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1
Murphy, Adrian Gerard, Rory Casey, David William Fennelly, Alison Reynolds, Miriam Tosetto, John Hyland, Kieran Sheahan, et al. "The effect of novel small molecule drugs in human explants across the disease sequence in colorectal cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e13570-e13570. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13570.
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e13570 Background: The treatment of metastatic colorectal cancer has been improved by combining cytotoxic chemotherapy with bevacizumab. Newer anti-angiogenic agents are required to improve survival rates as response rates with the current therapies are modest. The preclinical development of such drugs is time-consuming and new methods are required to test the efficacy of lead drugs which represent the entire tumor micro-environment. Methods: Chemical screens were performed in zebrafish larvae to identify hits that affected intersegmental angiogenesis. Five lead drugs were then tested for cytotoxicity using the crystal violet assay. These drugs were tested using ex vivo colorectal tumor explants to determine their effect on secretion of IL-1β, TNF, IL-6 and VEGF. Human explants from 20 patients (Dukes A-D) were cultured for 72 hours and the levels of the above factors measured by ELISA. Comparisons were made between early (Dukes A&B) and late stages (Dukes C&D). Results: One thousand drugs were screened and 5 were found to reduce intersegmental angiogenesis in zebrafish larvae: AM1, AM2, AM3, AM4 and AM5. The drugs did not affect cell growth levels at 10 µM concentration. From the explant studies: AM1 decreased secretion of VEGF in late stages (p=0.005) and IL-6 in early stages (p=0.009). AM2 decreased VEGF in early (p=0.004) and late stages (p=0.02). AM3 decreased TNF secretion in late stages (p=0.02) and IL-6 secretion in early (p=0.009) and late stages (p<0.0001). AM4 decreased VEGF secretion in early stages (p=0.001), IL-6 in early stages (p<0.001) and late stages (p=0.03) and IL-1β in early stages (p=0.002). AM5 decreased IL-6 secretion in the early stages (p=0.03) and IL-1β in the early stages (p=0.001).Overall, IL-1β secretion was reduced by AM4, AM3 and AM5 (p<0.05). IL-6 secretion was reduced by AM1, AM3 and AM4 (p=0.001). TNF secretion was reduced by AM3 (p=0.02) and VEGF secretion was reduced by AM1, AM2 and AM4 (p<0.005). Conclusions: These studies show these drugs have stage-specific effects in colorectal tumor explants and may have the potential as new anti-angiogenic agents in colorectal cancer.
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Ogoshi, Maho, Shigenori Nobata, and Yoshio Takei. "Potent osmoregulatory actions of homologous adrenomedullins administered peripherally and centrally in eels." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 295, no. 6 (December 2008): R2075—R2083. http://dx.doi.org/10.1152/ajpregu.90688.2008.
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The teleost adrenomedullin (AM) family consists of three groups, AM1/AM4, AM2/AM3, and AM5. In the present study, we examined the effects of homologous AM1, AM2, and AM5 on drinking and renal function after peripheral or central administration in conscious freshwater eels. AM2 and AM5, but not AM1, exhibited dose-dependent (0.01–1 nmol/kg) dipsogenic and antidiuretic effects after intra-arterial bolus injection. The antidiuretic effect was significantly correlated with the degree of associated hypotension. To avoid the potential indirect osmoregulatory effects of AM-induced hypotension, infusion of AMs was also performed at nondepressor doses. Drinking was enhanced dose-dependently at 0.1–3 pmol·kg−1·min−1 of AM2 and AM5, matching the potency and efficacy of angiotensin II (ANG II), the most potent dipsogenic hormone known thus far. AM2 and AM5 infusion also induced mild antidiuresis, while AM1 caused antinatriuresis. Additionally, AMs were injected into the third and fourth ventricles of conscious eels to assess their site of dipsogenic action. However, none of the AMs at 0.05–0.5 nmol induced drinking, while ANG II was highly dipsogenic. AM2 and ANG II injected into the third ventricle increased arterial pressure while AM5 decreased it in a dose-dependent manner, and both AM2 and AM5 decreased blood pressure when injected into the fourth ventricle. These data suggest that circulating AM2 and AM5 act on a target site in the brain that lacks the blood-brain barrier. Collectively, the present study showed that AM2 and AM5 are potent osmoregulatory hormones in the eel, and their actions imply involvement in seawater adaptation of this euryhaline species.
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Cuenca-Estrella, Manuel, Teresa M. Dı́az-Guerra, Emilia Mellado, and Juan L. Rodrı́guez-Tudela. "Detection of Resistance to Amphotericin B inCandida Isolates by Using Iso-Sensitest Broth." Antimicrobial Agents and Chemotherapy 45, no. 7 (July 1, 2001): 2070–74. http://dx.doi.org/10.1128/aac.45.7.2070-2074.2001.
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ABSTRACT A major limitation of the National Committee for Clinical Laboratory Standards M27-A methodology is reliable detection of amphotericin B (AMB) resistance. The results obtained by using Iso-Sensitest, a synthetic medium, to detect AMB resistance were analyzed and compared with those obtained with RPMI and antibiotic medium 3 (AM3). The ability to detect AMB resistance with RPMI is not enhanced by using a higher inoculum, glucose supplementation at a final concentration of 20 g/liter, spectrophotometric reading, or 24 h of incubation time. Testing using AM3 and an inoculum of 103 CFU/ml detects resistance. Identification of resistant isolates is not improved by glucose supplementation, changes in reading method, or changes in incubation time. However, the use of AM3 as assay medium and an inoculum of 105 CFU/ml did not allow detection of AMB resistance. Testing using Iso-Sensitest medium appears to be similar to AM3 in detecting resistance. The most pronounced discrimination is achieved by testing in Iso-Sensitest supplemented with glucose and spectrophotometric reading after 24 h of incubation. The reproducibility of MIC testing was greatest for Iso-Sensitest-based procedures. Use of Iso-Sensitest produces both highly reproducible MICs and reliable identification of AMB-resistant Candida isolates.
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Beale, S., B. Shafai, P. LaRocca, and E. Cusson. "Adaptive Forced Balancing for Multivariable Systems." Journal of Dynamic Systems, Measurement, and Control 117, no. 4 (December 1, 1995): 496–502. http://dx.doi.org/10.1115/1.2801106.
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Active magnetic bearing (AMB) actuators support rotors without friction but require feedback control for stabilization and performance. Autobalancing compensation causes AMBs to spin a rotor about its inertial axis to eliminate synchronous force transmission from mass unbalance. Because mass unbalance constitutes a sinusoidal sensor disturbance within the bandwidth, conventional methods can either cause instability or fail to preserve desired bandwidth. We introduce a new method called adaptive forced balancing (AFB) which overcomes these problems. We consider AFB with a frequency tracking capability for SISO systems (i.e., single-end AMB suspensions) and show how to extend it for the MIMO case as applied to a double-end AMB suspension.
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Zhang, Tao, Wei Ni, Sha Sha Wu, Hui Ping Zhang, and Jian Xiang Ji. "Rotor Vibration Control of Active Magnetic Bearing System Using Adaptive Forced Balancing Method." Applied Mechanics and Materials 268-270 (December 2012): 1527–30. http://dx.doi.org/10.4028/www.scientific.net/amm.268-270.1527.
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The adaptive forced balancing (AFB) method was used to estimate and eliminate the rotor vibration with unknown amplitudes and frequencies in active magnetic bearing (AMB) feedback control systems. Firstly, the rotor vibration producing mechanisms of AMB were analyzed. Then, the AFB under the assumption of unknown rotational frequency and amplitude are designed. Finally the simulation results show that the AFB method proposed in this paper makes it possible to completely reject unknown sinusoidal disturbance in a closed loop control system
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Lobato-Freitas, Carolina, Andreia Machado Brito-da-Costa, Ricardo Jorge Dinis-Oliveira, Helena Carmo, Félix Carvalho, João Pedro Silva, and Diana Dias-da-Silva. "Overview of Synthetic Cannabinoids ADB-FUBINACA and AMB-FUBINACA: Clinical, Analytical, and Forensic Implications." Pharmaceuticals 14, no. 3 (February 25, 2021): 186. http://dx.doi.org/10.3390/ph14030186.
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ADB-FUBINACA and AMB-FUBINACA are two synthetic indazole-derived cannabinoid receptor agonists, up to 140- and 85-fold more potent, respectively, than trans-∆9-tetrahydrocannabinol (∆9-THC), the main psychoactive compound of cannabis. Synthesised in 2009 as a pharmaceutical drug candidate, the recreational use of ADB-FUBINACA was first reported in 2013 in Japan, with fatal cases being described in 2015. ADB-FUBINACA is one of the most apprehended and consumed synthetic cannabinoid (SC), following AMB-FUBINACA, which emerged in 2014 as a drug of abuse and has since been responsible for several intoxication and death outbreaks. Here, we critically review the physicochemical properties, detection methods, prevalence, biological effects, pharmacodynamics and pharmacokinetics of both drugs. When smoked, these SCs produce almost immediate effects (about 10 to 15 s after use) that last up to 60 min. They are rapidly and extensively metabolised, being the O-demethylated metabolite of AMB-FUBINACA, 2-(1-(4-fluorobenzyl)-1H-indazole-3-carboxamide)-3-methylbutanoic acid, the main excreted in urine, while for ADB-FUBINACA the main biomarkers are the hydroxdimethylpropyl ADB-FUBINACA, hydroxydehydrodimethylpropyl ADB-FUBINACA and hydroxylindazole ADB-FUBINACA. ADB-FUBINACA and AMB-FUBINACA display full agonism of the CB1 receptor, this being responsible for their cardiovascular and neurological effects (e.g., altered perception, agitation, anxiety, paranoia, hallucinations, loss of consciousness and memory, chest pain, hypertension, tachycardia, seizures). This review highlights the urgent requirement for additional studies on the toxicokinetic properties of AMB-FUBINACA and ADB-FUBINACA, as this is imperative to improve the methods for detecting and quantifying these drugs and to determine the best exposure markers in the various biological matrices. Furthermore, it stresses the need for clinicians and pathologists involved in the management of these intoxications to describe their findings in the scientific literature, thus assisting in the risk assessment and treatment of the harmful effects of these drugs in future medical and forensic investigations.
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Oakley, Karen L., Caroline B. Moore, and David W. Denning. "In Vitro Activity of the Echinocandin Antifungal Agent LY303,366 in Comparison with Itraconazole and Amphotericin B against Aspergillus spp." Antimicrobial Agents and Chemotherapy 42, no. 10 (October 1, 1998): 2726–30. http://dx.doi.org/10.1128/aac.42.10.2726.
