Alterations in the coagulation system of active smokers from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study.

Smoking is an important and preventable risk factor of cardiovascular diseases with effects on blood coagulation. Our aim was to analyze the influence of smoking on coagulation parameters. Concentrations or activities of blood coagulation factors were compared in 777 active smokers and 1,178 lifetime non-smokers of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. The association with mortality was examined using Cox regression. The findings show that AS had a tendency toward thrombosis. They displayed significantly higher values for fibrinogen, soluble fibrinogen, factor XIII, and tissue factor pathway inhibitor; whereas FVII, FVIII, FXII, von Willebrand factor (vWF), and thrombomodulin were decreased. The Cox regression analysis showed fibrinogen, FVIII, vWF, thrombomodulin, and tissue factor pathway inhibitor to be independent risk factors for mortality in active smokers with hazard ratios of 1.16 (95% CI: 1.02-1.31), 1.40 (1.22-1.59), 1.37 (1.22-1.56), 1.19 (1.07-1.31), and 1.22 (1.06-1.40) per increase of one standard deviation. We conclude that active smokers have an increased thrombogenic potential associated with significant changes in the coagulation system. Individual parameters of the coagulation system are independent predictors of mortality. Therefore, parameters of the coagulation system, apart from other risk factors for cardiovascular disease (e.g., lipids or life-style) should be determined for risk prediction in active smokers.

C-reactive protein and lipoprotein-associated phospholipase A2 in smokers and nonsmokers of the Ludwigshafen Risk and Cardiovascular Health study.

Measurement of high sensitivity CRP (hsCRP) and lipoprotein-associated phospholipase A2 (LpPLA2) provides information on systemic inflammation and stability of atherosclerotic plaques. Data analyzing the effect of smoking on these parameters are sparse. The aim of our study was the analysis of these parameters in active smokers and never-smokers. The study included 777 smokers and 1,178 never-smokers, of whom 221 and 302 died during a follow-up, respectively. The values of LpPLA2 and hsCRP were significantly higher in smokers than in never-smokers. Mortality was highest in smokers and never-smokers with elevation of both biomarkers. Multivariate adjusted hazard ratios for patients in the highest tertile of both hsCRP and LpPLA2 compared with patients in the lowest tertile of both markers were 1.85 (1.04-3.28) in never-smokers and 1.94 (1.10-3.45) in smokers. Our data confirmed the predictive value of hsCRP and LpPLA2. However, there were a relevant number of patients with an increase of only one of these parameters. Therefore, beside other risk factors for cardiovascular disease, both parameters should be determined at least in high risk patients.

Impact of traffic-related air pollution on health.

Road transport contributes significantly to air quality problems through vehicle emissions, which have various detrimental impacts on public health and the environment. The aim of this study was to assess the impact of traffic-related air pollution on health of Warsaw citizens, following the basics of the Health Impact Assessment (HIA) method, and evaluate its social cost. PM10 was chosen as an indicator of traffic-related air pollution. Exposure-response functions between air pollution and health impacts were employed. The value of statistical life (VSL) approach was used for the estimation of the cost of mortality attributable to traffic-related air pollution. Costs of hospitalizations and restricted activity days were assessed basing on the cost of illness (COI) method. According to the calculations, about 827 Warsaw citizens die in a year as a result of traffic-related air pollution. Also, about 566 and 250 hospital admissions due to cardiovascular and respiratory diseases, respectively, and more than 128,453 restricted activity days can be attributed to the traffic emissions. From the social perspective, these losses generate the cost of 1,604 million PLN (1 EUR-approx. 4.2 PLN). This cost is very high and, therefore, more attention should be paid for the integrated environmental health policy.

Inhalation of macrolides: a novel approach to treatment of pulmonary infections.

