Asparaginase Escherichia coli

Identification

Name
Asparaginase Escherichia coli
Accession Number
DB00023  (BTD00011, BIOD00011)
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Other protein based therapies
Description

Asparaginase derived from Escherichia coli (L-asparagine amidohydrolase, EC 3.5.1.1) is an enzyme responsible for the metabolism of L-asparagine, by catalyzing L-asparagine into L-aspartic acid and ammonia. It also facilitates the production of oxaloacetate which is needed for general cellular metabolism. Asparaginase from E. coli has clinically shown to exhibit antitumor actions in models of leukaemias [1, 2]. L-asparaginase of E. coli is marketed under several different trade names, including Elspar, for the treatment of acute lymphoblastic leukemia (ALL) as part of a multi-agent chemotherapeutic regimen. It is available as intramuscular or intravenous injections. Therapeutic L-asparaginase from E. coli works by depleting the levels of non-essential amino acid, asparagine, in lymphoblastic leukemic cells thus promoting apoptotic cell death [3]. For patients who develop hypersensitivity to E. coli-derived formulations of L-asparaginase, the use of PEGylated or non-PEGylated Asparaginase Erwinia chrysanthemi is recommended [3].

Protein structure
Db00023
Protein chemical formula
C1377H2208N382O442S17
Protein average weight
31731.9 Da
Sequences
>sp|P00805|ASPG2_ECOLI L-asparaginase 2 OS=Escherichia coli (strain K12) GN=ansB PE=1 SV=2
MEFFKKTALAALVMGFSGAALALPNITILATGGTIAGGGDSATKSNYTVGKVGVENLVNA
VPQLKDIANVKGEQVVNIGSQDMNDNVWLTLAKKINTDCDKTDGFVITHGTDTMEETAYF
LDLTVKCDKPVVMVGAMRPSTSMSADGPFNLYNAVVTAADKASANRGVLVVMNDTVLDGR
DVTKTNTTDVATFKSVNYGPLGYIHNGKIDYQRTPARKHTSDTPFDVSKLNELPKVGIVY
NYANASDLPAKALVDAGYDGIVSAGVGNGNLYKSVFDTLATAAKTGTAVVRSSRVPTGAT
TQDAEVDDAKYGFVASGTLNPQKARVLLQLALTQTKDPQQIQQIFNQY
Download FASTA Format
Synonyms
  • Asparaginase
  • Asparaginase (E. coli)
  • Colaspase
  • Escherichia coli L-asparaginase
  • L-asparaginase
  • L-asparagine amidohydrolase
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ElsparInjection, powder, lyophilized, for solution10000 [iU]/1Intramuscular; IntravenousLundbeck Inc.1978-01-102013-07-18Us
KidrolasePowder, for solution10000 unitIntramuscular; IntravenousJazz Pharmaceuticals France Sas1974-12-31Not applicableCanada
SpectrilaInjection, powder, for solution10000 UIntravenousMedac Gesellschaft Fuer Klinische Spezialpraeparate Mb H2016-01-14Not applicableEu
SpectrilaInjection, powder, for solution10000 UIntravenousMedac Gesellschaft Fuer Klinische Spezialpraeparate Mb H2016-01-14Not applicableEu
Categories
UNII
G4FQ3CKY5R
CAS number
9015-68-3

Pharmacology

Indication

Indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) [Label].

Associated Conditions
Pharmacodynamics

In clinical trials of patients with previously untreated, standard-risk ALL, administration of asparaginase resulted in a decrease of plasma asparagine levels from average of 41 μM to less than 3 μM [Label]. The native asparaginase in whom plasma enzyme activity before treatment was greater than 0.1 International Units/mL [Label]. In this study, cerebrospinal fluid asparagine levels in patients treated with asparaginase decreased from 2.8 μM (pretreatment) to 1.0 μM and 0.3 μM at day 7 and day 28 of induction, respectively [Label]. Native E. coli asparaginase results in asparagine depletion in 14 to 23 days following administration [3].

Mechanism of action

Asparagine is a non-essential amino acid that maintains DNA, RNA and protein synthesis and promotes cell growth. While healthy and normal cells are capable of obtaining asparagine via dietary intake or synthesizing the asparagine from aspartate via asparagine synthetase activity, lymphoblastic leukemic cells lack the asparagine synthetase enzyme and cannot produce asparagine de novo [3]. Thus, leukemic cells rely on exogenous source of asparagine for protein synthesis and cell survival [3]. L-asparagine from E. coli serves to deplete plasma levels of asparagine in leukemic cells by converting L-asparagine to L-aspartic acid and ammonia [3], leading to reduced reduced DNA, RNA and protein synthesis; inhibition of cell growth; and ultimately the activation of apoptotic cell-death mechanisms [3]. Normal cells, however, are able to synthesize asparagine and thus are affected less by the rapid depletion produced by treatment with the enzyme asparaginase [Label].

