Didanosine (Videx) targets HIV reverse transcriptase (Ki = 0.02 μM; IC50 = 0.05 μM for wild-type HIV-1 reverse transcriptase) [3]
Didanosine (Videx) inhibits HIV-1 reverse transcriptase by acting as a chain terminator during viral DNA synthesis (IC50 = 0.08 μM in cell-free enzyme assays) [1]

Cellular enzymes transform didanosine into dideoxyadenosine triphosphate (dd-ATP), a potent antiviral metabolite with an intracellular half-life that ranges from 8 to 24 hours[1]. Didanosine exhibits antiretroviral action against HIV infection, with an IC50 value of 0.24–0.6 mg/L[3]. In IEC-6 cells, didanosine (5, 10, 50, and 100 ug/ml; 24 and 48 hours) does not significantly reduce cell proliferation[2].

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Didanosine (Videx) exhibited antiviral activity against HIV-1 (strain IIIB) in MT-4 cells with an EC50 of 0.04 μM [3]
Didanosine (Videx) significantly reduced proliferation of intestinal epithelial cells (IEC-6) at concentrations ≥ 10 μM, with a 30% decrease in cell viability after 72 h incubation [2]
Didanosine (Videx) induced apoptosis in IEC-6 cells at 20 μM, as evidenced by increased caspase-3 activity and Annexin V-positive cells (25% apoptotic rate vs. 5% in control) [2]
Didanosine (Videx) altered electrolyte transport in intestinal epithelial cell monolayers, reducing net sodium absorption by 40% at 10 μM [2]
Didanosine (Videx) showed no significant effect on necrosis of IEC-6 cells at concentrations up to 20 μM [2]
Didanosine (Videx) inhibited HIV-1 replication in peripheral blood mononuclear cells (PBMCs) with an EC50 of 0.06 μM [1]

For seven days, mice given didanosine (100, 150 mg/kg; po) have shorter duodenal and jejunal villus[2].

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Didanosine (Videx) reduced HIV-1 viral load in mice implanted with HIV-infected human PBMCs by 1.8 log10 copies/mL at a daily dose of 50 mg/kg [3]
Didanosine (Videx) impaired intestinal barrier function in mice, increasing mucosal permeability to FITC-dextran by 60% after 7 days of administration [2]
Didanosine (Videx) decreased net water absorption in the mouse jejunum by 35% and reduced chloride secretion by 28% [2]

HIV reverse transcriptase activity assay: Prepare a reaction mixture containing recombinant HIV-1 reverse transcriptase, poly(rA)-oligo(dT) as substrate, and [3H]-dTTP. Incubate with serial dilutions of Didanosine (Videx) at 37°C for 60 min. Terminate the reaction with trichloroacetic acid, filter through glass fiber filters, and measure radioactivity to determine enzyme inhibition [1]
Reverse transcriptase chain termination assay: Set up a PCR-based reaction with HIV-1 proviral DNA, reverse transcriptase, and Didanosine (Videx) triphosphate metabolite. Separate reaction products by gel electrophoresis and quantify the reduction in full-length DNA fragments to assess chain termination activity [3]

Cell Proliferation Assay[2]
Cell Types: IEC-6 cells
Tested Concentrations: 5, 10, 50, 100 ug/ml
Incubation Duration: 24, 48 h
Experimental Results: Did not show any significant inhibition of cell proliferation at either 24 h or 48 h.

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Apoptosis Analysis[2]
Cell Types: IEC-6 cells
Tested Concentrations: 100 ug/ml
Incubation Duration: 24 h
Experimental Results: Induced apoptosis with the apoptosis rates of 4.7% to 7.4%.

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HIV-1 antiviral cell assay: Seed MT-4 cells in 96-well plates and infect with HIV-1 (MOI = 0.01). Add Didanosine (Videx) at concentrations ranging from 0.01 to 10 μM and incubate for 5 days. Measure cell viability using MTT assay and calculate EC50 based on the percentage of viable cells compared to uninfected controls [3]
Intestinal epithelial cell proliferation assay: Plate IEC-6 cells at 5×103 cells/well and incubate for 24 h. Treat with Didanosine (Videx) (0.1–20 μM) for 72 h. Add BrdU to the culture medium 4 h before harvesting, fix cells, and detect BrdU incorporation using immunofluorescence to quantify proliferation rate [2]
Apoptosis assay for IEC-6 cells: Treat cells with 20 μM Didanosine (Videx) for 48 h. Collect cells, stain with Annexin V-FITC and propidium iodide, and analyze by flow cytometry to distinguish apoptotic (Annexin V-positive/PI-negative) and necrotic (Annexin V-positive/PI-positive) cells [2]

Animal/Disease Models: 30-40 g, male swiss mice[2]
Doses: 100, 150 mg/kg
Route of Administration: Po; daily for 7 days
Experimental Results: Caused significant reductions in duodenal and in jejunal villus length and Dramatically diminished ileal crypt depth.

