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`JANSSEN EXHIBIT 2088
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`JANSSEN EXHIBIT 2088
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`
`
`Principles and PractiCe of
`ENDOCRINOLOGY
`
`.
`w
`AND
`METAB OLISM
`
`THIRD EDITION
`
`A v E
`
`DITOR
`Kenneth L. Becker
`
`ASSOCIATE EDITORS
`John P. Bilezikian
`William]. Bremner
`Wellington Hung
`C. Ronald Kahn
`
`D. Lynn Loriaux
`Eric S. Nylén
`Robert W. Rebar
`
`Gary L. Robertson
`Richard H. Snider, Jr.
`Leonard Wartofsky
`With 330 Contributors
`
`$429 LlPPlNCOTT WILLIAMS 8 WILKINS
`
`V A Wolters Kluwer Company
`Philadelphia - Baltimore - New York - London
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`Printed in the USA
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`___’__—_____._._——_—h
`Library of Congress Cataloging-in-l’ublication Data
`
`.
`.
`s.
`,
`Principles and practice of endocrinology and metabolism / editor, Kenneth [ Becker .
`associate editors, John P. Bilezikian
`[et al.].--3rd ed.
`P‘ ,‘ cm.
`Includes bibliographical references and index.
`ISBN 07817-17505
`1. Endocrinology. 2. Endocrine glai'ids-ADiseases. 3. Metabolism--Disorders. l. Becker,
`Kenneth L.
`{DNLM1 l. Endocrine Diseases. 2. Metabolic Diseases. WK 100 P957 2000]
`RCr’H/‘i .l’h7 2000
`h l (Mr—dd l
`
`00-022095
`fl
`
`Care {we been taken to confirm the accuracy of the information presented and to
`rally accepted practices. However, the authors, editors, and publisher are
`describe gene
`not regpmhfiale for errors or omissions or for any consequences from application of the
`information in this bool; and make no warranty, expressed or implied, with respect to
`completeness, or accuracy of the contents of the publication. Application
`the currency,
`a particular situation remains the professional responsibilitv of
`of this information in
`
`the practitioner.
`The authors, editors, and PUbli>lwr have exerted everv effort to ensure that drug
`selection and dosage set forth in this text are in accordance with current recommenda—
`tions and practice at the time of publication. However, in view of ongoing research
`7
`.
`4
`i
`changes in government regulations, and the constant flow of information relating to
`drug therapy and drug reactions, the reader is urged to check the package insert for each
`drug for any change in indications and dosage and for added warnings and precautions.
`lhis is particularly important when the recommended agent is a new or infrequently
`employed drug.
`I
`"'
`'
`"’
`'
`Somedru’siil
`Administrmgh}Ehrlicdlical dc\ lgth lprcscnted in this publication have lood and Drug
`bi
`I )ccarance or united use in restricted research settings. It is the
`rcsponsi ‘1 it} of health care providers to ascertain the FDA status of each drug or device
`planned for use in their clinical practice.
`
`10987654321
`
`

`

`70.
`
`71.
`
`73.
`
`74.
`
`.
`
`76.
`
`77.
`
`78.
`
`79.
`
`80.
`
`81.
`
`tions causing steroid 21—hydroxy1ase deficiency. l’roc Natl Acad Sci U S A
`1988;831:4436.
`OWerbaeh D, Crawford YM, Draznin MB. Direct analysis of CYPZIB genes
`in 21-hydroxyiase deficiency using polymerase chain reaction amplifica-
`tion. Mol Endocrinol 1990; 4:125.
`Mornet E, Crete l’, Kuttenn F, et a1. Distribution of deletions and seven
`point mutations on CY1‘2113 genes in three clinical forms of steroid 21-
`hydroxylase deficiency. Am J Hum Genet 1991; 48:79.
`. Higashi Y, Hiroinasa '1', Tanae A, et al. Effects of individual mutations in the
`I’-450(C21) pseudogene on the I’-450(C21) activity and their distribution‘in
`the patient genomes of congenital steroid 21-hydroxylase defiCiency. I 1310-
`chem 1991; 1091638.
`‘
`Speiser l’W, Dupont I, Zhu D, et al. Disease express‘ion and molecular
`genotype in Congenital adrenal hyperplasia due to 21-hydroxy1ase defi-
`ciency. I Clin Invest 1992; 90:584.
`‘
`_
`7
`Wedell A, 'I'hilen A, Ritzen EM, et a1. Mutational spectrum of the sterOid 21—
`hydroxylase gene in Sweden: implications for-genetic diagnosis and assOCia-
`tioii with disease manifestation.) Clin Endocrinol Metab 1994; 7821145.
`lligashi Y, Tanae A, tnoue 11, et al. Aberrant splicing and missense muta-
`tions cause steroid 21-hydroxylase [l’»415()(C21)] deficiency (in humans: pos—
`sible gene conversion products. Proc Natl ACfld-SCI U S A 1)88; 83.7486.
