Aminophylline

Targets (4)Enzymes (4)Biointeractions (7)

Identification

Name
Aminophylline
Accession Number
DB01223  (APRD00329)
Type
Small Molecule
Groups
Approved
Description

Aminophylline is a drug combination that contains theophylline and ethylenediamine in a 2:1 ratio. Once in the body, theophylline is released and acts as a phosphodiesterase inhibitor, adenosine receptor blocker, and histone deacetylase activator. Similar to other theophyllines, aminophylline is indicated for the treatment of lung diseases such as asthma, chronic bronchitis, and COPD. The majority of aminophylline medications are discontinued and the remaining medications on the market are in short supply.

Structure
Thumb
Similar Structures
Synonyms
  • Aminophyllin
  • Aminophylline
  • Somophyllin
  • Theophylline ethylenediamine
Product Ingredients
IngredientUNIICASInChI Key
Aminophylline dihydrateC229N9DX945897-66-5FXNJPZOEDHBGEY-UHFFFAOYSA-N
Active Moieties
NameKindUNIICASInChI Key
Theophyllineunknown0I55128JYK58-55-9ZFXYFBGIUFBOJW-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AminophyllineInjection, solution25 mg/1mLIntravenousHospira, Inc.2006-11-072006-11-07Us
AminophyllineInjection, solution25 mg/1mLIntravenousHospira, Inc.2006-11-072006-11-07Us
Aminophylline Inj 25mg/mlSolution25 mgIntravenousOmega Laboratories Ltd1984-12-31Not applicableCanada
Aminophylline Inj 50mg/mlSolution50 mgIntravenousOmega Laboratories Ltd1984-12-31Not applicableCanada
Aminophylline Injection 50mg/mlSolution50 mgIntravenousHospira, Inc.1981-12-312012-08-03Canada
Aminophylline Injection USPSolution25 mgIntravenousPfizer1981-12-31Not applicableCanada
Aminophylline Tab 0.1gmTablet100 mgOralLederle Cyanamid Canada Inc.1951-12-312000-08-02Canada
Aminophylline Tab 100mgTablet97.5 mgOralStanley Pharmaceuticals, A Division Of Vita Health Products Inc.1957-12-312002-07-31Canada
Jaa Aminophylline Tab 100mgTablet100 mgOralJaapharm Canada Inc.1993-12-312016-08-10Canada
PhyllocontinTablet, extended release225 mgOralPurdue Pharma1993-12-312011-08-04Canada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AminophyllineInjection, solution25 mg/1mLIntravenousGeneral Injectables & Vaccines2009-01-01Not applicableUs
AminophyllineInjection, solution25 mg/1mLIntravenousMedical Purchasing Solutions, Llc2005-02-28Not applicableUs
AminophyllineInjection, solution25 mg/1mLIntravenousGeneral Injectables & Vaccines2010-07-012011-02-01Us
AminophyllineInjection, solution25 mg/1mLIntravenousHospira, Inc.2005-05-10Not applicableUs
AminophyllineInjection25 mg/1mLIntravenousAmerican Regent1982-06-152008-05-16Us
AminophyllineInjection, solution25 mg/1mLIntravenousCardinal Health2011-02-11Not applicableUs
AminophyllineTablet200 mg/1OralWest-Ward Pharmaceuticals Corp1976-05-282015-08-16Us
AminophyllineInjection, solution25 mg/1mLIntravenousGeneral Injectables & Vaccines, Inc2010-07-01Not applicableUs
AminophyllineInjection25 mg/1mLIntravenousAmerican Regent1982-06-152008-10-09Us
AminophyllineInjection, solution25 mg/1mLIntravenousHF Acquisition Co LLC, DBA HealthFirst2018-09-13Not applicableUs
International/Other Brands
Minomal / Somophyllin / Truphylline
Categories
UNII
27Y3KJK423
CAS number
317-34-0
Weight
Average: 420.4264
Monoisotopic: 420.198199306
Chemical Formula
C16H24N10O4
InChI Key
FQPFAHBPWDRTLU-UHFFFAOYSA-N
InChI
InChI=1S/2C7H8N4O2.C2H8N2/c2*1-10-5-4(8-3-9-5)6(12)11(2)7(10)13;3-1-2-4/h2*3H,1-2H3,(H,8,9);1-4H2
IUPAC Name
bis(1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione); ethane-1,2-diamine
SMILES
NCCN.CN1C2=C(NC=N2)C(=O)N(C)C1=O.CN1C2=C(NC=N2)C(=O)N(C)C1=O

Pharmacology

Indication

For the treatment of bronchospasm due to asthma, emphysema and chronic bronchitis.

