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Antiallergic and antitussive drugs
F.A. Nelemans
17
Antiallergic and antitussive drugs
Editorial note Several drugs used in bronchial asthma and cough are dealth with in other chapters. These include xanthine compounds (Chapter 1), the opiates and derivatives such as dextromethorphan (Chapter 8), sympathomimetic and parasympatholytic agents (Chapter 1 4 ) , the antihistamines (Chapter 16) and the corticosteroids (Chapter 41).
DRUGS U S E D IN B R O N C H I A L A S T H M A (SED-tl, 322; SEDA-12, 144)
Nebulizer solutions and paradoxical bronchoconstriction The fact that nebulizer solutions can sometimes cause severe and even fatal complications is not new. The most severe problems arose nearly two decades ago with an epidemic o f deaths in the United Kingdom and some other countries following the use o f isoprenaline (isoproterenol) or other aerosols. Among the possible explanations advanced was the toxicity o f the propellant or sensitization o f the myocardium to the effects o f adrenaline by the active component itself (SED-11, 326). In the course o f 1988, the U.K. Committee on Safety o f Medicines f o u n d it necessary to draw attention to the risk that nebulizers couM cause paradoxical bronchoconstriction (1R). In the course o f 2 years, the Committee had been notified o f 17 such cases, all involving 9 1989 Elsevier Science Publishers B.V. (Biomedical Division)
Side Effects of Drugs Annual 13 M.N.G. Dukes and L. Beeley, editors
bronchodilator solutions; in 2 o f the cases a young child and an adult - the nebulizer reaction was at least a contributory cause o f death. In only 4 cases was the drug being given because o f a recent exacerbation o f reversible airways disease; all the other cases were stable asthmatics or patients with other forms o f reversible airways disease who were on regular nebulizer therapy when the paradoxical reaction occurred. However, bronchospasm tended to be noted where there had been some change in treatment, and in 1 case it occurred during the assessment o f pulmonary function. In the Committee's view, the reactions probably resulted f r o m the formulation o f the nebulizer solutions concerned: "Hypotonicity or hypertonicity, the presence o f preservatives (such as benzalkonium chloride), edetic acid, sulphites and metabisulphite have all been shown to cause bronchoconstriction.' But, as the Committe adds, it is not possible to ascertain whether these agents were responsible in the cases now reported. The Committee's own advice to physicians is to remain watchful f o r worsening ofairways disease in patients o f any age. Some reports on reactions o f this type have been published and have been discussed in recent years in these volumes. In certain o f these cases one can be fairly sure o f the causal responsibility o f the formulation used. Mann and others in 1984 described cases involving ipratropium bromide and advanced reasons f o r believing that the hypotonicity o f the product as sold at that time was the cause o f the problem (2c). Later it was shown that benzalkonium chloride and edetic acid, present in the same product, couM cause bronchoconstriction, whereas ipratropium reformulated as a nebulizer without these components did
not (3c). The 'Lancet' has concluded editorially, in
Antiallergic and antitussive drugs Chapter 17 the light o f this exprience, that all nebulizer solutions should be isotonic and preservativefree; this may reduce their risks and naturally at the same time increase their efficacy as antiasthmatics (4R). Removal o f preservatives naturally creates a need f o r some other means o f preventing bacterial contamination; the obvious solution is to provide these solutions in sterile f o r m in unit-dose vials, which can be filled into a nebulizer when required.
135 tensive 'prescription-event' monitoring study by Prof. Inman's group; by the late summer of 1988, the first few hundred reports to be examined still pointed only to headache and nausea as adverse effects (8r
COUGH REMEDIES (SED-11, 329; SEDA12, 145)
Clistin | Hexapneumine | Azelastine (SEDA-12, 144) Azelastine is a phthalazinone derivative with antagonistic activity in vitro and in vivo against histamine and other mediators. In double-blind trials azelastine showed its activity in exercise-induced asthma and in allergen challenge in patients with extrinsic asthma. Side effects had a low incidence; several patients reported a transient bitter or altered taste sensation. The frequency of fatigue and drowsiness was not statistically different from placebo in most studies. No serious side effects occurred in the trials which involved some hundreds of patients (5r).
Cromoglicate disodium (cromolyn sodium) (SED-11, 322; SEDA-12, 144) A patient with a documented history of lactase deficiency has been described in whom symptoms of lactose intolerance (nausea, bloating, abdominal cramps and flatulence) developed 2 hours after the initial use of lntal capsules. Rechallenge with the same medication gave the same symptoms. On the other hand, there were no symptoms after the use of lactose-free cromoglicate disodium products (6c).
