Immuno-pharmacokinetics of Meglumine Antimoniate in Patients With Cutaneous Leishmaniasis Caused by Leishmania (Viannia).
Leishmania
antimonials
hysteresis
pharmacodynamics
pharmacokinetics
Journal
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
ISSN: 1537-6591
Titre abrégé: Clin Infect Dis
Pays: United States
ID NLM: 9203213
Informations de publication
Date de publication:
18 05 2021
18 05 2021
Historique:
received:
25
06
2020
pubmed:
21
8
2020
medline:
3
7
2021
entrez:
21
8
2020
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 32818964
pii: 5895071
doi: 10.1093/cid/ciaa1206
pmc: PMC8130027
doi:
Substances chimiques
Antiprotozoal Agents
0
Meglumine Antimoniate
75G4TW236W
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e484-e492Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 107595/Z/15/Z
Pays : United Kingdom
Organisme : FIC NIH HHS
ID : D43 TW006589
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI129910
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.
Références
PLoS Comput Biol. 2007 Oct;3(10):2032-42
pubmed: 17967053
J Infect Dis. 2006 Aug 15;194(4):503-11
pubmed: 16845635
Biometals. 2003 Sep;16(3):441-6
pubmed: 12680707
J Antimicrob Chemother. 2014 Jan;69(1):139-49
pubmed: 23975742
Am J Trop Med Hyg. 2005 Apr;72(4):421-2
pubmed: 15827279
Drug Resist Updat. 2011 Apr;14(2):107-17
pubmed: 21440486
J Antimicrob Chemother. 2018 Aug 1;73(8):2104-2111
pubmed: 29757380
Am J Trop Med Hyg. 2001 Mar-Apr;64(3-4):187-93
pubmed: 11442216
PLoS Negl Trop Dis. 2017 Jul 13;11(7):e0005713
pubmed: 28704369
Nat Rev Immunol. 2016 Sep;16(9):581-92
pubmed: 27424773
PLoS Negl Trop Dis. 2013;7(3):e2130
pubmed: 23556016
Bioinorg Chem Appl. 2003;:189-98
pubmed: 18365053
Contact Dermatitis. 2013 Jun;68(6):331-8
pubmed: 23692033
Cell Mol Biol (Noisy-le-grand). 2000 Mar;46(2):393-405
pubmed: 10774928
J Infect Dis. 2000 Nov;182(5):1497-502
pubmed: 11023473
J Biol Chem. 2001 Feb 9;276(6):3971-6
pubmed: 11110784
Infect Immun. 2014 Jul;82(7):2872-80
pubmed: 24752514
Methods Mol Biol. 2012;804:281-95
pubmed: 22144159
J Pharm Pharm Sci. 2014;17(1):34-91
pubmed: 24735761
Infect Immun. 2020 Feb 20;88(3):
pubmed: 31818959
Front Pharmacol. 2019 Jun 20;10:657
pubmed: 31281253
Nat Rev Microbiol. 2004 Apr;2(4):289-300
pubmed: 15031728
Free Radic Biol Med. 2020 Sep;157:3-14
pubmed: 31899344
Infect Immun. 2000 Jan;68(1):288-93
pubmed: 10603400
Am J Trop Med Hyg. 2010 Aug;83(2):351-6
pubmed: 20682881
Biomed Res Int. 2015;2015:143720
pubmed: 26125021
Nat Immunol. 2010 Sep;11(9):814-9
pubmed: 20711192
Antimicrob Agents Chemother. 1995 Feb;39(2):516-9
pubmed: 7726524
Am J Trop Med Hyg. 1998 Jun;58(6):824-7
pubmed: 9660473
J Infect Dis. 2014 Jul 1;210(1):146-53
pubmed: 24443541
Antimicrob Agents Chemother. 2014;58(1):144-52
pubmed: 24145529
PLoS Negl Trop Dis. 2012;6(4):e1627
pubmed: 22545172
Int J Mol Sci. 2013 Mar 15;14(3):6044-66
pubmed: 23502468
Antimicrob Agents Chemother. 2019 Apr 25;63(5):
pubmed: 30833428
J Biol Chem. 1985 May 10;260(9):5342-50
pubmed: 3988757
Arch Toxicol. 2010 Mar;84(3):227-32
pubmed: 19911167
J Infect Dis. 2006 May 15;193(10):1375-83
pubmed: 16619185
Annu Rev Nutr. 2009;29:133-52
pubmed: 19400701
Infect Immun. 2000 Nov;68(11):6289-93
pubmed: 11035737
Biochem Pharmacol. 2000 Jan 1;59(1):95-104
pubmed: 10605938
J Infect Dis. 2007 Feb 15;195(4):602-8
pubmed: 17230422
Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8331-8
pubmed: 24843148
Antimicrob Agents Chemother. 2003 Oct;47(10):3073-9
pubmed: 14506011
Drug Metab Rev. 1997 Feb-May;29(1-2):261-307
pubmed: 9187522
Am J Trop Med Hyg. 2013 Oct;89(4):750-4
pubmed: 23980130
Pharm Res. 1993 Jun;10(6):889-94
pubmed: 8321858
J Infect Dis. 1998 Sep;178(3):911-4
pubmed: 9728572
Expert Opin Drug Deliv. 2008 Jul;5(7):805-23
pubmed: 18590464
Antimicrob Agents Chemother. 2017 Feb 23;61(3):
pubmed: 27956421
J Theor Biol. 2009 Feb 21;256(4):655-62
pubmed: 19056402