Search

The study focused on exploring the potential of pristine boron nitride nanocluster (B12N12) as an effective adsorbent and sensing material for the removal and detection of Nimorazole (NM). Through density functional theory simulations, the research revealed promising findings indicating that the interaction between NM and B12N12 is not only experimentally feasible but also exothermic and spontaneous. Additionally, the influence of solvent, particularly water, was investigated, with results demonstrating that the presence of water does not significantly impact these interactions. Furthermore, the impact of temperature on the thermodynamic parameters was considered, with results indicating that the adsorption process is more favorable at lower temperatures. The study also utilized frontier molecular orbital calculations, which revealed a substantial change in the bandgap of B12N12 during the adsorption process of NM. Specifically, the bandgap was found to increase by 70.795%, from 6.716 (eV) to 11.470 (eV), indicating significant alterations in the electronic properties of B12N12 upon interaction with NM. Moreover, the investigation included Quantum Theory of Atoms in Molecules (QTAIM) and Natural Bond Orbital (NBO) studies, which provided insights into the nature of these interactions, indicating a physisorption nature. Overall, the theoretical findings strongly suggest that B12N12 has the potential to serve as an excellent adsorbent and sensor for the removal and detection of NM. This research contributes valuable knowledge to the field of nanomaterials and offers a promising direction for the development of effective strategies for addressing the challenges associated with NM removal and detection. [ABSTRACT FROM AUTHOR]

This novel work reports nimorazole (NIMO) radiosensitizer reduction upon electron transfer in collisions with neutral potassium (K) atoms in the lab frame energy range of 10-400 eV. The negative ions formed in this energy range were time-of-flight mass analyzed and branching ratios were obtained. Assignment of different anions showed that more than 80% was due to the formation of the non-dissociated parent anion NIMO•- at 226 u and nitrogen dioxide anion NO2- at 46 u. The rich fragmentation pattern revealed that significant collision induced the decomposition of the 4-nitroimidazole ring, as well as other complex internal reactions within the temporary negative ion formed after electron transfer to neutral NIMO. Other fragment anions were only responsible for less than 20% of the total ion yield. Additional information on the electronic state spectroscopy of nimorazole was obtained by recording a K+ energy loss spectrum in the forward scattering direction (θ ≈ 0°), allowing us to determine the most accessible electronic states within the temporary negative ion. Quantum chemical calculations on the electronic structure of NIMO in the presence of a potassium atom were performed to help assign the most significant lowest unoccupied molecular orbitals participating in the collision process. Electron transfer was shown to be a relevant process for nimorazole radiosensitisation through efficient and prevalent non-dissociated parent anion formation.

Background: Tumor hypoxia is associated with resistance to radiotherapy and chemotherapy. In head and neck squamous cell carcinoma (HNSCC), nimorazole, an oxygen mimic, combined with radiotherapy (RT) enabled to improve loco-regional control (LRC) in some patients with hypoxic tumors but it is unknown whether this holds also for radiochemotherapy (RCTx). Here, we investigated the impact of nimorazole combined with RCTx in HNSCC xenografts and explored molecular biomarkers for its targeted use. Methods: Irradiations were performed with 30 fractions in 6 weeks combined with weekly cisplatin. Nimorazole was applied before each fraction, beginning with the first or after ten fractions. Effect of RCTx with or without addition of nimorazole was quantified as permanent local control after irradiation. For histological evaluation and targeted gene expression analysis, tumors were excised untreated or after ten fractions. Using quantitative image analysis, micromilieu parameters were determined. Results: Nimorazole combined with RCTx significantly improved permanent local control in two tumor models, and showed a potential improvement in two additional models. In these four models, pimonidazole hypoxic volume (pHV) was significantly reduced after ten fractions of RCTx alone. Our results suggest that nimorazole combined with RCTx might improve TCR compared to RCTx alone if hypoxia is decreased during the course of RCTx but further experiments are warranted to verify this association. Differential gene expression analysis revealed 12 genes as potential for RCTx response. When evaluated in patients with HNSCC who were treated with primary RCTx, these genes were predictive for LRC. Conclusions: Nimorazole combined with RCTx improved local tumor control in some but not in all HNSCC xenografts. We identified prognostic biomarkers with the potential for translation to patients with HNSCC. [ABSTRACT FROM AUTHOR]

