Nitroimidazole Drugs Research Articles

MRI Spectrum of Toxic Encephalopathy-An Institutional Experience.

There are numerous toxins that affect our nervous system, both central and peripheral. Innumerable differentials exist in patients of acute encephalopathy and the list can be narrowed down with appropriate imaging. Specific neuroradiological features point to a particular diagnosis in a substantial number of cases. Through this study, we aimed to demonstrate the varied imaging findings of toxic encephalopathy on MRI encountered at our institute. A retrospective analysis of the patients clinically diagnosed as toxic encephalopathy and referred for imaging between March 2015 and December 2019 was done. A total of 25 patients were included. Patient records were reviewed for clinical details, laboratory investigations, and treatment; the institute Picture Archiving and Communication System provided the imaging findings. Patients presenting were aged between 22 and 55 years (mean-34.3 years). Four patients (16%) presented with imaging findings characteristic of Marchiafava-Bignami disease and six patients (24%) had MRI findings of Wernicke encephalopathy. Three patients (12%) had methanol poisoning sequelae while imaging findings of nitroimidazole drug toxicity were observed in another three patients (12%). Two patients (8%) each of carbon monoxide poisoning and lead toxicity were seen. We had one patient (4%) each of isoniazid, methyl iodide, dextropropoxyphene toxicity, chronic toluene abuse, and hyperglycemia-induced hemiballismus-hemichorea. Our study illustrates the amalgamated spectrum of MRI appearances in various subgroups of toxic encephalopathies. Imaging substantiated by relevant history and clinical manifestations can accurately diagnose the possible causative agent in the majority of the cases.

2D Strategy for the Construction of an Enzyme-Activated NIR Fluorophore Suitable for the Visual Sensing and Profiling of Homologous Nitroreductases from Various Bacterial Species.

Nitroreductases (NTRs) mediate the reduction of nitroaromatic compounds to the corresponding nitrite, hydroxylamine, or amino derivatives. The activity of NTRs in bacteria facilitates the metabolic activation and antibacterial activity of 5-nitroimidazoles. Therefore, NTR activity correlates with the drug susceptibility and resistance of pathogenic bacteria. As such, it is important to develop a rapid and visual assay for the real-time sensing of bacterial NTRs for the evaluation and development of antibiotics. Herein, an activatable near-infrared fluorescent probe (HC–NO2) derived from a hemicyanine fluorophore was designed and developed based on two evaluation factors, including the calculated partition coefficient (Clog P) and fluorescence wavelength. Using HC–NO2 as the special substrate of NTRs, NTR activity can be assayed efficiently, and then, bacteria can be imaged based on the detection of NTRs. More importantly, a sensitive in-gel assay using HC–NO2 has been developed to selectively identify NTRs and sensitively determine NTR activity. Using the in-gel assay, NTRs from various bacterial species have been profiled visually from the “fluorescence fingerprints”, which facilitates the rapid identification of NTRs from bacterial lysates. Thus, various homologous NTRs were identified from three metronidazole-susceptible bacterial species as well as seven unsusceptible species, which were confirmed by the whole-genome sequence. As such, the evaluation of NTRs from different bacterial species should help improve the rational usage of 5-nitroimidazole drugs as antibiotics.

Well-Designed Construction of Yttrium Orthovanadate Confined on Graphitic Carbon Nitride Sheets: Electrochemical Investigation of Dimetridazole.

Antibiotics are the most important drugs for people and animals to fight bacterial illnesses. Overuse of antibiotics has had unintended consequences, such as antibiotic resistance and ecosystem eradication owing to toxic chemical discharge, which have a negative influence on the biome. Herein, we report the synthesis of a hollow ellipsoid-shaped yttrium vanadate/graphitic carbon nitride (YVO4@CN) nanocomposite by a hydrothermal approach followed by a sonochemical method for the effective detection of dimetridazole (DMZ). The synergic and coupling effect between both the phases offer non-linear cumulative ramifications which can positively enhance the individual properties of the materials under consideration. This positive hybrid effect increases the conductivity, shortens the ion-diffusion pathway, enhances the electron/ion transportation, and provides more active sites and electron-conducting channels. The accurate optimization of the experimental conditions proposes good electrocatalytic activity for the YVO4@CN catalyst, exhibiting a good response toward DMZ detection. It reveals an extensive linear concentration range (0.001-153.3 and 176.64-351.6 μM), a low detection limit (0.8 nM), higher sensitivity (4.98 μA μM-1 cm-2), appreciable selectivity, increased operational stability (2200 s), and good cycle stability (60 cycles). The electrochemical performance of YVO4@CN indicates its practical application in real-time sample analysis of several families of nitroimidazole drugs.

