Effets du cannabis oral et du dronabinol sur la capacité à conduire [Effects of oral cannabis and dronabinol on driving capacity]

Two retrospective epidemiologic studies have shown that cannabis is the main psychoactive substance detected in the blood of drivers suspected of driving under the influence of psychotropic drugs. An oral administration double-blind crossover study was carried out with eight healthy male subjects, aged 22 to 30 years, all occasional cannabis smokers. Three treatments and one placebo were administered to all participants at a two week interval: 20 mg dronabinol, 16.5 mg D9-tétrahydrocannabinol (THC) and 45.7 mg THC as a cannabis milk decoction. Participants were asked to report the subjective drug effects and their willingness to drive under various circumstances on a visual analog scale. Clinical observations, a psychomotor test and a tracking test on a driving simulator were also carried out. Compared to cannabis smoking, THC, 11-OH-THC and THC-COOH blood concentrations remained low through the whole study (<13.1 ng THC/mL,<24.7 ng 11-OH-THC/mL and<99.9 ng THC-COOH/mL). Two subjects experienced deep anxiety symptoms suggesting that this unwanted side-effect may occur when driving under the influence of cannabis or when driving and smoking a joint. No clear association could be found between these adverse reactions and a susceptibility gene to propensity to anxiety and psychotic symptoms (genetic polymorphism of the catechol-O-methyltransferase). The questionnaires have shown that the willingness to drive was lower when the drivers were assigned an insignificant task and was higher when the mission was of crucial importance. The subjects were aware of the effects of cannabis and their performances on the road sign and tracking test were greatly impaired, especially after ingestion of the strongest dose. The Cannabis Influence Factor (CIF) which relies on the molar ratio of active and inactive cannabinoids in blood provided a good estimate of the fitness to drive.

Effects of long-term estrogen replacement therapy in postmenopausal women with coronary risk factors

Objective: Hormone replacement therapy (HRT) with estrogen alone or in concert with progesterone may exert beneficial effects on coronary endothelium-dependent vasomotion in postmenopausal women without traditional coronary risk factors. We aimed to evaluate the effect of HRT on coronary vasomotor function in postmenopausal women with traditional coronary risk factors such as hypertension, hypercholesterolemia and smoking as compared to those without HRT. Methods: Combining N-13 ammonia with PET, myocardial blood flow (MBF) was measured in ml/g/min at rest, during cold pressor test (CPT, reflecting predominantly endothelium-dependent vasomotion)and during pharmacologic vasodilation (representing predominantly endothelium-independent vasomotion) in 48 postmenopausal women with various coronary risk factors during a mean follow up (FU) of 20_9 months. postmenopausal women wer grouped according to HRT: group 1 with HRT (n_18), group 2 without HRT (n_18) and group 3 with HRT at baseline but not at FU (n_12). Results: during FU, HRT did not significantly affect lipid profile and plasma glucose levels. At baseline resting MBF was similar between groups (Table).After the FU, in group 2 and 3 the endothelium-related increase in MBF from rest to CPT (_ MBF) was significantly less than at baseline (*p_0.05) (Table). Conversely, in group 1 _MBF to CPT at FU was not significantly different from the baseline study. The group comparison of CPT-induced _MBF in group 2 and group 3 after the FU period was significantly different from group 1 (p_0.006 by ANOVA). Finally, in all three groups, hyperemic MBFs during pharmacologic vasodilation did not differ significantly between baseline and FU (Table). Conclusion: In postmenopausal women with coronary risk factors, HRT may counterbalance the adverse effects of traditional coronary risk factors on endothelium-dependent coronary vasomotion. Consequently, in addition to standard management of coronary risk factors, HRT may exert beneficial effects on the coronary endothelium that may delay the progression of coronary artery disease in postmenopausal women.

Nicotine vaccines for smoking cessation.

