In vitro and in vivo evaluation of kojic acid against Toxoplasma gondii in experimental models of acute toxoplasmosis

In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), emerged in Wuhan, China. Despite containment measures, SARS-CoV-2 spread in Asia, Southern Europe, then in America and currently in Africa. Identifying effective antiviral drugs is urgently needed. An efficient approach to drug discovery is to evaluate whether existing approved drugs can be efficient against SARS-CoV-2. Doxycycline, which is a second-generation tetracycline with broad-spectrum antimicrobial, antimalarial and anti-inflammatory activities, showed in vitro activity on Vero E6 cells infected with a clinically isolated SARS-CoV-2 strain (IHUMI-3) with median effective concentration (EC50) of 4.5 ± 2.9 µM, compatible with oral uptake and intravenous administrations. Doxycycline interacted both on SARS-CoV-2 entry and in replication after virus entry. Besides its in vitro antiviral activity against SARS-CoV-2, doxycycline has anti-inflammatory effects by decreasing the expression of various pro-inflammatory cytokines and could prevent co-infections and superinfections due to broad-spectrum antimicrobial activity. Therefore, doxycycline could be a potential partner of COVID-19 therapies. However, these results must be taken with caution regarding the potential use in SARS-CoV-2-infected patients: it is difficult to translate in vitro study results to actual clinical treatment in patients. In vivo evaluation in animal experimental models is required to confirm the antiviral effects of doxycycline on SARS-CoV-2 and more trials of high-risk patients with moderate to severe COVID-19 infections must be initiated.

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Two 2-Hydroxy-3-Alkyl-1,4-Naphthoquinones with In Vitro and In Vivo Activities against Toxoplasma gondii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.9.2284 ◽

1998 ◽

Vol 42 (9) ◽

pp. 2284-2289 ◽

Cited By ~ 8

Author(s):

Anis A. Khan ◽

Mohamed Nasr ◽

Fausto G. Araujo

Keyword(s):

Toxoplasma Gondii ◽

Murine Models ◽

Intracellular Replication ◽

Acute Toxoplasmosis

ABSTRACT Two 3-alkyl-substituted 2-hydroxy-1,4-naphthoquinones, NSC 113452 (NSC52) and NSC 113455 (NSC55), were evaluated for activity againstToxoplasma gondii in vitro and in murine models of acute toxoplasmosis. In vitro, both NSC52 and NSC55 significantly inhibited intracellular replication of T. gondii. In vivo, each compound was examined alone and in combination with other drugs currently used for treatment of human toxoplasmosis. Although none of the compounds protected mice against death when administered orally, both were significantly protective when administered intraperitoneally. In addition, a significant increase in survival was observed when suboptimal doses of each compound were used in combination with suboptimal doses of pyrimethamine or sulfadiazine. These results indicate that combinations of NSC52 or NSC55 with pyrimethamine or sulfadiazine have promising activity against T. gondii.

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In Vitro and In Vivo Anti-Toxoplasma Activities of Dracocephalum kotschyi Extract in Experimental Models of Acute Toxoplasmosis

Acta Parasitologica ◽

10.1007/s11686-021-00491-4 ◽

2021 ◽

Author(s):

Mustafa Ghanadian ◽

Faham Khamesipour ◽

Seyed Hossein Hejazi ◽

Seyed Mostafa Razavi ◽

Hassan Sadraei ◽

...

