JANSSEN EXHIBIT 2088
`
`Amerigen v. Janssen lPR2016-00286
`
`JANSSEN EXHIBIT 2088
`Amerigen v. Janssen IPR2016-00286
`
`

`
`Principles and Practice of
`ENDOCRINOLOGY
`
`
`
`AND
`METAB OLISM
`
`THIRD EDITION
`
`L 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
`
`LlPl3lNCOTT WILLIAMS 8 \X/ILKINS
`
`' A Wolters Kluwer Company
`Philadelphia - Baltimore - New York - London
`Buenos Aires - Hong Kong - Sydney - Tokyo
`
`

`
`.»lci;ii1'sitioizs Editor: Lisa i\IcAllister
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`Pmductimi Editor: Shannon Garza, Silverchair Science + C()[11[nu11iCati()n5
`J‘.Imziifizctiniiifq i\lii2z:Iggci': Colin \\/arnocl-;
`Cover [)esi;qiii*2': Joan Greenfield
`Coni;Ios‘i!or: Silverchair Science «- Communications
`Printer: World Color/Rand McNally
`
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`ernment employees are not covered by the abovevmentioned copyright.
`
`Printed in the USA
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`
`Library of Congress Cataloging-in-Publication Data
`
`Principles and practice of endocrinology and metabolism / editor, Kenneth L. Becker;
`associate editors, John I’. Bile’/.ikian
`[et al.].--3rd ed.
`p. ;cm.
`lncludes bibliographical references and index.
`ISBN 0-7817-1750-7
`1. Endocrinology. 2. Lndocrine glands——Diseases. 3. Metabolisin--Disorders. l. Becker,
`Kenneth L.
`1. L’ndocrine Diseases. 2. Metabolic Diseases. WK 100 P957 2000]
`{l).\Jl-;\l:
`l{Cr'>~}t% .l’(>7 2000
`h l ti.4——clc2 l
`
`00-022095
`
`
`Care has been tal-;en to confirm the accuracy of the information presented and to
`describe generally accepted practices. However, the authors, editors, and publisher are
`not rysptjllhlblt’ for errors or omissions or for any consequences from application of the
`mformatioii in this bool; and make no warranty, expressed or implied, with respect to
`the currency, completeness, or accuracy of the contents of the publication. Application
`of this information in a particular situation remains the professional responsibility of
`the practitioner.
`The authors, editors, and publisher have exerted every effort to ensure that drug
`selection and dosage set forth in this text are in accordance with current recoininenda—
`tions and practice at the time of publication. However, in view of ongoing research,
`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.
`This is particularly important when the recommended agent is a new or infrequentlv
`employed drug.
`'
`Some drugs and medical devices presented in this publication have Food and Drug
`Administration (FDA) clearance for limited use in restricted research settings. It is the
`responsibility of health care providers to ascertain the l’l)A status of each drug or device
`planned for use in their clinical practice.
`
`1098765-1321
`
`

`
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`. Owerbach D, Crawford YM, Draznin MB. Direct analysis of CYl’21B genes
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`Effects of individual mutations in the
`. Higashi Y, lliromasa T, Tanae A, 0101-
`. -
`-
`..
`..
`.
`I
`. :i
`,
`C21) activity and their distribution in
`P'430(C-)1) l’»‘‘11d‘’lv““* 0“ H“ P V” (
`d 21-1i)’droX)’lase deficienC)’1 1 310‘
`the patient genomes of congenital steroi
`Chem (Tokyo) 1991; 1091638’
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`.
`..
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`. Dicl<ei'inaii Z, Grant DR; 1511111111‘
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`J
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`. Nikoshkov l\,
`141113 5/ VI‘‘miS"G
`ylase (l’450c21) pinpoint residues
`mutants of liiiiiian steroid 21-hydrolxl
`my] Biol Chem 1998; 27316163.
`important for enzyme activity and sta 71
`C. Characterization of two genes
`. Moriiet 15, Dupont L V1191‘ AI White P
`(P-450 110). J Biol Chem 1989;
`encoding hunian steroid 11]}-1iydr0v“Yl“5e
`26‘l:20%1‘
`g of CDNA encoding steroid 11]}-
`. Chua SC, Szabo 1’, V1191‘ Ar Cl 31‘ Clonin
`, {S ‘U S ’\ 1987; 8427193.
