Both nedocromil sodium and cromolyn sodium are anti-inflammatory drugs that may be used in the therapy of allergic diseases. These diseases include asthma, allergic rhinitis, and allergic ocular disorders. Additional therapeutic uses have been proposed. Nedocromil and cromolyn are both available in the United States for asthma therapy, but only cromolyn is available for the treatment of the other conditions. Recent publications in the evidence-based literature have upheld the safety profile of nedocromil and cromolyn but increasingly suggest that other topical anti-inflammatory agents are more effective and have comparable safety at recommended doses. Nedocromil sodium and cromolyn sodium both can be used prophylactically prior to isolated allergen exposures and must be used regularly for maintenance therapy. No consistent, severe adverse reactions occur with either drug.
Cromolyn sodium and nedocromil sodium are two nonsteroidal anti-inflammatory medications that may be used in the treatment of asthma, allergic rhinitis, and allergic eye disease. They are not, however, chemically or mechanistically related to the prostaglan-din synthetase inhibitors commonly known as nonsteroidal anti-inflammatory drugs.
Cromolyn and nedocromil are chromone compounds that were synthesized and developed in 1965 and 1979, respectively. Khellin, a chromone derived and purified from seed extracts of the plant Ammi visnaga, had been utilized for centuries in several eastern Mediterranean countries as a diuretic and smooth muscle relaxant. A purified form was noted in the 1940s to provide complete, prolonged relief of asthma.
Cromolyn sodium is a derivative of chromone-2-carboxylic acid, whereas nedocromil sodium is a pyranoquinoline. Despite their chemical and structural differences, they both exert remarkably similar anti-inflammatory actions. Both cromolyn sodium and nedocromil sodium are water soluble, fat insoluble, and totally ionized at physiological pH. These physical and chemical properties suggest that all biological activities are the result of drug interactions with an unidentified surface receptor.
Since the second edition of this volume, the mechanisms of action have been elucidated further, and several evidence-based studies have compared the efficacy of these compounds separately and together to other anti-inflammatory agents. The salient points will be reviewed here.
Table Mechanisms of Action of Cromolyn and Nedocromil
1. Block
chloride channels, thereby decreasing:
Mast cell
degranulation
Activation of
eosinophils
Nerve
conduction through sensory neurons
2. No
intrinsic bronchodilatory, anticholinergic, or antihistaminic activity
Cromolyn and nedocromil both apparently exert their effects on a variety of chloride channels of cells. These channels include a volume-activated chloride channel in endothelial cells, a calcium-independent chloride channel in cultured mast cells, calcium-dependent fluctuations in tracheal smooth muscle, and a calcium- and voltage-dependent chloride channel on airway epithelium. Reduction of neuropeptide release and tachykinin receptor antagonism have been proposed as alternative mechanisms of action. In the rabbit model, nedocromil sodium first activates and then suppresses chloride ion flux in the vagus nerve (mainly composed of nonmyelinated C-fibers). These actions induce a slow, sustained nerve depolarization, thereby reducing sensitivity to subsequent action potentials.
By blocking the activity of chloride channel pathways on cells, such as mast cells, eosinophils, epithelial cells, endothelial cells, fibroblasts, and sensory neurons, these drugs dampen the inflammatory responses associated with allergic disease. This impairment of chloride channels may be related to drug-induced phosphorylation of a 78-kDa protein thought to be associated with the termination of mast cell mediator release. A structurally similar protein, moesin, interacts with the cellular cytoskeleton, and its phosphorylation by cromolyn may help to explain the inhibitory effects of cromolyn and nedocromil on chloride channels. These drugs may imitate a natural inhibitory process, thus accounting for their lack of toxicity.
In summary, the clinical activity of these drugs apparently derives from their downregulation of a variety of cells involved in the inflammatory response, both allergic and nonallergic factors. Of particular importance is their ability to downregulate eosinophil-driven inflammation. Neither cromolyn nor nedocromil has intrinsic bronchodilatory, anticholinergic, or antihistaminic activity.
Bothnedocromil and cromolyn are effective agents in the therapy of both seasonal and perennial forms of allergic rhinitis. However, this discussion will be limited to the use of cromolyn because nasal preparations of nedocromil are not commercially available in the United States. Cromolyn is available in an aqueous form, both with and without prescription, for the therapy of allergic rhinitis. As with asthma, cromolyn administration prevents both the early and late nasal responses to allergen and decreases both activated and indolent eosinophils found in nasal secretions and biopsies.
As in asthma, nasal cromolyn should be administered once the rhinitis is reasonably controlled and it should be given prior to exposure. Thus, therapy for seasonal allergic rhinitis should be initiated before the allergy season begins. This drug can be highly effective in blocking symptoms resulting from isolated allergy exposure when it is administered immediately before mowing the lawn or visiting a relative with a pet.
It is important to remember that cromolyn is a preventive agent that needs to be used regularly during allergen exposure. It has no immediate effect. Its initial dose is two sprays four times daily, but this dosage frequency potentially can be reduced after the first 2-3 wk of therapy. Guy
The safety profile of nasal cromolyn is excellent, permitting its purchase in the United States without a prescription. Therefore, it is an excellent drug for use in children for whom nasal corticosteroids are considered undesirable. Nonetheless, nasal corticoster-oids have a superior therapeutic effect compared to nasal cromolyn. Moreover, additional medications are usually necessary to achieve an acceptable clinical response to cromolyn, especially where congestion is a troublesome nasal symptom.
Cromolyn may be effective in the management of several allergic eye diseases. All of these disorders appear to involve mast cells and eosinophils. These conditions include seasonal allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, and giant papillary conjunctivitis. Nedocromil is more efficacious than cromolyn in the treatment of vernal keratoconjunctivitis and is effective in patients whose chronic symptoms of allergic conjunctivitis are not controlled fully by cromolyn. Ocular preparations of nedocromil, however, are not commercially available in the United States. Current evidence supports preferential use of topical antihistamines (e.g., azelastine, levocabastine, or olopatadine) or mast cell stabilizers (e.g., lodoxamide) for allergic eye conditions.
Ocular cromolyn therapy is virtually as effective as oral antihistamines for seasonal allergic conjunctivitis. It reduces itching, stinging, and photo sensitivity. Therapeutic response in seasonal allergic conjunctivitis may be related to allergen-specific immunoglobulin E antibody levels.
As with other allergic diseases, the drug should be started when the patient is relatively free of symptoms. It is administered at a dose of one to two drops four times daily. Ocular cromolyn is not effective acutely. However, it can also be used prophylactically before specific allergen exposure.
Vernal keratoconjunctivitis is recurrent, bilateral, interstitial inflammation of the conjunctivae that occurs more frequently in warm, dry climates. Most affected patients develop symptoms before puberty and symptoms usually resolve by 25 yr of age. Symptoms of severe itching, tearing, burning, mucoid discharge, and photophobia may occur perennially but are characteristically worse during spring and summer months. Abnormalities may include giant papillae on upper tarsal conjunctivae, corneal plaques, scarring, and decreased visual acuity.
Several studies indicate that ocular cromolyn is effective for vernal keratoconjunctivitis. Beneficial effects seem to occur within 1 wk of initiating therapy and are manifested by decreased pruritus and mucus secretion. The dosage is one to two drops four times daily. Nedocromil is significantly more effective than cromolyn in treating vernal keratoconjunctivitis and is more effective in controlling keratitis, reducing the need for additional topical corticosteroid treatment.
Atopic keratoconjunctivitis is the ocular counterpart to atopic dermatitis. However, only a small percentage of patients with atopic dermatitis develop atopic keratoconjunctivitis. Associated symptoms include severe itching, burning, mucoid discharge, and photosensitivity. Cataracts and keratoconus may develop. Double-blind placebo-controlled crossover studies have shown beneficial effects of cromolyn on discharge, photophobia, papillary hypertrophy, and both limbal and corneal changes. In addition, dosage reductions for topical corticosteroids have been reported.
Evidence suggests that giant papillary conjunctivitis is triggered by an inflammatory response to any foreign substance, such as a contact lens or ocular prosthesis, which irritates the upper tarsal conjunctivae. Because pathological changes are similar to those seen in allergic eye disorders, cromolyn has been employed. A reduction in symptoms and an increased tolerance to contact lens wear has been demonstrated in many patients. The dose is the same as for other ocular disorders. Affected patients should discontinue contact lens wear while the condition persists and should consider switching to disposable contact lenses once it resolves.
Nedocromil and cromolyn are two of the safest drugs available for treatment of allergic diseases. They have shown little, if any, toxicity in more than 25 yr of clinical use. Local irritation is the most common side effect. Nedocromil is perceived by some patients (about 12%) to have an unpleasant taste that may limit its use.
Both nedocromil sodium and cromolyn sodium are useful anti-inflammatory drugs in the therapy of allergic diseases. These diseases include asthma, allergic rhinitis, and allergic ocular disorders. Additional therapeutic uses have been proposed. Nedocromil and cromolyn are both available in the United States for asthma therapy, but only cromolyn is available for the treatment of the other conditions.
Recent publications in the evidence-based literature have upheld the safety profile of the chromones, but increasingly suggest that other topical anti-inflammatory agents (e.g., glucocorticosteroids or ocular antihistamine preparations) are more effective and have comparable safety at recommended doses. Cromolyn appears to be more effective when combined with a b-agonist. There are no data to support that addition of chromones to inhaled corticosteroids enhances efficacy. Whether other drugs can be utilized with cromolyn or nedocromil to achieve greater effectiveness and comparable safety remains to be seen. Refinements of existing formulations may also achieve greater efficacy. At present, cromolyn and nedocromil appear to be niche drugs that can be of great clinical importance for some patients.
June 18, 2011 – 7:45 am
Nedocromil sodium and cromolyn sodium have demonstrated the ability to prevent asthma exacerbations leading to emergency department visits and hospitalization, especially in children. Nonetheless, the role of chromones in asthma management is still debated. The updated National Heart, Lung, and Blood Institute asthma guidelines, the Cochrane Database Systematic Reviews, and the Childhood Asthma Management Program study suggest that inhaled steroid preparations should be first-line agents in all patients with persistent disease, effectively relegating cromolyn and nedocromil to second-line agents (i.e., they are not “preferred”). The Cochrane Database Systematic Reviews suggests that publication bias has overestimated the beneficial effects of cromolyn as maintenance asthma therapy and concludes that efficacy of cromolyn over placebo is unproven. Others argue strongly that cromolyn and nedocromil effectively preserve lung function in most patients and have strong safety profiles. Key features of their efficacy are summarized below.
Table Asthma-Inducing Agents Inhibited by Cromolyn and Nedocromil
Allergens
(both early and late responses)
Chemicals
(mediators)
Adenosine
monophosphate
Hypertonic
saline
Neurogenic
NO2
SO2
Citric acid
Sodium
metabisulfite
Bradykinin
Substance P
Neurokinin A
Capsaicin
Physical
factors
Fog
Exercise
Cold air
Both cromolyn and nedocromil effectively block the asthmatic response to a variety of stimuli. These include not only allergen-induced reactions, but also those related to neurogenic, chemical, and physical factors, such as substance P, bradykinin, nitric oxide, sulfur dioxide, sodium metabisulfite, cold air, citric acid, and fog. In addition, they can prevent exercise-induced bronchospasm. The drugs thus protect against a wide array of asthma-inducing stimuli.
Their action is clearly anti-inflammatory. Biopsy and bronchoalveolar lavage studies obtained after provocative challenges or during long-term therapy both demonstrate significant reductions in inflammatory markers. Both drugs decrease the number of indolent and activated eosinophils found in bronchoalveolar lavage fluid and biopsy specimens of respiratory mucosa. In addition, cromolyn decreases the amount of albumin present in bronchoalveolar lavage fluid.
Numerous in vitro findings complement these in vivo effects. These findings include inhibition of macrophage release of neutrophil chemotactic factor, decreased eosinophil chemotaxis, and inhibition of eosinophil and mast cell degranulation, among other activities.
Chronic administration of both drugs produces clinical improvement manifested by decreased symptom scores, gradual increases in forced expired volume in 1s (FEVj), decreased peak flow diurnal variability, and decreased bronchial hyperresponsiveness following histamine or methacholine challenge. However, acute administration of cromolyn or nedocromil has no effect on bronchoconstriction induced by directly acting spasmogens such as histamine or methacholine. Both cromolyn and nedocromil decrease bronchodilator use and also reduce the dosage of inhaled corticosteroids necessary to control asthma. These effects are seen in both allergic and nonallergic asthmatics.
Table Key Features of Cromolyn and Nedocromil Use in Asthma
Anti-inflammatory
Decrease
bronchial hyperresponsiveness
Block early-
and late-phase reaction
Prevent
bronchospasm to allergic and numerous, nonallergic stimuli
Maintenance
prophylaxis
Major role in
mild to moderate persistent asthma
May be
corticosteroid-sparing
Excellent
safety profile
Table Features Distinguishing Nedocromil from Cromolyn
Nedocromil
blocks the late-phase pulmonary response to allergy challenge when given
before or shortly after provocative challenge. Cromolyn is only effective if
it is given before challenge.
Nedocromil
inhalation blocks the release of cytotoxic mediators in aspirin-sensitive asthmatics
whose platelets are challenged with aspirin in vitro. Cromolyn inhalation
does not.
Nedocromil may
be more effective in preventing asthma resulting from nonallergic triggers,
such as NO2, SO2, metabisulfite, and adenosine
monophosphate.
Nedocromil may
be more effective in blocking eosinophil chemotaxis.
Nedocromil has
a faster onset of action.
Cromolyn may
inhibit angiotensin-converting enzyme inhibitor-induced cough through
inhibition of sensory nerve activation.
Cromolyn may
potentially alleviate refractory atopic dermatitis.
Cromolyn may
influence the common cold.
Nedocromil may
require less frequent dosing as a maintenance regimen.
Nedocromil is
more efficacious than cromolyn in the treatment of vernal
keratoconjunctivitis and is effective in patients whose chronic symptoms of
allergic conjunctivitis are not controlled fully by cromolyn. Ocular
preparations of nedocromil are not commercially available in the United
States.
Cromolyn and nedocromil are very similar in their clinical effects, and there are no dramatic differences between these two drugs.
Both drugs will prevent the early- and late-phase allergic response when they are administered before an allergen challenge. However, nedocromil will prevent the late-phase response when it is administered after an allergen challenge, whereas cromolyn will not. Both drugs exert their effects on nonallergic asthma stimuli. Nedocromil, however, seems to be slightly more effective in blocking asthma caused by nitric oxide, sulfur dioxide, sodium metabisulfite, and adenosine monophosphate. In addition, nedocromil may be more effective at inhibiting eosinophil chemotaxis. Specifically, nedocromil, but not cromolyn, inhibits chemotaxis of eosinophils induced by platelet-activating factor and leukotriene B4.
Whether or not these observations result in clinically detectable differences between the two agents is unclear. However, some evidence suggests subtle clinical differences exist between the two drugs:
1.  Nedocromil may have a faster onset of action. It exerted its beneficial effects within a few days in one study, while cromolyn effects may take 2-4 wk.
