In-vitro and in-vivo antileishmanial activity of inexpensive Amphotericin B formulations: Heated Amphotericin B and Amphotericin B-loaded microemulsion

ABSTRACTThe present study aimed to develop an optimized dendrimeric delivery system for amphotericin B (AmB). Fifth-generation (5.0G) poly(propylene imine) (PPI) dendrimers were synthesized, conjugated with mannose, and characterized by use of various analytical techniques, including Fourier transform infrared spectroscopy (FTIR),1H nuclear magnetic resonance (1H-NMR) spectroscopic analysis, and atomic force microscopy (AFM). Mannose-conjugated 5.0G PPI (MPPI) dendrimers were loaded with AmB and evaluated for drug loading efficiency,in vitrodrug release profile, stability, hemolytic toxicity to human erythrocytes, cytotoxicity to and cell uptake by J774A.1 macrophage cells, antiparasitic activity against intracellularLeishmania donovaniamastigotes,in vivopharmacokinetic and biodistribution profiles, drug localization index, toxicity, and antileishmanial activity. AFM showed the nanometric size of the MPPI dendrimers, with a nearly globular architecture. The conjugate showed a good entrapment efficiency for AmB, along with pH-sensitive drug release. Highly significant reductions in toxicity toward human erythrocytes and macrophage cells, without compromising the antiparasitic activity of AmB, were observed. The dendrimeric formulation of AmB showed a significant enhancement of the parasiticidal activity of AmB toward intramacrophagicL. donovaniamastigotes. In thein vitrocell uptake studies, the formulation showed selectivity toward macrophages, with significant intracellular uptake. Further pharmacokinetic and organ distribution studies elucidated the controlled delivery behavior of the formulation. The drug localization index was found to increase significantly in macrophage-rich organs.In vivostudies showed a biocompatible behavior of MPPIA, with negligible toxicity even at higher doses, and promising antileishmanial activity. From the results, we concluded that surface-engineered dendrimers may serve as optimized delivery vehicles for AmB with enhanced activity and low or negligible toxicity.

Download Full-text

In Vivo Antimalarial and In Vitro Antileishmanial Activity of 4- Aminoquinoline Derivatives Hybridized to Isoniazid or Sulfa or Hydrazine Groups

Letters in Drug Design & Discovery ◽

10.2174/1570180813666160927113743 ◽

2017 ◽

Vol 14 (5) ◽

pp. 597-604 ◽

Cited By ~ 3

Author(s):

Roberta Soares ◽

Luciana Antinarelli ◽

Isabela Souza ◽

Fernanda Lopes ◽

...

Keyword(s):

Antileishmanial Activity

Download Full-text

In-vitro and in-vivo evaluation of a new amphotericin B emulsion-based delivery system

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/38.3.485 ◽

1996 ◽

Vol 38 (3) ◽

pp. 485-497 ◽

Cited By ~ 15

Author(s):

Eryvaldo Sόcrates Tabosa Do Egito ◽

Martine Appel ◽

Hatem Fessi ◽

Gillian Barrett ◽

Francis Puisieux ◽

...

Keyword(s):

Amphotericin B ◽

Delivery System ◽

In Vivo Evaluation

Download Full-text

Mode of action of amphotericin B on chick embryo fibroblasts and on mouse Ehrlich tumour cells: a cytological and cytochemical analysis

Journal of Cell Science ◽

10.1242/jcs.18.3.441 ◽

1975 ◽

Vol 18 (3) ◽

pp. 441-451

Author(s):

F. De Paermentier ◽

R. Bassleer ◽

A. Lepoint ◽

C. Desaive ◽

G. Goessens ◽

...

