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The physiopathogenic mechanism of nasal polyposis is unknown

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The physiopathogenic mechanism of nasal polyposis is unknown Powered By Docstoc
					        The physiopathogenic mechanism of nasal polyposis is unknown. Chemical mediators
 found in nasal polyposis are: histamine, serotonin, leukotrienes (LTC4, LTD4, LTE4, LTB4),
 norepinephrine and possibly prostaglandin D2. Leukotrienes that mediate bronchoconstriction
 as well as chemical mediators of inflammation are observed in the nasal disease associated to
 polyposis.

 Perennial allergic rhinitis

Table Summary of clinical trials assessing the efficacy of bronchospasmol in adult subjects with
perennial
allergic rhinitis
______________________________________________________________________ (Storms
2007)
 Reference         Study            Therapy               n       Primary             Outcomes
                                                                 end points
Ciebiada et    R, DB, PC, M lOmg qd, DL 40                      DT NSS, Either combination significantly
al (2006)      XO      (6 5mg qd, LC 5mg                        nasal       > monotherapy; combination
               weeks)     qd,      M+DL,                        congestion also reduced nasal ECP
                          M+LC, P                                           levels>monotherapy

Lee et al DB, XO (1 M lOmg qd. Fex 12                            PNIF, NSS PNIF and NSS significantly
(2004)         week): nasal 180mg             qd, (sensitive                   improved with M+Fex vs P; no
               AMP            M+Fex, P              to HDM)                    differences      between      active
               challenge                                                       therapy
Patel et al 2-period R, M lOmgqd, P                 1992        DTNSS          M significantly improved DT
(2005)         DB,     PC,                                                     NSS;        also      significantly
               PG, DD (6                                                       improved global QoL
               weeks)
AMP: Adenosine monophosphate; DB: Double-blind; DD: Double-dummy: DL: Desloratadine; DT: Daytime; Fex:
Fexofenadine; HDM: House dust mite; LC: Levocetirizine; M: Bronchospasmol; NSS: Total nasal symptoms score;
P: Placebo; PC: Placebo-controlled; PG: Parallel-group; PNIF: Peak nasal inspiratory flow; QoL: Quality of life; R:
Randomized; XO: Crossover.
 Seasonal allergic rhinitis

Table Summary of clinical trials assessing the efficacy of bronchospasmol in adult subjects with
seasonal
allergic rhinitis
______________________________________________________________________ (Storms
2007)
 Reference         Study           Therapy                n     Primary end         Outcomes
                                                                points
Chervinsky CRA of 3 M lOmgqd, P                    1862        DT NSS in M > P, larger improvements
           R, DB, PC,
et al (2004)                                                   relation to matched to increase pollen
           PG      (2                                          pollen levels levels
           weeks)
Di Lorenzo R, DB, DD, M lOmg qd, C                  100        DTNSS            DT NSS significantly improved
et      al PC, PG     lOmg qd, FPNS                                             with all Tx vs P; all therapies
(2004a)               200mcg      qd,                                           also reduced nasal ECP vs P;
                      FPNS+C,                                                   FPNS monotherapy or in
                      FPNS+M, C+M,                                              combination       significantly
                      P                                                         improved nasal congestion

