, 4.
`Nana New England
`Journof Medicine
`al
`
`1821
`
`v
`
`1812 ÿ
`1928 @ ,b
`
`1028, yñ,
`
`Fatabllshed ia, 18t8 as:-The. NEW ENGLAND -dOIIBNAL OP DtEtfIOIäA ANb Sb8á88R
`
`VOLUME 317
`
`SEPTEMBER 24, 1987
`
`NUMBER ?1i3
`
`Case. Records o
`r&ást'Vk[
`Massachusetts Gene
`Renal Failure 64 Years after R
`m al of a
`Hypoplastiò Kidney.,..
`RAYMOND M. HAKIM AND PAUL B
`
`ao E. í7 l.$%,
`
`,,8yy,
`
`¡.
`
`7SL
`
`787
`
`793
`
`799
`
`805;
`
`Original, Articles
`Sickle -Cell Trait as a Risk Factor for Sudden
`Death in Physical Training
`JOHN A KARK DAVID M. POSEY,
`HAROLD R. SSoRUMACUER, AND °W +ARLrs,f, Spann
`. VentricularArrhythmias ia.Patients with
`Hypertensive
`Ventricular
`Hypertrophy. ..........,. ...... .á...,.,
`JAMES M, MCLENÀCHAV, EsEDER. HENDERSON,
`KAREN L Mona, ANO HENRY /. DARme,.
`Opsopophagocytic Killing Antibody to Pseu
`domonas aeruginosa Mncoid Exopoly.
`saccharidein Older Nöncoloùized
`Patients with Cystic F,ibrosis
`GERALD $ Patin, JAMas. M. SAUNDERS,
`PETER AMES' MoRVÜN S.'ETWARVE;
`liARVEyY AUERRACIi, JOHANNA GOLDFARB,
`DAVID P. SPEERT, AND SANDRA HURWITCH
`Prevention anrl.'Reversal of Nitrate Toler. -
`ante in Patients with Congestive
`Heart Failure ........... ,. ....., r.
`MntDt4 PAOaER, WAt from
`tPAVL D, KESSLER, STantett Car-r4it
`NORMÁ lvfanect, AND MADELINE MTh .%
`In Vivo Induction and Reversal ofNitro-
`glycerin Tolerance in Human Coronary
`Arteries
`awn:'. C. MAY, JEFFREY J. POPMA,
`WILLIAM H. BLAOK, SAUL SCHAEFER,
`ant DAVIDHILIS
`HOWARD It, LSS, BSí$,¡Au1N D. LEvliet:
`Special Article
`The Ímpact of Televised Movies about
`Suicide: A JtéplicativeStu4y.;
`DAVID - P. PHILLIPS AND DANIELj. PAIOHI'
`
`liditorials
`The 7tiéks of SickleeCell Trait: Cau
`Common Sense.
`óúiv 4N. S7iüuïtiuu.
`
`SERIALS
`
`Cardiac Hypertrophy 5u'Hypertension
`ÈñwARa D. FRouuctt
`
`831
`
`-
`
`Correspondence
`Duplicite Publication on Postùenopausal'8one
`Tess
`Measles Outbreak m an Immumzed School
`Population .
`Diabetes Mellitus a nd,Atherosclerosis . ......
`IntravascularSienta after`Tiansluminal Angie.
`play
`Impaired, Immune Response to Polysaccharides .<.
`Twenty- five -Year Follow -up of a Patient Treated
`with Lung Lavage for Pulmonary Alveolar_
`Protemosis
`"Natural" PoHd4ium Supplements......
`.
`. e......., ,..
`Snoring and Calf Pain .,.
`,
`Alternative to Heimlich Maneuver ....:....... .
`
`Rook Reviews 4 .........................
`
`833.
`
`834
`886
`
`886
`83'1
`
`840
`840
`840:
`
`841
`
`Notices .......... ......
`
`SO9
`
`. ......,..
`
`844
`
`Medical Intelligence
`Drug Therapy: The US of Ketoconazole as
`an Inhibitor of Steroid Production
`NicOLETTA SOME.
`
`812
`
`Corrections
`The, N111 Consensus Development Program: A
`Decade later .......................
`Postdischarge Mortality front Suicide and Motor.
`Vehicle Injuries among Vietnam -Era
`Veterans
`_ ................ . .