Evaluating the efficacy of nitazoxanide in uncomplicated amebic liver abscess.

Amebic liver abscess is treated successfully with metronidazole or another nitroimidazole drug followed by a luminal amebicide. Metronidazole has long been preferred, but has been associated with several adverse effects including intolerance in certain clinical situations. Mechanisms of metronidazole resistance and mutagenic potential have been described. Effects of the use of drug in pregnant women and infants of lactating women are unknown. Nitazoxanide was proven to be efficacious in treating invasive intestinal amebiasis. Therefore, the present study was undertaken to assess the efficacy and safety of nitazoxanide as compared to metronidazolein patients with uncomplicated amebic liver abscess. Patients with clinical and ultrasonography features suggestive of liver abscess, positive amebic serology, and/or anchovy sauce appearance on aspirationof the pus were included in the study and randomized into two parallel treatment groups. Group M received metronidazole, 2-2.5g/day intravenous (IV), for inpatients, or 2-2.4g/day oral, for outpatients in three divided doses for 14days. Group N received nitazoxanide 500mg BD per oral for 10days. A total of sixty subjects fulfilling the inclusion criteria were randomized equally into two groups, group M and group N. Number of patients achieving symptomatic clinical response (SCR) was similar in the two groups (80% vs. 76.7%, p = 1.00), though time to achieve symptomatic clinical response was significantly lower in metronidazole group as compared to that in nitazoxanide group. Greater proportion of patients achieved early clinical response (ECR) in metronidazole group as compared to nitazoxanide group. Complete resolution of abscess, at 6months, was noted in 18 (60%) patients in the M group and 22 (73.3%) patients in the N group (p = 0.273). Metronidazole was associated with significantly greater frequency of adverse effects than nitazoxanide. This study shows equivalent efficacy of nitazoxanide in uncomplicated amebic liver abscess as compared to metronidazole, with better tolerability and advantage of simultaneous luminal clearance, thus reducing chances of recurrence. CTRI/2019/01/017249.

The Role of Nitroreductases in Resistance to Nitroimidazoles.

Simple SummaryAntimicrobial resistance continues to be a major global health threat. It is estimated by the WHO that 700,000 people die each year because of drug resistance, and this is predicted to rise to 10 million by 2050. As well as the increased cost, which is forecast to exceed $100 trillion, as more expensive drugs have to be deployed, illnesses often last longer and require hospital treatment. This, in turn, increases the strain on often-inadequate healthcare systems. As resistances continue to grow, finding alternatives is crucial. This review showed that nitroreductases play a role in drug activation but are also associated with resistance mechanisms. These mechanisms require further investigation to fully understand them before they can be utilised against multidrug-resistant organisms. This will depend on committed collaborations between the private and public sector to translate academic research into the clinic.Antimicrobial resistance is a major challenge facing modern medicine, with an estimated 700,000 people dying annually and a global cost in excess of $100 trillion. This has led to an increased need to develop new, effective treatments. This review focuses on nitroimidazoles, which have seen a resurgence in interest due to their broad spectrum of activity against anaerobic Gram-negative and Gram-positive bacteria. The role of nitroreductases is to activate the antimicrobial by reducing the nitro group. A decrease in the activity of nitroreductases is associated with resistance. This review will discuss the resistance mechanisms of different disease organisms, including Mycobacterium tuberculosis, Helicobacter pylori and Staphylococcus aureus, and how these impact the effectiveness of specific nitroimidazoles. Perspectives in the field of nitroimidazole drug development are also summarised.

Genetic Diversity of the Flavohemoprotein Gene of Giardia lamblia: Evidence for High Allelic Heterozygosity and Copy Number Variation.

