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Despite known treatments, tuberculosis (TB) remains the worlds top infectious killer, highlighting the pressing need for new drug regimens. To prioritize the most efficacious drugs for clinical testing, we previously developed a PK-PD translational platform with bacterial dynamics that reliably predicted short-term monotherapy outcomes in Phase IIa trials from preclinical mouse studies. In this study, we extended our platform to include PK-PD models that account for drug-drug interactions in combination regimens and bacterial regrowth in our bacterial dynamics model to predict cure at the end of treatment and relapse 6 months post-treatment. The Phase III STAND trial testing a new regimen comprised of pretomanid (Pa), moxifloxacin (M), and pyrazinamide (Z) (PaMZ) was suspended after a separate ongoing trial (NC-005) suggested that adding bedaquiline (B) to the PaMZ regimen would improve efficacy. To forecast if the addition of B would, indeed, benefit the PaMZ regimen, we applied an extended translational platform to both regimens. We predicted currently available short- and long-term clinical data well for drug combinations related to BPaMZ. We predicted the addition of B to PaMZ to shorten treatment duration by 2 months and to have similar bacteriological success to standard HRZE treatment (considering only treatment success but not withdrawal from side effects and other adverse events), both at the end of treatment for treatment efficacy and 6 months after treatment has ended in relapse prevention. Using BPaMZ as a case study, we have demonstrated our translational platform can predict Phase II and III outcomes prior to actual trials, allowing us to better prioritize the regimens most likely to succeed.

TBI-223, a novel oxazolidinone for tuberculosis, is designed to provide improved efficacy and safety compared to linezolid in combination with bedaquiline and pretomanid (BPaL). We aim to optimize the dosing of TBI-223 within the BPaL regimen for enhanced therapeutic outcomes. TBI-223 is investigated in preclinical monotherapy, multidrug therapy, and lesion penetration experiments to describe its efficacy and safety versus linezolid. A translational platform incorporating linezolid and BPaL data from preclinical experiments and 4 clinical trials (NCT00396084, NCT02333799, NCT03086486, NCT00816426) is developed, enabling validation of the framework. TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200-2400 mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months.

Metronidazole and nimorazole are antibiotics of a nitroimidazole group which also may be potentially utilized as hypoxia radiosensitizers for the treatment of cancerous tumors. Hyperpolarization of 15N nuclei in these compounds using SABRE‐SHEATH (Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei) approach provides dramatic enhancement of detection sensitivity of these analytes using magnetic resonance spectroscopy and imaging. Methanol‐d4 is conventionally employed as a solvent in SABRE hyperpolarization process. Herein, we investigate SABRE‐SHEATH hyperpolarization of isotopically labeled [15N3]metronidazole and [15N3]nimorazole in nondeuterated methanol and ethanol solvents. Optimization of such hyperpolarization parameters as polarization transfer magnetic field, temperature, parahydrogen flow rate and pressure allowed us to obtain an average 15N polarization of up to 7.2–7.4 % for both substrates. The highest 15N polarizations were observed in methanol‐d4 for [15N3]metronidazole and in ethanol for [15N3]nimorazole. At a clinically relevant magnetic field of 1.4 T the 15N nuclei of these substrates possess long characteristic hyperpolarization lifetimes (T1) of ca. 1 to ca. 7 min. This study represents a major step toward SABRE in more biocompatible solvents, such as ethanol, and also paves the way for future utilization of these hyperpolarized nitroimidazoles as molecular contrast agents for MRI visualization of tumors. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the available evidence comparing the use of the bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) regimen for 6 months with that of standard-of-care regimens for patients with multidrug-resistant or rifampin-resistant tuberculosis (MDR/RR-TB). Methods: This was a systematic review of clinical trials comparing the use of the BPaLM regimen with the standard of care in patients with MDR/RR-TB. The main outcome measure was an unfavorable endpoint (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, and recurrence), and secondary outcome measures included adverse events and serious adverse events. We searched the MEDLINE, EMBASE, Google Scholar, LILACS, and ClinicalTrials.gov databases, from their inception to January 31, 2024, with no limitation as to language or year of publication. The risk of bias was assessed by using the Cochrane risk-of-bias tool, and the quality of evidence was based on the Grading of Recommendations Assessment, Development and Evaluation approach. Results: A total of 3,668 studies were retrieved; only one (a randomized clinical trial) met the inclusion criteria and was included. In patients with MDR/RR-TB, treatment with the BPaLM regimen, when compared with the standard of care, reduced the risk of an unfavorable outcome (composite, number needed to treat [NNT] = 7); early treatment discontinuation (NNT = 8); adverse events and discontinuation (NNT = 12); and serious adverse events (NNT = 5). Conclusions: This systematic review of the use of BPaLM in patients with MDR/RR-TB, although it included only one study, showed that BPaLM is more effective than is the standard of care and has a better safety profile. That has major implications for guidelines on the treatment of MDR/RR-TB. [ABSTRACT FROM AUTHOR]

The intestinal parasites Giardia lamblia and Entamoeba histolytica are major causes of morbidity and mortality associated with diarrheal diseases. Metronidazole is the most common drug used to treat giardiasis and amebiasis. Despite its efficacy, treatment failures in giardiasis occur in up to 5%-40% of cases. Potential resistance of E. histolytica to metronidazole is an increasing concern. Therefore, it is critical to search for more effective drugs to treat giardiasis and amebiasis. We identified antigiardial and antiamebic activities of the rediscovered nitroimidazole compound, fexinidazole, and its sulfone and sulfoxide metabolites. Fexinidazole is equally active against E. histolytica and G. lamblia trophozoites, and both metabolites were 3- to 18-fold more active than the parent drug. Fexinidazole and its metabolites were also active against a metronidazole-resistant strain of G. lamblia. G. lamblia and E. histolytica cell extracts exhibited decreased residual nitroreductase activity when metabolites were used as substrates, indicating nitroreductase may be central to the mechanism of action of fexinidazole. In a cell invasion model, fexinidazole and its metabolites significantly reduced the invasiveness of E. histolytica trophozoites through basement membrane matrix. A q.d. oral dose of fexinidazole and its metabolites at 10 mg/kg for 3 days reduced G. lamblia infection significantly in mice compared to control. The newly discovered antigiardial and antiamebic activities of fexinidazole, combined with its FDA-approval and inclusion in the WHO Model List of Essential Medicines for the treatment of human African trypanosomiasis, offer decreased risk and a shortened development timeline toward clinical use of fexinidazole for treatment of giardiasis or amebiasis.

