Antibacterial

In human peripheral blood mononuclear cells (PBMC), polymyxin B (10 μg/mL, 6 hours) decreases the production of TNF-α and IL-10 [3]. MICs of 0.5 mg/l for E. Coli strain IH3080 are demonstrated by Polymyxin B Sulfate's antibacterial properties.

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Polymyxin B, a cyclic peptide antibiotic, is considered to be a rather selective antagonist of protein kinase C. This drug is therefore widely used to evaluate the involvement of protein kinase C in cellular processes. In the present study, we investigated the effects of polymyxin B on the activity of calmodulin-dependent cyclic 3':5'-nucleotide phosphodiesterase in vitro. The drug potently inhibited this enzyme (IC50 80 nM in the presence of 500 microM Ca2+), while about 200-fold higher concentrations were required to inhibit protein kinase C to the same extent. Phosphodiesterase inhibition was competitive with respect to Ca2+ and calmodulin. Evidence for the formation of a complex between polymyxin B and calmodulin was obtained by polyacrylamide gel electrophoresis under non-denaturing conditions, and by affinity chromatography of calmodulin on polymyxin B-agarose. We therefore suggest that, at least in vitro, polymyxin B is a potent and selective inhibitor of calmodulin. [8]

At 20 mg/kg and 5 mg/kg No, Polymyxin B (5–20 mg/kg, IV; once daily for 7 days) reached nephrotoxicity endpoints in the Sprague-Dawley rat model[2].

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A mouse model of lung or thigh infection demonstrates antibacterial activity when treated with Polymyxin B Sulfate (0.5-120 mg/kg; s.c.).
The mouse bactericidal effect of Polymyxin B Sulfate (2 mg/kg, s.c.) against E. coli strain IH3080 is strong.

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The pharmacokinetics of polymyxin B were well described by a model comprising parallel linear and saturable pathways for absorption and elimination. Plasma binding of polymyxin B was constant (P > 0.05) over the range ∼0.9-37 mg/L; average (±SD) percentage bound was 91.4 ± 1.65. In thigh infection, antibacterial effect was well correlated with fAUC/MIC (R2 = 0.89). Target values of fAUC/MIC for stasis and 1 log10 kill were 1.22-13.5 and 3.72-28.0, respectively; 2 log10 kill was not achieved for any strain, even at the highest tolerated dose. There was no difference (P > 0.05) in antibacterial activity between polymyxin B and colistin with equimolar doses. It was not possible to achieve stasis in lung infection, even at the highest dose tolerated by mice. [5]

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Polymyxin B, a relatively toxic antibiotic, has potent endotoxin-neutralizing properties that may be beneficial as adjunctive therapy in gram-negative sepsis. Polymyxin B nonapeptide (deacylated polymyxin B) is devoid of antibiotic activity but retains the capacity to disorganize the outer membrane of gram-negative bacteria. To evaluate the potential therapeutic usefulness of this derivative, we produced purified polymyxin B nonapeptide, tested its in vivo toxicity in animals, and evaluated its in vitro antiendotoxin activity. Effectiveness as an antiendotoxin agent was assessed by examining the ability of polymyxin B nonapeptide to block the enhanced release of toxic oxygen radicals induced by lipopolysaccharide in human neutrophils (priming). In vivo, at doses of 1.5 and 3.0 mg/kg, polymyxin B nonapeptide did not exhibit the neuromuscular blocking, neurotoxic, or nephrotoxic effects that were observed with polymyxin B sulfate. Both polymyxin B and polymyxin B nonapeptide inhibited lipopolysaccharide-induced neutrophil priming in a concentration-dependent manner, but the parent compound, polymyxin B, was 63 times more effective on a weight basis. The inhibitory activity of both compounds, however, diminished rapidly when they were added after the start of the lipopolysaccharide-neutrophil incubation. We conclude that polymyxin B nonapeptide is less toxic than polymyxin B and, at the doses tested, lacks the neurotoxicity and nephrotoxicity of the parent compound. Polymyxin B nonapeptide retains the antiendotoxin activity of polymyxin B but is much less potent. The findings suggest that these compounds block an early step in the neutrophil priming process, possibly lipopolysaccharide attachment to or insertion into the neutrophil membrane.[4]