`liydroxylase (1’450C11)
`A Pmc
`}1\(C1et acli Cloning of CDNA and genomic
`. Kawainoto '1‘, Mitsuuchi Y, 1
`, ~
`-
`<
`\ t 1990; 269:345.
`DNA for luumm Cymchmmc P7430HB.}f3El:I:tSl.LCLlt0111I1g and expression of a
`. Kawainoto '1', Mitsuuchi Y, Oliiiislii T,
`,
`,
`_ — ,
`1
`~
`.
`' related to primary a1doste-
`cDNA for hiiinan C)/l(i(l1r0Il1L 1’ 43011-95 15
`.
`.,.
`~
`0,-173309.
`ronism. Biochcm BI01’1‘Y>‘I“” C‘”"m”n 1991. The product of the CYl’11B2
`. Curiiow KM, Tusie-Luiia MT, Pascoe L, C1 -1
`biosyiitliesis in the human adrenal cortex.
`gene is required for aldosterone
`ctaLM0]CCu1ar biology of 11[H1ydmXy_
`Mo1Endocrinol 1991; 521513.
`. White l’C, l’ascoe L, Ciirnow KM,
`.
`_
`,. ,
`-~ eiiz mes. I Steroid Biochem
`1,139 and 11[3—hydroxysteroid dchydrogrn ist
`y
`M01 Biol 1992; 43:827.
`et 11 Mutations in the CYl’11B1 gene caus-
`>
`.
`tension cluster in exons 6, 7,
`. Ciirnow KM, Slutsker 1., Vitek I,
`.
`,
`,
`isii ind hyper
`ing congenital adienal 11)/PCTPI‘
`‘
`‘
`.-
`'A 1993; 9014552.
`_
`“ml 8' M“ N“! Ami S“ U S
`1. A imitation in CYl’11B1 (Art»'r~'t48—>His)
`‘V
`uficiency in Jews of Moroccan
`. White PC, Dupont L NOW M1 “‘ “
`.
`.
`,.
`'
`—h droxylfibk 51‘
`associated with steroid 11]} Y
`0ri1’il"‘]Clm[nVCSH991;S7:166_L hi Y, et al. A nonsense mutation
`. Naiki Y, Kawamoto T, Mitsuuc
`D in CYPH131 causes steroid 11[3-hydroxylase defi-
`('l'GGl16'I'AGlStoP
`_.
`, i
`1)t)3,-7711677.
`Cum)‘ Mthb 1
`Frame shift by insertion of 2 basepairs
`ciency.] Clin Endo
`llelniberg A, Ausserer B, Koflcr R
`_
`,.';l11‘1ll
`aer1asiaduetoster-
`in codon 394 of
`CY1’111’1 fj‘,?"“.“,f1:°nf’(L:iiii l3ii((l(rJLcIiiiiiolyl\}/letiaab 1992; 7511278.
`oid ll beta-liydr0XYl
`“SCH” l8L,“3,,‘,
`1-1, [garaslii Y. Missense mutation in
`. Nakagawa Y, Yamada M,
`.38 1] fig/\[(31y]) causes steroid 11 beta-hydroxylase
`’“f’" ‘
`t)<)5;132:286.
`CYl’ltBl (coat
`H
`Classic steroid 11 beta-hydroxylase
`deficiency. 1lUI‘l E1“l‘mm0
`‘ Yang LX, Tod“ K, Miyahara K, et al.
`on in exoii 7 of CYl’11B1. Biochern
`*-
`iiisversi
`used by a C >G tr.
`1“
`6:723.
`.
`deficiency ca
`‘
`t’
`’
`'
`0111'“““ 19%’ 2]
`i isin ' con ’Cn1l'1l
`Biophys Res C
`,
`_,
`,
`i (jYI’11Bl muta ions c. 1
`3.,
`3,
`s
`an K, johicr K, £111‘
`. Geley S, Kapel
`{
`I H bL,h_hydroxylase deficiency. I Clin Endo-
`adreiial liyperplasia L Ht‘ 9
`‘
`.