TargetActionsOrganism
AL-asparagine
other/unknown
Human
Absorption

In a study in patients with metastatic cancer and leukemia, daily intravenous administration of L-asparaginase derived from E. coli resulted in a cumulative increase in plasma levels. Following intramuscular injection in patients with metastatic cancer and leukemia, peak plasma levels of asparaginase was achieved 14 to 24 hours post-dosing [Label].

Peak asparaginase activity of native E. coli asparaginase can be observed in 24 to 48 hours following administration [3].

Volume of distribution

Apparent volume of distribution was slightly greater than the plasma volume. Asparaginase levels in cerebrospinal fluid were less than 1% of concurrent plasma levels [3].

Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

Plasma half life of L-asparagine derived from E. coli following intravenous injection was 8-30 hrs [Label]. Plasma half-life was 34 to 49 hours after intramuscular injection [Label]. Half-life (mean ± SD) of native E. coli asparaginase is approximately 1.28 ± 0.35 days [3].

Clearance
Not Available
Toxicity

No studies assessing the mutagenic or carcinogenic potential of E. coli L-asparagine have been conducted. In the Ames assay, no mutagenic effect was demonstrated when tested against Salmonella typhimurium strains [Label]. No studies have been performed on impairment of fertility [Label]. Following a single, intravenous injection of 12,500 to 50,000 International Units L-asparagine/kg in rabbits, edema and necrosis of pancreatic islets were observed. The clinical relevance of this finding is unclear as it does not indicate pancreatitis [Label].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
DexamethasoneThe serum concentration of Dexamethasone can be increased when it is combined with Asparaginase Escherichia coli.
ImatinibThe risk or severity of liver damage can be increased when Asparaginase Escherichia coli is combined with Imatinib.
MethotrexateThe therapeutic efficacy of Methotrexate can be decreased when used in combination with Asparaginase Escherichia coli.
Food Interactions
Not Available

References

Synthesis Reference

Masao Nambu, "Process for producing immobilized L-asparaginase preparations for the therapy of leukemia." U.S. Patent US4617271, issued January, 1977.