`
`844
`
`844
`
`Owned, Published, and ©Copyrïgbted, 1987, by the Massachusetts Medical Society
`rilE New EN4AND joi áugt. or MEDW[NL (ISSN 0028.4798) h published weekly frr m cdton'ai ..pees At tO Shdttuck.Slrcet, Boson,, MA 0211
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`POSTMASTER Send address change; to 1440 Main S(ree , Waltham, MA 0224
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`JANSSEN EXHIBIT 2163
`Mylan v. Janssen IPR2016-01332
`
`

`

`012
`
`THE NEW ENGLANDJOURNAL OF MEDIOINE.
`
`Sept. 2 , 1987
`
`MEDICAL INTELLIGENCE,
`
`a141 tArta, ..
`.,4Y$ >
`
`+"
`
`DRUG THERAPY
`join: A. OASts, M.D., >,îaüar
`AGAsrAiie,]1: W000, M,D.,ArructataCditot
`THE USE OF RETOCONAZOLEAS AN
`INHIBITQR OF STEROID PRODUCTION
`NiconexrA SoNiNO, -M.D,
`
`tj ETOCONAZOLE. is an imidazole derivative
`.L.. that is chemically' related to mtconazole (Fig, 1),
`It is an oral antimycotic agent with broad- spectrum
`activity and low toxicity.t'3 The drug is considered to
`represent an important innovatiön in the tréatment of
`fungal disease and bas; been used extensively in (clini-
`cal practice for the past five years. The development of
`gynecomastta in some patients treated formycosis first:
`led tb the investigation of the drtig's effect on the pro-
`duction of testosterone,4A Thereafter, ketoconazole
`was shown to be a potent inhibitor of gonadal: and
`adrenal steroid synthesis in vitra and in- vtvoas'IO Thee
`finding of its important endocrine effects has aroused
`a new interest In this agent, l t Extensive studies have
`been carried out to elupidate its mechanismof°action,
`In addition; there have, been clinical trials to assess its
`therapeutic potential. Because ketoconazole acts as ä
`steroid inhibitorwith differenfalselectivity, kit a new
`therapeutic tool in the management of conditions in
`which it is beneficial to suppress gouadal'or adrenal
`hormone production; Such as prostate caliber and
`Cushing's Syndrome, respectively.
`MEcrretvrnt or Amigos
`Ketoconazole inhibits the synthesis of ergosterol in
`fungi and of cholesterol in mammalian cells -12,13 In
`addition, it interferes with cytochrome P-450 enzyme
`systems in several organs - namely, the testis,, ova-
`y,6 adrenaligland,7kidney R and liver. RI Like other
`imidazole drugs, it appears to, interact with cyfo -.
`chrome P-450 at the heme iron site 12,18
`SteroidogenesIs
`The most sensitive site of action in humans appears,
`to be the C1720 lyase (Fig. 2), explaining the greater
`suppressibihty of testosterone secretion, as compared
`with cortisol secretion, in humans after a single dose of
`200 or 400 mg.to,ts'_A similar finding has been reported
`
`Dow thenapadment of Biochemistry, Slate University óf Next York at But-
`(alo, Buffed, N.Y:, and theInstitute of Medical$entlodes, University of Padua,
`Padua, Italy, Addica} teptiat requests to Dr Sonino at the Institute of Menke!.
`Semiotics, University of Padua, via Ospedale 105, 35190 Padua, Italy
`
`in male beagle dogs ?0 Inhibition of C1..7so lyase has
`been demonstrated by an increase in ratios, of' precur-
`sor ( 17a- hydroxyprogesteroneor17a ,20ä- Mhydroxy
`progesterone or both) to product (androstenedione or
`testosterone) both in vivol4t2oand invitraiszt'23 All
`in vitro studies to test dl7,2o, lyase have used :testis
`preparations, but clinical data show that both gonadal
`and adrenal androgens decrease after ketoconazole
`indicating interference with
`administration 7,,
`adrenal C to 2O lyasç as well, the extent of this inhibi.
`don has not been determined Since there is evidence
`that 17a- hydroxylase and C17 -20 lyase activities reside
`that ketoèona-
`in a single enzyme, it is not
`zole inhibits 179- hydroxyla-se as well (Fig. 2),2'
`Cholesterol side -chain- eleavagç blockade by keto-
`conazole has been demonstrated in both, testicular and
`adrenal tissue preparations, í42F,28 In vitro studies in
`rat testicular miçtosomes have shown that cholesterol
`side -chain cleavagehas a higher sensitivity toketocon.>
`azole than does 01 7.40 lyase,2 r species- dependent .
