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IdentificationPharmacologyInteractionsReferencesTrialsEconomicsPropertiesSpectraTaxonomyTioconazole
Identification
- Name
- Tioconazole
- Accession Number
- DB01007 (APRD01262)
- Type
- Small Molecule
- Groups
- Approved
- Description
Tioconazole is an antifungal medication of the Imidazole class used to treat infections caused by a fungus or yeast. Tioconazole topical (skin) preparations are also available for ringworm, jock itch, athlete's foot, and tinea versicolor or "sun fungus". Tioconazole interacts with 14-alpha demethylase, a cytochrome P-450 enzyme that converts lanosterol to ergosterol, an essential component of the yeast membrane. In this way, tioconazole inhibits ergosterol synthesis, resulting in increased cellular permeability.
- Structure
Structure for Tioconazole (DB01007)
- Synonyms
- Tioconazol
- Tioconazole
- Tioconazolum
- Product Ingredients
Ingredient UNII CAS InChI Key Tioconazole hydrochloride T1QKM21KYB 61675-64-7 UKQXXGSDDSCAHA-UHFFFAOYSA-N - Over the Counter Products
Name Dosage Strength Route Labeller Marketing Start Marketing End CareOne Tioconazole 1 Ointment 6.5 g/100g Vaginal American Sales Company 2008-01-07 Not applicable US 
Equaline Tioconazole 1 Ointment 6.5 g/100g Vaginal Supervalu 2016-03-08 Not applicable US Equate tioconazole 1 day Ointment 6.5 g/100g Vaginal Walmart Stores 2007-11-01 Not applicable US Good Neighbor Pharmacy Tioconazole 1 Ointment 6.5 g/100g Vaginal Amerisource Bergen 2008-02-20 Not applicable US Gynecure External Cream 1% (refill) Cream 1 % Topical Pfizer Canada Inc., Consumer Healthcare Division Not applicable Not applicable Canada 
Gynecure Vaginal Ointment 6.5% W/w Ointment 6.5 % Vaginal Pfizer Canada Inc., Consumer Healthcare Division 1995-12-31 2002-11-11 Canada Gynecure Vaginal Ovule 300mg Suppository 300 mg Vaginal Pfizer Canada Inc., Consumer Healthcare Division 1995-12-31 2002-08-06 Canada Healthy Accents Tioconazole 1 Ointment 6.5 g/100g Vaginal Dza Brands, 2008-04-06 Not applicable US Image Essentials Tioconazole Treatment Ointment 6.5 g/100g Vaginal Kmart Corporation 2014-12-26 2018-10-26 US Leader Ticonazole Ointment 6.5 g/100g Vaginal Cardinal Health 2018-04-20 Not applicable US - Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Gynecure Com.pk.vag Ont6.5%vulvar Crm1% W/w Tioconazole (1 %) + Tioconazole (6.5 %) Cream; Ointment Topical; Vaginal Pfizer Canada Inc., Consumer Healthcare Division 1995-12-31 1997-08-12 Canada Gynecure Com.pk.vag Ont6.5%vulvar Crm1% W/w Tioconazole (1 %) + Tioconazole (6.5 %) Cream; Ointment Topical; Vaginal Pfizer Canada Inc., Consumer Healthcare Division 1995-12-31 1997-08-12 Canada Gynecure Com.pk.vag Ovule300mg Vulv.crm1%w/w Tioconazole (1 %) + Tioconazole (300 mg) Cream; Suppository Topical; Vaginal Pfizer Canada Inc., Consumer Healthcare Division 1995-12-31 1997-08-12 Canada Gynecure Com.pk.vag Ovule300mg Vulv.crm1%w/w Tioconazole (1 %) + Tioconazole (300 mg) Cream; Suppository Topical; Vaginal Pfizer Canada Inc., Consumer Healthcare Division 1995-12-31 1997-08-12 Canada Gynecure Tandempk.vag Ont6.5%/vulv.crm1%-w/w Tioconazole (1 %) + Tioconazole (6.5 %) Cream; Ointment Topical; Vaginal Pfizer Canada Inc., Consumer Healthcare Division 1997-03-27 2002-11-11 Canada Gynecure Tandempk.vag Ont6.5%/vulv.crm1%-w/w Tioconazole (1 %) + Tioconazole (6.5 %) Cream; Ointment Topical; Vaginal Pfizer Canada Inc., Consumer Healthcare Division 1997-03-27 2002-11-11 Canada Gynecure Tandempk.vag Ov.300mg/vulv.crm1%w/w Tioconazole (1 %) + Tioconazole (300 mg) Cream; Suppository Topical; Vaginal Pfizer Canada Inc., Consumer Healthcare Division 1996-12-02 2002-11-11 Canada Gynecure Tandempk.vag Ov.300mg/vulv.crm1%w/w Tioconazole (1 %) + Tioconazole (300 mg) Cream; Suppository Topical; Vaginal Pfizer Canada Inc., Consumer Healthcare Division 1996-12-02 2002-11-11 Canada - International/Other Brands
