Bioresorbable, electrospun nonwoven for delayed and prolonged release of temozolomide and nimorazole.

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.

DAHANCA 10 - Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group.

PURPOSE: To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC). PATIENTS AND METHODS: Patients eligible for primary radiotherapy and who had Hb values below 14.0 g/dl were randomized to receive accelerated fractionated radiotherapy with or without darbepoetin alfa. Patients also received the hypoxic radiosensitizer nimorazole. Darbepoetin alfa was given weekly during radiotherapy or until the Hb value exceeded 15.5 g/dl. RESULTS: Following a planned interim analysis which showed inferiority of the experimental treatment the trial was stopped after inclusion of 522 patients (of a planned intake of 600). Of these, 513 were eligible for analysis (254 patients treated with darbepoetin alfa and 259 patients in the control group). Overall, the patients were distributed according to the stratification parameters (gender, T and N staging, tumor site). Treatment with darbepoetin alfa increased the Hb level to the planned value in 81% of the patients. The compliance was good without excess serious adverse events. The results showed a poorer outcome with a 5-year cumulative loco-regional failure rate of 47% vs. 34%, Hazard Ratio (HR): 1.53 [1.16-2.02], for the darbepoetin alfa vs. control arm, respectively. This was also seen for the endpoints of event-free survival (HR: 1.36 [1.09-1.69]), disease-specific death (HR: 1.43 [1.08-1.90]), and overall survival (HR: 1.30 [1.02-1.64]). There was no enhanced risk of cardio-vascular events observed in the experimental arm or any significant differences in acute or late radiation related morbidity. All univariate analyses were confirmed in a multivariate setting. CONCLUSION: Correction of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival.

Locally advanced head and neck cancer treated with accelerated radiotherapy, the hypoxic modifier nimorazole and weekly cisplatin. Results from the DAHANCA 18 phase II study.

PURPOSE/OBJECTIVE: A phase II clinical trial evaluating the feasibility and outcome of treating locally advanced head and neck squamous cell carcinoma (HNSCC) with accelerated radiotherapy, the hypoxic modifier nimorazole and weekly cisplatin. MATERIAL AND METHODS: A total of 227 patients with stage III or IV HNSCC of the larynx, oropharynx, hypopharynx, or oral cavity where included between January 2007 and December 2010. The prescribed radiotherapy (RT) dose was 66-68 Gy in 2 Gy fractions, 6 F/W. The hypoxic radiosensitiser nimorazole was given orally at a dose of 1200 mg/m(2) before each fraction. Concomitant cisplatin (40 mg/m(2)) i.v. was given once a week for a maximum of six cycles. Outcome data were evaluated in terms of loco-regional tumour control (LRC), event-free survival (EFS) and overall survival (OS). Morbidity data were evaluated based on the DAHANCA routine registration. Human papillomavirus (HPV)-status was estimated by immunohistochemical staining of p16. RESULTS: Included were 178 (78%) men and 49 (22%) women with a median age of 57 years. All except five patients received RT as prescribed. At least five series of cisplatin was given to 164 (72%) of the patients, and 149 patients (66%) received the full dose of nimorazole. The five-year actuarial LRC, EFS and OS rates were 80%, 67% and 72%, respectively. The LRC rates according to site were: oropharynx: 88%, larynx: 77%, hypopharynx 72% and oral cavity 49%, respectively. HPV/p16 staining was obtained in 141 of the 150 oropharyngeal cancers. Of these, 112 (79%) were p16 pos and 29 (21%) were p16 neg. LRC for the p16 neg oropharyngeal cancers was poorer than for the p16 pos (74% vs. 91%; p = 0.02). Tube feeding during treatment was necessary for 146 (64%) patients. At 12 months this number was reduced to 6%. CONCLUSION: The treatment was tolerable in this cohort of locally advanced HNSCC patients. Acute and late toxicity was comparable to similar studies of chemoradiotherapy, and the outcome superior to the data reported in the literature. This strongly indicates that RT of advanced head and neck cancer must include as well hypoxic modification, accelerated fractionation as chemoradiotherapy to yield optimal outcome.

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.

Compliance and toxicity of the hypoxic radiosensitizer nimorazole in the treatment of patients with head and neck squamous cell carcinoma (HNSCC).

