Fusilev

Generic Name: Levoleucovorin Calcium
Class: Antidotes
VA Class: VT102
Chemical Name: (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl] amino]benzoyl}-L-glutamate pentahydrate
Molecular Formula: C20H21CaN7O7 • 5H2O

Introduction

Folic acid derivative; active levorotatory (l) isomer of racemic leucovorin.1 2 3 4 5 7 10 17

Uses for Fusilev

Toxicity Associated with Folic Acid Antagonists

IV rescue therapy after high-dose methotrexate therapy (to control the duration of exposure of sensitive cells to methotrexate) for treatment of osteosarcoma (designated an orphan drug by FDA for this use).1 2 3 6 17

Antidote to diminish the toxicity and counteract the effects of unintentional overdosage of methotrexate (e.g., resulting from impaired elimination) and other folic acid antagonists (designated an orphan drug by FDA for this use).1 6 17

Slideshow: 2014 Update - First Time Brand-to-Generic Switches

Colorectal Cancer

In combination with fluorouracil for the palliative treatment of advanced-stage colorectal cancer.1 10002

Has been studied for treatment of advanced-stage colorectal cancer in combination with fluorouracil and other agents (i.e., irinotecan, oxaliplatin).10003 10004 10005 10006 However, use in such combination regimens not fully established.19

Other Uses

Manufacturer states that levoleucovorin should not be used for the treatment of pernicious anemia and megaloblastic anemias secondary to lack of vitamin B12; such use may alleviate hematologic manifestations while allowing neurologic complications to progress.1

Fusilev Dosage and Administration

General

Toxicity Associated with Folic Acid Antagonists

  • Methotrexate Overdosage or Rescue after High-dose Methotrexate Therapy
  • Monitoring of serum methotrexate concentration and patient's renal function required to determine optimum dose and duration of levoleucovorin therapy.1 Monitor Scr and methotrexate concentrations at least once daily.1

  • Maintain adequate hydration (3 L daily) and administer sodium bicarbonate to maintain urinary pH at ≥7 during therapy.1

  • Monitor fluid and electrolyte status in patients experiencing delayed early methotrexate elimination and renal failure until methotrexate concentration declines to 0.05 micromolar (5 × 10-8M) and renal failure has resolved.1

Administration

Administer IV.1 Do not administer intrathecally.1

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV injection;1 has been administered by IV infusion in various published studies.17

Use strict aseptic technique since drug product contains no preservatives.1

Do not admix or infuse concomitantly with other drugs.1 17

Reconstitution and Dilution (Powder for Injection)

Add 5.3 mL of 0.9% sodium chloride injection to vial containing 50 mg of levoleucovorin to provide a solution containing 10 mg/mL.1

Use of sodium chloride containing preservatives (e.g., benzyl alcohol) not studied.1 Use of solutions other than 0.9% sodium chloride to reconstitute levoleucovorin not recommended.1

Levoleucovorin solution may be administered following reconstitution or may be further diluted with 0.9% sodium chloride injection or 5% dextrose injection to a concentration of 0.5–5 mg/mL.1 17

Dilution (Commercially Available Solution)

Commercially available solution (10 mg/mL) may be further diluted with 0.9% sodium chloride injection or 5% dextrose injection to a concentration of 0.5 mg/mL.1

Rate of Administration

Administer by IV injection at a rate not >160 mg of levoleucovorin per minute (e.g., 16 mL/minute as 10-mg/mL solution).1 17 (See Rate of Administration under Cautions.)

Dosage

Available as levoleucovorin calcium; dosage expressed in terms of levoleucovorin.1

Levoleucovorin is dosed at one-half the usual dosage of racemic leucovorin.1 2

Pediatric Patients

Toxicity Associated with Folic Acid Antagonists
Rescue after High-dose Methotrexate Therapy
IV

The manufacturer makes no specific recommendations regarding dosage in pediatric patients;1 17 however, safety and efficacy of levoleucovorin have been evaluated in 16 patients 6–21 years of age.1

7.5 mg every 6 hours for 60 hours or longer starting 24 hours after completion of methotrexate (12 g/m2 over 4 hours) has been evaluated in clinical studies.1

7.5 mg every 3 hours for 18 doses starting 12 hours completion of methotrexate (12 g/m2 over 6 hours) also has been evaluated in clinical studies.1

Adults

Toxicity Associated with Folic Acid Antagonists
Rescue after High-dose Methotrexate Therapy
IV

7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses, starting at 24 hours after initiation of methotrexate (12 g/m2) infusion for patients with normal methotrexate elimination (i.e., serum methotrexate concentration approximately 10 micromolar [10-5 M] at 24 hours, 1 micromolar [10-6 M] at 48 hours, and 0.2 micromolar [2 × 10-7 M]) at 72 hours after administration).1