Nedocromil (Tilade) (SED-11, 323; SEDA12, 144) Like cromoglicate disodium, nedocromil has a high degree of safety. Nausea (3.8~ and headache (4.807o) are the most commonly observed side effects. They are mild, temporary, diminish during chronic therapy and do not provide a reason for stopping the therapy (7r). Nedocromil is currently the subject of an ex-
Clistin and Hexapneumine have the following composition: biclotymol 0.1980 g, glyceryl-guaia colate 0.2000 g, pholcodine 0.1330 g, chlorpheniramine maleate 0.0133 g, excipient Q.S.P. 100 ml and carbinoxamine maleate U.S.P. 40 mg, dextromethorphan hydrobromide B.P. 100 mg, ammonium chloride I.P. 2400 rag, sodium citrate I.P. 2400 mg, syrupy base Q.S.P. 100 ml. The posology was 1 teaspoon 3 times a day. Both drugs have been compared in a parallel-design, double-blind clinical trial (9c). The patients' subjective improvement in severity of the symptoms was recorded; 46 patients on Hexapneumine and 49 on Clistin could be evaluated; 26 patients in the Hexapneumine group had concurrent chemotherapy. There were 10 different diagnosis groups! In the Hexapneumine group 2 patients complained of drowsiness, 2 of dryness of the mouth; in the Clistin group 6 complained of drowsiness, 1 of dryness of the mouth or constipation. As there are so many different diagnoses and so much co-medication, it is impossible to draw any valuable conclusions.
Noscapine (SED-11, 330) Noscapine has long been regarded as being relatively free from side effects. In the last few years, however, the Swedish Adverse Reactions Advisory Committee has received some 20 reports of abdominal pain in connection with intake of noscapine. A typical case involves an otherwise healthy adult who develops an irritant cough and takes a dose of noscapine. After a period ranging from 15 minutes to 4 hours he suffers intense abdominal pain radiating under the sternum and costal arches, and sometimes accompanied by
Chapter 17 F.A. Nelemans
136 nausea. In most cases the pain subsides spontaneously within l - 3 hours, but some patients have sought help at emergency departments and have received analgesics. Some were re-exposed and developed the same symptoms anew. Recently, the Committee has also received reports on 4 cases of chest pain and dyspnea following intake of noscapine. The time course was similar to that of the abdominal pain. Two patients had re-exposure and the symptoms recurred. The WHO international register of side effects reported from national centers includes 4 non-Swedish reports on abdominal pain but none on chest pain. There is no explanation so far for these unusual adverse effects (10cr).
ly small series, severe peripheral neuropathy occurring at 5 and 9 months respectively led to the withdrawal of 9 patients, and by the end of the trial neuropathy had developed in 3 further patients. Although the drug was found to be effective in increasing PaO 2 in hypoxemic patients, the experience showed that caution is necessary, especially in patients with signs of neuropathy prior to or during treatment. Weight loss ranging from 4 to 15 kg was observed in 5 patients developing sensory peripheral neuropathy (9r). Finally, it is worth mentioning that almitrine has been shown to cause an increase in pulmonary artery pressure both at rest and during exercise (13r).
Squill
A 21-year-old woman took for 5 months daily 3 x 100 ml of Gee's Linctus (opiate squill linctus). Her complaints were progressive muscular weakness, frequent vomiting with some upset in bowel habit and a slow forceful heart beat. Digoxin (0.5 nmol/l) was detected in the plasma (11r
Ambroxol, one of the so-called neuroactive drugs, stimulates the synthesis and release of surfactant by Type II pneumocytes. In a double-blind study I l0 patients received daily 75 mg ambroxol orally and 104 patients a placebo. Two patients in the placebo group dropped out because of adverse reactions (dyspepsia). The total side effects, including mild ones, were 20o70 for the placebo group and 24o70 for the ambroxol group. Gastrointestinal disturbances (pyrosis and dyspepsia) were 20o70 in the ambroxol group and 16o70 in the placebo group (14c).
MISCELLANEOUS
Desensitization (SED-11, 325; SEDA-12, 145)
Squill is a constituent of many cough linctuses because of its weak expectorant effect. Squill preparations contain cardiac glycosides. Abuse of such a cough linctus may lead to a manifest cardiac glycoside intoxication.
