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Journal of Aerosol Medicine Deposition, Clearance, and Effects in the Lung

Date: 19930000/P
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Smaldone, G.C.
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MARG, MARGINALIA
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Intl Society for Aerosols in Medicine
Journal of Aerosol Medicine
Suny at Stony Brook
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05 Jun 1998
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Page 41: sme69e00
It AUIOMAIIC MANf1SONIC AtA050111ER (AMSA) OUBR[Ull(1), GUIIIfRM(2), BADRE(2) (1) Centre Hospitalier lYON SUD 69310 PI[RRf-B[N11[ - IYUN, Irance (2) C[RISM, 10UI0N NAVAL, france f Back in 1958, Guillero and Badre apprehended the interest of eanosonic aerosols as part of the therapy for f.N.l affections. In 1966, they developped the first nanosanic aarosolirer, and in 1986, Benon, tory, Badre and Guillerm presented the mannsonic aerosols during the 6th congress of 1SAN in Vichy. IAe principle of ^anosanic aerosolirors resides in the rum6i- nation of 3 functions : - aerosol production - intermittent emission of sound uaves to multiply the pene- tration of medicinal aerosol in the E.N.I sphere - release of an adjustable overpressure when the patient is swallowing to force open the Custachian lube and ensure the penetration of the medieinal aerosol througn the [ustad:ian lube. For years, the outstanding benefits of this new technique re- •ained counteracted by the difficulty to synchronite the release of the overpressure with the svalloving. Recently, 6uillera, 8adre and Col. conceived an AufOMAItC MANOSONIC AEAOSOLIZEA (AHSA) uhich, thanks to a unique fluid tech- nique, salves the proble+ of synchronilation. The handiness of this unique AUfOMAIIC NANOSONIC A[Rl1SOt REA (AMSA), r.hich can be used by children already from age 3, allovs Its' dafly use In speclalited canters but also at home. the results of a aulticentrlc study of 81 treated palient are presented and confire the very good efficiency of this technique. Studies on the effect of dry powder Inhalers upon peak inspiralory flow (PIF) in volunteers I~~',,~~~~~4aMartin G.P. LMarriott C.,'Ganderton D., aLee, K.CSuen, K.O. and~M. Yianneskis LDepartment of Pharmacy, King's Collegae London (KCI.). Manresa Road, London SW3 6LX; Department of Mechanical Engineering, KCL, Strand, London WC2R 2LS The site of deposition of inhaled drug particles is determined by the patient, formulation and desigq of the drypowder inhaler device (DPID). Energy inPut from the pauent's inspiratory effort is required to deaggregrte micronised drug particles or remove them from a carrier surface and propagate them into the airway. Little is known of the effect of DPID design on inhalation flow rates (IF). The present study was carried out to provide more information on this effect. Informed, adult, healthy volunteers (16 male, 15 female), trained to breathe out to residual volume followed by a rapid deep inhalation, look part in the study. Four DP1Ds (randomly allocated to each volunteer) with specially designed adaptors were connected to a Vitalograph spirometer that was modified to measure IF. No drug was administered but all measurements were made in conditions designed to sifjyulate normal use by a patient. The measured PIF (I min' , mean ± SD) i11 males and females were: Control, 333.0 ± 97.6 and 213.9 ± 70.5; Rotahaler (R), 216.6 t 45.6 and 160.1 ± 43.7; S inhaler JS), 185.7 ± 40.8 and 133.6 t 36.0; Turbohaler (T), 81.8 ± 2.8 and 55.6 t 13.0; and Inhalator Ingelheim (1) 70.4 ± 18.6 and 48.3 s 13.2, respectively. The relatively high built- in resistance and narrower air channels in I and T reduce the flow and presumably increase turbulence more than in R or S. Aerosolisation of drug particles requires high IF whereas low IF result in effective deposition. Compromise in the above two opposing criteria is a major challenge in DPID design for use in asthmatics. 41 11IDI-uerosul depositiuu "siutlicS by a combiuation Of in vlrrD and in VIPo IIIC:IStyr'CIIICIItS p,llunrrt and H.M:dthys I)ivision of 1'ncunlulagy, Medical I)cpartcnlcnt, Elnivcrsity of Freiburg, 1)-78IX) Frciburg, (iermany To investigate the deposition pattern of the DISPOSAOLE", a new little spaceywe first sucked the delivered aerosol from the MDl through the spacer and a connected aerosol filter, using radio- labelled #y-agonist-MDI II).We were able to show that 88.6%t7.3 of the aerosol remained in the device if used as a reservoir versus 39.5% t 7.3 if used as a spacer. '1'herefitre the device was tested in ril•u only as a spacer. Five voluntt:crs inhaled with a slow vital capacity breathing mantlcuvrc 2 separate doses of a labeled N1D1 with and without the DISPOSABLE". Prior to this each labeled h1D1 was controlled for linearity of aerosol delivery and the total- ly delivered drug per puff was measured in vitro as described above. Additionally we compared the relative deposition in the spacer in t'itro and in viro. Our data show: 1. Aerosol delivery per puff is vcry constant. 2. It takes 5 - 10 puffs to reach a constant relation between aerosol dtclwsiuon in the spacer and in the tiller (in vivu). 3. 47.6% ± 9.4 of the totally delivered activily per puff remained in the spacer (in t'iyv). 4.The pulmonary dcposition increased from 23.5% ±9.9 to 28% ±6.8 (if calculated spacer+corporal deposi- tion = 100%) while it increased from 14.3% ±4.5 to 22.3% ±4.1 in relation to the totally delivered activity measured in vitro With this spacer. We conclude that it is nteessary to nlcasure the oulpul of a MDI. The spacer has to be preluaded to achieve constanlly rcprtrducibin in ['ilv data. 1. Kiihlcr D. et at., Rcspiration 53; 65-73,1988 PLOW CFUIRACTBRISTICS OF DRY POWDER IMRALBRS Lee. K.C'.`, Suen, K.o.', Yiannzskis, M.`, Mdrtiott, C.t, M.trt iu, G.P.1, Tim,in:. 1.1 t and G.,ndetton, D. t Centte for Raat Ttvnsfer r,uJ Plui.l F•low FLeasurement, King's College London, Stt.vnd, l.ondon WC21, 2LS, UK; Iy~.•l•.n[m.•n[ of 1'h.,un.rsy. Kinu•:: collrg" L,t~•i.>n, M.urtasa Pont, .Lon.lou SW 1 61,X, UK. Thc -usttuctiuu at ,Iry I-w.l., inh.,l- I,•vicrs (UP1Us) nwy intlueuca thu --tosoy rloud cl-,..r.,cteristics duting inh.tlation and heuce the ttaction of drug depositrd in [he aitwcrys. Although they h.rvr leceivect little attention to date, this study iuvestigatas the flow properties of aeiosoy clouds emetying ftom 4 DPIDs. The DPIDs were ,activated by an inh.,lation simulation awchine which can ptoduce a:;uvriou pt.~r,sute rlnouah earb ,1•:vic.• identicul to tlw av.•ra,)11 of thnt g,.•n.•t.,te.l by 20 Iu„ltlry volLtntrets 11.1-1.44 kP., .I•.),.•r„liny „^ r6,• l.:vi-). rh., flow aud tutbui.•u.-.• y~•nat.,t.•.1 by ,.uh ,i••vtr,• w.,t.• yu.,ntiti.z.l with timu-t-olv.•d mo.,ssutun,cwu ut tl,r ttan::ient .lischurg, using laset-Dopplc•t anc•mometty techniyues. The flow p.itterus produced by the DPtDa were recorded on video using laser-sheet flow visualisation and analysed with image processing techniclues. The variation of the flow rate through the DPIDs with the pressure drop across the test section is shown in tP,e tigure Lelow; the highest flow rates were obtained with the Rotahalet (R) followed by the Spinh.tyer (S), Tutbohaler IT) and Inhalator Ingelheim (II. The tutlxtluuce ]evels 5 nun downstream of the cantre nf the nwuth[,ier,i w.a re 1.60, 5•08, 3.23 and 1.99 m/s for the R, 5, T and I d.-vices respectively. ~S y 5 2 ° ° ~ ~ i i • " O y 0 O I • a~ Q 00 ° o e 0 o e e a a ii: 0.0 0.5 1.0 Pressure Dntp. k Pa a an ° Rotaltaler • Spinhaler • Turbohaler ° Inhailator