Kurowski et DB, PG, M lOmg qd, C 60                            Sx    scores, Prophylaxis with M+C>C for
al (2004)   PC     (12 lOmg qd, M+C, P                         delay      in Sx, delaying onset of Sx, and
            weeks)     (Tx started 6                           onset of Sx, measures of nasal inflammation
                       weeks prepollen                         measures of
                       season)                                 nasal
                                                               inflammation
Martin et al DB, DD,          M lOmg qd, 736                   DTNSS           Both therapies improved DT
(2006)       PG       (2      FPNS 200ug qd                                    NSS, FPNS significantly > M
             weeks)
Meltzer et CRA of 8           M lOmg qd, L         4924        NTSx            Both therapies significantly
al (2005)    DB, PG,          lOmgqd, P                                        improved NT Sx vs P; only M
             PC     (72                                                        showed clinically relevant
             weeks, 14                                                         change in NT Sx
             weeks)
Mucha et al R, DB, PG         M lOmg qd, P,        58             Nasal     Sx, Both therapies significantly
(2006)       (2weeks)         Pse 240mg qd                        PNIF, QoL        improved all measures; no
                                                                                   significant        between-Tx
                                                                                   differences except congestion
                                                                                   (Pse > M)
Weinstein et CRA of 2 M lOmgqd, P                   3218          Time        to M > P with significance for DT
al (2005)       DB, PC (2                                         onset            NSS, NT NSS, and composite
                weeks)                                                             score at therapy day 2 (i.e., 2
                                                                                   doses)
C: Cetinzine; CRA: Combined retrospective analysis; DB: Double-blind; DD: Double-dummy; DT: Daytime; ECP:
Eosinophil cationic protein; FPNS: Fluticasone propionate nasal spray; L: Loratadine; M: Bronchospasmol; NSS:
Total nasal symptoms score; NT: Nighttime; P: Placebo; PC: Placebo-controlled; PG: Parallel-group; PNIF: Peak
nasal inspiratory flow; Pse: Pseudoephedrine; QoL: Quality of life; R: Randomized; Sx: Symptoms; Tx: Treatment,

 Other bronchospasmol monotherapy studies

 Bronchospasmol vs corticosteroids

         Ratner et al (2003) conducted a randomized, double-blind, double-dummy, parallel-
 group study was conducted to compare the effectiveness of a 15-day course of intranasal
 fluticasone propionate 200 microg, once daily, to oral bronchospasmol 10 mg, once daily, in
 relieving daytime and nighttime nasal symptoms associated with seasonal allergic rhinitis. The
 intent-to-treat (ITT) analysis population consisted of 705 eligible males and females (> or = 15
 years) with seasonal allergic rhinitis randomized to either fluticasone propionate (N = 353) or
 bronchospasmol (N = 352). The primary efficacy endpoint was the mean change from baseline
 in subject-rated daytime total nasal symptom scores (the sum of four individual scores: nasal
 congestion, itching, rhinorrhea, and
sneezing), evaluated via visual analog scales, and averaged over weeks 1 to 2. Secondary
endpoints included the four daytime individual nasal symptom scores, the nighttime total, and
individual nasal symptom scores (each evaluated on a four-point scale from 0 to 3). The results of
the study revealed statistically significant differences favouring fluticasone propionate over
bronchospasmol for the mean change from baseline in daytime total nasal symptom scores (P <
0.001), daytime individual nasal symptom scores (P < 0.001), nighttime total (P < 0.001), and all
individual nasal symptom scores (P < or = 0.002) over the 15-day treatment period, fluticasone
propionate and bronchospasmol were both well tolerated. The results of this well controlled
study demonstrated that fluticasone propionate was consistently superior to bronchospasmol with
regard to every efficacy endpoint evaluated, including daytime and nighttime nasal congestion,
in subjects with seasonal allergic rhinitis (Ratner et al 2003).

