Cure of Mice Infected with
            <i>Trypanosoma rhodesiense</i>
            by
            <i>cis</i>
            -Diamminedichloroplatinum (ii) and Disulfiram Rescue

Wysor, M.S.; Zwelling, Leonard A.; Sanders, James E.; Grenan, Marie M.

doi:10.1126/science.7201165

Cited by 25 publications

(6 citation statements)

References 5 publications

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“…In the two mice, which received a single 6 mg/kg body-weight dose of cisplatin, appearance of parasitemia was followed by slow but complete recovery; this could be due to the immunostimulation property of cisplatin which has been clearly demonstrated in several reports (11,29,30). Cisplatin has a trypanocidal activity in mice (31). The preliminary result in this study clearly demonstrates the antiplasmodium properties of cisplatin in both the in vitro and in vivo systems.…”

Section: Discussionsupporting

confidence: 49%

Cure With Cisplatin (Ii) of Murine Malaria Infection and in Vitro Inhibition of a Chloroquine-Resistant Plasmodium Falciparum Isolate

Nair

Bhasin

1994

JJMSB

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SUMMARY:Antiplasmodium properties of cisplatin [cis-platinum (II) diammine dichloride], a neoplastic drug, have been assessed in in vivo and in vitro model systems of malarial parasite. A well-tolerated dose of 6 mg/kg body weight of the compound cured the mice infected with Plasmodium berghei and the amount of cisplatin required for in vitro inhibition (IC50) of a chloroquineresistant Plasmodium falciparum isolate was smaller than either chloroquine or quinine. The minimum inhibitory concentration (MIC) needed to prevent the in vitro multiplication of asexual blood parasites was 30 ng/ml. Late ring and trophozoite stages of the erythrocytic cycle were the most susceptible, whereas schizont and early ring stages were the least sensitive to the toxic effect of cisplatin. Multiple smaller doses were more effective in curing malaria in mice than a single large dose. In a few of the mice treated with a single intraperitoneal large dose of 6 mg/kg body weight, there was a delay in appearance of parasitemia but most of them recovered completely but slowly. This compound exerts its toxicity mainly by randomly damaging and cross-linking DNA strands as shown by Southern hybridization with a synthetic oligonucleotide probe, which is a repeat sequence in the falciparum genome. The report clearly demonstrates the antimalarial potentials of this compound and suggests a closer evaluation of this and other related compounds, specially in combination with antimalarial drugs to probe their synergistic properties.241

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Section: Discussionsupporting

confidence: 49%

Cure With Cisplatin (Ii) of Murine Malaria Infection and in Vitro Inhibition of a Chloroquine-Resistant Plasmodium Falciparum Isolate

Nair

Bhasin

1994

JJMSB

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“…In 1979, cisplatin showed significant activity against T. rhodiense [85] and T. cruzi [86]; cisplatin analogs and ruthenium, palladium, rhenium were also reported to be active against Trypanosomes parasites [81,[87][88][89][90][91][92][93].…”

Section: Gold Complexes As Potential Anti-trypanosomiasis Agentsmentioning

confidence: 99%

Gold complexes as potential anti-parasitic agents

Navarro

2009

Coordination Chemistry Reviews

215

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“…The drug combination using DSF offers important advantages, which may be both economical (Cvek, 2012;Soave et al, 2016) and pharmacological, since this compound protects normal cells (Jia and Huang, 2021), can diminish the toxicity of different drugs such as cis-diamminedichloroplatinum (Wysor et al, 1982), including myocardial protection (Sonawane et al, 2018) and circa 30% of the CD patients develop heart disease, characterized by arrhythmias among other cardiac manifestations (Saraiva et al, 2021). It is worth mentioning that DSF can suppress cardiac arrhythmogenesis (Sander et al, 2021).…”

Section: •-mentioning

confidence: 99%

“…Kona et al, 2011), such as cancer therapy (Cvek, 2012;Meraz-Torres et al, 2020;Kannappan et al, 2021;Lu et al, 2021;Lu et al, 2022) and chemoprevention (Askgaard et al, 2014;Yang et al, 2015;Harrington et al, 2020). The DSF and/or DETC combination can enhance antitumoral activities of drugs such as cisplatin (O'Brien et al, 2012;Nechushtan et al, 2015), but diminish adverse reactions (Wysor et al, 1982;Elliott et al, 1983;Bodenner et al, 1986;Roemeling et al, 1986). In addition, DSF can overcome resistance, via different mechanisms (Schmidtova et al, 2019;Yang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

The repositioned drugs disulfiram/diethyldithiocarbamate combined to benznidazole: Searching for Chagas disease selective therapy, preventing toxicity and drug resistance

Almeida-Silva

Menezes

Fernandes

et al. 2022

Front. Cell. Infect. Microbiol.

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Chagas disease (CD) affects at least 6 million people in 21 South American countries besides several thousand in other nations all over the world. It is estimated that at least 14,000 people die every year of CD. Since vaccines are not available, chemotherapy remains of pivotal relevance. About 30% of the treated patients cannot complete the therapy because of severe adverse reactions. Thus, the search for novel drugs is required. Here we tested the benznidazole (BZ) combination with the repositioned drug disulfiram (DSF) and its derivative diethyldithiocarbamate (DETC) upon Trypanosoma cruzi in vitro and in vivo. DETC-BZ combination was synergistic diminishing epimastigote proliferation and enhancing selective indexes up to over 10-fold. DETC was effective upon amastigotes of the BZ- partially resistant Y and the BZ-resistant Colombiana strains. The combination reduced proliferation even using low concentrations (e.g., 2.5 µM). Scanning electron microscopy revealed membrane discontinuities and cell body volume reduction. Transmission electron microscopy revealed remarkable enlargement of endoplasmic reticulum cisternae besides, dilated mitochondria with decreased electron density and disorganized kinetoplast DNA. At advanced stages, the cytoplasm vacuolation apparently impaired compartmentation. The fluorescent probe H2-DCFDA indicates the increased production of reactive oxygen species associated with enhanced lipid peroxidation in parasites incubated with DETC. The biochemical measurement indicates the downmodulation of thiol expression. DETC inhibited superoxide dismutase activity on parasites was more pronounced than in infected mice. In order to approach the DETC effects on intracellular infection, peritoneal macrophages were infected with Colombiana trypomastigotes. DETC addition diminished parasite numbers and the DETC-BZ combination was effective, despite the low concentrations used. In the murine infection, the combination significantly enhanced animal survival, decreasing parasitemia over BZ. Histopathology revealed that low doses of BZ-treated animals presented myocardial amastigote, not observed in combination-treated animals. The picrosirius collagen staining showed reduced myocardial fibrosis. Aminotransferase de aspartate, Aminotransferase de alanine, Creatine kinase, and urea plasma levels demonstrated that the combination was non-toxic. As DSF and DETC can reduce the toxicity of other drugs and resistance phenotypes, such a combination may be safe and effective.

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Cure of Mice Infected with Trypanosoma rhodesiense by cis -Diamminedichloroplatinum (ii) and Disulfiram Rescue

Cited by 25 publications

References 5 publications

Cure With Cisplatin (Ii) of Murine Malaria Infection and in Vitro Inhibition of a Chloroquine-Resistant Plasmodium Falciparum Isolate

Cure With Cisplatin (Ii) of Murine Malaria Infection and in Vitro Inhibition of a Chloroquine-Resistant Plasmodium Falciparum Isolate

Gold complexes as potential anti-parasitic agents

The repositioned drugs disulfiram/diethyldithiocarbamate combined to benznidazole: Searching for Chagas disease selective therapy, preventing toxicity and drug resistance

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