DROPWORKS - EXHIBIT 1017
`
`

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`’l!)
`
`H R()Pl‘»\\ >l()l'R\:\l
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`()l" \1l’l)l(',;\| Rl’\F‘\R(lll
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`
`C0193 -process
`H illl
`
`H
`H
`
`u H H
`
`2<0°c
`H
`Ill + 30 C013 —'-—~
`
`,
`
`Fl
`5
`W
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`s
`
`l
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`'l
`
`J
`l P
`F
`
`
`
`+ 30 Col“: + l2 HF
`
`ECF-process
`
`(CH3CH2CH2)3N + 42 F- ——+
`
`(CF3CF2CF2)3N + 21 HF + 42 e'
`
`42H+ + 42e'-—~ 21H2
`
`Fig. .2. Perfluorinating routes to perflu—
`orocarbons.
`
`CF2=CF2
`
`
`izliFs
`+ n CF2=CF2
`‘ CF3CFZI
`
`V
`C2F5(C2F4lnl
`
`+Br2
`(for “:3
`
`+CH2=CHRI
`
`CF (CF ) Br
`3
`2 7
`
`PFOB
`
`C2F5(C2F4)HCH2CHIR
`
`Zn/MeOH;
`Hlei
`
`C2F5(CzF4)nCH2CH2R
`
`"R R ..
`F H
`
`Fig. A" Building block route to perfluo-
`rocarbons and to RFRH-diblock com-
`pounds.
`
`‘
`C7HISCOCI
`
`
`ECF
`
`(FIA
`F
`C7FISCOF + glvv + o
`
`+ others
`
`“RM 101" (Miteni)
`
`C0935“ H+®®++othm
`
`cis—
`
`trans-
`
`perfluorodecalin (PFD)
`
`Fig. 4, Product mixtures obtained by
`industrial perfiuorination 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. ()n the contrary, "by-products" which are
`perfluorinated, and the physico—chemieal proper~
`ties of which are close to those of the aimed
`(maior) product, might be aeeeptable,
`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 periluiirobuty‘ltetrahydrofuran
`and perlluoroprt)pyltetrahydropyran. The
`latter
`two are commercialised as a mixture by Miteni.
`italy, under the trade name RM, 101. and can be
`
`

`

`Max 1%. goon
`
`H KUI’EA\ JUI 'RVAI (”5 \lEl)l(IAl. RFSEARCH
`
`ll]
`
`ES
`1
`
`17
`
`Fig. 5. (Baschromatogramm of crude perfluorodecalin.
`Peaks No. 12 and 15 correspond to cis» and trans— per-
`lluormlecalin. (From Rudiger 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 periluorodecalin. 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 (IHF and/or C=(2 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. 0).
`
`Reactions with nucleophilic agents. as shown in
`Fig. 6 with the ltt'droxyl ion. lead not only to mul-
`tiple formation of hydrogen fluoride, but nucle-
`opltilic 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 personnel 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 Usr, ()F PFCs
`
`Perfluorocarhons 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 shall be referred to very
`briefly (Table 1 and 2).
`A comparison of fluorine with the other halo~
`gens and with hydrogen shows that fluorine has
`the highest
`ionization potential
`ll’ and highest
`electronegativity xp. but the lowest polarizability
`av. whereas its van der Waals radius rv is not
`much larger 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 (I—F bond making
`it stronger than any other C—X bond. There is an—
`other, most important peculiarity of the CF 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 bond strength increases in
`
`H
`F
`»
`_
`—¢—(::—crf— —— -CF=CF-CF2- fig!» ctoicr=cr- 1°»
`-HF
`-HF2
`F F
`
`Fig 0. Typical reactions of toxic impurities.
`
`

