HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Stavudine
sanilvudine · 1-(2,3-Dideoxy-beta-D-glycero-2-pentenofuranosyl)thymine · D4T · ZERIT · Stavir · Avostav · Virostav · STAVUDINE
Identifikatoren & physikalische Daten
| CAS No. | 3056-17-5 |
|---|---|
| Summenformel | C10H12N2O4 |
| Durchschnittliche Molmasse | 224,21 g/mol |
| Monoisotopische Masse | 224,07970686 g/mol |
| SMILES | Cc1cn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]c1=O |
| InChIKey | XNKLLVCARDGLGL-JGVFFNPUSA-N |
| PubChem CID | 18283 |
| ChEMBL | CHEMBL991 |
| ChEBI | CHEBI:63581 |
| EC No. | 641-374-0 |
| DTXSID | DTXSID1023819 |
Chemische & physikalische Eigenschaften
| XLogP | -0,8 |
|---|---|
| Polarare Oberfläche (TPSA) | 78,9 |
| H-Brücken-Donoren | 2 |
| H-Brücken-Akzeptoren | 4 |
| Frei drehbare Bindungen | 2 |
| Schwere Atome | 16 |
| Formalladung | 0 |
| Komplexität | 388 |
| Arzneimittel | Pharmaceuticals -> Listed in ZINC15 |
| LogP (Verteilungskoeffizient) | log Kow = -0.72 at 37 °C-0.8 |
| Color/Form | White to off white crystalline solidColorless granular solid from ethanol/benzene |
| Löslichkeit | 50 to 100 mg/mL at 70 °F (NTP, 1992)5-10 g/100 mL at 21 °C30 mg/mL in propylene glycol at 23 °CIn water, 83 mg/mL at 23 °C4.05e+01 g/LSoluble in water, sparingly soluble in ethanol (96 per cent), slightly soluble in methylene chloride. It shows polymorphism (5.9).5-10 g/100 mL at 21 ºC |
| Human Drugs | Breast FeedingLactationMilk, HumanAnti-Infective AgentsAntiviral AgentsAnti-HIV AgentsAnti-Retroviral AgentsReverse Transcriptase InhibitorsFDA approved drugs -> Active ingredient |
| Schmelzpunkt | 318 to 320 °F (NTP, 1992)159-160 °C165-166 °C159 - 160 °C159-160°C |
| Dampfdruck | 9.5X10-12 mm Hg at 25 °C /Estimated/ |
| Henry-Konstante | Henry's Law constant = 2.3X10-15 atm-cu m/mole at 25 °C /Estimated/4.3×109 mol/(m3Pa) at 25℃, HSDB (2015) |
| Physical Description | 2',3'-didehydro-3'-deoxythymidine appears as white crystalline solid or powder. Odorless. (NTP, 1992) |
| Other Experimental Properties | Hydroxyl radical reaction rate constant = 1.21X10-10 cu cm/molec-sec at 25 °C /Estimated/Ozone reaction rate constant = 2.1X10-16 cu cm/molec-sec at 25 °C /Estimated/ |
| Dichte | 1.374±0.06 g/cm3(Predicted) |
| Brechungsindex | -46 ° (C=0.69, H2O) |
| Lagerbedingungen | -20°C |
| Aggregatzustand | Solid |
| pKa (Säurekonstante) | 9.47±0.10(Predicted) |
| Farbe | White |
| BCS Class | 1,3 |
| Stabilität | Stable. Combustible. Incompatible with strong oxidizing agents. |
| InChI | 1S/C10H12N2O4/c1-6-4-12(10(15)11-9(6)14)8-3-2-7(5-13)16-8/h2-4,7-8,13H,5H2,1H3,(H,11,14,15)/t7-,8+/m0/s1 |
| InChIKey | XNKLLVCARDGLGL-JGVFFNPUSA-N |
| SMILES | CC1=CN([C@@H]2O[C@H](CO)C=C2)C(=O)NC1=O |
| CAS Datenbank | 3056-17-5(CAS DataBase Reference) |
| EPA chemische Informationen | Thymidine, 2',3'-didehydro-3'-deoxy- (3056-17-5) |
Sicherheit & Vorschriften
| GHS-Einstufung | DangerH302 (66.7%): Harmful if swallowed [Warning Acute toxicity, oral]P203, P260, P261, P263, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 3 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| Brandgefahren | Literature sources indicate that this chemical is combustible. (NTP, 1992) |
| Gesundheitsgefahren | SYMPTOMS: This compound may cause irritation. |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl stavudine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. |
| Reaktive Gruppe | Alcohols and Polyols |
| Special Reports | Zapor MJ et alAntiretrovirals, Part II: Focus on Non-protease Inhibitor Antiretrovirals (NRTIs, NNRTIs, and Fusion Inhibitors)Psychosomatics 45 (6): 524-35 (2004) |
| Reactivity Profile | 2',3'-DIDEHYDRO-3'-DEOXYTHYMIDINE is sensitive to heat. Incompatible with strong oxidizing agents (NTP, 1992). |
| Air and Water Reactions | Water soluble. |
| Hazard Classes and Categories | Acute Tox. 4 (66.7%) |
| Brandbekämpfung | Fires involving this material can be controlled with a dry chemical, carbon dioxide or Halon extinguisher. A water spray may also be used. (NTP, 1992) |
| Erste Hilfe | EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop. |
| Lagerbedingungen | Commercially available stavudine capsules should be stored in a tight container at a controlled room temperature of 15-30 °C. Stavudine powder for oral solution should be kept in a tight container at a controlled room temperature of 15-30 °C and protected from excessive moisture. Following reconstitution, the oral solution should be stored in a tight container at 2-8 °C. |
| Freisetung ohne Brand | SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned. |
| Entsorgungsverfahren | SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air qualitypotential migration in soil or watereffects on animal, aquatic, and plant lifeand conformance with environmental and public health regulations. |
| Personal Protective Equipment (PPE) | RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992) |