Almitrine dimesilate (SED-11, 330; SEDA12, 145) Up to now only limited data are available and the incidence of side effects is not well defined. Generally speaking, almitrine is well tolerated. Mild nausea and headache are the most frequently observed side effects. A major unexplained side effect is a worsening of dyspnea. This occurred in 4 of 21 patients receiving 200 mg/d (13r). Several other researchers have similarly reported a sensory peripheral neuropathy. This has been well-documented by Allen (12c), who treated 25 hypoxemic patients suffering from chronic bronchitis and emphysema; 12 of these received 50 mg almitrine b.d. while 13 received placebo. In this relative-
Ambroxol
The Committee on Allergen Standardization of the American Academy of Allergy and Immunology have collected data on 46 fatalities that occurred during immunotherapy or skin testing since 1945. As 7 - 1 0 million allergen injections are administered yearly, the risk of a fatal reaction is very low and it may be lessened even further if additional precautions are taken. Details as far as available are given. One point is worth mentioning here. The character and severity of the initial symptoms did not appear to predict the fatal outcome or indicate the cause of death (15a). The U.S. Food and Drug Administration in 1988 asked the medical community for help in quantifying the extent of the problem of fatalities associated with the use of allergenic
Antiallerg& and antitussive drugs
Chapter 17
extracts. The figures which they q u o t e as to the extent o f the supposed risk are similar to those cited a b o v e ( p r o d u c i n g an e s t i m a t e o f 0.2 deaths per million t r e a t m e n t s as a n a n n u a l average), but there is clearly a possibility o f s u b s t a n t i a l u n d e r r e p o r t i n g (16R).
137
Dextromethorphan (SEDA-12, 62) It m a y be n o t e d t h a t in Sweden dext r o m e t h o r p h a n was for some time sold w i t h o u t prescription, b u t as o f April 1987 the prescription r e q u i r e m e n t has been reimposed.
REFERENCES 1. Anonymous (1988) Nebuliser solutions and paradoxical bronchoconstriction. Current Problems, No. 22. Committee on Safety of Medicines, London. 2. Mann JS, Howarth PH, Holgate ST (1984) Bronchoconstriction induced by ipratropium bromide in asthma: relation to hypotonicity. Br. Med. J., 289, 469. 3. Rafferty P, Beasley R, Holgate ST (1988) Comparison of the efficacy of preservative free ipratropium bromide and Atrovent nebuliser solution. Thorax, 43, 446. 4. Editorial (1988) Nebulisers and paradoxical bronchoconstriction. Lancet, 2, 202. 5. Molliere M, Engel J (1987) Azelastine, a new asthma prophylactic and anti-allergy agent. Drugs Today, 23, 203. 6. Brandstetter RD, Conetta R, Glazer B (1986) Lactose intolerance associated with Intal capsules. N. Engl. J. Med., 315, 1613. 7. Anonymous (1987) Nedocromil sodico; nedocromil sodium. Drugs Today, 23, 132. 8. Anonymous (1988) 'Tilade' (nedocromil). P E M News, 5, 16. 9. Chakrab~rti A, Pandhi P, Jindal SK et al (1987) A comparative randomized double-blind clinical
trial of Hexapneumine and Clistine as antitussive agents. Int. J. Clin. Pharmacol. Ther. Toxicol., 25, 310. 10. Anonymous (1988) Noscapine - abdominal pain and pain in the chest. S A D R A C Bull., 50, 8. II. Mason B, Pugh SE, Holt DW (1987) Cardiac glycoside toxicity resulting from cough linctus abuse. Hum. Toxicol., 6, 251. 12. Allen MB (1988) Almitrine and peripheral neuropathy. Lancet, 2, 571. 13. Smith PKD, Gotz VP, Ryerson GG (1987) Almitrine bismesilate. Drug. Intell. Clin. Pharm., 21, 417. 14. Olivieri D, Zavalline G, Tomarini G et al (1987) Ambroxol for prevention of chronic exacerbations: long-term multicenter trial. Protective effect of ambroxol against winter semester exacerbations: a double-blind study versus placebo. Respiration, 51, 42. 15. Lockey RF, Benedict LM, Turkeltaub PC et al (1987) Fatalities from immunotherapy (IT) and skin testing (ST). J. Allergy Clin. Immunol., 79, 660. 16. Anonymous (1988) Reports of deaths with allergenic extracts. FDA Drug Bull., 18/3, 30.
