Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C19H23N5O3.C6H10O7 |
| Molecular Weight | 563.557 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 4 / 4 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
O[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O.COC1=CC(NCC2=C(C)C3=C(N)N=C(N)N=C3C=C2)=CC(OC)=C1OC
InChI
InChIKey=ZCJXQWYMBJYJNB-LRDBBFHQSA-N
InChI=1S/C19H23N5O3.C6H10O7/c1-10-11(5-6-13-16(10)18(20)24-19(21)23-13)9-22-12-7-14(25-2)17(27-4)15(8-12)26-3;7-1-2(8)3(9)4(10)5(11)6(12)13/h5-8,22H,9H2,1-4H3,(H4,20,21,23,24);1-5,8-11H,(H,12,13)/t;2-,3+,4-,5-/m.0/s1
Trimetrexate, a second-generation folate antagonist which was used under brand name NEUTREXIN with concurrent leucovorin administration (leucovorin protection) was indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS). Nevertheless, this product was discontinued. In present time, trimetrexate with a different combinations is in the phase II of clinical trial for the treatment the following cancer diseases: pancreatic cancer and colorectal cancer (in combination with fluorouracil and leucovorin) and to treat a refractory acute leukemia in combination with leucovorin. Trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of purine biosynthesis. The result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.
Originator
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL1926 |
|||
Target ID: P00374 Gene ID: 1719.0 Gene Symbol: DHFR Target Organism: Homo sapiens (Human) |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Curative | NEUTREXIN Approved UseNeutrexin (trimetrexate glucuronate for injection) with concurrent leucovorin administration (leucovorin protection) is indicated as an alternative therapy for the treatment of moderate-to-severe Pneumocystis carinii pneumonia (PCP) in immunocompromised patients, including patients with the acquired immunodeficiency syndrome (AIDS), who are intolerant of, or are refractory to, trimethoprim-sulfamethoxazole therapy or for whom trimethoprim-sulfamethoxazole is contraindicated. This indication is based on the results of a randomized, controlled double-blind trial comparing Neutrexin with concurrent leucovorin protection (TMTX/LV) to trimethoprim sulfamethoxazole (TMP/SMX) in patients with moderate-to-severe Pneumocystis carinii pneumonia, as well as results of a Treatment IND. Launch Date1993 |
|||
| Primary | Unknown Approved UseUnknown |
|||
| Primary | Unknown Approved UseUnknown |
|||
| Primary | Unknown Approved UseUnknown |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
3.1 mg/L |
30 mg/m² 1 times / day steady-state, intravenous dose: 30 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered: LEUCOVORIN CALCIUM |
TRIMETREXATE plasma | Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
15.8 mg × h/L |
30 mg/m² 1 times / day steady-state, intravenous dose: 30 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered: LEUCOVORIN CALCIUM |
TRIMETREXATE plasma | Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
11 h |
30 mg/m² 1 times / day steady-state, intravenous dose: 30 mg/m² route of administration: Intravenous experiment type: STEADY-STATE co-administered: LEUCOVORIN CALCIUM |
TRIMETREXATE plasma | Homo sapiens population: UNHEALTHY age: UNKNOWN sex: UNKNOWN food status: UNKNOWN |
Doses
| Dose | Population | Adverse events |
|---|---|---|
100 mg/m2 1 times / week multiple, intravenous MTD Dose: 100 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / week Sources: |
unhealthy, 49 years n = 1 Health Status: unhealthy Condition: pulmonary and pleural metastasis from cutaneous angiosarcoma Age Group: 49 years Sex: F Population Size: 1 Sources: |
Disc. AE: Death... AEs leading to discontinuation/dose reduction: Death (grade 5) Sources: |
75 mg/m2 single, intravenous MTD Dose: 75 mg/m2 Route: intravenous Route: single Dose: 75 mg/m2 Sources: |
unhealthy, 63 years n = 1 Health Status: unhealthy Condition: adenocarcinoma of the lung Age Group: 63 years Sex: F Population Size: 1 Sources: |
Disc. AE: Death... AEs leading to discontinuation/dose reduction: Death (grade 5) Sources: |
10 mg/m2 1 times / day steady, intravenous MTD Dose: 10 mg/m2, 1 times / day Route: intravenous Route: steady Dose: 10 mg/m2, 1 times / day Sources: |
unhealthy, adult n = 17 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 17 Sources: |
Other AEs: Gastrointestinal signs and symptoms... |
100 mg/m2 1 times / week multiple, intravenous MTD Dose: 100 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 4 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 4 Sources: |
DLT: Myelosuppression... Other AEs: Hematotoxicity... Dose limiting toxicities: Myelosuppression Other AEs:Hematotoxicity (grade 3, 2 patients) Sources: |
110 mg/m2 1 times / week multiple, intravenous MTD Dose: 110 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 110 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 3 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 3 Sources: |
DLT: Myelosuppression... |
130 mg/m2 1 times / week multiple, intravenous MTD Dose: 130 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 130 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 7 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 7 Sources: |