`(;8l:2S9(i.
`'11 Novel CYl’1lB1 mutations in con-
`ciinol Mttab 11)‘) i
`Chlmbm A) Ct
`-
`_ Mcrke D1’, Tajiiiia T,
`‘
`'
`beta-hydroXy1ase deficiency.
`Iasia due to steroid 11
`'enital adrenal liy}iC1P
`1998; 83:270.
`iicll“ 15119"Crm01 Metab
`M, et al. CY1’11B1 mutations causing
`-Wozak E
`. Ioehrer K, Geley 3/ S11“-“"‘°"
`beta-hydroxylase deficiency.
`‘
`non-classic «1(1‘L‘1\
`J; hypgrplasia due to 11
`Hum Mol Genet 1
`t:97i:‘(»:1t1%':’:)(-i J Chung B—C, Ct at. Assignment of the gene
`0. eoi 1
`,
`.
`~»
`—
`1 1-
`1
`‘lim-
`. Matteson K1: P10“
`_
`‘
`_ _,
`«
`i 17(1.hyd10xyld5L/17,20 lyasc) to humin (
`for adrenal l’4_w(lc17(51'~m.lL 1 M xti b 1986631789.
`niosonie 10.10"‘ Endocrmo
`L
`‘
`‘
`,.
`, d0_LL.(,m,-d ], I-Ianiu M, et al. Cytochrome l’450cl7 (ster-
`. Cliiiiii: 13]-Crilr(';‘lMSG/17,20—1yase): cloning of hunian adrenal and testis
`c
`s
`1
`-
`(i£;iN1/\7(l‘i:1)C,](1C-1te)L the same gene is expressed in both tissues.
`l‘ro<: Natl
`I
`.‘
`~ c U 5‘
`'\ 1987; 84141117.
`g\l:,]:,ik?L\;, Nagasliiiiia '1', Nomura Y, et al. A. /\ new 1,oiiipv.iI.iiid l'ieiei‘ozi;g1_iii=.
`
`'
`
`,
`
`.
`
`.
`
`Ch. 78: Corticosteroid Therapy
`
`751
`
`'
`
`mutation (W17X, 436 + 5G—>T) in the cytochrome 1’450c17 gene causes 17 alpha-
`hydroxy1ase/ 17,20—1yase deficiency. ] Clin Endocrinol Metab 1998; 83:199.
`Lachance Y, Luu-Tlie V, Labrie C, et al. Characterization of human 313-
`hydroxysteroid dehydrogenase/A5‘-A1 isornerase gene and its expression in
`mammalian cells.] Biol Chem 1990; 265120469.
`. Lorence MC, Corbin C], Kamimura N, et al. Structural analysis of the gene
`encoding human 30-hydroxysteroid dehydrogenase/A5”"—isonierase. Mol
`Endocrinol 1990; -111850.
`Lachance Y, Luu—'1'he V, Verreault H, et al. Structure of the human type II
`3[3—hydroxysteroid dehydrogenase/A"‘—A‘ isomerase (313-HSD) gene: adre-
`nal and gonadal specificity. DNA Cell Biol 1991; 10:701.
`. Berube D, l.L1t1~Tl1€ 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. Phenotypic variability and origins
`of mutations, in the gene encoding 3[l—hydroxysteroid dehydrogenase type
`11. Mol Endocrinol 2000; 24:75.
`. Rheaume E, Simard ], lvlorel Y, et al. Congenital adrenal hyperplasia due to
`point mutations in the type 11 3]}-liydroxysteroid dehydrogenase gene.
`Nature 1992; 1:239.
`. Chang YT, Kappy MS, lwamoto K, et al. Mutations in the type 11 3 beta-
`liydroxysteroid deliydrogenase (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, Rlieaurne E, Sanchez R, et al. Molecular basis of congenital adre-
`nal liyperplasia due to 313-liydroxysteroid deliydrogenase deficiency. Mol
`Eiidocriiiol 1993; 7:716.