• HNSCC xenografts depict heterogeneous expression of hypoxia gene signatures which weakly correlate with the histologic surrogate for hypoxia pimonidazole. • Untreated and radiochemotherapy (with and without nimorazole)-treated responder and non-responder tumor models depict specific differential expression and methylation profiles. • Nimorazole non-responder models exhibit increased expression of genes associated to retinol metabolism and xenobiotic metabolic process. • A subset of 15 genes upregulated in untreated nimorazole non-responder models showed prognostic value also in HNSCC patients, defining a high-risk group for loco-regional failure and overall survival after primary radiochemotherapy. Hypoxia remains a challenge for the therapeutic management of head and neck squamous cell carcinoma (HNSCC). The combination of radiotherapy with nimorazole has shown treatment benefit in HNSCC, but the precise underlying molecular mechanisms remain unclear. To assess and to characterize the transcriptomic/epigenetic landscape of HNSCC tumor models showing differential therapeutic response to fractionated radiochemotherapy (RCTx) combined with nimorazole. Bulk RNA-sequencing and DNA methylation experiments were conducted using untreated and treated HNSCC xenografts after 10 fractions of RCTx with and without nimorazole. These tumor models (FaDu, SAS, Cal33, SAT and UT-SCC-45) previously showed a heterogeneous response to RCTx with nimorazole. The prognostic impact of candidate genes was assessed using clinical and gene expression data from HNSCC patients treated with primary RCTx within the DKTK-ROG. Nimorazole responder and non-responder tumor models showed no differences in hypoxia gene signatures However, non-responder models showed upregulation of metabolic pathways. From that, a subset of 15 differentially expressed genes stratified HNSCC patients into low and high-risk groups with distinct outcome. In the present study, we found that nimorazole non-responder models were characterized by upregulation of genes involved in Retinol metabolism and xenobiotic metabolic process pathways, which might contribute to identify mechanisms of resistance to nitroimidazole compounds and potentially expand the repertoire of therapeutic options to treat HNSCC. [ABSTRACT FROM AUTHOR]

Infections caused by Mycobacterium abscessus (Mab), an environmental non-tuberculous mycobacterium, are difficult to eradicate from patients with pulmonary diseases such as cystic fibrosis and bronchiectasis even after years of antibiotic treatments. In these people, the low oxygen pressure in mucus and biofilm may restrict Mab growth from actively replicating aerobic (A) to non-replicating hypoxic (H) stages, which are known to be extremely drug-tolerant. After the exposure of Mab A and H cells to drugs, killing was monitored by measuring colony-forming units (CFU) and regrowth in liquid medium (MGIT 960) of 1-day-old A cells (A1) and 5-day-old H cells (H5). Mab killing was defined as a lack of regrowth of drug-exposed cells in MGIT tubes after >50 days of incubation. Out of 18 drugs tested, 14-day treatments with bedaquiline-amikacin (BDQ-AMK)-containing three-drug combinations were very active against A1 + H5 cells. However, drug-tolerant cells (persisters) were not killed, as shown by CFU curves with typical bimodal trends. Instead, 56-day treatments with the nitrocompounds containing combinations BDQ-AMK-rifabutin-clarithromycin-nimorazole and BDQ-AMK-rifabutin-clarithromycin-metronidazole-colistin killed all A1 + H5 Mab cells in 42 and 56 days, respectively, as shown by lack of regrowth in agar and MGIT medium. Overall, these data indicated that Mab persisters may be killed by appropriate drug combinations. [ABSTRACT FROM AUTHOR]

[Display omitted] Glioblastoma multiforme is the most aggressive and lethal form of brain tumour due to the high degree of cancer cells infiltration into surrounding brain tissue. No form of monotherapy can guarantee satisfactory patient outcomes and is only of palliative importance. To find a potential option of glioblastoma treatment the bioresorbable, layer nonwoven mats for controlled temozolomide and nimorazole release were obtained by classical and coaxial electrospinning. Optimization of fibre structure that enables delayed and controlled drug release was performed. The studied bioresorbable polymers were poly(L-lactide-co- ε -caprolactone) and poly(L-lactide-co-glycolide-co-trimethylene carbonate). The physicochemical properties of polymers were determined as well as drug release profiles of nonwoven mats. A combination of coaxial electrospinning and electrospray technique provided three-phased release profiles of temozolomide and nimorazole: the slow release of very low drug doses followed by accelerated release and saturation phase. Results form the basis for further investigation since both studied polymers possess a great potential as nimorazole and temozolomide delivery systems in the form of layered nonwoven implants. [ABSTRACT FROM AUTHOR]

Abstract Background Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with 18F-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo. Methods In vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic (

