to be de- 725
Transcript
VOLUME 8 1 NUMBER 4
Allergic bronchopulnlonary ;+spe:gillosis
I C, Peters MS, Schrolter AL, Kephart GM, Gleich GJ. Localiza- tion of eosinophil major basic protein in chronic urticaria. J invest Dermatol 1983;81:39-43.
16. Kurup VP, Ting EY. Fink IN. Immunochemical characteriza- tion of Aspergillus antigens. Infect Immun 1983;41:698-701.
17. Husu SM, Raine L. The use of avidin-biotin-peroxidase com- plex (ABC) in diagnosis and research pathology. In: De Lellis RA. ed. Advances in immunohistochemistry. New York: Mas- son Publishing, 1984:31-42.
18. Knutsen AL, Tsai CC. Graft-versus-host like illness in a child with phenobarbital hypersensitivity. Pediatrics 1986;78:4.
19. Bedrossian CWM, Greenberg SD, Singer D, Jensen J, Ro- senberg H. The lung in cystic fibrosis of the pancreas. Hum Pathol 1976;7: 195-204.
20. Frigas E, Loegering DA, Solley GO, Farrow FM, Gleich GJ. Elevated levels of eosinophil granule major basic protein in the
sputum of patients with bronchial ahlhm;i \4:.vo c’hrr Proc 1981;56:345-53.
21. Davis WB, Fells GA. Sun X-H, Gadek JE, ;\‘i?:er A. (:lystal RG. Eosinophil-mediated injury to lung parenchymal ceils and interstitial matrix: a possible role for eobinoph:ls in chronic inflammatory disorders of the lower respirac!)r: ITI~‘I 1 i‘lin Invest 1984:74:269.
22. Slavin RG, Hutcheson PS, Knutsen AP. Participation oi cell- mediated immunity in allergic bronchopulmonarb aspergll- losis. Int Arch Allergy Appl lmmunol 1987;tii ,137~11
23. Leatherman VW. Michael AF, Schwartz BA. Helldai JR Lung T cells in hypersensitivity pneumot&L, ;\:t:. Intern Mcd 1984; 100:390-92.
24. Hunninghake GW, Crystal RG. Pulmonary sarco~oos;s. a dis- order mediated by excess helper T-lymphocyte xtivtty II sites of disease activity. N Engl J Med 19X1 :30’;:4;:+-7~~
Double-blind placebo-contrakd study of loratadine, mequitazine, and placebo in the symptomatic treatment of seasonal allergic rhinitis
W. Skassa-Brociek, MD,* J. Bousquet, MD,* F. Mantes,* M. Verdier,* D. Schwab,** M . Lherminier,** and F.-B * Michel, MD * I Montpellier and Levallois-Perret, France
Loratadine is a long-acting H, antagonist devoid of anticholinergic and sedative effects. A double-blind, placebo-controlled, parallel-group study was performed in 69 patients to compure efJicacy and safety of loratadine and mequitazine. Patients allergic to grass pollens were randomly assigned to one of the three treatment groups and followed up to 2 weeks during the peak of the pollen season. Symptoms of allergic rhinitis were evaluated at baseline and after 3, 7, and 14 days of treatment by the physician with patients rating their response daily on diaq cards. Both loratadine and mequitazine induced a significant relief of nasal symptoms when these were compared to placebo. Loratadine was found to be signijicantly superior to placebo qfter 3 days of treatment, whereas a significant improvement was only observed after 7 days in patients treated with mequitazine. For nonnasal symptoms, none of the two anti-H, antagonist induced a significant improvement, and this lack of effect may be related to low symptoms at baseline. Loratadine did not induce more side effects than placebo. Loratadine can be considered to be an effective and safe anti H, histamine with a rapid onset of action. (J AUEKW CLIN IMMUNOL 1988;81:725-30.)
From the *Clinique des Maladies Respiratires, Hopital l’Algue- longue, Montpellier, and **Laboratoires Unicet, Levallois Per- ret, France.
