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Corticotropin (Anti-inflammatory)

Class: Pituitary
VA Class: HS701
CAS Number: 9002-60-2
Brands: H.P. Acthar Gel

Warning(s)

REMS:

FDA approved a REMS for corticotropin to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of corticotropin and consists of the following: medication guide. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

A polypeptide hormone secreted by the basophilic cells of the anterior pituitary; stimulates the adrenal cortex to secrete cortisol and other hormones.b c p

Uses for Corticotropin (Anti-inflammatory)

Treatment of a wide variety of diseases and conditions; used for anti-inflammatory and immunosuppressant effects, and for its effects on blood and lymphatic systems in the palliative treatment of various glucocorticoid-responsive nonendocrine diseases.a c m p

Has limited therapeutic value in conditions responsive to corticosteroid therapy; in such cases, corticosteroids are considered the drugs of choice.a

Corticotropin therapy is not curative and generally suppresses the symptoms of chronic diseases without altering the natural course of the disease; considered to be supportive therapy to be used adjunctively with other indicated therapies.a c Generally, should be used for treatment only when disease is refractory to noncorticosteroid therapies.a

Diagnosis of Adrenocortical Insufficiency

Used in the diagnostic testing of adrenocortical insufficiency.a b c m p aa

30-minute cosyntropin test is preferable to corticotropin for rapid screening since it is less likely to cause allergic reactions.b m p (See Hypersensitivity Reactions under Cautions.)

Thyroiditis

Treatment of nonsuppurative thyroiditis.a

Hypercalcemia

Treatment of hypercalcemia associated with malignancy.a

Multiple Sclerosis

Symptomatic management of acute exacerbations associated with multiple sclerosis.a c i Higher dosages may be necessary to demonstrate clinically important effect.a

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Corticotropin did not affect the outcome or natural history of multiple sclerosis in clinical studies.a To date, insufficient data to determine if corticotropin can prevent new exacerbations of the disease.i

Previously considered therapy of choice; however, short-term, high-dose IV glucocorticoids (e.g., methylprednisolone) generally have replaced corticotropin because of a more rapid onset of action, more consistent effects, and fewer adverse effects.

Rheumatic Disorders and Collagen Diseases

Short-term adjunctive treatment of acute episodes or exacerbations of rheumatic disorders (i.e., psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, posttraumatic arthritis, acute and subacute bursitis, synovitis of osteoarthritis, acute nonspecific tenosynovitis, epicondylitis, acute gouty arthritis).a

Selected cases of rheumatoid arthritis (i.e., juvenile rheumatoid arthritis) may require low-dose corticotropin maintenance therapy.a

Limit treatment of gouty arthritis to a few days.a Rebound arthritic attacks may occur after corticotropin discontinuance; administer concomitant conventional therapy during corticotropin treatment and for several days following its discontinuance.a

Treatment during acute exacerbations or as maintenance therapy in selected cases of systemic lupus erythematosus, acute rheumatic carditis, and/or systemic dermatomyositis (polymyositis).a c

Dermatologic Diseases

Treatment of pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, severe psoriasis, severe seborrheic dermatitis, or mycosis fungoides.a

Allergic Conditions

Control of severe or incapacitating allergic conditions (i.e., seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, serum sickness) intractable to adequate trials of conventional treatment.a

Ocular Disorders

Treatment of severe acute and chronic allergic and inflammatory processes involving the eye and adnexa (e.g., allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and iridocyclitis, diffuse posterior uveitis and choroiditis, optic neuritis, sympathetic ophthalmia, chorioretinitis, anterior segment inflammation, allergic corneal marginal ulcer).a

Sarcoidosis

Management of symptomatic sarcoidosis.a w

Loeffler’s Syndrome

Symptomatic relief of acute manifestations of Loeffler’s syndrome not manageable by other means.a k

