Mechanism of action of antipruritic drugs.

Astemizole and terfenadine, two potent non-sedative H1 antihistamines, had no effect on itch measured objectively as nocturnal scratching and subjectively on a 10 cm line. Trimeprazine, however, a more sedative but less potent H1 antihistamine, was antipruritic, as was nitrazepam, a sedative benzodiazepine. We concluded (a) that antipruritic drugs act centrally by a property related to sedation; (b) H1 receptor antagonists have a peripheral antipruritic action only when itch is due to histamine release, as in the wealing disorders. Thus the new nonsedative H1 antihistamines have no place in the treatment of itch from other causes.     

Cognitive impairments among older drivers: medical examination and driving test

The aim of this study was to gain insight in the prevalence of cognitive impairments among active older drivers and in driving performance of cognitively impaired ones. The study was implemented in the existing Dutch relicensing procedure for older drivers and consisted of three evaluation moments: a medical screening (for all subjects), a neuropsychological assessment and a test-drive (for candidates with cognitive impairments). In total, 2992 drivers were medically evaluated. In 4% of cases indications for impaired cognitive functioning were observed that could be evaluated and confirmed with neuropsychological tests. Eighty subjects performed an on-road test. Of these subjects, 57% were allowed to renew their driver's license, while in the remaining 43% no new licenses or restricted licenses were issued. During the test-drive, slow reactions and attention deficits were the most important causes for impaired fitness to drive.     

Analysis of terfenadine in human plasma using microbore high-performance liquid chromatography–electrospray ionisation mass spectrometry

An assay based on combined microbore high-performance liquid chromatography–positive ion electrospray ionisation mass spectrometry with selected ion recording has been developed for the measurement of the antihistamine drug terfenadine in human plasma. A deuterated analogue of terfenadine was synthesised for use as an internal standard and extraction of terfenadine was carried out on C₁₈ solid phase extraction columns. The limit of detection of terfenadine in plasma is 0.1 ng/ml and the intra-assay coefficient of variation at 1 ng/ml is 10.1%. Plasma concentrations of terfenadine measured in six normal subjects following a 120 mg oral dose are reported.     

First-line treatment of seasonal (ragweed) rhinoconjunctivitis: a randomized management trial comparing a nasal steroid spray and a nonsedating antihistamine

OBJECTIVE: To determine whether better health-related quality of life (HRQL) is achieved by initiating treatment of seasonal (ragweed) rhinoconjunctivitis (hay fever) with a nasal steroid (fluticasone) backed up by a nonsedating antihistamine (terfenadine) or whether it is better to start with the antihistamine and add the nasal steroid when necessary. DESIGN: Randomized, nonblind, parallel-group management study during the 6 weeks of the ragweed pollen season in 1995. PATIENTS: Sixty-one adults with ragweed pollen hay fever recruited from patients who had participated in previous clinical studies and from those who responded to notices in the local media. SETTING: Southern Ontario. INTERVENTIONS: Nasal steroid group: 200 micrograms of fluticasone nasal spray when needed (up to 400 micrograms/d) starting about 1 week before the ragweed pollen season and continued throughout, with 1 to 2 tablets of terfenadine daily (maximum 120 mg/d) if needed. Antihistamine group: 1 60-mg tablet of terfenadine when needed (maximum 120 mg/d) starting about 1 week before the ragweed pollen season and continued throughout, with 200-400 micrograms/d of fluticasone nasal spray (maximum 400 micrograms/d) if needed. OUTCOME MEASURES: HRQL before, at the height of and toward the end of the ragweed pollen season; HRQL was measured using the Rhinoconjunctivitis Quality of Life Questionnáire. RESULTS: Overall, HRQL tended to be better in the group of patients whose first-line treatment was with fluticasone (p = 0.052), but the difference between the 2 groups was small and not clinically important. Just over half (52% [16/31]) of the patients in the fluticasone group did not need additional help with terfenadine, whereas only 13% (4/30) of those in the terfenadine group did not need additional help with fluticasone (p = 0.002). CONCLUSIONS: There is little difference in the therapeutic benefit between the 2 approaches for the treatment of ragweed pollen hay fever. Therefore, the approach to treatment should be based on patient preference, convenience and cost. Regardless of the treatment, at least 50% of patients will need to take both types of medication in combination to control symptoms adequately.     