`sensitivity may - account for this finding; Adrenocorti-
`cal steroid biosynthesis is also inhibited at ;the 1113-
`hydroxylationt a2s -si and 18- hydroxylation. steps,»
`Ketoconazole ts more potent .invitro than metyrapone
`in the inhibition of both, l lß- hydroxylate and tholes- ,
`terol side -chain, cleavage' (Fig. 2).n
`The effects of ketoconazole on estrogen synthesis
`have not been fully clarified. In contrast to in vitro
`findings that the agent inhibits rat ovarian¢'ssand tes,
`titulars and human placental" azomatase, in vivo
`studies- have shown that the estradiohtestosterone''
`ratio is increased in men given ketoconazole 3537 No
`data are available on estrogen levels hi Women dur-
`ing,treatment. An inhibitory effect on oversecretion of
`estrogen by adrenal tumors has been repdrteda25'se
`Ris of interest that much higher concentrations are
`required to affect cytochrome P -450- dependent en-
`zymes in mammalian tissues than to inhibit fungal
`çytachrómç F.459.16414.6 T%;s_tnay explain why en-
`docrine effects become evident in patients tidy at high
`doses. Concentrations 12 times higher than those suffi-
`cient for antifungal activity are needed to inhibit an-
`drogen synthesis in testis nicrosomes> Cholesterol
`side -chain cleavage in testes and adrenals and adrenal
`1lß- hydroxylase are inhibited at even higher, con -
`centrationss9
`
`Steroid Transport and Action
`In addition- to a direct: action on multiple enzyme'
`systems in different steroidogenic glands, other' mech-
`anisms by which ketoconazole may produce endocrine
`effects have been described, A glucocotticoid antago-
`nist activity,, which acts by occupying glucoeorticoid
`receptors, has been observed in cultured hepatoma
`cells.` Displacement of dihydrotestosterone and, to a
`greater extent, estradiol from sex -hormone- binding
`globulin by ketoconazole is observed in vitro at, drug'
`concentrations equivalent to those in patients receiv-
`ing high therapeutiad'oses. ii Cortisol binding to corti-
`costeroid - binding globulin is not affected.' " Iit normal
`volunteeis and, in patients on a high -dose regimen,
`
`

`

`Vol. 317 Ne 13
`
`MEDICAL INTELLIGENCE - SOMNO.
`
`813
`
`Figure,t, Structure ofKeto$oriazole,-
`
`a significant elevation of the estradigl:testosteráne ra-
`tio (both tqtal. and free hormone) occurs,35,32 but the
`percentagest of bound and free fractions of both hor-
`mones are notsignificandyaltered; thus`, thedisplate-
`ment of estradiol from,, its binding globulin is not
`relevant in vivo,,%3s,36 The increased estradiol testos-
`teronç ratio may be an iru ortant factor in the deveh
`opment of gynçcomastia,4Z a pnncipal side effect of
`the drug. 4,5'8,35
`Ketoconazole seems to have no direct effect at the
`pituitary level on the secretion of either adrenocortico-
`tropm4frior luteinfzing hormones in rat tissue studied
`in vivo and in vitro, This is in agreement with clinical
`findings, as discussed below.