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ABSTRACT LY303,366 (LY) is a novel derivative of the echinocandin class of antifungal agents. The in vitro activities of LY, itraconazole (ITZ), and amphotericin B (AMB) were assessed against 60Aspergillus isolates, including 35 isolates of A. fumigatus, eight isolates of A. terreus, eight isolates of A. flavus, eight isolates of A. niger and one isolate of A. nidulans. Four A. fumigatus isolates were resistant to ITZ. Susceptibility testing for all drugs was performed with a broth microdilution procedure. LY was tested in two media: antibiotic medium 3 (AM3) and Casitone with 2% glucose (CAS) with an inoculum of 2 × 103spores/ml. ITZ and AMB were tested in RPMI 1640 with 2% glucose with an inoculum of 1 × 106 spores/ml. All tests were incubated at 37°C for 48 h. A novel end point was used to determine a minimal effective concentration (MEC) for LY, i.e., almost complete inhibition of growth save a few tiny spherical colonies attached to the microplate. MICs were measured for ITZ and AMB with a no-growth end point. Ranges and geometric mean (GM) MECs were from 0.0018 to >0.5 and 0.0039 mg/liter and from 0.0018 to >0.5 and 0.008 mg/liter for LY in AM3 and LY in CAS, respectively. Differences between species were apparent, with A. flavus being significantly less susceptible to LY than any other species tested with both media (P ≤ 0.05). Ranges and GM MICs were from 0.125 to >16 and 0.7 mg/liter for ITZ and from 0.25 to 16 and 1.78 mg/liter for AMB. Minimal fungicidal concentrations (MFCs) were also determined for all drugs. GM MFCs were 0.018, 0.09, 19.76, and 12.64 mg/liter for LY in AM3, LY in CAS, ITZ, and AMB, respectively. LY in AM3 and LY in CAS were fungicidal for 86.7 and 68% of isolates, respectively (98% killing). In comparison, ITZ and AMB were fungicidal for 35 and 70% of isolates, respectively (99.99% killing). A reproducibility study was performed on 20% of the isolates. For 12 isolates retested, the MEC or MIC was the same or was within 1 dilution of the original value for 11, 11, 10, and 9 isolates for LY in AM3, LY in CAS, ITZ, and AMB, respectively. In conclusion, LY seems to be a promising antifungal agent with excellent in vitro activity against Aspergillusspp.
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Nobata, Shigenori, Maho Ogoshi, and Yoshio Takei. "Potent cardiovascular actions of homologous adrenomedullins in eels." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 294, no. 5 (May 2008): R1544—R1553. http://dx.doi.org/10.1152/ajpregu.00707.2007.
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Adrenomedullin (AM), known as a multifunctional hormone in mammals, forms a unique family of five paralogous peptides in teleost fish. To examine their cardiovascular effects using homologous AMs in eels, we isolated cDNAs encoding four eel AMs, and named AM1 (ortholog of mammalian AM), AM2, AM3 (paralog of AM2 generated only in teleost lineage), and AM5 according to the known teleost AM sequences. Unlike pufferfish, not only AM1 but AM2/3 and AM5 were expressed ubiquitously in various eel tissues. Synthetic mature AM1, AM2, and AM5 exhibited vasodepressor effects after intra-arterial injections, and the effects were more potent at dorsal aorta than at ventral aorta. This indicates that AMs preferentially act on peripheral resistance vessels rather than on branchial arterioles. The potency was in the order of AM2 = AM5 ≫ AM1 in both freshwater (FW) and seawater (SW) eels, which is different from the result of mammals in which AM1 is as potent as, or more potent than, AM2 when injected peripherally. The minimum effective dose of AM2 and AM5 in eels was 1/10 that of AM1 in mammals. The hypotension reached 50% at 1.0 nmol/kg of AM2 and AM5, which is much greater than atrial natriuretic peptide (20%), another potent vasodepressor hormone. Even with such hypotension, AMs did not change heart rate in eels. In addition, AM1 increased blood pressure at ventral aorta and dorsal aorta immediately after an initial hypotension at 5.0 nmol/kg, but not with AM2 and AM5. These data strongly suggest that specific receptors for AM2 and AM5 exist in eels, which differ from the AM1 receptors identified in mammals.
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Louie, Arnold, Pamela Kaw, Partha Banerjee, Weiguo Liu, George Chen, and Michael H. Miller. "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 45, no. 2 (February 1, 2001): 485–94. http://dx.doi.org/10.1128/aac.45.2.485-494.2001.
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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.
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Go, Seok Jo, Chi Yen Kim, Min Kyu Park, Young Jin Lee, and Bin Yao. "Development of Exclusive Controller and HILS for Active Magnetic Bearing System." Applied Mechanics and Materials 241-244 (December 2012): 1365–69. http://dx.doi.org/10.4028/www.scientific.net/amm.241-244.1365.
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The active magnetic bearing system has been studied for long period. Comparing with long research history, the AMB application into industrial field is shown slowly for various causes. One of primary factor is to make up exclusive controller which can generate fast linear current output. Thus, this paper developed the exclusive AMB controller mounted high speed DSP which can operate so fast control calculation that improve system response ability. Especially, to consider the fusion of AMB system and control software, the development is conducted in HILS system with dSPACE from the beginning. Although HILS system is adopted, the developed ABM controller simplified the whole system and could make up optimized control algorithm promptly by measuring and applying the system gain and characteristics of them monitored by the HILS system in real time.
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Otsubo, Takakazu, Kazuo Maruyama, Shigefumi Maesaki, Yoshitsugu Miyazaki, Eitaro Tanaka, Tomoko Takizawa, Kunikazu Moribe, Kazunori Tomono, Takayoshi Tashiro, and Shigeru Kohno. "Long-Circulating Immunoliposomal Amphotericin B against Invasive Pulmonary Aspergillosis in Mice." Antimicrobial Agents and Chemotherapy 42, no. 1 (January 1, 1998): 40–44. http://dx.doi.org/10.1128/aac.42.1.40.
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ABSTRACT We investigated the efficacy of long-circulating immunoliposomal amphotericin B (AmB) against invasive pulmonary aspergillosis in mice using three types of liposomal AmB: conventional liposomal AmB (AmBisome), a long-circulating liposomal AmB and prepared by coating the liposome surface with polyethylene glycol (PEG; PEG-L-AmB), long-circulating immunoliposomal AmB (34A-PEG-L-AmB). The survival rates for mice with invasive pulmonary aspergillosis treated with an intravenous dose of 2 mg of AmBisome, PEG-L-AmB, or 34A-PEG-L-AmB per kg of body weight were 16.7, 83.3, and 100%, respectively. Treatment with 34A-PEG-L-AmB produced a marked reduction in the number ofAspergillus fumigatus organisms in the lungs. Pharmacokinetic studies showed the presence of high AmB concentrations in the plasma of mice treated with PEG-L-AmB (40.8 μg/ml) and in the lungs of mice treated with 34A-PEG-L-AmB (42.3 μg/g). We conclude that 34A-PEG-L-AmB, a long-circulating immunoliposomal AmB, is a promising form of AmB against invasive pulmonary aspergillosis.
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Hickson, Ford, Max Appenroth, Uwe Koppe, Axel J. Schmidt, David Reid, and Peter Weatherburn. "Sexual and Mental Health Inequalities across Gender Identity and Sex-Assigned-at-Birth among Men-Who-Have-Sex-with-Men in Europe: Findings from EMIS-2017." International Journal of Environmental Research and Public Health 17, no. 20 (October 10, 2020): 7379. http://dx.doi.org/10.3390/ijerph17207379.
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Some men who have sex with men (MSM) were assigned female at birth (AFB) and/or identify as trans men. Little is known about how these men differ from other MSM. We compared sexual and mental health indicators from the European MSM Internet Survey (EMIS-2017), comparing men AFB and/or currently identifying as trans men with those assigned male at birth (AMB) who identified as men. EMIS-2017 was an opportunistic 33-language online sexual health survey for MSM recruiting throughout Europe. We used regression models adjusting for age, country of residence and employment status to examine differences across groups. An analytic sample of 125,720 men living in 45 countries was used, of which 674 (0.5%) were AFB and 871 (0.7%) identified as trans men. The two sub-groups were not coterminous, forming three minority groups: AFB men, AFB trans men and AMB trans men. Minority groups were younger and more likely unemployed. Anxiety, depression, alcohol dependence and sexual unhappiness were more prevalent in sex/gender minority men. Conversely HIV and STI diagnoses were less common. AMB trans men were most likely to have sexual risk behavior with steady partners and to have unmet health promotion needs, and were least likely to be reached by interventions. Sex assigned at birth and trans identification were associated with different sexual and mental health needs. To facilitate service planning and to foster inclusion, sex-assigned-at-birth and current gender identity should be routinely collected in health surveys.
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Goldblum, David, Kaspar Rohrer, Beatrice E. Frueh, Regula Theurillat, Wolfgang Thormann, and Stefan Zimmerli. "Ocular Distribution of Intravenously Administered Lipid Formulations of Amphotericin B in a Rabbit Model." Antimicrobial Agents and Chemotherapy 46, no. 12 (December 2002): 3719–23. http://dx.doi.org/10.1128/aac.46.12.3719-3723.2002.
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ABSTRACT Little is known about the ocular penetration of amphotericin B (AMB) and its lipid formulations, the current drug of choice in fungal endophthalmitis. The ocular distribution of AMB lipid complex (ABLC), liposomal AMB (L-AMB), and AMB deoxycholate (D-AMB) was studied in a rabbit model. D-AMB (1 mg/kg of body weight/day), ABLC (5 mg/kg/day), or L-AMB (5 mg/kg/day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7 consecutive days after induction of unilateral uveitis by intravitreal injection of endotoxin. AMB concentrations in aqueous humor, vitreous humor, and plasma were determined by high-pressure liquid chromatography 16 h after administration of a single dose or 24 h after the last of seven doses. After single-dose administration, L-AMB achieved at least eightfold-higher AMB concentrations in the aqueous of inflamed eyes than ABLC or D-AMB (1.21 ± 0.58 μg/ml versus 0.14 ± 0.04 and 0.11 ± 0.09 μg/ml, respectively). At that time point no drug was detectable in the vitreous. After 7 days of treatment, the concentration of AMB in the vitreous was higher after treatment with L-AMB (0.47 ± 0.21 μg/ml) than after treatment with ABLC (0.27 ± 0.18 μg/ml) and D-AMB (0.16 ± 0.04 μg/ml). Similarly, AMB concentration in the aqueous was higher after repeated doses of L-AMB (0.73 ± 0.43 μg/ml) than after repeated doses of ABLC (0.03 ± 0.02 μg/ml) or D-AMB (0.13 ± 0.06 μg/ml). No AMB was detected in noninflamed eyes. Following systemic administration, AMB distribution to the eye is inflammation dependent and occurs sequentially, first to the aqueous and then to the vitreous. Compared to D-AMB and ABLC, L-AMB reaches higher drug concentrations in both ocular compartments.