Bacterial strain and the inoculum [8]
The smooth, encapsulated E. coli strain IH3080 (O18:K1:H7) is a clinical isolate from the CSF of a human neonate with meningitis.10 The MICs of polymyxin B, NAB739 and NAB7061 for this strain, as determined by the agar dilution method using Mueller–Hinton agar according to the CLSI,14 are 0.5 mg/L, 1 mg/L and >32 mg/L, respectively.7 Bacterial suspensions for inoculation of mice were prepared at room temperature from fresh overnight cultures on 5% blood agar plates produced by the Statens Serum Institut. The inoculum was prepared by picking up colonies and suspending them in sterile 0.9% saline to an optical density of 0.12 at 540 nm, giving a density of 108 cfu/mL. Dilutions of this suspension were made in 0.9% saline. If not otherwise indicated, the suspension with 106 cfu/mL was used in the challenge studies. Preparation of the inoculum and inoculation were performed within 1 h. For each experiment, the size of the inoculum was determined by making 10-fold dilutions of the suspension used for the inoculum in 0.9% saline, of which 20 µL was plated on 5% blood agar plates with subsequent counting of colonies after incubation overnight at 35°C in ambient air.

Cell culture and cytokine measurement [3]
Human peripheral blood mononuclear cells (PBMC) were used to test the ability of PMB to neutralize the effect of LPS itself and as contaminant of three different S. mansoni recombinant proteins produced in E. coli in inducing cytokine production. PBMC were obtained through the Ficoll-Hypaque gradient and adjusted to a concentration of 3 × 106 cells/ml in RPMI 1640 containing 10% of normal human serum (AB+, heat-inactivated), 100 U/mL penicillin, 100 μg/mL streptomycin, 2 mM L-glutamine, 30 mM HEPES. Cells were cultured in vitro in the presence or absence of polymyxin B (10 μg/mL) and were stimulated with LPS (0.14 ng/mL, which is the mean of contaminant concentration in the cultures stimulated with S. mansoni antigens), S. mansoni recombinant protein rP24, rSm14, rSm22.6 (10 μg/mL) and with the mitogen phytohemaglutinin (PHA) (2 μg/mL). Unstimulated cells were also cultured as a control. Cultures were incubated at 37°C, 5% CO2 for 6, 12, 24 and 48 hours. After incubation, the supernatants were collected and maintained at -20°C, for later measurement of cytokines. Levels of TNF-α and IL-10 in culture supernatants were determined by ELISA sandwich technique, using commercially available kits, and the results were expressed in picograms per milliliter based on a standard curve.

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Addition of polymyxin B to the cultures [3]
Suspension of peripheral blood mononuclear cells (3 × 106 cells/mL) were pre-incubated with Polymyxin B in the concentration of 10 and 20 μg/mL for 30 minutes at 37°C, 5% CO2. They were then incubated with the different recombinant proteins (10 μg/mL) or LPS (0.14 ng/mL) and the cultures were incubated for 6 to 48 hours as described above. Polymyxin B (10 or 20 μg/mL) was also added each 12 hours, during all culture period.

Animal Model: Eight-week-old, 24-30 g, female Swiss mice[5]
Dosage: For the model of thigh infection, 0.5-120 mg/kg; for the lung infection mode, 5-120 mg/kg
Administration: S.c.
Result: demonstrated antibacterial activity against three strains of K. pneumoniae.

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Pharmacokinetics of polymyxin B in neutropenic infected mice [5]
The PK of polymyxin B was determined following single-dose administration of 2, 4, 8, 16 and 32 mg/kg of polymyxin B to neutropenic thigh-infected mice. Plasma samples were collected from three or four mice at each of multiple times up to 12 h following administration; the sampling schedule varied somewhat across the five doses to maximize the yield of information. The protein binding of polymyxin B in pooled plasma collected from infected neutropenic mice was determined by ultracentrifugation using previously described conditions and procedures to minimize adsorption of polymyxin B in protein-free supernatant samples.5 Binding was determined in drug-free plasma that had been spiked to achieve 10 polymyxin B concentrations across the range ∼0.9–37 mg/L, encompassing the relevant range of total plasma concentrations in the single-dose PK studies (described above) and the dose fractionation PK/PD studies (described below). Concentrations of polymyxin B in samples of supernatant obtained by ultracentrifugation and whole plasma were quantified as before.5,11