`. Sal<kal-Alkaddour H, Zliang L, Yang X, et al. Studies of 3 beta—hydroxy—
`steroid dehydrogenase genes in infants and children manifesting premature
`pubarche and increased adrenocorticotropiii-stirnulated delta 5-steroid lev-
`els. ] Clin 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. Proc 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, f’450ssc, in congenital lipoid adrenal hyper-
`plasia.]Clin1nvest 199]; 8821955.
`. 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 ]Z, Morton DH. The biochemical phenotypes of two inborn
`errors in the biosynthesis of aldosterone. I Clin Endocrinol1\/letab 1992; 74:1-115.
`. Harada N, Ogawa H, Sliozu M, Yamada K. Genetic studies to characterize
`the origin of the mutation in placental aroniatase 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 ivith sexual iiifantilisiii and polycystic ovaries. Proc Natl
`Acad Sci U S A1993; 90311673.
`la
`. Sim son ER, Zliao Y, A rarwal VR, et al. Aromatase ex iression in health
`and disease. Recent l’rog Horm Res 1997; 52:185.
`. Eckstein B, Cohen S, Farkas A, Rosler A. The nature of the defect in familial
`male pseudohermaphroditisni in Arabs of Gaza. I Clin Endocrinol Metab
`1989; 68:477.
`l\«lechanisms of androgen production in
`. Rosler A, Belanger A, Labrie F.
`male pseudohermaphroditisiii due to 17 beta-hydroxysteroid dehydroge-
`nase deficiency. I Clin Endocrinol Metab 1993; 751773.
`. Castro—Magana M, Aiigulo M, Uy ]. Male hypogonadisin with gynecomas-
`tia caused by late-onset deficiency of testicular 17-ketosteroid reductase.
`N Eiigl I Med 1993,‘ 32811297.
`. Pang S, Softness B, Sweeney W], New M1. Hirsutism, P0l}'C)’511C 0"‘111““
`disease, and ovarian 17-ketosteroid rediictase deficiency. N Engl ,1 Med
`1987; 316: 1295.
`. Andersson S, Moglirabi N. Pliysiology and molecular genetics of 17 beta-
`hydroxysteroid dehydrogenases. Steroids 1997; 62:143.
`. Moghrabi N, Hughes IA, Dunaif A7 r'\11C1€155‘’11 5' Delelerious mlsscnse
`.
`.
`.
`«
`.
`i
`2
`beta-hydroxyster-
`mummms and silentp()lyn10lPl11SI11 in the human 17 _
`I‘ b 1998
`oid deliydrogenase 3 gene (1’15D17B3)1 1 C11“ E“d"C“m’l N “M
`’
`8322855.
`‘ Nyckoff IA, Seal), EW, Hm-wit-,; S, et al. G1ucocortic0id-remediable a1dos-
`.
`,
`.
`.
`~'
`' . ":
`S‘.
`teronisin and pregnancy. llyPL1‘lL11>l(7l1 2000, 3:1 66x
`
`.
`
`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.
`1
`
`

`
`752
`
`PART V: THE ADRENAL GLANDS
`
`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 iirruais
`indicate the structural differ-
`ences between cortisol and each
`of the other molecules.
`(From
`Axelrod L. Cilucocorticoid ther-
`apy. Medicine [Baltimore] 1976,’
`55:39, and Axelrod L. Glucocor—
`ticoids.
`ln: Kelley WN, Harris
`ED Jr, Ruddy S, Sledge CB, eds.
`Textbook of rheumatology, 4th
`ed. Philadelphia: WB Saunders,
`1993779.)
