Establishment of four head and neck squamous cell carcinoma cell lines: importance of reference DNA for accurate genomic characterisation.

OBJECTIVE: There is significant interest in developing early passage cell lines with matched normal reference DNA to facilitate a precision medicine approach in assessing drug response. This study aimed to establish early passage cell lines, and perform whole exome sequencing and short tandem repeat profiling on matched normal reference DNA, primary tumour and corresponding cell lines. METHODS: A cell culture based, in vitro study was conducted of patients with primary human papillomavirus positive and human papillomavirus negative tumours. RESULTS: Four early passage cell lines were established. Two cell lines were human papillomavirus positive, confirmed by sequencing and p16 immunoblotting. Short tandem repeat profiling confirmed that all cell lines were established from their index tumours. Whole exome sequencing revealed that the matched normal reference DNA was critical for accurate mutational analysis: a high rate of false positive mutation calls were excluded (87.6 per cent). CONCLUSION: Early passage cell lines were successfully established. Patient-matched reference DNA is important for accurate cell line mutational calls.

Anterolateral thigh butterfly free flap for reconstruction of laryngopharyngeal defect: surgical considerations.

BACKGROUND: Reconstruction of a pharyngoesophageal defect remains a challenging problem, especially with involvement of the neck skin. This study aimed to demonstrate the surgical technique of utilising a butterfly modification of the anterolateral thigh flap. RESULTS: Reconstruction of the pharyngoesophageal defect was accomplished using the butterfly modification of the anterolateral thigh free flap. The flap was tubed on the leg while still being attached to the pedicle, to minimise the ischaemia time. CONCLUSION: Butterfly anterolateral thigh free flap allows for multi-layer closure of the neopharynx and can be utilised for reconstruction of pharyngoesophageal and neck skin defects.

Surgical management of advanced pleomorphic dermal sarcoma of the occipital scalp.

Pleomorphic dermal sarcoma is a rare neoplasm of mesenchymal origin that most commonly affects the head. We describe the presentation of a 61-year-old man with a 10-week history of an exophytic lesion affecting the occipital scalp, demonstrating rapid growth. The final histopathology revealed a completely excised 9cm pleomorphic dermal sarcoma (pT2aN0M0, Stage 3), one of the largest such lesions reported in the literature to date. This patient's management involved a wide local subperiosteal excision onto the cranium, with a reconstruction with an Integra dermal regeneration template (Integra LifeSciences, Princeton, NJ, USA) and healing with secondary intention. This was mainly due to poorly defined clinical margins on primary excision, the potential for further excision of involved margins (later confirmed as not needed) and the patient's comorbidities, making a return to theatre for definitive reconstruction undesirable.

Closure of tracheocutaneous fistula using prefabricated conchal bowl cartilage and a supraclavicular flap.

BACKGROUND: Tracheocutaneous fistula represents one of the most troublesome complications of prolonged tracheostomy. Simple closure of a fistula can be ineffective, particularly in the context of prior surgery and adjuvant radiation. As such, modes of repair have expanded to include locoregional flaps and even free tissue transfers. OBJECTIVE: This paper describes a case of persistent tracheocutaneous fistula in an irradiated patient who had undergone previous unsuccessful attempts at repair. METHOD AND RESULTS: The use of regional fasciocutaneous supraclavicular flap with prefabricated conchal bowl cartilage resulted in successful closure of the tracheocutaneous fistula. CONCLUSION: This represents a novel technique for closure of such fistulas in patients for whom previous attempts have failed. This mode of repair should be added to the surgeon's repertoire of reparative techniques.

Sunitinib in metastatic renal cell carcinoma: Experience from single center study, efficacy and safety.

