No description available.

The kinetics and mechanism of accumulation for liposomal ciprofloxacin (Lipo-CPFX) into the rat alveolar macrophage NR8383 cells were studied in vitro, in comparison to unformulated ciprofloxacin (CPFX). Upon incubation with CPFX or Lipo-CPFX, cellular drug accumulation was determined from the cell lysates or efflux was from the extracellular media by fluorescence-HPLC. The accumulation for Lipo-CPFX reached the asymptotic values at ≥ 2 hours, which was a result of uptake and efflux. The uptake appeared to be due to liposomes, mediated via cellular energy-independent mechanism like lipid fusion. In contrast, the efflux appeared to be due to ciprofloxacin, partly cellular energy-dependent, and involve probenecid-sensitive multidrug resistance proteins (MRPs). Overall, Lipo-CPFX enabled greater drug accumulation into the NR8383 cells than CPFX. This logically suggests a greater potential to treat respiratory infections especially caused by bacteria resistant to phagocytic killing.

Research suggests biological sex differences may affect pain perception, however the difference in analgesic tolerance between male and females not been extensively studied. Therefore, here we studied the response of male and female Sprague-Dawley rats to prolonged duration local anesthetics; including conventional amino-amide anesthetics (bupivacaine), site 1 sodium channel blockers (tetrodotoxin) and a prolonged duration liposomal formulation (Exparel). This study examined the incidence and duration of sensory and motor blockade; systemic side effects, as well as local neurotoxicity and myotoxicity in both male and female rodents in an in vivo model of sciatic nerve blockade. The data collected does not indicate a sexual dimorphism among the agents studied. / 2019-07-03T00:00:00Z

What is known and objective: Liposomal amphotericin B (L-AmB) is the cornerstone of many serious invasive fungal infections. Despite lower frequencies of commonly reported adverse events in clinical trials compared to conventional formulations, post-marketing complications continue to mount. Case description: We present a case of chest pain following the initial dose of L-AmB for cryptococcal meningitis. Electrocardiogram demonstrated no acute electrocardiogram findings. Upon rechallenge, the chest pain worsened was subsequently accompanied by ST-segment elevation. Emergent coronary angiography found no acute findings. What is new and conclusion: Providers should be aware of cardiac complications with L-AmB, including non-occlusive ST-segment elevation.

No description available.

No description available.

The goal of this research is to study how the cholesterol content in liposomal formulations affects the anticancer activity (e.g., cell growth suppression) of combretastatin A4 phosphate (CA4P). CA4P is a powerful antivascular agent currently under clinical trials for treating solid tumors. Liposomal CA4P has several advantages over free CA4P, including the reduced toxicities and the increased overall drug efficacy. In this thesis work, I have demonstrated that the proliferation of breast cancer MCF-7 cells varies with the cholesterol mole fraction in the formulation of liposomal CA4P in a biphasic manner, displaying a local minimum at the critical sterol mole fractions (Cr) for maximal superlattice formation. Cell proliferation was monitored using a fluorescence-based assay. Since cholesterol content determines membrane lateral organization, my results imply that membrane lateral organization plays an important role in regulating the anti-cancer activity of liposomal CA4P. This finding provides a new concept in the rational design of liposomal anti-cancer drugs. More than 20 anticancer drug formulations are in the market or under clinical trials. Most of them include cholesterol as a major component. My present study indicates that cholesterol is not just serving as a vesicle stabilizing agent, but also modulates the activity of liposomal drugs. The principle learned from CA4P can be extended to other liposomal anti-cancer drugs. This study is also significant from the membrane biophysics point of view. The data provide additional support for the sterol superlattice model and illustrate that the concept of sterol superlattice can be applied to biotechnology development. / Biochemistry

No description available.

Liposomal ciprofloxacin (Lipo-CPFX) is being developed for inhalation, with a goal of sustaining the therapeutic activity, compared to unformulated ciprofloxacin (CPFX). However, the kinetics and mechanism of its sustained local lung retention and pharmacological activity are yet to be fully characterized. This project hypothesized that Lipo-CPFX enables slower and sustained lung epithelial transport and uptake, compared to CPFX, thereby producing prolonged local pharmacological actions. The human bronchial epithelial Calu-3 cells were used as monolayers to characterize the kinetics and mechanism of transport and/or uptake, and to assess the effects of such slow kinetics for Lipo-CPFX on its inhibition against lipopolysaccharide (LPS)-induced proinflammatory IL-8 release. The transport fluxes for Lipo-CPFX across the highly restricted Calu-3 cell monolayers was transepithelial electrical resistance-independent, which suggested predominant transcellular transport. Compared to CPFX, Lipo-CPFX showed 6-18 times slower transport, while the flux was increased with increasing concentration proportionally without saturation. Its unaltered transport by cellular energy depletion, transport inhibition by a reduced temperature (4 oC) and endocytosis/lipid fusion inhibitors, filipin and LysoPC, and increased transport by excess empty liposomes collectively suggested cell energy-independent, lipid bilayer fusion mechanisms for the Lipo-CPFX transport across the Calu-3 cells. Likewise, Lipo-CPFX showed 2-4 fold lower cellular uptake than CPFX, proportional to concentration. Lipo-CPFX exhibited significant inhibitory activities at ≥ 0.01 mg/mL on LPS-induced IL-8 release from the Calu-3 cells, which was equipotent to CPFX. Upon 24 h pre-incubation, Lipo-CPFX caused 36.9 and 47.5 % inhibition at 0.01 and 0.05 mg/mL, respectively, while CPFX failed to do so. However, the effect was negated upon repeated wash of the mucosal cell surface, speculating the importance of cell membrane-associated drug/formulation on the inhibitory activities for Lipo-CPFX. Upon 24 h transport, Lipo-CPFX retained 79.0 % of the 4 µg dose on the mucosal cell surface, which was 1.9-times greater than 40.7 % for CPFX. As a result, when LPS was added at 24 h of the transport, Lipo-CPFX was still capable of causing 60.1 % inhibition, as its sustained local anti-inflammatory activity; CPFX however also exhibited equipotent inhibition, by virtue of comparable cellular drug uptake/transport.