`‘
`'l'usie-Luna M'l', 'l‘raktinan 1’, White RC. Determination of functional effects
`of imitations in the steroid 21-hydroxy(1§s7c;)glegie (CYI‘ZI) usmg recombi-
`m“ H ‘
`‘
`’z
`7'
`Biol Chem 1990; 27 :_
`.
`.
`.
`'l'usitetUiiiirri‘lMifirSltliser l’W, Dumic M, et al. A mutation (Pro-30(t‘ofheu) in
`CYI’ZI represents a potential iioiiclassic sterOid 21—hydr0xy1ase
`c ic1ency
`allele. Mol Endocrinol 1991; 5:685.
`al. Effects of individual mutations in the
`Higashi Y, I'liromasa '1‘, 'l'anae A, et—
`(C21) activity and their distribution in
`l’—450(C21) pseudogene on the R450
`‘
`d 21-hydroxy1ase deficiency. I Bio-
`the patient genomes of congenital steroi
`chem (Tokyo) 1991; 109:638.
`C Winter ISD. lntraadrenal steroid con—
`Dickei'man Z, Grant DR, Faiman
`nces and developmental changes. I Clin
`centrations in man: zonal differe
`E 1
`.
`Hb198-1;59:1031.
`g
`.
`Y
`1611;851:1131: Itidlaijlc S, vlamis-Gflrdik‘” A, et al. Naturally occurring
`mutants of human steroid 21-hydrox‘y1ase (l’450c2‘1) pjgfpogggiglegadues
`important for enzyme activity and stability-1 BIO] Chem _
`I} t‘r
`ln-
`Mornet It Dupont J Vitek A, White PC. Characterizaticga pay 0 81(982;
`eiicodingqluiinan steroid llii-hydroxylase (P430 11131 1
`10
`em
`.
`264:20961.
`g of cDNA encoding steroid 1113-
`. Chua SC, Szabo 1’; Vitt‘k A, or al. Clonin
`a
`1 Sci U S A 1987; 8427193.
`hydroxylase (1’450C11
`)‘ I’FOC NM] AC“ al. Cloning of cDNA and genomic
`. Kawamoto '1‘, Mitsuuclii Y, TOdd K, 0‘
`‘
`‘
`»' "
`LFEBS Lett1990;269:345.
`DNA for human cyt
`OChmmL P 430“!
`al. Cloning and expression of a
`. Kawamoto '1', Mitsuuchi Y, 0111115111 1’ et
`CDNA for human cytochrome l’-450aldos as related to primary aldoste.
`.
`.
`,.
`~
`990; 1731309.
`ronisin. Biochem Biopliys Res CommUIt1 it al. The product of the CYPllBZ
`. Ciirnow KM, 'I'usie-Luna M'l', l’ascoe
`hesis in the human adrenal cortex.
`gene is required for aldosterone biosyitt
`Mol Endocrinol 1991; 521513.
`et al. Molecular biology of llB—hydroxy-
`White l’C, l’ascoe L, Curnoyv KM
`, .
`I
`nase enzymes. I Steroid Biochem
`lase and 11Ii—liydroxysteroid dehydrogc
`£101 Bid iifizéfjtfirl Vitgk I, et al. Mutations in the CYl’llBl gene caus-
`urnow
`,
`-
`4/
`f,
`l
`r
`d “.1 l
`7
`1
`tr. 5 (1 £1
`ny
`$1011 cluste 111 LXOIIS 6,
`7
`1
`i
`l
`1
`ill
`I
`(111 1’Iltll
`r
`.
`“5C0” C
`'
`'L
`11
`>110}
`“
`' A 1993; 90:4552.
`.
`”V319? iwCOCDNAwttlinxtcfuNilirlléil et al. /\ mutation in CYI’llBl (AIS-448—>His)
`’
`lit
`.
`.
`‘1 L‘
`,
`associated with steroid 1113‘hydmxyhsc deficiency m Iews Of Moroccan
`origin. I Clin invest 1991';'S71:\/11'6t§fiiiclii
`Y, et al. A nonsense mutation
`l
`v
`)
`)
`i
`gig?llfll'Alngiiiiillmin IICYl‘llth1 causes steroid lip-hydroxylase 999‘
`.
`.
`.,
`1993;77-1677-
`ctency.] C11“ Endfiinii‘otli Nikifiljr R. Frame shift by insertion (if 2 basebairs
`llelinberglA, [linng’rltIBl/caiises congenital adrenal hyperplasia due—to ster-
`111‘COL10n 3M 014x tise deficiency. 1 Clin Endocrinol Metab 1))_; 7311278..
`old 11 beta—liycu Y? M Ogawa 1’1, [garashi Y. Missense mutation 1n
`flingim‘gcé {[13:31 1]_I>GG/\lGl)’1) Causes steroid 11 beta—hydroxylase
`V
`’llBl
`‘1’
`’
`r" A
`‘
`99’; 132286.
