Cannabinoid Activity-Is There a Causal Connection to Spasmolysis in Clinical Studies?

Cannabinoid drugs are registered for postoperative nausea and emesis, Tourette syndrome and tumor-related anorexia, but are also used for spasticity and pain relief, among other conditions. Clinical studies for spasmolysis have been equivocal and even conclusions from meta-analyses were not consistent. This may be due to uncertainty in diagnostic criteria as well as a lack of direct spasmolytic activity (direct causality). In this review we used the Hill criteria to investigate whether a temporal association is causal or spurious. METHODS: A systematic literature search was performed to identify all clinical trials of cannabinoids for spasticity. Studies were evaluated for dose dependency and time association; all studies together were analyzed for reproducibility, coherence, analogy and mechanistic consistency. A Funnel plot was done for all studies to identify selection or publication bias. RESULTS: Twenty-seven studies were included in this meta-analysis. The spasmolytic activity (effect strength) was weak, with a nonsignificant small effect in most studies and a large effect only in a few studies ("enriched" studies, low patient numbers). No dose dependency was seen and plotting effect size vs. daily dose resulted in a slope of 0.004. Most studies titrated the cannabinoid to the optimum dose, e.g., 20 mg/d THC. The effect decreased with longer treatment duration (3-4 months). The spasmolytic effect is consistent for different European countries but not always within a country, nor is the effect specific for an etiology (multiple sclerosis, spinal cord injury, others). For other criteria like plausibility, coherence or analogous effects, no data exist to support or refute them. In most studies, adverse effects were frequently reported indicating a therapeutic effect only at high doses with relevant side effects. CONCLUSIONS: Current data do not support a specific spasmolytic effect; a general decrease in CNS activity analogous to benzodiazepines appears more likely. Whether individual patients or specific subgroups benefit from cannabinoids is unclear. Further studies should compare cannabinoids with other, nonspecific spasmolytic drugs like benzodiazepines.

Comparison of two different assays and the predictive value of allergen components in house dust mite allergy.

AIM: In house dust mite (HDM) allergy diagnostics, the IMMULITE, ImmunoCAP and assays for allergen components (nDer p 1 and rDer p 2) are available. METHODS: Serum sIgE levels were compared and the predictive values for the detection of an early asthmatic response (EAR) were calculated with receiver operating characteristics and a log-logistic regression model. RESULTS: sIgE levels of IMMULITE and ImmunoCAP were similar (Dermatophagoides pteronyssinus [D. pter.] 47.3 ± 35.7 and 42.9 ± 34.4 kU.l-1; p = 0.23). ImmunoCAP slgEs exhibited similar accuracy in detecting an EAR, area under the curves (AUCs): D. pter. (0.76); Dermatophagoides farinae (0.79); nDer p 1 (0.69); and rDer p 2 (0.72). At low sIgE concentrations (3.5 kU.l-1), rDer p 2 was more specific and better predicted an EAR (probability rDer p 2: 62%; D. pter.: 19%).

Surfactant proteins in pediatric interstitial lung disease.

BACKGROUND: Children's interstitial lung diseases (chILD) comprise a broad spectrum of diseases. Besides the genetically defined surfactant dysfunction disorders, most entities pathologically involve the alveolar surfactant region, possibly affecting the surfactant proteins SP-B and SP-C. Therefore, our objective was to determine the value of quantitation of SP-B and SP-C levels in bronchoalveolar lavage fluid (BALF) for the diagnosis of chILD. METHODS: Levels of SP-B and SP-C in BALF from 302 children with chILD and in controls were quantified using western blotting. In a subset, single-nucleotide polymorphisms (SNPs) in the SFTPC promoter were genotyped by direct sequencing. RESULTS: While a lack of dimeric SP-B was found only in the sole subject with hereditary SP-B deficiency, low or absent SP-C was observed not only in surfactant dysfunction disorders but also in patients with other diffuse parenchymal lung diseases pathogenetically related to the alveolar surfactant region. Genetic analysis of the SFTPC promoter showed association of a single SNP with SP-C level. CONCLUSION: SP-B levels may be used for screening for SP-B deficiency, while low SP-C levels may point out diseases caused by mutations in TTF1, SFTPC, ABCA3, and likely in other genes involved in surfactant metabolism that remain to be identified. We conclude that measurement of levels of SP-B and SP-C was useful for the differential diagnosis of chILD, and for the precise molecular diagnosis, sequencing of the genes is necessary.

