Vidarabine

Pharmaceuticals -> Listed in ZINC15

Pharmaceutical

log Kow = -1.11

-2.115

Crystals from water

Needles from water

less than 1 mg/mL at 70 °F (NTP, 1992)

The monohydrate occurs as a white, crystalline powder and has a solubility of approximately 0.45 mg/mL in water at 25 °C. /Vidarabine monohydrate/

1.40e+01 g/L

>40.1 [ug/mL] (The mean of the results at pH 7.4)

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

500 to 518 °F (NTP, 1992)

257.0-257.5 °C (0.4 H2O)

257.00 °C. @ 760.00 mm Hg

Vidarabine is a white to off-white crystalline powder. (NTP, 1992)

Solid

156.4 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

161.28 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Warning

H361 (97.6%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 41 reports by companies from 4 notifications to the ECHA C&L Inventory.

SYMPTOMS: Symptoms of exposure to this compound include nausea, vomiting, diarrhea, rash, weakness, thrombophlebitis, hallucinations, psychoses, ataxia, tremor, and dizziness. It can cause gastrointestinal disturbances, confusion, anemia, leukopenia, thrombocytopenia, elevated liver enzymes and bilirubin, corneal changes, and sensitivity changes. In addition, it causes mild itching and irritation of the eyes, and moderate redness of the conjunctiva with temporary punctate keratitis. Anorexia, weight loss, and abnormal EKG have been reported. It causes headache, encephalopathy, decrease in hemoglobin, white blood count, platelet count, and malaise, pruritus, and hematemesis.

Proposed regulation to exempt marketing applications for certain antibiotic drug products, including vidarabine, from regulatory provisions governing marketing exclusivity and patents.[Federal Register: January 24, 2000 (Volume 65, Number 15)

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products. Vidarabine is included on this list.

VIDARABINE is an organic compound containing both amine and alcohol substituents. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

SMALL SPILLS AND LEAKAGE: If you spill this chemical, you should dampen the solid spill material with water, then transfer the dampened material to a suitable container. Use absorbent paper dampened with water to pick up any remaining material. Seal your contaminated clothing and the absorbent paper in a vapor-tight plastic bag for eventual disposal. Wash all contaminated surfaces with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Although an interaction has not been clearly established, concurrent administration of vidarabine and allopurinol has been associated with tremors, anemia, nausea, pain, and pruritus in some patients. Animal and in vitro studies suggest that allopurinol may interfere with the metabolism of vidarabine.

Acyclovir and vidarabine both exhibit anti-herpetic activity. Because different mechanisms of action of vidarabine and acyclovir have been reported, /the authors/ analyzed their combined anti-herpetic activity on plaque formation of herpes simplex virus (HSV)-1, HSV-2, and varicella-zoster virus (VZV) by isobolograms. The results indicate that acyclovir and vidarabine have a synergistic effect on wild type HSV-1, HSV-2, and VZV. ...

Adenosine slows conduction time through the AV node and can interrupt the reentry pathways through the AV node, resulting in the restoration of normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT), including PSVT associated with Wolff-Parkinson-White Syndrome. This effect may be mediated through the drug's activation of cell-surface A₁ and A₂ adenosine receptors. Adenosine also inhibits the slow inward calcium current and activation of adenylate cyclase in smooth muscle cells, thereby causing relaxation of vascular smooth muscle. By increasing blood flow in normal coronary arteries with little or no increase in stenotic arteries (with little to no increase in stenotic arteries), adenosine produces a relative difference in thallous (thallium) chloride TI 201 uptake in myocardium supplied by normal verus stenotic coronary arteries.

/SIGNS AND SYMPTOMS/ Ocular toxicity /including/ punctate keratopathy and hypersensitivity /may occur when using/ topical vidarabine (VIVA-A; 3% ointment) /to treat/ herpes simplex keratitis and conjunctivitis. /From table/

/SIGNS AND SYMPTOMS/ Iv vidarabine causes dose-related GI toxicity, acute neurotoxicities, painful peripheral neuropathy, weakness, hypokalemia, rash, elevated transaminases, anemia, and leukopenia or thrombocytopenia.

/SIGNS AND SYMPTOMS/ Like other ophthalmic ointments, vidarabine may produce a temporary visual haze. Burning, itching, and mild irritation of the affected eye are the most common adverse effects of topical vidarabine therapy; however, lacrimation, foreign body sensation, conjunctival injection, superficial punctate keratitis, pain, photophobia, punctal occlusion, and sensitivity may also occur. Uveitis, stromal edema, secondary glaucoma, trophic defects, corneal vascularization, and hyphema have also been reported, but appear to be disease related.

