`
`February 3, 1986
`Vol. 144, No. 3
`
`H EAl_T_i*i SC i ii :1 C F33 Ll HA {I Y
`LEADING AFITICLESUml"-.-'as'siiy oi l.fi'PA6IEsin
`
`THERAPEUTICS
`.
` Relinquishingififiithaersu Dr,
`
`Gordon Parker
`Single-dose therapy in the
`
`Compliance with asthma
`management of urinary tract
`infections. Judith A. Whilworih,136
`in paediatric practice.
`David R. Lines
`Side—effects of corticosteroid
`agents. J. Paul Seale.
`Bicycle accidents.
`--
`-
`-
`Douglas Cohen -
`-
`Mark R. Compton___?_139
`lnformational needs for the
`' effective prevention of accidents
`in childhood. Graham Vimpani.
`John Pearn. Jerry Mo|ler_{_115
`
`MEDICAL MISCELLANY
`Frederick III of Germany.
`James H. Leavesley_?;__143
`
`CASE REPORTS
`Child cyclist iniuries: a
`prospective study.
`Christopher J. Armson,
`Clifford W. Pol|ardj;j__144
`Pathological rupture of the spleen
`in transforming non-Hodgkin’s
`lymphoma. James D. Griffiths,
`Jue Chong Ding, Surender K. Juneja.
`Robert .18. Thomas, John J. Martin.
`
`Ian A. Cooper
`A case of uridine diphosphate
`galactose-4-epimerase
`deficiency detected by neonatal
`screening for galactosaemia.
`Francis G. Bowling,
`David KB. Fraser. Alan E. Clague,
`Alan Hayes. Darryl J. Morris___15O
`Acute, severe hepatitis due to
`Coxielia burneti infection.
`Raymond P. Kelly, David J. Byrnes,
`Jennifer Turner_?__j;_151
`
`146
`
`
`
`.,D
`ht.
`.__r_r.,
`..
`i"lBg£lem;i|3FHl}é$ll-"-."-
`.....v.35
`
`-s-'
`
`154
`Noticeiifluatfilv ‘-i" "'-"'~"'
`“ F ‘I55
`illateeltinga .‘
`.
`"-“"7”
`158
`_“
`Obituarie =
`-
`Book Fievl s__i__159
`
`
`
`LETTERS TO THE EDITOR'__j_163
`_
`__
`_.
`. _.
`..
`1-K‘
`---
`
`JANSSEN EXHIBIT 2069
`
`Wockhardt v. Janssen IPR2016-01582
`
`ORIGINAL ARTICLES
`Psychological disability in women
`who relinquish a baby for
`adoption. John T. Condon ___117
`Effects of intervention on
`medication compliance in children
`with asthma. Nerida A. Smith,
`J. Paul Seale, Philip Ley, John Shaw,
`Peter U. Bracs_?._?__119
`Intrapulmonary coin lesions: the
`changing patterns.
`David B. Francis,
`Paul V. Zimmerman _;_f__‘I22
`Glucagon and ureteric calculi.
`David R. Webb. Ian N. Nunn.
`'
`Donald McOmish, William S.C. Hare 124
`Effective palliation of melanoma
`with procarbazine and radio»-
`therapy given by a low-dose
`fractionation schedule.
`P. Grantley Gill, Richard L. Abbott,
`Ash Ahmad, Joan Zeicmanis
`Major hepatic resection for
`neoplasia: the Concord Hospital
`experience. Patrick C. Cregan,
`John W. Hollinshead. David J. Gillett 128
`
`126
`
`POINT OF VIEW
`Psychiatry, compensation and
`rehabilitation. Fiona K. Judd,
`Graham D. Burrovvs__;?_131
`
`-
`
`_:-Steven] C-1» Ausuaina Peal. F'uc.lIr.a1u:-n r-.'c..
`
`.’-151'; i;':ij:3£
`
`JANSSEN EXHIBIT 2069
`Wockhardt v. Janssen IPR2016-01582
`
`

`

`HE MEDICAL FOLJRNAL OF ALISTRAUA Vol. I44 February '3,
`
`i986
`
`Therapeutics
`
`139
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Side-effects of corticosteroid agents*
`
`cortico-
`ABSTRACT Anti—intlaniriiatory
`rcroid drugs are povvertul tlterapeutic agents
`tor a wide range of disorders. I-lowever, they
`to have recognized sirle-ettccts, niost of
`\-\-'lll(_'l'l are related to the dose and the duration
`-2-t therapy. Thus, short" courses of even high
`rinses of corticosteroid drugs have very few
`.It'_lV{_‘l":-E effects. A detailed l-tnovvleiiigc of the
`lung-term side-etfects of corticosteroid agents
`and their incidence will assist the physician
`w making informed iudgentents on the poten-
`tial benefits of treatment with these drugs.
`(Matti
`l Ausl "I986: 144: 139-142)
`
`he development ofcorticosteroid agents
`represented a ntajor advance in the
`treatment of nLtmt.‘t‘otlS inl'l:-nntnatory
`diseases of varying causes: regrettably.
