**3. Glucocorticotherapy**

In the literature review we performed, we found only one published article that covers the treatment of seasonal AR with systemic corticosteroids (Myging et al, 2000). They report that they could find only 5 studies published between 1960 and 1993 on systemic corticosteroids and AR, compared to more than 100 published studies on topical corticosteroids. There are several publications that compare topical corticosteroids with each other and with other drugs.

According to the 1994 Consensus (International Rhinitis Management Working Group, 1994), first-line therapy for the handling of seasonal AR in moderate cases with intermittent symptoms are antihistamines, and intranasal corticosteroids in severe cases with daily symptoms. In case of exacerbations during the pollen season, it is currently common practice to administer a short cycle of oral or intramuscular corticosteroids. It seems that systemic corticosteroids are highly effective for nasal blockage, but not so much for rhinorrhoea and sneezing. One high oral dose of 30 mg daily seems effective in controlling all nasal symptoms. Subcutaneous atrophy has been reported at the injection site, as well as local reactions, changes of pigmentation, etc.

The lack of reliable comparative studies and the fear of severe side effects have pushed studies and treatment towards therapy with inhaled corticosteroids.

#### **3.1 Systemic glucocorticosteroids**

Brown et al published the first placebo-controlled study of the use of systemic corticosteroids for the treatment of AR. They report that the use of 3 injections of 240 mg of

Ipratropium bromide is an anticholinergic compound related to atropine. It is poorly absorbed, but has high topical activity. It inhibits secretion for at least 4 hours, without the

Mechanism of action: It is capable of significantly reducing rhinorrhoea by acting selectively on the muscarinic receptors, which, when activated by acetylcholine released by the parasympathetic nervous system, induce the secretion of mucus by the nasal seromucous

Systemic cholinergic collateral effects rarely appear, but include changes in vision, tachycardia, urinary retention and dry mouth. However, it should be administered with

Ipratropium bromide is used in aqueous solution for topical nasal use in doses of two inhalations of 0.02 mg each three times a day in each nostril. The recommended dose should

It has been used for allergic (Kaiser et al, 1995) and non-allergic (Bronsky et al, 1995) perennial rhinitis, and acts by improving hydrorrhoea, with a maximum peak 1-4 hours after administration. It has barely any effect on nasal obstruction and sneezing, and its most frequent side effects are epistaxis, nasal dryness and headache (Kaiser et al, 1995; Bronsky et

In the literature review we performed, we found only one published article that covers the treatment of seasonal AR with systemic corticosteroids (Myging et al, 2000). They report that they could find only 5 studies published between 1960 and 1993 on systemic corticosteroids and AR, compared to more than 100 published studies on topical corticosteroids. There are several publications that compare topical corticosteroids with each other and with other

According to the 1994 Consensus (International Rhinitis Management Working Group, 1994), first-line therapy for the handling of seasonal AR in moderate cases with intermittent symptoms are antihistamines, and intranasal corticosteroids in severe cases with daily symptoms. In case of exacerbations during the pollen season, it is currently common practice to administer a short cycle of oral or intramuscular corticosteroids. It seems that systemic corticosteroids are highly effective for nasal blockage, but not so much for rhinorrhoea and sneezing. One high oral dose of 30 mg daily seems effective in controlling all nasal symptoms. Subcutaneous atrophy has been reported at the injection site, as well as

The lack of reliable comparative studies and the fear of severe side effects have pushed

Brown et al published the first placebo-controlled study of the use of systemic corticosteroids for the treatment of AR. They report that the use of 3 injections of 240 mg of

studies and treatment towards therapy with inhaled corticosteroids.

**2. Anticholinergics** 

glands.

al, 1995).

drugs.

**3. Glucocorticotherapy** 

appearance of systemic symptoms.

caution to patients with glaucoma or prostatic hypertrophy.

not be increased if there is no improvement.

local reactions, changes of pigmentation, etc.

**3.1 Systemic glucocorticosteroids** 

methylprednisolone in one-week intervals, achieved significant improvement of symptoms (Brown et al, 1960).

In the decade of the 70´s, other authors prescribed 2 injections of 80 mg of methylprednisolone with 14-day intervals to 8 patients with seasonal AR. Cortisol levels decreased after the injection, and patients began to recover and return to normal after 3 weeks (Ganderton & James, 1970).

McMillin scheduled an 80 mg injection of triamcinolone acetonide to 18 patients with severe AR, and measured morning plasmatic cortisol levels for 21 days. Although the levels descended on several occasions, the initial values were recovered after 3 weeks (Mc Millim, 1971).