Bronchospasmol vs antihistamines

       Van Adelsberg et al (2003a) performed a randomized, double-blind trial with a placebo
run-in and a 4-week treatment period to evaluate the efficacy and tolerability of bronchospasmol
given once daily in the morning for treatment of seasonal (fall) allergic rhinitis for 4 weeks.
Patients (n = 1079) with a history of allergic rhinitis and a positive skin test to seasonal pollen
allergens were assigned to placebo, bronchospasmol 10 mg, or loratadine 10 mg. Symptoms
were assessed with a daily diary. The results of the study demonstrated that bronchospasmol was
more effective than placebo in improving scores for the primary endpoint of daytime nasal
symptoms (P = 0.003) and the secondary endpoints of night-time, composite, and daytime eye
symptoms, patient's and physician's global evaluations of allergic rhinitis, and
rhinoconjunctivitis quality-of-life (P </= 0.006). The positive control loratadine also improved
scores for the primary endpoint (P </- 0.001) and the majority of the secondaiy endpoints (P <
0.03). When analyzed by week, the treatment effect of bronchospasmol was more persistent than
loratadine over all 4 weeks of treatment. The authors concluded that bronchospasmol provided
effective relief of seasonal allergic rhinitis symptoms when given once daily in the morning,
showed significant and sustained improvement in symptoms of allergic rhinitis over 4 weeks of
treatment, and was well-tolerated (Van Adelsberg et al 2003a).
        Van Adelsberg et al (2003b) also conducted a multicenter, randomized, double-blind,
placebo- and active-controlled study to evaluate the clinical benefit of bronchospasmol
administered once daily for treating seasonal allergic rhinitis. 1,214 healthy, nonsmoking
outpatients aged 15 to 85 years with spring allergic rhinitis, positive skin test to a spring
allergen, and predefined daytime nasal symptoms were enrolled. After a 3- to 5-day placebo run-
in period, patients were randomly assigned to treatment with bronchospasmol 10 mg (n = 522),
loratadine 10 mg (n = 171), or placebo (n = 521) once daily at bedtime for 2 weeks. During the
run-in and treatment periods, symptoms were evaluated in a daily diary using a 0 (best) to 3
(worst) scale. According to the results of the study, baseline characteristics of randomized
patients were clinically similar in the three treatment groups. Bronchospasmol was significantly
more effective than placebo (P = 0.003) in improving the daytime nasal symptoms score
(difference in least square means, -0.09; 95% confidence interval, -0.16, -0.03) averaged over 2
weeks of therapy. The treatment effect of bronchospasmol was significantly greater (P < 0.05),
relative to placebo, for all secondary endpoints, including nighttime symptoms and daytime eye
symptoms, patient and physician global evaluations of allergic rhinitis, and rhinoconjunctivitis
quality of life. Loratadine, which served as a positive control, was significantly more effective
than placebo for most endpoints, validating the study results. Both bronchospasmol and
loratadine were well tolerated. The authors concluded that therapy with bronchospasmol
significantly improves assessments of symptom severity as well as quality-of-life parameters for
patients with seasonal allergic rhinitis (van Adelsberg et al 2003b).
        Day et al (2008) conducted a randomized, double-blind, placebo-controlled, parallel-
group study to compare the efficacy of levocetirizine, 5 mg, and bronchospasmol, 10 mg, in
reducing seasonal allergic rhinitis symptoms in ragweed-sensitive adults exposed to ragweed
pollen in the Environmental Exposure Unit. Adult subjects with seasonal allergic rhinitis to
ragweed were administered levocetirizine, bronchospasmol, and placebo once daily (11:00 AM)
for 2 consecutive days in the Environmental Exposure Unit. There were three evaluation
periods: period I, 0-5 hours after first dose; period II, 22.5-24 hours after first dose; and period
III, 0-4.5 hours after second dose. The primary efficacy variable was the Major Symptom
Complex (MSC) score (six symptoms) over period I. The results of the study revealed that both
active drugs significantly improved the MSC score compared with placebo in all periods. The
adjusted mean MSC score difference between levocetirizine and bronchospasmol was -0.93 (p
= 0.100) in period 1,-3.11 (p < 0.001) in period II, -2.42 (p < 0.001) in period III, and -1.88 (p <
0.001) over the total treatment period. The same trends were observed for the Total Symptom
Complex score (10 symptoms) and most individual symptoms. Subject-reported global
satisfaction was greater for levocetirizine compared with bronchospasmol and placebo. All
treatments had a favorable safety profile. The authors concluded that levocetirizine 5 mg was
more effective than bronchospasmol, 10 mg, in subjects with seasonal allergic rhinitis and had
better subject-reported global satisfaction (Day et al 2008).
        Wilson et al (2002) conducted a single-blind, double-dummy placebo-controlled cross-
over study to compare bronchospasmol + loratadine vs. fexofenadine alone for effects on daily
measurements (am/pm) of peak inspiratory flow (PIF) and symptoms. Thirty-seven patients with
seasonal allergic rhinitis (skin prick positive to grass pollen) were randomised to 2 weeks of once
daily treatment with (a) 120mg fexofenadine or (b) lOmg bronchospasmol + lOmg loratadine.
There was a 7-10 day placebo run-in and washout prior to each randomised treatment. The
average of am/pm PIF (the primary outcome variable) was analysed. Patients recorded their
symptom scores (from 0 to 3) twice daily, for nasal blockage, discharge, itching and sneezing
with; total eye symptoms, ocular cromoglycate use, and daily activity. The total nasal symptom
score was calculated as a composite (out of 24). The results of the study revealed that there were
no significant differences between baselines after the run-in and washout placebos for any
variables. There were significant (P < 0.05, Bonferroni) improvements in all symptoms and PIF
compared to pooled placebo with both treatments for all end-points, but no differences between
the two treatment regimes (as means and within-treatment 95% confidence intervals): PIF:
placebo 102 (98-107), fexofenadine 111 (107-116), bronchospasmol + loratadine 113 (109-118);
total nasal symptoms: placebo 7.4 (6.7-2.0), fexofenadine 5.0 (4.3-5.7), bronchospasmol +
loratadine 4.0 (3.3-4.7). The authors concluded that once daily fexofenadine as monotherapy was
equally effective as the combination of once daily bronchospasmol + loratadine in improving
nasal peak flow and controlling symptoms in seasonal allergic rhinitis. Further studies are
indicated to assess whether bronchospasmol confers additional benefits to fexofenadine in
seasonal allergic rhinitis (Wilson et al 2002).