2.  The maintenance dosing frequency required for nedocromil may be less than that required for cromolyn. A twice-daily regimen is effective for some patients taking nedocromil. It may also assist in patients, such as adolescents, who may have difficulty adhering to more complex regimens.
3.  Nedocromil may be more effective than cromolyn in the treatment of nonallergic asthmatics. The rationale for this statement is its superior effect in blocking nonallergic asthma triggers.
4.  Nedocromil may control asthmatic cough more effectively than cromolyn. However, cromolyn may help to reduce the chronic cough associated with angiotensin-converting enzyme inhibitors, presumably due to its inhibition of sensory nerve activation.
5.  A certain percentage of patients will not take nedocromil because of an unpleasant taste. Most patients (about 88%) do not taste nedocromil. No unpleasant taste is associated with inhaled cromolyn.
6.  Cromolyn sodium is also commercially available in the United States as a solution form for nebulizer usage, whereas nedocromil sodium is not. This may be an advantage for asthmatic patients younger than 5 yr of age. Cromolyn sodium is approved for usage down to age 2 yr. Nedocromil is approved by the US Food and Drug Administration for nebulized usage in children but has never been marketed in this form in the United States.
No consistent difference between the cromolyn and nedocromil exists in clinical trials involving subjects with asthma. Some trials report clinical equivalence, while others report a relative advantage of one over the other in controlling certain asthma features.
It should be emphasized that neither drug is a bronchodilator. Indeed, both drugs seem to have irritative properties that will cause cough or wheeze in some patients whose asthma has not been adequately controlled. As a practical point, therefore, a brief therapeutic course of corticosteroids may be necessary to control active asthmatic inflammation before initiating these drugs.
Both drugs are indicated for maintenance control of mild to moderate persistent asthma and may additionally help to reduce the dependency on inhaled corticosteroids in severe, persistent asthma. Nedocromil is only available in the United States as a metered-dose inhaler (metered-dose inhaler). Cromolyn is available both as a metered-dose inhaler and as a nebulizer solution. Therefore, cromolyn may be used in infants and small children who cannot use a metered-dose inhaler. Cromolyn combined with albuterol (salbutamol) as a nebulizer solution was significantly more effective in a multicenter trial than either agent alone.
The initial dosage frequency for both cromolyn and nedocromil is four times daily once acute asthmatic inflammation is controlled. Dosage reductions to twice daily are almost always possible for maintenance therapy. Prophylactic administration prior to allergen exposure, such as a visit to a relative who resides with a pet to which the patient is allergic, is aunique therapeutic use for both drugs. Both should be administered 30 min before exposure and every 4 h while exposed. Both drugs effectively prevent exercise-induced bronchospasm when administered immediately prior to strenuous exercise. However, neither drug is as effective as a short-acting p-adrenergic agonist. Better efficacy has been reported for cromolyn when it is inhaled slowly from a large-volume (700 mL) holding chamber rather than a more rapid conventional inhalation. Alternatively, increasing the size of inhaled droplets (dependent on the nebulizer device used) may increase deposition. Results from either modification may be related to more homogeneous pulmonary distribution.
June 18, 2011 – 7:39 am
Atopic dermatitis is an inflammatory, immunoglobulin E-mediated skin disease characterized by intense pruritus, xerosis, and scaly, licheniform rash with a characteristic anatomical distribution. Therapy is directed at avoidance of inciting stimuli, moisture retention, emollients, antipruritics, and topical corticosteroids.
One report of a placebo-controlled, randomized, crossover study suggests that topical cromolyn may potentially benefit patients for whom the above therapeutic modalities have failed. Cromolyn prepared in an emollient base was applied to the skin of children and adolescents with moderate to severe atopic dermatitis. All subjects concomitantly applied a mid-potency topical steroid. Objective severity decreased significantly in the cromolyn-steroid group compared to the group treated with steroid alone. The study authors posit an additive anti-inflammatory effect based on the different mechanisms of action employed by corticosteroids and cromolyn.
Nedocromil may inhibit sensory nerve activation to reduce neurogenic itch and flare from histamine but does not modulate wheal diameter. It has not yet been evaluated clinically as a topical preparation.
Other reports have proposed that intranasal cromolyn or nedocromil (not commercially available in the United States as an intranasal preparation) may benefit the common cold. The causative viruses or atypical bacteria may produce a variety of inflammatory mediators, including histamine, cytokines, leukotrienes, and nitric oxide. Compared to placebo, both cromolyn and nedocromil provide a swifter resolution and reduced severity of symptoms in nonallergic subjects. Both drugs also reduce symptoms of virus-induced asthma exacerbations.
Systemic mastocytosis, a disease characterized by mast cell proliferation in multiple organ systems, usually features urticaria pigmentosa (brownish macules that transform into wheals upon stroking them) and recurrent episodes of flushing, tachycardia, pruritus, headache, syncope, abdominal pain, or diarrhea. Because it inhibits mast cell degranulation, orally administered cromolyn has some efficacy in mastocytosis, particularly for symptoms involving the gastrointestinal tract. However, cromolyn does not reduce plasma or urinary histamine levels in patients with mastocytosis.
Similarly, oral cromolyn has been employed as an alternative to an elimination diet in non-life-threatening food allergy, in irritable bowel syndrome, and atopic dermatitis where allergic sensitization to specific foods has been identified.
One group has reported that cromolyn has an antisickling effect in patients with sickle cell disease and concomitant allergic disease. The researchers postulate that the decrease in sickle cells may be a result of inhibitory effects of cromolyn on the calcium-activated potassium Gardos channel, which influences erythrocyte dehydration. Of the studied 18 patients with sickle cell disease, 10 were also taking hydroxyurea, and the report does not mention the duration of treatment or if the hydroxyurea dosage was altered. The clinical effect of reduced sickling activity was also not discussed. Clinical relevance therefore is uncertain.
May 6, 2011 – 8:59 am
The main goal of pharmacotherapy used in the treatment of allergic rhinitis (allergic rhinitis) is alleviating the hallmark symptoms of the disease (e.g., sneezing, rhinorrhea [runny nose], nasal congestion, nasal itching, ocular irritation). Although the triggers and allergic response durations may differ for patients with seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR), the symptoms of the two types of the disease are largely the same. Thus, similar agents are used to treat both forms of the disease.
Numerous therapies, including antihistamines, intranasal corticosteroids, leukotriene antagonists, decongestants, anticholinergic agents, and mast cell stabilizers, are employed in the treatment of allergic rhinitis symptoms. While currently available allergic rhinitis therapies collectively are very effective in controlling the symptoms of the disease, certain drug classes are better than others in relieving particular allergic rhinitis symptoms. For example, antihistamines are effective in relieving many symptoms associated with mild to moderate allergic rhinitis (e.g., sneezing, rhinorrhea, nasal itching, ocular irritation), but these agents are less effective than intranasal corticosteroids in treating more-severe disease involving prolonged inflammation, and are less effective at controlling nasal congestion. In addition to differing efficacy for particular allergic rhinitis symptoms, current therapies also differ in routes of administration and dosing frequencies. Thus, physicians must balance desired efficacy with convenience when recommending pharmacotherapy to an allergic rhinitis patient. TABLE Current Therapies Prescribed for Allergic Rhinitis summarizes the leading therapies available to treat allergic rhinitis in the seven major markets under study (United States, France, Germany, Italy, Spain, United Kingdom, and Japan), and TABLE: Comparison of Current Therapies for Allergic Rhinitis summarizes their relative advantages and disadvantages.
Second-generation antihistamines and intranasal corticosteroids are the most commonly prescribed allergic rhinitis therapies, and there are numerous marketed products within these drug classes. Thus, the discussion here focuses primarily on agents within these two drug classes. The less numerous leukotriene antagonists are also discussed in greater detail in the following sections.
Mast cell stabilizers and anticholinergics are also used in the treatment of allergic rhinitis symptoms. Mast cell stabilizers (e.g., cromolyn sodium [generics; also referred to as cromoglicic acid, disodium cromoglycate, or nedocromil sodium], pemirolast [Nikken Chemical’s Alegysal, generics], tranilast [Kissei’s Rizaban, generics]) are anti-inflammatory agents that address the symptoms of allergic rhinitis by preventing degranulation of mast cells and histamine release and, subsequently, synthesis of other inflammatory mediators. However, these agents require administration several times daily and take a period of days to weeks to reach maximum effect. Products containing cromolyn sodium are readily available over-the-counter (OTC) in all countries under study (AESGP, 2004[a]; AESGP, 2004[b]).
The anticholinergic agent ipratropium bromide (Boehringer Ingelheim’ s Atro-vent) effectively treats rhinorrhea by inhibiting secretions from the serous and seromucous glands lining the nasal mucosa, but has no effect on any other nasal symptoms. Also, like mast cell stabilizers, ipratropium bromide requires administration multiple times daily. Because of their frequent dosing schedules and inferior efficacy compared with other commercially available allergy medications, mast cell stabilizers and anticholinergics are not widely prescribed for allergic rhinitis, so these drug classes are not discussed in detail here.
Decongestants — administered orally or intranasally — are also routinely used in the treatment of nasal allergic rhinitis symptoms. (Ocular decongestant formulations can be used to treat eye redness and irritation associated with allergic rhinitis.) Therapies within this class are sympathomimetic agents that work by stimulating a-adrenergic receptors in vascular smooth muscle tissue. Oral and intranasal decongestants shrink mucous membranes and promote airflow and drainage, effectively reducing nasal congestion and, to a lesser extent, rhinorrhea. However, these agents do not address other common allergic rhinitis symptoms such as sneezing or itching. Consequently, oral and intranasal decongestants are most effective when used in combination with an antihistamine to treat allergic rhinitis.
Decongestant products are readily available OTC, and many second-generation antihistamines are now formulated with a decongestant as a fixed-combination product. Thus, this discussion of decongestants in the treatment of allergic rhinitis will be limited to their mention as fixed-combination products with second-generation antihistamines; decongestants are not discussed as a separate class here.
TABLE Current Therapies Prescribed for Allergic Rhinitis
Agent
Company / Brand
Daily Dose
Availability
Second-generation antihistamines
Fexofenadine + / – pseudoephedrine
Sanofi-Aventis’ Allegra / Telfast, Allegra-D 12 Hour
60 mg bid or 180 mg qd (for patients aged 12 years or older); 30 mg bid
(for patients aged 6-11 years)
US, France, Germany, Italy, Spain, UK, Japan
Cetirizine + / – pseudoephedrine
Pfizer / UCB / Daiichi / Sumitomo’s Zyrtec / Virlix
/ Cirrus, Zyrtec-D 12 Hour, generics
5-10 mg qd (for patients aged 6 years or older); 2.5 mg
bid or 5 mg qd (for patients aged 2-5 years); 2.5 mg bid or qd (for patients
aged 6-23 months)
US, France, Germany, Italy, Spain, UK, Japan
Desloratadine + / – pseudoephedrine
Schering-Plough’s Clarinex / Aerius / Neoclarityn, Clarinex-D
24 Hour
5 mg qd (for patients aged 12 years and older); 2.5 mg
qd (for patients aged 6-11 years); 1.25 mg qd (for patients aged 1-5 years);
1.0 mg qd (for patients aged 6-11 months)
US, France, Germany, Italy, Spain, UK
Levocetirizine
UCB’s Xyzal / Xusal
5 mg qd (for patients aged 6 years or older)
France, Germany, Italy, Spain, UK
Intranasal corticosteroids
Fluticasone
GlaxoSmithKline’s
2 sprays (50 g per spray) in
US, France, Germany, Italy, Spain,
propionate
Flonase / Flixonase, generics
each nostril qd or one spray in each nostril bid
(for patients aged 12 years or older); one spray (50 \ig per spray) in
each nostril qd (for patients aged 4-11 years)
UK, Japan
Mometasone
Schering-Plough’s
2 sprays (50 \ig per spray) in
US, France, Germany, Italy, Spain,
furoate
Nasonex
each nostril qd (for patients aged 12 years or
older); one spray (50 \ig per spray) in each nostril qd (for patients
aged 2-11 years)
UK
Leukotriene antagonists
Montelukast
Merck’s Singulair
10 mg qd (for patients aged 15 years or older); 5 mg
qd (for patients aged 6-14 years); 4 mg qd (for patients aged 2-5 years)
US, France, Germany, Italy, Spain, UK, Japan
aMontelukast is approved for the treatment of asthma in all seven countries under study. As of this writing, however, the drug is only indicated for treating seasonal allergic rhinitis in the United States and the United Kingdom.
bid = Twice daily; qd = Once daily.
TABLE: Comparison of Current Therapies for Allergic Rhinitis
Compound
Advantages
Disadvantages
Second-generation antihistamines
Fexofenadine
• Classified as a non-drowsy
antihis-tamine, with no label precautions cautioning against driving while
taking the drug.
• Label does not include PAR as an
approved indication.
• Only approved for children as young as
age six.
• Fixed fexofenadine / pseudoephed-rine
combination product is available in a 12-hour formulation, and a 24-hour
formulation has been approved by the FDA.
• Only available in oral tablet or
capsule formulations.
• Currently marketed in all seven
countries under study.
Cetirizine
• Indicated for both SAR and PAR.
• Approved for use in children as young
as six months in age.
• Available in oral tablet, chewable
tablet, and oral syrup formulations.
• Lower-priced generic versions are
currently available in most European countries.
• Currently marketed in all seven
countries under study.
• Not classified as a
“non-sedating” antihistamine.
• Due to the higher potential for
somnolence, product label includes a warning stating that patients taking
cetirizine should use caution when driving, operating machinery, or consuming
alcohol or other agents that can depress the CNS.
• Fixed cetirizine / pseudoephedrine
combination product is only available in a 12-hour formulation.
Desloratadine
• Classified as a non-drowsy antihistamine,
with no label precautions cautioning against driving while taking the drug.
• Currently not marketed in Japan.
• First second-generation antihis-tamine to
demonstrate proven, consistent efficacy in relieving nasal congestion.
• Indicated for both SAR and PAR.
• Approved for use in children as young
as six months in age.
• Available in oral tablet, rapidly
disintegrating tablet, and oral syrup formulations.
• Fixed desloratadine / pseudoephedrine
combination product is available in a 24-hour formulation.
Levocetizine
• Indicated for both SAR and PAR.
• First second-generation antihistamine
to be indicated for PER, which reflects the new classification put forth in
the ARIA report.
• Has demonstrated proven, consistent
efficacy in relieving nasal congestion.
• Only approved for children as young as
age six.
• Product label acknowledges that no
evidence from comparative clinical trials has indicated levocetirizine
negatively affects mental alertness, reactivity, or ability to drive, but the
label does state patients should consider their potential response to the
drug if they intend to drive, operate machinery, or participate in hazardous
activities, as sedating effects have been noted in clinical trials involving
levocetirizine.
• Only available in oral tablet
formulation.
• Currently not marketed in the United
States and Japan.
Intranasal corticosteroids
Intranasal fluticasone propionate
• Superior efficacy in relieving nasal
symptoms compared with oral second-generation antihistamines.
• Significantly reduced systemic
bioavailability compared with other intranasal corticosteroid products.
