In vitro stability and content release properties of phosphatidylglyceroglycerol containing thermosensitive liposomes.

Recently, we reported that 1,2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPGOG) prolongs the circulation time of thermosensitive liposomes (TSL). Since the only TSL formulation in clinical trials applies DSPE-PEG2000 and lysophosphatidylcholine (P-lyso-PC), the objective of this study was to compare the influence of these lipids with DPPGOG on in vitro stability and heat-induced drug release properties of TSL. The content release rate was significantly increased by incorporating DPPGOG or P-lyso-PC in TSL formulations. DPPC/DSPC/DPPGOG 50:20:30 (m/m) and DPPC/P-lyso-PC/DSPE-PEG2000 90:10:4 (m/m) did not differ significantly in their release rate of carboxyfluorescein with >70% being released within the first 10s at their phase transition temperature. Furthermore, DPPC/DSPC/DPPGOG showed an improved stability at 37 degrees C in serum compared to the PEGylated TSL. The in vitro properties of DPPGOG-containing TSL remained unchanged when encapsulating doxorubicin instead of carboxyfluorescein. The TSL retained 89.1+/-4.0% of doxorubicin over 3 h at 37 degrees C in the presence of serum. The drug was almost completely released within 120s at 42 degrees C. In conclusion, DPPGOG improves the in vitro properties in TSL formulations compared to DSPE-PEG2000, since it not only increases the in vivo half-life, it even increases the content release rate without negative effect on TSL stability at 37 degrees C which has been seen for DSPE-PEG2000/P-lyso-PC containing TSL

Non-ionic Gd-based MRI contrast agents are optimal for encapsulation into phosphatidyldiglycerol-based thermosensitive liposomes.

Thermosensitive liposomes (TSL) with encapsulated magnetic resonance imaging (MRI) longitudinal relaxation time (T-1) contrast agents (CAs) have been proposed for MRI assisted interventional thermotherapy in solid tumors. Here the feasibility of 6 clinically approved CAs (Gd-DTPA, Gd-BOPTA, Gd-DOTA, Gd-BT-DO3A, Gd-DTPA-BMA, and Gd-HP-DO3A) for formulation into TSL was investigated. CAs were passively encapsulated with 323 mOs kg(-1) into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine/1,2-distearoyl-sn-glycero-3-phosphocholine/1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol 50/20/30 (mol/mol) TSL (DPPG(2)-TSL) to obtain stable formulations. T-1 relaxivity (r(1)) and diffusive permeability to water (P-d) across the membrane were determined. Shelf life at 4 degrees C was investigated by determining lysolipid content up to 10 weeks after preparation. All preparations were monodispersed with comparable small vesicle sizes (similar to 135 nm). Neither zeta potential nor phase transition temperature (T-m) was affected by the CA. The formulations showed an increase in r1 in the temperature range between 38 and 44 degrees C. This correlated with the phase transition

Atrial fibrillation therapy in patients with a CRT defibrillator with wireless telemetry

BACKGROUND: Atrial fibrillation (AF) is a major cause of morbidity and mortality, especially in patients with congestive heart failure. OBJECTIVES: The purposes of this international, prospective multicenter study were to evaluate the efficacy of atrial shock therapy in patients with a cardiac resynchronization therapy defibrillator (CRT-D) and to evaluate the safety of the new CRT-D. The effectiveness of a new wireless telemetry system was also evaluated. METHODS: A total of 282 patients, without permanent AF, who had indications for a CRT-D were included. Atrial shock therapy was tested on both spontaneous and induced AF episodes. The effectiveness of the Medtronic wireless telemetry system (Conexus; Medtronic Inc., Minneapolis, MN, USA) was also tested. Secondary endpoints included the heart failure Clinical Composite Response, system performance evaluation, and adverse event summary. RESULTS: Atrial shock therapy was successful in 168 of 171 episodes (98.2%). Of these, 138 episodes were induced and 33 were spontaneous. Successful cardioversion occurred in 137 of the 138 induced-AF episodes (86.1% with 12 joule (J), 13.1% with 24 J, and 0.7% with 35 J). During the first 3 months of implant, there were 43 system-related complications in 37 subjects out of 278 subjects. There were 1,999 Conexus telemetry uses recorded during this study. This includes 282 uses during the implant procedure. There were no cases of complete loss of telemetry or any adverse events reported using this system. CONCLUSION: We achieved an atrial shock efficacy of 98.2% in patients who met standard CRT-D indications. The wireless telemetry performed well with no reported unanticipated adverse device effect

