Pentostatin

Class: Antineoplastic Agents
VA Class: AN200
Chemical Name: (R) - 3 - (2 - deoxy - β - D - erythro - pentofuranosyl) - 3,6,7,8 - tetrahydroimidazo[4,5 - d][1,3]diazepin - 8 - ol
Molecular Formula: C₁₁H₁₆N₄O₄
CAS Number: 53910-25-1
Brands: Nipent

• Experience of Supervising Clinician


• 
  

  Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.¹

  
  

• Dose-limiting Toxicity


• 
  

  Risk of dose-related toxicities; use of dosages higher than those specified not recommended.¹ Possible dose-limiting severe renal, liver, pulmonary, and CNS toxicities with higher than recommended doses of pentostatin (e.g., dosages as high as 20–50 mg/m² in divided doses over 5 days).¹ (See Prescribing Limits under Dosage and Administration.)

  
  

• Pulmonary Toxicity


• 
  

  Severe or fatal pulmonary toxicity when used in combination with fludarabine reported in patients with chronic lymphocytic leukemia (CLL).^{1 98} Use of pentostatin with fludarabine not recommended.^{1 98} (See Specific Drugs under Interactions.)

  
  

Introduction

Antimetabolite antineoplastic antibiotic; purine antagonist produced by Streptomyces antibioticus.^{1 2 3 4 5 9 10 11 18 20}

Uses for Pentostatin

Hairy Cell Leukemia

Used alone as first-line therapy for active hairy cell leukemia (leukemic reticuloendotheliosis), defined as disease involving clinically relevant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.^{1 15 59}

Used in patients with active hairy cell leukemia that responds inadequately to, or progresses during, interferon alfa therapy (i.e., disease that progresses despite ≥3 months of interferon alfa therapy or fails to respond to ≥6 months of therapy).^{1 15 59 97 110}

Pentostatin or cladribine considered first-line therapy because of apparent greater efficacy (i.e., higher complete response rate) compared with interferon alfa;^{15 59 99 100 101 102 103 104 105 106 107} however, cladribine may be preferred.^{99 100 103 105 106 107}

Chronic Lymphocytic Leukemia (CLL)

Used alone or in combination with other agents for treatment of chronic lymphocytic leukemia (CLL)†.^{22 59}

Cutaneous T-cell Lymphoma

Treatment of cutaneous T-cell lymphoma†⁵⁹ (e.g., mycosis fungoides†, Sézary syndrome†).^{2 76 77 85 119}

Pentostatin Dosage and Administration

General

• 
  

  Consult specialized references for procedures for proper handling and disposal of antineoplastics.¹

  
  


• 
  

  Hydrate with 500–1000 mL of 5% dextrose in 0.45% sodium chloride injection or a similar IV fluid prior to pentostatin administration; hydrate with an additional 500 mL of 5% dextrose or a similar IV fluid immediately after pentostatin administration to minimize risk of adverse renal effects.^{1 3 11 97} (See Renal Effects under Cautions.)

  
  

Administration

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

Administer by IV infusion or direct IV injection.¹

Handle cautiously; use of protective clothing and polyethylene gloves recommended during preparation of IV solution.¹ Treat spills and waste with 5% sodium hypochlorite solution prior to disposal.^{1 97}

Reconstituted and diluted solutions contain no preservatives; use within 8 hours of preparation.¹

IV Administration

Reconstitution

Reconstitute vial containing 10 mg of lyophilized pentostatin by adding 5 mL of sterile water for injection to provide a solution containing 2 mg/mL.¹ Shake thoroughly to ensure complete dissolution of the drug.^{1 97}

Dilution

Prior to administration by IV infusion, must be diluted in 5% dextrose injection or 0.9% sodium chloride injection.¹ Dilute entire contents of reconstituted vial with 25 or 50 mL of 5% dextrose injection or 0.9% sodium chloride injection to provide solutions containing 0.33 or 0.18 mg/mL, respectively.¹

Rate of Administration

Administer by IV infusion over 20–30 minutes.^{1 97}

Administer by IV injection over 5 minutes.^{1 9 97}

Dosage

Adults

Hairy Cell Leukemia

IV

4 mg/m² as a single dose every other week.^{1 3 4} Higher dosages not recommended.¹ (See Prescribing Limits under Dosage and Administration.)