Keyword(s):

Experimental Models ◽

Dracocephalum Kotschyi ◽

Acute Toxoplasmosis

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Enrofloxacin is able to control Toxoplasma gondii infection in both in vitro and in vivo experimental models

Veterinary Parasitology ◽

10.1016/j.vetpar.2011.12.039 ◽

2012 ◽

Vol 187 (1-2) ◽

pp. 44-52 ◽

Cited By ~ 32

Author(s):

Bellisa Freitas Barbosa ◽

Angelica Oliveira Gomes ◽

Eloisa Amália Vieira Ferro ◽

Danielle Reis Napolitano ◽

José Roberto Mineo ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Experimental Models ◽

Toxoplasma Gondii Infection

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Trovafloxacin is active against Toxoplasma gondii.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.8.1855 ◽

1996 ◽

Vol 40 (8) ◽

pp. 1855-1859 ◽

Cited By ~ 35

Author(s):

A A Khan ◽

T Slifer ◽

F G Araujo ◽

J S Remington

Keyword(s):

Toxoplasma Gondii ◽

Host Cells ◽

Intracellular Replication ◽

Congenital Infections ◽

Time To Death ◽

Significant Toxicity ◽

Acute Toxoplasmosis ◽

Toxic Drugs

Drugs currently used for treatment of toxoplasmosis in pregnant women, congenital infections, immunocompromised patients, and patients with the ocular disease are not always effective or may be dangerous to use; therefore, there is a need for more-effective and less-toxic drugs. Recently, we examined a group of fluoroquinolones for in vitro and in vivo activities against Toxoplasma gondii. Among those examined in vitro (ciprofloxacin, fleroxacin, ofloxacin, temafloxacin, and trovafloxacin), only trovafloxacin significantly inhibited intracellular replication of T. gondii without significant toxicity for host cells. In a murine model of acute toxoplasmosis, 100 or 200 mg of trovafloxacin per kg of body weight per day for 10 days protected 100% of infected mice against death. A dose of 50 mg/kg/day protected 90% of the mice, and a dose of 25 mg/kg/day effected prolongation of time to death. The other fluoroquinolones did not have such in vivo activities. These results indicate that trovafloxacin may be useful for treatment of toxoplasmosis in humans.

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In vitro and in vivo effects of rifabutin alone or combined with atovaquone against Toxoplasma gondii.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.9.2015 ◽

1996 ◽

Vol 40 (9) ◽

pp. 2015-2020 ◽

Cited By ~ 12

Author(s):

S Romand ◽

C Della Bruna ◽

R Farinotti ◽

F Derouin

Keyword(s):

Toxoplasma Gondii ◽

Synergistic Effects ◽

Survival Rates ◽

Culture Method ◽

In Vivo Studies ◽

Enzyme Linked Immunosorbent Assay ◽

Blood Brain ◽

Acute Toxoplasmosis

The efficacy of rifabutin (RIFA) alone or in combination with atovaquone (ATO) was examined in vitro and in a murine model of acute toxoplasmosis. In vitro studies were performed with MRC5 fibroblast tissue cultures, with quantification of Toxoplasma growth by enzyme-linked immunosorbent assay. For in vivo studies, mice were acutely infected with 10(4) tachyzoites of the virulent RH strain and were then treated perorally for 10 days from day 1 or day 4 postinfection. The efficacy of each drug regimen was assessed by determination of survival rates and sequential titration of parasites in blood, brain, and lungs by a tissue culture method. In vitro, RIFA was inhibitory for Toxoplasma growth at concentrations between 0.5 and 20 micrograms/ml; the 50% inhibitory concentration was estimated to be 1.68 micrograms/ml. When RIFA and ATO were combined, synergistic effects were noted for RIFA at 20 micrograms/ml combined with ATO at 0.01 or 0.02 microgram/ml and RIFA at 1, 2, or 5 micrograms/ml combined with ATO at 0.02 microgram/ml. In vivo, administration of RIFA at 200 mg/kg of body weight per day from day 1 to day 10 resulted in a 100% protection during treatment, with clearance of parasites from the blood, brain, and lungs. After the cessation of therapy, relapses occurred in the brain and lungs; the mortality was 46% at the end of the experiment (day 30). Among the mice treated with RIFA at 200 mg/kg/day from day 4 to day 14, no death was recorded during the treatment period and a marked reduction in parasite burdens was observed in blood and tissues; however, relapses occurred and 10% of mice survived until day 30. Administration of RIFA at 200 mg/kg/day in combination with ATO at 100 mg/kg/day resulted in a marked prolongation of survival compared with that for mice that received ATO or RIFA alone. However, in mice receiving the combination, parasite burdens in blood and organs were similar to those in mice treated with RIFA alone. These results confirmed the activity of RIFA in the treatment of acute toxoplasmosis and the potential of the combination of RIFA-ATO since the two drugs act synergistically against Toxoplasma gondii.