`
`has been found to be biphasic, with an initial hallifé
`to 33 hoursWe49 and a terminal half -life, of 8
`of 1
`hours,48,31 Protein -binding studies have shown a high
`percentage of ketoconazole bound to plasma proteins,
`mainly albumin: 99 percent in human whole blood, t7
`and 93, and 91 percent in human serum al serum con -
`centrations of 50 and 25 µg per milliliter:54 The drug
`is widely distributed in body fluids, with detectable
`concentrations in urine, saliva, sebum, and Cerumen
`after- a 200-mg oral dose» In a patient receiving 400
`mg per day, 'semen ketoconazole concentrations one
`and three hours after the dose were 0.9 and 0.25 ;ug per
`milliliter, indicating penetration into the genitouri-
`nary tract 4i One study found that after an 800 -mg
`dose, ketoconazole was measurable in the cerebrospi-
`nal fluids*
`Ketoconazole is extensively metabolized, into ink,
`rive compounds, primarily by the liver»,48 Metabo-
`the
`lites and unchanged drug are excreted mostly
`feces, with very little excretion into. the urine. Al-
`though renal,iínpairment does not seem to chow -acros-
`mulation of thedrug, hepatic insufficiency is a;contra-
`indication to its usek, since the agent is metabolized
`mainly by the liver and might worsen liver damage,by
`producing a toxic effect, el,ts
`In addition to its hepatotoxicity, ketoconazole's in-
`terference with some mixed-function oxidase- systems
`in liver microsornesis'6-;$s may have important non-
`endocrine clinical effects that resul i. front alterations in
`the hepatic metabolism of the drug. Possible drug in-
`teracticns,which are most likely due to interference
`with enzyme activities in liver microsomes, include
`potentiation of oral anticoagulants by kètoconazole,27
`markedly dinìinished serum concentrations of both ri
`fampin and ketoconazole upon simultaneous adminis-
`tration of those agents,* adelay in the post -dose peak
`of ketoconazolt concentration. during long -term ad;-
`
`MINERALOCORTIOOID
`
`GLUCOCORT1COID
`
`ANDROGEN
`
`CHOLESTEPtA.
`scc
`
`17 ON
`PRkfWENOLONE-I--Y17.0tFPSEGNENOLONE
`>s too
`Oß aSD,
`
`1
`17 ON
`' PROeESTERO¡IE 17-0HPROGESTERONE
`210N
`I1 011
`
`,
`
`117,20 LYASE
`PHDEHVDHOEPIANDneóTE80NE
`ON MSG
`
`17,20 LYAEyE
`,
`,
`
`y
`ANDHOSTENEDIONE.
`
`i 17a
`
`PEIARMACOLOGP
`The hormonal changes producedby theadministra=
`.don of ketoconazole are dose -dependent -and fully .re-
`versible ,5,7,s,te,IS,2o,35,4i,4s with recovery front steroid -
`ogenin blockade 8 to 16 hours after an oral dose.'06
`A considerable degree of variation in the btoavailábif-
`ity of the drug has been observed, lit pharmacoki
`netic studies.44,42
`In normal subjects given a single oral dose of 209 or
`400 mg of ketoconazole, the peak serum concentra
`tions occur at two hours and are 3
`to 4 and 5 to 8 µg per milliliter,
`respectively.4'464a Higher serum
`levels are found in patients taking
`800 to 1200 mg per day."' At eight
`hours; the drug is still measurable
`in serum, but it is undetectable. at
`24 höursc3506,47 Administration im-
`mediately after a meal results in
`lower serum, levels than does -ad-
`ministration during fasting.4668,49,_
`Gastric acidity is required for ab-
`sorption, which may be impaired
`by achlorhydria or antacid medi-
`eation.48,5e
`Serum or plasma levels of keto-
`conazole have been, determined by
`4s,4e;si
`bioassay
`and by more sen-
`sitive high- performanceiiquid chro
`matographiamethods.SZZ5s Even at .
`high, concentrations the drug does
`not interfere with hormone radio-
`immunoassays,5, t0,35,4L
`The serum clearance of the drug
`
`1
`ti-DEOxYCOaTICOSTERONE
`.11 OM
`
`C0e1OO5TERONE
`{B ON
`
`18&O14COÁTICOSTEHONE
`
`romp
`
`,
`
`11DEOxYCORTISOL
`*11 ON;
`
`CORTISOL
`
`TESTOSTERONE
`
`1
`
`ESTROGEN
`
`,
`
`ALDOS[EON6
`Ry
`
`Figure 2, Main Pathways of Adrenal Sterotdogenesis
`SCC`denotes cholesterol side -chain. cleavage; HSO hydroxysterold dehydrogenase,
`OH hydroxylase, and,OH D hydroxy dehydrogenase. Black bars Indicate ketoconazoie.
