Nationwide randomised trial evaluating elective neck dissection for early stage oral cancer (SEND study) with meta-analysis and concurrent real-world cohort.

BACKGROUND: Guidelines remain unclear over whether patients with early stage oral cancer without overt neck disease benefit from upfront elective neck dissection (END), particularly those with the smallest tumours. METHODS: We conducted a randomised trial of patients with stage T1/T2 N0 disease, who had their mouth tumour resected either with or without END. Data were also collected from a concurrent cohort of patients who had their preferred surgery. Endpoints included overall survival (OS) and disease-free survival (DFS). We conducted a meta-analysis of all six randomised trials. RESULTS: Two hundred fifty randomised and 346 observational cohort patients were studied (27 hospitals). Occult neck disease was found in 19.1% (T1) and 34.7% (T2) patients respectively. Five-year intention-to-treat hazard ratios (HR) were: OS HR = 0.71 (p = 0.18), and DFS HR = 0.66 (p = 0.04). Corresponding per-protocol results were: OS HR = 0.59 (p = 0.054), and DFS HR = 0.56 (p = 0.007). END was effective for small tumours. END patients experienced more facial/neck nerve damage; QoL was largely unaffected. The observational cohort supported the randomised findings. The meta-analysis produced HR OS 0.64 and DFS 0.54 (p < 0.001). CONCLUSION: SEND and the cumulative evidence show that within a generalisable setting oral cancer patients who have an upfront END have a lower risk of death/recurrence, even with small tumours. CLINICAL TRIAL REGISTRATION: NIHR UK Clinical Research Network database ID number: UKCRN 2069 (registered on 17/02/2006), ISCRTN number: 65018995, ClinicalTrials.gov Identifier: NCT00571883.

Health risks information reaches secondary school smokers.

This cross-sectional study aimed to assess smoking prevention and cessation education delivered as part of the UK National Curriculum and to evaluate the relative effectiveness of health, social influence and other/non-health components. In all, 1789 students aged 11-15 from 12 secondary schools completed online surveys assessing smoking status, factors known to be related to smoking and experience of smoking education. A total of 1421 of 1722 (83%) students remembered some school-based education. Of these, 803 (57%) said that the lessons changed their ideas about smoking. Multinomial logistic regression was used to assess whether lesson recall was associated with smoking status in a model adjusting for age, gender, ethnicity, family and best friend smoking status, socioeconomic status, and school. Quitters were more likely than smokers to report having changed their ideas about smoking as a result of a lesson (OR 5.78, 95% CI 2.44-13.72). The relative effectiveness of 16 lesson themes was assessed. Significantly more students changed their ideas about smoking as a result of 'health' compared with 'social influence' (chi(2) (1) 124.0, P < 0.001) or 'other/non-health' (chi(2) (1) 63.16, P < 0.001) topics. Mouth cancer was the most effective health topic and may provide a suitable model for both smoking and risky drinking prevention.

Suppression of the histamine-induced wheal and flare response by fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily and placebo in healthy Japanese volunteers.

BACKGROUND: The effects of the selective H1-receptor antagonist fexofenadine have been widely demonstrated in Western populations; however, to date, limited data comparing the effects of fexofenadine with other antihistamines have been reported in Japanese subjects. OBJECTIVE: To investigate the effect of fexofenadine and loratadine on the histamine-induced cutaneous wheal and flare response in healthy Japanese volunteers. METHODS: Eighteen healthy male and female Japanese volunteers aged 20-53 years were randomized to receive fexofenadine HCl 60 mg twice daily, loratadine 10 mg once daily or placebo in a 1-day, three-period, double-blind, crossover study. For each treatment, the wheal and flare response to 100 mg/mL histamine was assessed at baseline and at 1, 1.5, 2, 2.5, 3, 3.5, 4, 8, 12 and 24 hours post-dose. Blood samples were taken for pharmacokinetic analysis. RESULTS: Fexofenadine produced significantly greater percentage suppression of the overall wheal response compared with placebo and loratadine (43.1% versus 10.0% and 15.2%, respectively; p < 0.001). Similarly, fexofenadine significantly suppressed the overall flare response compared with placebo and loratadine (43.0% versus 3.5% and -8.9%, respectively; p < 0.01). Loratadine was statistically no different from placebo in terms of both overall wheal and flare suppression. Area under the curve analysis for wheal and flare reduction (0-12 hours post-dose) confirmed these findings. For wheal inhibition, fexofenadine had a significantly faster onset of action (defined as time to > or = 35% inhibition) compared with placebo (p < 0.001) and loratadine (p < 0.01); for flare, fexofenadine had a significantly faster onset of action than loratadine (p < 0.01). Mean maximum inhibition (the mean of the greatest inhibition achieved from baseline for each treatment) for wheal was achieved significantly faster with fexofenadine than loratadine (p < 0.01), and fexofenadine had a significantly longer duration of effect on suppressing wheal and flare compared with placebo and loratadine (p < 0.05 for all). The antihistamine effects of fexofenadine correlated significantly with its Cmax, while loratadine activity did not correlate significantly with its plasma levels. CONCLUSIONS: Fexofenadine is a potent suppressor of the histamine-induced wheal and flare response in healthy Japanese volunteers. These results support findings in Caucasian subjects, and confirm that fexofenadine has greater antihistaminergic activity than loratadine in this human model.

