6-Azauridine

Sixteen unselected patients with non-resectable hepatocellular carcinoma were treated in a phase I study with 261 cycles of D-galactosamine and 6-azauridine prior to 5-fluorouridine. Thirty % of the patients survived for more than 1 yr without signs of tumor progression and with an unchanged performance status. The compatibility of this chemotherapeutical method was quite satisfactory. The only extrahepatic side effect was a leukcopenia and/or thrombocytopenia which was reversible upon reduction of the 5-fluorouridine dose. The heterogeneity of the 16 patients treated to date does not allow a definite statistical evaluation of the reported clinical observations and results.

The effect of pyridoxine on 6-azauridine triacetate (6-AzUrd-TA) induced hyper beta-alaninemia was studied in New Zealand albino rabbits in three experiments. In each of the three experiments the animals were admin by gavage: Group 1 (Control), drinking water; Group 2, 6-AzUrd-TA; and Group 3, 6-AzUrd-TA with pyridoxine. While no beta-alanine was found in the control group or in pretreatment samples of the 6-AzUrd-Ta and 6-AzUrd-TA plus pyridoxine treated animals, high concn of this amino acid (191.0 + or - 91.6, 220.2 + or - 116.3, 103.2 + or - 64.4 nmol/ml) were found on the fourth and seventh days of 6-AzUrd-TA treatment with daily doses of 1.0 g/kg and 0.5 g/kg body weight, respectively. The drug induced hyper beta-alaninemia was significantly (p < or = 0.05) reduced in all three experiments by simultaneous pyridoxine admin in daily doses of 50 mg/kg body weight. These results indicate that daily repeated oral admin of 6-AzUrd-Ta causes elevation of serum beta-alanine, which can be partially prevented by oral admin of pyridoxine. They also indirectly support the hypothesis that 6-AzUrd-TA induced hyper beta-alaninemia is at least partially caused by the inhibition of beta-alanine degrading enzymes, that use pyridoxal phosphate as a coenzyme. /6-Azauridine triacetate/

Twenty-five metabolites (purines, pyrimidines, nucleosides and nucleosides) were tested for their simultaneous action with 6-azauridine (AzUrd) in inhibition of Newcastle disease virus (NDV) replication. With the exception of deoxyadenosine and cyclic AMP all natural adenine derivatives exerted a synergic effect with AzUrd like ATP. Glutamine in combination with AzUrd did not inhibit NDV replication. The inhibitory effect of the combination of AzUrd and adenine derivatives was reversible by guanosine, uridine and cytidine but not by orotic acid or orotidylic acid.

/SIGNS AND SYMPTOMS/ Moderate anemia, characterized by mild megaloblastic changes, reticulocytopenia, and elevated plasma iron concn, occurs after chronic use of high doses of drug ... /6-Azauridine triacetyl deriv/

/SIGNS AND SYMPTOMS/ Hematopoietic suppression appears to be relatively selective for erythropoiesis, with very little if any effect noted on normal leukocyte or platelet counts. /6-Azauridine triacetyl deriv/

/SIGNS AND SYMPTOMS/ Signs of mild CNS dysfunction, incl drowsiness, lethargy, and dizziness, have been reported with lower doses, while hyperreflexia, tremor, diplopia, expressive aphasia, and dysarthria may occur at higher doses ... GI intolerance may be experienced ... /6-Azauridine triacetyl deriv/

/SIGNS AND SYMPTOMS/ ... CNS depressant effect of pyrimidine nucleoside derivatives might relate to uridine binding affinity, so called uridine receptor. /6-AZAURIDINE TRIACETYL DERIV/