Tobacco smoke particles and indoor air quality (ToPIQ-II) - a modified study protocol and first results.

BACKGROUND: Environmental tobacco smoke (ETS)-associated particulate matter (PM) has to be seen as an independent health hazard and needs to be discussed separately from the already well-known toxic and carcinogenic compounds contained in cigarette smoke. We believe that brand-specific amounts of PM are of public interest and should be investigated. METHODS: An automatic environmental tobacco smoke emitter was developed and placed into a glass-chamber to generate cigarette smoke as reliably as possible. Cigarettes were smoked automatically according to a standardized protocol. Mean concentrations (Cmean) and area under the curve (AUC) of PM2.5 released by the brands P&S, Virginia (without filter) and the 3R4F standard research cigarette of the University of Kentucky, USA, were measured and compared with each other. RESULTS: Cmean PM2.5 of 3R4F reference was 1,725 µg/m(3), for P&S: 1,982 µg/m(3) and for Virginia without filter: 1,525 µg/m(3). AUC PM2.5 for 3R4F reference was: 527,644 µg/m(3)×sec, for P&S: 606,171 µg/m(3)×sec, and for Virginia without filter: 464,788 µg/m(3)×sec. CONCLUSIONS: Our modified ToPIQ-II study protocol shows significant brand-specific differences in the amounts of PM2.5 released by cigarettes into the environment, when compared to 3R4F reference cigarettes. We believe that information about PM-release of all relevant brands in relation to reference cigarettes should be published. In the light of PM as an independent risk factor for morbidity and mortality, this may serve as a basis for further epidemiologic investigations.

Airborne particulate matter in public transport: a field study at major intersection points in Frankfurt am Main (Germany).

BACKGROUND: Chronic particulate matter (PM) exposure is correlated to various health effects, even at low amounts. WHO has defined PM concentration limits as daily and annual mean values which were made legally binding in the European Union. While many studies have focused on PM concentrations in special environments, little is known about the average PM- exposure for both employees and passengers in the German public transportation system. METHODS: Particulate matter (PM10, PM2.5, PM1) - concentrations were monitored for 30 minutes at 15 different areas in Frankfurt am Main with major public traffic. Maximum and mean concentrations and, as a surrogate for the inhaled dosage, the Area Under the Curve (AUC) for 15 minutes of exposure were calculated. RESULTS: The WHO limits for PM10 and PM2.5 were exceeded at nearly all times and areas. Highest maximum concentrations were found at underground stations, subterranean railway stations and subterranean shopping arcades with much lower values obtained at surface points. In one measurement at a surface test point smokers who neglected the non-smoking policy could be identified as a major cause for a at least temporary strong increase of PM-load as seen in high maximum values and normal averages. CONCLUSIONS: Subterranean areas have high particulate matter contamination exceeding WHO limits. Improvement may be achieved by increased ventilation. Subterranean shops and kiosks, being workplaces with long term exposure, should be equipped with external air supply. The non- smoking policy of the "Deutsche Bahn" for public spaces should be enforced.

Drug induced liver injury: accuracy of diagnosis in published reports.

