A Novel Iodine–Dextrin Complex Exhibits No Acute or Subacute Toxicity and Enhances Azithromycin Efficacy in an LPS-Induced Sepsis Model

<b>Background/Objectives:</b> Our work was designed to study the physicochemical properties, safety profile, pharmacokinetics, and prophylactic efficacy of an original iodine-dextrin-based pharmaceutical formulation (PA), both alone and in combination with azithromycin (AZ), in a murine model of LPS-induced sepsis. <b>Methods/Results:</b> UV-vis and ¹H-NMR spectroscopy confirmed the formation of a stable iodine-dextrin complex, with triiodide anions stabilized by hydrogen bonding and donor-acceptor interactions. No clinical signs of acute toxicity were observed at doses up to 5000 mg/kg, and subacute administration (62.5 and 125 mg/kg) showed no adverse effects on hematological or biochemical parameters. A mild, non-pathological enlargement of thyrocytes and parallel increases in TSH, T3, and T4 levels were observed at 125 mg/kg, consistent with physiological adaptation to iodine. Pharmacokinetic analysis revealed high oral bioavailability (~92%), prolonged half-life (~21 h), and wide tissue distribution with low clearance. In the sepsis model, pretreatment with AZ+PA alleviated clinical symptoms, maintained body weight, and significantly improved hematological parameters, reducing WBCs and CRP levels. The combination also decreased plasma IL-6 and TNF-α concentrations more effectively than either agent alone, indicating a synergistic anti-inflammatory effect. Histological analysis confirmed that PA, particularly in combination with AZ, mitigated LPS-induced tissue injury in the liver, kidney, and lungs. <b>Conclusions:</b> These findings suggest that PA is a safe, bioavailable compound with immunomodulatory properties that enhance azithromycin's protective effects during systemic inflammation. This supports its potential use as a prophylactic agent in clinical settings, such as preoperative immune modulation to prevent sepsis-related complications.