Zidovudine

Structural formula
General
Non-proprietary name	Zidovudine
other names	Azidothymidine AZT 3'-azido-3'-deoxythymidine 1 - [(2 R , 4 S , 5 S ) -4-Azido-5-hydroxymethyl-oxolan-2-yl] -5-methyl-pyrimidine-2,4-dione ( IUPAC )
Molecular formula	C 10 H 13 N 5 O 4
Brief description	white to beige, crystalline, light-sensitive powder
External identifiers / databases
CAS number 30516-87-1 EC number 623-849-4 ECHA InfoCard 100.152.492 PubChem 35370 ChemSpider 32555 DrugBank DB00495 Wikidata Q198504
Drug information
ATC code	J05 AF01 J05 AR04 J05 AR01
Drug class	Antivirals nucleoside reverse transcriptase inhibitors (NRTIs)
Mechanism of action	competitive inhibition of reverse transcriptase
properties
Molar mass	267.24 g · mol -1
Physical state	firmly
Melting point	124-126 ° 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 Caution H and P phrases H: 351 P: 281
Toxicological data	3062 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 .

Zidovudine (also azidothymidine , AZT for short ) is a chemical derivative of the nucleoside thymidine . Pharmacologically , it belongs to the nucleoside reverse transcriptase inhibitors (NRTIs), a group of antiretroviral substances. Zidovudine is used to treat HIV-1 infected patients as part of combination antiretroviral therapy .

It is sold by the GlaxoSmithKline company .

chemistry

AZT is a nucleoside made from thymine and a modified deoxyribose with an azide function instead of the hydroxyl group at the 3 'position.

history

AZT was first synthesized in 1964 by Jerome P. Horwitz , who was a scientist at the Michigan Cancer Foundation at the time. The original aim was to develop a drug for the treatment of cancer , but it did not succeed. In February 1985, NIH scientist Hiroaki Mitsuya demonstrated the substance's effectiveness against HIV . This is based on the drug's ability to block the activity of the reverse transcriptase (RT) enzyme . The HIV virus uses this enzyme to replicate its RNA , i.e. to transcribe its genome into DNA. It thus fulfills a crucial function in the multiplication of the virus. Shortly thereafter, the pharmaceutical company Burroughs-Wellcome (now GlaxoSmithKline) bought the rights to the substance and successfully applied for a patent on AZT as an HIV drug in 1986 , which expired in 2005 (for the monopreparation). The American Food and Drug Administration (FDA) granted approval for AZT as a drug for the treatment of HIV on March 20, 1987; In 1990 it was approved as a preventive drug . Burroughs-Wellcome had already recognized the antiviral effectiveness in the 1960s and made the substance available when the group at the National Cancer Institute led by Samuel Broder , Horoaki Mitsuya and Robert Yarchoan systematically tested antivirals against HIV in 1984.

In the early days of AZT treatment, much higher doses were administered than today: 400 mg every four hours (even at night) was usual . This dosage sometimes led to severe side effects, including a. Anemia . Modern treatment plans use lower doses that are only given two to three times a day. With monotherapy or a combination of two, more than 500 to 600 mg of AZT are rarely given per day. The aim is to improve the patient's quality of life. In addition, AZT is now almost always combined with other drugs to counteract a mutation of the HI virus into an AZT- resistant form - it is far less likely that the virus will develop two resistances.

Mode of action

Cellular enzymes convert AZT into the active AZT-5'-triphosphate (AZTTP) in three successive steps. AZT-5'-triphosphate develops its effect in two ways: as a nucleoside analogue and thus a competing substrate for thymidine triphosphate, it causes the competitive inhibition of reverse transcriptase (RT) of the HIV virus. On the other hand, by being incorporated into the DNA , it stops the viral DNA synthesis. The latter is due to the absence of a 3'- hydroxyl group in the AZT, which makes it impossible to add further nucleotides to the DNA chain. Studies have shown that chain termination is the decisive factor in the inhibitory effect of AZT. AZT inhibits viral RT about a hundred times more effectively than cellular DNA polymerase . AZT also hydrolyzes to 3'-amino-2'-deoxythymidine, the triphosphate of which is a substrate for DNA polymerase α.

Side effects

Common side effects are headache , nausea , vomiting , loss of appetite , abdominal pain and occasionally fever . More serious side effects, especially anemia ( anemia ), neutropenia and leukopenia (reduction in white blood cells), depend on the dose and the individual constitution of the patient. Since AZT is now administered in significantly lower doses than when it was first introduced, serious side effects only occur occasionally. Anemia and a reduction in the white blood cell count , especially when AZT is taken in a three-way combination with an HIV protease inhibitor , are only very rarely observed.