Keyword(s):

Chick Embryo ◽

Amphotericin B ◽

Tumour Cells ◽

Total Protein Content ◽

Cell Multiplication ◽

Cytochemical Analysis ◽

Ehrlich Ascites ◽

Embryo Fibroblasts

Chick embryo fibroblasts cultivated in vitro and Ehrlich ascites tumor cells (in vivo or in vitro) have been treated with amphotericin B. Cell multiplication is strongly inhibited. Large clear zones appear in the fibroblast nucleoi (phase-contrast and electron-microscope observations). Many treated fibroblasts and tumour cells have a high DNA content (pre-mitotic or polyploid level; measurements by cytophotometry). However, the RNA content (cytophotometry) and the total protein content (cytophotometry and micro-interferometry) are relatively low in the tumour cells. As shown by autoradiography, DNA synthesis is active but RNA synthesis and, in some cases, protein synthesis are inhibited. Due to this unbalanced growth, the cells cannot divide.

Download Full-text

In Vitro Antileishmanial Activity of Nicotinamide

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.2.808-812.2005 ◽

2005 ◽

Vol 49 (2) ◽

pp. 808-812 ◽

Cited By ~ 35

Author(s):

D. Sereno ◽

A. Monte Alegre ◽

R. Silvestre ◽

B. Vergnes ◽

A. Ouaissi

Keyword(s):

Leishmania Major ◽

Growth Arrest ◽

Antileishmanial Activity ◽

Vitamin B ◽

Wild Type ◽

Intracellular Growth ◽

Cell Growth Arrest ◽

Transgenic Parasites

ABSTRACT Our study represents the first report demonstrating the antileishmanial activity of nicotinamide (NAm), a form of vitamin B3. A 5 mM concentration of NAm significantly inhibited the intracellular growth of Leishmania amastigotes and the NAD-dependent deacetylase activity carried by parasites overexpressing Leishmania major SIR2 (LmSIR2). However, the transgenic parasites were as susceptible as the wild-type parasites to NAm-induced cell growth arrest. Therefore, we conclude that NAm inhibits leishmanial growth and that overexpression of LmSIR2 does not overcome this inhibition. The mechanism of the inhibition is not defined but may include other in vivo targets. NAm may thus represent a new antileishmanial agent which could potentially be used in combination with other drugs during therapy.

Download Full-text

In Vitro and In Vivo Antifungal Activity of AmBisome Compared to Conventional Amphotericin B and Fluconazole against Candida auris

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00306-21 ◽

2021 ◽

Author(s):

Janet Herrada ◽

Ahmed Gamal ◽

Lisa Long ◽

Sonia P. Sanchez ◽

Thomas S. McCormick ◽

...

Keyword(s):

Antifungal Activity ◽

Amphotericin B ◽

Kidney Tissue ◽

Treated Group ◽

Untreated Group ◽

Candida Auris ◽

Fungal Burden ◽

In Vivo Antifungal Activity

Antifungal activity of AmBisome against Candida auris was determined in vitro and in vivo. AmBisome showed MIC50 and MIC90 values of 1 and 2 μg/mL, respectively. Unlike conventional amphotericin B, significant in vivo efficacy was observed in the AmBisome 7.5 mg/kg -treated group in survival and reduction of kidney tissue fungal burden compared to the untreated group. Our data shows that AmBisome shows significant antifungal activity against C. auris in vitro as well as in vivo.

Download Full-text

Impact of the Order of Initiation of Fluconazole and Amphotericin B in Sequential or Combination Therapy on Killing of Candida albicans In Vitro and in a Rabbit Model of Endocarditis and Pyelonephritis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.2.485-494.2001 ◽

2001 ◽

Vol 45 (2) ◽

pp. 485-494 ◽

Cited By ~ 40

Author(s):

Arnold Louie ◽

Pamela Kaw ◽

Partha Banerjee ◽

Weiguo Liu ◽

George Chen ◽

...

Keyword(s):