Diagnostic development must occur in parallel with drug development to ensure the longevity of new treatment compounds. Despite an increasing number of novel and repurposed anti-tuberculosis compounds and regimens, there remains a large number of drugs for which no rapid and accurate molecular diagnostic option exists. The lack of rapid drug susceptibility testing for linezolid, bedaquiline, clofazimine, the nitroimidazoles (i.e pretomanid and delamanid) and pyrazinamide at any level of the healthcare system compromises the effectiveness of current tuberculosis and drug-resistant tuberculosis treatment regimens. In the context of current WHO tuberculosis treatment guidelines as well as promising new regimens, we identify the key diagnostic gaps for initial and follow-on tests to diagnose emerging drug resistance and aid in regimen selection. Additionally, we comment on potential gene targets for inclusion in rapid molecular drug susceptibility assays and sequencing assays for novel and repurposed drug compounds currently prioritized in current regimens, and evaluate the feasibility of mutation detection given the design of existing technologies. Based on current knowledge, we also propose design priorities for next generation molecular assays to support triage of tuberculosis patients to appropriate and effective treatment regimens. We encourage assay developers to prioritize development of these key molecular assays and support the continued evolution, uptake, and utility of sequencing to build knowledge of tuberculosis resistance mechanisms and further inform rapid treatment decisions in order to curb resistance to critical drugs in current regimens and achieve End TB targets.Trial registration: ClinicalTrials.gov identifier: NCT05117788..

Nitroimidazoles are well-known antibacterial and antiprotozoal agents, effective against various infections. However, they may also exhibit genotoxic, carcinogenic and mutagenic effects. This study aimed to develop an analytical method to quantify nitroimidazole residues and their metabolites in honey using Ultra Performance Liquid Chromatography coupled with Orbitrap High-Resolution Mass Spectrometry (UPLC-Orbitrap-HRMS) and validate it according to Commission Implementing Regulation (EU) 2021/808. The method demonstrated limits of detection (LODs) ranging from 0.01 to 0.17 µg L−1 and limits of quantification (LOQs) from 0.020 to 0.29 µg L−1. Recovery rates ranged from 79.8% to 104%, with relative standard deviations (RSDs) between 4.2% and 19.6%. Analysis of 96 honey samples revealed nitroimidazole residues in 18.8% of them. These findings could enhance more effectively the Egyptian monitoring programs for these compounds in honey as to improve food safety. [ABSTRACT FROM AUTHOR]

PURPOSE: Intratumoral hypoxia in non-Hodgkins Lymphoma (NHL) may interfere with chimeric antigen receptor T-cell (CAR-T) function. We conducted a single-center pilot study (clinicaltrials.gov ID NCT04409314) of [18F]fluoroazomycin arabinoside, a hypoxia-specific radiotracer abbreviated as [18F]FAZA, to assess the feasibility of this positron emission tomography (PET) imaging modality in this population. METHODS: Patients with relapsed NHL being evaluated for CAR-T therapy received a one-time [18F]FAZA PET scan before pre-CAR-T lymphodepletion. A tumor to mediastinum (T/M) ratio of 1.2 or higher with regard to [18F]FAZA uptake was defined as positive for intratumoral hypoxia. We planned to enroll 30 patients with an interim futility analysis after 16 scans. RESULTS: Of 16 scanned patients, 3 had no evidence of disease by standard [18F]fluorodeoxyglucose PET imaging before CAR-T therapy. Six patients (38%) had any [18F]FAZA uptake above background. Using a T/M cutoff of 1.20, only one patient (a 68-year-old male with relapsed diffuse large B-cell lymphoma) demonstrated intratumoral hypoxia in an extranodal chest wall lesion (T/M 1.35). Interestingly, of all 16 scanned patients, he was the only patient with progressive disease within 1 month of CAR-T therapy. However, because of our low overall proportion of positive scans, our study was stopped for futility. CONCLUSIONS: Our pilot study identified low-level [18F]FAZA uptake in a small number of patients with NHL receiving CAR-T therapy. The only patient who met our pre-specified threshold for intratumoral hypoxia was also the only patient with early CAR-T failure. Future plans include exploration of [18F]FAZA in a more selected patient population.

Similarity of nitroimidazole and nitrofuran antibiotics in molecular structure and photophysical properties makes them difficult to distinguish via luminescence sensing technology. Herein, this is solved by a dye-encapsulated lanthanide metal--organic framework luminescent sensor. [ABSTRACT FROM AUTHOR]

Metronidazole (MTZ) is a 5‐nitroimidazole anti‐bacterial and anti‐protozoal drug. In human and companion animal medicine, MTZ remains widely used due to its effectiveness against anaerobic bacteria and protozoa. In farm animals, however, MTZ is currently prohibited in several countries due to insufficient data on nitroimidazoles. The purpose of this study was to assess its pharmacokinetics (PK) in geese after single intravenous (IV) and oral (PO) administrations. Fifteen‐month old healthy male geese (n = 8) were used. Geese were subjected to a two‐phase, single‐dose (10 mg/kg IV, 50 mg/kg PO), open, longitudinal study design with a two‐week washout period between the IV and PO phases. Blood was drawn from the left wing vein to heparinized tubes at 0, 0.085 (for IV only), 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 24, and 48 h. Plasma MTZ concentrations were measured using HPLC coupled to an UV detector, and the data were pharmacokinetically analyzed using PKanalix™ software with a non‐compartmental approach. MTZ was still quantifiable and well above the LLOQ at 24 h after both routes of administration. Following IV administration, terminal elimination half‐life, volume of distribution, and total clearance were 5.47 h, 767 mL/kg, and 96 mL/h/kg, respectively. For the PO route, the bioavailability was high (85%), and the mean peak plasma concentration was 60.27 μg/mL at 1 h. When parameters were normalized for the dose, there were no statistically significant differences for any of the PK parameters between the two routes of administration. The study shows that oral administration of MTZ seems to be promising in geese, although comprehensive research on its pharmacodynamics and multiple‐dose studies are necessary before its adoption in geese can be further considered. [ABSTRACT FROM AUTHOR]

Neglected tropical diseases (NTDs) are a significant global health problem. Additionally, anti-protozoan treatments are toxic, and their therapeutic regimens require prolonged treatment times and high concentrations of the drugs. Additionally, multi-resistant protozoan strains represent an important global emergency that must be addressed. For these reasons, global efforts are being made to identify new drug candidates that are capable of combating these kinds of diseases. This systematic review shows that 5-nitroimidazole derivatives have been successfully used against neglected tropical protozoan diseases (NTPDs), with a specific focus on three diseases: malaria, leishmaniasis, and human trypanosomiasis. Some nitroimidazole derivatives have been repurposed, and an important group of new drugs is available for the treatment of NTPDs. Finally, we address 5-nitroimidazoles using chemoinformatics and medicinal chemistry tools to describe the most recent and promising 5-nitroimidazole derivatives associated with anti-protozoal activity using their published in vitro and in vivo data. We show that 5-nitroimidazoles offer a broader spectrum of activity against a variety of protozoal pathogens. More importantly, these compounds demonstrate a significantly reduced systemic toxicity compared to other nitroimidazoles. This makes them a more favorable option in the treatment of protozoal infections, particularly in scenarios where the patient's tolerance to drug side effects is a critical concern. [ABSTRACT FROM AUTHOR]

