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Azelastine is an antiallergic agent which demonstrates histamine H1- receptor antagonist activity and also inhibits histamine release from mast cells following antigen and non-antigen stimuli. Azelastine antagonises histamine- and leukotriene-induced bronchospasm in animal studies and reduces airway responsiveness to inhaled antigen or distilled water, and exercise challenge. In comparative studies, orally administered azelastine in doses up to 4 mg/day consistently relieved symptoms in patients with seasonal or perennial rhinitis — comparable to inhaled sodium cromoglycate (cromolyn sodium) 80 mg/day, oral chlorpheniramine (chlorphenamine) and oral terfenadine 120 mg/day. In addition, azelastine administered as an intranasal spray was as effective as oral terfenadine 120 mg/day and intranasal budesonide 0.4 mg/day in alleviating symptoms of rhinitis.
Azelastine is also a potent antiasthmatic agent which produces significant and long lasting bronchodilation in patients with bronchial asthma. The drug is superior to placebo and comparable to oral ketotifen 2 mg/day and sustained release theophylline 700 mg/day when administered as a twice daily oral 4mg dose.
Azelastine is generally well tolerated: the most common adverse effects are altered taste perception and drowsiness. Adverse effects are mild and transient and result in withdrawal of treatment in less than 2% of patients. In a comparative study oral azelastine 2 or 4 mg/day produced no more sedation than terfenadine 120 mg/day.
Thus, barring unexpected findings with wider clinical use, azelastine offers an effective and well tolerated choice of treatment for patients with allergic rhinitis and/or bronchial asthma, which may be particularly beneficial in patients in whom inhaled drug treatment is contraindicated.
Azelastine has a selective and potent affinity for histamine H1-receptors in vitro and exerts a strong antihistaminic effect in both in vitro and in vivo studies. The drug inhibits histamine release from mast cells induced by antigen and non-antigen stimuli and is at least 5000 times more potent than ketotifen, sodium cromoglycate, theophylline and astemizole in this regard.
In asthmatic patients, single or multiple oral administration of azelastine 4mg inhibits histamine-induced bronchoconstriction and reduces the weal and flare response to intra-dermally injected histamine after only 4 hours. Azelastine weakly antagonises in vitro leukotriene-induced contractile responses and antigen- and non-antigen-induced leukotriene release, but has no effect on leukotriene-mediated bronchoconstriction in asthmatic patients.
Azelastine has negligible anticholinergic activity and inhibits serotonin-induced cutaneous anaphylaxis in rats at high dosages (25 mg/kg). In vitro platelet aggregation, paw oedema, and bronchoconstriction induced by platelet activating factor are inhibited by azelastine.
Azelastine administered as a single oral 4mg dose is a potent bronchodilator causing a marked effect within 1 hour and a maximum effect after 6 hours in patients with asthma or chronic obstructive bronchitis. Bronchoconstriction induced by inhaled allergen, distilled water, or exercise in asthmatic patients is markedly reduced by single oral azelastine doses of 2 to 8mg and the drug appears to inhibit the immediate (within 1 to 2 hours) and delayed (within 2 to 8 hours) bronchoconstrictor response.
The antiallergic properties of azelastine have been demonstrated in several animal models of allergy such as lung anaphylaxis and passive cutaneous anaphylaxis. In atopic patients, skin reactivity to antigen was reduced by up to 39% within 4 hours of an 8mg dose, and inhibition persisted for at least 1 week after withdrawal of treatment.
Although data are limited, azelastine appears to have a negligible effect on psychomotor performance and sedation over a dose range of 2 to 16mg. However, sedation may occur during concomitant alcohol administration.
The available information on the pharmacokinetics of azelastine in humans is largely based on unpublished data provided by the manufacturer, and additional published clinical studies are required to define more precisely the disposition of the drug. In healthy volunteers a single oral azelastine dose is almost completely (95%) absorbed. Peak plasma concentrations of 3 µg/L occur 4 to 5 hours after a single oral 4mg dose. After multiple azelastine doses (4mg twice daily) a mean peak plasma concentration of 10 µg/L is achieved in 2.3 hours. Absolute bioavailability of azelastine administered as an oral tablet is >80%. In animals azelastine is distributed primarily to peripheral tissues: concentrations are consistently low in the brain. Placental transfer of azelastine has been observed in animal studies. In healthy volunteers azelastine is 78 to 88% bound to plasma proteins. Elimination half-life is 25 hours after a single oral dose and 35.5 hours after multiple oral dosing, due possibly to the accumulation of demethyl-azelastine, a major pharmacologically active metabolite which has an elimination half-life of 42 hours. 75% of a single oral dose is recovered within 120 hours; urinary and fecal recovery is 25% and 50%, respectively.