• Currently marketed in all seven
countries under study.
• Indicated for children as young as age
four.
• Must be delivered via the nasal route,
which is less desirable to patients than oral formulations.
• “Steroid stigma” precludes
some patients from using this agent unless absolutely necessary.
Intranasal mometasone furoate
• Superior efficacy in relieving nasal
symptoms compared with oral second-generation antihistamines.
• Significantly reduced systemic
bioavailability compared with other intranasal corticosteroid products.
• Must be delivered via the nasal route,
which is less desirable to patients than oral formulations.
• “Steroid stigma” precludes
some patients from using this agent unless absolutely necessary.
• Indicated for children as young as age
two.
• Currently not marketed in Japan.
• Only currently available intranasal
corticosteroid that is indicated for the prophylaxis of nasal symptoms in SAR
patients.
Leukotriene antagonists
Montelukast
• Indicated for allergic rhinitis in children
as young as age two.
• Due to its alternative mechanism of
action (leukotriene inhibition), the drug is often used in combination with
oral second-generation antihistamines for patients who fail to achieve
adequate symptom relief with antihistamine monother-apy and who seek an
alternative to intranasal corticosteroids.
• Available in oral tablet and chew-able tablet
formulations for allergic rhinitis patients. (An oral granule formulation is
also available, but is only indicated for use in treating asthma in children
ages 12-23 months.)
• Efficacy is only comparable to oral second-generation
antihistamines, and has been shown to be inferior to that of intranasal
fluticasone propionate.
• Marketed for asthma in all countries
under study, but only formally approved for SAR in the United States and the United
Kingdom.
ARIA = Allergic Rhinitis and Its Impact on Asthma; CNS = Central nervous system; PAR = Perennial allergic rhinitis; PER = Persistent allergic rhinitis; SAR = Seasonal allergic rhinitis.
April 27, 2011 – 9:33 am
Rapitil 2% w/v Eye Drops
Nedocromil Sodium
Rapitil 2% Eye Drops (called Rapitil Eye Drops in this leaflet) contain a medicine called nedocromil sodium. This belongs to a group of medicines called anti-allergies.
It works by stopping the release of the natural substances in your eyes that can lead to an allergic reaction.
Stopping, treating and relieving the symptoms of ‘allergic conjunctivitis’ (inflammation of parts of the eye). Rapitil Eye Drops can be used for three types of allergic conjunctivitis:
‘Perennial allergic conjunctivitis’ in adults only: This type of allergy can happen at any time of the year and is often caused by animal fur or house dust mites. Signs include itchy, watery, red or inflamed eyes and puffy eyelids.
‘Seasonal allergic conjunctivitis’ in adults and children: This type of allergy, such as hay fever, can be caused by different pollens in different seasons of the year. Signs include itchy, watery, red or inflamed eyes and puffy eyelids.
‘Vernal kerato conjunctivitis’ in adults and children: This is a more severe type of allergy. Signs include bumps inside the upper eyelid, sensitivity to light and severe itching
You are allergic (hypersensitive) to nedocromil sodium, or any of the other ingredients of Rapitil Eye Drops (listed in Section 6 below)
Signs of an allergic reaction include: a rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue or around the eyes
Do not use this medicine if the above applies to you. If you are not sure, talk to your doctor or pharmacist before using Rapitil Eye Drops.
You wear soft contact lenses. You should not wear soft contact lenses while using these drops If you are not sure if this applies to you, talk to your doctor or pharmacist before using Rapitil Eye Drops.
Talk to your doctor before using this medicine if you are pregnant, might become pregnant or think you may be pregnant.
If you are breast-feeding or planning to breast-feed, talk to your doctor or pharmacist before taking or using any medicine.
Your eyesight may be affected after using this medicine. If this happens, do not drive or use any tools or machines until you can see clearly.
Important information about some of the ingredients of Rapitil Eye Drops
Rapitil Eye Drops contain benzalkonium chloride. This may cause your eyes to become irritated. It may also change the colour of your contact lenses.
Always use Rapitil Eye Drops exactly as your doctor or pharmacist has told you. You should check with your doctor or pharmacist if you are not sure.
If you wear hard or gas-permeable contact lenses, you should take them out while you use the eye drops. You should wait 10 minutes before you put the contact lenses back in
If you feel the effect of your medicine is too weak or too strong, do not change the dose yourself, but ask your doctor or pharmacist
Wash your hands
Remove the cap from the bottle
Tilt your head back
Squeeze one or two drops inside the
ower lid without touching your eye
Close your eye
Wipe away any excess liquid from the eyes with a clean tissue
Always put the cap back on the bottle as soon as you have used it
Repeat in the other eye as needed
How much to use
Adults, Elderly and Children aged 6 years and over Seasonal allergic conjunctivitis:
One drop into each eye twice each day
This can be increased to four times each day if needed
Do not use for more than 12 weeks Vernal kerato-conjunctivitis
One drop into each eye four times each day Adults and the Elderly only
Perennial allergic conjunctivitis:
One drop into each eye twice each day
This can be increased to four times each day if needed
Use the drops regularly Children under 6 years
This medicine is not recommended for children aged less than 6 years.
If you forget a dose, use your drops as soon as you remember. However, if it is nearly time for your next dose, skip the missed dose. Do not use a double dose to make up for a forgotten dose.
Keep using the eye drops for as long as your doctor or pharmacist advises you. If you stop using Rapitil Eye drops too early, your allergy symptoms may come back.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
Like all medicines, Rapitil Eye Drops can cause side effects, although not everybody gets them.
Stop using Rapitil Eye Drops and see a doctor as soon as possible if:
The itching, redness or swelling gets worse. You may be allergic to these drops
Talk to your doctor or pharmacist if any of the side effects gets serious or lasts longer than a few days, or if you notice any side effects not listed in this leaflet:
Stinging or burning in your eyes or blurring of eyesight. This should only last for a short time and occurs immediately after using the eye drops
Mild eye irritation
Change in the way things taste
Keep tnis meaicme in a sare place where children cannot see or reacn it. Do not use Rapitil Eye Drops after the expiry date which is stated on the label and carton. The expiry date refers to the last day of that month. Store below 25°C. Keep the bottle in the outer carton in order to protect from light. Rapitil Eye Drops are sterile when you buy them, so you must not keep them for more than four weeks after opening the bottle. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.
The solution contains 2% w/v of the active substance, nedocromil sodium
The other ingredients are disodium edetate, benzalkonium chloride and sodium chloride
Rapitil Eye Drops are available as a clear yellow solution supplied in a 5 ml plastic dropper bottle.
April 13, 2011 – 6:10 am
The current consensus in the scientific medical community is that
asthma is a chronic inflammatory condition of the bronchial mucosa that
may lead to basement membrane thickening, collagen deposition, and
airway remodeling. It is a disease characterized by airflow obstruction
and bronchial hyper-responsiveness.The National Institutes of Health
National Heart, Lung, and Blood Institute revised the asthma guidelines.
The revised guidelines recommend daily use of a low-dose inhaled
corticosteroid (ICS) or an alternative inhaled anti-inflammatory
medication including cromolyn or a leukotriene receptor antagonist for
the management of mild persistent asthma in children <5 years. For adults and children >5 years the recommendations include the
additional alternative use of nedocromil or sustained-release
theophylline treatment for mild persistent asthma.
Traditionally many physician who have treated pediatric patients used
cromolyn sodium (CS) as a first-line treatment in mild persistent
asthma. Several studies have demonstrated the benefit of cromolyn and
nedocromil in the daily symptom control of asthma. In many cases this
course of treatment was chosen secondary to concerns by medical
practitioners and parents of children with asthma because of the
theoretic risk of untoward effects that ICS might have on longitudinal
growth and development. More recently several studies have demonstrated
that the use of ICS does not have any long-term effects on growth
despite short-term reductions in growth velocity. As a result, the
widespread use of cromolyn has been supplanted by ICS and the
availability of leukotriene antagonists.
Cromolyn is available in multiple delivery devices or forms,
including an oral inhaler, nebulization solution, nasal inhaler, ocular
eye drops, and oral capsules. Thus, cromolyn has been available for use
in the treatment of asthma, allergic rhinitis, allergic conjunctivitis,
chronic idiopathic urticaria, mastocytosis, and idiopathic anaphylaxis.
Nedocromil has only been available as a metered dose inhaler (metered
dose inhaler), which has limited its use to primary pulmonary problems
of asthma and chronic cough. In addition, exercise-induced bronchospasm
and allergen-induced early- and late-phase declines in expiratory
airflow may be prevented with the use of cromolyn and nedocromil. The
action of these agents can be categorized as effects on mast cells,
neuromodulatory actions, and anti-inflammatory activity. This chapter
will review the chemistry, mechanisms of action, physiochemical
properties, clinical trials and comparative trials, clinical
administration, toxicity, benefits, and limitations of cromolyn and
nedocromil.
Cromolyn and nedocromil are members of the chromone group of chemical
compounds. The chemical formula for chromone is 5:6 benz-1:4 pyrone. In
1968, disodium cromoglycate (DSCG) or CS combined with isoproterenol
was introduced in the United Kingdom as the first anti-inflammatory
medication used in asthma. The addition of the bronchodilator was done
to prevent bronchoconstriction that can occur with inhalation of a
sodium salt. By 1973, cromolyn was approved by the Food and Drug
Administration (FDA) for the treatment of asthma and in 1983 for the
treatment of allergic rhinitis  Khellin was the first identified
chromone, which was extracted from seeds of the plant Amni visnaga, the
same plant from which cromolyn was derived. It was used as a diuretic
and smooth muscle relaxant, especially for the relief of ureteric colic.
Multiple compounds were synthesized using the khellin molecular
structure as a starting point. Two other chromones, K 18 and GR4, used
in the sensitized guinea pig lung with antigen challenge prevented the
release of histamine and slow-releasing substances of anaphylaxis
(SRS-A).
Dr. Roger Altounyan discovered cromolyn in 1964 after many trials
with other chromone compounds. As a young child he had a history of
atopy and eczema, and later he developed severe chronic asthma  In his
early experiments he performed bronchial allergen challenges on himself
to induce bronchoconstriction. Pretreatment of himself with K 18 and GR4
demonstrated a 50% and 70% protection, respectively, against allergen
challenge. In 1963, a K84 compound provided 57% protection when
administered one hour prior to allergen challenge, but subsequent
studies failed to reproduce these observations. This discovery led to a
desire to perform human trials aimed at clarifying any therapeutic
effectiveness of this compound to treat asthmatics. Since the drug was
effective prior to inhalation of antigen in the preliminary
observations, the first human trial involved prolonged administration of
K84 prior to antigen challenge. Disappointingly, this trial of K84 in
one adult patient showed no improvement in his asthma symptoms. Further
analysis determined that the protection from allergen challenge in the
initial K84 experiments might be due to an “impurity” in the compound.
Eventually it was determined that two K84 molecules, joined at the —5
position, were responsible for the clinical observations. Thus, a new
bischromone, CS, was brought to clinical medicine. A second molecule
known as GR4 was the starting compound that led to the synthesis of the
monochromone, nedocromil sodium.
A. Cromolyn
At physiological pH both cromolyn and nedocromil are small,
water-soluble, highly ionized compounds with negligible fat solubility
that are poorly absorbed from the gastrointestinal (GI) tract. These
properties are responsible for the inability of these drugs to enter the
intracellular space of cells leading to their excretion in the urine
(80%) and feces after biliary secretion (20%). CS binding to plasma
proteins is poor and reversible, which accounts for the extremely low
incidence of adverse drug interactions. Less than 1 % of an oral dose of
CS is absorbed from the gastrointestinal tract, but approximately 7% to
9% of an inhaled dose reaches the systemic circulation with peak plasma
levels achieved 10 to 15 minutes after inhalation. Relatively rapid
clearance occurs from the lung with up to 75% of the inhaled dose being
removed by two hours. Only 2% of the inhaled dose may remain in the lung
for 24 hours. Plasma half-life is less than two hours and is nearly
undetectable for four hours, suggesting that a rapid clearance from the
vascular space occurs.
B. Nedocromil
Nedocromil belongs to the structural class of pyranoquinolines. As
noted above nedocromil is water soluble, rapidly absorbed from the lung,
has negligible fat accumulation, and has minimal absorption from the GI
tract. Similar to CS, adverse drug reactions occur infrequently due to
the low to moderate protein binding capacity of nedocromil. Drugs that
do bind proteins readily are not displaced by nedocromil, resulting in
no changes in half-life or clearance of these other compounds.