/GENOTOXICITY/ In vitro, the drug has been shown to cause chromosome breaks and gaps when added to human leukocytes...

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

vidarabine

DILI Negative

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Acute Exposure/ ... very little toxicity to the eye /of rabbits/.[Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 973]

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Hepatic megalocytosis has also been associated with vidarabine use in rodents, but it is not known if this represents a preneoplastic condition.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 405]

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ There is some evidence that vidarabine can cause mutagenic or tumorigenic effects in animals (eg, liver tumors and kidney neoplasia in mice; intestinal, testicular, and thyroid neoplasia in rats). ...[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 405]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Vidarabine is teratogenic in rats and rabbits. Although there are no adequate and controlled studies to date in humans, vidarabine has been shown to induce fetal abnormalities in rabbits when given during fetal organogenesis at an im dosage of 5 mg/kg; teratogenic effects were not observed at dosages of 3 mg/kg or less. Vidarabine caused maternal toxicity at im dosages of 100 mg/kg or greater in rats, and frank fetal abnormalities occurred at dosages of 150-250 mg/kg.[McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 405]

For more Non-Human Toxicity Excerpts (Complete) data for VIDARABINE (9 total), please visit the HSDB record page.

Administration of the large volume of iv solution required to solubilize vidarabine may cause fluid overload in patients with CNS infections or impaired renal function. Vidarabine should be used with caution in patients with impaired liver or kidney function and in patients susceptible to fluid overload or cerebral edema. Serum AST (SGOT) concentration, leukocyte and platelet counts, hemoglobin, and hematocrit should be monitored in patients receiving the drug. Vidarabine is contraindicated in patients who are hypersensitive to the drug or any ingredient in the formulation.

The safety and effectiveness in pediatric patients below the age of 2 years have not been established.

A safe dosage of the drug for use in pregnant women has not been established. Vidarabine should be used during pregnancy only if the potential benefits outweigh the possible risks to the fetus. ... It is not known if vidarabine is distributed into milk. Because of the potential for serious adverse reactions from vidarabine in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

LD50 Mouse iv 442 mg/kg

LD50 Mouse sc 5086 mg/kg

LD50 Mouse ip 3057 mg/kg

LD50 Mouse oral 7800 ug/kg

For more Non-Human Toxicity Values (Complete) data for VIDARABINE (7 total), please visit the HSDB record page.

Proposed regulation to exempt marketing applications for certain antibiotic drug products, including vidarabine, from regulatory provisions governing marketing exclusivity and patents.[Federal Register: January 24, 2000 (Volume 65, Number 15)

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies discontinued drug products. Vidarabine is included on this list.

S - Sensory organs

J - Antiinfectives for systemic use

QS - Sensory organs

QJ - Antiinfectives for systemic use

Vidarabine is a synthetic purine nucleoside analogue with <i>in vitro</i> and <i>in vivo</i> inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), and varicella-zoster virus (VZV). The inhibitory activity of Vidarabine is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts Vidarabine into Vidarabine monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. <i>In vitro</i>, Vidarabine triphosphate stops the DNA replication of herpes virus by being incorporated into the DNA strand and preventing the formation of phosphodiester bridges between bases. This ultimately leads to destabilization of the viral DNA strands.

Vidarabine stops replication of herpes viral DNA in 2 ways: 1) competitive inhibition of viral DNA polymerase, and consequently 2) incorporation into and termination of the growing viral DNA chain. Vidarabine is sequentially phosphorylated by kinases to the triphosphate ara-ATP, which is the active form of vidarabine that acts as both an inhibitor and a substrate of viral DNA polymerase. By acting as a substrate for viral DNA polymerase, ara-ATP competitively inhibits dATP leading to the formation of ‘faulty’ DNA. Ara-ATP can also be incorporated into the DNA strand to replace many of the adenosine bases, resulting in the disruption of DNA synthesis.

The antiviral mechanism of action has not been established. Vidarabine appears to interfere with the early steps of viral DNA synthesis.

The antiviral mechanism of vidarabine is incompletely understood, but vidarabine is an inhibitor of viral DNA synthesis. Cellular enzymes phosphorylate vidarabine to the triphosphate, which inhibits viral DNA polymerase activity in a manner that is competitive with deoxyadenosine triphosphate. Vidarabine triphosphate is incorporated into both cellular and viral DNA, where it may act as a chain terminator. Vidarabine triphosphate also inhibits ribonucleoside reductase, RNA polyadenylation, and S-adenosylhomocysteine hydrolase (SAHH), an enzyme involved in transmethylation reactions.