`their
`'.sItl€.‘ipl'I3ElLl
`use must be tempered by an
`appreciation of their side-effects. which occur
`_-otnmonly. As with any potent
`therapeutic
`agents. the prescribing of corticosteroid therapy
`\l'li_‘|l..1ld be guided by a careful consideration of
`its perceived bettcfits and potential risks. This
`article will
`review the unwanted effects of
`systeinically adntinistercd anti-inflantntatory
`corticosteroid agents.
`the complications of
`In gerterttl.
`any of
`corticosteroid agents are related to the dose and
`the duration oftherapy.‘ Thus. most of the well
`known problems will arise only during long-
`term treatment. On the other hand. remarkably
`few. adverse effects ai'e associated with short
`courses of corticosteroid drugs.
`even
`in
`relatively high doses.’
`In view of this clear
`rlistinctiort. short—term and long—term treatments
`will he considered separately.
`'-
`Since prednisoite. prcdnisolone
`and
`ntcthylprcclnisolone are the most commonly
`used corticosteroid agents. most of the available
`:linical data on sidc—cffects concern these drugs.
`Sound reasons exist for the administration of one
`
`of these agents in preference to the tnore potent
`corticosteroid drugs. such as dcxtunethasone and
`netainethasone. Prcdnisone. prcdnisolone and
`its methyl analogue have less mirtcralocorticoid
`.activity than does cortisol, so their propensity
`to retain sodium and water will be less than that
`of cortisol. In addition. their biological half-lives
`are of irttennediate duration (12-36 hours),
`allowing a oncc—a-day dosage
`regimen.‘
`Furthermore, a patient's daily requirements can
`easily be obtained from the range of the available
`tablets and this facilitates the process of titrating
`dosage against disease to [ind the minimum close
`that will control
`the disease.
`In contrast.
`
`in an occasional «(tries on therapy with
`‘Filth -fl|'ll(.lf_‘
`corticosteroid agents.
`
`Department of Pharmacology, The University
`of Sydney. NSW 2006.
`.'.
`|".tul Scale, PhD. F-RACP,
`I. lniical I’l1.':rn1aL'o|ogy
`n\-tarlt R. Contoton, B5t', Re-ar-_'arc11 .‘\s~'.ist.1tit
`Hcprinls will not he av.—.tilolJ|e from the atithtm. The
`.~t:'|'IPs 0|" arItr_'|i?'~ on r.orItroslr_-roicl the-rapy will he
`tluhlishcd later in brtoklct torni.
`
`.>\ssoL'tate |’rrils-wit" in
`
`J. Paul Seale and Mark R. Compton
`
`although dcxantethasone and betatnethasonc are
`virtually devoid of Inincralocorticoid activity,
`they have much longer biological half-lives
`(36-54 hours) which are responsible for their
`profound sttpprcssion of the |typoth:ilantic—
`piIuitary—adrenal axis. Also. the ttwtilable tablet
`strengths do not allow for the same line titration
`of tninimal daily dosage that is possible with
`prednisone and prednisolone.
`
`Short-terin therapy
`Doses of up to 100 mg of prednisone a day may
`be taken for three weeks or less without any
`great risk of the occurrence of adverse effects.
`Occasionally. patients may notice weight gain.
`mild fluid retention. insomnia or mood changes
`(euphoria. depression or.
`rarely. psychosis).
`Adverse psychiatric reactions are more likely to
`occur in patients with preexisting psychological
`problems.’ The metabolic
`actions of
`corticosteroid drugs may
`lead to hyper-
`glycaetnia.
`Io kctoacidosis in diabetic indi-
`viduals
`and to
`ltypokalaemia. Superficial
`punctuate ulcerations oi‘ the gastric mucosa and
`associated haemorrhage may
`also occur.‘
`However. these effects are reversed when the
`drugs are discontinued. A rare but serious
`complication ofthe intravenous administration
`of corticosteroid drugs in asthmatic patients is
`the development of anaph_vlactoid reactions:
`these may be difficult to differentiate from an
`exacerbation of asthma.’
`Short courses of high—dose corticosteroid
`agents may produce transient abnormalities of
`the hypotha|amic—pituitary—adrenal axis such as
`reduced basal plasnta concentrations of cortisol.
`diminished adrenal gland responses to :ulreno—
`corticotrophin (ACT Ht and blunted responses
`to insulin-induced hypoglycacrnia." Two days
`after the administration of prcdnisolone E35 mg
`twice a day for five days). the cortisol responses
`of [0 normal men to both the induction of hypo-
`glycactnia and the administration of synthetic
`ACTH were reduced to about one-half their
`
`previous levc|s:‘ In a study of seven patients with
`chronic airflow obstruction. who were given
`prednisolone (20 mg twice a day for
`three
`weeks), basal plasma cortisol and plasma ACTH
`concentrations were suppressed at
`the com-
`pletion of treatment but returned to normal
`values within four days? Thus. it is evident that
`corticosteroid therapy can affect hypoIhalarnic—
`pituitary—adrenal function within a few days of
`iLs contmencement, even though the dysfunction
`usually disappears rapidly once treatment has
`been ceased.
`that patients
`Since these findings suggest
`theoretically may be at risk if they encounter
`stress within a few days of the abrupt discon-
`tinuation of corticosteroid therapy.