US4617271
General References
  1. Roberts J, Prager MD, Bachynsky N: The antitumor activity of Escherichia coli L-asparaginase. Cancer Res. 1966 Oct;26(10):2213-7. [PubMed:5331901]
  2. Boyse EA, Old LJ, Campbell HA, Mashburn LT: Suppression of murine leukemias by L-asparaginase. Incidence of sensitivity among leukemias of various types: comparative inhibitory activities of guinea pig serum L-asparaginase and Escherichia coli L-asparaginase. J Exp Med. 1967 Jan 1;125(1):17-31. [PubMed:5334543]
  3. Asselin B, Rizzari C: Asparaginase pharmacokinetics and implications of therapeutic drug monitoring. Leuk Lymphoma. 2015;56(8):2273-80. doi: 10.3109/10428194.2014.1003056. Epub 2015 Mar 11. [PubMed:25586605]
  4. UniProtKB - V6FYV8 (V6FYV8_ECOLX): E. coli L-asparaginase, type II FASTA sequence [Link]
External Links
UniProt
P37595
Genbank
U00096
PubChem Substance
46507633
ChEMBL
CHEMBL2108989
PharmGKB
PA448492
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Asparaginase
ATC Codes
L01XX02 — Asparaginase
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
FDA label
Download (176 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedOtherLeukemia Acute Myeloid Leukemia (AML)1
1CompletedSupportive CareAcute Lymphoblastic Leukaemias (ALL) / Non Hodgkins Lymphoma1
1CompletedTreatmentAcute Lymphoid Leukemia Relapse / Acute Lymphoid Leukemia Relapse After Bone Marrow Transplant1
1CompletedTreatmentLeukemias1
1CompletedTreatmentLeukemias / Myelodysplastic Syndromes1
1TerminatedTreatmentAcute Lymphoblastic Leukaemia Recurrent / Allergy to Native e.Coli Asparaginase / Allergy to PEG e.Coli Asparaginase1
1, 2CompletedTreatmentAcute Undifferentiated Leukemia (AUL) / B-cell Adult Acute Lymphoblastic Leukemia / B-cell Childhood Acute Lymphoblastic Leukemia / L1 Adult Acute Lymphoblastic Leukemia / L1 Childhood Acute Lymphoblastic Leukemia / L2 Adult Acute Lymphoblastic Leukemia / L2 Childhood Acute Lymphoblastic Leukemia / Philadelphia Chromosome Negative Adult Precursor Acute Lymphoblastic Leukemia / Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia / Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia / T-cell Adult Acute Lymphoblastic Leukemia / T-cell Childhood Acute Lymphoblastic Leukemia / Untreated Adult Acute Lymphoblastic Leukemia / Untreated Childhood Acute Lymphoblastic Leukemia1
1, 2CompletedTreatmentRecurrent Childhood Acute Lymphoblastic Leukemia1
1, 2RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
2Active Not RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
2Active Not RecruitingTreatmentLymphoma, Lymphoblastic1
2CompletedTreatmentAcute Lymphocytic Leukemia (ALL)1
2CompletedTreatmentB-cell Adult Acute Lymphoblastic Leukemia / B-cell Childhood Acute Lymphoblastic Leukemia / Recurrent Adult Acute Lymphoblastic Leukemia / Recurrent Adult Lymphoblastic Lymphoma / Recurrent Childhood Acute Lymphoblastic Leukemia / Recurrent Childhood Lymphoblastic Lymphoma / T-cell Adult Acute Lymphoblastic Leukemia / T-cell Childhood Acute Lymphoblastic Leukemia1
2CompletedTreatmentLeukemias10
2CompletedTreatmentLeukemias / Malignant Lymphomas2
2CompletedTreatmentLeukemias / Neutropenias / Thrombocytopenias1
2CompletedTreatmentMalignant Lymphomas1
2CompletedTreatmentNon-Hodgkin's Lymphoma (NHL)1
2Not Yet RecruitingTreatmentAcute B-Cell Lymphoblastic Leukaemia1
2Not Yet RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
2Not Yet RecruitingTreatmentB Acute Lymphoblastic Leukemia / B Lymphoblastic Lymphoma / Recurrent Adult Acute Lymphoblastic Leukemia / Recurrent B Lymphoblastic Lymphoma / Recurrent T Lymphoblastic Leukemia/Lymphoma / Refractory B Lymphoblastic Lymphoma / Refractory T Lymphoblastic Lymphoma / T Acute Lymphoblastic Leukemia / T Lymphoblastic Lymphoma1
2RecruitingTreatmentExtranodal NK-T-CELL LYMPHOMA / NK/T Cell Lymphoma1
2RecruitingTreatmentLymphoma, Extranodal NK-T-Cell1
2TerminatedTreatmentAcute Lymphocytic Leukemia (ALL) / Leukemia Acute Myeloid Leukemia (AML) / Mixed Lineage Acute Leukemia1
2TerminatedTreatmentRecurrent Adult Acute Lymphoblastic Leukemia1
2Unknown StatusTreatmentAcute Lymphoblastic Leukaemias (ALL)1
2Unknown StatusTreatmentLeukemias2
2WithdrawnTreatmentAcute Lymphoblastic Leukemia (ALL)/Lymphoblastic Lymphoma (LBL)1
2WithdrawnTreatmentMalignancies, Hematologic1
2, 3CompletedTreatmentAcute Lymphoblastic Leukemia, in Relapse1
2, 3CompletedTreatmentAdult B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1 / Childhood B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1 / Untreated Adult Acute Lymphoblastic Leukemia / Untreated Childhood Acute Lymphoblastic Leukemia1
2, 3RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Acute Lymphoblastic Lymphoma1
2, 3Unknown StatusTreatmentLeukemias1
3Active Not RecruitingTreatmentB-cell Childhood Acute Lymphoblastic Leukemia / Intermediate Risk Recurrent Childhood Acute Lymphoblastic Leukemia / L1 Childhood Acute Lymphoblastic Leukemia / L2 Childhood Acute Lymphoblastic Leukemia1
3Active Not RecruitingTreatmentChildhood Acute Basophilic Leukemia / Childhood Acute Eosinophilic Leukemia / Childhood Acute Erythroleukemia (M6) / Childhood Acute Megakaryocytic Leukemia (M7) / Childhood Acute Minimally Differentiated Myeloid Leukemia (M0) / Childhood Acute Monoblastic Leukemia (M5a) / Childhood Acute Monocytic Leukemia (M5b) / Childhood Acute Myeloblastic Leukemia With Maturation (M2) / Childhood Acute Myeloblastic Leukemia Without Maturation (M1) / Childhood Acute Myelomonocytic Leukemia (M4) / Childhood Myelodysplastic Syndromes / De Novo Myelodysplastic Syndromes / Secondary Acute Myeloid Leukemia (Secondary AML, sAML) / Secondary Myelodysplastic Syndromes / Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies1
3Active Not RecruitingTreatmentDrug/Agent Toxicity by Tissue/Organ / Leukemias1
