J Int Med Res (1979) 7, 235
A Double-Blind Clinical Study with Monydrin Tablets in Patients with Non-Allergic Chronic Rhinitis U Renvall, MD, University Hospital of Gothenburg (Sahlgrenska Sjukhuset), Ear, Nose and Throat Department, N Lindqvist, M Pharm Sci, Medical Department, Draco, Lund, Sweden
Oral combination preparations (antihistamine + sympathomimetic) are widely used for nasal and sinus congestion without the presence of allergy. The use of antihistamine in these cases may be questioned. Evaluation of the clinical effect of only a sympathomimetic agent on patients with nonallergic rhinitis is performed in a double-blind clinical study on seventy patients. Phenylpropanolamine (50 mg and 100 mg) was compared with placebo. It was found that 100 mg phenylpropanolamine was significantly more active than 50 mg or placebo administered orally as a sustained-release tablet twice daily. No side-effects such as eNS stimulation and influence on blood pressure were seen at any of the dose levels.
Introduction
Allergic rhinitis has been treated symptomatically with sympathomimetics and/or antihistamines for decades. Black 1937, Boyer 1938, and Murphy 1939 have shown that phenylpropanolamine by its vasoconstrictor effect upon the nasal mucosa can diminish the nasal airway-resistance and give good symptomatic relief. Antihistamines were introduced for the treatment of allergic rhinitis in 1942 (Halpern 1942) and has since then been used widely especially in combination with sympathomimetic agents. In patients with allergic rhinitis, the combination of an antihistamine and an a-receptor stimulant has been shown to give a better clinical effect than either of the components above (Aschan 1964, Callaghan et al 1967, Schibly, Radielovic & Biihlmann 1973, Empey 1975, LaageHellman, Jungert & Bruce 1977, Hansen 1978). Oral combination preparations are also
widely used for nasal and sinus congestion without any presence of allergy. It may be questioned whether antihistamines should be used for these indications. One clinical disadvantage with the use of antihistamines is sedation which may be troublesome in some patients (Goodman L S, Gillman A, The pharmacological basis of therapeutics, 5th ed., 1975, page 607). Therefore the aim of this investigation has been to evaluate the clinical effect and sideeffects of only a sympathomimeticum (phenylpropanolamine) in two different doses in patients with non-allergic rhinitis.
Materials and Methods
1. Population Seventy adults, thirty-two men and thirty-eight women, aged 15-78 years (mean age 42
0300-0605/79/030235-05 $02·00
©Cambridge Medical Publications Limited
236
The Journal ofInternational Medical Research
years). All the patients had typical rhinitis symptoms with nasal obstruction and/or nasal secretion. All the patients had suffered from the symptoms for a long time, most of them for many years. The case history has not revealed any allergic genesis and in most cases the diagnosis is therefore 'vasomotor rhinitis'. Some of the patients have accompanying symptoms, such as feeling of deafness, sneezing, etc. Before the start of the trial, all drugs with a decongestant effect on the mucosa were withdrawn. At the first visit, blood pressure was measured by the cuff method. In all the patients blood pressure was within normal limits.
3. Conditions and Assessments The trial was performed strictly double-blind and the patients were divided into three dose groups at random. At the first visit, the patients were questioned about the severity of their symptoms, possible causes, and possible sleeping disturbances. If the interview revealed that the symptoms were of an allergic nature, the patient was not enrolled in the study. Blood pressure was measured with the patient sitting. At 8.00 p.m. at the day of the interview (Day 1) the patients started the treatment. The patients were asked to classify their symptoms on a questionnaire the following morning according to a scoring system. On the fourth day, the patients returned to the clinic for another interview regarding nasal discomfort, difficulty with sleeping, and other effects (sideeffects) that could be related to the new drug. Blood pressure was also measured at this time.
2. Preparations and Dosage Phenylpropanolamine chloride 50 mg in a tablet of sustained-release type (Monydrin*) and a placebo tablet indistinguishable from the former in appearance and consistency were used. Three doses were tested: Placebo, 50 mg and 100 mg of phenylpropanolamine, administered morning and night (at 8.00 a.m, and 8.00 p.m.), The tablets were taken whole with half a glass of water. The different doses were administered as follows: Placebo: 2' placebo tablets morning and night 50 mg: 1 placebo tablet + 1 x 50 mg tablet morning and night 100 mg: 2 x 50 mg tablets morning and night. *AB Draco, subsidiary of AB Astra
Results Patients' evaluation after two doses Table 1 reports the patients' subjective evaluation of the effect on nasal symptoms in the morning of the day after their first visit to the clinic, i.e. after one evening and one morning dose. Physician's evaluation after six doses EFFECTS ON NASAL MUCOSA
The severity of the symptoms at the first and second visit are reported in Table 2.