`it may be
`prefe rable to withdraw an agent gradually over
`five to seven days. For sortie inflainirtatory
`tlisorders.
`it may be necessary to reduce the
`
`dosage of a cttrticrisleroid drug over a longer
`period oftirne to prevent recrudescence of the
`disease. Wltetever possible.
`once-a—da_v
`regimens should be prescribed, since they are
`more likely to result in rapid recovery of the
`hypothtiIamic—pituitary—adrcnal
`axis when
`corticosteroid therapy is ceased.‘-
`Awareness of the transient disturbances which
`may occur with short—term courses of cortico-
`steroid agents will ensure that these potent drugs
`are used safely and effectively.
`
`Long-term therapy
`It is with prolonged trcatrnent that the unwanted
`cfliicts. well known both to incdi ".t| practitioners
`and to [lie lay public. are likely to be encoun-
`tered.
`ln general. the lower the maintenance
`dose ofa corticosteroid agent. the less the risk
`of side-effects.
`
`In adults. it is likely that daily doses in excess
`of [0 mg of prednisone will eventually lead to
`some side.~effccts.7 It
`is probable that even
`smaller daily doses [for example.
`'i'.5 mg of
`prednisonet,
`if taken in the long term. are
`associated with complications in the elderly.“
`Thus. it is not possible to stipulate a daily dose
`at which the risk of side-c|'fects is non-existent.
`
`H_vpet‘tr?tt.\‘i0rr
`salt-retaining properties of
`Although the
`prcdnisone and prednisolonc are less than those
`of cortisol. these synthetic corticosteroid agents
`may still cause hypcrnatraeinia. fluid retention
`and hypertension. In addition. other mechan-
`isms. such as the enhancement of the vasocon—
`strictor effects of endogenous substances and
`increased concentrations of rcnin substrate‘-' have
`been postulated as contributing to the hyper-
`tensive effects of glucocorticoid hormones.
`These effects are probably related to the dose
`since long-temi |ow—dose therapy does not carry
`any appreciable risk. Ina study of 129 patients
`with chronic airliow obstruction who were tak-
`ing prcdnisone or pi-cdnisolonc (mean daily dose
`1- SD. 6.? i 3.3 mg l'or 9.7 i 5.5 years) and
`66 patients with rheumatoid arthritis who were
`taking prednisone or prednisolonc (8.4 t_— 2.7 mg
`for 8.4 : 2.7 years).
`there was
`a
`small.
`statistically significant increase in systolic blood
`pressure without
`a
`significant
`increase
`in
`diastolic blood pressure!“ However, multiple
`regression analysis showed that an increased
`systolic blood pressure level correlated with age
`and blood pressure before therapy. which
`suggested that
`these factors were the main
`determinants of increases in systolic blood
`pressure.
`It was concluded that low doses of
`prednisone or prednisolone are not important
`causes of hypertension.
`In the elderly, the incidence ofclevated blood
`pressure may be higher. Fifteen of 100 patients
`{aged 69 years or more) who were taking pred-
`nisolone tl2.S mg a day or less) for an average
`of -1.8 years developed hypertension ("defined as
`
`

`

`H0 Therapeutics
`
`than
`-ll diastolic blood pressure oi" greater
`|1:'\ ti1niHg or a systolic blood pressure olgrenlcr
`titan l8U tnmHgt. compared with three or‘ lllll
`age~tn:itc|ted and sex—maIchcd controls,“ The
`precise mechanisms by which elderly patients
`develop hypcrlettsiott, and other side—el‘t’ects of
`corticosteroid therapy. such as ostcoporosi.s.
`more
`re:tdiI_v
`than others
`have
`not been
`elucidated. Une possible contributory factor may
`he
`the increased plasma concentration of
`unbound corticosteroid drug due to the lower
`serum albttrttin level
`in the elderly."
`E.-’ecrt'rJ.-’_\‘t:’ rt't'.s'rttr‘btrttce.~;
`Since prednisone and prctlnisolone retain some
`ntineraloeorticoitl activity.
`they increase the
`distal
`t'enal tubular reabsotption of sodium iit
`exchange
`for potassium.
`bytlrogen and
`anttnonium ions which may lead to pypern:tt—
`metnia and |t_vpokzt|aentia in some individua|s.'1
`In large doses. cor1icosteroid drugs ntay cause
`hypokalacrnic alkalosis. However. alkalosis may
`develop in some patients without any evidence
`of potassium depletion, suggesting that increases
`in scrunt bicarbonate levels ntay be a direct
`effect of" corticosteroid therapy."-'
`0.rtc'opuro.sis
`Httients who receive prolonged therapy witlt
`greater than physiological doses ol‘ corticosteroid
`agents tend to develop some degree of osteo-
`porosis. Glueocorticoid agents decrease bone
`formation owing to a direct inhibition ol'osteo-
`blastic activity and they
`increase bone
`resorption. which leads to loss of bone —
`preferentially that ol trabecular bone in the spine
`and ribs)" Bone
`resorption occurs
`as
`a
`conseqttettce of secondary hypcrparathyroidisttt.