Continue therapy and maintain adequate hydration and urinary alkalinization (pH ≥7) until methotrexate concentration declines to <0.05 micromolar (5 × 10-8 M).1

If substantial clinical toxicity occurs in patients with mild abnormalities in methotrexate elimination or renal function, extend rescue therapy for an additional 24 hours (i.e., 14 doses over 84 hours) for subsequent methotrexate courses.1

Adjust dosage and duration of therapy based on methotrexate elimination pattern and patient’s renal function.1 (See Table 1 and Table 2.)

Table 1. Guidelines for Levoleucovorin Dosage Adjustment in Patients with Delayed Late Methotrexate Elimination

Serum Methotrexate Concentration

Leucovorin Dosage Adjustment

>0.2 micromolar (2 × 10-7 M) at 72 hours and >0.05 micromolar (5 × 10-8 M) at 96 hours following methotrexate administration

Continue levoleucovorin 7.5 mg IV every 6 hours until methotrexate concentration declines to <0.05 micromolar (5 × 10-8 M)1

Table 2. Guidelines for Levoleucovorin Dosage Adjustment in Patients with Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury

Serum Methotrexate and/or Scr Concentration

Leucovorin Dosage Adjustment and Monitoring

Methotrexate concentration ≥50 micromolar (5 × 10-5 M) at 24 hours or ≥5 micromolar (5 × 10-6 M) at 48 hours after methotrexate administration, or a ≥100% increase in Scr at 24 hours after methotrexate administration (e.g., an increase from 0.5 to 1 mg/dL or more)

Levoleucovorin 75 mg IV every 3 hours until methotrexate concentration declines to <1 micromolar (10-6 M), then levoleucovorin 7.5 mg IV every 3 hours until methotrexate concentration declines to <0.05 micromolar (5 × 10-8 M)1

If renal failure develops, monitor fluid and electrolyte status until methotrexate concentration declines to <0.05 micromolar (5 × 10-8 M) and renal failure has resolved1

Methotrexate Overdosage
IV

7.5 mg (approximately 5 mg/m2) every 6 hours until serum methotrexate concentration declines to <0.01 micromolar (10-8 M); initiate administration as soon as possible after overdosage and within 24 hours following methotrexate administration if delayed elimination is detected.1

If 24-hour Scr increases 50% over baseline, 24-hour methotrexate concentration is >5 micromolar (5×10-6 M), or 48-hour methotrexate concentration is >0.9 micromolar (9 × 10-7 M), increase dosage immediately to 50 mg/m2 IV every 3 hours until serum methotrexate concentration declines to <0.01 micromolar (10-8 M).1

Colorectal Cancer
IV

Levoleucovorin 100 mg/m2 by IV injection over ≥3 minutes followed by IV fluorouracil (370 mg/m2) or levoleucovorin 10 mg/m2 followed by IV fluorouracil (425 mg/m2); administer both drugs daily for 5 days and repeat regimen at 4-week intervals for 2 additional courses; thereafter may repeat regimen at intervals of 4–5 weeks provided toxicity from the previous course has resolved completely.1

Other fluorouracil/levoleucovorin regimens have been used.10001

Levoleucovorin dosage is not adjusted for toxicity.1 Reduce daily fluorouracil dosage by 20% for moderate hematologic or GI toxicity in the prior course and by 30% for severe toxicity.1 If no toxicity occurred in the prior course, may increase fluorouracil dosage by 10%.1

Special Populations

Patients with Delayed Methotrexate Elimination

Higher dosages and extended duration of therapy may be required if delayed methotrexate excretion is caused by third space fluid accumulation (i.e., ascites, pleural effusion), renal impairment, or inadequate hydration.1

Cautions for Fusilev

Contraindications

  • Known hypersensitivity to folic acid or folinic acid.1

Warnings/Precautions

Rate of Administration

Injection rate should not exceed 160 mg of levoleucovorin per minute (e.g., 16 mL/minute as 10-mg/mL solution) because of the calcium concentration (4.26 mg of Ca++ per 64 mg of levoleucovorin calcium pentahydrate) of the solution.1 17

Toxicity Potentiation with Concomitant Therapy

Levoleucovorin potentiates fluorouracil toxicity; must reduce fluorouracil dosage when the drugs are used concomitantly.1

