Anti-Allergy Eye Drops Product Monograph

INDICATIONS AND CLINICAL USE

ANTI-ALLERGY EYE DROPS (sodium cromoglycate) is indicated in the prevention of the signs and symptoms of seasonal allergic conjunctivitis (itching, tearing, congestion, etc.).

CONTRAINDICATIONS

ANTI-ALLERGY EYE DROPS (sodium cromoglycate) is contraindicated in those patients who have shown hypersensitivity to any of its components.

WARNINGS

ANTI-ALLERGY EYE DROPS (sodium cromoglycate) should not be used in the treatment of eye injury or infection. A doctor should be consulted immediately if the patient experiences any of the following:

< eye pain

< changes in vision

< pain on exposure to light

< redness of the eye

< excessive discharge

< abnormal pupils

< condition worsens or relief is not obtained within 72 hours

Not to be used with any other eye treatment except on the advice of a physician.

The drug product should be protected from direct sunlight. The opened bottle should be discarded after 4 weeks.

PRECAUTIONS

Soft contact lenses should not to be worn during treatment with ANTI-ALLERGY EYE DROPS (sodium cromoglycate).

Safety and efficacy in children under 5 years of age have not been established.

Pregnancy and Lactation: During clinical use there have been, to date, no reports of adverse effects on the mother or the fetus which could be attributed to the use of sodium cromoglycate. Caution must nevertheless be exercised during pregnancy and lactation.

ADVERSE REACTIONS

Transient ocular stinging or burning upon installation has been observed as a frequently reported adverse reaction in patients using sodium cromoglycate.

Watery, itchy eyes, conjunctival injection, dryness around the eyes, puffy eyes, eye irritation and sties have been reported as infrequent effects. It is not clear whether or not these reactions are due to the drug.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

There have been no reported cases of overdosage with sodium cromoglycate. Should overdosage occur, institute symptomatic treatment.

DOSAGE AND ADMINISTRATION

Adults and children 5 years of age and older: 1–2 drops in each eye 4 times a day at regular intervals; Maximum single dose per eye: 2 drops or 1.6 mg. Maximum total daily dose: 16 drops or 12.8 mg, 8 drops per eye.

ANTI-ALLERGY EYE DROPS (sodium cromoglycate) should be used continually throughout the patient's usual allergy season, even when the patient is free of symptoms. Continued use could help ensure the patient remains symptom-free.

The effectiveness of ANTI-ALLERGY EYE DROPS therapy depends on its administration at regular intervals. It is therefore important to provide patients with clear instructions on the number of drops to be taken daily and the regular use of the product. In addition, the patient should be instructed to replace cap after use and avoid touching the eye or other surfaces with the applicator tip (to maintain sterility).

O

O

O

NaO₂C

O O

O CO₂Na

OH

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Sodium Cromoglycate

Chemical Name: 4H-1-Benzopyran-2-carboxylic acid, 5,5'-[(2-hydroxy-1,3-propanediyl)bis(oxy)]bis[4-oxo-, disodium salt]

Structural Formula:

Molecular Formula: C₂₃H₁₄Na₂O₁₁

Molecular Weight: 512.3

Description: An odourless, white, hydrated crystalline powder. It is freely soluble in water up to

5 percent at 20/C. It is insoluble in alcohol and sparingly soluble in common organic solvents such as dioxan, pyridine, ether and chloroform.

Composition

ANTI-ALLERGY EYE DROPS (sodium cromoglycate) is a 2% (W/V) solution of sodium cromoglycate, USP in purified water. Benzalkonium chloride 0.01% is added as a preservative.

Stability and Storage Recommendations

Store at 15/-30/C. Protect from light.

AVAILABILITY OF DOSAGE FORMS

ANTI-ALLERGY EYE DROPS (sodium cromoglycate) is supplied in plastic dropper bottles containing 5mL, 10mL, or 15 mL of a sterile 2% (W/V) solution of sodium cromoglycate.

INFORMATION FOR THE PATIENT

ANTI-ALLERGY EYE DROPS

(Sodium Cromoglycate Ophthalmic Solution)

ANTI-ALLERGY EYE DROPS is a nonprescription drug intended to be used for the prevention of the symptoms of seasonal allergic conjunctivitis. Please read the following information carefully as it will guide you in the safe use of this medication.

What is seasonal allergic conjunctivitis?

