General Information of Drug (ID: DMUI0CH)

Drug Name
Tobramycin
Synonyms
Aktob; Brulamycin; Distobram; Gotabiotic; NEBRAMYCIN; Nebcin; Nebicin; Obracin; Obramycin; Sybryx; TOY; Tenebrimycin;Tenemycin; Tobacin; Tobi; Tobracin; Tobradex; Tobradistin; Tobralex; Tobramaxin; Tobramicin; Tobramicina; Tobramitsetin; Tobramycetin; Tobramycine; Tobramycinum; Tobrased; Tobrasone; Tobrex; Deoxykanamycin B; Nebramycin VI; TOBRAMYCIN SULFATE; Tobramycin for Inhalation; Tobramycin solution for inhalation; A 12253A; Lilly 47663; NF 6; Nebramycin 6; Nebramycin factir 6; Nebramycin factor 6; Nebcin (Sulfate); SPRC-AB01; TobraDex (TN); Tobracin (TN); Tobramicina [INN-Spanish]; Tobramycin, Free Base; Tobramycine [INN-French]; Tobramycinum [INN-Latin]; Tobrex (TN); Tobramycin (JP15/USP); Tobramycin[USAN:BAN:INN:JAN]; TOA-(1-6)2TB-(4-1)TOC; TOA-(1-6)TOB-(4-1)TOC; 1-Epitobramycin; 3'-Deoxykanamycin B
Indication
Disease Entry ICD 11 Status REF
Bacterial infection 1A00-1C4Z Approved [1]
Therapeutic Class
Antibiotics
Drug Type
Small molecular drug
Structure
3D MOL 2D MOL
#Ro5 Violations (Lipinski): 3 Molecular Weight (mw) 467.5
Topological Polar Surface Area (xlogp) -6.2
Rotatable Bond Count (rotbonds) 6
Hydrogen Bond Donor Count (hbonddonor) 10
Hydrogen Bond Acceptor Count (hbondacc) 14
ADMET Property
Absorption Cmax
The maximum plasma concentration (Cmax) of drug is 1.02 +/- 0.53 mg/L [2]
Absorption Tmax
The time to maximum plasma concentration (Tmax) is 1 h [2]
BDDCS Class
Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [3]
Clearance
The clearance of drug is 14.5 L/h in cystic fibrosis patients aged 6-58 years [2]
Elimination
93% of drug is excreted from urine in the unchanged form [3]
Half-life
The concentration or amount of drug in body reduced by one-half in 3 hours [2]
Metabolism
The drug is not metabolised [2]
MRTD
The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 19.25036 micromolar/kg/day [4]
Unbound Fraction
The unbound fraction of drug in plasma is 1% [5]
Vd
The volume of distribution (Vd) of drug is 85.1 L [2]
Water Solubility
The ability of drug to dissolve in water is measured as 1000 mg/mL [3]
Chemical Identifiers
Formula
C18H37N5O9
IUPAC Name
(2S,3R,4S,5S,6R)-4-amino-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[(2R,3R,5S,6R)-3-amino-6-(aminomethyl)-5-hydroxyoxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-6-(hydroxymethyl)oxane-3,5-diol
Canonical SMILES
C1[C@@H]([C@H]([C@@H]([C@H]([C@@H]1N)O[C@@H]2[C@@H]([C@H]([C@@H]([C@H](O2)CO)O)N)O)O)O[C@@H]3[C@@H](C[C@@H]([C@H](O3)CN)O)N)N
InChI
InChI=1S/C18H37N5O9/c19-3-9-8(25)2-7(22)17(29-9)31-15-5(20)1-6(21)16(14(15)28)32-18-13(27)11(23)12(26)10(4-24)30-18/h5-18,24-28H,1-4,19-23H2/t5-,6+,7+,8-,9+,10+,11-,12+,13+,14-,15+,16-,17+,18+/m0/s1
InChIKey
NLVFBUXFDBBNBW-PBSUHMDJSA-N
Cross-matching ID
PubChem CID
36294
ChEBI ID
CHEBI:28864
CAS Number
32986-56-4
DrugBank ID
DB00684
TTD ID
D07BCT
INTEDE ID
DR1606

Molecular Interaction Atlas of This Drug


Drug Therapeutic Target (DTT)
DTT Name DTT ID UniProt ID MOA REF
Bacterial 30S ribosomal RNA (Bact 30S rRNA) TTOVFH2 NOUNIPROTAC Modulator [6]

Drug-Metabolizing Enzyme (DME)
DME Name DME ID UniProt ID MOA REF
RNA cytidine acetyltransferase (hALP) DEZV4AP NAT10_HUMAN Substrate [7]
Aminoglycoside phosphotransferase (aph-Ib) DE5WGIM A0A075C7U3_CAMJU Substrate [8]
Aminoglycoside O-phosphotransferase (aphA6) DEWPAJD KKA6_ACIBA Substrate [9]
Aminoglycoside N-acetyltransferase (aacC2) DEJADS9 AAC6_ACIBA Substrate [9]
Kanamycin/gentamycin-resistance enzyme (aacA) DECXWN8 J3S7E2_CAMCO Substrate [8]
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This Drug

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Same Disease as Tobramycin
DDI Drug Name DDI Drug ID Severity Mechanism Disease REF
Cefotetan DM07TX3 Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Cefotetan. Bacterial infection [1A00-1C4Z] [29]
