- 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.
- 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.
- Long chain fatty acid conjugation remarkably decreases the aggregation induced toxicity of Amphotericin B. [Journal Article]
- IJInt J Pharm 2018 Jun 10; 544(1):1-13
- Amphotericin B is an antimicrobial membrane-acting drug used in the treatment of systemic fungal infections. However, the clinical utility of AmB is often low as a result of (i) dose-limiting toxicit...
Amphotericin B is an antimicrobial membrane-acting drug used in the treatment of systemic fungal infections. However, the clinical utility of AmB is often low as a result of (i) dose-limiting toxicity which is closely associated with its aggregation wherein the selectivity for its target i.e. ergosterol in fungal membranes is diminished and (ii) limited oral bioavailablity. The latter is attributed to the unfavorable physicochemical properties of the AmB e.g., low solubility, gastrointestinal instability, and poor intestinal permeability. The hypothesis of present work was that by applying a lipid conjugation approach the aggregation induced toxicity of AmB vis-à-vis permeability can be overcome. From the array of fatty acids, the oleic acid (OA) was selected for conjugation due to its great impact on increasing the Caco-2 permeability of AmB. AmB-OA conjugate was synthesized using standard carbodiimide chemistry and characterized thoroughly. Due to the reported strong correlation between the self-aggregation of AmB and toxicity, the aggregation behavior of AmB and AmB-OA was studied by in silico modeling and confirmed experimentally. In vitro hemolytic studies and viability assays in kidney cells (HEK 293 cells) suggested that AmB in aggregated was state highly toxic but not AmB-OA. In silico modeling suggested possible aggregation conformation of AmB-OA dimers that retains the selectivity for cholesterol even in aggregated state when embedded in in silico generated lipid bilayers. The results were further confirmed by assessing the interactions of monomeric and aggregated state of AmB and AmB-OA with that of cholesterol and ergosterol containing liposomes employing circular dichroism spectroscopy. The findings were subsequently corroborated by in vivo nephrotoxicity studies. To conclude, the lipid conjugation approach may be a promising strategy for reducing the dose-limiting toxicity of AmB.
- Central nervous system histoplasmosis: Multicenter retrospective study on clinical features, diagnostic approach and outcome of treatment. [Multicenter Study]
- MMedicine (Baltimore) 2018; 97(13):e0245
- Central nervous system (CNS) involvement occurs in 5 to 10% of individuals with disseminated histoplasmosis. Most experience has been derived from small single center case series, or case report lite...
Central nervous system (CNS) involvement occurs in 5 to 10% of individuals with disseminated histoplasmosis. Most experience has been derived from small single center case series, or case report literature reviews. Therefore, a larger study of central nervous system (CNS) histoplasmosis is needed in order to guide the approach to diagnosis, and treatment.A convenience sample of 77 patients with histoplasmosis infection of the CNS was evaluated. Data was collected that focused on recognition of infection, diagnostic techniques, and outcomes of treatment.Twenty nine percent of patients were not immunosuppressed. Histoplasma antigen, or anti-Histoplasma antibodies were detected in the cerebrospinal fluid (CSF) in 75% of patients. One year survival was 75% among patients treated initially with amphotericin B, and was highest with liposomal, or deoxycholate formulations. Mortality was higher in immunocompromised patients, and patients 54 years of age, or older. Six percent of patients relapsed, all of whom had the acquired immunodeficiency syndrome (AIDS), and were poorly adherent with treatment.While CNS histoplasmosis occurred most often in immunocompromised individuals, a significant proportion of patients were previously, healthy. The diagnosis can be established by antigen, and antibody testing of the CSF, and serum, and antigen testing of the urine in most patients. Treatment with liposomal amphotericin B (AMB-L) for at least 1 month; followed by itraconazole for at least 1 year, results in survival among the majority of individuals. Patients should be followed for relapse for at least 1 year, after stopping therapy.
- Visceral leishmaniasis in a Brazilian endemic area: an overview of occurrence, HIV coinfection and lethality. [Journal Article]
- RIRev Inst Med Trop Sao Paulo 2018 Mar 08; 60:e12
- The Brazilian municipality of Rondonópolis, Mato Grosso State, represents an important visceral leishmaniasis (VL) endemic area. This study described epidemiological and clinical aspects of the occur...