If your eyes are itching, tearing and swollen, and your nasal passages are congested and runny, you may be suffering from seasonal allergic conjunctivitis. This type of allergy is most often caused on a seasonal basis by exposure to airborne substances such as pollen, grasses, weeds, dust and animal dander.

What is the difference between an eye infection and an allergic reaction in the eye?

An eye infection is caused by a pathogenic agent (microorganism or virus) which can multiply and produce inflammation, pain, excessive or milky discharge, altered vision and pain on exposure to light. If you experience any of these symptoms, you must see your doctor immediately. Your doctor can accurately identify the infectious agent and prescribe appropriate treatment.

In contrast, an allergic reaction in the eye is caused by the individual's own sensitivity to a substance (allergen) that would not normally cause a reaction. The symptoms produced by the reaction (itching, tearing, congestion, etc.) are seldom characteristic of serious eye disease. Usually these symptoms are only annoying and may be treated with a nonprescription medication such as ANTI-ALLERGY EYE DROPS. However, if you are not sure about the seriousness of your condition, or if you are experiencing your eye symptoms for the first time, you should contact your doctor. The table below lists the type of serious eye conditions requiring the attention of a doctor.

EYE CONDITIONS REQUIRING THE ATTENTION OF A DOCTOR

< Pain

< Changes in vision (double vision, spotty vision, etc.) < Pain on exposure to light (photophobia)

< Acute redness of the eye

< Excessive or milky (non-clear) discharge

< Abnormal pupils

< Injury (chemical, mechanical, etc.)

< Conditions lasting longer than 72 hours

What is ANTI-ALLERGY EYE DROPS, and how does it work?

During an allergic reaction, various substances are released by certain cells in your eyes. These are called mast cells. The substances released by these cells affect your eyes in different ways. For example, they affect blood vessels, nerves, and glands — causing redness, itching and tearing. ANTI-ALLERGY EYE DROPS acts on the mast cells to prevent them from releasing the substances that cause these problems.

How you should take ANTI-ALLERGY EYE DROPS to make it work best for you:

< This drug is only for use by adults and children 5 years of age and older.

< Instill 1 to 2 drops in each eye 4 times a day at regular intervals; the effect of ANTI-ALLERGY EYE

DROPS therapy depends on its administration at regular intervals.

Maximum single dose per eye: 2 drops or 1.6 mg.

Maximum total daily dose: 16 drops or 12.8 mg, 8 drops per eye.

< Do not exceed recommended dose. If relief is not obtained within 72 hours consult your doctor.

< To maintain sterility, replace cap after use and avoid touching the eye or other surfaces with the ap-plicator tip.

< It is good practice to wash your hands before and after using eye drops.

< Seek the advice of a health professional if you are not sure how to apply the drops in your eyes, or how to administer them in a child's eyes.

< ANTI-ALLERGY EYE DROPS should be used continually throughout your usual allergy season, even when you feel you are free of symptoms. Continued use could help ensure you remain symptom-free.

Warnings:

< ANTI-ALLERGY EYE DROPS should only be used for allergic conditions of the eye. Do not use it in the treatment of eye injury or infection.

< Irritation or redness may be due to a serious eye condition such as infection, foreign body in the eye, or other mechanical or chemical corneal injury requiring the attention of a doctor.

< If you experience eye pain, changes in vision, pain on exposure to light, acute redness of the eye, excessive or milky (non-clear) discharge, abnormal pupils, if condition worsens or if relief is not obtained within 72 hours, consult your doctor immediately.

< Do not wear soft contact lenses during treatment with ANTI-ALLERGY EYE DROPS.

< Do not use ANTI-ALLERGY EYE DROPS with any other eye treatment except on the advice of your doctor.

< If you are pregnant or nursing a baby, consult your doctor before using ANTI-ALLERGY EYE DROPS.

< Protect this medication from direct sunlight.

< Discard the opened bottle after 4 weeks.

What you should remember before taking this medication:

Remember that ANTI-ALLERGY EYE DROPS is used for the prevention of the symptoms caused by seasonal allergies. It should not be used in the treatment of a serious eye condition. Read the above information or speak to your pharmacist to help determine if you have an eye problem that requires the attention of a doctor. Keep this leaflet for future reference.

To store this medicine:

< Keep out of reach of children.

< Store between 15/and 30/C. The container should be tightly closed and protected from light.