Nimorazole belongs to the imidazole‐based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for potential use as a hypoxia radiosensitizer for treatment of head and neck cancers. We envision the use of [15N3]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next‐generation MRI‐LINAC systems. Herein, we report the first steps to create long‐lasting (for tens of minutes) hyperpolarized state on three 15N sites of [15N3]nimorazole with T1 of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000‐fold at 1.4 T (corresponding to P15N of 3.2 %) by 15N−15N spin‐relayed SABRE‐SHEATH hyperpolarization technique, relying on simultaneous exchange of [15N3]nimorazole and parahydrogen on polarization transfer Ir‐IMes catalyst. The presented results pave the way to efficient spin‐relayed SABRE‐SHEATH hyperpolarization of a wide range of imidazole‐based antibiotics and chemotherapeutics. [ABSTRACT FROM AUTHOR]

This paper describes the chromatographic behavior of nimorazole combined medicine employing two adsorbents, twenty-seven four mobile phases and detection agents. Accordingly, the thin layer chromatography allowed the separation and identification of drugs nimorazole, chloramphenicol and nystatin using a simple, effective and inexpensive technique.

The formation of radical anions of nitroimidazolic radiosensitizers, nimorazole and metronidazole, and their unimolecular dissociation reactions upon high-energy collisions with He gas were investigated with a double focusing mass spectrometer equipped with an electrospray ionization (ESI) source. Radical anions of both, nimorazole and metronidazole, are readily formed in the ESI process, while for the metronidazole also the deprotonated anion is formed. A variety of dissociation channels is observed and the associated kinetic energy released in the dissociation for most of these channels is reported. The marker anion NO 2 − is observed in the dissociation of all studied anions. The release of NO radical from the radical anions is associated with surprisingly small kinetic energy release in comparison to simple nitroimidazoles. On the other hand, the highest kinetic energy release is noted for the release of the neutral side group from N1 position of the imidazole ring, which suggests that the substitution at the N1 plays a crucial role in the decomposition of anions of radiosensitizers. [ABSTRACT FROM AUTHOR]

We described a three-dimensional Mn 3 O 4 microcubes (3D–Mn 3 O 4 MCs) synthesised via a facile hydrothermal route for the determination of nimorazole (NMZ), an important drug that used in the treatment of head and neck cancer. The 3D–Mn 3 O 4 MCs possess large active area and high conductivity, and 3D–Mn 3 O 4 MCs film modified screen-printed carbon electrode (3D–Mn 3 O 4 MCs/SPCE) was fabricated which displayed excellent electrocatalytic ability towards NMZ. Under optimised working conditions, the modified electrode responded linearly to NMZ in the 0.025–8060 µM concentration range and the detection limit was 6 nM. A rapid, sensitive, selective, reproducible, and durable sensor was described. The practical feasibility of the sensor was demonstrated in human serum and NMZ tablet samples. The obtained results revealed the potential real-time applicability of the sensing device in biological analysis and pharmaceutical formulations. [ABSTRACT FROM AUTHOR]