BACKGROUND: By reducing the amount of nicotine that reaches the brain when a person smokes a cigarette, nicotine vaccines may help people to stop smoking or to prevent recent quitters from relapsing. OBJECTIVES: The aims of this review are to assess the efficacy of nicotine vaccines for smoking cessation and for relapse prevention, and to assess the frequency and type of adverse events associated with the use of nicotine vaccines. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Review Group specialised register for trials, using the term 'vaccine' in the title or abstract, or in a keyword (date of most recent search April 2012). To identify any other material including reviews and papers potentially relevant to the background or discussion sections, we also searched MEDLINE, EMBASE, and PsycINFO, combining terms for nicotine vaccines with terms for smoking and tobacco use, without design limits or limits for human subjects. We searched the Annual Meeting abstracts of the Society for Research on Nicotine and Tobacco up to 2012, using the search string 'vaccin'. We searched Google Scholar for 'nicotine vaccine'. We also searched company websites and Google for information related to specific vaccines. We searched clinicaltrials.gov in March 2012 for 'nicotine vaccine' and for the trade names of known vaccine candidates. SELECTION CRITERIA: We included randomized controlled trials of nicotine vaccines, at Phase II and Phase III trial stage and beyond, in adult smokers or recent ex-smokers. We included studies of nicotine vaccines used as part of smoking cessation or relapse prevention interventions. DATA COLLECTION AND ANALYSIS: We extracted data on the type of participants, the dose and duration of treatment, the outcome measures, the randomization procedure, concealment of allocation, blinding of participants and personnel, reporting of outcomes, and completeness of follow-up.Our primary outcome measure was a minimum of six months abstinence from smoking. We used the most rigorous definition of abstinence, and preferred cessation rates at 12 months and biochemically validated rates where available. We have used the risk ratio (RR) to summarize individual trial outcomes. We have not pooled the current group of included studies as they cover different vaccines and variable regimens. MAIN RESULTS: There are no nicotine vaccines currently licensed for public use, but there are a number in development. We found four trials which met our inclusion criteria, three comparing NicVAX to placebo and one comparing NIC002 (formerly NicQbeta) to placebo. All were smoking cessation trials conducted by pharmaceutical companies as part of the drug development process, and all trials were judged to be at high or unclear risk of bias in at least one domain. Overall, 2642 smokers participated in the included studies in this review. None of the four included studies detected a statistically significant difference in long-term cessation between participants receiving vaccine and those receiving placebo. The RR for 12 month cessation in active and placebo groups was 1.35 (95% Confidence Interval (CI) 0.82 to 2.22) in the trial of NIC002 and 1.74 (95% CI 0.73 to 4.18) in one NicVAX trial. Two Phase III NicVAX trials, for which full results were not available, reported similar quit rates of approximately 11% in both groups. In the two studies with full results available, post hoc analyses detected higher cessation rates in participants with higher levels of nicotine antibodies, but these findings are not readily generalisable. The two studies with full results showed nicotine vaccines to be well tolerated, with the majority of adverse events classified as mild or moderate. In the study of NIC002, participants receiving the vaccine were more likely to report mild to moderate adverse events, most commonly flu-like symptoms, whereas in the study of NicVAX there was no significant difference between the two arms. Information on adverse events was not available for the large Phase III trials of NicVAX.Vaccine candidates are likely to undergo significant changes before becoming available to the general public, and those included in this review may not be the first to reach market; this limits the external validity of the results reported in this review in terms of both effectiveness and tolerability. AUTHORS' CONCLUSIONS: There is currently no evidence that nicotine vaccines enhance long-term smoking cessation. Rates of serious adverse events recorded in the two trials with full data available were low, and the majority of adverse events reported were at mild to moderate levels. The evidence available suggests nicotine vaccines do not induce compensatory smoking or affect withdrawal symptoms. No nicotine vaccines are currently licensed for use in any country but a number are under development.Further trials of nicotine vaccines are needed, comparing vaccines with placebo for smoking cessation. Further trials are also needed to explore the potential of nicotine vaccines to prevent relapse. Results from past, current and future research should be reported in full. Adverse events and serious adverse events should continue to be carefully monitored and thoroughly reported.

Cigarette smoking and the risk of endometrial cancer.

