Leishmania Plasmodium

Amphotericin B interacts with cholesterol, the primary sterol found in mammalian membranes, limiting the drug's utility because of its comparatively high toxicity. In the subphase, amphotericin B is distributed either as a highly aggregated form or as a pre-micellar state[4]. B only eliminates unicellular Leishmania promastigotes (LPs) upon the formation of aqueous holes that are permeable to tiny cations and anions. A polarization potential is induced by amphotericin B (0.1 mM) in liposomes loaded with KCl and suspended in an iso-osmotic sucrose solution, signifying K+ leakage. The negative membrane potential virtually completely collapses when amphotericin B (0.05 mM) is added, showing Na+ penetration into the cells[3].

In the hamster scrapie model, amphotericin B causes the incubation period to be extended and the buildup of PrPSc to be reduced. In mice suffering from transmissible subacute spongiform encephalopathies (TSSE), amphotericin B significantly lowers PrPSc levels[4]. Amphotericin B directly affects Plasmodium falciparum and has an impact on parasitemia, hostsurvival in murine malaria, and the eryptosis of infected erythrocytes. In mice infected with Plasmodium berghei, amphotericin B tends to postpone the development of parasitemia and considerably postpones host death[5].

Absorption, Distribution and Excretion
The pharmacokinetics of amphotericin B vary depending on its form of administration (conventional amphotericin B (prepared with sodium deoxycholate), amphotericin B cholesterol sulfate complex, amphotericin B lipid complex, or amphotericin B liposomes). Therefore, pharmacokinetic parameters reported for one amphotericin B formulation should not be used to predict the pharmacokinetics of any other amphotericin B formulation. Amphotericin B is poorly absorbed in the gastrointestinal tract and must be administered via parenteral route to treat systemic fungal infections. In one study, after intravenous infusion of 30 mg amphotericin B over several hours, the mean peak serum concentration was approximately 1 μg/ml; at a dose of 50 mg, the mean peak serum concentration was approximately 2 μg/ml. Following infusion, serum amphotericin B concentrations did not exceed 10% of the administered dose. The mean lowest serum concentration (recorded before the next infusion) has been reported to be approximately 0.4 μg/ml when administered at a daily dose of 30 mg or every other day at a dose of 60 mg. Information on the distribution of amphotericin B is limited, but it is clearly multicompartmental. The reported volume of distribution after routine administration of amphotericin B is 4 L/kg; the reported steady-state volume of distribution after administration of amphotericin B cholesterol sulfate is 3.8–4.1 L/kg. Following intravenous injection of routine amphotericin B, the concentrations in the inflamed pleura, peritoneum, synovium, and aqueous humor are reported to be approximately 60% of the corresponding plasma concentrations; the drug also distributes in vitreous fluid, pleural fluid, pericardial fluid, peritoneal fluid, and synovial fluid. Amphotericin B has been reported to cross the placenta and reach lower concentrations in amniotic fluid. Following intravenous injection of routine amphotericin B, the drug concentration in cerebrospinal fluid is approximately 3% of the corresponding serum concentration. Intrathecal administration is usually required to achieve the necessary cerebrospinal fluid concentrations for inhibition. In patients with meningitis, intrathecal injection of 0.2–0.3 mg of conventional amphotericin B via subcutaneous reservoir sheath resulted in a peak cerebrospinal fluid (CSF) concentration of 0.5–0.8 μg/mL; 24 hours later, the CSF concentration was 0.11–0.29 μg/mL. Amphotericin B is cleared from the CSF via arachnoid villi and appears to be stored in the extracellular spaces of the brain, which may act as a drug reservoir. For more complete data on the absorption, distribution, and excretion of amphotericin B (14 items in total), please visit the HSDB record page.
Biological Half-Life
The distribution half-life of amphotericin B cholesterol sulfate complex is 3.5 minutes, and the elimination half-life is 27.5–28.2 hours. /Amphotericin B Cholesterol Sulfate Complex/ For patients with normal renal function prior to treatment, the initial plasma half-life after intravenous injection of conventional amphotericin B is approximately 24 hours. After the initial 24 hours, the clearance rate of amphotericin B slows down, and its elimination half-life has been reported to be approximately 15 days. Elimination half-life: Neonates: Large individual variability (range: 18 to 62.5 hours). Children: Large individual variability (range: 5.5 to 40.3 hours). Adults: Approximately 24 hours. Terminal half-life: Approximately 15 days. Note: There is significant individual variability in the clearance of amphotericin B in neonates. After discontinuation of the drug, amphotericin B may persist in neonates for up to 17 days. Based on a series of sacrifice experiments in rats following a single inhalation of 3.2 mg/kg amphotericin B aerosol, the elimination half-life of amphotericin B from the rat lungs was 4.8 days.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Although there is currently no information regarding the excretion of amphotericin B in breast milk, its high protein binding rate, large molecular weight, and near-zero oral absorption, coupled with its past direct administration to infants, lead most reviewers to conclude that it is safe for use by breastfeeding women. ◉ Effects on Breastfed Infants
No published information found as of the revision date. ◉ Effects on Lactation and Breast Milk
No published information found as of the revision date.