PurposeThe flavohemoprotein (gFlHb) in Giardia plays an important role in managing nitrosative and oxidative stress, and potentially also in virulence and nitroimidazole drug tolerance. The aim of this study was to analyze the genetic diversity of gFlHb in Giardia assemblages A and B clinical isolates.MethodsgFlHb genes from 20 cultured clinical Giardia isolates were subjected to PCR amplification and cloning, followed by Sanger sequencing. Sequences of all cloned PCR fragments from each isolate were analyzed for single nucleotide variants (SNVs) and compared to genomic Illumina sequence data. Identical clone sequences were sorted into alleles, and diversity was further analyzed. The number of gFlHb gene copies was assessed by mining PacBio de novo assembled genomes in eight isolates. Homology models for assessment of SNV’s potential impact on protein function were created using Phyre2.ResultsA variable copy number of the gFlHb gene, between two and six copies, depending on isolate, was found. A total of 37 distinct sequences, representing different alleles of the gFlHb gene, were identified in AII isolates, and 41 were identified in B isolates. In some isolates, up to 12 different alleles were found. The total allelic diversity was high for both assemblages (>0.9) and was coupled with a nucleotide diversity of <0.01. The genetic variation (SNVs per CDS length) was 4.8% in sub-assemblage AII and 5.4% in assemblage B. The number of non-synonymous (ns) SNVs was high in gFIHb of both assemblages, 1.6% in A and 3.0% in B, respectively. Some of the identified nsSNV are predicted to alter protein structure and possibly function.ConclusionIn this study, we present evidence that gFlHb, a putative protective enzyme against oxidative and nitrosative stress in Giardia, is a variable copy number gene with high allelic diversity. The genetic variability of gFlHb may contribute metabolic adaptability against metronidazole toxicity.

Recent Progress in the Discovery and Development of 2-Nitroimidazooxazines and 6-Nitroimidazooxazoles to Treat Tuberculosis and Neglected Tropical Diseases.

Nitroimidazole drugs have a long history as therapeutic agents to treat bacterial and parasitic diseases. The discovery in 1989 of a bicyclic nitroimidazole lead, displaying in vitro and in vivo antitubercular activity, spurred intensive exploration of this and related scaffolds, which led to the regulatory approval of pretomanid and delamanid as a new class of tuberculosis drugs. Much of the discovery work related to this took place over a 20-year period ending in 2010, which is covered in a number of cited reviews. This review highlights subsequent research published over the 2011–August 2020 timeframe, and captures detailed structure–activity relationship studies and synthetic strategies directed towards uncovering newer generation drugs for both tuberculosis and selected neglected tropical diseases. Additionally, this review presents in silico calculations relating to the drug-like properties of lead compounds and clinical agents, as well as chemical development and manufacturing processes toward providing bulk drug supplies.

Identification of Novel Functionalized Carbohydrazonamides Designed as Chagas Disease Drug Candidates.

Although several research efforts have been made worldwide to discover novel drug candidates for the treatment of Chagas disease, the nitroimidazole drug benznidazol remains the only therapeutic alternative in the control of this disease. However, this drug presents reduced efficacy in the chronic form of the disease and limited safety after long periods of administration, making it necessary to search for new, more potent and safe prototypes. We described herein the synthesis and the trypanocidalaction of new functionalized carbohydrazonamides (2-10) against trypomastigote forms of Trypanosoma cruzi. These compounds were designed through the application of molecular hybridization concept between two potent anti-T. cruzi prototypes, the nitroimidazole derivative megazol (1) and the cinnamyl N-acylhydrazone derivative (14) which have been shown to be twice as potent in vitro as benznidazole. The most active compounds were the (Z)-N'-((E)-3-(4-nitrophenyl)-acryloyl)-1-methyl-5- nitro-1H-imidazol-2-carbohydrazonamide (6) (IC50=9.50 μM) and the (Z)-N'-((E)-3-(4- hydroxyphe-nyl)-acryloyl)-1-methyl-5-nitro-1H-imidazol-2-carbohydrazonamide (8) (IC50=12.85 μM), which were almost equipotent to benznidazole (IC50=10.26 μM) used as standard drug. The removal of the amine group attached to the imine subunit in the corresponding N-acylhydrazone derivatives (11-13) resulted in less potent or inactive compounds. The para-hydroxyphenyl derivative (8) presented also a good selectivity index (SI = 32.94) when tested against mammalian cells from Swiss mice. The promising trypanocidal profile of new carbohydrazonamide derivatives (6) and (8) was characterized. These compounds have proved to be a good starting point for the design of more effective trypanocidal drug candidates.