Systemic antibiotic treatment is established for many pulmonary diseases, e.g., cystic fibrosis (CF), bronchiectasis and chronic obstructive pulmonary disease (COPD) where recurrent bacterial infections cause a progressive decline in lung function. In the last decades inhalative administration of antibiotics was introduced into clinical routine, especially tobramycin, colistin, and aztreonam for treatment of CF and bronchiectasis. Even though they are important in systemic treatment of these diseases due to their antimicrobial spectrum and anti-inflammatory and immunomodulatory properties, macrolides (e.g., azithromycin, clarithromycin, erythromycin, and telithromycin) up to now are not administered by inhalation. The number of in vitro aerosol studies and in vivo inhalation studies is also sparse. We analyzed publications on preparation and administration of macrolide aerosols available in PUBMED focusing on recent publications. Studies with solutions and dry powder aerosols were published. Publications investigating physicochemical properties of aerosols demonstrated that macrolide aerosols may serve for inhalation and will achieve sufficient lung deposition and that the bitter taste can be masked. In vivo studies in rats demonstrated high concentrations and areas under the curve sufficient for antimicrobial treatment in alveolar macrophages and epithelial lining fluid without lung toxicity. The obtained data demonstrate the feasibility of macrolide inhalation which should be further investigated.

Smoking denial in cardiovascular disease studies.

Assessment of self-reported smoking behavior in cardiovascular studies may lead to inaccurate measures of nicotine exposure. A more objective measurement of nicotine exposure can be done by measurement of plasma cotinine levels. The aim of the present study was to define the rate of discordance between the self-reported smoking behavior and biochemically defined smoking status. Data from 3,316 patients hospitalized for coronary angiography, who completed a questionnaire on smoking behavior, were analyzed. As a biochemical assessment of smoking status we used a cut-off serum cotinine level of 15 µg/l. Smoking denial, defined as a discrepancy between high cotinine levels and self-reported never- or ex-smoking status, was observed in 3.7 % of the study participants. In a logistic regression analysis with a step-wise inclusion of sex, age, CAD, previous MI, and educational level, only male sex (odds ratio male/female: 2.00, 95 % CI 1.22-3.33; p = 0.007) and age (odds ratio per year: 0.79, 95 % confidence interval 0.66-0.94, p = 0.008) were associated with smoking denial. In conclusion, a misclassification rate of 3.7 % in the evaluation of such an important risk factor may lead to blurred effects and favor false negative results. The results of the present study substantiate the importance of biochemical markers for smoking assessment in cardiovascular studies.

Market surveillance of in vitro diagnostics by the BfArM until end 2010: safety of IVD for therapeutic drug monitoring.

The European Directive 98/79/EC on in vitro diagnostic medical devices (IVD) regulates the marketing and post market surveillance of IVD in the European Economic Area. In cases of incidents and field corrective actions, the manufacturers have to inform the responsible Competent Authorities (CA). In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD. In this study all notifications regarding IVD for therapeutic drug monitoring (TDM) between begin 1999 until end of 2010 were analysed. A total of 2,851 notifications were received, of which 65 were related to IVD for TDM included in this study (54 tests vs. 11 analysers). Reports were received from manufacturers (58), CAs (5 cases) and users (2 cases). Most frequently IVD used for TDM of toxicologically relevant substances, antibiotics, antiepileptics and immunosuppressives were affected. Investigations of the manufacturers were able to identify the underlying root causes of product failures in 50 cases (76.9%), 40 (74.1%) of which were tests and 10 (90.9%) analysers. In 11 cases (16.9%, all tests), the root cause remained unclear and in 4 cases (6.2%, 3 tests, 1 analyser) a product failure was excluded. Product failures in tests were most commonly material defects (12 cases), interferences (7 cases) and manufacturing errors (7 cases), whereas in the analyser group software errors (5 cases) were most common. Corrective actions were performed in 56 cases (86.2%); 46 (85.2%) in tests, and 10 (90.9%) in analysers. In the group of tests these were predominantly (multiple entries) customer information (46 cases, mandatory in case of a recall), recall (29 cases), modifications in production or quality management (29 cases) and modifications of the instructions for use (9 cases). However, in the analyser group corrective actions were typically customer information (10 cases), recall (5 cases) and software-update (4 cases). The obtained data demonstrate that there are differences in the type of product failures between analysers and tests, which are followed by different corrective actions depending on the root causes of product failure accordingly. The results and the experience since 1999 suggest that the system for post marketing surveillance of IVD is an established tool to enhance product safety even though further optimisation is possible.

Market surveillance of in vitro diagnostics by the BfArM until end 2010: how safe are products for tumor diagnostics?

