- ..
`
`~OURNA l OF
`
`AND
`
`CLINICAL
`IMMUNOLOGY
`
`VOL. 101, NO. 4, PART 2
`
`APRIL 1998
`
`LANDMARKS I N FLUTICASONE PROPIONATE
`
`APR 2 1 1998
`J51128C~"
`iOI ffaGHtMQ A\1-W== CEN7EII
`•••mu
`·
`
`London, United Kingdom
`February 27, 1997
`
`Guest Editor
`Peter Barnes, DSc, FRCP
`
`Supported by an educational grant from
`Glaxo Wellcome
`
`OFFICIAL PUBLICATION OF THE
`AMERICAN ACADEMY OF ALLERGY,
`ASTHMA AND IMMUNOLOGY
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`Published monthly by
`~T~ Mosby
`
`ISSN 0091-67 49
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`

`

`SUPPLEMENT TO
`
`THE JOURNAL OF
`
`ALLERGY
`
`AND
`
`C LIN ICAL IMMU NOLOGY
`
`VOLUME 101
`
`April 1998
`
`NUMBER 4, PART 2
`
`LANDMARKS IN FLUTICASON E PROPIONATE
`
`London, United Kingdom
`February 27, 1997
`
`Guest Editor
`Peter Barnes, DSc, FRCP
`Department of Thoracic Medicine
`National Heart and Lung Institute
`Imperial College
`London, United Kingdom
`
`Supported by an educational grant from
`Glaxo Wellcome
`
`wesTON Ul"ARY
`APR211998
`
`