Berylliosis

Symptomatic relief of acute manifestations of berylliosis.a k

Aspiration Pneumonitis

Symptomatic relief of acute manifestations of aspiration pneumonitis.a k

Advanced Pulmonary and Extrapulmonary Tuberculosis

Adjunctive treatment with antituberculosis chemotherapy in fulminating or disseminated pulmonary tuberculosis.a x

Adjunctive treatment with antituberculosis chemotherapy in tuberculosis meningitis with subarachnoid block or impending block.a

Hematologic Disorders

Management of acquired (autoimmune) hemolytic anemia, secondary thrombocytopenia, erythroblastopenia (RBC anemia), and/or congenital (erythroid) hypoplastic anemia.a

Neoplastic Diseases

Alone or as a component of various chemotherapeutic regimens in the palliative treatment of neoplastic diseases of the lymphatic system (e.g., leukemias and lymphomas in adults and acute leukemias in children).a k

Nephrotic Syndrome and Lupus Nephritis

Can be used to induce diuresis or remission of proteinuria in nephrotic syndrome without uremia of the idiopathic type or due to lupus erythematosus.a

GI Diseases

Short-term palliative therapy for acute exacerbations and systemic complications of ulcerative colitis and/or regional enteritis.a

Has been used in patients with moderately to severely active or severe fulminant Crohn’s disease, including those with an abdominal mass, usually in patients who have not responded to oral therapy.100 101 102

Trichinosis

Treatment of trichinosis with neurologic or myocardial involvement.a

Infantile Spasms

Has been used in the short-term management of infantile spasms (designated an orphan drug by FDA for this use).f h l o

Primary Adrenocortical Insufficiency

Ineffective in the treatment of primary adrenocortical insufficiency and congenital adrenogenital syndrome.c

Corticotropin (Anti-inflammatory) Dosage and Administration

General

  • Perform verification tests to assess adrenocortical function prior to initiation of corticotropin therapy; administer corticotropin by the route of administration proposed for treatment.a c (See Diagnosis of Adrenocortical Insufficiency under Dosage and Administration and also see Treatment Considerations under Cautions.)

  • Following verification test, individualize dosage carefully according to diagnosis and general medical condition(s) of the patient.a c

Discontinuance of Therapy

  • Sudden withdrawal following prolonged corticotropin therapy may result in recurrent symptoms, possibly requiring an increase in corticotropin dosage followed by a more gradual withdrawal.a c (See Hypothalamic-Pituitary-Adrenal [HPA] Axis Suppression under Cautions.)

  • Gradually decrease corticotropin dosage by reducing the amount of each injection and/or administering injections at longer intervals, taking into consideration the diagnosis, the general medical condition(s) of the patient, and the duration of corticotropin administration.a c

Administration

Administer repository corticotropin injection by sub-Q or IM injection.a c m Do not administer IV.a

Corticotropin for injection has been administered IV, IM, and sub-Q; however, this formulation is no longer commercially available in the US.c

IM or Sub-Q Administration

Prior to administration, warm vial to room temperature by rolling it between palms of the hands for a few minutes.d z aa

Take caution not to overpressurize vial prior to withdrawing its contents.a

Dosage

Once an optimal response is achieved, use lowest effective dosage for shortest period of time needed to treat given condition; if necessary, gradual changes in dosing schedules may be made.a c

When determining the dose and frequency of administration of corticotropin, consider the severity of the disease, plasma and urine corticosteroid levels, and initial patient response.a c

1 mg of corticotropin is equivalent to 1 International Unit (IU, unit).e

Pediatric Patients

Usual Dosage
IM

0.8 mg/kg daily administered in divided doses every 12–24 hours.c e g

Alternatively, 25 mg/m2 daily in divided doses every 12–24 hours.c g

Infantile Spasms
IM

20–40 mg daily for 6 weeks, followed by a gradual taper.e Some authorities recommend an initial dose of 20 mg daily for 2 weeks, followed by 30–40 mg daily for an additional 4 weeks if no response is elicited with the lower dosage.f

