May23, 2000
`
`Eur J Med Res (2000) 5; 209-216
`
`EUROPEAN JOURNAL OF MEDICAL RESEARCH
`
`209
`
`© {. Holzapfel Publishers 2000
`
`PERFLUOROCARBONS — USEFUL TOOLS FOR MEDICINE*
`
`St. Riidiger, U. Grow, E. Kemnitz
`
`Institute of Chemistry, Humboldt-University, Berlin, Germany
`
`Abstract: Perfluorocarbons (PFCs) combine rather
`unique chemical and physical properties together
`with physiological
`inertness. Due to this,
`they
`have become useful
`tools in medicine. Whereas
`the majority of applications benefit from their ex-
`cellent oxygen solubility, there are several appli-
`cations making use of other PFC properties. The
`great importance of PFC ultra-purity is especially
`emphasized.
`
`Key words: perfluorocarbons, purification, oxygen
`transport, liquid ventilation, drug carrier
`
`INTRODUCTION
`
`There are two principal ways for manufacturing
`PFCs. The one starts from hydrogen containing or-
`ganic compounds having the skeleton (from car-
`bon andpossibly nitrogen and/or oxygen) of the
`aimed PFC, By special methods these compounds
`are perfluorinated,
`i.e. all hydrogen atoms are re-
`placed byfluorine, and all multiple bonds are sat-
`urated.
`Industrial perfluorination ‘methods com-
`prise electrochemical
`fluerination (ECF), cobalt
`trifluoride fluorination (CoF,), and to a certain ex-
`tent also fluorination with elemental fluorine.
`The other waystarts from preformed fluorinat-
`ed smali
`“building biocks” which are combined to
`form the aimed PFC. Examples for both ways are
`given in Fig. 2 and 3.
`
`PURIFICATION OF PFCs
`
`Unfortunately, as quite normal in chemical synthe-
`sis, all these reaction do not proceed as smoothly,
`completely, and exclusively as given in the exam-
`
` FF phr
`
`f
`Es
`Pict nel F
`XSF
`rE NF
`FA
`BS \
`Wai
`FCPF
`
`FTPA_ perfluorotripropylamine,
`(C,F,);N
`
`Over the last 3 decades, perfluorocarbon com-
`pounds (perfluorocarbons, PFCs), originally in-
`vented in
`the
`1940s
`in connection with the
`Manhattan-Project, have been attracting scientists
`all over the world because of their unique suit-
`ability for a variety of biological-medical applica-
`tions[1).
`“Blood substitute” is the perhaps most spectac-
`ular application of PFCs [2]. PFC-based,
`intravas-
`.
`FOr.
`cularily injectable oxygen transporting liquids
`
`F PFD_perfluorodecalin,F
`
`have already received approval
`for special pur-
`F
`F
`er
`poses (Fig. 1). Since such liquids have to be mis-
`F
`10" 20
`cible and compatible with human blood, theyare
`composed of perfluorocarbon(s) finely dispersed,
`emulsified,
`in an aqueous solution of salts, be-
`cause of the osmotic pressure, special polymers,
`because of the colloid-osmotic pressure, and glu-
`cose as energy ressource, Other important fields
`of PFC-use{3} are ophthalmology and liquid venti-
`lation,
`in both applications neat perfluorocarbons
`are used.
`
`.
`
`.
`
`NATURE AND SYNTHESIS OF PFCs
`
`FPMCP. perfluoromethyl-
`
`cyclohexylpiperidine,
`
`Perfluorocarbons are compounds consisting in a
`narrow sense of carbon and fluorine atoms only;
`in a broader sense all compounds ate summedup
`under this term having all
`their hydrogen atoms
`replaced byfluorine, and containing single bonds
`only, and fluorine is bond to carbon only. Typical
`examples are shownin Fig. 1.
