Excretion of the Polymyxin Derivative NAB739 in Murine Urine
Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotox...
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| Vydáno v: | Antibiotics (Basel) Ročník 9; číslo 4; s. 143 |
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27.03.2020
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| Abstract | Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than polymyxin B and are therapeutic in murine Escherichia coli pyelonephritis at doses only one-tenth of that needed for polymyxin B. Here we evaluated whether the increased efficacy is due to increased excretion of NAB739 in urine. Mice were treated with NAB739 and polymyxin B four times subcutaneously at doses of 0.25, 0.5, 1, 2, and 4 mg/kg. In plasma, a clear dose–response relationship was observed. The linearity of Cmax with the dose was 0.9987 for NAB739 and 0.975 for polymyxin B. After administration of NAB739 at a dose of 0.25 mg/kg, its plasma concentrations at all tested time points were above 0.5 µg/mL while after administration at a dose of 0.5 mg/kg its plasma concentrations exceeded 1 µg/mL. The Cmax of NAB739 in plasma was up to 1.5-times higher after single (first) administration and up to two-times higher after the last administration when compared to polymyxin B. Polymyxin B was not detected in urine samples even when administered at 4 mg/kg. In contrast, the concentration of NAB739 in urine after single administration at a dose of 0.25 mg/kg was above 1 µg/mL and after administration of 0.5 mg/kg its average urine concentration exceeded 2 µg/mL. At the NAB739 dose of 4 mg/kg, the urinary concentrations were higher than 35 µg/mL. These differences explain our previous finding that NAB739 is much more efficacious than polymyxin B in the therapy of murine E. coli pyelonephritis. |
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| AbstractList | Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than polymyxin B and are therapeutic in murine Escherichia coli pyelonephritis at doses only one-tenth of that needed for polymyxin B. Here we evaluated whether the increased efficacy is due to increased excretion of NAB739 in urine. Mice were treated with NAB739 and polymyxin B four times subcutaneously at doses of 0.25, 0.5, 1, 2, and 4mg/kg. In plasma, a clear dose-response relationship was observed. The linearity of [C.sub.max] with the dose was 0.9987 for NAB739 and 0.975 for polymyxin B. After administration of NAB739 at a dose of 0.25 mg/kg, its plasma concentrations at all tested time points were above 0.5 [micro]g/mL while after administration at a dose of 0.5 mg/kg its plasma concentrations exceeded 1 [micro]g/mL. The [C.sub.max] of NAB739 in plasma was up to 1.5-times higher after single (first) administration and up to two-times higher after the last administration when compared to polymyxin B. Polymyxin B was not detected in urine samples even when administered at 4 mg/kg. In contrast, the concentration of NAB739 in urine after single administration at a dose of 0.25 mg/kg was above 1 [micro]g/mL and after administration of 0.5 mg/kg its average urine concentration exceeded 2 [micro]g/mL. At the NAB739 dose of 4 mg/kg, the urinary concentrations were higher than 35 [micro]g/mL. These differences explain our previous finding that NAB739 is much more efficacious than polymyxin B in the therapy of murine E. coli pyelonephritis. Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than polymyxin B and are therapeutic in murine Escherichia coli pyelonephritis at doses only one-tenth of that needed for polymyxin B. Here we evaluated whether the increased efficacy is due to increased excretion of NAB739 in urine. Mice were treated with NAB739 and polymyxin B four times subcutaneously at doses of 0.25, 0.5, 1, 2, and 4 mg/kg. In plasma, a clear dose–response relationship was observed. The linearity of Cmax with the dose was 0.9987 for NAB739 and 0.975 for polymyxin B. After administration of NAB739 at a dose of 0.25 mg/kg, its plasma concentrations at all tested time points