`deficiency lair] Endilcfiiifiial Kfet al. Classic steroid 11 belit'hydranlase
`Ylmf1g LXI hid“ fi/lglli‘C;>G transvei‘sion in CXOH 7 0f CYI’llBL Blochern
`L e iciency cause
`r
`r‘ 7 (.723
`Biophys Res COT"idlilzylifigtwkjlei.al. CYI’t 1 Bl mutations causing 691180“;tal
`9?le iltKyiftLiISiisii due to 11 beta-hydroxylase defICiency.
`I C11“ En 0.
`M rum 1
`.
`t. .
`Cl‘inol Metab 1996; 812(2318‘:6.l n A C
`t '11 Novel CYI’llBl mutations in con—
`M “‘10 D1’,
`'l‘a'iina 1, Ha i
`t
`,
`‘
`‘1 .
`.
`beta-hydroxylase deficiency.
`geLnittil adrentlil liyperplasia due l;)7:)ll.101d 11
`J Clin Endocrinol Metab1998,83...k E
`M et al. CYl’llBl mutations causing
`JOehrer K, Geley S, Strasser—Wozaduc m 11
`I
`beta-hydi'oxylase deficiency.
`.
`.
`.
`’2‘ .
`-
`non-classic adrenal
`liyperplasia
`idium MOI lifi’ii‘idififdiiidd I, Chung B—C, et al. Assignment of the gene
`atteson
`,
`*
`01‘ ac rena
`.
`f
`i
`1 “ch (steroid 17(1-hydroxy1ase/17,20—lyase) to human chro-
`'
`.
`V
`.
`i
`9
`‘
`~
`1 crinol Metab 1986, 63.78 .
`_
`Zimmiilg' Jl’iCC‘l'13(E:—11:(C::11111'L1 I, l'laniu M, et al. Cytochrome l’430c17 (ster—
`-
`’
`‘
`‘
`r
`fliuinan adrenal and testis
`iung -
`,
`t
`‘
`.
`' x Lise/17,20 lyasc). cloning o
`‘
`‘
`V
`,
`c
`S
`t
`.
`oiéiNl/Zuiliilli‘iidftc): the WWW 21,9110 15‘ L‘XPTL‘SSt‘d in both tissues.
`l‘roi; \atl
`,
`~
`.‘
`S ’\ 1987; 84:407.
`3081?? l1J\lagashiina '1', Noinura Y, et al. A. A new tompound l11.9.1311‘11'1'fe'lt‘tllx
`
`86.
`
`87.
`
`88.
`
`89.
`
`90,
`
`91.
`
`97
`
`93.
`
`94.
`
`95.
`
`96.
`
`97.
`
`98.
`
`Ch. 78: Corticosteroid Therapy
`
`751
`
`99.
`
`mutation (W17X, 436 + 5G—>T) in the cytochrome l’450cl7 gene causes 17 alpha-
`hydroxylase/ 17,20-lyase deficiency. I Clin Endocrinol Metab 1998; 83:199.
`Lachance Y, Luu-The V, Labrie C, et al. Characterization of human 38-
`hydroxysteroid dehydrog,eiiase/A5-AI isornerase gene and its expression in
`mammalian cells] Biol Chem 1990; 26520469.
`. Lorence MC, Corbin CI, Kamimura N, et al. Structural analysis of the gene
`encoding human 3B-hydroxysteroid dehydrogenase/A5”“-isomerase. Mol
`Endocrinol 1990; 411850.
`Lachance Y, Luu—The V, Verreault H, et al. Structure of the human type II
`313—hydroxysteroid deliydrogenase/AR-A‘ isomerase (SB-HSD) gene: adre—
`nal and gonadal specificity. DNA Cell Biol 1991; 10:701.
`. Berube D, Luuil‘he V, Lachance Y, et al. Assignment of the human 313-HSD
`gene to the p13 band of chromosome 1. Cytogenet Cell Genet 1989; 52:199.
`. McCartin S, Russell A], Fisher RA, et al. l’henotypic variability and origins
`of mutations, in the gene encoding 3ti—hydroxysteroid dehydrogenase type
`11. Mol Endocrinol 2000; 24:75.
`. Rheaume E, Simard I, Morel Y, et a1. Congenital adrenal hyperplasia due to
`point mutations in the type 11 3B—hydroxysteroid dehydrogenase gene.
`Nature 1992; 1:239.
`. Chang YT, Kappy MS, lwamoto K, et al. Mutations in the type 11 3 beta-
`hydroxysteroid dehydrogenase (3 beta-HSD) gene in a patient with classic
`salt-wasting 3 beta-HSD deficiency congenital adrenal hyperplasia. Pediatr
`Res 1993; 34:698.
`. Simard I, Rlieaume E, Sanchez R, et al. Molecular basis of congenital adre-
`nal hyperplasia due to 3134iydroxysteroid dehydrogenase deficiency. Mol
`Endocrinol 1993; 7:716.