`EF RE EF Ep
`PFO__perfluorooctane
`Fnf Naf N74 NF
`1,
`oh
`:
`FR FF PF FP
`CaF ig
`
`Cy 9Fy3N
`FP EF BF &E,
`FA” eee se PFOB perfluorooctylbromide
`FP PE PP FF
`CgF ,7Br
`
`the Ist European Symposium on
`* Presented in part at
`Liquid Ventilation, Berlin, October 1999
`
`Fig. 1. Examples of perfluorocarbons used for medical
`applications,
`
`DROPWORKS - EXHIBIT 1017
`
`DROPWORKS - EXHIBIT 1017
`
`

`

`210
`
`EUROPEAN JOURNAL OF MEDICAL RESEARCH
`
`May23, 2000
`
`-CoF;-process
`HoH
`
`H
`a
`
`250°C
`H
`H + 30CoF, ——>
`{
`
`H HH :
`
`: FOP
`PE p
`F
`
`
`
`py
`fF
`il
`FF
`
`+ 30 CoF, + 12 HF
`
`ECF-process
`
`(CH;CH,CH,);N +. 42F7 —+ (CF3CF,CF,);N + 21 HF + 42e°
`
`42Ht + 42e° —+ 21H,
`
`Fig. 2. Perfluorinating routes to perflu-
`orocarbons.
`
`L/IF,
`CF,=CF, <> CF,CFJ
`
`+n CF,=CF,
`
`
`CAF(CFyal
`
`+Br,
`(for n=3
`
`CF (CF,)-Brmr
`PrOB
`
`+CH,=CHR'
`
`CF.(C,F,),CH,CHIR
`Zn/MeOH;
`H,/Ni
`
`CF(CF4),CH,CHR
`
`"RR"
`PCH
`
`Fig. 3. Building block route to perfluo-
`rocarbons and to RFRH-diblock com-
`pounds.
`
`.,
`C,H, ,COCI
`
`
`
`ECF
`
`F
`cr, cor + IA, +
`
`Qu
`GLA
`
`+ others
`
`"RM 101" (Miteni)
`
`CO OO + OD + OO + ome
`
`cis-
`
`trans-
`
`perfluorodecalin (PFD)
`
`Fig, 4. Product mixtures obtained by
`industrial perfluorination reactions.
`
`ples. Depending on their respective ways of manu-
`facture, the crude PFCs contain different types of
`by-products. Of these not all are necessarily im-
`purities. On the contrary, “by-products” which are
`perfluorinated, and the physico-chemical proper-
`ties of which are close to those of the aimed
`(major) product, might be acceptable,
`too, de-
`
`pending on the medical field of application. Thus,
`e.g., ECF of octanoic acid chloride yields, besides
`the aimed perfluoro octanoic acid fluoride, hugh
`amounts of both perfluorobutyltetrahydrofuran
`and perfluoropropyltetrahydropyran. The
`latter
`two are commercialised as a mixture by Miteni,
`Italy, under the trade name RM101, and can be
`
`

`

`May 23, 2000
`
`EUROPEAN JOURNAL OF MEDICAL RESEARCH
`
`211
`
`w
`
`rx)
`
`Fig. 5. Gaschromatogramm of crude perfluorodecalin.
`Peaks No. 12 and 13 correspondto cis- and trans- per-
`fluorodecalin. (From Riidiger S, Radeck W (1988) un-
`published).
`
`liquid ventilation (Fig. 4), Another
`used for, e.g.,
`example is the use of cis- and trans- perfluorodec-
`alin as mixture (Fig. 4) in, e.g., ophthalmology[4].
`In case that their physico-chemical properties dif-
`fer beyond acceptable limits, it opens in itself pos-
`sibilities to separate them by, e.g., distillation or
`other means.
`However, there are other types of impurities in
`the crude PFCs which are toxic, often in very low
`concentrations, and which have to be removed,
`therefore [5]. Fig. 5 shows a typical gaschromato-
`gramm of crude pertluorodecalin, giving an im-
`pression of the variety of differently fluorinated
`compounds which can be found in the product
`mixture,
`These potentially toxic impurities are com-
`pounds containing CHF and/or C=C within their
`molecules. Because of their high reactivity to-
`wards nucleophiles, these parts of the molecules
`are weakpoints of the otherwise stable fluorinated
`molecules (Fig. 6).
`
`Reactions with nucleophilic agents, as shown in
`Fig. 6 with the hydroxyl ion, lead not only to mul-
`tiple formation of hydrogen fluoride, but nucle-
`ophilic groups of biomolecules can react, too. As
`a consequence, complete removal of such impur-
`ities is an absolutely necessary and important task
`in preparing PFCs for medical use. Such an ulta-
`purification requires the application of specifically
`designed multistep processes, combining chemical
`treatments with physico-chemical ones
`[6].