The magnetic hypercrosslinked polystyrene was used for the first time as a sorbent in effervescence-assisted magnetic solid-phase extraction. An effervescent tablet composed of magnetic hypercrosslinked polystyrene, sodium bicarbonate, and citric acid was used for extraction of nitroimidazoles and their metabolites from honey samples prior to their LC-MS/MS determination. In the proposed method, the dispersing of the sorbent occurs without the help of additional energy sources (such as ultrasound and stirring devices) due to the intensive release of carbon dioxide during dissolution of the tablet. The magnetic properties of the sorbent make it possible to separate it without the use of centrifugation or filtration. As a result, the extraction procedure takes only 3 min. The effects of important parameters, including the molar ratio of sodium bicarbonate to citric acid, mass of magnetic hypercrosslinked polystyrene, mass of the tablet, and desorption conditions, were systematically studied. The proposed method was validated using spiked honey samples. Under the optimum experimental conditions, the proposed method provided the limit of detection and limit of quantification of 0.3 and 1 μg kg−1, respectively. Precision values expressed as relative standard deviation were < 16% for the intra-day and inter-day experiments. In general, the developed method is simple, fast, resource-efficient, and has good analytical characteristics. [ABSTRACT FROM AUTHOR]

Abstract Background The nitro group constitutes a significant functional moiety within numerous valuable substances, such as nitroimidazoles, a class of antimicrobial drugs exhibiting broad spectrum activity. Conventional chemical methods for synthesizing nitro compounds suffer from harsh conditions, multiple steps, and environmental issues. Biocatalysis has emerged as a promising alternative to overcome these drawbacks, with certain enzymes capable of catalyzing nitro group formation gradually being discovered in nature. Nevertheless, the practical application is hindered by the restricted diversity and low catalytic activity exhibited by the reported nitrifying enzymes. Results A novel N-oxygenase SaRohS harboring higher catalytic capability of transformation 2-aminoimidazole to azomycin was characterized from Saccharothrix sp. Phylogenetic tree analysis revealed that SaRohS belongs to the heme-oxygenase-like diiron oxygenase (HDOs) family. SaRohS exhibited optimal activity at pH 5.5 and 25 ℃, respectively. The enzyme maintained relatively stable activity within the pH range of 4.5 to 6.5 and the temperature range of 20 ℃ to 35 ℃. Following sequence alignment and structural analysis, several promising amino acid residues were meticulously chosen for catalytic performance evaluation. Site-directed mutations showed that threonine 75 was essential for the catalytic activity. The dual mutant enzyme G95A/K115T exhibited the highest catalytic efficiency, which was approximately 5.8-fold higher than that of the wild-type and 22.3-fold higher than that of the reported N-oxygenase KaRohS from Kitasatospora azatica. The underlying catalytic mechanism was investigated through molecular docking and molecular dynamics. Finally, whole-cell biocatalysis was performed and 2-aminoimidazole could be effectively converted into azomycin with a reaction conversion rate of 42% within 14 h. Conclusions An efficient N-oxygenase that catalyzes 2-aminoimidazole to azomycin was screened form Saccharothrix sp., its phylogenetics and enzymatic properties were analyzed. Through site-directed mutation, enhancements in catalytic competence were achieved, and the molecular basis underlying the enhanced enzymatic activity of the mutants was revealed via molecular docking and dynamic simulation. Furthermore, the application potential of this enzyme was assessed through whole cell biocatalysis, demonstrating it as a promising alternative method for azomycin production. Graphical Abstract

A rapid method was developed and validated for the simultaneous identification and quantitation of the residues of 5-nitroimidazoles and their metabolites in eggs by isotope dilution-ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The samples were extracted with acetonitrile, purified with octadecylsilane-bonded silica gel as sorbent, and defatted with n-hexane. The target compounds were separated in the LC system by gradient elution, and detected using an electrospray ionization (ESI) source in the positive ion mode with multiple reaction monitoring (MRM). Under the optimal conditions, the calibration curves for seven nitroimidazoles were linear in the concentration range of 0.5–20 ng/mL, with correlation coefficient exceeding 0.999. The limits of detection (LOD) and quantification (LOQ) were 0.1–0.25 and 0.3–1.0 μg/kg, respectively. The average recoveries at three spiked levels (0.5, 1.0 and 5.0 μg/kg) were 96.5%–112.7%, with relative standard deviations (RSDs) (n = 6) of 0.82%–8.14%. The proposed method was used for the determination of nitroimidazoles in egg samples from Food Analysis Performance Assessment Scheme (FAPAS) with satisfactory results. The RSDs between the results and the assigned values were less than 10%. This method could accurately detect the seven nitroimidazoles and was validated to be suitable for 38 batches of commercial eggs. The developed method is convenient, sensitive and accurate, and can be applied for daily monitoring of 5-nitroimidazoles and their metabolites in eggs.

Objectives. To develop the procedures for synthesis of hybrid molecules with potential anti-tubercular activity containing heterocyclic cores of 4-nitroimidazole and 1,3,4-thiadiazole within the framework of a double-drug strategy and predict bioactivity of target structures and drug-likeness physicochemical parameters.Methods. Target compounds were prepared by classical organic synthesis methods. The structure of the obtained compounds was characterized by melting points, 1H and 13C nuclear magnetic resonance spectroscopy, and high-resolution mass spectrometry. The calculation of the physicochemical parameters of the target compounds and prediction of their biological activity were carried out using publicly available software for cheminformatics and molecular modeling.Results. Acylation of propargylamine with (2-methyl-4-nitro-1H-imidazol-1-yl)acetic and (4-nitro-1H-imidazol-1-yl)acetic acids provided the corresponding amides, which were cyclized with seven different benzylamines in the presence of zinc triflate. In this way, seven new compounds were obtained at 20–30% yields. Ten arylamines were acylated with chloroacetyl chloride and the resulting chloroacetamides were converted into corresponding thio-oxahydrazides by the Willgerodt–Kindler reaction. Following acylation by (4-nitro-1H-imidazol-1-yl)acetic acid, these compounds were converted into the target hybrid imidazolyl-thiadiazoles at 29–54% yields.Conclusions. Two series of new heterocyclic compounds with a hybrid structure including a privileged 4-nitroimidazole moiety linked to the second heterocycle, imidazole, or thiadiazole, were obtained. The synthesis and characterization of compounds by physicochemical methods was aimed at searching for anti-tuberculosis activity. The bioactivity potential of target compounds was demonstrated by preliminary calculations performed using public prognostic programs.

Background: The nitro group constitutes a significant functional moiety within numerous valuable substances, such as nitroimidazoles, a class of antimicrobial drugs exhibiting broad spectrum activity. Conventional chemical methods for synthesizing nitro compounds suffer from harsh conditions, multiple steps, and environmental issues. Biocatalysis has emerged as a promising alternative to overcome these drawbacks, with certain enzymes capable of catalyzing nitro group formation gradually being discovered in nature. Nevertheless, the practical application is hindered by the restricted diversity and low catalytic activity exhibited by the reported nitrifying enzymes. Results: A novel N-oxygenase SaRohS harboring higher catalytic capability of transformation 2-aminoimidazole to azomycin was characterized from Saccharothrix sp. Phylogenetic tree analysis revealed that SaRohS belongs to the heme-oxygenase-like diiron oxygenase (HDOs) family. SaRohS exhibited optimal activity at pH 5.5 and 25 ℃, respectively. The enzyme maintained relatively stable activity within the pH range of 4.5 to 6.5 and the temperature range of 20 ℃ to 35 ℃. Following sequence alignment and structural analysis, several promising amino acid residues were meticulously chosen for catalytic performance evaluation. Site-directed mutations showed that threonine 75 was essential for the catalytic activity. The dual mutant enzyme G95A/K115T exhibited the highest catalytic efficiency, which was approximately 5.8-fold higher than that of the wild-type and 22.3-fold higher than that of the reported N-oxygenase KaRohS from Kitasatospora azatica. The underlying catalytic mechanism was investigated through molecular docking and molecular dynamics. Finally, whole-cell biocatalysis was performed and 2-aminoimidazole could be effectively converted into azomycin with a reaction conversion rate of 42% within 14 h. Conclusions: An efficient N-oxygenase that catalyzes 2-aminoimidazole to azomycin was screened form Saccharothrix sp., its phylogenetics and enzymatic properties were analyzed. Through site-directed mutation, enhancements in catalytic competence were achieved, and the molecular basis underlying the enhanced enzymatic activity of the mutants was revealed via molecular docking and dynamic simulation. Furthermore, the application potential of this enzyme was assessed through whole cell biocatalysis, demonstrating it as a promising alternative method for azomycin production. [ABSTRACT FROM AUTHOR]