Candida Albicans ◽

Amphotericin B ◽

Induced Resistance ◽

Rabbit Model ◽

In Vivo Studies ◽

Infection Model ◽

Simultaneous Exposure ◽

The Impact

ABSTRACT In vitro time-kill studies and a rabbit model of endocarditis and pyelonephritis were used to define the impact that the order of exposure of Candida albicans to fluconazole (FLC) and amphotericin B (AMB), as sequential and combination therapies, had on the susceptibility of C. albicans to AMB and on the outcome. The contribution of FLC-induced resistance to AMB for C. albicans also was assessed. In vitro, AMB monotherapy rapidly killed each of four C. albicans strains; FLC alone was fungistatic. Preincubation of these fungi with FLC for 18 h prior to exposure to AMB decreased their susceptibilities to AMB for 8 to >40 h. Induced resistance to AMB was transient, but the duration of resistance increased with the length of FLC preincubation. Yeast sequentially incubated with FLC followed by AMB plus FLC (FLC→AMB+FLC) showed fungistatic growth kinetics similar to that of fungi that were exposed to FLC alone. This antagonistic effect persisted for at least 24 h. Simultaneous exposure of C. albicans to AMB and FLC [AMB+FLC(simult)] demonstrated activity similar to that with AMB alone for AMB concentrations of ≥1 μg/ml; antagonism was seen using an AMB concentration of 0.5 μg/ml. The in vitro findings accurately predicted outcomes in our rabbit infection model. In vivo, AMB monotherapy and treatment with AMB for 24 h followed by AMB plus FLC (AMB→AMB+FLC) rapidly sterilized kidneys and cardiac vegetations. AMB+FLC(simult) and FLC→AMB treatments were slower in clearing fungi from infected tissues. FLC monotherapy and FLC→AMB+FLC were both fungistatic and were the least active regimens. No adverse interaction was observed between AMB and FLC for the AMB→FLC regimen. However, FLC→AMB treatment was slower than AMB alone in clearing fungi from tissues. Thus, our in vitro and in vivo studies both demonstrate that preexposure of C. albicans to FLC reduces fungal susceptibility to AMB. The length of FLC preexposure and whether AMB is subsequently used alone or in combination with FLC determine the duration of induced resistance to AMB.

Download Full-text

AMPHOTERICIN B TOPICAL EXTEMPORANEOUS PREPARATIONS FOR THE TREATMENT OF NON-DERMATOPHYTIC ONYCHOMYCOSIS

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2020.v13i12.39645 ◽

2020 ◽

pp. 135-139

Author(s):

KOMESMUNEEBORIRAK PHOJANA ◽

WERAWATGANONE PORNPEN ◽

MUANGSIRI WALAISIRI

Keyword(s):

Amphotericin B ◽

Chemical Stability ◽

High Performance ◽

Sodium Lauryl Sulfate ◽

Physical Stability ◽

Lauryl Sulfate ◽

Physical And Chemical ◽

Injection Product

Objective: At present, the nail preparation to cure onychomycosis, caused by non-dermatophyte molds, is not commercially available in Thailand. The physical and chemical stability of amphotericin B (AmB) extemporaneous preparations in the presence of 30% dimethyl sulfoxide (DMSO) and their in vitro nail permeation was evaluated. Methods: AmB extemporaneous preparations in the presence of 30% DMSO were prepared from a commercial sterile injection product, and cream or hydrophilic ointment. Physical stability was tested at 30°C for 2 months, or using 6 heating-cooling cycles. The chemical stability and in vitro nail permeation of AmB content were analyzed using high-performance liquid chromatography (HPLC). In vitro nail permeation was performed by applying 3.5 mg/mm2 of the tested formulation on nail clippings for 5 consecutive days. Results: The AmB cream and ointment extemporaneous preparations containing 30% DMSO, a permeation enhancer, were homogeneous and pale yellow to yellow cream or ointment. The AmB ointment was stable for up to 60 days. The ointment preparation allows in vitro penetration through nails up to 14.17 μg/cm2. The ointment preparation allows significantly better penetration through than the cream preparation due to the presence of DMSO, sodium lauryl sulfate (SLS), and water in the ointment preparation. Conclusion: The AmB extemporaneous ointment was successfully compounded from a commercial sterile injection product with a beyond-use date of 60 days. The ointment preparation is currently under further investigation for in vivo efficacy.

Download Full-text

New Triazole NT-a9 Has Potent Antifungal Efficacy against Cryptococcus neoformans In Vitro and In Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01628-19 ◽

2019 ◽

Vol 64 (2) ◽

Cited By ~ 1

Author(s):

Ren-Yi Lu ◽

Ting-Jun-Hong Ni ◽

Jing Wu ◽

Lan Yan ◽

Quan-Zhen Lv ◽

...

