Effect of the combination of cationic lipid and phospholipid on gene-knockdown using siRNA lipoplexes in breast tumor cells and mouse lungs.

Previously, using three types of cationic lipids, the effect of phospholipids in liposomal formulations on gene-knockdown efficacy was determined after in vitro and in vivo transfection with small interfering RNA (siRNA)/cationic liposome complexes (siRNA lipoplexes) containing various cationic lipids and phospholipids. In the present study, six other types of cationic lipids, namely N,N-dimethyl-N-tetradecyltetradecan-1-aminium bromide, N-hexadecyl-N,N-dimethylhexadecan-1-aminium bromide (DC-1-16), 2-[bis{2-(tetradecanoyloxy)ethyl}amino]-N,N,N-trimethyl-2-oxoethan-1-aminium chloride (DC-6-14), 1,2-di-O-octadecenyl-3-trimethylammonium propane chloride (DOTMA), 1,2-distearoyl-3-trimethylammonium-propane chloride (DSTAP) and 1,2-dioleoyl-3-dimethylammonium-propane were selected, and the effect of phospholipids in liposomal formulations containing each cationic lipid on gene-knockdown was evaluated. A total of 30 types of cationic liposomes composed of each cationic lipid with phosphatidylethanolamine containing unsaturated or saturated diacyl chains (C14, C16 or C18) were prepared. Regardless of the type of cationic lipid, the inclusion of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in the liposomal formulations resulted in injectable size of siRNA lipoplexes after mixing of siRNA and cationic liposomes. Transfection of their lipoplexes with luciferase (Luc) siRNA into human breast cancer MCF-7-Luc cells stably expressing Luc led to a strong knockdown of Luc. Furthermore, the systemic injection of siRNA lipoplexes composed of DC-1-16, DC-6-14, DOTMA or DSTAP with DOPE resulted in siRNA accumulation in the lungs. Significant gene-knockdown was observed in the lungs of mice following the systemic injection of siRNA lipoplexes containing DC-1-16 and DOPE. Cationic liposomes composed of DC-1-16 and DOPE serve as potential carriers for in vitro and in vivo siRNA transfection.

The cost-effectiveness of lanthanum carbonate in the treatment of hyperphosphatemia in patients with end-stage renal disease.

OBJECTIVE: To assess the cost-effectiveness of lanthanum carbonate (LC) as a second-line therapy for hyperphosphatemia in end-stage renal disease (ESRD) patients not achieving target phosphorus levels. METHODS: A cohort of ESRD patients not adequately maintained on calcium carbonate (CC) and three subgroups of patients with baseline phosphorus levels of 5.6 to 6.5 mg/dl, 6.6 to 7.8 mg/dl, and more than 7.9 mg/dl were modeled. The following policy options were considered: continued CC (Policy 1); LC trial-if successful continue LC, if unsuccessful switch to CC (Policy 2). The survival benefit of using second-line LC to improve phosphorus control has been extrapolated from the relationship between hyperphosphatemia and mortality. Lifetime UK National Health Service drug and monitoring costs, expected survival, and quality-adjusted life-years (QALYs) were examined (discounting at 3.5% per annum). RESULTS: Policy 2 had a cost-effectiveness ratio (cost/QALY) of pound25,033 relative to Policy 1. The results show it is particularly cost-effective to treat patients with phosphorus levels above 6.6 mg/dl. The outcomes did not vary significantly during the one-way sensitivity analysis carried out on important model parameters and assumptions except when the utility value for ESRD was decreased by more than 30%. CONCLUSIONS: Applying a cost-effectiveness threshold of pound30,000 per QALY, the model shows it is cost-effective to follow current treatment guidelines and treat all patients who are not adequately maintained on CC (serum phosphorus above 5.6 mg/dl) with second-line LC. This is particularly the case for patients with serum phosphorus above 6.6 mg/dl. Our estimates are probably conservative as the possible compliance difference in favor of LC and the reduced number of hypercalcemic events with LC relative to CC was not considered.