A systematic review of the literature on mechanisms of 5-nitroimidazole resistance in Trichomonas vaginalis.

Trichomonas vaginalis is the most common non-viral sexually transmitted infection. 5-Nitroimidazoles [metronidazole (MTZ) and tinidazole (TDZ)] are FDA-approved treatments. To better understand treatment failure, we conducted a systematic review on mechanisms of 5-nitroimidazole resistance. PubMed, ScienceDirect and EMBASE databases were searched using keywords Trichomonas vaginalis, trichomoniasis, 5-nitroimidazole, metronidazole, tinidazole and drug resistance. Non-English language articles and articles on other treatments were excluded. The search yielded 606 articles, of which 550 were excluded, leaving 58 articles. Trichomonas vaginalis resistance varies and is higher with MTZ (2.2-9.6%) than TDZ (0-2%). Resistance can be aerobic or anaerobic and is relative rather than absolute. Differential expression of enzymes involved in trichomonad energy production and antioxidant defenses affects 5-nitroimidazole drug activation; reduced expression of pyruvate:ferredoxin oxidoreductase, ferredoxin, nitroreductase, hydrogenase, thioredoxin reductase and flavin reductase are implicated in drug resistance. Trichomonas vaginalis infection with Mycoplasma hominis or T. vaginalis virus has also been associated with resistance. Trichomonas vaginalis has two genotypes, with greater resistance seen in type 2 (vs type 1) populations. 5-Nitroimidazole resistance results from differential expression of enzymes involved in energy production or antioxidant defenses, along with genetic mutations in the T. vaginalis genome. Alternative treatments outside of the 5-nitroimidazole class are needed.

Comparison of in vitro Susceptibility of Mycobacteria Against PA-824 to Identify Key Residues of Ddn, the Deazoflavin-Dependent Nitroreductase from Mycobacterium tuberculosis.

ObjectivePA-824 (Pretomanid), a bicyclic nitroimidazole drug, exhibits significant bactericidal activity toward Mycobacterium tuberculosis (MTB) in vitro and in vivo, but not against Mycobacterium smegmatis. Through catalytic bioreduction, deazaflavin-dependent nitroreductase (Ddn) within MTB directly converts PA-824 to potent bactericidal products. This study aimed to identify key MTB Ddn residues involved in PA-824 conversion toward development of in vitro surrogate markers for detection of mycobacterial resistance to PA-824.MethodsWe evaluated in vitro activity of PA-824 toward MTB and nontuberculous mycobacterial species using antimicrobial susceptibility testing. Ddn amino acid sequence alignments and phylogenetic analysis revealed putative key enzyme active site residues. Candidate MTB Ddn residues required for PA-824 conversion activity were evaluated for loss-of-function using recombinantly cloned Ddn mutant proteins expressed in Mycobacterium smegmatis.ResultsPA-824 minimum inhibitory concentrations of 90% of bacterial growth (MIC90s) against MTB and Mycobacterium kansasii were 0.12 mg/L and 8 mg/L, respectively, but >32 mg/L for Mycobacterium spp. M. avium, M. intracellulare, M. abscessus and M. fortuitum. MTB Ddn and M. kansasii Ddn homologous sequences shared the greatest similarity (89.3% amino acid identity). M. smegmatis expressing Ddn proteins with Y65L, A76V or Y133F substitutions (but not V75L, Q125K or V148I) were resistant to PA-824.ConclusionOur data demonstrated that PA-824 exhibited excellent and moderate levels of in vitro activity against MTB and M. kansasii, respectively. Substitutions of Ddn residues Y65, A76 or Y133 conferred mycobacterial resistance to PA-824.

Nitroimidazole-induced reversible neurotoxicity

The nitroimidazole group of drugs is commonly used in India and worldwide for diarrhea and other indications. People are taking it over the counter for their subsequent problems without consultation, and this is harmful to them on chronic use. Similarly, many indications such as amoebic liver abscess need long-duration therapy of these drugs which may present with its toxic effects. We report two cases of metronidazole and ornidazole overuse presented as central and peripheral nervous system toxicity. The magnetic resonance imaging changes similar to nitroimidazole drug toxicity can be seen in many other diseases, and it needs to correlate with a good history for the diagnosis to avoid unnecessary workup burden to the patient.