The efficacy of azelastine has been evaluated in patients with bronchial asthma, allergic rhinitis (seasonal and perennial) and, to a lesser extent, in patients with histaminemediated skin disorders.
Non-comparative studies in adult and young patients with bronchial asthma have shown that oral azelastine 4 mg/day consistently improves symptoms and reduces the severity and frequency of asthma attacks and the use of concomitant bronchodilators over treatment periods of 0.5 to 28 months. In comparative studies of up to 12 weeks duration, twice daily administration of oral azelastine 4 mg/day significantly improved peak expiratory flow rate and mean wheeze score compared with placebo, and was at least as effective as oral theophylline 700 mg/day (sustained release formulation) and oral ketotifen 2 mg/day with regard to improving respiratory function and reducing the use of concomitant bronchodilators. The relative efficacy of oral azelastine as an antiasthmatic agent remains to be investigated in longer term studies.
The effectiveness of azelastine administered orally or as an intranasal spray has been studied in patients with seasonal or perennial rhinitis. Oral azelastine 1 to 8 mg/day consistently improved hay fever symptoms and was as effective as chlorpheniramine 4mg given 4 times daily. Over a 6-week period, oral azelastine 4 mg/day or intranasal azelastine 0.56 mg/day was at least as efficacious as oral terfenadine at improving symptoms including rhinorrhoea, stuffy nose, coughing, and lacrimation. Intranasal azelastine 0.56 mg/day and intranasal budesonide 0.4 mg/day have comparable efficacy: after 2 weeks total symptom score improved by 67% in both treatment groups. Improvement was seen after 1 week of treatment with azelastine nasal spray and persisted for up to 6 weeks in another study.
In patients with perennial rhinitis, oral azelastine 2 or 4 mg/day produces good or excellent symptomatic improvement in about 75% of patients after 2 weeks, and in 87 to 96% of patients after treatment lasting up to 6 months. The most pronounced effect was seen during the first 4 weeks of treatment. In comparative studies, oral azelastine 2 or 4 mg/day was significantly superior to placebo and was as effective as inhaled sodium cromoglycate 20mg administered 4 times daily at improving total symptom score in 297 patients. Overall improvement rates after 4 weeks were 63% in patients who received azelastine and 66% in those who received sodium cromoglycate. Intranasally administered azelastine 0.56 mg/day was as effective as oral terfenadine 120 mg/day in 49 patients; total subjective symptom scores improved by 90% and 87%, respectively, while 46% and 37% of azelastine- and terfenadine-treated patients, respectively, showed good or excellent global improvement.
Preliminary data from non-comparative studies indicate that oral azelastine may be efficacious in the treatment of histamine-mediated skin disorders, but these findings require confirmation in controlled studies.
The adverse effect profile of azelastine has been compiled from published and unpublished clinical studies and data provided by the manufacturers. The incidence of adverse effects was 7 to 14% in asthmatic patients treated with oral azelastine 4 mg/day and 18 to 25% in patients receiving 8 mg/day. In patients with allergic rhinitis treated with oral azelastine 2 or 4 mg/day adverse effects were reported in 4 to 25% or 19 to 42%, respectively. 12% of patients receiving intranasally administered azelastine 0.56 mg/ day reported adverse effects, the most frequent being burning nose and an altered taste perception. After oral administration, altered taste (2 to 26%) and drowsiness (3 to 18%) were most common. Other adverse effects that affect less than 5% of patients include dry mouth and nose, weight gain, nausea, vomiting, stomach ache, epistaxis, thirst and skin rash.
All adverse effects are generally mild and transient in nature and cause treatment withdrawal in less than 2% of patients.
In 1 study azelastine 2 or 4 mg/day produced no more sedation than terfenadine 120 mg/day, a non-sedating antihistamine. No clinically relevant changes in blood pressure, haematological, hepatic or renal function have been noted during prolonged azelastine treatment.