The European Directive 98/79/EC on in vitro diagnostic medical devices (IVD) regulates the marketing and post market surveillance of IVD in the European Economic Area. In cases of incidents and field corrective actions the manufacturers have to inform the responsible Competent Authorities (CA). In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD. In this study all notifications regarding IVD (tests, calibrators, kits, and control materials, except laboratory analyzers) for tumor diagnostics received by the BfArM between begin 1999 until end of 2010 were analyzed. All notifications were analyzed in respect to the type of product, the source of notification, the underlying product defects and the corrective actions performed. In the observation period, a total of 2,851 notifications were received of which 84 were related to IVD for tumor diagnostics included in this study (clinical chemistry - 63, histology - 6, molecular biology - 3, rapid tests - 12). Reports were received from manufacturers (68 cases), CA (8 cases), users (4 cases) and other sources (4 cases). In the group of IVD based on clinical chemistry means, the affected products were mostly those for the measurement of prostate specific antigen (PSA, 14 cases), human chorion gonadotropine (13 cases), carcino embryonic antigen (6 cases), CA 19-9 (6 cases), α(1)-fetoprotein (6 cases) and CA 125 (5 cases), whereas in test strips 9 out of the 12 notifications were related to PSA. Investigations of the manufacturers were able to identify the underlying root causes of product failures in 66 cases (78.6%). In 10 cases (11.9%) the root cause remained unclear and in 6 cases and 2 cases (7.1% and 2.4%) a product failure was excluded or a user error was the underlying cause. Most common root causes of product failures were material defects (24 cases) and manufacturing errors (15 cases). Corrective actions were performed by the manufacturers in 64 cases (76.2%) and were predominantly (multiple entries possible) customer information (62 cases, mandatory in case of a recall), recalls (45 cases), modifications in production or quality management (45 cases) and design changes (14 cases). The obtained results suggest that the system for post marketing surveillance of IVD is an established tool to enhance product safety and provides valuable information on product specific problems serving for improvement of product safety.

Detection of hyphomycetes in the upper respiratory tract of patients with cystic fibrosis.

The respiratory tract of cystic fibrosis patients is colonised by bacteria and fungi. Although colonisation by slow growing fungi such as Pseudallescheria, Scedosporium and Exophiala species has been studied previously, the colonisation rate differs from study to study. Infections caused by these fungi have been recognised, especially after lung transplants. Monitoring of respiratory tract colonisation in cystic fibrosis patients includes the use of several semi-selective culture media to detect bacteria such as Pseudomonas aeruginosa and Burkholderia cepacia as well as Candida albicans. It is relevant to study whether conventional methods are sufficient for the detection of slow growing hyphomycetes or if additional semi-selective culture media should be used. In total, 589 respiratory specimens from cystic fibrosis patients were examined for the presence of slow growing hyphomycetes. For 439 samples from 81 patients, in addition to conventional methods, erythritol-chloramphenicol agar was used for the selective isolation of Exophiala dermatitidis and paraffin-covered liquid Sabouraud media for the detection of phaeohyphomycetes. For 150 subsequent samples from 42 patients, SceSel+ agar was used for selective isolation of Pseudallescheria and Scedosporium species,and brain-heart infusion bouillon containing a wooden stick for hyphomycete detection. Selective isolation techniques were superior in detecting non-Aspergillus hyphomycetes compared with conventional methods. Although liquid media detected fewer strains of Exophiala, Pseudallescheria and Scedosporium species, additional hyphomycete species not detected by other methods were isolated. Current conventional methods are insufficient to detect non-Aspergillus hyphomycetes, especially Exophiala, Pseudallescheria and Scedosporium species, in sputum samples of cystic fibrosis patients.

Lung deposition of inhaled alpha-1-proteinase inhibitor (alpha 1-PI) - problems and experience of alpha1-PI inhalation therapy in patients with hereditary alpha1-PI deficiency and cystic fibrosis.