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A METHODOLOGY FOR ESTIMATINC TIIE REC - IONAL bORAC7F.OF NRI1I1L17,EU f•1EUICA'I'ION: Al'- PLICA'l'ION '1'O SALUU'1'AMOI, by Finlay W. It, Stapleton K. k 7,uberbnhlcr I'.' I)ept. of Mcehanical lingineering, Univcrsity of Alberta, 1•:dnxminn, Allx:rla, Canada, 'r6(: 2C8 'Cystic Fibrosis and R:diatric 1'ulmonnry Clinic, 7-1119 Clinical Sclcmrs Ituild- inC, Iluivcrsity of Alhrrtn Ilnspilnl, 1•:dmrnuun, Alb,•rln, Cnnndn'r60. 2(1:1 A mr-tho,kdngy for prniicting reglonnl d,r.ages of inhnled nebullxer medi- cnlinn is pr-ntcd. '1'his mathndnlogy obtains lhn drug amlcnt of the. Inhalad pnrtiche;, as well as the total numtx:r nud si%Iw of Pnrlicles Inhnled, and has been applied to aalbutamoi (2.5mg Clnxo nebulcc) in a statistical annlplc or Uevilbisv I'ulmo-Neb nc.bulizers driven by a Dovilbiss I'uhno-Aid comprcscor. Ambient laboratory «roditions were tnnintained at 27" C and J.5-37% rclalive humidity. I)rug content is obtained by measuring the equilibrium sizle of the liq- uid parliclaa, using a Danlec pha.asl dnppler anemometer, as they exit a ver- tical tube attached To the nebulir.cr. Peprilihriunr size, which is 9.051jm ± 0.171im MMAD aflcr one minule of nebulization, is not rcached until after 5 r.m nlong the tubc for Ihu snl6utamnl/Dnvilbicc nnb,dizcr fnrtnulatlnn, 'rhe dry pnrtkic sizc Jistribulinn Is thcn crd,•rd,drrl uzinli the rvptilibrlurn pFrtlt:le ni%e Cquld.i0un of Il:rrun et al., .1. M•ruu,I. &'l. 19:0 11L6:11, 1988. 'I'hc rdnl.ivc humidity of tha gas phn.w: whcre tbe equilibrium Parlit•Ie sixe Is tncasured Is obtained by applying ma.zs consc.rvntion to a control volumc surrounding the ncbulimr and attachcd verticnl htbc, and lhc vnpor pracsnrc reduction causnd by snlbutrunnl in v9ntion is ol>lnimd frnm Ivrionic snlulinn data. The ratio of salt to drug in lho particlea is obtnitx:d from concenlralion messurenrnta of the nehulizcr salulion. (Conccutrnlinn incrca.ccc (in average by 28% during a nahulizntkm vcccion.) 'I'his data is then mupled with the known density of the drug and salt to givc the ntnsv of drug in thc Partlches. 7'hr. fraction of pnrticln depasiting in the. various rcgiuns of the. lung is then estintnled using dcpt,sition frnrtiuns frutn existing lung ddx,sitiom models for hygroscopic Pnrli- clcs. Combining thcse rcgionnl dcprx4itiun frnctions with thc mcssured parliclc sim and drug conlent distributiotrs, regional dusnge prerlictions are obinined. Vnrlut.inn it, the ocbulizer oulput during nrbnlizntinn cnnss•s rrginnnl dtwnges to vary throughuut a nebolizcr sstiion, net this vnrinliun is pn-mlr.rl. EFFECTS OF JET VELOCITY AND PARTICLE SIZE DISTRIBUTION ON DELIVERY OF PRESSURIZED METERED-DOSE INHALER AEROSOLS. Kim C.S. and L. Garcia, Health Ellects Research Laboratory, U.S. EPA, Research Triangle Park, NC 27711 and Pulmonary Division, Mount Sinai Medical Center, Miami Beach, FL 33140, USA. Because of a strong jet discharge, the majority of aerosols from the pressurized metered-dose inhalers IMDI) is lost in the oropharyngeal cavity and only a small portion of the aerosols is actually delivered to the lung. In order to use correctly or to improve MDI, it is essential to know jet dispersion characteristics, particle dynamics in the jet, and effects of these factors on drug delivery. In the present study, five MDIs Including Atrovent IBoehringer Ingelheiml. Breathaire (Ciba-Geigy), Intal IFisonsl. Tornalate (Breon), and Ventolin IGlaxol were studied for size distribution, jet velocity profile, oropharyngeal loss, and delivery efficiency. Size distribution of residual particles after complete vaporization of propellants and other volatile substances was measured by a 7-stage Andersen cascade impactor. The axial jet velocity was measured at a distance from 5 to 35 cm IS cm intervall from the actuator orifice and a complete cross-sectional velocity profile was measured at a 10 cm distance by means of a pitot tube. Oropharyngeal loss and delivery efficiency were determined by measuring total aerosol mass discharged from the MDI and a portion of the aerosol passing through an oropharyngeal model. Results showed that particle size varies widely among MDls from 3.1 to 8.4 pm in mass median aerodynamic diameter 1MMAD1 with GSD of =2.0 In dry air. Size distribution did not change significantly with humid air lRH=90%) except for Intal with which MMAD increased from 5.4 to 8.3 ym. Axial jet velocity ranged from 4.5 to 7.2 m/s at a 10 cm distance from the actuator orifice and rapidly decreased with Increasing distance from the orifice, reaching 1-3 m/s at a 30 cm distance. The )et velocity of Breathaire was the lowest among the MDls tested. Jet diameter was about 5 can at a 10 cm distance from the orifice. Oropharyngeal losses of the aerosols ranged from 27-87%; highest with Tornalate and lowest with Atrovent. The losses were correlated well with an Inertial parameter based on MMAD and axial jet velocity. This Is an abstrect of a proposed presentation and does not necessarily represenf EPA policy. Estimation of the lung deposition of hygroscopic drug aerosol particles produced with nebulizers. f-erron G. A., GSF - Forschungszentrum fOr Umwelt und Gcsundheit, Gn1b11. Projekl Inhalation. Ingolst8dler Landsir. I. DW8042 Neuherberg, Gennany. The Irygroscopic properties of a drug are inlportant parame- ters in delernlining aerosol particle deposition in the human respiratory tract. Regional lung deposition can be estimated by combining the properties of a nebulizer (Sterk et al., Bull. Eur. Physiopathol. Respir. 1984, 20: 65), the equilibrium change of the aerosol particle size during transport (Ferron and Gebhart, J. Aerosol Sci, 1988, 19: 1083), and the change in particle size and their deposition in the human respiratory tract (Ferron et al., 1991, J. Aerosol Sci. 22: S863). This methoti enables the calculation of the deposition of polydis- persc hygroscopic aerosol particles produced with a nebulizer in the human respiratory tract. This method has been applied to a jet and a ultrasonic neb- ulizer using the properties of the nebulizer for a physiological saline solution. It was found that the equilibrium change in particle size during transport was less than 10% and the change in regional deposition was also less 10%. Nebulizinga hypolonic (1.I g/1) or a hypertonic (72 g/I) saline solution in stead of a isotonic solution (9 g/I) the regional deposition changed by -20% and 25%. it is concluded that the hygro- scopic properties of the drug solution are important parame- ters in the estitnatioll of aerosol particle deposition. CAN DRU(i DELIVERY TO THE LUNGS BE INFLUENCIiD BY BREATHING DIFFERENT GAS CUMPOSI'1'IONST Ssltylz. H., Schulz, A., Heilmann• P., and J. Heyder GSF-Furschungsientrum fiir Umwelt und Gesundheit, Projekt Inhalation, 8042 Neuherberg/Munchen, FRG To see whether the deposition of particulate drugs in the lungs can he influenced by breathing gas compositions with different physical properties we studied intrapulmonary deposition of 0.5pm, 1pm, and 2µm inert test particles in six anesthetized, intubated beagle dogs. The particles were suspended in and the dogs were breathing mixlures of 20% oxygen, 10% nitrogen, balanced by either helium (He). or sulfur hexa0uoride (SF6), or nitrogen (N2). Particles were applied during a controlled inspiration from FRC to 80% TLC and a subsequent expiration to FRC. Differences in Reynolds numbers cause flow to be more turbulent in SF6, and more laminar in He as compared to N2. Particle deposition in He was comparable to that in N2. In contrast, breathing SF6 increased particle deposition of 2pm and Ipm particles (52.1 % vs. 36.3% and 23.6% vs. 16.3%), while depositiltn of 0.5pm particles was unaffected (10.0% vs. 11.9%). To ge1 information about the location of enhanced particle deposition in SF6 we performed additional experiments introducing 6ml aerosol boluses into different lung depths. These measurements showed that deposition of 2pm particles was enhanced throughout all lung depths but deposition of Ipm particles only in the lung periphery. The results indicate that the deposited fraction of particles delivered to the lung can be modified at various lung regions by varying gas composition and particle size. 42 Can detiv by the ad Everard ML Dep1s of Ci Adult Respi Nebulised be cNnicaay lunclion dui possiWe Ih gner drople netwliser Increases i An aaemali depositlon' convention auxillary _' An entrainr deFvery fro In vitro sluc that the pat subslanlial generated flow of 8 th drying Ilow A preamina with a gami containing minules. T MMD1.3pr palient usir deBvery w deposilion the olher , In conclusi size of dro the periph Ilowite el ; THE Il_ INSPIRE S'ihueHL Le Souef 1 Departr Princess Phermac Sciences Perlh, '.-. Aerosols children lung dep depositlc Twelve I older ch cystic fp aerosol, and sin were the Inlents t than ok Aerosol Index If children We con conslste nebuase or (2) It