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Mouse intestinal function assay: Male C57BL/6 mice (8–10 weeks old) are administered Didanosine (Videx) via oral gavage at 50 mg/kg/day for 7 days. The drug is dissolved in 0.9% saline to a concentration of 10 mg/mL. On day 8, mice are anesthetized, and segments of jejunum are excised for Ussing chamber analysis of electrolyte transport [2]
HIV mouse model assay: Immunodeficient NOD/SCID mice are intraperitoneally implanted with HIV-1-infected human PBMCs. Didanosine (Videx) is administered subcutaneously at 50 mg/kg once daily for 14 days, formulated in 5% DMSO and 95% saline. Blood samples are collected every 3 days to measure viral load by RT-PCR [3]

Absorption, Distribution and Excretion
Absorption is rapid (bioavailability 30-40%), with peak plasma concentrations occurring within 0.5 to 1.5 hours. Based on in vitro and animal studies, it is presumed that didanoxin is metabolized in the human body via the same pathway as endogenous purines. Purines are primarily excreted via the kidneys. Two pregnant women (at 21 and 24 weeks of amenorrhea, respectively) received a single oral dose of 375 mg didanoxin. Blood samples were collected from the pregnant women via intravenous puncture at 65 and 78 minutes post-administration, along with amniotic fluid and fetal blood samples. Didanoxin crosses the placenta, with fetal-to-maternal ratios of 0.14 and 0.19, respectively. The presence of food in the gastrointestinal tract typically reduces the rate and extent of oral didanoxin absorption. When didanoxin extended-release capsules are taken with food, peak plasma concentrations and AUCs are reduced by approximately 46% and 19%, respectively. A study showed that the bioavailability of chewable/dispersible buffered didanoxin tablets taken 30 minutes before a meal was similar to that taken on an empty stomach. When tablets were taken within 2 hours after a meal, peak plasma concentrations and AUC of didanoxin decreased by approximately 55%. Antacids can improve the oral bioavailability of didanoxin. After oral administration, didanoxin is rapidly but incompletely absorbed; peak plasma concentrations are typically reached within 0.25–1.5 hours after a single dose of chewable/dispersible tablets, buffered tablets, or oral solution with buffered powder. The bioavailability of didanoxin administered in chewable/dispersible buffered tablet form is approximately 20–25% higher than that administered in oral solution form with buffered powder, and the pharmacokinetics of 200 mg chewable/dispersible buffered tablets are substantially the same as those of 250 mg oral solution with buffered powder. For more complete data on the absorption, distribution, and excretion of didanoxin (17 types), please visit the HSDB records page.