A highly sensitive, accurate and robust LC-MS/MS method was developed and validated for determination of nimorazole (NMZ) in rat plasma using metronidazole (MNZ) as internal standard (IS). The analyte and IS were extracted from plasma by precipitating protein with acetonitrile and were chromatographed using an Agilent Poroshell 120, EC-C18 column. The mobile phase was composed of a mixture of acetonitrile and 0.1 % formic acid (85:15 v/v). The total run time was 1.5 min and injection volume was 5 μL. Multiple reaction monitoring mode using the transitions of m/ z 227.1 → m/ z 114.0 for MNZ and m/ z 172.10 → m/ z 128.1 for IS were monitored on a triple quadrupole mass spectrometer, operating in positive ion mode. The calibration curve was linear in the range of 0.25-200 ng/mL ( r2 > 0.9996) and the lower limit of quantification was 0.25 ng/mL in the rat plasma samples. Recoveries of NMZ ranged between 88.05 and 95.25%. The precision (intra-day and inter-day) and accuracy of the quality control samples were 1.25-8.20% and −2.50-3.10, respectively. The analyte and IS were found to be stable during all sample storage and analysis procedures. The LC-MS/MS method described here was validated and successfully applied to pharmacokinetic study in rats. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose To test the hypothesis that radiotherapy (RT) of head and neck squamous cell carcinoma (HNSCC) can be improved by hypoxic modification using nimorazole (NIM) in association with accelerated fractionation. Materials and methods The protocol was activated in March 2012 as an international multicenter randomized trial in patients with HNSCC. Tumors were treated to a dose of 66–70 Gy, 33–35 fractions, 6 fractions per week. NIM was administered in a dose of 1.2 g per m 2 , 90 min before the first daily RT fraction. The primary endpoint was loco-regional failure. The trial was closed prematurely by June 2014 due to poor recruitment. An associated quality assurance program was performed to ensure the consistency of RT with the protocol guidelines. Results The trial was dimensioned to include 600 patients in 3 years, but only 104 patients were randomized between March 2012 and May 2014 due to the inability to involve three major centers and the insufficient recruitment rate from the other participating centers. Twenty patients from two centers had to be excluded from the analysis due to the unavailability of the follow-up data. Among the remaining 84 patients, 82 patients were evaluable (39 and 43 patients in the RT + NIM and the RT-alone arms, respectively). The treatment compliance was good with only six patients not completing the full planned RT course, and 31 patients (79%) out of 39 allocated for NIM, achieving at least 90% of the prescribed drug dose. At the time of evaluation, 40 patients had failed to achieve persistent loco-regional tumor control, and a total of 45 patients had died. The use of NIM improved the loco-regional tumor control with an 18 month post-randomization cumulative failure rate of 33% versus 51% in the control arm, yielding a risk difference of 18% (CI −3% to 39%; P = 0.10). The corresponding values for overall death was 43% versus 62%, yielding a risk difference of 19% (CI −3% to 42%; P = 0.10). Sixteen patients, out of 55 patients analyzed for hypoxic gene expression, were classified as having more hypoxic tumors. Such patients, if treated with RT alone, had a higher loco-regional tumor failure rate as compared to the rest of the patients with known hypoxic status ( P = 0.05). Conclusion Although the trial was incomplete and suffered from a small number of patients, the results suggested an improvement in loco-regional tumor control and overall survival in patients with advanced HNSCC given the hypoxic modifier NIM in addition to accelerated fractionation RT. However, the trial also revealed that conducting multicenter and multinational study combining drug and RT in developing countries may suffer from uncontrolled and unsolvable problems. [ABSTRACT FROM AUTHOR]

A simple, rapid, sensitive, cost effective, and reproducible chemometrics assisted RP-HPLC method for the simultaneous estimation of the Ofloxacin and Nimorazole in pharmaceutical formulation was developed, optimized, and validated. A chemometrics assisted RP-HPLC method was developed. A developed method was optimized by using central composite design (CCD) in response surface methodology (RSM). Based on the trial and error, percentage of tetrahydrofuran in the mobile phase, flow rate, and buffer molarity were selected as factors. Resolution (Rs2) and retention time (tR2) were used for the estimation of system response during the optimization procedure. Derringer’s desirability function was used to concurrently optimize the selected two responses. Separation was achieved on a Phenomenex C18column (150 × 4.6 mm i.d, 5µ particle size) with a mobile phase consisting of 25% of Tetrahydrofuran and 75% of Phosphate buffer (25 mM), delivered at a flow rate of 1.2 mL/min with photodiode array detection at 294 nm. The developed and optimized method was fully validated for linearity accuracy, precision, robustness, and recovery. This validated method can be used for routine quality control analysis of ofloxacin and nimorazole in pharmaceutical dosage form. [ABSTRACT FROM AUTHOR]

Aims To study the pharmacokinetic characteristics of the hypoxic radiosensitiser nimorazole in patients with head and neck squamous cell carcinoma. Materials and methods The pharmacokinetics of the hypoxic radiosensitiser nimorazole were studied in 63 patients treated in the DAHANCA-5 trial. After the first day of treatment, serial venous blood samples were taken and plasma concentrations of nimorazole measured by high pressure liquid chromatography (HPLC). Plasma concentration profiles were subjected to non-compartmental pharmacokinetic analysis using validated PC-based software. The different pharmacokinetic parameters were calculated and correlated with the different patient- and treatment-related variables. Results HPLC measurements showed a linear relationship between peak plasma concentration and administered dose. The mean peak concentration adjusted for dose (in g/m 2 ) was 32.2 ± 0.9 μg/ml. The time of peak concentration ranged between 30 and 180 min (median 60 min). Plasma elimination occurred with a mean half-life of 3.35 ± 0.09 h and was not significantly altered as a function of dose. There was a well-established linear–linear relationship between area under the concentration–time curve (AUC; mean 191 ± 6 μg·h/ml) and administered dose, especially when expressed as g/m 2 . The mean apparent volume of distribution was 0.77 ± 0.02 l/kg. A statistically significant longer elimination half-life in men relative to women (mean difference 0.40 h; 95% confidence interval 0.77–0.03; P 0.03) was detected. Nimorazole was well tolerated; with 67% of patients reporting no toxicity; nausea/vomiting was the most reported toxicity in the remaining patients. Conclusion The study supports the current nimorazole dose scheduling in patients. [ABSTRACT FROM AUTHOR]