| Körperbelastung | Although it is not known whether stavudine is distributed into human milk, the drug is distributed into milk in rats. |
| Wechselwirkungen | These medications /didanosine or hydroxyurea/ in combination with stavudine may increase the risk of potentially fatal hepatotoxicity or pancreatitis.Medications that cause neuropathy (e.g., ethambutol, isoniazid, phenytoin, vincristine) should be used cautiously in patients receiving stavudine. Regimens containing stavudine, didanosine, and/or hydroxyurea are associated with an increased risk for neuropathy. Zidovudine and stavudine should not be used concomitantly because zidovudine antagonizes the effect of stavudine.In vitro studies detected an antagonistic antiviral effect between stavudine and zidovudine at a molar ratio of 20 to 1, respectivelyconcurrent use is not recommended until in vivo studies demonstrate that these medications are not antagonistic in their anti-HIV activityzidovudine may competitively inhibit the intracellular phosphorylation of stavudine and so these two medications in combination are not recommended.... If stavudine is used in conjunction with didanosine (with or without hydroxyurea), there is an increased risk of pancreatitis, peripheral neuropathy, and liver function abnormalities. In addition, fatal pancreatitis and hepatotoxicity may occur more frequently in patients treated with stavudine used in conjunction with didanosine and hydroxyurea. If stavudine is used concomitantly with didanosine, patients should be closely monitored. |
| Hepatotoxicity | Stavudine is a well known cause of liver injury and is regularly listed in case series of drug induced liver injury and acute liver failure. Mild and transient elevations in liver enzymes occur in up to half of patients on stavudine, but elevations above 5 times normal occur in only 5% to 13% of treated patients. Clinically apparent hepatotoxicity due to stavudine is well described and is usually marked by lactic acidosis, marked hepatic steatosis (microvesicular fat), and progressive hepatic synthetic dysfunction (LASH). This form of liver injury typically arises only after 2 to 6 months of therapy and is preceded by nonspecific prodromal symptoms of anorexia, nausea, vomiting, diarrhea, and weakness which is followed by dyspnea, jaundice and confusion. Lactic acidosis often accompanies the hepatic injury and may be the predominant clinical feature. Jaundice arises late and serum enzymes are unusually only mildly or moderated elevated, the pattern being mixed or actually cholestatic. Pancreatitis, myopathy and neuropathy may also occur. Lipodystrophy is frequently present. Liver histology during the early course of injury demonstrates marked microvesicular fat with little hepatocyte injury. Subsequently, cholestasis arises and the fatty change may evolve to a macrovesicular pattern. Late changes include ballooning cell degeneration, Mallory bodies and fibrosis. The hepatotoxicity associated with stavudine can be rapidly fatal, but is potentially reversable with intensive support and early withdrawal of therapy (Case 1). Monitoring of patients on stavudine demonstrates that asymptomatic elevations of serum lactate (hyperlactatemia) usually precedes the appearance of clinical symptoms and acidosis. Once lactic acidosis is present, however, the mortality rate is high (33% to 50%) (Case 2). Preexisting liver injury, female sex, older age, obesity, alcohol use and concurrent therapy with didanosine, ribavirin and tenofovir appear to increase the risk of this syndrome in patients taking stavudine. |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a log Kow of -0.72(2) and a regression-derived equation(3), indicates that stavudine is expected to have very high mobility in soil(SRC). Volatilization of stavudine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.3X10-15 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Stavudine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.5X10-12 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data were not available(SRC, 2005).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10(SRC), determined from a log Kow of -0.72(2) and a regression-derived equation(3), indicates that stavudine is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.3X10-15 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 0.17(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2005).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), stavudine, which has an estimated vapor pressure of 9.5X10-12 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase. Particulate-phase stavudine may be removed from the air by wet and dry deposition(SRC). Stavudine does not absorb light with wavelengths >290 nm(3) and is not expected to be susceptible to direct photolysis by sunlight(SRC). |