Associated Conditions
Pharmacodynamics

Aminophylline is the ethylenediamine salt of theophylline. Theophylline stimulates the CNS, skeletal muscles, and cardiac muscle. It relaxes certain smooth muscles in the bronchi, produces diuresis, and causes an increase in gastric secretion.

Mechanism of action

Aminophylline is the ethylenediamine salt of theophylline. After ingestion, theophylline is released from aminophylline, and theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin.

TargetActionsOrganism
AcGMP-inhibited 3',5'-cyclic phosphodiesterase A
inhibitor
Human
AAdenosine receptor A1
antagonist
Human
AAdenosine receptor A3
antagonist
Human
AHistone deacetylase 2
activator
Human
Absorption
Not Available
Volume of distribution
  • 0.3 to 0.7 L/kg
Protein binding

60%

Metabolism
Not Available
Route of elimination
Not Available
Half life

7-9 hours

Clearance
  • 0.29 mL/kg/min [postnatal age 3-15 days]
  • 0.64 mL/kg/min [postnatal age 25-57 days]
  • 1.7 mL/kg/min [ 1-4 years]
  • 1.6 mL/kg/min [4-12 years]
  • 0.9 mL/kg/min [13-15 years]
  • 1.4 mL/kg/min [16-17 years]
  • 0.65 mL/kg/min [Adults (16-60 years), non-smoking asthmatics]
  • 0.41 mL/kg/min [Elderly (>60 years). liver, and renal function]
  • 0.33 mL/kg/min [Acute pulmonary edema]
  • 0.54 mL/kg/min [COPD->60 years, stable non-smoker >1 year]
  • 0.48 mL/kg/min [COPD with cor pulmonale]
  • 1.25 mL/kg/min [Cystic fibrosis (14-28 years)]
  • 0.31 mL/kg/min [Liver disease -cholestasis]
  • 0.35 mL/kg/min [cirrhosis]
  • 0.65 mL/kg/min [acute hepatitis]
  • 0.47 mL/kg/min [Sepsis with multi-organ failure]
  • 0.38 mL/kg/min [hypothyroid]
  • 0.8 mL/kg/min [hyperthyroid]
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of Aminophylline can be decreased when combined with (R)-warfarin.
(S)-WarfarinThe metabolism of Aminophylline can be decreased when combined with (S)-Warfarin.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Aminophylline.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Aminophylline.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Aminophylline.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Aminophylline.
3,5-diiodothyropropionic acidThe metabolism of Aminophylline can be decreased when combined with 3,5-diiodothyropropionic acid.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Aminophylline.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Aminophylline.
5-androstenedioneThe metabolism of Aminophylline can be decreased when combined with 5-androstenedione.
Food Interactions
  • Limit caffeine intake.
  • Take with food.
  • Vitamin B6 needs increased, supplement recommended.

