One-pot synthesis of three-dimensional Mn3O4 microcubes for high-level sensitive detection of head and neck cancer drug nimorazole.

We described a three-dimensional Mn3O4 microcubes (3D-Mn3O4MCs) 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-Mn3O4 MCs possess large active area and high conductivity, and 3D-Mn3O4 MCs film modified screen-printed carbon electrode (3D-Mn3O4MCs/SPCE) was fabricated which displayed excellent electrocatalytic ability towards NMZ. Under optimised working conditions, the modified electrode responded linearly to NMZ in the 0.025-8060µM concentration range and the detection limit was 6nM. 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.

A rapid and sensitive determination of hypoxic radiosensitizer agent nimorazole in rat plasma by LC-MS/MS and its application to a pharmacokinetic study.

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 (r(2) > 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.

Study of the population pharmacokinetic characteristics of nimorazole in head and neck cancer patients treated in the DAHANCA-5 trial.

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.

Pilot study of nimorazole as a hypoxic-cell sensitizer with the "chart" regimen in head and neck cancer.

PURPOSE: A potential disadvantage of accelerated fractionation in radiotherapy is the lack of time for reoxygenation, so that hypoxia becomes a more potent cause of failure. Accordingly, we have combined nimorazole, the only hypoxic radiosensitizer shown to significantly improve local control in head and neck cancer, with continuous hyperfractionated accelerated radiation therapy (CHART). METHODS AND MATERIALS: Twenty-two patients with locally advanced (stage IV) squamous cell carcinoma of the head and neck were treated with escalating doses of nimorazole given concomitantly with CHART (three fractions of 1.5 Gy per day, spaced 5 1/2 hours apart, on 12 consecutive days). All patients received 1.2 g/m2 nimorazole 90 minutes before each first daily fraction. Seventeen patients received a further 0.6 g/m2 before each second daily fraction and six of these patients received an additional dose of 0.6 g/m2 before each third fraction. RESULTS: The three times daily schedule yielded mean plasma drug concentrations at the time of irradiation of 37.7 microg/ml with the morning fractions, 31.2 microg/ml with the afternoon fractions, and 30.4 microg/ml with the evening fractions. In view of these results the midday dose was increased to 0.9 microg/m2 in an ongoing Phase II study. Drug toxicity was limited to nausea and vomiting apart from two cases of mild paraesthesia at the highest dose level. CONCLUSIONS: Comparison with a historical group of patients, treated with the CHART regimen alone and matched for irradiation volume and technique, showed that nimorazole did not increase the severity of acute normal tissue radiation effects. Encouraging tumor responses have been seen in the patients receiving nimorazole with every radiotherapy fraction.

A phase I clinical study of Nimorazole as a hypoxic radiosensitizer.

Nimorazole, a 5-Nitromidazole compound has been shown in animal studies to have similar radiosensitizing properties to misonidazole at clinically acceptable dose levels. The drug is well absorbed in humans after oral administration with peak plasma levels occurring around 90 min after ingestion (range 35-135 min) and a plasma half life between 2 and 4.8 hours. Total doses of Nimorazole up to 60 grams given in daily doses with conventional radiation therapy have demonstrated a significant lack of side effects, in particular no demonstrable neurotoxicity.