- Encapsulation of the HSP-90 Chaperone Inhibitor 17-AAG in Stable Liposome Allow Increasing the Therapeutic Index as Assessed, in vitro, on Leishmania (L) amazonensis Amastigotes-Hosted in Mouse CBA Macrophages. [Journal Article]
- FCFront Cell Infect Microbiol 2018; 8:303
- The current long-term treatment for leishmaniasis causes severe side effects and resistance in some cases. An evaluation of the anti-leishmanial potential of an HSP90-inhibitor, 17-allylamino-17-deme...
The current long-term treatment for leishmaniasis causes severe side effects and resistance in some cases. An evaluation of the anti-leishmanial potential of an HSP90-inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), demonstrated its potent effect against Leishmania spp. in vitro and in vivo. We have previously shown that 17-AAG can kill L. (L) amazonensis promastigotes with an IC50 of 65 nM and intracellular amastigote at concentrations as low as 125 nM. As this compound presents low solubility and high toxicity in human clinical trials, we prepared an inclusion complex containing hydroxypropyl-β-cyclodextrin and 17-AAG (17-AAG:HPβCD) to improve its solubility. This complex was characterized by scanning electron microscopy, and X-ray diffraction. Liposomes-containing 17-AAG:HPβCD was prepared and evaluated for encapsulation efficiency (EE%), particle size, polydispersity index (PDI), pH, and zeta potential, before and after accelerated and long-term stability testing. An evaluation of leishmanicidal activity against promastigotes and intracellular amastigotes of L. (L) amazonensis was also performed. The characterization techniques utilized confirmed the formation of the inclusion complex, HPβCD:17-AAG, with a resulting 33-fold-enhancement in compound water solubility. Stability studies revealed that 17-AAG:HPβCD-loaded liposomes were smaller than 200 nm, with 99% EE. Stability testing detected no alterations in PDI that was 0.295, pH 7.63, and zeta potential +22.6, suggesting liposome stability, and suitability for evaluating leishmanicidal activity. Treatment of infected macrophages with 0.006 nM of 17-AAG:HPβCD or 17-AAG:HPβCD-loaded liposomes resulted in almost complete amastigote clearance inside macrophages after 48 h. This reduction is similar to the one observed in infected macrophages treated with 2 μM amphotericin B. Our results showed that nanotechnology and drug delivery systems could be used to increase the antileishmanial efficacy and potency of 17-AAG in vitro, while also resulting in reduced toxicity that indicates these formulations may represent a potential therapeutic strategy against leishmaniasis.
- Liposomes can both enhance or reduce drugs penetration through the skin. [Journal Article]
- SRSci Rep 2018 Sep 05; 8(1):13253
- The adequate formulation of topical vehicles to treat skin diseases is particularly complex. A desirable formulation should enhance the accumulation of the active drugs in the target tissue (the skin...
The adequate formulation of topical vehicles to treat skin diseases is particularly complex. A desirable formulation should enhance the accumulation of the active drugs in the target tissue (the skin), while avoiding the penetration enhancement to be so large that the drugs reach the systemic circulation in toxic amounts. We have evaluated the transcutaneous penetration of three drugs chosen for their widely variable physicochemical properties: Amphotericin B, Imiquimod and Indole. We incorporated the drugs in fluid or ultra-flexible liposomes. Ultra-flexible liposomes produced enhancement of drug penetration into/through human skin in all cases in comparison with fluid liposomes without detergent, regardless of drug molecular weight. At the same time, our results indicate that liposomes can impede the transcutaneous penetration of molecules, in particular small ones.
- Primary Oral Mucormycosis Due to Rhizopus microsporus after Allogeneic Stem Cell Transplantation. [Case Reports]
- IMIntern Med 2018; 57(17):2567-2571
- We herein report a rare case of oral mucormycosis following allogeneic hematopoietic stem cell transplantation. Oral mucormycosis due to Rhizopus microsporus manifested as localized left buccal mucos...
We herein report a rare case of oral mucormycosis following allogeneic hematopoietic stem cell transplantation. Oral mucormycosis due to Rhizopus microsporus manifested as localized left buccal mucositis with a 1-cm black focus before neutrophil recovery. Combination therapy with liposomal amphotericin B was initiated and surgical debridement was performed; however, the patient died due to progressive generalized mucormycosis. Considerable attention needs to be paid to the diagnosis and management of oral mucormycosis in post-transplant patients, thereby suggesting the importance of fully understanding the risk factors.