The Brazilian municipality of Rondonópolis, Mato Grosso State, represents an important visceral leishmaniasis (VL) endemic area. This study described epidemiological and clinical aspects of the occurrence, VL/HIV coinfection and lethality related to VL in Rondonópolis. Data from autochthonous cases reported between 2011 and 2016 were obtained from official information systems. During this period, 81 autochthonous cases were reported, with decreasing incidence through 2016. Contrastingly, the lethality rate was 8.6% overall, but varied widely, reaching a peak (20%) in 2016. Almost 10% of patients had VL/HIVcoinfection. The occurrence of VL prevailed among men (56.8%), brown-skinned (49.4%), urban residents (92.6%), aged 0-4 years (33.3%). Housewives or retired (29.6%) were the most affected occupational groups. Lower age was the main difference among the total VL cases and those who were coinfected or died. Clinically, fever, weakness and splenomegaly were more frequent among all VL cases and VL/HIV coinfected individuals. Bacterial infections (p=0.001) and bleeding (p<0.001) were associated with death due to VL. Pentavalent antimonial and liposomal amphotericin B were the first choices for treatment among all VL cases (71.6%) and those who died (71.4%), respectively. VL/HIV patients were equally treated with both drugs. These findings may support control measures and demonstrate the need for further investigations.
- Lipid-mediated mode of action of local anesthetics on lipid pores induced by polyenes, peptides and lipopeptides. [Journal Article]
- CSColloids Surf B Biointerfaces 2018 Jun 01; 166:1-8
- The effects of local anesthetics (LAs), namely, lidocaine (LDC), prilocaine (PLC), mepivacaine (MPV), bupivacaine (BPV), procaine (PC), and tetracaine (TTC), on the steady-state transmembrane conduct...
The effects of local anesthetics (LAs), namely, lidocaine (LDC), prilocaine (PLC), mepivacaine (MPV), bupivacaine (BPV), procaine (PC), and tetracaine (TTC), on the steady-state transmembrane conductance induced by the cis-side addition of the antifungal polyene macrolide antibiotic, nystatin (NYS), in planar lipid bilayers were studied. The addition of TTC to model membranes comprising DOPC and cholesterol (33 mol%) led to a nearly twenty-fold increase in the steady-state NYS-induced membrane conductance. BPV slightly enhanced the channel-forming activity of polyene. LDC, PLC, MPV, and PC did not affect the NYS-induced transmembrane current. We concluded that the effects of LAs on the channel-forming activity of NYS were in agreement with their effects on the elastic properties of model membranes. The ability of aminoamide LAs to promote calcein leakage from large unilamellar DOPC-vesicles was decreased in the following order: BPV > LDC ≈ PLC ≈ MPV. LDC, PLC, and MPV produced a graded leakage of fluorescent marker from liposomes, up to 10-13%. A initial sharp jump in fluorescence after the introduction of BPV was attributed to the solubilization of liposomes and the formation of mixed DOPC:BPV-micelles. Differential scanning microcalorimetry (DSC) of large unilamellar DPPC-vesicles showed that the main transition temperature (Tm) is continuously decreased upon increasing concentrations of TTC. A sharp drop in the enthalpy of the transition at higher TTC concentrations indicated a formation of anesthetic/lipid mixed micelles. In contrast to TTC, PC slightly decreased Tm, broadened the DSC signal and did not provoke vesicle-to-micelle transition. Both the calcein leakage and DSC data together with the results of measurements of threshold voltages that are required to cause the lipid bilayer breakdown might indicate an alteration in the curvature lipid packing stress, induced by BPV and TTC. The data presented here lend support to a lipid-mediated mode of LAs action on NYS pores via an alteration in curvature stress near the trans-mouth. Similar results were obtained for several lipid pores, formed by polyene amphotericin B, lipopeptide syringomycin E, and the peptides magainin and melittin. This finding further developed the concept of non-specific regulation of lipid pores by LAs. In conclusion, the combination of nystatin with LAs could be a novel treatment for efficient therapy of superficial and mucosal candidiasis.
- 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 probed Candida albicans and Cryptococcus neoformans with liposomes containing...
The fungal cell wall is a critically important structure that represents a permeability barrier and protective shield. We probed Candida albicans and Cryptococcus neoformans with 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. albicans mutants with altered cell wall thickness and composition were similar in both their in vitro AmBisome susceptibility and the ability of liposomes to penetrate the cell wall. AmBisome exposed to ergosterol-deficient C. albicans failed to penetrate beyond the mannoprotein-rich outer cell wall layer. Melanization of C. neoformans and 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.IMPORTANCE AmBisome 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 both Candida albicans and Cryptococcus neoformans intact, 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.
- Trypanosomiasis in a Young Infant from Rural Gujarat, India. [Case Reports]
- IPIndian Pediatr 2018 01 15; 55(1):69-70
- Human trypansomiasis due to infection by animal trypanosomes is rarely reported from India.
Human trypansomiasis due to infection by animal trypanosomes is rarely reported from India.
- Nanotechnological Strategies for Treatment of Leishmaniasis--A Review. [Review]
- 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.
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- 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.