Received for publication April 13, 1987. Accepted for publication Oct. 24, 1987. Reprint requests: J. Bousquet, MD, Clinique des Maladies Res-
piratires, Hopital 1’ Aiguelongue, 34059 Montpellier Cedex, France.
Pollen-induced allergic rhinitis is a very common disease. Anti-H, -receptor antagonists relieve nasal and ocular symptoms, but most available drugs induce side effects, such as drowsiness and seda- tion, and have variable anticholinergic activities. I’ ’ Newer compounds, such as astemizole,” terfenadine,4 and mequitazine, ‘. ’ have been found to be de-
725
726 Skassa-Brociek et al. J. ALLERGY CLIN. IMMUNOL. APRIL 1988
@-J$f ’ N
II
0 N I
C-0-CH,-CH, II
TABLE I. Scoring system for severity of symptoms
LORATADINE (SCH 29851)
0 No symptoms I Mild symptoms, do not interfere with daily activi-
ties and/or sleep 2 Moderate symptoms, some interference with daily
activities and/or sleep 3 Severe symptoms, significant or major interference
with daily activities and/or sleep
FIG. 1. Formula of loratadine. apy during the current year, and had not been treated with antihistamines, corticosteroids, or ketotifen during the past 2 weeks. None of the patients had received astemizole.
Before their inclusion in the study, patients were carefully evaluated for the presence of nasal symptoms (nasal dis- charge, stuffiness, sneezing, and itching) and nonnasal symptoms (itchy eyes, redness of the eyes, itchy ears, and/or itchy palate). According to their severity, each symp- tom was scored 0 to 3 (Table I), and only patients with moderate to severe symptoms of rhinitis were enrolled in the study.
void of sedative effects. The two former drugs are purely H, antagonists, whereas mequitazine was also found to have antileukotriene and anticholinergic activities.’
Patients were assigned to one of the three treatment groups by random order.
Study design The trial was a double-blind, placebo-controlled study.
Patients receiving mequitazine took one tablet (5 mg) in the morning before breakfast and one other tablet in the evening. Patients receiving loratadine took one tablet of placebo in the morning and one tablet of 10 mg of active drug in the evening. The placebo tablet was administered as the morning dose in the loratadine-treated group in order to blind the treatment. Patients receiving placebo took a tablet in the morning and another tablet in the evening. The compliance of treatment was assessed by counting the number of cap- sules at the end of the trial.
Loratadine is a new selective antihistamine with H, receptor-antagonist activities (Fig. 1). Results of pharmacokinetic and clinical8-‘0 studies demonstrate that this compound is safe and induces minimal side effects; in particular, it does not possess anticholin- ergic activity and is not sedative. Its plasma half-life is about 18 hours. Administered OD at a dose of 40 mg, loratadine was found to protect significantly al- lergic patients suffering from allergic rhinitis.
A double-blind, controlled study compared the safety and efficacy of a lower dosage of loratadine (10 mg OD) with mequitazine (5 mg twice daily) and placebo in the treatment of pollen-induced seasonal rhinitis .
MATERIAL AND METHODS Patients
Sixty-nine patients, ranging in age from 14 to 58 years, were enrolled in the study after informed consent was ob- tained. All patients fulfilled the following criteria: (1) Pa- tients had presented symptoms of seasonal allergic rhinitis for at least the past 2 years. (2) Skin prick tests were positive with a 11100 (wt/vol) standardized orchard grass-pollen extract” (Stallergenes Laboratories, Fresnes, France). All patients had elevated titers of serum orchard grass-pollen IgE (Phadebas RAST, Pharmacia Diagnostics, Uppsala, Sweden). (3) Patients did not receive specific immunother-
Patients were observed for up to 2 weeks and were ob- served on three occasions (days 3,7, and 14), At each clinic visit, subjective and objective assessments were made. The investigator made subjective assessments of nasal and ocular symptoms and examined the nose by anterior rhinoscopy. The severity of symptoms was scored according to a chart (Table I) and included nasal discharge, stuffiness, nasal itching, sneezing, itchy eyes, tearing, and other symptoms. Patients recorded their nasal and ocular symptoms on diary cards throughout the 2-week trial. At the end of the trial, the number of capsules taken by each patient was checked to assess the compliance of treatment.