Biooxidation of methyl group: Part 2. Evidences for the involvement of cytochromes P450 in microbial multistep oxidation of terfenadine

The actinomycete Streptomyces platensis grown in culture medium containing soybean peptones can transform terfenadine, an antihistamine drug, into its active metabolite fexofenadine. The microbial oxidation of methyl group of terfenadine into carboxylic acid could be an alternative to chemical ways to produce fexofenadine. This bioconversion requires three oxidation steps: a hydroxylation of one methyl group followed by the oxidation of the corresponding alcohol into the aldehyde and finally its oxidation into the carboxylic acid. The oxidation reaction of each step has been studied. Terfenadine and intermediates incubated with whole cells were not oxidized under argon whereas their biotransformation under ¹⁸O₂-enriched atmosphere gave labeled fexofenadine. P450 inhibitors, such as clotrimazole or fluconazole, inhibited oxidation activity of each step. While the two last steps could be catalyzed by dehydrogenases or oxidases, this study strongly demonstrates the role of at least one, or possibly several cytochromes P450, in the oxidation of terfenadine into fexofenadine by S. platensis cells. To our knowledge, this is one of the few examples of involvement of P450s in such three steps oxidation of a xenobiotic.     

Are problem drinkers dangerous drivers? An investigation of arrest for drinking and driving,serum gamma glutamyltranspeptidase activities,blood alcohol concentrations,and road traffic accidents: the Tayside Safe Driving Project.

Serum gamma glutamyltranspeptidase activity was measured in 440 drivers at the time of arrest for driving under the influence of alcohol. The results were compared with information gathered by the arresting police officer. One third of drivers over the age of 30 had abnormal gamma glutamyltranspeptidase activities at the time of arrest. Among drivers who required a driving license for their work, and older drivers, a disproportionately high number had raised gamma glutamyltranspeptidase activities indicating problem drinking. In drivers over the age of 30 a strong association was found between gamma glutamyltranspeptidase activities and road traffic accidents but not alcohol concentrations or previous convictions. These findings argue against the Department of Transport''s criteria for high risk offenders and indicate a clear need for new measures against problem drinkers among drinking and driving offenders.     

Effect of vibrating steering on grip strength in heavy vehicle drivers.

The grip strength in both hands of thirty-two heavy vehicle drivers and twenty-two nondrivers ranging from 30 to 60 years of age was investigated. Blood pressure, heart rate and other physical parameters were also investigated. The subjects were drawn at random from the employees of the North Bengal State Transport Corporation and Civil Aviation. Heavy vehicle drivers perform their duties 8 hr per day with an average speed of 60-70 km hour for 4-5 hr of continuous driving at a time. The only significant difference in the physical characteristics of heavy vehicle drivers and nondrivers was their body weight (p less than 0.05). The right and left wrist power of heavy vehicle drivers was respectively 6% and 3% higher than that of nondrivers. The mean blood pressure, heart rate and wrist width were found to be almost same in heavy vehicle drivers and nondrivers. From our studies we concluded that vibrating steering probably has no influence on the grip strength and that performing 8 hr of driving daily does not affect the blood pressure and heart rate in heavy vehicle drivers. However, further studies are needed to determine the influence of vibrating steering on grip strength.     

Leukoaraiosis Significantly Worsens Driving Performance of Ordinary Older Drivers

Background

Leukoaraiosis is defined as extracellular space caused mainly by atherosclerotic or demyelinated changes in the brain tissue and is commonly found in the brains of healthy older people. A significant association between leukoaraiosis and traffic crashes was reported in our previous study; however, the reason for this is still unclear.

Method

This paper presents a comprehensive evaluation of driving performance in ordinary older drivers with leukoaraiosis. First, the degree of leukoaraiosis was examined in 33 participants, who underwent an actual-vehicle driving examination on a standard driving course, and a driver skill rating was also collected while the driver carried out a paced auditory serial addition test, which is a calculating task given verbally. At the same time, a steering entropy method was used to estimate steering operation performance.