`'inhibition, and black- andwhite bars metyrapone. inhibition;
`
`

`

`814
`
`THE NEW ENGLAND JOURNAL OE MEDICINE
`
`Sept. 24, 1987
`
`ministration cf phenytoin,`l' accumulation of cyclow
`sporine during ketoconazole therapy )8 and inhibition
`of the disposition of methylprednisolone.si
`
`Side Effects
`The most common side effects at the doses usually
`employed for fungal infection (200 to 400 mg per day)
`are gastrointestinal reactions, pruritus, and alter -
`ations in hepaticfunettenas.47,4B56.60.62 About 1b en,
`cent of patients have transient abnormalities in liver
`function,5°'6 but the incidence of true hepatic injury -
`seemt to be very low (0,1 to I.0'percent).t7'SBM6GFatal
`hepatitis" and anaphylaxisó5 have also been. reported,
`The mechanism of liver damage induced by ketocona-
`zole is still unclean It seems to involve an idioryncrat-
`fc type of reaction that does not depend on the' daily
`dose or the duration of treatment. However, an im-
`mune hypersensitivity mechanism could not be ex-
`cluded in sonic cases. Biochemical tests and assess-
`ment for clinical signs of liver dysfunction at periodic
`intervals (i.e., biweekly for- the first two months and
`then monthly) are therefore advised. NO incteasedin.
`cidence of hepatotoxicity has been reported in pa;
`tientsreceivingprolonged high- dosetreatment (800 to
`1200 mg per day). In patients on a regimen of 200 to
`400 mg per day; gynecomastïa4 is very rarer At high=,
`er doses, endocrine effects, such as impairment of tes-
`ticular fùnction 9,66 and adrenal nsufficience"69 may
`occur. It is because ketoconazole produces such effects
`that it has been used to treat clinical conditions that
`may benefit from inhibition,of either gonadal or.adre-
`nal steroid production (see below).
`gocEN PRODr7CTION
`INAIBrrlON OF ANDROGEN
`A substantial decrease in total and free testosterone
`and androstenedione levelscoccurs in normal men two
`hours after a. single= 200-mg dose of ketoconazole.5 9
`Recovery from suppression begins at 8 hours, and is
`complete by 24 hours. There is a. compensatory in-
`crease in plasma luteinizing hormone and no changa
`in cortisol levels, as compared with values in persons
`receiving placebos suggesting that there is selective
`inhibition of Gt7.2o lyase at low doses 19 In patients'
`receiving high or repeated doses on a long -term basis;
`end -organ effects of diminished testosterone levels be-
`come apparent; with marked individual. variationss.
`Large differences in mean serum levels of both keto-
`conazole and testosterone are found among patients
`receiving thesame dosage; yet, an inverse correlation,
`between ketoconazole and testosterone concentrations
`is consistently observed as7,70,71;- During prolonged
`treatment with 800 to 1200 mg per day in a single dose
`for progressive systemic fungal, disease, testosterone
`levels are subnormal over 24 hours in some cases, re-
`sulting in reduced sperm counts (after four: months),
`azoospermia, decreased;ltbido, impotence, and gyne --
`comástia s Functional hypogonadism appears to be
`reversible upon drug. withdrawal.-
`Because of its marked effects on the androgen -
`gonadotropin feedback system in vivo, ketoconazole
`
`has been advocated, for use in a test of gonadotropin
`reserve in men.37 Additional studies are required to
`verify its feasibility and clinical, usefulness. In the first
`trials nine normal men received four doses of ketocon -.
`ázole (300, 60G, 900, and 1200 mg per day); each dose
`was given for one week. The response to luteinizing
`hormone -releasing hormone was assessed before and
`after each week. Increasesin luteinizing hormone and
`fol iclestifnulating hormone were maximal after the
`dose. of 900 mg per day. Ifowever, there was, great
`variability among subjects in the levels of both gona-
`dotropin and testosterone at each dose tested ,s7
`
`Therapeutic Use
`The pòtentinhibitory action of ketoconazole on ter-,
`tosterone synthesis (Fig 2) has been used with therä4
`pectic benefit in the management of prostate ,can
`The drug acts very quickly and has the
`cer:
`advantage over other treatments currently employed
`of also decreasing adrenal androgen production.72`74
`At divided dosesof 400 mg every eight hours, which
`prevent androgen levels front retuning to base lines
`castrate values are initially 'recorded. However; the
`rise in luteinizing hormone triggered by the fhli in
`testosterone leads to a progressive increase in testas-
`terobe levels? 3; Nevertheless, striking dirtiest im,
`provçment is seen in many patients; serum levels of
`prostatic: acid phosphatase decrease and considerable
`pain relief and regression; of some lesions occurs}
`gready reducing the need for analgesics.7t`7+ Indeed,,
`clinical improvement seems to be better than would be
`expected on the 'b'asi's et testosterone levels over the
`long terms Howbvet, in addition to impotente and
`gynecomastia, severe gastrdintestinal disturbances75
`and signs of adrenal msufciency71'2 may occur,. re-
`quiring dose reduction and glueocorticoid replace-
`ment, respectively. Further hormonal assessment dur-
`ing long +term treatment shows' a consistent rise 'in
`progesterone,, no changes in prolactin and estradiol;
`and an increased estradiol:testosterone ratio;s5`70 72
`The proposal to ùseketoconazole as a "sole treat.:
`meat" for prostate cancer=a has been questioned bet,
`cause of several problems that have arisen in some
`studies; sustained reductions in testosterone levels
`cannot be maintained large diurnal fluctuations in
`serum testosterone occur in most patient; and, coin,
`pitance with a high-dose regimen and strict eight =hoot,
`timing, of doses is somewhat dîfficidt.to obtain 70.71;zs..
