- A Mechanism of Binding of an Antifungal Antibiotic Amphotericin B to Lipid Membranes: An Insight from Combined Single Membrane Imaging, Micro-Spectroscopy, and Molecular Dynamics. [Journal Article]
- MPMol Pharm 2018 Aug 06
- Amphotericin B is a lifesaving polyene antibiotic used in the treatment of systemic mycoses. Unfortunately, the pharmacological applicability of this drug is limited owing to its severe toxic side ef...
Amphotericin B is a lifesaving polyene antibiotic used in the treatment of systemic mycoses. Unfortunately, the pharmacological applicability of this drug is limited owing to 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 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/or 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 and/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 the aqueous solution and lipid bilayers of different composition.
- 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.
- Bioanalysis of free and liposomal Amphotericin B in rat plasma using solid phase extraction and protein precipitation followed by LC-MS/MS. [Journal Article]
- JPJ Pharm Biomed Anal 2018 Jun 08; 158:288-293
- Amphotericin B (AMB) is a polyene macrolide antibiotic used for treating invasive fungal infections. Liposomal AMB (L-AMB) is a lipid dosage form which reduces the side effects and toxicity of the dr...
Amphotericin B (AMB) is a polyene macrolide antibiotic used for treating invasive fungal infections. Liposomal AMB (L-AMB) is a lipid dosage form which reduces the side effects and toxicity of the drug. The quantitation of free AMB (F-AMB) and L-AMB in vivo is important to monitor quality control of the liposomal formulation and to ensure its safety during clinical use. In this study, an original strategy was developed to separately determine F-AMB and L-AMB in rat plasma using LC-MS/MS. F-AMB was analyzed after separation by solid phase extraction, total AMB (T-AMB) was determined after protein precipitation and L-AMB was determined by difference. The method was fully validated. Calibration curves were linear in the ranges 0.7-120 μg/mL for T-AMB and 0.2-20 μg/mL for F-AMB. Accuracy and precision results were within acceptable variability limits, recoveries were consistent and reproducible, matrix effects were insignificant and analytes were stable under all the storage conditions tested. The method was successfully applied to a pharmacokinetic study in rats administered a single intravenous 6 mg/kg dose of L-AMB. The method will allow further clinical studies of L-AMB and provide useful technical support for the assay of other liposomal drug formulations.
- The initial effectiveness of liposomal amphotericin B (AmBisome) and miltefosine combination for treatment of visceral leishmaniasis in HIV co-infected patients in Ethiopia: A retrospective cohort study. [Journal Article]
- PNPLoS Negl Trop Dis 2018; 12(5):e0006527
- CONCLUSIONS: Initial parasitological failure rates were very low with AmBisome and miltefosine combination therapy. This regimen seems a suitable treatment option. Knowledge of predictors of poor outcome may facilitate better management. These findings remain to be confirmed in clinical trials.
- Fungal Infection Caused by Geotrichum capitatum in a Severe Aplastic Anemia Patient: a Case Report and Review of the Literature. [Case Reports]
- CLClin Lab 2018 May 01; 64(5):867-869
- CONCLUSIONS: Sequencing and mass spectrometric analysis could have a role for Geotrichum capitatum diagnosis. Curative effect of using a single antifungal drug was unsatisfactory. Using liposome amphotericin B combined with caspofungin might obtain certain curative effect. Early diagnosis and appropriate combined therapy were necessary to improve the outcome of patients with Geotrichum capitatum infection.
New Search Next
- Comparative efficacy, toxicity and biodistribution of the liposomal amphotericin B formulations Fungisome® and AmBisome® in murine cutaneous leishmaniasis. [Journal Article]
- IJInt J Parasitol Drugs Drug Resist 2018 Apr 12; 8(2):223-228
- Fungisome® (F), a liposomal amphotericin B (AmB) product, is marketed in India as a safe and effective therapeutic for the parasitic infection visceral leishmaniasis. Its potential in the treatment o...
Fungisome® (F), a liposomal amphotericin B (AmB) product, is marketed in India as a safe and effective therapeutic for the parasitic infection visceral leishmaniasis. Its potential in the treatment of cutaneous leishmaniasis (CL), a disfiguring form of the disease affecting the skin, is currently unknown. Here, we report the evaluation of the efficacy of F in the Leishmania major BALB/c murine model of CL, including a head-to-head comparison with the standard liposomal AmB formulation AmBisome® (A). Upon intravenous administration at dose levels of 5, 10 and 15 mg/kg of body weight (on days 0, 2, 4, 6 and 8), F showed clear signs of toxicity (at 15 mg/kg), while A did not. After complete treatment (day 10), the tolerated doses of 5 and 10 mg/kg F had significant antileishmanial activity (ED50 = 4.0 and 12.8 mg/kg for qPCR-based parasite load and lesion size, respectively), although less than that of A at identical doses (ED50 = 3.0 and 8.8 mg/kg). The efficacy of F was inferior compared to A because lower levels of the active agent AmB accumulated within the infected lesion. In conclusion, despite possibly being less safe and efficacious than A at equivalent doses, the moderate in vivo activity of F could indicate a role in the systemic pharmacotherapy of CL.