Results

The experimental results indicated that a normal older driver with leukoaraiosis was readily affected by external disturbances and made more operation errors and steered less smoothly than one without leukoaraiosis during driving; at the same time, their steering skill significantly deteriorated.

Conclusions

Leukoaraiosis worsens the driving performance of older drivers because of their increased vulnerability to distraction.     

Cognitive characteristics of older Japanese drivers

Background

Some causes of accidents among older drivers are: not paying attention to traffic signals; missing stop lines; and having to deal with and misjudging emergency situations. These causes of accidents reveal problems with attention and cognition. Such incidents are also related to driver perception and stress-coping mechanisms. It is important to examine the relation of stress reactions to attention and cognition as a factor influencing the causes of accidents commonly involving older drivers.

Finding

Subjects were 10 young drivers (23.3 ± 3.33 years) and 25 older drivers divided into two groups (older1 [60 to 65 years] and older2 [> 65 years]). This study revealed the correlation within driver stress inventory and driver coping questionnaires parameters was observed only in older drivers. They also needed a longer response time for Trail Making Test A and B. The factors affected the attention and cognition of older drivers by age but not driving experience itself, and coping parameters such as emotion focus, reappraisal, and avoidance were not included as stress inventory parameters. Being prone to fatigue was less for younger drivers than older drivers. Because they have shorter distances, shorter drive times, and no need for expressways, older drivers also had a significantly lower risk of thrill-seeking behaviour and more patience.

Conclusion

The intervention addressing their attention skills, aggressive feelings, and emotion focus should be considered. The technological improvements in cars will make older drivers feel safer and make driving easier which might lower the attention paid to the road, and regular driving training might be needed to assess and enhance their safety.     

Driving Performance on the Descending Limb of Blood Alcohol Concentration (BAC) in Undergraduate Students: A Pilot Study

Young drivers are overrepresented in collisions resulting in fatalities. It is not uncommon for young drivers to socially binge drink and decide to drive a vehicle a few hours after consumption. To better understand the risks that may be associated with this behaviour, the present study has examined the effects of a social drinking bout followed by a simulated drive in undergraduate students on the descending limb of their BAC (blood alcohol concentration) curve. Two groups of eight undergraduate students (n = 16) took part in this study. Participants in the alcohol group were assessed before drinking, then at moderate and low BAC as well as 24 hours post-acute consumption. This group consumed an average of 5.3 ± 1.4 (mean ± SD) drinks in an hour in a social context and were then submitted to a driving and a predicted crash risk assessment. The control group was assessed at the same time points without alcohol intake or social context.; at 8 a.m., noon, 3 p.m. and 8 a.m. the next morning. These multiple time points were used to measure any potential learning effects from the assessment tools (i.e. driving simulator and useful field of view test (UFOV)). Diminished driving performance at moderate BAC was observed with no increases in predicted crash risk. Moderate correlations between driving variables were observed. No association exists between driving variables and UFOV variables. The control group improved measures of selective attention after the third asessement. No learning effect was observed from multiple sessions with the driving simulator. Our results show that a moderate BAC, although legal, increases the risky behaviour. Effects of alcohol expectancy could have been displayed by the experimental group. UFOV measures and predicted crash risk categories were not sentitive enough to predict crash risk for young drivers, even when intoxicated.     

Case-control study of recidivist drivers involved in fatal highway accidents in Alberta in 1970-72.

A 3-year enpidemiologic study of fatal motor vehicle accidents was carried out by the Alberta Task Force on Highway Accidents. It was found that 11.1% of culpable drivers had been driving while impaired by alcohol on at least one occasion prior to the fatal accident, while only 3.3% of exonerated drivers had previous records. This significant difference led to a case-control study that demonstrated that the recidivist drivers (case group) differed significantly in a number of aspects from the innocent drivers (control group)--notably, age distribution, sex, whether drinking before the accident, blood alcohol concentration, ethnic distribution, class of accident and type of collision. Thus the recidivist driver is a greater threat to highway safety than the innocent driver and needs special attention by legislators and law enforcement agencies.     