The risk of endometrial cancer in relation to cigarette consumption was evaluated in a hospital-based case-control study of breast and genital neoplasms conducted in Milan, northern Italy. For the present analysis, 357 women (cases) with histologically confirmed endometrial cancer were compared to a group of 1122 women (controls) admitted for a large spectrum of acute conditions unrelated to smoking or to any of the known or potential risk factors for endometrial cancer. Compared with never-smokers, the multivariate relative risk estimates were for current 0.45 [95% confidence interval (CI) = 0.30-0.70] and 0.86 (95% CI = 0.50-1.46) for ex-smokers. The negative association of endometrial cancer with current smoking was not influenced by menopausal status as well as by other major identified potential confounding factors, i.e. menstrual and reproductive history, body mass index, oral contraceptive or estrogen replacement therapy use and family gynecologic cancer history. However, there was no evidence of a dose-risk effect, since the relative risks were similar in moderate and heavy smokers. The present study confirms that smoking is less frequent in cases hospitalized for endometrial cancer than in a comparison group of patients with non-smoking-related acute conditions. This negative association is perhaps explained in terms of reduced estrogen levels in smokers, though the influence and the importance of some uncontrolled selection bias (due, for instance, to longer hospital stay of smokers even when admission diagnosis was for non-smoking-related conditions) cannot be ruled out.

Smoking during pregnancy and fetal brain development

Background: Although the knowledge of adverse effects of smoking during pregnancy has increased in recent years, more research is needed to gain a better understanding of the effects of smoking during pregnancy. Smoking exposure is the most common preventable factor that causes adverse pregnancy outcomes. Aims and Methods: First, data on smoking habits during pregnancy from the Nordic Medical Birth Registers was used to study the national differences in trends of smoking during pregnancy. Second, the effects of prenatal smoking exposure on fetal brain development, assessed by brain MRI at term age, were studied by using data from the multidisciplinary PIPARI Study consisting of a 6-year cohort of VLBW/VLGA infants (n = 232, of which 18.1% were exposed to prenatal smoking) born in Turku University Hospital, Finland. Third, the effects of prenatal smoking exposure on psychiatric morbidity and use of psychotropic medication were studied in a cohort of children born from 1987–1989 in Finland (n = 175,869, of which 15.3% were exposed). The data used were obtained from population-based longitudinal registers from the National Institute of Health and Welfare, the Statistics Finland, and the Finnish Social Insurance Institution. Results: Smoking rates during pregnancy differed considerably between the countries. Smoking rates were highest among teenagers and women with lower socioeconomic positions. The smoking prevalence was found to be increasing among teenagers in both Finland and Norway. Prenatal smoking exposure was associated with smaller frontal lobe and cerebellar volumes in preterm infants. A clear association was found between prenatal smoking exposure and psychiatric morbidity treated with specialized hospital care and the use of various psychotropic medications. Conclusions: Prenatal smoking exposure had adverse effects on fetal brain development. These effects might explain part of the association found between smoking exposure and psychiatric problems in later life. Our study suggests that prenatal smoking exposure is linked with both mild and severe psychiatric problems. This study emphasizes the importance of efforts to reduce smoking during pregnancy.

Adverse gastrointestinal effects of arginine and related amino acids

Oral supplements of arginine and citrulline increase local nitric oxide (NO production in the small intestine and this may be harmful under certain circumstances. Gastrointestinal toxicity was therefore reviewed with respect to the intestinal physiology of arginine, citrulline, ornithine, and cystine (which shares the same transporter) and the many clinical trials of supplements of the dibasic amino acids or N-acetylcysteine (NAC. The human intestinal dibasic amino acid transport system has high affinity and low capacity. L-Arginine (but not lysine, ornithine, or D-arginine) induces water and electrolyte secretion that is mediated by NO, which acts as an absorbagogue at low levels and as a secretagogue at high levels. The action of many laxatives is NO mediated and there are reports of diarrhea following oral administration of arginine or ornithine ihine. The clinical data cover a wide span of arginine intakes f rom 3 g/d to > 100 g/d, but the standard of reporting adverse effects (e.g. nausea, vomiting, and diarrhea) was variable. Single doses of 3-6 g rarely provoked side effects and healthy athletes appeared to be more susceptible than diabetic patients to gastrointestinal symptoms at individual doses >9 g. This may relate to an effect of disease on gastrointestinal motility and pharmacokinetics. Most side effects of arginine and NAC occurred at single doses of >9 g in adults >140 mg/kg) often when part of a daily regime of similar to>30 g/d (>174 mmol/d). In the case of arginine, this compares with the laxative threshold of the nonabsorbed disaccharide alcohol, lactitol (74 g or 194 mmol). Adverse effects seemed dependent on the dosage regime and disappeared if divided doses were ingested (unlike lactitol). Large single doses of poorly absorbed amino acids seem to provoke diarrhea. More research is needed to refine dosage strategies that reduce this phenomenon. It is suggested that dipeptide forms of arginine may meet this criterion.

