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Levomepromazine (Nozinan) Reduces Nonspecific Bronchial Hyperreactivity in Asthmatics

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Eur Aespir J 1989, 2, 415--420 Levomepromazine (Nozinan) reduces nonspecific bronchial hyperreactivity in asthmatics P. Faurschou, F. Madsen, H. Pals, A. Rosetzsky Levomepromazine (Nozinan) reduces norupecific bronchial hyperreactivity in Dept of Pulmonary Medicine and Allergy, Gentofte asthmatics. P. Faurschou, F. Madsen, H. Pals, A. Rosetzsky. County Hospital, Denmark and Allergy Unit, Medi­ ABSTRACT: Ten patients with bronchial asthma were challenged with cal Depanment TI'A, St.ate University Hospit.al, histamine before and after receiving saline and active drug (levomepro­ Copenhagen, Denmark and The Chest Clinic, mazine or antazoline) (a total of six challenges). The antihistamlnlc effect Frederiksberg County Hospit.al, Denmark. of levomepromazine (25 mg) was found to be comparable to that of anta­ zoline (100 mg), evaluated from skin prick tests. Prechallenge forced Correspondence: F. Madsen, Allergy Unit 7511, Medical Dept TIA, SLate University Hospital, Tagens­ expiratory volume in one second (FEV ) was found to be larger after levomepromazlne than after antazollne (p<O.OS),1 Indicating a direct bron­ vej 20, OK 2200 Copenhagen N, Denmark. chodilating effect. This increased threshold airway calibre may have lnflu­ Keywords: Antazolinc: bronchial hist.amine challenge; enced the results of challenge, but change in provocative concentration bronchial hyperreactivity; bronchodilat.ation; levo­ producing 20% fall (PC2J was not statistically significantly correlated to mepromazine; ventilation. change In FEV • Levomepromazine Increased PC 2-doubllng concentra­ 1 20 tion compared to antazoline (p<O.OS). Variation was obser ved In two Received: April 15, 1987: accepted after revision minutes' ventilation during tidal volume breathing challenge. However, October 28, 1988. there was no statistically si.gniflcant variation In two minutes' ventilation during challenge after receiving levomepromazlne or antazoline. It was concluded that levomepromazlne possesses a bronchodilating capacity and reduces bronchial hyperreactivity. Eur Respir J., 1989, 2, 415-420. Nonspecific bronchial hyperreactivity is a part of the the local Ethical Committee. Anthropometric data are asthmatic syndrome [1, 2]. Several drugs, effective in the given in table 1. The patients had to be hyperrcactive, ) treatment of bronchial asthma, have also been shown to provocative concentration causing 20% fall (PC20 hista­ reduce response to bronchial challenge [3] . In particular mine <4 mg·ml· 1 (sec challenge protocol) and forced the inhaled ~ -adrenergic agonists, ipratropium and, to a expiratory volume in one second (FEV ) before the 2 1 lesser degree, methylxanthines have shown an acute effect challenge had to be above 50% of the predicted value on both bronchial asthma and nonspecific bronchial [5]. No patient had neuromuscular disorders, and all hyperreactivity. patients had normal chest roentgenograms. Thus, the bronchial challenge is a useful experimental model of bronchial asthma. Drugs which reduce non­ Design specific bronchial hyperreactivity may be of potential value in the treatment of bronchial asthma. Since levomepromazine has an antihistaminic effect, We have used the analgesic and sedative effect of the study was designed with placebo and antihistamine levomepromazine in almost 900 patients with acute control. The study was patient- and observer-blind, and myocardial infarction [4). Some of these patients had patients were randomized to receive the alternative treat­ reduced ventilatory capacity due to asthmatic attacks or ments on two different days (fig. 1). congestive