Dosage and Administration
The recommended daily dose for the prophylaxis and treatment of bronchial asthma is 4mg for adults and 2mg for children aged 6 to 12 years administered orally twice daily. A single 8mg evening dose may be given to patients with nocturnal or early morning symptoms. For the treatment of allergic rhinitis, 1 to 2mg twice daily administered orally is recommended. Recommended dosage requirements for patients with hepatic or renal dysfunction, children aged less than 6 years, and for intranasally administered azelastine are not available.
- Achterrath-Tuckermann U, Motta C, Stroman F, Szelenyi I. Azelastine inhibits late phase responses in animals. Abstract. New England and Regional Allergy Proceedings 9: 475, 1988a
- Achterrath-Tuckermann U, Motta C, Szelenyi I. Effect of azelastine on microviscosity of bronchial lavage obtained from actively sensitized and challenged guinea pigs. Agents and Actions 26: 70–72, 1989
- Achterrath-Tuckermann U, Simmet T, Luck W, Szelenyi I, Peskar BA. Inhibition of cysteinyl-leukotriene production by azelastine and its biological significance. Agents and Actions 24: 217–223, 1988b CrossRef
- Achterrath-Tuckermann U, Szelenyi I. Azelastine inhibits bronchial hyperreactivity to acetylcholine in guinea pigs. Experientia 44: 993–996, 1988 CrossRef
- Achterrath-Tuckermann U, Weischer CH, Szelenyi I. Azelastine, a new antiallergic/antiasthmatic agent, inhibits PAF-acether-induced platelet aggregation, paw edema and bronchoconstriction. Pharmacology 36: 265–271, 1988c CrossRef
- Albazzaz MK, Patel KR. Effect of azelastine on bronchoconstriction induced by histamine and leukotriene C4 in patients with extrinsic asthma. Thorax 43: 306–311, 1988 CrossRef
- Ambrossi L, Bariff F, Carino M, Catena E, Ceccarelli G, et al. Azelastine in the prophylactic treatment of bronchial asthma: an Italian multicentre comparison with ketotifen. Journal of International Medical Research 17: 218–225, 1989
- Atkins P, Merton H, Karpink P, Weliky I, Zweiman B. Azelastine inhibition of skin test reactivity in humans. Abstract. Journal of Allergy and Clinical Immunology 75: 167, 1985 CrossRef
- Baba M, Itakura Y, Maeda K, Akasaka T, Mukoyama T, et al. Clinical evaluation of Azeptin® in children: optimal dose study. Shonika Rinsho 41: 1395–1410, 1988
- Busse W, Randlev B, Sedgwick J. The effect of azelastine on neutrophil and eosinophil generation of Superoxide. Journal of Allergy and Clinical Immunology 83: 400–405, 1989 CrossRef
- Carino M, Sarno N, Iaia E, Ambrosi L. Protective effectiveness of azelastine against asthmatic response induced by distilled water inhalation challenge. Clinical Trials Journal 25: 80–86, 1988
- Chand N, Diamantis W, Sofia RD. Antagonism of histamine and leukotrienes by azelastine in isolated guinea pig ileum. Agents and Actions 19: 164–168, 1986a CrossRef
- Chand N, Mahoney TP, Diamantis W, Sofia RD. Inhibition of antigen-induced airway hyperreactivity (AIAH) to cold provocation by azelastine and selected antiasthmatic drugs in rat isolated tracheal segments. Journal of Allergy and Clinical Immunology 79: 179, 1987b
- Chand N, Nolan K, Diamantis W, Perhach Jr JL, Sofia RD. Inhibition of leukotriene (SRS-A)-mediated acute lung anaphylaxis by azelastine in guinea pigs. Allergy 41: 473–478, 1986b CrossRef
- Chand N, Nolan K, Diamantis W, Sofia RD. Inhibition of acute lung anaphylaxis by aerosolized azelastine in guinea pigs sensitized by three different procedures. Annals of Allergy 58: 344–349, 1987a