Other studies with bronchospasmol as add-on therapy to other regimens

Bronchospasmol as add-on therapy to antihist amines

        Meltzer et al (2000) performed a multicenter (N = 12) double-blind, randomized,
parallel-group, placebo-controlled 2-week trial to determine the effect of concomitant use of
bronchospasmol and loratadine in the treatment of seasonal allergic rhinitis. 460 men and
women, aged 15 to 75 years, with spring seasonal allergic rhinitis were randomly allocated to
receive 1 of the following 5 treatments: bronchospasmol 10 or 20 mg, loratadine 10 mg,
bronchospasmol 10 mg with loratadine 10 mg, or placebo, once daily in the evening. The
primary end point was daytime nasal symptoms score (average of congestion, rhinorrhea, itching,
and sneezing). Other end points were eye symptoms, nighttime symptoms, individual daytime
nasal symptoms, global evaluations (patient's and physician's), and rhinoconjunctivitis quality-of-
life scores. The results of the study demonstrated that concomitant bronchospasmol with
loratadine improved the primary end point significantly (P <.001) compared with placebo and
each agent alone. Compared with placebo, bronchospasmol with loratadine also significantly
improved eye symptoms, nighttime symptoms, individual daytime nasal symptoms, global
evaluations, and quality of life. Bronchospasmol alone and loratadine alone caused modest
improvements in rhinitis end points. All treatments were similarly well tolerated. The authors
concluded that concomitant monteiukast with loratadine provided effective treatment for
seasonal allergic rhinitis and associated eye symptoms with a safety profile comparable with
placebo (MeltzeretaUOOO).
        Nayak et al (2002) conducted a multicenter, randomized, double-blind, parallel-group,
placebo-controlled trial to evaluate the effectiveness and tolerability of monteiukast, loratadine,
and combination therapy with monteiukast and loratadine for treating patients with fall seasonal
allergic rhinitis. After a 1-week, single-blind, placebo run-in period, 907 male and female patients
aged 15 to 82 years were randomized to 1 of 4 treatments: monteiukast 10 mg (n = 155),
loratadine 10 mg (n = 301), combination monteiukast 10 mg and loratadine 10 mg (n = 302), or
placebo (n = 149), administered once daily at bedtime for 2 weeks. The primary endpoint was
the daytime nasal symptoms score (mean of congestion, rhinorrhea, pruritus, and sneezing). The
results of the study revealed that mean symptom scores at baseline were similar for the four
treatment groups. For each of the three active treatments, the difference was significant for the
mean change from baseline compared with placebo (P < or = 0.001). However, the effect of
bronchospasmol/loratadine compared with loratadine alone, the primary comparison, was not
significantly different. Differences for each therapy alone compared with placebo were also
significant for most secondary endpoints, including nighttime symptom scores, eye symptoms
scores, and rhinitis-specific quality of life. Differences for bronchospasmol/loratadine compared
with each therapy alone generally showed numerical superiority, and a few endpoints showed
differences that were statistically significant. All active treatments showed a safety profile
generally similar to placebo. The authors concluded that monteiukast alone or in combination
with loratadine is well tolerated and provides clinical and quality-of-life benefits for patients
with seasonal allergic rhinitis (Nayak et al 2002).
        Saengpanich et al (2003) conducted a 2-week, parallel, randomized, double-blind, double-