`

`Iv
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`h.
`
`Fl 'R( )I)F.’\l\ _l()l "RN-U, ()F .\1Fl)l(‘:\l. RFfil-‘ARCH
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`Ma)
`
`.3 s. 1000
`
`Table I. Examples of Biomedical Applications for PFC Liquids and their l-Iiiiulsions.
`
`‘um.inW
`”236.:
`
`
`
` Product Company Year Status and Purpose
`
`
`
`
`
`Fluosol DA
`(PFD’F’l‘l’A)
`Perftoran
`(l’FDJFPMCW
`
`(,ireen Cross (Iorp.
`Japan
`Russia
`
`()xygent
`(PFOB)
`
`Alliance Pharin.
`Corp. USA
`
`PFD. PFO
`
`Liquivent
`
`lmagent
`
`Bausch + Lomb
`USA; Europe
`
`Alliance Pharni.
`Corp. USA
`
`Alliance Pharm.
`Corp. USA
`
`1990
`
`1996
`
`19‘)"
`
`1998
`end of 1998
`
`actual
`
`actual
`
`actual
`
`Approval of emulsion for clinical use
`in coronary balloon angioplasty
`Approval for haemorrhagic shock
`patients: perfusion of isolated
`human organs
`
`Phase ll - temporary tissue
`oxygenation in 250 surgical patients
`Clinical trials with tnore than 3-H) patients
`Phase [II studies started
`
`Surgical tools in ophthalmology
`
`Liquid ventilation fluid under testing
`Phase lll ongoing
`
`Diagnostic imaging agent
`Phase III completed
`
`
`
`
`
`actualdifferent suppliersSeveral PFCs Cell culture media supplements
`
`
`
`Table 2. Atomic Properties of Fluorine in Comparison.
`
`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.
`
`Perfluorocarbons-
`0 are chemically highly inert, as a consequence
`they are physiologically acceptable, too;
`0 dissolve about 20 times more oxygen than
`water does, and even more carbon dioxide;
`0 have very low surface tension allowing them to
`wet any solid surface:
`' are strongly hydrophobic but also oleophobic,
`consequently, they are immiscible with water,
`and very
`limited miscible with oleophilic
`liquids;
`_
`0 are very poor solvents for all but fluorophilic
`solid substances;
`- have specific densities near 2 g/cm5, 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.
`
`0
`
`As basis of any medical use, physiological ac-
`ceptance of a PFC is a precondition. depending
`primarily on its purity only. Therefore, ultra-purifi-
`cation of the PFCs is absolutely necessary.
`Among other specific properties. the high oxygen
`(and carbon dioxide) solubility is most widely em-
`ployed. The Oz-solubility depends partly on mo-
`lecular volume and structure, but it varies not so
`much that its variation have to be taken into con- .
`sideration for a specific medical task (Fig. 7) [8].
`The ability of PFCs to dissolve large amounts of
`oxygen was decisive for their use in “blood substi-
`tutes", for organ preservation, and for liquid venti-
`lation. Unlike to blood, PFCs show a linear rela-
`
` [P [kcal/mol] 21‘, [Ml ru [A] xi,
`
`
`
`
`
`
`H
`313.6
`0.667
`{.20
`2.20
`F
`401.8
`0557
`1.47
`5.98
`CI
`299.0
`2.18
`1.73
`516
`Br
`272.4
`5.05
`1.8:.
`2.96
`
`4.7 1.982412l 2.66
`
`
`
`
`Data taken from Smart BE (1994) Characteristics of C—F
`Systems.
`in: Banks RE. Smart BE, Tatlow JC (ed)
`()rganofluorine Chemistry. Principles and Commercial
`Applications. Plenum Press, New York, London.
`
`Table}. Bond Dissoziation Energies of Ethanes
`
`D°(C-X) lkcal/moll
`cnjcurx
`(:rtcrz-x
`
`
`102.7
`100.1
`
`107.9 12.6.8
`
`x H
`
`F
`
`Data taken as above
`
`going from mono— to perfluorinated compounds.
`Because of the comparatively small size of fluo—
`rine. all hydrogen atoms in an organic molecule
`can be replaced principally by fluorine with the
`molecular structure remaining. Due to the slightly
`greater
`fluorine atoms.
`the resulting perfluoro—
`Compounds are somewhat stiffer than the hydrog-
`enated ones, and their carbon skeleton and with
`that
`their carbon—carbon bonds are completely
`shielded by fluorine. making them less accessible
`to any chemical attack. In summary, PFCs are of
`extraordinary chemical as well as thermal
`resis—
`[HHCC.
`
`