`In
`principal,
`time-consuming reactions with very
`strong nucleophiles at high temperatures can be
`used, followed by phase separation, distillation,
`extraction, and chromatography. The quality con-
`trol of the purified product,
`to confirm it
`is of
`medical grade, needs besides great experience of
`the personnei concerned with, advanced analyti-
`cal techniques which have to be combined with
`or checked against biological tests. For the latter,
`several types of cell culture tests have been intro-
`duced and employed (5, 7].
`The authors feel that quite often irreproducible re-
`sults, and nonconformity between the results of
`different researchers might have their origin in the
`use of PFCs having different degrees of purity.
`These few remarks, already, should emphasize the
`necessity of chemists and medical scientists to
`work together in this field.
`
`PROPERTIES AND MEDICALL Use OF PFCs
`
`Perfluorocarbons have rather unique properties.
`These can be explained on a molecular basis by
`the specific properties of fluorine and the C-F
`bond, some of which shail be referred to very
`briefly (Table 1 and 2).
`A comparison of fluorine with the other halo-
`gens and with hydrogen showsthat fluorine has
`the highest
`ionization potential
`IP and highest
`electronegativity %,, but the lowest polarizability
`@,. Whereas its van der Waals radius ry is not
`muchlarger than that of hydrogen.
`As consequences of the high ionization poten-
`tial of fluorine and especially of its low polariz-
`ability, the intermolecular interactions in liquid
`perfluorocarbons are very weak, and the surface
`energies are low. Due to its extraordinary high
`electronegativity, fluorine is always electron-with-
`drawing when bonded to carbon, causing a rela-
`tively high ionic character of the C-F bond making
`it stronger than any other C-X bond. There is an-
`other, most important peculiarity of the C-F bond,
`i.e., mammals do not have an enzym capable to
`cleave that bond.”
`the bond strength data
`The comparison of
`shows that fluorine is not only superior to hydro-
`gen, but also that the bondstrength increases in
`
`H
`
`- HF
`
`!>m-O-~CRy- ——» -CF=CF-CF,- ae -c(0)-cF=cF- Ss
`
`~
`
`Tir
`
`Fig. 6. Typical reactions of toxic impurities.
`
`

`

`nN
`
`tN
`
`EUROPEAN JOURNAL OF MEDICAL RESEARCH
`
`May 23, 2000
`
`Table 1, Examples of Biomedical Applications for PFC Liquids and their Emulsions,
`
`|
`ate
`
`
`
` Product Company Year Status and Purpose
`
`
`
`
`
`Fluosol DA
`(PFD/FTPA)
`Perftoran
`(PFD/FPMCP)
`
`Green Cross Corp.
`Japan
`Russia
`
`Oxygent
`(PFOB)
`
`Alliance Pharm.
`Corp. USA
`
`PFD, PFO
`
`Liquivent
`
`Bausch + Lomb
`USA/Europe
`Alliance Pharm.
`Corp. USA
`
`1990
`
`1996
`
`1997
`
`1998
`endof 1998
`
`actual
`
`actual
`
`Approval of emulsion for clinical use
`in coronary balloon angioplasty
`Approval for haemorrhagic shock
`patients; perfusion ofisolated
`human organs
`
`Phase II — temporarytissue
`oxygenation in 250 surgical patients
`Clinical trials with more than 340 patients
`Phase III studies started
`
`Surgical tools in ophthalmology
`.
`Liquid ventilation fluid undertesting
`Phase III ongoing
`
`Imagent
`
`actual
`
`Diagnostic imaging agent
`Alliance Pharm.
`Phase II completed
`Corp. USA
`
`different suppliers actualSeveral PFCs Cell culture media supplements
`
`
`
`
`
`Table 2. Atomic Properties of Fluorine in Comparison.
`
` IP [kcal/mol]—a, [A4] ry [A] Xp
`
`
`
`The fluorine and C-F bond pecularities imply
`many specific properties Of perfluorocarbons, sev-
`
`eral of them are valueable from a medical point of
`view.
`
`2.20
`1.20
`0.667
`313.6
`H
`3.98
`1.47
`0.557
`401.8
`F
`3.16
`1.75
`2.18
`299.0
`|
`2.96
`1.85
`3.05
`272.4
`Br
`
`
`
`
`241.2 4.7 1.98[ 2.66
`
`Data taken from Smart BE (1994) Characteristics of C-F
`Systems.