Table 1 Padents' subjective evaluation of the effect on nasal symptoms after two doses of the test drug Nasal obstruction (No.ofpatlents} Placebo
50mg
Free from symptoms Much better Better Unchanged Worse
9 12 2
10
Total
24
0 I
Nasal secretion (No.of'patients) IOOmg
Placebo
50mg
IOOmg
3
0
I
I
I
4 8
0 3 7
4
9
4 4 8
I
0
I
I
0
20
19
14
12
11
0 0
3 3
237
U Renvall and N Lindqvist Table 2 The severity of the symptoms at the first visit (initially) and the second visit (after six doses of the test drug)
Nasal obstruction (No. ofpatients) Placebo Score at second visit
50mg Score at second visit
lOOmg Score at second visit
1 2
1 2 3 4
1
3 4
234
2
2
1 7
2
Score at first visit
2
1 4
Score at first visit
3
Score at first visit
3
4
6
1
3
4
1 2
2
4
1 1 5 1 3 4
3
4
4
1 2
4
5
Nasal secretion (No. ofpatients) Placebo Score at second visit
50mg Score at second visit
lOOmg Score at second visit
1
1 2 3 4
1 234
6
6
2
3
4
6
2
2 3
1
Score at first visit
2
3
Score at first visit 3
5 3
4
Scoring system: Severity ofsymptoms Symptoms all day Symptoms large part of the day Symptoms occasionally No symptoms
2
2
1
2
1
Score at first visit
3
2 5
3
2
4
1 1 2
4
1 3
Score 4 3 2 1
From the table it can be seen, for example, that in the placebo group there were eleven patients with score 3 on nasal obstruction at the first visit. At the second visit one of these patients had score 4, a deterioration by one score unit. Six patients were unchanged and four were improved by one score unit. The direction of the change was tested using sign tests for the patients with score 2 or 3 (explained in Table 2) at the first visit. Note: These are the only patients that may experience a change in both directions. For nasal ohstruction in the 100 mg group there was a significant (p < 0·01) improvement,
eight patients being better and none being worse at the second visit. In the other situations considered, no significant difference was found. The effects of the different treatments, measured as the difference between scores at the second and first visit, were compared using pooled Wilcoxon tests. (The patients were stratified according to the score at the first visit. For one of the treatments the rank sums within strata were calculated. These rank sums were pooled using the inverse of the total number of patients within a stratum as a weighting factor. An approximate standard
238
The Journal ofInternational Medical Research
normal deviate was calculated). For nasal obstruction there was a significant (p < 0·05) difference between 100 mg and placebo and a significant (p < 0·05) difference between 100 mg and 50 mg. For nasal secretion there was a significant (p < 0·05) difference between 100 mg and 50 mg. No other significant differences were found. All statistical significances reported refer to two-tailed tests.
questioned about possible sleep disturbances, i.e. difficulty in falling asleep or disturbed rest. Table 3 reports the results. The results prove that, contrary to, for instance, ephedrine, not even high doses (l00 mg x 2) of phenylpropanolamine have any effect on the eNS.
EFFECTS ON SLEEPING
During both interviews, the patients were
EFFECTS ON BLOOD PRESSURE
Blood pressure was measured on Day I and Day 4. No significant change in blood pressure was noted neither in means nor in individual patients (Table 4).
