In THP-1 derived macrophages, stavudine (d4T) (50 μM) dramatically lowers IL-18 production, NLRP3 inflammasome gene expression, and Aβ 42-stimulated cellular production of IL-1β[3]. Stavudine (d4T) (50 μM) suppresses the phagocytosis of Aβ 42 by macrophages and prevents the formation of the NLRP3 inflammasome complex[3]. Stavudine (d4T) (10 μM, 7 or 14 days) increased hydrogen peroxide levels and strongly caused apoptosis in CEM cells, particularly after 14 days[4].

In male RjOrl Swiss mice, stavudine (d4T) (500 mg/kg, daily liquid, 2 weeks) can quickly cause fat depletion and minor liver damage at high doses[5].

Animal/Disease Models: Male RjOrl Swiss mice weighing 0.028-0.03 kg[1]
Doses: 500 mg/kg
Route of Administration: Daily liquid; 2 weeks
Experimental Results: decreased fat weight gain by 58%, 5.7 g in the control group and 4.9 g in the d4T treated group. Dramatically elevated plasma ALT and LDH levels. decreased plasma acetoacetic acid and beta-hydroxybutyric acid levels. decreased liver and muscle mtDNA levels at high dose concentration of 500 mg/kg.

Absorption, Distribution and Excretion
Following oral administration, stavudine is rapidly absorbed (bioavailability is 68-104%).
46 ± 21 L
Renal cl=272 mL/min [Healthy subjects receiving 80 mg PO]
594 +/- 164 mL/min [HIV-infected adult and pediatric patients following 1-hour IV infusion]
9.75 +/- 3.76 mL/min/kg [HIV- Exposed or -Infected Pediatric Patients(Age 5 weeks – 15 years) following 1-hour IV infusion]
Stavudine is rapidly absorbed following oral administration, and peak plasma concentrations of the drug are attained within 1 hour after the dose. Oral bioavailability of stavudine is reported to be about 86% in adults and 77% in pediatric patients 5 weeks to 15 years of age.
Data from single- and multiple-dose studies indicate that peak plasma concentrations and AUC of stavudine increase in proportion to dose over the dosage range 0.03 -4 mg/kg; there is no evidence that accumulation occurs following multiple doses.
Binding of stavudine to serum proteins is negligible over the concentration range of 0.01-11.4 ug/mL.
Distribution of stavudine into body tissues and fluids has not been fully characterized. The apparent volume of distribution of stavudine following a single oral dose averages 66 L in HIV-infected adults. Following a single IV dose in HIV-infected individuals, the volume of distribution is 58 L in adults and 0.73 L/kg in pediatric patients 5 weeks to 15 years of age.
For more Absorption, Distribution and Excretion (Complete) data for STAVUDINE (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
Phosphorylated intracellularly to stavudine triphosphate, the active substrate for HIV-reverse transcriptase.
The metabolic fate of stavudine has not been elucidated in humans. Intracellularly, in both virus-infected and uninfected cells, stavudine is converted to stavudine monophosphate by cellular thymidine kinase. The monophosphate is subsequently converted to stavudine diphosphate and then to stavudine triphosphate, presumably by the same cellular kinases involved in the metabolism of zidovudine. Intracellular (host cell) conversion of stavudine to the triphosphate derivative is necessary for the antiviral activity of the drug.
Phosphorylated intracellularly to stavudine triphosphate, the active substrate for HIV-reverse transcriptase.
Half Life: 0.8-1.5 hours (in adults)

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Biological Half-Life
0.8-1.5 hours (in adults)
Intracellular half life of stavudine triphosphate: Approximately 3.5 hours. /Stavudine triphosphate/
Normal renal function: Adults: 0.8 to 1.5 hours (intravenous); 1.14 to 1.74 hours (oral). Children (5 weeks to 15 years): 0.83 to 1/39 hours (intravenous); 0.7 to 1.22 hours (oral). Neonates (14 to 28 days) 1.3 to 1.88 (oral). Neonates (day of birth): 3.26 to 7.28 (oral). Renal function impairment (creatinine clearance 26 to 50 mL/min): Approximately 1 to 6 hours. Renal function impairment (creatinine clearance 9 to 25 mL/min): Approximately 3.7 to 5.5 hours. Renal function impairment (creatinine clearance > 50 mL/min): Approximately 1.3 to 2.1 hours. Renal function impairment (hemodialysis patients): Approximately 4.0 to 6.8 hours.
Twenty-two patients were studied after the first oral dose of 0.67, 1.33, 2.67, or 4 mg/kg of body weight; 17 of them underwent an additional steady-state pharmacokinetic evaluation after thrice-daily dosing of the above doses. ... The mean values for plasma elimination half-life ranged from 1 to 1.6 hr.

Toxicity Summary
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.

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Interactions
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, respectively; concurrent use is not recommended until in vivo studies demonstrate that these medications are not antagonistic in their anti-HIV activity; zidovudine 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.