GI toxicities (particularly stomatitis and diarrhea) observed more frequently, and possibly more severe and prolonged, with combined fluorouracil/levoleucovorin compared with fluorouracil monotherapy.1 Increased risk of severe GI toxicity in debilitated or geriatric patients.1 Diarrhea may result in clinical deterioration, leading to death; if diarrhea occurs, closely monitor patients until manifestations have completely resolved.1 Do not initiate or continue combination therapy in patients with manifestations of GI toxicity until such manifestations have completely resolved.1

Toxicity reported more frequently in patients receiving regimens containing low-dose (20 mg/m2) versus high-dose (200 mg/m2) racemic leucovorin in combination with fluorouracil.1

Concomitant use of racemic leucovorin and co-trimoxazole for treatment of Pneumocystis jiroveci (formerly P. carinii) pneumonia in HIV-infected patients associated with increased rates of treatment failure and morbidity.1 17 18

Seizures and/or syncope reported rarely, usually following concomitant therapy with fluoropyrimidines; most commonly reported in cancer patients with CNS metastases or other predisposing factors.1

Specific Populations

Pregnancy

Category C.1

Lactation

Not known whether distributed into milk; discontinue nursing or drug.1

Pediatric Use

Safety and efficacy have been evaluated in 16 patients 6–21 years of age.1 The manufacturer makes no specific recommendations regarding use in pediatric patients.1 17

Possible decreased anticonvulsant effect in pediatric patients receiving anticonvulsant therapy concomitantly with large amounts of folic acid; possible increased frequency of seizures in susceptible patients.1 (See Specific Drugs under Interactions.)

Geriatric Use

Patients with osteosarcoma: Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Patients with advanced colorectal cancer: No overall differences in adverse effects observed relative to younger adults;1 however, death due to severe enterocolitis, diarrhea, and dehydration reported in geriatric patients receiving weekly racemic leucovorin and fluorouracil therapy.1

Renal Impairment

Possible delayed methotrexate elimination; higher dosages and extended duration of therapy may be required.1 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Levoleucovorin rescue following high-dose methotrexate: Vomiting, stomatitis, nausea.1

Levoleucovorin in combination with fluorouracil: Diarrhea, nausea, stomatitis, vomiting, asthenia/fatigue/malaise, anorexia/decreased appetite, dermatitis, alopecia.1

Interactions for Fusilev

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (phenobarbital, phenytoin, primidone)

Decreased anticonvulsant effect if used concomitantly with large amounts of folic acid; possible increased frequency of seizures in susceptible pediatric patients1 13 14 16

Possible increased hepatic metabolism and decreased plasma phenytoin concentrations based on studies in rats12

Use concomitantly with caution1 15

Co-trimoxazole

Increased rates of treatment failure and morbidity observed in HIV-infected patients receiving combination therapy with leucovorin for treatment of P. jiroveci pneumonia1 17 18

Glucarpidase

Administration of glucarpidase 2 hours before racemic leucovorin reduces peak concentrations and exposure of leucovorin and 5-methyl-THF;21 similar effects expected with levoleucovorin22

Methotrexate concentrations measured by immunoassay within 48 hours after glucarpidase administration are unreliable21

Do not administer levoleucovorin within 2 hours before or after glucarpidase21 22

During first 48 hours after glucarpidase administration, administer levoleucovorin at same dosage administered prior to glucarpidase; beyond 48 hours, base dosage on methotrexate concentration21 22

Continue levoleucovorin therapy until methotrexate concentration remains below the levoleucovorin treatment threshold for ≥3 days21 22

Fluorouracil

Potentiation of fluorouracil antineoplastic activity and toxicity1

Methotrexate, intrathecal

Possible decreased methotrexate efficacy if used concomitantly with high doses of leucovorin10007

Fusilev Pharmacokinetics

Absorption

Bioavailability

Peak serum concentrations of active metabolite 5-methyltetrahydrofolic acid (5-methyl-THF) attained in an average 0.9 hours.1

Equipotent doses of IV levoleucovorin and IV racemic leucovorin result in similar systemic exposures to the l-isomer of leucovorin and to 5-methyl-THF.1 10011 10012

Distribution

Extent

Levoleucovorin is actively and passively transported across cell membranes.1

Small amounts of 5-methyl-THF distributed into CSF.1

Elimination

Metabolism

Metabolized to 5-methyl-THF, the primary circulating form of active reduced folate.1 7 8 10 Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by folylpolyglutamate synthetase.1

Elimination Route

Excreted in urine as unchanged drug and metabolites.10 17

Half-life

5.1 and 6.8 hours for THF and 5-methyl-THF, respectively.1

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C).1 Protect from light.1

Following reconstitution or further dilution in 0.9% sodium chloride injection, solutions may be stored up to 12 hours at room temperature.1

