Lipophilic platinum complexes entrapped in liposomes: improved stability and preserved antitumor activity with complexes containing linear alkyl carboxylato leaving groups

Lipophilic diaminocyclohexane (DACH) platinum complexes have shown significant promise in preclinical studies. One of these compounds,cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum(II) (NDDP), which contains two branched leaving groups of 10 carbons, showed a favorable toxicity profile in a liposomal formulation in early clinical trials. However, like many other DACH platinum compounds with branched leaving groups, it is unstable within the liposomes, thus preventing its widespread clinical evaluation. We studied the effect of the configuration of leaving groups on intraliposomal complex stability by studying a series of DACH platinum complexes containing linear alkyl carboxylato leaving groups of 5–18 carbons. The entrapment efficiency was greater than 90% for all liposomal preparations of the complexes and was independent of lipid composition and length of the leaving group. The drug leakage from the liposomes was minimal, but was directly related to the length of the leaving group. Intraliposomal stability was inversely related to the length of the leaving group and the content of DMPG (dimyristoyl phosphatidylglycerol) in the liposomes. The effect of length of leaving group on intraliposomal stability was minimal in compounds with leaving groups smaller than 10 carbons, but very pronounced in compounds with longer leaving groups. Stable liposomal formulations of selected compounds with leaving groups of 6 and 10 carbons had significant in vivo antitumor activity against both L1210/S and L1210/PDD leukemias. The results indicate (1) that compounds with linear leaving groups are much more stable within DMPG-containing liposomes than compounds with branched leaving groups and (2) that DMPG is required for in vivo antitumor activity. Stable and active liposomal formulations of selected compounds with linear leaving groups have been identified. These formulations are candidates for clinical development.Abbreviations DMPC dimyristoyl phosphatidylcholine - DMPG dimyristoyl phosphatidylglycerol - L-NDDP liposomalcis-bis-neodecanoato-trans-1,2-diaminocyclohexaneplatinum(II) The work reported in this paper was supported in part by NIH grants CA 41581, 45423, 50270, and 58342     

The epidemiology of back injuries in nurses at a large Canadian tertiary care hospital: implications for prevention

Two years of prospective data on 416 back injuries were gatheredat a 1100-bed acute and tertiary care hospital to assist targetprevention efforts. The rate of injury among 1645 nurses wasfound to be highest for those working on orthopaedic, medicine,neurology, spinal and surgery wards, indicating priorities forprevention. In fact, 51% of the orthopaedic nurses sustained at least oneback injury during the two-year period. Gender did not significantlyaffect the risk for back injury; however, injuries were slightlymore common in nurses with less seniority and younger nurseswere found to be at significantly increased risk of back injury.Almost 63% of the back injuries which occurred in nurses working8 h shifts on the high-risk wards occurred during the firsttwo hours of the shift. Lifting and transferring patients withassistance were the two most common mechanisms for back injury(22.6% and 23.3%, respectively). In total, injured nurses attributed52.3% of their injuries to inadequate training; inadequate staffingwas given as the primary reason for 13.8% of the injuries. Theresults suggest that training in the indications for and useof mechanical devices for lifting/transferring patients requiresintensification, and a ‘warm-up’ period should alsobe considered in the face of injuries occurring early in theshift if work activities cannot be evenly planned.     

10-propargyl-10-deazaaminopterin: an antifolate with activity in patients with previously treated non-small cell lung cancer.

PURPOSE: 10-propargyl-10-deazaaminopterin (PDX) has superior antitumor efficacy in mouse xenograft models, likely attributable to increased uptake by the RFC-1 folate transporter and greater intracellular polyglutamylation. In a previous Phase I trial, stomatitis was the dose-limiting (and only clinically significant) toxicity of PDX. The recommended Phase II dose was 150 mg/m(2) i.v. every 2 weeks. Responses observed in patients with non-small cell lung cancer (NSCLC) in the Phase I trial prompted this Phase II trial. EXPERIMENTAL DESIGN: Patients had stage IIIB or IV NSCLC and either no previous chemotherapy or progression after initial response or stable disease to one previous chemotherapy regimen. Initially, PDX was administered at a dose of 150 mg/m(2) every 2 weeks. However, to decrease the frequency of stomatitis, the last 10 patients were treated at a dose of 135 mg/m(2). We planned to correlate PDX effects with folate and homocysteine levels and the expression of genes associated with folate transport and polyglutamylation. RESULTS: Thirty-nine patients were enrolled, 38 of whom were evaluable for response. Four patients had confirmed, major objective responses (10% based on intent to treat, 95% confidence interval 3-25) lasting 4, 9, 12, and 15 months. Twelve patients (31%) had stable disease. The median survival was 13.5 months. The predicted 1- and 2-year survival rates were 56 and 36%, respectively. Two patients (5%) suffered grade 4 stomatitis, and 6 (15%) had grade 3. No clinically significant myelosuppression occurred. No correlation between homocysteine or serum folate levels and severity of stomatitis was observed. Area under the curve (calculated using a limited sampling model) correlated with mucositis grade. A trend was noted between folate transporter expression and treatment effect. CONCLUSIONS: The broad applicability of this new antifolate with limited toxicity and proven efficacy in NSCLC encourage further development of this compound. Several trials are now underway combining PDX with other chemotherapeutic agents and testing its efficacy in other cancers.