`In: Banks RE, Smart BE, Tatlow JC (ed)
`Organofluorine Chemistry, Principles and Commercial
`Applications. Plenum Press, New York, London.
`
`Table 3. Bond Dissoziation Energies of Ethanes
`
`D°(C-X) [kcal/mol]
`CH,CH,-X
`CF,CF,-X
`
`
`102.7
`100.1
`
`107.9 126.8
`
`Xx
`
`H
`F
`
`Data taken as above
`
`Perfluorocarbons-
`e are chemically highly inert, as a consequence
`-
`they are physiologically acceptable, too;
`e dissolve about 20 times more oxygen than
`water does, and even more carbon dioxide;
`e have very low surface tension allowing themto
`wet any solid surface;
`¢ are strongly hydrophobic but also oleophobic,
`consequently, they are immiscible with water,
`and very
`limited miscible with oleophilic
`liquids;
`e are very poor solvents for all but fluorophilic
`solid substances;
`e have specific densities near 2 g/cm, but their
`boiling points resemble those of the analogous
`hydrogenated compounds, so that
`they easily
`evaporate;
`are unusual compressible, hence, acoustic ve-
`locity in PFCs is low making them excellent
`contrast agents for ultrasound diagnosis.
`
`*
`
`As basis of any medical use, physiological ac-
`ceptance of a PFC is a precondition, depending
`going from mono- to perfluorinated compounds.
`primarily on its purity only. Therefore, ultra-purifi-
`Because of the comparatively small size of fluo-
`cation of the PFCs is absolutely necessary.
`rine, all hydrogen atoms in an organic molecule
`Among other specific properties, the high oxygen
`can be replaced principally by fluorine with the
`(and carbon dioxide) solubility is most widely em-
`molecular structure remaining. Due tothe slightly
`ployed. The O,-solubility depends partly on mo-
`greater
`fluorine atoms,
`the resulting perfluoro-
`lecular volume and structure, but it varies not so
`compounds are somewhatstiffer than the hydrog-
`muchthat its variation have to be taken into con- |
`enated ones, and their carbon skeleton and with
`sideration for a specific medical task (Fig. 7) [8].
`that
`their carbon-carbon bonds are completely
`The ability of PFCs to dissolve large amounts of
`shielded by fluorine, making them less accessible
`oxygen was decisive for their use in “blood substi-
`to any chemical attack. In summary, PFCs are of
`tutes”, for organ preservation, and for liquid venti-
`extraordinary chemical as well as thermal resis-
`tance.
`lation. Unlike to blood, PFCs showalinear rela-
`
`

`

`
`
`otherliquid
`water
`
`ethanol
`
`benzene
`
`acetone
`
`ethyl ether
`
`2.9
`
`24.2
`
`22.5
`
`28
`
`44.7
`
`sions one has to take into consideration a very,
`very small but decisive solubility [10]. This implies
`the necessity to make PFC-in-water emulsions for
`intravascular use of PFC-based oxygencarriers.
`Onthe other hand, PFCs are very limited miscible
`with or soluble in lipophilic liquids, too, depend-
`ing on the nature of the PFCtested as well as of
`the other solvent. The temperature above which
`two liquids become completely miscible, the criti-
`cal solution temperature (CST),
`is
`a valueable
`characteristics indicating the difference in the re-
`spective Hildebrandt’s solubility parameters [11].
`By using a specific lipophilic liquid as a standard
`the experimentally determined CSTs are used to
`discriminate between PFCs regarding their lipoph-
`ilicity and other properties: depending onit as e.g.
`the excretion rate in case of intravascular use.
`In
`this respect, n-hexane, olive oil, as well as n-bro-
`moalkanes have been -used as reference liquids
`{12, 13, 14]. The lower the CST the higher the li-
`pophilicity and the higher
`the excretion rate.
`CST(n-hexane)-values of some typical PFCs are
`shownin Fig. 8 [12, 13].
`remarks concerning
`At
`this point some short
`the emulsification behaviour of PFCs are neces-
`sary. If one of twoimmiscible liquids is finely dis-
`persed within the other, the resulting dispersion is
`thermodynamically (i.e.
`energetically) unstable
`and tends to decay into the two separate phases.