Kanamycin DM2DMPO Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Kanamycin. Bacterial infection [1A00-1C4Z] [30]
Ceftizoxime DM3VOGS Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Ceftizoxime. Bacterial infection [1A00-1C4Z] [29]
Cefoperazone DM53PV8 Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Cefoperazone. Bacterial infection [1A00-1C4Z] [29]
Cefprozil DM7DSYP Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Cefprozil. Bacterial infection [1A00-1C4Z] [29]
Ceftriaxone DMCEW64 Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Ceftriaxone. Bacterial infection [1A00-1C4Z] [29]
Streptomycin DME1LQN Moderate Increased risk of ototoxicity by the combination of Tobramycin and Streptomycin. Bacterial infection [1A00-1C4Z] [30]
Cefepime DMHVWIK Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Cefepime. Bacterial infection [1A00-1C4Z] [29]
Cefpodoxime DMJUNY5 Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Cefpodoxime. Bacterial infection [1A00-1C4Z] [29]
Gentamicin DMKINJO Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Gentamicin. Bacterial infection [1A00-1C4Z] [30]
Rabeprazole DMMZXIW Moderate Increased risk of hypomagnesemia by the combination of Tobramycin and Rabeprazole. Bacterial infection [1A00-1C4Z] [31]
Cefazolin DMPDYFR Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Cefazolin. Bacterial infection [1A00-1C4Z] [29]
Netilmicin DMRD1QK Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Netilmicin. Bacterial infection [1A00-1C4Z] [30]
Cefonicid DMTX2BH Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Cefonicid. Bacterial infection [1A00-1C4Z] [29]
Cefoxitin DMYTXVR Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Cefoxitin. Bacterial infection [1A00-1C4Z] [29]
⏷ Show the Full List of 15 DDI Information of This Drug
Coadministration of a Drug Treating the Disease Different from Tobramycin (Comorbidity)
DDI Drug Name DDI Drug ID Severity Mechanism Comorbidity REF
Remdesivir DMBFZ6L Moderate Decreased renal excretion of Tobramycin caused by Remdesivir mediated nephrotoxicity. 1D6YCoronavirus Disease 2019 [1D6YCoronavirus Disease 2019] [30]
Cefuroxime DMSIMD8 Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Cefuroxime. Acute bronchitis [CA42] [29]
Framycetin DMF8DNE Moderate Increased risk of ototoxicity by the combination of Tobramycin and Framycetin. Alcoholic liver disease [DB94] [30]
Inotersen DMJ93CT Major Increased risk of nephrotoxicity by the combination of Tobramycin and Inotersen. Amyloidosis [5D00] [32]
Cefamandole DMNEXZF Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Cefamandole. Anaerobic bacterial infection [1A00-1A09] [29]
Etidronic acid DM1XHYJ Moderate Increased risk of hypocalcemia by the combination of Tobramycin and Etidronic acid. Bone paget disease [FB85] [33]
Risedronate DM5FLTY Moderate Increased risk of hypocalcemia by the combination of Tobramycin and Risedronate. Bone paget disease [FB85] [33]
Mannitol DMSCDY9 Major Increased risk of nephrotoxicity by the combination of Tobramycin and Mannitol. Bronchiectasis [CA24] [34]
Iodipamide DMXIQYS Major Increased risk of nephrotoxicity by the combination of Tobramycin and Iodipamide. Cholelithiasis [DC11] [35]
Phenylbutazone DMAYL0T Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Phenylbutazone. Chronic pain [MG30] [36]
Ketoprofen DMRKXPT Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Ketoprofen. Chronic pain [MG30] [36]
Atracurium DM42HXN Major Additive neuromuscular blocking effects by the combination of Tobramycin and Atracurium. Corneal disease [9A76-9A78] [37]
Mivacurium DM473VD Major Additive neuromuscular blocking effects by the combination of Tobramycin and Mivacurium. Corneal disease [9A76-9A78] [37]
Pancuronium DMB0VY8 Major Additive neuromuscular blocking effects by the combination of Tobramycin and Pancuronium. Corneal disease [9A76-9A78] [37]
