Fatal rhabdomyolysis after acute sodium monensin (Rumensin®) toxicity: case report

Kouyoumdjian, João Aris; Morita, Maria da Penha Ananias; Sato, Adriana Komatsu; Pissolatti, Amália Fernanda

doi:10.1590/s0004-282x2001000400022

Cited by 41 publications

(39 citation statements)

References 4 publications

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“…However, preclinical pharmacological and safety data are scarce. Toxicity in humans has been reported in cases of accidental high-dose ingestion in people working with livestock (64,65). In our assays, salinomycin appeared to be the most toxic for HMEC-1 cells among the ionophores tested, but the selectivity index was similar to that of the antimalarial drug DHA.…”

Section: Discussionsupporting

confidence: 61%

Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

D’Alessandro

Corbett

Ilboudo

et al. 2015

Antimicrob Agents Chemother

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fThe drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission-blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P. falciparum mosquito stages is reported here. Gametocytogenesis of the P. falciparum strain 3D7 was induced in vitro, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC 50 ). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission-blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads.

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Section: Discussionsupporting

confidence: 61%

Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

D’Alessandro

Corbett

Ilboudo

et al. 2015

Antimicrob Agents Chemother

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“…Due to monensin toxicity in humans (78,79), it will be difficult to use monensin as a new therapeutic treatment against HCV. However, as shown in this study, monensin is a valuable tool for analyzing the late steps of HCV entry, i.e., membrane fusion.…”

Section: Discussionmentioning

confidence: 99%

New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin A

Fénéant

Potel

François³

et al. 2015

J Virol

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In our study, we characterized the effect of monensin, an ionophore that is known to raise the intracellular pH, on the hepatitis C virus (HCV) life cycle. We showed that monensin inhibits HCV entry in a pangenotypic and dose-dependent manner. Monensin induces an alkalization of intracellular organelles, leading to an inhibition of the fusion step between viral and cellular membranes. Interestingly, we demonstrated that HCV cell-to-cell transmission is dependent on the vesicular pH. Using the selective pressure of monensin, we selected a monensin-resistant virus which has evolved to use a new entry route that is partially pH and clathrin independent. Characterization of this mutant led to the identification of two mutations in envelope proteins, the Y297H mutation in E1 and the I399T mutation in hypervariable region 1 (HVR1) of E2, which confer resistance to monensin and thus allow HCV to use a pH-independent entry route. Interestingly, the I399T mutation introduces an N-glycosylation site within HVR1 and increases the density of virions and their sensitivity to neutralization with anti-apolipoprotein E (anti-ApoE) antibodies, suggesting that this mutation likely induces conformational changes in HVR1 that in turn modulate the association with ApoE. Strikingly, the I399T mutation dramatically reduces HCV cell-to-cell spread. In summary, we identified a mutation in HVR1 that overcomes the vesicular pH dependence, modifies the biophysical properties of particles, and drastically reduces cellto-cell transmission, indicating that the regulation by HVR1 of particle association with ApoE might control the pH dependence of cell-free and cell-to-cell transmission. Thus, HVR1 and ApoE are critical regulators of HCV propagation. IMPORTANCEAlthough several cell surface proteins have been identified as entry factors for hepatitis C virus (HCV), the precise mechanisms regulating its transmission to hepatic cells are still unclear. In our study, we used monensin A, an ionophore that is known to raise the intracellular pH, and demonstrated that cell-free and cell-to-cell transmission pathways are both pH-dependent processes. We generated monensin-resistant viruses that displayed different entry routes and biophysical properties. Thanks to these mutants, we highlighted the importance of hypervariable region 1 (HVR1) of the E2 envelope protein for the association of particles with apolipoprotein E, which in turn might control the pH dependency of cell-free and cell-to-cell transmission. H epatitis C virus (HCV) infection is a global public health problem affecting over 130 million individuals worldwide.Chronic HCV infection can result in liver cirrhosis and hepatocellular carcinoma (1). While previous interferon (IFN)-based therapies have been limited by drug resistance and marked toxicity (2), the recently clinically licensed direct-acting antivirals are expected to cure the large majority of infected patients without major adverse effects (3). Nevertheless, several challenges remain: high costs limit access to therapy ...

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“…The effect of monensin may be due to mitochondrial damage [23] and/or weakening of the antioxidative defence [24]. Monensin intoxication leads to severe rhabdomyolysis and acute renal failure with ultimate death of the patients [22,25]. The excessive Na + entry following monensin intoxication stimulates the Na + ,K + -ATPase [26], which may in turn lead to energy depletion, another well known trigger of eryptosis [27].…”

Section: Introductionmentioning

confidence: 99%

Monensin Induced Suicidal Erythrocyte Death

Bhavsar

Eberhard

Bobbala

et al. 2010

Cell Physiol Biochem

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Eryptosis, the suicidal erythrocyte death, is characterized by cell membrane scrambling and cell shrinkage. Eryptosis may be triggered by excessive hyperosmotic or isosmotic cell shrinkage leading to increase of cytosolic Ca²⁺ concentration. Eryptosis is further stimulated by the K⁺ ionophore valinomycin, which leads to exit of KCl and osmotically obliged water, or by energy (glucose) depletion, which compromises the function of the Na⁺/K⁺ ATPase thus increasing cytosolic Na⁺ concentration. The present study explored whether the Na⁺ ionophore monensin affects erythrocyte cell volume and eryptosis. The cell membrane scrambling was estimated from binding of annexin V to phosphatidylserine at the erythrocyte surface, cell volume from forward scatter in FACS analysis, cytosolic Ca²⁺ concentration from Fluo3 fluorescence and the cytosolic ATP concentration from a luciferase-based assay. Within 24 hours, exposure to monensin (0.1-10 µg/ml) significantly increased forward scatter, cytosolic Ca²⁺ concentration and annexin V-binding. Glucose depletion was followed by decreased forward scatter and increased cytosolic Ca²⁺ concentration and annexin V-binding. The effect on forward scatter was partially reversed, the effect on cytosolic Ca²⁺ concentration and annexin V binding augmented by additional treatment with monensin. In conclusion, monensin dissociates the alterations of cell membrane and cell volume in suicidal erythrocyte death.

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Fatal rhabdomyolysis after acute sodium monensin (Rumensin®) toxicity: case report

Cited by 41 publications

References 4 publications

Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

Salinomycin and Other Ionophores as a New Class of Antimalarial Drugs with Transmission-Blocking Activity

New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin A

Monensin Induced Suicidal Erythrocyte Death

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