Pharmacology, Tolerance, and Antiviral Activity of Vidarabine Monophosphate in Humans

The metabolism of 6-dimethylaminopurine arabinoside (ara-DMAP), a potent inhibitor of varicella-zoster virus replication in vitro, was studied in rats and cynomolgus monkeys. Rats dosed intraperitoneally or orally with ara-DMAP excreted unchanged ara-DMAP and one major metabolite, 6-methylaminopurine arabinoside (ara-MAP), in the urine. They also excreted allantoin and small amounts (<4% of the dose each) of hypoxanthine arabinoside (ara-H) and adenine arabinoside (ara-A). The relative amount of each urinary metabolite excreted remained fairly constant for intraperitoneal ara-DMAP doses of 0.3 to 50 mg/kg of body weight. Rats pretreated with an inhibitor of microsomal N-demethylation, SKF-525-A, excreted more unchanged ara-DMAP and much less ara-MAP than did rats given ara-DMAP alone. Rats pretreated with the adenosine deaminase inhibitor deoxycoformycin excreted more ara-MAP and much less ara-H and allantoin.ara-MAP was shown to be a competitive alternative substrate inhibitor of adenosine deaminase (Ki = 16 ,IM).Rats given ara-DMAP intravenously rapidly converted it to ara-MAP and purine metabolism end products; however, ara-A generated from ara-DMAP had a half-life that was four times longer than that of ara-A given intravenously. In contrast to rats, cynomolgus monkeys dosed intravenously with ara-DMAP formed ara-H as the major plasma and urinary end metabolite. Rat liver microsomes demethylated ara-DMAP much more rapidly than human liver microsomes did. ara-DMAP is initially N-demethylated by microsomal enzymes to form ara-MAP. This metabolite is further metabolized by either adenosine deaminase, which removes methylamine to form ara-H, or by microsomal enzymes, which remove the second methyl group to form ara-A.Varicella-zoster virus (VZV) causes both chicken pox and shingles. Chicken pox is usually a mild disease in nonimmunocompromised patients, but shingles, the recurrent herpes zoster virus infection, can be very painful and severe. Both intravenous (i.v.) adenine arabinoside (ara-A) and oral (p.o.) or i.v. acyclovir have been used to treat VZV and herpes zoster virus infections. However, acyclovir is the preferred method of treatment for shingles (12,22). The effective doses of acyclovir for VZV are high compared with those used to treat herpes simplex virus, another herpesvirus (5, 10, 12). Therefore, a compound with both potent and selective activity against VZV would be useful.Two uridine analogs, (E)-5-(2-bromovinyl)-2'-deoxyuridine and (E)-5-(2-bromovinyl)-2'-uracil arabinoside, show potent antiviral activity against VZV (8) and have therapeutic potential. A 6-alkoxypurine arabinoside, 6-methoxypurine arabinoside, has anti-VZV activity with minimal in vitro cell toxicity, but it is extensively metabolized (2).We report here the disposition and metabolism of another active compound, an N6-alkyl-substituted adenine arabinoside. This compound, 6-dimethylaminopurine arabinoside (ara-DMAP), inhibits VZV replication in vitro (50% inhibitory concentration [IC50], 1 ,uM) without significant in vitro toxi...

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Metabolism and pharmacokinetics of the anti-varicella-zoster virus agent 6-dimethylaminopurine arabinoside

Lambe

Resetar

Spector

et al. 1992

“…Because Ara-A has low aqueous solubility, it was given in the form of Ara-AMP in these experiments. Ara-AMP is a prodrug, which, upon dephosphorylation to Ara-A in the blood, is able to cross the cell membrane (35). As shown in Table 5, all the mice treated with either of the two drug combinations were cured.…”

mentioning

confidence: 94%

9-(2′-Deoxy-2′-Fluoro-β- d -Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance

Ranjbarian

Vodnala

Alzahrani

et al. 2017

Current chemotherapy against African sleeping sickness, a disease caused by the protozoan parasite Trypanosoma brucei, is limited by toxicity, inefficacy, and drug resistance. Nucleoside analogues have been successfully used to cure T. brucei-infected mice, but they have the limitation of mainly being taken up by the P2 nucleoside transporter, which, when mutated, is a common cause of multidrug resistance in T. brucei. We report here that adenine arabinoside (Ara-A) and the newly tested drug 9-(2=-deoxy-2=-fluoro-␤-D-arabinofuranosyl) adenine (FANA-A) are instead taken up by the P1 nucleoside transporter, which is not associated with drug resistance. Like Ara-A, FANA-A was found to be resistant to cleavage by methylthioadenosine phosphorylase, an enzyme that protects T. brucei against the antitrypanosomal effects of deoxyadenosine. Another important factor behind the selectivity of nucleoside analogues is how well they are phosphorylated within the cell. We found that the T. brucei adenosine kinase had a higher catalytic efficiency with FANA-A than the mammalian enzyme, and T. brucei cells treated with FANA-A accumulated high levels of FANA-A triphosphate, which even surpassed the level of ATP and led to cell cycle arrest, inhibition of DNA synthesis, and the accumulation of DNA breaks. FANA-A inhibited nucleic acid biosynthesis and parasite proliferation with 50% effective concentrations (EC 50 s) in the low nanomolar range, whereas mammalian cell proliferation was inhibited in the micromolar range. Both Ara-A and FANA-A, in combination with deoxycoformycin, cured T. brucei-infected mice, but FANA-A did so at a dose 100 times lower than that of Ara-A.KEYWORDS 9-(2=-deoxy-2=-fluoro-␤-D-arabinofuranosyl) adenine, FANA-A, Trypanosoma brucei, adenosine kinase, drug resistance, methylthioadenosine phosphorylase, nucleoside transporters, trypanosome T rypanosoma brucei is transmitted by tsetse flies and causes African sleeping sickness in humans and nagana in cattle (1, 2). The disease is characterized by two stages. Initially, the parasites are restricted to circulating in the blood and lymph systems, but in the advanced stages of the disease, they are also found in the cerebrospinal fluid, which leads to coma and death if the patient is not treated. There is no existing vaccine, and available treatments are specific to the disease stage and the parasite subspecies. High toxicity, complex administration protocols, and drug resistance all contribute to the urgent need for new therapies.

“…In neonates, however, herpesvirus encephalitis usually results from dissemination of virus acquired from maternal genital infections, and these are usually caused by HSV-2 (14). If left untreated, the mortality rate associated with this disease is approximately 70 to 80% (33,34,36,38 a 12-h period for 10 days, was found to significantly reduce the mortality due to HSV-1 encephalitis from 70 to ca. 28% among those patients (36).…”

Section: Discussionmentioning

confidence: 99%

“…The use of the more watersoluble derivative, ara-AMP, which is undergoing clinical trials for efficacy against herpesvirus infections in humans, has been suggested as a solution to this particular problem (10,37,38). Another probiem with ara-A lies in the fact that this purine.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the efficacy of vidarabine, its carbocyclic analog (cyclaradine), and cyclaradine-5'-methoxyacetate in the treatment of herpes simplex virus type 1 encephalitis in mice

Shannon¹,

Westbrook²,

Arnett³

et al. 1983

The relative therapeutic effects of vidarabine (9-,-D-arabinofuranosyladenine), cyclaradine (the adenosine deaminase-resistant carbocyclic analog of vidarabine), and cyclaradine-5'-methoxyacetate in the parenteral treatment of systemic herpes simplex virus type 1 infections in Swiss mice were determined. Among control mice inoculated intraperitoneally with virus, a mortality rate of 95% was observed. The intraperitoneal administration of nontoxic doses of vidarabine (125 to 250 mg/kg per day) or cyclaradine (113 to 450 mg/kg per day), by daily injections for 7 days beginning 4 h after virus inoculation, reduced mortality to 0 to 10%, Amnong control animals inoculated intracerebrally with 32 50% lethal doses of virus, 100%to mortality was observed, with a mean survival time of 4.6 days.Treatment with either drug at equimolar dose levels ranging from ca. 32 to 750 mg/kg per day produced significant (P < 0.0005), dose-dependent increases in the mean survival time of animals dying of herpesvirus encephalitis. Mice inoculated intracerebraily with 10 50o lethal doses of virus exhibited 97% mortality and a mean survival time of 5.5 to 6.4 days. Treatment with vidarabine, cyclaradine, or cyclaradine-5'-methoxyacetate significantly increased the mean survival time of dying animals and, at doses ranging from 250 to 750 mg/kg per day, produced significant increases in survival. The three drugs displayed equivalent antiviral efficacy in vivo. Drug toxicity (measured by weight loss) was not detected in mice treated with cyclaradine or cyclaradine-5'-methoxyacetate at 750 mg/kg per day, whereas severe toxicity (weight loss of -3 g) was observed in mice treated with vidarabine at an equivalent dose level. Thus, cyclaradine or its 5'-methoxyacetic acid ester may possess some advantage over vidarabine in the treatment of severe herpesvirus infections and should therefore be considered for clinical trials in humans.