`tion between the amount of dissolved oxygen and
`The dispersion can be more or less stabilized by
`oxygen partial pressure,
`i.e. the solubility follows
`introducing surface active agents which become
`Henry’s Law. Oxygen is dissolved physically only,
`enriched at
`the liquid-liquid interface.
`Ideally,
`there are no specific interactions with the PFC [9].
`such agents should bear in their molecules two
`On the contrary, due to the very weak intermolec-
`ular interactions in PFCs,
`there is sufficient free
`spatially separated groups, one, e.g., hydrophilic
`and the other, e.g., fluorophilic as in “fluorosur-
`space between the PFC molecules to be occupied
`by oxygen or other low molecular gases. By the
`factants”. Such surfactants arrange themselves in
`‘the interface in a waythat their hydrophilic part is
`way, similar amounts of oxygen can be dissolved
`orientated towards the water phase andthe fluo-
`in, e.g., diethylether (Fig. 7).
`rophilic (i.e.hydrophobic) one towards the PFC.
`The very lowsurface tension of PFCs makesit
`As a result, the free energy of the system can be-
`possible that PFCs wet any solid surface even
`polytetrafluoroethylene, Teflon®. However,_its
`come that
`low that
`thermodynamically stable
`systems might be formed, eventually, as in case of |
`spreading behaviour on surfaces already wetted
`the so-called microemulsions. When stable emul-
`with water as they are within lungs has to be in-
`sions have to be made, consisting of water dis-
`vestigated experimentally.
`persed in PFC (water-in-PFC), special fluorosur-
`PFCs are practically insoluble in water. Only to
`factants have to be used, whereas PFC-in-water
`explain the droplet growth in PFC-in-water emul-
`
`May 23, 2000
`
`EUROPEAN JOURNAL OF MEDICAL RESEARCH
`
`3
`
`213
`
`perfluorocarbon
`F- CORA 40
`
`FIBA
`
`Cre) erp
`
`CScrs FBTHF
`
`crF)-NF)
`FPMCP
`
`45
`
`49
`
`43
`
`F-AANM:,
`PFOB
`
`53
`
`Fig. 7. Oxygen solubility of selected perfluorocarbons
`and some other liquids (mL O,/100 mL liquid at 760
`mmltg O, }.
`
`22
`PFD
`59
`rN FIBA
`One FDMCM $3.3 CH, FMDBD21.2
`(@-oXNP) FCOM 44.2
`CEC FMCH
`82
`
`3
`
`cr-{F)-NF) FPMCP
`
`FE AAA,
`
`PFO
`
`39
`
`37
`
`BAYS“ PFOCIL
`
`-7.5
`
`.
`
`EAASSs: PFOB
`
`-24.5
`
`Fig. 8. Critical solution temperatures (CST)
`of selected perfluorcarbons in n-hexane (°C)
`(Data taken in part from [12].
`
`

`

`Peeee
`
`214
`
`EUROPEAN JOURNAL OF MEDICAL RESEARCH
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`May 23, 2000
`
`emulsions can also be stabilized by entrapping the
`PFCdroplets in, e.g., swollen micelles of lecithin.
`Among the several
`factors affecting emulsion
`stability, PFC-lipophilicity as well as PFC-diffusion
`through water play an important role, properties
`which are well-balanced in only some PFCs as,
`e.g., in PFOB.
`A drawback of PFCs is that they are very poor
`solvents for all but fluorophilic substances. There-
`fore,
`it
`is almost impossible to obtain therapeuti-
`cally or diagnostically useful concentrations of
`pharmaceutics dissolved in a PFC. To overcome
`this disadvantage, other developments are need-
`ed, which are discussed in detail below.
`The high specific gravity of PFCs resulting from
`the replacement of the light hydrogen atoms by
`the comparatively heavier fluorine atoms is help-
`ful
`in the light of liquid ventilation to introduce
`PFC in the lungs [15] even in case these are (part-
`ly) filled with water, and for the use of PFCs in
`ophthalmology[16]. In ophthalmology, PFC is used
`to flatten a detached and possibly foldedretina at
`the eye’s backgroundthat it becomes re-attached.
`Surprisingly, PFCs having molecular weights
`which are about three times higher than those of
`the respective hydrogenated compounds boil at
`nearly the same temperature. The low boiling
`points together with low heats of evaporation are
`further indices for very low intermolecular interac-
`tions. As a consequence, PFCs can be very easily
`evaporated, thus leaving the lungs in case of liq-
`uid ventilation, within short
`time although the
`body temperature is
`far below their respective
`boiling points.