Nedocromil has only one available vehicle of medication-inhalation, a 2
mg per actuation metered dose inhaler, with <10% deposition of the total dose in the lung. The peak plasma concentration is reached at 15 minutes in asthmatic patients and the drug is excreted after pulmonary absorption in the urine and GI tract from swallowing (90%) and biliary excretion IV. Drug Distribution in the Lung The total delivered dosage and distribution of chromones in the lung are important factors in determining efficacy in the treatment of asthma. The inhalation airflow rate as well as the method of inhalation will determine the amount of drug reaching the lung  Cromolyn is available as an metered dose inhaler (1 mg and 5 mg), Spinhaler® and nebulizer solution (20 mg/ 2mL). An inhalation rate of 30L/min delivers a dose of 5.5% and 11.8% with the 5 mg and 1 mg metered dose inhaler, respectively, to the lung. This proportion increases to 16.1% with the addition of a 10 cm spacer using the 1 mg metered dose inhaler. Therefore, using a large volume spacer will increase the amount of drug delivered to the lung. Increase of 8.6% to 11.8% (a nearly 40% increase) of drug delivery to the lung when the inhalation rate was reduced from 70L/min to 30L/min. This increased drug deposition in the lung resulted in protection against allergen challenge. The use of a spinhaler at lower rates of inspiratory airflow reduces deposition in the lung. This requires the clinician to give specific instruction on the use of each delivery device for optimal drug effect. The peak plasma level reflects the dose of drug delivered to the lung. The peak plasma concentration with 1% aqueous cromolyn solution in healthy volunteers was 8.8 ng/mL using 2mL cromolyn alone, 17.2 ng/mL with 5 mL of cromolyn and isotonic saline, and 24.5 ng/mL with 0.3 mL of a β2-agonist (procaterol), cromolyn, and isotonic saline  The addition of a β2-agonist to cromolyn increased drug delivery to the lung. This has been interpreted that the bronchodilation effect will enhance drug deposition into the lung. The amount of cromolyn delivered to the lung can be measured by the 24-hour urinary excretion of DSCG. The addition of a large-volume spacer with DSCG metered dose inhaler increased from 1.82% to 6.13% of the delivered dose as measured by the 24-hour urinary excretion of DSCG. The 24-hour urinary excretion of DSCG increased by a factor of 1.53 with the addition of salbutamol in children with moderate to severe asthma. V. Cromone Mechanism of Action The exact mechanism of action of cromolyn and nedocromil has not been determined. Multiple mechanisms involving ion channel blockade, blockade of signaling of heat shock protein or G-protein, or even blockade of capsaicin receptor have been identified. However, the final common mechanism appears to be an inhibition of mast cell activation. Studies have reported that the phosphorylation of a 78-kDa-molecular-weight protein prevents mediator release in mast cells. More specifically in rat peritoneal mast cells, both medications are reported to phosphorylate a 78-kDa protein from the β and y subunits of the IgE binding protein (FCsRI), which may impair a cell volume-dependent chloride current  Wang et al. reported that protein kinase C inhibitors prevented phosphorylation of the 78-kDa protein by cromolyn and that this protein was insensitive to protein kinase C activators and Ca +. This suggests that regulation of an atypical protein kinase C may be involved as an additional mechanism where cromolyn inhibits mast cell activation. The protein kinase C isoenzymes are an important step in signaling cascade involved in the process of mast cell degranulation. Other proteins with molecular weights of 42, 59, and 68-kDa are activated in 10 seconds after the mast cell is challenged with allergen or compound 48/80, whereas the 78-kDa protein responds after 30 to 60 seconds  It is possible that termination of mediator release may be associated with phosphorylation of this 78-kDa protein  More recently this 78-kDa protein has been identified as moesin, a member of the 4.1 ERM superfamily, which includes ezrin, radixin, and merlin  These ERM proteins possess actin-binding domains and co-localize with actin at the plasma membrane surface  Thus, it is possible that moesin may interact with the cytoskeleton and prevent mast cell activation and secretion of mediators Furthermore, Garland and Mongor reported that cromolyn inhibited histamine release from rat peritoneal mast cells using phosphatidylserine and calcium  Both calcium and phosphatidylserine are required for the action of protein kinase C. This suggests that cromolyn may inhibit protein kinase C, which prevents mediator release in the mast cell. Another study reported that chromones act to inhibit the activation of a chloride current in cells undergoing shape and volume changes. Both cromolyn and nedocromil can inhibit chloride transport  In rat mucosal mast cells cromolyn has been reported to block an “intermediate conductance” chloride channel, which may inhibit the antigen-induced mediator secretion. Report of that both medications inhibit chloride current in activated pulmonary endothelial cells exposed to hypotonic saline and reduce open-channel availability of single chloride channels in sheep airway epithelial cells. Thus if the chloride current isn’t activated the membrane will not be hyperpolarized to allow for subsequent mast cell degranulation. Cromolyn can prevent extracellular calcium influx into the cytoplasm of the mast cell. The calcium channel activation that occurs after cross-linking membrane-bound IgE by antigen can be inhibited when mast cells are incubated with cromolyn. Thus, by inhibiting calcium influx and mediator release cromolyn may prevent allergic inflammatory responses. As previously described, cromolyn and nedocromil do not enter the intracellular space due to their physiochemical properties. It is likely that the effects of cromolyn are due to the binding of a membrane receptor at the cell surface. A specific binding site has been reported on rat basophil leukemia cells. Later work by other investigators reported that these RBL-2H3 cells were insensitive to the inhibitory effects of CS The inhalation of adenosine results in bronchoconstriction in asthmatic patients. Tamaoki et al. reported that inhaled adenosine also caused microvascular leakage in sensitized rats. Pretreatment with capsaicin or the tachykinin neurokinin-1 receptor antagonist FK888 prevents this microvascular leakage with inhaled adenosine. Moreover, cromolyn also prevents this adenosine-induced vascular extravasation of fluid. Cromolyn inhibited part of the heat shock protein 90 (Hsp 90) complex in vitro. The Hsp90 protein may be involved in signaling cascade, leading to mast cell degranulation. This protein can act to prevent protein aggregation and promote refolding in vitro. Both morphine and certain anesthetic muscle relaxants are known mast cell activators, but the mechanism of this effect has not been completely elucidated. One possible mechanism of morphine and d-Tubocurarine mast cell activation may be through activation of G-proteins. At concentrations of 10 µM and 100 µM DSCG reduced the stimulation of these G-proteins by morphine by 50% and 80%, respectively, possibly through direct inhibition of the G-proteins and resultant suppression of mast cell activation. Another possible mechanism for cromolyn may involve guanosine 3′, 5′ cyclic monophosphate (cGMP). A study with rat peritoneal mast cells showed that exogenously applied cGMP and treatment with DSCG produced a potent inhibition of histamine release. Cromolyn and nedocromil have a wide spectrum of activity that includes: inhibition of mediator release from mast cells, eosinophils, and neutrophils; protection against allergen-induced and exercise-induced bronchospasm; and prevention of the early- and late-phase asthmatic response Sheard and Blair were the first to report that CS prevented the antigen-induced release of histamine and SRS-A (leukotrienes) from passively sensitized human lung  More recently, pretreatment of rat peritoneal mast cells with DSCG prior to anti-DNP exposure resulted in
significant inhibition of histamine release in a dose-dependent manner. Both cromolyn and nedocromil inhibit histamine and PGD2 release from human mast cells; block activation of human eosinophils; inhibit activation, chemotaxis, and mediator release from neutrophils; inhibit IgE antibody function from mononuclear cells; inhibit the Sµ to Se switch; inhibit TNF-a release; and reduce mRNA for TNF-α from rat peritoneal cells. When atopic asthmatic patients are stimulated with Dermatophagoides farinae, cromolyn has been shown to inhibit the production of IL-5 and IFN-y by sensitized human peripheral blood mononuclear cells. A significant decrease in TNF-a and IL-5 was reported in sensitized human lung specimens from atopic patients  In addition to IL-5, Oh et al. reported that DSCG reduced secretion of IL-4 and IL-13 in PBMC from atopic patients. In bronchoalveolar lavage (BAL) and nasal lavage fluid, cromolyn reduced the increase in neutrophils, myeloperoxidase, soluble intercellular adhesion molecule-1, IL-6, and TNF-α. In patients with bronchopulmonary dysplasia (BPD), cromolyn was reported to decrease TNF-a and IL-8 in lung lavage fluid. Shin et al. reported significant inhibition of TNF-a release in the rat mast cell line RBL-2H3 pretreated with DSCG prior to antigen challenge. In 1969, Kennedy reported a reduction in sputum eosinophils with cromolyn treatment compared to placebo  More recently bronchial biopsy specimens had a reduction in EG2+ eosinophils, AA1+ mast cells, and CD4+, CD8+, CD3+, and CD68+ lymphocytes in patients treated with 12 weeks of cromolyn. Furthermore, a reduced expression of ICAM-1 and vascular cell adhesion molecule-1 were seen on bronchial epithelium and vascular endothelium after treatment with cromolyn CS has been beneficial in the treatment of aspirin-sensitive asthma (ASA) subjects. Amayasu et al. reported that ASA patients treated with cromolyn for one week resulted in an improvement in asthma symptoms, and demonstrated a significant decrease in blood and sputum eosinophils and sputum eosinophilic cationic protein (ECP) levels compared with placebo. Furthermore, there was an improvement in bronchial hypersensitivity in almost all patients. In addition to their effects on mast cells, cromolyn and nedocromil inhibit the expression of membrane receptors for complement (C3b) and IgG (Fc) in human neutrophils  Both medications have been reported to inhibit activation of human neutrophils by platelet-activating factor (PAF) or zymosan-activated serum  Cromolyn treatment decreases oxygen radical production in guinea-pig alveolar macrophages in response to zymosan in a concentration-dependent manner by 72%  The combination medication reproterol (32-agonist) and DSCG is used in Europe for the treatment of asthma. The combined reproterol and DSCG showed a significant inhibition of histamine release compared to another β2-agonist (salbutamol) in rat mast cells. A study in human lung mast cells demonstrated that CS is a weak inhibitor of histamine release when given 15 minutes before allergen challenge. CS effectiveness is inversely related to the intensity of immunologic stimulation. At a concentration of 1000 uM, cromolyn inhibits histamine release by 25% and PGD2 release by 85%. Since PGD2 is a potent bronchoconstrictor, this may be an important effect of cromolyn. Church et al. reported that the inhibitory effects of cromolyn on human mast cells are increased with a longer preincubation time. However, human skin mast cells are unresponsive to cromolyn, which is further supported by previous observations that cromolyn does not inhibit mast cell degranulation or the wheal and flare response in vivo. Nedocromil and cromolyn have been shown to inhibit the release of preformed (granule associated) and newly generated eicosanoid mediators from activated eosinophils. These specific proteins are eosinophil granule-associated peroxidase and eosinophilic cationic protein. In rat mono-cytes and peritoneal macrophages, as well as in human monocytes and alveolar macrophages, nedocromil has been reported to inhibit FcsR2-mediated activation. Bruijnzeel et al. reported that nedocromil blocked the chemotactic response of eosinophils to PAF and leukotriene B4. In the human airway, nedocromil has been reported to decrease IL-6 and lysosomal enzyme release from alveolar macrophages. In addition, nedocromil reduces histamine and tryptase release five minutes after allergen challenge in bronchial segments of allergic asthmatic patients. This is accompanied by a reduction of eosinophils in BAL fluid 48 hours after challenge  A longer-term study comparing 16 weeks of treatment with nedocromil versus regular albuterol showed a reduction in the number of activated eosinophils in those patients treated with nedocromil on bronchial biopsy  Furthermore, nedocromil decreases the release of TNF-a, IL-8, and soluble ICAM-1 from human bronchial epithelial cells. The bronchoconstriction induced by sulfur dioxide and bradykinin is inhibited by both cromolyn and nedocromil. Inhaled sodium metabisulfate generates sulfur dioxide in the airways with both of these agents causing bronchoconstriction in asthma subjects. The mechanism of action of sulfur dioxide may be through stimulation of laryngeal afferent nerve fibers in experimental animals  Nedocromil has been shown to prevent the bronchial hyper-responsiveness in dogs exposed to sulfur dioxide Bradykinin may have broader effects than sulfur dioxide by causing vascular vasodilatation and increased vascular permeability in addition to the bronchoconstrictor effect. The cough and dyspnea induced by bradykinin is blocked by cromolyn and nedocromil  In experimental animals, bradykinin has been reported to stimulate afferent C-fibers to release substance P (a mast cell histamine releaser), neurokinin A, and calcitonin gene-related peptide, which all have bronchoconstrictor properties. Nedocromil decreased cough in asthmatic patients and was initially marketed specifically for cough-related asthma. The angiotensin-converting enzyme (ACE) inhibitor-induced cough, a known complication of this class of medications, is inhibited by CS. Thus, the inhibition of bradykinin by chromones is likely to be the mechanism of action in preventing ACE inhibitor-induced cough. The substance P-induced histamine release from human mast cells is inhibited with nedocromil. There are a few case reports of successful treatment of ACE inhibitor-induced cough with inhaled cromolyn. The case reports involve a total of 13 patients of whom most had cromolyn added and continued on the ACE inhibitor  Four of the 13 patients had the ACE inhibitor stopped and were given cromolyn for seven days before the ACE inhibitor was resumed. The cough resolved in three of these patients. Only one trial evaluated the efficacy of cromolyn for treatment of the ACE inhibitor-induced cough. This was a double-blind crossover study of 10 patients. The median cough score decreased significantly in the cromolyn treated group  Alternatively, another small study with six diabetic patients on ACE inhibitors treated with nedocromil reported only one patient with cough relief. In canine airways, cromolyn has been shown to block both myelinated and non-myelinated (C) fibers. It is important to note that C-fibers respond to chemical irritants rather than mechanical stimulation and this may be a factor in the nonspecific irritation of the airways in asthma. Jackson reported that the stimulation of the cough reflex with inhalation of citric acid in a dog model is blocked by nedocromil but not cromolyn. In contrast, nedocromil was ineffective in the inhibition of citric acid-induced cough in asthmatic patients. Adenosine and adenosine 5′ monophosphate (AMP) result in bronchoconstriction in asthmatic patients by not normal subjects. Both CS and nedocromil inhibit adenosine-induced bronchoconstriction, although various studies show nedocromil to be more effective. The inhalation of hypertonic saline (5-15%) produced microvascular leakage in rat trachea. Pretreatment with DSCG reduced this extravasation in a dose-dependent manner. In addition, pr
etreatment with DSCG inhibited the microvascular extravasation from inhaled substance P in this study. Both cromolyn and nedocromil have been shown to have a protective effect in exercise-induced bronchospasm in both children and adults Also, these medications have an equal protective effect in response to cold air and bradykinin, substance P, neurokinin A, adenosine, and hypertonic saline  However, nedocromil has been shown to be more effective against sulfur dioxide and sodium metabisulfate  On the other hand, Altounyan showed that 10 times the dose of cromolyn is needed to provide 50% protection against sulfur dioxide challenge as compared to the dose needed for allergen challenge. An important clinical observation, potentially useful to allergic asthma subjects acutely exposed to allergen, was demonstrated when three doses of nedocromil given acutely over 90 minutes prior to antigen challenge resulted in the inhibition of the late asthmatic response. Furthermore, neither cromolyn nor nedocromil prevent the bronchoconstrictor response to inhaled histamine or methacholine. However, prolonged treatment may reduce bronchial hyper-reactivity. The use of cromolyn in allergen challenge studies has given variable results. CI,13 reported greater protection to allergen challenge (76% vs. 43%) with a slower inspira-tory rate and use of a spacer device when cromolyn was taken 30 minutes before allergen challenge. This is likely to due to a dose-dependent delivery of active drug. Similarly, exercise challenge studies have produced variable results. Protective effect with cromolyn of 38%, 56%, and 68% with doses of two puffs of 1 mg, two puffs of 5 mg, and four puffs of 5mg, respectively, given 30 minutes before exercise z, whereas no difference between the 1 mg and 5 mg dose of cromolyn was demonstrated in another study  Alternatively, Schoeffel et al. showed that two puffs of the 1 mg cromolyn dose provided >50%
protection in nine patients, which increased to 13 patients when four
puffs of the 1 mg dose were given.
Several studies have shown that ICS are more effective than cromolyn
in patients with severe asthma. However, some studies in mild to
moderate asthmatics have shown either comparable efficacy or an even
better response to ICS. On the other hand, the addition of cromolyn to
ICS failed to show any beneficial effect. A more recent review of 24
placebo-controlled trials of cromolyn concluded, “there is insufficient
evidence for a beneficial effect of CS as maintenance treatment in
children with asthma.” Further review of this study shows that cromolyn
is more effective in older children. In addition, a recent review
reported no significant difference between DSCG and placebo in children
with asthma. The use of cromolyn versus placebo administered via face
mask with spacer device in 167 children aged one to four years found no
difference in the primary outcome measure of symptom-free asthma days
between the two groups. Long-term studies with cromolyn have reported
good asthma control and improvement in lung function with a lower dosage
of cromolyn.
Children on cromolyn and ICS for prolonged periods had no evidence of
irreversible airway changes in a retrospective study in 175 infants in
three treatment groups.
One group of mild asthmatics was treated with as needed
bronchodilators, moderate asthmatics were treated with CS, and the
severe asthmatics were treated with ICS. In this study the final
pulmonary function tests (PFT) improved in both the cromolyn and ICS
groups compared to bronchodilators alone. However, the overall change in
pulmonary function from start to end of a study showed a significant
improvement of FVC only in the ICS group. Overall, the clinical outcomes
showed improvements in the frequency of hospitalizations in both the
cromolyn group and the ICS-treated group. Likewise, a reduction in
emergency department (ED) visits was observed in the ICS-treated group
when compared to the bronchodilator group, despite the perceived mild
severity of the latter group. Furthermore, a delay in starting cromolyn
was associated with an unfavorable effect in clinical outcomes, whereas
no effects were observed with delay of initiation of ICS.