Activity of methylgerambullin from Glycosmis species (Rutaceae) against Entamoeba histolytica and Giardia duodenalis in vitro

Entamoeba histolytica and Giardia duodenalis are widespread intestinal protozoan parasites which both spread via cysts that have to be ingested to infect a new host. Their environment, the small intestine for G. duodenalis and the colon for E. histolytica, contains only very limited amounts of oxygen, so both parasites generate energy by fermentation and substrate level phosphorylation rather than by oxidative phosphorylation. They both contain reducing agents able to reduce and activate nitroimidazole drugs such as metronidazole which is the gold standard drug to treat Entamoeba or Giardia infections. Although metronidazole works well in the majority of cases, it has a number of drawbacks. In animal models, the drug has carcinogenic activity, and concerns about a possible teratogenic activity remain. In addition, the treatment of G. duodenalis infections is hampered by emerging metronidazole resistance. Plant-derived drugs play a dominant role in human medicine, therefore we tested the activity of 14 isolated plant compounds belonging to seven different classes in vitro against both parasites. The tests were performed in a new setting in microtiter plates under anaerobic conditions. The compound with the highest activity was methylgerambullin, a sulphur-containing amide found in Glycosmis species of the family Rutaceae with an EC50 of 14.5 μM (6.08 μg/ml) after 24 h treatment for E. histolytica and 14.6 μM (6.14 μg/ml) for G. duodenalis. The compound was successfully synthesised in the laboratory which opens the door for the generation of new derivatives with higher activity.

HQSAR and random forest-based QSAR models for anti-T. vaginalis activities of nitroimidazoles derivatives

Trichomonas vaginalis is the causative agent of trichomoniasis, a highly prevalent sexually transmitted infection worldwide. Nitroimidazole drugs, such as metronidazole and tinidazole, are the only recommended treatment, but cases of resistance represent at least 5%. In case of resistance or therapeutic failure, posology with higher doses is used, culminating in the increase of the toxic effects of the treatment. In this context, the development of new drugs becomes an eminent necessity. Hologram quantitative structure-activity relationship (HQSAR) models using nitroimidazole derivatives were generated to discover the relationship between the different chemical structures and the activity against cells and the selectivity against susceptible and resistant strains. One model of each strain was chosen for interpretation, both showed good internal coefficient (q2LOO values: 0.607 for susceptible strain and 0.646 for resistant strain subsets) and great values in other internal and external validations metrics. From the contribution of fragments to HQSAR models, several differences between the most and least potent compounds were found: 5-nitroimidazole contributes positively while 4-nitroimidazole negatively. QSAR models employing random forest (RF-QSAR) machine learning technique were also built and a robust model was obtained from resistant strain activity prediction (q2LOO equals to 0.618). The constructed HQSAR and RF-QSAR models were employed to predict the activity of three newly planned nitroimidazole derivatives in the design of new drugs candidates against T. vaginalis strains.

Translation of 1H and 19F NMR‐based activity assays to in vitro characterization of nucleoside hydrolase activity in cell extracts and whole cells