`. Sakkal-Alkaddour H, Zhang L, Yang X, et a1. Studies of 3 beta-hydroxy-
`steroid dehydrogenase genes in infants and children manifesting premature
`pubarche and increased adrenocorticotropin-stimulated delta 5-steroid lev—
`els.IC1in Endocrinol Metab 1996; 8123961.
`Chung BC, Matteson K], Voutilainen R, et al. Human cholesterol side-chain
`cleavage enzyme, I’450scc: cDNA cloning, assignment of the gene to chromo-
`some 15, and expression in the placenta. l’roc Natl Acad Sci U S A 1986; 8328962.
`Lin D, Gitelman SE, Saenger 1’, Miller WL. Normal genes for the cholesterol
`side chain cleavage enzyme, P450ssc, in congenital lipoid adrenal hyper-
`plasia. I Clin Invest 1991; 8811955.
`Miller WL. Congenital lipoid adrenal hyperplasia: the human gene knockout
`for the steroidogenic acute regulatory protein. I Mol Endocrinol 1997; 19:227.
`Ulick S, Wang IZ, Morton DH. 'llie biochemical phenotypes of two inborn
`errors in the biosynthesis of aldosterone. I Clin Endocrinol Metab 1992; 74:1415.
`Harada N, Ogawa H, Shozu M, Yamada K. Genetic studies to characterize
`the origin of the mutation in placental arornatase deficiency. Am I Hum
`Genet 1992; 51:666.
`lto Y, Fisher CR, Conte FA, et al. Molecular basis of aromatase deficiency in
`an adult female with sexual infantilism and polycystic ovaries. Proc Natl
`Acad Sci U S A1993; 90311673.
`Simpson ER, Zhao Y, Agarwal VR, et al. Aromatase expression in health
`and disease. Recent l’rog Horm Res 1997; 52:185.
`Eckstein 8, Cohen S, Farkas A, Rosier A. The nature of the defect in familial
`male pseudohermaphroditisin in Arabs of Gaza. I Clin Endocrinol Metab
`1989; 68:477.
`Rosier A, Belanger A, Labrie F. Mechanisms of androgen production in
`male pseudohermaphroditisin due to 17 beta«hydroxysteroid dehydroge-
`nase deficiency. I Clin Endocrinol Metab 1992; 75:773.
`Castro—Magana M, Angulo M, Uy I. Male hypogonadism with gynecomas—
`tia caused by late-onset deficiency of testicular 17»ketoster0id reductase.
`N Engl I Med 1993; 32821297.
`.
`4
`Pang S, Softness B, Sweeney WI, New Ml. Hirsutism, polycystic ovarian
`disease, and ovarian l7-ketosteroid reductase defiCiency. N Engl .1 MQd
`1987; 316: 1295.
`.
`.
`Andersson S, Moghrabi N. Physiology and molecular genetics of 17 bem-
`hydroxysteroid dehydrogenases. Steroids 1997; 621‘143-
`_
`‘
`.
`‘
`‘ ‘nse
`Moghrabi N, Hughes IA, Dunaif A, Andersson S. Deleteriouzmisscmr—
`mutations and silent polymorphism in the human 17b-etaihhyl‘pigy15998-
`oid dehydrogenase 3 gene (HSD17B31 1 C11“ EndOCI'an
`L a
`’
`iii-1313:; IA, Seely EW, Hurwitz S, et al. G1ucdcorticoid-reinediable aldos-
`teronism and pregnancy. Hypertension 2000; 35:666.
`
`107.
`
`108.
`
`109.
`
`110.
`
`111.
`
`.
`
`113.
`
`114.
`
`115.
`
`116.
`
`117.
`
`118.
`
`119.
`
`120.
`
`
`
`C H A P T E R 7 8
`
`
`CORTICOSTEROID THERAPY
`
`LLOYD AXELROD
`
`This chapter examines the risks associated with the use of glu-
`cocorticoids and of mineralocorticoids for various illnesses, and
`provides guidelines for the administration of these commonly
`prescribed substances.
`
`

`

`752
`
`PART V: THE ADRENAL GLANDS
`
`CH,OH
`
`
`
`CORTISOL
`(HYDROCORTISONE)
`
`CH,OH
`0:0
`
`-OH
`
`HO
`
`PREDNISOLONE
`
`CH3.
`METHYL PREDNISOLONE
`
`FIGURE 78-1. The structures of
`commonly used glucocorticoids.
`In the depiction of cortisol, the
`21 carbon atoms of the glucocor-
`ticoid skeleton are indicated by
`numbers and the four rings are
`designated by letters. The arrows
`indicate the structural differ-
`ences between cortisol and each
`of the other molecules.
`(From
`Axelrod L. Glucocorticoid ther-
`apy. Medicine [Baltimore] 1976;
`55:39, and Axelrod L. Glucocor-
`ticoids.
`In: Kelley WN, Harris
`ED Jr, Ruddy S, Sledge CB, eds.