Smoking: What Has Been Addressed in Brazilian Journals

The topic of tobacco smoking, in its several aspects, has been receiving increasing attention among researchers over the past few years, which has been reflected in more data and more solid scientific literature on the subject in national journals. This article aims to review the studies that focused on smoking published between January 2010 and June 2012, in Arquivos Brasileiros de Cardiologia (Brazilian Archives of Cardiology), Brazilian Journal of Medical and Biological Research, Clinics (Sao Paulo), Jornal Brasileiro de Pneumologia (Brazilian Journal of Pulmonology), Revista da Associacao Medica Brasileira (Journal of the Brazilian Medical Association) and Revista Brasileira de Cirurgia Cardiovascular (Brazilian Journal of Cardiovascular Surgery). During the aforementioned period 58 articles were published, 52 of which were original ones, addressing several aspects of smoking, such as effects on health, epidemiology, cessation and experimental studies.

Being stoned: A review of self-reported cannabis effects

Although there has been considerable research into the adverse effects of cannabis, less attention has been directed toward subjective effects that may be associated with ongoing cannabis use. Examination of self-reported cannabis effects is an important issue in understanding the widespread use of cannabis. While reviews have identified euphoria as a primary factor in maintaining cannabis use, relaxation is the effect reported most commonly in naturalistic studies of cannabis users, irrespective of the method used. Self-reported effects in 12 naturalistic and 18 laboratory studies were compared. Regardless of methodology there was considerable variation in the effects experienced. Variation has been reported in terms of opposite effects being experienced by different individuals, variation of effects by individuals within a single occasion and between occasions of use. Factors that might explain this variation are outlined. Limitations of the available literature and suggested directions for future research are discussed.

Surveillance for adverse events after DTwP/Hib vaccination in Brazil: sensitivity and factors associated with reporting

We estimated the sensitivity, i.e., the proportion of all cases of adverse events following immunization (AEFIs) reported to the Brazilian passive surveillance for adverse events following immunization (PSAEFI) with the diphtheria-tetanus-whole-cell pertussis-Haemophilus influenzae type b (DTwP-Hib) vaccine, as well as investigating factors associated with AEFIs reporting. During 2003–2004, 8303 AEFIs associated with DTwP-Hib were reported; hypotonic-hyporesponsive episodes (HHEs), fever and convulsions being the most common. Cure without sequel was achieved in 98.4 per cent of the cases. The mean sensitivity of the PSAEFI was 22.3 per cent and 31.6 per cent, respectively, for HHE and convulsions, varying widely among states. Reporting rates correlated positively with the Human Development Index and coverage of adequate prenatal care, correlating negatively with infant mortality rates. Quality of life indicators and the degree of organization of health services are associated with greater PSAEFI sensitivity. In addition to consistently describing the principal AEFIs, PSAEFI showed the DTwP/Hib vaccine to be safe and allayed public fears related to its use

Effects of creatine supplementation on renal function: a randomized, double-blind, placebo-controlled clinical trial