Atrial fibrillation therapy in patients with a CRT defibrillator with wireless telemetry.

BACKGROUND: Atrial fibrillation (AF) is a major cause of morbidity and mortality, especially in patients with congestive heart failure. OBJECTIVES: The purposes of this international, prospective multicenter study were to evaluate the efficacy of atrial shock therapy in patients with a cardiac resynchronization therapy defibrillator (CRT-D) and to evaluate the safety of the new CRT-D. The effectiveness of a new wireless telemetry system was also evaluated. METHODS: A total of 282 patients, without permanent AF, who had indications for a CRT-D were included. Atrial shock therapy was tested on both spontaneous and induced AF episodes. The effectiveness of the Medtronic wireless telemetry system (Conexus; Medtronic Inc., Minneapolis, MN, USA) was also tested. Secondary endpoints included the heart failure Clinical Composite Response, system performance evaluation, and adverse event summary. RESULTS: Atrial shock therapy was successful in 168 of 171 episodes (98.2%). Of these, 138 episodes were induced and 33 were spontaneous. Successful cardioversion occurred in 137 of the 138 induced-AF episodes (86.1% with 12 joule (J), 13.1% with 24 J, and 0.7% with 35 J). During the first 3 months of implant, there were 43 system-related complications in 37 subjects out of 278 subjects. There were 1,999 Conexus telemetry uses recorded during this study. This includes 282 uses during the implant procedure. There were no cases of complete loss of telemetry or any adverse events reported using this system. CONCLUSION: We achieved an atrial shock efficacy of 98.2% in patients who met standard CRT-D indications. The wireless telemetry performed well with no reported unanticipated adverse device effect

Size of thermosensitive liposomes influences content release.

Thermosensitive liposomes (TSL) in combination with regional hyperthermia represent a powerful tool for tumor specific drug delivery. The objective of this study was to investigate the influence of vesicle size on the biophysical properties of TSL TSL were composed of DPPC/DSPC/1,2-dipalmitoyl-sn-glycero-3-phosphoglyceroglycerol (DPPG(2)) 50:20:30 (mol/mol) (DPPG(2)-TSL) and DPPC/P-Lyso-PC/DSPE-PEG2000 90:10:4 (mol/mol) (PEG/Lyso-TSL) with encapsulated fluorescent dye carboxyfluorescein, anticancer drug doxorubicin or magnetic resonance contrast agent gadodiamide. Extrusion was performed with polycarbonate filters of distinct pore size to obtain TSL with different diameters (50 to 200 nm). Phase transition temperature (T-m) of the bilayer forming phospholipids was not influenced by vesicle size in the tested range. However, vesicle size had a major impact on in vitro content release properties of TSL in the investigated temperature range between 30 and 45 degrees C. Generally, vesicle size was inversely related to content release properties with increased content release rates for decreased vesicle sizes. Size dependency of content release properties varied between all tested formulations and DPPG(2)-TSL were generally less affected by size changes in the range of 100 to 150 nm as compared to PEG/Lyso-TSL. Independent from gadodiamide release, vesicle size influenced the signal intensity of DPPG(2)-TSL also at temperatures below T-m due to improved water exchange for smaller vesicles. Liposomes around 100 nm in size are routinely used in vivo, hence a quality control for TSL preparations is required prior to use. Even small changes in size or a wider size distribution might affect stability and release properties and thus yield in decreased efficacy or unwanted side effects of drug loaded TSL during in vivo applications