- The Viscoelastic Properties of the Fungal Cell Wall Allow Traffic of AmBisome as Intact Liposome Vesicles. [Journal Article]
- MBIOMBio 2018 Feb 06; 9(1)
- The fungal cell wall is a critically important structure that represents a permeability barrier and protective shield. We probedCandida albicansandCryptococcus neoformanswith liposomes containing amp...
The fungal cell wall is a critically important structure that represents a permeability barrier and protective shield. We probedCandida albicansandCryptococcus neoformanswith liposomes containing amphotericin B (AmBisome), with or without 15-nm colloidal gold particles. The liposomes have a diameter of 60 to 80 nm, and yet their mode of action requires them to penetrate the fungal cell wall to deliver amphotericin B to the cell membrane, where it binds to ergosterol. Surprisingly, using cryofixation techniques with electron microscopy, we observed that the liposomes remained intact during transit through the cell wall of both yeast species, even though the predicted porosity of the cell wall (pore size, ~5.8 nm) is theoretically too small to allow these liposomes to pass through intact.C. albicansmutants with altered cell wall thickness and composition were similar in both theirin vitroAmBisome susceptibility and the ability of liposomes to penetrate the cell wall. AmBisome exposed to ergosterol-deficientC. albicansfailed to penetrate beyond the mannoprotein-rich outer cell wall layer. Melanization ofC. neoformansand the absence of amphotericin B in the liposomes were also associated with a significant reduction in liposome penetration. Therefore, AmBisome can reach cell membranes intact, implying that fungal cell wall viscoelastic properties are permissive to vesicular structures. The fact that AmBisome can transit through chemically diverse cell wall matrices when these liposomes are larger than the theoretical cell wall porosity suggests that the wall is capable of rapid remodeling, which may also be the mechanism for release of extracellular vesicles.IMPORTANCEAmBisome is a broad-spectrum fungicidal antifungal agent in which the hydrophobic polyene antibiotic amphotericin B is packaged within a 60- to 80-nm liposome. The mode of action involves perturbation of the fungal cell membrane by selectively binding to ergosterol, thereby disrupting membrane function. We report that the AmBisome liposome transits through the cell walls of bothCandida albicansandCryptococcus neoformansintact, despite the fact that the liposome is larger than the theoretical cell wall porosity. This implies that the cell wall has deformable, viscoelastic properties that are permissive to transwall vesicular traffic. These observations help explain the low toxicity of AmBisome, which can deliver its payload directly to the cell membrane without unloading the polyene in the cell wall. In addition, these findings suggest that extracellular vesicles may also be able to pass through the cell wall to deliver soluble and membrane-bound effectors and other molecules to the extracellular space.
- Nanotechnological Strategies for Treatment of Leishmaniasis--A Review. [Journal Article]
- JBJ Biomed Nanotechnol 2017; 13(2):117-33
- The World Health Organization (WHO) estimates that more than one billion people suffer from neglected tropical diseases. Leishmaniasis is a widespread disease, affecting 12 million people around the ...
The World Health Organization (WHO) estimates that more than one billion people suffer from neglected tropical diseases. Leishmaniasis is a widespread disease, affecting 12 million people around the world with about 1–2 million estimated new cases occurring every year. Although pentavalent antimonial drugs are the most frequently prescribed treatments for leishmaniasis, they produce severe side effects, including cardiotoxicity and hepatotoxicity. Other compounds, such as amphotericin B, pentamidine and miltefosine, are second choice drugs, but they also produce side effects that can endanger the patient's life. Nowadays, there are two approaches to develop new therapies: one is the search for new drugs and the other is the optimization of actual drug formulation. Traditional drug discovery takes 10 to 12 years in general and involves high costs; around one billion dollars on average to develop a drug. A possibility to improve leishmaniasis treatment would be the application of nanotechnology-drug delivery systems which can enhance the therapeutic potency of existing drugs by optimizing their adsorption, distribution, metabolism and excretion (ADME) and reducing toxicity. In this review we will discuss examples how nanotechnology-drug delivery systems have been used to improve the therapeutic aspects of existing antileishmanial drugs.
- Occurrence and improvement of renal dysfunction and serum potassium abnormality during administration of liposomal amphotericin B in patients with hematological disorders: A retrospective analysis. [Journal Article]
- DMDiagn Microbiol Infect Dis 2018; 90(2):123-131
- Liposomal amphotericin B (L-AMB) has the potential to cause two major adverse events, renal dysfunction and serum potassium abnormality; however, appropriate clinical management of these events remai...
Liposomal amphotericin B (L-AMB) has the potential to cause two major adverse events, renal dysfunction and serum potassium abnormality; however, appropriate clinical management of these events remains unclear. We retrospectively analyzed data regarding 128 hematology patients who received L-AMB in our institute and examined the association between clinical characteristics and renal dysfunction or serum potassium abnormality. We found that the median weight-normalized dose of L-AMB was 2.69mg/kg and the median administration period was 16days. The overall occurrence rates of renal dysfunction and hypokalemia were 55.7% and 76.6%, respectively. Multivariate analysis revealed that pre-existing renal dysfunction (P=0.017) and concomitant use of nephrotoxic (P<0.0001) or antifungal drugs (P=0.012) were independent risk factors for renal dysfunction. A higher infusion volume did not mitigate the risk of renal dysfunction. Hypokalemia occurred significantly less often in men (P=0.028) and in patients who concomitantly used nephrotoxic drugs (P=0.013). Approximately 40% of the adverse events were improved at 30days after L-AMB termination and there was no significant association between these adverse events improvement and L-AMB dosage or infusion volume. Of note, hyperkalemia was observed in more patients who received allogeneic hematopoietic stem cell transplantation (P=0.0303) and concomitant treatment with nephrotoxic drugs (P=0.0281). These results suggest that imprudent reduction of L-AMB dose or redundant intravenous infusion may have minimal benefit for critical patients with suspected invasive fungal infection.