Tubocurarine DMBZIVP Major Additive neuromuscular blocking effects by the combination of Tobramycin and Tubocurarine. Corneal disease [9A76-9A78] [37]
Methoxyflurane DML0RAE Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Methoxyflurane. Corneal disease [9A76-9A78] [32]
Mycophenolic acid DMU65NK Moderate Altered absorption of Tobramycin due to GI flora changes caused by Mycophenolic acid. Crohn disease [DD70] [38]
Ethacrynic acid DM60QMR Major Increased risk of ototoxicity by the combination of Tobramycin and Ethacrynic acid. Essential hypertension [BA00] [39]
Mefenamic acid DMK7HFI Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Mefenamic acid. Female pelvic pain [GA34] [36]
Dexlansoprazole DM1DBV5 Moderate Increased risk of hypomagnesemia by the combination of Tobramycin and Dexlansoprazole. Gastro-oesophageal reflux disease [DA22] [31]
Furosemide DMMQ8ZG Major Increased risk of nephrotoxicity by the combination of Tobramycin and Furosemide. Heart failure [BD10-BD1Z] [34]
Bumetanide DMRV7H0 Major Increased risk of ototoxicity by the combination of Tobramycin and Bumetanide. Heart failure [BD10-BD1Z] [34]
Givosiran DM5PFIJ Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Givosiran. Inborn porphyrin/heme metabolism error [5C58] [30]
Exjade DMHPRWG Major Increased risk of nephrotoxicity by the combination of Tobramycin and Exjade. Mineral absorption/transport disorder [5C64] [40]
Neostigmine DM6T2J3 Moderate Additive neuromuscular blocking effects by the combination of Tobramycin and Neostigmine. Myasthenia gravis [8C6Y] [37]
Naproxen DMZ5RGV Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Naproxen. Osteoarthritis [FA00-FA05] [36]
Carboplatin DMG281S Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Carboplatin. Ovarian cancer [2C73] [41]
Aspirin DM672AH Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Aspirin. Pain [MG30-MG3Z] [42]
Etodolac DM6WJO9 Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Etodolac. Pain [MG30-MG3Z] [36]
Diflunisal DM7EN8I Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Diflunisal. Pain [MG30-MG3Z] [36]
Ibuprofen DM8VCBE Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Ibuprofen. Pain [MG30-MG3Z] [36]
Esomeprazole DM7BN0X Moderate Increased risk of hypomagnesemia by the combination of Tobramycin and Esomeprazole. Peptic ulcer [DA61] [31]
Choline salicylate DM8P137 Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Choline salicylate. Postoperative inflammation [1A00-CA43] [36]
Bromfenac DMKB79O Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Bromfenac. Postoperative inflammation [1A00-CA43] [36]
Everolimus DM8X2EH Major Increased risk of nephrotoxicity by the combination of Tobramycin and Everolimus. Renal cell carcinoma [2C90] [43]
Temsirolimus DMS104F Major Increased risk of nephrotoxicity by the combination of Tobramycin and Temsirolimus. Renal cell carcinoma [2C90] [43]
Salsalate DM13P4C Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Salsalate. Rheumatoid arthritis [FA20] [36]
Meloxicam DM2AR7L Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Meloxicam. Rheumatoid arthritis [FA20] [36]
Oxaprozin DM9UB0P Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Oxaprozin. Rheumatoid arthritis [FA20] [36]
Flurbiprofen DMGN4BY Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Flurbiprofen. Rheumatoid arthritis [FA20] [36]
Sulfasalazine DMICA9H Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Sulfasalazine. Rheumatoid arthritis [FA20] [44]
Salicyclic acid DM2F8XZ Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Salicyclic acid. Seborrhoeic dermatitis [EA81] [42]
Cephapirin DMV2JNY Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Cephapirin. Sepsis [1G40-1G41] [45]
Ifosfamide DMCT3I8 Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Ifosfamide. Solid tumour/cancer [2A00-2F9Z] [30]