Aim: Trichomonas vaginalis is a flagellated protozoan that is sexually transmitted and causes trichomonosis. It is one of the public health problems caused by sexually transmitted diseases. However, for a long time it received less attention than other parasitic and sexually transmitted diseases. Recently, the parasite has been associated with increased cases of HIV, miscarriages, infertility, pelvic inflammatory diseases and cervical and prostate cancers. Given the increasing resistance to the nitroimidazole class of drugs used in its treatment, different alternatives are needed. New drugs are increasingly being derived from natural products containing a large number of active compounds. In addition, different synthetic products or derivatives from old drugs are also used as an alternative for the treatment of trichomonosis. In this study, it was investigated whether Helianthemum ledifolium variates [H. ledifolium (L.) Miller var. ledifolium (L.) Miller; H. ledifolium (L.) Miller var. microcarpum Willk.; H. ledifolium (L.) Miller var. lasiacarpum (Willk.) Bornm.] growing naturally in Turkey. Herein aqueous and methanol extracts prepared by maceration method from the above-ground parts were evaluated for their in vitro anti-trichomoniasis activity against Trichomonas vaginalis. Materials and Methods: The extracts prepared from H. ledifolium taxa were added to the parasite grown in culture and checked at regular intervals to check for viability. Each measurement was performed twice and averaged. Descriptive statistics of the data set are expressed as mean ± standard deviation (SD). The values of lethal doses were determined using probit analysis for certain periods of time depending on specific concentrations (LD50 and LD90). Results: Extracts prepared from H. ledifolium variates inhibited the growth of T. vaginalis in a dose-dependent manner starting from the 4th hour. LD50 values for 4th hour were 2.39 mg for ledifolium water extract, 6.63 mg for ledifolium methanol, 2.39 mg for lasiocarpium water, 1.99 mg for lasiocarpium methanol, 5.77 mg for microcarpium water, 8.76 mg for microcarpium methanol. Conclusion: This study data showed us that Helianthemum ledifolium varieties may be a potential natural medicine that can be used in parasite treatment. However, standardization studies should be carried out on plant extracts, and in vitro studies should be supported by in vivo studies. [ABSTRACT FROM AUTHOR]

In the present work, the herb (Poria cocos (Schw.) Wolf) residue, as an environmentally friendly and renewable biomass source, was converted into novel biochar. Biochar/sodium alginate mixed matrix membrane was fabricated. On this basis, a biochar/sodium alginate mixed matrix membrane‐based in‐syringe solid‐phase extraction was developed combined with ultra‐high performance liquid chromatography‐tandem mass spectrometry to determine nitroimidazoles in water samples. The factors including times of exaction, type, and volume of elution solvent, and sample solution pH were thoroughly optimized. Then the correlation coefficient was 0.9995–0.9997. The limit of detection of four analytes was between 0.006 and 0.014 ng/mL, and the recovery was between 79.02% and 99.1%. Consequently, the established method would provide a new perspective on monitoring nitroimidazoles in water samples. [ABSTRACT FROM AUTHOR]

Three series of energetic nitroimidazoles and polynitrobenzenes derivatives containing different substituents (for instance -NH2, -N3) were designed and have been optimized at the B3LYP-D3/6- 311+G*** level. The effects of multiple substituents on the properties of these energetic materials were analyzed. The electronic structure, energy gap, heat of formation, detonation performance, thermal stability, and surface electrostatic potential of the compounds were systematically studied. As the number of -NH2 substituents increases, the energy of ΔEHOMO-LUMO descends, and the electronic absorption spectrum of the derivatives moves to a low frequency. The substitution of - NH2 on the benzene ring is not conducive to increasing HOF value of energetic materials. Among all mentioned compounds, trinitroimidazole substituted polynitrobenzene displays the most attractive detonation pressure (33 GPa), and with a high density of 1.88 g/cm³, which has exceeded TATB (31.1 GPa, 1.94 g/cm³). [ABSTRACT FROM AUTHOR]

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Copyright of Veterinarska Stanica is the property of Croatian Veterinary Institute and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

New all-oral regimens for rifampin-resistant tuberculosis (RR-TB) are being scaled up globally. Measurement of drug concentrations in hair assesses long-term drug exposure. Delamanid (DLM) is likely to be a key component of future RR-TB treatment regimens, but a method to describe its quantification in hair via liquid chromatography-tandem mass spectrometry (LC-MS/MS) has not previously been described. We developed and validated a simple, fast, sensitive, and accurate LC-MS/MS method for quantifying DLM and its metabolite DM-6705 in small hair samples. We pulverized and extracted two milligrams of hair in methanol at 37 °C for two hours, and diluted 1:1 with water. A gradient elution method eluted DLM, DM-6705, and the internal standard OPC 14714 within 3 min, bringing overall analysis time to 5.5 min. The method has limits of detection (LOD) of 0.0003 ng/mg for DLM and 0.003 ng/mg for DM-6705. The established linear dynamic ranges are 0.003-2.1 ng/mg and 0.03-21 ng/mg for DLM and DM-6705, respectively. Eleven of 12 participant hair samples had concentrations within DLM's linear dynamic range, while all 12 samples had concentrations within the quantifiable range for DM-6705. The ranges of concentrations observed in these clinical samples for DLM and DM-6705 were 0.004-0.264 ng/mg hair and 0.412-12.041 ng/mg hair respectively. We demonstrate that while DLM was detected in hair at very low levels, its primary metabolite DM-6705 had levels approximately 100 times higher. Measuring DM-6705 in hair may accurately reflect long-term adherence to DLM-containing regimens for drug-resistant TB.