`There are further PFC properties worth to be
`mentioned because of medical
`relevance. Thus,
`the low acoustic velocity makes them a valueable
`ultrasound contrast agent, for instance as stable
`gaseous PFC-in-water dispersions [18]. Further-
`more, fluorine atoms are as suited as hydrogen for
`nuclear magnetic resonance experiments. Because
`fluorine resonates at another (lower) frequency
`range than hydrogen (provided the magnetic field
`is
`the same), conventional magnetic resonance
`tomographs are not useful, unfortunately. How-
`ever, on an experimental level, excellent °F imag-
`es have been obtained already[19].
`The great interest in perfluorocarbons for medi-
`cal uses arose with the advent of PFC-based blood
`substitutes,
`as
`they were called at
`that
`time.
`Scientists, at
`the beginning mostly chemists, all
`over the world were confronted with the very dif-
`ficult task to find or develope a PFC representing
`a good compromise between sufficient intravascu-
`lar dwell time, fast excretion from the patient, and
`long term stability of its aqueous emulsion using
`physiologically tolerable emulsifier. Hundreds of
`compounds were tested in this respect,
`some
`taken from industry, most were specially synthe-
`‘sized (see, e.g., Fig. 1).
`Perfluorooctyl bromide (“PFOB”or “Perflubron”)
`is the PFC-constituent of a blood substitute intro-
`duced by Alliance Pharmaceuticals, USA, which is
`the nowadays most advancedtested one. In accor-
`
`dance with the explanations given above, the bro-
`mine atom in PFOB (seeFig. 1) is a weak-point at
`which comparatively easily a chemical attack is
`possible. Correspondingly,
`some
`authors
`[34]
`question the broadly accepted physiological inert-
`ness. As mentioned above, manufacturing of med-
`ical grade PFCs
`is
`a
`laborious task. Therefore,
`once that a manufacturing line for an ultra-pure
`PFCis implemented, the PFCis available for test-
`ing of all kinds of medical uses as in case of
`PFOB. However,
`it
`is neither the only one nor
`necessarily the best one for a special purpose, but
`possibly the only one available in larger quantities
`of medical grade.
`Despite the large number and great variety of
`PFCs tested, their physico-chemical characteristics
`lay within rather narrowlimits.One wayto extent
`these limits is the introduction of Br- or Cl-atoms
`in the molecule, as in PFOB (perfluorooctylbro-
`mide)
`or
`in
`perfluoro-(a,@-dichlorooctane).
`Another way to extend these limits is
`in going
`from “true” perfluorocarbons to perfluorocarbon
`derivatives,
`the molecules of which consist ofat
`least two different parts, one a fluorocarbon, and
`the other a hydrocarbon. Such compounds are
`knownsince 1964 [20], the synthetic route is given
`in Fig. 3. A typical exampleof these perfluoroal-
`kylalkanes, or so-called Ry-Ry diblock compounds
`is shown in the following.
`
`CF-( CF) m-CF3-CH)-(CH)),-CH
`
`Surprisingly, such compounds can be physio-
`logically acceptable, too, like PFCs [21]. However,
`in contrast
`to PFCs, because of their structure
`these compoundshave a certain interfacial activity
`(22], making them valueable co-surfactants for
`PFC-in-water as well for water-in-PFC emulsions,
`In addition, by selecting the respective length of
`both the perfluoro- and the hydrocarbon part, one
`has the possibility to design a PFC-like compound
`having desired boiling point, specific density and
`liphophilicity. One can design tailor-made com-
`pounds which fit best for ophthalmology [23] but
`also for emulsification [24], and which open a
`minor possibility for making solutions of com-
`pounds of medical interest [25].
`
`Use oF PFCs For LiQUID VENTILATION
`
`Since PFC liquids dissolve large amounts of respir-
`atory gases, their suitability for liquid ventilation
`is under study for several years [26]. Experiments
`with both experimental schemes, filling the lungs
`partially with PFC (Partial Liquid Ventilation,
`PLV), and filling the lungs totally with PFC (Total
`Liquid Ventilation, TLV), have demonstrated that
`oxygenation and carbon dioxide washout can be
`maintained sufficiently [27],
`though the latter
`methodinvolves greater technical problems to be
`solved.