- GyneCure / Monistat 1 / Trosyd / Trosyl / Vagistat-1
- Categories
- 14-alpha Demethylase Inhibitors
- Anti-Infective Agents
- Antifungal Agents
- Antifungal Agents (Vaginal)
- Antifungals for Dermatological Use
- Antifungals for Topical Use
- Azole Antifungals
- Chemically-Induced Disorders
- Cytochrome P-450 CYP2C19 Inhibitors
- Cytochrome P-450 CYP2C19 Inhibitors (strong)
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2E1 Inhibitors
- Cytochrome P-450 CYP2E1 Inhibitors (strong)
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (moderate)
- Cytochrome P-450 Enzyme Inhibitors
- Dermatologicals
- Enzyme Inhibitors
- Genito Urinary System and Sex Hormones
- Gynecological Antiinfectives and Antiseptics
- Hormone Antagonists
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Imidazole and Triazole Derivatives
- Imidazole Derivatives
- Steroid Synthesis Inhibitors
- UNII
- S57Y5X1117
- CAS number
- 65899-73-2
- Weight
- Average: 387.711
Monoisotopic: 385.981416859 - Chemical Formula
- C16H13Cl3N2OS
- InChI Key
- QXHHHPZILQDDPS-UHFFFAOYSA-N
- InChI
- InChI=1S/C16H13Cl3N2OS/c17-12-1-2-13(14(18)7-12)15(8-21-5-4-20-10-21)22-9-11-3-6-23-16(11)19/h1-7,10,15H,8-9H2
- IUPAC Name
- 1-{2-[(2-chlorothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}-1H-imidazole
- SMILES
- ClC1=C(COC(CN2C=CN=C2)C2=C(Cl)C=C(Cl)C=C2)C=CS1
Pharmacology
- Indication
For the local treatment of vulvovaginal candidiasis (moniliasis).
- Associated Conditions
- Pharmacodynamics
Tioconazole is a broad-spectrum imidazole antifungal agent that inhibits the growth of human pathogenic yeasts. Tioconazole exhibits fungicidal activity in vitro against Candida albicans, other species of the genus Candida, and against Torulopsis glabrata. Tioconazole prevents the growth and function of some fungal organisms by interfering with the production of substances needed to preserve the cell membrane. This drug is effective only for infections caused by fungal organisms. It will not work for bacterial or viral infections.
- Mechanism of action
Tioconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme that converts lanosterol to ergosterol, an essential component of the yeast membrane. In this way, tioconazole inhibits ergosterol synthesis, resulting in increased cellular permeability. Tioconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms and the uptake of purine, impair triglyceride and/or phospholipid biosynthesis, and inhibit the movement of calcium and potassium ions across the cell membrane by blocking the ion transport pathway known as the Gardos channel.
Target Actions Organism ALanosterol 14-alpha demethylase antagonistYeast ULanosterol 14-alpha demethylase inhibitorHuman - Absorption
Systemic absorption following a single intravaginal application of tioconazole in nonpregnant patients is negligible.
- Volume of distribution
- Not Available
- Protein binding
- Not Available
- Metabolism
Orally administered tioconazole is extensively metabolized. The major metabolites are glucuronide conjugates.
- Route of elimination
- Not Available
- Half life
- Not Available
- Clearance
- Not Available
- Toxicity
Symptoms of overdose include erythema, stinging, blistering, peeling, edema, pruritus, urticaria, burning, and general irritation of the skin, and cramps.