were above 0.5 µg/mL while after administration at a dose of 0.5 mg/kg its plasma concentrations exceeded 1 µg/mL. The Cmax of NAB739 in plasma was up to 1.5-times higher after single (first) administration and up to two-times higher after the last administration when compared to polymyxin B. Polymyxin B was not detected in urine samples even when administered at 4 mg/kg. In contrast, the concentration of NAB739 in urine after single administration at a dose of 0.25 mg/kg was above 1 µg/mL and after administration of 0.5 mg/kg its average urine concentration exceeded 2 µg/mL. At the NAB739 dose of 4 mg/kg, the urinary concentrations were higher than 35 µg/mL. These differences explain our previous finding that NAB739 is much more efficacious than polymyxin B in the therapy of murine E. coli pyelonephritis. Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than polymyxin B and are therapeutic in murine Escherichia coli pyelonephritis at doses only one-tenth of that needed for polymyxin B. Here we evaluated whether the increased efficacy is due to increased excretion of NAB739 in urine. Mice were treated with NAB739 and polymyxin B four times subcutaneously at doses of 0.25, 0.5, 1, 2, and 4 mg/kg. In plasma, a clear dose-response relationship was observed. The linearity of Cmax with the dose was 0.9987 for NAB739 and 0.975 for polymyxin B. After administration of NAB739 at a dose of 0.25 mg/kg, its plasma concentrations at all tested time points were above 0.5 µg/mL while after administration at a dose of 0.5 mg/kg its plasma concentrations exceeded 1 µg/mL. The Cmax of NAB739 in plasma was up to 1.5-times higher after single (first) administration and up to two-times higher after the last administration when compared to polymyxin B. Polymyxin B was not detected in urine samples even when administered at 4 mg/kg. In contrast, the concentration of NAB739 in urine after single administration at a dose of 0.25 mg/kg was above 1 µg/mL and after administration of 0.5 mg/kg its average urine concentration exceeded 2 µg/mL. At the NAB739 dose of 4 mg/kg, the urinary concentrations were higher than 35 µg/mL. These differences explain our previous finding that NAB739 is much more efficacious than polymyxin B in the therapy of murine E. coli pyelonephritis.Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than polymyxin B and are therapeutic in murine Escherichia coli pyelonephritis at doses only one-tenth of that needed for polymyxin B. Here we evaluated whether the increased efficacy is due to increased excretion of NAB739 in urine. Mice were treated with NAB739 and polymyxin B four times subcutaneously at doses of 0.25, 0.5, 1, 2, and 4 mg/kg. In plasma, a clear dose-response relationship was observed. The linearity of Cmax with the dose was 0.9987 for NAB739 and 0.975 for polymyxin B. After administration of NAB739 at a dose of 0.25 mg/kg, its plasma concentrations at all tested time points were above 0.5 µg/mL while after administration at a dose of 0.5 mg/kg its plasma concentrations exceeded 1 µg/mL. The Cmax of NAB739 in plasma was up to 1.5-times higher after single (first) administration and up to two-times higher after the last administration when compared to polymyxin B. Polymyxin B was not detected in urine samples even when administered at 4 mg/kg. In contrast, the concentration of NAB739 in urine after single administration at a dose of 0.25 mg/kg was above 1 µg/mL and after administration of 0.5 mg/kg its average urine concentration exceeded 2 µg/mL. At the NAB739 dose of 4 mg/kg, the urinary concentrations were higher than 35 µg/mL. These differences explain our previous finding that NAB739 is much more efficacious than polymyxin B in the therapy of murine E. coli pyelonephritis. Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than polymyxin B and are therapeutic in murine pyelonephritis at doses only one-tenth of that needed for polymyxin B. Here we evaluated whether the increased efficacy is due to increased excretion of NAB739 in urine. Mice were treated with NAB739 and polymyxin B four times subcutaneously at doses of 0.25, 0.5, 1, 2, and 4 mg/kg. In plasma, a clear dose-response relationship was observed. The linearity of C with the dose was 0.9987 for NAB739 and 0.975 for polymyxin B. After administration of NAB739 at a dose of 0.25 mg/kg, its plasma concentrations at all tested time points were above 0.5 µg/mL while after administration at a dose of 0.5 mg/kg its plasma concentrations exceeded 1 µg/mL. The C of NAB739 in plasma was up to 1.5-times higher after single (first) administration and up to two-times higher after the last administration when compared to polymyxin B. Polymyxin B was not detected in urine samples even when administered at 4 mg/kg. In contrast, the concentration of NAB739 in urine after single administration at a dose of 0.25 mg/kg was above 1 µg/mL and after administration of 0.5 mg/kg its average urine concentration exceeded 2 µg/mL. At the NAB739 dose of 4 mg/kg, the urinary concentrations were higher than 35 µg/mL. These differences explain our previous finding that NAB739 is much more efficacious than polymyxin B in the therapy of murine pyelonephritis. |
| Audience | Academic |
| Author | Kuka, Janis Grinberga, Solveiga Liepinsh, Edgars Vaara, Timo Sevostjanovs, Eduards Vaara, Martti Dambrova, Maija |
| AuthorAffiliation | 3 Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Aizkraukles Str 21, LV1006 Riga, Latvia; janis.kuka@farm.osi.lv (J.K.); eduards@osi.lv (E.S.); solveiga@osi.lv (S.G.); maija.dambrova@farm.osi.lv (M.D.) 1 Northern Antibiotics Ltd., FI-02150 Espoo, Finland; martti.vaara@northernantibiotics.com (M.V.); timo.vaara@northernantibiotics.com (T.V.) 2 Department of Bacteriology and Immunology, Helsinki University Medical School, FI-00014 Helsinki, Finland |
| AuthorAffiliation_xml | – name: 2 Department of Bacteriology and Immunology, Helsinki University Medical School, FI-00014 Helsinki, Finland – name: 1 Northern Antibiotics Ltd., FI-02150 Espoo, Finland; martti.vaara@northernantibiotics.com (M.V.); timo.vaara@northernantibiotics.com (T.V.) – name: 3 Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Aizkraukles Str 21, LV1006 Riga, Latvia; janis.kuka@farm.osi.lv (J.K.); eduards@osi.lv (E.S.); solveiga@osi.lv (S.G.); maija.dambrova@farm.osi.lv (M.D.) |
| Author_xml | – sequence: 1 givenname: Martti orcidid: 0000-0002-7971-0560 surname: Vaara fullname: Vaara, Martti – sequence: 2 givenname: Timo surname: Vaara fullname: Vaara, Timo – sequence: 3 givenname: Janis orcidid: 0000-0002-0411-0229 surname: Kuka fullname: Kuka, Janis – sequence: 4 givenname: Eduards surname: Sevostjanovs fullname: Sevostjanovs, Eduards – sequence: 5 givenname: Solveiga surname: Grinberga fullname: Grinberga, Solveiga – sequence: 6 givenname: Maija orcidid: 0000-0002-1739-0928 surname: Dambrova fullname: Dambrova, Maija – sequence: 7 givenname: Edgars orcidid: 0000-0003-2213-8337 surname: Liepinsh fullname: Liepinsh, Edgars |
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| Cites_doi | 10.3390/ijms18020414 10.1086/592577 10.1155/2015/679109 10.1002/phar.2209 10.1128/AAC.00405-08 10.1093/jac/dkt039 10.1007/978-3-030-16373-0_20 10.1093/jac/dkx394 10.3389/fphys.2018.01855 10.1016/j.peptides.2018.12.006 10.1016/j.peptides.2012.03.033 10.1111/j.1476-5381.2010.00873.x 10.1002/med.21494 10.1111/j.1476-5381.2010.00872.x |
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| Keywords | mouse pyelonephritis NAB739 extremely multiresistant strains of Enterobacteriaceae polymyxin B |
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| SubjectTerms | Calibration Chemical properties Composition E coli Excretion extremely multiresistant strains of Enterobacteriaceae Identification and classification Kidneys Linearity Monkeys mouse pyelonephritis NAB739 Polymyxin B Polymyxins Pyelonephritis Quality control Urinary tract diseases Urinary tract infections Urine Urogenital system |
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| Title | Excretion of the Polymyxin Derivative NAB739 in Murine Urine |
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