Following dilution in 5% dextrose injection, solutions may be stored for up to 4 hours at room temperature.1

Injection

2–8°C.1 Protect from light.1

Following dilution in 0.9% sodium chloride injection or 5% dextrose injection, solutions may be stored for up to 4 hours at room temperature.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility1 17

Compatible

Dextrose 5% in water

Sodium chloride 0.9%

Drug Compatibility
Admixture Compatibility17

Incompatible

Fluorouracil

Y-Site Compatibility17

Compatible

Irinotecan HCl

Oxaliplatin

Incompatible

Fluorouracil

Actions

  • The pharmacologically active levorotatory (l) isomer of racemic d,l-leucovorin.1 2 3 4 5 7 10 Constitutes approximately 50% of racemic leucovorin;1 2 3 5 7 8 10 17 exerts effects at half the dose of racemic leucovorin.4

  • A reduced derivative of folic acid; does not require reduction by dihydrofolate reductase to participate in reactions utilizing folates.1

  • Counteracts the therapeutic and toxic effects (e.g., hematologic toxicity) of folic acid antagonists (e.g., methotrexate);1 2 no effect on other established toxicities of methotrexate resulting from drug and/or metabolite precipitation in kidneys (e.g., nephrotoxicity).1

  • Enhances therapeutic and toxic effects of fluoropyrimidines (e.g., fluorouracil) by stabilizing binding of fluorouracil metabolite (5-fluoro-2′-deoxyuridine 5′-monophosphate [FdUMP]) to thymidylate synthase (enzyme responsible for DNA repair and replication), thus enhancing inhibition of this enzyme.1

Advice to Patients

  • Risk of diarrhea, vomiting, stomatitis, and nausea.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses (e.g., renal impairment).1

  • Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Levoleucovorin Calcium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use

50 mg (of levoleucovorin)

Fusilev

Spectrum

Injection, for IV use

10 mg (of levoleucovorin) per mL (175 and 250 mg)

Fusilev

Spectrum

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions February 15, 2013. 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

1. Spectrum Pharmaceuticals, Inc. Fusilev (levoleucovorin calcium) powder for injection and injection solution prescribing information. Irvine, CA; 2011 Apr.

2. Goorin A, Strother D, Poplack D et al. Safety and efficacy of l-leucovorin rescue following high-dose methotrexate for osteosarcoma. Med Pediatr Oncol. 1995; 24:362-7. [PubMed 7715542]

3. Jaffe N, Jorgensen K, Robertson R et al. Substitution of l-leucovorin for d,l-leucovorin in the rescue from high-dose methotrexate treatment in patients with osteosarcoma. Anticancer Drugs. 1993; 4:559-64. [PubMed 8292813]

4. Zittoun J. Pharmacokinetics and in vitro studies of l-leucovorin. Comparison with the d and d,l-leucovorin. Ann Oncol. 1993; 4 Suppl 2:1-5. [PubMed 8353099]

5. Zittoun J, Marquet J, Pilorget JJ et al. Comparative effect of 6S, 6R and 6RS leucovorin on methotrexate rescue and on modulation of 5-fluorouracil. Br J Cancer. 1991; 63:885-8. [PubMed 2069845]

6. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to May 16, 2008. Rockville, MD; from FDA website ().

7. Zittoun J, Tonelli AP, Marquet J et al. Pharmacokinetic comparison of leucovorin and levoleucovorin. Eur J Clin Pharmacol. 1993; 44:569-73. [PubMed 8405015]

8. Etienne MC, Thyss A, Bertrand Y et al. l-folinic acid versus d,l-folinic acid in rescue of high-dose methotrexate therapy in children. J Natl Cancer Inst. 1992; 84:1190-5. [PubMed 1635087]

9. Meropol NJ, Petrelli NJ, Rustum YM et al. A phase II and pharmacokinetic study of 6S-leucovorin plus 5-fluorouracil in patient with colorectal carcinoma. Invest New Drugs. 1995; 13:149-55. [PubMed 8617578]

10. DeVito JM, Kozloski GD, Tonelli AP et al. Bioequivalence of oral and injectable levoleucovorin and leucovorin. Clin Pharm. 1993; 12:293-9. [PubMed 8458180]

11. Trissel LA, Martinez JF, Xu QA. Incompatibility of fluorouracil with leucovorin calcium or levoleucovorin calcium. Am J Health Syst Pharm. 1995; 52:710-5. [PubMed 7627739]

12. Yamasaki D, Tsujimoto M, Ohdo S et al. Possible mechanisms for the pharmacokinetic interaction between phenytoin and folinate in rats. Ther Drug Monit. 2007; 29:404-11. [PubMed 17667793]

13. Lewis DP, Van Dyke DC, Willhite LA et al. Phenytoin-folic acid interaction. Ann Pharmacother. 1995 Jul-Aug; 29:726-35.