Alpha-1-proteinase inhibitor (α1-PI) is the most relevant protease inhibitor in the lung. Patients with hereditary deficiency of α1-PI suffer from an impaired hepatic synthesis of α1-PI in the liver and in consequence an insufficient concentration of the protease inhibitor in the lung followed by development of lung emphysema due to an impaired protease antiprotease balance and a local relative excess of neutrophil elastase (NE). In contrast, patients with cystic fibrosis (CF) are characterised by a normal synthesis of α1-PI and a severe pulmonary inflammation with a strong excess of NE in the lung followed by progressive loss of lung function. In principle, both patient groups may benefit from an augmentation of α1-PI. Intravenous augmentation, which is established in patients with α1-PI deficiency only, is very expensive, subject to controversial discussions and only about 2% of the administered protein reaches lung interstitium. Inhalation of α1-PI may serve as an alternative to administer high α1-PI doses into the lungs of both patient groups to restore the impaired protease antiprotease balance and to diminish the detrimental effects of NE. However, prerequisites of this therapy are the reproducible administration of sufficient doses of active α1-PI into the lung without adverse effects. In our review we describe the results of studies investigating the inhalation of α1-PI in patients with α1-PI deficiency and CF. The data demonstrate the feasibility of α1-PI inhalation for restoration of the impaired protease antiprotease balance, attenuation of the inflammation and neutralisation of the excess activity of NE. Likely, inhalation of α1-PI serves as cheaper and more convenient therapy than intravenous augmentation. However, inhalation will be further optimised by use of novel nebulisers and optimised breathing techniques.

Field safety notices released by manufacturers in cases of failure of products for infection testing: analysis of cases reported to the BfArM between 2005 and 2007.

The European Directive 98/79/EC for in vitro diagnostic medical devices (IVD) regulates marketing and post marketing surveillance of IVD in the European Economic Area. Manufacturers have to inform the responsible Competent Authorities (CA) about incidents and field safety corrective actions (FSCA) related to IVD. In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD, only few IVD as specified in Annex II of the Directive are under the responsibility of the Paul Ehrlich Institute (PEI). In case of a FSCA manufacturers have to inform customers by means of a Field Safety Notice (FSN) which should be sent to BfArM prior to release and is published on the BfArM homepage. Between beginning of 2005 and end of 2007 the BfArM received a total of 1025 reports regarding IVD. From these, 38 related to tests, reagents, calibrators, and control materials for infection testing, 13 related to analysers and general consumables (n = 8 and n = 5, respectively) based on culture techniques, and 7 related to analysers and general consumables (n = 5 and n = 2, respectively) based on molecular biological methods. FSCA were performed in Germany in 32 (84.2%) of all notifications related to tests reagents, calibrators, and control materials as well as in 13 (100%) and 7 (100%) of notifications related to analysers and consumables based on culture techniques and molecular biological methods, respectively. A number of relevant deficiencies regarding the quality of the FSN were separately demonstrated for FSN in German and English language. In brief, manufacturers often sent their FSN to the BfArM with delay. Additionally, a subset of FSN provided insufficient information on the product related risks or the measures to be performed by the customer to mitigate product related risks. Furthermore, customer confirmation forms often were missing in the FSN sent to the BfArM. Our data suggest that for IVD for infection testing FSCA and FSN are frequently performed. For better vigilance performance, manufacturers could shorten the time until release and improve the contents of FSN to ensure the safety of IVD in cases of product related corrective actions.

[Safety of high risk in vitro diagnostic medical devices : international and national measures]. / Die Sicherheit von Hochrisiko-in-vitro-Diagnostika : Internationale und nationale Massnahmen.

The European Directive 98/79/EC for in vitro diagnostic medical devices (IVD) [1] regulates the marketing and post marketing surveillance of IVD in the European Union. In accordance with this regulation, those legally responsible for the IVD product have to report all incidents and corrective measures with IVD to the national competent authority. In Germany, these are the Federal Institute for Drugs and Medical Devices (BfArM) and for high risk products, as specified in Annex II of the Directive 98/79/EC, the Paul Ehrlich Institute (PEI). From 2002 to 2007, PEI registered 204 reports concerning incidents with and recalls of IVD medical devices. The majority of incident reports (84.4%) were sent by IVD manufacturers to the PEI. The reporting ratio of the IVD users amounted to 8.5%; in 12 cases (7.1%) PEI was informed via Vigilance Reports from other European competent authorities concerning incidents and recalls with IVD. The experience from 6 years' IVD surveillance showed that the German market surveillance system ensures a high level of safety concerning the in vitro diagnostic medical devices of Annex II list A and B of Directive 98/79/EC. However, the current system can be further optimized.