- Affected organisms
- Yeast and other fungi
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
References
- General References
- Not Available
- External Links
- Human Metabolome Database
- HMDB0015142
- KEGG Drug
- D00890
- KEGG Compound
- C08082
- PubChem Compound
- 5482
- PubChem Substance
- 46508604
- ChemSpider
- 5282
- BindingDB
- 50370218
- ChEBI
- 77898
- ChEMBL
- CHEMBL1200438
- Therapeutic Targets Database
- DAP001268
- PharmGKB
- PA164746156
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Tioconazole
- ATC Codes
- G01AF08 — Tioconazole
- G01AF — Imidazole derivatives
- G01A — ANTIINFECTIVES AND ANTISEPTICS, EXCL. COMBINATIONS WITH CORTICOSTEROIDS
- G01 — GYNECOLOGICAL ANTIINFECTIVES AND ANTISEPTICS
- G — GENITO URINARY SYSTEM AND SEX HORMONES
- G01AF — Imidazole derivatives
- G01A — ANTIINFECTIVES AND ANTISEPTICS, EXCL. COMBINATIONS WITH CORTICOSTEROIDS
- G01 — GYNECOLOGICAL ANTIINFECTIVES AND ANTISEPTICS
- G — GENITO URINARY SYSTEM AND SEX HORMONES
- AHFS Codes
- 84:04.08.08 — Azoles
- FDA label
- Download (784 KB)
Clinical Trials
Pharmacoeconomics
- Manufacturers
- Pfizer laboratories div pfizer inc
- L perrigo co
- Novartis consumer health inc
- Packagers
- Johnson & Johnson Healthcare
- Novartis AG
- Walgreen Co.
- Dosage forms
Form Route Strength Cream; ointment Topical; Vaginal Cream; suppository Topical; Vaginal Ointment Vaginal 6.5 % Suppository Vaginal 300 mg Ointment Vaginal 6.5 g/100g Ointment Topical 300 mg/1g Ointment Vaginal 65 mg/1g Cream Topical 1 % Cream Topical 10 mg Ointment Vaginal 300 mg/1 - Prices
Unit description Cost Unit Monistat-Derm 2% Cream 28.35 gm Tube 41.99USD tube Monistat-Derm 2% Cream 15 gm Tube 32.0USD tube Monistat 1 combination pack 16.81USD each Monistat 1 6.5% ointment 3.6USD g Vagistat-1 6.5% ointment 3.6USD g Tioconazole 1 6.5% ointment 1.75USD g DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP 4.4 Not Available - Predicted Properties
Property Value Source Water Solubility 0.0165 mg/mL ALOGPS logP 4.86 ALOGPS logP 5.3 ChemAxon logS -4.4 ALOGPS pKa (Strongest Basic) 6.77 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 2 ChemAxon Hydrogen Donor Count 0 ChemAxon Polar Surface Area 27.05 Å2 ChemAxon Rotatable Bond Count 6 ChemAxon Refractivity 94.53 m3·mol-1 ChemAxon Polarizability 36.84 Å3 ChemAxon Number of Rings 3 ChemAxon Bioavailability 1 ChemAxon Rule of Five No ChemAxon Ghose Filter Yes ChemAxon Veber's Rule Yes ChemAxon MDDR-like Rule Yes ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 0.966 Blood Brain Barrier + 0.9814 Caco-2 permeable + 0.5812 P-glycoprotein substrate Non-substrate 0.5819 P-glycoprotein inhibitor I Non-inhibitor 0.911 P-glycoprotein inhibitor II Non-inhibitor 0.5295 Renal organic cation transporter Inhibitor 0.5164 CYP450 2C9 substrate Non-substrate 0.8248 CYP450 2D6 substrate Non-substrate 0.9116 CYP450 3A4 substrate Non-substrate 0.7558 CYP450 1A2 substrate Inhibitor 0.946 CYP450 2C9 inhibitor Inhibitor 0.8757 CYP450 2D6 inhibitor Inhibitor 0.9032 CYP450 2C19 inhibitor Inhibitor 0.926 CYP450 3A4 inhibitor Inhibitor 0.8406 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.9934 Ames test Non AMES toxic 0.8092 Carcinogenicity Non-carcinogens 0.8543 Biodegradation Not ready biodegradable 0.9869 Rat acute toxicity 2.7335 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.7187 hERG inhibition (predictor II) Inhibitor 0.6506
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as benzylethers. These are aromatic ethers with the general formula ROCR' (R = alkyl, aryl; R'=benzene).