`

` }
`
`l.
`
`May .3". Juno
`
`Hl ROPFAN l()l'R\’;\l. OF MEDICAL RESEARCH
`
`‘
`
`2.13
`
`perfluorocarbon
`
`other liquid
`
`water
`ethanol
`
`benzene
`acetone
`
`2.9
`24.2
`
`22.5
`28
`
`ethyl ether
`
`44.7
`
`t- WNW 40
`l" ' PM
`
`(Kg PH)
`
`[F5
`0
`
`C4“)
`
`FB'fllF
`
`cri—(E-NG}
`FPMCP
`
`45
`
`49
`
`43
`
`r. /\/\/\/‘B,
`PFOB
`
`53
`
`Fig, 7. Oxygen solubility of selected perfluorocarbons
`and some other liquids (mL 01/100 mL liquid at 760
`mmiig 02).
`
`tion between the amount of dissolved oxygen and
`oxygen partial pressure.
`i.e. the solubility follows
`Henry's Law. Oxygen is dissolved physically only,
`there are no specific interactions with the PFC [9].
`On the contrary, due to the very weak intermolec—
`ular interactions in PFCs,
`there is sufficient free
`space between the PFC molecules to be occupied
`by oxygen or other low molecular gases. By the
`way, similar amounts of oxygen can be dissolved
`in, e.g.. diethylether (Fig, 7).
`The very low surface tension of PFCs makes it
`possible that PFCs wet any solid surface even
`polytetrafluoroethylene, Teflon®. However,
`its
`spreading behaviour on surfaces already wetted
`with water as they are within lungs has to be in—
`vestigated experimentally.
`PFCs are practically insoluble in water. Only to
`explain the droplet growth in PFC-in—water emul-
`
`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 PFCLbased oxygen carriers.
`()n the other hand, PFtZs are very limited miscible
`with or soluble in lipophilic liquids. too, depend-
`ing on the nature of the PFC tested as well as of
`the other solvent.
`'l‘he'teniperature 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 I11].
`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 on it as e.g.
`the excretion rate in case of intravascular use.
`in
`
`this respect. n-hexane, olive oil, as well as n-hro-
`moalkanes have been .used as reference liquids
`[12. 15. 14]. The lower the CST the higher the li-
`pophilicity and the higher
`the excretion rate.
`CSTtn—hexane)—values of some typical PFCs are
`shown in Fig. 8 [12. 15].
`remarks concerning
`At
`this point some short
`the emulsification behaviour of PFCs are neces—
`
`sary. if one of [Wu iministible 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.
`The dispersion can be more or less stabilized by
`introducing surface active agents which become
`enriched at
`the liquid—liquid interface.
`ideally,
`such agents should bear in their molecules two
`spatially separated groups, one. e.g., hydrophilic
`and the other, e.g.. fluorophilic as in “fluorosur—
`factants". Such surfactants arrange themselves in
`' the interface in a way that their hydrophilic part is
`orientated towards the water phase and the fluo-
`rophilic (i.e.hydrophobic) one towards the PFC.
`As a result, the free energy of the system can be-
`come that
`low that
`thermodynamically stable
`systems might be formed. eventually, as in case of
`the so—called microemulsions. When stable emul—
`sions have to be made, consisting of water dis-
`persed in PFC (water-in-PFC). special
`fluorosur—
`factants have to be used, whereas PFC-in—water
`
`1--ng FTBA
`
`s9
`
`PFD
`
`22
`
`@‘Q FDMCM 53.3 @[Elfl FMDBD21.2
`
`3
`
`Qoxfio FCOM 44.2 @flu
`
`FMCH
`
`8.2
`
`cr,—®-@ FPMCP
`
`39
`
`F- /\/\/\/‘CI PFOCl
`
`-7.5
`
`,
`
`F- /\/\/\/ PFO
`
`37
`
`F-/\/\/\/‘3, PFOB _24.5
`
`Fig. 8. Critical solution temperatures (CST)
`of selected perfluorcarbons in n-hexane (°C)
`(Data taken in part from [12“,
`
`