Concomitant use of any other antiallergic medication was not permitted during the trial.
Possible adverse effects of the treatment were carefully evaluated at each clinic visit, and temperature, pulse rate, respiration rate, blood pressure, and weight were recorded. Laboratory examinations, including hematology, and uri-
VOLUME 81 WMBER 4
Loratadine and mequitazine in allergic ~+~nh 727
TABLE II. Homogeneity between groups
Group Loratadine Mequitazine --^-- .____-- ..-II
Placebo
No. of patients enrolled No. of patients evaluated for efficacy Age (yr) Sex (% M) Weight (kg) Seasonal allergy (%) Seasonal and perennial allergies (%) Duration of symptoms (yr) Severity of symptoms at baseline
22 23 22 22
30 2 8 33 t 8 68.2 50
63 -+ 10 63 t 8 100 95
0 5 9-c6 10 t 5
10.4 f 8.2 11.1 r 3.1
Results expressed in mean -r- standard deviation or in percentages
Results expressed in mean 2 standard deviation; statistical analysis by analysis of variance. *pL/P, p value between results obtained with loratadine and placebo. tpM/P, p value between results obtained with mequitazine and placebo; only significant results are indicated.
728 Skassa-Brociek et al.
LORATADINE MEQUITAZINE
27.
36.4x 9. IX 9. IX
45.5x
PLACEBO
FIG. 2. Physician’s evaluation of efficacy of loratadine, mequitazine, and placebo at the end point visit; treatment failure (01, no change ( ); fair improvement (HI, and good to excellent improvement (B).
nary and blood chemistry, classically determined in clinical trials, were performed before and after the trial.
Pollen counts
Pollen counts were performed during the period of the trial by means of a filter trap used both in Europe and in the United States, according to the technique of Cour.12
Statistical analysis
For analysis of sex, race, allergy diagnosis, and adverse effects (total and specific), a Fisher’s exact test was used. A 2 by 2 Fisher’s exact test was used to test pair-wise comparisons. For all efficacy parameters and the demo- graphic parameters (age, weight, duration of allergic con- dition and episode, and number of prior episodes), an anal- ysis of variance model was used. The least-square means procedure (LSMEANS procedure, GLM, SAS Institute, Ra- leigh, N.C.) was used to test pair-wise comparisons. Be- cause of the large variability of symptoms, a Kruskal-Wallis test with Mann-Whitney test used for pair-wise comparisons on the Pooled data was done to confirm the results of the analysis of variance.
RESULTS Homogeneity between groups
All patients were Eurocaucasians. The homogenity between groups is indicated in Table II. There was no significant difference between the groups studied. All patients enrolled were studied for safety. Five patients could not be evaluated for efficacy, since three used concomitant treatments that were not allowed, one was not receiving treatment during the trial, and incorrect inclusion criteria was followed with the other patient.
Assessment of safety
It can be observed in Table mequitazine are well tolerated.
J. ALLERGY CLIN. IMMUNOL. APRIL 1988
III that loratadine and The incidence of mild
adverse reactions in the loratadine- and mequitaine- treated groups was comparable; the tolerance of pla- cebo was worse than that of both treated groups. No abnormalities in laboratory measurements or in as- sessment of vital signs were observed.
Assessment of efficacy
Results of the efficacy of the treatments are pre- sented in Table IV. Loratadine treatment was found to be significantly superior to placebo treatment in reducing total symptom scores or nasal symptom scores. For nonnasal symptom scores, the difference was not significant; however, the baseline scores were low. Mequitazine treatment was also found to be sig- nificantly superior to placebo treatment in reducing total and nasal symptom scores, and again, there was no significant difference for nonnasal symptom scores. There was no significant difference between mequitazine and loratadine treatment, although only patients treated with loratadine presented a significant (p < 0.04) improvement of total symptom scores at day 3 when results were compared to placebo.