Treatment of systemic diseases by inhalation of biomolecule aerosols.

Clinical experience since many years has shown that aerosol inhalation is an established route for the treatment of pulmonary diseases. In contrast, treatment of systemic diseases by means of aerosol inhalation is a novel therapeutic approach. This was caused for a long time by a lack of accuracy, efficiency, and reproducibility of the administered drug doses due to a poor knowledge of the physiological background of aerosol inhalation, an insufficient inhaler technology as well as a suboptimal breathing procedure. However, these problems have been solved in the last years and nowadays modern aerosol delivery systems allow the production of an aerosol with a defined and optimised particle size combined with an optimized breathing maneuver and optimization of the efficacy of the technology. Clinical studies demonstrated that only a small number of morphological factors (e.g., exogen allergic alveolitis, active sarcoidosis, active smoking) influence alveolar drug deposition and the inhaled systematically active compounds caused no relevant allergic reactions even after inhalation for longer time periods. Up to now, most data are available for the inhalation of insulin which has been introduced in clinical treatment for a short time. However, a lot of other molecules have been tested in aerosol inhalation studies. This review describes some examples other than insulin in the field of inhalant treatment of systemic diseases.

Selective isolation of Pseudallescheria and Scedosporium species from respiratory tract specimens of cystic fibrosis patients.

BACKGROUND: Fungi of the Pseudallescheria/Scedosporium complex are known to be colonizers and infectious agents of the respiratory tract of cystic fibrosis (CF) patients. Colonized CF patients are at high risk for the development of disseminated scedosporiosis after lung transplantation. The detection of these fungi may be difficult, because they grow slowly and so will be overgrown by faster-developing microorganisms on the media routinely used in diagnostic laboratories. OBJECTIVES: To examine the usefulness of the isolation medium SceSel+ agar as a diagnostic tool for clinical samples from CF patients. METHODS: 150 respiratory tract samples from 42 CF patients were inoculated on SceSel+ agar. During the incubation phase, which lasted up to 30 days at 36 +/- 1 degrees C, the cultures were inspected every 2 or 3 days. RESULTS: The isolation of Scedosporium species was successful in 3 samples (2%) with standard microbiological media and procedures, while the isolation rate on SceSel+ agar was 5.3% (8 of 150 specimens). CONCLUSIONS: Our results suggest that standard microbiological media and procedures are not sufficient to detect colonization of the respiratory tract by Pseudallescheria/Scedosporium in CF patients. By use of SceSel+ agar, fungi belonging to this complex were isolated more frequently. Therefore, this semiselective mycological isolation medium should be used for the detection of these fungi in the respiratory tract of CF patients, especially in patients in whom a fungal infection is assumed or who are scheduled for lung transplantation.

Influence of smoking and body weight on adipokines in middle aged women.

OBJECTIVE: Quitting smoking was associated with an undesirable weight gain. Both, cigarette smoking and obesity were accompanied by subclinical systemic inflammation. This may cause unfavourable changes in (plasma) adipokine concentration. The aim of the present study was to establish the influence of moderate cigarette smoking on the concentration of the adipokines leptin and adiponectin and the pro-inflammatory factors CRP, SAA, IL-6 and TNF-a in non-obese (n=138) and obese (n=175) perimenopausal women of the DRECAN-2005 survey. RESULTS: Among non-obese women, adiponectin was significantly lower in smokers than in non-smokers (16.88 +/-6.85 vs. 20.63 +/-10.04 microg/ml; P<0.05). Leptin tended to lower values, too. Among obese women, none significant differences in adiponectin or leptin concentration were observed between smokers and non-smokers. In obese smokers and obese non-smokers, the adiponectin concentrations were significantly lower and the leptin concentrations were significantly higher than in non-obese non-smokers. Non-obese smokers showed significantly higher leukocyte count (6.50 +/- 1.83 vs. 5.51 +/- 1.31 GPT/l; P<0.001) and serum amyloid A concentration (7.81 +/- 1.25 vs. 4.22 +/- 1.43 mg/l; P<0.05) than non-obese non-smokers. There were only tendencies to higher concentration of CRP, IL-6, and TNF-alpha. In obese women, moderate cigarette smoking was not associated with higher leukocyte count or concentration of SAA. Among non-smokers, overweight was associated higher concentration of leptin (22.16 +/- 12.16 vs. 11.49 +/- 6.37 ng/ml; P<0.001) and with significantly lower concentration of adiponectin (16.29 +/- 8.01 vs. 20.77 +/- 9.99 microg/ml; P<0.001). Among smokers, overweight was associated with higher leptin concentration only (obese: 18.62 +/- 13.46 vs. non-obese: 8.84 +/- 4.92 ng/ml; P<0.01). CONCLUSIONS: In non-obese middle aged women, even moderate cigarette smoking adversely influences the serum concentration of adiponectin and SAA. Overweight hides possible effects of smoking on cytokines and adipokines.