`which is caused by corticosteroid—induccd
`hypercrtleittria and inhibition ot'c-nteral calcium
`absorption." Not all patients develop osteo-
`porosis. but postntettoptittsal women and elderly
`or itrtmohilized patients are at high risk olthis
`complication. Since current pbarniacological
`approaches at best halt. rather than reverse.
`conicoste roid-induced osteoporosis. one should
`aim to detect
`this problem before serious
`complictttiorts such as conipression lhtctures ol‘
`the vertebral column have occurred. While the
`reliable detection of early changes requires
`sophisticated tecliniques
`such as photon
`tthsorptiotttetry. plain .v.—ray Iilms of the spine
`may also provide useful
`iriformat'ion. Once
`patients at risk have been identified. propltylaxis
`with vitamin D and calcium supplements. or
`vitamin D and hytlrochlorothiazide therapy it"
`hypercalciuria
`is
`}‘Jt'L.‘-.it':l'll.
`should
`be
`considered .' " Since no proof yet exists that such
`a programme of prophylaxis is el'fectivt:. therapy
`should be etnbarketl upon in preference to
`witnessing the
`relentless progression of
`osteoporosis
`in
`susceptible
`individuals.
`Alternate-day tre:1tn'ient. which reduces the
`incidence of some of
`the
`side—el’fects
`ol‘
`corticosteroid drugs. would appear to have no
`advantage over daily use in terms of
`the
`tlevelopntent t.1l'osteopeitiu."'
`C'tttttt'tct.ra.-t‘
`tjfli’t‘t.s'
`Easy hrttising. purpura and ecchymoses. which
`are quite common in older patients on |or1g—temt
`
`February 3,
`
`i986 Vol.
`
`‘l-l-"l THE MEDICAL JOURNAL OF AUSTls‘.’\l_|r’\
`
`C0t'ltc'ostcl‘t'\id trcatinent. typically involve the
`face anti neck. the extensor surlitces of the artns
`and the hands and the areas below the knees.
`Although the mechanism is rtol clearly under-
`stood.
`it
`is
`thought
`to be related to the
`diminislted pltagt::cytosis ol' estrtn-:tsat'cd blootl
`and changes in connective tissue.” Hirsutistn has
`been reported in apprositnatcl y 105? ofpaticrtts
`and depends on the duration of treatment.“
`At:neiii.)I"ttt lesions that itllect the Iitce and upper
`trunk rnay occur in it minority of patients on
`long—te rm the rapy.‘ -‘
`Gmtt-"tit frttpt'tt'rtttcttt
`ln children.
`long-term use of corticosteroid
`agents inhibits linear bone growth and epi-
`pltyseal closure. reducing skeletal growth. To
`tacilitate the early detection ofgrovvth retarda-
`tion it is essential that regular measurements of
`height and weight are plotted on percentile
`charts. Fortunately. accelerated growth back to
`the child‘s height percentile usually follows the
`cessation of cortiec.-steroid therapy as the atl-
`ministration of corticosteroid drugs also inhibits
`epiphyseal closure. However. this growth catch-
`up may not occur after long-term use of high-
`dose corticosteroid llterapy.
`leaving the child
`permanently stunted.
`ll
`single doses of
`prednisone or prednisolone. which have a
`relatively short biological hall"-lile. are taken in
`the morning. this regimen is least likely to affect
`the maximal secretion ofgrowtlt hormdnc in the
`early hours of the morning.”'
`Glttcme t‘nroi’errtttce
`impair carbohydrate
`Glucocorticoid agents
`metabolism by increasing hepatic g|uconco-
`genesis and by decreasing the utilization of
`glucose by various tissues.” Fasting blood
`glucose concentrations are within norrrtttl ranges
`in most patients who are taking corticosteroid
`drugs but usually some reduction in the ability
`to respond to a glucose load is present. with a
`pattern in a glucose tolerance test
`that
`is
`indicative of insulin resistance. This impairment
`otglueose tolerttrtce is greatest when cortico-
`steroid treatment begins and the response
`improves considerably during long—term
`therapy.” The development ol’ovet't' diabetes is
`unusual except in individuals with pre—e.sisting
`abnormal results of :1 glucose tolerance test.
`Corticusterc-id—induced diabetes is usually mild
`and can be ntartaged along conventional lines
`b_v dietary measures. the arlminislration oforal
`hypoglycaemic agents and the judicious use of
`insulin, ifneeessary. It is frequently reversible
`on cesszttion tifconicostertiid therapy. although
`the reversal ofthe diabetic state tnay take several
`months.”‘
`
`.~'l.rc,ti.'t'c ttet't'o.rt3 of the _,t‘é*titra'tt! heart’
`The use of corticosteroid agents is one of many
`factors which may predispose patients to the
`development of aseptic necrosis ofthe lcntoral
`head. Among the numerous theories that are
`advanced as a basis tor this unusual complica-
`tion of corticosteroid therapy.
`the currently
`litvotned explanation is that
`fat
`ttticroemboli
`occlude subchrondntl end-a rterioles and lead to
`hone—cell death."-‘ The typical
`radiological
`appearance is that oI'a lucent area betwcctt the
`
`collapsed bone and the overlying cartilage.