Trichomoniasis, the most prevalent non‐viral sexually transmitted infection in the world, is caused by the parasitic protozoan Trichomonas vaginalis. Studies have indicated an association between T. vaginalis and a higher susceptibility to various other infections including chlamydia, HIV, and syphilis. The parasite has shown increasing resistance to the current treatment of 5‐nitroimidazole drugs such as metronidazole. T. vaginalis is incapable of de novo synthesis of purine and pyrimidine rings, so it must rely on salvage pathway enzymes such as adenosine/guanosine preferring nucleoside ribohydrolase (AGNH) and uridine nucleoside ribohydrolase (UNH) to scavenge nucleobases. Both enzymes have been screened to identify fragment inhibitors with high ligand efficiencies to use as starting points for drug design. AGNH and UNH can be validated as antitrichomonal targets by demonstrating a correlation between enzyme inhibition and antitrichomonal activity. Escherichia coli cells with endogenous nucleoside ribohydrolase gene expression of rihA (ybeK), rihB (yieK) and rihC (yaaF) were used as a surrogate to develop protocols for observing in vitro enzyme activity. A 1H NMR‐based activity assay for AGNH using adenosine as the substrate and an 19F NMR‐based activity assay for UNH using 5‐fluorouridine as the substrate were previously developed for compound screening. These assays proved remarkably robust for observing nucleoside hydrolase activity in cell extracts and in whole cells. Signals for substrate and product are clearly distinguishable from background signals arising from the cell contents. Reactions have been shown to be cell‐dependent, indicating that both enzymes are intracellular and that substrate can rapidly enter the cells. Similar experiments are now in progress using T. vaginalis strains to validate the molecular mechanisms of inhibition.Support or Funding InformationResearch was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R15AI128585 to BJS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Study on simultaneous determination of three nitroimidazole residues in honey by high performance liquid chromatography–resonance Rayleigh scattering spectra

A novel and high sensitivity method that high performance liquid chromatography combined with resonance Rayleigh scattering is established for the determination of nitroimidazole residues in honey, including Metronidazole (MNZ), Ornidazole (ONZ) and Tinidazole imidazole (TNZ). In pH 3.8 BR buffer solution, the three nitroimidazole drugs separated by HPLC, and then reacted with a post-column derivatization Phloxine B (PB) in the reaction tube to form 1:1 ion-association complex, which Leads to significant enhancement of the RRS signal. This paper optimized the experimental conditions of post-column derivation and discussed the mechanism of reaction for the enhancement of RRS signal. Under the optimal experimental conditions, the RRS signals of the three nitroimidazole drugs were enhanced with the increase of its concentration in the respective linear range. The detection limit (S/N) of MNZ, ONZ and TNZ was: 0.013 μg·mL−1, 0.049 μg·mL−1 and 0.27 μg·mL−1, respectively. The recovery rate was 97.4%–102.2%, and the relative standard deviation (RSD) does not exceed 5.3%, the reliability of this technique is verified, and the result of this method is satisfyingly.

Phase solubility studies and anti-Trichomonas vaginalis activity evaluations of metronidazole and methylated β-cyclodextrin complexes: Comparison of CRYSMEB and RAMEB

Metronidazole (MTZ) is a 5-nitroimidazole drug used for the treatment of Trichomonas vaginalis parasitic infection. Aqueous formulations containing MTZ are restricted because apparent solubility in water of this drug is low. In this context, two methylated-β-cyclodextrins (CRYSMEB and RAMEB) were used as a tool to increase apparent solubility of MTZ in water. CRYSMEB was limited by its own solubility in water (15% w/w, 12.59 mM), while RAMEB at a concentration of 40% w/w (300.44 mM) allowed a maximal increase of apparent solubility of MTZ (3.426% w/w, 200.19 mM). From our knowledge, this corresponds to the highest enhancement of MTZ apparent aqueous solubility ever reported in the literature using methylated cyclodextrins. In vitro evaluations showed that anti-T. vaginalis activity of MTZ formulated with CRYSMEB and RAMEB was preserved.

A review on metronidazole: an old warhorse in antimicrobial chemotherapy.

The 5-nitroimidazole drug metronidazole has remained the drug of choice in the treatment of anaerobic infections, parasitic as well as bacterial, ever since its development in 1959. In contrast to most other antimicrobials, it has a pleiotropic mode of action and reacts with a large number of molecules. Importantly, metronidazole, which is strictly speaking a prodrug, needs to be reduced at its nitro group in order to become toxic. Reduction of metronidazole, however, only takes place under very low concentrations of oxygen, explaining why metronidazole is exclusively toxic to microaerophilic and anaerobic microorganisms. In general, resistance rates amongst the pathogens treated with metronidazole have remained low until the present day. Nevertheless, metronidazole resistance does occur, and for the treatment of some pathogens, especially Helicobacter pylori, metronidazole has become almost useless in some parts of the world. This review will give an account on the current status of research on metronidazole's mode of action, metronidazole resistance in eukaryotes and prokaryotes, and on other 5-nitroimidazoles in use.