DLT: Myelosuppression... Disc. AE: Hematotoxicity... Dose limiting toxicities: Myelosuppression AEs leading todiscontinuation/dose reduction: Hematotoxicity (grade 2, 2 patients) Sources: |
15 mg/m2 single, intravenous MTD Dose: 15 mg/m2 Route: intravenous Route: single Dose: 15 mg/m2 Sources: |
unhealthy, adult n = 18 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 18 Sources: |
Other AEs: Gastrointestinal signs and symptoms... |
155 mg/m2 1 times / week multiple, intravenous (max) MTD Dose: 155 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 155 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 29 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 29 Sources: |
Disc. AE: Hematotoxicity... AEs leading to discontinuation/dose reduction: Hematotoxicity (grade 2, 12 patients) Sources: |
155 mg/m2 1 times / week multiple, intravenous MTD Dose: 155 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 155 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 2 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 2 Sources: |
DLT: Myelosuppression... |
50 mg/m2 1 times / week multiple, intravenous MTD Dose: 50 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 50 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 7 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 7 Sources: |
DLT: Myelosuppression... |
75 mg/m2 1 times / week multiple, intravenous MTD Dose: 75 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 75 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 8 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 8 Sources: |
DLT: Myelosuppression... |
90 mg/m2 1 times / week multiple, intravenous MTD Dose: 90 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 90 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 6 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 6 Sources: |
DLT: Myelosuppression... Disc. AE: Hematotoxicity... Dose limiting toxicities: Myelosuppression AEs leading todiscontinuation/dose reduction: Hematotoxicity (grade 2, 1 patient) Sources: |
AEs
| AE | Significance | Dose | Population |
|---|---|---|---|
| Death | grade 5 Disc. AE |
100 mg/m2 1 times / week multiple, intravenous MTD Dose: 100 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / week Sources: |
unhealthy, 49 years n = 1 Health Status: unhealthy Condition: pulmonary and pleural metastasis from cutaneous angiosarcoma Age Group: 49 years Sex: F Population Size: 1 Sources: |
| Death | grade 5 Disc. AE |
75 mg/m2 single, intravenous MTD Dose: 75 mg/m2 Route: intravenous Route: single Dose: 75 mg/m2 Sources: |
unhealthy, 63 years n = 1 Health Status: unhealthy Condition: adenocarcinoma of the lung Age Group: 63 years Sex: F Population Size: 1 Sources: |
| Gastrointestinal signs and symptoms | 10 mg/m2 1 times / day steady, intravenous MTD Dose: 10 mg/m2, 1 times / day Route: intravenous Route: steady Dose: 10 mg/m2, 1 times / day Sources: |
unhealthy, adult n = 17 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 17 Sources: |
|
| Myelosuppression | DLT | 100 mg/m2 1 times / week multiple, intravenous MTD Dose: 100 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 4 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 4 Sources: |
| Hematotoxicity | grade 3, 2 patients | 100 mg/m2 1 times / week multiple, intravenous MTD Dose: 100 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 100 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 4 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 4 Sources: |
| Myelosuppression | DLT | 110 mg/m2 1 times / week multiple, intravenous MTD Dose: 110 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 110 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 3 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 3 Sources: |
| Myelosuppression | DLT | 130 mg/m2 1 times / week multiple, intravenous MTD Dose: 130 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 130 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 7 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 7 Sources: |
| Hematotoxicity | grade 2, 2 patients Disc. AE |
130 mg/m2 1 times / week multiple, intravenous MTD Dose: 130 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 130 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 7 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 7 Sources: |
| Gastrointestinal signs and symptoms | 15 mg/m2 single, intravenous MTD Dose: 15 mg/m2 Route: intravenous Route: single Dose: 15 mg/m2 Sources: |
unhealthy, adult n = 18 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 18 Sources: |
|
| Hematotoxicity | grade 2, 12 patients Disc. AE |
155 mg/m2 1 times / week multiple, intravenous (max) MTD Dose: 155 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 155 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 29 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 29 Sources: |
| Myelosuppression | DLT | 155 mg/m2 1 times / week multiple, intravenous MTD Dose: 155 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 155 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 2 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 2 Sources: |