A Finnish cross-sectional study of school children was divided into
three groups—bronchodilators only, cromolyn, and ICS—reported improved
PFT in the cromolyn group. This study involved 297 children: 60/297
(20%) on ronchodilators as needed for symptoms, 169/297 (57%) on
cromolyn or nedocromil, and 68/297 (23%) or ICS with budesonide or
beclomethasone. Thus, the majority of children in this study were on
chromones medication. The decrease in at least one of the parameters of
pulmonary function or the MMEF) was highest in the ICS group and lowest
in the chromone group. Analysis of the chromone group demonstrated that
the FVC and FEV1 were higher in the cromoglycate group (p <
0.05). This study only followed spirometry over one year and had
disproportionate numbers of participants in the study groups. Today the
ICS have proven to be beneficial and asthma guidelines have changed. The
percentage of patients with mild, moderate, and severe asthma on ICS
has steadily increased in the last decade.
De Baets et al. compared cromolyn to budesonide in a small
double-blind crossover study. This study involved 13 subjects (43-66
months) given inhaled cromolyn lOmg tid or budesonide 100 µg tid
for two months. A significant difference in morning peak flows was
demonstrated in the ICS group [160L/min vs. 150L/min (p<0.03). Fewer
asthma exacerbations were reported in the ICS group as well, 7 versus 16
on cromolyn (p < 0.005). However, there were no differences in bronchial hyper-responsiveness observed. The use of cromolyn therapy in early infancy and childhood has given conflicting data. While some studies have suggested that cromolyn may not be effective in the first year of life, one report verified that children under one year did show improvement with cromolyn  A reduction in symptoms and bronchodilator use has been observed with the use of cromolyn in a group of premature infants and children. In contrast, a recent review by the Cochrane database concluded that “cromolyn sodium cannot be recommended for the prevention of chronic lung disease in preterm infants”. The enigma of persistent wheezing after bronchiolitis has led investigators to experiment with preventive therapy during active disease. A single subsequent wheezing episode was lower in a group of children with bronchiolitis treated with cromolyn or budesonide. Prevention of the high cost of care from hospitalization favored the use of both medications in a subgroup of atopic children. Another method used to assess the efficacy of therapy is to match pharmacy records to outcomes of emergency visits or need for hospitalization. Such investigations are fraught with numerous confounding variables but point out important trends in subjects using medication. One study reviewed inhaled anti-inflammatory medication dispensing through an analysis of automated pharmacy records of 11,195 children ages 3 to 15 years with a diagnosis of asthma. The outcome measures were ED visits and hospitalization for asthma. The adjusted relative risk (RR) for ED visits with the use of either cromolyn or ICS were 0.4 (95% CI 0.3, and 0.5 (95% CI 0.4,0,9) respectively. For hospitalizations, the adjusted RR with cromolyn and ICS were 0.6 (95% CI 0.4, and 0.4 (95% CI 0.3,0,7) respectively. Thus, a record of the patient obtaining one of these agents (use can not be demonstrated) is highly associated with prevention of ED visits and hospitalization for asthma. A second investigation of pharmacy records analyzed the number of hospitalizations for asthma in 16,941 members from a Health Maintenance Organization (HMO) related to the use of ICS, cromolyn, and β-agonists . The primary outcome measure was time to the first hospitalization for asthma after dispensing. Dispensing one cromolyn inhaler was associated with a significant decreased RR of hospitalization of 0.8  for ages 0 to 17 years but was not protective in adults with RR of 0.8 (95% CI 0,6-1,1) for ages 18 to 44 years and RR of 0.8 (95% CI 3.1-6.0) for ages >45 years. For ICS the overall RR was 0.5. Furthermore, the RR for
the dispensing of >8 canisters of β-agonists was 4.3 (95% CI
3.1-6.0). This study was limited to one specific HMO and excluded
patients on Medicaid/Medicare.
Recently a study done by the Severe Asthma Research Committee in
Japan compared cromolyn to salbutamol. This study investigated 232
children with persistent asthma classified as either severe (64%) or
moderate (35%). DSCG (20mg) nebulized solution mixed with salbutamol was
compared to either agent of DSCG and salbutamol alone. The primary
outcome measure was the change in daily asthma symptom score.
The combination medication improved this score by 39% when compared
to salbutamol and 38% compared to DSCG. Although the individual agents
resulted in improvement, the combination was superior.
Similar studies with DSCG and bronchodilators also showed an
improvement in asthma symptoms. DSCG powder combined with isoprenaline
resulted in a 59% improvement with the combination medication compared
to only a 44% improvement with isoprenaline alone. A reduction of 33% to
35% in asthma severity classification was observed in 189 patients
treated with cromolyn (p < 0.00005).
For adult patients there were two critical clinical trials involving
cromolyn performed through the Medical Research Council (MRC) and the
Drug Committee of the American Academy of Allergy (AAA). The Medical
Research Council  trial involved 103 patients in four groups—cromolyn,
isoproterenol, cromolyn and isoproterenol, and placebo—for 12 months.
After eight weeks, the dose of cromolyn was reduced from 20 mg tid to a
twice-daily dosage and finally to a daily dose. At the end of the study
no outcome difference was found between patients receiving the full or
reduced dosage. Although pivotal, the power of the study to make this
observation may be problematic given the low number of subjects and
multiple treatment arms.
The American Academy of Allergy trial involved 252 patients comparing
cromolyn with placebo in a crossover design over eight weeks. The
investigators observed a significant treatment effect in 80% of the
patients receiving the placebo first.
Group of patients controlled on cromolyn spincaps that were switched
to placebo. After four weeks, the patients with worsening asthma were
treated with cromolyn or placebo. The patients treated with cromolyn had
significant improvement in their daily symptom scores for overall
asthma severity and pulmonary function parameter of FVC and PEF when
compared to the placebo treated subjects
Ideally, inhaled chromone therapy would reduce the need for oral
corticosteroid use in asthma. In an early study, the addition of
cromolyn to oral corticosteroids resulted in a 41% reduction in dose
after six months and withdrawal of steroids in 25% of patients after 1.5
years
As nedocromil is a newer agent when compared to cromolyn and comes in
only a single form, there is less information to draw conclusions from.
Most of the studies show a beneficial effect of nedocromil when
compared to placebo. Children with grass pollen asthma responded better
to nedocromil compared to placebo. In a study by Konig et al. , the use
of nedocromil did not prevent viral-induced bronchospasm but did improve
their recovery, overall symptoms, and PEFR on nedocromil. A third
investigation that compared nedocromil to placebo resulted in an
advantage to nedocromil with total symptom score reduction of 50%. In
addition, significant improvement in daytime and nighttime asthma,
morning and evening PEF, and use of rescue bronchodilators was shown
with the regular use of nedocromil.
Currently there is only one study comparing nedocromil to the use of
ICS. Children treated with beclomethasone dipropionate had a significant
improvement in nonspecific bronchial hyper-reactivity but no difference
in symptom scores, bronchodilator use, or pulmonary function changes.
At least three studies have demonstrated beneficial outcomes of
pulmonary function improvement, symptom scores, bronchodilator use, and
even corticosteroid sparing effect. An improvement in FEV1/FVC when
nedocromil was added to ICS in 120 children. In 76 asthmatic adults an
improvement in symptoms, bronchodilator use, and PEFR was observed when
nedocromil was added to ICS. Furthermore, Bone reported a reduction in
the dosage of ICS with the use of a nedocromil inhaler in adults.
The CAMP study measured several variables related to childhood asthma
treatment between four study groups: 311 patients on budesonide
compared with 208 patients on placebo, 312 patients on nedocromil
compared with 210 patients on placebo. The outcome measures included:
spirometry, AM/PM peak flows, methacholine challenge, use of study
medication, albuterol use, courses of prednisone, physician office
visits, ED visits, hospitalizations, and height. Overall the spirometry
showed no significant differences in either the budesonide or nedocromil
groups. However, there were some exceptions. In the nedocromil group
the FVC before bronchodilation was lower than in the placebo group, 0.6
versus 2.4, respectively (p = 0.02). In the budesonide group the FEV1/FVC before bronchodilation was 0.2 versus 1.8 in the placebo group (p = 0.001).
Four months after discontinuation of the study medication, the
nedocromil group had a smaller decrease in the baseline FEV1/FVC before
and after bronchodilation: 1.1 versus 2.5 (p = 0.01) and 1.2 versus 2.2 (p = 0.03), respectively. The budesonide group had a 43% lower rate of hospitalizations (p = 0.04)
compared with nedocromil, which showed no significant difference
compared to placebo. Urgent visits and prednisone courses were reduced
in the budesonide group by 45% (p < 0.001) and 43% (p < 0.001), respectively. The nedocromil group showed a reduction of 27% (p = 0.02) and 16% (p = 0.01), respectively, compared to placebo.
In 1993, a multistudy analysis of 4723 patients in 127 trials
reported that nedocromil was better than placebo in multiple variables:
daytime and nighttime asthma symptoms, cough, daily mean PEF, and FEV1,
rescue bronchodilator use, and patient satisfaction. This analysis
showed a 50% reduction in ICS dose when a higher nedocromil dose was
used.
A few studies have compared cromolyn to nedocromil, whereas others
have compared cromolyn, nedocromil, and ICS. No differences in PFT could
be found in 195 children treated with cromolyn, nedocromil, or ICS.
Similarly, there were no differences found in efficacy when comparing
cromolyn to nedocromil in another paper  Review of the Cochrane database
also could find no difference in efficacy between DSCG and nedocromil
during the post-exercise pulmonary functions in either the maximum
percent decrease in FEV1 or complete protection.
50% reduction of ICS dose with the addition of cromolyn or nedocromil
in adults. They reported that nedocromil was more effective than
cromolyn in symptom control and reduction of bronchodilator use.
Nedocromil superior in controlling symptoms; however, both cromolyn
and nedocromil were effective with decreasing non-specific bronchial
hyper-reactivity and the need for rescue bronchodi-lators. Nedocromil
was more effective against sulfur dioxide challenge, but that there was
no difference between cromolyn and nedocromil with protection against
inhaled allergen. This suggests that nedocromil may be superior in
controlling neuronal-induced mechanisms of bronchospasm when compared to
cromolyn. In contrast, another study involving 306 younger, milder
allergic asthmatics found the use of cromolyn to produce improved
results when compared to nedocromil. Exercise-challenge induced
bronchospasm was controlled with both of the two chromones and both were
more effective than placebo.
A comparison of nebulized cromolyn to nebulized nedocromil in
children <2 years was conducted in 23 asthmatic children (19/23
males), treated for two months with cromolyn, nedocromil, then placebo.
No significant differences in symptom scores between the treatment
groups were reported. However, in the cromolyn group there was a trend
for older children to respond to cromolyn (16.4 months) versus
nedocromil (12.1 months).
Both medications have been used to treat patients with ASA.
Nedocromil and DSCG in 10 patients with ASA who were treated with lysine
acetylsalicylate. They reported that DSCG and nedocromil use resulted
in a maximal decrease in FEV1 to 20% ±3% and 18% ±4%, respectively (p < 0.01) during challenge without a significant difference between the two medications.
In vitro comparisons of basophil histamine release after stimulation
with anti-IgE, anti-IgE + IL-3, and ryegrass allergen showed unexpected
findings. Nedocromil augmented histamine release only with ryegrass and
cromolyn did not affect histamine release.
XII. Cromolyn for Allergic Rhinitis
In recent years, the one airway hypothesis linking disease and
therapy in the lung and nose simultaneously suggests a need to briefly
review the effect of the chromones on nasal allergy. Intranasal cromolyn
is available over the counter as an aqueous preparation topical spray.
Several studies have reported that intranasal cromolyn is superior to
placebo in the treatment of seasonal allergic rhinitis (seasonal
allergic rhinitis). In particular, a decrease in mouth breathing, nasal
congestion, rhinorrhea, postnasal drip, and sneezing in 66 patients
treated with intranasal cromolyn for ragweed rhinitis was observed.
Similarly, a decrease in rhinitis symptoms and, in this case, ocular
symptoms, was observed in 88 patients treated with cromolyn for
pollen-induced seasonal allergic rhinitis  A decrease in rhinitis
symptoms measured by the average daily rhinitis symptom score resulted
in decreased antihistamine use with cromolyn in a small study of 47
patients (p < 0.01). Perennial allergic rhinitis symptoms were decreased with cromolyn. In contrast, two studies showed that intranasal cromolyn was equivalent to placebo. Intranasal cromolyn and nedocromil were equivalent in reducing allergic rhinitis symptoms compared to placebo in a study by Schuller et al. involving 233 patients. Overall, rhinitis symptoms were significantly reduced with nedocromil as recorded by the symptom summary card (p=0.02). A comparison of terfenadine, a non-sedating antihistamine, with cromolyn was found to be equivalent  Terfenadine was subsequently withdrawn from the market due to cardiac dysrhythmia problems. This study cannot be extrapolated to other antihistamines. This study also showed that cromolyn had a significant reduction in the number of eosinophils (p = 0.025) measured by nasal cytology scores, whereas terfenadine patients showed no significant differences. When cromolyn is compared to nasal corticosteroids, both flunisolide and beclomethasone have shown greater efficacy. However, both nasal corticosteroids and intranasal cromolyn are more effective than placebo for allergic rhinitis. Cromolyn is available for use in allergic disease and asthma as a single-dose vial for oral nebulization, metered dose inhaler (oral and nasal), and ophthalmic preparation. Oral cromolyn, although poorly absorbed from the GI tract, has been used in the treatment of mastocytosis, chronic idiopathic urticaria, and Gl-associated anaphylaxis with anecdotal success. CS for oral inhalation is available as 1 and 5 mg per actuation metered dose inhaler, 20 mg 1 % aqueous solution, and 20 mg capsules for use with the Spinhaler or E-haler (Eclipse). The 1 mg per actuation metered dose inhaler and 20 mg 1% aqueous solution are available in the United States. Intranasal cromolyn is available over the counter as a 4% solution. The recommended dosage is one spray per nostril four times daily. When cromolyn was first developed it was combined with isoprenaline to prevent the bronchoconstriction associated with the inhalation of the sodium salt.  The blood levels of cromolyn can be increased by the addition of a β2-agonist.  Furthermore, the clinical response of cromolyn is improved with addition of a β2-agonist.  In light of the favorable outcomes with ICS compared to cromolyn alone, new research may be needed to compare the use of cromolyn in combination with a β2-agonist compared to ICS to ascertain the correct circumstances and delivery method in asthma therapy. Nedocromil sodium is available as a 2 mg metered dose inhaler. Two studies on the nedocromil dosing frequencies reported no overall difference, but Wells reported that patients in the higher dose frequency required few courses of oral steroids. The CAMP study evaluated long-term use of nedocromil and reported a reduction in urgent care visits and fewer courses ofprednisone. However, another study with short-term use of nedocromil reported significant differences compared with placebo. Compliance with medication regimens remains an issue with all patients. Traditionally, inhaled cromolyn is dosed four times daily while nedocromil is dosed twice daily. Furukawa et al. studied the same children on cromolyn four, three, or twice daily for one-month intervals. They reported that pulmonary function during the twice-daily use for a month showed a trend toward deterioration compared with the month of dosing three times daily. In a similar study with adults, no difference in those patients allowed to reduce their cromolyn dose (2.5 doses/day) compared to those on four daily doses was seen  In general, cromolyn is started four times daily and is often reduced to twice daily when asthma has been controlled. Whether there would be equal efficacy if the same total mg dose was delivered twice daily versus four times daily is unclear. Overall, both oral inhaled cromolyn and nedocromil are well tolerated with minimal side effects. The side effects reported with cromolyn include: throat irritation, cough, nasal congestion, mild bronchospasm, urticaria, angioedema, anaphylaxis, anaphylactoid reaction, and pulmonary infiltration with eosinophilia (PIE), cardiac tamponade and eosinophilia, dysuria, dermatitis, and myositis  One patient experienced a near-death exacerbation as he tried to use DSCG during an asthma attack. The adverse effects of intranasal cromolyn include: sneezing, nasal burning or stinging  It has been reported that ocular cromolyn can result in contact dermatitis, allergic conjunctivitis, and chemosis . A 63-year-old male treated with DSCG ophthalmic solution developed allergic conjunctivitis and IgE antibodies to DSCG were demonstrated in serum by RAST. Anti-CS antibodies have been documented by intracutaneous and RAST testing. Increased lymphocyte proliferation and elevated production of migration inhibition factor in response to cromolyn stimulation and increased serum immunoglobulin G binding of cromolyn in one patient with PIE compared to cromolyn-tolerant patients. Drug interactions have not been documented with cromolyn. Overall, cromolyn can be used safely in elderly patients with hypertension, heart disease, seizure disorders, or prostate disease. Cromolyn is classified as category B in pregnancy. Patients who will benefit from intranasal cromolyn include: children >2 years, elderly patients, patients with
comorbidities, patients reluctant to take medications, patients and
athletes who undergo drug monitoring to avoid corticosteroids.