The diagnosis of drug induced liver injury (DILI) is based primarily on the exclusion of alternative causes. To assess the frequency of alternative causes in initially suspected DILI cases, we searched the Medline database with the following terms: drug hepatotoxicity, drug induced liver injury, and hepatotoxic drugs. For each term, we used the first 100 publications. We reviewed references, selected those reports relevant to our study, and retrieved finally 15 publications related to DILI and alternative causes. A total of 2,906 cases of initially assumed DILI were analyzed in these 15 publications, with diagnoses missed in 14% of the cases due to overt alternative causes. In another 11%, the diagnosis of DILI could not be established because of confounding variables. Alternative diagnoses included hepatitis B, C, and E, CMV, EBV, ischemic hepatitis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, Gilbert's syndrome, fatty liver, non alcoholic steatohepatitis, alcoholic liver diseases, cardiac and thyroid causes, rhabdomyolysis, polymyositis, postictal state, tumors, lymphomas, chlamydial and HIV infections. Causality assessment methods applied in these 15 publications were the CIOMS (Council for International Organizations of Medical Sciences) scale alone (n = 5) or combined with the Maria and Victorino (MV) scale (n = 1), the DILIN (Drug-Induced Liver Injury Network) method (n = 4), or the Naranjo scale (n = 1); the qualitative CIOMS method alone (n = 3) or combined with the MV scale (n = 1). In conclusion, alternative diagnoses are common in primarily suspected DILI cases and should be excluded early in future cases, requiring a thorough clinical and causality assessment.

Particulate matter (PM) 2.5 levels in ETS emissions of a Marlboro Red cigarette in comparison to the 3R4F reference cigarette under open- and closed-door condition.

INTRODUCTION: Potential health damage by environmental emission of tobacco smoke (environmental tobacco smoke, ETS) has been demonstrated convincingly in numerous studies. People, especially children, are still exposed to ETS in the small space of private cars. Although major amounts of toxic compounds from ETS are likely transported into the distal lung via particulate matter (PM), few studies have quantified the amount of PM in ETS. STUDY AIM: The aim of this study was to determine the ETS-dependent concentration of PM from both a 3R4F reference cigarette (RC) as well as a Marlboro Red brand cigarette (MRC) in a small enclosed space under different conditions of ventilation to model car exposure. METHOD: In order to create ETS reproducibly, an emitter (ETSE) was constructed and mounted on to an outdoor telephone booth with an inner volume of 1.75 m3. Cigarettes were smoked under open- and closed-door condition to imitate different ventilation scenarios. PM2.5 concentration was quantified by a laser aerosol spectrometer (Grimm; Model 1.109), and data were adjusted for baseline values. Simultaneously indoor and outdoor climate parameters were recorded. The time of smoking was divided into the ETS generation phase (subset "emission") and a declining phase of PM concentration (subset "elimination"); measurement was terminated after 10 min. For all three time periods the average concentration of PM2.5 (Cmean-PM2.5) and the area under the PM2.5 concentration curve (AUC-PM2.5) was calculated. The maximum concentration (Cmax-PM2.5) was taken from the total interval. RESULTS: For both cigarette types open-door ventilation reduced the AUC-PM2.5 (RC: from 59 400 ± 14 600 to 5 550 ± 3 900 µg*sec/m3; MRC: from 86 500 ± 32 000 to 7 300 ± 2 400 µg*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 600 ± 150 to 56 ± 40 µg/m3, MRC from 870 ± 320 to 75 ± 25 µg/m3; p < 0.001) by about 90%. Cmax-PM2.5 was reduced by about 80% (RC: from 1 050 ± 230 to 185 ± 125 µg/m3; MRC: from 1 560 ±500 µg/m3 to 250 ± 85 µg/m3; p < 0.001). In the subset "emission" we identified a 78% decrease in AUC-PM2.5 (RC: from 18 600 ± 4 600 to 4 000 ± 2 600 µg*sec/m3; MRC: from 26 600 ± 7 200 to 5 800 ± 1 700 µg*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 430 ± 108 to 93 ± 60 µg/m3; MRC: from 620 ± 170 to 134 ± 40 µg/m3; p < 0.001). In the subset "elimination" we found a reduction of about 96-98% for AUC-PM2.5 (RC: from 40 800 ± 11 100 to 1 500 ± 1 700 µg*sec/m3; MRC: from 58 500 ± 25 200 to 1 400 ± 800 µg*sec/m3; p < 0.001) and Cmean-PM2.5 (RC: from 730 ± 200 to 27 ± 29 µg/m3; MRC: from 1 000 ± 450 to 26 ± 15 µg/m3; p < 0.001). Throughout the total interval Cmax-PM2.5 of MRC was about 50% higher (1 550 ± 500 µg/m3) compared to RC (1 050 ± 230 µg/m3; p < 0.05). For the subset "emission" - but not for the other periods - AUC-PM2.5 for MRC was 43% higher (MRC: 26 600 ± 7 200 µg*sec/m3; RC: 18 600 ± 4 600 µg*sec/m3; p < 0.05) and 44% higher for Cmean-PM2.5 (MRC: 620 ± 170 µg/m3; RC: 430 ± 108 µg/m3; p < 0.05). CONCLUSION: This method allows reliable quantification of PM2.5-ETS exposure under various conditions, and may be useful for ETS risk assessment in realistic exposure situations. The findings demonstrate that open-door condition does not completely remove ETS from a defined indoor space of 1.75 m3. Because there is no safe level of ETS exposure ventilation is not adequate enough to prevent ETS exposure in confined spaces, e.g. private cars. Additionally, differences in the characteristics of cigarettes affect the amount of ETS particle emission and need to be clarified by ongoing investigations.