References

General References
Not Available
External Links
Human Metabolome Database
HMDB0015354
KEGG Drug
D00227
PubChem Compound
9433
PubChem Substance
46508784
ChemSpider
9062
ChEBI
2659
ChEMBL
CHEMBL1370561
Therapeutic Targets Database
DAP000613
PharmGKB
PA164781029
Drugs.com
Drugs.com Drug Page
Wikipedia
Aminophylline
ATC Codes
R03DA20 — Combinations of xanthinesR03DA55 — Aminophylline, combinationsR03DB05 — Aminophylline and adrenergicsR03DA05 — Aminophylline
AHFS Codes
  • 86:16.00 — Respiratory Smooth Muscle Relaxants
MSDS
Download (72.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedNot AvailableBladder Cancers1
0Not Yet RecruitingTreatmentAcute Kidney Injury (AKI)1
1CompletedBasic ScienceMountain Sickness1
1CompletedTreatmentAcute Mountain Sickness and Fatigue1
1CompletedTreatmentHigh Altitude Pulmonary Hypertension1
1RecruitingTreatmentPremature Obstetric Labor1
1, 2CompletedPreventionPhysiological Function in Low Oxygen Environment1
2CompletedTreatmentAnaesthesia1
2CompletedTreatmentCardiac Arrest1
3CompletedTreatmentAsthma Bronchial1
3CompletedTreatmentPost-Dural Puncture Headache1
4CompletedPreventionAcute Kidney Injury (AKI)1
4CompletedPreventionPatients Being Assessed With Nuclear Stress Testing of the Heart Using the Stress Agent Regadenoson (Lexiscan ®)1
4CompletedPreventionPatients With Severe Chronic Kidney Disease Being Evaluated With Nuclear Stress Testing of the Heart Using the Stress Agent Regadenoson (Lexiscan ®)1
4RecruitingOtherAdverse Drug Events / Cataracts / Mydriasis1
4SuspendedDiagnosticCoronary Artery Disease1
4TerminatedNot AvailableAsthma Bronchial1
Not AvailableCompletedTreatmentAcute Kidney Injury (AKI)1
Not AvailableCompletedTreatmentFunction of Renal Transplant1
Not AvailableNot Yet RecruitingTreatmentAsthma Acute / Asthma in Children1
Not AvailableUnknown StatusBasic ScienceVenoarteriolar Reflex1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Amend
  • C.O. Truxton Inc.
  • Cardinal Health
  • Carlisle Laboratories Inc.
  • Dispensing Solutions
  • G & W Labs
  • General Injectables and Vaccines Inc.
  • Hospira Inc.
  • Kaiser Foundation Hospital
  • Lake Erie Medical and Surgical Supply
  • Major Pharmaceuticals
  • Murfreesboro Pharmaceutical Nursing Supply
  • PCA LLC
  • Pharmedix
  • Prescript Pharmaceuticals
  • West-Ward Pharmaceuticals
Dosage forms
FormRouteStrength
InjectionIntravenous25 mg/1mL
Injection, solutionIntravenous25 mg/1mL
SolutionOral105 mg/5mL
TabletOral100 mg/1
TabletOral200 mg/1
SolutionIntravenous50 mg
SolutionIntravenous25 mg
TabletOral100 mg
TabletOral97.5 mg
Tablet, extended releaseOral225 mg
Tablet, extended releaseOral350 mg
SuppositoryRectal250 mg/1
SuppositoryRectal500 mg/1
Prices
Unit descriptionCostUnit
Aminophylline 250 mg/10 ml vial0.48USD ml
Aminophylline 25 mg/ml0.41USD ml
Phyllocontin-350 350 mg Sustained-Release Tablet0.31USD tablet
Aminophylline 100 mg tablet0.26USD tablet
Phyllocontin 225 mg Sustained-Release Tablet0.24USD tablet
Aminophylline powder0.17USD g
Aminophylline 200 mg tablet0.15USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility2E+005 mg/LMERCK INDEX (1996)
logP-3.03Not Available
Predicted Properties
PropertyValueSource
logP-0.77ChemAxon
pKa (Strongest Acidic)7.82ChemAxon
pKa (Strongest Basic)-0.78ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area69.3 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity44.93 m3·mol-1ChemAxon
Polarizability16.86 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9778
Blood Brain Barrier+0.5908
Caco-2 permeable-0.6802
P-glycoprotein substrateSubstrate0.7341
P-glycoprotein inhibitor INon-inhibitor0.9164
P-glycoprotein inhibitor IINon-inhibitor0.9673
Renal organic cation transporterNon-inhibitor0.7935
CYP450 2C9 substrateNon-substrate0.8073
CYP450 2D6 substrateNon-substrate0.8093
CYP450 3A4 substrateSubstrate0.5482
CYP450 1A2 substrateNon-inhibitor0.8726
CYP450 2C9 inhibitorNon-inhibitor0.9332
CYP450 2D6 inhibitorNon-inhibitor0.9633
CYP450 2C19 inhibitorNon-inhibitor0.9184
CYP450 3A4 inhibitorNon-inhibitor0.8031
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8858
Ames testNon AMES toxic0.6724
CarcinogenicityNon-carcinogens0.8696
BiodegradationNot ready biodegradable0.9149
Rat acute toxicity2.4979 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7876
hERG inhibition (predictor II)Inhibitor0.6143
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-001i-1900000000-f6d60952fa154f363515