| Myelosuppression | DLT | 50 mg/m2 1 times / week multiple, intravenous MTD Dose: 50 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 50 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 7 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 7 Sources: |
| Myelosuppression | DLT | 75 mg/m2 1 times / week multiple, intravenous MTD Dose: 75 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 75 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 8 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 8 Sources: |
| Myelosuppression | DLT | 90 mg/m2 1 times / week multiple, intravenous MTD Dose: 90 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 90 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 6 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 6 Sources: |
| Hematotoxicity | grade 2, 1 patient Disc. AE |
90 mg/m2 1 times / week multiple, intravenous MTD Dose: 90 mg/m2, 1 times / week Route: intravenous Route: multiple Dose: 90 mg/m2, 1 times / week Sources: |
unhealthy, adult n = 6 Health Status: unhealthy Condition: solid cancer Age Group: adult Sex: unknown Population Size: 6 Sources: |
Overview
| CYP3A4 | CYP2C9 | CYP2D6 | hERG |
|---|---|---|---|
OverviewOther
| Other Inhibitor | Other Substrate | Other Inducer |
|---|---|---|
Drug as victim
| Target | Modality | Activity | Metabolite | Clinical evidence |
|---|---|---|---|---|
| yes | likely (co-administration study) Comment: concomitant administration of SPORANOX (itraconazole) and trimetrexate may inhibit the metabolism of trimetrexate |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Metabolic disposition of trimetrexate, a nonclassical dihydrofolate reductase inhibitor, in rat and dog. | 1990 Nov-Dec |
|
| Pneumocystis carinii dihydrofolate reductase used to screen potential antipneumocystis drugs. | 1991 Jul |
|
| Phase II clinical trial of 5-fluorouracil, trimetrexate, and leucovorin (NFL) in patients with advanced pancreatic cancer. | 2003 |
|
| Design, synthesis, and biological evaluation of 2,4-diamino-5-methyl-6-substituted-pyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors. | 2004 Jul 1 |
|
| p14ARF expression increases dihydrofolate reductase degradation and paradoxically results in resistance to folate antagonists in cells with nonfunctional p53. | 2004 Jun 15 |
|
| Superior depletion of alloreactive T cells from peripheral blood stem cell and umbilical cord blood grafts by the combined use of trimetrexate and interleukin-2 immunotoxin. | 2004 Nov |
|
| Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance. | 2004 Oct |
|
| Characterization of a folate transporter in HeLa cells with a low pH optimum and high affinity for pemetrexed distinct from the reduced folate carrier. | 2004 Sep 15 |
|
| Tolerance by selective in vivo expansion of foreign major histocompatibility complex-transduced autologous bone marrow. | 2005 Aug 15 |
|
| Prediction of genotoxicity of chemical compounds by statistical learning methods. | 2005 Jun |
|
| Highly efficient transduction of repopulating bone marrow cells using rapidly concentrated polymer-complexed retrovirus. | 2005 May 13 |
|
| A phase I/II study of trimetrexate and capecitabine in patients with advanced refractory colorectal cancer. | 2005 Oct |
|
| Towards species-specific antifolates. | 2006 |
|
| Complete regression of large solid tumors using engineered drug-resistant hematopoietic cells and anti-CD137 immunotherapy. | 2006 Aug |
|
| Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates. | 2006 Dec |
|
| A phase II trial of S-1 monotherapy in metastatic colorectal cancer after failure of irinotecan- and oxaliplatin-containing regimens. | 2006 Dec 18 |
|
| The inverse relationship between reduced folate carrier function and pemetrexed activity in a human colon cancer cell line. | 2006 Feb |
|
| The protection against trimetrexate cytotoxicity in human bone marrow by sequence-dependent administration of raloxifene, 5-fluorouracil/trimetrexate. | 2006 Nov-Dec |
|
| Dihydrofolate reductase as a target for chemotherapy in parasites. | 2007 |
|
| Commentary: a case for minimizing folate supplementation in clinical regimens with pemetrexed based on the marked sensitivity of the drug to folate availability. | 2007 Jul |
|
| Raloxifene and selective cell cycle specific agents: a case for the inclusion of raloxifene in current breast cancer treatment therapies. | 2007 May-Jun |
|
| Effects of folate and folylpolyglutamyl synthase modulation on chemosensitivity of breast cancer cells. | 2007 Nov |
|
| Epigenetic mechanisms involved in differential MDR1 mRNA expression between gastric and colon cancer cell lines and rationales for clinical chemotherapy. | 2008 Aug 1 |
|
| Radiation recall dermatitis: case report and review of the literature. | 2008 Jan |
|
| Chemical and genetic validation of dihydrofolate reductase-thymidylate synthase as a drug target in African trypanosomes. | 2008 Jul |
|
| Impairments in antifolate transport are common in retinoblastoma tumor samples. | 2008 Mar |
|
| Effect of folate derivatives on the activity of antifolate drugs used against malaria and cancer. | 2008 May |
|