`
`GLUCOCORTICOIDS
`
`CORTISOL
`(HYDROCORTISONE)
`
`PREDNISOLONE
`
`éH,(
`METHYL PREDNISOLONE
`
`CH,OH
`=O
`
`lC
`
`"OH
`
`1
`
`CH,OH
`l __ O
`C’
`-OH
`
`CORTISONE
`
`pREDN|SONE
`
`DEXAMETHASONE
`
`STRUCTURE OF COMMONLY USED GLUCOCORTICOIDS
`
`Figure 78-1 indicates the structures of several commonly used
`glucocorticoidslrl Cori‘i'sol (Ii_i/drocortisoiic’) 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.-l!" 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.-‘ 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-‘l).1»3 The commonly used glucocorticoids are classified as
`s/iort-zictziig, iiitcriiwilintc-zictiiig, and long-nctiiig on the basis of
`the duration of corticotropin (ACTH) suppression after a single
`dose, equivalent in a_ntiinflammatory activity to 50 mg of pred-
`rtisone (Table 78-1).“' The relative potencies of the glucocor-
`ticoids correlate with their affinities
`for
`the intracellular
`gluc()ct>rtic()id receptor.“ The observed potency of a glucocorti-
`coid, however, is determined not only by the intrinsic biologic
`P0'f9{1Cy, but also by the duration of action."'7 Consequently, the
`Flelative potency of two glucocorticoids varies as a function of
`tie 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 lmlf—lifc (Tug) of .1 gin-
`cocorticoid and its potency is weak. The T1/2 of cortisol in the
`
`1
`
`,
`
`'
`
`.
`
`-
`.
`circulation is in the range of 80 to l15't’T1tI1‘Llt355
`1
`H , E1
`other commonly used agents are cortisone,
`.1
`nisone, 3.4 to 3.8 hours; prednisolone, 2-1 t0 3-5 ‘OWE mu ‘Y ‘
`.
`..
`>th1sone 1.8 to 4.7
`prednisolone, 1.3 to 3.1 hours, and
`h‘We Com qmble
`hours.‘/7'8 Prednisolone and clexanietias()Clmr1< more P;Ot«em
`circulating T]/gs, but dexamethasone is uhctmyy T
`Oflq flu.-
`u
`.
`u
`'
`w
`‘
`_
`C
`C
`Similarly, the correlation between the circ Tche Ii-311111/21Cti:)né3S of
`.
`.
`l
`c
`< ‘
`cocorticoid and its diirntioii ofnetioii 151p:)i0:MlfiOn mg’ the dun
`glucocorticoids do not have an equa d L1‘
`I
`tion of action may be a function of the _"5“
`‘.
`I
`f
`t.
`Tl
`{
`.
`fACTH su 7pt'eSSl0I1 is not simp y a. unc ion
`iecurationo
`1
`_
`_
`,
`,,
`,
`.
`.
`--
`hr
`activity, because xaiiations in
`of the level of antiinflamma ( y _
`qchieved by doses of
`the duration of ACTH suppression are t
`’
`.
`.
`,.
`.
`.
`.
`,
`,7
`tjinfIammdt()I‘y activity. The
`-
`V .'
`‘
`-
`'
`glucocorticoids with comparable an
`d b m mdividml ml
`duration of ACTH suppression produce
`y c
`ta
`.
`,
`'
`~
`l’ited.5
`~
`cocorticoid, however, probably is dose F9 I
`
`TABLE 78-1.
`
`Commonly Used Glucocorticoids
`
`Duration of Action‘
`
`SHORT-ACTING
`Cortisol (hydrocortisone)
`Cortisone
`Prediiisone
`Prednisolone
`Methylprediiisolone
`INTERMEDIATE-ACTING
`Triamciiiolone
`
`chm)‘
`ticoid
`Cor
`P0l9"CYl
`
`Glucocorticoid
`Dose (mg)
`
`corticoid
`,
`,
`Activity
`
`-5-U1U1Ix)Ix)U1C
`
`Yes‘:
`Yes:
`N0
`N0
`N0
`
`N0
`
`LONG-ACTING
`Betamethasone
`Dexamethasoiie
`
`-
`
`_ )
`0 (0
`0 75
`'
`
`N0
`N‘,
`'1» ’ts.NY
`.- *‘
`..{ m llartu JG. (()I‘llL()slt FOIL
`‘
`.,
`.
`_
`I
`‘The classification by dunition ofaetion is lJ15L(.
`(
`h
`I
`I
`State] Med l‘)(x(»;(i6:ts’27.
`I
`‘ H1, r('lL‘ti"’L’. Cortisol l>' dl‘lJllrdrll)’
`‘The values given for glucocorticoitl potent)’ ‘
`assigned a value of 1.