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Metabolism/Metabolites
It is rapidly metabolized intracellularly to its active fraction, 2,3-dideoxyadenosine-5-triphosphate (ddA-TP). It is subsequently further metabolized in the liver to produce hypoxanthine, xanthine, and uric acid.
The metabolic pathway of didanoxin in humans has not been fully assessed; however, since didanoxin is an analog of inosine (a naturally occurring purine nucleoside), it is presumed that the metabolic pathway of this drug is the same as the elimination pathway of endogenous purines.
Intracellularly, didanoxin is converted to dideoxyinosine-5'-monophosphate. …This monophosphate derivative is then amination to dideoxyadenosine-5'-monophosphate by adenylate succinate synthase/lyase, and phosphorylated to dideoxyadenosine-5'-diphosphate and dideoxyadenosine-5'-triphosphate by other enzymes (e.g., purine nucleoside monophosphate kinase, purine nucleoside diphosphate kinase). Didanoxin's conversion to a triphosphate derivative within host cells is essential for its antiviral activity. Didanoxin undergoes two main metabolic pathways. One pathway, though smaller in proportion, is the primary pathway for its antiretroviral activity. This pathway involves the phosphorylation and reversible amination of didanosin monophosphate by adenosine succinate synthase and adenosine succinate lyase, producing dideoxyadenosine monophosphate (ddATP). ddATP is then further phosphorylated to triphosphate (ddATP) by purine nucleoside monophosphate kinase and purine nucleoside diphosphate kinase. The intracellular half-life of ddATP is 1224 hours, suggesting that didanoxin may require less frequent dosing compared to zidovudine or zalcitabine. Besides inhibiting viral reverse transcriptase, ddATP can also be incorporated into DNA, terminating the replication chain of both cellular and viral DNA. Although dideoxyadenosine phosphorylation is crucial to the drug's antiviral mechanism, it accounts for only a small portion of the overall drug metabolism. Approximately 40% of the total dose is excreted unchanged in the urine, about 50% as hypoxanthine, and about 4% as uric acid. The remainder is not renally cleared through metabolism and/or bile excretion. The primary metabolic pathway involves purine nucleotide phosphorylase metabolizing the drug to uric acid, simultaneously generating hypoxanthine. The compound either re-enters the purine nucleotide pool or is further metabolized to xanthine and uric acid by xanthine oxidase.
Biological half-life
It is 30 minutes in plasma and over 12 hours in the intracellular environment.
In HIV-infected adults, the mean plasma half-life of didanosin is 0.97–1.6 hours (range: 0.3–4.64 hours). In HIV-infected children and adolescents, the mean plasma half-life is 0.8 hours (range: 0.51–1.2 hours).

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Didanosin (Videx) has an oral bioavailability of 42-45% in humans [3]
Didanosin (Videx) is rapidly absorbed after oral administration, reaching peak plasma concentration (Cmax) of 1.2-1.8 μg/mL within 0.5-1.5 hours [1]
The volume of distribution (Vd) of didanoxin (Videx) is 1.0-1.5 L/kg [3]
The plasma elimination half-life (t1/2) of didanoxin (Videx) in humans is 0.6-1.5 hours [1]
Renal excretion is the main elimination route, accounting for 60-70% of the administered dose. It is excreted unchanged in the urine [3]
Didanosin (Videx) has low plasma protein binding (<5%) [1]

Interactions
Ciprofloxacin absorption is significantly reduced when used concomitantly with didanoxin. This interaction is due to the formation of complexes between magnesium and aluminum ions and the ciprofloxacin molecule, resulting in a non-absorbable complex. In vitro studies in MT-4 cells, peripheral blood lymphocytes, and macrophages have shown that didanoxin and zidovudine have a synergistic antiretroviral effect against HIV-1 (HTLV-IIIB strain). While its clinical significance is unclear, some HIV-infected patients have reported confusion when taking triazolam and didanoxin concurrently; the confusion resolved after discontinuation of both drugs, and no relapse occurred upon restarting didanoxin treatment alone. Confusion may occur with benzodiazepines alone, and further research is needed to determine if interactions exist. Concomitant use of oral antacids may increase the oral bioavailability of didanoxin. For more complete data on interactions of didanoxin (16 in total), please visit the HSDB record page.

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Didanosin (Videx) can cause dose-dependent gastrointestinal toxicity, including diarrhea and abdominal pain, when administered to humans at doses exceeding 200 mg/day[3].
In mice, oral administration of didanoxin (Videx) at a dose of 200 mg/kg/day for 14 consecutive days resulted in mild intestinal mucosal inflammation[2].
The LD50 of didanoxin (Videx) in mice is 1500 mg/kg (oral)[1]. Didanoxin (Videx) has minimal inhibitory effect on cytochrome P450 enzymes, resulting in very few drug interactions[3]. Long-term (≥6 months) use of didanoxin (Videx) may lead to peripheral neuropathy in humans, with an incidence of 10-15% at therapeutic doses[3].

[1]. Analytical profiles of drug substances and excipients. Journals & Books, 1993, 185-227.

[2]. Evaluation of HIV protease and nucleoside reverse transcriptase inhibitors on proliferation, necrosis, apoptosis in intestinal epithelial cells and electrolyte and water transport and epithelial barrier function in mice. BMC Gastroenterol. 2010 Aug 11;10:90.

[3]. Didanosine. Drugs, 1999, 58, 1099-1135.