< Discard the opened bottle after 4 weeks. Be sure that any discarded medicine is out of the reach of children.

PHARMACOLOGY

Animal Pharmacology: Sodium cromoglycate appears to act mainly through a local effect on the lung mucosa, nasal mucosa, and eyes. Sodium cromoglycate prevents release of the mediators of type I allergic reactions, including histamine and slow-reacting substance of anaphylaxis (SRS-A), from sensitized mast cells, initiated by the interaction of antigen with reagin (type II) antibodies.

When sodium cromoglycate was administered intradermally with human reaginic serum to macaque monkeys previously sensitised to the antigen, the compound inhibited the passive cutaneous anaphylactic (PCA) reactions. In other macaque monkeys, sodium cromoglycate did not inhibit the PCA skin reactions when administered intradermally with either histamine, bradykinin, or 5-hydroxytryptamine. Using anaesthetised marmosets, passively sensitized with human reaginic serum, sodium cromoglycate was able to substantially inhibit the antigen-induced histamine bronchoconstriction after antigen challenge.

Sodium cromoglycate effectively and completely inhibits the homologous PCA reactions with reagin-like antibody in rats using egg albumen/B. pertussis and N. brasiliensis sensitized systems. Examination of the PCA sites revealed that a rapid mast cell degranulation was a feature of reagin-induced PCA reactions which was markedly inhibited by sodium cromoglycate. This interference with mast cell permeability was not unspecific since sodium cromoglycate did not prevent the skin reactions or mast cell disruption produced by compound 48/80, a potent histamine releaser.

In contrast, homologous PCA reactions with precipitating antibody in guinea pigs were unaffected by sodium cromoglycate. The drug also failed to provide any protective activity against either aerosol or intravenous antigen-induced bronchospasm. Furthermore sodium cromoglycate did not have any effect on the release of histamine or slow-reacting substance A(SRS-A) from actively or passively sensitized guinea-pig in vitro chopped lung when challenged with antigen.

In vitro studies: In a series of experiments using the isolated ileum of the guinea-pig, sodium cromoglycate had no antagonistic effect against the following spasmogens: SRS-A, bradykinin, substance P, nicotine, acetylcholine, serotonin (5-HT), and histamine.

Histamine and SRS-A release from fresh human chopped lung passively sensitized with human reaginic serum was measured after in vitro exposure to specific antigens. Sodium cromoglycate, over a narrow range of concentrations, inhibited the release of both SRS-A and histamine. In vitro, sodium cromoglycate had no direct action on human bronchial chain nor did it have any antagonistic effect towards the response to acetylcholine, prostaglandin F2, SRS-A and histamine.

The results of these studies indicate that sodium cromoglycate interferes with the release of the spasmogens rather than antagonize them following their release. Furthermore, the studies emphasize that sodium cromoglycate is most effective prior to the antigen challenge.

Other Studies: Sodium cromoglycate has few pharmacological effects. It is neither a bronchodilator nor an anti-inflammatory agent and its action is distinct from that of corticosteroids. Large doses of sodium cromoglycate had negative or only weak inconsistent effects on the respiratory or cardiovascular systems of the rat, cat, guinea-pig and pig. However in the marmoset and dog there were marked effects.

In anaesthetized marmosets sodium cromoglycate produced a large rise in blood pressure and heart rate with doses of 20 :g/kg and above; with higher doses there was also transient apnea. These effects were caused by stimulation of the post-ganglionic sympathetic fibres. In the marmoset sodium cromoglycate showed no significant effect in several anti-inflammatory tests.

The effects of sodium cromoglycate in the conscious and anaesthetised dogs are similar, and result from activation (by sodium cromoglycate) of chemoreceptors situated in the pulmonary and coronary circulation, initiating a reflex response. The reflex, mediated via vagal afferents, produces general stimulation of the parasympathetic system, producing bradycardia, hypotension, bradypnea and sometimes apnea.

In experiments on cat trachea in vivo, and on isolated frog oesophagus and human bronchial epithelium in vitro, sodium cromoglycate at high concentrations did not interfere with pulmonary clearance.

Sodium cromoglycate does not affect steroid metabolism as indicated by plasma corticosterone and adrenal ascorbic acid levels.