- Chand N, Pillar J, Diamantis W, Perchach Jr JL, Sofia RD. Inhibition of calcium ionophore (A23187)-stimulated histamine release from rat peritoneal mast cells by azelastine implications for its model of action. European Journal of Pharmacology 96: 227–233, 1983 CrossRef
- Chand N, Pillar J, Diamantis W, Sofia RD. Inhibition of IgE-mediated allergic histamine release from rat peritoneal mast cells by azelastine and selected antiallergic drugs. Agents and Actions 16: 318–322, 1985 CrossRef
- Connell JT, Perhach JL, Weiler JM, Rosenthal R, Hamilton L, et al. Azelastine (AZ) a new antiallergy agent: efficacy in ragweed hay fever. Abstact. Annals of Allergy 52 (Part 2): 392, 1985
- Diamantis W, Chand N, Harrison JE, Rooney BA, Sofia RD. Inhibition of IgE-mediated passive cutaneous anaphylaxis (PCA) by azelastine in rat. Abstract. Journal of Allergy and Clinical Immunology 73: 184, 1984
- Fields DAS, Pillar J, Diamantis W, Perhach Jr JL, Sofia RD, et al. Inhibition by azelastine of nonallergic histamine release from rat peritoneal mast cells. Journal of Allergy and Clinical Immunology 73: 400–403, 1984 CrossRef
- Fischer B, Schmutzler W. Inhibition by azelastine of the immunologically induced histamine release from isolated guinea pig mast cells. Arzneimittel-Forschung/Drug Research 31(II): 1193–1195, 1981
- Fujimori T, Harada K. Inhibitory effect of azelastine against platelet activating factor (PAF) on human platelet. Medical Consultation and New Remedies 23(10): 2251–2253, 1986
- Fujimura M. Clinical picture of allergic bronchitis in atopic patients with cough. Allergy no Rinsho 9: 66–69, 1989
- Gould CAL, Ollier S, Aurich R, Davies RJ. A study of the clinical efficacy of azelastine in patients with extrinsic asthma, and its effect on airway responsiveness. British Journal of Clinical Pharmacology 26: 515–525, 1988 CrossRef
- Hinogaki Y, Hidano N. Efficacy of E-0659 (azelastine) in atopic dermatitis, eczema and contact dermatitis. Medical Consultation and New Remedies 25: 581–586, 1988
- Horak F, Jäger S. The biological exposition test. Berichte 5/79 Umwelt Bundes Amt, 355–359, E. Schmidt, Berlin, 1980
- Horak F, Jäger S. The Vienna Challenge Chamber — a new method of allergy exposition tests. Wiener Klinische Wochenschrift 99: 509–510, 1987
- Iwata M, Nishiura T, Ishiguro H, Ikuta J, Tano M, et al. Effect of azelastine on bronchial hyperresponsiveness. Allergy 38: 428–433, 1988
- Jackson RT, Todd NW, Turner Jr JS. Ear, nose and throat diseases. In Speight (Ed.) Avery’s Drug Treatment, 3rd ed., pp. 360–386, ADIS Press Limited, Auckland, 1987
- Kaji R, Kamijo T, Kojima S. Inhibitory effects of a new antiallergic agent, azelastine, on passive cutaneous anaphylaxis and expulsion of Nippostrongylus brasiliensis. Immunopharmacology 3: 49–52, 1981 CrossRef
- Katayama S, Akimoto N, Shionoya H, Morimoto T, Katoh Y. Anti-allergic effect of azelastine hydrochloride on immediate type hypersensitivity reactions in vivo and in vitro. Arzneimittel-Forschung/Drug Research 31(II): 1196–1203, 1981
- Katayama S, Tsunoda H, Sakuma Y, Kai H, Tanaka I, et al. Effect of azelastine on the release and action of leukotriene C4 and D4. International Archives of Allergy and Applied Immunology 83: 284–289, 1987 CrossRef
- Kemp JP, Meltzer EO, Orgel HA, Welch MJ, Bucholtz GA, et al. A dose-response study of the bronchodilator action of azelastine in asthma. Journal of Allergy and Clinical Immunology 79: 893–899, 1987 CrossRef
- Kojima S, Kitamura Y, Takatsuk. Prolonged infection of Nippostrongylus brasiliensis in genetically mast cell depleted W/Wv mice/ Correspondence. Immunology, in press, 1989