PURPOSE: To evaluate the compliance and toxicity of the hypoxic radiosensitizer nimorazole in head and neck cancer patients. METHODS: A retrospective study of patients with head and neck squamous cell carcinoma (HNSCC), treated in Denmark between 1990 and 2013. All patients treated with radical radiotherapy (± chemotherapy) [66-70 Gy; 33-35 fractions; 2 Gy/fraction; 5-6 fractions/week] concomitant with the hypoxic radiosensitizer nimorazole. Nimorazole was administered as oral tablets in doses of approximately 1.2 g/m(2) body surface area in connection with the first of each daily radiation treatment. A second daily dose of 1 g was given in connection with the second radiotherapy fraction in the accelerated fractionation regimen. The compliance was estimated as the percentage of the initially prescribed dose, which was received by each patient. The main side effects were recorded. RESULTS: A total of 1049 patients were investigated. The tolerance to nimorazole was fair: 58% of patients received the full prescribed total dose. Nausea and vomiting were the major complaints: among the 260 patients with dose reductions due to known side effects, (87%) were due to nausea/vomiting. All side effects ceased when treatment was interrupted, and neither severe nor long lasting side effects were observed. Female patients were significantly more likely to have dose reduction (OR 2.02; 95% CI 1.50-2.70), and nausea/vomiting. Patients aged more than 70 years were significantly more likely to have dose reduction. Patients who received less than 1100 mg/m(2) were significantly less likely to have dose reduction (OR 0.58; CI 0.44-0.78), and nausea/vomiting, compared to those who received 1100-1300 mg/m(2). The tolerance was also less in the group of patients received accelerated chemoradiotherapy (OR 1.70; CI 1.20-2.50) with more association with nausea/vomiting (OR 2.09; CI 1.40-3.10). CONCLUSION: The compliance to nimorazole is fair, with tolerable acute, but neither persistent nor late, toxicity. It can be administered with chemotherapy and different radiotherapy fractionation schedules.

Reevaluation of the radiosensitizing effects of sanazole and nimorazole in vitro and in vivo.

Sanazole (AK-2123, 3-nitrotriazole derivative, N1-(3-methoxypropyl)-2-(3-nitro-1 H-1,2,4-triazol-1-yl)acetamide) and nimorazole (5-nitroimidazole derivative, 4-(2-(5-nitro-1H-1-imidazolyl)ethyl)morpholine) have been tested clinically as hypoxic cell radiosensitizers, mainly outside Japan. To determine if these sensitizers deserve clinical investigation in Japan, we reevaluated the radiosensitizing effects of these compounds in vitro and in vivo, in comparison with a fluorinated 2-nitroimidazole derivative KU-2285 (N1-(2-hydroxyethyl)-1,2-difluoro-3-(2-nitro-1 H-1-midazolyl)propanamide). KU-2285 is a known and established radiosensitizer, but is not suitable for clinical studies because of the high cost of synthesis. In vitro, the radiosensitizing effects of the three compounds on SCCVII (squamous cell carcinoma line in C3H mice) tumor cells were examined at 0.5 and 1 mM under aerobic or hypoxic conditions, using a colony assay. In vivo, SCCVII tumors grown subcutaneously in the hind legs of C3H/HeN mice were irradiated with or without prior intraperitoneal administration of 100, 200 or 400 mg/kg of the drugs. Thereafter, tumor growth delay was measured. In vitro, no sensitizing effect was observed under aerobic conditions at 1 mM. Under hypoxic conditions, the sensitizer enhancement ratio (SER) determined at 1% cell survival level for sanazole, nimorazole and KU-2285 was 1.55, 1.45 and 1.95, respectively, at 1 mM, and 1.40, 1.40 and 1.75, respectively, at 0.5 mM. In vivo, all three compounds had significant radiosensitizing effects; their effects appeared to decrease in the order of KU-2285, sanazole, and nimorazole. It was suggested that sanazole may be more suitable for clinical trials than nimorazole.

Treatment of head and neck cancer with CHART and nimorazole: phase II study.