`During a
`Ill-year period. six patients twlto
`representecl ttpprortitttately I5? ol'ul| patients in
`one study who wet'e receiving corticosteroid
`drugs for pulmonary diseases} developed aseptic
`necrosis olthe liaiitoral head.” Atypical patient
`had been receiving greater than physiological
`(loses ofcoiticosteroitl drugs for more than three
`months. and more oficn for years. Recipients
`ol' renal transplants have an increased incidence
`oI' aseptic necrosis of bone. presumably as a
`long-term scqttela of corticosteroid treatment.
`In tt recent Ausualian survey. six ol‘5.".’ renal
`transplant recipienLs who survived tor more than
`10 years developed aseptic necrosis of bone
`which involved other _ioinLs in addition to the
`hip.-‘” A review of the literature sttggcsts that
`high doses of corticosteroid agents in the lirst
`month alicr transplantation were associated with
`an increased prevalence of aseptic necrosis.”
`Patients with other disorders such as hyperuri~
`caemia. alcoholism. hypcrlipidaemia or poly~
`evthaentia. who also take corticosteroid drttgs.
`may he at greater risk of developing aseptic
`necrosis than those without these disorders.”
`Pepin" tth'eti:tti'ott
`Support tor the theory that cor1icosteroid drugs
`Idad to the development of peptic ulceration has
`waxed :tnd waited over the years. The widely
`accepted clinical notion that
`there was an
`association was dispelled in I976 by Conn and
`Blitzcr. when they rev iewcd 42 l‘£tl‘tt.‘lt)I1‘ltZt'2tJ con-
`trollcd trials and found that there was no sig~
`niticant
`relationship between corticosteroid
`therapy and peptic ulceration unless the drug
`was taken for more than 30 days or in large
`doses.-" The burning question has been
`rekindled recently by Messer et al.. who
`reviewed 71 controlled trials in which patients
`were randoinized to receive corticosteroid
`therapy or non-steroidal tlterapy for at least lour
`days."-‘-’ The incidence of peptic ulcers was L8 ‘ii-
`in the corticosteroid—treated group compared
`with 0.3% in control ptttients.” Thus. current
`evidence suggests a small bttt signilicant a.ssocia~
`tion between corticosteroid therapy and peptic
`ulceration. However.
`in view ol‘
`this
`low
`incidence it is illogical to institute prophylztctic
`tlterapy — with antacids or with ltistatnine
`i-l3—receptor antagonists — in all patients who
`are receiving corticosteroid drugs. If a patient
`is sufliciently unlucky as to develop an ulcer
`during corticosteroid treatment. he or she should
`be ntanaged with conventional therapy. In the
`absence of convincing evidence that "steroid
`ulcers" are resistant to therapy,
`there are no
`compelling reasons to discontinue corticosteroid
`treatment unless life-threatening cotrtplicalions
`of the ulcer have supervened.
`Syntptorns of gasttointestinttl intolerance such
`as dyspepsia and nausea may occur. in which
`case antacid therapy is useful. It is important
`to choose agents such as alutniniunt hydroxide.
`magnesiuttt trisilicate and ntagncsiurrt hydroxide
`which do not appear to affect the absorption of
`pred ni solone.“
`Rrittcrcur."r.='s
`
`Acute pancrealilis is a rare but serious compli-
`
`

`

`l'l'll: MEDlCAl
`
`JOLJRNAI. (JF AL.lEiTRALlA Vol.
`
`I44 Fehrttary ’.,
`
`l‘.}8b
`
`Therapeutics
`
`1 41
`
`corticostct'oid agent on the (lay oi" plasttta
`sattttpling. A tttorttittg cortisol cottcerttratiott oi"
`greater than [L28 utttoh’L (Ill ugt|l'llttttLt
`indi-
`catcs that basal hy|)otlt;t1atttic-pituitary—adt‘ena|
`tunetiott has recovered. Adrenal teserve is then
`ttssessetl b_t
`‘.1 tett':tcos:tctt'itt {ACT H l Sllltlllidl it in
`test. If" the ntornittg plasma cortisol level is less
`than 0.28 |.lltttll."L llU|.tg."1LlU1T1Ll.
`then
`cort ieostcroitl tteattttettt should be continued tor
`another one to two ntotttlts before another
`
`tttorning plasma sample is collected.
`In most circttntstances. tl _iustil'tttble alternative
`to these tiiagrtostic tests of adrenal function is
`to adtttinister
`supplctttental
`t.'ttI'ticttsterttid
`therapy during pltysiologieal stt'css tsuelt as
`aceidettts. sttrgietti procedures. Iehrile illnesses.
`repeated votttitittg or deh_vdr:ttion) for a year
`after the ntedicatiott is discontinued. Depending
`upon the clinical urgency. therapy can be given
`paretttcrally or by mouth in a daily dose that
`is eqttivalent to 200-'l00 mg of hydt'ocortisone.'“
`A syndtttnte called “steroid psettdorheuttta-
`tistrt"_ which is distinct from simple adrenal
`insttlliciency. has l:te'en recogttizcd in patients
`who take their corticosteroid therapy ct'rLtll.C:Ill_\-'
`or whose dosage is
`reduced abruptly.