In the decade of the 80´s, various clinicians studied the results of administering an injection of 5 mg of betamethasone dipropionate, another of 3 mg of betamethasone phosphate, with 3 mg of betamethasone acetate, and a third of 40 mg of methylprednisolone. These injections were administered to 60 patients with significant AR, who were divided into 3 groups depending on the type of injection (Ohlander et al, 1980)

Methylprednisolone and beclomethasone dipropionate (BDP) reduced the production of endogenous cortisol for at least 14 days, while the combination of phosphate and betamethasone acetate did not suppress plasma cortisol in 12 days. Glycaemia increased in the 3 groups in the first two days following the injection.

Hedner et al, prescribed an injection of 80 mg of methylprednisolone to 14 patients with AR. Baseline cortisol and plasma cortisol response to hypoglycaemia had moderate but significant reductions at 2 weeks, although they returned to normal in 4 weeks (Hedner & Persson, 1981).

Almost in parallel, Borum et al performed two trials in 24 patients with AR. In the first, they gave an injection of 80 mg of methylprednisolone at the start of the pollen season, and in the second, they gave it at the peak of the pollen season (Borum et al, 1987). In the first group, the effect lasted the entire season (at least 5 weeks), with all symptoms disappearing. In the second group, the injection had a rapid effect on nasal obstruction, which disappeared and did not return in the remaining 5 weeks of pollen season. Rhinorrhoea and sneezing did not disappear as noticeably as in the first group and reappeared in a few weeks. The use of rescue anti-Hl, however, was clearly inferior in both groups, compared to placebo.

Laursen et al studied the effect of a 5 g injection of betamethasone dipropionate and 2 mg of betamethasone, immediately before the start of the birch pollen season (study was performed in Denmark). They found that these patients had fewer symptoms, especially nasal obstruction, than patients treated with placebo, with the effect lasting 4 weeks (Laursen et al, 1987).

In 1988, the following year, these same authors performed a double-blind placebo-controlled trial with 30 adults with rhinoconjunctivitis (RC) who were allergic to seasonal birch pollen (Laursen et al, 1988). The patients were treated with 100 micrograms of BDP in each nostril twice a day for 4 weeks. Patients received either a placebo or an injection of 5 mg of BDP and 2 mg of betamethasone phosphate, immediately before the start of the birch pollen season. The authors concluded that an injection of BDP and betamethasone phosphate immediately before the birch pollen season produced a significant reduction in rhinoconjunctivitis symptoms, compared to placebo and topical steroid treatment.

Treatment of Allergic Rhinitis: Anticholinergics, Glucocorticotherapy,

anti-inflammatory effect 5000 times more powerful than hydrocortisone.

compared to 13% who had received placebos (Cockcroft et al, 1976)

in patients who had received the corticosteroid (Peluchi et al, 1995).

permeability.

**3.2.2 Budesonide** 

**3.2.3 Fluticasone propionate** 

with fluticasone (Melzer et al, 1990).

allergic individuals.

selectivity and affinity for glucocorticoid receptors.

effects.

Leukotriene Antagonists, Omalizumab and Specific-Allergen Immunotherapy 87

inhibiting their synthesis of histamines. It lowers the number of eosinophils, lessening the release of cytotoxic proteins, and reduces mucosal oedema by decreasing vascular

BDP may cause non-serious local side effects, such as epistaxis, nasal pruritus and, rarely, mycotic infection, but it is doubtful that it causes mucosal atrophy in long-term treatments. It is used in nasal spray, with a standard dose of 100 micrograms every 6 hours. It has an

Cockcroftf performed a study for 42 days on patients with AR. At 35 days, there was a decrease in clinical symptoms in 86% (*P*<.05) of patients who had been treated with BDP,

In a 4-week study, Peluchi compared azelastine at doses of 0.56 mg/day with BDP at doses of 200 micrograms/day and placebo. Both drugs were effective, reducing eosinophilia more

A non-halogenated corticosteroid, budesonide is an anti-inflammatory drug 2-3 times more powerful than BDP (Bryson & Faulds, 1992). It has a half-life of 2 hours, and is inactivated in the liver by oxidative metabolism after systemic absorption. It has the same mechanism of action as BDP, and may cause temporary epistaxis, nasal pruritus and sneezing as collateral

The average recommended dose is 100 micrograms every 12 hours in each nostril. Prophylactic administration protects against immediate allergic reactions. Therefore,

Cimetidine influences the pharmacokinetics and pharmacodynamics of budesonide after concomitant oral and intravenous administration, although it is of little clinical significance.