SIDE-EFFECTS
The patients experienced the following side-effects as a consequence of the treatment: Placebo: Tiredness I patient More alert I patient Phenylpropanolamine 50 mg: Slight drowsiness I patient Perspiration during the night, flushing cheeks I patient and neck I patient Severe nausea I patient Phenylpropanolamine 100 mg: Nausea on two occasions I patient Nausea
Table 3 Difficulty with sleeping - Before and after six doses of the test drug (=Day 1 and Day 4)
Difficulty in falling asleep
Disturbed rest
Dose
No. ofpatients Day 4 Day 1
No.ofpatients Day 1 Day 4
Placebo 50mg 100mg
5 7 5
10 11 11
3 5 2
8 11 9
Table 4 Blood pressure - Before and after six doses of the test drug
Mean
Placebo No. ofpatients: 26 Before After
50mg No. ofpatients: 25 Before After
lOOmg No. ofpatients: 18 Before After
138/87
137/86
131/86
135/87
137/86
127/84
U Renvall and N Lindqvist Discussion The present study shows that there is a need for 100 mg phenylpropanolamine in a tablet of sustained-release type administered twice a day to receive an acceptable decongestion of the nasal mucosa. Previous studies have shown a good clinical effect with 50 mg phenylpropanolamine in combination with an antihistaminic agent, brompheniramine, on 'vasomotor rhinitis' (Axelsson 1972). Elimination of the antihistamine therefore seems to require a compensation in the form of a doubled dose of phenylpropanolamine. The reason for this might perhaps be ascribed to the anticholinergic effect of antihistamine, but should be further investigated. The reason for recording blood pressure is that, theoretically, administration of an (J.receptor stimulating adrenergic can cause a general peripheral vasoconstriction with a consequent increase in blood pressure. The literature does not prove such an effect, but systemic, controlled studies are missing. The present study proves that no increase in blood pressure occurs despite a concomitant obvious decongestion of the nasal mucosa. It is well known that ephedrine at high dosage gives obvious CNS effects (Goodman L S, Gillman A, The pharmacological basis of therapeutics, 5th ed., 1975, page 501). In animals it has been shown that the CNS effect of phenylpopanolamine is only one-eighth that of ephedrine (Schulte et aI1941). No incidence of CNS effects has been noted at the dosage of one 50 mg tablet phenylpropanolamine in sustained-release b.i.d, The effect on the central nervous system is, however, a question of the dosage, and it was therefore of interest to study if the 100 mg dosage in a sustainedrelease tablet b.i.d, was safe in this respect. Difficulty in falling asleep and disturbed rest are typical symptoms of CNS stimulation. No such symptoms were noted in this study. The reduced frequency of sleep disturbances can probably be referred to the fact that, in some cases, they were caused by nasal obstruction which was improved, or disappeared completely, during the treatment. Statistical analysis has been carried out by C-] Lamm, Techn.D, AB Draco.
239 Conclusion Patients suffering from non-allergic chronic rhinitis can be effectively treated with a sympathomimetic agent, phenylpropanolamine, when given ina dosage of 100 mg in a sustained-release tablet (Monydrin), twice daily. Phenylpropanolamine 50 mg twice daily did not show any statistically significant relief of the nasal symptoms. No side-effects, such as CNS stimulation or influence on the blood pressure, were seen at either of the dose levels.
REFERENCES Aschan G (1964) Experimental klinisk provning av N-hydroxiaetylpromethazin chlorid (Aprobit ® ) kombinerat med ephedrin hydrochlor. pa naspassagen. Ldkartidningen 42,32 Axelsson A (1972) Vasomotor rhinitis treated with Lunerin (Draco), a new sympathomimetic antihistaminic preparation. Acta Allergologica 27, 186 Black J H (1937) The control of allergic manifestations. Lancet 57, 101 BoyerW E (1938) The clinical use of phenyl-propanol-amine hydroc1oride (Propadrine) in the treatment of allergic conditions. Journal of Allergy and Clinical Immunology 9,509 Callaltlhan R P et al (1967) Combination therapy in hay fever and allergic rhinitis. Practitioner 198, 713 Empey DW (1975) A double-blind crossover trial of pseudoephedrine and triprolidine alone and in combination for the treatment of allergic rhinitis. Annals ofAllergy 34,41 HalpemB N (1942) Les antihistaminiques de synthese. Essais de Chimiotherapie des etats allergiques. Archives internationales de Pharmacodynamie et de Therapie LXVIII 339 Hansen S (1978) Dubbelblind crossover prdvning Lunerinl Brompheniramine pa barn. (in press) Laage-Hellman J E, Jungert S & Bruce L (1977) Sympatomimetikum kontra kombinationspreparat vid allergisk rinit. Opuscula Medica MurphyJ A (1939) Propadrine hydrochloride in the treatment of allergic manifestations. Pensylvania Medical Journal 43, 65 Schlbli R A, Radlelovic P & Biihlmann A A (1973) Die Wirkung eines neuen oralen Schnupfenmittels (HSP 525 A) auf den Stromungswtderstand der Nase. International Journal of Clinical Pharmacology and Biopharmacie 8, 58 Schulte J W et al (1941) Further study of central stimulation from sympathomimetic amines. Journal of Pharmacology and Experimental Therapeutics 71, 62
A Double-Blind Clinical Study with Monydrin Tablets in Patients with Non-Allergic Chronic Rhinitis U Renvall, MD, University Hospital of Gothenburg (Sahlgrenska Sjukhuset), Ear, Nose and Throat Department, N Lindqvist, M Pharm Sci, Medical Department, Draco, Lund, Sweden
Oral combination preparations (antihistamine + sympathomimetic) are widely used for nasal and sinus congestion without the presence of allergy. The use of antihistamine in these cases may be questioned. Evaluation of the clinical effect of only a sympathomimetic agent on patients with nonallergic rhinitis is performed in a double-blind clinical study on seventy patients. Phenylpropanolamine (50 mg and 100 mg) was compared with placebo. It was found that 100 mg phenylpropanolamine was significantly more active than 50 mg or placebo administered orally as a sustained-release tablet twice daily. No side-effects such as eNS stimulation and influence on blood pressure were seen at any of the dose levels.