BACKGROUND AND PURPOSE: Causes of failure of radiotherapy in squamous cell carcinoma of the head and neck probably include repopulation and hypoxia. Very accelerated schedules such as continuous hyperfractionated accelerated radiation therapy (CHART) overcome the repopulation problem but allow limited time for reoxygenation, so a hypoxic-cell sensitizer may be especially beneficial. Nimorazole is the only such agent to have shown a significant effect in a randomized controlled trial in head and neck cancer. Accordingly we studied the combination of CHART and nimorazole. METHODS: Sixty-one patients with advanced stage III (21) or IV (40) squamous cell carcinoma of the head and neck unsuitable for surgery were treated in a phase II study of the combination. The radiation dose was 56.75 Gy in 36 fractions in 12 consecutive days. Nimorazole was administered orally or enterally 90 min before radiotherapy at a dose of 1.2, 0.9, and 0.6 g/m(2) with the first, second and third daily fractions, respectively. This dosage consistently yielded plasma concentrations above 30 microg/ml. RESULTS: All the patients have been followed for a minimum of 2 years since treatment. Loco-regional control at 2 years is 55%, stage III 62% and stage IV 50%. Normal tissue effects were the same as those previously seen with CHART, except for a possible slight increase in acute skin reaction. Nimorazole toxicity was somewhat greater than with once daily administration in previous studies. Grade 3 nausea or vomiting occurred in 22% of patients. Two patients developed grade 1 peripheral neuropathy, and one patient died during treatment of encephalopathy, which was probably an idiosyncratic reaction to the drug. CONCLUSIONS: Local control rates are higher than those previously seen with CHART, suggesting a positive effect of nimorazole. Further studies of hypoxia-modifying agents with accelerated radiotherapy are warranted, and nimorazole is the simplest of these.

A gardnerellose clínica / Clinical gardnerella infection

Os autores estudaram um grupo de 492 mulheres adultas, näo grávidas, todas em clínica privada e que haviam se queixado, basicamente, de corrimento com odor fétido. A hipótese de contaminaçäo vaginal por Gardnerella foi levantada e confirmada através de colposcopia (fina colpite), colpocitologia e bacterioscopia do conteúdo vaginal. Do grupo em estudo, 117 pacientes receberam o mesmo tratamento com dose única de 2g de nimorazol VO (casal) e 10 comprimidos vaginais contendo nimorazol, cloranfenicol e nistatina. Um dos critérios de cura foi clínico, pela constataçäo do desaparecimento do sintoma maior: o odor fétido. No grupo tratado, obtivemos 63, 24 por cento de cura, sendo que 36, 75 por cento das pacientes do grupo de 117 foram tratadas mas näo voltaram para o diagnóstico citológico de cura. O presente estudo visa chamar a atençäo do médico para a gardnerellose como DST, valorizando a queixa de odor fétido nas secreçöes genitais, já que ela estava presente em 100 por cento das pacientes em estudo.

Low concentrations of nitroimidazoles: effective radiosensitizers at low doses.

PURPOSE: There have been various reports that nitroimidazole radiosensitizers are less effective modifiers of radiation response in the clinically relevant x-ray dose regions (0-4 Gy) than they are at doses used in classical in vitro experiments. Our studies at low concentrations of etanidazole led us to question this generalization, and our purpose was to further investigate low concentrations at low doses, using the microscopic location of cells to facilitate these experiments. The observations are compared with data on these drugs in the literature using other methods and systems. METHODS AND MATERIALS: Survival of V79 cells after irradiation in hypoxia +/- drug at various concentrations was assessed using the Cell Analyser (DMIPS) for low doses, in comparison with the standard clonogenic assay (higher doses). Enhancement ratios (ERs) were calculated at 80% and 2% survival, respectively. RESULTS: Etanidazole (SR-2508) consistently gave higher ERs at low doses (measured at 80% survival) than at high doses (survival 2%), when cells were exposed to drug concentrations below approximately 2 mM (e.g., at 1 mM, ER80% = 2.2, ER2% = 1.8 in CHO cells after 1 h preincubation at 37 degrees C). Preincubation of cells for 1 h or 15 min at 37 degrees C with etanidazole prior to irradiation increased the ERs at high and low doses but did not change the "cross-over" behavior (ER80% > ER2% at low concentrations, ER2% > ER80% above 2 mM, regardless of pretreatment at 37 degrees C or cell line, CHO and V79 cells), whereas the 5-nitroimidazole nimorazole consistently gave the same ERs whether determined at high or low radiation doses (e.g., at 1 mM, 1 h preincubation at 37 degrees C ER80% = ER2% = 1.3). This crossover behavior also occurred after irradiation/preincubation at 0 degrees C. The 2-nitroimidazole predecessor, misonidazole, shows the same cross-over behavior. CONCLUSION: Two nitroimidazoles at low concentrations appear to be as effective sensitizers (or better) at low doses (80% S); at high doses (2% S).