heart failure. In these pati.ents we have ob­ One technician performed the skin prick test and another served improved ventilatory capacity, lower respiratory the bronchial challenge. They were not informed about frequency, and an increase in tidal volume after admini­ the treatment and were not aware that saline (placebo) stration of levomepromazine in doses from 25-400 mg. was always given as the first injection. This was known Since these clinically observed effects may be of by the physician giving the injections (fig. 1). Levomepro­ potential value in the treatment of chronic obstructive mazine and antazoline (Antistin) were given in a double­ pulmonary disease, this study was designed to test the blind manner. Antazoline was chosen as the control drug effect of levomepromazine on nonspecific bronchial because of its antihistaminic and sedative effect Each hyperreactivity in patients with bronchial asthma. patient had completed the study with in one week. Methods Skin sensitivity Ten stable asthmatics were included after informed Skin prick tests were performed with unbuffered his­ consent had been obtained. The study was approved by tamine dihydrochloride, 1 mg·mJ·1 and 10 mg·mJ·I, and 416 P. FAURSCHOU ET AL. 0.1 mg intracutaneously (ic). Wheal reactions were piratory manoeuvre. Thus, the hand grip strength is a measured after 15 min, marked with a pencil and trans­ measurement of neuromuscular performance. Hand grip ferred to paper by means of tape. Digital planimetry was strength was tested three times with an interval of 5 s. 2 used to measure the area reported in cm . Geometric The largest value was reported as the result. Hand grip 1 2 mean area and coefficient of variation (1 mg·ml- 0.10 strength 1.19 kPa·cm· , coefficient of variation 9%. 2 1 cm , 54%), (10 mg·ml- 0.28 cm2 , 37%), (0.1 mg ic 6.57 2 cm , 8%). Bronchial challenge Hand grip strength Before each challenge a standardized interview took place to ensure that patients had abstained from: Hand grip strength was measured with a vigorimeter smoking (4 h), inhaled P2-adrenergic agonists (8 h), (Gebraader Martin, Tuttlingen, BRD) which measures oral P2 -adrenergic agonists (12 h), methylxanthine (48 the hand grip strength [6). This test was used, since h), ipratropium (12 h), and antihistamines (4 wks). Ster­ levomepromazine has a sedative effect and valid oids were continued unchanged. No patient had had res­ piratory tract infections within 3 wks. determination of FEV1 demands a maximum forced ex- , Table 1. - Anthropometry, FEV1 immunoglobulin E (lgE), skin prick test, eosinophils and smoking habits Patient Age 1 Skin prick Eosinophils Cigarettes Sex Height FEY1 Duration lgE KU·/" of asthma test ~10 HEP in blood per day and/or RAST per J.Ll n yrs cm % pred yrs (0-120) ~class 2 1 20 F 166 54 18 100 + 25 20 2 41 F 160 68 6 69 + 6 20 3 45 M 175 68 3 140 244 2 4 27 M 185 34 3 461 538 15 5 39 M 181 76 36 59 + 169 0 6 24 F 178 94 1 69 910 0 7 52 F 167 101 6 173 656 0 8 44 F 165 78 6 53 940 3-4 9 23 M 174 71 1.5 29 + 1040 0 10 37 F 170 97 7 95 + 250 10 : FEY1 forced expiratory volume in one second; RAST: radio-allergosorbent test. BASELINE= SPT HGS BHP~ PRE-DRUG 9 1. INJECTION POST NaCI MEASURE­ SPT HGS BHP~ MENTS= NaCI·DRUG - -+--- --- i. m. LEVOMEPROMAZINE 2. INJECTION ANTAZOLINE POST-DRUG MEASURE­ SPT HBHP~ HHGS MENTS= DRUG SIGNATURES: BP: BLOOD PRESSURE SPT: SKIN PRICK TEST BHP: BRONCHIAL HISTAMINE PROVOCATION HGS: HAND GRIP STRENGTH Fig. 1. - Study protocol. Time schedule for the patients. REDUCTION OF BRONCHIAL HYPERREACTIVITY BY LEVOMEPROMAZINE 417 ) A standard tidal volume breathing inhalation challenge concentration of histamine chloride (PC20 FEV1 result­ was used [1, 7]. The aerosol was generated by a Wright ing in a 20% decrease in FEV 1 was detennined by