Diagnostic development must occur in parallel with drug development to ensure the longevity of new treatment compounds. Despite an increasing number of novel and repurposed anti-tuberculosis compounds and regimens, there remains a large number of drugs for which no rapid and accurate molecular diagnostic option exists. The lack of rapid drug susceptibility testing for linezolid, bedaquiline, clofazimine, the nitroimidazoles (i.e pretomanid and delamanid) and pyrazinamide at any level of the healthcare system compromises the effectiveness of current tuberculosis and drug-resistant tuberculosis treatment regimens. In the context of current WHO tuberculosis treatment guidelines as well as promising new regimens, we identify the key diagnostic gaps for initial and follow-on tests to diagnose emerging drug resistance and aid in regimen selection. Additionally, we comment on potential gene targets for inclusion in rapid molecular drug susceptibility assays and sequencing assays for novel and repurposed drug compounds currently prioritized in current regimens, and evaluate the feasibility of mutation detection given the design of existing technologies. Based on current knowledge, we also propose design priorities for next generation molecular assays to support triage of tuberculosis patients to appropriate and effective treatment regimens. We encourage assay developers to prioritize development of these key molecular assays and support the continued evolution, uptake, and utility of sequencing to build knowledge of tuberculosis resistance mechanisms and further inform rapid treatment decisions in order to curb resistance to critical drugs in current regimens and achieve End TB targets.Trial registration: ClinicalTrials.gov identifier: NCT05117788..

Following the approval of delamanid and pretomanid as new drugs to treat drug-resistant tuberculosis, there is now a renewed interest in bicyclic nitroimidazole scaffolds as a source of therapeutics against infectious diseases. We recently described a nitroimidazopyrazinone bicyclic subclass with promising antitubercular and antiparasitic activity, prompting additional efforts to generate analogs with improved solubility and enhanced potency. The key pendant aryl substituent was modified by (i) introducing polar functionality to the methylene linker, (ii) replacing the terminal phenyl group with less lipophilic heterocycles, or (iii) generating extended biaryl side chains. Improved antitubercular and antitrypanosomal activity was observed with the biaryl side chains, with most analogs achieved 2- to 175-fold higher activity than the monoaryl parent compounds, with encouraging improvements in solubility when pyridyl groups were incorporated. This study has contributed to understanding the existing structure-activity relationship (SAR) of the nitroimidazopyrazinone scaffold against a panel of disease-causing organisms to support future lead optimization.

The discovery of azomycin provided the major impulse for the systematic search for medicines showing activity against anaerobic protozoa. Nowadays, many other interesting applications have been found for nitroimidazoles as therapeutic agents. This research led to the acquisition of numerous new 4-amine-5-nitroimidazole derivatives, which have a structure analogous to metronidazole, characteristic of medicines most widely used in the treatment of anaerobic bacteria, protozoa and parasitic infections. The therapeutic activity of the described compounds is analyzed and confirmed with predictive methods.

Metronidazole (MTZ) is one of the basic medications used in the therapy of anaerobic and microaerophilic bacterial infections and a mainstay drug in protozoal infections. MTZ was initially used only against parasites. Later was found excellent benefit against anaerobic bacteria. Nowadays, MTZ is a generally accepted and widely used as an antimicrobial in the therapy of a wide range of infections extending from amoebiasis to bacterial septicaemia. Nitroimidazoles, one of which is metronidazole, have been known for their large spectrum of activity as well as their low incidence of resistance for already more than 55 years. However, as with nearly all antibacterial drugs, resistances are on the rise and susceptibility testing is of special interest. MTZ is a bactericidal drug that works via a four-step process that finally leads to the death of the microorganism by damaging the host cell's DNA. Furthermore, there are common resistant strains depicted in this paper and the mechanism behind the resistance is then discussed. Clinical indications are illustrated, using dosing regimens and examples, to give clear advice on when and how to use metronidazole. MTZs use in Helicobacter pylori eradication and Clostridium difficile infections is nowadays still considered essential even though other possibilities do exist. Besides the bacterial indications, MTZ is also used in protozoal infections by Trichomonas vaginalis, Giardia lamblia and Entamoeba histolytica. [ABSTRACT FROM AUTHOR]

Nitroimidazoles are important compounds in medicine, biology, and the food industry. The growing need for their structural assignment, as well as the need for the development of the detection and screening methods, provides the motivation to understand their fundamental properties and reactivity. Here, we investigated the decomposition of protonated ronidazole [Roni+H]+ in low-energy and high-energy collision-induced dissociation (CID) experiments. Quantum chemical calculations showed that the main fragmentation channels involve intramolecular proton transfer from nitroimidazole to its side chain followed by a release of NH2CO2H, which can proceed via two pathways involving transfer of H+ from (1) the N3 position via a barrier of TS2 of 0.97 eV, followed by the rupture of the C–O bond with a thermodynamic threshold of 2.40 eV; and (2) the –CH3 group via a higher barrier of 2.77 eV, but with a slightly lower thermodynamic threshold of 2.24 eV. Electrospray ionization of ronidazole using deuterated solvents showed that in low-energy CID, only pathway (1) proceeds, and in high-energy CID, both channels proceed with contributions of 81% and 19%. While both of the pathways are associated with small kinetic energy release of 10–23 meV, further release of the NO• radical has a KER value of 339 meV. [ABSTRACT FROM AUTHOR]

Medication adherence is critical to the effectiveness of benznidazole (BZ) therapy for the treatment of Chagas disease. Assessing BZ adherence using traditional plasma sampling methods presents numerous challenges in resource-limited settings. Dried blood spot (DBS) sampling of BZ can be used to overcome logistical barriers and provides a less invasive method for assessing BZ levels. A BZ DBS assay using liquid chromatography-tandem mass spectrometry was developed and applied to a clinical study of infants and children being treated with BZ for Trypanosoma cruzi infection in Argentina. The assay was validated over a concentration range of 9.8-5,000 ng/mL. Inter-assay and intra-assay measures ranged from -2.9% to 2.7% and 0.5% to 8.3% for accuracy and from 3.5% to 12% and 1.6% to 13.6% for precision, respectively. The mean recovery of BZ was greater than 91%. Partitioning ratios for DBSs/plasma ranged from 0.95 to 1.02. A cohort of 10 infants and six children with T. cruzi infection being treated with BZ had median BZ concentrations of 1.2 (IQR 0.29, 2.14) µg/mL with seven of 65 (11%) samples above the BZ treatment goal of 3 μg/mL for adults. The reported DBS assay is a simple and accurate method for the quantitative measurement of BZ that can be applied to facilitate urgently needed clinical studies of BZ for the treatment of Chagas disease and assess BZ adherence in resource-limited settings.