BACKGROUND: The 5-year survival rate for metastatic renal cell carcinoma (RCC) is estimated to be <10%. RCC is highly resistant to chemotherapy. Targeted agents are now first choice of therapy for metastatic RCC such as sunitinib and sorafenib. METHODS: This study is a retrospective analysis of 15 patients having metastatic RCC treated with sunitinib. Apart from three patients, all had clear cell histology. Thirteen patients received dosage of 50 mg/d (4 weeks on/2 weeks off cycles). In 14 patients sunitinib was used as 1st line. The primary end point was objective response rate. Secondary end points were progression free survival (PFS) and safety. RESULTS: Until date of reporting, 3 out of 15 patients are currently on sunitinib. The most common Memorial Sloan = Kettering Cancer Centre poor prognostic factor was an interval of <1 year between diagnosis and starting of treatment (80%). The objective response rate was 13.66% (complete response [CR] + partial response [PR] = 0 + 2). Clinical benefit rate (CR + PR + stable disease) was 60% (n = 9). Median PFS in this study was 7.5 months, with a range of 2-22 month. Median overall survival (OS) of patients in this study was 12 months with a range of 3-24 month. An impact of the dose or/and number of cycles on response was seen in this study, with patients having average cycles >3 showing better response rates, PFS and OS. Major toxicities seen were fatigue ( n= 7), diarrhea (n = 3) and skin rash (n = 4) with majority patients experienced Grade 1-2 toxicities. While Grade 3-4 toxicities include fatigue (n = 1), mucositis (n = 1) and nausea (n = 1). CONCLUSIONS: These results confirm efficacy and safety profile of sunitinib in metastatic RCC, particularly as a first line. Sunitinib produced a 60% disease control rate for metastatic RCC in Indian patients, with acceptable rates of toxicity at a dose of 50 mg daily. Response rates were well matched to other studies confirming the efficacy of sunitinib.

Genital tuberculosis: Comparative study of the diagnostic modalities.

BACKGROUND: Genital tuberculosis (GTB) is one of the major causes for severe tubal disease leading to infertility. Unlike pulmonary tuberculosis (TB), the clinical diagnosis of GTB is difficult because in the majority of cases the disease is either asymptomatic or has varied clinical presentation. Routine laboratory tests are of little value in the diagnosis. The objective of this study was to compare the modalities of polymerase chain reaction (PCR) technique, acid fast bacilli (AFB) culture and AFB staining. MATERIALS AND METHODS: The women visiting in vitro fertility center during December 2012 and May 2013 were included in this study. A total of 227 aseptically collected endometrial tissue samples were processed. AFB staining, AFB culture and PCR were carried out using standard procedures. RESULT: Out of 227 patients suspected of GTB, 133 were found to be positive either by AFB smear microscopy, culture or PCR. Out of 133 samples, two samples (1.5%) were found to be positive by all three methods, i.e. microscopy, culture and PCR, 11 (4.8%) were found to be positive by both PCR and culture, whereas 126 (86%) samples were found to be positive only by PCR. The PCR has failed to detect seven cases that were positive by conventional culture method. CONCLUSION: Our study showed that the conventional methods of diagnosis like microscopy and culture are less sensitive when compared with PCR. PCR also helped in early diagnosis of infection. However simultaneously, false negative results were an important limitation of this method. PCR negative samples were found to be positive by culture methods. Deoxyribose nucleic acid PCR is not reliable for TB due to false positive or negative result. Thus, we suggest both culture and PCR as important diagnostic methods for detection of GTB.

Diffusion-weighted MRI "claw sign" improves differentiation of infectious from degenerative modic type 1 signal changes of the spine.

BACKGROUND AND PURPOSE: Modic type 1 degenerative signal changes can mimic/suggest infection, leading to additional costly and sometimes invasive investigations. This retrospective study analyzes the utility and accuracy of a novel, diffusion-weighted "claw sign" for distinguishing symptomatic type 1 degeneration from vertebral diskitis/osteomyelitis. MATERIALS AND METHODS: Seventy-three patients with imaging features resembling type 1 degeneration were classified clinically into 3 groups: true degenerative type 1 changes (n = 33), confirmed diskitis/osteomyelitis (n = 20), and radiologically suspected infection later disproved clinically (n = 20). A claw sign was defined on DWI as well-marginated, linear, regions of high signal situated within the adjacent vertebral bodies at the interface of normal with abnormal marrow. Two blinded neuroradiologists independently rated the presence of the claw sign, along with T2 disk signal and disk and endplate enhancement to determine the utility of each for identifying degeneration versus infection. RESULTS: When the 2 neuroradiologists identified a definite claw, 38 of 39 patients (97%) and 29 of 29 patients (100%) proved to be infection-free. When the readers identified a probable claw, 14 of 14 patients (100%) and 16 of 19 patients (84%) proved to be infection-free. Conversely, when the readers identified the absence of claw sign (diffuse DWI pattern), there was proved infection in 17 of 17 cases (100%) and 13 of 14 cases (93%). CONCLUSIONS: In patients with type 1 signal changes of the vertebral disk space, a claw sign is highly suggestive of degeneration and its absence strongly suggests diskitis/osteomyelitis.