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In Vitro and In Vivo Activities of 1-Hydroxy-2-Alkyl-4(1H)Quinolone Derivatives against Toxoplasma gondii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01001-09 ◽

2009 ◽

Vol 54 (1) ◽

pp. 517-521 ◽

Cited By ~ 13

Author(s):

Lara Liv Bajohr ◽

Ling Ma ◽

Christian Platte ◽

Oliver Liesenfeld ◽

Lutz F. Tietze ◽

...

Keyword(s):

Toxoplasma Gondii ◽

Mouse Model ◽

Toxoplasmic Encephalitis ◽

Peritoneal Cells ◽

Acute Toxoplasmosis ◽

Quinolone Derivatives

ABSTRACT 1-Hydroxy-2-dodecyl-4(1H)quinolone (HDQ) was recently identified as a Toxoplasma gondii inhibitor. We describe here two novel 1-hydroxyquinolones, which displayed 50% inhibitory concentrations 10- and 5-fold lower than that of HDQ. In a mouse model of acute toxoplasmosis, these two compounds and HDQ reduced the percentages of infected peritoneal cells and decreased the parasite loads in lungs and livers. Compound B showed a tendency toward lowering parasite loads in brains in a mouse model of toxoplasmic encephalitis.

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Recombinant Bactericidal/Permeability-Increasing Protein (rBPI21) in Combination with Sulfadiazine Is Active against Toxoplasma gondii

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.4.758 ◽

1999 ◽

Vol 43 (4) ◽

pp. 758-762 ◽

Cited By ~ 10

Author(s):

Anis A. Khan ◽

Lewis H. Lambert ◽

Jack S. Remington ◽

Fausto G. Araujo

Keyword(s):

Toxoplasma Gondii ◽

Synergistic Effects ◽

Day Treatment ◽

Protozoan Parasite ◽

Time To Death ◽

Significant Survival ◽

Mathematical Analyses ◽

Acute Toxoplasmosis

ABSTRACT The activity of recombinant bactericidal/permeability-increasing protein (rBPI21), alone or in combination with sulfadiazine, on the intracellular replication of Toxoplasma gondii was assessed in vitro and in mice with acute toxoplasmosis. rBPI21 markedly inhibited the intracellular growth of T. gondii in human foreskin fibroblasts (HFFs). Following 72 h of exposure, the 50% inhibitory concentration of rBPI21 for T. gondii was 2.6 μg/ml, whereas only slight cytotoxicity for HFF cells was observed at the concentrations tested. Subsequent mathematical analyses revealed that the combination of rBPI21 with sulfadiazine yielded slight to moderate synergistic effects against T. gondii in vitro. Infection of mice orally with C56 cysts or intraperitoneally (i.p.) with RH tachyzoites resulted in 100% mortality, whereas prolongation of the time to death or significant survival (P = 0.002) was noted for those animals treated with 5 to 20 mg of rBPI21 per kg of body weight per day. Treatment with rBPI21 in combination with sulfadiazine resulted in significant (P = 0.0001) survival of mice infected i.p. with tachyzoites but not of mice infected orally with T. gondii cysts. These results indicate that rBPI21 is active in vitro and in vivo against T. gondii and that its activity is significantly enhanced when it is used in combination with sulfadiazine. To our knowledge, this is the first report of the activity of rBPI21 against a protozoan parasite.

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