Rhabdomyolysis, acute renal failure, and death after monensin ingestion

Caldeira, Carlos; Neves, William S.; Cury, Patrí­cia Maluf; Serrano, Patricia Martín; Baptista, Maria Alice Sperto Ferreira; Burdmann, Emmanuel A.

doi:10.1053/ajkd.2001.28618

Cited by 45 publications

(35 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There do not appear to have been any systemic effects from this dose, with no hepatic or renal problems identified. In contrast, acute rhabdomyolysis, renal failure, and death has been reported following human ingestion of monensin, a polyether ionophore veterinary antibiotic (5). In our patient the rise in creatinine kinase was short lived and consistent with the degree of local muscle necrosis.…”

Section: Discussioncontrasting

confidence: 49%

Accidental human injection of Excenel RTU™: Ceftiofur hydrochloride in cottonseed oil

Gwynne‐Jones

Lyall

Hung

et al. 2008

Clinical Toxicology

View full text Add to dashboard Cite

Introduction. There is little knowledge within the medical community of the existence of veterinary antibiotics in oil-based suspensions and the adverse effects that may occur with accidental human injection. Case report. A farmer injected an unknown quantity of Excenel RTU TM into her right thigh. Despite early debridement she developed a deep infection and recurrent chronic inflammation in the subcutaneous tissues and muscle secondary to the cottonseed oil suspension. Radical debridement and extensive split skin grafting was required but she still has had recurrences 12 months after injury. Discussion. Prompt surgical debridement should be performed as in cases of oil based veterinary vaccines. Despite being an antibiotic there is a significant risk of infection from a dirty needle following inoculation and multiple cultures should be taken and appropriate broad spectrum antibiotics used. Radical debridement and skin grafting necessitating specialist plastic surgical attention may be required.

show abstract

Section: Discussioncontrasting

confidence: 49%

Accidental human injection of Excenel RTU™: Ceftiofur hydrochloride in cottonseed oil

Gwynne‐Jones

Lyall

Hung

et al. 2008

Clinical Toxicology

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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 ...

show abstract

“…However, monensin has been characterized by a narrow safety margin and may cause lethal toxicoses, especially when coadministered with other drugs (Nebbia et al, 1999). Furthermore, accidental poisoning in animals (Nebbia et al, 1999) and an isolated case of lethal monensin ingestion in a human patient suggest that large doses of lysosomal inhibitors must be considered potentially dangerous for humans (Caldeira et al, 2001). Nevertheless the possibility to use lysosomal inhibitors to manipulate hepatic (or pulmonary) drug extraction to achieve a higher systemic availability for drugs that show a pronounced first pass effect is of interest.…”

Section: Hepatic Disposition Of Basic Drugs 233mentioning

confidence: 99%

Ion-Trapping, Microsomal Binding, and Unbound Drug Distribution in the Hepatic Retention of Basic Drugs

Siebert¹,

Hung²,

Chang³

et al. 2003

J Pharmacol Exp Ther

View full text Add to dashboard Cite

This study investigated the relative contribution of ion-trapping, microsomal binding, and distribution of unbound drug as determinants in the hepatic retention of basic drugs in the isolated perfused rat liver. The ionophore monensin was used to abolish the vesicular proton gradient and thus allow an estimation of ion-trapping by acidic hepatic vesicles of cationic drugs. In vitro microsomal studies were used to independently estimate microsomal binding and metabolism. Hepatic vesicular ion-trapping, intrinsic elimination clearance, permeability-surface area product, and intracellular binding were derived using a physiologically based pharmacokinetic model. Modeling showed that the ion-trapping was significantly lower after monensin treatment for atenolol and propranolol, but not for antipyrine. However, no changes induced by monensin treatment were observed in intrinsic clearance, permeability, or binding for the three model drugs. Monensin did not affect binding or metabolic activity in vitro for the drugs. The observed ion-trapping was similar to theoretical values estimated using the pHs and fractional volumes of the acidic vesicles and the pK a values of drugs. Lipophilicity and pK a determined hepatic drug retention: a drug with low pK a and low lipophilicity (e.g., antipyrine) distributes as unbound drug, a drug with high pK a and low lipophilicity (e.g., atenolol) by ion-trapping, and a drug with a high pK a and high lipophilicity (e.g., propranolol) is retained by ion-trapping and intracellular binding. In conclusion, monensin inhibits the ion-trapping of high pK a basic drugs, leading to a reduction in hepatic retention but with no effect on hepatic drug extraction.Basic lipophilic compounds are characterized by a high volume of distribution as a result of extensive tissue uptake. The main mechanisms of such a distribution pattern are nonspecific binding to membrane phospholipids (Bickel and Steele, 1974;Francesco and Bickel, 1977;Romer and Bickel, 1979), binding to microsomal protein (Hung et al., 2002), and the sequestration of the compounds into acidic vesicular compartments such as lysosomes or mitochondria (Daniel et al., 1995). A potential consequence of an apparent irreversible sequestration of basic drugs into acidic vesicles is a potentially reduced drug bioavailability (de Duve et al., 1974;Ohkuma and Poole, 1978) or drug interactions (Daniel and Wojcikowski, 1999b;Nebbia et al., 1999). Lysosomal trapping of basic lipophilic drugs has also been demonstrated to be an important determinant of disposition for desipramine and chloroquine and psychotropic compounds such as the piperidine and piperazine-type neuroleptics (Daniel et al., 2001). The lysosomotropic properties of basic drugs are particularly important determining drug disposition and pharmacokinetics in lysosome-rich organs such as lungs, kidneys, or the liver.Specific studies determining the relative contribution of ion-trapping and microsomal binding to the hepatic retention of drugs or relating the relative uptake to the ph...

show abstract

Rhabdomyolysis, acute renal failure, and death after monensin ingestion

Cited by 45 publications

References 16 publications

Accidental human injection of Excenel RTU™: Ceftiofur hydrochloride in cottonseed oil

Accidental human injection of Excenel RTU™: Ceftiofur hydrochloride in cottonseed oil

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

Ion-Trapping, Microsomal Binding, and Unbound Drug Distribution in the Hepatic Retention of Basic Drugs

Contact Info

Product

Resources

About