Dataset Information

Immuno-pharmacokinetics of Meglumine Antimoniate in Patients With Cutaneous Leishmaniasis Caused by Leishmania (Viannia).

ABSTRACT:

Background

Control of cutaneous leishmaniasis (CL) relies on chemotherapy, yet gaps in our understanding of the determinants of therapeutic outcome impede optimization of antileishmanial drug regimens. Pharmacodynamic (PD) parameters of antimicrobials are based on the relationship between drug concentrations/exposure and microbial kill. However, viable Leishmania persist in a high proportion of individuals despite clinical resolution, indicating that determinants other than parasite clearance are involved in drug efficacy.

Methods

In this study, the profiles of expression of neutrophils, monocytes, Th1 and Th17 gene signatures were characterized in peripheral blood mononuclear cells (PBMCs) during treatment with meglumine antimoniate (MA) and clinical cure of human CL caused by Leishmania (Viannia). We explored relationships of immune gene expression with plasma and intracellular antimony (Sb) concentrations.

Results

Our findings show a rapid and orchestrated modulation of gene expression networks upon exposure to MA. We report nonlinear pharmacokinetic/pharmacodynamic (PK/PD) relationships of Sb and gene expression dynamics in PBMCs , concurring with a time lag in the detection of intracellular drug concentrations and with PK evidence of intracellular Sb accumulation.

Conclusions

Our results quantitatively portray the immune dynamics of therapeutic healing, and provide the knowledge base for optimization of antimonial drug treatments, guiding the selection and/or design of targeted drug delivery systems and strategies for targeted immunomodulation.

SUBMITTER: Gomez MA

PROVIDER: S-EPMC8130027 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Publications

Immuno-pharmacokinetics of Meglumine Antimoniate in Patients With Cutaneous Leishmaniasis Caused by Leishmania (Viannia).

Gómez María Adelaida MA Navas Adriana A Prieto Miguel Dario MD Giraldo-Parra Lina L Cossio Alexandra A Alexander Neal N Gore Saravia Nancy N

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20210501 10

<h4>Background</h4>Control of cutaneous leishmaniasis (CL) relies on chemotherapy, yet gaps in our understanding of the determinants of therapeutic outcome impede optimization of antileishmanial drug regimens. Pharmacodynamic (PD) parameters of antimicrobials are based on the relationship between drug concentrations/exposure and microbial kill. However, viable Leishmania persist in a high proportion of individuals despite clinical resolution, indicating that determinants other than parasite clea ...[more]

PMID: 32818964

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Project description:BackgroundAmerican cutaneous leishmaniasis (ACL) is a complicated disease producing about 67.000 new cases per year. The severity of the disease depends on the parasite species; however in the vast majority of cases species confirmation is not feasible. WHO suggestion for ACL produced by Leishmania braziliensis, as first line treatment, are pentavalent antimonial derivatives (Glucantime or Sodium Stibogluconate) under systemic administration. According to different authors, pentavalent antimonial derivatives as treatment for ACL show a healing rate of about 75% and reasons for treatment failure are not well known.MethodsIn order to characterise the clinical and parasitological features of patients with ACL that did not respond to Glucantime, a cross-sectional observational study was carried out in a cohort of 43 patients recruited in three of the Colombian Army National reference centers for complicated ACL. Clinical and paraclinical examination, and epidemiological and geographic information were recorded for each patient. Parasitological, histopathological and PCR infection confirmation were performed. Glucantime IC50 and in vitro infectivity for the isolated parasites were estimated.ResultsPredominant infecting Leishmania species corresponds to L. braziliensis (95.4%) and 35% of the parasites isolated showed a significant decrease in in vitro Glucanatime susceptibility associated with previous administration of the medicament. Lesion size and in vitro infectivity of the parasite are negatively correlated with decline in Glucantime susceptibility (Spearman: r = (-)0,548 and r = (-)0,726; respectively).ConclusionA negative correlation between lesion size and parasite resistance is documented. L. braziliensis was found as the main parasite species associated to lesion of patients that underwent treatment failure or relapse. The indication of a second round of treatment in therapeutic failure of ACL, produced by L. braziliensis, with pentavalent antimonial derivatives is discussable.

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Dataset Information

Immuno-pharmacokinetics of Meglumine Antimoniate in Patients With Cutaneous Leishmaniasis Caused by Leishmania (Viannia).

Background

Methods

Results

Conclusions

Publications

Immuno-pharmacokinetics of Meglumine Antimoniate in Patients With Cutaneous Leishmaniasis Caused by Leishmania (Viannia).

Similar Datasets

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