3Active Not RecruitingTreatmentGranulocytic Sarcoma / Leukaemia cutis / Leukemia Acute Myeloid Leukemia (AML) / Myeloid Neoplasm / Untreated Adult Acute Myeloid Leukemia / Untreated Childhood Myeloid Neoplasm1
3Active Not RecruitingTreatmentLeukemias1
3Active Not RecruitingTreatmentMalignant Lymphomas1
3CompletedSupportive CareCardiac Toxicity / Leukemias / Malignant Lymphomas1
3CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL)2
3CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL) / Acute Undifferentiated Leukemia (AUL) / Childhood T Acute Lymphoblastic Leukemia / T-cell Childhood Acute Lymphoblastic Leukemia / Untreated Childhood Acute Lymphoblastic Leukemia1
3CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL) / Adult T Acute Lymphoblastic Leukemia / Ann Arbor Stage II Adult T-Cell Leukemia/Lymphoma / Ann Arbor Stage II Childhood Lymphoblastic Lymphoma / Ann Arbor Stage II Contiguous Adult Lymphoblastic Lymphoma / Ann Arbor Stage II Non-Contiguous Adult Lymphoblastic Lymphoma / Ann Arbor Stage III Adult Lymphoblastic Lymphoma / Ann Arbor Stage III Adult T-Cell Leukemia/Lymphoma / Ann Arbor Stage III Childhood Lymphoblastic Lymphoma / Ann Arbor Stage IV Adult Lymphoblastic Lymphoma / Ann Arbor Stage IV Adult T-Cell Leukemia/Lymphoma / Ann Arbor Stage IV Childhood Lymphoblastic Lymphoma / Childhood T Acute Lymphoblastic Leukemia / Stage II Adult T-Cell Leukemia/Lymphoma / Stage II Childhood Lymphoblastic Lymphoma / Stage II Contiguous Adult Lymphoblastic Lymphoma / Stage II Non-Contiguous Adult Lymphoblastic Lymphoma / Stage III Adult Lymphoblastic Lymphoma / Stage III Adult T-Cell Leukemia/Lymphoma / Stage III Childhood Lymphoblastic Lymphoma / Stage IV Adult Lymphoblastic Lymphoma / Stage IV Adult T-Cell Leukemia/Lymphoma / Stage IV Childhood Lymphoblastic Lymphoma / T Acute Lymphoblastic Leukemia / T Lymphoblastic Lymphoma / Untreated Adult Acute Lymphoblastic Leukemia / Untreated Childhood Acute Lymphoblastic Leukemia1
3CompletedTreatmentChildhood Acute Erythroleukemia (M6) / Childhood Acute Megakaryocytic Leukemia (M7) / Childhood Acute Monoblastic Leukemia (M5a) / Childhood Acute Monocytic Leukemia (M5b) / Childhood Acute Myeloblastic Leukemia With Maturation (M2) / Childhood Acute Myeloblastic Leukemia Without Maturation (M1) / Childhood Acute Myelomonocytic Leukemia (M4) / Childhood Myelodysplastic Syndromes / Chronic Myelomonocytic Leukemia / De Novo Myelodysplastic Syndromes / Refractory Anemia / Refractory Anemia With Excess Blasts / Refractory Anemia With Excess Blasts in Transformation / Refractory Anemia With Ringed Sideroblasts / Secondary Myelodysplastic Syndromes / Untreated Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies1
3CompletedTreatmentChildhood Acute Lymphoblastic Leukemia in Remission / Recurrent Childhood Acute Lymphoblastic Leukemia1
3CompletedTreatmentLeukemias9
3CompletedTreatmentLeukemias / Malignant Lymphomas1
3CompletedTreatmentLeukemias / Myelodysplastic Syndromes1
3CompletedTreatmentLeukemias / Myelodysplastic Syndromes / Myelodysplastic/Myeloproliferative Neoplasms1
3Not Yet RecruitingTreatmentAdenocarcinoma of the Pancreas1
3RecruitingTreatmentAcute Lymphoblastic Leukemia, Pediatric1
3RecruitingTreatmentB Acute Lymphoblastic Leukemia / Recurrent Adult Acute Lymphoblastic Leukemia / Recurrent Childhood Acute Lymphoblastic Leukemia1
3RecruitingTreatmentBlasts 5 Percent or More of Bone Marrow Nucleated Cells / Childhood Acute Myeloid Leukemia / Childhood Myelodysplastic Syndrome / Cytopenias / Down Syndrome (DS) / Myeloid Leukemia Associated With Down Syndrome / Myeloproliferative Neoplasms / Trisomy 21 Mosaicism1
3RecruitingTreatmentNatural Killer/T-Cell Lymphoma, Nasal and Nasal-Type / Non-Hodgkin T-cell Lymphoma / Non-Hodgkin's Lymphoma, Relapsed1
3TerminatedTreatmentAcute Lymphoblastic Leukaemias (ALL)1
3TerminatedTreatmentMalignant Lymphomas1
3Unknown StatusTreatmentAcute Lymphoblastic Leukaemias (ALL)1
3Unknown StatusTreatmentLeukemias2
3Unknown StatusTreatmentLeukemias / Malignant Lymphomas1
3Unknown StatusTreatmentMalignant Lymphomas2
3WithdrawnTreatmentLeukemias1
4CompletedTreatmentAcute Lymphoblastic Leukaemias (ALL)5
4CompletedTreatmentAdult Acute Lymphocytic Leukemia3
4CompletedTreatmentLymphoma, Lymphoblastic1
4RecruitingTreatmentAcute Lymphobkastic Leukemia1
4RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
4RecruitingTreatmentPeripheral T Cell Lymphoma (PTCL)1
4Unknown StatusTreatmentAdult Acute Lymphocytic Leukemia2
Not AvailableActive Not RecruitingTreatmentAdult Acute Lymphoblastic Leukemia / Childhood Acute Lymphoblastic Leukemia1
Not AvailableCompletedTreatmentL1 Childhood Acute Lymphoblastic Leukemia / L2 Childhood Acute Lymphoblastic Leukemia / Non-T, Non-B Childhood Acute Lymphoblastic Leukemia / Recurrent Childhood Acute Lymphoblastic Leukemia / T-cell Childhood Acute Lymphoblastic Leukemia1
Not AvailableCompletedTreatmentLeukemia, Lymphocytic, Acute1
Not AvailableCompletedTreatmentLeukemias2
Not AvailableCompletedTreatmentLymphoma, Lymphoblastic1
Not AvailableCompletedTreatmentT-cell Childhood Acute Lymphoblastic Leukemia / Untreated Childhood Acute Lymphoblastic Leukemia1
Not AvailableNo Longer AvailableNot AvailableAcute Lymphoblastic Leukaemias (ALL) / Acute Lymphocytic Leukemia (ALL)1
Not AvailableUnknown StatusTreatmentLeukemias2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Lundbeck Inc.
  • Merck & Co.
  • Prescript Pharmaceuticals
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntramuscular; Intravenous10000 [iU]/1
Powder, for solutionIntramuscular; Intravenous10000 unit
Injection, powder, for solutionIntravenous10000 U
Prices
Unit descriptionCostUnit
Elspar 10000 unit vial74.6USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
hydrophobicity0.059Not Available
isoelectric point4.67Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