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Nimtrakul, Pataranapa, Waree Tiyaboonchai, and Supaporn Lamlertthon. "Amphotericin B Loaded Nanostructured Lipid Carriers for Parenteral Delivery: Characterization, Antifungal and In vitro Toxicity Assessment." Current Drug Delivery 16, no. 7 (October 3, 2019): 645–53. http://dx.doi.org/10.2174/1567201816666190729145223.
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Background: Amphotericin B (AmB) is important for the treatment of systemic fungal infections. Nowadays, only intravenous administration (IV) of AmB has been available due to its low aqueous solubility. Two forms of AmB are available. The first is Fungizone®, a mixture of AmB and sodium deoxcycholate that produces severe nephrotoxicity. The second are lipid-based formulations that reduce nephrotoxicity, but they are costly and require higher dose than Fungizone®. Thus, a cheaper delivery system with reduced AmB toxicity is required. Objective: To develop and characterize AmB loaded-nanostructured lipid carriers (AmB-loaded NLCs) for IV administration to reduce AmB toxicity. Methods: AmB-loaded NLCs with different solid lipids were prepared by the high-pressure homogenization technique. Their physicochemical properties and the drug release profile were examined. The molecular structure of AmB, antifungal and hemolysis activities of developed AmB-loaded NLCs were also evaluated. Results: AmB-loaded NLCs ~110 to ~140 nm in diameter were successfully produced with a zeta potential of ~-19 mV and entrapment efficiency of ~75%. In vitro release showed fast release characteristics. AmB-loaded NLCs could reduce the AmB molecular aggregation as evident from the absorbance ratio of the first to the fourth peak showing a partial aggregation of AmB. This result suggested that AmB-loaded NLCs could offer less nephrotoxicity compared to Fungizone®. In vitro antifungal activity of AmB-loaded NLCs showed a minimum inhibitory concentration of 0.25 µgmL-1. Conclusion: AmB-loaded NLCs present high potential carriers for effective IV treatment with prolonged circulation time and reduced toxicity.
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Risovic, Verica, Michael Boyd, Eugene Choo, and Kishor M. Wasan. "Effects of Lipid-Based Oral Formulations on Plasma and Tissue Amphotericin B Concentrations and Renal Toxicity in Male Rats." Antimicrobial Agents and Chemotherapy 47, no. 10 (October 2003): 3339–42. http://dx.doi.org/10.1128/aac.47.10.3339-3342.2003.
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ABSTRACT The purpose of this study was to determine the effects of various lipid and mixed-micelle formulations on the oral absorption and renal toxicity of amphotericin B (AMB) in rats. The maximum concentration of AMB in plasma and the area under the concentration-time curve for 0 to 24 h for AMB were elevated in rats administered triglyceride (TG)-rich AMB formulations in comparison to those in rats given (i) AMB preformulated as a micelle containing sodium deoxycholate with sodium phosphate as a buffer (DOC-AMB), (ii) an AMB-lipid complex suspension, or (iii) AMB solubilized in methanol. Furthermore, our findings suggest that AMB incorporated into TG-based oral formulations has less renal toxicity than DOC-AMB.
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Dórea, E. L., L. Yu, I. De Castro, S. B. Campos, M. Ori, E. M. Vaccari, C. da S. Lacaz, and A. C. Seguro. "Nephrotoxicity of amphotericin B is attenuated by solubilizing with lipid emulsion." Journal of the American Society of Nephrology 8, no. 9 (September 1997): 1415–22. http://dx.doi.org/10.1681/asn.v891415.
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Nephrotoxicity is the major adverse effect of conventional amphotericin B (AMB/D), often limiting administration of full dosage. The new liposomal amphotericin B seems to be less toxic. The new liposomal amphotericin B seems to be less toxic. In this study, it is proposed that solubilizing the standard AMB/D preparation with 10% lipid emulsion will attenuate nephrotoxicity. Rats were injected with either AMB/D (Fungizone), AMB, AMB/D plus lipid emulsion (AMB/D/LE), or sodium deoxycholate (D). Renal function studies were performed on day 5. To assess a direct tubular toxic effect, isolated rat proximal tubule suspensions and inner medullary collecting duct cells in culture were exposed to AMB/D, AMB, AMB/D/LE, liposomal amphotericin B, and D for 60 min in normoxia. Lactate dehydrogenase (LDH) release was assessed as an index of cell injury. Creatinine clearance (ml/min per 100 g) averaged 0.79 +/- 0.04 in control rats, 0.29 +/- 0.09 in AMB rats (P < 0.001 versus control), 0.38 +/- 0.04 in AMB/D rats, 0.46 +/- 0.05 in D rats, and 0.78 +/- 0.03 in AMB/LE rats. Renal blood flow (ml/min per 100 g) was 3.45 +/- 0.31 in control, 1.29 +/- 0.28 in AMB, 1.42 +/- 0.23 in AMB/D, 3.03 +/- 0.39 in D, and 2.71 +/- 0.21 in AMB/D/LE rats. The fractional excretion of potassium (%) was 27.3 +/- 1.18 in control rats, 61.6 +/- 7.00 in AMB/D rats, 58.4 +/- 15.32 in AMB rats, and 37.9 +/- 2.06 in AMB/D/LE rats. LDH release (%) in proximal tubules incubated with AMB/D and D was 43.6 +/- 3.39 and 58.6 +/- 4.20, respectively. Addition of lipid emulsion decreased LDH release: 21.6 +/- 1.22 for AMB/D/LE and 26.4 +/- 3.03 for deoxycholate plus lipid emulsion. AMB did not demonstrate any toxic effect in proximal tubule suspensions. D was not toxic to inner medullary collecting duct cells at 0.16 mg/ml, whereas D at a higher dose and AMB induced a significant LDH release. Addition of lipid emulsion did not affect the antifungal activity as assessed by the Etest method. In conclusion, an alternative way of administering standard AMB with reduced nephrotoxicity is proposed.
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Nimtrakul, Pataranapa, Desmond B. Williams, Waree Tiyaboonchai, and Clive A. Prestidge. "Copolymeric Micelles Overcome the Oral Delivery Challenges of Amphotericin B." Pharmaceuticals 13, no. 6 (June 11, 2020): 121. http://dx.doi.org/10.3390/ph13060121.
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Classified as a Biopharmaceutical Classification System (BCS) class IV drug, amphotericin B (AmB) has low aqueous solubility and low permeability leading to low oral bioavailability. To improve these limitations, this study investigated the potential of AmB-loaded polymeric micelles (AmB-PM) to increase intestinal absorption. AmB-PM were prepared with polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol copolymer (Soluplus®) as a polymeric carrier and used a modified solvent diffusion and microfluidics (NanoAssemblr®) method. AmB-PM have a mean particle size of ~80 nm and are mono-disperse with a polydispersity index <0.2. The entrapment efficiency of AmB was up to 95% and achieved with a high drug loading up to ~20% (w/w) with a total amount of incorporated drug of 1.08 ± 0.01 mg/mL. Importantly, compared to free drug, AmB-PM protected AmB from degradation in an acidic (simulated gastric) environment. Viability studies in Caco-2 cells confirmed the safety/low toxicity of AmB-PM. In vitro cellular absorption studies confirmed that AmB-PM increased AmB uptake in Caco-2 cells 6-fold more than free AmB (i.e., 25% compared with 4% within 30 min). Furthermore, the permeability of AmB across Caco-2 monolayers was significantly faster (2-fold) and more pronounced for AmB-PM in comparison to free drug (3.5-fold increase). Thus, the developed AmB-PM show promise as a novel oral delivery system for AmB and justifies further investigation.
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Walker, Scott, Sandra A. N. Tailor, Mark Lee, Lisa Louie, Marie Louie, and Andrew E. Simor. "Amphotericin B in Lipid Emulsion: Stability, Compatibility, and In Vitro Antifungal Activity." Antimicrobial Agents and Chemotherapy 42, no. 4 (April 1, 1998): 762–66. http://dx.doi.org/10.1128/aac.42.4.762.
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ABSTRACT Newer formulations of amphotericin B (AmB) complexed with liposomes or lipid suspensions have been developed. Preliminary studies have suggested that AmB in Intralipid (IL) may be as effective as, but less toxic than, conventional formulations of AmB, but few data are available regarding its stability, compatibility, or in vitro antifungal activity. A compatibility study was done to evaluate the effects of AmB concentrations in IL containing either 10 or 20% soybean oil. The effects of temperature, shaking, and AmB and IL concentrations on the stability of AmB-IL suspensions were analyzed by visual inspection and liquid chromatography. The in vitro antifungal activity of AmB-IL, compared to that of AmB alone against reference strains of Candida species was determined by using a broth macrodilution method in accordance with National Committee for Clinical Laboratory Standards guidelines (M27-T). Samples of AmB-IL which were lightly shaken retained more than 90% of the AmB concentration over 21 days when stored at either 4 or 23°C. Varying the AmB concentration did not appear to affect the stability of AmB-IL. However, a precipitate was formed when mixtures with more than 30% lipid as a proportion of the total volume were centrifuged. AmB-IL and AmB alone had similar in vitro antifungal activities against reference strains of yeasts. Further pharmacologic and clinical studies with AmB-IL are warranted, although AmB should not be combined with IL in concentrations capable of producing a precipitate.
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Ruijgrok, Elisabeth J., Marcel H. A. M. Fens, Irma A. J. M. Bakker-Woudenberg, Els W. M. van Etten, and Arnold G. Vulto. "Nebulized Amphotericin B Combined with Intravenous Amphotericin B in Rats with Severe Invasive Pulmonary Aspergillosis." Antimicrobial Agents and Chemotherapy 50, no. 5 (May 2006): 1852–54. http://dx.doi.org/10.1128/aac.50.5.1852-1854.2006.
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ABSTRACT Nebulized amphotericin B (AMB) combined with intravenous AMB was studied in persistently leukopenic rats with invasive pulmonary aspergillosis. Pulmonary concentrations of AMB after aerosol treatment were substantially higher than after intravenous liposomal AMB. Nebulized liposomal AMB in addition to intravenous AMB resulted in significantly prolonged survival compared to controls.
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Bekersky, Ihor, Robert M. Fielding, Dawna E. Dressler, Jean W. Lee, Donald N. Buell, and Thomas J. Walsh. "Plasma Protein Binding of Amphotericin B and Pharmacokinetics of Bound versus Unbound Amphotericin B after Administration of Intravenous Liposomal Amphotericin B (AmBisome) and Amphotericin B Deoxycholate." Antimicrobial Agents and Chemotherapy 46, no. 3 (March 2002): 834–40. http://dx.doi.org/10.1128/aac.46.3.834-840.2002.