The physician’s evaluation performed at the end of the study demonstrated that none of the patients treated by placebo was found to have a good to excellent response to the treatment, whereas 36.4% of patients treated with loratadine and 45.5% of patients who received mequitazine were classified in this category (Fig. 2). Moreover, although 50% of patients treated by placebo reported either a treatment failure or no change in their symptoms, this lack of efficacy was only observed in 27.3% of patients treated with either loratadine or mequitazine.
Pollen counts
Grass-pollen counts were high during the whole study. They were ranging from 15 / m3 to 65 / m3 of air (Fig. 3).
DISCUSSION
This controlled, randomized, double-blind, parallel- group study compared loratadine with a reference anti- histamine, mequitazine, and with a placebo in patients suffering from seasonal allergic rhinitis. The demo- graphic and disease characteristics were comparable between treatment groups. Grass-pollen counts were high during the trial so that results can be ana- lyzed. This study confirmed previous studies with mequitazine4. s and loratadine, 40 mg (data in file) OD, and demonstrated that these two anti-H, antag- onists are safe and effective.
ioratadine and mequitazine ir, aiierqir ~ir~~rii: 729
60
I 1 I I I I I I I I I I 1
19 20 21 22 23 24 25 26 27 28 29 30 31
MAY JUNE JULY 1
FIG. 3. Grass-pollen counts during the trial period.
Side effects were minimal in both treated groups. The sedation noticed for most anti-H, histamines’ was virtually absent in the loratadine-treated group and was totally absent in the mequitazine-treated group. Only one patient treated with loratadine and one pa- tient placed in the placebo group reported somnolence. Other H, antagonists lacking CNS effects have similar or higher rates of reported sedation.34 Other side ef- fects were very low in the loratadine-treated group (one case of pruritus), and there was no side effect reported in the mequitazine-treated group.
Both active treatments were significantly more ef- fective than the placebo treatment in reducing total symptoms and nasal symptoms. However, no signif- icant difference could be observed for nonnasal symp- toms. This may be related (1) to the lower baseline rate of nonnasal symptoms and (2) on the mode of selection of patients based mainly on nasal symptoms. Another possible alternative is the lower activity of anti-H, histamines on palate itching, ear itching, or conjunctivitis. There was no significant difference be- tween loratadine and mequitazine treatment in this study. In another trials it was demonstrated that me- quitazine was significantly more effective than ter- fenadine used in many clinical studies as the reference drug.
In the physician’s evaluation of efficacy, the pla- cebo effect of most antiallergic treatments was dem- onstrated, since 50% of the patients believed they received a beneficial effect, but none of them reported a good to excellent response. On the other hand, both
loratadine and mequitazine were found to be effective by a substantial number of patients. Anti-H, antago- nists usually induce relief of symptoms in 70% to 75% of patients,” I3 and we observed similar findings with either loratadine or mequitazine. The exact reason for the lack of efficacy of anti-H, antagonists is not totally clear but may be related to the heterogeneity of the nasal allergic response, since many different media- tors are released.
These findings demonstrate that loratadine, 10 mg OD, is effective in controlling symptoms of allergic rhinitis. Moreover, this study indicates that loratadine is rapidly effective, since a significant improvement of the patients was noticed after 3 days of treatment.