`

`.1,4:“..123$;».7;““le
`
`2H
`
`lfl'R()PE;\\ VIOI'RNAI. ()li .\ll{l)l(I:\l. RF‘I‘IARLH
`
`May 35. 1mm
`
`emulsions can also be stabilized by entrapping the
`PF(‘. droplets 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 iluorophilic 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 [HI 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 folded retina at
`the eye‘s background that 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 satne 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 19F imag-
`es have been obtained already HQ].
`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. I).
`Perlluorooctyl bromide ("PF()B" or “Perflubron")
`is the PFC—constituent of a blood substitute intro—
`duced by Alliance Pharmaceuticals, I’SA, which is
`the nowadays most advanced tested one. In accor-
`
`dance with the explanations given above. the bro—
`mine atom in PR )B (see Fig. I) is a weak—point at
`which comparatively easily a chemical attack is
`possible.
`(Iorrespondingly,
`some
`authors
`ljfll
`question the broadly accepted physiological inert—
`ness. As mentioned above. manufacturing of med—
`ical grade PFCs
`is
`a
`laborious task.
`’l'herefore.
`once that a manufacturing line for an ultra—pure
`PFC is implemented. the PFC is 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 narrow limits. One way to extent
`these limits is the introduction of Br- or Cl—atoms
`in the molecule. as in PFOB tperfluon)octylbro—
`mide)
`or
`in
`perfluoro—tu.u)—dichlorooctane).
`Another way to extend these limits is
`in going
`from “true" perfluorocarbons to perfluorocarbon
`derivatives.
`the molecules of which consist of at
`least two different parts. one a fluorocarbon, and
`the other a hydrocarbon, Such compounds are
`known since 1964 [20]. the synthetic route is given
`in Fig. 5. A typical example of these perfluoroal—
`kylalkanes. or so—called RFRH diblock compounds
`is shown in the following.
`
`CF54 CF2 i... -CF_,-CH1-( CH. in-CH.
`
`Surprisingly. such compounds can be physio—
`logically acceptable. too. like PFCs [2”. However.
`in contrast
`to PFCs. because of their structure
`these compounds have 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 corn-
`pounds which fit best for ophthalmology {251 but
`also for emulsification [24]. and which open a
`minor possibility for making solutions of com-
`pounds of medical interest [25].
`
`USE or 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
`method involves greater technical problems to be
`solved.
`In addition to maintaining respiration,
`PFCs are able to replace water or aqueous liquids,
`e.g.
`in case of lung edema. and to inflate an im-
`mature lung in. e.g.. newborn infants.
`
`

`

`May 15. 2mm
`
`El R()PEA;\ l0l’RNAl ()l‘ MEDICAL RE\E:\RCH
`
`Iv
`
`Jl
`
`Concerning the selection of appropriate PFCs.
`the requirements a PFC to be used for 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 blood substitute. too. Despite its general impor—
`tance. gassolubility is not a characteristic to be
`taken into account selecting a PFC because of the
`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 [50, 14]. These carriers transpon the PFC
`to the lung, where it 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 l31l. 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 Lise
`of the large surface of the lung (about 160 ml) 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 [52],
`the problems encoun«
`tered are far from being solved
`
`OUTLOOK
`
`The principal suitability of perflumocarbons and
`related compounds for medical use is known for
`long.
`tip 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.
`llowever.
`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 a\ailable
`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 Rudiger
`institute of Chemistry
`Humboldt-University
`Hessische Str. 1—2
`D—10115 Berlin, Germany
`Phone
`+49 50 2093 7328
`Fax
`+49 30 2093 7277
`e-maii
`stephan-ruedigerachemiehu-berlin.de
`
`