- Liposomal amphotericin B in travelers with cutaneous and muco-cutaneous leishmaniasis: Not a panacea. [Journal Article]
- PNPLoS Negl Trop Dis 2017; 11(11):e0006094
- CONCLUSIONS: In conditions close to current medical practice, the therapeutic window of L-AmB was narrow in travellers with CL or MCL, with the possible exception of those infected with L. infantum. Strict follow-up is warranted when using L-AmB in patients with mild disease.
- Cost-effectiveness of liposomal amphotericin B in hospitalised patients with mucocutaneous leishmaniasis. [Journal Article]
- TMTrop Med Int Health 2017; 22(12):1569-1578
- CONCLUSIONS: In the treatment of mucocutaneous leishmaniasis, L-AmB is a cost-effective alternative to SbV and AmB-D owing to its higher effectiveness, safety and shorter course.
- Stability and drug release studies of an antimycotic nanomedicine using HPLC, dynamic light scattering and atomic force microscopy. [Journal Article]
- JPJ Pharm Biomed Anal 2018 Jan 30; 148:149-155
- Much attention has been paid to nanoparticle-based drug delivery systems to selectively deliver drugs to target organs and tissues. In this study, AmBisome, an antimycotic nanomedicine containing amp...
Much attention has been paid to nanoparticle-based drug delivery systems to selectively deliver drugs to target organs and tissues. In this study, AmBisome, an antimycotic nanomedicine containing amphotericin B, was chosen as a typical nanomedicine, and analyzed using dynamic light scattering (DLS), an easy method to measure size, and size distribution, atomic force microscopy (AFM) and high-performance liquid chromatography (HPLC). AFM allowed the analysis of shape, besides a detailed size and size distribution. HPLC is useful to quantify the released amount of amphotericin B as it succeeded in a rapid separation of AmBisome and free amphotericin B. The aggregation or collapse of AmBisome and release of amphotericin B occurred upon 75% methanol addition or dilution with buffer around pH 4. Therefore, it is important to analyze nanomedicines using multiple analytical methods, and to integrate them for the quality and quantity evaluation of nanomedicines.
- Efficacy and Safety of Liposomal Amphotericin B for Visceral Leishmaniasis in Children and Adolescents at a Tertiary Care Center in Bihar, India. [Journal Article]
- AJAm J Trop Med Hyg 2017; 97(5):1498-1502
- Liposomal amphotericin B is being used increasingly to reduce the burden of kala-azar from the Indian subcontinent. There are studies which have evaluated efficacy and safety of liposomal amphoterici...
Liposomal amphotericin B is being used increasingly to reduce the burden of kala-azar from the Indian subcontinent. There are studies which have evaluated efficacy and safety of liposomal amphotericin B for visceral leishmaniasis in all age groups. However, the only study that specifically addressed treatment of childhood visceral leishmaniasis did not include all ages or document renal and liver function. We, therefore, felt it was important to reassess the efficacy and safety of single dose liposomal amphotericin B in children and adolescents. A total of 100 parasitologically confirmed visceral leishmaniasis patients aged < 15 years were included in this study. Participants consisted of 65 males and 35 females. All of them had come from the endemic region of Bihar. They were administered one dose intravenous infusion of liposomal amphptericin B at 10 mg/kg body weight. Efficacy was assessed as initial and final cure at 1 and 6 months, respectively, and safety of all participants who were recruited in the study. The initial and final cure rate by per protocol analysis was 100% and 97.9%, respectively. Chills and rigors were the most commonly occurring adverse events (AEs). All the AEs were mild in intensity, and none of the patients experienced any serious AEs. No patients developed nephrotoxicity. Our finding indicates that liposomal amphotericin B at 10 mg/kg body weight is safe and effective in children. Results of our study support the use of single dose liposomal amphotericin B in all age group populations for elimination of kala-azar from the Indian subcontinent.
- The care and feeding of a commercial liposomal product: liposomal amphotericin B (AmBisome®). [Journal Article]
- JLJ Liposome Res 2017; 27(3):173-179
- AmBisome (liposomal amphotericin B) is among the earliest approved liposomal therapeutics, and has been in commercial use since the early 1990s. This review provides examples of non-clinical, regulat...
AmBisome (liposomal amphotericin B) is among the earliest approved liposomal therapeutics, and has been in commercial use since the early 1990s. This review provides examples of non-clinical, regulatory, clinical label expansion, adverse event management, and supply chain control reflecting the real world challenges of a commercial liposomal therapeutic. We review examples of post-approval clinical development in severe lung infections, development of US and European guidance documents around liposomal therapeutics, the creation of a suitable placebo for blinded clinical trials, response to findings of a possible new category of adverse event (what turned out to be pseudohyperphosphatemia), challenges in handling the finished product in a setting with high risk of exposure of the product to temperatures outside of the established label storage conditions, and elements of continuingly increased aseptic processing requirements for manufacturing.
- The direct costs of treating human visceral leishmaniasis in Brazil. [Journal Article]
- RSRev Soc Bras Med Trop 2017 Jul-Aug; 50(4):478-482
- CONCLUSIONS: This analysis indicates the economic feasibility of replacing N-methyl glucamine antimoniate with liposomal amphotericin B, which allows a shorter treatment period with less toxicity compared with other treatments, provided that the purchase value used by the WHO and transferred to the MH is maintained.
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- Mucosal leishmaniasis mimicking T-cell lymphoma in a patient receiving monoclonal antibody against TNFα. [Case Reports]
- PNPLoS Negl Trop Dis 2017; 11(9):e0005807