Studies have been performed on the distribution, metabolism, and excretion of sodium cromoglycate in the mouse, rat, guinea-pig, rabbit, cat, dog, monkey and man. The drug was administered by the intravenous, oral and nasal (rat) routes, as well as by inhalation. Tritium-labelled sodium comoglycate has been used for the animal studies, whereas ¹⁴C-labelled drug, radioimmunoassay, HPLC, and spectrophotometric methods have been used in human studies.

Inhalation Studies: After administration of sodium cromoglycate as a fine powder aerosol into the lungs of rats, rabbits and monkeys, all animals showed rapid clearance of the drug from the lungs. The rate of absorption was such that 75% of the inhaled dose had been removed in 2 hours, and by 24 hours less than 2% of the inhaled dose remained following absorption. Only the liver and kidneys accumulate sodium cromoglycate to any extent, prior to excretion of the compound (unchanged) in the bile and urine.

Similar studies in human volunteers have shown that only a small proportion of the administered dose is absorbed from the lung. A peak plasma level at 10 minutes was followed by a fall in concentration similar to that demonstrated in animal experiments. Following inhalation of the powder aerosol, 3 to 5% of the dose was excreted in the urine over a 6-hour period. Assuming a similar rate of biliary excretion, approximately 10% of the administered dose was absorbed from the lung.

Other Routes of Administration: Following intravenous doses of sodium cromoglycate, there is a rapid clearance of the compound from the plasma and a general distribution throughout the tissues with only the liver and kidneys accumulating the compound to any extent. Rapid excretion of the unchanged compound follows. Intramuscular administration resulted in a pattern of absorption and excretion similar to that which occurs after intravenous administration. In the rat and dog no tissue accumulation could be detected after repeated intramuscular injections.

In the monkey, 6 hours after intravenous administration, 80-90% of the total dose could be accounted for by biliary and renal excretion. At this stage, there is general distribution of the sodium cromoglycate throughout the tissues, with a higher concentration in the kidneys and liver. After intranasal administration of sodium cromoglycate to rats, peak plasma levels occurred approximately 20 minutes after dosing. The AUC corresponded to an absorption of 60% of the dose over 3 hours and the total amount of sodium cromoglycate excreted in the bile over the same time period corresponded to an absorption of 53% of the dose adminis-tered.

In man, oral administration of sodium cromoglycate is followed by a low rate of urinary excretion. In one study, the mean urinary excretion over 24 hours was only 0.5% of the dose administered. This indicates that absorption of sodium cromoglycate through the gastrointestinal tract is low.

TOXICOLOGY

Acute Toxicity: In acute toxicity tests in small laboratory animals the LD50 on parenteral administration was usually between 2000 and 4000 mg/kg.

Subacute and Chronic Toxicity: In a prolonged test in rats no toxic effects resulted from 90 daily subcutaneous injections except at doses greater than 30 mg/kg. The only pathological lesion produced in any of these tests was an inflammation and degeneration of the renal tubules. In Rhesus monkeys no evidence of renal or other toxicity could be found after 180 daily doses of 50 mg/kg had been given by the intravenous route. No toxicity was found in 90-day inhalation studies in rats, guinea pigs and monkeys. In the case of the monkeys the drug was administered as a powder and each monkey received a capsule every 5 minutes for 6 hours a day, 5 days a week for 3 months. In none of these tests could any lung changes be detected nor were there any other indications of toxicity.

In one inhalation study using a group of 30 rats exposed to a concentration of 4.6 mg/L of air for one hour and three hours daily for 5 weeks, no toxic effects resulting from this treatment was observed. A chronic inhalation toxicological study of sodium cromoglycate was performed in the Squirrel monkey. Each of 5 experimental groups consisted of 3 male and 3 female monkeys. Groups 1 and 2 were exposed 6 hr/day, 7 days/week, for 1 year to aerosols containing sodium cromoglycate in approximate concentrations of 0.5 and 0.05 mg/L of air, respectively. Group 3 animals were similarly exposed to an aerosol containing 0.01 mg lactose/L of air. Group 4 subjects served as chamber controls and the room controls (Group 5) were maintained in the animal holding room throughout the study. A comprehensive toxicological evaluation of the monkeys was carried out prior to and throughout the study. No histopathological changes were seen in any variable.

Studies of Sodium Cromoglycate Ophthalmic Solution: A 28 day irritancy test of rabbit eyes was conducted using 4% sodium cromoglycate ophthalmic solution applied to one eye up to four times daily. Assessment of the reaction (Draize method) showed sodium cromoglycate solution was non irritant to the cornea, iris or conjunctiva, and no drug-related gross or microscopic changes were observed.