Introduction
Allergic rhinitis has been treated symptomatically with sympathomimetics and/or antihistamines for decades. Black 1937, Boyer 1938, and Murphy 1939 have shown that phenylpropanolamine by its vasoconstrictor effect upon the nasal mucosa can diminish the nasal airway-resistance and give good symptomatic relief. Antihistamines were introduced for the treatment of allergic rhinitis in 1942 (Halpern 1942) and has since then been used widely especially in combination with sympathomimetic agents. In patients with allergic rhinitis, the combination of an antihistamine and an a-receptor stimulant has been shown to give a better clinical effect than either of the components above (Aschan 1964, Callaghan et al 1967, Schibly, Radielovic & Biihlmann 1973, Empey 1975, LaageHellman, Jungert & Bruce 1977, Hansen 1978). Oral combination preparations are also
widely used for nasal and sinus congestion without any presence of allergy. It may be questioned whether antihistamines should be used for these indications. One clinical disadvantage with the use of antihistamines is sedation which may be troublesome in some patients (Goodman L S, Gillman A, The pharmacological basis of therapeutics, 5th ed., 1975, page 607). Therefore the aim of this investigation has been to evaluate the clinical effect and sideeffects of only a sympathomimeticum (phenylpropanolamine) in two different doses in patients with non-allergic rhinitis.
Materials and Methods
1. Population Seventy adults, thirty-two men and thirty-eight women, aged 15-78 years (mean age 42
0300-0605/79/030235-05 $02·00
©Cambridge Medical Publications Limited
236
The Journal ofInternational Medical Research
years). All the patients had typical rhinitis symptoms with nasal obstruction and/or nasal secretion. All the patients had suffered from the symptoms for a long time, most of them for many years. The case history has not revealed any allergic genesis and in most cases the diagnosis is therefore 'vasomotor rhinitis'. Some of the patients have accompanying symptoms, such as feeling of deafness, sneezing, etc. Before the start of the trial, all drugs with a decongestant effect on the mucosa were withdrawn. At the first visit, blood pressure was measured by the cuff method. In all the patients blood pressure was within normal limits.
3. Conditions and Assessments The trial was performed strictly double-blind and the patients were divided into three dose groups at random. At the first visit, the patients were questioned about the severity of their symptoms, possible causes, and possible sleeping disturbances. If the interview revealed that the symptoms were of an allergic nature, the patient was not enrolled in the study. Blood pressure was measured with the patient sitting. At 8.00 p.m. at the day of the interview (Day 1) the patients started the treatment. The patients were asked to classify their symptoms on a questionnaire the following morning according to a scoring system. On the fourth day, the patients returned to the clinic for another interview regarding nasal discomfort, difficulty with sleeping, and other effects (sideeffects) that could be related to the new drug. Blood pressure was also measured at this time.
2. Preparations and Dosage Phenylpropanolamine chloride 50 mg in a tablet of sustained-release type (Monydrin*) and a placebo tablet indistinguishable from the former in appearance and consistency were used. Three doses were tested: Placebo, 50 mg and 100 mg of phenylpropanolamine, administered morning and night (at 8.00 a.m, and 8.00 p.m.), The tablets were taken whole with half a glass of water. The different doses were administered as follows: Placebo: 2' placebo tablets morning and night 50 mg: 1 placebo tablet + 1 x 50 mg tablet morning and night 100 mg: 2 x 50 mg tablets morning and night. *AB Draco, subsidiary of AB Astra
Results Patients' evaluation after two doses Table 1 reports the patients' subjective evaluation of the effect on nasal symptoms in the morning of the day after their first visit to the clinic, i.e. after one evening and one morning dose. Physician's evaluation after six doses EFFECTS ON NASAL MUCOSA
The severity of the symptoms at the first and second visit are reported in Table 2.