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ABSTRACT Unilamellar liposomal amphotericin B (AmBisome) (liposomal AMB) reduces the toxicity of this antifungal drug. The unique composition of liposomal AMB stabilizes the liposomes, producing higher sustained drug levels in plasma and reducing renal and hepatic excretion. When liposomes release their drug payload, unbound, protein-bound, and liposomal drug pools may exist simultaneously in the body. To determine the amounts of drug in these pools, we developed a procedure to measure unbound AMB in human plasma by ultrafiltration and then used it to characterize AMB binding in vitro and to assess the pharmacokinetics of nonliposomal pools of AMB in a phase IV study of liposomal AMB and AMB deoxycholate in healthy subjects. We confirmed that AMB is highly bound (>95%) in human plasma and showed that both human serum albumin and α1-acid glycoprotein contribute to this binding. AMB binding exhibited an unusual concentration dependence in plasma: the percentage of bound drug increased as the AMB concentration increased. This was attributed to the low solubility of AMB in plasma, which limits the unbound drug concentration to <1 μg/ml. Subjects given 2 mg of liposomal AMB/kg of body weight had lower exposures (as measured by the maximum concentration of drug in serum and the area under the concentration-time curve) to both unbound and nonliposomal drug than those receiving 0.6 mg of AMB deoxycholate/kg. Most of the AMB in plasma remained liposome associated (97% at 4 h, 55% at 168 h) after liposomal AMB administration, so that unbound drug concentrations remained at <25 ng/ml in all liposomal AMB-treated subjects. Although liposomal AMB markedly reduces the total urinary and fecal recoveries of AMB, urinary and fecal clearances based on unbound AMB were similar (94 to 121 ml h−1 kg−1) for both formulations. Unbound drug urinary clearances were equal to the glomerular filtration rate, and tubular transit rates were <16% of the urinary excretion rate, suggesting that net filtration of unbound drug, with little secretion or reabsorption, is the mechanism of renal clearance for both conventional and liposomal AMB in humans. Unbound drug fecal clearances were also similar for the two formulations. Thus, liposomal AMB increases total AMB concentrations while decreasing unbound AMB concentrations in plasma as a result of sequestration of the drug in long-circulating liposomes.
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Bekersky, Ihor, Robert M. Fielding, Dawna E. Dressler, Jean W. Lee, Donald N. Buell, and Thomas J. Walsh. "Pharmacokinetics, Excretion, and Mass Balance of Liposomal Amphotericin B (AmBisome) and Amphotericin B Deoxycholate in Humans." Antimicrobial Agents and Chemotherapy 46, no. 3 (March 2002): 828–33. http://dx.doi.org/10.1128/aac.46.3.828-833.2002.
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ABSTRACT The pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) (liposomal AMB) and the conventional formulation, AMB deoxycholate (AMB-DOC), were compared in a phase IV, open-label, parallel study in healthy volunteers. After a single 2-h infusion of 2 mg of liposomal AMB/kg of body weight or 0.6 mg of AMB-DOC/kg, plasma, urine, and feces were collected for 168 h. The concentrations of AMB were determined by liquid chromatography tandem mass spectrometry (plasma, urine, feces) or high-performance liquid chromatography (HPLC) (plasma). Infusion-related side effects similar to those reported in patients, including nausea and back pain, were observed in both groups. Both formulations had triphasic plasma profiles with long terminal half-lives (liposomal AMB, 152 ± 116 h; AMB-DOC, 127 ± 30 h), but plasma concentrations were higher (P < 0.01) after administration of liposomal AMB (maximum concentration of drug in serum [C max], 22.9 ± 10 μg/ml) than those of AMB-DOC (C max, 1.4 ± 0.2 μg/ml). Liposomal AMB had a central compartment volume close to that of plasma (50 ± 19 ml/kg) and a volume of distribution at steady state (V ss) (774 ± 550 ml/kg) smaller than the V ss of AMB-DOC (1,807 ± 239 ml/kg) (P < 0.01). Total clearances were similar (approximately 10 ml hr−1 kg−1), but renal and fecal clearances of liposomal AMB were 10-fold lower than those of AMB-DOC (P < 0.01). Two-thirds of the AMB-DOC was excreted unchanged in the urine (20.6%) and feces (42.5%) with >90% accounted for in mass balance calculations at 1 week, suggesting that metabolism plays at most a minor role in AMB elimination. In contrast, <10% of the liposomal AMB was excreted unchanged. No metabolites were observed by HPLC or mass spectrometry. In comparison to AMB-DOC, liposomal AMB produced higher plasma exposures and lower volumes of distribution and markedly decreased the excretion of unchanged drug in urine and feces. Thus, liposomal AMB significantly alters the excretion and mass balance of AMB. The ability of liposomes to sequester drugs in circulating liposomes and within deep tissue compartments may account for these differences.
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Trejtnar, František, Jana Mandíková, Jana Kočíncová, and Marie Volková. "Renal Handling of Amphotericin B and Amphotericin B-Deoxycholate and Potential Renal Drug-Drug Interactions with Selected Antivirals." Antimicrobial Agents and Chemotherapy 58, no. 10 (June 23, 2014): 5650–57. http://dx.doi.org/10.1128/aac.02829-14.
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ABSTRACTAmphotericin B (AmB) is excreted via the renal excretion route. This excretion process may result in nephrotoxicity. However, relevant information on the precise renal excretion mechanisms is not available. The aim of the study was to analyze the possible interaction of AmB or its prodrug AmB deoxycholate (AmB-DOC) with the typical renal organic anion transporters (OATs) and organic cation transporters (OCTs), using cellular and organ models. The relevant transport systems were then investigated in terms of the drug-drug interactions of AmB-DOC with antivirals that might potentially be used concomitantly. To analyze the renal excretion mechanisms of [3H]AmB, perfused rat kidney was employed. HeLa and MDCK II cells transiently transfected with human OAT1 (hOAT1) or hOCT2 were used as the cellular models. A significant tubular secretion of AmB was demonstrated in the perfused rat kidney. The cellular studies performed confirmed the active transport of AmB into cells. AmB did not interact with hOAT1 but strongly inhibited hOCT2. In contrast, AmB-DOC inhibited both hOAT1 and hOCT2. However, [3H]AmB cellular uptake by hOAT1 and hOCT2 was not found. AmB-DOC interacted significantly with adefovir, tenofovir, and cidofovir in hOAT1-transfected cells at supratherapeutic concentrations. In conclusion, the significant potency of AmB and AmB-DOC for inhibiting the transporters was demonstrated in this study. The secretion of AmB in the renal tubules is likely not related to the transporters here, since the drug was not proven to be a substrate for them. Drug-drug interactions of AmB and the antivirals used in this study on the investigated transporters are not probable.
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Inselmann, G., A. Volkmann, and H. T. Heidemann. "Comparison of the Effects of Liposomal Amphotericin B and Conventional Amphotericin B on Propafenone Metabolism and Hepatic Cytochrome P-450 in Rats." Antimicrobial Agents and Chemotherapy 44, no. 1 (January 1, 2000): 131–33. http://dx.doi.org/10.1128/aac.44.1.131-133.2000.
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ABSTRACT The effects of conventional amphotericin B (AmB) dissolved in sodium deoxycholate on microsomal cytochrome P-450 concentrations and propafenone metabolism to 5-hydroxy-propafenone andN-desalkyl-propafenone were compared with those of liposomal AMB (Li-AMB) in rats. AmB (3 mg/kg/day, intravenously [i.v.]) given for 4 days caused a significant decrease in the concentration of hepatic microsomal cytochrome P-450 (0.43 ± 0.06 nmol/mg versus 0.62 ± 0.05 nmol/mg for the control [P < 0.05]). Following the application of Li-AMB (15 mg/kg/day, i.v.), hepatic microsomal cytochrome P-450 concentrations were unchanged at 0.64 ± 0.08 nmol/mg. AmB decreased ex vivo propafenone metabolism to 5-hydroxy-propafenone andN-desalkyl-propafenone significantly. Sodium deoxycholate (the vehicle of AmB) by itself induced a significant decline of 5-hydroxy-propafenone and N-desalkyl-propafenone production, while microsomal cytochrome P-450 concentrations remained unchanged. In contrast, Li-AMB did not change the levels of production of 5-hydroxy-propafenone or of N-desalkyl-propafenone at either substrate concentration tested (50 μmol and 200 μmol). Microsomal AmB concentrations were significantly higher following Li-AMB application (21.1 ± 6.2 μg/g versus 3.7 ± 1.4 μg/g for AmB [P < 0.05]). We conclude that Li-AMB, in contrast to AmB, decreases neither hepatic microsomal cytochrome P-450 nor hepatic propafenone metabolism in rats ex vivo. Sodium deoxycholate alone decreases propafenone metabolism in a similar way to AmB, suggesting that it participates in AmB-induced disturbance of hepatic metabolic function.
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Nath, Christa E., Peter J. Shaw, Robyn Gunning, Andrew J. McLachlan, and John W. Earl. "Amphotericin B in Children with Malignant Disease: a Comparison of the Toxicities and Pharmacokinetics of Amphotericin B Administered in Dextrose versus Lipid Emulsion." Antimicrobial Agents and Chemotherapy 43, no. 6 (June 1, 1999): 1417–23. http://dx.doi.org/10.1128/aac.43.6.1417.
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ABSTRACT In a prospective, randomized clinical trial, the toxicity of 1 mg of amphotericin B (AmB) per kg of body weight per day infused in 5% dextrose was compared with that of AmB infused in lipid emulsion in children with malignant disease. In an analysis of 82 children who received a full course of 6 days or more of AmB (117 courses), it was shown that there were significant increases in plasma urea and creatinine concentrations and in potassium requirement after 6 days of therapy with both AmB infused in dextrose and AmB infused in lipid emulsion, with there being no difference between the two methods of AmB administration. An intent-to-treat comparison of the numbers of courses affected by acute toxicity (fever, rigors) and chronic toxicity (nephrotoxicity) also indicated that there was no significant difference between AmB infused in dextrose (78 courses) and AmB infused in lipid emulsion (84 courses). The pharmacokinetics of AmB were investigated in 20 children who received AmB in dextrose and 15 children who received AmB in lipid emulsion. Blood samples were collected up to 24 h after administration of the first dose, and the concentration of AmB in plasma was analyzed by a high-performance liquid chromatography assay. The clearance (CL) of AmB in dextrose (0.039 ± 0.016 liter · h−1 · kg−1) was significantly lower (P < 0.005) than the CL of AmB in lipid emulsion (0.062 ± 0.024 liter · h−1 · kg−1). The steady-state volume of distribution for AmB in dextrose (0.83 ± 0.33 liter · kg−1) was also significantly lower (P < 0.005) than that for AmB in lipid emulsion (1.47 ± 0.77 liter · kg−1). Although AmB in lipid emulsion is apparently cleared faster and distributes more widely than AmB in dextrose, this study did not reveal any significant advantage with respect to safety and tolerance in the administration of AmB in lipid emulsion compared to its administration in dextrose in children with malignant disease.