In general, nedocromil is well tolerated with a good safety record.
On the other hand, nedocromil has been associated with an unpleasant
taste, nausea, and vomiting.
There has been a concern with growth rate and the use of ICS in
children. A recent study compared bone mineral density in children on
fluticasone propionate (FP) versus nedocromil for two years. No
significant difference in growth was observed between the groups;
adjusted mean growth rates were 6.1 cm/yr with FP and 5.8 cm/yr with
nedocromil.
Both cromolyn and nedocromil have no effect on normal host defense,
no known teratogenic effects, and do not influence the development of
neo-plastic disease  A 10-year follow-up study with cromolyn showed no
adverse effects.
In summary, both cromolyn and nedocromil can be useful as adjuvant
therapy in the treatment of asthma. Their benefits have been seen in a
reduction in ED visits and hospitalizations for asthma, and a decrease
in allergen/exercise-induced bronchospasm and frequency of prednisone
use. Furthermore, cromolyn has been useful in the treatment of allergic
rhinitis and allergic conjunctivitis, with occasional use in other
systemic diseases.
April 13, 2011 – 6:09 am
Asthma is defined by the Global Initiative for Asthma (GINA) as a
chronic inflammatory disorder of the airways, causing an increase in
airway hyper-responsiveness that leads to recurrent episodes of
wheezing, breathlessness, chest tightness, and coughing. These episodes
are usually associated with widespread but variable airflow obstruction
that is often reversible. This revised definition emphasizes two crucial
characteristics of asthma: first, the central role of chronic airway
inflammation in the pathophysiology of asthma, and second, the variable
nature of the disease. Appreciation of the key role of the underlying
inflammation in asthma implies that anti-inflammatory agents are the
cornerstone of asthma therapy. Recognition of the variable nature of
asthma implies that a flexible approach is needed in the management of
this disease.
The goals of successful asthma management include achieving and
maintaining asthma control. A patient’s asthma is under control if the
patient has minimal (ideally no) chronic symptoms, has no limitations on
activities, experiences neither exacerbations nor emergency visits, and
attains and maintains lung function close to normal, while avoiding
adverse events from asthma medications. Good control of asthma can be
achieved in a majority of patients if exposure to risk factors (e.g.,
smoking) is avoided and if the currently available antiasthma drugs are
used properly. However, the Asthma Insights and Reality surveys
demonstrated that a significant proportion of patients worldwide
continue to have symptoms and lifestyle restrictions and to require
emergency care. Moreover, the use of anti-inflammatory preventative
medication was low, even in patients with severe persistent asthma.
These surveys thus point out that in many patients worldwide, asthma
control is still suboptimal, despite the availability of effective
therapies.
In this chapter we still divide the pharmacotherapy of asthma in
reliever therapy using rescue medications on the one hand, and
maintenance therapy using controller medications on the other hand. As
will be discussed later, the use of the rapid- and long-acting inhaled
β2-agonist formoterol as both a reliever and controller medication
already underlined that this distinction has become rather artificial.
The advent of the combination formoterol/budesonide in a single inhaler
further closes the gap between reliever and controller therapy, since
this combination is currently under investigation as single-inhaler
therapy in patients with persistent asthma of different levels of
severity. However, for reasons of clarity, we still find it useful to
discuss the pharmacotherapy of reliever and controller medications
separately. It is also imperative to educate the asthmatic patient about
the different treatments as part of an asthma (self-) management plan,
and the words “reliever” and “controller” remain useful in educational
terms.
Reliever medications are medications that act quickly to relieve
bronchoconstriction and the accompanying acute symptoms such as
shortness of breath, chest tightness, wheezing, and cough. These
quick-relief or rescue medicines include rapid-acting inhaled
β2-agonists, inhaled anticholinergics, systemic glucocorticosteroids,
short-acting theophylline, and short-acting oral β2-agonists.
Rapid-acting inhaled β2-agonists are the cornerstone for treatment of
episodic bronchoconstriction and acute exacerbations of asthma, and
should be available to every asthmatic patient suffering from mild to
severe persistent asthma to provide rapid relief of symptoms. These
rapid-acting inhaled β2-agonists, such as albuterol (salbutamol) and
terbutaline, should be used as required for symptom control (“as
needed”) instead of as regularly scheduled therapy four times daily
They are also indicated for the pretreatment of exercise-induced asthma
It is important to keep in mind, both for asthmatic patients and their
treating physicians, that the increased use of rapid-acting inhaled
pVagonists, especially during the night, is a warning of worsening of
asthma, indicating the need to start or to augment a maintenance
anti-inflammatory therapy.
Since formoterol has both a rapid onset and a long duration of
action, this inhaled β2-agonist can also be used “as needed”. In
patients with moderate persistent asthma who are taking regular inhaled
corticosteroids (ICS), the use of formoterol as rescue medication
improved asthma control compared to as-needed use of terbutaline. In a
large international real-life asthma study (the RELIEF study), use of
formoterol as needed had a similar safety profile to salbutamol, and its
use as a reliever therapy was associated with fewer asthma symptoms and
exacerbations
Interestingly, reductions of exacerbations with
as-needed formoterol versus salbutamol increased with increasing age and
asthma severity. However, the open label design of the study might
introduce a significant potential for bias, implying that further
studies are needed to identify the role of formoterol as a reliever
therapy.
The combination of formoterol and the inhaled corticosteroid
budesonide has been made available as a convenient fixed combination of
these agents, marketed under the product name Symbicort®. Although this
formoterol/budesonide combination in a single inhaler was first launched
for the maintenance treatment of moderate and severe persistent asthma,
the rapid action of both compounds also offers the opportunity to use
Symbicort as a rescue therapy. Indeed, budesonide is an inhaled
corticosteroids with significant acute effects in improving lung
function. As stated above, the long-acting pVagonist formoterol has also
a fast onset of action, comparable to the short-acting salbutamol.
Consequently, the combination of formoterol/budesonide has a faster
onset of action than salmeterol/ fluticasone, improving shortness of
breath and lung function already three minutes after administration.
Triggers are factors that cause asthma symptoms by provoking acute
bronchoconstriction or precipitate asthma exacerbations by inducing
airway inflammation. Interestingly, most triggers, including allergens,
respiratory
infections (e.g., rhinovirus), air pollutants (e.g., passive
smoking), and weather changes, can provoke both acute symptoms due to
bronchocon-striction and acute exacerbations of asthma due to enhanced
inflammation of the airways
From a pathophysiological point of view, it
is thus logical to use both the rapid-acting inhaled β2-agonist
formoterol and the inhaled corticosteroids budesonide in case of asthma
symptoms triggered by one of these risk factors. Indeed by using the
formoterol/budesonide combination as rescue therapy it is expected that
not only the acute symptoms due to the broncho-constriction will be
rapidly relieved (by the formoterol component), but that also the
possibly ensuing exacerbation will be prevented (by the budesonide
component, preventing an escalation of the inflammatory changes in the
airways). Thus, by promptly increasing the number of inhalations of the
combination formoterol/budesonide when experiencing an onset of
worsening symptoms, asthmatic patients could prevent the development of
an exacerbation. It is, however, not known if increasing the number of
inhalations of the combination formoterol/budesonide from a single
inhaler is more efficacious than increasing both drugs separately in the
treatment of an acute exacerbation. Convenience comes at a price, but
higher efficacy of the single-inhaler therapy in this clinical situation
needs further documentation.
Short-acting theophylline may be considered for relief of symptoms,
but as a bronchodilator theophylline is less effective than an inhaled
β2-agonist, and its onset of action is significantly slower than that of
a rapid-acting β2-agonist
Moreover, since theophylline has the
potential for severe adverse effects, short-acting theophylline should
not be administered to patients who are already on long-term treatment
with slow-release theophylline, unless the serum concentration of
theophylline is known.
Short-acting oral β2-agonists could be used as rescue therapy in the
few patients who are unable to use aerosolized medications
appropriately. However, adverse side effects such as cardiac arrhythmia,
tachycardia, tremor, and hypokalemia occur more frequently with this
oral therapy compared to treatment with inhaled rapid-acting
β2-agonists. Administering the rapid-acting β2-agonists by inhalation is
thus preferred, since this route of administration has the advantage of
delivering effectively high concentrations of medications directly to
the airways, while the systemic side effects are minimized.
Last, systemic glucocorticosteroids are the “final” rescue therapy,
since they are crucial in the treatment of severe acute exacerbations.
Systemic corticosteroids such as prednisolone or methylprednisolone
prevent the progression of an asthma exacerbation, decreasing the need
for hospitalization or emergency department visit. Even after emergency
treatment of an acute asthma attack, systemic corticosteroids prevent
early relapse. The pharmacotherapy of asthma attacks, including the use
of systemic glucocorticosteroids, is discussed in greater detail.
The choice of therapy depends upon the severity of a patient’s
asthma, but is also influenced by the availability and cost of
antiasthma medications, and by the characteristics of the individual
patient.
Intermittent Asthma
If over a period of at least three months a patient experiences less
than once a week symptoms of cough, dyspnea, or wheezing, the patient
has intermittent asthma. Nocturnal asthma symptoms are rare and occur
less than twice a month. The patient is asymptomatic in between
exacerbations and has a normal lung function (peakflow as well as FEV1).
No maintenance treatment with a controller medication is recommended
for intermittent asthma. Patients with intermittent asthma who
experience rare but severe exacerbations, however, should be treated as
having moderate persistent asthma.
Persistent Asthma
If a patient experiences symptoms more than once a week over a
three-month period, or has nocturnal asthma symptoms more than twice a
month, the patient has persistent asthma. Patients with persistent
asthma require controller medication every day.
Inhaled Corticosteroids
ICS are the cornerstone therapy for patients with persistent asthma
at all levels of severity, and are considered the most effective
anti-inflammatory therapy. Numerous studies have demonstrated that
treatment with inhaled corticosteroids decreases the pathological signs
of airway inflammation in asthmatics z, reduces the airway
hyper-responsiveness z, and improves lung function. More importantly,
both symptoms and the frequency and severity of exacerbations are
reduced in patients with persistent asthma treated with inhaled
corticosteroids
Even in patients with mild persistent asthma of recent
onset, once-daily treatment with low-dose budesonide significantly
decreased the risk of severe exacerbations and improved asthma control
In this inhaled steroid treatment as regular therapy in early asthma
(START) study, inhaled corticosteroids treatment also resulted in more
symptom-free days and better lung function measurements compared to
placebo
The ideal inhaled glucocorticoid should display maximal
antiasth-matic effects, without systemic bioactivity. The main
determinants of efficacy are dose and potency of the compound, and the
percentage of lung deposition from the delivery device. Both the
receptor affinity and intrinsic activity determine the potency of a
glucocorticoid
On the other hand, adverse effects of inhaled
corticosteroids result from systemic exposure, implicating that the main
determinants of safety are the oral and pulmonary bioavailability of
the drug
The therapeutic ratio is the ratio of safety (risk) to
efficacy (benefit), and is shifted into the favorable range if the
receptor affinity and lung tissue affinity of an inhaled corticosteroids
are high and the oral bioavailability—due to a rapid metabolic
inactivation—is low. The glucocorticoids flunisolide and triamcinolone
have a less favorable therapeutic ratio, since both inhaled
corticosteroids have a low receptor and lung tissue affinity and a high
oral bioavailability (±20%). The newer inhaled corticosteroids
fluticasone propionate, mometasone furoate, and ciclesonide have a high
receptor and lung tissue affinity and a very low oral bioavailability
(less than 1 %), so that a favorable therapeutic ratio can be expected.
Moreover, the systemic availability of fluticasone propionate is
substantially less in patients with moderate to severe asthma than in
healthy controls, indicating that inhaled corticosteroids with minimum
oral bioavailability that are absorbed through the lungs need to be
assessed in patients who are receiving doses appropriate for disease
severity, and not (only) in normal volunteers. On the other hand, in
mild or moderate asthma, maximal clinical benefit is already attained
with lower doses of highly potent corticosteroids. Further increase of
dose does not add to efficacy, but compromises safety in the milder
spectrum of the disease.
Alternative Maintenance Treatments of Mild Persistent Asthma Several
other medications, including theophylline, leukotriene modifiers, and
cromones, can be used instead of inhaled corticosteroids in the
treatment of patients with mild asthma. Sustained-release theophylline
can be used as a second-line controller medication in asthma. In
patients with mild persistent asthma, monotherapy with sustained-release
theophylline is effective in controlling asthma symptoms and improving
lung function. Although theophylline is usually less effective than low
doses of inhaled corticosteroids z, it is less expensive. While
dose-response studies showed an increasing bronchodilator response of
theophylline above plasma concentrations of 10mg/L, the
anti-inflammatory effects of theophylline are seen at concentrations
that are usually less than 10mg/L. At these low doses (plasma
concentration 5-10 mg/L) theophylline is easier to use, side effects are
uncommon, and the problems of drug interaction are less of an issue.