Σκοπός της παρούσας μελέτης είναι η εκτίμηση της συσχέτισης ανάμεσα στην κυτταροτοξικότητα και την μείωση της ακεραιότητας λιποσωμικών μεμβρανών που προκαλούνται από έκδοχα. Εάν υπάρχει, μπορεί να προταθεί η χρήση των λιποσωμάτων ως in vitro τεχνική για την εκτίμηση της κυτταρο-τοξικότητας εκδόχων. Μελετήθηκε η κυτταροτοξικότητα σε 4 κυτταρικές σειρές ( A549, PC3, MDA-MB, MCF-7 ) και η επίδραση στην ακεραιότητα λιποσωμάτων των παρακάτω εκδόχων που χρησιμοποιούνται σε σκευάσματα τοπικής χορήγησης: Labrafac Hydro, Labrafac CC, Transcutol, Cremofor, DL- Lactic acid και Capmul σε συγκεντρώσεις 1% και 10% (v/v) Για την μέτρηση της κυτταροτοξικότητας (στις 6 και 24 ώρες επώασης) χρησιμοποιήθηκε η μέθοδος του MTT (Thiazolyl Blue Tetrazolium Bromide) ενώ για την εκτίμηση της μεμβρανικής ακεραιότητας λιποσωμάτων [χρησιμοποιήθηκαν MLV (πολυστοιβαδιακά) και SUV (μικρά μονοστοιβαδιακά) λιποσώματα, με διάφορες λιπιδικές συστάσεις [PC (φωσφατιδυλοχολίνη), HPC (υδρογονωμένη φωσφατιδυλοχολίνη) και DSPC( διστεαρουλο φωσφατιδυλοχολίνη) με ή χωρίς Chol (χοληστερόλη)] μετρήθηκε η διαφυγή της εγκλωβισμένης στα λιποσώματα καλσεΐνης. Τα πειραματικά αποτελέσματα, έδειξαν ότι η επιβίωση-πολλαπλασιασμός των κυττάρων επηρεάζεται λιγότερο ή περισσότερο από τα έκδοχα: Labrafac Hydro (1% και 10%), Transcutol (10%), Cremofor (1% και 10%), Capmul (1% και 10%) και Lactic acid (1% και 10%) ενώ πολύ λιγότερο από τα έκδοχα Labrafac CC(1% και 10%) καθώς και από το Transcutol 1%. Σε ότι αναφορά την ακεραιότητα των λιποσωμάτων ( έως 24 ώρες επώασης) τα έκδοχα Cremofor, Labrafac, Capmul, Lactic acid και Labrafac hydro επηρεάζουν όλες τις λιπιδικές συστάσεις και τύπους λιποσωμάτων που μελετήθηκαν, ενώ τα έκδοχα Transcutol και Labrafac CC επηρεάζουν πολύ λιγότερο τις πιο ρευστές λιπιδικές μεμβράνες, και σχεδόν καθόλου τις σκληρές. Φαίνεται ότι είναι πιθανή η συσχέτιση των δύο σειρών αποτελεσμάτων. / The aim of this thesis is to study if a correlation may exist between the cytotoxicity of excipients and their effect on the integrity of liposomal membranes. If such a correlation exists perhaps the effect on liposome integrity may be used as an in vitro system to predict excipient cytotoxicity. Methods: The cell toxicity in four cell lines ( A549, PC3, MDA-MB, MCF-7 ) and the influence on liposome integrity of several commonly used excipients was studied. The following excipients which are used in topical formulations were studied: Labrafac Hydro, Labrafac CC, Transcutol, Cremofor, DL- Lactic acid and Capmul at concentrations of 1% and 10% (v/v). For the measurement of cell toxicity (6 and 24 hours of incubation) the MTT-assay (Thiazolyl Blue Tetrazolium Bromide) was used, whereas for the evaluation of the liposome membrane integrity MLV (MultiLaminar Vesicles) and SUV (Small Unilaminar Vesicles) liposomes with different lipid compositions [PC (phosphatidyl choline), HPC (hydrogenated phospatidyl choline) and DSPC (distearoylphosphatidylcholine) with or without Chol (cholesterol)] were prepared and the escape of the calcein encapsulated in the liposomes was measured at different time points during their incubation in presence of the excipients. Results: The experimental results showed that the cell survival-proliferation is influenced more or less by the following excipients (in increasing effect order): Labrafac Hydro (1% and 10%), Transcutol (10%), Cremofor (1% and 10%), Capmul (1% and 10%) and Lactic acid (1% and 10%) while the effect of Labrafac CC(1% and 10%) as well as Transcutol 1%, is minimal. As far as the integrity of the liposomes (up to 24 hours of incubation) is concerned, the excipients Cremofor, Labrafac, Capmul, Lactic acid and Labrafac hydro affect all the lipidic compositions and types of liposomes that were studied, whereas the excipients Transcutol and Labrafac CC influenced only minimally the more liquid membranes and had no effect on the more rigid lipid compositions. It seems that a correlation between the two series of results is possible.