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Pharmacokinetics/pharmacodynamics of polymyxin B in thigh and lung infection models [5]
Treatment with subcutaneously administered polymyxin B sulphate (daily dose range 0.5–120 mg/kg in the thigh infection model and 5–120 mg/kg in the lung infection model) commenced 2 h following inoculation. The maximum dose tolerated by mice was 120 mg/kg per day. The following dose-fractionated regimens were used against strain FADDI-KP032 in the thigh infection model: once-daily administration of 0.5, 10, 20, 30 and 45 mg/kg; 12 hourly administration of 5, 10, 15, 22.5, 30 and 45 mg/kg; 8 hourly administration of 0.83, 1.67, 5, 3.33, 6.67, 7.5, 10, 15, 20, 25, 30 and 40 mg/kg; and 4 hourly administration of 1.67, 3.33, 5, 7.5, 10, and 15 mg/kg. In the remaining PK/PD studies the daily doses were divided equally and administered at 8 hourly intervals. Bacterial burdens in lungs or thighs (dependent on the model) were determined at 2 h after inoculation (untreated controls) and 24 h later (untreated controls and polymyxin B-treated mice), as described previously.5
For strains FADDI-KP032 and ATCC BAA-2146, the antibacterial effects of polymyxin B and colistin were compared in the thigh infection model. For FADDI-KP032, equimolar daily doses of each polymyxin were studied at four dose levels (polymyxin B sulphate at 22.5, 45, 90 and 120 mg/kg/24 h, corresponding to colistin sulphate at 21.9, 43.9, 87.7 and 117.1 mg/kg/24 h; n = 4 for each treatment). For ATCC BAA-2146, the comparison was conducted with the first three equimolar dose levels. For each polymyxin, the daily dose was divided equally and administered 8 hourly.

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Dose-fractionation studies with subcutaneous polymyxin B were conducted in neutropenic mice in which infection with three strains of K. pneumoniae had been produced in thighs or lungs. Dosing (thigh infection 0.5-120 mg/kg/day; lung infection 5-120 mg/kg/day) commenced 2 h after inoculation, and bacterial burden was measured 24 h later. Plasma exposure measures for unbound polymyxin B were from population pharmacokinetic analysis of single doses and plasma protein binding by ultracentrifugation. The inhibitory sigmoid dose-effect model was employed to determine the relationship between exposure and efficacy. Antibacterial activities of polymyxin B and colistin against thigh infection were compared at equimolar doses generating exposures resulting in maximal antibacterial activity. [5]

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Mouse peritonitis model [7]
Inoculation was performed by intraperitoneal injection of 0.5 mL of the E. coli suspension. After the inoculation, the mice were observed for 5 h for clinical signs of infection such as lack of curiosity, social withdrawal, changes in body position and pattern of movement, distress and pain. Cfu values in the peritoneum were determined at 1, 4 and 7 h post-inoculation, if not otherwise indicated. After the mice had been sacrificed by cervical dislocation, peritoneal washes were performed by injecting 2 mL of sterile saline intraperitoneally, followed by gentle massage of the abdomen and opening the peritoneum to collect fluid. Peritoneal fluids were serially diluted (10-fold dilutions) and 20 µL was plated on selective blue agar plates produced at the Statens Serum Institut with subsequent counting of colonies after incubation overnight at 35°C in ambient air. No antibiotic carry-over effect in terms of growth inhibition was observed in the spot 10-fold denser than the spot that was counted. All cfu values are averages (of raw cfu values) ±SD from determinations performed from three or four animals.
NAB737 and NAB739 (1, 2 and 4 mg/kg body weight) and polymyxin B (2 mg/kg) were administered at 1 and 3 h post-inoculation as subcutaneous injections in the neck region in a volume of 0.2 mL per dose. Control mice received saline.
NAB7061 (5 mg/kg subcutaneously) and erythromycin (10 mg/kg subcutaneously) were administered at 1 h post-inoculation and a second dose of NAB7061 (5 mg/kg subcutaneously) was given at 3 h post-inoculation. Controls included treatment with either drug alone, as well as treatment with saline only.

Metabolism / Metabolites
Route of Elimination: The drug is excreted slowly by the kidneys.