[1]. Amphotericin B Appl Microbiol Biotechnol. 2005 Aug;68(2):151-62.

[2]. In-vitro and in-vivo antileishmanial activity of inexpensive Amphotericin B formulations: Heated Amphotericin B and Amphotericin B-loaded microemulsion. Exp Parasitol. 2018 Sep;192:85-92.

[3]. Amphotericin B kills unicellular leishmanias by forming aqueous pores permeable to small cations and anions. J Membr Biol. 1996 Jul;152(1):65-75.

[4]. Pharmacological studies of a new derivative of amphotericin B, MS-8209, in mouse and hamster scrapie. J Gen Virol. 1994 Sep;75 (Pt 9):2499-503.

[5]. Amphotericin B encapsulated in micelles based on poly(ethylene oxide)-block-poly(L-amino acid) derivatives exerts reduced in vitro hemolysis but maintains potent in vivo antifungal activity. Biomacromolecules. 2003 May-Jun;4(3):750-7.

It has been reported that (1R,3S,5R,6R,9R,11R,15S,16R,17R,18S,33R,35S,36R,37S)-33-[(2R,3S,4S,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxacyclohexane-2-yl]oxy-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo[33.3.1]neocetane-19,21,23,25,27,29,31-heptene-36-carboxylic acid exists in Trichoderma brevicompactum, Trichoderma virens, and other organisms with relevant data.
Streptomyces, a macrolide antifungal antibiotic, was isolated from Nodosa nodosa from soil in the Orinoco River region of Venezuela.
See also: Amphotericin B (note moved to).

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Mechanism of Action
Amphotericin B typically exhibits antifungal activity at clinically used concentrations, but at high concentrations or against highly susceptible fungi, it has bactericidal activity. Amphotericin B exerts its antifungal activity primarily by binding to sterols (e.g., ergosterol) in the fungal cell membrane. This binding prevents the cell membrane from functioning as a selective barrier, leading to leakage of intracellular substances. Cell death is partly due to altered permeability, but other mechanisms may also contribute to the in vivo antifungal activity of amphotericin B against certain fungi. Amphotericin B is inactive in vitro against microorganisms (e.g., bacteria) whose cell membranes do not contain sterols.
The binding of amphotericin B to sterols in mammalian cells (e.g., certain kidney cells and erythrocytes) may be the cause of some of the toxicities reported with conventional amphotericin B therapy. At commonly used therapeutic concentrations, amphotericin B does not appear to cause hemolysis of mature red blood cells, and the anemia induced by conventional intravenous amphotericin B therapy is likely due to the drug's action on actively metabolizing and dividing red blood cells. ...The nephrotoxicity associated with conventional intravenous amphotericin B appears to involve multiple mechanisms, including direct vasoconstriction of renal arterioles, thereby reducing blood flow to the glomeruli and tubules, and dissolution of the cholesterol-rich lysosomal membranes of renal tubular cells. ...

C47H79NO20

978.12

1202017-46-6

Amphotericin B;1397-89-3;Amphotericin B-13C6

14956

Deep yellow prisms or needles from n,n-dimethylformamide
YELLOW TO ORANGE POWDER

170 °C (gradual decomposition)

12

18

3

65

1670

19

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)