Alternatively, 150 mg/m2 daily administered in divided doses every 12 hours for 2 weeks, followed by a gradual taper.e

Dosages of 5–160 mg/kg daily have been administered for up to 12 months.g l

Adults

Chronic administration of dosages >40 mg daily may be associated with uncontrollable adverse effects.a

Usual Dosage
IM or Sub-Q

40–80 mg administered every 24–72 hours.c l

Diagnosis of Adrenocortical Insufficiency
IM or Sub-Q

40 mg usually achieves close to maximum adrenocortical stimulation; however, up to 80 mg may be administered as a single injection.a c l

Alternatively, may administer one or more injections at a lower dose.a c As little as 20 mg may be sufficient in some patients.l

Multiple Sclerosis
IM

80–120 mg daily for 2–3 weeks.a c d g

Prescribing Limits

Adults

Diagnosis of Adrenocortical Insufficiency
IM or Sub-Q

Dosages >80 mg (as a single dose) have not been studied.l

Multiple Sclerosis
IM

Dosages >120 mg daily have not been studied.l

Special Populations

No special population dosage recommendations at this time.a

Cautions for Corticotropin (Anti-inflammatory)

Contraindications

  • Scleroderma.a c

  • Osteoporosis.a p

  • Systemic fungal infections.a p

  • Ocular herpes simplex.a p (See Ocular Effects under Cautions.)

  • Recent surgery.a c p

  • History of or current peptic ulcer.a c p

  • CHF.a c p

  • Hypertension.a p

  • Conditions accompanied by primary adrenocortical insufficiency or adrenocortical hyperfunction.a c

  • Known hypersensitivity to proteins of porcine origin.a p

Warnings/Precautions

Warnings

Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression

When given for prolonged periods, corticotropin may suppress pituitary release of corticotropin and cause hypothalamic-pituitary insufficiency.a c

The degree and duration of hypothalamic-pituitary insufficiency is highly variable among patients and depends on the dose, frequency and time of administration, and duration of therapy.a c

Relative adrenocortical insufficiency may occur if corticotropin is withdrawn abruptly.c Corticotropin should be withdrawn very gradually following long-term therapy.c

Adrenocortical insufficiency may persist for up to 12 months in patients who receive the drug for prolonged periods.k

Until recovery occurs, signs and symptoms of adrenal insufficiency may develop if subjected to stress (e.g., infection, surgery, trauma) and replacement therapy may be required.a c

Treatment Considerations

Corticotropin should not be administered until adrenal responsiveness has been verified with the route of administration that will be used during treatment.a c Monitor for rise in urinary and plasma corticosteroid values as this confirms a direct stimulatory effect.a

Complications of corticotropin therapy are dependent upon dose and duration of use; consider risk-benefit ratio for each patient.a

Maximal adrenal stimulation is limited during therapy initiation (i.e., first few days); consider concomitant administration of other agents if an immediate therapeutic effect is desired.a c

Prolonged corticotropin therapy should be accompanied by rapidly acting corticosteroids at the initiation of, during, and following unusual stressful situations.a Prolonged therapy may render irreversible adverse effects.a

Ocular Effects

Prolonged use may result in posterior subcapsular cataracts and glaucoma, with possible damage to the optic nerve.a c

May enhance the establishment of secondary fungal and viral infections of the eye.a c (See Increased Susceptibility to Infection under Cautions.)

Immunosuppression

Increased susceptibility to infections secondary to corticotropin-induced immunosuppression.a c (See Increased Susceptibility to Infection under Cautions.)

Administration of smallpox vaccine not recommended.a

Administration of other immunizations should be undertaken with caution, especially in patients receiving large doses of corticotropin since neurologic complications and lack of antibody response may arise.a c (See Nervous System Effects and also Pediatric Use under Cautions.)