`Textbook of rheumatology, 4th
`ed. Philadelphia: WB Saunders,
`1993:779.)
`
`GLUCOCORTICOIDS
`
`CH,OH
`=O
`
`IC
`
`—OH
`
`J
`
`CH,OH
`I __
`0’0
`—OH
`
`.
`
`CO RTISONE
`
`PREDNISONE
`
`DEXAMETHASONE
`
`.
`'
`,
`1
`.
`-
`circulation is in the range of 80 to 115'm1nutes. The Tm? of
`other commonly used agents are cortisone, 0.5 hours, pled-
`nisone, 3.4 to 3.8 hours; prednisolone, 2.1 to 3.5 hours; methyl-
`Pl‘ednisolone, 1.3 to 3.1 hours,- and dexamethasone 1.8 to 4.7
`and dexamethasone have comparable
`hourslm I’rednisolone
`s clearly more potent.
`circulating Tms, but dexamethasone ‘
`]
`t' YT
`f
`)1
`_
`Similarly, the correlation between the c1rcu a 1m,
`1/2 0 a b u
`cocorticoid and its duration ofactioa is poor. The many alctjtgis of
`glucocorticoids do not have an equal duration, anc tic ura-
`tion of action ma be a function of the dose.
`.-
`.
`The duration if ACTH suppression Is not sunply a function
`of the level of antiinflammatory activity, 138981159 Val‘mtlonf 111
`the duration of ACTH suppressionnare achleved by'dosesnof
`glucocorticoids with comparable antnnflammatorYFCIII’lt}? 4‘9
`duration of ACTH suppression produced by an mt 1"“ ua ta 11'
`.
`.
`-.
`»
`,
`d5"
`cocort1c01d, however, probably is dose relate
`
`.i
`
`TABLE 78-1.
`
`Commonly Used Glucocorticoids
`co-
`GI“
`orticoid
`T’otencyl
`
`Duration of Action"
`
`.
`.
`Glucocorticmd
`Dose (mg)
`
`.
`.
`cortrcoxd
`.
`.
`ACIIV'I)’
`
`SHORT-ACTING
`Cortisol (hydrocortisonc)
`Cortisone
`I’rednisone
`Prednisolone
`Methylprednisolone
`INTERMEDIATE-ACTING
`'I'riamcinolone
`
`1
`0’8
`‘1
`4
`5
`
`5
`
`7
`”9
`ED
`3
`3
`4
`4
`
`yes:
`Yest
`Na
`No
`No
`
`No
`
`No
`LONG-ACTING
`No
`Betamethasone
`25
`069
`Dexamethasone
`30
`0'73
`arter G. Corticosteroids. NY
`,
`.
`.
`.
`J
`”The classification by duration ofaction is timid 0“ H
`» Cortisol is arbitrarily
`,
`'
`_
`.
`H‘L‘ n-latiu.
`State] Med 1966;66:827.
`4
`.
`pothcy «
`’The values given for glucocorticmd
`’\t 1050‘- ('IOSL‘ to or within the basal
`l
`assigned a value of 1.
`iMineralocorticoid effects are dose rCIdIL‘ .
`r
`:lreffect may be detectable.
`physiologic range for glucocorticoid actn'ity, no huf\,1pdicim’iH‘lltimmcl 197655239;
`(Data from Axelrod L. Glucocorticoid them?” n iblatt DI’ eds. Handbook OI drug
`Axelrod L. Adrenal (-()rtic()§ICT(IiL{5' In: Miller Rlx, (virtU 1 \xelmd L. Cilucocorticoids.
`therapy. New York: Iilsevier North-I lolland. 1‘)792m)",‘.m,tlt
`)k Uf rheumatology, 4th ed,
`In: Kelley WN, I IarristDJr, Ruddy S, Sledge CB, eds, Iext KM
`Philadelphia: WB Saunders, 19932779.)
`\f—
`
`STRUCTURE OF COMMONLY USED GLUCOCORTICOIDS
`
`Figure 78-1 indicates the structures of several commonly used
`glucocorticoids.L2 Cortisol (In/drawrtisoae) is the principal circu-
`lating glucocorticoid in humans.
`Glucocorticoid activity requires a hydroxyl group at carbon
`11 of the steroid molecule. Cortisone and prednisone are 11-
`keto compounds. Consequently, they lack glucocorticoid activ-
`ity until they are converted in vivo to cortisol and prednisolone,
`the corresponding 11-hydroxyl compounds.“ This conversion
`occurs predominantly in the liver. Thus, topical application of
`cortisone is ineffective in the treatment of dermatologic dis-
`eases that respond to topical application of cortisol." Similarly,
`the antiinflammatory action of cortisone delivered by intraartic-
`ular injection is minimal compared with the effect of cortisol
`administered in the same manner.3 Cortisone and prednisone
`are used only for systemic therapy. All glucocorticoid prepara-
`tions marketed for topical or local use are 11-hydroxyl com-
`pounds, which obviates the need for biotransformation.
