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Antiallergic and antitussive drugs
F.A. Nelemans
17 Antiallergic and antitussive drugs ASTHMA Editorial note Several of the drugs used in bronchial asthma and cough are dealt with primarily in other chapters. They include xanthine compounds (Ch. 1), the opiates (Ch. 8), sympathomimetic and parasympatholytic agents (Ch. 14), the antihistamines (Ch. 16), and the corticosteroids (Ch. 41). Cromolyn sodium (disodium cromoglycate) (SED 9, 275; SEDA-5, 169; SEDA-6, 171; SEDA- 7, 189) Hypersensitivity reactions to cromolyn sodium are uncommon, but well documented. They may occur after many months of use of this drug. Regular taking of prednisolone ( 1 0 - 4 0 mg daily) does not give protection as has been shown by the case of a 41-year-old man with severe asthma. After 11 months' use o f cromolyn sodium by oral inhalation 4 times per day he complained o f burning sensations in the eyes. On the next day, he developed an itchy erythematous facial rash and periorbital edema. Cromolyn sodium inhalation was stopped and the symptoms disappeared' within 3 days (lC). Kall6s and Kall6s in 1982 reviewed in extenso the available evidence on pseudoallergic reactions due to cromolyn (16R). Surveying the world literature on the drug up to that m o m e n t they detected 13 cases of facial rash, urticaria and/or generalized dermatitis, 1 of nasal congestion, 19 of severe bronchospasm and/or pulmonary edema, eventually culminating in shock, 4 of eosinophilic or granulomatous pulmonary infiltration, 5 of gastrointestinal disturbances, 2 of dysuria and urinary frequency, 1 o f liver disease and vasculitis, 1 of pericar-
Side Effects of Drugs Annual 8 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1984 ISBN 0 444 90339 9 $0.80 per article per page (transactional system) $0.20 per article per page (licensing system)
ditis, and 3 of polymyositis. They do however remind the reader that there must be much unpublished material, e.g. 4 cases o f anaphylactic shock known to them personally but not described in print. They consider that at present there is no proof that the adverse reactions to cromolyn which mimic allergic processes of the immediate or delayed t y p e are mediated by IgE and/or specifically reactive lymphocytes; consequently these reactions fulfil the criteria which characterize pseudoallergic reactions. Kall6s and Kall6s also note the much higher incidence o f adverse reactions when cromolyn is used orally ( 5 0 - 1 0 0 mg q.i.d.) to prevent food allergic reactions, a matter discussed earlier in these volumes. All in all, they conclude that inhaled cromolyn produces major adverse reactions, most probably of pseudo-allergic origin, in at least 2% of cases, whilst oral use produces minor reactions in about 29% of patients. A striking negative finding with respect to adverse effects relates to the absence in man of serious effects upon the kidney circulation, despite the fact that such effects had been detected around 1970 when the drug was investigated toxicologically in monkeys (17); such instances point to the risks of allowing animal toxicity studies to determine the fate o f a new drug. Ostler reported earlier on 2 cases of an acute chemotic reaction of the conjunctiva (SEDA-7, 189). He later reported that uninterrupted use of cromolyn sodium relieved the symptoms and signs in one of the patients, suggesting that when he used medication after being without it for a period o f time, the drug acted as an allergen and induced degranulation o f the mast cells, whereas continuous use of the drug stabilized the mast cells, resulting in rehef of the symptoms. The alpha-1 AT levels in both patients were found to be normal ( 1 5 0 240 as compared with a normal range of 1 1 1 - 2 7 0 in the laboratory). The alpha-1 AT level in the tears was not determined in the crucial period but was previously found
Antiallergic and antitussive drugs in the presence of normal serum ievels (2c). These data suggest that a deficiency of alpha-1 AT played no role in the reaction.