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Benzylethers
- Direct Parent
- Benzylethers
- Alternative Parents
- Dichlorobenzenes / N-substituted imidazoles / Aryl chlorides / Thiophenes / Heteroaromatic compounds / Dialkyl ethers / Azacyclic compounds / Organopnictogen compounds / Organonitrogen compounds / Organochlorides show 1 more
- Substituents
- Benzylether / 1,3-dichlorobenzene / Chlorobenzene / Halobenzene / Aryl chloride / Aryl halide / N-substituted imidazole / Azole / Heteroaromatic compound / Thiophene show 14 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- imidazoles, thiophenes, ether, dichlorobenzene (CHEBI:77898)
Targets
- Kind
- Protein
- Organism
- Yeast
- Pharmacological action
- Yes
- Actions
- Antagonist
- General Function
- Sterol 14-demethylase activity
- Specific Function
- Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.
- Gene Name
- ERG11
- Uniprot ID
- P10613
- Uniprot Name
- Lanosterol 14-alpha demethylase
- Molecular Weight
- 60674.965 Da
References
- 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]
- Ballard SA, Lodola A, Tarbit MH: A comparative study of 1-substituted imidazole and 1,2,4-triazole antifungal compounds as inhibitors of testosterone hydroxylations catalysed by mouse hepatic microsomal cytochromes P-450. Biochem Pharmacol. 1988 Dec 15;37(24):4643-51. [PubMed:3202901]
- Fliri AF, Loging WT, Thadeio PF, Volkmann RA: Biological spectra analysis: Linking biological activity profiles to molecular structure. Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):261-6. Epub 2004 Dec 29. [PubMed:15625110]
- Bellamine A, Lepesheva GI, Waterman MR: Fluconazole binding and sterol demethylation in three CYP51 isoforms indicate differences in active site topology. J Lipid Res. 2004 Nov;45(11):2000-7. Epub 2004 Aug 16. [PubMed:15314102]
- Guinea J, Sanchez-Somolinos M, Cuevas O, Pelaez T, Bouza E: Fluconazole resistance mechanisms in Candida krusei: the contribution of efflux-pumps. Med Mycol. 2006 Sep;44(6):575-8. [PubMed:16966178]
- Chau AS, Chen G, McNicholas PM, Mann PA: Molecular basis for enhanced activity of posaconazole against Absidia corymbifera and Rhizopus oryzae. Antimicrob Agents Chemother. 2006 Nov;50(11):3917-9. Epub 2006 Sep 11. [PubMed:16966400]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Sterol 14-demethylase activity
- Specific Function
- Catalyzes C14-demethylation of lanosterol; it transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.
- Gene Name
- CYP51A1
- Uniprot ID
- Q16850
- Uniprot Name
- Lanosterol 14-alpha demethylase
- Molecular Weight
- 56805.26 Da
References
- 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]
- 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]
- Fliri AF, Loging WT, Thadeio PF, Volkmann RA: Biological spectra analysis: Linking biological activity profiles to molecular structure. Proc Natl Acad Sci U S A. 2005 Jan 11;102(2):261-6. Epub 2004 Dec 29. [PubMed:15625110]
- Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. [PubMed:10592235]
Enzymes
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Oxygen binding
- Specific Function
- Catalyzes the formation of aromatic C18 estrogens from C19 androgens.
- Gene Name
- CYP19A1
- Uniprot ID
- P11511
- Uniprot Name
- Aromatase
- Molecular Weight
- 57882.48 Da
References
- 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]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- Curator comments
- Current data supporting this enzyme inhibition is limited to one in vitro study.
- 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
References
- 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]
- Zhang W, Ramamoorthy Y, Kilicarslan T, Nolte H, Tyndale RF, Sellers EM: Inhibition of cytochromes P450 by antifungal imidazole derivatives. Drug Metab Dispos. 2002 Mar;30(3):314-8. [PubMed:11854151]
- Sweeney BP, Bromilow J: Liver enzyme induction and inhibition: implications for anaesthesia. Anaesthesia. 2006 Feb;61(2):159-77. doi: 10.1111/j.1365-2044.2005.04462.x. [PubMed:16430569]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Steroid 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 oxidizes a variety of structurally un...
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- 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]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- 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
- 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]
- Zhang W, Ramamoorthy Y, Kilicarslan T, Nolte H, Tyndale RF, Sellers EM: Inhibition of cytochromes P450 by antifungal imidazole derivatives. Drug Metab Dispos. 2002 Mar;30(3):314-8. [PubMed:11854151]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- 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
- 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]
- Zhang W, Ramamoorthy Y, Kilicarslan T, Nolte H, Tyndale RF, Sellers EM: Inhibition of cytochromes P450 by antifungal imidazole derivatives. Drug Metab Dispos. 2002 Mar;30(3):314-8. [PubMed:11854151]
Drug created on June 13, 2005 07:24 / Updated on December 14, 2018 17:08