Pipecuronium DM5F84A Major Additive neuromuscular blocking effects by the combination of Tobramycin and Pipecuronium. Tonus and reflex abnormality [MB47] [37]
Doxacurium DMKE7L9 Major Additive neuromuscular blocking effects by the combination of Tobramycin and Doxacurium. Tonus and reflex abnormality [MB47] [37]
Vecuronium DMP0UK2 Major Additive neuromuscular blocking effects by the combination of Tobramycin and Vecuronium. Tonus and reflex abnormality [MB47] [37]
Rocuronium DMY9BMK Major Additive neuromuscular blocking effects by the combination of Tobramycin and Rocuronium. Tonus and reflex abnormality [MB47] [37]
Sirolimus DMGW1ID Major Increased risk of nephrotoxicity by the combination of Tobramycin and Sirolimus. Transplant rejection [NE84] [43]
Mycophenolate mofetil DMPQAGE Moderate Altered absorption of Tobramycin due to GI flora changes caused by Mycophenolate mofetil. Transplant rejection [NE84] [38]
Tacrolimus DMZ7XNQ Major Increased risk of nephrotoxicity by the combination of Tobramycin and Tacrolimus. Transplant rejection [NE84] [43]
Olsalazine DMZW9HA Moderate Increased risk of nephrotoxicity by the combination of Tobramycin and Olsalazine. Ulcerative colitis [DD71] [44]
Plazomicin DMKMBES Moderate Increased risk of ototoxicity by the combination of Tobramycin and Plazomicin. Urinary tract infection [GC08] [30]
⏷ Show the Full List of 53 DDI Information of This Drug

References

1 How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73.
2 FDA Approved Drug Products: TOBI PODHALER (tobramycin) inhalation
3 BDDCS applied to over 900 drugs
4 Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
5 Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
6 Mechanism of action of aminoglycoside antibiotics.Binding studies of tobramycin and its 6'-N-acetyl derivative to the bacterial ribosome and its subunits.Eur J Biochem.1979 Dec;102(1):73-81.
7 Genetic analysis of bacterial acetyltransferases: identification of amino acids determining the specificities of the aminoglycoside 6'-N-acetyltransferase Ib and IIa proteins. J Bacteriol. 1992 May;174(10):3196-203.
8 Cloning and expression of novel aminoglycoside phosphotransferase genes from Campylobacter and their role in the resistance to six aminoglycosides. Antimicrob Agents Chemother. 2017 Dec 21;62(1). pii: e01682-17.
9 Relationship between antimicrobial resistance and aminoglycoside-modifying enzyme gene expressions in Acinetobacter baumannii. Chin Med J (Engl). 2005 Jan 20;118(2):141-5.
10 Arylamine N-acetyltransferase in human red blood cells. Biochem Pharmacol. 1992 Sep 25;44(6):1099-104.
11 A population and family study of N-acetyltransferase using caffeine urinary metabolites. Clin Pharmacol Ther. 1993 Aug;54(2):134-41.
12 Effect of H2-receptor antagonists on rat liver cytosolic acetyl CoA:arylamine N-acetyltransferase activity. Drug Metab Dispos. 1992 Jan-Feb;20(1):74-8.
13 Crystallization and preliminary X-ray characterization of arylamine N-acetyltransferase C (BanatC) from Bacillus anthracis. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007 Oct 1;63(Pt 10):862-4.
14 Identification of cytochrome P450 and arylamine N-acetyltransferase isoforms involved in sulfadiazine metabolism. Drug Metab Dispos. 2005 Jul;33(7):969-76.
15 NAT1 genotypes do not predict response to mesalamine in patients with ulcerative colitis. Z Gastroenterol. 2008 Mar;46(3):259-65.
16 Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-acetyltransferase 2 and CYP1A2 activities. Eur J Clin Pharmacol. 1999 Jan;54(11):869-76.
17 Aminoglycoside resistance resulting from tight drug binding to an altered aminoglycoside acetyltransferase. Antimicrob Agents Chemother. 2003 May;47(5):1577-83.
18 Effect of common NAT2 variant alleles in the acetylation of the major clonazepam metabolite, 7-aminoclonazepam. Drug Metab Lett. 2007 Jan;1(1):3-5.