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Xu, Hongmei, Fangfang Teng, Feilong Zhou, Li Zhu, Yi Wen, Runliang Feng, and Zhimei Song. "Linolenic acid-modified MPEG-PEI micelles for encapsulation of amphotericin B." Future Medicinal Chemistry 11, no. 20 (October 2019): 2647–62. http://dx.doi.org/10.4155/fmc-2018-0580.
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Aim: To encapsulate amphotericin B (AmB) with reduced toxicity and comparable activity. Results & methodology: The α-linolenic acid (ALA)-modified monomethoxy polyethylene glycol-g-PEI-g-ALA conjugate was employed to prepare AmB-loaded micelles (AmB-M). In vitro activity and release behavior of AmB-M were investigated. AmB-M enhanced AmB's water-solubility to 1.2 mg/ml, showing good storage stability. AmB-M could achieve a sustained and slow release of AmB, low hemolysis activity and negligible kidney toxicity when compared with commercial AmB injection. Antifungal activity and biofilm inhibition experiments confirmed that the antifungal activity of AmB-M against Candida albicans was similar to that of AmB injection. Conclusion: Monomethoxy polyethylene glycol-g-PEI-g-ALA micelles could be a preferable choice to treat systemic fungal infections as an efficient drug delivery system.
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Otsubo, Takakazu, Shigefumi Maesaki, Mohammad Ashraf Hossain, Yoshihiro Yamamoto, Kazunori Tomono, Takayoshi Tashiro, Junzo Seki, Yoshifumi Tomii, Satoru Sonoke, and Shigeru Kohno. "In Vitro and In Vivo Activities of NS-718, a New Lipid Nanosphere Incorporating Amphotericin B, againstAspergillus fumigatus." Antimicrobial Agents and Chemotherapy 43, no. 3 (March 1, 1999): 471–75. http://dx.doi.org/10.1128/aac.43.3.471.
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ABSTRACT We evaluated the in vitro and in vivo potencies of a new lipid nanosphere that incorporates amphotericin B (AmB), NS-718, againstAspergillus fumigatus. The in vitro activity of NS-718 (the MIC at which 90% of strains are inhibited [MIC90], 0.25 μg/ml) against 18 isolates of A. fumigatus was similar to that of deoxycholate AmB (D-AmB; Fungizone; MIC90, 0.25 μg/ml), but NS-718 was more potent than liposomal AmB (L-AmB; AmBisome; MIC90, 1.0 μg/ml). The in vivo efficacy of NS-718 in a rat model of invasive pulmonary aspergillosis was compared with those of D-AmB and L-AmB. A low dose (1 mg/kg of body weight) of L-AmB was ineffective (survival rate, 0%), although equivalent doses of D-AmB and NS-718 were more effective (survival rate, 17%). However, a higher dose of NS-718 (3 mg/kg) was more effective (survival rate, 100%) than equivalent doses of D-AmB and L-AmB (survival rate, 0%). To explain these differences, pharmacokinetic studies showed higher concentrations of AmB in the plasma of rats treated with NS-718 than in the plasma of those treated with D-AmB. Our results suggest that NS-718, a new preparation of AmB, is a promising antifungal agent with activity against pulmonary aspergillosis.
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Stergiopoulou, Theodouli, Joseph Meletiadis, Tin Sein, Paraskevi Papaioannidou, Thomas J. Walsh, and Emmanuel Roilides. "Synergistic Interaction of the Triple Combination of Amphotericin B, Ciprofloxacin, and Polymorphonuclear Neutrophils against Aspergillus fumigatus." Antimicrobial Agents and Chemotherapy 55, no. 12 (September 12, 2011): 5923–29. http://dx.doi.org/10.1128/aac.00548-11.
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ABSTRACTAspergillusis damaged by polymorphonuclear neutrophils (PMNs) by means of nonoxidative and oxidative mechanisms, which may be affected by antifungal and antibacterial agents that patients with invasive pulmonary aspergillosis often receive. The pharmacodynamic interactions among deoxycholate amphotericin B (AMB), ciprofloxacin (CIP), and human PMNs againstAspergillus fumigatusgrowth are unknown. We therefore studied the interactions between 0.032 to 2.0 μg/ml of AMB, 0.1 to 50 μg/ml of CIP at a fixed AMB/CIP ratio of 1:3.125, and PMNs from six donors at an effector-to-target (E:T) ratio of 400:1 against a clinicalA. fumigatusisolate using an XTT metabolic assay and the Bliss independence pharmacodynamic-interaction model. CIP exhibited no antifungal activity alone or in combination with PMNs. Synergy was found between AMB and PMNs, with interaction indices (II) of 0.06 to 0.21; the highest interaction of 21% ± 3.6% was observed at 0.22 ± 0.09 μg/ml of AMB. The AMB and CIP (AMB+CIP) combination was synergistic (II = 0.39) at low AMB concentrations and antagonistic (II = 1.39) at high AMB concentrations, with a maximal synergistic interaction of 16% ± 3.7% observed at 0.16 ± 0.08 μg/ml of AMB. The triple combination AMB+CIP+PMNs was synergistic, with interaction indices of 0.05 to 0.20, and a maximal synergistic interaction of 24% ± 4% was observed at 0.20 ± 0.07 μg/ml of AMB. The increased percentage of Bliss synergy of the triple combination AMB+CIP+PMNs (24% ± 4%) was the product of those of the constituent double combinations AMB+PMNs (21% ± 3.6%) and AMB+CIP (16% ± 3.7%). Thus, the antifungal activity of AMB, at clinically relevant concentrations, was enhanced in combination with PMNs and CIP againstA. fumigatusgrowth in a concentration-dependent manner.
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Groll, Andreas H., Diana Mickiene, Stephen C. Piscitelli, and Thomas J. Walsh. "Distribution of Lipid Formulations of Amphotericin B into Bone Marrow and Fat Tissue in Rabbits." Antimicrobial Agents and Chemotherapy 44, no. 2 (February 1, 2000): 408–10. http://dx.doi.org/10.1128/aac.44.2.408-410.2000.
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ABSTRACT The distribution of the three currently available lipid formulations of amphotericin B (AmB) into bone marrow and fat tissue was evaluated in noninfected rabbits. Groups of four animals each received either 1 mg of AmB deoxycholate (D-AmB) per kg of body weight per day or 5 mg of AmB colloidal dispersion, AmB lipid complex, or liposomal AmB per kg per day for seven doses. Plasma, bone marrow, fat, and liver were collected at autopsy, and AmB concentrations were determined by high-performance liquid chromatography. At the investigated dosages of 5 mg/kg/day, all AmB lipid formulations achieved at least fourfold-higher concentrations in bone marrow than did standard D-AmB at a dosage of 1 mg/kg/day. Concentrations in bone marrow were 62 to 76% of concurrent AmB concentrations in the liver. In contrast, all AmB formulations accumulated comparatively poorly in fat tissue. The results of this study show that high concentrations of AmB can be achieved in the bone marrow after administration of lipid formulations, suggesting their particular usefulness against disseminated fungal infections involving the bone marrow and against visceral leishmaniasis.
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Blum, Gerhard, Caroline Hörtnagl, Emina Jukic, Thomas Erbeznik, Thomas Pümpel, Hermann Dietrich, Markus Nagl, Cornelia Speth, Günter Rambach, and Cornelia Lass-Flörl. "New Insight into Amphotericin B Resistance in Aspergillus terreus." Antimicrobial Agents and Chemotherapy 57, no. 4 (January 14, 2013): 1583–88. http://dx.doi.org/10.1128/aac.01283-12.
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ABSTRACTAmphotericin B (AMB) is the predominant antifungal drug, but the mechanism of resistance is not well understood. We compared thein vivovirulence of an AMB-resistantAspergillus terreus(ATR) isolate with that of an AMB-susceptibleA. terreusisolate (ATS) using a murine model for disseminated aspergillosis. Furthermore, we analyzed the molecular basis of intrinsic AMB resistancein vitroby comparing the ergosterol content, cell-associated AMB levels, AMB-induced intracellular efflux, and prooxidant effects between ATR and ATS. Infection of immunosuppressed mice with ATS or ATR showed that the ATS strain was more lethal than the ATR strain. However, AMB treatment improved the outcome in ATS-infected mice while having no positive effect on the animals infected with ATR. Thein vitrodata demonstrated that ergosterol content is not the molecular basis for AMB resistance. ATR absorbed less AMB, discharged more intracellular compounds, and had better protection against oxidative damage than the susceptible strain. Our experiments showed that ergosterol content plays a minor role in intrinsic AMB resistance and is not directly associated with intracellular cell-associated AMB content. AMB might exert its antifungal activity by oxidative injury rather than by an increase in membrane permeation.
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Sánchez-Brunete, J. A., M. A. Dea, S. Rama, F. Bolás, J. M. Alunda, R. Raposo, M. T. Méndez, S. Torrado-Santiago, and J. J. Torrado. "Treatment of Experimental Visceral Leishmaniasis with Amphotericin B in Stable Albumin Microspheres." Antimicrobial Agents and Chemotherapy 48, no. 9 (September 2004): 3246–52. http://dx.doi.org/10.1128/aac.48.9.3246-3252.2004.
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ABSTRACT Hydrophilic albumin microspheres are proposed as a new delivery system for amphotericin B (AMB; AMB microspheres). The acute toxicity of AMB microspheres was lower than that of the AMB-deoxycholate (AMB-Doc) reference formulation in hamsters. Lethal doses in healthy and infected animals were improved at least eight times. Intravenous bolus administration of doses of AMB microspheres up to 40 mg/kg of body weight did not produce acute symptoms of toxicity. The efficacy of this new formulation was tested against Leishmania infantum-infected hamsters at doses of 2, 10, 20, and 40 mg/kg. With the 2-mg/kg dose, the activity of AMB, as assessed through the parasite load reductions in the liver and spleen and the evolution of antibody levels, was also improved (P < 0.05) by use of the AMB microsphere system. At the higher doses of 10, 20, and 40 mg/kg, reductions in parasite levels of more than 99% were achieved in the liver and spleen after the administration of AMB microspheres. A pharmacokinetic study was performed to study the serum, liver, and spleen AMB concentrations after administration of AMB microspheres and the reference formulation. Interestingly, a significant accumulation of AMB in the spleen and liver was observed after AMB microsphere administration. Our results suggest that this new formulation is a promising alternative to the conventional AMB-Doc formulation for the treatment of visceral leishmaniasis.
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Santos, Délia C. M., Marta L. Lima, Juliano S. Toledo, Paula A. Fernandes, Marta M. G. Aguiar, Ángeles López-Gonzálvez, Lucas A. M. Ferreira, Ana Paula Fernandes, and Coral Barbas. "Metabolomics as a tool to evaluate the toxicity of formulations containing amphotericin B, an antileishmanial drug." Toxicology Research 5, no. 6 (2016): 1720–32. http://dx.doi.org/10.1039/c6tx00253f.