A double-blind, placebo- and positive-internal-controlled (alprazolam) investigation of the cognitive and psychomotor profile of pregabalin in healthy volunteers.

RATIONALE: Pregabalin potently and selectively binds to the alpha(2)-delta subunit of voltage-dependent calcium channels, reducing calcium influx and modulating release of downstream excitatory neurotransmitters, such as glutamate. Pregabalin has demonstrated robust efficacy for several disease states, but its neuropharmacology is still being elucidated. OBJECTIVE: This study was conducted to evaluate the cognitive and psychomotor effects of oral pregabalin (150 mg t.i.d.) using alprazolam (1 mg t.i.d.) as a positive internal control and placebo. METHODS: Twenty-four healthy volunteers were randomised to a double-blind, three-way crossover study. Each period consisted of 3-day double-blind treatment followed by 1 day of single-blind placebo. Psychometrics included tests of Choice Reaction Time (CRT), CNS arousal (Critical Flicker Fusion, CFF), vigilance (Rapid Visual Information Processing, RVIP), serial memory scanning (Sternberg Short-Term Memory Scanning Test, STM), divided attention (Compensatory Tracking Task, CTT), Brake Reaction Time (BRT) in an on-the-road vehicle, and subjective Line Analogue Rating Scales (LARS) for sedation. RESULTS: Pregabalin showed no significant effects on the objective psychometrics-CRT, BRT, RVIP, STM-compared with placebo. Pregabalin produced a limited, significant decrement on CFF and CTT and a significant effect on the LARS. Pregabalin was associated with improvement relative to placebo in BRT. The positive control, alprazolam, produced significant impairment on all objective measures and significant impairment on the LARS, thus establishing the sensitivity of the test battery used in the study. CONCLUSIONS: Pregabalin did not differ on most assessments from placebo, producing only minor, transient impairment on some objective cognitive and psychomotor measures, suggesting a relatively benign CNS side-effect profile.

Effects of fexofenadine and hydroxyzine on brake reaction time during car-driving with cellular phone use.

Antihistamines are a mainstay treatment for allergic rhinitis; however, many older agents cause adverse events, including sedation and central nervous system (CNS) impairment. Research has shown sedating effects of antihistamines on driving; currently, no known study has examined whether cellular phone usage while driving further compounds impairment in individuals administered antihistamines. The aim of this study was to examine this endpoint. In a randomized, double-blind, placebo-controlled, three-way crossover study, healthy volunteers received fexofenadine HCl 120 mg, hydroxyzine HCl 30 mg and placebo. Brake reaction time (BRT) was used to examine driving performance across four conditions: driving only; driving while completing simple calculations; complex calculations; and conversing on a cellular phone. Subjective sedation assessments were also conducted. Brake reaction time with and without cellular phone usage in fexofenadine-treated subjects did not differ significantly from placebo in any condition. In contrast, hydroxyzine-treated subjects were significantly more sedated and had slower BRTs, suggesting slower hazard recognition and brake application, compared with the fexofenadine and placebo groups in all conditions. Importantly, cellular phone operation was an additive factor, increasing BRTs in hydroxyzine-treated volunteers. Fexofenadine did not impair CNS function in subjects involved in a divided attention task of driving and cellular phone operation.

A single-center, randomized, double-blind, placebo-controlled, crossover investigation of the effects of fexofenadine hydrochloride 180 mg alone and with alcohol, with hydroxyzine hydrochloride 50 mg as a positive internal control, on aspects of cognitive and psychomotor function related to driving a car.