Comorbidities and Crash Involvement among Younger and Older Drivers

Previous studies identified comorbidities as predictors of older driver performance and driving pattern, while the direct impact of comorbidities on road crash risk in elderly drivers is still unknown. The present study is a cross-sectional aimed at investigating the association between levels of comorbidity and crash involvement in adult and elderly drivers. 327 drivers were stratified according to age range in two groups: elderly drivers (age ≥70 years old, referred as older) and adult drivers (age <70 years old, referred as younger). Driving information was obtained through a driving questionnaire. Distance traveled was categorized into low, medium and high on the basis of kilometers driven in a year. CIRS-illness severity (IS) and CIRS-comorbidity indices (CI) in all populations were calculated. Older drivers had a significantly higher crash involvements rate (p = .045) compared with the younger group based on the number of licensed drivers. Dividing comorbidity indices into tertiles among all licensed subjects, the number of current drivers significantly decreased (p<.0001) with increasing level of comorbidity. The number of current drivers among older subjects significantly decreased with increasing comorbidity level (p = .026) while no difference among younger group was found (p = .462). Among younger drivers with increasing comorbidity level, the number of road accidents significantly increased (p = .048) and the logistic regression analysis showed that comorbidity level significantly associated with crash involvement independent of gender and driving exposure. Older subjects with high level of comorbidity are able to self-regulate driving while comorbidity burden represents a significant risk factor for crash involvements among younger drivers.     

Negativity Bias in Dangerous Drivers

The behavioral and cognitive characteristics of dangerous drivers differ significantly from those of safe drivers. However, differences in emotional information processing have seldom been investigated. Previous studies have revealed that drivers with higher anger/anxiety trait scores are more likely to be involved in crashes and that individuals with higher anger traits exhibit stronger negativity biases when processing emotions compared with control groups. However, researchers have not explored the relationship between emotional information processing and driving behavior. In this study, we examined the emotional information processing differences between dangerous drivers and safe drivers. Thirty-eight non-professional drivers were divided into two groups according to the penalty points that they had accrued for traffic violations: 15 drivers with 6 or more points were included in the dangerous driver group, and 23 drivers with 3 or fewer points were included in the safe driver group. The emotional Stroop task was used to measure negativity biases, and both behavioral and electroencephalograph data were recorded. The behavioral results revealed stronger negativity biases in the dangerous drivers than in the safe drivers. The bias score was correlated with self-reported dangerous driving behavior. Drivers with strong negativity biases reported having been involved in mores crashes compared with the less-biased drivers. The event-related potentials (ERPs) revealed that the dangerous drivers exhibited reduced P3 components when responding to negative stimuli, suggesting decreased inhibitory control of information that is task-irrelevant but emotionally salient. The influence of negativity bias provides one possible explanation of the effects of individual differences on dangerous driving behavior and traffic crashes.     

Performance enhancement in rally car drivers via heat acclimation and race simulation

To investigate the combined use of an interactive racecar simulator and heat acclimation on psychomotor (driving) performance, eight rally drivers underwent 4 days of repeated heat (50 degrees C) exposure (1 h x day(-1)) during which they performed a simulated rally drive (3x12-min stages each separated by a 2-min break), after first cycling for 15 min at 125 W to induce some degree of fatigue and heat storage prior to beginning the rally. During the rally stages, a generic set of pace notes were read to the subject by a co-driver. In each simulation, sweat loss, heart rate, core (rectal) and skin temperatures were recorded and driving and psychomotor performance were assessed by recording stage times and time to complete a psychomotor test. Levels of physiological and perceived thermal strain were also recorded. Significant decreases in rally stage times (88 s; P<0.005), psychomotor test time (18 s; P<0.01), final core (0.25 degrees C; P<0.001) and skin (0.44 degrees C; P<0.005) temperatures, heart rate (16 beats x min(-1); P<0.05) and physiological (15 W x m(-2); P<0.005) and perceived thermal (3.7 units; P<0.01) strain were evident by the end of the final simulation, and a significant (P<0.05) increase in sweat sensitivity (+0.33 g x h(-1) x degrees C(-1)) was also recorded. These results suggest that both heat acclimation and race simulation can improve the psychomotor performance of rally drivers, although the relative contribution of each factor was not determined here. However, in a practical setting, these factors would not be used in isolation. After performing the acclimation and simulation protocol prior to an actual rally, drivers subjectively reported improvements in tolerating a high thermal load and in their ability to control the rally vehicle.     

