PubTransformer

A site to transform Pubmed publications into these bibliographic reference formats: ADS, BibTeX, EndNote, ISI used by the Web of Knowledge, RIS, MEDLINE, Microsoft's Word 2007 XML.

In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi infection: A multivariate approach.

Abstract Combination therapies based on the available drugs have been proposed as promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been found to modify the evolution of the experimental infection. The objective of this study was to evaluate the combined effect of benznidazole (BZ) and clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro and their efficacy in a murine model. Life-stages of T. cruzi, BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and isobolograms and combination index (CI) were obtained. Swiss mice were infected with trypomastigotes and different treatment schedules were performed, each of which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated by comparing parasitemia, qPCR, survival and histological analysis. These results were analyzed using multivariate analysis to determine the combined effect of the drugs in vivo. CLO + BZ showed synergistic activity in vitro against the clinically relevant life-stages of T. cruzi. The most susceptible forms were the intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60), with no toxicity upon mammalian cells. The combination of both drugs CLO (1.25 mg/kg) and BZ (6.25 mg/kg), in vivo, significantly diminished the parasitic load in blood and the mortality rate. CLO + BZ presented a similar inflammatory response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ (6.25 mg/kg). Finally, the results from the principal component analysis reaffirmed that both drugs administered in combination presented higher activity compared with the individual administration in the acute experimental model.
PMID
Related Publications

In Vitro and In Vivo Trypanosomicidal Action of Novel Arylimidamides against Trypanosoma cruzi.

Efficacy of essential oil of Syzygium aromaticum alone and in combination with benznidazole on murine oral infection with Trypanosoma cruzi IV.

Molecular and biological characterization of a highly pathogenic Trypanosoma cruzi strain isolated from a patient with congenital infection.

Clomipramine and Benznidazole Act Synergistically and Ameliorate the Outcome of Experimental Chagas Disease.

Clomipramine and benznidazole association for the treatment of acute experimental Trypanosoma cruzi infection.