Tuberculosis (TB) is a leading infectious disease that caused the deaths of a total of 1.5 million people in 2020 and is one of the top causes of death globally. India is a country with the highest TB burden, and it may affect all age groups. It is caused by the Mycobacterium tuberculosis bacteria, an intracellular pathogen, and its multidrug and extensively drug-resistant strains, which continue to emerge and spread, resulting in the deadliest infectious disease. After a gap of more than 40 years, the FDA approvals over the past decade of three second-line anti-TB drugs, bedaquiline, delamanid, and pretomanid, have been major forward steps in the management of drug-resistant-TB (DR-TB). Many medicinal plants such as Zanthoxylum leprieurii, Lantana camara, and Cryptolepis sanguinolenta have extensive therapeutic potential and represent a prospective option to fight against DR-TB. Some novel compounds are in the early clinical trial phases such as DprE1 inhibitors TBA-7371 and BTZ-043, and many others that are showing promising futures. This review describes DR-TB and its current chemotherapy guidelines including novel and repurposed drugs that are included in the anti-TB regimens, medicinal plants that have therapeutic potential for the development of drug-hit candidates, drugs that are currently in clinical development, host-directed therapy, and new drug delivery systems to better understand the novel therapeutic approaches that are currently being studied for the efficacious and safe management of DR-TB, a worldwide health problem. [ABSTRACT FROM AUTHOR]

The discovery of azomycin provided the major impulse for the systematic search for medicines showing activity against anaerobic protozoa. Nowadays, many other interesting applications have been found for nitroimidazoles as therapeutic agents. This research led to the acquisition of numerous new 4-amine-5-nitroimidazole derivatives, which have a structure analogous to metronidazole, characteristic of medicines most widely used in the treatment of anaerobic bacteria, protozoa and parasitic infections. The therapeutic activity of the described compounds is analyzed and confirmed with predictive methods. [ABSTRACT FROM AUTHOR]

Neuroendocrine prostate cancer (NEPC), a lethal form of the disease, is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, we identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity. ONEUCT2 drives tumor aggressiveness in NEPC, partially through regulating hypoxia signaling and tumor hypoxia. Specifically, ONECUT2 activates SMAD3, which regulates hypoxia signaling through modulating HIF1α chromatin-binding, leading NEPC to exhibit higher degrees of hypoxia compared to prostate adenocarcinomas. Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients.

Tuberculosis and parasitic diseases, such as giardiasis, amebiasis, leishmaniasis, and trypanosomiasis, all urgently require improved treatment options. Recently, it has been shown that antitubercular bicyclic nitroimidazoles such as pretomanid and delamanid have potential as repurposed therapeutics for the treatment of visceral leishmaniasis. Here, we show that pretomanid also possesses potent activity against Giardia lamblia and Entamoeba histolytica, thus expanding the therapeutic potential of nitroimidazooxazines. Synthetic analogues with a novel nitroimidazopyrazin-one/-e bicyclic nitroimidazole chemotype were designed and synthesized, and structure-activity relationships were generated. Selected derivatives had potent antiparasitic and antitubercular activity while maintaining drug-like properties such as low cytotoxicity, good metabolic stability in liver microsomes and high apparent permeability across Caco-2 cells. The kinetic solubility of the new bicyclic derivatives varied and was found to be a key parameter for future optimization. Taken together, these results suggest that promising subclasses of bicyclic nitroimidazoles containing different core architectures have potential for further development.

BackgroundThe effectiveness of anti-parasite treatment with benznidazole in the chronic Chagas disease (ChD) remains uncertain. We evaluated, using data from the NIH-sponsored SaMi-Trop prospective cohort study, if previous treatment with benznidazole is associated with lower mortality, less advanced cardiac disease and lower parasitemia in patients with chronic ChD.MethodsThe study enrolled 1,959 ChD patients and abnormal electrocardiogram (ECG) from in 21 remote towns in Brazil. A total of 1,813 patients were evaluated at baseline and after two years of follow-up. Those who received at least one course of benznidazole were classified as treated group (TrG = 493) and those who were never treated as control group (CG = 1,320). The primary outcome was death after two-year follow-up; the secondary outcomes were presence at the baseline of major ChD-associated ECG abnormalities, NT-ProBNP levels suggestive of heart failure, and PCR positivity.ResultsMortality after two years was 6.3%; it was lower in the TrG (2.8%) than the CG (7.6%); adjusted OR: 0.37 (95%CI: 0.21;0.63). The ECG abnormalities typical for ChD and high age-adjusted NT-ProBNP levels suggestive of heart failure were lower in the TrG than the CG, OR: 0.35 [CI: 0.23;0.53]. The TrG had significantly lower rates of PCR positivity, OR: 0.35 [CI: 0.27;0.45].ConclusionPatients previously treated with benznidazole had significantly reduced parasitemia, a lower prevalence of markers of severe cardiomyopathy, and lower mortality after two years of follow-up. If used in the early phases, benznidazole treatment may improve clinical and parasitological outcomes in patients with chronic ChD.Trial registrationClinicalTrials.gov, Trial registration: NCT02646943.

Nitroimidazolic radiosensitizers are used in radiation therapy to selectively sensitize cancer cells deprived of oxygen, and the actual mechanism of radiosensitization is still not understood. Selecting five radiosensitizers (1-methyl-5-nitroimidazole, ronidazole, ornidazole, metronidazole, and nimorazole) with a common 5-nitroimidazolic ring with different substitutions at N1 and C2 positions of the imidazole moiety, we investigate here their binding to nucleobases (A, T, G, and C) and nucleosides (As, Td, Gs, and Cd) via the positive electrospray ionization mass spectrometry experiments. In addition, quantum chemical calculations at the M062x/6-311+G(d,p) level of theory and basis set were used to determine binding energies of the proton bound dimers of a radiosensitizer and a nucleobase. The positive electrospray ionization leads to the formation of proton bound dimers of all radiosensitizers except 1-methyl-5-nitroimidazole in high abundance with C and smaller abundance with G. Ronidazole and metronidazole formed less abundant dimers also with A, while no dimers were observed to be formed at all with T. In contrast to the case of the nucleoside Td, the dimer intensity is as high as that with Cd, while the abundance of the dimer with Gs is smaller than that of the former. The experimental results are consistent with the calculations of binding energies suggesting proton bound dimers with C and G to be the strongest bound ones. Finally, a barrier-free proton transfer is observed when protonated G or C approaches the nitroimidazole ring. [ABSTRACT FROM AUTHOR]

Background and aims: Trichomoniasis is the most common non-viral sexually transmitted infection worldwide; although it is treated by a 5-nitroimidazole drug family such as metronidazole (MTZ) with numerous side effects, and in this regard, alternative new drugs are required. Therefore, this study examined the anti-Trichomoniasis effect of the hydroalcoholic extract of some traditional medicinal plants of Iran in vitro. Methods: In this experimental study, the hydroalcoholic extracts of medicinal plants were prepared by maceration at a stock concentration of 20 mg/mL in the saline solution and then used for in vitro anti-trichomonas experiments. Trichomonas vaginalis trophozoites were isolated from the patient and cultured in a Trypticase Yeast extract Iron-Serum-33 medium. In addition, 200 μL of the culture medium containing 5 × 104 trophozoites was diluted in plate wells, and 10 doses were separately added on trophozoites for each extract serially diluted between 0.12 and 16 mg/mL in triplicate. The plates were incubated for 48 hours at 37 °C with 5% CO2. The number of trophozoites was counted with a hemocytometer and Trypan blue staining. Finally, the half maximal inhibitory concentration (IC50) was calculated by probit analysis. Results: Among the tested plants, Eugenia caryophyllata, Camellia sinensis, and Terminalia chebula Retz showed the best anti-trichomonal activity with IC50 values of 1.21, 1.62, and 1.66 mg/mL, respectively. All tested extracts had more IC50 than MTZ (IC50 100 mg/mL), an antiprotozoal drug used as a positive control. Conclusion: According to the results of this study, E. caryophylata, C. sinensis and T. chebula Retz affected the growth of T. vaginalis. Thus, it is recommended that other studies use this plant for the treatment of trichomoniasis infection. [ABSTRACT FROM AUTHOR]