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Salama, Suzette, and Coleman Rotstein. "Reduction in the Nephrotoxicity of Amphotericin B when Administered in 20% Intralipid." Canadian Journal of Infectious Diseases 8, no. 3 (1997): 157–60. http://dx.doi.org/10.1155/1997/827297.
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The administration of amphotericin B (AmB) is often limited by the development of nephrotoxicity. In a pilot crossover trial, aqueous AmB followed by a new preparation of a mixture of AmB with 20% intralipid (AmB-IL) was administered to 10 immunocompromised patients for systemic fungal infections caused byCandidaspecies. Mean total dose and duration of therapy with AmB-IL exceeded that of aqueous AmB (649±165 mg versus 394±105 mg, P=0.061 and 13.2±2.5 days versus 9±2.1 days, P=0.31). However, mean creatinine clearance of the patients rose during AmB-IL therapy by 10.7±7.7 mL/min (P=0.03). AmB-IL warrants further investigation to assess its stability and efficacy for treating serious fungal infections.
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Araújo, Ivonete Batista, C. Ramon N. Brito, Isabel A. Urbano, Victor A. Dominici, Miguel A. Silva Filho, Walteçá L. L. Silveira, Bolívar P. G. L. Damasceno, Aldo Cunha Medeiros, and E. Sócrates T. Egito. "Similarity between the in vitro activity and toxicity of two different fungizone™ / lipofundin™ admixtures." Acta Cirurgica Brasileira 20, suppl 1 (2005): 129–33. http://dx.doi.org/10.1590/s0102-86502005000700022.
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PURPOSE: Amphotericin B (AmB), an antifungal agent that presents a broad spectrum of activity, remains the gold standard in the antifungal therapy. However, sometimes the high level of toxicity forbids its clinical use. The aim of this work was to evaluate and compare the efficacy and toxicity in vitro of Fungizon™ (AmB-D) and two new different AmB formulations. METHODS: three products were studied: Fungizon™, and two Fungizon™ /Lipofundin™ admixtures, which were diluted through two methods: in the first one, Fungizon™ was previously diluted with water for injection and then, in Lipofundin™ (AmB-DAL); the second method consisted of a primary dilution of AmB-D as a powder in the referred emulsion (AmB-DL). For the in vitro assay, two cell models were used: Red Blood Cells (RBC) from human donors and Candida tropicallis (Ct). The in vitro evaluation (K+ leakage, hemoglobin leakage and cell survival rate-CSR) was performed at four AmB concentrations (from 50 to 0.05mg.L-1). RESULTS: The results showed that the action of AmB was not only concentration dependent, but also cellular type and vehicle kind dependent. At AmB concentrations of 50 mg.L-1, although the hemoglobin leakage for AmB-D was almost complete (99.51), for AmB-DAL and AmB-DL this value tended to zero. The p = 0.000 showed that AmB-D was significantly more hemolytic. CONCLUSION: The Fungizon™-Lipofundin™ admixtures seem to be the more valuable AmB carrier systems due to their best therapeutic index presented.
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Montagna, Maria Teresa, Grazia Lovero, Caterina Coretti, Osvalda De Giglio, Domenico Martinelli, Andrea Bedini, Mario Delia, Antonio Rosato, Mauro Codeluppi, and Giuseppina Caggiano. "In vitro activities of amphotericin B deoxycholate and liposomal amphotericin B against 604 clinical yeast isolates." Journal of Medical Microbiology 63, no. 12 (December 1, 2014): 1638–43. http://dx.doi.org/10.1099/jmm.0.075507-0.
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We determined the in vitro antifungal activity of liposomal amphotericin B (L-AmB) against 604 clinical yeast isolates. Amphotericin B deoxycholate (D-AmB) was tested in parallel against all the isolates. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) M27-A3 method. Overall, L-AmB was highly active against the isolates (mean MIC, 0.42 µg ml−1; MIC90, 1 µg ml−1; 97.2 % of MICs were ≤1 µg ml−1) and comparable to D-AmB (mean MIC, 0.48 µg ml−1; MIC90, 1 µg ml−1; 97.3 % of MICs were ≤1 µg ml−1). The in vitro activity of D-AmB and L-AmB was correlated (R 2 = 0.61; exp(b), 2.3; 95 % CI, 2.19–2.44, P<0.001). Candida albicans (mean MICs of D-AmB and L-AmB, 0.39 µg ml−1 and 0.31 µg ml−1, respectively) and Candida parapsilosis (mean MICs of D-AmB and L-AmB, 0.38 µg ml−1 and 0.35 µg ml−1, respectively) were the species most susceptible to the agents tested, while Candida krusei (currently named Issatchenkia orientalis) (mean MICs of D-AmB and L-AmB, 1.27 µg ml−1 and 1.13 µg ml−1, respectively) was the least susceptible. The excellent in vitro activity of L-AmB may have important implications for empirical treatment approaches and support its role in treatment of a wide range of invasive infections due to yeasts.
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Weiler, Stefan, Rosa Bellmann-Weiler, Michael Joannidis, and Romuald Bellmann. "Penetration of Amphotericin B Lipid Formulations into Pleural Effusion." Antimicrobial Agents and Chemotherapy 51, no. 11 (September 4, 2007): 4211–13. http://dx.doi.org/10.1128/aac.01087-07.
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ABSTRACT The penetration of the amphotericin B (AMB) lipid formulations (liposomal AMB, AMB colloidal dispersion, and AMB lipid complex formulations) into pleural effusions in seven critically ill patients was assessed. AMB was detected in all pleural effusion samples at concentrations ranging from 0.02 to 0.43 μg/ml. The penetration ratio was 3 to 44%.
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Fan, Yuying, Yue Wang, and Jianping Xu. "Comparative Genome Sequence Analyses of Geographic Samples of Aspergillus fumigatus—Relevance for Amphotericin B Resistance." Microorganisms 8, no. 11 (October 28, 2020): 1673. http://dx.doi.org/10.3390/microorganisms8111673.
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Amphotericin B (AMB) is a major fungicidal polyene agent that has a broad spectrum of action against invasive fungal infections. AMB is typically used as the last-line drug against serious and life-threatening infections when other drugs have failed to eliminate the fungal pathogens. Recently, AMB resistance in Aspergillus fumigatus has become more evident. For example, a high rate of AMB resistance (96%) was noted in the A. fumigatus population in Hamilton, Ontario, Canada. AMB-resistant strains have also been found in other countries. However, the mechanism of AMB resistance remains largely unknown. Here, we investigated the potential genes and mutations associated with AMB resistance using whole-genome sequences and examined AMB resistance distribution among genetic populations. A total of 196 whole-genome sequences representing strains from 11 countries were examined. Analyses of single nucleotide polymorphisms (SNPs) at the whole-genome level revealed that these strains belonged to three divergent genetic clusters, with the majority (90%) of AMB resistant strains located in one of the three clusters, Cluster 2. Our analyses identified over 60 SNPs significantly associated with AMB resistance. Together, these SNPs represent promising candidates from which to investigate the putative molecular mechanisms of AMB resistance and for their potential use in developing rapid diagnostic markers for clinical screening of AMB resistance in A. fumigatus.
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Heinemann, V., B. Kähny, U. Jehn, D. Mühlbayer, A. Debus, K. Wachholz, D. Bosse, H. J. Kolb, and W. Wilmanns. "Serum pharmacology of amphotericin B applied in lipid emulsions." Antimicrobial Agents and Chemotherapy 41, no. 4 (April 1997): 728–32. http://dx.doi.org/10.1128/aac.41.4.728.
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Application of amphotericin B in lipid emulsions (AmB/L) reduced membrane toxicity in vitro and decreased amphotericin B-associated toxic side effects in vivo when compared to that of amphotericin B applied in 5% glucose (AmB/G). Therefore, a comparative analysis of the pharmacological parameters of AmB/L and AmB/G was performed. Thirteen patients were analyzed, and nine of these patients received a subsequent treatment with AmB/G and AmB/L. In patients in both treatment groups amphotericin B showed a biphasic elimination from serum, with a prolonged terminal half-life of approximately 27 h. Patients treated with AmB/L showed significantly lower peak concentrations (44.2%; P = 0.008) and correspondingly lower area under the drug concentration-time curve (AUC) values (64.3%; P = 0.015) compared to the values for the same patients treated with AmB/G at a dose range of 0.6 to 1.5 mg/kg of body weight. The enhanced clearance of AmB/L may be due to a faster initial elimination of amphotericin B-lipid aggregates by the reticuloendothelial system. Lower peak concentrations and AUC values in serum and a correspondingly faster deposition of AmB/L in tissues may at least partly explain the lower toxicity of AmB/L. A comparative pharmacokinetic analysis with data for a single patient treated with AmB/L demonstrated that hemodialysis did not significantly affect the disposition of amphotericin B.
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Andes, D., N. Safdar, K. Marchillo, and R. Conklin. "Pharmacokinetic-Pharmacodynamic Comparison of Amphotericin B (AMB) and Two Lipid-Associated AMB Preparations, Liposomal AMB and AMB Lipid Complex, in Murine Candidiasis Models." Antimicrobial Agents and Chemotherapy 50, no. 2 (February 2006): 674–84. http://dx.doi.org/10.1128/aac.50.2.674-684.2006.
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ABSTRACT It is generally accepted that the lipid formulations of amphotericin B (AMB) are not as potent as conventional AMB on a milligram-per-kilogram basis. We used a neutropenic murine disseminated candidiasis model to compare the in vivo potencies of AMB, liposomal AMB (L-AMB), and AMB lipid complex (ABLC) pharmacodynamically. The pharmacokinetics of the antifungals were examined in serum and in three organs commonly seeded in disseminated candidiasis (kidneys, liver, and lung). Both single-dose time-kill studies and multiple-dosing-regimen studies were used with each of the compounds. Determinations of the numbers of CFU in the kidneys were performed following the administration of three escalating single doses of the polyenes at various times over 48 h. The areas under the time-kill curves (AUTKs) for each dose level of the drugs were compared by analysis of variance (ANOVA). In the multiple-dosing-regimen studies with five Candida isolates, AMB, L-AMB, and ABLC were administered daily for 72 h. The organism burdens in the mouse kidneys were similarly used as the treatment end point. Additional multiple regimen-dosing-studies were performed with a single Candida albicans isolate, and the microbiologic outcomes in four internal organs (kidneys, liver, spleen, and lung) were examined at the end of therapy (48 h). The relationship between the dose and the drug exposure expressed by the pharmacokinetics of the dosing regimens in serum and organ tissue were analyzed by using a maximum-effect model. ANOVA was used to compare the drug exposures necessary to achieve the 25% effective dose (ED25), ED50, ED75, and 1 log10 killing. Comparison of AUTKs suggested that AMB was 4.3- to 5.9-fold more potent than either ABLC or L-AMB. The time-kill curves for both lipid formulations were very similar. In the multiple-dosing-regimen studies, AMB was 5.0- to 8.0-fold more potent than each of the lipid formulations against five Candida isolates in the kidneys. Similar differences in potency (5.1- to 7.2-fold) were observed in the other end organs. The difference in pharmacokinetics in serum accounted for much of the difference in potency between AMB and ABLC (ratio of serum ABLC area under the curve of effective doses to serum AMB area under the curve of effective doses, 1.2). The differences in the kinetics in the various end organs between AMB and L-AMB were better at explaining the disparate potencies at these infection sites (ratio of organ L-AMB area under the curve of effective doses to organ AMB area under the curve of effective doses, 1.1).