17
Antiallergic and antitussive drugs
Editorial note Several drugs used in bronchial asthma and cough are dealth with in other chapters. These include xanthine compounds (Chapter 1), the opiates and derivatives such as dextromethorphan (Chapter 8), sympathomimetic and parasympatholytic agents (Chapter 1 4 ) , the antihistamines (Chapter 16) and the corticosteroids (Chapter 41).
DRUGS U S E D IN B R O N C H I A L A S T H M A (SED-tl, 322; SEDA-12, 144)
Nebulizer solutions and paradoxical bronchoconstriction The fact that nebulizer solutions can sometimes cause severe and even fatal complications is not new. The most severe problems arose nearly two decades ago with an epidemic o f deaths in the United Kingdom and some other countries following the use o f isoprenaline (isoproterenol) or other aerosols. Among the possible explanations advanced was the toxicity o f the propellant or sensitization o f the myocardium to the effects o f adrenaline by the active component itself (SED-11, 326). In the course o f 1988, the U.K. Committee on Safety o f Medicines f o u n d it necessary to draw attention to the risk that nebulizers couM cause paradoxical bronchoconstriction (1R). In the course o f 2 years, the Committee had been notified o f 17 such cases, all involving 9 1989 Elsevier Science Publishers B.V. (Biomedical Division)
Side Effects of Drugs Annual 13 M.N.G. Dukes and L. Beeley, editors
bronchodilator solutions; in 2 o f the cases a young child and an adult - the nebulizer reaction was at least a contributory cause o f death. In only 4 cases was the drug being given because o f a recent exacerbation o f reversible airways disease; all the other cases were stable asthmatics or patients with other forms o f reversible airways disease who were on regular nebulizer therapy when the paradoxical reaction occurred. However, bronchospasm tended to be noted where there had been some change in treatment, and in 1 case it occurred during the assessment o f pulmonary function. In the Committee's view, the reactions probably resulted f r o m the formulation o f the nebulizer solutions concerned: "Hypotonicity or hypertonicity, the presence o f preservatives (such as benzalkonium chloride), edetic acid, sulphites and metabisulphite have all been shown to cause bronchoconstriction.' But, as the Committe adds, it is not possible to ascertain whether these agents were responsible in the cases now reported. The Committee's own advice to physicians is to remain watchful f o r worsening ofairways disease in patients o f any age. Some reports on reactions o f this type have been published and have been discussed in recent years in these volumes. In certain o f these cases one can be fairly sure o f the causal responsibility o f the formulation used. Mann and others in 1984 described cases involving ipratropium bromide and advanced reasons f o r believing that the hypotonicity o f the product as sold at that time was the cause o f the problem (2c). Later it was shown that benzalkonium chloride and edetic acid, present in the same product, couM cause bronchoconstriction, whereas ipratropium reformulated as a nebulizer without these components did
not (3c). The 'Lancet' has concluded editorially, in
Antiallergic and antitussive drugs Chapter 17 the light o f this exprience, that all nebulizer solutions should be isotonic and preservativefree; this may reduce their risks and naturally at the same time increase their efficacy as antiasthmatics (4R). Removal o f preservatives naturally creates a need f o r some other means o f preventing bacterial contamination; the obvious solution is to provide these solutions in sterile f o r m in unit-dose vials, which can be filled into a nebulizer when required.
135 tensive 'prescription-event' monitoring study by Prof. Inman's group; by the late summer of 1988, the first few hundred reports to be examined still pointed only to headache and nausea as adverse effects (8r
COUGH REMEDIES (SED-11, 329; SEDA12, 145)
Clistin | Hexapneumine | Azelastine (SEDA-12, 144) Azelastine is a phthalazinone derivative with antagonistic activity in vitro and in vivo against histamine and other mediators. In double-blind trials azelastine showed its activity in exercise-induced asthma and in allergen challenge in patients with extrinsic asthma. Side effects had a low incidence; several patients reported a transient bitter or altered taste sensation. The frequency of fatigue and drowsiness was not statistically different from placebo in most studies. No serious side effects occurred in the trials which involved some hundreds of patients (5r).
Cromoglicate disodium (cromolyn sodium) (SED-11, 322; SEDA-12, 144) A patient with a documented history of lactase deficiency has been described in whom symptoms of lactose intolerance (nausea, bloating, abdominal cramps and flatulence) developed 2 hours after the initial use of lntal capsules. Rechallenge with the same medication gave the same symptoms. On the other hand, there were no symptoms after the use of lactose-free cromoglicate disodium products (6c).