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There has been only a small amount of information available on the PK of polymyxin B in mice. He et al. reported data from a study involving a single intravenous dose of 3 mg/kg, and Bowers et al. used a single 10 mg/kg intraperitoneal dose; plasma samples were collected for 6 and 4 h, respectively. To minimize animal numbers we have conducted studies in thigh-infected mice and assumed the PK of polymyxin B does not differ between thigh- and lung-infected animals. Previous studies have shown that the PK of ceftazidime and avibactam in thigh- and lung-infected mice did not differ between the two infection sites. The total plasma polymyxin B concentration versus time profiles from the single-dose PK studies in neutropenic infected mice in the present study are shown in Figure 1, and the PK parameter estimates from the population PK modelling are in Table 1. Close examination of the profiles indicates some degree of non-linearity in the PK across the 2–32 mg/kg range of polymyxin B subcutaneous doses. Non-linearity has also been observed for colistin following single subcutaneous doses spanning a more limited range (10–40 mg/kg) in neutropenic infected mice. In the current study with polymyxin B, various approaches to accommodate non-linearity were investigated in the population PK analysis. The superior model incorporated parallel linear and saturable pathways for both absorption from the subcutaneous injection site and elimination from the body (Figure 2). All parameters in the final model were required to describe the PK profiles. The visual predictive checks demonstrate excellent predictive performance of the model across the studied dose range (Figure 3). [5]
The protein binding of polymyxin B in plasma of neutropenic infected mice was concentration independent over the concentration range of ∼0.9–37 mg/L (P > 0.05). For the 10 concentrations spanning this range, the mean (±SD) percentage of polymyxin B bound was 91.4 ± 1.65. Thus, the average unbound fraction of polymyxin B in plasma was 0.086, and this was the value used in determining the values of fAUC/MIC, fCmax/MIC and fT>MIC for each of the dosing regimens in the PK/PD studies. The unbound fraction of polymyxin B in the plasma of neutropenic infected mice (0.086) was almost identical to that reported previously for colistin (0.084). It is evident that the unbound fractions of polymyxin B, colistin and some polymyxin analogues are substantially lower in plasma of mice compared with those in humans. This is most likely the result of inter-species qualitative and/or quantitative differences in the plasma proteins involved in the binding of the polymyxins or in the concentrations of endogenous compounds that modify the binding. When translating PK/PD data to the clinical setting, it is important to recognize that the unbound fractions of polymyxin B and colistin in the plasma of neutropenic infected mice are substantially lower than the corresponding values for plasma of critically ill patients. [5]
In the thigh infection model, the bacterial burdens at initiation of the polymyxin B regimens for strains ATCC BAA-2146, FADDI-KP032 and FADDI-KP042 were 6.30 ± 0.67 (n = 8), 6.81 ± 0.13 (n = 12) and 6.92 ± 0.13 (n = 8) log10 cfu/thigh, respectively. The relationship between the antibacterial effect of polymyxin B and fAUC/MIC in the dose-fractionation study for FADDI-KP032 in the thigh infection model is shown in Figure 4(a). The R2 value of 0.89 for the fit of the inhibitory sigmoid dose–effect model for the fAUC/MIC index was marginally higher than the corresponding value for fCmax/MIC (R2 = 0.88) and substantially higher than that for fT>MIC (R2 = 0.50); the data for the last two indices are shown in Figure S1 (available as Supplementary data at JAC Online). This is in keeping with the results of studies with colistin and polymyxin B against P. aeruginosa and A. baumannii that indicate that fAUC/MIC is the PK/PD index that best describes the antibacterial effect of the polymyxins, although in some reports fCmax/MIC was only modestly inferior to fAUC/MIC, as in the current study The daily doses of polymyxin B needed to generate the fAUC/MIC values at the upper end of the exposure–response relationship (Figure 4a) were the maximum that were tolerated by the mice. The PK/PD model parameters for the fAUC/MIC index of polymyxin B against all three strains of K. pneumoniae in the thigh infection model were estimated with good precision (Table 2). The value of fAUC/MIC required to achieve 50% of the maximal drug effect (Emax) was similar to that reported for colistin against P. aeruginosa and A. baumannii in the murine thigh infection model. However, it is notable that the Emax for polymyxin B (2.13–2.90 log10 cfu/thigh) was substantially smaller than was observed for colistin against three strains each of P. aeruginosa (4.97–6.84 log10 cfu/thigh) and A. baumannii (3.78–4.61 log10 cfu/thigh) in the same model.5 In keeping with the smaller Emax for polymyxin B in the present study, it was not possible to determine a target value of fAUC/MIC for 2 log10 kill (Table 2); the target values for stasis and 1 log10 kill for polymyxin B against K. pneumoniae are in generally good agreement with the corresponding values for colistin against P. aeruginosa and A. baumannii in the murine thigh infection model. There was a relatively wide range of target values for stasis and 1 log10 kill for polymyxin B against the three strains of K. pneumoniae (Table 2). Similar or larger variability across strains has been observed in murine infection studies with non-polymyxin antibiotics against other bacterial species. As more information emerges on the clinical population PK of polymyxin B and the relationship between its plasma exposure and nephrotoxicity in patients, the PK/PD target values reported in Table 2, together with values from future studies on additional strains, can be translated to assist in development of optimized dosing regimens, as is occurring with colistin.[5]