The undesirable side effects of AZT could be due to the sensitivity of the DNA polymerase γ; this polymerase is an enzyme in the mitochondria of the cells that may be impaired in its function by AZT. The mitochondrial toxicity of AZT and the cell damage it causes have been intensively investigated. One study showed that after ten years of treatment, the mitochondrial DNA of patients shows damage that corresponds to the normal aging processes of two to three decades. The clinical significance of these findings is still unclear.

Concorde study

Based on the results of the large Concorde study carried out in the mid-1990s with 1749 HIV patients, the AZT dosage used until 1994 had to be reduced considerably. In this multi-year study (mean observation time 3.3 years), AZT was administered immediately to an HIV patient group (877 patients), in another HIV patient group, treatment was initially carried out with placebo and only at a comparatively late point in time with AZT (872 patients) . The Concorde study changed the therapy expectations associated with AZT, because in the patient group treated immediately there were more deaths (96:76), more frequent treatment discontinuations due to severe side effects (99:38) and also more frequent dose reductions (148: 37). Since the global dose reduction and the combination of AZT with other classes of combination therapy (HAART), the chances of survival of HIV patients have improved significantly.

Criticism of AZT

The initial hope of being able to strike the decisive blow against HIV and AIDS with AZT soon turned out to be excessive. In addition to the toxicity - which occurred especially with the high doses that were usual in the past - the development of resistance was the main problem. Other NRTIs (from 1991) and other groups of active substances such as NNRTIs and HIV protease inhibitors (from 1995) have therefore been developed and the drugs are preferably used in triple combinations within the framework of HAART. This enables better control of HIV multiplication and significant life extensions can be achieved. Due to the lower dosage of AZT, toxicity is less of a problem than in the past and the development of resistance is more difficult in HAART. Even triple combinations cannot completely switch off HIV, and even in low doses, the long-term mitochondrial toxicity of AZT is a particular problem. In some situations, newer NRTIs such as abacavir or tenofovir are preferred . It remains to be seen whether AZT will retain its current status in the long term after new substances such as fusion inhibitors, integrase inhibitors, coreceptor antagonists and maturation inhibitors have been established. At the moment, however, despite all its problems and weaknesses, AZT is still an indispensable part of many regimens, even after 20 years, as it has been proven to be effective, is the best researched and longest known HIV drug and z. B. also the liquor accessibility is favorable.

Some AIDS deniers claim that despite reliable scientific knowledge about the connection between HIV and AIDS, it is not HIV that causes AIDS, but AZT among other things.

Manufacturing

Several multi-step syntheses for zidovudine, starting from thymidine , are described in the literature.

Trade names

Monopreparations

Retrovir (D, A, CH)

Combination preparations

Combivir (D, A, CH), Trizivir (D, A, CH)

Individual evidence

1. ↑ ^{a b} Hermann Ammon (Ed.): Hunnius Pharmaceutical Dictionary . 8th edition, de Gruyter, Berlin 2004. ISBN 3-11-015792-6 .
2. ↑ ^{a b} Data sheet 3′-Azido-3′-deoxythymidine from Sigma-Aldrich , accessed on November 3, 2016 ( PDF ).
3. ↑ Entry on zidovudine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
4. ↑ H. Gupta, S. Kumar, SK Roy, RS Gaud: Patent protection strategies. In: Journal of pharmacy & bioallied sciences. Volume 2, number 1, January 2010, pp. 2-7, doi : 10.4103 / 0975-7406.62694 , PMID 21814422 , PMC 3146086 (free full text).
5. ↑ limited preview in the Google book search
6. ↑ limited preview in the Google book search
7. ↑ Derek Lowe, Das Chemiebuch, Librero 2017, p. 466
8. ↑ T. Yamaguchi, I. Katoh, S. Kurata: Azidothymidine causes functional and structural destruction of mitochondria, glutathione deficiency and HIV-1 promoter sensitization. Eur J Biochem . 2002 Jun; 269 (11): 2782-2788, PMID 12047388 .
9. ↑ BAPayne, IJ Wilson, CA Hateley, R. Horvath, M. Santibanez-Koref: Nat Genet . 2011 Jun 26. PMID 21706004 .
10. ^ Concorde Coordinating Committee. Concorde: MRC / ANRS randomized double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. The Lancet . 1994 Apr 9; 343 (8902): 871-881, PMID 7908356 .
11. ^ Jon Cohen: The Duesberg Phenomenon. (PDF; 47 kB) Science , 1994 1642-1644. doi : 10.1126 / science.7992043 .
12. ^ Axel Kleemann , Jürgen Engel, Bernd Kutscher and Dietmar Reichert: Pharmaceutical Substances. 4th edition, 2 volumes. Thieme-Verlag, Stuttgart 2000, ISBN 978-1-58890-031-9 ; online since 2003 with biannual additions and updates.

