Tipiracil
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Identification
- Summary
Tipiracil is a thymidine phosphorylase inhibitor used as an adjunct treatment of adult patients with certain types of gastric or colorectal malignancies.
- Brand Names
- Lonsurf
- Generic Name
- Tipiracil
- DrugBank Accession Number
- DB09343
- Background
Tipiracil is a thymidine phosphorylase inhibitor. It is used in combination with trifluridine, in a ratio of 1:0.5, to form TAS-102. The main function of Tipiracil in TAS-102 is to increase trifluridine bioavailability by inhibiting its catabolism.2 TAS-102 is indicated for the treatment of metastatic colorectal cancer which has been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, or with an anti-VEGF or anti-EGFR therapy.1
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
- Weight
- Average: 242.662
Monoisotopic: 242.057053323 - Chemical Formula
- C9H11ClN4O2
- Synonyms
- 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidinedione
- 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1H-pyrimidine-2,4-dione
- Tipiracil
- Tipiracilo
Pharmacology
- Indication
Tipiracil is also available as a combination product with Trifluridine, which is indicated either alone or in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.13 This combination product is also used for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma and were previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan and if appropriate, HER2/neu-targeted therapy.13
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Metastatic colorectal cancer Combination Product in combination with: Trifluridine (DB00432), Bevacizumab (DB00112) •••••••••••• ••••• •••••••• ••••••••• •••• ••••••••••••••••• ••••••••••• ••• ••••••••••• •••••••••• ••••••• •••• •••••••••• ••• ••••••••• •••• •••••••• •• ••••••••• ••••••• •••••• Used in combination to treat Metastatic colorectal cancer Combination Product in combination with: Trifluridine (DB00432) •••••••••••• ••••• •••••••••• ••••••• •••• •••••••••• •••••••• ••••••••• •••• ••••••••••••••••• ••••••••••• ••• ••••••••••• ••• ••••••••• •••• •••••••• •• ••••••••• ••••••• •••••• Used in combination to treat Metastatic gastroesophageal junction adenocarcinoma Regimen in combination with: Trifluridine (DB00432) •••••••••••• ••••• ••••• ••••••••••••••••• •• ••••••••••••••••••• ••••••••••••• ••••••• ••••••••••• ••••• • •• •••• ••••••••••••••••• •••••••• •••••••• •••••••••••• ••••••••••••• ••••• •• ••••• •• •••••••• •••••••• •••••••••• ••••••• •••• •••••••••• •••••••••••• •••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
Tipiracil prevents trifluridine conversion into 5-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, which is an inactive major metabolite, by inhibiting the enzyme thymidine phosphorylase. Thus, tipiracil is able to increase trifluridine bioavailability. On the other hand, thymidine phsophorylase is a known platelet-derived endothelial cell growth factor and its inhibition generates an indirect antiangiogenic benefit.3
- Mechanism of action
Tipiracil is a thymidine phosphorylase inhibitor. Its function prevents the breakdownof the active component of trifluridine, thus increasing the bioavailability of trifluridine and boosting its systemic presence.1 In addition, it is reported that thymidine phosphorylase is an angiogenic factor usually overexpressed in solid tumors.4 There is a direct association of thymidine phosphorylase with a poor prognosis; where the tumors with an elevated expression of this enzyme tend to present an increased angiogenesis and ergo, be more malignant. Therefore, it has been suggested that tipiracil presents an aditional function by downregulating tumoral angiogenesis.5
Target Actions Organism AThymidine phosphorylase inhibitorHumans - Absorption
Absorption of tipiracil is suggested to be done by the gastrointestinal tract. 8 Administration of a single 35 mg/m2 dose of TAS-102 containing tipiracil and trifluridine, generates the absoprtion rates of tipiracil of AUC 301 ng h/ml, maximum observed plasma concentration (Cmax) 69 ng/ml and time for maximum observed plasma concentration (Tmax) 3 h. 6 The consumption of a high-fat and high-calorie meal can decrease Cmax and AUC by 40%.7
A standardized high-fat, high-calorie meal decreased tipiracil Cmax and AUC by approximately 40% in patients with cancer following administration of a single dose of LONSURF 35 mg.14
- Volume of distribution