Toxicity Summary
Polymyxin B sulfate has a bactericidal action against almost all gram-negative bacilli except the Proteus group. Polymyxin B sulfate interacts with the lipopolysaccharide of the cytoplasmic outer membrane of Gram-negative bacteria, altering membrane permeability and causing cell death. It does not need to enter the cell.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because it is poorly absorbed after topical application, polymyxin B is considered a low risk to the nursing infant. Only water-miscible cream or gel products should be applied to the breast because ointments may expose the infant to high levels of mineral paraffins via licking.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

[1]. Endotoxin removal: how far from the evidence? The EUPHAS 2 Project. Contrib Nephrol. 2010;167:119-125.

[2]. Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity. Antimicrob Agents Chemother. 2017 Mar 24;61(4):e02391-16.

[3]. Polymyxin B as inhibitor of LPS contamination of Schistosoma mansoni recombinant proteins in human cytokine analysis. Microb Cell Fact. 2007 Jan 3;6:1.

[4]. Purification, toxicity, and antiendotoxin activity of polymyxin B nonapeptide. Antimicrob Agents Chemother. 1989 Sep;33(9):1428-34.

[5]. Pharmacokinetics/pharmacodynamics of systemically administered polymyxin B against Klebsiella pneumoniae in mouse thigh and lung infection models. J Antimicrob Chemother. 2018 Feb 1;73(2):462-468.

[6]. Novel polymyxin derivatives are effective in treating experimental Escherichia coli peritoneal infection in mice. J Antimicrob Chemother. 2010 May;65(5):981-5.

[7].Antagonism of endotoxic glucose dyshomeostasis by protein kinase C inhibitors. Am J Physiol.1991 Jul;261(1 Pt 2):R26-31.

[8]. Polymyxin B is a selective and potent antagonist of calmodulinEur J Pharmacol.1991 May 25;207(1):17-22.

Polymyxin b has been reported in Paenibacillus polymyxa with data available.
Polymyxin B sulfate is a mixture of polymyxins B1 and B2, obtained from Bacillus polymyxa strains. They are basic polypeptides of about eight amino acids and have cationic detergent action on cell membranes. Polymyxin B is used for infections with gram-negative organisms, but may be neurotoxic and nephrotoxic. All gram-positive bacteria, fungi, and the gram-negative cocci, N. gonorrhea and N. menigitidis, are resistant. It is appropriate for treatment of infections of the urinary tract, meninges, and blood stream, caused by susceptible strains of Pseudomonas aeruginosa.
A mixture of polymyxins B1 and B2, obtained from BACILLUS POLYMYXA strains. They are basic polypeptides of about eight amino acids and have cationic detergent action on cell membranes. Polymyxin B is used for treatment of infections with gram-negative bacteria, but may be neurotoxic and nephrotoxic. Polymyxin B sulphate is a cyclic peptide.
A mixture of polymyxins B1 and B2, obtained from BACILLUS POLYMYXA strains. They are basic polypeptides of about eight amino acids and have cationic detergent action on cell membranes. Polymyxin B is used for treatment of infections with gram-negative bacteria, but may be neurotoxic and nephrotoxic.
See also: Polymyxin B Sulfate (annotation moved to).

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In conclusion, to the best of our knowledge, this is the first study to report the PK/PD of either polymyxin B or colistin against K. pneumoniae in a dynamic infection model. The study revealed that in the neutropenic murine thigh infection model fAUC/MIC is the PK/PD index that best correlates with bacterial killing. The fAUC/MIC target values for stasis and 1 log10 kill were in the same range as those reported for colistin against P. aeruginosa and A. baumannii in the same dynamic infection model. However, in a comparative component of the current study the maximal killing was substantially lower for both polymyxin B and colistin against K. pneumoniae, suggesting a difference in the responsiveness of this pathogen to the polymyxins. Murine lung infection with K. pneumoniae was even less responsive to systemically administered polymyxin B than were P. aeruginosa and A. baumannii lung infections treated systemically with colistin. As more is learned about the population PK of polymyxin B and the relationship between its plasma exposure and risk of nephrotoxicity in critically ill patients, the results of the current study will assist in the design of optimized dosing strategies for polymyxin B.[5]