`Nevertheless} good results are generally reported,
`especially in patients previously castrated or with
`castrate testosterone levels produced by administra-
`hormone analogues In
`tion of
`such patients, ketoconazole; by suppressing adrenal
`androgen output, brings about further objective or
`subjective remissions.X1.75 Indeed, a. rationale for com-
`bined treatment with , ketoconazole and superaedv
`analogues of gonadotropin-releasing hormone in this
`has been suggested by the more pronounced .
`androgen suppression obtained with both drugs than
`with either alone, in studies in both hunxans7s,76 and
`
`

`

`Vol 317 No 13
`
`MEDICAL INTELLIGENCE -SONINO
`
`815
`
`animals 77 Improvement has been reported in some
`patients in whom the combination drug treatment was
`introduced after other treatment methods had been
`used2S However, it has not been proved that the com-
`bined treatment is more effective than ketoconazole
`alone, and further evidence is needed before it can be
`recommended
`Successful therapy with ketoconazole for up to 12
`months has been reported in three children (S 3 to 3.9
`years old) with precocious puberty and autonomous
`Leydig -cell hyperactivity with low basal and,gonado-
`tropin- releasing hormone- snmulated gonadotrapin
`levels -7a Divided doses (up to 600 ing per day), were,
`employed, with striking behavioral. and clinical'im-
`provement. The growth rate and, sk'eletal matt-ration
`were both reduced, and low levels of testosterone and
`adrenal androgens were maintained in the presence of
`high levels of 17a- hydroxyprogesterone. Basal cortisol
`levels were in the normal range for age. Similar results
`have been obtained in another child (4.2 years old),
`with gonadotropin- independent precocious puberty
`and tuberous sclerosis, who was Ms() successfully
`treated for suc months with ketoconazole. (600 mg per
`day) 79 In three older children (5 0 to 7.4 years of
`age), an "escape" phenomenon occurred after one to
`three months of continuous treatment with 600 mg per
`day, probably because of the onset of puberty -like
`pituitary function In these children, combined treat
`'ment with ketoconazole and a gonadotropin- releasing
`hormone analogue restored hormonal level's to the
`prepubertal range 80 No signs of liver dysfunction or
`other side effects occurred in any child. In these pre-
`liminary studies, ketoconazole was a safe and effective
`inhibitor of testosterone overproduction in children.
`However, the long -term safety of high -dose treatment
`with the agent in children needs to be established.
`selective inhibition of andro -
`Finally, because of
`gen production at low doses,i0 ketoconazole might be
`useful in the management of hirsutism. However, no
`clinical data on this issue are available at present,
`except for reports of a few patients who had regression
`of their hirsutism whild receiving ketoconazole for
`Cushing's syndromes"' and one patient with hirsut-
`ism and polyeystic ovary syndrome who had striking,
`improvement two months after, starting ketoconazolé
`therapy (200 mg twice daily) A2 On the other hand,
`the effects on estrogen production are still controver-
`sial, and it is not known whether the drug'affects hot -,
`tonal cyclicity Thus, the possible interference of ke-
`toconazole with the human menstrual cycle should be
`evaluated.