Optimum duration of therapy not determined.¹ If clinical improvement is observed (in the absence of any major toxicity), continue therapy until a complete response is achieved.¹ Clinical evidence suggests 2 additional doses following achievement of a complete response.^{1 97 98}

If a complete or partial response is not achieved after 6 months of therapy, discontinue therapy.¹ If a partial response is achieved, continue therapy until a complete response is achieved.¹ If after 12 months of therapy only a partial response is achieved, discontinue therapy.¹

Dosage Modification for Toxicity and Contraindications for Continued Therapy

Hematologic Toxicity

IV

Patients with initial ANC >500 cells/mm³: If ANC decreases during treatment to <200 cells/mm³, temporarily withhold therapy and resume when ANC returns to predose levels.¹

No dosage adjustments necessary when starting therapy in patients with anemia, neutropenia, or thrombocytopenia.¹

Dosage adjustments not necessary during treatment in patients with thrombocytopenia or anemia managed with appropriate hematologic monitoring and/or therapy.¹

Neurologic Toxicity

IV

If patient exhibits evidence of nervous system toxicity (e.g., lethargy, seizures, coma), withhold or discontinue therapy.¹

Dermatologic Toxicity

IV

If patient experiences a severe rash, withhold therapy.¹

Infectious Complications

IV

In patients with an active underlying infection, withhold therapy.¹ Resume therapy once infection is controlled.¹

Renal Toxicity

IV

Withhold individual doses and determine Cl_cr in patients with an increased predose S_cr.¹ (See Renal Impairment under Dosage and Administration.)

Prescribing Limits

Adults

Hairy Cell Leukemia

IV

Maximum 4 mg/m² as a single dose every other week.^{1 3 4} Risk of severe toxicity (e.g., renal, hepatic, pulmonary, CNS) increases with higher dosages (e.g., 20–50 mg/m² in divided doses over 5 days).^{1 2 97 98}

Not recommended more frequently than every 2 weeks;^{2 97 98} if weekly therapy is used, ≤3 successive weekly doses recommended by some clinicians.²

Patients unable to achieve a complete or partial response to therapy: Maximum 6 months.¹

Patients with only a partial response to therapy: Maximum 12 months.¹

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.¹

Renal Impairment

Hairy Cell Leukemia

IV

Withhold individual doses and determine Cl_cr in patients with an elevated predose S_cr.¹

Insufficient data to recommend an initial or subsequent dose of pentostatin in patients with impaired renal function (i.e., Cl_cr<60 mL/minute); 2 patients with Cl_cr of 50–60 mL/minute achieved complete responses without unusual toxicity when treated with 2 mg/m² of pentostatin.¹

Administer to patients with impaired renal function only when potential benefits justify possible risks of toxicity.^{1 2 98} (See Renal Effects under Cautions.)

Geriatric Patients

Select dosage with caution, usually starting at the low end of the dosing range, because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Pentostatin

Contraindications

• 
  

  Known hypersensitivity to pentostatin or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Hematologic Effects

Risk of severe myelosuppression (e.g., anemia, thrombocytopenia, neutropenia) especially during initial courses of treatment.¹

Neutropenia may be severe and may worsen during initial courses of therapy.¹ Monitor hematologic function (e.g., CBC) frequently for neutropenia.¹ If severe neutropenia continues beyond initial therapy cycles, evaluate patients for disease status (e.g., bone marrow examination).¹ (See Adequate Patient Evaluation and Monitoring under Cautions.)

Frequency and severity of myelosuppression appear related to underlying disease type and tumor mass.^{2 10 46 85 97 98 105 107} Myelosuppression occurs more frequently and is more severe in patients with preexisting malignancy with bone marrow involvement than in those without such involvement (e.g., in mycosis fungoides); such toxicity also may occur at relatively low dosages.^{2 10 105 107}

Infectious Complications

Risk of worsening and potentially fatal infections in patients with preexiting infections.¹ Weigh risks and benefits of therapy in patients with preexisting or secondary infections.^{1 10} In patients with evidence of infection, temporarily withhold therapy and attempt to control infection before initiating or resuming therapy.^{1 9}

Pulmonary Toxicity

Risk of severe pulmonary toxicity reported with high dosages (e.g., 20–50 mg/m² in divided doses over 5 days).¹

Risk of severe and/or fatal pulmonary toxicity when administered concomitantly with fludarabine; do not use fludarabine with pentostatin.¹ (See Specific Drugs under Interactions and also see Boxed Warning.)

Potentially fatal acute pulmonary edema reported when pentostatin was administered concomitantly with carmustine, etoposide, and high-dose cyclophosphamide in an ablative regimen as preparation for a bone marrow transplant.¹ (See Specific Drugs under Interactions.)

