Stavudine Chemische Eigenschaften,Einsatz,Produktion Methoden
R-Sätze Betriebsanweisung:
R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.
S-Sätze Betriebsanweisung:
S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
S36:DE: Bei der Arbeit geeignete Schutzkleidung tragen.
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%.
Chemische Eigenschaften
Colourless solid
Verwenden
Stavudine (Zidovudine EP Impurity A) is used as an antiviral. A reverse transcriptase inhibitor.
Indications
Stavudine (d4T, Zerit) is a thymidine nucleoside analogue
that is active against HIV-1 and HIV-2. It is approved
for the therapy of HIV infection as part of a
multidrug regimen and is also used for postexposure
prophylaxis.
Definition
ChEBI: A nucleoside analogue obtained by formal dehydration across positions 2 and 3 of thymidine. An inhibitor of HIV-1 reverse transcriptase
Antimicrobial activity
Stavudine is active against HIV-1, HIV-2 and HTLV-1.
Acquired resistance
Resistance to stavudine is identical to that seen for zidovudine.
Mutations at positions 41, 67 and 70, and positions 210,
215 and 219 (the ‘thymidine analog mutations’) of the reverse
transcriptase genes are associated with diminished antiretroviral
efficacy.
Allgemeine Beschreibung
Stavudine, 2'3'-didehydro-2'-deoxythymidine (D4T, Zerit), isan unsaturated pyrimidine nucleoside that is related to thymidine.The drug inhibits the replication of HIV by a mechanismsimilar to that of its close congener, AZT.Stavudine is bioactivatedby cellular enzymes to a triphosphate.
Stavudine is available as capsules for oral administration.The drug is acid stable and well absorbed (about 90%) followingoral administration. Stavudine has a short half-life(1–2 hours) in plasma and is excreted largely unchanged(85%–90%) in the urine.As with ddC, the primary doselimitingeffect is peripheral neuropathy.
Stavudine isrecommended for the treatment of adults with advancedHIV infection who are intolerant of other approved therapiesor who have experienced clinical or immunological deteriorationwhile receiving these therapies.
Air & Water Reaktionen
Water soluble.
Reaktivität anzeigen
Stavudine is sensitive to heat. Incompatible with strong oxidizing agents .
Hazard
Moderately toxic by ingestion.
Brandgefahr
Literature sources indicate that Stavudine is combustible.
Pharmazeutische Anwendungen
An analog of thymidine formulated for oral administration.
Pharmakokinetik
Oral absorption: 86%
C
max 40 mg twice daily: 0.54 mg/L
Plasma half-life: 1.4 h
Volume of distribution: 0.66 L/kg
Plasma protein binding: <5%
Absorption and distribution
It is rapidly absorbed with or without food. CNS penetration is moderate. The estimated semen:plasma ratio is >1. It is secreted into breast milk.
Metabolism and excretion
The metabolic fate in humans has not been elucidated. Renal elimination accounts for approximately 40% of overall clearance at a rate almost twice that of endogenous creatinine, indicating glomerular filtration and active tubular secretion. Clearance decreases as creatinine clearance decreases and the dosage should be adjusted in patients with reduced renal function. Pharmacokinetics are not significantly altered in patients with hepatic impairment.
Clinical Use
Treatment of HIV infection in adults and children
Nebenwirkungen
The adverse effects with which stavudine is most frequently
associated are headache, diarrhea, skin rash,
nausea, vomiting, insomnia, anorexia, myalgia, and
weakness. Peripheral neuropathy consisting of numbness,
tingling, or pain in the hands or feet is also common
with higher doses of the drug. Significant elevation
of hepatic enzymes may be seen in approximately 10 to
15% of patients. Lactic acidosis occurs more frequently
with stavudine than with other NRTIs. Viral resistance
to stavudine may develop, and cross-resistance to zidovudine
and didanosine may occur.
Vorsichtsmaßnahmen
Stavudine possesses several clinically significant interactionswith other drugs. Although hydroxyurea enhancesthe antiviral activity of stavudine and didanosine,combination therapy that includes stavudine anddidanosine, with or without hydroxyurea, increases therisk of pancreatitis. Combinations of stavudine and didanosineshould not be given to pregnant women becauseof the increased risk of metabolic acidosis.Zidovudine inhibits the phosphorylation of stavudine;thus, this combination should be avoided.
Stavudine Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Epoxy
Kalium-tert-butanolat
Thymidine
Methansulfonylchlorid
Ethylacetat
Anhydrous pyridine
Uridine, 5-methyl-, 2',3',5'-triacetate
Uridine, 2',3'-dideoxy-2'-iodo-5-methyl-, 5'-(2,2-dimethylpropanoate)
Thymidine, 2',3'-didehydro-3'-deoxy-5'-O-[(1,1-dimethylethyl)diphenylsilyl]- (9CI)
((2S,5R)-5-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)methyl acetate
(R)-5-(TERT-BUTYLDIPHENYLSILOXYMETHYL)DIHYDRO-2(3H)FURANONE
5-Methyluridin
1-(3,5-ANHYDRO-2-DEOXY-BETA-D-THREO-PENTOFURANOSYL)-5-METHYLPYRIMIDINE-2,4(1H,3H)-DIONE
[(2S,5R)-5-(5-methyl-2,4-dioxo-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]methyl benzoate
5'-O-TRITYL-2',3'-DEHYDROTHYMIDINE
2,3'-ANHYDROTHYMIDINE
Tributylamin
Trimethylorthoformiat
Downstream Produkte
