-
Molecular BioSystems Sep 2015Amphotericin B and anidulafungin are widely used antifungal drugs for the treatment of systemic and serious mycoses. Amphotericin B is a relatively toxic drug which has...
Amphotericin B and anidulafungin are widely used antifungal drugs for the treatment of systemic and serious mycoses. Amphotericin B is a relatively toxic drug which has long been established. This study is first of its kind to systematically investigate the nature of binding to DNA, and to evaluate intercalation of AMP-B or ANIDULA with the aid of UV-Vis, ITC, and CD spectroscopy. The binding affinity of AMP-B with exclusion sites of 4.68 base pairs (1.2 × 10(5) M(-1)) was found to be higher than that of ANIDULA with exclusion sites of 6.67 base pairs (3.78 × 10(4) M(-1)); consistent with the binding affinity values obtained for AMP-B (10(5) M(-1)) and ANIDULA (10(4) M(-1)). The binding of two drugs with double-stranded DNA was favoured by negative enthalpy as well as negative entropy changes. The intercalation of drugs to duplex polynucleotide induced changes in the intrinsic CD spectra and revealed comparatively higher affinity towards AMP-B than ANIDULA. Molecular docking studies revealed that the negative binding energy was higher in the case of AMP-B reflecting more affinity towards single-stranded DNA. The results of the cytotoxicity, immunoblotting, and gene specific LA-QPCR assay have indicated that ANIDULA is less genotoxic than AMP-B. Hence, the superiority of ANIDULA over AMP-B as a systemic antifungal drug has been established beyond doubt.
Topics: Amphotericin B; Anidulafungin; Animals; Calorimetry; Circular Dichroism; DNA; DNA Damage; Echinocandins; Genome; Mammals; Molecular Conformation; Molecular Docking Simulation; Oxidative Stress; Thermodynamics
PubMed: 26194629
DOI: 10.1039/c5mb00366k -
Clinical Chemistry and Laboratory... May 2023Amphotericin B (AmB) is the gold standard for treating invasive fungal infections. New liposomal-containing AmB formulations have been developed to improve efficacy and...
OBJECTIVES
Amphotericin B (AmB) is the gold standard for treating invasive fungal infections. New liposomal-containing AmB formulations have been developed to improve efficacy and tolerability. Serum/plasma C-reactive protein (CRP) values are widely used for monitoring infections and inflammation. CRP shows a high affinity to phosphocholine and it aggregates structures bearing this ligand, e.g. phosphocholine-containing liposomes. Therefore, we studied the interaction between CRP and phosphocholine-containing liposomal AmB preparations and .
METHODS
CRP was prepared by affinity chromatography. Liposomal AmB (L-AmB, AmBisome) was spiked (final concentrations of L-AmB: 150 mg/L) to CRP-containing serum (final CRP concentration: 300 mg/L). Following the addition of L-AmB, complex formation was monitored turbidimetrically. The size of CRP-L-AmB complexes was assessed using gel filtration. CRP was monitored in patients receiving either L-Amb or AmB lipid complex (ABLC).
RESULTS
Following addition of L-AmB to CRP-containing plasma, turbidimetry showed an increase in absorbance. These results were confirmed by gel permeation chromatography. Similarly, effects were observed following intravenous administration of AmBisome: a decline in CRP values was observed. In patients receiving L-Amb, decline of CRP concentration was faster than in patients receiving ABLC.
CONCLUSIONS
experiments are suggestive of a complexation between CRP and liposomes in plasma. Interpretation of CRP values following administration of AmBisome might be impaired due to this complexation. formation of complexes between liposomes and CRP might contribute, or even lead, to intravascular microembolisation. Similar effects have been described following the administration of Intralipid and other phosphocholine-containing liposomes.
Topics: Humans; Amphotericin B; Antifungal Agents; Liposomes; C-Reactive Protein; Phosphorylcholine
PubMed: 36691951
DOI: 10.1515/cclm-2022-1213 -
The American Review of Respiratory... Feb 1971
Topics: Aerosols; Aged; Amphotericin B; Coccidioidomycosis; Humans
PubMed: 5100092
DOI: 10.1164/arrd.1971.103.2.289 -
The Journal of Antimicrobial... May 1994Encapsulation of amphotericin B in liposomes or complexing of the compound with other lipid carriers brings about a major reduction in toxicity. Although animal... (Review)
Review
Encapsulation of amphotericin B in liposomes or complexing of the compound with other lipid carriers brings about a major reduction in toxicity. Although animal experimental studies have shown an increased therapeutic index for a variety of such lipid formulations resulting in higher dose-dependent efficacy rates, clinical data on pharmacokinetics and efficacy are still scanty. AmBisomeR, Amphotericin B Lipid Complex (ABLC) and AmphocilR (Amphotericin B Colloidal Dispersion, ABCD) have quite different structural and pharmacokinetic characteristics; however, it is not clear whether these differences are important with respect to tolerance and efficacy. At this moment, most published clinical data are available for AmBisomeR, which shows encouraging results in a variety of invasive fungal infections. AmBisomeR has been safely administered in high dosages up to 5 mg/kg/day. Randomized comparative trials with liposomal and other lipid-complexed amphotericin B formulations versus conventional amphotericin B are urgently needed to assess their respective clinical values.