Vocal cord dysfunction in adolescents.

RATIONALE FOR THE STUDY: Vocal cord dysfunction (VCD) often presents with dramatic and abrupt symptoms. To diagnose VCD, visualization by direct laryngoscopy is required and because patients are usually asymptomatic, a specific method to provoke VCD is needed. Approaches to predict VCD by alterations of the flow-volume loop have been investigated. METHODS: Adolescents with clinical suspicion of VCD were invited to participate. After an initial pulmonary function test (PFT), direct laryngoscopy was performed. This was followed by a methacholine challenge test (MCT); the methacholine dose causing a 20% drop in forced expiratory volume after 1 sec (FEV(1) ) (PD(20) FEV(1) ) was calculated. Then a second laryngoscopy was conducted. PFT changes before and after MCT were compared with the data of 14 healthy controls (HCs). RESULTS: Thirty-five patients (8-19 years) were investigated. Three showed anatomical alterations. Of the remaining 32 patients, 14 had VCD and 18 had bronchial hyperresponsiveness (non-VCD). In 29 patients with a positive MCT, PD(20) FEV(1) methacholine was significantly lower in VCD compared with non-VCD (VCD 0.24 ± 0.4 mg, non-VCD 0.73 ± 0.73 mg, P = 0.0006). A PD(20) FEV(1) < 0.24 mg methacholine predicted VCD with a sensitivity of 85% and a specificity of 75%. VCD patients showed significantly lower PFT parameters after challenge; FEV(1) : VCD 58.5 ± 20.1%, non-VCD 80.2 ± 18.0%, and HCs 98.7 ± 16.6% (P < 0.0001). CONCLUSIONS: The combination of MCT and laryngoscopy may be able to differentiate between VCD and non-VCD. VCD patients showed a positive reaction at lower methacholine doses and displayed greater airway obstruction after MCT. PFTs and MCT do not replace direct laryngoscopy in the diagnosis of VCD in adolescents.

Early impact of smoking on lung function, health, and well-being in adolescents.

BACKGROUND: Smoking is the single most important risk factor for the development of chronic obstructive pulmonary disease, and more than 80% of adult smokers started smoking before the age of 20. The aim of our study was to evaluate the early impact of smoking on lung function, health, and well-being in adolescents. METHODS: Twenty-four non-smokers (10 male, 14 female, mean age 17.6 years) and 24 smokers (mean of 3.5 pack-years; 15 male, 9 female, mean age 17.8 years) were compared in terms of lung function, bronchial hyperreactivity (BHR), levels of exhaled carbon monoxide (eCO), exhaled nitric oxide (eNO), and blood counts. A questionnaire containing items from the ISAAC study was used to detect differences in health and well-being. RESULTS: There were no significant differences in lung function values between non-smokers and smokers (VC 95% vs. 103%, FEV(1) 106% vs. 116%, FEV(1) %/VC MAX 94.6% vs. 95.2%), whereas BHR significantly differed (P < 0.05). Furthermore, significant differences were found for eCO, eNO, Hb, leukocytes, and neutrophils. Health and well-being in terms of sleep and physical activity were significantly worse in smokers. CONCLUSION: Our results suggest an early impact of smoking on health after as few as 3.5 pack-years. Early signs of smoking are an increase in BHR, changes in blood count and a decrease of eNO even before changes in lung function become apparent.