`

`SUPPLEMENT TO
`
`THE JOURNAL OF
`
`AND
`
`ALLERGY
`CLINICAL IMMUNOLOGY
`~•,1 Mosby
`
`VOLUME 101
`
`NUMBER 4, PART 2
`
`Copyright © 1998 by Mosby, Inc.
`
`CONTENT S
`April 1998
`
`Landmarks in Fluticasone Propionate
`
`Current issues for establishing inhaled corticosteroids as the
`antiinflammatory agents of choice in asthma
`
`Peter J. Barnes. DSc, FRCP, Londo11, U11ited Kingdom
`
`Development of fluticasone propionate and comparison with
`other inhaled corticosteroids
`
`Malcolm Johnson, PhD, Middlesex. United Kingdom
`
`Pharmacokinetics and pharmacodynamics of inhaled
`corticosteroids
`
`H. D ercndmf, PhD, G. Hochhaus, PhD, B. M eibohm, PhD, H. M ol/nur1111, MD,
`and J. Barth, MD, Gainesville, Fla., a11d Bodwm, Germ111iy
`
`Clinical relevance of inhaled corticosteroids and HPA axis
`suppression
`
`Robert G. Dluh); MD, B osto11, M ass.
`
`Effects of inhaled corticosteroids on growth
`
`Caffie MacKenzie, MD, Sheffield, United Kingdom
`
`S427
`
`S434
`
`S440
`
`S447
`
`S451
`
`Effects of inhaled corticosteroids on bone density and metabolism
`
`S456
`
`Ashley Woodcock, MD, FR CP, Ma11chester. United Kingdom
`
`Relative safety and efficacy of inhaled corticosteroids
`
`S460
`
`Neil Bames, FR CP, Lo11do11. U.K.
`
`. ,,
`Vol, 101, No. 4, Part 1, April 1998. The Joumal of Allagy mu/ Cli11ical fll111111110/0K_1· (ISSN 0091-6749) is published monthly, except semimonthly in
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`Page 2A April 1998
`
`J ALLERGY CUN IMMUNOL
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Development of fluticasone propionate and
`comparison with other inhaled corticosteroids
`
`Malcolm Johnson, PhD Middlesex, United Kingdom
`
`Fluticasone propionate (FP) is a trifluorinated glucocorticoid
`based on the androstane nucleus. It was selected for develop(cid:173)
`ment from structure-activity relationships (topical anti-in(cid:173)
`flammatory, cutaneous vasoconstriction, and hypothalamic(cid:173)
`pituitary-adrenal axis suppression) of a series of 1713•
`carbothioates. FP is 3-, 300-, and 1000-fold more lipophilic
`than beclomethasone dipropionate, budesonide, and triam(cid:173)
`cinolone acetonide, respectively. FP has an absolute affinity
`(K0 ) for the glucocorticoid receptor of 0.5 nmol/L and a rela(cid:173)
`tive receptor affinity 1.5-fold higher than beclomethasone-17-
`monopropionate (17-BMP) and mometasone furoate, 3-fold
`higher than budesonide, and 20-fold higher than flunisolide
`and triamcinolone acetonide. The rate of association of FP
`with the receptor is faster and the rate of dissociation slower
`than other corticosteroids. The resulting half-life of the FP
`active steroid-receptor complex is > 10 hours, compared with
`approximately 5, 7.5, and 4 hours for budesonide, 17-BMP,
`and triamcinolone acetonide, respectively. FP has high selec(cid:173)
`tivity for the glucocorticoid receptor, with little or no activity
`at other steroid receptors. FP is more potent than be(cid:173)
`clomethasone dipropionate, budesonide, triamcinolone ace(cid:173)
`tonide, and mometasone furoate in inhibiting human T-cell
`migration and proliferation, inhibiting CD4+ T-cell cytokine
`and basophil histamine release, attenuating adhesion mole(cid:173)
`cule expression, stimulating inflammatory cell apoptosis, and
`inducing cellular antiprotease release. In asthma patients,
`FP decreases the number of CD3+, CD4+, CDS+, and
`CD25+ T cells, mast cells, and eosinophils in bronchial bi(cid:173)
`opsies, in addition to suppressing CDla-dendritic and lgE+
`cells and HLA-DR. FP, therefore, has a good pharmacologic