`
`PHARMACODYNAMICS
`
`HALF-LIFE, POTENCY, AND DURATION OF ACTION
`
`The important differences among the systemically used gluco~
`Corticoid compounds are duration of action, relative glucocorti-
`coid potency, and relative mineralocorticoid potency (Table
`78-1)?2 The commonly used glucocorticoids are classified as
`short-acting,
`intc’riMediate—acting, and long-acting on the basis of
`the duration of corticotropin (ACTH) suppression after a single
`dose, equivalent in antiinflammatory activity to 50 mg of pred-
`nlsone (Table 78-1).; The relative potencies of the glucocor-
`t1cords correlate with their affinities
`for
`the intracellular
`glucocorticoid receptor.“ The observed potency of a glucocorti-
`c01d, however, is determined not only by the intrinsic biologic
`potency, but also by the duration of action.” Consequently, the
`relative potency of two glucocorticoids varies as a function of
`the time interval between the administration of the two steroids
`and the determination of the potency. In particular, failure to
`account for the duration of action may lead to a marked under-
`estimation of the potency of dexamethasone.7
`The correlation between the circulating half—life (Tl/2) of a glu-
`cocorticoid and its potency is weak. The T1 /2 of cortisol in the
`
`

`

`In short, the slight differences in the circulating T1/25 of the glu-
`Cocorticoids contrast with their marked differences in potency and
`duration of ACTH suppression. Thus, the duration of action of a
`glllcocorticoid is not determined by its presence in the Circulation.
`This is consistent with the mechanism of action of sterOid hor-
`mones. A steroid molecule binds to a specific intracellular receptor
`protein (see Chap. 4). This steroid-receptor complex modifies tple
`Process of transcription by which RNA is transcribed from t .e
`DNA template. This process alters the rate of synthesis of specific
`Proteins. The steroid thereby modifies the phenotypic expression
`0f the genetic information. Thus, the glucocorticoid continues to act
`inSide the cell after it has disappeared from the Circulation. More-
`over, the events initiated by the glucocortICOid may continue to
`occur, or a product of these events (such as a spec1f1c protein) may
`be present after the disappearance of the glucocorticoid.
`
`BIOAVAILABILITY, ABSORPTION, AND BIOTRANSFORMATION
`Normally, a person's plasma cortisol level is much lower after
`the oral administration of cortisone than after an equal dose of
`cortisol.9 Consequently, although oral cortisone mfay be ad:-
`quate replacement therapy in chronic adrenal insuf ic1ency,1
`e
`oral form of this agent should not be used when larger, pliar
`inacologic effects are sought. Comparable plasma pre niso one
`leVels are achieved in normal persons after equivalent. ora
`dOses of prednisone and prednisolone.” After the administra-
`tiofi 0f either of these corticosteroids, however, there is vyIidfi
`variation in individual prednisolope concentrations, w 1C
`ma refl
`'
`i it
`in absor tion.
`‘
`lyn cofiffa::lt:tlflfe ilriarked ri§es that follow the intramuscular
`inlection of hydrocortisone, plasma'cortisol levels rise little pr
`“0t at all after an intramuscular injection of cortisone aceta e.
`When it is given intramuscularly, cortisone acetate does;31not pro-
`Vide adequate plasma cortisol levels and offers npl a var; age
`over hydrocortisone delivered by the same route.
`Te exp arc?
`tiOn for the failure of intramuscular cortisone acetate to prov1 e
`adeqllate plasma cortisol levels is unknown: It may reflect polor
`abSOFPtion from the Site of injection. Alternatively, intlramuscu ar
`cortisone acetate, which reaches the liver throqjgl} tiesycstlelrrg:
`circulation, may be metabolically inactivated e1 ore '1‘
`c
`_
`COrlVerted to cortisol in the liver, in contrast to ora cortisone ace
`tate, Which reaches the liver through the portal Circulation.
`
`PLASMA TRANSPORT PROTEINS
`
`ations occur in the capacity of
`.
`.
`ns circadian fluctu
`In “0
`ortin) to bind cortisol and
`rmal huma
`I
`‘
`.
`,
`corticosteroid-binding globulin (transc
`prednisolone. Patients who have been treated With prednisone
`for a prolonged period have no diurnal variation in thle blndlrlig
`capacity of corticosteroid-binding globulin for cortiso. or prefi—
`nisolone, and both capacities are reduced in comparison W111
`normal persons. Thus, long—term glucocorticmd therapyfpot onhy
`alters the endogenous secretion of sterOIds, but also aT1e'CtS t e
`transport of some glucocorticoids in the Circulation.
`115 .rgay
`explain why the disappearance of prednisolone is more rzpi m
`t1‘03e persons who have previously received glucocorticm s,
`
`GLUCOCORTICOID THERAPY
`IN THE PRESENCE OF LIVER DISEASE
`Plasma cortisol levels are normal in patients with hepatic disease.