BACKGROUND: Antihistamines (H(1)-receptor antagonists) are the mainstay of symptomatic therapy for allergic disorders. Antihistamines are needed that cause no disruptive effects on cognitive and psychomotor function. It is essential that antihistamines maintain the integrity of the cognitive system, not only in ambulatory patients at increased risk of drug-induced traffic- or work-related accidents, but also in students and others whose cognitive or intellectual impairment may adversely affect their performance.Objective; The goal of this study was to investigate the acute effects of fexofenadine hydrochloride 180 mg, alone and with a "social" dose of alcohol, on subjective feelings of sedation and on a battery of objective measures related to driving a car. These measures included information processing, psychomotor speed, and reaction time in an on-the-road car-driving task. Hydroxyzine hydrochloride 50 mg was included in the study as a positive internal control to validate the sensitivity of the psychometri tests to nonspecific impairment. METHODS: In this randomized, double-blind, 6-way, crossover study conducted at the Human Psychopharmacology Research Unit, Medical Research Centre (University of Surrey, Guildford, United Kingdom), 18 healthy volunteers received fexofenadine 180 mg, hydroxyzine 50 mg, and placebo alone and with alcohol (0.3 g/kg body weight or approximately 0.43-0.50 g/L blood-alcohol concentration). Treatment periods were separated by a washout period of at least 6 days. Subjects performed tests of cognitive and psychomotor performance at 1, 3, and 5 and hours after dosing. The test battery included subjective ratings of sedation, critical flicker fusion (CFF), choice reaction time (including recognition reaction time [RRT], motor reaction time [MRT], total reaction time [TRT], and brake reaction time [BRT]. RESULTS: Eighteen healthy male volunteers (median age, 30.5 years [range, 23-44 years]) were entered into the study. Fexofenadine alone and with alcohol had no significant effect on performance compared with placebo and was not distinguishable from placebo in any of the objective or subjective tests at any point. However, impairment was evident following the administration of hydroxyzine. Hydroxyzine caused significant impairment in CFF (P < 0.05), RRT (P < 0.001), and TRT (P < 0.001) compared with placebo. Hydroxyzine with alcohol significantly disrupted performance on all of the above measures with respect to both placebo and fexofenadine (P < 0.05) as well as MRT (P < 0.001). No significant treatment effects on BRT were found. CONCLUSION: Fexofenadine 180 mg did not have disruptive effects on objective measures related to driving a car and aspects of psychomotor and cognitive function, even when combined with a dose of alcohol equivalent to 0.3 g/kg body weight, in a study in which the psychometric assessments were shown to be sensitive to impairment.

The effects of carbon dioxide in champagne on psychometric performance and blood-alcohol concentration.

AIMS: To assess the effects of carbon dioxide (CO(2)) in champagne on psychomotor performance and blood-alcohol concentration (BAC). METHODS: Twelve subjects consumed ethanol (0.6 g/kg body weight) served as champagne or champagne with the CO(2) removed, in a crossover study. RESULTS: Champagne produced significantly greater BACs and significantly increased reaction times in a divided attention task, than degassed champagne. CONCLUSIONS: The CO(2) in champagne may accelerate absorption of alcohol, leading to more rapid or severe intoxication.

The effects of acute doses of fexofenadine, promethazine, and placebo on cognitive and psychomotor function in healthy Japanese volunteers.

BACKGROUND: Genetic variations in cross-cultural metabolic capability may attenuate the lack of central nervous system effects of fexofenadine. OBJECTIVE: To compare the pharmacodynamics of fexofenadine and promethazine versus placebo in Japanese volunteers. METHODS: In this randomized, crossover, double-blind study, 24 subjects received single doses of fexofenadine 60 mg and 120 mg, promethazine 25 mg, and placebo, with a 6-day washout period between treatments. Objective measures included critical flicker fusion, choice reaction time, and a compensatory tracking task. A line analog rating scale evaluated self-rated sedation. A rapid visual information-processing task evaluated vigilance at baseline and at 2 hours. RESULTS: Fexofenadine was not significantly different from placebo on any test at any timepoint. In contrast, promethazine impaired critical flicker fusion thresholds (F[3,63] = 5.37, P = 0.0023); increased recognition reaction time (F[3,63] = 13.63, P < 0.0001) and total reaction time (F[3,63] = 12.23, P < 0.0001) components of the choice reaction time test; reduced tracking accuracy (F[3,63] = 14.25, P < 0.0001) and increased reaction times to peripheral stimuli (F[3,63] = 9.29, P < 0.0001) in the compensatory tracking task; reduced the number of valid responses (F[3,63] = 14.86, P < 0.0001) and impaired reaction times (F[3,63] = 12.02, P < 0.0001) in the rapid visual information-processing task test; and impaired subjective ratings of sedation (F[3,63] = 7.55, P = 0.0002), compared with placebo. CONCLUSIONS: A battery of tests sensitive to impairment by promethazine failed to show any negative cognitive or psychomotor effects with fexofenadine 60 and 120 mg. Fexofenadine is an intrinsically non-impairing antihistamine in Japanese subjects.