Renal Effects

Severe dose-related renal toxicity reported, usually occurring with dosages higher than those recommended for hairy cell leukemia.^{1 9 98 105} Mild to moderate renal toxicity also reported in patients with normal renal function prior to pentostatin therapy.^{1 7 46} In patients treated with the recommended dosage and adequate hydration, increases in S_cr generally are minor and reversible.^{1 9 98 107}

Hydrate patients prior to and immediately after pentostatin administration to minimize risk of adverse renal effects.^{1 3 11 97}

Prior to each dose and at other appropriate periods during therapy, assess renal function (e.g., S_cr and/or Cl_cr).^{1 9}

Hemolytic-uremic syndrome, possibly fatal, reported in patients receiving high dosages of pentostatin for cutaneous T-cell lymphoma;^{120 121} syndrome resolved with plasma exchange and glucocorticoid therapy.¹²⁰

Dermatologic Effects

Rash (e.g., erythematous, papular, and vesiculobullous) reported;^{1 3 4 5 8 12 80 107} may be severe and worsen during continued therapy.^{1 107 110} Withhold drug in patients who develop a severe rash.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm;¹ teratogenicity and embryotoxicity demonstrated in animals.¹

Avoid pregnancy during therapy.¹ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Hepatic Effects

Risk of severe hepatic toxicity with higher than recommended doses.¹

Reversible elevations in liver function tests reported.^{1 5 7 9 11 12 75} Monitor hepatic function regularly.^{1 9 97 98}

Major Toxicities

Neurotoxicity

Potentially severe and rarely fatal neurologic effects (e.g., seizures, coma) reported.^{2 32} Effects may be dosage schedule-dependent;^{2 8 32 75} temporarily withhold or discontinue therapy in patients exhibiting evidence of nervous system toxicity.^{1 9 97 98}

General Precautions

Adequate Patient Evaluation and Monitoring

Toxic drug with a low therapeutic index; therapeutic response unlikely without some evidence of toxicity.^{1 2} Administer only under supervision of qualified clinicians experienced in therapy with cytotoxic agents.¹

Closely observe for signs of hematologic and nonhematologic toxicity during therapy.^{1 9}

Prior to and during therapy, monitor hematologic function; frequent monitoring recommended during the first several courses of therapy in patients at increased risk of myelosuppression (e.g., those with hairy cell leukemia).^{1 2 9 10} Bone marrow examination may be required to determine disease status when severe neutropenia continues beyond the initial cycles.¹ (See Hematologic Effects under Cautions.)

Perform peripheral blood cell counts for evidence of peripheral hairy cells to evaluate response to therapy.¹ Bone marrow aspirations and biopsies may be required at 2- to 3-month intervals.^{1 3}

Assess renal function (e.g., S_cr and/or Cl_cr) prior to and during therapy.^{1 9} (See Renal Effects under Cautions.)

Monitor hepatic function regularly.^{1 9 97 98} (See Hepatic Effects under Cautions.)

If severe adverse effects occur during therapy, discontinue the drug or reduce dosage and institute appropriate measures.^{1 9} (See Dosage Modification for Toxicity and Contraindications for Continued Therapy under Dosage and Administration.)

Increased risk of greater toxicity in patients with poor performance status; use in these patients only if the anticipated benefits outweigh the potential risks.^{1 2 10}

Specific Populations

Pregnancy

Category D.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established.^{1 97}

Studied in a limited number of pediatric patients for treatment of acute leukemia;^{2 17} some evidence suggests that the drug may be better tolerated in this age group than in adults.^{2 75 98}

Geriatric Use

Safety and efficacy not established.⁹⁸ Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults;¹ monitor renal function in geriatric patients because of possible age-related decreases in renal function that may increase their risk of pentostatin-induced toxicity.¹

Renal Impairment

Use only when anticipated benefits outweigh the potential risks.^{2 98} Monitor renal function (e.g., S_cr and/or Cl_cr) initially and periodically.¹ (See Renal Effects under Cautions.)

Common Adverse Effects

Nausea,^{1 2 3 4 5 9 11 12 59 75 80 107} vomiting,^{1 2 3 4 5 9 11 12 59 75 80 107} fever,^{1 2 4 9} rash,¹ fatigue,¹ cough,¹ upper respiratory infection,¹ herpes zoster,¹ dyspnea,¹ leukopenia,¹ pruritus,¹ chills,¹ headache,¹ diarrhea,¹ myalgia,¹ abdominal pain,¹ asthenia,¹ anorexia,¹ rhinitis,¹ stomatitis,¹ anemia,¹ pain,¹ pharyngitis,¹ sweating,¹ thrombocytopenia,¹ unspecified GU disorder.^{1 a}