`profile for a topical steroid with increased intrinsic glucocor(cid:173)
`ticoid potency and potent anti-inflammatory activity.
`(J Allergy Clin Immunol 1998;101:S434-9.)
`
`Key words: Flwicasone propionate, inhaled corticosteroids,
`strncture-activity relationships, asthma
`
`To exert anti-inflammatory activity, a corticosteroid
`molecule must penetrate the cellular membrane and
`demonstrate affinity for the steroid binding site on the
`glucocorticoid receptor (GR), leading to activation of
`the receptor. 1 Dimerization of the active steroid-recep(cid:173)
`tor complex occurs, and this can then enter the nucleus,
`bind to glucocorticoid-responsive elements on a target
`gene, influence gene transcription, and either inhibit
`proinflammatory or potentiate endogenous anti-inflam(cid:173)
`matory mechanisms. Alternatively, a direct interaction
`
`From International Medical Affairs, Respiratory, Glaxo Wcllcomc Re(cid:173)
`search and Development, Middlesex, United Kingdom.
`Reprint requests: Malcolm Johnson, PhD, International Medical Affairs,
`Respiratory, Glaxo Wcllcomc Research and Development, Stockley
`Park West, Uxbridge, Middlesex, UK, UBI I lBT.
`Copyright © 1998 by Mosby, Inc.
`0091-6749/98 $5.00 + 0 1/0/86611
`
`5434
`
`Abbreviations used
`BDP: Beclomethasone dipropionate
`17-BMP: Beclomethasone-17-monopropionate
`FP:
`Fluticasone propionate
`GR: Glucocorticoid receptor
`GRE: Glucocorticoid-responsive element
`RBA: Relative receptor binding affinity
`
`of the GR complex with transcription factors may also
`be an important determinant of steroid action and a key
`mechanism by which glucocorticoids exert some anti(cid:173)
`inflammatory activity. 1
`The early development of corticosteroids based on the
`structure of cortisol focused on increasing topical po(cid:173)
`tency and improving glucocorticoid selectivity. The first
`structure-activity studies attempted to find compounds
`with greater anti-inflammatory activity. This was
`achieved either by the insertion of an additional double
`bond at the 1,2 position in the ster9id nucleus; by the
`introduction of 6a-fluoro, 6a-methyl, or 9a-fluoro sub(cid:173)
`stituents; or by a combination of these changes (Fig. 1).
`Although anti-inflammatory potency was potentiated,
`mineralocorticoid activity was increased to an even
`greater extent. 2 This effect was counteracted by further
`substitutions with a-hydroxyl, a-methyl, or (3-methyl at
`the 16 position, for example, in dexamethasone (Fig. 1).
`A novel finding was that an ester function at the 16a,
`17a, or 21a hydroxyl grqup was preferred, and this gave
`rise to betamethasone 17-valerate, triamcinolone 16,17-
`acetonide, and beclomethasone-17 ,21-dipropionate. 2
`These compounds have proved to be of value in the
`treatment of the inflammatory component of bronchial
`asthma and rhinitis and have shown little detectable
`systemic activity when delivered by the topical route.
`However, concern that long-term therapy may result in a
`wide range of unacceptable systemic side effects such as
`adrenal suppression, bone fracture, osteoporosis, and
`inhibition of growth in children highlighted the need for
`steroids with a better therapeutic index.
`DEVELOPMENT OF FLUTICASONE PROPIONATE
`The development of fluticasone propionate was an
`attempt to produce a potent corticosteroid that exhib(cid:173)
`ited improved airway selectivity (Table I) compared with
`earlier compounds. Lipophilicity was identified as an
`important physicochemical property for increased up(cid:173)
`take and retention in lung tissue, resulting in enhanced
`lung-systemic distribution and greater affinity for the
`
`