Optimization of postoperative period after surgical interventions on the cervix

The article presents the results of research on optimizing postoperative period in patients who underwent surgical interventions on cervix.134 patients were examined who underwent radiowave conization of the cervix for histologically confirmed CIN-2. By simple randomization, they were divided into two groups: Group I (66 women) received 2.0 ceftriaxone intraoperatively, and also Tamistol® vaginally for 1 suppository once a day for 3 days before surgery and for 12 days in postoperative period; patients of Group II (68 women) underwent only intraoperative prophylactic administration of 2.0 ceftriaxone.The laboratory studies after the operative intervention, in particular, revealed a higher microbial load in Group II than in Group I after 21 days and 1.5 months after operation. In addition, when comparing subjective and objective clinical indices, it was noted that the course of the postoperative period in Group I was easier than in Group II.It is proved that the use of complex prophylaxis that included local application of myramistin enhanced decontamination of vagina and cervix with bacterial and viral flora, benign сourse of postoperative period, fewer complications as well as faster and more complete epithelization of cervix after intervention. Considering the high incidence of sexually transmitted diseases in population, increase of the number of multimicrobal associations and the growing resistance of microbes to antibiotics the rationality of local antiseptic therapy in the complex of purulent-septic complications prevention in case of planned surgical interventions on cervix is concluded.Local application of the drug Tamistol® showed its high effectiveness against such pathogens as Atopobium vag. and Mobiluncus mul., considered highly specific markers of bacterial vaginosis. Given the increasing resistance of these microorganisms to nitroimidazole drugs, the proven high efficacy of myramistin against these microorganisms allows us to draw conclusions about the preferred choice of the drug Tamistol® for the prevention of purulentseptic complications during surgical interventions.

Click Chemistry-Facilitated Structural Diversification of Nitrothiazoles, Nitrofurans, and Nitropyrroles Enhances Antimicrobial Activity against Giardia lamblia.

Giardia lamblia is an important and ubiquitous cause of diarrheal disease. The primary agents in the treatment of giardiasis are nitroheterocyclic drugs, particularly the imidazoles metronidazole and tinidazole and the thiazole nitazoxanide. Although these drugs are generally effective, treatment failures occur in up to 20% of cases, and resistance has been demonstrated in vivo and in vitro Prior work had suggested that side chain modifications of the imidazole core can lead to new effective 5-nitroimidazole drugs that can combat nitro drug resistance, but the full potential of nitroheterocycles other than imidazole to yield effective new antigiardial agents has not been explored. Here, we generated derivatives of two clinically utilized nitroheterocycles, nitrothiazole and nitrofuran, as well as a third heterocycle, nitropyrrole, which is related to nitroimidazole but has not been systematically investigated as an antimicrobial drug scaffold. Click chemistry was employed to synthesize 442 novel nitroheterocyclic compounds with extensive side chain modifications. Screening of this library against representative G. lamblia strains showed a wide spectrum of in vitro activities, with many of the compounds exhibiting superior activity relative to reference drugs and several showing >100-fold increase in potency and the ability to overcome existing forms of metronidazole resistance. The majority of new compounds displayed no cytotoxicity against human cells, and several compounds were orally active against murine giardiasis in vivo These findings provide additional impetus for the systematic development of nitroheterocyclic compounds with nonimidazole cores as alternative and improved agents for the treatment of giardiasis and potentially other infectious agents.

Nitroimidazoles: Molecular Fireworks That Combat a Broad Spectrum of Infectious Diseases.

Infectious diseases claim millions of lives every year, but with the advent of drug resistance, therapeutic options to treat infections are inadequate. There is now an urgent need to develop new and effective treatments. Nitroimidazoles are a class of antimicrobial drugs that have remarkable broad spectrum activity against parasites, mycobacteria, and anaerobic Gram-positive and Gram-negative bacteria. While nitroimidazoles were discovered in the 1950s, there has been renewed interest in their therapeutic potential, particularly for the treatment of parasitic infections and tuberculosis. In this review, we summarize different classes of nitroimidazoles that have been described in the literature in the past five years, from approved drugs and clinical candidates to examples undergoing preclinical or early stage development. The relatively "nonspecific" mode of action and resistance mechanisms of nitromidazoles are discussed, and contemporary strategies to facilitate nitroimidazole drug development are highlighted.