Autophagy is a critical cellular adaptive response in tumor formation. Nutritional deficiency and hypoxia exacerbate autophagic flux in established malignancies, promoting tumor cell proliferation, migration, metastasis, and resistance to therapeutic interventions. Pro-survival autophagy inhibition may be a promising treatment option for advanced cancer. Furthermore, excessive or persistent autophagy is cytotoxic, resulting in tumor cell death. Targeted autophagy activation has also shown significant promise in the fight against tumor drug resistance. Several research groups have examined the ability of natural products (NPs) such as alkaloids, terpenoids, polyphenols, and anthraquinones to serve as autophagy inhibitors or activators. The data support the capacity of NPs that promote lethal autophagy or inhibit pro-survival autophagy from being employed against tumor drug resistance. This paper discusses the potential applications of NPs that regulate autophagy in the fight against tumor drug resistance, some limitations of the current studies, and future research needs and priorities. [ABSTRACT FROM AUTHOR]

With the development of nanomedicine technology, stimuli-responsive nanocarriers play an increasingly important role in antitumor therapy. Compared with the normal physiological environment, the tumor microenvironment (TME) possesses several unique properties, including acidity, high glutathione (GSH) concentration, hypoxia, over-expressed enzymes and excessive reactive oxygen species (ROS), which are closely related to the occurrence and development of tumors. However, on the other hand, these properties could also be harnessed for smart drug delivery systems to release drugs specifically in tumor tissues. Stimuli-responsive nanoparticles (srNPs) can maintain stability at physiological conditions, while they could be triggered rapidly to release drugs by specific stimuli to prolong blood circulation and enhance cancer cellular uptake, thus achieving excellent therapeutic performance and improved biosafety. This review focuses on the design of srNPs based on several stimuli in the TME for the delivery of antitumor drugs. In addition, the challenges and prospects for the development of srNPs are discussed, which can possibly inspire researchers to develop srNPs for clinical applications in the future. [ABSTRACT FROM AUTHOR]

Background: Treatment of drug-resistant tuberculosis with bedaquiline-pretomanid-linezolid regimen has demonstrated good treatment efficacy. Given linezolid's toxicity profile, prudence suggests reconsidering its dose and duration. We determined the effectiveness and safety of structured dose reduction of linezolid with bedaquiline and pretomanid in adults with pre-extensively drug-resistant (pre-XDR) or treatment-intolerant/nonresponsive multidrug-resistant (MDRTI/NR) pulmonary tuberculosis., Method: Adults with pre-XDR or MDRTI/NR pulmonary tuberculosis were enrolled in a multicenter, parallel-group, randomized clinical trial in India. Patients were randomized to 26 weeks of bedaquiline, pretomanid, and daily linezolid, at 600 mg for 26 weeks (arm 1); 600 mg for 9 weeks followed by 300 mg for 17 weeks (arm 2); or 600 mg for 13 weeks followed by 300 mg for 13 weeks (arm 3). Study end points included sustained cure, bacteriological failure, toxicity, and death., Results: Of 403 patients enrolled, 255 (63%) were <30 years old, 273 (68%) had prior tuberculosis episodes, and 238 (59%) were malnourished. At the end of treatment, after excluding those with negative baseline cultures, cure was seen in 120 (93%), 117 (94%), and 115 (93%) in arms 1, 2, and 3 respectively. Myelosuppression seen in 85 patients each in arms 1 and 2 and 77 patients in arm 3, not significantly different. Peripheral neuropathy was noticed in 66 patients (30, 17, and 19 in arms 1, 2, and 3) at 10-26 weeks (P = .02). The linezolid dose was reduced because of toxicity in 13, 2, and 4 patients in arms 1, 2, and 3, respectively., Conclusions: In adults with pre-XDR or MDRTI/NR pulmonary tuberculosis, structured linezolid dose reduction to 300 mg/d is as effective as the standard 600-mg dose but with fewer cases of peripheral neuropathy when given with bedaquiline and pretomanid., Clinical Trials Registration: Clinical Trial Registry of India (CTRI/2021/03/032189)., Competing Interests: Potential conflicts of interest. Umesh Alavadi was an employee of the United States Agency for Internation Development (USAID) during the initial period of study conduct and J. J. is an employee of The UNION. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Hypoxia is a characteristic of solid tumors, but whether significant hypoxia exists in the hepatocellular carcinoma remains unclear. This animal study aims to explore the value of dynamic contrast-enhanced ultrasound (CEUS) quantitative parameters to evaluate the oxygen status in two rat hepatoma models., Materials and Methods: N1S1 and McA-RH7777 S-D rat orthotopic hepatoma models were established. Once the tumors reached a diameter of 10-15 mm, CEUS and oxygen partial pressure (pO2) polarography were performed. Immunohistochemical staining for HIF-1α and pimonidazole was conducted after euthanizing the rats. Correlation between quantitative CEUS parameters, pO 2, and the immunohistochemical integrated optical density (IOD) was analyzed to assess the predictive ability of CEUS quantitative parameters for the tissue oxygen environment., Result: Eleven N1S1 models and ten McA-RH7777 models were established successfully. There was no significant difference in pO 2 (35.5 mmHg vs 32.2 mmHg, P = 0.917), IOD of HIF-1α (13.4 vs 20.0, P = 0.159) and pimonidazole (0.70 vs 1.30, P = 0.926) between the tumor and the peritumoral liver tissue. The pO 2 values were correlated with CEUS quantitative parameters including mean time-intensity curves (mTIC) (P = 0.003), peak intensity (PKI) (P = 0.010), area under the curve (AUC) (P = 0.009), area under the wash-in curve (WiAUC) (P = 0.006), and arrival time (AT) (P = 0.033). The IOD of HIF-1α correlated with AUC (P = 0.022), WiAUC (P = 0.009), ascending slope (AS) (P = 0.044), and falling time (FT) (P = 0.009). Multiple linear regression indicated that the "short AT" was an independent protective factor for hypoxia (β = -2.347, 95% CI: -4.948, -0.394, P = 0.022), and CEUS had the ability to predict the tumor pO 2 (P = 0.003)., Conclusion: No evidence of significant hypoxia was identified in two rat orthotopic hepatoma models. Quantitative CEUS parameters correlated with the oxygen status of the tumor, which could be utilized to predict the tumor tissue pO 2 ., Competing Interests: Declarations. Ethics approval and consent to participate: This animal study was approved by Animal Care and Ethics Committee of the First Medical Center of PLA General Hospital (No. 2023-X19-90). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