Predicting short term response to anti-inflammatory therapy in young children with asthma.

BACKGROUND: Currently available anti-inflammatory treatment for young children with asthma includes inhaled corticosteroids (ICS) and the leukotriene receptor antagonist (LTRA) montelukast. OBJECTIVE: To evaluate potential biomarkers of predicting short-term (6-week) response to ICS and LTRAs in children with asthma. METHODS: A total of 102 children aged 4 to 7 years with episodic asthma were enrolled in an open labelled single-centre study. Biomarkers and asthma characteristics were evaluated as predictors of treatment. Of 102 patients 45 became symptomatic during observation and were randomised to treatment either to montelukast or fluticasone for 6 weeks. RESULTS: Forced Expiratory Volume in one second (FEV1) increased with both treatments: FEV1 at randomisation was 90.2% and after therapy 106.8% with fluticasone vs. 90.8% and 103.7% for montelukast, respectively, showing that montelukast and fluticasone were equally effective in this age group (p = 0.44). Strong correlations to a favourable treatment response were pre-bronchodilatory FEV1 (p < 0.001) and airway reversibility (p = 0.04) at time of randomisation. None of the other biomarkers (methacholine testing, exhaled nitric oxide [eNO], presence of allergy, total Immunoglobulin E [IgE], cumulative specific IgE, eosinophils and parental smoking) were predictive. CONCLUSION: Despite the small sample size and the open-label design, the study suggests that the use of pre-bronchodilatory FEV1 and airway reversibility appears to be a good indicator of short-term anti-inflammatory therapy in young children with asthma.

Outpatient rehabilitation of workers with musculoskeletal disorders using structured workplace description.

OBJECTIVES: In most industrialized countries musculoskeletal disorders contribute considerably (25%) to illness induced work absence. A special interest to reduce worker absences exists in highly specialized industries such as jet manufacturing, where specific knowledge is hard to replace. We investigated the reduction and sustainability in sick leave days by a workplace oriented outpatient rehabilitation program based on structured information exchange between occupational physicians and therapists. METHODS: Sick leave days reduction and return-to-work-ratios were analysed for 79 male blue collar workers with musculoskeletal disease, who voluntarily participated in an outpatient rehabilitation treatment between 2002 and 2005. During rehabilitation therapy standardized workplace descriptions were given to the therapists and individual return-to-work (rtw) schemes were implemented. Therapy lasted from 3 to 4 weeks followed by workplace reintegration. Off-work-time was calculated from 0 to 6 years before and 0 to 3 years after rehabilitation from insurance and industrial medical reports. RESULTS: A total of 97% of the patients returned to their original job at the workplace, usually directly after the rehabilitation. Average sick leave days per year were reduced from 48.8 +/- 32.8 days before to 34.2 +/- 37.3 days after the rehabilitation. The therapy interrupted an increase in sick leave days over the years stabilizing absence at a low level for at least 2 years. Duration of illness related work absence was the only significant predictor for sick leave reduction (P < 0.05). Other common risk factors for musculoskeletal diseases like smoking or body mass index did not significantly influence the therapeutic effect. CONCLUSIONS: Our results support evidence that information exchange for workplace description and rehabilitation therapist may help to reduce sick leave days and achieve very high rtw-ratio. However it is important to observe the effects of this shared information for longer intervals.

Glycine affects valproate hepatotoxicity.