Increased Susceptibility to Infection

May increase susceptibility to and mask symptoms of infection.a c

May aid in the establishment of bacterial, viral, or fungal infections, including those of the eye.a c Possible decreased resistance and inability to localize infections.a

Do not use, except in life-threatening situations, in patients with viral infections or bacterial infections not controlled by anti-infectives.c

Institute appropriate anti-infective therapy if infection is present.a

Closely observe patients with latent tuberculosis or a positive tuberculin skin test since disease reactivation may occur; institute chemoprophylaxis in cases of prolonged corticotropin therapy.a c cc

Fluid and Electrolyte Disturbances

Sodium retention with resultant edema, potassium loss, and elevation of BP may occur.a b c Hypokalemic alkalosis and CHF may occur.a c

Dietary sodium restriction is advisable and potassium supplementation may be necessary.a c

Increased calcium excretion and possible hypocalcemia.a c

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions manifested by skin reactions (urticaria, pruritus, scarlatiniform exanthema), dizziness, nausea, vomiting, and mild fever, and, in some instances, anaphylactic shock, wheezing, circulatory failure, and death;c may occur even in patients who have not previously been treated with the drug.c

If hypersensitivity reaction occurs, discontinue immediately and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, maintenance of an adequate airway, oxygen). c

Prolonged duration of therapy increases risk of hypersensitivity reactions.a

Hypersensitivity skin testing should be performed before treatment of patients with suspected sensitivity to porcine proteins.a c

Antibody Formation

Prolonged duration of therapy may be associated with formation of antibodies to the drug and theoretically result in loss of adrenal stimulation.c

General Precautions

Nervous System Effects

May precipitate psychic symptoms and/or exacerbate preexisting symptoms ranging from mood alterations to a psychotic state.a c

May cause increased intracranial pressure with papilledema (pseudotumor cerebri), usually after treatment.a c

Endocrine and Metabolic Effects

Exaggerated response to corticotropin in hypothyroidism.a c p

May decrease glucose tolerance, produce hyperglycemia, and aggravate or precipitate diabetes mellitus, especially in patients predisposed to diabetes mellitus.c Use with caution in patients with diabetes mellitus; worsening of symptoms possibly necessitating an increase in insulin or oral antidiabetic agent dosage.a c

GI Effects

Use with caution in patients with diverticulitis since worsening of symptoms may occur.a c

Musculoskeletal Effects

Muscle wasting, muscle pain or weakness, delayed wound healing, and atrophy of the protein matrix of the bone resulting in osteoporosis, vertebral compression fractures, aseptic necrosis of femoral or humeral heads, or pathologic fractures of long bones are manifestations of protein catabolism which may occur during prolonged corticotropin therapy.a c

Use with caution in patients with myasthenia gravis since worsening of symptoms may occur.a c

Specific Populations

Pregnancy

Category C.a p q

Lactation

Not known whether corticotropin is distributed into milk.a p Discontinue nursing or the drug.a

Pediatric Use

With long-term use, may retard bone growth in children; avoid long-term administration.a c If therapy is necessary, administer intermittently and monitor carefully.a

Increases in intracranial pressure (pseudotumor cerebri) causing papilledema, oculomotor or abducens nerve paralysis, visual loss, and headache reported in children receiving corticotropin.c

Geriatric Use

With prolonged therapy, muscle wasting, muscle pain or weakness, delayed wound healing, and atrophy of the protein matrix of the bone resulting in osteoporosis, vertebral compression fractures, aseptic necrosis of femoral or humeral heads, or pathologic fractures of long bones may occur.c May be especially serious in geriatric or debilitated patients.c

Hepatic Impairment

Possible exaggerated response in patients with cirrhosis.a c p

Renal Impairment

Corticotropin may worsen existing renal insufficiency; use with caution.a c

Common Adverse Effects

Associated with long-term therapy: Bone loss, cataracts, indigestion, muscle weakness, back pain, bruising, acne, hyperpigmentation, menstrual irregularities, oral candidiasis.a c k (See Warnings/Precautions under Cautions.)