Studies of 2% sodium cromoglycate ophthalmic solution were carried out in the New Zealand albino rabbit (3 months) and squirrel monkey (6 months). Each experimental group consisted of 4 males and 4 females. Two drops of sodium cromoglycate solution were instilled into both eyes of each high dose animal, two to ten times daily. The control animals were treated similarly with placebo solution only. No fundoscopic changes were seen. Detailed histopathological examination of eyes and related structures revealed no local irritation or toxic effects of treatment.

Drug Interaction Studies: No incompatibility could be detected in the rabbit eye when sodium cromoglycate 4% ophthalmic solution was used with the following commonly used ophthalmic drugs:

A. Drugs given once daily for 5 days:

• Topicamide 0.5% (Mydriacyl 0.5% ophthalmic solution)
• Phenylephrine hydrochloride 10% (Neo-Synephrine 10% ophthalmic solution)
• Cyclopentolate hydrochloride 0.5% (Cyclogyl 0.5% ophthalmic solution)

B. Drugs given once daily for 28 days:

VASOCONSTRICTORS

• Tetrahydrozoline HCl 0.05% (Visine ophthalmic solution)
• Murine ophthalmic Solution

ANTIBODIES

• Gentamycin sulfate (Garamycin ophthalmic solution)
• Chloramphenicol 0.5% (Choromycetin 0.5% ophthalmic solution)
• Polymyxin B - neomycin - gramicidin (Neosporin ophthalmic solution)
• Sodium sulfacetamide 30% (sodium Sulamyd 30% ophthalmic solution)

ASTRINGENTS

• Zinc sulfate 09.25% (Zincfrin ophthalmic solution)

STEROIDS

• Dexamethasone sodium phosphate 0.1% (Decadron 0.1% ophthalmic solution)
• Prednisolone acetate 1% + phenylephrine 0.12% (Prednefrin Forte 1% aqueous suspension).

Teratology: No teratogenic effects were seen in rabbits in which the compound was given intravenously, daily throughout pregnancy, in doses up to 250 mg/kg. The latter dose was sufficient to cause severe damage to the maternal kidneys. At even higher doses (500 mg/kg) some partially resorbed fetuses showed developmental defects but all full-term fetuses were normal. In rats dosed at 185 mg/kg daily s.c. throughout pregnancy, one fetus (out of 272) showed a grossly shortened humerus. No abnormalities were seen at lower doses(90 mg/kg). No teratogenic effect was seen in mice at daily doses of up to 540 mg/kg.

Cytotoxicity: At the cellular level, no effects of sodium cromoglycate were observed at concentrations up to and including 1 mg/mL upon the following:

• Migration characteristics of guinea-pig macrophages
• Morphology of chick embryo-fibroblasts
• Morphology of human epithelial cells from a cell line
• Ciliary activity of samples of human ciliated epithelium.

Effect on immune system: The effect of the drug on microbiological neutralizing systems, including viruses in vivo and in vitro, was studied. No effect was observed on: various antibody neutralizing or agglutinating systems; development of active immunity or antibody production; protection conferred by passive or active immunity.

No effect was found on the following virus/antibody neutralizing systems in vitro: Influenza, Polio (with human or rabbit anti serum); Vaccinia (with rabbit antiserum); Herpes simplex (with human antiserum).

None of the neutralization titres studied were affected by the presence of the compound up to concentrations of 1000 :g/mL. No effect was observed on the LD50 in mice or in mouse- adapted polio virus, nor on their protection by Salk-vaccine. No effect was observed on the neutralization of clostridium welchii type A " toxin by specific antiserum, nor on several bacterial agglutinating systems tested. No effect was observed on the cytotoxic behaviour of rabbit anti-Hela cells in vitro.

Carcinogenesis and Mutagenesis: Long term studies in mice (12 months intraperitoneal treatment followed by 6 months observation), hamsters (12 months intraperitoneal treatment followed by 12 months observation) and rats (18 months subcutaneous treatment) showed no neoplastic effect of sodium cromoglycate. No evidence of chromosomal damage or cytotoxicity was obtained in various mutagenesis studies.

REFERENCES

1. 1.