Effect of some ultraviolet light absorbers on photo-stabilization of azadirachtin-A.

The effect of photo-stabilization of Azadirachtin-A (Aza-A) was examined when exposed to sunlight and ultraviolet light in the presence of four structurally different ultraviolet stabilizers namely 4-aminobenzoic acid, 2,4-dihydroxybenzophenone, 4,4'-dihydroxybenzophenone and phenyl salicylate. The percentages of Aza-A recovered at different time intervals from slides exposed to different light conditions with and without UV stabilizers as well as kinetic studies indicated that the addition of phenyl salicylate in methanolic solution of Aza-A (in 1:1 mole ratio) provides the best photo-stabilization of Aza-A molecule among the four UV stabilizers studied.

Bioreductively-activated prodrugs for targeting hypoxic tissues: elimination of aspirin from 2-nitroimidazole derivatives.

2-Nitroimidazoles were synthesised substituted with aspirin or salicylic acid, as leaving groups linked through the (imidazol-5-yl)methyl position. Activation of aqueous solutions by CO2*- (a model one-electron reductant) resulted in release of aspirin or salicylate, probably via the 2-hydroxyaminoimidazole. The analogous 2-nitroimidazole with bromide as leaving group eliminated bromide in < 1 ms via the radical-anion.

Prodrugs for targeting hypoxic tissues: regiospecific elimination of aspirin from reduced indolequinones.

A series of regioisomeric derivatives of a 1-methylindole-4,7-dione were synthesised, substituted with a 2-acetoxybenzoate leaving group linked through the (indol-2-yl)methyl or (indol-3-yl)methyl (or propenyl) positions. Reductive elimination of the leaving group occurred from the (indol-3-yl)methyl derivatives but not the 2-substituted regioisomers, indicating that only the C-3 position may be utilised in bioreductively-activated drug delivery, which was demonstrated with an aspirin prodrug.

Comparison of bactericidal activities of intermittent and continuous infusion dosing of vancomycin against methicillin-resistant Staphylococcus aureus and Enterococcus faecalis.

STUDY OBJECTIVE: To describe the pharmacokinetic profiles of vancomycin administered by continuous infusion and intermittent dosing and compare the duration of activity of the regimens. DESIGN: Randomized, open-label, crossover study. SETTING: Clinical research center at an academic medical center. SUBJECTS: Twelve healthy, nonpregnant volunteers age 27.6 +/- 2.3 years. INTERVENTION: Subjects received the following intravenous vancomycin regimens: 1 g every 12 hours; 2 g continuous infusion over 24 hours; and 1 g continuous infusion over 24 hours. Dosages were administered with and without gentamicin 2 mg/kg. MEASUREMENTS AND MAIN RESULTS: Serum samples were collected, drug concentrations determined, and bactericidal activity measured against two isolates each of methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. Subjects had poor tolerability for continuous infusions. Trough concentration for the intermittent regimen was 5.5 +/- 1.9 mg/ml, and steady-state concentrations were 8.8 +/- 1.6 and 16.9 +/- 1.9 mg/ml for 1 and 2 g continuous infusions, respectively. In general, all regimens provided bactericidal activity throughout the study interval. Against one isolate of E. faecalis, 2 g continuous infusion plus gentamicin provided cidal activity for a significantly greater percentage of the dosing interval (p<0.001). CONCLUSION: Continuous infusion does not greatly improve the activity of vancomycin and should not be routinely administered. However, it may prove useful against isolates with reduced susceptibility to the agent.

Indolequinone bioreductive drugs: kinetic factors which influence selectivity for hypoxia.