`INHIBITION or C.PRTiSQL PRODUern9N
`When ketoconazole is administered to subjects
`with normal function of the hypothalamic- pituitary-
`adrenal axis, the plasma cortisol response to adre-
`nocorticotropin .is blunted for up to eighthoürs,after a
`single dose of 400 or 600 mg,7.8°8'n83 However, ba-
`sal cortisol levels are not affected or are only slight-
`ly lower, even during long -term high -dose treatment
`
`(up to 1200 mg per day).7'7pa,ys Signs of adrenal
`insufficiency are uncommon,ss'67 -69,71 probably be-
`cause of a compensatory rise in adrenocorticotropin
`levelsst7M2
`
`Therapeutic Use
`Because ketoconazole is a potent: inhibitor of corti-
`sol production, through the inhibition of both adreno-
`cortical 11P- bydroxylase and, cholesterol side -chain
`cleavage (Fig. 2), it has been used in clinical trials of
`palliative treatment of Cushing's syndrome. Drug
`control of hypercortiso sm Is suitable for patients un-
`dergoing surgery, as well as for those treated with ex-
`ternal pituitary radiation and those in whom more
`definitive treatment is delayed.
`In patients with an adrenal tumor or pituitary-
`dependent Cushing's disease, plasma cortisol, levels
`are suppressed and the cortisol response to adrenocor-
`ticotropin is blunted after administration of ketocona-
`zole; inhibition of cortisol production by the drug has
`been confirmed in vitro in tissue slices of the excised
`!86 Beneficial, en-
`tumors or hyperptastic adrenalssl?
`docrine' effects of ketoconazole at dosep.ranging from
`200 to 1000 mg per day have been observed in patients
`with Cushing's disease and in patients with either
`adrenal adenomas or carcinomas." increasing doses
`(from 400 to 1200 mg per day) have been used to
`reduce excess- steroid effects in a patient with Cush-
`ing's syndrome secondary to a functioning adrenal -
`rest tumor of the liver, ?s in a, patient with prima-
`ry adrenocortical micronodular adenomatpsïs,se and
`in one with Cushing's syndrome due to ectopiepro-
`duetion of adrenocorticotropin by a small -cell lung
`cancer,80 with improvement in clinical symptoms.
`Since ketoconazole interferes with Ci7- 20)yase and
`is a more potent inhibitor of cholesterol side -chain
`cleavage activity, it can be expected that patients
`treated with the agent will he free of side effects such.
`as mineralocorticoid eitcess or worsening of hirsutism,
`which may occur during treatment with metyrapone,
`-hydroxyl -
`which acts predominantly on 1'6- and 1
`ases (Fig 2). On the other hand, the antiandrogenid
`effects of ketoconazole may be disturbing in male pa-
`tients. We used prolonged ketoconazole therapy (two..
`to six months) in five patientswith pituitary- depend-
`ent Cushing's disease and recurrent hypercortisolism
`alter transsphenoidal surgery &i A sixth patient was
`treated to two weeks before undergoing: bilateral ads
`renalectomy. A dose of 400 mg °every 12 hours was
`given during the first month and lowered thereafter,
`depending, on individual responses. Urinary cortisol
`levels decreased to normal in all patients, and rapid
`clinical improvements were observed"' No patient
`had signs of drug toxicity, Female patients had regres-
`sion of hirsutism, whereas in the only male patient,
`who was treated for four months, gynecomastia devel-
`oped: We are now treating additional patients with
`Cushing's disease with ketoconazole, (600 mg per
`day). Drug doses necessary to maintain cortisol levels
`within the normal range in this condition are relatively
`
`

`

`1116
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`Sept. 24, 1987
`
`25- hydroxyvitamin D by a cytochrome P -450 enzyme,
`in liver mitochondria is also impaired.
`
`CONCLUSIONS
`Recent research has extended the use of the anti -,
`mycotic agent ketoconazole to endocrine conditions,
`Crucial factors modulating the drug's effects are the
`dosage and timing of administration. Relatively low
`and singledaily, dosesare less likely to affect the endo-
`ctine`system, whereas high or divided dosea produce
`themawmum endocrine effects. As a potent testicular,
`and adrenal steroid inhibitor with a predominant an-
`tiandrogenic action, ` ketoconazole is suitable for treat':
`ment of prostatic carcinoma, especially in combina-
`don with gonadotropin -releasing hormone analogues.
