Dabigatran for thromboprophylaxis after robotic assisted laparoscopic prostatectomy: retrospective analysis of safety profile and effect on blood coagulation.

OBJECTIVE: The aims of this study were to analyse the efficacy and safety of orally administered dabigatran in prostate cancer patients who have undergone robotic assisted laparoscopic prostatectomy (RALP) and to analyse the effects of RALP on selected markers of coagulation activity. MATERIAL AND METHODS: Data were collected prospectively on the first 400 patients who underwent RALP at Helsinki University Central Hospital between 2009 and 2011. As thromboprophylaxis, intermittent compression devices were used in association with anaesthesia. Dalteparin sodium at 2500 IU was administered on the preoperative evening and at 5000 IU daily until discharge. Then patients were prescribed 220 mg dabigatran etexilate once daily for the next 15 days. Bleeding and thromboembolic complications were recorded. A set of routine coagulation analyses was undertaken in 61 patients preoperatively, on the first, second and eight postoperative days. RESULTS: One patient with obesity- and cancer-related risk factors developed venous thromboembolism 18 days after the operation. Nine patients (2.3%) had postoperative blood loss or bleeds, eight patients required blood transfusions and three underwent reoperation before dabigatran administration. Increased fibrinogen, factor VIII, d-dimer and thrombocytosis were observed postoperatively, reflecting coagulation activity. CONCLUSIONS: RALP activates coagulation, and thromboprophylaxis for high-risk patients even after minimally invasive surgery may be beneficial. Orally administered dabigatran after discharge from hospital appears safe for venous thromboembolism prophylaxis after RALP.

Influence of the spacer of cationic gemini amphiphiles on the hydration of lipoplexes.

The impact of the length of gemini surfactant spacer on complexation and condensation of calf thymus DNA by cationic mixed phospholipid/gemini liposomes was investigated by monitoring the conformational changes of DNA by circular dichroism and the lipid hydration level by the emission characteristics of the fluorescent probe laurdan included in the lipid bilayer. The length of the spacer was shown to influence, on one hand, the hydration level and the organization of the corresponding liposomes and, on the other, the variation of lipid hydration level and the DNA conformation upon complexation. In fact, in correspondence with the longest spacer we observed more hydrated liposomes, probably organized in domains, a higher extent of dehydration promoted by the addition of DNA, and a minor extent of DNA conformational change. The physicochemical features of lipoplexes were shown to depend on the [cationic headgroup]/[DNA single base] ratio.

Counterion-controlled transition of a cationic gemini from submicroscopic to giant vesicles.

While much is known about the self-assembly of lipids on nanoscale, our understanding of their biologically relevant mesoscale organization remains incomplete. Here, we show for a cationic gemini lipid a sharp and reversible transition from small vesicles with an average diameter of approximately 40 nm to giant vesicles (GVs) with an average diameter of approximately 11 microm. This transition is dependent on proper [NaCl] and specific temperature. Below this transition and in the vicinity of the air/water interface, a series of mesoscale morphological transitions was observed, revealing complex structures resembling biological membranes. On the basis of microscopy experiments, a tentative [NaCl] versus temperature shape/size phase diagram was constructed. To explain this unprecedented transition, we propose a novel mechanism whereby a specific interaction of Cl(-) counterion with the cationic gemini surfactant initiates the formation of a commensurate solute counterion lattice with low spontaneous curvature. In keeping with the high bending rigidity of NaCl crystal, this tightly associated ionic lattice enslaves membrane curvature and the mesoscale 3-D organization of this lipid.

Impact of reductive cleavage of an intramolecular disulfide bond containing cationic gemini surfactant in monolayers and bilayers.

The properties of a novel disulfide-bond-containing gemini surfactant bis[N,N-dimethyl-N-hexadecyl-N-(2-mercaptoethyl)ammonium bromide] disulfide (DSP) were studied using a Langmuir balance, supported monolayers, differential scanning calorimetry, giant vesicles, and LUVs. In 150 mM NaCl the cmc for DSP was 7.5 microM whereas that of the monomer N,N-dimethyl-N-hexadecyl-N-(2-mercaptoethyl)ammonium bromide (MSP) was 12.1 microM. Both surfactants exhibited single endotherms upon DSC, with peak temperatures Tm at 21.7 and 20.1 degrees C for DSP and MSP, respectively. The endotherm for MSP was significantly broader indicating less cooperative melting. Both in monolayers and in vesicles reductive cleavage of the disulfide bond of DSP could be obtained by glutathione (GSH). For Langmuir films of DSP the addition of GSH into the subphase led to a decrease in surface pressure pi as well as surface dipole potential psi. Although the cleavage by GSH was significantly slower in the presence of a charge saturating concentration of DNA, it did not prevent the reaction. The resulting monomers detached from supported monolayers, leading to loss of affinity of the surface for DNA. Disruption of giant vesicles containing DSP within approximately 30 s following a local injection of GSH was observed, revealing membrane destabilization.

Cationic lipid membranes-specific interactions with counter-ions.

Lipids bearing net electric charges in their hydrophilic headgroups are ubiquitous in biological membranes. Recently, the interest in cationic lipids has surged because of their potential as non-viral transfection vectors. In order to utilize cationic lipids in transfer of nucleic acids and to elucidate the role of charged lipids in cellular membranes in general, their complex interactions within the membrane and with the molecules in the surrounding media need to be thoroughly characterized. Yet, even interactions between monovalent counter-ions and charged lipids are inadequately understood. We studied the interactions of the cationic gemini surfactant (2R,3R)-2,3-dimethoxy-1,4- bis(N-hexadecyl-N,N-dimethylammonium)butane dibromide (RR-1) with chloride, bromide, fluoride, and iodide as counter-ions by differential scanning calorimetry and Langmuir balance. Chloride interacts avidly with RR-1, efficiently condensing the monolayer, decreasing the collapse pressure, and elevating the main transition temperature. With bromide and iodide clearly different behaviour was observed, indicating specific interactions between RR-1 and these counter-ions. Moreover, with fluoride as a counter-ion and in pure water identical results were obtained, demonstrating inefficient electrostatic screening of the headgroups of RR-1 and suggesting fluoride being depleted on the surface of RR-1 membranes.