Nedocromil (Tilade) (SED-11, 323; SEDA12, 144) Like cromoglicate disodium, nedocromil has a high degree of safety. Nausea (3.8~ and headache (4.807o) are the most commonly observed side effects. They are mild, temporary, diminish during chronic therapy and do not provide a reason for stopping the therapy (7r). Nedocromil is currently the subject of an ex-
Clistin and Hexapneumine have the following composition: biclotymol 0.1980 g, glyceryl-guaia colate 0.2000 g, pholcodine 0.1330 g, chlorpheniramine maleate 0.0133 g, excipient Q.S.P. 100 ml and carbinoxamine maleate U.S.P. 40 mg, dextromethorphan hydrobromide B.P. 100 mg, ammonium chloride I.P. 2400 rag, sodium citrate I.P. 2400 mg, syrupy base Q.S.P. 100 ml. The posology was 1 teaspoon 3 times a day. Both drugs have been compared in a parallel-design, double-blind clinical trial (9c). The patients' subjective improvement in severity of the symptoms was recorded; 46 patients on Hexapneumine and 49 on Clistin could be evaluated; 26 patients in the Hexapneumine group had concurrent chemotherapy. There were 10 different diagnosis groups! In the Hexapneumine group 2 patients complained of drowsiness, 2 of dryness of the mouth; in the Clistin group 6 complained of drowsiness, 1 of dryness of the mouth or constipation. As there are so many different diagnoses and so much co-medication, it is impossible to draw any valuable conclusions.
Noscapine (SED-11, 330) Noscapine has long been regarded as being relatively free from side effects. In the last few years, however, the Swedish Adverse Reactions Advisory Committee has received some 20 reports of abdominal pain in connection with intake of noscapine. A typical case involves an otherwise healthy adult who develops an irritant cough and takes a dose of noscapine. After a period ranging from 15 minutes to 4 hours he suffers intense abdominal pain radiating under the sternum and costal arches, and sometimes accompanied by
Chapter 17 F.A. Nelemans
136 nausea. In most cases the pain subsides spontaneously within l - 3 hours, but some patients have sought help at emergency departments and have received analgesics. Some were re-exposed and developed the same symptoms anew. Recently, the Committee has also received reports on 4 cases of chest pain and dyspnea following intake of noscapine. The time course was similar to that of the abdominal pain. Two patients had re-exposure and the symptoms recurred. The WHO international register of side effects reported from national centers includes 4 non-Swedish reports on abdominal pain but none on chest pain. There is no explanation so far for these unusual adverse effects (10cr).
ly small series, severe peripheral neuropathy occurring at 5 and 9 months respectively led to the withdrawal of 9 patients, and by the end of the trial neuropathy had developed in 3 further patients. Although the drug was found to be effective in increasing PaO 2 in hypoxemic patients, the experience showed that caution is necessary, especially in patients with signs of neuropathy prior to or during treatment. Weight loss ranging from 4 to 15 kg was observed in 5 patients developing sensory peripheral neuropathy (9r). Finally, it is worth mentioning that almitrine has been shown to cause an increase in pulmonary artery pressure both at rest and during exercise (13r).
Squill
A 21-year-old woman took for 5 months daily 3 x 100 ml of Gee's Linctus (opiate squill linctus). Her complaints were progressive muscular weakness, frequent vomiting with some upset in bowel habit and a slow forceful heart beat. Digoxin (0.5 nmol/l) was detected in the plasma (11r
Ambroxol, one of the so-called neuroactive drugs, stimulates the synthesis and release of surfactant by Type II pneumocytes. In a double-blind study I l0 patients received daily 75 mg ambroxol orally and 104 patients a placebo. Two patients in the placebo group dropped out because of adverse reactions (dyspepsia). The total side effects, including mild ones, were 20o70 for the placebo group and 24o70 for the ambroxol group. Gastrointestinal disturbances (pyrosis and dyspepsia) were 20o70 in the ambroxol group and 16o70 in the placebo group (14c).
MISCELLANEOUS
Desensitization (SED-11, 325; SEDA-12, 145)
Squill is a constituent of many cough linctuses because of its weak expectorant effect. Squill preparations contain cardiac glycosides. Abuse of such a cough linctus may lead to a manifest cardiac glycoside intoxication.