`Although the clearance of cortisol is reduced in patiepts w1t its;
`rhosis,
`the hypothalamic-pituitary—adrenal (HIA)
`ioigeostc
`f
`mechanism remains intact. Consequently, the decrease
`ra te‘ o1
`metabolism is accompanied by decreased synthesis of cor iso
`see Cha .205.
`.
`.
`.
`.
`( The canverlion of prednisone to prednisolone is impaired in
`patients with active liver disease.11 This is largely offset by a
`decreased rate of elimination of prednisolone from the plasma
`in these patients.11 In patients with liver disease, the plasma
`availability of prednisolone is quite variable after oral doses of
`
`Ch. 78: Corticosteroid Therapy
`
`753
`
`either prednisone or prednisolone.12 This is further complicated
`by the lower percentage of plasma prednisolone that is bound
`to protein in patients with active liver disease; the unbound
`fraction is inversely related to the serum albumin concentra—
`tion. An increased frequency of prednisone side effects is
`observed at low serum albumin levels.12 Both these findings
`may reflect impaired hepatic function. Because the impairment
`of conversion of prednisone to prednisolone is quantitatively
`small
`in the presence of liver disease and is offset by a
`decreased rate of clearance of prednisolone, and because of the
`marked variability in plasma prednisolone levels after the
`administration of either corticosteroid, there is no clear man-
`date to use prednisolone rather than prednisone in patients
`with active liver disease or cirrhosis.8 If prednisone or pred-
`nisolone is used, however, a somewhat lower than usual dose
`should be given if the serum albumin level is low.8
`
`GLUCOCORTICOID THERAPY
`AND THE NEPHROTIC SYNDROME
`
`When hypoalbuminemia is caused by the nephrotic syndrome,
`the fraction of prednisolone that is protein bound is decreased.
`The unbound fraction is inversely related to the serum albumin
`concentration. The unbound prednisolone concentration remains
`normal, however.l3l14 Because the pharmacologic effect is deter-
`mined by the unbound concentration, altered prednisolone
`kinetics do not explain the increased frequency of predniso-
`lone-related side effects in these patients.
`
`GLUCOCORTICOID THERAPY
`AND HYPERTHYROIDISM
`
`The bioavailability of prednisolone after an oral dose of pred-
`nisone is reduced in patients with hyperthyroidism because of
`decreased absorption of prednisone and increased hepatic
`clearance of prednisolone.”
`
`GLUCOCORTICOIDS DURING PREGNANCY
`
`Glucocorticoid therapy is well tolerated in pregnancy.16 Gluco-
`corticoids cross the placenta, but there is no compelling evi-
`dence that this produces clinically significant HPA suppression
`or Cushing syndrome in neonates,16 although subnormal
`responsiveness to exogenous ACTH may occur. Similarly, there
`is no evidence that glucocorticoids increase the incidence of
`congenital defects in humans.16 Glucocorticoids do appear to
`decrease the birth weight of full—term infants; the long-term
`consequences of this are unknown. Because the concentrations
`of prednisone and prednisolone in breast milk are. low, the
`administration of these drugs to the mother of a nursmg infant
`is unlikely to produce deleterious effects in the infant.
`
`GLUCOCORTICOID THERAPY AND AGE
`
`and methylprednisolone
`of prednisolone
`clearance
`The
`decreases with age.17/15 Despite the higher prednisolone levels
`seen in elderly subjects compared with young subiects after com-
`parable doses, endogenous plasma cortisol levels are suppressed
`to a lesser extent in the elderly.17 These findings may be associ-
`ated with an increased incidence of side effects and suggest the
`need to use smaller doses in the elderly than in young patients.
`
`DRUG INTERACTIONS
`
`The concomitant use of medications can alter the effectiveness
`of glucocorticoids; the reverse also is true.‘9
`
`EFFECTS OF OTHER MEDICATIONS ON GLUCOCORTICOIDS
`
`The metabolism of glucocorticoids is accelerated by substances
`that induce hepatic microsomal enzyme activity, such as pheny-
`
`

`

`754
`
`PART V: THE ADRENAL GLANDS
`
`toin, barbiturates, and rifampin. The administration of these medi-
`cations can increase the corticosteroid requirements of patients
`with adrenal insufficiency or lead to deterioration in the condi-
`tions of patients whose underlying disorders are well controlled
`by glucocorticoid therapy. These substances should be avoided in
`patients receiving corticosteroids. Diazepam does not alter the
`metabolism of glucocorticoids and is preferable to barbiturates in
`this setting. If drugs that induce hepatic microsomal enzyme activ-
`ity must be used in patients taking corticosteroids, an increase in
`the required dose of corticosteroids should be anticipated.
`Conversely, ketoconazole increases the bioavailability of large
`doses of prednisolone (0.8 mg/kg) because of inhibition of hepatic
`microsomal enzyme activity.20 Oral contraceptive use decreases
`the clearance of prednisone and increases its bioavailability.21
`The bioavailability of prednisone is decreased by antacids in
`doses comparable to those used clinically.22 The bioavailability
`of prednisolone is not
`impaired by sucralfate, HZ-receptor
`blockade, or cholestyramine.
