Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors.

PURPOSE: Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule. PATIENTS AND METHODS: Patients received a single 24-hour infusion of 5-FU (2,300 mg/m(2) on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO bid on days 1 through 3) and 5-FU (10 to 15 mg/m(2) PO bid on day 2). RESULTS: Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was seen with 5-FU 15 mg/m(2) PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m(2) PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected in plasma during oral 5-FU-eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19. CONCLUSION: The recommended oral dosage of 5-FU (10 mg/m(2) PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.

Transmission of human immunodeficiency virus (HIV) by blood transfusions screened as negative for HIV antibody.

Since early 1985, blood donations in the United States have been screened for antibody to human immunodeficiency virus (HIV). To identify instances of HIV transmission by antibody-negative donations, we investigated 13 persons seropositive for HIV who had received blood from 7 donors who were screened as negative for HIV antibody at the time of donation. Twelve of the 13 recipients had no identifiable risk factors for HIV infection other than the transfusions they had received. On evaluation 8 to 20 months after transfusion, HIV-related illnesses had developed in three recipients, and the acquired immunodeficiency syndrome had developed in one. All seven donors were found to be infected with HIV. On interview, six reported a risk factor for HIV infection, and five had engaged in high-risk activities or had had an illness suggestive of acute retroviral syndrome within the four months preceding their HIV-seronegative donation. Thus, these donors had apparently been infected only recently, and so were negative at the time of blood donation according to available antibody tests. We conclude that there is a small but identifiable risk of HIV infection for recipients of screened blood. To minimize this risk, the reasons for deferral of donation need to be communicated more effectively to blood donors who are at high risk of HIV infection, and new assays that detect HIV infection earlier should be evaluated for their effectiveness in screening donated blood.

PIP: Since early 1985, blood donations in the US have been screened for antibody to human immunodeficiency virus (HIV). To identify instances of HIV transmission by antibody-negative donations, this study investigated 13 persons seropositive for HIV who had received blood from 7 donors who were screened as negative for HIV antibody at the time of donation. 12 of the 13 recipients had no identifiable risk factors for HIV infection other than the transfusions they had received. On evaluation 8 to 20 months after transfusion, HIV-related illnesses had developed in 3 recipients, and the acquired immunodeficiency syndrome had developed in 1. All 7 donors were found to be infected with HIV. On interview, 6 reported a risk factor for HIV infection, and 5 had engaged in high-risk activities or had had an illness suggestive of acute retroviral syndrome within the 4 months preceding their HIV-seronegative donation. Thus, these donors had apparently been infected only recently, and so were negative at the time of blood donation according to available antibody tests. This study concludes that there is a small but identifiable risk of HIV infection for recipients of screened blood. To minimize this risk, the reasons for deferral of donation need to be communicated more effectively to blood donors who are at high risk of HIV infection, and new assays that detect HIV infection earlier should be evaluated for their effectiveness in screening donated blood.