- Kouga M. Clinical effects of E-0659 on bronchial asthma in children. Journal of New Remedies and Clinics 35(10): 47–59. 1986
- Little M, Ecklund P, Casale T. Azelastine’s therapeutic action in asthma. Abstract. Journal of Allergy and Clinical Immunology 81: 278, 1988 CrossRef
- Magnussen H. The inhibitory effect of azelastine and ketotifen on histamine-induced bronchoconstriction in asthmatic patients. Chest 91: 855–858, 1987 CrossRef
- Magnussen H, Reuss G, Jörres R, Aurich R. The effect of azelastine on exercise-induced asthma. Chest 93: 937–940, 1988 CrossRef
- Magnussen H, Reuss G, Jörres R, Aurich R. Duration of the effect of a single dose of azelastine on histamine-induced bronchoconstriction. Journal of Allergy and Clinical Immunology 83: 467–471, 1989 CrossRef
- Makino S, Motojima S. Long-term treatment of bronchial asthma with azelastine. Medical Consultation and New Remedies 23(6): 173–182, 1986
- Mailing HJ. Immunotherapy Position Paper. Allergy (Suppl.) 1–33, 1988
- Meltzer EO, Storms WW, Pierson WE, Cummins LH, Orgel HA, et al. Efficacy of azelastine in perennial allergic rhinitis: clinical and rhinomanometric evaluation. Journal of Allergy and Clinical Immunology 82(3): 447–455, 1988 CrossRef
- Morante R, Rubino A, Caci A, Porfido FA, Ciampini M. Azelastine, a new drug for the symptomatic treatment of allergic rhinitis: initial experience in Italy. Riforma Medica 101(12): 541–544, 1986
- Motojima S, Ohashi Y, Otsuka T. Effects of azelastine on allergen- and exercise-induced asthma. Asian Pacific Journal of Allergy & Immunology 3: 174–178, 1985
- Mue S, Tamura G, Yamauchi K, Ohtsu H, Takishima T. Efficacy and safety of azelastine in the treatment of asthmatics: Japanese experience. Drugs of Today 25(Suppl. 6): 29–38, 1989
- Nakamura T, Nishizawa Y, Sato T, Yamato C. Effect of azelastine on the intracellular Ca2+ mobilization in guinea pig peritoneal macrophages. Eur J Pharmacol 148: 35–41, 1988 CrossRef
- Ohno H, Moriguchi N, Matsumoto K. Clinical studies of azelastine on bronchial asthma in children. Medical Consultation and New Remedies: 1003–1010, 1988
- Ohsako S, Go KK. Results of the clinical use of E-0659 (Azeptin®) for the treatment of allergic rhinitis in children. Journal of New Remedies and Clinics 32(5) (Suppl.): 1983
- Okuda M, Baba S, Tsutsumi M, Furuuchi I, Okuzawa Y, et al. Clinical effects of E-0659 on allergic rhinitis. Oto-Rhino-Laryngology Tokyo 23(Suppl. 6): 441–461, 1980
- Okuda M, Furunai I, Tsutsumi M, Ishii T, Otsuka H, et al. Effects of E-0659, disodium cromoglicate and placebo on perennial allergic rhinitis — double-blind trial. Oto-Rhino-Laryngology Tokyo 26(Suppl. 6): 563–605, 1983a
- Okuda M, Ishii T, Furuuchi I, Tsutsumi M, Otsuka H, et al. Clinical effects of the oral antiallergic agent E-0659 (azelastine hydrochloride) on allergic rhinitis — double-blind trial with azelastine. Oto-Rhino-Laryngology Tokyo 26(Suppl. 6): 124–163, 1983b
- Okuda M, Sasaki Y, Ishii T, Shirai N, Saito Y, et al. Investigation of the prophylactic and therapeutic effects of azelastine in Japanese cedar pollinosis. Jibi Inkoka Tenbo 32(Suppl. 1): 37–54, 1989
- Ollier S, Gould CAL, Davies RJ. The effect of single and multiple dose therapy with azelastine on the immediate asthmatic response to allergen provocation testing. Journal of Allergy and Clinical Immunology 78(2): 358–364, 1986 CrossRef
- Osako S. High-dose therapy with E-0659 for allergic rhinitis. Medical Consultation and New Remedies 20(5): 187–196, 1983
- Perhach J, Connell J, Hamilton L, Diamond L, Weiler J, et al. Multicenter trial of azelastine in allergic rhinitis. Journal of Allergy and Clinical Immunology 73 (Suppl.): 144, 1984