Interactions for Corticotropin (Anti-inflammatory)

Specific Drugs

Drug

Interaction

Comments

Amphotericin B

May enhance the potassium-wasting effects of corticotropinc (see Fluid and Electrolyte Disturbances under Cautions)

May decrease adrenocortical responsiveness to corticotropinc

Monitor serum potassiumc

Anticoagulants, oral

Conflicting reports of diminished as well as enhanced response to anticoagulantsc dd ee

Rarely, increase in oral anticoagulant dosage may be required for increases in blood coagulabilityc ee

Use caution when initiating or discontinuing corticotropin in patients stabilized on oral anticoagulant therapyc

Barbiturates

Possible increased glucocorticoid metabolism resulting in decreased corticosteroid effect c

Diuretics, potassium-depleting (e.g., thiazides, furosemide, ethacrynic acid)

Possible enhanced potassium-wasting effects of corticotropina c

Monitor serum potassiumc

Insulin

Possible antagonism of hypoglycemic effects of insulinr

NSAIAs

Possible increased risk of GI ulceration c l

Possible decreased serum salicylate concentrations;c when corticotropin is discontinued, serum salicylate concentration may increase, possibly resulting in salicylate intoxicationc

Use concurrently with cautiona

Use aspirin and corticotropin with caution in patients with hypothrombinemiaa

Phenytoin

Possible increased glucocorticoid metabolism resulting in decreased corticosteroid effect c

Vaccines and toxoids

May cause a diminished response to vaccinesa c p

Supraphysiologic dosages of corticotropin can aggravate neurologic reactions to some vaccinesa c p

Concurrent administration of smallpox vaccine not recommendeda

Administer other vaccines concurrently with cautiona c

Corticotropin (Anti-inflammatory) Pharmacokinetics

Absorption

Bioavailability

Corticotropin is rapidly inactivated by proteolytic enzymes in the GI tract and is administered parenterally.c l p

Absorbed over 8–16 hours following IM administration; peak concentrations of 17-hydroxycorticosteroid (17-OHCS) occur during this period.c m z Peak 11-hydroxycorticosteroid concentrations following sub-Q administration of 80 units of repository corticotropin injection in healthy individuals is evident in 3–12 hours; baseline concentrations attained in 10–25 hours (mean: 16 hours).aa

Onset

Diagnosis of adrenocortical insufficiency: Plasma corticosteroid concentrations generally close to maximum stimulation 1 hour after administration.l

Duration

Following IM administration of repository corticotropin injection, duration of action is 18 hours secondary to delayed uptake from tissues; duration dependent upon dose.a c m p y z

Distribution

Extent

Distributed to liver and kidneys; highest concentrations found in kidneys.l bb

Rapidly removed from plasma by many tissues.a c m n

Does not cross placenta.c m

Elimination

Metabolism

Rapidly metabolized in the blood.z Exact metabolic fate unknown.c Circulating corticotropin may also be enzymatically cleaved by plasmin-plasminogen system and/or by aminopeptidases in the muscle and skin.c m n

Elimination Route

Not substantially eliminated in the urine.l

Half-life

>3 hours following IM or sub-Q administration of repository corticotropin injection.l

15–20 minutes following IV administration of corticotropin for injection (no longer commercially available in the US). a l

Stability

Storage

Parenteral

Solution for Injection

2–8°C (may be exposed to 2–15°C).a c m aa

Intact vials stable for <72 hours at room temperature.j

Actions

  • Stimulates the adrenal cortex to secrete cortisol, corticosterone, aldosterone, and other weakly androgenic substances.a c m p s

  • Steroidogenic and trophic effects of corticotropin are mediated by activation of adenylate cyclase and increased production of cyclic adenosine monophosphate (cAMP).l p u v

  • Corticotropin also stimulates growth of adrenal cortex and may possess extra-adrenal effects (i.e., melanocyte stimulation, tissue lipase activation).a c