`

`J ALLERGY CUN IMMUNOL
`VOLUME 101 , NUMBER 4, PART 2
`
`Johnson S435
`
`Cortisol
`
`CHpH
`I
`co
`
`OH
`R2
`
`0
`
`y
`
`Dexamethasone
`
`0
`
`Triamcinolone
`
`Bec_Iomethasone
`
`--OH
`
`0
`
`Fluticasone
`
`COSCH2F
`,.ococ2H5
`"
`
`0
`
`I
`I
`F
`
`FIG. 1. Structural modifications of cortisol that produced the corticosteroids: dexamethasone, triamcinolone
`acetonide, beclomethasone dipropionate, and fluticasone propionate.
`
`GR. The androstane nucleus, which is highly lipophilic,
`was therefore selected as the basis of the chemical
`program.3 Topical activity was assessed by inhibition of
`croton oil-induced inflammation of the ear in a mouse
`
`model4 and inhibitory act1v1ty at the hypothalamic(cid:173)
`pituitary-adrenal ( HP A) axis assessed by measuring re(cid:173)
`ductions in circulating corticosteroids in response to
`ether stress.5 The vasoconstriction/skin blanching assay6
`
`

`

`S436 Johnson
`
`J A LLERGY CUN IMMUNOL
`APRIL 1998
`
`O Mcthylprcdnisolonc
`.6. Triamcinolone acetonidc
`y"Budcsonidc
`□ Fluticasone propionate
`
`10
`
`20
`
`. 0
`
`50
`
`40
`Timc (min)
`
`60
`
`70
`
`80
`
`90
`
`2
`
`,
`
`Time {h)
`
`(j
`
`7
`
`9
`
`10
`
`A
`
`:;
`:::,
`§
`5
`,n
`C:
`'6
`C:
`3
`" c:: ·u
`~
`"'
`
`B
`Hrn 9 1
`80
`70
`60
`~ 50
`,n 40
`C:
`'5
`C:
`3
`
`30
`
`<.>
`
`:.J c:: ·u
`0. "'
`
`20
`
`10
`
`FIG. 2. Kinetics of (A) association and (Bl disSO\:iation of methyl(cid:173)
`prednisolone, triamcinolone acetonide, budesonide, and flutica(cid:173)
`sone propionate with the glucocorticoid receptor in human lung
`tissue. Data from references 10 and 14.
`
`was then used to confirm activity in human beings and to
`rank compounds in order of anti-inflammatory potency.
`The androstane 17!3-carbo>.)'lates, which lack the nor(cid:173)
`mal two-carbon side-chain of anti-inflammatory cortico(cid:173)
`steroids at the 17 position, were of particular interest.3
`The 17cx-hydroxyl,17l3-carbo>.)'lic acid was without activ(cid:173)
`ity in the vasoconstriction assay, with esterification being
`necessary for topical activity. Enzymatic hydrolysis of
`either ester function, which can occur in vivo, would
`therefore lead to inactive metabolites. The 17!3-carbox(cid:173)
`ylate series was superseded by the corresponding 1713-
`carbothioates.3 Fluoromethyl analogues were, in gen(cid:173)
`eral, more active than the corresponding chloromethyl
`compounds, with the 17-propionate being preferred over
`the acetate or butyrate; in addition, the presence of an
`cx.-CH3 at posilion 16 reduced HPA axis-suppre sing
`activity (Table II). The most active compound in the
`anti-inflammatory and vasoconstriction tests was the
`6o:,9a-difluoro, l 7a-propionyl, 1713-carbothioate (fluti(cid:173)
`casone propionate), which was approximately 2-fold and
`10-fold more potent than BDP and fluocinolone ace(cid:173)
`tonide, respectively (Table II). Its low activity in inhib-
`
`TABLE I. Criteria for improved airway selectivity
`of corticosteroids
`
`Pharmacodynamics
`• High glucocorticoid receptor affinity
`• Optimal glucocorticoid receptor kinetics
`• High intrinsic steroid potency/high topical anti-inflamma-
`tory activity
`• High glucocorticoid receptor specificity
`Pharmacokinetics
`• Low oral bioavailability
`• Increased uptake/retention in Jung tissue
`• Rapid systemic clearance
`• Extrapulmonary metabolism to inactive metabolite(s)
`• High Jung:systemic distribution ratio
`
`iting HPA axis function resulted from FP undergoing
`complete first-pass metabolism in the liver to the inac(cid:173)
`tive 17!3-carboxylic acid. X-ray crystallography has
`shown that the carbonyl of the 17!3-substituent lies below
`the plane of the ring rather than above it, which is
`observed for other anti-inflammatory steroids. 7 This
`unusual shape, in which the carbothioate ester has
`increased accessibility, may explain why FP readily un(cid:173)
`dergoes enzymatic hydrolysis. FP therefore has a high
`calculated therapeutic index (anti-inflammatory poten(cid:173)
`cy/HPA inhibitory potency) of 91, compared with 0.4
`and 1.0 for BDP and fluocinolone acetonide, respective(cid:173)
`ly.8
`FP is 3 and 300 times more lipophilic than BDP and
`budcsonide, respectively, and > 1000-fold more li(cid:173)
`pophilic than either flunisolide or triamcinolone ace(cid:173)
`tonide.9 This degree of lipophilicity gives FP increased
`deposition in lung tissue and a slower release from the
`lung lipid compartment. In human lung fragments and
`nasal tissue in vitro, uptake and retention of corticoste(cid:173)
`roids is in the rank order FP > BDP > 17-BMP >
`budesonide > flunisolidc > hydrocortisone. 10 • J 1 In pa(cid:173)
`tients with asthma, after inhalation of a 1 mg dose, FP
`exhibits a lung:systcmic distribution ratio of 70 to 100, 12
`compared with previous reports of 7 to 10 for budes(cid:173)
`onide.13
`
`RECEPTOR PHARMACOLOGY
`FP has a high affinity for the human lung GR (0.5
`nmol/L), 14 which is 1.5-fold higher than 17-BMP and
`mometasone furoate, 3-fold higher than budesonide,
`and 1()-fold higher than triamcinolone acetonide and
`flunisolide (Table III). Unlike budesonide, which is a
`racemic mi.,ture of 22R and 22S enantiomers, FP does
`not have a chiral center and therefore the measured
`affinity represents the affinity of the molecule and not
`the contribution of the individual enantiomers. In con(cid:173)
`trast to 17-BMP, the metabolite of BDP that has a
`relative receptor binding affinity (RBA) 5-fold higher
`than the parent molecule, budesonide, with an RBA of
`7.8, undergoes a marked reduction in activity when
`metabolized to either 6-hydroxy-budesonide (RBA =
`0.06) or 16-cx-hydroxy-prednisolone (RBA = 0.03). The
`
`

