Establishment of a Low Dose Canine Endotoxemia Model to Test Anti-Inflammatory Drugs: Effects of Prednisolone

Vries, F. De; Leuschner, J; Jilma, Bernd; Derhaschnig, Ulla

doi:10.1177/039463201302600404

Cited by 7 publications

(5 citation statements)

References 28 publications

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“…We showed that the liposomal formulation further improved the tolerance profile of the detoxified LPS characterized by a significant decrease of its inflammatory activity and reduction of its pyrogenic activity by a factor 10. In addition, while LPS were described to induce severe sepsis symptoms at 0.1 to 2µg/kg doses ( 52 , 53 ), F2Lipo-MP-LPS was found to be well tolerated in dogs in intravenous administration up to 10µg/kg.…”

Section: Discussionmentioning

confidence: 99%

A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models

Chettab,

Fitzsimmons,

Novikov

et al. 2023

Front. Immunol.

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Bacterial lipopolysaccharides (LPS) are potent innate immunostimulants targeting the Toll-like receptor 4 (TLR4), an attractive and validated target for immunostimulation in cancer therapy. Although LPS possess anti-tumor activity, toxicity issues prevent their systemic administration at effective doses in humans. We first demonstrated that LPS formulated in liposomes preserved a potent antitumor activity per se upon systemic administration in syngeneic models, and significantly enhance the antitumor activity of the anti-CD20 antibody rituximab in mice xenografted with the human RL lymphoma model. Liposomal encapsulation also allowed a 2-fold reduction in the induction of pro-inflammatory cytokines by LPS. Mice receiving an intravenous administration demonstrated a significant increase of neutrophils, monocytes and macrophages at the tumor site as well as an increase of macrophages in spleen. Further, we chemically detoxified LPS to obtain MP-LPS that was associated with a 200-fold decrease in the induction of proinflammatory cytokines. When encapsulated in a clinically approved liposomal formulation, toxicity, notably pyrogenicity (10-fold), was limited while the antitumor activity and immunoadjuvant effect were maintained. This improved tolerance profile of liposomal MP-LPS was associated with the preferential activation of the TLR4-TRIF pathway. Finally, in vitro studies demonstrated that stimulation with encapsulated MP-LPS reversed the polarization of M2 macrophages towards an M1 phenotype, and a phase 1 trial in healthy dogs validated its tolerance upon systemic administration up to very high doses (10µg/kg). Altogether, our results demonstrate the strong therapeutic potential of MPLPS formulated in liposomes as a systemically active anticancer agent, supporting its evaluation in patients with cancer.

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Section: Discussionmentioning

confidence: 99%

A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models

Chettab,

Fitzsimmons,

Novikov

et al. 2023

Front. Immunol.

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“…More than 35 years ago, some pharmacokinetic reports were published (1)(2)(3)(4). More recently, prednisolone concentration-time data have been made available but without thorough PK-analyses (5,6). The PK studies cited above were performed on few dogs and since then technical improvements have made the analytical techniques for drug quantification in plasma more sensitive.…”

Section: Introductionmentioning

confidence: 99%

Prednisolone in Dogs—Plasma Exposure and White Blood Cell Response

et al. 2021

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Glucocorticoids such as prednisolone are commonly used in dogs but there is sparse quantitative pharmacokinetic and pharmacodynamic information of this drug in this species. The objective of this study was to quantitatively characterize the concentration-effect relationship for prednisolone in dogs on neutrophil and lymphocyte trafficking and cortisol suppression. Nine beagles, 2–12 years old and part of a group for teaching/research were used in a 4-way crossover experiment including two treatments, active or placebo, administered either per os (PO) or intravenously (IV). Plasma was analyzed for prednisolone and cortisol using ultra-high performance liquid chromatography – tandem mass spectrometry. Leucocyte counts were performed in whole blood. Data was then analyzed by non-linear mixed effect modeling to estimate pharmacokinetic and pharmacodynamic parameters. After administration of prednisolone sodium succinate IV, the typical value (between subject variation) for total body prednisolone clearance was 1,370 ml/h·kg (13.4%). The volumes of the central and peripheral compartment were 2,300 ml/kg (10.7%) and 600 ml/kg (16.0%), respectively. The terminal plasma half-life was 1.7 h. The prednisolone plasma concentration producing 50% of the maximum response was 10 ng/mL (90.3%), 22.5 ng/ml (52.3%) and 0.04 ng/mL (197.3%) for neutrophil, lymphocyte and cortisol response, respectively. The administered dose (1 mg/kg) increased neutrophil and decreased lymphocyte numbers but not over the entire dosage interval of 24 h, due to the short half-life. However, glucocorticoids have a wide range of responses. An anti-inflammatory response due to altered gene transcription might have a longer duration. Future studies on the anti-inflammatory potency together with data presented are needed to optimize future dosage recommendations in dogs.

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“…This effect was also described in a canine endotoxemia model. Treatment with prednisolone attenuated IL-6 and TNF α concentrations dose-dependently [ 105 ]. Furthermore, the chemokine CCL17 was significantly increased in dogs with canine atopic dermatitis.…”

Section: Resultsmentioning

confidence: 99%

Methylprednisolone Induces Extracellular Trap Formation and Enhances Bactericidal Effect of Canine Neutrophils

Steffensen

Imker

Lassnig

et al. 2021

IJMS

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Methylprednisolone is a glucocorticoid and can negatively influence immune defense mechanisms. During bacterial infections in the dog, neutrophils infiltrate infected tissue and mediate antimicrobial effects with different mechanisms such as phagocytosis and neutrophil extracellular trap (NET) formation. Here, we investigated the influence of methylprednisolone on canine NET formation and neutrophil killing efficiency of Gram positive and Gram negative bacteria. Therefore, canine blood derived neutrophils were treated with different concentrations of methylprednisolone over time. The survival factor of Staphylococcus pseudintermedius, Streptococcus canis or Escherichia coli was determined in presence of stimulated neutrophils. Additionally, free DNA and nucleosomes as NET marker were analyzed in supernatants and neutrophils were assessed for NET formation by immunofluorescence microscopy. Methylprednisolone concentrations of 62.5 and 625 µg/mL enhanced the neutrophil killing of Gram positive bacteria, whereas no significant influence was detected for the Gram negative Escherichia coli. Interestingly, higher amounts of free DNA were detected under methylprednisolone stimulation in a concentration dependency and in the presence of Streptococcus canis and Escherichia coli. The nucleosome release by neutrophils is induced by bacterial infection and differs depending on the concentration of methylprednisolone. Furthermore, immunofluorescence microscopy analysis identified methylprednisolone at a concentration of 62.5 µg/mL as a NET inducer. In summary, methylprednisolone enhances NET-formation and time-dependent and concentration-dependent the bactericidal effect of canine neutrophils on Gram positive bacteria.

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Establishment of a Low Dose Canine Endotoxemia Model to Test Anti-Inflammatory Drugs: Effects of Prednisolone

Cited by 7 publications

References 28 publications

A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models

A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models

Prednisolone in Dogs—Plasma Exposure and White Blood Cell Response

Methylprednisolone Induces Extracellular Trap Formation and Enhances Bactericidal Effect of Canine Neutrophils

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