Ketotifen (Zaditen) (SEDA-5, 15 7; SEDA-7, 189) Ketotifen is an orally active antihistamine with antiallergic properties. Side effects are rarely a problem. In a double-blind study with 40 skin-test-positive perennial asthma patients (20 ketotifen, 20 placebo) (1 mg twice a day for 12 weeks) the only side effect was drowsiness. The drowsiness occurred in 8 patients on ketotifen and in 3 patients on placebo (p = 0.078). Sedation in the ketotifen group appeared suddenly and was rated as mild in 4 patients (duration 3 - 8 days), moderate in 3 (duration 7 - 1 2 days) and severe in 1 (duration 18 days). Even in the latter case it was not necessary to interrupt the treatment nor to reduce the dosage (3). In an open trial o f 433 outpatients with bronchial asthma (219 men and 214 women, and 20% under 12 years, recruited from 74 hospitals) the dosage was 0 . 5 - 1 mg twice a day for children and 1 mg twice a day for adults during 3 months. The most c o m m o n side effect was once again drowsiness (22% of the adults and 11.5% o f the children). In 4% the drowsiness was rated as severe. 10 patients dropped out because o f adverse reactions. Other side effects were weight gain (3 adults, 2 children), vertigo (3 adults) and dyspepsia (3 adults) (4). Recently a patient was described in whom oral ketotifen was associated with erythema multiforme bullosum (5e). The ketotifen treatment (1 mg twice daily) had started 1 month beforehand. The diagnosis was confirmed by biopsy and a challenge test. The family and personal history pointed to various types of hypersensitivity reaction.
Desensitization (SEDA- 7, 190) In 242 patients treated with 3500 injections of polymerized ragweed for immunotherapy two very mild systemic reactions were observed as the only side effects. The patients developed high levels of blocking antibody (6e). In a 3-year double-blind study 40 typical grass pollen allergic patients were allocated to specific i m m u n o t h e r a p y (hyposensitiza-
171 tion) with whole pollen allergens and purified pollen allergens (2 isolated t i m o t h y major allergens, Ag 19 and Ag 25). The systemic side effects set in after 1 . 5 - 5 hours and lasted without further treatment for 30 min to 10 hours. Treatment with the 2-component extract showed a preponderance of minor systemic side effects (arthralgia, rhinitis, tiredness, headache, conjunctivitis, nausea, fluqike symptoms) but major systemic side effects (urticaria, angioedema, asthma) were equally distributed between treatments with the two extracts. Major systemic side effects complicated the treatment before the first grass pollen season in 33% of the patients versus only 3% during the subsequent perennial therapy. Systemic and local (side) effects were delayed when using aluminium-absorbed extracts. Major systemic side effects were predicted by means of high nasal sensitivity but not by immediate local skin reactions (7). Tiaramide (SEDA- 7, 189) 29 patients with moderate to severe bronchial asthma cooperated in a doubleblind cross-over study using placebo, salbutamol and tiaramide (800 mg/d). No difference in therapeutic effect was found between tiaramide and salbutamol; both were better than placebo. Few patients experienced side effects with tiaramide; these comprised headache, diarrhea and nausea (8).
Mueolytic agents (SED 9, 2 77; SEDA-4, 121; SEDA-5, 1 70; SEDA-6, 1 71; SEDA-7, 189) Although the clinical usefulness of mucolytic agents is still under discussion, all authors agree that side effects are no problem. In a balanced article on bromhexine Jr pointed out that few side effects have been detected with this agent. Reactivation o f intestinal ulcers is the most important, but has only been described in a few patients. As far as the author knows no hematemesis, melena or other complications have been found (9r). Milder gastrointestinal symptoms have been referred to in earlier volumes in this series. In a group of 27 patients (16 males and 11 females) the tolerance of ambroxol was excellent in 15, good in 10, moderate in 1; in 1 patient with duodenal ulcer there
F.A. Nelemans
172 were complaints about pyrosis and dyspepsia (10c). In a double-blind study 224 pregnant women received ambroxol or placebo daily over a period of 5 days (500 rnl infusion of 5% glucose with 1000 rag ambroxol or placebo within 2 hours). All these women were already in premature labor or had premature rupture of the membranes between the 28th and 36th week. Side effects such as nausea were described in 3 women on placebo and in 5 on ambroxol. All 8 had received betamimetic drugs (11c). Acetylcysteine (NACJ is used not only as a mucolytic but also systemically as an antidote in paracetamol poisoning. Side effects are rare.
centrations of Mesna (usually 1:1 diluted solution) have been used in 29 patients without severe complications. There were 2 cases of bronchospasm and 1 case produced blood-tinged sputum (13).