Table 1 Padents' subjective evaluation of the effect on nasal symptoms after two doses of the test drug Nasal obstruction (No.ofpatlents} Placebo
50mg
Free from symptoms Much better Better Unchanged Worse
9 12 2
10
Total
24
0 I
Nasal secretion (No.of'patients) IOOmg
Placebo
50mg
IOOmg
3
0
I
I
I
4 8
0 3 7
4
9
4 4 8
I
0
I
I
0
20
19
14
12
11
0 0
3 3
237
U Renvall and N Lindqvist Table 2 The severity of the symptoms at the first visit (initially) and the second visit (after six doses of the test drug)
Nasal obstruction (No. ofpatients) Placebo Score at second visit
50mg Score at second visit
lOOmg Score at second visit
1 2
1 2 3 4
1
3 4
234
2
2
1 7
2
Score at first visit
2
1 4
Score at first visit
3
Score at first visit
3
4
6
1
3
4
1 2
2
4
1 1 5 1 3 4
3
4
4
1 2
4
5
Nasal secretion (No. ofpatients) Placebo Score at second visit
50mg Score at second visit
lOOmg Score at second visit
1
1 2 3 4
1 234
6
6
2
3
4
6
2
2 3
1
Score at first visit
2
3
Score at first visit 3
5 3
4
Scoring system: Severity ofsymptoms Symptoms all day Symptoms large part of the day Symptoms occasionally No symptoms
2
2
1
2
1
Score at first visit
3
2 5
3
2
4
1 1 2
4
1 3
Score 4 3 2 1
From the table it can be seen, for example, that in the placebo group there were eleven patients with score 3 on nasal obstruction at the first visit. At the second visit one of these patients had score 4, a deterioration by one score unit. Six patients were unchanged and four were improved by one score unit. The direction of the change was tested using sign tests for the patients with score 2 or 3 (explained in Table 2) at the first visit. Note: These are the only patients that may experience a change in both directions. For nasal ohstruction in the 100 mg group there was a significant (p < 0·01) improvement,
eight patients being better and none being worse at the second visit. In the other situations considered, no significant difference was found. The effects of the different treatments, measured as the difference between scores at the second and first visit, were compared using pooled Wilcoxon tests. (The patients were stratified according to the score at the first visit. For one of the treatments the rank sums within strata were calculated. These rank sums were pooled using the inverse of the total number of patients within a stratum as a weighting factor. An approximate standard
238
The Journal ofInternational Medical Research
normal deviate was calculated). For nasal obstruction there was a significant (p < 0·05) difference between 100 mg and placebo and a significant (p < 0·05) difference between 100 mg and 50 mg. For nasal secretion there was a significant (p < 0·05) difference between 100 mg and 50 mg. No other significant differences were found. All statistical significances reported refer to two-tailed tests.
questioned about possible sleep disturbances, i.e. difficulty in falling asleep or disturbed rest. Table 3 reports the results. The results prove that, contrary to, for instance, ephedrine, not even high doses (l00 mg x 2) of phenylpropanolamine have any effect on the eNS.
EFFECTS ON SLEEPING
During both interviews, the patients were
EFFECTS ON BLOOD PRESSURE
Blood pressure was measured on Day I and Day 4. No significant change in blood pressure was noted neither in means nor in individual patients (Table 4).
