deoxycholic-acid and Leishmaniasis

The therapeutic efficacy of daily amphotericin B infusion is related to its maximum concentration in blood; however, trough levels may be useful in intermittent regimens of this antifungal drug.. : High performance liquid chromatography (HPLC) was used to determine the minimum concentration (Cmin) of amphotericin B in the serum of patients receiving deoxycholate (D-Amph) or liposomal amphotericin B (L-AmB) for the treatment of cryptococcal meningitis (n=28), histoplasmosis (n=8), paracoccidioidomycosis (n=1), and leishmaniasis (n=1).. Daily use of D-Amph 30 to 50 mg or L-AmB 50 mg resulted in a similar Cmin, but a significant increase ocurred with L-AmB 100 mg/day. The geometric mean Cmin tended to decrease with a reduction in the dose and frequency of intermittent L-AmB infusions: 357 ng/mL (100 mg 4 to 5 times/week) > 263 ng/mL (50 mg 4 to 5 times/week) > 227 ng/mL (50 mg 1 to 3 times/week). The impact on Cmin was variable in patients whose dose or therapeutic scheme was changed, especially when administered the intermittent infusion of amphotericin B. The mean Cmin for each L-AmB schedule of intermittent therapy was equal or higher than the minimum inhibitory concentration of amphotericin B against Cryptococcus isolates from 10/12 patients. The Cmin of amphotericin B in patients with cryptococcal meningitis was comparable between those that survived or died.. By evaluating the Cmin of amphotericin B, we demonstrated the therapeutic potential of its intermittent use including in the consolidation phase of neurocryptococcosis treatment, despite the great variability in serum levels among patients.

Topics: Amphotericin B; Antifungal Agents; Chromatography, High Pressure Liquid; Deoxycholic Acid; Histoplasmosis; Humans; Leishmaniasis; Meningitis, Cryptococcal; Paracoccidioidomycosis

The search for new drugs for the treatment of leishmaniasis is an important strategy for improving the current therapeutic arsenal for the disease. There are several limitations to the available drugs including high toxicity, low efficacy, prolonged parenteral administration, and high costs. Steroids are a diverse group of compounds with various applications in pharmacology. However, the antileishmanial activity of this class of molecules has not yet been explored. Therefore, in the present study, we investigated the antileishmanial activity and cytotoxicity of novel steroids against murine macrophages with a focus on the derivatives of cholesterol (CD), cholic acid (CA), and deoxycholic acid (DA). Furthermore, the mechanism of action of the best compound was assessed, and in silico studies to evaluate the physicochemical and pharmacokinetic properties were also conducted. Among the sixteen derivatives, schiffbase2, CD2 and deoxycholic acid derivatives (DOCADs) were effective against promastigotes of Leishmania species. Despite their low toxicity to macrophages, the majority of DOCADs were active against intracellular amastigotes of L. amazonensis, and DOCAD5 exhibited the best biological effect against these parasitic stages (IC

Topics: Administration, Oral; Animals; Cell Cycle Checkpoints; Cholesterol; Cholic Acid; Deoxycholic Acid; Dose-Response Relationship, Drug; Drug Discovery; Leishmania; Leishmaniasis; Macrophages, Peritoneal; Membrane Potential, Mitochondrial; Mice, Inbred BALB C; Mitochondria; Models, Biological; Molecular Structure; Oxidative Stress; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trypanocidal Agents

Determination of the neutrophil gelatinase-associated lipocalin (NGAL) level can be used to detect acute kidney injury (AKI) earlier than determination of the serum creatinine (SCr) level in settings such as cardiac surgery, contrast nephropathy, and intensive care units. We hypothesized that urine NGAL (UrNGAL) would be an early biomarker of drug nephrotoxicity. To test this, we studied hemodynamically stable patients treated with amphotericin B (AmB). We measured the SCr and UrNGAL levels at the baseline and daily after initiation of AmB up to day 14 or development of AKI by the use of the SCr criterion. AKI was defined according to a Kidney Disease: Improving Global Outcomes (KDIGO) criterion (an increase in the SCr level by ≥0.3 mg/dl within 48 h or an SCr level ≥1.5 times the baseline level within 7 days). We studied 24 patients with a mean age of 48.4 ± 16.4 years. Most patients were male, and the patients received AmB (12 received AmB deoxycholate and 12 received liposomal AmB) for the treatment of leishmaniasis (91.7%). Overall, 17/24 patients fulfilled a KDIGO criterion for AKI. Peak UrNGAL levels were higher in patients with AKI than in patients without AKI and in recipients of AmB deoxycholate than in recipients of liposomal AmB. The diagnostic performance of the UrNGAL level on day 5 for the detection of AKI was moderate, with the area under the curve (AUC) being 0.68 (95% confidence interval [CI], 0.41 to 0.95). In the subgroup receiving AmB deoxycholate, however, the AUC rose to 0.89 (95% CI, 0.67 to 1.00). In a patient-level analysis, we found that AKI could be detected 3.2 days earlier by the use of the UrNGAL criterion than by the use of the SCr criterion (times to AKI by the UrNGAL and SCr criteria, 3.7 ± 2.5 versus 6.9 ± 3.3 days, respectively; P = 0.001). Future studies should evaluate if a treatment strategy oriented toward evaluation of UrNGAL levels will improve outcomes. These findings for AmB-induced AKI in leishmaniasis patients could serve as a basis for the investigation of urine biomarkers in the early detection of drug nephrotoxicity in other clinical settings.

Topics: Acute Kidney Injury; Adult; Amphotericin B; Creatinine; Deoxycholic Acid; Drug Combinations; Female; Hemodynamics; Humans; Leishmaniasis; Lipocalins; Male; Middle Aged; Prospective Studies

Oryzalin is a dinitroaniline drug that has attracted recent interest for the treatment of leishmaniasis. Its use as an antiparasitic therapeutic agent is limited by the low water solubility associated with an in vivo rapid clearance, leading to the administration of larger and possibly toxic doses in in vivo studies, and the use of solvents that may lead to undesirable side effects. In the present work oryzalin-containing lipid nanoparticles were produced by a emulsion-solvent evaporation technique using a composition suitable for parenteral administration, i.e., tripalmitin (solid lipid) and a complex mixture of three emulsifying agents (soya lecithin, Tween® 20 and sodium deoxycholate). Physicochemical characterization included the determination of mean particle size, polydispersity index, zeta potential, encapsulation efficiency and DSC studies. Final formulations revealed values of <140 nm (PI<0.2) and zeta potential of ≈-35 mV, as well as encapsulation efficiency >75%. The effects of various processing parameters, such as lipid and surfactant and composition and concentration, as well as the stability during the harsh procedures of autoclaving (121°C/15 min) and freeze-drying were also evaluated. Formulations revealed to be stable throughout freeze-drying and moist-heath sterilization without significant variations on physicochemical properties and no significant oryzalin losses. The use of a complex surfactant mixture proved crucial for preserving formulation stability. Particularly, lecithin appears as a key component in the stabilization of tripalmitin-based oryzalin-containing lipid nanoparticles. Finally, cell viability studies demonstrated that the incorporation of oryzalin in nanoparticles decreases cytotoxicity, thus suggesting this strategy may improve tolerability and therapeutic index of dinitroanilines.

Topics: Antiprotozoal Agents; Cell Line, Tumor; Cell Survival; Deoxycholic Acid; Dinitrobenzenes; Drug Stability; Humans; Lecithins; Leishmaniasis; Nanoparticles; Particle Size; Polysorbates; Sulfanilamides; Surface Properties; Surface-Active Agents; Triglycerides