Medline ® Abstracts for References 142-145
of 'Fluoropyrimidine-associated cardiotoxicity: Incidence, clinical manifestations, mechanisms, and management'
http://www.esmo.org/Conferences/Past-Conferences/ESMO-2014-Congress/News-Articles/TAS-102-Improves-Overall-and-Progression-Free-Survival-in-Patients-With-Metastatic-Colorectal-Cancer-Refractory-to-Standard-Therapies (Accessed on March 12, 2015).
no abstract available
https://investor.lilly.com/releasedetail.cfm?ReleaseID=870557 (Accessed on March 12, 2015).
no abstract available
Uridine rescue from the lethal toxicity of 5-fluorouracil in mice.
Klubes P, Cerna I, Meldon MA
Cancer Chemother Pharmacol. 1982;8(1):17-21.
To determine the relationship between 5-fluorouracil (FUra) toxicity and its RNA- and DNA-directed actions we examined the ability of continuous SC infusions with uridine (Urd), thymidine (dThd), or deoxyuridine (dUrd) to rescue mice from the lethal toxicity of FUra. Male B6D2F1 mice were treated with a single IP injection of FUra (800 mg/kg) followed in 24 h by a 5-day infusion with either 0.9% NaCl or Urd (0.1, 1, 5, or 10 g/kg/day). Survivors were then followed up for 30 days after FUra treatment. Urd (1, 5, or 10 g/kg/day) rescued mice from the lethal toxicity of FUra, whereas Urd (0.1 g/kg/day) was as ineffective as 0.9% NaCl as a rescue agent. With variable doses of FUra followed in 24 h by a Urd infusion (5 g/kg/day) for 5 days. Urd rescued mice treated with FUra (400, 600, or 800 mg/kg) but was ineffective against higher doses of FUra (1,000 or 1,200 mg/kg). Mice treated with FUra (800 mg/kg) followed in 24 h by a 5-day infusion with either dThd (1, 5, or 10 g/kg/day) or a dUrd (1 or 5 g/kg/day) could not be rescued from the lethal toxicity of FUra. In all experiments deaths occurred between 6 and 12 days after FUra. These results, which demonstrate a specificity for Urd, but not for either dThd or dUrd, for rescuing mice from the lethal toxicity of FUra, suggest the importance of the RNA- rather than the DNA-directed actions of FUra as a determinant of its toxicity in mice.
Phase I and pharmacokinetic studies of high-dose uridine intended for rescue from 5-fluorouracil toxicity.
Leyva A, van Groeningen CJ, Kraal I, Gall H, Peters GJ, Lankelma J, Pinedo HM
Cancer Res. 1984 Dec;44(12 Pt 1):5928-33.
The clinical effects and pharmacokinetics of high-dose uridine were determined in seven patients with advanced-stage cancer and in one healthy volunteer. Uridine was also examined for its effect on 5-fluorouracil toxicity in two patients. Uridine was administered as a 1-hr i.v. infusion at doses of 1 to 12 g/sq m. Plasma and urine samples were analyzed for uridine and uracil using high-pressure liquid chromatography. In 23 courses of uridine alone, the only toxicity observed was transient shivering after one of two courses at 12 g/sq m. This side effect was also seen after administration of uridine (10 g/sq m) during combination with 5-fluorouracil. The pretreatment plasma uridine concentration was elevated from low micromolar to millimolar levels with uridine administration at doses up to 12 g/sq m. Maximal areas under the concentration-time curve were about 5 mmol/liter/hr. Both peak plasma level and area under the curve for uridine increased linearly with dose. Uridine plasma decay curves were biphasic with a terminal half-life of 118 min. Half-life, volume of distribution (634 ml/kg), and total clearance (4.98 ml/kg/min) appeared to be independent of dose. Plasma uracil concentration increased gradually after administration of uridine to plateau levels. Maximal plasma uracil concentrations were about one-tenth that of peak uridine concentrations. The plasma uracil level declined with a half-life of about 40 min after uridine levels decreased to 300 microM. Total urinary excretion of uridine was 24% of the dose, while the amount of uracil recovered in urine was 3.4%. In two patients, uridine rescue was attempted during 5-fluorouracil dose escalation. Uridine at 5 to 6 g/sq m given on 1 or on 2 days after 5-fluorouracil did not prevent myelosuppression and gastrointestinal toxicity associated with increasing plasma concentrations of 5-fluorouracil. These data show that uridine administered as a 1-hr infusion at doses which provide peak plasma uridine concentrations in the millimolar range is well tolerated. Rapid elimination of uridine primarily due to catabolism results in modest exposure to substantially elevated plasma uridine concentrations. Preliminary findings suggest that prolonged treatment with uridine may be required to test its potential to rescue patients from 5-fluorouracil toxicity.