The factors influencing the kinetics of the oxygen-sensitive reduction of indolequinones, including those bearing leaving groups in the (indol-3-yl)methyl position, have been studied. The hydroquinones derived from some representative indolequinones were found to autoxidize slowly in oxygenated solution at rates (effective rate constant with O2 approximately 40-300 M-1 s-1) that cannot compete with the reductive elimination of leaving groups. The rates of reaction between hydroquinone and O2 were even slower in the presence of approximately 4 microM superoxide dismutase (effective rate constant approximately 2-7 M-1 s-1), indicating the role of superoxide radicals in hydroquinone autoxidation. Since the release of the leaving groups from the hydroquinones is not significantly oxygen-sensitive, tumour selectivity requires specific reduction by enzymes that are overexpressed in some tumours. Conversely, the release of leaving groups from semiquinone radicals is inhibited by oxygen too efficiently unless the semiquinone reacts with targets on a timescale of milliseconds. Modification of redox properties has been explored with the aim of changing this oxygen sensitivity. The new 2-phenylindolequinones are approximately 60-100 mV higher in reduction potential than 2-alkyl derivatives but this is insufficient to decrease the rate of electron transfer from semiquinone to oxygen to a degree which might confer hypoxia-selective cytotoxicity. These results are discussed in the context of toxicity of EO9 and related compounds towards hypoxic rather than anoxic cells.

Indolequinone antitumor agents: reductive activation and elimination from (5-methoxy-1-methyl-4,7-dioxoindol-3-yl)methyl derivatives and hypoxia-selective cytotoxicity in vitro.

A series of indolequinones bearing a variety of leaving groups at the (indol-3-yl)methyl position was synthesized by functionalization of the corresponding 3-(hydroxymethyl)indolequinone, and the resulting compounds were evaluated in vitro as bioreductively activated cytotoxins. The elimination of a range of functional groups-carboxylate, phenol, and thiol-was demonstrated upon reductive activation under both chemical and quantitative radiolytic conditions. Only those compounds which eliminated such groups under both sets of conditions exhibited significant hypoxia selectivity, with anoxic:oxic toxicity ratios in the range 10-200. With the exception of the 3-hydroxymethyl derivative, radiolytic generation of semiquinone radicals and HPLC analysis indicated that efficient elimination of the leaving group occurred following one-electron reduction of the parent compound. The active species in leaving group elimination was predominantly the hydroquinone rather than the semiquinone radical. The resulting iminium derivative acted as an alkylating agent and was efficiently trapped by added thiol following chemical reduction and by either water or 2-propanol following radiolytic reduction. A chain reaction in the radical-initiated reduction of these indolequinones (not seen in a simpler benzoquinone) in the presence of a hydrogen donor (2-propanol) was observed. Compounds that were unsubstituted at C-2 were found to be up to 300 times more potent as cytotoxins than their 2-alkyl-substituted analogues in V79-379A cells, but with lower hypoxic cytotoxicity ratios.

Oxidative denitrification of the antitumour drug hydroxyguanidine.

The oxidative denitrification of the antitumour agent hydroxyguanidine (HOG) has been investigated by radiolysis methods and EPR spectroscopy. The azide radical (N3.), a model one-electron oxidant, reacts with HOG with the rate constant 5.1 x 10(9) dm3 mol(-1) s(-1) to yield the guanidino carbon-centred radical (HOG.) which rapidly eliminates nitric oxide (k = 3.1 x 10[3] s[-1]) with the concomitant formation of urea. The HOG. undergoes conjugation with molecular oxygen to form a peroxyl radical (HOGOO.) with a rate constant 8.8 x 10(8) dm3 mol(-1) s(-1). The HOGOO. radical also eliminates nitric oxide but may act as a precursor to the peroxynitrite (ONOO-) ion. The oxidation of HOG by the dibromide radical (Br2.-) was found to release nitric oxide with a yield of 95% relative to Br2.- as determined from the combined yields of inorganic nitrite, nitrate and a HOG/nitric oxide-adduct. This study provides a possible mechanistic basis for the oxidative denitrification of HOG which may contribute to the observed toxicity of the drug both in vitro and in vivo and for the oxidation of nonphysiological hydroxyguanidines to NO. via nitric oxide synthase-independent pathways.

Influence of piperacillin-tazobactam on pharmacokinetics of gentamicin given once daily.