Cough remedies
Mofoxine (Arphosal) is an antitussive substance possibly having antiphlogistic and sedative properties. When it was administered to 41 children ( 1 - 1 2 years) in an a m o u n t of 4 mg/kg per day, no side effects, either clinical or biochemical, were observed (14). A 21-year-old female had 2 epileptic attacks after swallowing 25 mg of tipepidine hibenzate (3 -di(2-thienyl)methylene- 1-methA 49-year-old woman had ingested about ylpiperidinium 4-hydroxybenzophenone-250 tablets of paracetamol and a bottle of sherry. carboxylate). Under EEG control she took She had for many years taken phenytoin and again a therapeutic dose and epileptiform phenobarhitone for the control of epilepsy. The changes in the EEG were detected. The plasma paxacetamol on admission (at least 8 hx post ingestion) was 146 rag/1. Intravenous NAC piperidine ring can be considered as con150 mg/kg over 15 win was started. Within 5-10 vulsant, its convulsant action being antagrain a patchy erythematous rash appeared over the onized by GABA. It is therefore not entirely patients face and arms and she complained of surprising that, after having given the patient wheeziness and difficulty in breathing. The in- 300 mg vitamin B6 per day intramuscularly fusion was discontinued and the symptoms sub. for 8 consecutive days and then rechallengsided within 10 rain (12c). ing here with the drug, the EEG remained normal ( 15 c). Using the De Vilbiss inhaler various cop REFERENCES 1. Adverse Drug Reactions Advisory Committee (1982) Seven case studies. Med. J. Aust., 1, 524. 2. Ostler HB 0982) Alpha-l-Antitrypsin and ocular sensitivity to r Lancet, 2, 1287. 3. Baronti A, Vibelli C (1983) Ketotffen in skintest-positive perennial asthma. Curr. Ther. Res., 33, 401. 4. V~elli C, Rudelli G (1982) Multicentre study for the evaluation of ketotifen in the prophylaxis of bronchial asthma: an interim report. Curt. Ther. Res., 32, 686. 5. Goihman-Yahr M, Rothemberg A, EssenfeldYahr E (1983) Erythema multiforme and ketotifen. J. Am. Acad. Derm., 8, 429. 6. Grammer LC, Zeiss CR, Suszko IM et al (1982) A double-blind placebo-controlled trial of polymerized whole ragweed for immunotherapy of ragweed allergy. Am. Acad. All. Immunol., 69, 494. 7. ~sterballe O 0982) Side effects during immunotherapy with purified grass pollen extracts. Allergy 37, 553. 8. Bonifazi F, Sanguinetti CM, Vennarucci LS,
Gasparini S (1982) La tiaramide, un nuovo farmaco per via oraie, nel trattamento dell'asma. Riv. Pat. Clin. Tubercol. Pneumol., 53, 69. 9. J~rgensen PH (1982) Bromhexin, en genvurdering ud fra litteraturen. Ugeskr. Laeg., 144, 1327. 10. Piantedosi FV, Cordedda M (1982) Efficacia terapeutica e tollerabilita dell'ambroxol in uno studio su 27 pazienti broncopneumopatici. Osp. Ital. Pediatr., 17, 812. 11. Wauer RR, Schmalisch G, Menzel K et al (1982) The antenatal use of ambtoxol Coromhexine metabolite VIII) to prevent hyaline membrane disease: a controlled double-blind study. Biol. Res. Pregn., 3, 84. 12. Vale JA, Wheeler DC (1982) Anaphylactoid reactions to acetylcysteine. Lancet, 2, 988. 13. Choi KH, Kim KR, Kim JM et al (1982) Clinical effects of mercaptoethane sylphonate (MESNA) in various respiratory diseases. Tuber. Resp. Dis., 29, 157. 14. Romagny G, Karman JF (1982) Int~r~t d'une mol~cule tussipl~gique nouvelle en l~diatrie. La mofoxine. Prog. M~d. /Paris/, 5, 87. 15. Cuomo RM (1982) On the possible convulsive activity of an antitussive piperidinic
Antiallergic and antitussive drugs derivative ('tipepidina ~enzato') in man. Acta NeuroL, 37, 110. 16. Kallds P, Kallds L (1982) Pseudo-allergic reactions due to disodium cromogiycate. In: Pseudo-Allergic Reactions. Involvement o f Drugs and Chemicals, VoL 3, pp. 122-132. Karger,
173 Basel. 17. Parker JM (1983) Paper delivered to the Drug Information Association, Washington DC, July 1983 (Personal communication to the Editor).