Following a single dose of LONSURF (35 mg/m2) in patients with advanced solid tumours, the apparent volume of distribution (Vd/F) for tipiracil hydrochloride was 333 L.14
- Protein binding
The plasma protein binding of tipiracil is below 8%.13
- Metabolism
Tipiracil does not undergo much metabolism upon first pass. It is not metabolized by the liver or hepatocytes, nor by the cytochrome P450 enzymes. The only tipiracil-derived metabolite found in very small quantities in human plasma, urine or faeces is 6-hydroxymethyluracil (6-HMU) which is not unique of tipiracil. This metabolite is though to be formed either by enterobacterial metabolism. In plasma, this two metabolites can be found in a proportion of tipiracil 53.1% and 6-HMU 30.9%.8
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- Route of elimination
After single oral administration of LONSURF (60 mg) with [14C]-tipiracil hydrochloride, recovered radioactivity was 77% of the dose, which consisted of 27% urinary excretion and 50% fecal excretion. Tipiracil was the major component and 6-HMU was the major metabolite in urine and feces.13
- Half-life
After administration of LONSURF 35 mg/m2, the mean elimination and steady-state half-life (t1/2) of tipiracil was 2.1 hours and 2.4 hours respectively.13
- Clearance
Following a single dose of LONSURF (35 mg/m2) in patients with advanced solid tumours, the oral clearance (CL/F) for tipiracil hydrochloride was 109 L/hr.14
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
TAS-102 is a cytotoxic drug, therefore this combination drug can cause myelosupression, including neutropenia, anemia, thrombocytopenia, and febrile neutropenia. According to pre-clinical studies, TAS-102 presents also embryo-fetal toxicity.1
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAmantadine The excretion of Tipiracil can be decreased when combined with Amantadine. Amiloride The excretion of Tipiracil can be decreased when combined with Amiloride. Aminohippuric acid The excretion of Tipiracil can be decreased when combined with Aminohippuric acid. Amiodarone The excretion of Tipiracil can be decreased when combined with Amiodarone. Apalutamide The excretion of Tipiracil can be decreased when combined with Apalutamide. - Food Interactions
- Take with food.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Product Ingredients
Ingredient UNII CAS InChI Key Tipiracil hydrochloride 4H59KLQ0A4 183204-72-0 KGHYQYACJRXCAT-UHFFFAOYSA-N - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Lonsurf Tipiracil hydrochloride (8.19 mg/1) + Trifluridine (20 mg/1) Tablet, film coated Oral Taiho Pharmaceutical Co., Ltd. 2015-09-22 Not applicable US LONSURF Tipiracil (8.19 MG) + Trifluridine (20 MG) Tablet, film coated Oral Les Laboratoires Servier 2016-09-22 Not applicable Italy LONSURF Tipiracil (6.14 MG) + Trifluridine (15 MG) Tablet, film coated Oral Les Laboratoires Servier 2016-09-22 Not applicable Italy Lonsurf Tipiracil hydrochloride (8.19 mg) + Trifluridine (20 mg) Tablet, film coated Oral Les Laboratoires Servier 2016-09-08 Not applicable EU Lonsurf Tipiracil hydrochloride (6.14 mg) + Trifluridine (15 mg) Tablet, film coated Oral Les Laboratoires Servier 2016-09-08 Not applicable EU
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Diazines
- Sub Class
- Pyrimidines and pyrimidine derivatives
- Direct Parent
- Halopyrimidines
- Alternative Parents
- Pyrimidones / Aryl chlorides / Hydropyrimidines / Imidolactams / N-alkylpyrrolidines / Vinylogous amides / Heteroaromatic compounds / Ureas / Lactams / Carboximidamides show 7 more
- Substituents
- Amidine / Aromatic heteromonocyclic compound / Aryl chloride / Aryl halide / Azacycle / Carboximidamide / Carboxylic acid amidine / Halopyrimidine / Heteroaromatic compound / Hydrocarbon derivative show 16 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- NGO10K751P
- CAS number
- 183204-74-2
- InChI Key
- QQHMKNYGKVVGCZ-UHFFFAOYSA-N
- InChI
- InChI=1S/C9H11ClN4O2/c10-7-5(12-9(16)13-8(7)15)4-14-3-1-2-6(14)11/h11H,1-4H2,(H2,12,13,15,16)
- IUPAC Name
- 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]-1,2,3,4-tetrahydropyrimidine-2,4-dione
- SMILES
- ClC1=C(CN2CCCC2=N)NC(=O)NC1=O
References
- General References
- Kish T, Uppal P: Trifluridine/Tipiracil (Lonsurf) for the Treatment of Metastatic Colorectal Cancer. P T. 2016 May;41(5):314-25. [Article]
- Lenz HJ, Stintzing S, Loupakis F: TAS-102, a novel antitumor agent: a review of the mechanism of action. Cancer Treat Rev. 2015 Nov;41(9):777-83. doi: 10.1016/j.ctrv.2015.06.001. Epub 2015 Jun 6. [Article]