14. Steinweg DL, Bentley ML. Seizures following reduction in phenytoin level after orally administered folic acid. Neurology. 2005; 64:1982. [PubMed 15955964]

15. Tidwell BH, Cleary JD. Comment: leucovorin-phenytoin: a drug-drug interaction?. Ann Pharmacother. 1995; 29:1303-4. [PubMed 8672847]

16. Seligmann H, Potasman I, Weller B et al. Phenytoin-folic acid interaction: a lesson to be learned. Clin Neuropharmacol. 1999 Sep-Oct; 22:268-72.

17. Spectrum Pharmaceuticals, Irvine, CA: Personal communication.

18. Safrin S, Lee BL, Sande MA. Adjunctive folinic acid with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia in AIDS patients is associated with an increased risk of therapeutic failure and death. J Infect Dis. 1994; 170:912-7. [PubMed 7930736]

19. Levoleucovorin Final Determination. Published August 2008. .

21. BTG International Inc. Voraxaze (glucarpidase) for injection prescribing information. West Conshohocken, PA; 2012 Jan

22. BTG International Inc. West Conshohocken, PA: Personal communication.

23. Justice RL. Fusilier (levoleucovorin): FDA supplement approval. NDA number: 020140/5-002. Silver Spring, MD: US Food and Drug Administration. From FDA website. Accessed 2012 Aug 29.

10001. Scheithauer W, Kornek G, Marczell A et al. Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study. J Clin Oncol. 1997; 15:908-14. [PubMed 9060527]

10002. Goldberg RM, Hatfield AK, Kahn M et al. Prospectively randomized North Central Cancer Treatment Group trial of intensive-course fluorouracil combined with the l-isomer of intravenous leucovorin, oral leucovorin, or intravenous leucovorin for the treatment of advanced colorectal cancer. J Clin Oncol. 1997; 15:3320-9. [PubMed 9363861]

10003. Tournigand C, Cervantes A, Figer A et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol. 2006; 24:394-400. [PubMed 16421419]

10004. Tournigand C, André T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004; 22:229-37. [PubMed 14657227]

10005. Cheeseman SL, Joel SP, Chester JD et al. A ’modified de Gramont’ regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002; 87:393-9. [PubMed 12177775]

10006. Seymour MT, Maughan TS, Ledermann JA et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet. 2007; 370:143-52. [PubMed 17630037]

10007. Bedford Laboratories. Leucovorin calcium for injection prescribing information. Bedford, OH; 2008 Sep.

10008. Spectrum Pharmaceuticals, Inc. Fusilev (levoleucovorin calcium) powder for injection prescribing information. Irvine, CA; 2008.

10009. Zittoun J, Tonelli AP, Marquet J et al. Pharmacokinetic comparison of leucovorin and levoleucovorin. Eur J Clin Pharmacol. 1993; 44:569-73. [PubMed 8405015]

10010. Etienne MC, Thyss A, Bertrand Y et al. l-folinic acid versus d,l-folinic acid in rescue of high-dose methotrexate therapy in children. J Natl Cancer Inst. 1992; 84:1190-5. [PubMed 1635087]

10011. Schalhorn A, Kuhl M, Heil K et al. Comparative pharmacokinetics of d,l-folinic acid and of the pure l-folinic acid. Proceedings of ASCO. 1990; 9:66. Abstract No. 253.

10012. Meropol NJ, Petrelli NJ, Rustum YM et al. A phase II and pharmacokinetic study of 6S-leucovorin plus 5-fluorouracil in patient with colorectal carcinoma. Invest New Drugs. 1995; 13:149-55. [PubMed 8617578]

10013. Rustum YM, Zhang ZG, Frank C et al. Pharmacokinetics of the biologically active isomer, 6S-leucovorin in patients with advanced colorectal cancer. Proceedings of American Association for Cancer Research. 1991; 32:174. Abstract No. 1037.

10014. Schuller J, Czejka M, Pietrzak C et al. Serum and tissue levels of l-folinic acid (fa) after IV bolus of either racemic (d,l) fa or pure l-entantiomer (l-fa). Proceedings of ASCO. 1996: 15:175. Abstract No. 353.

10015. DeVito JM, Kozloski GD, Tonelli AP et al. Bioequivalence of oral and injectable levoleucovorin and leucovorin. Clin Pharm. 1993; 12:293-9. [PubMed 8458180]

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