The effect of piperacillin-tazobactam on the pharmacokinetics of gentamicin given once daily was studied. Healthy adult volunteers each received four drug regimens in randomized order: gentamicin 7 mg/kg i.v. once daily (1) by itself, (2) with piperacillin 4 g and tazobactam 0.5 g (both as the sodium salt) every six hours i.v., (3) with piperacillin 4 g and tazobactam 0.5 g i.v. every eight hours, and (4) with piperacillin 8 g and tazobactam 1 g by continuous i.v. infusion over 24 hours. All the gentamicin doses were infused over 30 minutes two hours after piperacillin-tazobactam. Blood samples were drawn before and at the end of each gentamicin infusion and at intervals up to 12 hours after the start of each gentamicin infusion. Samples were assayed for gentamicin concentration by an enzyme-multiplied immunoassay technique and for piperacillin and tazobactam concentrations by high-performance liquid chromatography. Six women and four men completed all four drug regimens. For the gentamicin-alone regimen, the mean +/- S.D. area under the concentration-versus-time curve was 78.06 +/- 10.28 micrograms/mL.hr, the mean +/- S.D. peak concentration (30 minutes after the end of an infusion) was 20.28 +/- 2.54 micrograms/mL, and the mean +/- S.D. half-life was 2.41 +/- 0.24 hours. The values for gentamicin alone did not differ significantly from those for gentamicin in any of the combination regimens. Coadministration of once-daily gentamicin and piperacillin-tazobactam in various i.v. infusion regimens did not affect the pharmacokinetics of once-daily gentamicin.

Oral bioavailability and pharmacokinetics of ciprofloxacin in patients with AIDS.

Few reports on the effects of AIDS on the absorption of orally (p.o.) administered agents exist. To help fill this informational gap, we administered ciprofloxacin to 12 patients with AIDS by two dosing regimens (400 mg given intravenously [i.v.] and 500 mg given p.o. every 12 h) in a randomized, crossover fashion. Pharmacokinetic parameters were determined by noncompartmental methods. Mean values (+/- standard deviations [SD]) for p.o. ciprofloxacin were as follows: peak concentration of drug in serum (Cmax), 2.94 +/- 0.51 microg/ml; time to Cmax, 1.38 +/- 0.43 h; area under the concentration-time curve from 0 to 12 h (AUC(0-12)), 12.13 +/- 3.21 microg x h/ml; and half-life (t(1/2)), 3.86 +/- 0.48 h. Mean values (+/- SD) for i.v. ciprofloxacin were as follows: Cmax, 3.61 +/- 0.82 microg/ml; time to Cmax, 1.0 h; AUC(0-12), 11.92 +/- 2.92 microg x h/ml; and t(1/2), 3.98 +/- 0.94 h. The mean percent absolute bioavailability for ciprofloxacin was calculated to be 82% +/- 13%, similar to the value for healthy volunteers. We conclude that ciprofloxacin when administered p.o. to patients with AIDS is well absorbed, as evidenced by excellent bioavailability and is not affected by gastrointestinal changes in the absence of infectious gastroenteritis and severe diarrhea.

2-Cyclopropylindoloquinones and their analogues as bioreductively activated antitumor agents: structure-activity in vitro and efficacy in vivo.

A series of 2-cycloalkyl- and 2-alkyl-3-(hydroxymethyl)-1-methylindoloquinones and corresponding carbamates have been synthesized and substituted in the 5-position with a variety of substituted and unsubstituted aziridines. Cytotoxicity against hypoxic cells in vitro was dependent upon the presence of a 5-aziridinyl or a substituted aziridinyl substituent for 3-hydroxymethyl analogues. The activity of 5-methoxy derivatives was dependent upon the presence of a 3-(carbamoyloxy)methyl substituent. Increasing the steric bulk at the 2-position reduced the compounds' effectiveness against hypoxic cells. A 2-cyclopropyl substituent was up to 2 orders of magnitude more effective than a 2-isopropyl substituent, suggesting possible radical ring-opening reactions contributing to toxicity. Nonfused 2-cyclopropylmitosenes were more effective than related fused cyclopropamitosenes reported previously. The reduction potentials of the quinone/semiquinone one-electron couples were in the range -286 to -380 mV. The semiquinone radicals reacted with oxygen with rate constants 2-8 x 10(8) dm3 mol-1 s-1. The involvement of the two-electron reduced hydroquinone in the mediation of cytotoxicity is implicated. The most effective compounds in vitro were the 2-cyclopropyl and 5-(2-methylaziridinyl) derivatives, and of these, 5-(aziridin-1-yl)-2-cyclopropyl-3-(hydroxymethyl)-1-methylindole-4 ,7-dione (21) and 3-(hydroxymethyl)-5-(2-methylaziridin-1-yl)-1,2-dimethylindole+ ++-4,7-dione (54) were evaluated in vivo. Both compounds showed antitumor activity both as single agents and in combination with radiation, with some substantial improvements over EO9 (3) at maximum tolerated doses and as single agents against the RIF-1 tumor model and comparable efficacy in the KHT tumor model.