Topics: Amphotericin B; Animals; Drug Carriers; Humans; Lipids; Liposomes
PubMed: 8089064
DOI: 10.1093/jac/33.5.907 -
AAPS PharmSciTech Feb 2019Cutaneous leishmaniasis is a neglected parasitic disease. Treatment is preferably performed with pentavalent antimony associated or not with amphotericin B (AmB). This...
Cutaneous leishmaniasis is a neglected parasitic disease. Treatment is preferably performed with pentavalent antimony associated or not with amphotericin B (AmB). This study aimed to develop an emulgel with different chemical enhancers of cutaneous release. Initially, AmB emulsions were obtained with the chemical promoters, oleic acid and geraniol and without promoter, then for the evaluation of the formulations, a preliminary stability study was carried out where the formulations were submitted to centrifugation, before and after the freeze-thaw cycle and analyzed appearance, color, pH, spreadability, viscosity, conductivity, droplet size, assay, in vitro release study, in vitro antileishmania activity in Leishmania major promastigotes, and macrophage toxicity in the MTT test. The emulsions were yellowish, with no signs of instability after the centrifugation test. The pH range corresponded to that of the skin, which is 4.6 to 5.8, before and after the freeze-thaw cycle, the formulations had good spreadability and did not present significant viscosity differences before and after the freeze-thaw cycle, presenting a non-Newtonian characteristic. AmB content was within the kinetic model of zero order release, the formulation of 3% AmB and 5% oleic acid (formulation 1) was chosen to proceed with the antileishmania activity test and showed potential activity against the in vitro parasite with significant reduction of cytotoxicity on murine macrophages, indicating that the formulation is promising for the treatment of cutaneous leishmaniasis.
Topics: Amphotericin B; Animals; Antiprotozoal Agents; Drug Compounding; Drug Liberation; Drug Stability; Emulsions; Hydrogen-Ion Concentration; Leishmaniasis, Cutaneous; Mice; Viscosity
PubMed: 30805739
DOI: 10.1208/s12249-019-1323-1 -
Journal of Pediatric Oncology Nursing :... Jul 1994
Review
Topics: Amphotericin B; Chemistry, Pharmaceutical; Deoxycholic Acid; Drug Stability; Drug Storage; Humans
PubMed: 7917139
DOI: 10.1177/104345429401100308 -
Journal of Controlled Release :... Jan 2022Antifungal drugs such as amphotericin B (AmB) interact with lipids and phospholipids located on fungal cell membranes to disrupt them and create pores, leading to cell...
Antifungal drugs such as amphotericin B (AmB) interact with lipids and phospholipids located on fungal cell membranes to disrupt them and create pores, leading to cell apoptosis and therefore efficacy. At the same time, the interaction can also take place with cell components from mammalian cells, leading to toxicity. AmB was selected as a model antifungal drug due to the complexity of its supramolecular chemical structure which can self-assemble in three different aggregation states in aqueous media: monomer, oligomer (also known as dimer) and poly-aggregate. The interplay between AmB self-assembly and its efficacy or toxicity against fungal or mammalian cells is not yet fully understood. To the best of our knowledge, this is the first report that investigates the role of excipients in the supramolecular chemistry of AmB and the impact on its biological activity and toxicity. The monomeric state was obtained by complexation with cyclodextrins resulting in the most toxic state, which was attributed to the greater production of highly reactive oxygen species upon disruption of mammalian cell membranes, a less specific mechanism of action compared to the binding to the ergosterol located in fungal cell membranes. The interaction between AmB and sodium deoxycholate resulted in the oligomeric and poly-aggregated forms which bound more selectively to the ergosterol of fungal cell membranes. NMR combined with XRD studies elucidated the interaction between drug and excipient to achieve the AmB aggregation states, and ultimately, their diffusivity across membranes. A linear correlation between particle size and the efficacy/toxicity ratio was established allowing to modulate the biological effect of the drug and hence, to improve pharmacological regimens. However, particle size is not the only factor modulating the biological response but also the equilibrium of each state which dictates the fraction of free monomeric form available. Tuning the aggregation state of AmB formulations is a promising strategy to trigger a more selective response against fungal cells and to reduce the toxicity in mammalian cells.
Topics: Amphotericin B; Animals; Antifungal Agents; Deoxycholic Acid; Ergosterol; Mammals; Phospholipids
PubMed: 34933052
DOI: 10.1016/j.jconrel.2021.12.019 -
The National Medical Journal of India 1993During the recent epidemic of kala-azar in Bihar, we identified a group of patients who were unresponsive to the two commonly used drugs--sodium stibogluconate and...