`The latter agents prevent the compensatory increase
`in luteinizing hormone and the consequent stimula-
`tion, of testicular steroidogenesis that cart overcome
`the enzyme blockade induced by ketoconazole. It
`should bepointed. out that the available reports are
`still preliminary, International multicenter studies are
`in progress to define the-role of high-dose ketoconazole
`in the treatment of prostatic cancer. -9 Further studies
`will show whether ketoconazole can be pf yalue in the
`management of conditions of androgen excess, such as
`some forms of bromism and precocious puberty due,
`to autonomous Leydig Dell, hyperfunction.
`In addition, ketoconazole has proved to be useful in
`treating Cushing's syndrome of various causes be,
`cause of its ability to correct the severe complications
`of the disease quickly. liecauseof its differentialselec-
`tivvity, the drug can,be used as an alternative; tb steroid
`inhibitors that produce side effects- Moreover, during
`prolonged treatment of pituitary- dependent Cush -
`ing's disease with ketoconazole, cscapefrom ádrenaF,
`inhibitibít does not seem to occur. However the drug.
`interaction with the hypothalamic-pituitary- adrenal
`axis has, not been fiilly'clarifed.
`I am indebted. to Dr Alexander. G. Brownie for his eomments'and'....
`suggestiontittul to Mrs, Esther Old** far assiétitnetin the itrepara-
`don or thamánusodp6
`..
`
`lower than those employed to suppress testosterone in
`prostatic cancer, and are well tolerated.:
`Longterm administration of ketoconazole (8 to 15
`months with 600: to 800 mg per day) hi other groups of
`patients with pituitary- dependent Cushing's disease
`has also resulted in decreased cottisol levels and im=
`pressive clinical improvement,70'9' including regres-
`sion of psychiatric symptoms.9e It is noteworthy that
`unlike the findings in patients with an intact hypo-
`thàlamie- pituitary- adrenal axis, there was no Marked
`increase in adrënocottitotropin levels during long-
`term administration ïn,any patient with Cushing's du --
`ease. itsdeed,, little changeS' or a decrease" in plasma
`à tleenoeortitcotropin concentrations was observed In
`these patient's,, however; the adrenocorticotropin re-
`sponse to corticotxopin- releasing hormone during ad-
`thin jstration' of ketoconazole was unchanged91 or even
`enhanced?? as -coínpared With the pretreatment re-
`spotte; This finding argues, against an additional îrn
`hibitory effect at the pituitary level and is in agree-
`ment with the results ofprevious studies in animals."
`Although no conclusions can be drawn from, the
`data available, long -term treatment with adrenal in-
`hibitors m1ht modify the sensitivityy of the hypo-
`thalamic- pituitary, -adrenal axis in Cushing's disease,
`since unexpectedly low adrenocorticotropin,levels
`have also been kind during prolonged combined ad-
`ministration of inetyraponeand aminoglutethinlide.9s
`One patient had marked regression of a functioning
`metastatic adrenal carcinoma while receiving pallia-
`tive, ketoconazole treatment As in advanced prostate
`cancer,7I,72,7aitis not known whethet the drug acts on
`tumor cells by more than one mechanism.
`Onnext Eznars.
`
`Cholesterol
`Serum cholesterol levels were decreased after high -
`dose ketoconazole treatment' in patients with ad-
`vanced prostate cancer.7n." The inhibition of cho-
`lesterol synthesis seems to be: dose -dependent 94
`However, the effects of ketoconazole on cholesterol in
`humans need further evaluation with attention to po-
`tendal benefits and harm since the consequences of
`an accumulation of cholesterol precursors are not
`known9h,9S
`
`Vitamin D
`The inhibitory action of ketoconazole on kidney nil-.
`tochondrial 24- hydroxylation of 25- hydroxyvitamin
`D14,27 has led to further investigation of the effect
`of this agent on 25- hydroxyvitamin D metabolism.
`In cultured chick kidney cells, ketoconazole and mi-
`conazole at therapeutic concentrations function as
`competitive inhibitors of both 1- hydroxylase and
`24- hydroxylase activities 96 These hydroxylases are
`also,.cytochrome P450= dependent enzymes. Alter
`ketoconazole administration to normal volunteers, a
`dose- dependent reduction in serum 1,25- dihydroxy-
`vitamin. D levels with no change in serum levels of
`25- hydroxyvitamin D and parathyroid hormone was
`observeds7 It is not known whether the formation, of
`
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