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elt und r Landstr. parame- le human :stimated al., Bull. brium (Ferron he change spiratory This polydis- nebulizer nic neb- rsiological tange in d the bulizing a ))Uhon in 3sition hygro- parame- T GAS , Projekt lungs can it physical im, 1pm, ed beagle breathing er helium icles were 'LCanda numbers in He as to that in n of 2µm 6), while 11.956). particle roducing urcments ghout an he lung particles gions by Can delivery of nebulised antibiotics be improved by the addition of a drying chamber? EYCtardltL, Peckham D+,Peddns AC'. Depts of Child Health and Medical Physics' Queens Medical Centre and AduN Respiratory Unit ,City Hospital, Noltingham" UK. Nebulised antibiotics for the treatment at cystic librosis have been shown to be c6nically uselul but their ellec6veness decreases with deteriorating lung WtcNon due to increased deposition of drug in Ihe central airways' II is possible that Improved peripheral deposition can be achieved by generating iner droplets but increasing the ellectiveness of the battles within a nebuliser substantlally Increases the lime taken 10 nebllGse a dose hence increases the Inconvenience for patients. An aMemalive approach was devised with the aim of improving peripheral deposition while maintaining a high rate of drug deNvery. The output from a conventional jet nebuYser Ilows through a 'drying charnber' which has an auxiliary air supply which dries droplets as they pass through the chamber. An entrainment valve adjacent to the nebufzer helps to maximise Jrug defvery from the chamber. In vitro studies using a Malvern 2600 laser particle sizer have demonstrated that the particle size of Genlamicin droplets generated by a nebulizer can be substanUaAy by this means. The mass median diameter ol droplets generated by a Cirrus nebubsar was tound to be 4.5 pm using a driving gas Now 018 Vmin. This tell to 1.4 pm with the addition of a drying chambcr using a drying Ilow o18 urmn. A preiminary study assessing deposition of TcmDTPA labelled gentamidn with a gamma carnera was carded in three patients with cystic librosis 4mis conlaining 160 mgs of genlamicin were delivered via three syslems lor 9 minutes The systems used were a Cirnis nebutser (C), a MicroCirrus (MC- MM01.3pm ) and a Cirrus with drying chamber (CrD). The total dose to the patient using the CID system was greater than that using C while the rate of delivery was substantially greater than for MC. Peripheral vs central deposition of gentamicin was greater with the CID system than with either of the other systems. In conclusion this deAvery system appears to be ellective in reducing particle size of droplets and in preGminary studies it improves the delivery of drug to he peripheries of the Wrgs in patients with cyslic librosis Ilowile at a1 Am Rev Respir Dis 136: 1445-9, 1987 THE INFLUENCE OF AGE ON DEPOSITION OF NASALLY INSPIRED AEROSOLS IN INFANTS AND OLDER CHILDREN. Chi jil1, CoNis GGt, Newbury AM2, Chan K3, Bower G2, Sly PD4, Le Souel PNt. tDeparlments of Respiratory Medicine and 2Nuclear Medicine, Princess Margaret Hospital lor Chikiren. Perth, 3Department of Pharmacy, University of Sydney, Sydney, and 40ivision of Clinical Sciences, Western Austraian Research Institute for Child Health, Perth, Western Australia. Aerosols are being used for clinical and research purposes In children without adequate in vim knowledge of total and regional kup deposition at different ages. We therefore aimed to quantity deposition of aerosol from Inlanoy through to late adolescence. Twelve Infants (median age 0.8 year, range 0.3-1.4 years) and 12 older children (median age tO.C years, range 6.3-18.0 years) with cyslic librosis were studied. All the sub)ects Inhaled radioiabelled aerosol, generated by a Turret nebu9ser, via the nasal route. Planar and single-photon emission computed tomography (SPECT) scans were rhen oblakred. Inlants had lower lung deposition (median 1.3%, range 0.3-1.6%) than older children (median 2.5%, range 1.6-3.8%) (p-0.0001). Aerosol deposition was more central In Infanls (median penetration Index from planar scans 0.49, range 0.39-0.76) than In older chlldren (median 0.63, range 0.29-0.70) (p.0.03). We oonclude that infants have lower lung deposition and this Is consistent with either: (1) thelr Inspiratory flows being less than nebuNser flow so that they do not Inhale the enUre nebuliser output, or (2) the nose aqing as a bettor fNter In the Infant. RadfdabeNkw of a Cortlcosterdde with r'"c and Luno DeoosNlon after Release from a Metered Dose Inhaler (MDn A. Bldlinamaier•, J. Waitzinger•, A. Hammermaler', W. Fleischer•• and H. Jaeger• • L.A.B. GmbH & Co, Neu-Ulm •' Boehringer Inpelhelm KG, Ingelheim/Rheln With a new metfwd It was possible for the first time to radidahel the conicosleroide Bunlsdlde wllh'°'"Tc withirr the MD1. The method employed was modified to that already successfuNy used to label the B,-agonlst lerroterd it, 2j. Wahln a cascade ImpaGor, which was used to correlate this dlstribullon of active drug with the distribution of radloactivky, the amount of recovered active drug corresponded exadly with the recovery of radioactMky on each layer of the device. Result: The size dtstdbutlon of the radldabeNed drug Is Idenaoel to the uriabdled drug. In a funher study the lung deposition of °°"'Tc radlolabeeed tluntsdlde will be examined atter release from three diNerent devices: MDI with moWhplece, MDI with spacer and MDI wah spacer and valve. For analysis of the lung deposition gamma camera Imaging will be used. These results will also be presented and discussed. I Clinlcal Study at L.A.B. with study code 89264 2 KONer, O.; Fleischer, W. and Matthys, H.: New Method for Easy Labelling of Beta-2-Antagonisls In the Meterd Dose Inhaler with Technetium 98m. Respiration 1988; 53:65. REGIONAL DEPOSITION AND REGIONAL VENTILATION DURING INHALATION OF PENTAMIDINE O'Riordan T.G.and G.C. Smaldone. Pulmonary/Critical Care Division, State University of New York, Stony Brook, New York 11794-8172. Previous studies have suggested a link between reduced upper lobe ventilation and the pulmonary distribution of deposited pentamidine that may be responsible for localized Pneumocyslis cariniipneumonia (Baskin, Ann Inlern Med. 113: 677-683, 1990; Jules-Elysee, Ann Intern Med. 112: 750-757, 1990). However, regional ventilation has not been measured during delivery of aerosolized pentamidine and clinical studies of relapse have not assessed other factors that might inlluence aerosol deposition. The purpose of this study was to measure the relationship between regional deposition of aerosolized pentamidine and regional ventilation, and the influence of particle size and airway caliber on this relationship. Ten subjects with HIV infection who were receiving prophylaxis with aerosolized penlamidine were recruited. Using Krypton (81mKr) we simultaneously measured regional ventilalion during Irealmenl with aerosolized pentamidine (labeled with lechnetium ("mTc)i. Two nebulizers were used (Respirgard II and Fisoneb) which produced particles of different size. In addition, patients were studied with and without a bronchodilalor because changes in airway geometry can aflect sites at particle deposition. There was no significant correlation between regional ventilation and regional particle deposition (r-0.00, linear regression). Parlicle deposition in the upper lobes, relative to the lower lobes, was less than would be predicted by regional ventilation by a ratio of 0.84t 0.03 (mean t SE). Using two way ANOVA, the upper to lower zone deposition pattern was not affected by eilher nebulizer or by the use of albuterol. The Fisoneb had signilicantly more central deposition relative to the jet nebulizer (mean t SE, sKC/P: Fisoneb 1.3 10.1, Respirgard 1.1 t 0.1, p-0.005, Iwo way ANOVA). The use of a bronchodllalor did not signllicantly affect the central/peripheral deposition pattern. In patients undergoing prophylaxis with aerosolized pentamidine, differences In deposition between upper and lower lung regions are not simply accounted for by dilferences in regional ventilation, but are determined by other mechanisms. Supported by NIH Aids Clinical Trials Group Al 25893. 43 I
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S'IS Y OF AN 1 F1'tRO. AEROSOL t,l ING DEPOSITION •C.N.Ahmcd, •W.Balach:mdran, and +P.Bamcs. Univcrsity of Surrey. Guildford. Suney. UK. +Bespak Pk, Kings Lynn, Norfolk, UK. It is known that the charge on the panicles in a drug aerosol plays a role in their deposition in the lung. The work of Yu and Hashish I1,2- has made a significant contribution in terms of theoretical studics on various lung deposition mechanisms of inhaled drug aerosols. Yu's model was limited to lower dclxwition efficicncics (h< l): wlrorcas IL•tshish extendcd the cfficieucy limit to h=1. Ilowcvcr, lhis mtxk.l has ouly Ixxn tuvtcd using experimcnhd dala obtained by Melandri ct aL(31. limited to particle site nmge 11.3 - Lll<tm. and charge levels uptu 230 electnwtic charges per particle. Nevenhclcss, both these groups have sMrwn that the dcptnilion is dmnimucd by the electrostatic forces particularly in the alveolar region. We have re- examined not only the basic accumplitms used in these models Mn also used the recent published muqthtanetric data fur the human lung by Ilorsfield Cl at. 141 to develop an integrated deposition modcl. Our mtxlcl was for the sake of casc of programming. realised in the form of a sprcad-shccl using the Microsoft Excel application on an Apple Macintosh computer rather than a mainframe computer. This resulted in a tool for the rapid production of results which were readily reconciled to IMtsc of othcr wtxkers. lit order lo provide a Icsl for the model we cxpcrimculally measured the inherent charge levels of aboul 35 commercially available inhalers. Mnh metered ikr+c inhalers (MDI's) as well as dry powder inhalers (DPI's). The inherent charge levels found in these devices range from 4 - 200 electronic charge per particle. The reason for this wide range of charge levels lics in not only the material of the dispensing devices but also on the way drug aerosol is generated and in the formulation of the product. Based on the measured data a computer prediction could be made as to where the drug particles would dcposit in the lung By controlling the charge and size of the particles it could be possible to target the drugs to specific regions of the lung and to increase the deposition efficiency. References:- 1. Yu C.P, and Diu CK, (19g2). ' A aenparativc study uf acnr•ol dcposition in diffcrcnl lung modcls". Am. Ind.tlyg.Asstr.1..43, pp5a-56. 