Creatine (CR) supplementation is commonly used by athletes. However, its effects on renal function remain controversial. The aim of this study was to evaluate the effects of creatine supplementation on renal function in healthy sedentary males (18-35 years old) submitted to exercise training. A randomized, double-blind, placebo-controlled trial was performed. Subjects (n = 18) were randomly allocated to receive treatment with either creatine (CR) (similar to 10 g day(-1) over 3 months) or placebo (PL) (dextrose). All subjects undertook moderate intensity aerobic training, in three 40-min sessions per week, during 3 months. Serum creatinine, serum and urinary sodium and potassium were determined at baseline and at the end of the study. Cystatin C was assessed prior to training (PRE), after 4 (POST 4) and 12 weeks (POST 12). Cystatin C levels (mg L-1) (PRE CR: 0.82 +/- 0.09; PL: 0.88 +/- 0.07 vs. POST 12 CR: 0.71 +/- 0.06; PL: 0.75 +/- 0.09, P = 0.0001) were decreased over time, suggesting an increase in glomerular filtration rate. Serum creatinine decreased with training in PL but was unchanged with training in CR. No significant differences were observed within or between groups in other parameters investigated. The decrease in cystatin C indicates that high-dose creatine supplementation over 3 months does not provoke any renal dysfunction in healthy males undergoing aerobic training. In addition, the results suggest that moderate aerobic training per se may improve renal function.

The azo dye Disperse Orange 1 induces DNA damage and cytotoxic effects but does not cause ecotoxic effects in Daphnia similis and Vibrio fischeri

Azo dyes constitute the largest group of colorants used in industry and can pass through municipal waste water plants nearly unchanged due to their resistance to aerobic treatment, which potentially exposes humans and local biota to adverse effects. Unfortunately, little is known about their environmental fate. Under anaerobic conditions, some azo dyes are cleaved by microorganisms forming potentially carcinogenic aromatic amines. In the present study, the azo dye Disperse Orange 1, widely used in textile dyeing, was tested using the comet, Salmonella/microsome mutagenicity, cell viability, Daphnia similis and Microtox (R) assays. The human hepatoma cell line (HepG2) was used in the comet assay and for cell viability. In the mutagenicity assay. Salmonella typhimurium strains with different levels of nitroreductase and o-acetyltransferase were used. The dye showed genotoxic effects with respect to HepG2 cells at concentrations of 0.2, 0.4, 1.0, 2.0 and 4.0 mu g/mL. In the mutagenicity assay, greater responses were obtained with the strains TA98 and YG1041, suggesting that this compound mainly induces frameshift mutations. Moreover, the mutagenicity was greatly enhanced with the strains overproducing nitroreductase and o-acetyltransferase, showing the importance of these enzymes in the mutagenicity of this dye. In addition, the compound induced apoptosis after 72 h in contact with the HepG2 cells. No toxic effects were observed for either D. similis or Vibrio fischeri. (C) 2011 Elsevier B.V. All rights reserved.

Coronary events and exposure to environmental tobacco smoke: a case-control study from Australia and New Zealand

Objectives-To estimate the relative risk of coronary heart disease (CHD) associated with exposure to environmental tobacco smoke (ETS). Design-Population-based case-control study. Subjects-Cases were 953 people identified in a population register of coronary events, and controls were 3189 participants in independent community-based risk factor prevalence surveys from the same study populations. Setting-Newcastle, Australia and Auckland, New Zealand. Main outcome measures-Acute myocardial infarction or coronary death. Results-After adjusting for the effects of age, education, history of heart disease, and body mass index, women had a statistically significant increased risk of a coronary event associated with exposure to ETS (relative risk (RR) = 1.99; 95% confidence interval (CI)= 1.40-2.81). There was little statistical evidence of increased risk found in men (RR = 1.02, 95% CI = 0.81-1.28). Conclusion-Our study found evidence for the adverse effects of exposure to ETS on risk of coronary heart disease among women, especially at home. For men the issue is unclear according to the data from our study. Additional studies with detailed information on possible confounders and adequate statistical power are needed. Most importantly, they should use methods for measuring exposure to ETS that are sufficiently accurate to permit the investigation of dose-response relationships.