Novel devices for individualized controlled inhalation can optimize aerosol therapy in efficacy, patient care and power of clinical trials.

In the treatment of pulmonary diseases the inhalation of aerosols plays a key role - it is the preferred route of drug delivery in asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. But, in contrast to oral and intravenous administration drug delivery to the lungs is controlled by additional parameters. Beside its pharmacology the active agent is furthermore determined by its aerosol characteristics as particle diameter, particle density, hygroscopicity and electrical charge. The patient related factors like age and stage of pulmonary disease will be additionally affected by the individual breathing pattern and morphometry of the lower airways. A number of these parameters with essential impact on the pulmonary drug deposition can be influenced by the performance of the inhalation system. Therefore, the optimization of nebulisation technology was a major part of aerosol science in the last decade. At this time the control of inspiration volume and air flow as well as the administration of a defined aerosol bolus was in the main focus. Up to date a more efficient and a more targeted pulmonary drug deposition - e.g., in the alveoli - will be provided by novel devices which also allow shorter treatment times and a better reproducibility of the administered lung doses. By such means of precise dosing and drug targeting the efficacy of inhalation therapy can be upgraded, e.g., the continuous inhalation of budesonide in asthma. From a patients' perspective an optimized inhalation manoeuvre means less side effects, e.g., in cystic fibrosis therapy the reduced oropharyngeal tobramycin exposure causes fewer bronchial irritations. Respecting to shorter treatment times also, this result in an improved quality of life and compliance. For clinical trials the scaling down of dose variability in combination with enhanced pulmonary deposition reduces the number of patients to be included and the requirement of pharmaceutical compounds. This review summarises principles and advances of individualised controlled inhalation (ICI) as offered by the AKITA inhalation system.

Safety of laboratory analyzers for infection testing - results of the market surveillance by the BfArM until End 2007.

The European Directive 98/79/EC on in vitro diagnostic medical devices (IVD) stipulates the marketing and post market surveillance of IVD in the European Economic Area. In cases of issues and field corrective actions, the manufacturers have to inform the responsible Competent Authorities (CA). In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible CA for most IVD, with a small subset of IVD for immune hematological and infectiological testing as well as tissue typing as specified in Annex II of the Directive, being within the responsibility of the Paul-Ehrlich-Institute (PEI). In this study, all issues regarding laboratory analyzers for infection testing and their consumables, but not reagents, kits and general culture media, reported to the BfArM between begin 1999 and end of 2007 were analyzed in respect to the sources of report, the underlying product failure and the performed corrective actions. Within the observation period a total of 1471 reports for IVD were received of which 73 related to the IVD for infection testing were included in our study. Reports were predominantly received from manufacturers (56) and competent authorities (15). Affected products were most frequently those for immunological analysis (42) whereas those based on culturing techniques (17) and molecular biological techniques (14) played only minor roles. In all these groups, laboratory analyzers (55) were more frequently affected than their consumables (18). Investigations of the manufacturers were able to identify the underlying root causes of product failures in 62 cases (84.9%). In 2 cases (2.7%) the root cause remained unclear and in 9 cases (12.3%) a product failure was excluded or a user error was the underlying cause. Product failures in laboratory analyzers were most frequently caused by software errors (31) and constructional faults (8) whereas the predominant cause of product failure in consumables were errors in production and quality control (8). Manufacturers issued corrective measures in 66 cases (90.4%) from which 49 and 17 were related to laboratory analyzers and their consumables, respectively. Based on the underlying root causes of product failures these were predominantly customer information (48), recalls (40), software-updates (30) and design changes (9) in the product group of laboratory analyzers as well as customer information (16), recalls (12) and modifications of production and quality management (11) in the group of consumables. The results and experiences obtained since 1999 suggest that the system for post marketing surveillance of IVD is an established tool to ensure product safety, even though the current system can be further enhanced.