Almitrine dimesilate (SED-11, 330; SEDA12, 145) Up to now only limited data are available and the incidence of side effects is not well defined. Generally speaking, almitrine is well tolerated. Mild nausea and headache are the most frequently observed side effects. A major unexplained side effect is a worsening of dyspnea. This occurred in 4 of 21 patients receiving 200 mg/d (13r). Several other researchers have similarly reported a sensory peripheral neuropathy. This has been well-documented by Allen (12c), who treated 25 hypoxemic patients suffering from chronic bronchitis and emphysema; 12 of these received 50 mg almitrine b.d. while 13 received placebo. In this relative-
Ambroxol
The Committee on Allergen Standardization of the American Academy of Allergy and Immunology have collected data on 46 fatalities that occurred during immunotherapy or skin testing since 1945. As 7 - 1 0 million allergen injections are administered yearly, the risk of a fatal reaction is very low and it may be lessened even further if additional precautions are taken. Details as far as available are given. One point is worth mentioning here. The character and severity of the initial symptoms did not appear to predict the fatal outcome or indicate the cause of death (15a). The U.S. Food and Drug Administration in 1988 asked the medical community for help in quantifying the extent of the problem of fatalities associated with the use of allergenic
Antiallerg& and antitussive drugs
Chapter 17
extracts. The figures which they q u o t e as to the extent o f the supposed risk are similar to those cited a b o v e ( p r o d u c i n g an e s t i m a t e o f 0.2 deaths per million t r e a t m e n t s as a n a n n u a l average), but there is clearly a possibility o f s u b s t a n t i a l u n d e r r e p o r t i n g (16R).
137
Dextromethorphan (SEDA-12, 62) It m a y be n o t e d t h a t in Sweden dext r o m e t h o r p h a n was for some time sold w i t h o u t prescription, b u t as o f April 1987 the prescription r e q u i r e m e n t has been reimposed.
REFERENCES 1. Anonymous (1988) Nebuliser solutions and paradoxical bronchoconstriction. Current Problems, No. 22. Committee on Safety of Medicines, London. 2. Mann JS, Howarth PH, Holgate ST (1984) Bronchoconstriction induced by ipratropium bromide in asthma: relation to hypotonicity. Br. Med. J., 289, 469. 3. Rafferty P, Beasley R, Holgate ST (1988) Comparison of the efficacy of preservative free ipratropium bromide and Atrovent nebuliser solution. Thorax, 43, 446. 4. Editorial (1988) Nebulisers and paradoxical bronchoconstriction. Lancet, 2, 202. 5. Molliere M, Engel J (1987) Azelastine, a new asthma prophylactic and anti-allergy agent. Drugs Today, 23, 203. 6. Brandstetter RD, Conetta R, Glazer B (1986) Lactose intolerance associated with Intal capsules. N. Engl. J. Med., 315, 1613. 7. Anonymous (1987) Nedocromil sodico; nedocromil sodium. Drugs Today, 23, 132. 8. Anonymous (1988) 'Tilade' (nedocromil). P E M News, 5, 16. 9. Chakrab~rti A, Pandhi P, Jindal SK et al (1987) A comparative randomized double-blind clinical
trial of Hexapneumine and Clistine as antitussive agents. Int. J. Clin. Pharmacol. Ther. Toxicol., 25, 310. 10. Anonymous (1988) Noscapine - abdominal pain and pain in the chest. S A D R A C Bull., 50, 8. II. Mason B, Pugh SE, Holt DW (1987) Cardiac glycoside toxicity resulting from cough linctus abuse. Hum. Toxicol., 6, 251. 12. Allen MB (1988) Almitrine and peripheral neuropathy. Lancet, 2, 571. 13. Smith PKD, Gotz VP, Ryerson GG (1987) Almitrine bismesilate. Drug. Intell. Clin. Pharm., 21, 417. 14. Olivieri D, Zavalline G, Tomarini G et al (1987) Ambroxol for prevention of chronic exacerbations: long-term multicenter trial. Protective effect of ambroxol against winter semester exacerbations: a double-blind study versus placebo. Respiration, 51, 42. 15. Lockey RF, Benedict LM, Turkeltaub PC et al (1987) Fatalities from immunotherapy (IT) and skin testing (ST). J. Allergy Clin. Immunol., 79, 660. 16. Anonymous (1988) Reports of deaths with allergenic extracts. FDA Drug Bull., 18/3, 30.