Interactions for Pentostatin

Specific Drugs

Drug	Interaction	Comments
Allopurinol	Possible abnormalities in renal or hepatic function8 Fatal hypersensitivity vasculitis reported; causal relationship not established1	Abnormalities usually resolve following discontinuance of allopurinol; some clinicians suggest that pentostatin and allopurinol not be used concurrently8
Carmustine	Potentially fatal acute pulmonary edema and hypotension reported with combination chemotherapy regimen of pentostatin, carmustine, etoposide, and high-dose cyclophosphamide prior to bone marrow transplant1
Cyclophosphamide	Potentially fatal acute pulmonary edema and hypotension reported with a combination chemotherapy regimen of pentostatin, carmustine, etoposide, and high-dose cyclophosphamide prior to bone marrow transplant1
Etoposide	Potentially fatal acute pulmonary edema and hypotension reported with a combination chemotherapy regimen of pentostatin, carmustine, etoposide, and high-dose cyclophosphamide prior to bone marrow transplant1
Fludarabine	Possible severe and/or fatal pulmonary toxicity (e.g., pneumonitis)1 98	Concomitant therapy not recommended1 98 (See Boxed Warning)
Vidarabine	Possible increased plasma vidarabine concentrations and/or half-life18 52 58 63 91 and greater toxicity compared with pentostatin therapy alone58

Pentostatin Pharmacokinetics

Limited data available on pharmacokinetics of pentostatin.^{97 98}

Absorption

Duration

Inhibition of adenosine deaminase by a single dose may persist in some cells for ≥1 week.²

Distribution

Extent

Distributes rapidly to all body tissues in animals.^{1 2 73 74}

Distributes relatively poorly into CSF, with peak CSF concentrations averaging approximately 10% of concurrent plasma concentrations in animals and humans.^{1 16 17 18}

Enters erythrocytes via a facilitated transport system common to other nucleosides or by simple diffusion.^{2 18 72}

Not known whether distributed into milk.¹

Plasma Protein Binding

Approximately 4%.¹

Elimination

Elimination Route

Approximately 30–90% excreted in urine as unchanged drug and/or metabolites.^{1 2 18 19}

Half-life

Terminal half-life averages 4.9–5.7 hours.^{1 9 97}

Special Populations

In patients with renal impairment (Cl_cr<60 mL/minute), half-life averages approximately 18 hours.^{1 2}

Stability

Storage

Parenteral

Powder for Injection

2–8°C.^{1 25}

Use reconstituted and diluted solutions within 8 hours when stored at room temperature in ambient light; discard unused portions.¹

Compatibility

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

Parenteral

Solution Compatibility^HID

Compatible
Dextrose 5% in water
Ringer’s injection, lactated
Sodium chloride 0.9%

Drug Compatibility

Y-Site CompatibilityHID

Compatible
Fludarabine phosphate
Melphalan HCl
Ondansetron HCl
Paclitaxel
Sargramostim

ActionsActions

• 
  

  Precise mechanism(s) of action in hairy cell leukemia and other lymphoid malignancies not fully elucidated.^{1 4 5 10 29 50 52 53}

  
  


• 
  

  Potent transition-state (tight-binding) inhibitor of adenosine deaminase (an enzyme involved in purine metabolism) ^{1 2 9 10 11 18 20 29 49 52 53 55 56 57} that appears to regulate intracellular adenosine concentrations via irreversible deamination of adenosine and deoxyadenosine.^{2 18 53 55 56 57}

  
  


• 
  

  Inhibition of adenosine deaminase results in intracellular accumulation of toxic levels of adenine deoxynucleotides (e.g., deoxyadenosine triphosphate [dATP]) and in the presence of deoxyadenosine can lead to cell death.^{1 2 10 27 28 29 30 49 52 53 54 55 57 97 98}

  
  


• 
  

  Cytotoxic effects do not appear to be attributable directly to the drug or its metabolites; appear to result indirectly from effects of the substrates for adenosine deaminase (adenosine and deoxyadenosine) and/or their metabolites.^{26 49 52 58 97 98}

  
  


• 
  

  Inhibits RNA synthesis, causes DNA strand breaks, disrupts ATP-dependent cellular processes, and inhibits adenosylhomocysteinase (S-adenosylhomocysteine hydrolase); all of which also may contribute to lymphocytotoxic effects.^{1 2 5 27 29 49 52 53}

  
  


• 
  

  Cytotoxic and growth-inhibitory effects of adenosine deaminase inhibition appear greater in T cells than in B cells.^{2 48 57}

  
  

Advice to Patients

• 
  

  Importance of immediately informing a clinician of any adverse reactions (e.g., fever, rash).¹

  
  


• 
  

  Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses or infections.¹

  
  


• 
  

  Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed;¹ necessity for clinicians to advise women to avoid pregnancy during therapy and advise pregnant women of risk to the fetus.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  
  


• 
  

  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.