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Lewis, Russell E., Guangling Liao, Jinggou Hou, Georgios Chamilos, Randall A. Prince, and Dimitrios P. Kontoyiannis. "Comparative Analysis of Amphotericin B Lipid Complex and Liposomal Amphotericin B Kinetics of Lung Accumulation and Fungal Clearance in a Murine Model of Acute Invasive Pulmonary Aspergillosis." Antimicrobial Agents and Chemotherapy 51, no. 4 (January 29, 2007): 1253–58. http://dx.doi.org/10.1128/aac.01449-06.
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ABSTRACT The reformulation of amphotericin B (AMB) into a lipid complex (AMB lipid complex [ABLC]) or liposomal carrier (liposomal AMB [L-AMB]) changes the rate and extent of drug distribution to the lung. The importance of pharmacokinetic differences among the various lipid AMB formulations in the treatment of invasive pulmonary aspergillosis (IPA) remains unknown. We compared the kinetics of AMB lung accumulation and fungal clearance of ABLC- and L-AMB-treated mice with acute IPA. BALB/c mice were immunosuppressed with cyclophosphamide and cortisone before intranasal inoculation with 1.5 × 106 Aspergillus fumigatus 293 conidia. ABLC or L-AMB was administered in daily intravenous doses (1, 5, or 10 mg/kg of body weight), starting 12 h after infection and continuing until day 5. At predetermined times (0, 24, 72, and 120 h), mice were euthanized, and lungs were harvested for determinations of lung fungal burdens (quantitative PCR) and total AMB lung tissue concentrations. Both ABLC and L-AMB were effective at reducing lung fungal burdens at doses of ≥5 mg/kg/day. Clearance of A. fumigatus during the first 24 h was associated with AMB tissue concentrations of >4 μg/g. At 5 mg/kg/day, ABLC produced a more rapid fungal clearance than did L-AMB, but at the end of therapy, fungal burden reductions were similar for both formulations and were not improved with higher dosages. These data suggest that ABLC delivers active AMB to the lung more rapidly than does L-AMB, resulting in faster Aspergillus clearance in an experimental model of IPA. However, pharmacodynamic differences between the two formulations were less apparent when mice were dosed at 10 mg/kg/day.
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Chen, Tao, Lawrence Mwenge, Shabir Lakhi, Duncan Chanda, Peter Mwaba, Síle F. Molloy, Adrian Gheorghe, et al. "Healthcare Costs and Life-years Gained From Treatments Within the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) Trial on Cryptococcal Meningitis: A Comparison of Antifungal Induction Strategies in Sub-Saharan Africa." Clinical Infectious Diseases 69, no. 4 (March 13, 2019): 588–95. http://dx.doi.org/10.1093/cid/ciy971.
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Abstract Background Mortality from cryptoccocal meningitis remains high. The ACTA trial demonstrated that, compared with 2 weeks of amphotericin B (AmB) plus flucystosine (5FC), 1 week of AmB and 5FC was associated with lower mortality and 2 weeks of oral flucanozole (FLU) plus 5FC was non-inferior. Here, we assess the cost-effectiveness of these different treatment courses. Methods Participants were randomized in a ratio of 2:1:1:1:1 to 2 weeks of oral 5FC and FLU, 1 week of AmB and FLU, 1 week of AmB and 5FC, 2 weeks of AmB and FLU, or 2 weeks of AmB and 5FC in Malawi, Zambia, Cameroon, and Tanzania. Data on individual resource use and health outcomes were collected. Cost-effectiveness was measured as incremental costs per life-year saved, and non-parametric bootstrapping was done. Results Total costs per patient were US $1442 for 2 weeks of oral FLU and 5FC, $1763 for 1 week of AmB and FLU, $1861 for 1 week of AmB and 5FC, $2125 for 2 weeks of AmB and FLU, and $2285 for 2 weeks of AmB and 5FC. Compared to 2 weeks of AmB and 5FC, 1 week of AmB and 5FC was less costly and more effective and 2 weeks of oral FLU and 5FC was less costly and as effective. The incremental cost-effectiveness ratio for 1 week of AmB and 5FC versus oral FLU and 5FC was US $208 (95% confidence interval $91–1210) per life-year saved. Clinical Trials Registration ISRCTN45035509. Conclusions Both 1 week of AmB and 5FC and 2 weeks of Oral FLU and 5FC are cost-effective treatments.
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Tran, Thi H. Yen, Thi T. Giang Vu, and Thi M. H. Pham. "Preparation and Characterization of Liposomes Double-loaded with Amphotericin B and Amphotericin B/hydroxypropyl-beta-cyclodextrin Inclusion Complex." Pharmaceutical Nanotechnology 9, no. 3 (August 13, 2021): 236–44. http://dx.doi.org/10.2174/2211738509666210310160436.
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Background: Amphotericin B (AMB) is water-insoluble polyene, which has a broad spectrum of antifungal activity. The hydrophobic drug only exits in the phospholipid bilayer, leading to a low-drug liposomal loading capacity. Objectives: This study is designed to prepare water-soluble inclusion complex (IC) between AMB and cyclodextrin (CD) to formulate liposomal vesicles, double-loaded with drug molecules in the phospholipid bilayer and AMB/CD IC in the aqueous core. Methods: Water-soluble AMB/CD IC was prepared by pH adjustment of the aqueous media and consequently characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). Liposomes double-loaded with AMB were formulated by the thin-film hydration method and accordingly evaluated for vesicle size, polydispersity index, entrapment efficiency, zeta potential, and in vitro drug leakage. Results: Hydroxypropyl β cyclodextrin (HP-β-CD) better solubilized AMB than both α-CD and β- CD e.g., the concentration of water-soluble AMB/HP-β-CD IC could reach 465 μg/mL. Both DSC and SEM data illustrated that the drug no longer existed in its crystalline form, in AMB/HP-β-CD IC. Liposomes double-loaded with hydrophilic AMB/HP-β-CD IC and hydrophobic AMB had a diameter of 270 nm, polydispersity index less than 0.27, and zeta potential ca.-42.8 mV. Moreover, liposomes double-loaded with AMB enhanced drug-liposomal loading capacity by 25%, less leaked drug in phosphate buffer pH 7.4 at 37°C in comparison to liposomes loaded with only hydrophobic AMB. Conclusion: Liposomes double-loaded with AMB and AMB/HP-β-CD IC increased drug-encapsulation ability and in vitro stability, suggesting potential drug delivery systems.
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Wasan, K. M., and J. S. Conklin. "Evaluation of renal toxicity and antifungal activity of free and liposomal amphotericin B following a single intravenous dose to diabetic rats with systemic candidiasis." Antimicrobial Agents and Chemotherapy 40, no. 8 (August 1996): 1806–10. http://dx.doi.org/10.1128/aac.40.8.1806.
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Since fungal infections are prevalent in diabetic patients, in whom treatment is often complicated by underlying renal disease and dyslipidemias, the purpose of the present study was to determine if the antifungal activity and nephrotoxic effects of amphotericin B (AmB) and liposomal AmB (L-AmB) are different in nondiabetic (normolipidemic) rats compared with those in diabetic (dyslipidemic) rats with systemic candidiasis. Non diabetic and diabetic rats infected with Candida albicans received a single intravenous dose of either AmB (0.8 mg of AmB per kg of body weight), L-AmB (0.8, 2, or 4 mg of AmB per kg), or an equivalent volume of normal saline (1 ml). Renal function was assessed by insulin clearance, and antifungal activity was determined by measuring the numbers of CFU of C. albicans that were present in the right kidney following drug treatment. AmB at 0.8 mg/kg and L-AmB at 0.8, 2, and 4 mg/kg are effective antifungal agents in both diabetic and nondiabetic rats. However, while there was approximately a 4-fold decline in the mean number of CFU per gram of kidney in nondiabetic rats, there was only approximately a 2.5-fold decline for the comparable dose (AmB, 0.8 mg/kg) in diabetic rats. There also appeared to be a similar fold reduction of L-AmB at all of the dosages tested. AmB treatment significantly improved renal function in diabetic and nondiabetic rats with systemic candidiasis. Although L-AmB at all doses tested significantly improved renal function in diabetic rats with systemic candidiasis, only L-AmB at doses of 2 and 4 mg/kg significantly improved renal function in nondiabetic rats with systemic candidiasis. These findings suggest that following administration of a single intravenous dose, AmB and L-AmB appear to be less effective in killing C. albicans isolates in diabetic than in nondiabetic rats, while they were found to improve the renal functions of rats in both treatment groups.
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Kirkpatrick, William R., Brent J. Coco, and Thomas F. Patterson. "Sequential or Combination Antifungal Therapy with Voriconazole and Liposomal Amphotericin B in a Guinea Pig Model of Invasive Aspergillosis." Antimicrobial Agents and Chemotherapy 50, no. 4 (April 2006): 1567–69. http://dx.doi.org/10.1128/aac.50.4.1567-1569.2006.
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ABSTRACT We evaluated combinations of voriconazole (VRC) and liposomal amphotericin B (L-AMB) in a guinea pig invasive aspergillosis model. Simultaneous VRC and L-AMB was most effective, although VRC monotherapy was also effective. These regimens as well as sequential L-AMB followed by VRC were more effective than L-AMB alone or VRC followed by L-AMB.
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Cordonnier, Catherine, Thomas J. Walsh, and Mark Bresnik. "Liposomal Amphotericin B (L-AMB) Is Superior to Amphotericin B Deoxycholate (AmB-d) in Preventing Breakthrough Fungal Infections in Patients with Prolonged Neutropenia and Fever: Results of a Sub-Group Analysis of an Empirical Antifungal Therapy Trial." Blood 104, no. 11 (November 16, 2004): 1336. http://dx.doi.org/10.1182/blood.v104.11.1336.1336.