`

`J ALLERGY CLIN IMMUNOL
`VOLUME 101, NUMBER 4, PART 2
`
`Johnson S437
`
`TABLE II. Structure-activity of halomethyl-androstane-17!3-carbothioate analogues
`
`z
`
`F
`F
`F
`H
`F
`F
`F
`
`y
`
`H
`H
`F
`F
`F
`F
`F
`
`X
`
`CI
`F
`CI
`F
`F
`F
`F
`
`R
`
`C2Hs
`C2Hs
`C1H~
`C2Hs
`CH3
`C3H1
`C2Hs
`
`16
`
`H
`H
`o:CH,
`o:CH3
`t,CH3
`o:CH3
`j3CH3
`
`Topical anti-
`inflammatory
`activity•
`
`HPA
`suppressiont
`
`Cutaneous
`vasoconstriction:l=
`
`20
`63
`56
`113
`76
`55
`197
`
`100
`149
`0.04
`1.0
`2.9
`0.7
`> 100
`
`916
`1984
`124
`945
`392
`299
`1048
`
`Results arc expressed relative to fluocinolonc acetonidc as standard (100). Data from Reference 3.
`''Assessed with the croton oil car assay in micc.4
`tAsscssed with the ether stress assay in rodcnts.5
`tA>sesscd with the skin blanching test in human volunteers."
`§Structure of fluticasonc propionate.
`
`TABLE Ill. Comparison of corticosteroid(cid:173)
`glucocorticoid receptor affinity in human lung and
`potency in the cutaneous vasoconstriction test
`
`Corticosteroid
`
`Fluocinolonc acetonidc
`Bcclomcthasonc-17-
`monopropionatc
`Triamcinolone acctonide
`Flunisolidc
`Momctasonc furoatc
`Budcsonidc
`Fluticasone propionate
`
`Relative
`glucocorticoid
`receptor
`affinity*
`
`Relative
`vasoconstrictor
`activityt
`
`1.0
`3.3
`
`0.5
`0.45
`3.3
`2.5
`5.0
`
`1.0
`2.0
`
`0.4
`0.5
`3.0
`1.5
`5.0
`
`TABLE IV. Corticosteroid-induced inhibition of
`human inflammatory cells
`
`IC50 (nmol/L)
`
`Basophil
`T-cell
`histamine Eosinophil
`T-cell
`IL-5
`release* proliferationt release:l= apoptosis§
`
`7.7
`
`9.8
`
`1.7
`0.3
`
`0.2
`
`10.0
`
`1.0
`
`0.2
`
`().()5
`
`1.0
`
`2().()
`
`0.6
`0.3
`
`0.03
`
`138.7
`
`23.8
`
`8.5
`
`1.7
`
`Corticosteroid
`
`Bcclomcthasonc
`dipropionatc
`Triamcinolone
`acetonidc
`Budcsonidc
`Momctasone
`furoatc
`Fluticasonc pro-
`pinnate
`
`Activities arc quoted relative to tluocinolonc acctonidc as standard (1.0J.
`"Data from Reference 14.
`t Data from Reference 6.
`
`"Data from Rcforcncc 19,
`t Data frnm Reference l S.
`+Data from Reference 20.
`§Data from Reference 21.
`
`17()-carbm.-ylic acid metabolite of FP has negligible
`pharmacologic activity, with an RBA < 0.01 at the GR."
`The rate of association of steroid with the cytosolic GR
`is fastest for FP, followed by budesonide, triamcinolone
`acetonide, and methyl prednisolone (Fig. 2). In contrast,
`the rate of dissociation of FP from the receptor complex
`is slower than that of budesonide, triamcinolone ace(cid:173)
`tonide, dexamethasone, and methyl prednisolone (Fig.
`2).fffhese differences in GR kinetics for FP result in
`differences in the stability of the steroid-receptor com(cid:173)
`plex, which mediates the biologic and therapeutic activ(cid:173)
`ity of glucocorticoids. 1 The half-life of the steroid(cid:173)
`receptor complex for FP is > 10 hours, compared with
`approximately 3.5, 4.0, 5.0, and 7.5 hours for flunisolide,
`triamcinolone acetonide, budesonide, and 17-BMP, re(cid:173)
`spectively.9 FP is highly selective for the GR with < 0.001
`of the relative potency at human androgen; estrogen,
`and mineralocorticoid receptors. 15 The selectivity ratio
`of FP for the GR over the progestagen receptor is 1430,
`compared with 267 and 237 for 17-BMP and budes(cid:173)
`onide, respectively.
`
`ANTI-INFLAMMATORY ACTIVITY
`The steroid receptor profile of FP imparts a high
`topical anti-inflammatory activity. The active FP-GR
`complex binds to the GRE on target genes (EC511 = 3
`nmol/L) or interacts directly with activating protein-1
`and/or nuclear factor-kB transcription factors (EC50
`range 0.01 to 0.1 nmol/L) at significantly lower concen(cid:173)
`trations than either dexamethasone or budesonide. 16
`This has a good correlation with the respective potency
`of FP in inhibiting ORE-dependent cytokine (IL-6, IL-8)
`synthesis (IC5 0 range 5 to 10 nmol/L) and non-GRE(cid:173)
`dependent cytokines such as tumor necrosis factor-a
`(TNFu) and granulocyte-macrophage colony stimulating
`factor (IC50 range 0.01 to 0.1 nmol/L).
`There is also a good correlation between the relative
`affinity of these corticosteroids for the GR and their
`relative potency in a number of intact inflammatory cell
`systems (Table IV). For example, FP is more potent than
`dexamethasone, BDP, and budesonide in inhibiting hu(cid:173)
`man T-ccll migration 17 and proliferation, 1~ with IC50
`
`