`It
`is
`characterized by
`lever.
`attorettia.
`trtttlaise.
`mynlgia and artht1tlgia.' These sytnptoms resolve
`after increasing the dose ofcorticosteroitl agent:
`a more gradual reduction ofcortieostemid dntgs
`prevents their rect.trt‘ettce.
`
`the onset ol
`tltcrap_\-.
`cttltitn oi" cnrticoslcrttitl
`which is not related to the dose. dttrulion or type
`ol' corticosteroid drug that is used. in a review
`oi" Ill patients with t.|rttg—itttlttt.-ed pattcrezttttis.
`corticosteroid agettts \\t':re the most ctitttttttttt
`.it'l'cotIet‘s. being itttplicated in it crises.-"'
`.t'vt't-'uptttlt_t-
`Corticosteroid tnyopatlty presents as we:tl<ticss
`and wastittg lit
`the [l1"tlXlI1‘l:tl
`limb and girdle
`tttttsetIl&tttIt'c. Allltttuglt the dosage o|' cortico-
`steroid agent has |’ret;uertt|_\' been high and
`sustained over many months.
`there does not
`tppear to be good correlation hetwcett the total
`dose. the dttratitttt of treatment. the patient‘s age
`ar sex and the severity of the tttyopathy Since
`tlte ittcidertce is higher witlt tlte tluorittated coni-
`.'osteroid drugs stteh as triatttcinolotte.-'5 such
`agents sltottld not he used itt
`the long term.
`’aticttts Llstltlll) recover vtithitt a few weeks of
`tlte cessation of the corticosteroid Iltcrapy.
`tC)t'ttt't'tr tj,|_‘)‘et"r.t'
`-\lthough an increase in intraoculztr pt'esst.tre is
`tttore common with the topical adtttirtistration
`-it" corticosteroid prcpatutiorts. it can also occur
`with systemic cotticosteroid agents but only alter
`nottths or years ol'treatntent.“* The risk. whiclt
`appears to he genetically detertttined. is greatest
`in individuals with ittyopia or diabetes. The
`proposed tttecltanisttt involves inereasetl produc-
`tiott of aqueous hLtI‘I‘t0|.II‘ and swelling oi" the
`collagen in the tratbccular tnesitvt-ttt'k in the
`drainage angle oI‘the anterior ehntttber. leading
`to an increased resistance to aqueous outtlow.1“
`lttereases in intraocttlttt pressure are usually
`reversible it‘ corticosteroid therapy is ceased.
`Posterior s'l,Ibc:tpsUl.tt‘ cataracts have been
`'.lt)CtJl1lt:I't1I3d in patients who are receiving long-
`term corticosteroid therapy. The usual ntinitttuttt
`time required lor the onset of cataracts is one
`year of
`treattttent with at
`least
`10 mg qt’
`predttisotte a d;ty."° There is some evidence to
`suggest that this cotttplieatiott is more contmott
`in cltildren and in patients with rhettmatoid
`arthritis, In view of these ocular complietttions.
`It is prudent for all patiettts who are being treated
`tvitlt long-terttt eotticosteroid therapy to undergo
`regular opltthttltttotogiutl examinations.
`Rt'ti.s‘etrt' .‘ttttttertttttirt.-' pressttt'e
`A sntall proportion olipatients. usually children
`.tr young women. develop pupilluedenta and
`signs ol‘ raised intraeranial pressure when their
`.urticosteroid dosage is being reduced. This
`syndrottte has been designated either as "benign
`tntracranial hypertension" or as "pseudotuntour
`ccrebri". The usual treatntent is to increase the
`corticosteroid dose tentporarily to relieve the
`syntptottts and then to attempt a more gradual
`w i tltdrawal .37
`
`lttfeetit‘Jtt.s'
`Cortieosteroid drugs itttpuir cell—tttet.liated ittt—
`murtity by decreasing the number of circulating
`lyntpltoeytes and tttonocytes. by blocking the
`settsitiration o|' lytttpltocytes to antigen and by
`inhibiting tlte responsiveness of tttottocytes to
`the chetrtotactic factors that are elaborated by
`lyrttphoeytes.-‘“ Atttibody lortttation and lt1I"t'tt'J\i'tItr
`are not 3|'l’ected significantly by eortictisteroid
`drugs.
`in spite of the recognized etiects oi’
`
`cortieos-teroid agettts attd espct'itttent:tl studies
`that have dcntortstrated an ittcreased risk of
`ittlcclitttt with
`ttttttterotts
`itgcttls
`itt
`cttrticttstctt.tItl-tt'cutcd attitnttls. it has been tttttrc
`dillieult to doeutttent the degree ot ittcreased
`sttseeptibility in clinical sttttlies.“ Nev-crtltcless.
`it is getter;t|l_\' agreed that tfttttiertts who are l{Il\'ll‘lj_.‘
`lttttg-terttt eortteosteroiti dtttgs are pl'Ct.ll.‘~‘.t’1tl.’-iL‘li
`to bacterial
`t tttycobaetcritt.