Methadone maintenance treatment and drugs

The mental and physical capabilities of drivers in traffic are often seriously challenged these days. Not only do they need to concentrate on driving, predict connections between various phenomena, take appropriate judgements in current situations and foresee the sequence of measures to be taken, but they are also expected to be emotionally stable, etc. The problem with drugs in traffic is often encountered when assessing the actual safe driving capability of a person in a given moment, for example after a car accident or a police check, or medical check-ups that are required for a driving license. The Road Traffic Safety Law considers methadone a drug. Drug addicts do not meet the health standards required of drivers. This research program deals with the attitude of drivers who are in methadone maintenance treatment programs with respect to the driving ability as well as the effects of methadone use in combination with other drugs on driving. It has been established that drivers undergoing the methadone maintenance program, regularly drive not only under the influence of methadone but also under the influence of marijuana (20%) and heroin (18%) and sometimes under the influence of marijuana (58.6%), heroin (55.7%), and alcohol (48.6%). Certain initiatives have been taken by some therapists to give, under certain circumstances, a clean bill of health to responsible methadone maintenance patients who have an adequate level of responsibility for themselves and their deeds, in order to help them obtain a driving license. Since it has been established that methadone maintenance patients use methadone quite commonly in combination with illegal drugs and/or alcohol, the classification of this type of addicts among possible driving candidates remains disputable. Long term interdisciplinary research is still required to determine the basic principles required to asses and possibly admit this type of drivers to participate in traffic, as well as to determine which professional therapists can participate and evaluate the driving capabilities of these patients.     

A new cytochrome P450 belonging to the 107L subfamily is responsible for the efficient hydroxylation of the drug terfenadine by Streptomyces platensis

Fexofenadine, an antihistamine drug used in allergic rhinitis treatment, can be produced by oxidative biotransformation of terfenadine by Streptomyces platensis, which involves three consecutive oxidation reactions. We report here the purification and identification of the enzyme responsible for the first step, a cytochrome P450 (P450)-dependent monooxygenase. The corresponding P450, designated P450_terf, was found to catalyze the hydroxylation of the t-butyl group of terfenadine and exhibited UV–Vis characteristics of a P450. Its interaction with terfenadine led to a shift of its Soret peak from 418 to 390 nm, as expected for the formation of a P450–substrate complex. In combination with spinach ferredoxin:NADP(+) oxidoreductase and ferredoxin, and in the presence of NADPH, it catalyzed the hydroxylation of terfenadine and some of its analogues, such as terfenadone and ebastine, with k_m values at the μM level, and k_cat values around 30 min⁻¹. Sequencing of the p450_terf gene led to a 1206 bp sequence, encoding for a 402 aminoacid polypeptide exhibiting 56–65% identity with the P450s from the 107L family. These results confirmed that P450s from Streptomyces species are interesting tools for the biotechnological production of secondary metabolites, such as antibiotics or antitumor compounds, and in the oxidative biotransformation of xenobiotics, such as drugs.     

Reaching the hard-to-reach: a probability sampling method for assessing prevalence of driving under the influence after drinking in alcohol outlets