SIDE-EFFECTS
The patients experienced the following side-effects as a consequence of the treatment: Placebo: Tiredness I patient More alert I patient Phenylpropanolamine 50 mg: Slight drowsiness I patient Perspiration during the night, flushing cheeks I patient and neck I patient Severe nausea I patient Phenylpropanolamine 100 mg: Nausea on two occasions I patient Nausea
Table 3 Difficulty with sleeping - Before and after six doses of the test drug (=Day 1 and Day 4)
Difficulty in falling asleep
Disturbed rest
Dose
No. ofpatients Day 4 Day 1
No.ofpatients Day 1 Day 4
Placebo 50mg 100mg
5 7 5
10 11 11
3 5 2
8 11 9
Table 4 Blood pressure - Before and after six doses of the test drug
Mean
Placebo No. ofpatients: 26 Before After
50mg No. ofpatients: 25 Before After
lOOmg No. ofpatients: 18 Before After
138/87
137/86
131/86
135/87
137/86
127/84
U Renvall and N Lindqvist Discussion The present study shows that there is a need for 100 mg phenylpropanolamine in a tablet of sustained-release type administered twice a day to receive an acceptable decongestion of the nasal mucosa. Previous studies have shown a good clinical effect with 50 mg phenylpropanolamine in combination with an antihistaminic agent, brompheniramine, on 'vasomotor rhinitis' (Axelsson 1972). Elimination of the antihistamine therefore seems to require a compensation in the form of a doubled dose of phenylpropanolamine. The reason for this might perhaps be ascribed to the anticholinergic effect of antihistamine, but should be further investigated. The reason for recording blood pressure is that, theoretically, administration of an (J.receptor stimulating adrenergic can cause a general peripheral vasoconstriction with a consequent increase in blood pressure. The literature does not prove such an effect, but systemic, controlled studies are missing. The present study proves that no increase in blood pressure occurs despite a concomitant obvious decongestion of the nasal mucosa. It is well known that ephedrine at high dosage gives obvious CNS effects (Goodman L S, Gillman A, The pharmacological basis of therapeutics, 5th ed., 1975, page 501). In animals it has been shown that the CNS effect of phenylpopanolamine is only one-eighth that of ephedrine (Schulte et aI1941). No incidence of CNS effects has been noted at the dosage of one 50 mg tablet phenylpropanolamine in sustained-release b.i.d, The effect on the central nervous system is, however, a question of the dosage, and it was therefore of interest to study if the 100 mg dosage in a sustainedrelease tablet b.i.d, was safe in this respect. Difficulty in falling asleep and disturbed rest are typical symptoms of CNS stimulation. No such symptoms were noted in this study. The reduced frequency of sleep disturbances can probably be referred to the fact that, in some cases, they were caused by nasal obstruction which was improved, or disappeared completely, during the treatment. Statistical analysis has been carried out by C-] Lamm, Techn.D, AB Draco.
239 Conclusion Patients suffering from non-allergic chronic rhinitis can be effectively treated with a sympathomimetic agent, phenylpropanolamine, when given ina dosage of 100 mg in a sustained-release tablet (Monydrin), twice daily. Phenylpropanolamine 50 mg twice daily did not show any statistically significant relief of the nasal symptoms. No side-effects, such as CNS stimulation or influence on the blood pressure, were seen at either of the dose levels.
REFERENCES Aschan G (1964) Experimental klinisk provning av N-hydroxiaetylpromethazin chlorid (Aprobit ® ) kombinerat med ephedrin hydrochlor. pa naspassagen. Ldkartidningen 42,32 Axelsson A (1972) Vasomotor rhinitis treated with Lunerin (Draco), a new sympathomimetic antihistaminic preparation. Acta Allergologica 27, 186 Black J H (1937) The control of allergic manifestations. Lancet 57, 101 BoyerW E (1938) The clinical use of phenyl-propanol-amine hydroc1oride (Propadrine) in the treatment of allergic conditions. Journal of Allergy and Clinical Immunology 9,509 Callaltlhan R P et al (1967) Combination therapy in hay fever and allergic rhinitis. Practitioner 198, 713 Empey DW (1975) A double-blind crossover trial of pseudoephedrine and triprolidine alone and in combination for the treatment of allergic rhinitis. Annals ofAllergy 34,41 HalpemB N (1942) Les antihistaminiques de synthese. Essais de Chimiotherapie des etats allergiques. Archives internationales de Pharmacodynamie et de Therapie LXVIII 339 Hansen S (1978) Dubbelblind crossover prdvning Lunerinl Brompheniramine pa barn. (in press) Laage-Hellman J E, Jungert S & Bruce L (1977) Sympatomimetikum kontra kombinationspreparat vid allergisk rinit. Opuscula Medica MurphyJ A (1939) Propadrine hydrochloride in the treatment of allergic manifestations. Pensylvania Medical Journal 43, 65 Schlbli R A, Radlelovic P & Biihlmann A A (1973) Die Wirkung eines neuen oralen Schnupfenmittels (HSP 525 A) auf den Stromungswtderstand der Nase. International Journal of Clinical Pharmacology and Biopharmacie 8, 58 Schulte J W et al (1941) Further study of central stimulation from sympathomimetic amines. Journal of Pharmacology and Experimental Therapeutics 71, 62