`

`S438 Johnson
`
`J ALLERGY CUN IMMUNOL
`APRIL 1998
`
`values of 0.3, 5.9, 2.0, and 0.8 nmol/L. Similarly, anti(cid:173)
`CD3/CD28-induced IL-5 and IL-4 secretion from CD4+
`T cells is inhibited by corticosteroids, with a rank
`order of potency of FP > mometasone furoate >
`budesonide > BDP > triamcinolone acetonide. 19 FP
`inhibits anti-IgE-stimulated histamine release from
`human basophils with an IC50 of 0.03 nmol/L, com(cid:173)
`pared with 0.3, 0.6, 1, and 20 nmol/L for mometasone
`furoate, budesonide, BDP, and triamcinolone ace(cid:173)
`tonide, respectively. 2° Corticosteroids, in the presence
`of IL-5, induce concentration-dependent apoptosis of
`eosinophils, with FP (EC50 = 1.7 nmol/L) being 5
`times more potent than budesonide and approxi(cid:173)
`mately 10 times more potent than triamcinolone
`acetonide and flunisolide. 21 FP is also potent in
`inhibiting cytokine-induced adhesion molecule ex(cid:173)
`pression. At 1 nmol/L, FP inhibits TNFo:-stimulated
`E-selectin in human endothelial cells,22 whereas
`8-fold higher concentrations of budesonide are re(cid:173)
`quired for the same effect. At a concentration of 100
`nmol/L, FP is more effective than budesonide or
`triamcinolone acetonide in inhibiting intracellular ad(cid:173)
`hesion molecule-1 expression in airway epithelial
`cells.23 Finally, Abbin ante-Nissen et al. 24 have shown
`that corticosteroids induce the synthesis of the anti(cid:173)
`protease, secretory
`leukocyte protease
`inhibitor
`(SLPI), in human airway epithelial cells. FP is the
`most potent steroid in inducing SLPI, with an EC50 of
`0.1 nmol/L compared with 1, 5, and 2 nmol/L for
`triamcinolone acetonide, methylprednisolone, and
`dexamethasone, respectively.
`The rank order of affinity of corticosteroids at the GR
`and their anti-inflammatory potency in vivo are similar.
`In the McKenzie test, in which the cutaneous vasocon(cid:173)
`strictor and skin blanching response is used to rank
`anti-inflammatory potency of topical corticosteroids,6
`FP is 1.5-, 2.5-, and 3-fold more potent than 17-BMP,
`mometasone furoate, and budesonide, respectively, and
`10-fold more potent than triamcinolone acetonide and
`flunisolide (Table III). This is in agreement with Dahl(cid:173)
`berg et al.,25 who had previously reported that the RBA
`predicts relative potency for inhibition of edema.
`
`CLINICAL STUDIES
`In patients with asthma, FP treatment (1 mg twice
`daily for 2 months) significantly reduced the numbers of
`mast cells (by 80.2% ), eosinophils (by 93.6% ), and T
`cells (CD3, CD4, CDS, CD25; mean reduction of 86.5%)
`in bronchial biopsy specimens.26 Similarly, the presence
`of dendritic (CDla), IgE+, and HLA-DR+ cells in the
`lamina propria was decreased after FP 1 mg daily for 3
`months,27 suggesting attenuation of antigen recognition,
`processing, and presentation. Finally, FP (500 µ,g twice
`daily for 8 weeks) results in a marked decrease in the
`bronchoalveolar lavage levels of metalloprotease and an
`increase in the concentration of the endogenous tissue
`inhibitor of metalloproteases (TIMPS),28 both of which
`have been implicated in matrix protein deposition and
`basement membrane thickening. FP, therefore, has good
`
`activity against the chronic inflammatory component of
`bronchial asthma and may attenuate the degree of
`airway remodeling.
`The development of FP has resulted in a corticoste(cid:173)
`roid molecule with increased intrinsic glucocorticoid
`potency and potent anti-inflammatory activity, coupled
`with improved airway selectivity.29 FP is of considerable
`clinical importance in the treatment of asthma and
`rhinitis.
`
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