2. Ilashish A.11. (1988), Te inBucnce of electrostalic charge on the depusition (if Iherapeulic aerosols.' PhD Ihcsis University of Srmlhampton. UK. FUNCTIONAI. ASPh:CTS OF All( Jlsl' NF.BIlI.17,ERS RI;I,EVANT TO LII'OSOMI? AND DRU(: STABII,fI'S'. R,W Nivent, J.P. Ilullcr2 and 1.1). Brain2. Amgen Inc., Thousand Oaks, CA 91 320 1 and Harvard School of Public Health. Dept. of Environmental Health, Boston. MA 02115 2. Some drug formulations, including tiposomes and proteins, can be damaged during aemsolization. The level of damage is a function of the forces that the drug is exposed to on a single passage , through the nebulizerjet and the total number of times this occurs before the drug escapes as inhalable aerosol. A Collison nebulizer was modified to stud)• the damage that single and multiple passes across a nebulizer jet would inflict on liposome dispersions (distearyl phosphatidyl-choline: dipalmitoyl phosphatidylglycerol 9:1 mole ratio) containing fluorescent calcein.'fhe influence of nebulizer reservoir volume was also studied. A model was developed to predict the quantities of undamaged liposomes (or rlmg) remaining in the nebulizer as (1) a funclion of time of nebulization or 12) the number of passages through the nebulizer jet. This model includes a probability index of the liposomes 'sensitivity' to nebulization. At 10psig a single passage of 20ml of dispersion (-INmol lipid and 2.5Ng encapsulated calcein) produced 2.3±0.7% (n=3) release of encapsulated calcein in the nebulizer dispersion compared with 8.2t0.696 at 40psig. 7 passages at 10psig and 18 passages at 40 psig (equivalent to I mrn of nebulization at these driving pressures) produced 8.8t0.2% and 36.2t1.9% release respectively. A 10m1 starting volume caused 70.0t2.8% (N=3) release after 20min nebulization at 30psig compared with 42.8t1.2% using 100m1. Supported by NIH # HL-0 19170 and a grant from Merck-Frosst. DEPOSITION FROM A NEW POWDER INHALER BY GAMMA-SCINTIGRAPHY G R Pitcairn, G Lunghetti, P Ventura and S P Newman Pharmaceutical Profiles Ltd, Nottingham UK; and Chiesi Farmaceutici, Parma, Italy. A Tc99m radiolnbclling method has been developed in order to study deposition of salbutnmol from a new powder inhaler (Chiesi) capable of delivering 8(1 metcrcd doses, each of 200 µg salbulamol and 12 mg lactose. The radionuclide was added to the micronised drug substance in chlorofluorocarbon-11, and the dried powder was ground, sieved and blended with lactose. The size distributions of unlabelled drug, labelled drug and radiolabel were similar (respirable fractions, < 5 µm, 16.3 90, 16.7 % and 15.0 % respectively). Subsequently, radiolabelled salbutamol powder aerosols were inhaled by 10 healthy volunteers (5 malc, 5 female). The mean (SEM) lung deposition was 14.1 (1.0) % and 11.7 (0.7) % of the dose for "fast" (46.1 Umin) and "slow" (27.8 1/Inin) peak inhalation flow rates respectively, and was higher with fast inhalation in 8 of the 10 subjects. The deposition pattern within central, intermediate and peripheral lung zones was similar for the two inhalation modes. More than 75 % of the dose was deposited in the oropharynx at each flow rate, and the remainder of the dose was either retained on the mouthpiece or was exhaled. It is concluded that the new Chiesi powder inhaler has a delivery efficicncy, as assessed by garnma-scintigmphy, broadly comparable to that of other currently available powder inhaler devices. Relative Bloavallability to the Lang orSalbutamol from a MDI and a New htnltidose Dry 1'owder Inhaler Itindle Mt.,Ch[ps(yn Ht.BePecra E=.,The School of Pharmacyt,University of Bradford,Bradford,Wesl Yorkshire & Innovata Biomed LId2.,St. Albaae,flcrts.,UK. A simple method of evaluating relative bioavailabilily of salbutaamol to the lung using urinary excretion data has recently been described (Hindle M.&Chryatyn tl.,Brit.l.Clin.Pharmaco1.34:311-315,1992). This methodology was utilized to compare the lung delivery of salhutamol alter inhalation from a Ventolin® MDI and a new multidose dry powder inhaler(DPI) which was designed to deliver ltxptg salbutamnl per puff in a lactose carrier where the total powder per inhalation was approx. Img (PCf WO92101/771). The study was designed as a randumixed single dose crossover in 10 experienced volunteers who Inhaled on separate occassions two actuations from either the MDI or the DPI. Urinesamples were collected from each volunteer at 30mias and then cumulatively for 24 hours after inhalation from each device. Unchanged salbutamol and its sulphale metabolite were determined In each sample using a sensitive and specific HPI.C assay described by Hindlc and Chrystyn in the above reference. The urinary recovery or salbutamol in the 30min sample expressed as a percentage of the total recovery of salbutamol and metabolite in 24 hours averaged(s.d.) 3.7(1.1)96 for the MD1 and 4.8(t.8)% for the DPI. The ratio between the percent unchanged satbutamol in the urine at 30mins for The DPI as compared to the equivalent value Gn each individual following Inhalation from the MDI reprecents the relative bioavaitability of salbutamol to the lung fom the two inhalers and can be treated in a similar fashion to AUC ratioa in bioequivalence calculations for orally administered drugs. The mean ratio DPI/MDI was 1.311 and the 95% confidence interval for the ratio altcr log transformation was 0.97 - 1.77. The Cl indicated that bioequivalcnce was not proven but implied that in these volunteers delivery of satbutamol to the lung was more efficient from the DPI. These data provide preliminary evidence that the new multidose DPI is capable of providing equivalent bioavailabitty of salbutamol to the lung as compared to an MDI under circumstances where both produets deliver the same absolute dose per puff. In vitro evidence suggests that the DPI operates efficiently at tow flow rates however further studies in patienu will be required to establish how variations in Inspiralory flow influence lung deposition from this device. 44
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PARTICLE RETENTION AND CLEARANCE Plenary Lecture Vinzenz Im liof Medizinische Universitgtsklinik Inselspital Abteilung Pneumologie CH-3010 Bern, Switzerland The majority of lung diseases are caused by inhaled particulate compounds such as cigarette smoke, virus containing water droplets, bacteria, pollens and occupational or environmental pollutant aerosols. An increasing number of diagnostic and mainly therapeutic aerosols (bronchodilators, antiinflammatory drugs, antibiotics, antiproteases, surfactant) are also delivered to the respiratory tract. The fate of these inhaled soluble or insoluble particles, regardless whether their effect is considered useful or noxious depend critically upon the site of particle deposition and above all their retention and clearance. It is widely accepted that phagocytosis by alveolar macrophages is the most effective clearan- ce mechanism for insoluble particles deposited in the alveolar region. These macrophages may either reach the mucociliary "escalator" or move into the interstitium. The retention of insoluble particles in the alveolar compartment may last for months or even years. Soluble substances are mainly cleared by means of transepithelial transport. In the conducting i.e. ciliated airways (trachea, bronchi and bronchioli) submicrometric soluble particles can penetrate into the bronchial epithelium. Insoluble particles are reported to be retained in the liquid layer of the airway wall (sol- and gel-phase) and are cleared mainly towards the pharynx by the mucociliary activity. It was generally believed that this clearance is completed within 24-36 hours. There is growing evidence, however, that the retention in the conducting airways may last considerably longer. Surface active material (surfactant) at the air-mucus interface has been reported to promote retention. There is also evidence that phagocytosis by airway macrophages plays an important role in the clearance of such particles.