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Objectives: Novel synthetic polymyxin derivatives including NAB737 and NAB739 are as effective as polymyxin B in vitro against the common opportunistic pathogen Escherichia coli. Another derivative, NAB7061, lacks direct antibacterial action but sensitizes E. coli to several other antibacterial agents including macrolides. The renal handling of NAB739 and NAB7061 in rats differs from that of polymyxin B. Furthermore, the affinities of NAB739 and NAB7061 for isolated rat kidney brush border membrane are significantly lower than that of polymyxin B. Here we investigate the in vivo antibacterial effect of these compounds. Methods: The polymyxin derivatives were evaluated in an experimental murine peritonitis model. Immunocompetent mice were infected intraperitoneally with E. coli IH3080 and were subcutaneously treated with NAB737, NAB739 or NAB7061. Results: A >4.0 log(10) reduction in bacterial load compared with saline control was achieved 6 h after initiation of treatment with 1 mg/kg of NAB739 twice or 4 mg/kg of NAB737 twice. Combination therapy with NAB7061 (5 mg/kg) twice and erythromycin (10 mg/kg) resulted during the same time course in a >2.0 log(10) reduction in bacterial load compared with saline control. Neither NAB7061 nor erythromycin was effective as monotherapy. Together with the ability to reduce bacterial load, the NAB compounds also improved the clinical status of the mice. Conclusions: We found that the three novel synthetic polymyxin B derivatives had a potent in vivo bactericidal effect against E. coli. [8]

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Activation of protein kinase C (PKC) by bacterial lipopolysaccharide had recently been implicated in the pathogenetic sequence of gram-negative sepsis, endotoxicosis, hyperinsulinism, and the alterations in glucoregulation that eventuate in glucose dyshomeostasis. This study used the peptide antibiotic polymyxin B (PMX-B) and H-7, an isoquinoline sulfonamide, as inhibitors of PKC activation to evaluate responses to provocative insulin and glucose tolerance tests in control vs. endotoxic rats. Fed male rats were treated with either Salmonella enteritidis endotoxin (ETX; 0.33 mg/kg iv) or saline 120 min before intravenous insulin tolerance testing (IVITT) with human insulin (1 U/kg) or intravenous glucose tolerance testing (IVGTT) with D-glucose (1.2 g/kg). H-7 in dimethyl sulfoxide at 25 mg/kg, PMX-B in saline at 0.25 mg/kg, or the respective vehicles were administered 5 min before the tolerance tests. Neither H-7 nor PMX-B had any significant acute effects on basal plasma glucose or lactate values. The decline in plasma with IVITT was augmented by ETX; however, concomitant H-7 or PMX-B attenuated the insulin hypoglycemia. The computed half-life of glucose in the IVGTT was decreased by ETX; however, concomitant H-7 or PMX-B decreased the tolerance alteration. In addition, both H-7 and PMX-B attenuated the rise in insulin induced by the IVGTT. Thus the hyperinsulinism and the glucoregulatory disturbances in endotoxicosis may be mediated by PKC activation and ameliorated by PKC inhibition.[7]

C56H98N16O13

1203.47672

1188.734

1404-26-8

1405-20-5 (sulfate); 1404-26-8

4868

White to light yellow solid powder

1.3±0.1 g/cm3

1572.3±65.0 °C at 760 mmHg

904.7±34.3 °C

0.0±0.3 mmHg at 25°C

1.593

-3.4

18

18

29

85

2150

0

WQVJHHACXVLGBL-UHFFFAOYSA-N

InChI=1S/C56H98N16O13/c1-7-32(4)13-11-12-16-44(75)63-36(17-23-57)51(80)72-46(34(6)74)56(85)68-39(20-26-60)48(77)67-41-22-28-62-55(84)45(33(5)73)71-52(81)40(21-27-61)65-47(76)37(18-24-58)66-53(82)42(29-31(2)3)69-54(83)43(30-35-14-9-8-10-15-35)70-49(78)38(19-25-59)64-50(41)79/h8-10,14-15,31-34,36-43,45-46,73-74H,7,11-13,16-30,57-61H2,1-6H3,(H,62,84)(H,63,75)(H,64,79)(H,65,76)(H,66,82)(H,67,77)(H,68,85)(H,69,83)(H,70,78)(H,71,81)(H,72,80)

N-[4-amino-1-[[1-[[4-amino-1-oxo-1-[[6,9,18-tris(2-aminoethyl)-15-benzyl-3-(1-hydroxyethyl)-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide

N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,21S)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1R)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide; 1404-26-8; POLUMYXIN B; WQVJHHACXVLGBL-BPJDFBQWSA-N;

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)

H2O : ~33.33 mg/mL

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.)