Valproate is a widely used anticonvulsant drug. Valproate is linked to hepatotoxicity which is rare but potentially lethal. The pathomechanism is not yet completely understood. Previous studies have shown a protective effect of glycine on this toxicity in rat hepatocytes (Vance et al., 1994). In the present study we investigated the hepatoxicity of 1-4 mM valproate in combination with glycine through absorption of neutral red from human hepatoma cells (Hep G2) in monolayer cell culture. Cell toxicity was measured by enzyme release with standard photometric test kits. In addition, a histomorphological evaluation was performed. A significant increase in the IC50 value of valproate cytotoxicity after addition of 12 mmol/l glycine was found. The average release of mitochondrial glutamate dehydrogenase as indicator of cell membrane damage decreased after addition of glycine. Cells treated with valproate in combination with 12 mmol/l glycine showed less histomorphological deformation of the nucleus and improved cell adherence. In conclusion a hepatoprotective effect of glycine on valproate-induced toxicity is also given in human hepatocytes. A nonspecific hepatoprotective effect of glycine can be assumed at least in vitro.

Occupational exposure to inhalable wood dust in the member states of the European Union.

The aim of this study was to estimate occupational exposure to inhalable wood dust by country, industry, the level of exposure and type of wood dust in 25 member states of the European Union (EU-25) for the purposes of hazard control, exposure surveillance and assessment of health risks. National labour force statistics, a country questionnaire (in 15 member states, EU-15), a company survey (in Finland, France, Germany and Spain), exposure measurements (from Denmark, Finland, France, Germany, The Netherlands and the United Kingdom) and expert judgements were used to generate preliminary estimates of exposure to different types of wood dust. The estimates were generated according to industrial class (six wood industries, four other sectors) and level of exposure (five classes). These estimates were reviewed and finalized by national experts from 15 member states. Crude estimates were generated also for 10 new member states (EU-10). The basic data and final estimates were included in the WOODEX database. In 2000-2003, about 3.6 million workers (2.0% of the employed EU-25 population) were occupationally exposed to inhalable wood dust. Of those, construction employed 1.2 million exposed workers (33%), mostly construction carpenters. The numbers of exposed workers were 700,000 (20%) in the furniture industry, 300,000 (9%) in the manufacture of builders' carpentry, 200,000 (5%) in sawmilling, 150,000 (4%) in forestry and <100,000 in other wood industries. In addition, there were 700,000 exposed workers (20%) in miscellaneous industries employing carpenters, joiners and other woodworkers. The numbers of exposed workers varied by country ranging from <3,000 in Luxembourg and Malta to 700,000 in Germany. The highest exposure levels were estimated to occur in the construction sector and furniture industry. Due to limited exposure data there was considerable uncertainty in the estimates concerning construction woodworkers. About 560,000 workers (16% of the exposed) may be exposed to a level exceeding 5 mg m(-3). Mixed exposure to more than one species of wood and dust from wooden boards was very common, but reliable data on exposure to different species of wood could not be retrieved. This kind of assessment procedure integrating measurement data, company data, country-specific data and expert judgement could also serve as one model for the assessment of other occupational exposures.

Severe isolated pulmonary Langerhans cell histiocytosis in a 6-year-old girl.

UNLABELLED: Langerhans cell histiocytosis (LCH) usually affects different organs or bones. Isolated pulmonary disease is rare in childhood. We report about a 6-year-old girl with progressive pulmonary insufficiency, onset of clubbing at 4 years of age and honeycombing lung infiltrations on X-ray films. The radiological suspicion of primary pulmonary LCH was confirmed by the presence of CD1a positive cells in the bronchoalveolar lavage fluid. Other organs were not involved. The girl was treated according to the LCH-III International Study Protocol with a good response. Follow-up showed no reactivation of LCH but a reduced vital capacity and signs of interstitial pulmonary involvement on a CT scan. CONCLUSION: Langerhans cell histiocytosis should be considered in the aetiology of cystic lung diseases. Early responders to treatment have a high likelihood of becoming free of disease. However, pulmonary fibrosis is an important mechanism of lung remodelling in pulmonary Langerhans cell histiocytosis and the long-term prognosis is unclear.