| Expositionspfade | Following oral administration, stavudine is rapidly absorbed (bioavailability is 68-104%). |
| Milk Concentrations | Although it is not known whether stavudine is distributed into human milk, the drug is distributed into milk in rats. |
| Toxizitätsübersicht | Stavudine inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. |
| Signs and Symptoms | Side effects include peripheral neuropathy tingling, burning, numbness, or pain in the hands or feet), fatal lactic acidosis has been reported in patients treated with stavudine (ZERIT) in combination with other antiretroviral agents, severe liver enlargement, inflammation (pain and swelling) of the liver, and liver failure. |
| Soil Adsorption/Mobility | The Koc of stavudine is estimated as 10 (SRC), using a log Kow of -0.72(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that stavudine is expected to have very high mobility in soil. |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ ... Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity./SIGNS AND SYMPTOMS/ Lactic acidosis and severe hepatomegaly with steatosis, including some fatalities, have been reported in patients receiving stavudine and also have been reported in patients receiving other nucleoside reverse transcriptase inhibitors (NRTIs). Although relative rates of lactic acidosis have not been assessed in prospective well-controlled studies, longitudinal cohort and retrospective studies suggest that this adverse effect may occur more often with antiretroviral regimens that include stavudine. Female gender, obesity, and long-term therapy with NRTIs also may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received antiretroviral regimens that included both stavudine and didanosine. In addition, deaths attributed to hepatotoxicity have occurred in patients who received antiretroviral regimens that included stavudine, didanosine, and hydroxyurea./SIGNS AND SYMPTOMS/ Rapidly ascending neuromuscular weakness, which has been fatal in some cases, has been reported rarely in patients receiving stavudine in conjunction with other antiretroviral agents. Most reported cases of motor weakness occurred in the setting of lactic acidosis or symptomatic elevations of serum lactate concentrations. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barre syndrome (including respiratory failure), and symptoms may continue or worsen following discontinuance of antiretroviral therapy./CASE REPORTS/ Pancreatitis, which has been fatal in some cases, has occurred in patients receiving stavudine in conjunction with didanosine (with or without hydroxyurea) and has been reported in both treatment-naive and previously treated patients, regardless of degree of immunosuppression. In an early clinical study evaluating stavudine, pancreatitis was observed in less than 1% of adult patients receiving stavudine monotherapy. Patients receiving didanosine in conjunction with stavudine (with or without hydroxyurea) may be at increased risk of pancreatitisthere have been at least 2 fatalities related to pancreatitis in patients receiving didanosine concomitantly with stavudine, indinavir, and hydroxyurea. There also has been at least one death related to pancreatitis in a patient receiving didanosine in conjunction with stavudine and nelfinavir.For more Human Toxicity Excerpts (Complete) data for STAVUDINE (8 total), please visit the HSDB record page. |
| Artificial Pollution Sources | Stavudine's production and use as an antiviral(1) and in the treatment of AIDS(2) may result in its release to the environment through various waste streams(SRC). |
| Carcinogen Classification | No indication of carcinogenicity to humans (not listed by IARC). |
| Wassergefährdungsklasse (WGK) | 2 |
| Zollcode | 29349990 |
| RTECS-Nr. | XP2075000 |
| R-Sätze (R) | 36/37/38 |
| Toxizität | LD50 oral in rat: 4gm/kg |
| Gefahrensymbole | Xi |
| Sicherheitshinweise (S) | 26-36 |
| Lagerklasse | 11 - Combustible Solids |
| Gefahrstoffdaten | 3056-17-5(Hazardous Substances Data) |
Anwendungen & Verwendung
Beschreibung
Stavudine, a dideoxynucleoside analog of thymidine, has been introduced in the U.S.A. for the treatment of late-stage AIDS patients who are refractory to other AIDS treatments. Similar as other currently available agents for AIDS treatment such as zidovudine (AZT), didanosine, and zalcitabine, the anti-HIV activity of these 2'3'- dideoxynucleosides is ascribed to the inhibitory effect of their corresponding 5'- triphosphates against the HlVsncoded RNAdependent DNA polymerase (reverse transcriptase). While some of these drugs have rapid development of drug resistance, stavudine is active against AZT-resistant HIV strains. It has a favorable pharmacokinetic profile with more complete and less variable oral absorption than AZT and didanosine and has a bioavailability of 80-90%.
Verwenden
Stavudine (Zidovudine EP Impurity A) is used as an antiviral. A reverse transcriptase inhibitor.