Therapeutic Uses

Anti-HIV drug; antimetabolite; reverse transcriptase inhibitor. Didanoxin is indicated for the treatment of HIV-1 infection when used in combination with other antiretroviral drugs. Additionally, didanoxin is indicated for the treatment of adults and children with advanced HIV infection for more than 6 months who are unable to tolerate zidovudine or have experienced significant clinical or immunological deterioration during zidovudine treatment; didanoxin is also indicated for the treatment of adults with advanced HIV infection who have previously received zidovudine treatment. /Included on US product label/
Diddanoxin may also be used in combination with zidovudine. /Not included on US product label/
Drug Warnings

Patients with renal impairment (i.e., creatinine concentration below 60 ml/min) may be at increased risk of adverse reactions during didanoxin treatment due to decreased drug clearance or metabolic alterations; dose reduction is recommended for such patients. Each didanoxin chewable/dispersible buffer tablet contains 8.6 mEq magnesium hydroxide, which may lead to excessive magnesium overload in patients with clinically significant renal impairment, especially during long-term use; alternative formulations of didanoxin should be considered for such patients. Pancreatitis occurred in 3% (2 of 60) of children treated with didanoxin at daily doses below 300 mg/m², and in 13% (5 of 38) of children at higher daily doses. Although neuropathy has been rarely reported in children taking didanoxin, the signs and symptoms of neuropathy in children can be difficult to assess, therefore physicians should closely monitor children for this adverse reaction. Retinal changes and optic neuritis have been reported in a small number of children taking didanoxin. The manufacturer recommends that all children taking this medication undergo a cycloplegic retinoscopy every 6 months and be examined immediately if any changes in vision occur. Because antacids containing magnesium, calcium, or aluminum may reduce the oral absorption of ciprofloxacin, the manufacturer of didanoxin recommends that didanoxin (in the form of chewable/dispersible buffered tablets, buffered oral solution powder, or non-buffered pediatric oral solution powder mixed with an antacid) should be taken at least 2 hours or 6 hours before oral ciprofloxacin. In 8 HIV-infected patients, the steady-state AUC of ciprofloxacin was reduced by an average of 26% when taken 2 hours before chewable/dispersible buffered didanoxin tablets. In healthy individuals taking both ciprofloxacin and didanoxin-placebo buffered tablets, the AUC of ciprofloxacin was reduced by an average of 98%. For more complete data on drug warnings for didanoxin (29 total), please visit the HSDB Records page.

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Pharmacodynamics
Didanoxin is a nucleoside reverse transcriptase inhibitor (NRTI) active against human immunodeficiency virus type 1 (HIV-1). Unlike other nucleoside analogs, didanoxin is a hypoxanthine linked to a sugar ring. Upon phosphorylation, didanoxin produces active metabolites that competitively bind to viral DNA. These metabolites competitively inhibit HIV reverse transcriptase, thereby terminating DNA chain synthesis. Didanoxin is effective against HIV and is often used in combination with other antiviral therapies. Studies have shown that transitioning from long-term AZT therapy to didanoxin therapy is beneficial. Didanoxin is less acid-resistant and therefore is often used in combination with antacids.

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Didanosin (Videx) is a nucleoside reverse transcriptase inhibitor (NRTI) used to treat HIV-1 infection in adults and children[3]
Didanosin (Videx) is converted into its active metabolite didanosin triphosphate in cells, which competes with deoxyadenosine triphosphate for incorporation into viral DNA[1]
This drug is suitable for use in combination with other antiretroviral drugs to treat HIV infection[3]
Didanosin (Videx) has been approved by the FDA since 1991[3]

C10H12N4O3

236.23

236.09

69655-05-6

Didanosine-d2

135398739

White to off-white solid powder

1.8±0.1 g/cm3

531.2±60.0 °C at 760 mmHg

193-195 °C

275.0±32.9 °C

0.0±1.5 mmHg at 25°C

1.798

-1.31

2

5

2

17

348

2

C1C[C@@H](O[C@@H]1CO)N2C=NC3=C2N=CNC3=O

BXZVVICBKDXVGW-NKWVEPMBSA-N

InChI=1S/C10H12N4O3/c15-3-6-1-2-7(17-6)14-5-13-8-9(14)11-4-12-10(8)16/h4-7,15H,1-3H2,(H,11,12,16)/t6-,7+/m0/s

9-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]-3H-purin-6-one

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: ≥ 2.08 mg/mL (8.80 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 20.8 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: ≥ 2.08 mg/mL (8.80 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 20.8 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: ≥ 2.08 mg/mL (8.80 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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