A fluorinated glucocorticoid with significant topical activity, fluticasone propionate (FP) (Flixonase; GlaxoSmithKline, London, UK) is structurally similar to cortisol, with certain variations that increase its lipophilic properties and its potency of action. It has high

FP possesses an anti-inflammatory potency twice than that of BDP which is linked to its effect on various cellular elements and the mediators of the inflammation (Barnes, 1992). It reduces the number of activated eosinophils in the nose during antigenic stimulation in

FP significantly reduces the number of T lymphocytes, and reduces the number of nonactivated basophils, neutrophils and eosinophils. Meltzer studied nasal eosinophilia in 497 patients treated with fluticasone or placebo, and found a decrease (*P*<.01) in patients treated

The lipolytic character of topical corticosteroids is significant, since it leads to increased drug retention in the tissues. The recommended dose is 200 mg/day (two applications of 50

treatment of seasonal rhinitis should be started before exposure to the allergen.

That same year, other authors found a significant reduction in plasma cortisol 3 weeks after an injection of 80 mg of methylprednisolone, but not during treatment with 200 micrograms of intranasal budesonide. They found no differences between the two therapies in terms of nasal obstruction, but there was a tendency to favour topical treatment with budesonide in terms of sneezing and rhinorrhoea (Pichler et al, 1988).

Brooks et al, treated 31 patients with rhinitis for 5 days with placebo or methylprednisolone in daily doses of 6, 12 or 24 mg, divided into 3 daily doses. They achieved significant improvement in nasal obstruction with 6 mg, and with all symptoms except for sneezing with 24 mg (Brooks et al, 1993)

Based on the literature, systemic corticosteroids seem to have a significant effect on nasal obstruction, but less so on sneezing and rhinorrhoea. These studies demonstrated a reduction in cortisol plasma levels after an IM injection of corticosteroids. The effect is greatest at 3 days and disappears after 3 weeks.

We have not found any published study on whether systemic corticosteroids should be added due to a lack of improvement with topical corticosteroids or other drugs.

#### **3.2 Topical (intranasal) glucocorticosteroids**

Several studies have shown the inhibitory efficacy of topical corticosteroids in the delayed response of allergic reactions. Symptoms that occur 2-11 hours after nasal provocation by an allergen are completely eliminated with their administration. Initially, it was thought that topical corticosteroids did not inhibit the early response; however, there is clear evidence that they also act on symptoms immediately. Studies have shown their efficacy in reducing both specific and non-specific nasal hyperreactivity.

It has been shown that the effective dose of antihistamines (loratadine oral) can be reduced with the use of fluticasone in nasal spray, in the treatment of seasonal AR. The conclusion is that the efficacy and decreased inflammation is greater with fluticasone (decreases eosinophilic cationic proteins and the number of eosinophils, and improves scores on quality-of-life questionnaires).

A reduction has been shown in the number of subepithelial cells (CD3+, CD4+, CD8+) in patients treated with topical corticosteroids. Recent studies have demonstrated a reduction in the expression of adhesion molecules (ICAM-l) in patients treated over long periods of time. Their anti-inflammatory effects are increased by the decrease in chemotaxis and the activation of eosinophils. In terms of symptoms, this translates into decreased obstruction, pruritus, sneezing and rhinorrhoea. Currently, various compounds are used.

#### **3.2.1 Beclometasone dipropionate**

Introduced in 1973 for topical nasal treatment, beclometasone dipropionate (BDP) is a potent local steroid, with absorption at therapeutic doses. It was the first steroid that proved effective in the topical treatment of hay fever.

BDP acts by penetrating the cell membrane and binding with cytoplasmic receptors. The compound formed is transferred to the nucleus, where it binds to the DNA molecule. It seems to act by emptying histamine deposits, reducing the number of mast cells and inhibiting their synthesis of histamines. It lowers the number of eosinophils, lessening the release of cytotoxic proteins, and reduces mucosal oedema by decreasing vascular permeability.

BDP may cause non-serious local side effects, such as epistaxis, nasal pruritus and, rarely, mycotic infection, but it is doubtful that it causes mucosal atrophy in long-term treatments.

It is used in nasal spray, with a standard dose of 100 micrograms every 6 hours. It has an anti-inflammatory effect 5000 times more powerful than hydrocortisone.

Cockcroftf performed a study for 42 days on patients with AR. At 35 days, there was a decrease in clinical symptoms in 86% (*P*<.05) of patients who had been treated with BDP, compared to 13% who had received placebos (Cockcroft et al, 1976)

In a 4-week study, Peluchi compared azelastine at doses of 0.56 mg/day with BDP at doses of 200 micrograms/day and placebo. Both drugs were effective, reducing eosinophilia more in patients who had received the corticosteroid (Peluchi et al, 1995).