- Mechanism of Binding of Antifungal Antibiotic Amphotericin B to Lipid Membranes: An Insight from Combined Single-Membrane Imaging, Microspectroscopy, and Molecular Dynamics. [Journal Article]
- MPMol Pharm 2018 Sep 04; 15(9):4202-4213
- Amphotericin B is a lifesaving polyene antibiotic used in the treatment of systemic mycoses. Unfortunately, the pharmacological applicability of this drug is limited because of its severe toxic side ...
Amphotericin B is a lifesaving polyene antibiotic used in the treatment of systemic mycoses. Unfortunately, the pharmacological applicability of this drug is limited because of its severe toxic side effects. At the same time, the lack of a well-defined mechanism of selectivity hampers the efforts to rationally design safer derivatives. As the drug primarily targets the biomembranes of both fungi and humans, new insights into the binding of amphotericin B to lipid membranes can be helpful in unveiling the molecular mechanisms underlying both its pharmacological activity and toxicity. We use fluorescence-lifetime-imaging microscopy combined with fluorescence-emission spectroscopy in the microscale to study the interaction of amphotericin B with single lipid bilayers, using model systems based on giant unilamellar liposomes formed with three lipids: dipalmitoylphosphatidylcholine (DPPC), dimirystoylphosphatidylcholine (DMPC), and 1-palmitoyl-2-oleoylphosphatidylcholine (POPC). The results show that amphotericin B introduced into the water phase as a DMSO solution binds to the membrane as dimers and small-molecular aggregates that we identify as tetramers and trimers. Fluorescence-detected linear-dichroism measurements revealed high orientational freedom of all the molecular-organization forms with respect to the membrane plane, which suggests that the drug partially binds to the membrane surface. The presence of sterols in the lipid phase (cholesterol but particularly ergosterol at 30 mol %) promotes the penetration of drug molecules into the lipid membrane, as concluded on the basis of the decreased orientation angle of amphotericin B molecules with respect to the axis normal to the membrane plane. Moreover, ergosterol facilitates the association of amphotericin B dimers into aggregated structures that can play a role in membrane destabilization or permeabilization. The presence of cholesterol inhibits the formation of small aggregates in the lipid phase of liposomes, making this system a promising candidate for a low-toxicity antibiotic-delivery system. Our conclusions are supported with molecular simulations that reveal the conformational properties of AmB oligomers in both aqueous solution and lipid bilayers of different compositions.
- Disseminated histoplasmosis in an immunocompetent patient from an endemic area: A case report. [Case Reports]
- MMedicine (Baltimore) 2018; 97(29):e11486
- CONCLUSIONS: Emphasizing histoplasmosis as a cause of fever of unknown origin in an immunocompetent patient, this case highlights the need for an index of suspicion and the importance of prompt diagnosis, as any delay of treatment can be life threatening.
- Antileishmanial Activity of Amphotericin B-loaded-PLGA Nanoparticles: An Overview. [Review]
- MMaterials (Basel) 2018 Jul 09; 11(7)
- In recent decades, nanotechnology has made phenomenal strides in the pharmaceutical field, favouring the improvement of the biopharmaceutical properties of many active compounds. Many liposome-based ...
In recent decades, nanotechnology has made phenomenal strides in the pharmaceutical field, favouring the improvement of the biopharmaceutical properties of many active compounds. Many liposome-based formulations containing antitumor, antioxidant and antifungal compounds are presently on the market and are used daily (for example Doxil®/Caelyx® and Ambisome®). Polymeric nanoparticles have also been used to entrap many active compounds with the aim of improving their pharmacological activity, bioavailability and plasmatic half-life while decreasing their side effects. The modulation of the structural/morphological properties of nanoparticles allows us to influence various technological parameters, such as the loading capacity and/or the release profile of the encapsulated drug(s). Amongst the biocompatible polymers, poly(D,L-lactide) (PLA), poly(D,L-glycolide) (PLG) and their co-polymers poly(lactide-co-glycolide) (PLGA) are the most frequently employed due to their approval by the FDA for human use. The aim of this review is to provide a description of the foremost recent investigations based on the encapsulation of amphotericin B in PLGA nanoparticles, in order to furnish an overview of the technological properties of novel colloidal formulations useful in the treatment of Leishmaniasis. The pharmacological efficacy of the drug after nanoencapsulation will be compared to the commercial formulations of the drug (i.e., Fungizone®, Ambisome®, Amphocil® and Abelcet®).