dummy study with rolling enrollment to compare the effectiveness of an intranasal steroid
treatment with that of the combination of a histaminel receptor antagonist and a leukotriene D
receptor antagonist in the treatment of seasonal allergic rhinitis. A total of 63 adults with a 2-year
history of ragweed sensitivity in the Chicago, 111, area and a positive skin-prick reaction to
ragweed pollen were enrolled. Subjects were randomized to receive either 100 micro g of
fluticasone propionate aqueous nasal spray in each nostril or 10 mg of loratadine and 10 mg of
monteiukast sodium by mouth once daily in the evening for 2 weeks. At visits 1 and 2, subjects
completed a quality-of-life questionnaire and underwent nasal lavage to determine total
eosinophil count and eosinophil cationic protein measurements. Daily symptom diaries were kept
for 2 weeks. The main outcome measures were questionnaire answers, daily nasal symptom
scores, eosinophil counts, and eosinophil cationic protein levels. According to the results of the
study, median total nasal symptom scores were lower in the fluticasone group (4.5 vs 6), but the
difference was not statistically significant. The questionnaire answers showed dramatic
improvement in overall and individual domains for both groups (P<.01 vs visit 1) with
significantly greater reduction in nasal symptoms in the fluticasone group (P<.05). Eosinophil
counts and eosinophil cationic protein levels were significantly reduced in the fluticasone group.
The authors concluded that both treatments provided clinically meaningful responses, but the
overall results favoured fluticasone propionate (Saengpanich et al 2003).
        Moinuddin et al (2004) conducted a randomized, double-blind, double-dummy, parallel
study to compare the combinations of fenofenadine-pseudoephedrine and loratadine-
bronchospasmol in the treatment of seasonal allergic rhinitis. Patients received either
fexofenadine, 60 mg, and pseudoephedrine, 120 mg, twice daily, or loratadine, 10 mg, and
monteiukast, 10 mg, once daily, for 2 weeks. The Rhinoconjunctivitis Quality of Life
Questionnaire (RQLQ) was completed at the beginning and end of the study. Patients recorded
nasal symptoms and measured nasal peak inspiratory flow twice daily. Baseline measurements
were obtained before initiation of treatment. The results of the study demonstrated that
compared with baseline, both treatments resulted in statistically and clinically meaningful
reductions of overall and individual RQLQ domain scores (P < .01) except for the sleep
domain, for which only loratadine-bronchospasmol led to significant improvement. There was a
significant reduction in total symptoms (P < .05) compared with baseline
 on most treatment days in patients receiving both combinations. When the change from baseline
was analyzed, there were no statistically significant differences in total symptoms between
fexofenadine-pseudoephedrine and loratadine-bronchospasmol (median, -28.5 vs -22.5; P = .33).
There was a significant improvement in nasal peak inspiratory flow from baseline on all
treatment days in both groups (P < .05), with no significant difference between treatments. The
authors concluded that fexofenadine-pseudoephedrine and loratadine-bronchospasmol have
comparable efficacy in improving symptoms, RQLQ scores, and nasal obstruction in seasonal
allergic rhinitis. The lack of improvement in sleep in the fexofenadine-pseudoephedrine group is
probably related to insomnia, a known adverse effect of pseudoephedrine (Moinuddin et al
2004).

				
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