[1]. The role of stavudine in the management of adults with HIV infection. Antivir Ther. 1997;2(4):207-218.

[2]. Antiretroviral activity of stavudine (2',3'-didehydro-3'-deoxythymidine, D4T). Antiviral Res. 1995;27(3):189-203.

[3]. Stavudine Reduces NLRP3 Inflammasome Activation and Modulates Amyloid-β Autophagy. J Alzheimers Dis. 2019;72(2):401-412.

[4]. Protective effect of acetyl-L-carnitine against oxidative stress induced by antiretroviral drugs. FEBS Lett. 2006;580(28-29):6612-6616.

[5]. High doses of stavudine induce fat wasting and mild liver damage without impairing mitochondrial respiration in mice. Antivir Ther. 2007;12(3):389-400.

Therapeutic Uses
Stavudine in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. Additionally, stavudine is indicated for the treatment of patients with HIV infection who have received prolonged previous treatment with zidovudine. /Included in US product labeling/

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Drug Warnings
Lactic acidosis and severe hepatomegaly with steatosis, including some fatalities, have been reported rarely in patients receiving stavudine and also have been reported in patients receiving other NRTIs. Female gender, obesity, and long-term therapy with NRTIs may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received antiretroviral regimens that included both didanosine and stavudine. Stavudine should be used with caution in patients with known risk factors for liver disease; however, lactic acidosis and severe hepatomegaly with steatosis have been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, sudden unexplained weight loss), respiratory symptoms (tachypnea, dyspnea), or neurologic symptoms (including motor weakness) might be indicative of lactic acidosis development, and patients should be advised to contact their clinician immediately if these symptoms occur. Stavudine therapy should be discontinued in any patient with clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked increases in serum aminotransferase concentrations). Permanent discontinuance of stavudine therapy should be considered in patients with confirmed lactic acidosis. Because an increased risk of potentially fatal hepatotoxicity may occur in patients receiving stavudine in conjunction with didanosine and hydroxyurea, patients receiving such regimens should be closely monitored for signs of hepatotoxicity.
Lactic acidosis is a serious complication of antiretroviral therapy. Symptomatic hyperlactatemia is a milder form of this syndrome, but its incidence is unclear. In this prospective ongoing observational study of a large cohort of HIV-infected adults, hyperlactataemia was diagnosed in 64 patients. Incidences were 18.3/1000 person-years with antiretroviral therapy, and 35.8/1000 person-years for stavudine (d4T) regimens. Ten of the 64 patients developed lactic acidosis during the first 13 months of treatment (incidence 2.9/1000 treated person-years). In four of ten patients, symptoms were absent or mild. More patients on d4T first-line therapy developed lactic acidosis than patients previously treated with other drugs (p = 0.008). Despite the occurrence of one death, the subsequent outcome for the remaining patients was favourable after antiretroviral therapy was stopped and supportive treatment with vitamins and antioxidants initiated. The early diagnosis of cases was the result of great vigilance and, combined with routine measurements of the anion gap, might be the most crucial factor explaining the low mortality rate observed here.
Potentially severe peripheral neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in about 52% of patients receiving stavudine alone and in 8-21% of patients receiving stavudine in conjunction with other antiretroviral agents (indinavir and either lamivudine or didanosine). Stavudine-associated peripheral neuropathy appears to be dose-related, and has been reported most frequently in patients with advanced HIV, patients with a history of peripheral neuropathy, or patients receiving other neurotoxic drugs, including didanosine. Symptoms of peripheral neuropathy generally resolve if stavudine therapy is promptly discontinued; however, symptoms may worsen temporarily in some patients following discontinuance of the drug. If such symptoms resolve completely, patients may tolerate resumption of stavudine therapy using a reduced dosage. If neuropathy recurs after stavudine therapy is reinitiated, consideration should be given to permanently discontinuing the drug.
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 pancreatitis; there 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. Stavudine, didanosine, hydroxyurea, and any other agent toxic to the pancreas should be discontinued in any patient who develops suspected pancreatitis.
For more Drug Warnings (Complete) data for STAVUDINE (20 total), please visit the HSDB record page.

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Pharmacodynamics
Stavudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Stavudine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.

C10H12N2O4

224.21

224.079

3056-17-5

Stavudine sodium;134624-73-0;Stavudine-d4;1219803-67-4

18283

White to light yellow solid powder

1.5±0.1 g/cm3

440.6±55.0 °C at 760 mmHg

159-160°C

220.3±31.5 °C

0.0±2.4 mmHg at 25°C

1.646

-1.25

2

4

2

16

388

2

CC1=CN(C(=O)NC1=O)[C@H]2C=C[C@H](O2)CO

XNKLLVCARDGLGL-JGVFFNPUSA-N

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

1-[(2R,5S)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]-5-methylpyrimidine-2,4-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (11.15 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (11.15 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (11.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 0.5% CMC Na : 30mg/mL

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Solubility in Formulation 5: 120 mg/mL (535.21 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)