17 Antiallergic and antitussive drugs ASTHMA Editorial note Several of the drugs used in bronchial asthma and cough are dealt with primarily in other chapters. They include xanthine compounds (Ch. 1), the opiates (Ch. 8), sympathomimetic and parasympatholytic agents (Ch. 14), the antihistamines (Ch. 16), and the corticosteroids (Ch. 41). Cromolyn sodium (disodium cromoglycate) (SED 9, 275; SEDA-5, 169; SEDA-6, 171; SEDA- 7, 189) Hypersensitivity reactions to cromolyn sodium are uncommon, but well documented. They may occur after many months of use of this drug. Regular taking of prednisolone ( 1 0 - 4 0 mg daily) does not give protection as has been shown by the case of a 41-year-old man with severe asthma. After 11 months' use o f cromolyn sodium by oral inhalation 4 times per day he complained o f burning sensations in the eyes. On the next day, he developed an itchy erythematous facial rash and periorbital edema. Cromolyn sodium inhalation was stopped and the symptoms disappeared' within 3 days (lC). Kall6s and Kall6s in 1982 reviewed in extenso the available evidence on pseudoallergic reactions due to cromolyn (16R). Surveying the world literature on the drug up to that m o m e n t they detected 13 cases of facial rash, urticaria and/or generalized dermatitis, 1 of nasal congestion, 19 of severe bronchospasm and/or pulmonary edema, eventually culminating in shock, 4 of eosinophilic or granulomatous pulmonary infiltration, 5 of gastrointestinal disturbances, 2 of dysuria and urinary frequency, 1 o f liver disease and vasculitis, 1 of pericar-
Side Effects of Drugs Annual 8 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1984 ISBN 0 444 90339 9 $0.80 per article per page (transactional system) $0.20 per article per page (licensing system)
ditis, and 3 of polymyositis. They do however remind the reader that there must be much unpublished material, e.g. 4 cases o f anaphylactic shock known to them personally but not described in print. They consider that at present there is no proof that the adverse reactions to cromolyn which mimic allergic processes of the immediate or delayed t y p e are mediated by IgE and/or specifically reactive lymphocytes; consequently these reactions fulfil the criteria which characterize pseudoallergic reactions. Kall6s and Kall6s also note the much higher incidence o f adverse reactions when cromolyn is used orally ( 5 0 - 1 0 0 mg q.i.d.) to prevent food allergic reactions, a matter discussed earlier in these volumes. All in all, they conclude that inhaled cromolyn produces major adverse reactions, most probably of pseudo-allergic origin, in at least 2% of cases, whilst oral use produces minor reactions in about 29% of patients. A striking negative finding with respect to adverse effects relates to the absence in man of serious effects upon the kidney circulation, despite the fact that such effects had been detected around 1970 when the drug was investigated toxicologically in monkeys (17); such instances point to the risks of allowing animal toxicity studies to determine the fate o f a new drug. Ostler reported earlier on 2 cases of an acute chemotic reaction of the conjunctiva (SEDA-7, 189). He later reported that uninterrupted use of cromolyn sodium relieved the symptoms and signs in one of the patients, suggesting that when he used medication after being without it for a period o f time, the drug acted as an allergen and induced degranulation o f the mast cells, whereas continuous use of the drug stabilized the mast cells, resulting in rehef of the symptoms. The alpha-1 AT levels in both patients were found to be normal ( 1 5 0 240 as compared with a normal range of 1 1 1 - 2 7 0 in the laboratory). The alpha-1 AT level in the tears was not determined in the crucial period but was previously found
Antiallergic and antitussive drugs in the presence of normal serum ievels (2c). These data suggest that a deficiency of alpha-1 AT played no role in the reaction.