Moreover, the side effects of theophylline may be reduced by gradually
increasing the dose until therapeutic—anti-inflammatory—concentrations
are achieved.
Leukotriene modifiers, including the 5-lipoxygenase inhibitor
zileuton and the cysteinyl leukotriene receptor antagonists
(montelukast, pranlukast, and zanrlukast), could serve as an alternative
to inhaled corticosteroids in patients with mild chronic asthma.
Leukotriene modifiers have, indeed, a small and variable bronchodilator
effect, improving lung function and reducing asthma symptoms
However,
the effect of leukotriene modifiers as mono-therapy in mild persistent
asthma is less than that of low doses of inhaled corticosteroids.
Moreover, the effect of leukotriene receptor antagonists as single-agent
asthma treatment on asthma exacerbations is small, and less than that
obtained by inhaled corticosteroids at doses equivalent to 400 µg/day
beclometha-sone. Since leukotriene modifiers are administered as a
tablet, this route of administration is an advantage in asthma patients
who are unable to use aerosolized medications (metered-dose inhalers,
dry powder inhalers, and nebulized aerosols) correctly. A second
indication for leukotriene modifiers are patients with aspirin-sensitive
asthma who may respond well to this new class of antiasthma drugs, but
these patients often have more severe persistent asthma, needing a
combination of several drug classes to control their asthma.
The cromones sodium cromoglycate or nedocromil may be used as
controller therapy in mild persistent asthma. Since cromones produce
only minimal side effects and do not influence growth velocity, they are
of special interest in children with mild allergic asthma. However,
both nedocromil and sodium cromoglycate are less effective than inhaled
corticosteroids. Since cromones prevent the acute airflow limitation
induced by exercise, they can be administered prophylactically before
sporting. A major drawback to using cromones as a maintenance treatment,
however, is the fact that they need to be administered three to four
times a day, which is inconvenient for both asthmatic children and their
parents, thereby decreasing therapy compliance and thus endangering
clinical effectiveness.
Several patient groups, including children, pregnant women, and the
older adult asthmatics, need special consideration when the management
of asthma is discussed. We will focus here on the management of asthma
in pregnant women and in women who want to become pregnant. The greatest
risk to pregnant patients with asthma and to their babies is poorly
controlled asthma, since this can result in low birth weight, increased
prematurity, and increased perinatal mortality
The inhaled
corticoster-oids beclomethasone dipropionate and budesonide, inhaled
short-acting β2 agonists, theophylline (at therapeutic
levels), and sodium cromoglycate are not associated with an increased
incidence of fetal abnormalities
It is important to reassure pregnant
patients with asthma that these treatments are both safe and necessary.
inhaled corticosteroids remain the cornerstone of pharmacotherapy of
persistent asthma in pregnant women, and have been demonstrated to
prevent exacerbations of asthma specifically in pregnancy. Since the
majority of the safety data and experience concerns beclomethasone
dipropionate and budesonide, we recommend to use these inhaled
corticosteroids in pregnant women with chronic persistent asthma.
Combination of an inhaled corticosteroids and a Long-Acting β2-Agonist
When low to medium doses of inhaled corticosteroids fail to achieve
control of asthma, long-acting inhaled β2-agonists (formoterol or
salmeterol) should be added before increasing the dose of inhaled
corticosteroids. Numerous clinical studies have demonstrated that—in
patients with moderate to severe asthma—the addition of long-acting
inhaled β2-agonists to a daily therapy with inhaled corticosteroids
improves symptoms, increases lung function, decreases the rate of asthma
exacerbations, and is more effective than increasing the dose of
inhaled corticosteroids twofold or more. Indeed, most of the therapeutic
benefit of inhaled corticosteroids is achieved with a total daily dose
of <500 µg/day beclomethasone dipropionate (<400 µg) day
budesonide or <250 (µg/day fluticasone propionate), indicating a relatively flat dose-response curve of inhaled corticosteroids in adults with asthma. However, since there is considerable individual variability in the response to inhaled corticosteroids in asthma, some patients—especially the more severe asthmatics with frequent exacerbations—may obtain a greater benefit at higher doses. The greater efficacy of adding a long-acting inhaled β2-agonist to an inhaled corticosteroids than increasing the dose of inhaled corticosteroids has led to the development of fixed combination inhalers (formoterol plus budesonide; salmeterol plus fluticasone). Recently, the Gaining Optimal Asthma Control (GOAL) study demonstrated that in patients whose asthma is not controlled as defined by GINA/ NIH guidelines, asthma control was achieved more rapidly and in more patients with salmeterol/fluticasone combination therapy than with fluticasone monotherapy In this one-year, randomized, double-blind, parallel-group study of more than 3400 patients with uncontrolled asthma, treatment with either fluticasone or salmeterol/fluticasone combination was stepped up until total control was achieved. Importantly, asthma control was achieved at a lower corticosteroid dose with salmeterol/fluticasone combination versus fluticasone, and patients that achieved control recorded very low rates of exacerbations (0.07-0.27/patient/yr) and near-maximal health status scores (as assessed by the Asthma Quality of Life Questionnaire) Even in patients entering the GOAL study as corticosteroid-naive, combination therapy showed greater efficacy than fluticasone monotherapy. This contrasts with the OPTIMA-A trial, in which little additional benefit was obtained with the addition of formoterol to the inhaled corticosteroids budesonide in corticosteroid-naive patients with mild asthma. However, this difference may be explained by differences in patient selection (patients with very mild asthma) in the OPTIMA-A trial versus uncontrolled moderate to severe asthmatics in the GOAL study and in primary outcome selection (single endpoint of time to first severe asthma exacerbation in the OPTIMA-A trial versus composite measure of total control in the GOAL study). Since both short-term and long-term treatment with long-acting inhaled β2-agonists do not influence the chronic airway inflammation in patients with asthma z, it is imperative that this therapy should always be combined with inhaled corticosteroids. Indeed, two clinical trials performed by the National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network clearly demonstrated the risks of monotherapy with the long-acting inhaled β2-agonist salmeterol in adult patients with persistent asthma. In the SOCS (Salmeterol or Corticosteroids) trial, patients with moderate asthma who were treated with salmeterol alone experienced more asthma exacerbations and more treatment failures than patients treated with the inhaled corticosteroids triamcinolone in monotherapy Moreover, a similar worsening of asthma control, including an increase in asthma exacerbations and a decrease in pulmonary function, was observed in the SLIC (Salmeterol ± Corticosteroids) trial. This study examined if the addition of salmeterol on a scheduled basis in patients with moderate asthma permitted a reduction in dose (or even elimination) of inhaled corticosteroids over time. Discontinuation of inhaled corticosteroids in this SLIC trial was clearly not safe, indicating that long-acting inhaled β2-agonists cannot be used as monotherapy in patients with persistent asthma. To ensure that the long-acting inhaled β2-agonist is always accompanied by an ICS, the use of fixed combination inhalers, delivering corticosteroids and long-acting β2-agonist together, is strongly recommended. Moreover, these fixed combination inhalers appear at least as effective as giving each drug separately, and are more convenient for patients, thereby increasing compliance. Other Medications as Add-On Therapy to inhaled corticosteroids in Patients with Moderate to Severe Asthma In patients with moderate to severe asthma theophylline may be used as an add-on therapy to low or high doses of inhaled corticosteroids when further asthma control is needed. Compared to long-acting inhaled β2-agonists however, theophylline is less effective as add-on therapy and is associated with more frequent adverse effects, but it is less expensive. Leukotriene modifiers (cysteinyl leukotriene receptor antagonists and the 5-lipoxygenase inhibitor zileuton) can be used as add-on therapy to inhaled corticosteroids in patients whose asthma is not controlled with low or even high doses of inhaled corticosteroids. In these patients with moderate (to severe) asthma, adding the leukotriene receptor antagonist montelukast to the inhaled corticosteroids budesonide was superior to adding placebo and appeared as effective as doubling the dose of inhaled budesonide. When studying the effects of the leukotriene receptor antagonist zafirlukast on the rate of asthma exacerbations, it is important to consider the dose of zafirlukast used in the clinical studies. At the licensed dose (20 mg twice per day) adding zafirlukast to inhaled corticosteroids was inferior to doubling the dose of ICS, whereas at higher than licensed doses (80 mg twice per day) zafirlukast as add-on therapy to inhaled corticosteroids appeared as effective as doubling the dose of inhaled corticosteroids. Leukotriene modifiers are less effective than long-acting inhaled β2-agonists as add-on therapy , although one study suggests a similar preventative effect on asthma exacerbations when montelukast was added to low-dose fluticasone, compared to add-on therapy with salmeterol. Some patients with severe persistent asthma remain inadequately controlled despite combined available therapy. These patients represent a significant unmet medical need, since they are at high risk of serious exacerbations and asthma-related mortality. Omalizumab is an anti-IgE humanized recombinant monoclonal antibody, which suppresses IgE-mediated allergic reactions by binding to free IgE. Results from several clinical trials have shown that omalizumab decreases the number of exacerbations and the need for emergency medical interventions in patients with severe allergic asthma on high-dose inhaled corticosteroids or on ICS/long-acting β2-agonist combination therapy Moreover, significantly greater improvements were achieved with omalizumab compared with placebo in asthma symptom scores and asthma-related quality of life. Omalizumab is thus indicated for the prevention of asthma exacerbations and control of asthma symptoms when given as add-on therapy for adult and adolescent patients with severe persistent allergic asthma who remain inadequately controlled, despite daily high-dose inhaled corticosteroids plus a long-acting inhaled β2-agonist. April 13, 2011 – 6:02 am (Patanol solution 0.1%) Olopatadine hydrochloride is an ophthalmic antihistamine that inhibits release of histamine from mast cells and is a relatively selective histamine H1 antagonist. It inhibits type 1 immediate hypersensitivity reactions. Olopatadine hydro-chloride is indicated in the temporary relief of itching caused by allergic conjunctivitis. H1 antagonists have an established and valued place in the symptomatic treatment of various immediate hypersensitivity reactions. In addition, the central properties of some of the series are of therapeutic value for suppressing motion sickness or for sedation. H1 antagonists are most useful in acute types of allergy that present with symptoms of rhinitis, urticaria, and conjunctivitis. Their effect is confined to the suppression of symptoms attributable to the histamine released by the antigen-antibody reaction. In bronchial asthma, histamine antagonists have limited efficacy and are not used as sole therapy. In the treatment of systemic anaphylaxis, in which autacoids other than histamine play major roles, the mainstay of the therapy is epinephrine; histamine antagonists have only a subordinate and adjuvant role. The same is true for severe
angioedema, in which laryngeal swelling constitutes a threat to life. Other allergies of the respiratory tract are more amenable to therapy with H1 antagonists. The best results are obtained in seasonal rhinitis and conjunctivitis (hay fever, pollinosis), in which these drugs relieve the sneezing, rhinorrhea, and itching of eyes, nose, and throat. A gratifying response is obtained in most patients, especially at the beginning of the season when pollen counts are low; however, the drugs are less effective when the allergens are most abundant, when exposure to them is prolonged, and when nasal congestion is prominent. Topical preparations of antihistamines such as levocabastine (Livostin), azelastine (Astelin), ketotifen (Zaditor), and olopatadine (Patanol) have been shown to be effective in allergic conjunctivitis and rhinitis. Nasal sprays or topical ophthalmic preparations of these agents are available in the United States. Histamine causes the release of inflammatory cytokines and eicosanoids and increases expression of endothelial adhesion molecules. In addition, H1-receptors can, either via constitutive activity or after stimulation by agonists, activate the proinflammatory transcription factor NF-kB. Thus, H1 antihistamines have been investigated for potential antiinflammatory properties. Although H1 antihistamines do exhibit a variety of antiinflammatory effects in vitro and in animal models, in many cases the doses required are higher than those normally achieved therapeutically, and clinical effectiveness has not yet been proven. Cromolyn sodium (Crolom), which prevents the release of histamine and other autacoids from mast cells, has found limited use in treating conjunctivitis that is thought to be allergen-mediated, such as vernal conjunctivitis. Lodoxamide tromethamine (Alomide) and pemirolast (Alamast), mast-cell stabilizers, are also available for ophthalmic use. Nedocromil (Alocril) also is primarily a mast-cell stabilizer with some antihistamine properties. Olopatadine hydrochloride (Patanol), ketotifen fumarate (Zaditor), and azelastine (Optivar) are H1 antagonists with mast-cell-stabilizing properties. Epinastine (Elestat) antagonizes H1 and H2 receptors and exhibits mast-cell-stabilizing activity. April 13, 2011 – 5:55 am Nedocromil sodium is a mast-cell stabilizer that inhibits release of mediators from inflammatory cell types associated with asthma, including histamine from mast cells and beta-glucuronidase from macrophages. It may also suppress local production of leukotrienes and prostaglandins and inhibit development of bronchoconstriction responses to inhaled antigen and other challenges such as cold air. It is  indicated in the maintenance of mild to moderate bronchial asthma and treatment of itching caused by allergic conjunctivitis. Nedocromil, a well-tolerated drug (2 inhalations 4 times a day at regular intervals to provide 14 mg / day), is indicated for maintenance therapy in the management of patients with mild to moderate bronchial asthma. Nedocromil has no intrinsic bronchodilating, glucocorticoid, or antihistaminic properties. Therefore, it should not be used in status asth-maticus. It inhibits the in vitro activation of, and mediator release from, a variety of inflammatory cell types associated with asthma, including eosinophils, neutrophils, macrophages, mast cells, monocytes and platelets. In vitro, nedocromil inhibits the release of mediators including histamine, leukotriene C4 and prostaglandin D2. Similar studies with human bronchoalveolar cells showed inhibition of histamine release from mast cells and beta-glucuronidase release from macrophages. Nedocromil inhibits the development of early and late bronchoconstriction responses to inhaled antigen. The development of airway hyperresponsiveness to nonspecific bronchoconstrictors was also inhibited in airway microvasculature leakage. Nedocromil is bound to plasma proteins to the extent of 89%, is not metabolized, and is excreted unchanged. Cromolyn was synthesized in 1965 