3. YAHAV Y, KATZNELSON D, BENZARAY S. Persistent cough
`~ a form - fruste of asthma. Eur J Respir Dis 1982: 63: 43-
`6,
`4. SAMPSON SR. Sensory neurophysiology of airways. Am Rev
`Respir Dis 1977: 115: 107-15.
`. TAYTARD A. BEAUMONT D, Puset JC, et al. Treatment of
`bronchial asthma with terfenadine: a randomized controlled
`trial. Br J Clin Pharmaco! 1987; 24: 743-6.
`
`sa
`
`G. Ciprandi, M.A. Tosca, A. ludice, S. Buscaglia,
`L. Fasce, G.W. Canonica
`Allergy and Clinical Immunology Service
`Dept. of Internal Medicine, University of Genoa
`V. le Benedetto XV, 6
`Genoa 16132
`Italy
`
`Letters to the editor
`
`Peranaesthetic anaphylactoid shock due
`mannitol
`
`to
`
`the 0.1 molar dilution. Controls (7 = 14) with normal
`donorcells showed higher HR in 8 cases (57°) to
`nondilute mannitol (18.6°, + 10.6, mean + SD), but
`there was practically no HR to the 0.1 molar dilu-
`tion (1.0%, + 1.3). Only thiopental also induced HR:
`40°, in the nondilute and 7°, in the 10-fold dilute
`solution. Here controls revealed similar results to
`both concentrations (32.9+21.9 and 6.2%, + 6.5)
`(Table 1).
`Fromthe clinical development, the positive spe-
`cific skin test, and the higher tendency to release
`histamine in a 0.1 molar concentration, we con-
`cluded hypersensitivity to mannitol as the cause of
`this life-threatening anaphylactoid reaction. In spite
`of the widespread use of mannitol, only 5 cases of
`hypersensitivity have been reported (1-4, 6). The
`induced HR byhyperosmolar(1.1 M) mannitol also
`in normal controls demonstrates its potencytolib-
`erate histamine as previously reported by Findlay
`et al. (2). Thus the incident might be aggravated by
`the foregoing use of other histamine releasing drugs
`as thiopental and suxamethonium. Further studies
`will be necessary to elucidate the mechanism of —
`probably IgE-mediated - hypersensitivity in this pa-
`
`Table 1. Percent histamine release induced by mannitol and thiopental
`
`Contro's
`
`Atopic
`Patient
`{n=7)
`
`
`Nonatopic
`(n=7)
`
`Allergic and pseudoallergic reactions due to anaes-
`thetics, especially muscle relaxants, are well known.
`Weinvestigated a case of severe anaphylactoid shock
`during general anaesthesia, in which mannitol ap-
`pears to have been the causative agent.
`A 40-year-old man had to undergo retromaxillary
`tumourresection. Twogeneral anaesthesias had pre-
`viously been done without any complications. There
`Wasno history of asthmaor atopy. Anaesthesia was
`realized with thiopental, suxamethonium, fentanyl,
`alcuronium and an ethrane-inhalation-mixture. The
`induction period passed uneventfully. About 90 min
`after intubation, before surgical intervention, an in-
`fusion of 20°,, mannitol (100 ml) was given. Minutes
`later, hypotension and tachycardia suddenly ap-
`peared, followed by ventricularfibrillation. No cu-
`taneous changes or bronchospasm were observed.
`Immediate cardiopulmonaryresuscitation with cat-
`echolamines and repeated defibrillation were suc-
`cessfully initiated; the patient recovered the same
`day without any sequelae.
`Anallergological study was carried out 8 weeks
`later. Routine skin tests and RAST determinations
`(Phadebas, Pharmacia) with commoninhalant aller-
`gens as well as with latex, thiopental and suxame-
`thonium were negative. Prick tests with thiopental
`(S0 mg/ml), suxamethonium (10 mg/ml), alcuronium
`(S mg/ml),
`fentanyl
`(0.05 mg/ml)
`and mannitol
`(200 mg/ml equal 1,1 M) — all tested in their com-
`mercial forms — were negative. Intradermaltesting at
`& 1:100 dilution revealed a clear positive reaction
`(wheal of 7 mm diameter with flare) only to manni-
`tol. Control testing in 10 voluntary persons at the
`Same mannitol concentrationresulted in all negative.
`Consecutively,
`the i vitro leukocyte histamine re-
`lease (HR) induced by the drugs in serial 10-fold
`dilutions was studied; histamine was measuredby a
`RIA-method (5) using a commercial assay (Immu-
`Notech). Mannitol induced 20°, HR oftotal leuko-
`cyte histamine in the 1.1 molar solution and 9°, in
`
`Mannitol:
`20 mg/mi
`200 mg/ml
`Thiopental
`5.9+7,2
`6.6463
`7
`5 mg/ml
`
`
`
`50 mg/ml 26.74 15.9 40 39.0426.5
`
`0.6+0.8
`17.749.9
`
`1.4+1.6
`19.6412.1
`
`9
`20
`
`All values are given after deduction of spontaneous histamine release {mean+SD).
`Atopic: mean age 32.6 years (21-55y)}; nonatopic: mean age 32.6 y (19-5 ty).
`
`61
`
`MYLAN INST. EXHIBIT 1090 PAGE 1
`
`

`

`
`
`Letters ¢o the editor
`
`tient. Clinicians should be aware of this potential
`side effect of mannitol.
`
`References
`
`5S. Moret AM, DELAAGE MA, Immunouanalysis of histamine
`through a novel chemical derivatization. J Allergy Clin Immu-
`nol 1988: 82: 646-S4.
`6. SpanTH GL, SpaetH EM, Spaetu PG, Lucier AC. Anii-
`phylactic reaction to mannitol. Arch Ophthal 1967; 18: 583.
`
`}. ACKLAND SP, HILLCOAT BL. Immediate hypersensitivily to
`mannitol: a potential cause of apparent hypersensitivity to
`cisplatin (letter). Cancer Treat Rep 1985: 69: 562-63.
`2. FINDLAY SR, KaGty-SospoTKa A, LICHTENSTEIN LM. f-
`vitro basophil histamine release induced by mannitol in a pa-
`Went with a manuaitol-induced anaphylactoid reaction. J Allergy
`Clin Immunol 1984: 73; 578-83
`3. LamB JD, KeoGu JAM. Anaphylactoidreaction to mannitol.
`Can Anaesth Soc J 1979: 26: 436,
`4. MCNEILL TY. Hypersensilivity reaction to mannito!. Drug
`Intell Clin Pharm 1985: J9; 552-53.
`
`Peter Schmid, M.D.
`Brunello Wiithrich, M.D., Prof.
`Allergy Unit
`Departinent of Dermatology
`University Hospital
`Gloriastrasse 31
`CH-8091 Ziirich
`Switzerland
`
`62
`
`
`
`MYLAN INST. EXHIBIT 1090 PAGE 2
`
`