Keyword(s):

Cryptococcus Neoformans ◽

Amphotericin B ◽

Pathogenic Fungi ◽

Control Group ◽

Survival Times ◽

Content Type ◽

Fungal Burden ◽

Wide Range

ABSTRACT In the past decades, the incidence of cryptococcosis has increased dramatically, which poses a new threat to human health. However, only a few drugs are available for the treatment of cryptococcosis. Here, we described a leading compound, NT-a9, an analogue of isavuconazole, that showed strong antifungal activities in vitro and in vivo. NT-a9 showed a wide range of activities against several pathogenic fungi in vitro, including Cryptococcus neoformans, Cryptococcus gattii, Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, with MICs ranging from 0.002 to 1 μg/ml. In particular, NT-a9 exhibited excellent efficacy against C. neoformans, with a MIC as low as 0.002 μg/ml. NT-a9 treatment resulted in changes in the sterol contents in C. neoformans, similarly to fluconazole. In addition, NT-a9 possessed relatively low cytotoxicity and a high selectivity index. The in vivo efficacy of NT-a9 was assessed using a murine disseminated-cryptococcosis model. Mice were infected intravenously with 1.8 × 106 CFU of C. neoformans strain H99. In the survival study, NT-a9 significantly prolonged the survival times of mice compared with the survival times of the control group or the isavuconazole-, fluconazole-, or amphotericin B-treated groups. Of note, 4 and 8 mg/kg of body weight of NT-a9 rescued all the mice, with a survival rate of 100%. In the fungal-burden study, NT-a9 also significantly reduced the fungal burdens in brains and lungs, while fluconazole and amphotericin B only reduced the fungal burden in lungs. Taken together, these data suggested that NT-a9 is a promising antifungal candidate for the treatment of cryptococcosis infection.

Download Full-text

Amphotericin B Penetrates into the Central Nervous System through Focal Disruption of the Blood-Brain Barrier in Experimental Hematogenous Candida Meningoencephalitis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01626-19 ◽

2019 ◽

Vol 63 (12) ◽

Author(s):

Vidmantas Petraitis ◽

Ruta Petraitiene ◽

Jessica M. Valdez ◽

Vasilios Pyrgos ◽

Martin J. Lizak ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Amphotericin B ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Blue Dye ◽

Bolus Administration ◽

Blood Brain ◽

Mri Scans

ABSTRACT Hematogenous Candida meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeation and low cerebrospinal fluid (CSF) concentrations but is effective in the treatment of HCME. In order to better understand the mechanism of CNS penetration of AmB, we hypothesized that AmB may achieve focally higher concentrations in infected CNS lesions. An in vitro blood-brain barrier (BBB) model was serially infected with Candida albicans. Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 μg/ml was then provided, and the vascular and CNS compartments were sampled 4 h later. For in vivo correlation, rabbits with experimental HCME received a single dose of DAMB at 1 mg/kg of body weight or LAMB at 5 mg/kg and were euthanized after 1, 3, 6, and 24 h. Evans blue dye solution (2%, 2 ml/kg) administered intravenously (i.v.) at 1 h prior to euthanasia stained infected regions of tissue but not histologically normal areas. AmB concentrations in stained and unstained tissue regions were measured using ultraperformance liquid chromatography. For selected rabbits, magnetic resonance imaging (MRI) scans performed on days 1 to 7 postinoculation were acquired before and after i.v. bolus administration of gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) at 15-min intervals through 2 h postinjection. The greatest degree of penetration of DAMB and LAMB through the in vitro BBB occurred after 24 h of exposure (P = 0.0022). In vivo the concentrations of LAMB and DAMB in brain abscesses were 4.35 ± 0.59 and 3.14 ± 0.89 times higher, respectively, than those in normal tissue (P ≤ 0.019). MRI scans demonstrated that Gd-DTPA accumulated in infected areas with a disrupted BBB. Localized BBB disruption in HCME allows high concentrations of AmB within infected tissues, despite the presence of low cerebrospinal fluid concentrations.

Download Full-text