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PARTICLE RETENTION AND CLEARANCE Poster Symposium Vinzenz Im Hof Medizinische Universittitsklinik Inselspital Abteilung Pneumologie CH-3010 Bern, Switzerland and Grallam Patrick Medical Research Council Radiobiology Unit Chilton, Oxon OXII ORD, Great Britain CHANGES DURWG AS7HMA' Anderson', Nuclear I University Ithas: Clin Immu rate of w_ subsequent likely to 4 In 10 asthn ventilation humid air Initial lun using a gat right lung significant after ISH significant most Ilkel significantl transient :_ responsible cilia beat : additional Asthmatic Heahhy Oerhard In Poystryn 2{mt and boluses ne these aera pe) a11er activity In B The reten could be h collimated (between The slow after 24h . the2Jm f 15%oflh effect on th The rest inhalatlon I clearance (FAP) with about 2 /m that tor !- 28%. For. value was - particles, and Iron m Theee r ahways m size.
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CHANGES IN MUCOCILIARY CLEARANCE (MCC) DURING AND AFTER 1SOCAPNIC HYPERVENTILA7ION USH) IN ASTHMATIC AND HEALTHY SUBJECTS. Jt Daviskas' SD Anderson', I Gonda', P Cook ; R Fulton' Depts of Respiratory' & Nuclear Medidne', Royal Prince Alfred Hospital, & Dept of Pharmacy" University of Sydney, Sydney,Australia. It has been previously proposed (Smith CM Anderson SD; I. Allergy +Gin Irnmurrol 77:729-736, 1986) that during hyperpnoea with dry air the I rate of water loss exceeds the rate of return resulting in a decrease & subsequent hyperosmolarity of the periciliary fluid layer (PFL). MCC is likely to be affected by these changes of the PFL. MCC was measured in 10 asthmatic & 8 healthy subjects on 3 separate days aftera) resung ventilation with ambient air 2) ISH with dry air & 3) ISH with warm humid air for 45 min. The radioaerosol used was ~"Tc-sulphur colloid. Initial lung radioactivity & post Intervention retention was quantified using a garrrma camera and subsequent computer analysis for the whole right lung & for defined regions of interest. Only asthmatics had a ' significant reduction in MCC rate during ISH with dry air. However, ,fafter ISH with dry air both asthmatic & healthy sub)ects had a significant Increase In MCC rates. These findings suggest that the PFL is most likely changed during ISH with dry air, however it affected MCC significantly only in the asthmatics. ISH with dry air probably causes transient hyperosrnolarity of PFL which triggers release of mediators f responsible for the observed increase in MCC rate through Increased cilia beat frequency. However, in the asthrnatlcs time are likely to be r addit(onal mediators due to the presence of intlarnmatory cells. Mean % Clearance for whole right lung During Intervention Post Intervention Rest Dry ISH Humid ISH Rest Dry ISH Humid ISH Asthmatic 14, 10:P40.0127.6 nco.os N 10.8 p~ p<~a Healthy I`4 r61~ 1~l.7 1.fit_ __ _ 267P 13.9 0005 <0.0115 NS ~ The Clearance of Polystyrene Particles from Human Intrathoracic Airways Gerhard Scheuch, Wolfgang Kreyling ~ Friedel Haas and With Slahlhofen GSF-Forschungszentrum lix Umwelt und Gesundheit, Instilut fur Biophysikalische Strahlenforschung, FrankluNMain ' Projekt Inhalation, Munchen Polystryrene (PSL) particles with aerodynamic diameters (d,.) between 2Nm and 6 Nm were labelled with r'~1n and inhaled as small aerosol S boluses now the and of a clean air Inhalation (shallow bolus). The volume of these aerosol boluses was about 20 cm'. By various breath holding periods (to) after Inhalation Ihese particles were deposited in the airways. The at~iv8y in the kings after inhalalion varied between 0.5 and 4 kBq. The retention of the deposited particles as function of time after deposition, could be followed by measuring the activity in the kings with an array of 4 collimated scintillation counters. Six healthy nonsmoking male subjects (between 30 and 60 years old) volunteered In this study. The slowly cleared fraction (A) of particles which was found in the lungs after 24h decreased with Increasing geometric particle size. About 60% or the 2{an particles were found in the lungs after one day, but only about 5- 15 % of the 61nrr particles. The period of breath holding had no significant effed on the A-value. The resuNs of previous clearance measurements after a shallow bolus inhalation had shown that the fraction A of the lung deposit undergoing slow clearance was about 56% for Iron oxide or fused aluminium-oxide particles (FAP) with d., = 3- 4 jan. This corresponds to a geometric diameter ds of about 2 farr kx both materials. For these aerosols it had been also found that for larger particles (d.. . 6 frm, d, . 3.6 pm) A was reduced to about 26%. For PSL particles d„ and dy are neaAy IdenGcal. Using PSL the A- value was about 60 % for da . 2 pm and about 28% for ds . 3.7 pm par8des, a result wfridr is in agreemenr with experimental findings for FAP and Iron oxide with similar ds. These results indicate that the fast clearance of particles from ciliated airways may either depend on particle material or the geometrical partide size. The Evaluaton of Regional, Puknonary Mucociliary Clearance and Epilhelial Permeabi8y with Radioaerosol Scintigraphy S. Erdem, A. Saymer, Y. Duman. E. Derebek. Z. Burak. Ege University Department of Nuclear Medicine, Bornova-IZMIR- TURKEY It's possible to evaluate the physiologic mechanisms, like mucocilary clearance (MC) and pulmonary epithelial permeability (PEP) with radioaerosd srdntigraphy. Mucociliary function exists in the airway except the alveolii. II radioaerosols are achieved to be deposited on the large airways before they reach to the alveolii, we can beinlormed about MC by measuring their clearence rate. The most appropriate particles for this procedure are human albumine labelled with Tc99m, as their mean diameter be 5 pm( range, 2 to 6 pm). In order to determine the PEP, those particles should be in appropriate size and they also should have the characteristics of crossing the aNeolar-capilary membrane. Having the diameter of 0.98 Nm (range, 0.72 to 1.33 pm) DTPA (Disalenetriaminopentaasericaside) is the most appropriate one to manage this prodecure. PEP can be evaluated by measuring the crossing rate of particles from the alveolli into the blood. Using these prodecures on 18 healthy subjeas, we aimed to explore the differences of MC and PEP between the upper, medial and lower zones of the Iung. MC values of the superior, medial and Inferior zones are (time to reach to the hall of the maximum value in minutes) 34.5 x2.5, 35.5 ~ 2.5, 35.0 ± 2.5 and PEP values of the superior medial and the inlerior zones are (Percentage of decreasement in minutes) 1.113 ± 0.142, 0.887 ± 0.142 and 0.722 ± 0.142, respectively. It was clear that, there was not a signilicant difference of MC between dinerent lung zonea On the other hand, PEP decreased from the upper parts to the lower zones. In conclusion, MC and PEP can be evaluated accurately and easily with radioaerosol scinligraphy and they may be used as a ~ dignostic modaliliy by determining the etfect of various lung diseases on those mechanisms. CLEARANCE MEASUREMENTS WITII ULTRA- FINE PARTICLES. C. Roth, G. Scheuch and W. Stahlhofen GSF-Forbchungszcntr. L Umwclt und Guundlu:it GmbH Institut fOr Biuphysikalischc Strahlcnfurschung, Paul-Ehrlich-Str. 20, D-(>lxNl FrankfurUhf, FRG. The behavior of ultrafine particles in the human respiratory tract is slill not exactly understood. Usually from the time-dependent declining lung retention function regional deposition values are derived. But the question is controversial from which compartments of the lungs the slow and fast cleared fractions of particles are origi- nating. '('hcrc('orc with a newly developed aerosol inhuiation device, small volumes of aerosol (boluses) are inspired predominantly into the conducting airways of the human lungs. The aerosol is injected by a fast-operating valve system using preselected volumes near the end of a clean air inhalation of 1(M)0 cm3. The ultrafine radioaerusol is generaled by controlled condensation of vaporized tttindium chelate and complete degradation of the particles to indium oxide in a high temperature furnace. The aerosol leaving the furnace is passed through a differential mobil- ity analyser to obtain a monodisperse fraction with variable modal diameters between 10 and 50 not. The retained particle activity in the lungs is measured during the next days by scintillation lung counting facilities. Clearance curves for several subjects and several particle sizes show a fast and a slow cleared fraction being in contradiction to the concept that fast clearance represents clearance from the tracheobronchial region. 47