in an attempt to improve on the bronchodilator activity of khellin. This chromone, derived from the plant Ammi visnaga, had been used by the ancient Egyptians for its spasmolytic properties. Although devoid of the bronchodilating effect of the parent compound, cromolyn was found to inhibit antigen-induced bronchospasm as well as the release of histamine and other autacoids from sensitized rat mast cells. Cromolyn has been used in the United States for the treatment of asthma since 1973. The initial clinical results were disappointing, in retrospect largely owing to a misplaced hope that cromolyn would reduce or eliminate the need for systemic glucocor-ticoids in the treatment of patients with relatively severe asthma. However, its therapeutic role has been reevaluated in recent years, and cromolyn has emerged as one of the first-line agents in the treatment of mild to moderate asthma. Nedocromil, a compound with similar chemical and biological properties, became available in 1992. Cromolyn and nedocromil have a variety of activities that may relate to their therapeutic efficacy in asthma. These include inhibiting mediator release from bronchial mast cells; reversing increased functional activation in leukocytes obtained from the blood of asthmatic patients; suppressing the activating effects of chemotactic peptides on human neutrophils, eosinophils, and monocytes; inhibiting para-sympathetic and cough reflexes and inhibiting leukocyte trafficking in asthmatic airways. For asthma, cromolyn is given by inhalation using either solutions (delivered by aerosol spray or nebulizer) or, in some countries but not in the United States, powdered drug (mixed with lactose and delivered by a special turboinhaler). The pharmacological effects result from the topical deposition of the drug in the lung, since only about 1% of an oral dose of cromolyn is absorbed. Once absorbed, the drug is excreted unchanged in the urine and bile in about equal proportions. Peak concentrations in plasma occur within 15 minutes of inhalation, and excretion begins after some delay such that the biological half-life ranges from 45 to 100 minutes. The terminal half-time of elimination following intravenous administration is about 20 minutes. Cromolyn and nedocromil generally are well tolerated by patients. Adverse reactions are infrequent and minor and include bronchospasm, cough or wheezing, laryngeal edema, joint swelling and pain, angioedema, headache, rash, and nausea. Such reactions have been reported at a frequency of less than 1 in 10,000 patients. Very rare instances of ana-phylaxis also have been documented. Nedocromil and cromolyn can cause a bad taste. The main use of cromolyn (Intal) and nedocromil (Tilade) is to prevent asthmatic attacks in individuals with mild to moderate bronchial asthma. These agents are ineffective in treating ongoing bronchoconstriction. When inhaled several times daily, cromolyn inhibits both the immediate and the late asthmatic responses to antigenic challenge or to exercise. With regular use for more than 2 to 3 months, bronchial hyperreactivity is reduced, as measured by response to challenge with histamine or metha-choline. Nedocromil generally is more effective than cromolyn in animal models and human beings. Nedocromil is approved for use in asthmatic patients 12 years of age and older; cromolyn is approved for all ages. Cromolyn and nedocromil generally are less effective than inhaled glucocorticoids in controlling asthma. Cromolyn (2 mg inhaled four times daily) was less effective than 200 µg twice daily of beclomethasone or 4 mg four times daily of nedocromil. Although nedocromil was roughly comparable with 200 µg beclomethasone inhaled twice daily, nedocromil was not as effective in controlling symptoms, reducing bronchodilator use, or improving bronchial hyperreactivity. In a second study, 4 mg nedocromil four times daily was as effective as 100 µg beclomethasone four times daily. Nedocromil is useful in patients with mild to moderate asthma as added therapy, as an alternative to regularly administered oral and inhaled β-adrenergic agonists and oral methylxanth
ines, and possibly as an alternative to low-dose inhaled glucocorticoids. The addition of cromolyn to inhaled glucocorticoid therapy yields no additional benefit in moderately severe asthma. Nedocromil may allow a reduction of steroids in patients receiving high doses of inhaled steroids. In patients with systemic mastocytosis who have GI symptoms owing to an excessive number of mast cells in the GI mucosa, an oral preparation of cromolyn (Gastro-crom) is effective in reducing symptoms. The benefits reflect local action rather than systemic absorption; cromolyn is poorly absorbed, and only the GI symptoms are improved in the treated patients. April 13, 2011 – 5:36 am A disorder of the tracheobronchial tree characterized by mild to severe obstruction to airflow which is at least partially reversible. Symptoms vary, generally episodic or paroxysmal, but may be persistent. The clinical hallmark is wheezing, but cough or chest tightness may be the predominant symptom. Commonly misdiagnosed as recurrent pneumonia or chronic bronchitis. • Acute symptoms are characterized by narrowing of large and small airways due to spasm of bronchial smooth muscle, edema and inflammation of the bronchial mucosa, and production of mucus • Occurs in a setting in which asthma is likely and other, rarer conditions have been excluded System(s) affected: Pulmonary Genetics: Search for an asthma gene underway: there is a familial association of reactive airway disease (RAD), atopic dermatitis, and allergic rhinitis Incidence/Prevalence in USA: • 10 million new cases each year, however, there is confusion due to lack of a uniform definition • 7-19% of children • A leading cause of missed school days — 7.5 million/ year Predominant age: • 50% of cases are children under 10 • Young adult (16-40 years); but may occur at any age Predominant sex: • Children under 10: Male > Female
• Puberty: Male = Female
• Adult onset: Female > Male
Variation in pattern of symptoms: paroxysmal, constant, abnormal pulmonary function tests may occur without symptoms
• Wheezing
• Cough
• Chest tightness
• Chest pain
• Periodicity of symptoms
• Exercise-induced wheezing or cough
• Prolonged expiration
• Nocturnal attacks
• Pulsus paradoxus
• Tachycardia
• Hypoxia
• Accessory respiratory muscle use
• Flattened diaphragms
• Nasal polyp; seen in cystic fibrosis and aspirin sensitivity, not in uncomplicated asthma
• Clubbing is not seen in asthma
• Growth is usually normal
• Pectus carinatum
• Allergic factors
– Airborne pollens
– Molds
– House dust (mites)
– Cockroaches
– Animal dander
– Feather pillows
• Other factors
– Tobacco smoke and other pollutants
– Infections, especially viral
– Aspirin
– Exercise
– Cold air
– Sinusitis
– Gastroesophageal reflux
– Sleep (peak expiratory flow rate [PEFR] lowest at 4 am)
• Current research focuses on inflammatory response (including
abnormal release of chemical mediators, eosinophil chemotactic factor,
neutrophil chemotactic factor, and leukotrienes, etc.)
Risk Factors
• Positive family history of asthma or atopy
• Viral lower respiratory infection during infancy
• Environmental tobacco smoke
• Inner city dwelling
Differential Diagnosis
Foreign body aspiration — always consider, especially with unilateral
wheeze; cystic fibrosis; viral respiratory infections (croup,
bronchiolitis); epiglottitis; bronchopulmonary aspergillosis;
tuberculosis; hyperventilation syndrome; mitral value prolapse; habit
cough; recurrent pulmonary emboli; congestive heart failure; chronic
obstructive pulmonary disease; hypersensitivity pneumonitis; vascular
anomalies; mediastinal mass; tracheobronchomalacia; vocal cord
dysfunction
Laboratory
• CBC normal
• Nasal eosinophils
• Immunoglobulins
– Screen for immunodeficiency (IgA, IgG subclasses)
– IgE markedly elevated in allergic bronchopulmonary aspergillosis (ABPA)
• Sweat test in chronic childhood asthmatics
• Arterial blood gases in status asthmaticus
• Theophylline level [therapeutic: 5-15 µg/mL (28-84 µmol/L)]
Drugs that may alter lab results: Antihistamines may alter allergy skin testing
Disorders that may alter lab results: N/A
Pathological Findings
Smooth muscle hyperplasia; mucosal edema; thickened basement
membrane; inflammatory response; hyperinflated lungs; mucus plugging;
bronchiectasis is not seen except in association with ABPA
Special Tests
• Pulmonary function tests — reversible airway obstruction (increased airway resistance, decreased airflow rates)
• Allergy testing
• PPD
• Exercise tolerance testing
• Cold air provocation
• Ventilation-periusion scan
• Methacholine challenge
Imaging
Chest x-ray (hyperinflation, atelectasis, air leak)
Diagnostic Procedures
• Chest x-ray: do at least one, but not necessary with each exacerbation (right middle lobe atelectasis common)
• Spirometry: decreased FEV1
• Bronchoscopy: rarely indicated
• Laryngoscopy with exercise challenge to diagnose vocal cord dysfunction
Appropriate Health Care
• Outpatient
• Inpatient for bronchospasm not relieved by beta-agonists and steroids
General Measures
• Environmental control of irritants
– Molds may grow in vaporizers
– Frequent bathing of pets
• Consider hyposensitization — not usually helpful in persistent asthma
• Education essential
• Use spacer device with all metered dose inhalers (MDI)
• Six major classes of drugs are used:
– Steroids (budesonide, fluticasone, prednisone, etc)
– Mast cell stabilizers (cromolyn and nedocromil)
– Beta-agonists (albuterol, bitolterol, salmeterol, etc.);
increase in response to symptoms
– Methylxanthines (theophylline) OAnticholinergics (atropine, ipratropium)
– Leukotriene modifiers
• Prophylactic management with anti-inflammatories (inhaled steroids, cromolyn, leukotriene modifiers)
• Delivery systems
– Children < 2 — nebulizer or MDI with valved spacer and mask
– Children 2-4 years — MDI and valved spacer
– Over 5 years — MDI with spacer or dry powder inhaler
• The following are NOT recommended: mist, large volumes of fluid, breathing exercises, IPPB
• Supplemental oxygen essential for hypoxemia in exacerbations
Activity
Early diagnosis and appropriate treatment facilitate unrestricted activity
Diet
No special diet
Patient Education
• American Lung Association, 1740 Broadway, New York, NY 10019, (212)315-8700
• Asthma and Allergy Foundation of America, Suite 305. Washington, DC 20036, (800)7-ASTHMA, (800)727-8462
• Asthma Logbook, Teton NewMedia, (877)306-9793
Drug(s) of Choice
• Mild intermittent asthma: brief wheezing < 2 times a week: – Intermittent beta-agonist (MDI or nebulizer) — albuterol. 2 puffs 1.25-5 mg of 0,5% solution (0.25-1.0 mL) • Mild persistent asthma: symptoms > 2 times a week but < 1
time a day; affecting activity with PEFR variability < 20%. Medicate daily. – Inhaled steroids (low doses) preferred – Cromolyn qid or nedocromil bid (2 puffs or 2 mL nebulized) – Consider zafirlukast (Accolate) or montelukast (Singulair) • Moderate persistent asthma: weekly symptoms interfering with sleep or exercise, occasional ER visits, PEFR 60-80% of predicted, PEFR variability >30%. Medicate on regular maintenance schedule.
– Inhaled steroids 400-800 /jg/day.
– If not controlled with moderate dose inhaled steroid (600;Ug/day), add long-acting beta agonist
– Fluticasone-salmeterol (Advair) (combination drug) helpful with compliance
– Consider montelukast
• Severe persistent asthma: frequent symptoms affecting activity,
nocturnal symptoms, frequent hospitalizations, PEFR <60% predicted
– High dose inhaled steroids; some patients may need alternate day oral steroids
– Salmeterol as long-acting bronchodilator
– Fluticasone-salmeterol (Advair) helpful with compliance
– Theophylline often useful, particularly for nighttime symptoms
– Consider montelukast
– Consider cromolyn, ipratropium
• Acute exacerbation
– Outpatient management
– Inhaled beta-agonist (albuterol), 1.0 mL/5 mg (dose varies 0.25-1.0 mL with 2 mL NS) to reverse airflow obstruction
– Levalbuterol (Xopenex) is expensive and of no additional benefit
– Short course of steroids, 2 mg/kg po qam for 5-7 days
– IV aminophylline adds toxicity only
– Observe at least one hour; look for increased work of breathing, air leak syndromes, atelectasis. lowered PEFR
– Hospital management
– Steroids: methylprednisolone (Solu-Medrol) 2 mg/kg IV once, then 1 mg/kg IVq6h
– Frequent nebulized beta-agonist, even continuous at 5-30 mg/hr
– Ipratropium neb (250-300 meg) and/or aminophylline IV drip if not responding well
– Rarely: isoproterenol orterbutaline IV; magnesium sulfate IV; mechanical ventilation
Contraindications:
• Sedatives, mucolytics
• Antibiotics are usually not necessary
• Avoid beta-adrenergic blocking drugs
Precautions:
• Chronic use of beta agonists may be deleterious; use only when
needed (chronic asthma may necessitate chronic use). If beta-agonist
used more than twice a week, patient should also be on an
anti-inflammatory.
• Do not use salmeterol alone — mortality increased, especially in blacks.
Significant possible interactions: Erythromy-cin and ciprofloxacin slow theophylline clearance and can increase levels 15-20%
Alternative Drugs
• Ketotifen
• H1-antagonists
• Troleandomycin (TAO)
• Methotrexate
• Immune globulin IV
• Furosemide (Lasix)
• Omalizumab (Xolair), a monoclonal, IgE binding antibody, can be
used in patients with moderate to severe persistent asthma, poorly
controlled with inhaled steroids and other first-line treatments;
administer SC dose q 2-4 weeks; expensive (up to $12,000/year)
– Patients should have positive skin test or RAST
– Patient IgE should be elevated, but < 700 lU/mL
(drug may be ineffective in patients with very high IgE levels)
• Monitor PEFR at home — record for trend; call if < 70% baseline, ER if < 50% baseline
• pH and arterial blood gases
• Oximetry with status asthmaticus
• Electrolytes — frequent albuterol lowers potassium
• Written and periodically revised action plan is helpful
• Review MDI technique periodically
• Co-management is essential
– Understand medication, inhalers, nebulizers, peak flow meters
– Monitor symptoms, possibly peak flows
– Pre-arranged action plan for exacerbations
– Written guidelines
• Investigate and control triggering factors (pollutants, exercise, house-dust mite, roaches, molds, animal dander) if severe
• Annual influenza immunization
• Avoid aspirin
• Avoid suifites (food additives)
• Respiratory failure; mechanical ventilation
• Atelectasis — most common in right middle lobe
• Flaccid paralysis after exacerbation (self-limited) and rare
• Death
• Air leak syndromes (pneumothorax, etc.)
• SIADH
• Altered theophylline metabolism
• Steroid myopathy
• Inhaled steroid safety has been established
• Excellent, with attention to general health and use of medications to control symptoms
• In childhood asthma, < 50% “outgrow if”
• Mortality risk increases with:
– Greater than 3 emergency room visits/yr
– Nocturnal symptoms
– History of ICU admission
– Mechanical ventilation
– Greater than 2 hospitalizations/yr
– Systemic steroid dependence
– History of syncope with asthma
– History of noncompliance
• Mortality rates are increasing
• If responsive to treatment is poor, review diagnosis and compliance prior to adding more potent therapy
Associated Conditions
• Reflux esophagitis
• Sinusitis
Age-Related Factors
Pediatric: 50% of new cases of asthma occur in children below 10 years
Geriatric: Unusual for initial episode to occur
Pregnancy
• About 50% of asthma patients have no changes, 25% seem to improve and 25% have worse symptoms
• Stress prevention
• Avoid medications with contraindications
Synonyms
• Bronchial asthma
• Reactive airway disease
International Classification of Diseases
493.00 Extrinsic asthma, unspecified 493.10 Intrinsic asthma, unspecified 493.90 Asthma, unspecified
See Also
Cystic fibrosis
Bronchitis, acute
Immunodeficiency diseases
Bronchiolitis
Laryngotracheobronchitis
Epiglottitis
Congestive heart failure
Chronic obstructive pulmonary disease & emphysema
Hypersensitivity pneumonitis
Tuberculosis
Other Notes
Antihistamines are not contrain-dicated in asthma
Abbreviations
ABPA = allergic bronchopulmonary aspergillosis
PFT = pulmonary function test
RAD = reactive airway disease
PEFR = peak expiratory flow rate
MDI = metered dose inhaler
NS = normal saline
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