The comparison of the efficacy among three different nimorazole regimens in the treatment of bacterial vaginosis.

The efficacy of 3 different nimorazole regimens in treating bacterial vaginosis in women was evaluated. The regimens consisted of: Nimorazole 2 g single dose (Group I), 1 g per day for 3 days (Group II), and 1 g per day for 7 days (Group III) orally. In a simple randomized trial of 90 cases (30 cases in each group) with demonstrated clinical bacterial vaginosis on the presence of 3 of 5 of the following signs: (1) Characteristic thin homogenous discharge; (2) vaginal pH greater than 4.5; (3) release of a fishy amine odor from vaginal fluid mixed with 10% KOH; (4) presence of clue cells (usually representing at least 20% of vaginal epithelial cells); and (5) vaginal fluid contains few or no lactobacilli. Cure rates for bacterial vaginosis by nimorazole were 70.0% (21/30), 83.3% (25/30), and 90.0% (27/30) in Group I, II, and III, respectively. Thus nimorazole is another effective drug for the treatment of bacterial vaginosis.

Rapid eradication of trichomonads by single-dosed nimorazole.

Previous in vitro studies demonstrated the rapidity of trichomonacidal action of nimorazole (Naxogin 500) which was twice that of metronidazole and many times that of tinidazole. Since rapid eradication of parasites can lead to a significant decrease in transmission rate, and hence, a lower prevalence of this sexually transmitted disease, a pilot study was designed to investigate the in vivo speed of action of nimorazole. Twenty females with positive wet smears for trichomonas vaginalis were treated with a single 2 gram-dose of nimorazole orally. Without any antiseptics, specimens of vaginal discharge were collected at 0 hour (before treatment), 3, 24 and 72 hours for parasite count and culture. After a single treatment with 2 g of nimorazole the cure rate was 65 per cent at 3 hours and 100 per cent at all points thereafter. The result of this pilot study supports previous in vitro findings that nimorazole rapidly eradicates vaginal parasites.

Comparative study of aminosidine, etophamide and nimorazole, alone or in combination, in the treatment of intestinal amoebiasis in Kenya.

417 patients suffering from intestinal amoebiasis were randomly allocated to 6 different treatment groups in a controlled study in 3 District Hospitals in Kenya. The patients received either aminosidine (A), etophamide (E), nimorazole (N), or the combinations NA, NE, EA. Treatment in all cases was given twice daily for 5 days. Before and after treatment, rectosigmoidoscopy was done in each patient, and stool examination with characterization of invasive (IF) and non invasive (NIF) forms of amoeba was done daily throughout treatment, and on Days 15, 30 and 60 of follow-up. Clinical cure was good after all the treatments, varying from 90 to 100%; parasitological cure at the end of treatment was 100% in the NA and EA treatments groups, and 98% in A group. The incidence of relapses was nil in the EA group, followed by 3% in NA and 6% in A groups. Anatomical cure (healing of ulcers) was 97.8% in the NA group, 95.5% in the N group and 88.5% in the A group. Drug tolerance was excellent or good after all the treatments, except that the EA combination produced diarrhoea in 76.5% of patients. Overall analysis of the findings, including tolerance of the various treatments, showed that aminosidine either alone or in combination with nimorazole gave the best results. Ulcers seen on rectosigmoidoscopy were more common in patients excreting invasive forms of amoebae in their stools.

Efficacy of various drugs for treatment of giardiasis. A comparative study.

A total of 172 patients with giardiasis were treated with four of the drugs most commonly used for this infection. All drugs were used in their usual posologic schedules. The cure rates achieved with furazolidone, nimorazole, metronidazole, and tinidazole were; respectively, 72%, 94%, 87%, and 97%, while in a control group given no medication stools of only 35% of the patients became negative. Side effects were of minor importance in patients treated with nimorazole and metronidazole, and were somewhat more frequent and severe in those treated with furazolidone. Tinidazole produced no side effects.