`.*il:l.|Tlil_\'l.Il\.‘ttL't.‘l.|5-.
`listcriut. viral lltetpes. c_vttttttegult1n-'irttt-tl. l'ttttg;tl
`tcattdida.
`cr_vptoeocettst
`and parasitic
`ltoxttp|usttt:t. pneutttttcystis) ittl'eclion:-.3" In the
`case oi" tuhercttlosis. preventive ttteasttres should
`be taken.
`ltt patients with positive results of
`Matttoutr. skin tests to intermediate strengtlt
`tuberculin (S TU}. but ttortttal chest radiograplt
`filttts. ntodcst doses pl" corticosteroid agents
`tltl—l5 mg ol'predttisolone it day! do not appkar
`to carry an ittcrettscd risk of tttbcrculosis.—“'
`Therefore. such indivitluals do not benefit frotn
`
`pI't'tpl'I);'lttctiu.‘ therapy with isoniazid. However.
`it’ patiettts have t‘atiiolo-__-ieal
`t'eatttt'es that are
`consistent with inactive pultttonary tuberculosis.
`they wLlI‘t't.tI1l treatment with two drugs suclt as
`isottiazid and etltattthutol or riI‘.tntpicin.“’ Tltc
`physician should be alert to the possibility of"
`hotlt contttton and unusual trtlcctions in patients
`who are receiving corticosteroid agents. pur~
`tieularty if these are cotttbirted with other
`intttturtosuppressartt drugs.
`Adt'ett.ttt" .s'ttppre.s.s'iott
`to treating itttlatttttttatory diseases with cortico-
`steroid agents. it is contttton to begin witlt high
`doses to obtain some measure of cortttttl. 'l‘ltet'c-
`fore. the dose is reduced. according to intlices
`otdisease activity. ttntil :1 satisf:-tetttt'y' ntaittlen—
`urtce dose is reached. Ultitnttteiy it may be
`possible to cease the adntinistratiott oi‘ cortico-
`stetttitl tltetapy :t|tt_tgctlter, itt which case certain
`guidelines should he observed.
`It
`is generally
`accepted that derattgctttent of adrenal function
`occurs after it few days of higlt-dose cortico~
`steroid therapy. in contrast to the rapid recovery
`alter treatment that is limited to two to three
`weeks.
`long—Ierttt daily therapy with cortico-
`steroid drugs may suppress
`ltypothaltttttic—
`pituitary~ttt|rena| function for up to nine months
`alter the cessation of tretttntent.“ Thet'et'ort:.
`it
`is important to keep the daily tttaitttcttance dose
`as low as possible. or
`to use a|ternatc—day
`therapy.” because both of these strategies —
`particularly the latter — l'l'tl1'1llTllIt‘.I? the chances
`of blunting the
`stress
`response ol‘
`the
`ltypoth:t1tttttic—pituitary—adrenal axis.
`Since the recovery ofthe adrenal cortex lags
`behind that ofthe pituitary. one cttn usually as-
`sttme that full integrity has been restored when
`the adrenal gland can ntouttt an adequate
`secretory response of cortisol
`to synthetic
`ACTH." Tlterelitre. the following approach for
`the withd rawal ol‘ cot'tieosteroid Ll‘lcl‘:£I[)_V is sug
`gested.“ First. wean the patient
`to “physio-
`logical" doses of at corticosteroid agent tsuclt
`as 20 mg of ltydrocortisone or 5 mg til‘ pred-
`nisone] to be taken for one to two months: then
`halve the dose for the next one to two rnottths:
`attd then detettttitte the morning plasttta cortisol
`concerttratiott. omitting the ntornittg dose of
`
`.
`
`.
`
`.
`
`-’\' Ertt:-l
`
`References
`s "lctttic
`l. Melhy
`JL'. Clitttcal pltttrtttucolugy of
`eottteosteroids. .-titit .'ttct- .".listmrr::'o.l ?it_t-ftti! ll.F-"F:
`ll-SF
`J.
`ljlIIllI'T1L’ CA. Arttrnoll Di .
`tflitttcal cottiplitrations oI'
`eoiticttstertlid tltcr;tp_v.
`sir-fart
`t’.”.I't'tr Mtrtlr /lH‘J'
`l‘J’]"3; 5?‘.
`l33l-l_’-—t2.
`(Tttatt CS. Brown 16. Ultter \’t".-K. Zittttttettnatt PV.
`I-iydrocurtisonc—indttced t]IllJpll)'lil.!‘.l\. ti-lm! J .‘ltt.\'t' IU3-1;
`l-ll
`-3-14-'~l-sift.
`. Slttet.-1-L t'-". Lockwood Dean H. Pitttttary adrenal reeovety
`Iollowittg short-terttt suppression with cortiettstcroids.
`_-hit J tlrlttrl
`l‘.l7‘.l'. b6; 9lll—‘:ll=l.
`. Welth J, Clark TJ H. Recovt.-ry oi" ['|lt.I§-lII:! corticotrophtn
`and cortisol
`levels after
`it
`Ilttee-week course ol
`prcdnisulotte.
`Ir'i"toru.t'
`l‘)l$t; Sift: 22-24.