Comparative serum bactericidal activities of ceftizoxime and cefotaxime against intermediately penicillin-resistant Streptococcus pneumoniae.

In a randomized crossover study involving 12 healthy volunteers, 1 g of ceftizoxime or cefotaxime was administered intravenously every 12 h for a total of three doses on two separate weekends. The duration of serum bactericidal titers (SBTs) greater than 1:2 and the time serum drug concentrations remained above the MIC (T > MIC) were determined against three clinical isolates of Streptococcus pneumoniae with intermediate resistance to penicillin. The duration of SBTs and T > MIC for both antimicrobial agents exceeded 50% of the dosing interval for all isolates. Ceftizoxime's T > MIC was statistically greater than that of cefotaxime, indicating that its longer half-life in serum (1.7 h) compared with that of cefotaxime (approximately 1 h) compensates for its slightly lower microbiologic activity against the penicillin-resistant pneumococci tested in this study.

Comparison of bronchopulmonary pharmacokinetics of clarithromycin and azithromycin.

The bronchopulmonary and plasma pharmacokinetics of clarithromycin (CLA; 500 mg given twice daily for nine doses) or azithromycin (AZ; 500 mg for the first dose and then 250 mg once daily for four doses) were assessed in 41 healthy nonsmokers. Bronchoalveolar lavage was performed at 4, 8, 12, or 24 h after administration of the last dose. The concentrations (mean +/- standard deviation) of CLA, 14-hydroxyclarithromycin, and AZ were measured in plasma, epithelial lining fluid (ELF), and alveolar macrophage (AM) cells by high-performance liquid chromatography assay. The concentrations of CLA achieved in ELF were 34.02 +/- 5.16 micrograms/ml at 4 h, 20.63 +/- 4.49 micrograms/ml at 8 h, 23.01 +/- 11.9 micrograms/ml at 12 h, and 4.17 +/- 0.29 microgram/ml at 24 h, whereas at the same time points AZ concentrations remained below the limit of assay sensitivity (0.01 microgram/ml) for all but two subjects. The concentrations of CLA in the AM cells were significantly higher than those of AZ at 8 h (703 +/- 235 and 388 +/- 53 micrograms/ml, respectively). However, the ratio of the concentration in AM cells/concentration in plasma was significantly higher for AZ than for CLA for all time points because of the lower concentration of AZ in plasma. These results indicate that while AZ has higher tissue concentration to plasma ratios, as shown by other investigators, the absolute concentrations of CLA in AM cells and ELF are higher for up to 8 and 12 h, respectively, after administration of the last dose.

Chemical properties which control selectivity and efficacy of aromatic N-oxide bioreductive drugs.

Pulse radiolysis was used to generate radicals from one electron reduction of 1,2,4-benzotriazine-1,4-dioxides (derivatives of tirapazamine), and of imidazo [1,2-a]quinoxaline-4-oxides (analogues of RB90740), which have selective toxicity towards hypoxic cells. Radicals from the mono N-oxides (from the latter compounds) react with oxygen approximately 10-40 times faster than does the tirapazamine radical. Radicals from the tirapazamine analogues studied react with oxygen up to approximately 10 times slower than tirapazamine radicals. The quinoxaline N-oxide radicals are involved in prototropic equilibria with pK(a) values (5.5 to 7.4) spanning that reported for tirapazamine (6.0). Generation of radicals radiolytically in the presence of H donors (formate, 2-propanol, deoxyribose) indicate a chain reaction ascribed to H abstraction by the drug radical. The protonated drug radical is much more reactive than the radical anion (H abstraction rate constant approximately equal to 10(2) - 10(3) dm3 mol-1 s-1). Chain termination is ascribed to drug radical-radical reactions, i.e. radical stability in anoxia, with rate constants 2k approximately equal to 1 x 10(7) to 2 x 10(8) dm3 mol-1 s-1 at pH approximately 7.4. Estimates of the reduction potentials of the drug-radical couples in water at pH 7 for two of the mono-N-oxides were in the range-0.7 to 0.8 V vs NHE at pH 7.