`In addition to maintaining respiration,
`PFCs are able to replace water or aqueousliquids,
`e.g.
`in case of lung edema, and to inflate an im-
`mature lung in, e.g., newborn infants.
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`Concerning the selection of appropriate PFCs,
`the requirements a PFC to be usedfor liquid ven-
`tilation has to meet are similar to those in case of
`blood substitutes,
`though not
`identical. An obvi-
`ous precondition is its physiological inertness, de-
`pending on ultra-high purity of the PFC, as in case
`of bloodsubstitute, too. Despite its general impor-
`tance, gas solubility is not a characteristic to be
`taken into account selecting a PFC because ofthe
`low variability mentioned above. The vapor pres-
`sure and correspondingly the boiling temperature
`of a PFC could be expected to be crucial because
`low boiling PFCs (i.e. with high vapor pressure)
`are known to cause gas emboli, and might cause
`hyperinflation of
`the lung when administered
`intravenously in emulsified form [28]. However,if
`administered intratracheally, PFCs having boiling
`points even below 37°C have been reported in
`the patent
`literature to be advantageously [29].
`The lipophilicity of a PFC can be of importance
`for liquid ventilation, too. In case of the elimina-
`tion of fluorocarbons as components of blood
`substitutes from the body,
`the rate determining
`step is the dissolution of PFC in circulating lipid
`carriers [30, 14]. These carriers transport the PFC
`io the lung, whereit is eliminated into the air. The
`higher the lipophilicity of the PFC the higher the
`transportation and excretion rate. If, however, the
`lung contains already substantially amounts of the
`PFC, depending on the lipophilicity of the latter
`they will become dissolved in circulating lipids.
`As
`a consequence,
`the PFC will probably be
`found in all parts of the body especially in adi-
`pose tissue [31]. The therapeutic benefit of liquid
`ventilation would be greatly improved if the PFC
`administered can be used as carrier for other ther-
`apeutical agents, too. Interesting agents are, e.g.,
`antiinflammatory or antiinfectious agents, other
`types of drugs,
`lung surfactants, or nutrients,
`to
`mention some. In this respect one could make use
`of the large surface of the lung (about 160 m2) for
`the resorption of water insoluble agents, which
`are conventionally difficult
`to administer. How-
`ever, as specified above, PFCs are very poor sol-
`vents so that
`therapeutical useful concentrations
`of a solute are very unlikely to be obtained.
`Therefore, special developments are necessary to
`make use of PFCs as carriers, e.g. development of
`PFCs or better fluorocarbons specifically adapted
`to dissolve a drug, or implementing water-in-PFC
`emulsion for transporting water soluble agents, or
`developing stable dispersions of the therapeutic
`agent in PFC. Although first attempts in this field
`are already reported [32],
`the problems encoun-
`tered are far from being solved.
`
`OUTLOOK
`
`The principal suitability of perfluorocarbons and
`related compounds for medical use is known for
`long. Up to now, there are so many papers pub-
`lished and patents filed covering all aspects of
`synthesis of fluorocarbons and their use in biolo-
`gy and medicine that
`it
`is
`impossible to review
`
`them comprehensively. From a chemical point of
`view,
`there are a great many fluorocarbons suit-
`able for medical use because of their physical-
`chemical properties. However,
`the medical
`re-
`searcher who wants to test a fluorocarbon should
`be sure that the material is of real medical grade,
`to get reliable and comparable results. Such high-
`ly purified compounds are very limited available
`on the market, unfortunately,
`Despite the ‘great variety of medical applica-
`tions already tested, the inherent potential of the
`fluorocarbons is by far not exhausted. Future in-
`vestigations will probably not be focussed pre-
`dominantly on the oxygen solubility but on other
`aspects of their use, some of which are discussed
`above.
`
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`Received: January 4, 2000 / Accepted: March 10, 2000
`
`Address for corresrondence:
`Dr. Stephan Riidiger
`Institute of Chemistry
`Humboldt-University
`Hessische Str. 1-2
`D-10115 Berlin, Germany
`Phone
`+49 30 2093 7328
`Fax
`+49 30 2093 7277
`e-mail
`stephan=ruediger@chemie.hu-berlin.de
`
`le
`
`