Effect of HMG CoA reductase inhibitors on low-density lipoprotein cholesterol and C-reactive protein: systematic review and meta-analysis.

OBJECTIVE: HMG CoA reductase inhibitors (statins) have been claimed to decrease C-reactive protein (CRP), independent of their effect on low-density lipoprotein cholesterol (LDL-C). We conducted a systematic review and meta-analysis to investigate whether a relationship between the average effect of statins on LDL-C and CRP exists. DATA SOURCES: The literature search of the Medline and Cochrane databases between 1980 and August 2007 yielded 65 statin intervention studies with 94 treatment arms involving 16,260 patients reporting changes in both LDL-C and CRP. DATA EXTRACTION AND STATISTICAL METHOD: From each study relative changes in LDL-C and CRP were extracted. Random effects meta-analysis was used to obtain pooled summary estimates of the average study specific LDL-C and CRP reductions, in total and stratified by dose and type of statin. Weighted correlation analysis and metaregression analysis was used to investigate the relationship between the LDL-C and CRP changes adjusted for baseline values, type of statin and dose. RESULTS: Pooled summary estimates of statin-induced changes in LDL-C and CRP levels were -34.7% (95% CI: -37.7% to -31.8%) and -30.8% (95% CI: -39.4% to -22.3%), respectively. We found a positive correlation between the average LDL-C and CRP reduction (r = 0.49, p = 0.010) which increased when adjusting for pre-treatment concentrations (r = 0.79, p < 0.001). The effect of statins on CRP were strongly related to the changes in LDL-C and baseline concentrations, independent of the type and dose of statin used. CONCLUSION: Our meta-analysis shows a strong correlation between statin-induced reductions in LDL-C and CRP, which has not been evident from individual studies. Measuring CRP in addition to LDL-C in the monitoring of statin treatment is currently not warranted.

[Are test systems for diagnostics of infectious diseases safe? Experiences of the BfArM based on all notifications received until end of 2005]. / Wie sicher sind Testsysteme zur Diagnostik von Infektionskrankheiten? Erfahrungen des Bundesinstitutes für Arzneimittel und Medizinprodukte mit den dort bis Ende 2005 eingegangenen Meldungen.

The European Directive 98/79/EC for in vitro diagnostic medical devices (IVD) regulates the marketing and post marketing surveillance of IVD in the European Economic Area. Manufacturers have to inform the responsible Competent Authorities about incidents and field corrective actions related to IVD. In Germany, the Federal Institute for Drugs and Medical Devices (BfArM) is the responsible Competent Authority for most IVD, while a small subset of IVD, specified in Annex II of the Directive 98/79/EC for immune hematological and infectiological testing as well as tissue typing, is under the responsibility of the Paul-Ehrlich-Institute (PEI). Until the end of 2005 the BfArM received a total of 653 notifications regarding IVD. From these 115 related to IVD for analysis of the infection status (reagents, control materials, calibrators, culture media and analyzing equipment). Most of the reports originated from manufacturers (57.4 %), while other sources of reports played only minor roles. Product failures of test reagents, control materials, calibrators as well as culture media were frequently caused by manufacturing errors and biological contamination. Analyzing equipment was typically affected by software malfunction. Through the investigations of the manufacturers product failures were confirmed in most cases and consequently corrective actions were performed in the large majority of incidents. The corrective actions frequently included customer information, product recalls, changes in the production process and/or the quality management or software upgrades for the analyzing equipment. Our data suggest that the existing system for post marketing surveillance is an important tool to ensure product safety of IVD even though it should be further optimized in the future.

Systemic treatment by inhalation of macromolecules--principles, problems, and examples.