19 Prizidilol, an antihypertensive with precapillary vasodilator and beta-adrenoceptor blocking actions, in primary hypertension. Clin Pharmacol Ther. 1981 May;29(5):588-93.
20 Novel aminoglycoside 2''-phosphotransferase identified in a gram-negative pathogen. Antimicrob Agents Chemother. 2013 Jan;57(1):452-7.
21 The antibiotic Furvina targets the P-site of 30S ribosomal subunits and inhibits translation initiation displaying start codon bias. Nucleic Acids Res. 2012 Nov 1;40(20):10366-74.
22 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
23 The antibiotic arms race: current and emerging therapy for Klebsiella pneumoniae carbapenemase (KPC) - producing bacteria.Expert Opin Pharmacother. 2018 Oct 22:1-13.
24 Omadacycline Enters the Ring: A New Antimicrobial Contender.Pharmacotherapy. 2018 Dec;38(12):1194-1204.
25 Microbiological Profile of Sarecycline, a Novel Targeted Spectrum Tetracycline for the Treatment of Acne Vulgaris.Antimicrob Agents Chemother. 2018 Dec 21;63(1). pii: e01297-18.
26 ClinicalTrials.gov (NCT01961830) Intrapulmonary Pharmacokinetics of ME1100 in Healthy Volunteers. U.S. National Institutes of Health.
27 Clinical pipeline report, company report or official report of Tetraphase Pharmaceuticals.
28 Clinical pipeline report, company report or official report of Tetraphase Pharmaceuticals.
29 Agencia Espaola de Medicamentos y Productos Sanitarios Healthcare "Centro de informacion online de medicamentos de la AEMPS - CIMA.".
30 Cerner Multum, Inc. "Australian Product Information.".
31 FDA. U.S. Food and Drug Administration "FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of proton pump inhibitor drugs (PPIs).".
32 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
33 Chang JT, Green L, Beitz J "Renal failure with the use of zoledronic acid." N Engl J Med 349 (2003): 1676-9 discussion 1676-9. [PMID: 14573746]
34 Athlin L, Domellof L, Holm S "Gentamicin treatment in severe surgical infections: serum levels, interactions, toxicity and efficacy." Acta Chir Scand 147 (1981): 225-30. [PMID: 7034430]
35 Wong GT, Lee EY, Irwin MG. Contrast induced nephropathy in vascular surgery.?Br J Anaesth. 2016;117 Suppl 2:ii63-ii73. [PMID: 27566809]
36 Assael BM, Chiabrando C, Gagliardi L, Noseda A, Bamonte F, Salmona M "Prostaglandins and aminoglycoside nephrotoxicity." Toxicol Appl Pharmacol 78 (1985): 386-94. [PMID: 4049389]
37 Burkett L, Bikhazi GB, Thomas KC Jr, Rosenthal DA, Wirta MG, Foldes FF "Mutual potentiation of the neuromuscular effects of antibiotics and relaxants." Anesth Analg 58 (1979): 107-15. [PMID: 571233]
38 Product Information. CellCept (mycophenolate mofetil). Roche Laboratories, Nutley, NJ.
39 Bates DE, Beaumont SJ, Baylis BW "Ototoxicity induced by gentamicin and furosemide." Ann Pharmacother 36 (2002): 446-51. [PMID: 11895059]
40 Product Information. Exjade (deferasirox). Novartis Pharmaceuticals, East Hanover, NJ.
41 Product Information. Paraplatin (carboplatin). Bristol-Myers Squibb, Princeton, NJ.
42 Farag MM, Mikhail MR, Abdel-Meguid E, Abdel-Tawab S "Assessment of gentamicin-induced nephrotoxicity in rats treated with low doses of ibuprofen and diclofenac sodium." Clin Sci 91 (1996): 187-91. [PMID: 8795442]
43 Product Information. Prograf (tacrolimus). Fujisawa, Deerfield, IL.
44 Novis BH, Korzets Z, Chen P, Bernheim J "Nephrotic syndrome after treatment with 5-aminosalicylic acid." Br Med J (Clin Res Ed) 296 (1988): 1442. [PMID: 3132281]
45 Engle JE, Drago J, Carlin B, Schoolwerth AC "Letter: Reversible acute renal failure after cephalothin." Ann Intern Med 83 (1975): 232-3. [PMID: 1147461]