Drinking alcoholic beverages in places such as bars and clubs may be associated with harmful consequences such as violence and impaired driving. However, methods for obtaining probabilistic samples of drivers who drink at these places remain a challenge--since there is no a priori information on this mobile population--and must be continually improved. This paper describes the procedures adopted in the selection of a population-based sample of drivers who drank at alcohol selling outlets in Porto Alegre, Brazil, which we used to estimate the prevalence of intention to drive under the influence of alcohol. The sampling strategy comprises a stratified three-stage cluster sampling: 1) census enumeration areas (CEA) were stratified by alcohol outlets (AO) density and sampled with probability proportional to the number of AOs in each CEA; 2) combinations of outlets and shifts (COS) were stratified by prevalence of alcohol-related traffic crashes and sampled with probability proportional to their squared duration in hours; and, 3) drivers who drank at the selected COS were stratified by their intention to drive and sampled using inverse sampling. Sample weights were calibrated using a post-stratification estimator. 3,118 individuals were approached and 683 drivers interviewed, leading to an estimate that 56.3% (SE = 3,5%) of the drivers intended to drive after drinking in less than one hour after the interview. Prevalence was also estimated by sex and broad age groups. The combined use of stratification and inverse sampling enabled a good trade-off between resource and time allocation, while preserving the ability to generalize the findings. The current strategy can be viewed as a step forward in the efforts to improve surveys and estimation for hard-to-reach, mobile populations.     

Topical levocabastine-a review of therapeutic efficacy compared with topical sodium cromoglycate and oral terfenadine on days with high pollen counts

Levocabastine is a new H(1)-receptor antagonist specifically developed for the topical treatment of seasonal allergic rhinoconjunctivitis. Clinical experience to date clearly demonstrates that levocabastine eye drops and nasal spray are effective and well tolerated for the treatment of this allergic disorder. Analysis of data from a number of comparative trials reveals that topical levocabastine is at least as effective as sodium cromoglycate and the oral antihistamine terfenadine, even on days with high pollen counts (>/= 50 pollen particles/m(3) ) when symptoms are severe. Coupled with a rapid onset of action and twice daily dosing, these findings make topical levocabastine an attractive alternative to other therapeutic approaches as a first-line therapy for the treatment, of this common condition.     

Hypersomnolence and accidents in truck drivers: A cross-sectional study

Truck drivers are more likely to suffer severe injury and death due to certain truck driving characteristics. Identifying and preventing factors associated with accidents in this population is important to minimize damage and improve road safety. Excessive daytime sleepiness is a major public health problem, leading to impaired cognitive function, reduced alertness, and increased risk of motor vehicle crashes. The aim of this cross-sectional study was to determine the prevalence and predictors of hypersomnolence (defined as an Epworth Sleepiness Scale score greater than 10) among truck drivers. Three hundred male truck drivers were studied. Quality of sleep was assessed by the Pittsburgh Sleep Quality Index, and the association between demographic, clinical, and occupational data with excessive sleepiness was analyzed. The mean daily sleep duration was 5.6+/-1.3 h, and poor quality of sleep was found in 46.3% of the individuals. Hypersomnolence was found in 46% of the drivers and was associated with younger age, snoring, and working >10 h without rest. A positive correlation between hypersomnolence and previous accidents was detected (p=0.005). These results show that sleep deprivation and hypersomnolence are frequent among truck drivers. The treatment of sleep-disordered breathing and the implementation of educational programs, particularly targeting younger drivers and promoting increased awareness of the deleterious effects of sleep loss and work overload, may help to reduce hypersomnolence and accidents among truck drivers.     

Prolonged effect of an H1-receptor blocker antihistamine on the histamine content of white blood cells and mast cells

Hormonal imprinting usually takes place perinatally at the first encounter between the developing receptor and its target hormone, determining the future binding capacity of the receptor for life. Molecules similar to a hormone can cause faulty imprinting also with life-long consequences. Hormone production of the imprinted cell is also durably influenced. In cytogenic organs imprinting can also be provoked in adulthood. At present the effect of a single terfenadine treatment in adult rats on the histamine content of peritoneal cells (lymphocytes, mast cells and the monocyte-macrophage-granulocyte group), white blood cells (lymphocytes, granulocytes, monocytes) and thymic lymphocytes was studied 3 weeks after treatment to clarify the effect of prolonged treatment with an antihistamine in adulthood.The cells were studied by flow cytometric analysis. Peritoneal mast cells contained significantly more and thymic lymphocytes significantly less histamine than controls. In the other cells the differences were not significant. The results support earlier observations on the effect of antihistamines on mast cell histamine release (inhibition) and call attention to the fact that this effect is durable (hormonal imprinting provoked in adults).