`(.}0,;c to or within the ha,~:al
`C
`I
`V
`3Mineralocorticoid effects are dose re
`latpd. r\tltl;:sLef~fcCt Km", bu dL.M~mi,1L.4
`physiologic range for glucoeorticoid n(‘ll\’ll)'« no st Mmiicmc Hmlmnmvl 1g7(,;55:3<);
`(Data from Axelrod L. Ciliietictirtictltvlfll#1:::l]§yCreeiil.wlatt Dl, eds. llalndbook of dgug
`Axelrod L.Adrenalcorticosteroids. In:
`I
`L’
`‘ " ,'
`I
`1
`\xL.imd L. G llL‘0C0l‘llC(llt s‘.
`therapy. New York: lilsevier North-I lollaiid, l‘?79'N)f)’.fl::]_,‘;mk of rheumatology, 4th ed.
`ln: Kelley WN, l larris I.-‘Djr, Ruddy 5, 51'-‘dl»5'~' CB’ ed?"
`(
`I’liiladelphia: WB Saunders, 19932779.)
`:
`
`

`
`In short, the slight differences in the circulating T1/ZS Of the 81”‘
`Cocorticoids contrast with their marked differences in Potelfcl’ and
`duration of ACTH suppression. Thus, the duration of action of a
`glucocorticoid 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 the
`Process of transcription by which RNA is transcribed from ‘e
`DNA template. This process alters the rate of synthesis of specific
`Proteins. The steroid thereby modifies the phef1(_3tYP1C Pxpresslon
`of the genetic information. Thus, the glucocorticoid corztiimes 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 33 3 Speclflc Fromm) may
`be present after the disappearance of the gluC0COrt1C01d-
`
`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‘) Consequently, although oral cortisone
`be age-
`quate replacement therapy in chronic adrenal insuf 1C1eI'1Cy,1
`62
`Oral form of this agent should not be used when larglel} Pllar’
`macologic effects are sought. Comparable Plasma Ere mm on?
`levels are achieved in normal persons after eélulvaleflt, Om
`doses of prednisone and prednisolone.3/1° After the administra-
`tion of either of these corticosteroids, h0WeVef, there 15 Wlflfi
`variation in individual prednisolone concentrations, Whic
`may reflect variability in absorption.8
`t follow the intramuscular
`In contrast to the marked rises tha
`ortisol levels rise little or
`.
`injection of hydrocortisone, Plasma C
`not at all after an intramuscular iniection of cortisone aCet3t€-
`When it is given intramuscularly, cortisone acetate doe:not pro-
`Vide adequate plasma cortisol levels and offers iipl a vat; 38‘?
`0Ver hydrocortisone delivered by the same route.
`ie ex? at‘;
`tion for the failure of intramuscular cortisone acetate to Pm“ e
`adequate plasma cortisol levels is unknown.‘ It ma)’ reflect P01“
`absorption from the site of injection. Alte1‘11€1t1V91Y/ mtlmmuscu Br
`cortisone acetate, which reaches the liver throlijgfi t‘e_‘t3Y5::nE:
`circulation, may be metabolically inactivated e1 ore '1‘ Cc
`_
`C0r1Verted to cortisol in the liver, in contrast to Ora cortisone ace
`late, which reaches the liver through the portal circulation.
`
`PLASMA TRANSPORT PROTEINS
`In normal humans circadian fluctuations occur in the cap.aCitY 0;
`corticosteroid-binding globulin (transcortin) lg b“}g1C°rr:ds:iS‘:)rI‘1e
`Prednisolone. Patients who have been treate . W1_
`ll’ b. d.