`t\-1_t-la».
`-\H. Baeott
`I".-1. Dztly JR. Single daily dose
`corticosteroid treatrnertt: cl'I’cct on adrenal Itmcttott and
`therapeutic eI't'tcae_v in varintts diseases. .-Imt Rttt-um .t'3t'.t-
`ltfft: Pitt:
`t-19-I53.
`lnr Clark
`. Cochrane GM. Sysletttic stetoids in astltttta.
`TIH. ed. Sterrttds in asthma. Balgowlztlt: Atlis I-‘tress.
`l‘?ti.1;
`lt}3-IIU.
`-tystctttic
`cornplieutions of
`. Thomas TPL. The
`corticosteroid Il1t!I'tt'Ft§ in the elderly Ur-'rralI'tt0ln.t,'_\ I984;
`3|)‘ E10415.
`cltttieal
`. Swttrlr SL. Dluhy RU. Cttrtteostcmids:
`phurntaeology and therapetttie use Cm-r illtet-:t;tt'tttt':.s
`l‘.l']'Ft:
`I9 t‘1l‘t.' Edi-I'll}.
`.li1i_'lL'i0Il Si-ID. Beevcrs l‘rCx. M_vet's' K. Does tong-ternt
`low—dose t.'ortico2-lcroltl therapy cause ltyperteru-'ittn'.' C'.tt'rr
`Sci"
`IUHI; ol
`tsuppl Tl‘ Rlil-t—3tl3s.
`. Leu ts GP. Juskn \I-"J. Burke
`Graves L. Predttistlnc
`side-ct'|'cets and serurn-protein levels.
`.l'_.rtm'er
`llT.I't: 2:
`T.'Fl-'.I'ti|.
`. David DR. Gfltltn) NIH. Cusltitutn P. Attrettal gILteoeorti-
`cords after 20 years: kl review oi‘ their clinical ly relevant
`consequences. J‘ Ctim-tttr Dir IWII; 22:
`lit?-‘ill.
`l3:!_\li|}l; DJ. Gluestcortieoid-induced osteopont-sis.
`J .'--t':'(.’ I083: RUE}. 7-(if)-3-llfi.
`-.‘l at Bone loss in
`Ulttcl; US, Murplty \’lt'A. Hahn T].
`adults reeetx-ing alternate day gittcocttrticoid thcntpyi tt
`contpatrtsun with daily tltcratpy.
`.-lirtlttt'tt.t i't‘a’tt‘ttIM Mil: 142
`302-RFI8.
`ii. Shubiit ll. Long-tct-in tli\c or more years: atltninisnatittrt
`ofeorticostcrutds ttt tilttltttuttilrlr diseases. D11: n‘_"Imtt I965."
`-«tit: 187-2'10.
`|lart0,!_! M. Gattlitr MA.
`
`lb.
`
`I-"laser R. Et'I'ct:t ol' vorticit-
`
`

`

`M2 Therapeutics
`
`Feliruaw 3, I986 Vul.
`
`‘I-'44 THE MEDICAL JCJLJRNAL OF AUE-TRALI-=
`
`iitirmmie. Lr.L‘li'£'i Nh-1. 2:
`
`¥ilI'.'|'tli(lE- slfl scrum |_!l'l"\\lil
`Jib-,1.‘,“R.
`. Olitlski JM. Kimitierliug C}. Illiccis iii" giiicmmrticisiiix
`nn t_'LlI+|lti‘1_\-lil'I.iiL" nietaihitliani.
`.-trir J .’l-mi Sr-I
`I‘.-Wu. 271:
`2ti2—JIIi.
`lL"i1Il.l|’<.‘!-i si|'ll1i: dluhulic
`Miller SE. Nt‘IIH('i[| _|M. C'li:iic';1|
`:1)'F|liTl|l'|'lU uppezaring ulicr -atvriiid Iher::p_\.
`if-’u.ri_:;:-.-iii .1-It-ii’
`J l‘l(-1-91'. -I0:
`fihtl-tutu-1.
`. Richards-. M, Eiuniiaigu .'\1. Kl:ilI:il\"|'[11C)'(.’T B. Aseptic
`nec Ft'|?1l!- 0|" the |'criit-ml heart!
`in €.'l!F[it.'l|{\ll.‘l't1iLi
`lrtluluii
`[‘lIlIl1[Ii1ii.|'_\'
`di~.s:.i.~'i:.
`.~lit'.ii
`ilHt'I‘H film!
`I|l.*ii'l:
`I-"iii:
`|4T_\—l-lT'_‘i.
`l)Ci'il_\'C1.l
`iii.
`M'.ll1Un_\-
`.lF. Slicil AER. Etlieredge SH. L'l
`and tlieir
`mniplicuiiuna iiI'
`renal
`l|'.'J|'W[}i.'1|'1lE][it1Il
`|)i'L‘.\'L‘Iilin11. Mm’! .lri.ii
`I932: 3: 43h-429.
`. Cnnn Hlfl. Blitzer BL.
`.'\'iii1ii:~':mL-iutiiiii ui -.idi'ermuui'Ii-
`
`Books received
`
`(Continued from page 1