In laboratory animals, vidarabine is rapidly deaminated in the gastrointestinal tract to Ara-Hx.

In laboratory animals, Vira-A is rapidly deaminated in the gastrointestinal tract to arabinosylhypoxanthine (Ara-Hx).

Vidarabine is rapidly deaminated, possibly within the cornea, by adenosine deaminase to ara-hypoxanthine. Ara-hypoxanthine also possesses antiviral activity but substantially less than that of vidarabine.

Intracellular adenosine is rapidly metabolized either via phosphorylation to adenosine monophosphate by adenosine kinase, or via deamination to inosine by adenosine deaminase in the cytosol. Half Life: Less than 10 secs

Drugs that are chemically similar to naturally occurring metabolites, but differ enough to interfere with normal metabolic pathways. (From AMA Drug Evaluations Annual, 1994, p2033)

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.

Systemetic absorption of vidarabine should not be expected to occur following ocular administration and swallowing lacrimal secretions.

Vira-A is rapidly deaminated to arabinosylhypoxanthine (Ara-Hx), the principal metabolite. ...Because of the low solubility of Vira-A, trace amounts of both Vira-A and Ara-Hx can be detected in the aqueous humor only if there is an epithelial defect in the cornea. If the cornea is normal, only trace amounts of Ara-Hx can be recovered from the aqueous humor. Systemic absorption of Vira-A should not be expected to occur following ocular administration and swallowing lacrimal secretions.

Vidarabine is poorly absorbed following oral, im, or SC administration. Following iv administration of vidarabine, 75-87% of the dose is rapidly deaminated by adenosine deaminase to ara-hypoxanthine. Ara-hypoxanthine also possesses antiviral activity but substantially less than that of vidarabine. Following slow iv administration of vidarabine 10 mg/kg in adults, peak plasma concentrations of the drug range from 0.2-0.4 ug/mL and peak plasma concentrations of ara-hypoxanthine range from 3-6 ug/mL. Plasma concentrations of vidarabine and ara-hypoxanthine are higher and more prolonged in patients with renal impairment.

Vidarabine and ara-hypoxanthine are widely distributed into body tissues and fluids and readily cross the blood-brain barrier. In patients with normal meninges, ara-hypoxanthine concentrations in the CSF are about 33-35% of concurrent plasma concentrations. Vidarabine crosses the placenta in animals. It is not known if vidarabine is distributed into milk. ... Vidarabine is 20-30% bound and ara-hypoxanthine is 0-3% bound to plasma proteins.

Vidarabine and ara-hypoxanthine are excreted mainly by the kidneys. Within 24 hours following iv administration of vidarabine 15 mg/kg in patients with normal renal function, 1-3% of the dose is excreted in urine as vidarabine and 41-53% of the dose is excreted as ara-hypoxanthine. There is no evidence of fecal excretion of the drug or metabolite.

MEDICATION

THERAP CAT: ANTIVIRAL

A nucleoside antibiotic isolated from Streptomyces antibioticus. It has some antineoplastic properties and has broad spectrum activity against DNA viruses in cell cultures and significant antiviral activity against infections caused by a variety of viruses such as the herpes viruses, the VACCINIA VIRUS and varicella zoster virus

VIRA-A Vidarabine, 3% ointment, ophthalmic: Discontinued

VIRA-A (vidarabine) eq 187.4 mg base/ml, injectable; injection: Discontinued

Used as an initial treatment for the termination of paroxysmal supraventricular tachycardia (PVST), including that associated with accessory bypass tracts, and is a drug of choice for terminating stable, narrow-complex supraventricular tachycardias (SVT). Also used as an adjunct to thallous chloride TI 201 myocardial perfusion scintigraphy (thallium stress test) in patients who are unable to exercise adequately, as well as an adjunct to vagal maneuvers and clinical assessment to establish a specific diagnosis of undefined, stable, narrow-complex SVT.

Ophthalmic Ointment 3% (equivalent to vidarabine, Vira-A, Parke-Davis anhydrous 2.8%)

Parenteral: Concentrate, for injection, for iv infusion, 200 mg/ml (equivalent to 187.4 mg of anhydrous vidarabine per ml). Vira-A (with benzethonium chloride and phosphate buffers), Parke-Davis

/Vidarabine/ not currently approved for use in the United States