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Norman PS. Newer antihistaminic agents. ,I ALLERGY CLIN IMMUNOL 1985;76:366-8. Norman PS Review of nasal allergy: update [The John Sheldon Memorial Lecture]. J ALLERGY Cr.rw IMMWOL. 1983;72: 421-32. Wilson JD, Hillas JL. Astemizole, a new long-acting antihis- tamine in the treatment of hay fever. Chn Allergy 1983;13: 131-40. Dugue P, Bimbaum J, Poisson A, Charpin J. Clinical studies with terfenadine in seasonal allergic rhinitis in France. AR- neimittelforsch 1982;32: 1206-S. Leophonte P, Leophonte-Domairon F. Carme S, et al. Etude comparative de la mequitazine et de la terfenadine dam Ies rhinites allergiques. Allergie Immunoiogie 1984;3:213-22. Nicholson AN. Antihistamines and sedation. Lancet 1983; 2:211-12. Rossoni G. Omini C, Folco GC, et al. Bronchodilating activity of mequitazine. Arch lnt Pharmacodyn Ther 1984:268: 128-35.
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8. Barnett A, Iorio LC, Kreutner W, et al. Evaluation of the CNS Il. Bousquet J. Djoukhadar F, Hewitt B, G&in B, Michel FB. properties of SCH 29851, a potential nonsedating antihista- Shelflife of a pollen and a mite standardized extract. Clin mine. Agents Actions 1984;14:590-8. Allergy 1985;15:29-34.
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10. Roman IJ, Kassem N, Gural RP, Herron J. Suppression of in the treatment of hay fever: an international double-blind histamine-induced wheal response by loratadine (SCH 29851) study comparing a weekly treatment (10 and 25 mg) with a over 28 days in man. Ann Allergy 1986;57:253-6. placebo. Curr Ther Res 1981;29:1981-6.
In vitro IgM rheumatoid-factor production induced by tetanus toxoid
Arnold I. Levinson, MD, and Leslie Tar, MD Philadelphia, Pa.
In vitro stimulation of lymphocytes from healthy donors with well-dejned polyclonal B cell activators may elicit the production of rheumatoid factor (RF) as well as other autoantibodies. Antigen stimulation may also result in polyclonal B cell activation, but it is not known if RF production is a feature of this response. Therefore, peripheral blood mononuclear cells from 36 healthy volunteers previously immunized to tetanus toxoid (TT) were stimulated in vitro for 9 days with a conventional antigen, IT, or pokeweed mitogen, a standard polyclonal B cell activator. Culture supernatants were analyzed for total IgG, total IgM, and IgM RF by ELISA. ‘IT-induced IgM RF production was observed in IO/36 experiments compared to 18136 experiments in which cells were cultured with pokeweed mitogen, with a similar magnitude of response to these respective stimulants. The in vitro IgM-RF response to IT did not require a recent in vivo TT booster immunization and was observed at an antigen dose that elicits polyclonal B cell activation but not IgG spectfic anti-IT antibody. IT-induced IgM RF responder cultures demonstrated higher levels of total IgG and total IgM production than cultures not secreting IgM RF in response to TT. These results indicate that IgM RF production is a concomitant of the polyclonal B cell response elicited by a conventional antigen. Unlike other model systems, this antigen-induced RF response was not mediated by the action of IgG antibody containing immune complexes. (J ALLERGY CLIN I&WuNOL 1988;81:730-6.)
RFs are autoantibodies directed against the Fc frag- ment of IgG. They were intially described in the serum of patients with rheumatoid arthritis and traditionally have been considered important pathogenic factors in this disease. ’ However, patients without arthritic con-
From the Allergy and Immunology Department, University of Penn- sylvania School of Medicine, and Rheumatology-Immunology Center, Veterans Administration Medical Center, Philadelphia, Pa.
Supported by a Merit Review Grant from the Veterans Administra- tion.
Received for publication Dec. 19, 1986. Accepted for publication Oct. 24, 1987. Reprint requests: Arnold I. Levinson, MD, University of Pennsyl-
vania School of Medicine, Allergy & Immunology Section, 5 15 Johnson PavilionlG2,36th and Hamilton Walk, Philadelphia, PA 19104.
ditions not infrequently have IgM RF in their serum, particularly if they are suffering from conditions as- sociated with chronic inflammation.2 The mechanisms responsible for IgM RF production remain poorly un- derstood. One hypothesis is that IgM RF is produced in response to an altered structural configuration of the IgG molecule that might occur after its complexing