linear nebulizer filled with 2 ml of solution and driven inLerpolation between the last two points on the log dose by compressed air at 1.2 bar and at an air flow of 13 response curve. FEY 1 and forced vital capacity (FYC) 1 l·min· • Pressure was monitored continuously on a ma­ were measured on a calibrated dry wedge spirometer nometer calibrated against a mercury column. Under these (Vitalograph Ltd, Buckingham, England). At least two conditions the output is 148 ).1g·min· 1 (so 7 ).1g·min· 1). technically correct forced expiratory manoeuvres with a The output was determined by calibration of the actual variation of less than 5% were obtained, and the highest set-up. The complete nebulizer including valve box was value was used for further calculations. Values are re­ weighed on a Mettler balance and output reported as the ported at ambient temperature, atmospheric pressure and mean and standard deviation of ten determinations. Under saturated with water vapour (ATPs). these conditions the count aerodynamic diameter of 95% of the dry particles varied between 0.5 )lm and 1.8 ).lm. Blood pressure and pulse The aerosol was led through a unidirectional valve (Astra­ Meditek). Since the inspiratory flow during inhalation of The mean values and coefficient of variation were: the aerosol was higher than the air flow through the systolic blood pressure 116 mmHg, 9%; diastolic blood nebulizer, accessory air was led through the system via 1 pressure 76 mmHg, 13%; pulse 78·min· , 10%. an air vent. Ventilation was determined by measurement of expired air. Exhalations were performed through a dry gasometer (Vedras, type 2E, Copenhagen, Denmark) Statistics calibrated against a wet Tissot spirometer before and after the study. Reproducibility of 2 minutes' ventilation Logarithmic transformation of results was carried out, measurements during spontaneous tidal breathing (with­ since results varied over several orders of magnitude. out aerosol inhalation) has previously been found to be Means were calculated together with the 95% confidence high [8]. Reproducibility, expressed as the residual stan­ interval for the mean. When means were compared, the dard deviation
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    Forensic Screening of 300 Drugs in Blood Utilizing Exactive Plus High-Resolution Accurate Mass Spectrometer and ExactFinder Software Kristine Van Natta, Marta Kozak, Xiang He Forensic Toxicology use Only Drugs analyzed Compound Compound Compound Atazanavir Efavirenz Pyrilamine Chlorpropamide Haloperidol Tolbutamide 1-(3-Chlorophenyl)piperazine Des(2-hydroxyethyl)opipramol Pentazocine Atenolol EMDP Quinidine Chlorprothixene Hydrocodone Tramadol 10-hydroxycarbazepine Desalkylflurazepam Perimetazine Atropine Ephedrine Quinine Cilazapril Hydromorphone Trazodone 5-(p-Methylphenyl)-5-phenylhydantoin Desipramine Phenacetin Benperidol Escitalopram Quinupramine Cinchonine Hydroquinine Triazolam 6-Acetylcodeine Desmethylcitalopram Phenazone Benzoylecgonine Esmolol Ranitidine Cinnarizine Hydroxychloroquine Trifluoperazine Bepridil Estazolam Reserpine 6-Monoacetylmorphine Desmethylcitalopram Phencyclidine Cisapride HydroxyItraconazole Trifluperidol Betaxolol Ethyl Loflazepate Risperidone 7(2,3dihydroxypropyl)Theophylline Desmethylclozapine Phenylbutazone Clenbuterol Hydroxyzine Triflupromazine Bezafibrate Ethylamphetamine Ritonavir 7-Aminoclonazepam Desmethyldoxepin Pholcodine Clobazam Ibogaine Trihexyphenidyl Biperiden Etifoxine Ropivacaine 7-Aminoflunitrazepam Desmethylmirtazapine Pimozide Clofibrate Imatinib Trimeprazine Bisoprolol Etodolac Rufinamide 9-hydroxy-risperidone Desmethylnefopam Pindolol Clomethiazole Imipramine Trimetazidine Bromazepam Felbamate Secobarbital Clomipramine Indalpine Trimethoprim Acepromazine Desmethyltramadol Pipamperone