`
`EFFECTS OF GLUCOCORTICOIDS ON OTHER MEDICATIONS
`
`The concurrent administration of a glucocorticoid and a salicy-
`late may reduce the serum salicylate level. Conversely, reduc-
`tion of the corticosteroid dose during the administration of a
`fixed dose of salicylate may lead to a higher and possibly toxic
`serum salicylate level. This interaction may reflect the induc-
`tion of salicylate metabolism by glucocorticoids.”
`Glucocorticoids may increase the required dose of insulin or
`oral hypoglycemic agents, antihypertensive drugs, or glaucoma
`medications. They also may alter the required dose of sedative-
`hypnotic or antidepressant therapy. Digitalis toxicity can result
`from hypokalemia caused by glucocorticoids, as from hypo-
`kalemia of any cause. Glucocorticoids can reverse the neuro‘
`muscular blockade induced by pancuronium.
`
`CONSIDERATIONS BEFORE INITIATING THE USE OF
`GLUCOCORTICOIDS AS PHARMACOLOGIC AGENTS
`
`Cushing syndrome (see Chap. 75) is a life»threatening disorder.
`The 5-year mortality was higher than 50% at the beginning of the
`era of glucocorticoid and ACTH therapy.“ Infection and cardio-
`vascular complications were frequent causes of death. High-dose
`exogenous glucocorticoid therapy is similarly hazardous.
`Table 78—2 summarizes the important questions to consider
`before initiating glucocorticoid therapy?‘ These questions enable
`the physician to assess the potential risks that must be weighed
`against the possible benefits of treatment. The more severe the
`underlying disorder, the more readily can systemic glucocorti-
`coid therapy be justified. Thus, corticosteroids are commonly
`used in patients with severe forms of systemic lupus erythemato-
`sus, sarcoidosis, active vasculitis, asthma, chronic active hepatitis,
`transplantation rejection, pemphigus, or diseases of comparable
`severitv. Generally,
`systemic corticosteroids should not be
`administered to patients with mild rheumatoid arthritis or mild
`bronchial asthma; such patients should receive more conserva-
`tive therapy first. Although these patients may experience symp-
`tomatic relief from glucocorticoids,
`it may prove difficult 'to
`withdraw the drugs. Consequently,
`they may unnecessarily
`exPerience Cushing syndrome and Hl’A suppression.
`
`DURATION OF THERAPY
`The anticipated duration of glucocorticoid therapy is another
`critical issue. The use of glucocorticoids for 1 to 2 weeks for a
`condition such as poison ivy or allergic rhinitis is unlikely to be
`assoc1ated with serious side effects in the absence of a contraindi-
`cation. An exception to this rule is a corticosteroid-induced psy-
`chosis. This complication may occur after only a few days of
`high-dose glucocorticoid therapy, even in patients with no previ-
`ous history of psychiatric disease (see Chap. 201)?“27 Because the
`risk of so many complications is related to the dose and duration
`
`TABLE 78-2.
`Considerations before the Use of Glucocorticoids as
`Pharmacologic Agents
`
`i-Pb’r
`
`How serious is the underlying disorder?
`How long will therapy be required?
`What is the anticipated effective corticosteroid dose?
`Is the patient predisposed to any of the potential hazards of glucocorti-
`coid therapy?
`Diabetes mellitus
`
`Osteoporosis
`Peptic ulcer, gastritis, or esophagitis
`Tuberculosis or other chronic infections
`
`p1
`.0
`
`Hypertension and cardiowiscular disease
`Psychological difficulties
`Which glucocorticoid preparation should be used?
`Have other modes of tlierapv been used to minimize the glucocorticoid
`dosage and to minimize the side effects of glucocorticoid therapy?
`Is an alternate-day regimen indicated?
`(Modified from Thorn GW. Clinical considerations in the use of corticosteroids.
`N Eiigl] Med 1966; 227-1775.)W
`
`7.
`
`of therapy, the smallest possible dose should be prescribed for
`the shortest possible period. If hypoalbuminemia is present, the
`dose should be reduced. If long-term treatment is indicated, the
`use of an alternate-day schedule should be conSidered.
`
`LOCAL USE
`
`A local corticosteroid preparation should be used whenever pos-
`sible because systemic effects are minimal when these substances
`are administered correctly. Examples include topical therapy-m
`dermatologic disorders, corticosteroid aerosols in bronchial
`asthma and allergic rhinitis, and corticoster01d enemas in ulcer-
`ative proctitis. Systemic absorption of Inhaled glucocorticolds
`leading to Cushing syndrome and HI’A suppreSSion is a rare
`occurrence when these agents are administered correctly at pre-
`scribed doses.”29 The intraarticular injection ()f‘COI‘hCOSterOldS
`may be of value in carefully selected patients if strict aseptic tech—
`niques are used an