Aerosol inhalation is an established route of medical administration for the treatment of pulmonary diseases. In contrast, aerosol inhalation for treatment of systemic diseases is a novel therapeutic approach. Clinical use of the latter therapy for many years has been limited by the lack of accuracy, efficiency, and reproducibility of the administered doses. Usually, only a small fraction of inhaled drug reached the target region within the lungs. Further problems were the risk of potential allergic reactions in the respiratory tract and a potential variability of drug absorption from the alveoli into the circulation. These problems have been solved in the last years by modern aerosol delivery systems allowing the production of an aerosol with a defined and optimised aerosol particle size combined with an optimized breathing maneuver and optimization of the efficacy of the technology. Furthermore, there were no observations of relevant allergic reactions after inhalation of systemically active drugs in numerous studies. Studies demonstrated that only a small number of morphological factors influence alveolar drug deposition (e.g., exogen allergic alveolitis, active sarcoidosis, active smoking). In consequence, an increasing number of studies investigated the systemic effect of inhaled high molecular weight substances (e.g., insulin, heparin, interleukin-2) and demonstrated that controlled aerosol therapy may serve as a non-invasive alternative for drug application by means of a syringe. Our review briefly summarizes the mechanisms for pulmonary absorption of macromolecules and gives an overview on prior research in the field of inhalant treatment of systemic diseases.

Inhaled insulin--does it become reality?

After more than 80 years of history the American and European Drug Agencies (FDA and EMEA) approved the first pulmonary delivered version of insulin (Exubera) from Pfizer/Nektar early 2006. However, in October 2007, Pfizer announced it would be taking Exubera off the market, citing that the drug had failed to gain market acceptance. Since 1924 various attempts have been made to get away from injectable insulin. Three alternative delivery methods where always discussed: Delivery to the upper nasal airways or the deep lungs, and through the stomach. From these, the delivery through the deep lungs is the most promising, because the physiological barriers for the uptake are the smallest, the inspired aerosol is deposited on a large area and the absorption into the blood happens through the extremely thin alveolar membrane. However, there is concern about the long-term effects of inhaling a growth protein into the lungs. It was assumed that the large surface area over which the insulin is spread out would minimize negative effects. But recent news indicates that, at least in smokers, the bronchial tumour rate under inhaled insulin seems to be increased. These findings, despite the fact that they are not yet statistical significant and in no case found in a non-smoker, give additional arguments to stop marketing this approach. Several companies worked on providing inhalable insulin and the insulin powder inhalation system Exubera was the most advanced technology. Treatment has been approved for adults only and patients with pulmonary diseases (e.g., asthma, emphysema, COPD) and smokers (current smokers and individuals who recently quitted smoking) were excluded from this therapy. Pharmacokinetics and pharmacodynamics of Exubera are similar to those found with short-acting subcutaneous human insulin or insulin analogs. It is thus possible to use Exubera as a substitute for short-acting human insulin or insulin analogs. Typical side effects of inhaled insulin were coughing, shortness of breath, sore throat and dry mouth. Physical exercise increases the transport of inhaled insulin into the circulation and in consequence the likelihood of hypoglycemia. Other problems were the inability to deliver precise insulin doses, because the smallest blister pack available contained the equivalent of 3 U of regular insulin and this dose would make it difficult for many people using insulin to achieve accurate control, which is the real goal of any insulin therapy. For example, someone on 60 U of insulin per day would lower the blood glucose about 90 mg/dl (5 mmol) per 3 U pack, while someone on 30 U a day would drop 180 mg/dl (10 mmol) per pack. Precise control was not possible, especially compared with an insulin pump that can deliver one twentieth of a unit with precision. Another disadvantage was the size of the device. The Exubera inhaler, when closed, was about the size of a 200 ml water glass. It opened to about twice the size for delivery. To our information also other companies (Eli Lilly in cooperation with ALKERMES, Novo Nordisk (AERx, Liquid), Andaris (Powder)) stopped further development and it is unclear whether an inhaled form of insulin will ever be marketed, because of the problems that have occurred. Only Mannkind (Technosphere, Powder) is still working on a Phase III trial. However, our review will briefly summarize the experience regarding inhalant administration of insulin and will describe potential future developments for this type of therapy focussing on the lung.