For more Human Toxicity Excerpts (Complete) data for 6-AZAURIDINE (8 total), please visit the HSDB record page.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... 6-Azauridine /was found/ to be potent abortifacient in mice ... Most opportune time for abortifacient action in mice was during implantation of ovum.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Admin ... to pregnant mice for 3 wk resulted in no teratogenicity in first pregnancy. However, if ... admin in successive pregnancies, incr teratogenic effects were noted, which were dose-related. With high dosage resorption rate in fourth pregnancy was 100%. Consistent defect was malformation of tail.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ ... /It was reported/ that single doses of 1 mg/gm over 3 days from the 4th to the 6th day of gestation interrupted all mouse pregnancies. ... Utilizing the triacetyl derivative produced abortions and one fetus with skeletal, palate and renal defects in Rhesus monkeys.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Embryotoxic effects were compared of intramuscularly (im) and intraamniotically (ia) administered 6-azauridine (Riboazauracil Spofa) in random-bred mice H-Velaz. Effects of single doses (0.25 mg, 2.5 mg, 25.0 mg and 250.0 mg for im and 0.0025 mg, 0.025 mg and 2.5 mg for ia administration) on days 11, 12, 13 and 14 were evaluated as a sum of dead fetuses and fetuses with cleft lip and/or palate, fetuses with limb deformities and fetuses with deformities constituting the syndrome of caudal regression (hypoplasia of the caudal part of the trunk, absent tail, short tail, curled tail). Considering the sensitivity peaks of the morphogenetic processes which were observed, the dose-response relationships, the transformation of the teratogenic to a lethal effect and critical period extension with increasing doses, it was found that the effects of ia and im administered 6-azauridine did not differ. It was concluded that ia administered 6-azauridine had direct effect on embryonic morphogenetic processes and that this, too, was the essential mechanism of embryotoxicity of im administered 6-azauridine. The value of the intraamniotic technique for establishing the direct embryotoxic effect is discussed.

For more Non-Human Toxicity Excerpts (Complete) data for 6-AZAURIDINE (16 total), please visit the HSDB record page.

LD50 Cat ip 2400 mg/kg

LD50 Dog ip 3400 mg/kg

LD50 Mouse ip 11250 mg/kg

LD50 Rat ip 9400 mg/kg

For more Non-Human Toxicity Values (Complete) data for 6-AZAURIDINE (6 total), please visit the HSDB record page.

Antimetabolites that are useful in cancer chemotherapy.

Drugs used to treat or prevent skin disorders or for the routine care of skin.

Azaribine is well absorbed after oral admin ... After absorption, azaribine is almost entirely deacetylated to azur /azauridine/ in blood, with some monoacetyl deriv detectable. Peak plasma concn of azur are reached after 2 to 4 hr, and plasma disappearance curve with half-time of approx 6 to 8 hr is observed. /6-Azauridine triacetyl deriv/

Unlike azauracil, azur /azauridine/ does not cross blood-brain barrier and is not detectable in CSF. When neurotoxic manifestations have been encountered, significant concn of azauracil ... measured in CSF. Approx 95% of ingested dose of azaribine is excreted in urine as azur within 16 hr. /6-Azauridine triacetyl deriv/

2',3',5'-Triacetyl-6-azauridine was administered orally to eleven patients with far advanced neoplastic disease. The compound was absorbed rapidly from the gastrointestinal tract, in contrast to free 6-azauridine. Significant blood levels of 6-azauridine were maintained during the 8-hour period intervening between doses of the acetylated derivative. Depression of the conversion of orotic acid to uridine nucleotides was demonstrated in patients undergoing therapy, by studies of the fate of intravenously injected orotic acid-7-C14 and of the urinary excretion of orotidine and orotic acid. The metabolic effects and clinical changes observed were comparable to those produced by equivalent doses of intravenously administered 6-azauridine. /2',3',5'-Triacetyl-6-azauridine/

DISTRIBUTION OF (14)C WAS SIMILAR IN NORMAL RATS & RATS WITH ADJUVANT INDUCED POLYARTHRITIS, AFTER ADMIN OF (14)C-6-AZAURIDINE...EXCEPT THAT HEPATIC (14)C CONCN WERE TWOFOLD HIGHER IN LATTER GROUP OF ANIMALS. ABOUT 1 HR AFTER IV DOSE...TO PREGNANT RATS, FETAL CONCN OF (14)C WERE ONE-THIRD THOSE OF MATERNAL CIRCULATION.