- Puthiamadathil JM, Weinberg BA: Emerging combination therapies for metastatic colorectal cancer - impact of trifluridine/tipiracil. Cancer Manag Res. 2017 Oct 3;9:461-469. doi: 10.2147/CMAR.S113320. eCollection 2017. [Article]
- Hotchkiss KA, Ashton AW, Schwartz EL: Thymidine phosphorylase and 2-deoxyribose stimulate human endothelial cell migration by specific activation of the integrins alpha 5 beta 1 and alpha V beta 3. J Biol Chem. 2003 May 23;278(21):19272-9. Epub 2003 Mar 13. [Article]
- Peters GJ, Bijnsdorp IV: TAS-102: more than an antimetabolite. Lancet Oncol. 2012 Dec;13(12):e518-9. doi: 10.1016/S1470-2045(12)70426-6. [Article]
- Cleary JM, Rosen LS, Yoshida K, Rasco D, Shapiro GI, Sun W: A phase 1 study of the pharmacokinetics of nucleoside analog trifluridine and thymidine phosphorylase inhibitor tipiracil (components of TAS-102) vs trifluridine alone. Invest New Drugs. 2017 Apr;35(2):189-197. doi: 10.1007/s10637-016-0409-9. Epub 2017 Jan 23. [Article]
- Yoshino T, Kojima T, Bando H, Yamazaki T, Naito Y, Mukai H, Fuse N, Goto K, Ito Y, Doi T, Ohtsu A: Effect of food on the pharmacokinetics of TAS-102 and its efficacy and safety in patients with advanced solid tumors. Cancer Sci. 2016 May;107(5):659-65. doi: 10.1111/cas.12912. Epub 2016 Mar 28. [Article]
- Lee JJ, Seraj J, Yoshida K, Mizuguchi H, Strychor S, Fiejdasz J, Faulkner T, Parise RA, Fawcett P, Pollice L, Mason S, Hague J, Croft M, Nugteren J, Tedder C, Sun W, Chu E, Beumer JH: Human mass balance study of TAS-102 using (14)C analyzed by accelerator mass spectrometry. Cancer Chemother Pharmacol. 2016 Mar;77(3):515-26. doi: 10.1007/s00280-016-2965-2. Epub 2016 Jan 19. [Article]
- EMA.europa [Link]
- EMA.europa [Link]
- Australia TGA: Trifluridine/Tipiracil Clinical Evaluation Report [Link]
- FDA Approved Drug Products: LONSURF (trifluridine and tipiracil) tablets, for oral use [Link]
- FDA Approved Drug Products: LONSURF (trifluridine and tipiracil) tablets, for oral use (August 2023) [Link]
- EMA Product Information: LONSURF (trifluridine and tipiracil) tablets, for oral use [Link]
- External Links
- PubChem Compound
- 6323266
- PubChem Substance
- 310265218
- ChemSpider
- 13243748
- BindingDB
- 50531739
- 1670304
- ChEBI
- 90879
- ChEMBL
- CHEMBL235668
- ZINC
- ZINC000100032379
- Wikipedia
- Tipiracil
- FDA label
- Download (490 KB)
- MSDS
- Download (30 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Not Available Metastatic Colorectal Cancer (CRC) 1 somestatus stop reason just information to hide Not Available Completed Not Available Metastatic Colorectal Adenocarcinoma 2 somestatus stop reason just information to hide Not Available Completed Not Available Metastatic Colorectal Cancer (CRC) 2 somestatus stop reason just information to hide Not Available Completed Treatment Gastric Adenocarcinoma / Metastatic Adenocarcinoma of the Gastroesophageal Junction 1 somestatus stop reason just information to hide Not Available Enrolling by Invitation Not Available Solid Tumors 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Tablet Oral Tablet, film coated Oral - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7799783 No 2010-09-21 2026-12-16 US US5744475 No 1998-04-28 2016-03-28 US US6479500 No 2002-11-12 2020-03-16 US US9527833 No 2016-12-27 2034-06-17 US USRE46284 No 2017-01-24 2026-12-16 US US10456399 No 2019-10-29 2037-02-03 US US10457666 No 2019-10-29 2034-06-17 US US10960004 No 2021-03-30 2037-02-03 US US9943537 No 2018-04-17 2034-09-05 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 245ºC (decomposition) Not Available water solubility 5 mg/ml (warmed) Sigma-aldrich MSDS - Predicted Properties
Property Value Source Water Solubility 0.731 mg/mL ALOGPS logP -0.21 ALOGPS logP -2 Chemaxon logS -2.5 ALOGPS pKa (Strongest Acidic) 7.28 Chemaxon pKa (Strongest Basic) 11.55 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 3 Chemaxon Polar Surface Area 85.29 Å2 Chemaxon Rotatable Bond Count 2 Chemaxon Refractivity 69.89 m3·mol-1 Chemaxon Polarizability 22.48 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-052e-9310000000-a047dc6b4a723ddce31b Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0006-0090000000-dc59edfb74f56b1335a0 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0006-0190000000-53c90c24a2fd7e4cdd26 