Dideoxyinosine

Description

Didanosine is an orally active purine dideoxynucleoside analog indicated for adult and pediatric patients with advanced HIV infection who are either intolerant or significantly deteriorated on zidovudine. It appears to increase CD4 cell counts and decrease p24 antigen levels.Major adverse effects are pancreatitis, peripheral neuropathy and diarrhea.Unlike zidovudine, didanosine exhibits insignificant bone marrow suppression.

Chemical Properties

White Powder

Originator

National Cancer Institute(NIH) (U.S.A.)

Uses

Antiviral;Transrcriptase inverse inhibitor

Uses

Used as an antiviral

Uses

2,3-Dideoxyinosine is a potent anti-retroviral agent. It is most effective in combination therapy for the treatment of HIV and related lymphoma.

Definition

ChEBI: A purine 2',3'-dideoxyribonucleoside that is inosine in which the hydroxy groups at both the 2' and the 3' positions on the sugar moiety have been replaced by hydrogen.

Indications

Didanosine (ddI, Videx) is an adenosine analogue with activity against HIV-1, HIV-2, and HTLV-I. It is approved as part of a multidrug regimen for the therapy of HIV infection and is also used as postexposure HIV prophylaxis

Manufacturing Process

In a 500 ml flask with a shoulder was separately charged 50 ml of medium (pH 7.0) containing 0.5 g/dl of yeast extract, 1.0 g/dl of peptone, 1.0 g/dl of meat extract and 0.5 g/dl of NaCl followed by sterilization. One platinum loop of each microorganism shown in Table which had been preincubated in bouillon agar medium at 30°C for 16 hours was inoculated on the medium followed by shake culture at 30°C for 16 hours. After the cells were isolated from the obtained culture solution by centrifugal separation, the cells were washed with 0.05 M Tris-HCl buffer (pH 7.2) and further centrifuged to give washed cells.
The washed cells described above were added to 0.05 M Tris-HCl buffer (pH 7.2) containing 1 g/dl of 2',3'-dideoxyadenosine in a concentration of 5 g/dl followed by reacting at 30°C for 2 hours. The amount of 2',3'-dideoxyinosine produced at this stage is shown in the next Table.
This way 2',3'-dideoxyinosine may be produced from 2',3'-dideoxyadenosine in a short period of time, by contacting microorganisms supplied at low cost, products containing the same or treated products thereof, with a substrate.

brand name

Videx (Bristol-Myers Squibb).

Therapeutic Function

Antiviral

Antimicrobial activity

Didanosine is active against HIV-1, HIV-2 and HTLV-1.

Acquired resistance

Codon changes at positions 65 or 74 in HIV reverse transcriptase are associated with reduced susceptibility.

General Description

Didanosine (Videx, ddI) is 2',3'-dideoxyinosine (ddI), a synthetic purine nucleoside analog that is bioactivatedto 2',3'-dideoxy-ATP (ddATP) by host cellularenzymes.The metabolite, ddATP, accumulates intracellularly,where it inhibits RT and is incorporated intoviral DNA to cause chain termination in HIVinfectedcells. The potency of didanosine is 10-to 100-foldless than that of AZT with respect to antiviral activity andcytotoxicity, but the drug causes less myelosuppressionthan AZT causes.
Didanosine is recommended for the treatment of patientswith advanced HIV infection who have received prolongedtreatment with AZT but have become intolerant to, or experiencedimmunosuppression from, the drug. AZT and ddIact synergistically to inhibit HIV replication in vitro, andddI is effective against some AZT-resistant strains of HIV.Painful peripheral neuropathy (tingling, numbness, and painin the hands and feet) and pancreatitis (nausea, abdominalpain, elevated amylase) are the major dose-limiting toxicitiesof didanosine. Didanosine is given orally in the form ofbuffered chewable tablets or as a solution prepared from thepowder. Both oral dosage forms are buffered to preventacidic decomposition of ddI to hypoxanthine in the stomach.

General Description

Fluffy white solid or powder. Condenses at 347°F and darkens at approximately 572°F. Odorless.

Air & Water Reactions

Water soluble.

Health Hazard

SYMPTOMS: Symptoms of exposure to a related compound include cutaneous eruptions, fever, mouth sores, thrombocytopenia, neutropenia, reversible peripheral neuropathy, gastrointestinal distress, headache, nausea and vomiting.

Fire Hazard

Flash point data for Dideoxyinosine are not available; however, Dideoxyinosine is probably combustible.

Pharmaceutical Applications

An analog of deoxyadenosine, formulated for oral administration.

Mechanism of action

Didanosine (ddl) is a purine dideoxynucleoside, which is an analogue of inosine. Chemically, it is 2′,3′-dideoxyinosine, and it differs from inosine by having hydrogen atoms in place of the 2′- and 3′-hydroxyl groups on the ribose ring. Didanosine is a pro-drug that is bioactivated by metabolism to dideoxyadenosine triphosphate, which is a competitive inhibitor of viral RT and is incorporated into the developing viral DNA in place of deoxyladenosine triphosphate. As such, this agent causes chain termination because of the absence of a 3′-hydroxyl group. Didanosine inhibits HIV RT and exerts a virustatic effect on the retroviruses. Combined with ZDV, antiretroviral activity of ddI is increased.