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Abstract In a trial of empirical antifungal therapy in persistently febrile neutropenic patients, L-AMB was shown to be comparable in overall efficacy with significantly less nephrotoxicity and infusion-related reactions when compared to AmB-d. In addition, significantly fewer proven breakthrough invasive fungal infections (IFI) occurred in the L-AMB treatment group. (Walsh TJ, et al, NEJM1999; 340: 764–71). In order to better evaluate the maximum efficacy benefit of L-AMB in a higher risk patient subset, a sub-group analysis was performed on those patients with duration of neutropenia greater than or equal to the median duration for the entire study population. The results of this sub-group analysis are presented. Methods: From the original data set, the median duration of neutropenia from the time of treatment initiation was determined. Clinical success (defined by a composite endpoint), frequency of proven breakthrough IFI and all cause mortality were reported by treatment group for patients with duration of neutropenia greater than or equal to the median. Investigator-reported proven breakthrough IFI were reviewed and verified by an independent, blinded expert. Results: A total of 687 patients were enrolled in the trial. Median duration of neutropenia following initiation of antifungal therapy was 7 days (range 1–50). 392 patients had neutropenia >/= 7 days, (L-AMB=205), (AmB-d=187). Clinical success: L-AMB: 128/205 (62.4%); AmB-d: 112/187 (59.9%), and all cause mortality: L-AMB: 19/205 (9.3%); AmB-d: 24/187 (12.8%) were not significantly different. The frequency of proven breakthrough IFI favored L-AMB: L-AMB: 7/205 (3.4%); AmB-d: 18/187 (9.6%), p=0.01. Organisms isolated: L-AMB: 2 Candida spp (blood); 4 Aspergillus spp. (3 pneumonia, 1 wound); 1 Mucor sp (pneumonia). AmB-d: 9 Candida spp (8 blood, 1 pneumonia); 7 Aspergillus spp (4 pneumonia, 1 sinus, 1 pericarditis, 1 wound); 1 Cryptococcus albidus (blood); 1 unclassified mould (pneumonia). The difference in emergent proven IFI for the patients with neutropenia <7d trended in favor of L-AMB, but was not statistically significant: L-AMB 3/138 (2.2%); AmB-d 8/157 (5.1%). Conclusions: Overall clinical success and all cause mortality remained equivalent for the 2 treatment arms in the subset of patients with prolonged neutropenia. However, L-AMB significantly reduced the frequency of proven breakthrough IFI in this high-risk patient population. These data support the efficacy of L-AMB as empirical therapy, particularly for persistently neutropenic patients at higher risk for invasive fungal infections.
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Baginski, Maciej, Kamil Sternal, Jacek Czub, and Edward Borowski. "Molecular modelling of membrane activity of amphotericin B, a polyene macrolide antifungal antibiotic." Acta Biochimica Polonica 52, no. 3 (August 5, 2005): 655–58. http://dx.doi.org/10.18388/abp.2005_3426.
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Amphotericin B (AmB) is a well known polyene macrolide antibiotic used to treat systemic fungal infections. Despite its toxicity AmB is still regarded as a life-saving drug. The lack of adequate knowledge of the AmB mechanism of action is a serious obstacle to efficient development of new less toxic derivatives. Complementary to various experimental approaches, computational chemistry methods were used to study AmB mechanism of action. A programme lasting for a decade, that was run by our group covered studies of: i) molecular properties of AmB and its membrane targets, ii) structure and properties of AmB membrane channels, and iii) interaction of AmB with the membrane.
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Dong, Pu-Ting, Cheng Zong, Zeina Dagher, Jie Hui, Junjie Li, Yuewei Zhan, Meng Zhang, Michael K. Mansour, and Ji-Xin Cheng. "Polarization-sensitive stimulated Raman scattering imaging resolves amphotericin B orientation in Candida membrane." Science Advances 7, no. 2 (January 2021): eabd5230. http://dx.doi.org/10.1126/sciadv.abd5230.
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Ergosterol-targeting amphotericin B (AmB) is the first line of defense for life-threatening fungal infections. Two models have been proposed to illustrate AmB assembly in the cell membrane; one is the classical ion channel model in which AmB vertically forms transmembrane tunnel and the other is a recently proposed sterol sponge model where AmB is laterally adsorbed onto the membrane surface. To address this controversy, we use polarization-sensitive stimulated Raman scattering from fingerprint C═C stretching vibration to visualize AmB, ergosterol, and lipid in single fungal cells. Intracellular lipid droplet accumulation in response to AmB treatment is found. AmB is located in membrane and intracellular droplets. In the 16 strains studied, AmB residing inside cell membrane was highly ordered, and its orientation is primarily parallel to phospholipid acyl chains, supporting the ion channel model. Label-free imaging of AmB and chemical contents offers an analytical platform for developing low-toxicity, resistance-refractory antifungal agents.
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Vazquez, J. A., M. T. Arganoza, J. K. Vaishampayan, and R. A. Akins. "In vitro interaction between amphotericin B and azoles in Candida albicans." Antimicrobial Agents and Chemotherapy 40, no. 11 (November 1996): 2511–16. http://dx.doi.org/10.1128/aac.40.11.2511.
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The use of azole prophylaxis as a measure to prevent invasive fungal infections in high-risk patients is increasing and is now the standard of care in many institutions. Previous studies disagree on whether preexposure of Candida albicans to azoles affects their subsequent susceptibility to amphotericin B (AmB). The present in vitro study indicates that azole exposure generates a subpopulation of cells that are not affected by subsequent exposure to AmB. These cells that are phenotypically resistant to AmB tolerated by most cells not exposed to azole. The percentage of cells that convert to phenotypic resistance to AmB varies with the concentration and the azole. Itraconazole is more effective than fluconazole in generating cells that are phenotypically resistant to AmB and that tolerate an otherwise lethal transient exposure to AmB. Until cells that are not exposed to fluconazole are simultaneously challenged with AmB, they are not protected to a significant extent from killing by AmB. Cells that are challenged with continuous exposure to AmB also acquire phenotypic resistance to AmB at increased frequencies by azole preexposure, but this requires that the azole be continuously present during incubation with AmB. In addition, Candida cells taken from mature colonies that are not actively growing are not susceptible to the short-term killing effects of AmB without azole preexposure. The adaptive responses of C. albicans to AmB and potentially other antifungal agents that may result from prior exposure to azoles in vitro or potentially in microenvironments in vivo that induce physiological changes may have major clinical implications.
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Yeo, Eun-Jin, Ji-Hye Ryu, Young-Suk Cho, Yang-Sook Chun, L. Eric Huang, Myung-Suk Kim, and Jong-Wan Park. "Amphotericin B blunts erythropoietin response to hypoxia by reinforcing FIH-mediated repression of HIF-1." Blood 107, no. 3 (February 1, 2006): 916–23. http://dx.doi.org/10.1182/blood-2005-06-2564.
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AbstractAmphotericin B (AmB) is widely used for treating severe systemic fungal infections. However, long-term AmB treatment is invariably associated with adverse effects such as anemia. The erythropoietin (EPO) suppression by AmB has been proposed to contribute to the development of anemia. However, the mechanism whereby EPO is suppressed remains obscure. In this study, we investigated the possibility that AmB inhibits the transcription of the EPO gene by inactivating HIF-1, which is a known key transcription factor and regulator of EPO expression. EPO mRNA levels were markedly attenuated by AmB treatment both in rat kidneys and in Hep3B cells. AmB inactivated the transcriptional activity of HIF-1α, but did not affect the expression or localization of HIF-1 subunits. Moreover, AmB was found to specifically repress the C-terminal transactivation domain (CAD) of HIF-1α, and this repression by AmB required Asn803, a target site of the factor-inhibiting HIF-1 (FIH); moreover, this repressive effect was reversed by FIH inhibitors. Furthermore, AmB stimulated CAD-FIH interaction and inhibited the p300 recruitment by CAD. We propose that this mechanism underlies the unexplained anemia associated with AmB therapy.
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Rios Rubiras, Bernat. "Espais de fabricació comunitaris en l’educació primària: Involucrant l’alumnat de Grau en el procés de creació de projectes STEM amb espais de fabricació digital." Ciències: revista del professorat de ciències de Primària i Secundària, no. 42 (June 29, 2021): 40–45. http://dx.doi.org/10.5565/rev/ciencies.442.
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Aquest article relata una activitat desenvolupada al llarg del primer quadrimestre amb l’alumnat de 4t del Grau en Educació Primària de la Universitat Autònoma de Barcelona (UAB). Es tracta d’una activitat desenvolupada conjuntament amb l’espai de fabricació UAB OpenLabs de la facultat d’Enginyeria. L’activitat va permetre a l’alumnat guanyar confiança amb noves tecnologies com ara la talladora làser, la talladora de vinil i el disseny amb Inkscape. Al mateix temps va generar espais perquè es desenvolupessin les pràctiques inherents de l’enginyeria amb un objectiu d’impacte en l’entorn, fent d’aquesta una activitat STEM amb impacte comunitari.
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Magalhães, Thais Furtado Ferreira, Marliete Carvalho Costa, Rodrigo Assunção Holanda, Gabriela Freitas Ferreira, Vanessa Silva Dutra Carvalho, Gustavo Jose Cota Freitas, Noelly Queiroz Ribeiro, et al. "N-acetylcysteine reduces amphotericin B deoxycholate nephrotoxicity and improves the outcome of murine cryptococcosis." Medical Mycology 58, no. 6 (January 9, 2020): 835–44. http://dx.doi.org/10.1093/mmy/myz129.
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Abstract Cryptococcosis is a life-threatening fungal infection, and its current treatment is toxic and subject to resistance. Drug repurposing represents an interesting approach to find drugs to reduce the toxicity of antifungals. In this study, we evaluated the combination of N-acetylcysteine (NAC) with amphotericin B (AMB) for the treatment of cryptococcosis. We examined the effects of NAC on fungal morphophysiology and on the macrophage fungicidal activity 3 and 24 hours post inoculation. The therapeutic effects of NAC combination with AMB were investigated in a murine model with daily treatments regimens. NAC alone reduced the oxidative burst generated by AMB in yeast cells, but did not inhibit fungal growth. The combination NAC + AMB decreased capsule size, zeta potential, superoxide dismutase activity and lipid peroxidation. In macrophage assays, NAC + AMB did not influence the phagocytosis, but induced fungal killing with different levels of oxidative bursts when compared to AMB alone: there was an increased reactive oxygen species (ROS) after 3 hours and reduced levels after 24 hours. By contrast, ROS remained elevated when AMB was tested alone, demonstrating that NAC reduced AMB oxidative effects without influencing its antifungal activity. Uninfected mice treated with NAC + AMB had lower concentrations of serum creatinine and glutamate-pyruvate transaminase in comparison to AMB. The combination of NAC + AMB was far better than AMB alone in increasing survival and reducing morbidity in murine-induced cryptococcosis, leading to reduced fungal burden in lungs and brain and also lower concentrations of pro-inflammatory cytokines in the lungs. In conclusion, NAC + AMB may represent an alternative adjuvant for the treatment of cryptococcosis.