`for a prolonged period have no diurnal variation in tile
`in inig
`Capacity of corticosteroid-binding globulin for CO1‘tlSO. or prefi-
`nisolone, and both capacities are reduced
`comparison W111
`normal persons. Thus, long-term Slucocoftlcold thempyféwt Onhy
`alters the endogenous secretion of steroids, but also a lects t e
`transport of some glucocorticoids in the circulation. Tiis réiay
`explain why the disappearance of prednisoloqe is motre I’i5:1Pl
`in
`those persons who have previousl)’ recewed 55 ucocor mo
`5'
`
`GLUCOCORTICOID THERAPY
`IN THE PRESENCE OF LIVER DISEASE
`Plasma cortisol levels are normal in patients with h9_P“tlC d_‘tsleaS.e;
`Although the clearance of cortisol is reduced in patiepts W10
`rhosis,
`the hypothalamic—pituitary—adrenal (HIA)
`iolge tn of
`mechanism remains intact. Consequently, the decreasef ra
`O1
`metabolism is accompanied by decreased 5Y“the51S 0 Cor is
`(See Cha .205).
`,
`.
`.
`.
`-
`The Cgnversion of prednisone to prednisolone is impaired in
`patients with active liver disease.“ This 15 largely Offset bY 3
`decreased rate of elimination of prednisolone from the plasma
`in these patients.“ 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.” 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.” 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.S If prednisone or pred-
`nisolone is used, however, a somewhat lower than usual dose
`should be given if the serum albumin level is lOW.S
`
`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 unboimd fraction is inversely related to the serum albumin
`concentration. The unbound prednisolone concentration remains
`normal, l1OW€V€I‘.13'H 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,“ although subnormal
`responsiveness to exogenous ACTH may occur. Similarly, there
`is no evidence that glucocorticoids increase the incidence of
`congenital defects in humans.“ 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 nursing infant
`is unlikely to produce deleterious effects in the infant.
`
`GLUCOCORTICOID THERAPY AND AGE
`
`and methylprednlsolone
`of prednisolone
`clearance
`The
`decreases with age.17»15 Despite the higher prednisolone levels
`seen in elderly subjects compared with young sub]ects after com-
`parable doses, endogenous plasma cortisol levels are suppressed
`to a lesser extent in the elderly.” 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.”
`
`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 rifarnpin. 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?" Oral contraceptive use decreases
`the clearance of prednisone and increases its bioavailability?‘
`The bioavailability of prednisone is decreased by antacids in
`doses comparable to those used clinically.23 The bioavailability
`of prednisolone is not
`impaired by sucralfate, H2-receptor
`blockade, or cliolestyramine.
`
`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.33
`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 vasciilitis, asthma, chronic active hepatitis,
`transplantation rejection, pemphigus, or diseases of comparable
`severity. 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 eXpCfi€1}C€_’
`5YmP'
`tomatic relief from glucocorticoids,
`it may prove difficult to
`withdraw the drugs. Consequently,
`they may unnecessarily
`experience Cushing syndrome and HPA suppression.
`
`DURATION OF THERAPY
`duration of gliicocorticoid therapy is another
`condition Suéh 1: useof gliicocorltrcoids foril to 2 weeks for a
`associated VvithcSe1§>(())E15S();1i
`'LI‘f.%iC‘I‘lEItli1S is unlikely to be
`Cation. An exception to t1r(‘i:(I..uf.eCiS‘1,I’\
`ic
`sence'of'a contraindi.
`‘_
`h H _
`_
`_
`s a corticosteroid-induced psy-
`.
`Chosis. Ihis 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. 20‘1).3“«37 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
`
`. 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 inellitus
`
`~
`
`Osteoporosis
`Peptic ulcer, gastritis, or esophagitis
`Tiiberculosis or other chronic infections
`
`Hypertension and cardiovascular disease
`Psychological difficulties
`. Which glucocorticoid preparation should be used?
`. Have other modes of therapy 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 coiisideratiom in the use of corticosteroids:
`N Engl] Med 1966; 27-1:775.)
`
`.
`
`of therapy, the smallest possible dose should be prescribed for
`the shortest possible period. If hypoalbuminemia
`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 therapylin
`dermatologic disorders, corticosteroid aerosols in bronchial
`asthma and allergic rhinitis, and corticosteroid enemas in ulcer-
`ative proctitis. Systemic absorption of inhaled glucocorticoids
`leading to Cushing syndrome and HPA suppression is a rare
`occurrence when these agents are administered correctly at pre-
`scribed doses 33139 The intraarticular