  • Primary physiologic and pharmacologic effects are secondary to secretion of cortisol, a glucocorticoid with some mineralocorticoid activity.c

  • In pharmacologic doses, cortisol decreases inflammation and suppresses the immune response by a variety of mechanisms.c k

  • Elevated plasma cortisol suppresses corticotropin release (negative-feedback mechanism).a f k

  • Mechanism of action in the management of infantile spasms unknown, but thought to involve suppression of excess corticotropin-releasing factor (CRF) synthesis by exogenous corticotropin.f

Advice to Patients

  • In patients receiving long-term therapy, importance of reducing dose gradually and not discontinuing the drug abruptly.a c

  • Importance of notifying a clinician of any infections, signs of infections (e.g., fever, sore throat, pain during urination, muscle aches), or injuries that occur during therapy or within 12 months after therapy is discontinued.c

  • Importance of informing patients that symptoms of diabetes mellitus may worsen, necessitating changes in dosages of insulin or oral antidiabetic agents.a c

  • Importance of informing patients that symptoms of myasthenia gravis and diverticulitis may worsen with corticotropin therapy.a c

  • Importance of informing patients that precipitation of psychic symptoms or worsening of preexisting symptoms may occur.a c

  • Patients should carry identification cards listing the diseases for which they are being treated, the drug they are receiving and its dosage, and the name and telephone number of their physician.c

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs (e.g., aspirin), as well as any concomitant illnesses (e.g., osteoporosis, CHF).a d

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.a

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Corticotropin, Repository

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IM or subcutaneous use

80 units/mL

H.P. Acthar Gel (with gelatin and phenol)

Questcor

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 27, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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101. Chun A, Chadi RM, Korelitz BI et al. Intravenous corticotropin vs. hydrocortisone in the treatment of hospitalized patients with Crohn’s disease: a randomized double-blind study and follow-up. Inflamm Bowel Dis. 1998; 4:177-81. [PubMed 9741018]

102. Felder JB, Adler DJ, Korelitz BI. The safety of corticosteroid therapy in Crohn’s disease with an abdominal mass. Am J Gastroenterol. 1991; 86:1450-5. [IDIS 289909] [PubMed 1656728]

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c. AHFS drug information 2008. McEvoy GK, ed. Corticotropin. Bethesda, MD: American Society of Health-System Pharmacists; 2008:3275-78.

d. Questcor Pharmaceuticals Inc. H.P. Acthar Gel safety/frequently asked questions information. From H.P. Acthar Gel web site http://www.acthar.com.

e. Gunn VL, Nechyba C, eds. The Harriet Lane handbook: a manual for pediatric house officers. 16th ed. Philadelphia, PA: Mosby; 2002:647.

f. Johnston MV. Seizures in childhood. In: Kliegman RM, Behrman RE, Jenson HB et al., eds. Nelson textbook of pediatrics. 18th ed. Philadelphia: WB Saunders Company; 2007:2457-75.

g. Gal P, Reed MD. Appendix: Medications. In: Kliegman RM, Behrman RE, Jenson HB et al., eds. Nelson textbook of pediatrics. 18th ed. Philadelphia: WB Saunders Company; 2007:2955-99.

h. Mackay MT, Weiss Sk, Adams-Webber T et al. Practice parameter: medical treatment of infantile spasms: report of the American academy of neurology and the child neurology society. Neurology. 2004; 62:1668-81. [PubMed 15159460]

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k. AHFS drug information 2008. McEvoy GK, ed. Corticosteroids general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2008: 3080-93.

l. Questcor Pharmaceuticals Incorporated, Union City, CA: Personal communication.

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p. AMA Division of Drugs. AMA drug evaluations. Chicago: American Medical Association; 1994:1–10.

q. Corticotropin/Cosyntropin. In: Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:384.

r. AMA Division of Drugs. AMA drug evaluations. Chicago: American Medical Association; 1983:1037.

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