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DEPOSITION OF PARTICLES IN MOUTH AND THROAT AND FINDINGS IN PHARYNX AND LARYNX IN ASTIIMATICS Svartenoren K., Lindestad P.A., Svartengren M., Bylin G., Philipson K., Camner P. Depts. Respir. Agerg. Dis. and Logoped. Phoniatr., Huddinge University Hospital, Huddinge; Inst. Environ. Med. and Dept. Environ. Hyg., Kerolinska lnstitutet, Stockholm, Sweden. Mouth and throat, and lung deposition was estimated in 16 asthmatics after inhalation of 3.6 pm (aerodynamic diameterl monodisperse Teflon particles labelled with 11 rln. The particles were inhaled at 0.5 Vs with maximally deep breaths. Radioactivity was measured by scanning over mouth and throat, lungs and stomach immediately after the inhalation. The amount of particles deposited in mouth and throat was estimated from the measured activities in mouth wash, head and neck, and stomach. Pharynx and larynx were video recorded using a fiberoptic technique with the same inhalatiorl procedure. Deposition in mouth and throat varied largely among the subjects with a range from 9 to 76% (median 12%, mean t SD 26.0 t 24.2%)• We found an extremely high deposition (> 70%) in three subjects. Fiberoptic examination revealed anatomical and functional abnormalities in their pharynx. These results strongly indicate that pharyngeal abnormalities are one reason for high deposition of particles in mouth and throat. TRACHEOBRONCHIAL CLEARANCE DURING 72 HOURS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE Ericsson C.H., Svartengren K., Svartengren M., Mossberg B.. Blomquist M., Philipson K., Camner P. Depts. Respir. Med. Allerg., S6ders/ukhuset and Huddinge Hospital, Stockho/m and Irist. Environ. Med. and Dept. Environ. Hyg-, Karollnska Institutet, Stockholm, Sweden. Tracheobronchial clearance and airway symptoms, especially sputum production, were studied in 14 patients, smoker or ex-smokers, with chronic bronchitis and/or COPD. Clearance of 11 rIn-labelled 3.6 pm Teflon particles was measured at two occasions at an interval of two weeks. Lung retention of the Teflon particles was measured at 0, 24, 48 and 72 hours with a profile scanner. The patients were interviewed on smoking history, airway symptoms, medication etc. The volume of expectorated sputum was measured at three occasions; during physiotherapy and after the two clearance measurements. The retentions at all the time points results were reproducible at the two measurements (r > 0.901. The 24-h retentions were 56.4: 16% Imean ± SDI and 55.5 ± 13.3%, respectively, the 48-h retentions were 50.6 ± 16.1 % and 51.0 t 12.6%, respectively and the 72-h retentions were 48.0 i 14% and 47.9 3 12.9%, respectively. The last clearance phase seemed to be completed at 72 hours. We also intend to correlate bronchial clearance to sputum volumes. The patients in the present study have lower retentions than healthy subjects earlier investigated with the some method Indicating a more central deposition of test particles. Earlier studies have shown that mucociliary transport is usually severely decreased In chronic bronehitislCOPD. The present results show that short- term clearance in these patients is effective, probably due to productive cough. HUMAN TRACHEOBRONCHIAL DEPOSITION AND EFFECT OF TWO CHOLINERGIC AEROSOLS Anderson M., Svartengren M., Dahlbiick M., Nerbrink O., Philipson K., Camner P. Dept. Environ. Hyg. and Inst. Environ. Med., Karollnska lnstRutet Stockholm, Sweden. Department of Pharmacology Z Astra Dreco AB, Lund, Sweden. The effects of two methacholine aerosols generated by a Pad Inhalierboy Imass median diameter, MMD - 7pm) and MAD2 (MMD - 3 pm) were measured In ten healthy subjects. Each subject was challenged at three occations with each aerosol and lung physiologic parameters reflecting both small and large airways were measured. Also deposition of 3.6 pm radiolabelled Teflon particles was studied before and after bronchial challenge. The aerosol distribution as well as output from the nebulizers were measured and these data together with results from this and seven earlier strrdies on deposition of Teflon particles of different sizes were used to calculate the dose of the two methacholine aerosols to the tracheobronchial region. The eNect on resistance In both small and large airways was similar for the two aerosols, as was the deposition of 3.8 pm particles. The calculated dose from the Pari was two times higher than from the MAD2. The results indicate that a certain dose to the tracheobronchial part of the lung gives a larger effect B the mass is spread on many small particles than on fever large ones. REGIONAL DEPOSITION OF 3.8 pm PARTICLES AND LUNG FUNCTION IN PATIENTS WITH CHRONIC OBSTRUCTIVE BRONCHITIS Svartenoren K., Ericsson C.H., Svartengren M., Mossberg B., Philipson K., Camner P. Dept. Respir. Allerg. Dis., Huddinge Nniversity Hospital, Huddinge and Respir. Med. Allerg., Sddersjukhuset, Stockholm; Inst. Environ. Med. and Dept. Environ. Hyg•, Karolinska lnstitutet, Stockholm, Sweden. In 14 patients with chronic bronchitis with a varying degree of airway obstruction, regional deposition of 3.6 pm (aerodynamic diameter) t 1 t In-labelled Teflon particles was studied twice. The particles were inhaled with maximally deep inhalations at 0.5 1ls. Lung retention was measured at 0, 24, 48 and 72 hrs using a profile scanner. The fast clearance phase seemed to be finished at 72 hrs. The retention after 72 hrs (RetlZl was considered to represent the alveolarly deposited fraction. The Ret72 values were normally distributed with means t SD of 48.0 t 14.0% and 47.9 * 12.9% for the two exposures and the values in the two exposures were highly correlated fr-0.97). Airway resistance IRaN,1 and specific airway resistance iSRaM,I correlated with Ret72, r-0.63 and r-0.80, respectively, in a similar way as in healthy subjects. Lung function tests reflecting smaller airways (FEF76-ea%and single breath N2 test phase sll) were poorly correlated to Ret72, r-0.40 and 0.20, respectively. The study indicates that regional lung deposition can be studied by measurements of Ret7z In obstructive bronchitis patients and that Ret7z in these patients is dependent on changes in large, rather than small, airways. 48 CLEARANC CONDUCTI Saioes M.B, Toxicology We are eve clearance of dosimdry r Radiolabele4 airavays In i The spray w tube iesena burdem of Nel(fl) co microepbere at the dosin was tested a than 3 days microsplren respectivel airways wit alaminoai8i deposited I dogs, but 4 Only I dog In both - paeicles re months. T sites with a 1.Sx10). examiaaNo portion of retained tb portion of this ptocei of the ' - Environme ACg4-76E INTRAI TRACII MEASI RETEN 0 Mercer, Universi Rocheste intratrac and Ion than inh trxasurit gsSr-lab techniqt contamv halothan Retentio 180 day detectio exposun (1) cont size 20 t were ot differen differen uniform the foil Long-t slow to These r do not. term ret
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rtitute4 Diaso a Pad 11MMD set was aiologic wsured. studied as well to data dies on used to to the naa and position vas two certain effact if =a ones. uddlnpe Environ. ckholm, prea of iynimic on. The 0.6 1/s. a profile 72 his. sent the iormagy .9% for e highly airway -0.80, unction N2 tast i 0.20, ion can onchitis changas CLEARANCE OF PARTICLES DEPOSITED IN THE CONDUCTING AIRWAYS OF BEAGLE DOGS Snipes M.B., Griffith, W.C., Nikula, KJ. and Guilmette, R.A. Inhalation Toxicology Reaearch Institute, P.O. Box 5890. Albuquerque, NM 87185, USA We are evaluating a new procedure to study tracheobronchial retention and ckarance of pankks is order to provide she infomntion necessary for improved dosimetry modeling of potential human exposures to radioactive panicks. Radiokbeled psaicles in 20 pL of saline solution were sprayed onto conducting airways is the luogs of 16 anesthetized, apneic Beagle dogs, I to 4 years old. The spray was delivered via a nricrospny nozek on The end of a polyethylene lube inserted through the biopsy chsanel of a fiberupric hronchoscope. Thoncic burdena of the radionuclides were quantified for as long as 42 days with ^ NaI(Pl) counting system. In the Grst rut, 3-4 µm polystyrene latex (PSL) mkrospberes (I.Sx107; 0.3 nrg) were used In 8 dogs. Internal airway d'umetets at the dosing sites were 15, 8, and 4 mm. One site was used per resr, each dog was rested at each site. Seven to 54% of the nrkruspheres were retained longer Than 3 days in the IS-mm airways of 5 dogs. Six to 69% and 2 to 94A6 of the microspheres were rehined longer than 3 days in g- and 4-nrnr airways, respectively, of all dogs. In a second study, 8 dogs were doscd in 4- and 15-nrm alrways with a 21) µL auspcurkm of Oxrut les polydisperse radiulaiieled fused aluminoailicate psnicles having a nuaa median dianterer of 1.5 pm. The deposited particles ckared from the 4-nun deposition aitca within 2 days in 2 dogs, but 40-50% of the panicks were retained for kmger than 3 days in Sr dogs. Only 1 dog retained panicles at the IS-nrm deposition site for mure than 3 days. In both studies, relenlion and ckarance patterns varied considersbly, but the particles relained bnger than 3 days cleared with hslf-limes on the order of momhs. Three dogs were sacrificed 6 days a8er dosing 4- and IS-mm airway sites with a mixture of radiolabeled and fluorescent PSL microsphercs (3-4 µm; 1.Sx10). The lungs were fixed by intravascular perfusiun. Histological examination of the lung proximal and distal to the dosing sites showed that sonic portion of the dose of aucrosphercs bad di5tributed to the alveoli and was retained there, which was not expccted. We are attempling to determine why a portion of The particles deposited an airway surfaces moved imu.alvcoli using this procedure. Possible reasons include the numbcrs of panicles and/or volumc of the dosing suspension. IResearch supported by the Offirv: of flcalth and Environmental Research, U.S. Department of Energy under Comtnct No. DE- AC04-76EV01013.1 INTRATRACHEAL INSTILLATION VS. INTRA- TRACHEAL INHALATION OF PARTICLES FOR MEASURING EFFECTS ON PARTICULATE LUNf: RETENTION Oberdnrster. G-, Cox, C., Gelcin, R., Ferin, 1., Corson, N., Mercer, P., and K. Nguyen University of Rochester, Dept. of Environmental Medicine, Rochester, NY 14642, USA Intrattacheal instillations are often used to evaluate pulmonary short- and long-term effects since they are less «lne- and cost-consuming than inhalation studies.. We compared the two techniques in rats by measuring the retention kinetics of intrabracheally instilled or inhaled 85Sr-labelled polystyrene particles (3.3 µm diam.) using a new technique for inhalation via the trachea to avoid any external fur contamination. For both techniques, ruts were anesthetized with halothane and the particles were administered via oral intubation. Retention of <40 µg particles delivered was followed over a period of 180 days by external counting of lung 85Sr activity in a collimated detection system. Groups of rats had been subjected to 12 weeks of exposure prior to delivery of the 95Sr-labelled particles as follows: (1) control; (2) TiO2-F (particle size 250 nm); (3) TiO2-D (particle size 20 nm, ullraftne); (4) SiO2 (cristobalite). The following results were obtained: The short-term retention half-times (T 1/2) of the different groups were longer, more variable and not significantly different after instillation, whereas after inhalation they were more uniform yet showed a signi8cant trend toward faster clearance with the following ranking: Control, TiO2-F, TiO2-D, SiO2 (fastest). Long-term T 1/2 showed the following ranking of the groups (from slow to fast): SiO2, TiO2-D, TiO2-F, control, with both techniques. These results show long-term retention kinetics of instilled particles do not differ significantly from that of inhaled particles, but slron- tems retention kinetics differ substantially. 49 PARTICLE RETENTION IN TIIE CONI)UCTING AIRWAYS OF IIAMSTERS: A STEREOLOGICAL APPROACH AND A COMPARISON WITII INf1ALATION DATA Gc,cr h1 Waber U.. Im Ilof V. and P.QC1X Institute of Anatonry, Dcpamncnt of liistology, University of Bern, 3(1(10 Bcm 9. Switzcdand We were interested in the total numbcr of particles retained in the conducting airways and their distribution pattern as a function of the breathing pattern, as well as in the interaction of particlcs with airway IlracnlplwgCs. 'lllercfnn:, we studied the lungs of seven Syrian Golden hatustcn cxpuscd to an acrosol of 6 fmt prdystyrcnc panicles under controlled conJitions in a vcutilation chambcr. Four of thcm were ventilated with a tidal volumc V1=1.(hul and a bfeathing frequency f=60min-I (group A), three of them with V1=0.5nsl and the same f (group B). Immediately after the inhalation the lungs of all animals were fixcd by intravascular pcrfusiun and processcd for light and clccttnn nsicroscopy and for slcrcolugicul analysis (fractionator). The structural and stcrcolugical analyses revealed that Ihc rctcnlion patlcm of Osc particles was signiftcantly different between the Iwo groups. In group A 64.2% (SD 21.0) of thc particles were retained in the intrapulmonary conducting airways will 35.814, (SI) 21.0) in Ilx) cxlnllxthllonary airways (trachea and maiu bnmchi). whereas in gmup B these uumlxers were 75.3'K, (SI) 32.3) and 2439i. (SI) 32.7). Ilctxc the iotrapulmuuary rclcntion was smallcr in the anitlrals wilh a(argcr VI. In the :mimah uf Iwlh groups Iwrdly any particles were found (Atagtxytized by airway nsacruplwgcs in Ihc exlrapuinsonary alrway5, whereas in tlse inlrapulmonary conducting airways thcre were 37.6% (SD 21.3) of Ihc particles phagocytizcd in group A and 56.3% (SD 24.0) in group B. This correlates roughly with the rctcntion pattcm. The lolal nunshcr of panicics rclained in Wc conducting airways cslituatcd slcrcologically was in gcwd agrcamont with the total nurulxr of particles deposited in the lung as dctcnnincd during the inhalalion in the anim:ds of group A. In the animals of group B, however, time total IWlrlber of relaillel( particles was conSidCrably snlaHer than the total numlxr of lutal dclwsilcd paniclcs suggcsling a dc(wsilion clscwhcre (iuhala(iun syslcm, alveolar dclwsition). We conclude that the speed of time acruxd inllucnccs the rclcntion patlcm, which appears again to be an imlwnatu dctcnuinant fur thc rate of phagtx:ytosis. MECHANISMS OF INTRACELLULAR DISSOLUTION OF INORGANIC PARTICLES IN ALVEOLAR MACROPHAGES KreyJing W.G.-, Forderkunz S.', Klein D. r, L(idtke K.-U. , Neuner M.~ and Summer K.H. ; GSF Forschungszentrum fur Umwell und GesundheH, Prolekt Infurlalion~, Inslitut fur Toxlkdogie+, D-8042 Neuherberg, F.R. Germany Alveolar macrophages (AM) are the first line of defense of the Immune appa- ralus of the respiratory Iract against inhaled particulate pollutants. Recently, we showed that AM of various species including man can dissolve inorganic paNcles Insracellulady which are not soluble In the epHheilal lining fluid of the lungs. To investigate this phenomenon we developed an AM culture assay In- cubating AM with physico-chemically uniform cobalt oxide (s7CoaO4) test particles during 2 weeks, measuring the kinetics of intracellular particle dis- solution (IPD). We found. IPD In cultured AM Is representative for the kinetics of an Imponant AM mediated cloarance mechanism In the peripheral lung. In vilro dissolution sludles without AM showed that the kinetlcs of test particle dissolution in medium using a combination of a pH value of 5 and a 1 mM concentration of a chelator (citrate or EDTA) was comparable to the kinetics of IPD In AM, while none of the (ndivdrrel factors led to a substanlial dissolu- tion of the test panicles. Indeed, a phagolysosomal pH (PLpH) of 4.5-5 In AM Is roponed In the literature but the presence and role of chelating agents and their concenlralions In the particle containing vacude are openly discussed. In gel chromatographically separated cytosols of AM Incubated with s7Co3O4 lest particles for 5 days. dissolved Co was fourxi in a single band, klentifled to be metallothlonein (MT) by its elulkm volume and a MT-specHlc Immuno-sor- bem method (ELISA). MT Is an ubiquitous low molecular weight protein with high affinity for dlvalent metals. Adding of Zn2 t, a stimulanl of MT gene ex- pression In various mammalian cells, to the AM culture resulted in a 10-fold inductlon of MT but increased neither the level of cytosdic Co nor the totally dissoved Co fraclion. These studies demonstrate that both PLpH and MT are associated with IPD of the inorganic test particles In AM and that MT mediates the Imracellular reten- tion and metabolism of dissolved Co in AM and its transport out of AM.