SPR720 is a phosphate ester prodrug that is converted rapidly in vivo to SPR719, the active moiety, which exhibits potent in vitro activity against clinically relevant mycobacterial species including Mycobacterium avium complex (MAC) and Mycobacterium abscessus . SPR720 is in clinical development for the treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD) due to MAC. This study evaluated the safety and the intrapulmonary pharmacokinetics of SPR719 in healthy volunteers. A total of 30 subjects received oral SPR720 1,000 mg once daily for 7 days followed by bronchoscopy and bronchoalveolar lavage, with blood samples collected for plasma pharmacokinetic assessments. Mean SPR719 area under the concentration-time curve from time 0 to 24 hours (AUC 0-24 ) and maximum concentration ( C max ) for plasma, epithelial lining fluid (ELF), and alveolar macrophages (AM) were 52,418 ng·h/mL and 4,315 ng/mL, 59,880 ng·h/mL and 5,429 ng/mL, and 128,105 ng·h/mL and 13,033 ng/mL, respectively. The ratios of ELF to total plasma concentrations of SPR719 based on AUC 0-24 and C max were 1.14 and 1.26, and the ratios of AM to total plasma concentrations of SPR719 based on AUC 0-24 and C max were 2.44 and 3.02, respectively. When corrected for protein binding, the ratios of ELF to unbound plasma concentrations of SPR719 for AUC 0-24 and C max were 19.87 and 21.88, and the ratios of AM to unbound plasma concentrations of SPR719 for AUC 0-24 and C max were 42.50 and 52.53, respectively. No unexpected safety findings were observed. Results from this study of the intrapulmonary disposition of SPR719 support further investigation of SPR720 as a potential oral agent for the treatment of patients with NTM-PD.This study is registered with Clinicaltrials.gov as NCT05955586., Competing Interests: K.A.R. and M.H.G. were consultants to Spero Therapeutics, Inc. X.T.U., S.L.W., and K.A.H. are employees of Spero Therapeutics, Inc.

Hypoxia plays a critical role in tumor biology, influencing cancer progression, treatment resistance, and patient prognosis. While 18-Fluorine fluoredeoxyglucose ([18F]F-FDG) PET imaging has been the standard for metabolic assessment, its limitations in accurately depicting hypoxic tumor regions necessitate the exploration of non-FDG hypoxia tracers. This review aims to evaluate emerging non-FDG radiotracers, such as nitroimidazole derivatives, copper-based agents, gallium-based agents and other innovative compounds, highlighting their mechanisms of action, biodistribution, and clinical applications. We will discuss the advantages and challenges associated with hypoxia imaging, as well as recent advancements in imaging techniques that enhance the assessment of tumor hypoxia. By synthesizing current research, this review seeks to provide insights into the potential of non-FDG hypoxia tracers for improving cancer diagnosis, treatment planning, and monitoring, ultimately contributing to more personalized and effective cancer care., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Hypoxia at the solid tumor site is generally related to the unrestricted proliferation and metabolism of cancerous cells, which can cause tumor metastasis and aggravate tumor progression. Besides, hypoxia plays a substantial role in tumor treatment, and it is one of the main reasons that malignant tumors are difficult to cure and have a poor prognosis. On account of the tumor specific hypoxic environment, many hypoxia-associative nanomedicine have been proposed for tumor treatment. Considering the enhanced targeting effect, designing hypoxia-associative nanomedicine can not only minimize the adverse effects of drugs on normal tissues, but also achieve targeted therapy at the lesion site. Mostly, there can be three strategies for the treatment of hypoxic tumor, including improvement of hypoxic environment, hypoxia responsive drug release and hypoxia activated prodrug. The review describes the design principle and applications of tumor hypoxia-associative nanomedicine in recent years, and also explores its development trends in solid tumor treatment. Moreover, this review presents the current limitations of tumor hypoxia-associative nanomedicine in chemotherapy, radiotherapy, photodynamic therapy, sonodynamic therapy and immunotherapy, which may provide a reference for clinic translation of tumor hypoxia-associative nanomedicine. [Display omitted] • A summary of progress on tumor hypoxia-associative nanomedicine is provided. • The design principle of tumor hypoxia-associative nanomedicine is elaborated. • The applications of tumor hypoxia-associative nanomedicine are reviewed. • The limitations of tumor hypoxia-associative nanomedicine are presented. [ABSTRACT FROM AUTHOR]

Hypoxia, an essential feature of high-altitude environments, has a significant effect on drug metabolism. The hypoxia-gut microbiota-CYP450/drug transporter axis is emerging as a vital factor in drug metabolism. However, the mechanisms through which the gut microbiota mediates the regulation of CYP450/drug transporters under high-altitude hypoxia have not been well defined. In this study, we investigated the mechanisms underlying gut microbial changes in response to hypoxia. We compared 16S ribosomal RNA gene sequences of the gut microbiota from plain and hypoxic rats. As a result, we observed an altered gut microbial diversity and composition in rats under hypoxia. Our findings show that dysregulated gut microbiota changes CYP3A1 and MDR1 expressions in high-altitude hypoxic environments. Thus, our study reveals a novel mechanism underlying the functioning of the hypoxia-gut microbiota-CYP450/drug transporter axis. [ABSTRACT FROM AUTHOR]

Three novel series of derivatives by introducing a 1,2,3-triazoles moiety, 1,2,4-triazoles moiety or a nitroimidazoles ring to the ursolic acid (UA) nucleus were designed and synthesized. The biological activity of these compounds was evaluated to assess their hypoxia-inducible factor-1α (HIF-1α) and cyclooxygenase-2 (COX-2) inhibitory activities along with HIF-1α inhibitory and anti-inflammatory effects. Compound 7e exhibited the highest activity of all the synthesized compounds, which was higher activity than observed for the positive control UA. [ABSTRACT FROM AUTHOR]

Hypoxia-induced intratumoral heterogeneity poses a major challenge in tumor therapy due to the varying susceptibility to chemotherapy. Moreover, the spatial distribution patterns of hypoxic and normoxic tissues makes conventional combination therapy less effective. In this study, a tumor-acidity and bioorthogonal chemistry mediated in situ size transformable nanocarrier (NP@DOX DBCO plus iCPPA N3) was developed to spatially deliver two combinational chemotherapeutic drugs (doxorubicin (DOX) and PR104A) to combat hypoxia-induced intratumoral heterogeneity. DOX is highly toxic to tumor cells in normoxia state but less toxic in hypoxia state due to the hypoxia-induced chemoresistance. Meanwhile, PR104A is a hypoxia-activated prodrug has less toxic in normoxia state. Two nanocarriers, NP@DOX DBCO and iCPPA N3 , can cross-link near the blood vessel extravasation sites through tumor acidity responsive bioorthogonal click chemistry to enhance the retention of DOX in tumor normoxia. Moreover, PR104A conjugated to the small-sized dendritic polyamidoamine (PAMAM) released under tumor acidity can penetrate deep tumor tissues for hypoxic tumor cell killing. Our study has demonstrated that this site-specific combination chemotherapy is better than the traditional combination chemotherapy. Therefore, spatial specific delivery of combinational therapeutics via in situ size transformable nanocarrier addresses the challenges of hypoxia induced intratumoral heterogeneity and provides insights into the combination therapy. [Display omitted] • A tumor-acidity and bioorthogonal chemistry mediated in situ size transformable nanocarrier was developed. • The nanocarrier exhibited the ability to enhance tumor accumulation and retention. • The nanocarrier can spatially deliver DOX and PR104A to normoxic and hypoxic tumor cells. • The site-specific combined chemotherapy can overcome hypoxia-induced intratumoral heterogeneity. [ABSTRACT FROM AUTHOR]