The effects of chronic exposure to traffic derived air pollution on the ocular surface

Objectives: The purpose of this study was to explore the clinical relevance of chronic exposure to ambient levels of traffic derived air pollution on the ocular surface. Methods: A panel study involving 55 volunteers was carried out in Sao Paulo, Brazil. We measured the mean individual levels of nitrogen dioxide (NO(2)) exposure for 7 days. All subjects answered the Ocular Symptom Disease Index (OSDI) and a symptoms inventory. Subsequently, subjects underwent Schirmer I test, biomicroscopy, vital staining and tear breakup time (TOUT) assessment. Subject`s mean daily exposure to NO(2) was categorized in quartiles. Statistical analysis was performed using one-way ANOVA, Tukey HSD and Chi-Square tests. Results: A dose-response pattern was detected between OSDI scores and NO(2) quartiles (p < 0.05). There was a significant association between NO(2) quartiles and reported ocular irritation (X(2) = 9.2, p < 0.05) and a significant negative association between TBUT and NO(2) exposure (p < 0.05, R = -0.316. Spearman`s correlation). There was a significant increase in the frequency of meibomitis in subjects exposed to higher levels of NO(2) (p < 0.05). Conclusions: Subjects exposed to higher levels of traffic derived air pollution reported more ocular discomfort symptoms and presented greater tear film instability, suggesting that the ocular discomfort symptoms and tear breakup time could be used as convenient bioindicators of the adverse health effects of traffic derived air pollution exposure. (C) 2010 Elsevier Inc. All rights reserved.

Comparison of the effects of tramadol, codeine, and ketoprofen alone or in combination on postoperative pain and on concentrations of blood glucose, serum cortisol, and serum interleukin-6 in dogs undergoing maxillectomy or mandibulectomy

Objective-To compare analgesic effects of tramadol, codeine, and ketoprofen administered alone and in combination and their effects on concentrations of blood glucose, serum cortisol, and serum interleukin (IL)-6 in dogs undergoing maxillectomy or mandibulectomy. Animals-42 dogs with oral neoplasms. Procedures-30 minutes before the end of surgery, dogs received SC injections of tramadol (2 mg/kg), codeine (2 mg/kg), ketoprofen (2 mg/kg), tramadol + ketoprofen, or codeine + ketoprofen (at the aforementioned dosages). Physiologic variables, analgesia, and sedation were measured before (baseline) and 1, 2, 3, 4, 5, and 24 hours after surgery. Blood glucose, serum cortisol, and serum IL-6 concentrations were measured 1, 3, 5, and 24 hours after administration of analgesics. Results-All treatments provided adequate postoperative analgesia. Significant increases in mean +/- SD blood glucose concentrations were detected in dogs receiving tramadol (96 +/- 14 mg/dL), codeine (120 +/- 66 mg/dL and 96 +/- 21 mg/dL), ketoprofen (105 +/- 22 mg/dL), and codeine + ketoprofen (104 +/- 16 mg/dL) at 5, 1 and 3, 5, and 3 hours after analgesic administration, respectively, compared with preoperative (baseline) values. There were no significant changes in physiologic variables, serum IL-6 concentrations, or serum cortisol concentrations. Dogs administered codeine + ketoprofen had light but significant sedation at 4, 5, and 24 hours. Conclusions and Clinical Relevance-Opioids alone or in combination with an NSAID promoted analgesia without adverse effects during the 24-hour postoperative period in dogs undergoing maxillectomy or mandibulectomy for removal of oral neoplasms. (Am J Vet Res 2010;71:1019-1026)

Patient based method of assessing adverse events in clinical trials in rheumatology: the revised Stanford Toxicity Index

We describe the progress towards developing a patient rated toxicity index that meets all of the patient-important attributes defined by the OMERACT Drug Safety Working Party, These attributes are frequency, severity. importance to patient, importance to the clinician, impact on economics, impact on activities, and integration of adverse effects with benefits. The Stanford Toxicity Index (STI) has been revised to collect all attributes with the exception of impact on activities. However, since the STI is a part of the Health Assessment Questionnaire (HAQ). impact on activities is collected by the HAQ. In particular, a new question asks patients to rate overall satisfaction, taking into consideration both benefits and adverse effects. The nest step in the development of this tool is to ensure that the STI meets the OMERACT filter of truth, discrimination, and feasibility. Although truth and feasibility have been confirmed by comparisons within the ARAMIS database, discrimination needs to be assessed in clinical trials.