Pharmacokinetics

Oral absorption: c. 40%
C_max 400 mg once daily: 0.93 mg/L
Plasma half-life: c. 1.4 h
Volume of distribution: c. 1 L/kg
Plasma protein binding: <5%
Absorption
Bioavailability is reduced by about half when taken with food and the drug should be given at least 30 min before a meal. The peak plasma concentration achieved by enteric-coated tablets is less than half that of buffered tablets.
Distribution
Central nervous system (CNS) penetration is relatively poor. Median concentrations in semen (455 ng/mL; range < 50–2190 ng/mL) are greater than those in blood (<50 ng/mL; range <50–860 ng/mL). It is secreted in breast milk.
Metabolism
Based upon animal studies it is presumed that metabolism occurs by the pathways responsible for the elimination of endogenous purines by xanthine oxidase. Metabolism may be altered in patients with severe hepatic impairment; however, no specific dose adjustment is recommended.
Excretion
Renal clearance by glomerular filtration and active tubular secretion accounts for 50% of total body clearance. Urinary recovery accounts for about 20% of the oral dose in adults. The half-life increases three-fold in patients requiring dialysis. Patients with a creatinine clearance <60 mL/min may be at greater risk of toxicity.

Clinical Use

Treatment of HIV infection (in combination with other antiretroviral drugs)

Clinical Use

The most common adverse effect produced by didanosine is diarrhea.Abdominal pain, nausea, vomiting, anorexia, and dose-related peripheral neuropathy may occur. Pancreatitis occurs rarely, as do hyperuricemia, bone marrow suppression, retinal depigmentation, and optical neuritis. Resistance to didanosine appears to result from mutations different from those responsible for zidovudine resistance.

Side effects

Most serious are pancreatitis (fatal and non-fatal), lactic acidosis and severe hepatomegaly with steatosis (fatal and nonfatal), retinopathy, optic neuritis and dose-related peripheral neuropathy. Patients with low body weight may require dose modification. A strong association with non-cirrhotic portal hypertension has been described.
The combination with stavudine should be avoided in pregnant women as fatal cases of lactic acidosis have been reported. Caution should also be exercised in patients with known risk factors for liver disease. Therapy should be stopped in patients who develop clinical or laboratory evidence of lactic acidosis or hepatotoxicity. Monitoring lactate levels prospectively is not recommended as mild hyperlactatemia occurs in asymptomatic patients and has a poor positive predictive value for the development of lactic acidosis.
Caution should be exercised in co-administering other drugs with known neurotoxicity and in patients with a history of neuropathy. Treatment should stop if symptoms and signs of neuropathy are observed, but the condition is usually reversible and patients with resolved neuropathy may be retreated at a reduced dosage. Retinal depigmentation has been observed in children and twice-yearly dilated retinal examination is recommended.

Drug interactions

Potentially hazardous interactions with other drugs
Allopurinol: concentration of didanosine increased - avoid.
Antibacterials: ciprofloxacin, tetracyclines, and other antibiotics affected by indigestion remedies - do not administer within 2 hours of didanosine.
Antivirals: absorption of atazanavir reduced (give at least 2 hours before or 1 hour after didanosine tablets); manufacturer of darunavir advises to take didanosine 1 hour before or 2 hours after darunavir; didanosine tablets reduce absorption of indinavir (give at least 1 hour apart); concentration possibly increased by ganciclovir, valganciclovir and tenofovir - avoid with tenofovir; give didanosine and ritonavir at least 2.5 hours apart; increased risk of side effects with ribavirin and stavudine - avoid; concentration reduced by tipranavir (give tipranavir and didanosine capsules at least 2 hours apart); give didanosine 2 hours before or 4 hours after rilpivirine.
Cytotoxics: increased risk of toxicity with hydroxycarbamide - avoid.
Orlistat: absorption of didanosine possibly reduced.

Metabolism

Didanosine is less toxic than ZDV. The CSF fluid/plasma ratio of ddI is 0.2. Didanosine is ultimately converted to hypoxanthine, xanthine, and uric acid through the usual metabolic pathway for purines. The latter is a nontoxic metabolic product.
Didanosine is given in advanced HIV infection, ZDV intolerance, or significant clinical/immunologic deterioration.

Precautions

Buffering agents that are compounded with didanosineto counteract its degradation by gastric acid mayinterfere with the absorption of other drugs that requireacidity (e.g., indinavir, delavirdine, ketoconazole, fluoroquinolones,tetracyclines, dapsone). An enteric-coatedformulation (Videx EC) that dissolves in the basic pH ofthe small intestine is not susceptible to these interactions.Ganciclovir and valganciclovir can increase bloodlevels of didanosine.The use of zalcitabine with didanosineis not recommended because that combination carriesan additive risk of peripheral neuropathy.The combinationof didanosine with stavudine increases the riskof pancreatitis, hepatotoxicity, and peripheral neuropa-thy. Stavudine should not be given with didanosine topregnant women because of the increased risk of metabolicacidosis.