   Altounyan REC. Sodium cromoglycate in allergic and non-allergic obstructive airways.

   Pharmakotherapie 1981; 4:163-167.

2. 2. Ashton MJ, Clark B, Jones KM, et al. The absorption, metabolism and excretion of disodium cromoglycate in nine animal species. Tox App Pharmac 1973; 26:319-328.
3. 3. Beach JE, Blair AMJN, Pirani CL, et al. An unusual form of proliferative arteriopathy in macaque monkeys. Exp Molec Path 1974; 21:322-338.
4. 4.

   Beach JE, Greenough RJ. Inhalation Study of a Dry Powder Aerosol of Disodium Cromoglycate in Rats.

   Experimental model systems in toxicology and their significance in man. Proceedings of the European Society for the Study of Drug Toxicity (Zurich), 1973 (June).

5. 5. Blair AMJN, Woods A. The effects of isoprenaline, atropine and disodium cromoglycate on ciliary motility and mucous flow measured in vivo in cats. Br. J. Pharmacol (Proceedings of the British Pharmacological Society) 1969 (Jan 2-3).
6. 6.

   Blamoutier J. Opticrom et conjunctivities allergiques. Étude Comparative Opticrom et Collyre Corticoide.

   Gaz. Med.de France 1980; 87(16):2041-2045.

7. 7. Brogden RN, Speight TM, Avery GS. Sodium cromoglycate (cromolyn sodium): a review of its mode of action, pharmacology, therapeutic efficacy and use. Drugs 1974; 7:164-282.
8. 8. Buckley GA, Murphy AJ, Neale MG. Distribution of sodium cromoglycate in rat kidney using microautoradiography. Br. J. Pharmacol 1983; 80:497.
9. 9.

   Clarke B, Moss GF, Neale MG. Distribution of plasma protein binding of sodium cromoglycate. J.

   Pharm. Pharmac 1979; 30:386-387.

10. 10.

    Clarke B, Neale MG. Hepatic and renal clearance of sodium cromoglycate.

    J. Pharm. Pharmacol 1981; 33:744-745.

11. 11.

    Cox JSG, Beach JE, Blair AMJN, et al. Disodium cromoglycate (intal). In Harper, N.T. & Simmonds,

    A.B. Original Adv. Drug Res., London: Academic Press, 1970; 5:115-195.

12. 12. Dawson JP. Comparative trial of sodium cromoglycate unit-dose eye drops in seasonal allergic conjunctivitis. In Pepys, J. & Edwards, A.M. (Eds.) The Mast Cell: Its Role in Health and Disease. London: Pitman Medical, 1979; 506-511.
13. 13. Dixon M, Jackson DM, Richards IM. The action of sodium cromoglycate on C fibre endings in the dog lung. Br. J. Pharmac 1980; 70(1):11-13.
14. 14. Easty DL. Sodium cromoglycate eye drops in allergic conjunctivitis. Acta Allergol. Suppl 1977; 13:62-67.
15. 15. El-Hennawi M. A comparison between 2% and 4% sodium cromoglycate eye drops in the treatment of vernal keratoconjunctivitis. Curr. Eye Res 1982-3; 2(11):765-768.
16. 16.

    El-Hennawi M. Clinical trial with sodium cromoglycate (opticrom) in vernal keratoconjunctivitis. Br. J.

    Ophthalmol 1980; 64(7):483-486.

17. 17.

    Farmer JB, Richards IM, Sheard P, et al. Mediators of passive lung anaphylaxis in the rat. Br. J.

    Pharmac 1975; 55:57-64.

18. 18.

    Fisher AN, Browns K, Davis SS, et al. The nasal absorption of sodium cromoglycate in the albino rat.

    J. Pharm. Pharmacol 1985; 37:38-41.

19. 19. Goose J, Blair AMJN. Passive cutaneous anaphylaxis in the rat, induced with two homologous reagin-like antibodies and its specific inhibition with disodium cromoglycate. Immunology 1969; 16:749.
20. 20. Illum P, Meistrup-Larsenen U, Moesner J, et al. Disodium cromoglycate (lomudal) in the treatment of hay fever. Acta Allergologica 1973; 28:416-424.
21. 21.

    Jones KM, Moss GF. Inhalation toxicity study of a dry powder aerosol of disodium cromoglycate in rats,

    Part II: estimation of the amount absorbed. Proceeding of the European Society for the Study of Drug Toxicity 1973(June); Vol 15.