A crucial element of cancer treatment is radiation therapy that is used to destroy tumors and cancer cells through radiation. Another essential component is immunotherapy that helps immune system to combat cancer. The combination of both radiation therapy and immunotherapy is being focused recently for the treatment of many tumors. Chemotherapy includes the use of some chemical agent to control the growth of cancer, whereas irradiation involves the use of radiations of high energy to kill cancer cells. The union of both became the strongest practice in cancer treatment techniques. Specific chemotherapies are combined with radiation in the treatment of cancer after proper preclinical assessment of their effectiveness. Some classes of compounds include platinum-based drugs, antimicrotubules, antimetabolites (5-Fluorouracil, Capecitabine, Gemcitabine, Pemetrexed), topoisomerase I inhibitors, alkylating agents (Temozolomide), and other agents (Mitomycin-C, Hypoxic Sensitizers, Nimorazole)., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Purpose To assess the predictive value of hypoxia imaging by 18 F-FAZA PET in identifying tumors that may benefit from radiotherapy combined with nimorazole, a hypoxic radiosensitizer. Material and methods Rats of two tumor models (Rhabdomyosarcoma and 9L-glioma) were divided into two treated groups: radiotherapy (RT) alone or RT plus nimorazole. 18 F-FAZA PET images were obtained to evaluate tumor hypoxia before the treatment. Treatment outcome was assessed through the tumor growth time assay, defined as the time required for tumor to grow to 1.5 times its size before irradiation. Results For rhabdomyosarcomas, the benefit of adding nimorazole to RT was not significant when considering all tumors. When stratifying into more and less hypoxic tumors according to the median 18 F-FAZA T/B ratio, we found that the combined treatment significantly improved the response of the “more hypoxic” subgroup, while there was no significant difference in the tumor growth time between the two treatment modalities for the “less hypoxic” subgroup. For 9L-gliomas, a clear benefit was demonstrated for the group receiving RT + nimorazole. However, the individual responses within the RT + nimorazole group were highly variable and independent of the 18 F-FAZA uptake. Conclusions 18 F-FAZA PET may be useful to guide hypoxia-directed RT using nimorazole as radiosensitizer. It identified a subgroup of more hypoxic tumors (displaying T/B ratio > 2.72) that would benefit from this combined treatment. Nevertheless, the predictive power was limited to rhabdomyosarcomas and ineffective for 9L-gliomas. [ABSTRACT FROM AUTHOR]

Highlights: [•] Radical anions of nimorazole and misonidazole were observed for the first time. [•] Key finding is that radical anions are directly formed via electrospray ionization. [•] First report of fragmentation of positive and negative ions of radiosensitizers. [•] The fragmentation depends on the nature of the charge. [•] Misonidazole shows more complex fragmentation than nimorazole. [Copyright &y& Elsevier]

Abstract: Background and purpose: CA IX is suggested to be an endogenous marker of hypoxia in tumours like squamous cell carcinomas of the head and neck (HNSCC). The aim of the present study was to investigate whether CA IX served as a prognostic factor for outcome in a large population of HNSCC and if CA IX was able to discriminate the tumours that did benefit from hypoxic modification with nimorazole. Materials and methods: Paraffin-embedded formalin-fixed pre-treatment tumour tissue was available from 320 of the 414 patients treated in the randomized DAHANCA 5 protocol with primary radiotherapy±the hypoxic radiosensitizer nimorazole. CA IX was measured using immunohistochemistry and results were divided into four groups of CA IX expression: <1%, 1–10%, 10–30% and >30% of the tumour area with positive membrane staining. Locoregional control and disease-specific survival were used as endpoints. Results: Expression of CA IX was not correlated to any of the tumour or patient characteristics investigated. Furthermore, CA IX did not serve as a prognostic marker in the total cohort as well as in the group of 150 patients treated without nimorazole. Finally, no relation was found between the different expression levels of CA IX and the influence of nimorazole when locoregional control or disease-specific survival was used as endpoints. Conclusions: This is to date one of the largest studies of CA IX in HNSCC. The data suggest that CA IX have no prognostic or predictive potential in patients with cancer in the head and neck treated with conventional radiotherapy and concomitant nimorazole. [Copyright &y& Elsevier]