| Quantitative correlation between promoter methylation and messenger RNA levels of the reduced folate carrier. | 2008 May 1 |
|
| Current status and perspectives regarding the treatment of osteo-sarcoma: chemotherapy. | 2008 Sep |
|
| A mapping of drug space from the viewpoint of small molecule metabolism. | 2009 Aug |
|
| Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study. | 2009 Dec |
|
| Interpretable correlation descriptors for quantitative structure-activity relationships. | 2009 Dec 24 |
|
| Structures of dihydrofolate reductase-thymidylate synthase of Trypanosoma cruzi in the folate-free state and in complex with two antifolate drugs, trimetrexate and methotrexate. | 2009 Jul |
|
| Trimetrexate and folinic acid: a valuable salvage option for Pneumocystis jirovecii pneumonia. | 2009 Jun 19 |
|
| Radiation recall with anticancer agents. | 2010 |
|
| Academia-pharma intersect: providing a broader perspective on drug development synergies between academia and industry. | 2010 |
|
| S9511: a Southwest Oncology Group phase II study of trimetrexate, 5-fluorouracil, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach. | 2010 Apr |
|
| The immunobiology of cord blood transplantation. | 2010 Dec |
|
| Gateways to clinical trials. | 2010 Dec |
|
| High-resolution structures of Trypanosoma brucei pteridine reductase ligand complexes inform on the placement of new molecular entities in the active site of a potential drug target. | 2010 Dec |
|
| A review of synergy concepts of nonlinear blending and dose-reduction profiles. | 2010 Jan 1 |
|
| Emax model and interaction index for assessing drug interaction in combination studies. | 2010 Jan 1 |
|
| Applying Emax model and bivariate thin plate splines to assess drug interactions. | 2010 Jan 1 |
|
| Application and review of the separate ray model to investigate interaction effects. | 2010 Jan 1 |
|
| Efficient experimental design and nonparametric modeling of drug interaction. | 2010 Jan 1 |
|
| Comparison of methods for statistical analysis of combination studies. | 2010 Jan 1 |
|
| Comparison of methods for evaluating drug-drug interaction. | 2010 Jan 1 |
|
| Synthesis and biological evaluation of biguanide and dihydrotriazine derivatives as potential inhibitors of dihydrofolate reductase of opportunistic microorganisms. | 2010 Jun |
|
| Anticancer agents against malaria: time to revisit? | 2010 Mar |
|
| Cancer chemotherapy: targeting folic acid synthesis. | 2010 Nov 19 |
Sample Use Guides
Neutrexin (trimetrexate glucuronate for injection) is administered at a dose of 45 mg/m2 once daily by intravenous infusion over 60 minutes. Leucovorin must be administered daily during treatment with Neutrexin and for 72 hours past the last dose of Neutrexin. Leucovorin may be administered intravenously at a dose of 20 mg/m2 over 5 to 10 minutes every 6 hours for a total daily dose of 80 mg/m2, or orally as 4 doses of 20 mg/m2 spaced equally throughout the day. The oral dose should be rounded up to the next higher 25 mg increment. The recommended course of therapy is 21 days of Neutrexin and 24 days of leucovorin.
Route of Administration:
Intravenous
Carboxypeptidase G2 (CPG2), an enzyme produced by Pseudomonas strain RS-16, hydrolyzes the glutamate residue from methotrexate and other folates. The possibility of enhancing trimetrexate cytotoxicity by CPG2 induced folate depletion was investigated in vitro in a human leukemia cell line, CCRF-CEM, and in three sublines of these cells each with a different methotrexate resistance phenotype. Trimetrexate alone was cytotoxic against the parent and all the resistant cell lines with the drug concentrations required to decrease the cell count to 50% of control in the nanomolar range (1.4, 1.6, 1.5, and 0.7 nM in CCRF-CEM, CCRF-CEM/E, CCRF-CEM/P, and CCRF-CEM/T, respectively) following 5 days of exposure.
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| Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
14286
Created by
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FDA ORPHAN DRUG |
14686
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FDA ORPHAN DRUG |
8385
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NCI_THESAURUS |
C2153
Created by
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DTXSID90273968
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54949
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C1265
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38725
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352122
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82952-64-5
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m11163
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SUB04976MIG
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100000084647
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L137U4A79K
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DBSALT002433
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CHEMBL119
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C056321
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AA-34
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ACTIVE MOIETY
SUBSTANCE RECORD