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CLERANCE OF REFRACTORY CERAMIC FIBERS (RCF) FROM THE RAT LUNG: DEVELOPMENT OF A MODEL Its C. E Zhang L.. Oberdoerster G.. Mast R. W.. Glass L. and M. I. Utell. State University of New York at Buffalo. Amherst NY, Carborundum Com- pany, Niagara Falls, NY, and University of Rochester Medical Center, Rochester, NY, USA The clearance of fibcrs from the respiratory tract has been found to depend on liber dimensions. Describing such clearance by a mathematical model would require knowledge of the fiber distribution plot in lung tissue at diL fcrent time points during and a0cr exposure. Rcccntiy, chronic inhalation cxpnsures (61Hmrs/day; Sdays/wcck; 2ycars; cxpcnure crnu:cnamlkms: 3. 9. 16 and 30 mg/m- I ) have been pcrlomtcd in rats to evaluate the biological responses of inhaled refractory ceramic fibers (RCF) at different concentra- tions. The lung burden data in the accessory lobe of the rat lung were col- lected after 13, 26, 39. 52. 65. 78 and 104 weeks of exposure and different post cxpnsurc periods of up to 91 weeks. The sirs distribution of the retained lilxrs in the lung a( dittcrem time points was also nreasured in these experiments. We used the liber sizc and lung burden data in develop a mathematical model of fiber clearance from the lung. The results showed that the clearancc rate did not depend upon fiber size but there appeared to be a slight decrease in clearance rate at the highest exposure concentration (30 mg/m~). The clearance rate of several different types of RCF deter- mined from the experimental data bascd on the mathematical model had a half time of about 200 days compared to a typical half time of 60 to 70 days when rates are exposed to low concentrations of insoluble spherical parti- cles. We conclude from these studies that: I) lung clearance of RCF fibers in rats is significantly prolongcd compared to nonfibmus particles, even fol- lowing relatively low exposurc conccnlmtions; and 2) Ilurc dncs nul appear to be a preferential clearance of a specific RCF libcr sizc. INDUCED BRONCHOCONSTRICTION AND MUCOCILIARY CLEARANCE IN ASTHMA O'Riordan T. G- and G. C. Smaldone. Division of Pulmonary/Critical Care, State University of New York, Stony Brook. NY 11794-8172. Patients with severe asthma have evidence of airflow obstruction and reduced clearance of secretions. We have previously reported an association between bronchial obstruction and impairment of mucoclliary clearance (MC) in patients with acute exacerbalions of asthma (Am Rev Resp Dls 1991; 143: 993-997) and also In patients with chronic stable asthma (Am Rev Respir Dls 1992; 146: 598- 603). To further lest the significance of this association, we Induced bronchial obstruction using methacholine and asked whether acute bronchial obstruction can directly affect MC. Asthmatic subjects with normal spiromelry and documented hyperresponsiveness to methacholine were studied. In five subjecls, two studies were performed : a control study in which MC was measured after inhalation of a saline aerosol and another study after inhalation of the same aerosol containing methacholine. Airway mucus was labeled with inhaled radioactive particles. Palterns of deposition for the radiolabeled particles were quantified using the specific central to peripheral ratio (sClP), determined by a1a3Xenon equilibrium Image, which measured regional lung volume. The retention of deposited particles was measured for two hours using a gamma camera. By controlling breathing pattern, we attempted to match the sC/P for the control and methacholine studies for each subject (mean ±SE: control sC/P.1.8 ± 0.4, methacholine sC/P.1.8 t0.5, pNS paired I lest; correlation between conlrol and methacholine sC/P r-0.989. p<0.001). The mean MC rate was greater for the methacholine studies (mean ±SE % retention: at 60 minutes: control - 68±10%, methacholine 61t12%; at 120 minutes: control.60t12%, melhacholine-56t11%) but statistical significance was not achieved using paired I test or by separation of 95% confidence inlervals. We conclude that methacholine induced bronchooonstriclion Is not associated with Impaired MC. This Is in contrast to the marked Impairmenl of MC reported in patients with airway obstruction due to severe asthma. (Supported by Al 16337 from the National Institutes of Heallh). Magnetometric Analysis of Pulmonary Retention of Particles IFerin. 7., 1OberdBrster, G. and 2S.C. Soderholm IDepartment of Environmental Medicine,University of Rochester, Rochester, NY 14642, USA; 2Natl. Inst. Occup. Health & Safety, Morgantown, WV 26505, USA Groups of rats were exposed to mixed aerosols of magnetite (Fe203) and titanium oxide (TiOZ) by single or multiple exposures. Using an array of 8 flux-gate magnelometers the rat lung burden of magnetite particles was analyzed in vivo. The maximum of the magnetic signal is independent of the location of the magnetic material within the space of the total lungs, a significant improvetnent over previous magnetometric systems. After magnetization of the retained particles by an external magnetic field of short duration (-0.01 sec.) the magnetic signal and its relaxation over 15 min. were recorded. The magnetometric signal was compared to the actual content of Fe2O~ determined by chemical analysis. The Ti02 content was also assessed. The results showed that the magnetic signal was linearly proportional to the amount of the Fey03, when rats were measured at the same post-exposure times. Complementary in vitro results showed that lower viscosity of the environment surrounding the particleS and lower concentration of FeZ03 in the tissue decrease the measurable magnetic signal triggered by the same mass of Fe203. To determine the lung burdens quantitatively by magnetometry a correction factor for viscosity and concentration is required. On the other hand, the magnetometric signal may be indicative for the translocation of the particles within the lung tissue, from the alveoli into the intcrstitium. Therefont, magnetometry, in addition to being a non-invasive method for total particle retention measurement, may also be useful for assessing particle translocation within the lung. This work was supported in part by NIOSH Grant OH02772. IIEALTII EFFECTS OF FIBROUS ItEROSOLS CORRELItTED TO TIIEIR PHYSICO-C1IEMICAL PROPERTIES Spurny,K.R. Aerosol Chemist,Eichenweg St.6,5948 Schmallenberg Germany Flne mineral fibrous aerosols(asbeslos and other mineral fibers) are fibrogenic and carcinogenic by animal and by man.Own investigations as well as several published experimental and epidemiologi- cal data have shown,that the particle shape,size, persistence,chemical and physical properties-,etc., can be correlated to the aerodynamic behavior of this aerosol,to its separation and deposition me- chanism in the uper and in the lower airways and to the biochemical and molecular-biological interactions between incorporated fibrous parti- cles and cells. The same is also valid for the lung clearance and for the pathological effects of fibers incorpora- ted in cells. Asbestos will be now more and more substituted by othermineral and man-made mineral fibers(tfi7MFl. The experimentally evaluated physical,chemical, biological and physiological properties of new products of MMMF can be therefore used as scree- ning tests for approximative prediction of their expected toxic and carcinogenic helth effetcs and health risks. 50 Al

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