Taxonomy

Description
This compound belongs to the class of organic compounds known as monoalkylamines. These are organic compounds containing an primary aliphatic amine group.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Amines
Direct Parent
Monoalkylamines
Alternative Parents
Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Organopnictogen compound / Hydrocarbon derivative / Primary aliphatic amine / Aromatic heteropolycyclic compound
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Details1. cGMP-inhibited 3',5'-cyclic phosphodiesterase A
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
Gene Name
PDE3A
Uniprot ID
Q14432
Uniprot Name
cGMP-inhibited 3',5'-cyclic phosphodiesterase A
Molecular Weight
124978.06 Da
References
  1. Hirota K, Yoshioka H, Kabara S, Koizumi Y, Abe H, Sato T, Matsuki A: Spasmolytic effects of colforsin daropate on serotonin-induced pulmonary hypertension and bronchoconstriction in dogs. Acta Anaesthesiol Scand. 2002 Mar;46(3):297-302. [PubMed:11939921]
  2. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Details2. Adenosine receptor A1
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Purine nucleoside binding
Specific Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name
ADORA1
Uniprot ID
P30542
Uniprot Name
Adenosine receptor A1
Molecular Weight
36511.325 Da
References
  1. Yamamoto S, Nakanishi O, Matsui T, Shinohara N, Kinoshita H, Lambert C, Ishikawa T: Intrathecal adenosine A1 receptor agonist attenuates hyperalgesia without inhibiting spinal glutamate release in the rat. Cell Mol Neurobiol. 2003 Apr;23(2):175-85. [PubMed:12735630]
  2. Lerman BB: Response of nonreentrant catecholamine-mediated ventricular tachycardia to endogenous adenosine and acetylcholine. Evidence for myocardial receptor-mediated effects. Circulation. 1993 Feb;87(2):382-90. [PubMed:8425287]
Details3. Adenosine receptor A3
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
G-protein coupled adenosine receptor activity
Specific Function
Receptor for adenosine. The activity of this receptor is mediated by G proteins which inhibits adenylyl cyclase. Possible role in reproduction.
Gene Name
ADORA3
Uniprot ID
P0DMS8
Uniprot Name
Adenosine receptor A3
Molecular Weight
36184.175 Da
References
  1. Stella L, de Novellis V, Marabese I, Berrino L, Maione S, Filippelli A, Rossi F: The role of A3 adenosine receptors in central regulation of arterial blood pressure. Br J Pharmacol. 1998 Oct;125(3):437-40. [PubMed:9806324]
Details4. Histone deacetylase 2
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Activator
General Function
Transcription factor binding
Specific Function
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...
Gene Name
HDAC2
Uniprot ID
Q92769
Uniprot Name
Histone deacetylase 2
Molecular Weight
55363.855 Da
References
  1. Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ: A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8921-6. Epub 2002 Jun 17. [PubMed:12070353]

Enzymes

Details1. Cytochrome P450 1A2
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  2. Macias WL, Bergstrom RF, Cerimele BJ, Kassahun K, Tatum DE, Callaghan JT: Lack of effect of olanzapine on the pharmacokinetics of a single aminophylline dose in healthy men. Pharmacotherapy. 1998 Nov-Dec;18(6):1237-48. [PubMed:9855322]
  3. CYP1A2, CTEP document, NIH [File]
  4. Cytochrome P450 Drug Interactions [File]
Details2. Cytochrome P450 2E1
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Details3. Cytochrome P450 3A4
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
Details4. Cytochrome P450 2C19
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da

Drug created on June 13, 2005 07:24 / Updated on December 14, 2018 16:26