literature

• E. De Clercq: HIV resistance to reverse transcriptase inhibitors. In: Biochemical Pharmacology 1994; 47: 155-169.
• HP Rang, MM Dale, JM Ritter: Pharmacology , 3rd edition. Pearson Professional Ltd, 1995.
• J. Balzarini, L. Naesens, S. Aquaro, T. Knispel, C.-F. Perno, E. De Clercq, C. Meier: Intracellular Metabolism of CycloSaligenyl 3'-Azido-2'-3'-dideoxythymidine Monophosphate, a Prodrug of 3'-Azido-2'-3'-dideoxythymidine (Zidovudine). In: Molecular Pharmacology . 1999; 56: 1354-1361.
• T. Yamaguchi, I. Katoh, S. Kurata: Azidothymidine causes functional and structural destruction of mitochondria, glutathione deficiency and HIV-1 promoter sensitization. In: Eur J Biochem. 2002 Jun; 269 (11): 2782-2788. PMID 12047388 PDF .
• JG de la Asuncion, ML Del Olmo, LG Gomez-Cambronero, J. Sastre, FV Pallardo, J. Vina: AZT induces oxidative damage to cardiac mitochondria: protective effect of vitamins C and E. In: Life Sci . 2004 Nov 19; 76 (1): 47-56. PMID 15501479 .
• I. Papparella, G. Ceolotto, L. Berto, M. Cavalli, S. Bova, G. Cargnelli, E. Ruga, O. Milanesi, L. Franco, M. Mazzoni, L. Petrelli, GG Nussdorfer, A. Semplicini : Vitamin C prevents zidovudine-induced NAD (P) H oxidase activation and hypertension in the rat. In: Cardiovasc Res . 2007 Jan 15; 73 (2): 432-438. PMID 17123493 .
• DJ Feola, BA Garvy: Combination exposure to zidovudine plus sulfamethoxazole-trimethoprim diminishes B-lymphocyte immune responses to Pneumocystis murina infection in healthy mice. In: Clin Vaccine Immunol. 2006 Feb; 13 (2): 193-201. PMID 16467325 .
• AC Collier AC, RJ Helliwell, JA Keelan, JW Paxton, MD Mitchell, MD Tingle: 3'-azido-3'-deoxythymidine (AZT) induces apoptosis and alters metabolic enzyme activity in human placenta. In: Toxicol Appl Pharmacol . 2003 Oct 15; 192 (2): 164-173. PMID 14550750
• O. Benveniste, J. Estaquier, JD Lelievre, JL Vilde, JC Ameisen, C. Leport: Possible mechanism of toxicity of zidovudine by induction of apoptosis of CD4 + and CD8 + T-cells in vivo. In: Eur J Clin Microbiol Infect Dis. 2001 Dec; 20 (12): 896-897 PMID 11837644 .
• D. Mondal, L. Pradhan, M. Ali, KC Agrawal: HAART drugs induce oxidative stress in human endothelial cells and increase endothelial recruitment of mononuclear cells: exacerbation by inflammatory cytokines and amelioration by antioxidants. In: Cardiovasc Toxicol . 2004; 4 (3): 287-302. PMID 15470276 .
• JG de la Asuncion, ML del Olmo, J. Sastre, A. Millan, A. Pellin, FV Pallardo, J. Vina: AZT treatment induces molecular and ultrastructural oxidative damage to muscle mitochondria. Prevention by antioxidant vitamins. In: J Clin Invest. 1998 Jul 1; 102 (1): 4-9. PMID 9649550 .
• J. Garcia-de-la-Asuncion, LG Gomez-Cambronero, ML Olmo, FV Pallardo, J. Sastre, J. Vina: Vitamins C and E prevent AZT-induced leukopenia and loss of cellularity in bone marrow. Studies in mice. In: Free Radic Res. 2007 Mar; 41 (3): 330-334. PMID 17364962 .
• Concorde: MRC / ANRS randomized double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Concorde Coordinating Committee. In: Lancet. 1994 Apr 9; 343 (8902): 871-881. PMID 7908356 .

Movies

The effects of zidovudine (AZT) played an important role in the film Dallas Buyers Club (2013) .

Web links

Wiktionary: Zidovudine  - explanations of meanings, word origins, synonyms, translations

• Chapter 7: Antiretrovirals and Essential Drugs in HIV Book. The book on HIV and AIDS.
• Chapter 6.2: Substance classes, drug overview in the HIV book. The book on HIV and AIDS.

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