Itraconazole (ITZ) is an antifungal agent used clinically to treat mycotic infections. However, its therapeutic effects are limited by low solubility in aqueous media. Liposome-based delivery systems (LDS) have been proposed as a delivery mechanism for ITZ to alleviate this problem. Furthermore, PEGylation, the inclusion in the formulation of a protective "stealth sheath" of poly(ethylene glycol) around carrier particles, is widely used to increase circulation time in the bloodstream and hence efficacy. Together, these themes highlight the importance of mechanistic and structural understanding of ITZ incorporation into liposomes both with and without PEGylation because it can provide a potential foundation for the rational design of LDS-based systems for delivery of ITZ, using alternate protective polymers or formulations. Here we have combined atomistic simulations, cryo-TEM, Langmuir film balance, and fluorescence quenching experiments to explore how ITZ interacts with both pristine and PEGylated liposomes. We found that the drug can be incorporated into conventional and PEGylated liposomes for drug concentrations up to 15 mol % without phase separation. We observed that, in addition to its protective properties, PEGylation significantly increases the stability of liposomes that host ITZ. In a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer without PEGylation, ITZ was found to reside inside the lipid bilayer between the glycerol and the double-bond regions of POPC, adopting a largely parallel orientation along the membrane surface. In a PEGylated liposome, ITZ partitions mainly to the PEG layer. The results provide a solid basis for further development of liposome-based delivery systems.

Cholesterol plays a crucial role in modulating the physicochemical properties of biomembranes, both increasing mechanical strength and decreasing permeability. Cholesterol is also a common component of vesicle-based delivery systems, including liposome-based drug delivery systems (LDSs). However, its effect on the partitioning of drug molecules to lipid membranes is very poorly recognized. Herein, we performed a combined experimental/computational study of the potential for the use of the LDS formulation for the delivery of the antifungal drug itraconazole (ITZ). We consider the addition of cholesterol to the lipid membrane. Since ITZ is only weakly soluble in water, its bioavailability is limited. Use of an LDS has thus been proposed. We studied lipid membranes composed of cholesterol, 1-palmitoyl-2-oleoyl- sn -glycerol-3-phosphocholine (POPC), and ITZ using a combination of computational molecular dynamics (MD) simulations of lipid bilayers and Brewster angle microscopy (BAM) experiments of monolayers. Both experimental and computational results show separation of cholesterol and ITZ. Cholesterol has a strong preference to orient parallel to the bilayer normal. However, ITZ, a long and relatively rigid molecule with weakly hydrophilic groups along the backbone, predominantly locates below the interface between the hydrocarbon chain region and the polar region of the membrane, with its backbone oriented parallel to the membrane surface; the orthogonal orientation in the membrane could be the cause of the observed separation. In addition, fluorescence measurements demonstrated that the affinity of ITZ for the lipid membrane is decreased by the presence of cholesterol, which is thus probably not a suitable formulation component of an LDS designed for ITZ delivery.

Introduction:Recent studies indicate that the therapeutic effects of endocardial cell transplantation in chronic heart failure (iCHF) may be lost with an increasing number of injections.Aim: To evaluate global and regional contractility and diastolic function of the left ventricle of patients with advanced iCHF who received endomyocardial cardiopoietic mesenchymal stem cells (MCSs) or sham procedures.Material and methods: The study included patients (mean age: 60.8 ±7.1 years) with iCHF (left ventricular ejection fraction (LVEF) < 35%) and a history of hospitalization for heart failure within 12 months before the screening despite optimal medical therapy. The patients underwent transmyocardial MCS transplantation (n = 5) or a sham procedure (n = 5). The wall motion score index (WMSI), LVEF, transmitral E-velocity, E-wave deceleration time, E/A-ratio, and E/e′-mean were measured with two-dimensional echocardiography on days 1 and 30.Results: A total of 170 segments were analyzed, including 48 targeted segments where 92 injections of 0.5 ml of MCS were performed. In the MSC group, a decrease in regional contractility was observed in 30.6% and 18.9% of the segments on days 1 and 30, respectively. This was accompanied by an increase in WMSI by 0.32 ±0.06 and 0.19 ±0.18 (day 1, p = 0.02, day 30, p = 0.03) and a non-significant reduction in LVEF on day 1 (3.15 ±1.23%, p = 0.065).Conclusions: We did not observe differences in the parameters of diastolic function during the follow-up in both groups.

Right ventricular outflow tract obstruction is a narrowing of the way that conducts blood from the right ventricle to the pulmonary artery. Left ventricular outflow tract obstruction is a stenosis of the path that leads blood from the left ventricle to the aorta. Combination of right and left ventricular outflow tract obstruction is a very rare finding. We report a case of a 67-year-old male with asymptomatic biventricular outflow tract obstruction. We discuss the clinical presentation, diagnostic procedures, treatment opportunities for the patient based on review of literature and actual recommendations. JRCD 2017; 3 (2): 50-53