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0596-0950000000-00c3e3926a6578e5ffab Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-007o-7940000000-d6c01bdf73773aaf3ced Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-00dl-5900000000-c04c7dcb747f44872491 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001l-9600000000-9bf68a8aa262d48f12db Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 146.50981 predictedDeepCCS 1.0 (2019) [M+H]+ 149.50237 predictedDeepCCS 1.0 (2019) [M+Na]+ 158.78993 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- May have a role in maintaining the integrity of the blood vessels. Has growth promoting activity on endothelial cells, angiogenic activity in vivo and chemotactic activity on endothelial cells in vitro
- Specific Function
- 1,4-alpha-oligoglucan phosphorylase activity
- Gene Name
- TYMP
- Uniprot ID
- P19971
- Uniprot Name
- Thymidine phosphorylase
- Molecular Weight
- 49954.965 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:9260930, PubMed:9687576). Functions as a Na(+)-independent, bidirectional uniporter (PubMed:21128598, PubMed:9687576). Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient (PubMed:15212162, PubMed:9260930, PubMed:9687576). However, may also engage electroneutral cation exchange when saturating concentrations of cation substrates are reached (By similarity). Predominantly expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (PubMed:15783073). Implicated in monoamine neurotransmitters uptake such as histamine, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, serotonin and tyramine, thereby supporting a physiological role in the central nervous system by regulating interstitial concentrations of neurotransmitters (PubMed:16581093, PubMed:17460754, PubMed:9687576). Also capable of transporting dopaminergic neuromodulators cyclo(his-pro), salsolinol and N-methyl-salsolinol, thereby involved in the maintenance of dopaminergic cell integrity in the central nervous system (PubMed:17460754). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Also transports guanidine and endogenous monoamines such as vitamin B1/thiamine, creatinine and N-1-methylnicotinamide (NMN) (PubMed:12089365, PubMed:15212162, PubMed:17072098, PubMed:24961373, PubMed:9260930). Mediates the uptake and efflux of quaternary ammonium compound choline (PubMed:9260930). Mediates the bidirectional transport of polyamine agmatine and the uptake of polyamines putrescine and spermidine (PubMed:12538837, PubMed:21128598). Able to transport non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). Also involved in the uptake of xenobiotic 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:12395288, PubMed:16394027). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- acetylcholine transmembrane transporter activity
- Gene Name
- SLC22A2
- Uniprot ID
- O15244
- Uniprot Name
- Solute carrier family 22 member 2
- Molecular Weight
- 62579.99 Da
References
- Martinez-Perez J, Riesco-Martinez MC, Garcia-Carbonero R: The safety of trifluridine and tipiracil for the treatment of metastatic colorectal cancer. Expert Opin Drug Saf. 2018 Jun;17(6):643-650. doi: 10.1080/14740338.2018.1475557. Epub 2018 May 23. [Article]
- Australia TGA: Trifluridine/Tipiracil Clinical Evaluation Report [Link]
- Tipiracil EMA [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Multidrug efflux pump that functions as a H(+)/organic cation antiporter (PubMed:16330770, PubMed:17509534). Plays a physiological role in the excretion of cationic compounds including endogenous metabolites, drugs, toxins through the kidney and liver, into urine and bile respectively (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). Mediates the efflux of endogenous compounds such as creatinine, vitamin B1/thiamine, agmatine and estrone-3-sulfate (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). May also contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- antiporter activity
- Gene Name
- SLC47A1
- Uniprot ID
- Q96FL8
- Uniprot Name
- Multidrug and toxin extrusion protein 1
- Molecular Weight
- 61921.585 Da
References
- Martinez-Perez J, Riesco-Martinez MC, Garcia-Carbonero R: The safety of trifluridine and tipiracil for the treatment of metastatic colorectal cancer. Expert Opin Drug Saf. 2018 Jun;17(6):643-650. doi: 10.1080/14740338.2018.1475557. Epub 2018 May 23. [Article]
- Australia TGA: Trifluridine/Tipiracil Clinical Evaluation Report [Link]
- Tipiracil EMA [File]
Drug created at November 27, 2015 20:26 / Updated at June 02, 2024 21:56