- Piacenza G, Ciampini M, Mantellini E, Ferretti G. Preventive effectiveness of azelastine in bronchial asthma. Double-blind comparison with ketotifen. Rivista di Patologia e Clinica 42(5): 275–284, 1987
- Piper PJ. Leukotrienes: possible mediators in bronchial asthma. European Journal of Respiratory Disease 129 (Suppl.): 45–64, 1983
- Rafferty P, Harrison PJ, Aurich R, Holgate ST. The in vivo potency and selectivity of azelastine as an H1 histamine-receptor antagonist in human airways and skin. Journal of Allergy and Clinical Immunology 82: 1113–1118, 1988a CrossRef
- Rafferty P, Phillips G, Ollier S, Holgate ST. Attenuation of allergen induced bronchoconstriction by azelastine. Abstract. European Respiratory Journal 1(Suppl. 2): 195, 1988b
- Rhodes BJ, Iwamoto P, Donnelly AL, Perhach JL, Weiler JM. Azelastine in seasonal allergic rhinitis: the Iowa experience. Abstract. Annals of Allergy 56: 528, 1986
- Sawai H, Adachi Y, Matsuno M, Adachi Y, Murakami G, et al. Clinical evaluation of azelastine in children with bronchial asthma. Shonika Shinryo 52: 2057–2061, 1989
- Shapiro GG, Bierman CW, Pierson WE, Furukawa CT, Altman LC, et al. Azelastine differential induced blockade of histamine nasal challenge test. Abstract. Journal of Allergy and Clinical Immunology 79: 255, 1987 CrossRef
- Spector SL, Perhach JL, Rohr AS, Rachelefsky GS, Katz RM, et al. Pharmacodynamic evaluation of azelastine in subjects with asthma. Journal of Allergy and Clinical Immunology 80: 75–80, 1987 CrossRef
- Storms W, Middleton E, Dvorin D, Kemp J, Spector S, et al. Azelastine (azel) in the treatment of asthma. Abstract. Journal of Allergy and Clinical Immunology 75: 167, 1985 CrossRef
- Takishima T, Mue S, Ishihara T, Ishikawa H, Taguchi S, et al. Clinical studies on the effects of E-0659 granules on bronchial asthma. Medical Consultation and New Remedies 22(5): 113–124, 1985
- Taniguchi K, Takanaka K. Inhibitory effects of various drugs on phorbol myristate acetate and n-formyl methionyl leucylphenylalanine induced −O2 − production in polymorphonuclear leukocytes. Biochemical Pharmacology 33: 3165–3169, 1985 CrossRef
- Tasaka K, Akagi M. Anti-allergic properties of a new histamine antagonist, 4-(p-chlorobenzyl)-2-[N-methyl-perhydroazepinyl-(4)]-1-(2H)-phthalazinone hydrochloride (azelastine). Arzneimittel-Forschung/Drug Research 29(I): 488–493, 1979
- Tatsumi K, Ou T, Yamada H, Yoshimura H. Studies on metabolic fate of a new antiallergic agent, azelastine (4- (p-chlorobenzyl)-2-[N-methylperhydroazepinyl-(4)]-1-(2H)-phthalazi-none hydrochloride). Japanese Journal of Pharmacology 30: 37–48, 1980 CrossRef
- Tinkelman D, Bucholtz G, Kemp J, Repsher L, Spector S, et al. The long term use of azelastine (Az) in asthmatics. Abstract. New England Regional Allergy Proceedings 9: 365, 1988
- Weiler JM, Donnelly A, Campbell BH, Connell JT, Diamond L et al. Multicentre, double-blind, multiple dose, parallel-groups efficacy and safety trial of azelastine, chlorpheniramine, and placebo in the treatment of spring allergic rhinitis, Journal of Allergy and Clinical Immunology 82: 801–811, 1988 CrossRef
- Yoshida M, Tezuka T. Clinical efficacy of azelastine in eczema and dermatitis. Journal of New Remedies and Clinics 37(6): 171–174, 1988
- Zechel H-J, Brock N, Lenke D, Achterrath-Tuckermann U. Pharmacological and toxicological properties of azelastine, a novel antiallergic agent. Arzneimittel-Forschung/Drug Research 31(II): 1184–1193, 1981
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