Anti-endothelial properties of 1,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of calcitriol.

BACKGROUND: Calcitriol [1,25-(OH)(2)D(3)] is a strong anti-proliferative agent both in vitro and in vivo. Earlier studies have established that calcitriol inhibits the growth factor-stimulated proliferation of endothelial cells (EC) and angiogenesis. However, the lethal calcemic side effects of calcitriol prohibit its use as a therapeutic agent. Several analogs of vitamin D have been developed to minimize these calcemic side effects. 1,25-dihydroxy-3-epi-vitamin D(3) (3-epiD(3)), a naturally formed vitamin D metabolite is one such analog. OBJECTIVE: To demonstrate that 3-epiD(3), a calcitriol analog, inhibits endothelial cell proliferation and induces apoptosis. RESULTS: Treatment of EC with 3-epiD(3) showed 60% inhibition (P < 0.006) of proliferation. Cell viability assays corroborated these results. Pro-apoptotic caspase-3 activity was increased fourfold (P < 0.01) in 3-epiD(3)-treated cells over controls. 3-epiD(3) induced apoptosis in EC as shown by genomic DNA fragmentation. Cell cycle analysis of 3-epiD(3)-treated EC revealed a G0/G1 arrest. CONCLUSIONS: 3-epiD(3), a low-calcemic, natural analog of calcitriol, inhibits EC proliferation by causing a G0/G1 arrest and induces apoptosis more effectively than 1,25-(OH)(2)D(3). These results suggest that 3-epiD(3) is a potent inhibitor of EC growth.

Central venous catheter removal versus in situ treatment in neonates with coagulase-negative staphylococcal bacteremia.

OBJECTIVE: To determine how often neonates with coagulase-negative staphylococcal (CONS) bacteremia can be treated successfully without removing the central venous catheter (CVC). METHODS: A cohort study of CONS bacteremia and CVCs was conducted in infants in a neonatal intensive care unit in a 5-year period (1994 through 1998). CONS bacteremia was defined as at least two positive blood cultures within 3 days of each other. RESULTS: Fifty-six infants had early removal CVC (ER-CVC) within 3 days, and 63 infants had late removal CVC (LR-CVC) >3 days after the first positive blood culture. All cases of CONS bacteremia were treated with vancomycin. There was no significant difference between infants in the ER-CVC and LR-CVC groups in terms of recurrence of bacteremia or case fatalities. CONS bacteremia of >3 days duration was more frequent in LR-CVC patients than ER-CVC patients: 43% vs. 13% (relative risk, 3.4; 95% confidence interval, 1.6 to 7.2). CONS bacteremia was successfully treated without CVC removal in 46% of LR-CVC cases. Seventy-nine percent of LR-CVC cases with CONS bacteremia lasting 1 or 2 days were treated successfully without CVC removal. The success rate decreased to 44% with a 3- to 4-day duration of bacteremia. None of 19 infants with CONS bacteremia lasting >4 days was treated successfully until CVCs were removed. CONCLUSIONS: Prolonged CONS bacteremia was avoided by early removal of CVCs. Retention of CVCs was successful in 46% of neonates with CONS bacteremia in whom it was attempted, but it was never successful if bacteremia lasted >4 days.