BACKGROUND
During the recent epidemic of kala-azar in Bihar, we identified a group of patients who were unresponsive to the two commonly used drugs--sodium stibogluconate and pentamidine. We evaluated the use of amphotericin B in these patients because it has been shown to be active in experimental animals against amastigotes and promastigotes, it has been found to be useful in South American patients and is now recommended by the World Health Organization as a second line drug.
METHODS
We selected 300 patients who were unresponsive to sodium stibogluconate and pentamidine (out of 500 patients with kala-azar confirmed by demonstration of Leishmania donovani bodies in their splenic aspirates). Amphotericin B was given in a dose of 1 mg/kg body weight on alternate days starting with 0.05 mg/kg body weight with daily increments till a 1 mg dose was reached. A total dose of 20 mg/kg was given initially and repeated if the parasites persisted. The investigations done before and after treatment were splenic or bone marrow aspiration, measurement of the spleen and liver size, body weight, total and differential white cell counts, haemoglobin level, total serum protein, blood urea, serum creatinine, serum potassium, blood sugar, serum alanine and aspartate transaminase, electrocardiography and a chest X-ray. The efficacy of treatment was assessed at the end of treatment and after 6 months of follow up.
RESULTS
After treatment with amphotericin B, 298 (99%) of the patients had been cured of their disease as evidenced by the disappearance of fever, reduction of hepatosplenomegaly, clearance of the parasites from the spleen and bone marrow and an absence of relapse on 6 months of follow up. Two hundred and sixty-eight (89%) patients required 1 g of the drug, 24 (8%) required 1.5 g and 6 (2%) required 2 g. All patients had shivering and fever during the infusion. Two had a cardiac arrest from which they could not be revived. Other complications included anorexia, stomatitis, jaundice, hypokalaemia and a rise in blood urea. However, these were only mild and improved after treatment was stopped.
CONCLUSION
Amphotericin B is an effective drug for patients with kala-azar unresponsive to treatment with sodium stibogluconate and pentamidine, but it should be administered under close medical supervision.
Topics: Adolescent; Adult; Aged; Amphotericin B; Child; Child, Preschool; Drug Resistance; Female; Follow-Up Studies; Humans; India; Infant; Leishmaniasis, Visceral; Male; Middle Aged
PubMed: 8477209
DOI: No ID Found -
Clinical Infectious Diseases : An... Mar 1992Since 1955, when amphotericin B was introduced into clinical therapy, a lore has grown up surrounding its use that often lacks evidential basis. Matters such as rate of... (Review)
Review
Since 1955, when amphotericin B was introduced into clinical therapy, a lore has grown up surrounding its use that often lacks evidential basis. Matters such as rate of intravenous injection, periodicity of administration, dosage, and the monitoring of therapy should not be shrouded in a mystique that is passed on from one generation of house officers to another. Factual rationalization of the use of amphotericin B should be pursued and is attempted in this article.
Topics: Amphotericin B; Anemia; Heart; Humans; Kidney; Molecular Structure; Mycoses; Nervous System
PubMed: 1562682
DOI: 10.1093/clinids/14.supplement_1.s114 -
Acta Tropica Dec 2021Acanthamoeba spp. are the causative agents of a sight-threatening infection of the cornea known as Acanthamoeba keratitis (AK). Amphotericin B - deoxycholate (AB)...
Acanthamoeba spp. are the causative agents of a sight-threatening infection of the cornea known as Acanthamoeba keratitis (AK). Amphotericin B - deoxycholate (AB) is used in the treatment of infectious keratitis, however, its topical administration has side effects as blepharitis, iritis, and painful instillation. In this context, the preheating of AB can decrease its toxicity by the formation of super aggregates (hAB). hAB associated with a thermoreversible in situ gelling ophthalmic system is a promising option due to the latter biocompatibility, low toxicity, and high residence time on the ocular surface. Our objective was to develop a topical ocular formulation of hAB for the treatment of AK. After heating at 70°C for 20 min, hAB was incorporated into a thermoreversible gelling system. The amebicidal activity of AB and hAB was evaluated against trophozoites and cysts of A. castellanii (ATCC 50492) and a regional clinical isolate (IC01). The results showed that the preheating of AB did not change the pharmacological action of the drug, with the amebicidal effect of AB and hAB under trophozoites and cysts of Acanthamoeba spp. The thermoreversible system remained stable, allowing the increase of drug retention time. For assessment of cytotoxicity, HUVEC (ATCC® CRL-1730) cells were challenged with AB and hAB for 48h. Cell viability was assessed, and hAB did not show cytotoxicity for HUVEC cells. As far as we know this was the first study that showed the preheated AB associated with a thermoreversible in situ gelling ophthalmic system as a promising system for topical ocular topical administration of hAB for AK therapy.
Topics: Acanthamoeba; Acanthamoeba Keratitis; Amebicides; Amphotericin B; Animals; Trophozoites
PubMed: 34562424
DOI: 10.1016/j.actatropica.2021.106144