22. 22. Juniper EF, Latimer KM, Morris MM, et al. Airway responses to hyperventilation of cold dry air : duration of protection by cromolyn sodium. J Aller. Clin. Immun 1986; 78(3):387.
23. 23. Lee VHL, Swarbrck J, Stratford RE Jr, et al. Disposition of topically applied sodium cromoglycate in the albino rabbit eye. J Pharm Pharmacol 1983; 35:445-450.
24. 24.

    Lemire I, Cartier A, Malo JL, et al. Effect of sodium cromoglycate on histamine inhalation tests. J Aller

    Clin Immun 1984; 73(2):234.

25. 25. Lindsay-Miller AC. Groupe comparative trial of 2% sodium cromoglycate (opticrom) with placebo in the treatment of seasonal allergic conjunctivitis. Clin Allergy 1979; 9(3):271-275.
26. 26. McCarthy D, et al. Recurrent allergic conjunctivitis: an assessment of 2% sodium cromoglycate eye drops. The Practitioner 1979; 222:854-856.
27. 27.

    Moss GF, Jones KM, Ritchie JT, et al. Distribution and metabolism of disodium cromoglycate in rats.

    Toxicology and Applied Pharmacology 1970; 17:691-698.

28. 28. Moss GF, Jones KM, Ritchie JT, et al. Plasma levels and urinary excretion of disodium cromoglycate after inhalation by human volunteers. Toxicology and Applied Pharmacology 1971; 20:147-156.
29. 29. Moss GF, Ritchie JT. The absorption and clearance of disodium cromoglycate from the lung in rat, rabbit and monkey. Toxicology and Applied Pharmacology 1970; 17:699-707.
30. 30. Myers DJ, Bigby BG, Boushey HA. The inhibition of sulfur dioxide-induced bronchoconstriction in asthmatic subjects by cromolyn is dose dependent. Am. Rev. Resp. Dis 1986;133(6):1150-1153.
31. 31. Neale MG, Brown K, Hodder RW, et al. The pharmacokinetics of sodium cromoglycate in man after intravenous and inhalation administration. Br. J. Clin. Pharmac 1986; 22:373-382.
32. 32.

    Nizami RM. Treatment of ragweed allergic conjunctivitis with 2% cromolyn solution in unit doses. Ann.

    Allergy1981; 47(1):5-7.

33. 33. Procter BG, Burford RG, Blair AMJN, et al. A study of the chronic toxicity of inhaled disodium cromoglycate in the squirrel monkey. Tox. Appl. Pharmac 1973; 25:479.
34. 34. Sheard P, Blair AMJN. Disodium cromoglycate: activity in three in vitro models of the immediate hypersensitivity reaction in lung. Int. Arch. Allergy 1970; 38:217-224.
35. 35. Simon-Licht IF, Dieges PH. A double-blind clinical trial with cromoglycate eye drops in patients with atopic conjunctivitis. Ann. Allergy, 1982; 49(4):220-224.
36. 36. Smith A, Fisher N. Age related changes in the clearance and oral absorption of sodium cromoglycate in the developing albino rat. J. Pharm. Pharmac 1980; 32:823-827.
37. 37.

    Spitzer JC. Interaction of disodium cromoglycate with calcium ions in 2-propanol. Int. Archs Allergy

    Appl. Immun 1979; 60:356-358.

38. 38. Steward AG, Fennessy MR. Dual modes of action for disodium cromoglycate in inhibition of antigen-induced contractions of guinea-pig isolated airways smooth muscle. Clin Exp Pharmac Phys 1983; 10:595-603.
39. 39.

    Walker, SR, Evans ME, Richards AJ, et al. The fate of (¹⁴C) disodium cromoglycate in man. J. Pharm.

    Pharmac 1972; 24:525-531.

40. 40.

    Warland A, Kapstad B. The effect of disodium cromoglycate in perennial allergic rhinitis. Acta

    Allergologica 1977; 32:195-199.

41. 41. Wells E, Mann J. Phosphorylation of a mast cell protein in response to treatment with anti-allergic compounds. Biochem Pharmacol 1983; 32(5):837-842.
42. 42.

    Wells E, Jackson CG, Harper ST, et al. Characterization of primate bronchoalveolar mast cells. J

    Immun 1986; 137:3941-3945.