Stavudine

Structural formula
General
Non-proprietary name	Stavudine
other names	1 - [(2 R , 5 S ) -5- (hydroxymethyl) -2,5-dihydrofuran-2-yl] -5-methylpyrimidin-2,4-dione; dde Thd; DTH; d4T;
Molecular formula	C 10 H 12 N 2 O 4
External identifiers / databases
EC number	641-374-0
ECHA InfoCard	100.169.180
PubChem	18283
DrugBank	DB00649
Wikidata	Q423984
Drug information
ATC code	J05 AF04
Drug class	Antiviral , nucleoside reverse transcriptase inhibitors
Mechanism of action	Competitive inhibition of reverse transcriptase
properties
Molar mass	224.21 g · mol -1
Melting point	168.1 ° C ( polymorph I); 165.5 ° C (polymorph II); 169.5 ° C (polymorph IV);
solubility	soluble in water (6.6 g l −1 at 25 ° C)
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances	no GHS pictograms
	no GHS pictograms
H and P phrases	H: no H-phrases
	P: no P-phrases
Toxicological data	1000 mg kg −1 ( LD 50 , mouse , oral )
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Stavudine (d4T) (trade name: Zerit ^® ; manufacturer: Bristol-Myers Squibb ) is a drug for the treatment of HIV- 1 infected patients as part of an antiretroviral combination therapy , but is rarely used in western industrialized countries today.

It belongs to the group of nucleoside reverse transcriptase inhibitors (NRTIs).

properties

Stavudine can come in four different crystal forms. The polymorphic forms I, II and IV differ in terms of their melting points at 168.1 ° C, 165.5 ° C and 169.5 ° C. Form I is the thermodynamically stable form at room temperature . Form III is 1/3 hydrate with a stoichiometric ratio of active ingredient to water of 3: 1 in the crystal lattice .

pharmacology

The antiretroviral activity of stavudine has been demonstrated in vitro . The substance is about 5–10 times weaker than zidovudine in vitro . In combination with other antiviral agents, synergistic effects could be demonstrated. The development of stavudine-resistant HI viruses has been demonstrated in vitro.

Pharmacokinetics

The bioavailability of stavudine is good. About 90% are absorbed orally. Simultaneous consumption with food has only minor, clinically irrelevant, effects. After ingestion of 40 mg, peak concentrations of approx. 0.8–1.0 mg / l are achieved in the plasma. CSF concentrations: up to approx. 70% of the plasma concentrations. Elimination half-life: approx. 1.6 hours. Intracellular half-life of the biologically active triphosphate: approx. 3.5 hours.

Side effects

Strongly mitochondrially toxic, lipoatrophy , peripheral neuropathies (PNP), especially in combination with DDI, rarely diarrhea , nausea, headache, hepatic steatosis , pancreatitis, very rarely: lactic acidosis . Contraindicated in PNP. Avoid neurotoxic drugs (ethambutol, cisplatin, INH, vincristine etc.).

development

The substance was synthesized in 1966 by Jerome P. Horwitz .

Web links

Individual evidence

↑ ^a ^b ^c ^d Lu, J .; Rohani, S .: Polymorphic Crystallization and Transformation of the Anti-Viral / HIV Drug Stavudine in Org Process Res Dev . 13 (2009) 1262-1268, doi : 10.1021 / op900004c .
↑ ^a ^b Entry on stavudine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
↑ Data sheet 2 ′, 3′-Didehydro-3′-deoxythymidine, ≥98% (TLC) from Sigma-Aldrich , accessed on November 18, 2019 ( PDF ).
^ JR Horwitz, J. Chua, MA Da Rooge, M. Noel, IL Klundt: Nucleosides. IX. The formation of 2 ', 2'-unsaturated pyrimidine nucleosides via a novel beta-elimination reaction. In: The Journal of organic chemistry. Volume 31, Number 1, January 1966, pp. 205-211, PMID 5900814 .

[Lu-1] Lu, J .; Rohani, S .: Polymorphic Crystallization and Transformation of the Anti-Viral / HIV Drug Stavudine in Org Process Res Dev . 13 (2009) 1262-1268, doi : 10.1021 / op900004c .

[ChemIDplus-2] Entry on stavudine in the ChemIDplus database of the United States National Library of Medicine (NLM) .

[Sigma-3] Data sheet 2 ′, 3′-Didehydro-3′-deoxythymidine, ≥98% (TLC) from Sigma-Aldrich , accessed on November 18, 2019 ( PDF ).

[4] JR Horwitz, J. Chua, MA Da Rooge, M. Noel, IL Klundt: Nucleosides. IX. The formation of 2 ', 2'-unsaturated pyrimidine nucleosides via a novel beta-elimination reaction. In: The Journal of organic chemistry. Volume 31, Number 1, January 1966, pp. 205-211, PMID 5900814 .