Pentostatin

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injection	10 mg	Nipent	Hospira
			Pentostatin for Injection

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2009. 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

Only references cited for selected revisions after 1984 are available electronically.

1. Bedford Laboratories. Pentostatin for injection prescribing information. Bedford, OH; 2006 Aug.

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3. Blick M, Lepe-Zuniga JL, Doig R et al. Durable complete remissions after 2′-deoxycoformycin treatment in patients with hairy cell leukemia resistant to interferon alpha. Am J Hematol. 1990; 33:205-9. [PubMed 2301379]

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5. Ho AD, Thaler J, Mandelli F et al. The European Organization for Research and Treatment of Cancer Leukemia Cooperative Group. Response to pentostatin in hairy-cell leukemia refractory to interferon-alpha. J Clin Oncol. 1989; 7:1533-8. [PubMed 2789273]

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7. Lembersky BC, Ratain MJ, Westbrook C et al. Rapid response to 2′-deoxycoformycin in advanced hairy cell leukemia after failure of interferons alpha and gamma. Am J Hematol. 1988; 27:60-2. [PubMed 3128105]

8. Johnston JB, Glazer RI, Pugh L et al. The treatment of hairy-cell leukaemia with 2′-deoxycoformycin. Br J Haematol. 1986; 63:525-34. [PubMed 3488071]

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31. Johnston JB, Glazer RI, Pugh L et al. The treatment of hairy-cell leukaemia with 2′-deoxycoformycin. Br J Haematol. 1986; 63:525-34. [PubMed 3488071]

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38. Grever MR, Siaw MF, Coleman MS et al. Inhibition of K and NK lymphocyte toxicity by an inhibitor of adenosine deaminase and deoxyadenosine. J Immunol. 1982; 129:365-9.

39. Lum CT, Schmidtke JR, Sutherland DE et al. Inhibition of human T-cell rosette formation by the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA). Clin Immunol Immunopathol. 1978; 10:258-61. [PubMed 307473]

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41. Carson DA, Seegmiller JE. Effect of adenosine deaminase inhibition upon human lymphocyte blastogenesis. J Clin Invest. 1976; 57:274-82. [PubMed 176177]

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43. Parks RE Jr, Dawicki DD, Agarwal KC et al. Role of nucleoside transport in drug action: the adenosine deaminase inhibitor, deoxycoformycin, and the antiplatelet drugs, dipyridamole and dilazep. Ann NY Acad Sci. 1985; 451:188-203. [PubMed 3878117]

44. Chen SF, Stoeckler JD, Parks RE Jr. Transport of deoxycoformycin in human erythrocytes: measurement by adenosine deaminase titration and radioisotope assays. Biochem Pharmacol. 1984; 33:4069-79. [PubMed 6334522]

45. Agarwal RP Recovery of 2′-deoxycoformycin-inhibited adenosine deaminase of mouse erythrocytes and leukemia L1210 in vivo. Cancer Res. 1979; 39:1425-7.

46. Prentice HG, Russell NH, Lee N et al. Therapeutic selectivity of and predication of response to 2′-deoxycoformycin in acute leukaemia. Lancet. 1981; 2:1250-4. [IDIS 141104] [PubMed 6118669]

47. Grever MR, Leiby JM, Kraut EH et al. Low-dose deoxycoformycin in lymphoid malignancy. J Clin Oncol. 1985; 3:1196-201. [PubMed 2993534]

48. Piga A, Ganeshaguru K, Green ES et al. Selective toxicity of purine nucleosides to human leukaemic cells. Adv Exp Med Biol. 1989; 253(Suppl B):291-8.

49. Wortmann RL, Holcenberg J, Poplack DG. Relationship of 5′-nucleosidase activity and antileukemic effect in 2′-deoxycoformycin therapy. Cancer Treat Rep. 1982; 66:387-90. [IDIS 145479] [PubMed 6275991]

50. Leung KL, Yu AL. Natural killing (NK) activity in T-cell chronic lymphocytic leukemia (T-CLL) treated with deoxycoformycin (DCF). Cancer Res. 1981; 22:277.

51. Aye MT, Dunne JV. Effect of 2′-deoxycoformycin on erythroid, granulocytic, and T-lymphocyte colony growth. Blood. 1981; 58:1043-6. [IDIS 143285] [PubMed 6975136]

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