Ketotifen (Zaditen) (SEDA-5, 15 7; SEDA-7, 189) Ketotifen is an orally active antihistamine with antiallergic properties. Side effects are rarely a problem. In a double-blind study with 40 skin-test-positive perennial asthma patients (20 ketotifen, 20 placebo) (1 mg twice a day for 12 weeks) the only side effect was drowsiness. The drowsiness occurred in 8 patients on ketotifen and in 3 patients on placebo (p = 0.078). Sedation in the ketotifen group appeared suddenly and was rated as mild in 4 patients (duration 3 - 8 days), moderate in 3 (duration 7 - 1 2 days) and severe in 1 (duration 18 days). Even in the latter case it was not necessary to interrupt the treatment nor to reduce the dosage (3). In an open trial o f 433 outpatients with bronchial asthma (219 men and 214 women, and 20% under 12 years, recruited from 74 hospitals) the dosage was 0 . 5 - 1 mg twice a day for children and 1 mg twice a day for adults during 3 months. The most c o m m o n side effect was once again drowsiness (22% of the adults and 11.5% o f the children). In 4% the drowsiness was rated as severe. 10 patients dropped out because o f adverse reactions. Other side effects were weight gain (3 adults, 2 children), vertigo (3 adults) and dyspepsia (3 adults) (4). Recently a patient was described in whom oral ketotifen was associated with erythema multiforme bullosum (5e). The ketotifen treatment (1 mg twice daily) had started 1 month beforehand. The diagnosis was confirmed by biopsy and a challenge test. The family and personal history pointed to various types of hypersensitivity reaction.
Desensitization (SEDA- 7, 190) In 242 patients treated with 3500 injections of polymerized ragweed for immunotherapy two very mild systemic reactions were observed as the only side effects. The patients developed high levels of blocking antibody (6e). In a 3-year double-blind study 40 typical grass pollen allergic patients were allocated to specific i m m u n o t h e r a p y (hyposensitiza-
171 tion) with whole pollen allergens and purified pollen allergens (2 isolated t i m o t h y major allergens, Ag 19 and Ag 25). The systemic side effects set in after 1 . 5 - 5 hours and lasted without further treatment for 30 min to 10 hours. Treatment with the 2-component extract showed a preponderance of minor systemic side effects (arthralgia, rhinitis, tiredness, headache, conjunctivitis, nausea, fluqike symptoms) but major systemic side effects (urticaria, angioedema, asthma) were equally distributed between treatments with the two extracts. Major systemic side effects complicated the treatment before the first grass pollen season in 33% of the patients versus only 3% during the subsequent perennial therapy. Systemic and local (side) effects were delayed when using aluminium-absorbed extracts. Major systemic side effects were predicted by means of high nasal sensitivity but not by immediate local skin reactions (7). Tiaramide (SEDA- 7, 189) 29 patients with moderate to severe bronchial asthma cooperated in a doubleblind cross-over study using placebo, salbutamol and tiaramide (800 mg/d). No difference in therapeutic effect was found between tiaramide and salbutamol; both were better than placebo. Few patients experienced side effects with tiaramide; these comprised headache, diarrhea and nausea (8).
Mueolytic agents (SED 9, 2 77; SEDA-4, 121; SEDA-5, 1 70; SEDA-6, 1 71; SEDA-7, 189) Although the clinical usefulness of mucolytic agents is still under discussion, all authors agree that side effects are no problem. In a balanced article on bromhexine Jr pointed out that few side effects have been detected with this agent. Reactivation o f intestinal ulcers is the most important, but has only been described in a few patients. As far as the author knows no hematemesis, melena or other complications have been found (9r). Milder gastrointestinal symptoms have been referred to in earlier volumes in this series. In a group of 27 patients (16 males and 11 females) the tolerance of ambroxol was excellent in 15, good in 10, moderate in 1; in 1 patient with duodenal ulcer there
F.A. Nelemans
172 were complaints about pyrosis and dyspepsia (10c). In a double-blind study 224 pregnant women received ambroxol or placebo daily over a period of 5 days (500 rnl infusion of 5% glucose with 1000 rag ambroxol or placebo within 2 hours). All these women were already in premature labor or had premature rupture of the membranes between the 28th and 36th week. Side effects such as nausea were described in 3 women on placebo and in 5 on ambroxol. All 8 had received betamimetic drugs (11c). Acetylcysteine (NACJ is used not only as a mucolytic but also systemically as an antidote in paracetamol poisoning. Side effects are rare.
centrations of Mesna (usually 1:1 diluted solution) have been used in 29 patients without severe complications. There were 2 cases of bronchospasm and 1 case produced blood-tinged sputum (13).
