ABSTRACT
OBJECTIVE: Malaria parasites invade, grow and multiply inside erythrocytes and obtain nourishment from haemoglobin. Then, the released haem group is oxidized to haematin and inert dimeric haemozoin bio-crystals form, which provides the parasite a unique way to avoid the toxicity associated with the haem group. Therefore, antimalarial drugs are designed to inhibit dimer formation; however, recent electrochemical studies indicate that an inert dimer also promotes a toxic oxidizing environment. Therefore, this work explores drug reactivity in the presence of monomers and dimers to evaluate their contribution to redox activity. MATERIALS AND METHODS: Three medicines mixed with haemozoin or ß-haemozoin in carbon paste electrodes were tested using cyclic voltammetry. RESULTS: The data indicated again that the substances modify the natural redox state of haemozoin and ß-haemozoin. This effect could be attributed to the natural oxidation potential of the drugs. In addition, it was found that the oxidation potential decreased through quinine, lumefantrine and artemether with the same tendency in the presence of haemozoin but with less current density. Additionally, it was observed that the oxidation response between the monomer haemozoin and antimalarial drugs is carried out at more negative potentials. CONCLUSIONS: Together, the total results indicate that antimalarials per se can contribute to oxidation processes and that in combination with monomeric or dimeric haemozoin can increase or decrease the oxidizing power of the haemozoin forms. The various oxidizing environments suggest that the cell membranes can also be damaged by the unique presence of the antimalarial.
Subject(s)
Antimalarials/chemistry , Artemether/chemistry , Hemoglobins/chemistry , Lumefantrine/chemistry , Quinine/chemistry , Animals , Electrodes , Hemiptera/chemistry , Humans , Oxidation-Reduction , Particle Size , Surface PropertiesABSTRACT
AbbreviationsSAHAsuberoylanilide hydroxamic acidEhHDACHistone Deacetylase from Entamoeba histolyticaRgRadius of gyrationRMSDroot-mean-square deviationRMSFroot-mean-square fluctuationMDSmolecular dynamics simulationVMDVisual Molecular DynamicsNAMDNanoscale Molecular DynamicsPBCperiodic boundary conditionsPMEParticle Mesh Ewald3Dthree-dimensionalCαalpha carbonFDAFood and Drug AdministrationnsnanosecondsGPU CUDAGraphics Processing Unit Compute Unified Device ArchitectureCommunicated by Ramaswamy H. Sarma.
Subject(s)
Amebiasis/drug therapy , Amebiasis/parasitology , Entamoeba histolytica/physiology , Metronidazole/therapeutic use , Vorinostat/therapeutic use , Entamoeba histolytica/drug effects , Entamoeba histolytica/enzymology , Histone Deacetylases/chemistry , Metronidazole/chemistry , Metronidazole/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Phylogeny , Structural Homology, Protein , Trophozoites/drug effects , Trophozoites/physiology , Vorinostat/chemistry , Vorinostat/pharmacologyABSTRACT
OBJECTIVE: Metronidazole is an antibiotic widely used in different medical conditions such as trichomoniasis, amoebiasis, and giardiasis among others. Its use has been associated with toxicity; however, it is not well characterized. In this review, we discuss the different therapeutic uses of metronidazole and its side effects in order to aid future investigation in this field. MATERIALS AND METHODS: Relevant information, original research articles, clinical trials, and reviews were collected from PubMed to know the state of the art of the different therapeutic uses of metronidazole and the reported side effects. RESULTS: Metronidazole was used by the first time in 1959, to treat an infection caused by Trichomonas vaginalis; subsequently, new therapeutic properties were discovered. Nowadays, Metronidazole is used to treat infections caused by Bacteroides, Fusobacteria and Clostridia, rosacea, oral and dental infections, bone and joint infections, gynecologic infections, endocarditis, septicemia, and respiratory tract infections. It also can be used to treat Crohn´s disease or even like prophylaxis, before surgical procedures. Metronidazole is well tolerated with mild to moderate side effects such as nausea, abdominal pain, and diarrhea. Nevertheless, serious neurotoxicity, optic neuropathy, peripheral neuropathy, and encephalopathy have been reported in rare cases. Their genotoxic effects observed in animal models are controversial in humans. CONCLUSIONS: The therapeutic use of metronidazole had increased worldwide. Even though it is widely used, metronidazole has been associated with neurotoxicity and genotoxicity; however, its side effects are not well established. Conversely, its veterinary use is restricted in some countries because of its tumor association. Subsequently, further studies are needed to discover the secure use of metronidazole and describe new usages for this drug.