Authors

Mayor MeshTerms
Keywords

Benznidazole

Clomipramine

Synergism

Trypanosoma cruzi

Journal Title experimental parasitology
Publication Year Start




PMID- 29726395
OWN - NLM
STAT- MEDLINE
DCOM- 20180529
LR  - 20180529
IS  - 1090-2449 (Electronic)
IS  - 0014-4894 (Linking)
VI  - 189
DP  - 2018 Jun
TI  - In vitro and in vivo drug combination for the treatment of Trypanosoma cruzi
      infection: A multivariate approach.
PG  - 19-27
LID - S0014-4894(17)30653-7 [pii]
LID - 10.1016/j.exppara.2018.04.016 [doi]
AB  - Combination therapies based on the available drugs have been proposed as
      promising therapeutic alternatives for many diseases. Clomipramine (CLO) has been
      found to modify the evolution of the experimental infection. The objective of
      this study was to evaluate the combined effect of benznidazole (BZ) and
      clomipramine (CLO) against different life-stages of Trypanosoma cruzi in vitro
      and their efficacy in a murine model. Life-stages of T. cruzi,
      BZ-partially-resistant (Y) strain, were incubated with BZ and CLO and
      isobolograms and combination index (CI) were obtained. Swiss mice were infected
      with trypomastigotes and different treatment schedules were performed, each of
      which consisted of 30 consecutive daily doses. Treatment efficacy was evaluated
      by comparing parasitemia, qPCR, survival and histological analysis. These results
      were analyzed using multivariate analysis to determine the combined effect of the
      drugs in vivo. CLO + BZ showed synergistic activity in vitro against the
      clinically relevant life-stages of T. cruzi. The most susceptible forms were the 
      intracellular amastigotes (CI: 0.20), followed by trypomastigotes (CI: 0.60),
      with no toxicity upon mammalian cells. The combination of both drugs CLO
      (1.25mg/kg) and BZ (6.25mg/kg), in vivo, significantly diminished the parasitic
      load in blood and the mortality rate. CLO + BZ presented a similar inflammatory
      response in cardiac and skeletal muscle (amount of inflammatory cells) to BZ
      (6.25 mg/kg). Finally, the results from the principal component analysis
      reaffirmed that both drugs administered in combination presented higher activity 
      compared with the individual administration in the acute experimental model.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Strauss, Mariana
AU  - Strauss M
AD  - Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro
      de Estudios e Investigacion de la Enfermedad de Chagas y Leishmaniasis, Catedra
      de Fisica Biomedica, Facultad de Ciencias Medicas, Santa Rosa 1085, Cordoba
      X5000ESU, Argentina.
FAU - Rodrigues, Jean Henrique S
AU  - Rodrigues JHS
AD  - Laboratorio de Inovacao Tecnologica no Desenvolvimento de Farmacos e Cosmeticos, 
      Universidade Estadual de Maringa, Colombo 5790, Parana, Brazil.
FAU - Lo Presti, Maria Silvina
AU  - Lo Presti MS
AD  - Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro
      de Estudios e Investigacion de la Enfermedad de Chagas y Leishmaniasis, Catedra
      de Fisica Biomedica, Facultad de Ciencias Medicas, Santa Rosa 1085, Cordoba
      X5000ESU, Argentina.
FAU - Bazan, Paola Carolina
AU  - Bazan PC
AD  - Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro
      de Estudios e Investigacion de la Enfermedad de Chagas y Leishmaniasis, Catedra
      de Fisica Biomedica, Facultad de Ciencias Medicas, Santa Rosa 1085, Cordoba
      X5000ESU, Argentina.
FAU - Baez, Alejandra Lidia
AU  - Baez AL
AD  - Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro
      de Estudios e Investigacion de la Enfermedad de Chagas y Leishmaniasis, Catedra
      de Fisica Biomedica, Facultad de Ciencias Medicas, Santa Rosa 1085, Cordoba
      X5000ESU, Argentina.
FAU - Paglini-Oliva, Patricia
AU  - Paglini-Oliva P
AD  - Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro
      de Estudios e Investigacion de la Enfermedad de Chagas y Leishmaniasis, Catedra
      de Fisica Biomedica, Facultad de Ciencias Medicas, Santa Rosa 1085, Cordoba
      X5000ESU, Argentina.
FAU - Nakamura, Celso Vataru
AU  - Nakamura CV
AD  - Laboratorio de Inovacao Tecnologica no Desenvolvimento de Farmacos e Cosmeticos, 
      Universidade Estadual de Maringa, Colombo 5790, Parana, Brazil.
FAU - Bustamante, Juan Manuel
AU  - Bustamante JM
AD  - University of Georgia, Center for Tropical and Emerging Global Diseases, D.W.
      Brooks Dr. S310 Coverdell Center, Athens, GA 30602, USA.
FAU - Rivarola, Hector Walter
AU  - Rivarola HW
AD  - Instituto de Investigaciones en Ciencias de la Salud (INICSA) UNC-CONICET, Centro
      de Estudios e Investigacion de la Enfermedad de Chagas y Leishmaniasis, Catedra
      de Fisica Biomedica, Facultad de Ciencias Medicas, Santa Rosa 1085, Cordoba
      X5000ESU, Argentina. Electronic address: [email protected]
LA  - eng
PT  - Journal Article
DEP - 20180418
PL  - United States
TA  - Exp Parasitol
JT  - Experimental parasitology
JID - 0370713
RN  - 0 (Nitroimidazoles)
RN  - 0 (Trypanocidal Agents)
RN  - NUV44L116D (Clomipramine)
RN  - YC42NRJ1ZD (benzonidazole)
SB  - IM
MH  - Animals
MH  - Chagas Disease/*drug therapy
MH  - Clomipramine/*pharmacology/therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Drug Therapy, Combination
MH  - Female
MH  - Inhibitory Concentration 50
MH  - Male
MH  - Mice
MH  - Multivariate Analysis
MH  - Muscle, Skeletal/parasitology/pathology
MH  - Myocardium/pathology
MH  - Nitroimidazoles/*pharmacology/therapeutic use
MH  - Parasitemia/drug therapy
MH  - Principal Component Analysis
MH  - Real-Time Polymerase Chain Reaction
MH  - Trypanocidal Agents/*pharmacology/therapeutic use
MH  - Trypanosoma cruzi/*drug effects
OTO - NOTNLM
OT  - Benznidazole
OT  - Clomipramine
OT  - Synergism
OT  - Trypanosoma cruzi
EDAT- 2018/05/05 06:00
MHDA- 2018/05/31 06:00
CRDT- 2018/05/05 06:00
PHST- 2017/12/22 00:00 [received]
PHST- 2018/02/18 00:00 [revised]
PHST- 2018/04/15 00:00 [accepted]
PHST- 2018/05/05 06:00 [pubmed]
PHST- 2018/05/31 06:00 [medline]
PHST- 2018/05/05 06:00 [entrez]
AID - S0014-4894(17)30653-7 [pii]
AID - 10.1016/j.exppara.2018.04.016 [doi]
PST - ppublish
SO  - Exp Parasitol. 2018 Jun;189:19-27. doi: 10.1016/j.exppara.2018.04.016. Epub 2018 
      Apr 18.