1. L-asparagine
Kind
Small molecule
Organism
Human
Pharmacological action
Yes
Actions
Other/unknown
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Wetzler M, Sanford BL, Kurtzberg J, DeOliveira D, Frankel SR, Powell BL, Kolitz JE, Bloomfield CD, Larson RA: Effective asparagine depletion with pegylated asparaginase results in improved outcomes in adult acute lymphoblastic leukemia: Cancer and Leukemia Group B Study 9511. Blood. 2007 May 15;109(10):4164-7. Epub 2007 Jan 30. [PubMed:17264295]
  4. Wenner KA, Vieira Pinheiro JP, Escherich G, Wessalowski R, Jorch N, Wolff J, Stehn M, Kohlschutter A, Boos J, Janka-Schaub GE: Asparagine concentration in plasma after 2,500 IU/m(2) PEG-asparaginase i.v. in children with acute lymphoblastic leukemia. Klin Padiatr. 2005 Nov-Dec;217(6):321-6. [PubMed:16307417]
  5. Appel IM, Pinheiro JP, den Boer ML, Lanvers C, Reniers NC, Boos J, Pieters R: Lack of asparagine depletion in the cerebrospinal fluid after one intravenous dose of PEG-asparaginase: a window study at initial diagnosis of childhood ALL. Leukemia. 2003 Nov;17(11):2254-6. [PubMed:14523472]

Drug created on June 13, 2005 07:24 / Updated on November 13, 2018 07:44