- Effect of Anti-Leishmania Drugs on the Structural and Elastic Properties of Ultradeformable Lipid Membranes. [Journal Article]
- JPJ Phys Chem B 2018 Jul 26; 122(29):7332-7339
- Drugs for treating Leishmaniasis, a parasitic tropical orphan disease, currently have several limitations on their use, which topical treatments could alleviate. Topical treatment requires penetratio...
Drugs for treating Leishmaniasis, a parasitic tropical orphan disease, currently have several limitations on their use, which topical treatments could alleviate. Topical treatment requires penetration of drugs deep into the skin, which is aided by encapsulation within ultradeformable liposomes. Penetrability depends on the flexibility of the lipid membrane, which may be affected by the drugs. We have studied the biophysical effects of four anti-Leishmania drugs (miltefosine (Milt), amphotericin B (AmpB), indole (Ind), and imiquimod (Imiq)) on a soy phosphatidylcholine/sodium cholate membrane. Using diffuse X-ray scattering techniques, we determined bending modulus ( KC) and chain order parameter ( SX-ray) of the membrane at several drug concentrations. Form factor scattering data allowed construction of electron density profiles, which yielded bilayer thickness and area per lipid. Results show that AmpB had the largest effect on KC and SX-ray, causing the bilayer to lose integrity at high concentrations. Imiq and Ind induced slight membrane stiffening, whereas Milt had little effect. Imiq also notably decreased chain order at high concentrations. These results will aid in the design of new topical treatments, where Milt, Ind, and Imiq could be used at any concentration without affecting liposome integrity or physical properties, whereas AmpB should not be used at high concentrations.
- Combination therapy with liposomal amphotericin b (ambisome), n-methylglucamine antimoniate (glucantime), and pentamidine isethionate in a refractory visceral leishmaniasis case. [Case Reports]
- RSRev Soc Bras Med Trop 2018 May-Jun; 51(3):393-396
- Visceral leishmaniasis is a systemic disease that is potentially severe and endemic in Brazil. It clinically manifests as fever, weight loss, swelling, hepatosplenomegaly, paleness, and edema. In thi...
Visceral leishmaniasis is a systemic disease that is potentially severe and endemic in Brazil. It clinically manifests as fever, weight loss, swelling, hepatosplenomegaly, paleness, and edema. In this study, we discuss a case of a 1-year-old child diagnosed with refractory visceral leishmaniasis after being treated with liposomal amphotericin B in two distinct occasions. Considering the persistent clinical features and weak response to conventional treatment, a combination therapy with liposomal amphotericin B (ambisome), n-methylglucamine antimoniate (glucantime), and pentamidine isethionate was initiated, and response to treatment was good.
- Mucosal leishmaniasis: the experience of a Brazilian referral center. [Journal Article]
- RSRev Soc Bras Med Trop 2018 May-Jun; 51(3):318-323
- CONCLUSIONS: There is a scarcity of effective ML treatment alternatives, and based on our observations, fluconazole is not a valid treatment option.
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- Disseminated histoplasmosis mimicking relapsed chronic lymphocytic leukaemia. [Case Reports]
- BCBMJ Case Rep 2018 Jun 28; 2018
- Histoplasma microconidia when inhaled are presented in antigenic form to T cells, limiting the extent of infection; however, defects in cellular immunity results in disseminated disease. Chronic lymp...
Histoplasma microconidia when inhaled are presented in antigenic form to T cells, limiting the extent of infection; however, defects in cellular immunity results in disseminated disease. Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disorder resulting in functionally impaired lymphocytes, predisposing patients to various opportunistic infections. The author reports a recently treated patient with CLL presenting with constitutional symptoms accompanied by hepatosplenomegaly and diffuse adenopathy. Considering the recent diagnosis and treatment of CLL, initial suspicion was relapsed disease. However, considering the immune deficiency associated with CLL and its treatment, infectious aetiologies were strongly considered. Further investigation revealed a case of disseminated histoplasmosis mimicking CLL in this reported patient. Considering appropriate diagnosis and timely therapy, the reported patient had good prognosis despite being diagnosed with disseminated histoplasmosis. This case highlights consideration of disseminated histoplasmosis in patients presenting with diffuse adenopathy along with hepatomegaly and/or splenomegaly in the right clinical setting.