Cough remedies
Mofoxine (Arphosal) is an antitussive substance possibly having antiphlogistic and sedative properties. When it was administered to 41 children ( 1 - 1 2 years) in an a m o u n t of 4 mg/kg per day, no side effects, either clinical or biochemical, were observed (14). A 21-year-old female had 2 epileptic attacks after swallowing 25 mg of tipepidine hibenzate (3 -di(2-thienyl)methylene- 1-methA 49-year-old woman had ingested about ylpiperidinium 4-hydroxybenzophenone-250 tablets of paracetamol and a bottle of sherry. carboxylate). Under EEG control she took She had for many years taken phenytoin and again a therapeutic dose and epileptiform phenobarhitone for the control of epilepsy. The changes in the EEG were detected. The plasma paxacetamol on admission (at least 8 hx post ingestion) was 146 rag/1. Intravenous NAC piperidine ring can be considered as con150 mg/kg over 15 win was started. Within 5-10 vulsant, its convulsant action being antagrain a patchy erythematous rash appeared over the onized by GABA. It is therefore not entirely patients face and arms and she complained of surprising that, after having given the patient wheeziness and difficulty in breathing. The in- 300 mg vitamin B6 per day intramuscularly fusion was discontinued and the symptoms sub. for 8 consecutive days and then rechallengsided within 10 rain (12c). ing here with the drug, the EEG remained normal ( 15 c). Using the De Vilbiss inhaler various cop REFERENCES 1. Adverse Drug Reactions Advisory Committee (1982) Seven case studies. Med. J. Aust., 1, 524. 2. Ostler HB 0982) Alpha-l-Antitrypsin and ocular sensitivity to r Lancet, 2, 1287. 3. Baronti A, Vibelli C (1983) Ketotffen in skintest-positive perennial asthma. Curr. Ther. Res., 33, 401. 4. V~elli C, Rudelli G (1982) Multicentre study for the evaluation of ketotifen in the prophylaxis of bronchial asthma: an interim report. Curt. Ther. Res., 32, 686. 5. Goihman-Yahr M, Rothemberg A, EssenfeldYahr E (1983) Erythema multiforme and ketotifen. J. Am. Acad. Derm., 8, 429. 6. Grammer LC, Zeiss CR, Suszko IM et al (1982) A double-blind placebo-controlled trial of polymerized whole ragweed for immunotherapy of ragweed allergy. Am. Acad. All. Immunol., 69, 494. 7. ~sterballe O 0982) Side effects during immunotherapy with purified grass pollen extracts. Allergy 37, 553. 8. Bonifazi F, Sanguinetti CM, Vennarucci LS,
Gasparini S (1982) La tiaramide, un nuovo farmaco per via oraie, nel trattamento dell'asma. Riv. Pat. Clin. Tubercol. Pneumol., 53, 69. 9. J~rgensen PH (1982) Bromhexin, en genvurdering ud fra litteraturen. Ugeskr. Laeg., 144, 1327. 10. Piantedosi FV, Cordedda M (1982) Efficacia terapeutica e tollerabilita dell'ambroxol in uno studio su 27 pazienti broncopneumopatici. Osp. Ital. Pediatr., 17, 812. 11. Wauer RR, Schmalisch G, Menzel K et al (1982) The antenatal use of ambtoxol Coromhexine metabolite VIII) to prevent hyaline membrane disease: a controlled double-blind study. Biol. Res. Pregn., 3, 84. 12. Vale JA, Wheeler DC (1982) Anaphylactoid reactions to acetylcysteine. Lancet, 2, 988. 13. Choi KH, Kim KR, Kim JM et al (1982) Clinical effects of mercaptoethane sylphonate (MESNA) in various respiratory diseases. Tuber. Resp. Dis., 29, 157. 14. Romagny G, Karman JF (1982) Int~r~t d'une mol~cule tussipl~gique nouvelle en l~diatrie. La mofoxine. Prog. M~d. /Paris/, 5, 87. 15. Cuomo RM (1982) On the possible convulsive activity of an antitussive piperidinic
Antiallergic and antitussive drugs derivative ('tipepidina ~enzato') in man. Acta NeuroL, 37, 110. 16. Kallds P, Kallds L (1982) Pseudo-allergic reactions due to disodium cromogiycate. In: Pseudo-Allergic Reactions. Involvement o f Drugs and Chemicals, VoL 3, pp. 122-132. Karger,
173 Basel. 17. Parker JM (1983) Paper delivered to the Drug Information Association, Washington DC, July 1983 (Personal communication to the Editor).