Comparison of in vitro closure time (PFA-100) with whole blood electrical aggregometry and platelet surface antigen expression in healthy volunteers

It was the aim of this study to compare in vitro closure time (PFA-100), reflecting platelet-related primary hemostasis, to more platelet-specific tests like whole blood electrical aggregometry and platelet surface antigen expression in healthy volunteers. In vitro closure time was measured using a PFA-100. Platelet surface antigen expression (CD63, CD62-P, CD42b, CD36, CD31) was determined in accordance with the consensus protocol for flow-cytometric characterisation of platelet function. Platelet aggregometry was performed using a whole blood electrical aggregometer (ADP and arachidonic acid as agonists). Analysis of the obtained data revealed only a few significant correlations between the different platelet function tests used. This finding can be explained by the various aspects of platelet function being focused by these tests in different extents. Whenever platelet function is analysed, the investigator should be aware of the specific and limited evidence of the method used. For screening purposes, it may be useful to introduce a platelet function index, referring to basal platelet activity, platelet adhesion and platelet aggregation at low and high shear stress forces.     

Therapeutic plasma exchange and plasma infusion in thrombotic microvascular syndromes

Plasma exchange (PE) is the most important treatment in thrombotic microangiopathies (TMAs) mainly encompassing thrombotic thrombocytopenic purpura (TTP) and adult hemolytic syndrome (HUS). This therapeutic measure has substantially improved clinical outcome. One plasma volume corresponding to 40 ml/kg of body weight is exchanged daily until the platelet count is above 150 x 10(9)/l or 100 x 10(9)/l and continues to rise or remains constantly after cessation of treatment. Exacerbations and late recurrences demand reapplication of daily PE. Twice daily PEs are initiated if the response to initial treatment is poor. The importance of additional or alternate measures including glucocorticoids, antiplatelet agents, splenectomy, intravenous immunoglobulins, protein A columns, vincristine, cyclosporine, and cyclophosphamide is uncertain. Whether cryosupernatant plasma (CSP) or solvent/detergent-treated (SDP) plasma is superior to standard fresh frozen plasma (FFP) remains to be determined. Methylene blue-treated plasma (MBP) seems to be less effective than standard FFP.     

To What Extent Can We Trust Home Blood Pressure Measurement? A Randomized,Controlled Trial

Increasingly, patients measure and record their home blood pressure. However, the accuracy with which they report their readings to their physicians is largely unknown. The authors assessed the accuracy and quality of self-reported home blood pressure values in an ambulatory managed care population. Forty-eight hypertensive outpatients were randomly allocated to either receive information about the storage capabilities of a home blood pressure measuring device or not to receive such information. All patients were asked to record the measurement results in a logbook twice daily over a 7-day period. The main outcome measure was the difference in the number of fictional or manipulated reports per group and the difference in missing values. The combined parameter manipulated or fictional registrations occurred significantly less frequently in the informed group than in the noninformed group. (10/728 vs. 29/616; relative risk, 0.292; 95% confidence interval, 0.15-0.57; Pearson chi squared=13.15; p<0.0001). Informed patients had fewer missing registrations than the noninformed (13/728 vs. 41/616 measurements; relative risk, 0.27; 95% confidence interval, 0.15-0.47; Pearson chi squared =20.5; p<0.0001). The mean of the fictional data did not differ systematically from the mean of the correctly reported individual blood pressure values. There was no trend to over- or underestimate blood pressure values in the noninformed group. With this study design, it was possible to identify manipulation of home blood pressure values for the first time. Accuracy and interpretation of home blood pressure measurement may be increased by using devices with a memory function.     

Preclinical activity of a new platinum analogue,lobaplatin, in cisplatin-sensitive and -resistant human testicular,ovarian, and gastric carcinoma cell lines

Lobaplatin [1,2-diamminomethylcyclobutane-platinum(II) lactate] is a new platinum compound with interesting preclinical activity and apparently no nephro- or neurotoxicity that is currently undergoing clinical phase II studies. Little is known about the cross-resistance between cisplatin and lobaplatin. The activity of this new compound in comparison with cisplatin and carboplatin was evaluated in cisplatin-sensitive and cisplatin-resistant human testicular, gastric, and ovarian carcinoma cell lines using 96 h continuous drug exposure in a sulforhodamine-B assay. In three cisplatin-sensitive testicular carcinoma cell lines, lobaplatin and cisplatin showed comparable antitumor activity. The 50% growth-inhibitory concentrations (IC₅₀ values) determined for cisplatin ranged from 0.1 to 0.4 μM, and those found for lobaplatin ranged from 0.25 to 0.5 μM. Carboplatin showed markedly lower cytotoxicity in all cell lines tested. Lobaplatin was not cross-resistant to cisplatin in a 10-fold cisplatin-resistant testicular carcinoma cell line and showed only weak cross-resistance in a 20-fold cisplatin-resistant ovarian carcinoma cell line. In contrast, complete cross-resistance between cisplatin and lobaplatin occurred in two cisplatin-resistant human gastric carcinoma cell lines, which were 3.3- and 9-fold resistant to cisplatin and 3.1- and 6.5-fold resistant to lobaplatin, respectively. Furthermore, lobaplatin showed significant activity against cisplatin-resistant human ovarian and testicular carcinoma xenografts in vivo. These data indicate a high level of activity for lobaplatin at clinically achievable concentrations in drug-sensitive testicular, ovarian, and gastric carcinoma cell lines and a lack of complete cross-resistance to cisplatin. Further clinical development of lobaplatin is clearly warranted.     

In vitro susceptibility of 15 strains of zygomycetes to nine antifungal agents as determined by the NCCLS M38-A microdilution method

The in vitro susceptibility of 15 strains of six genera of zygomycetes including Rhizopus oryzae (Rhizopus arrhizus), Rhizopus stolonifer, Mucor circinelloides (three), Absidia corymbifera (three), Rhizomucor pusillus (three), Cunninghamella bertholletiae (two), and Syncephalastrum racemosum (two) to nine antifungal agents were determined by the NCCLS M38-A broth microdilution method. Geometric means of the minimal inhibitory concentrations (MIC) were: amphotericin B 0.07 mg l(-1) (range 0.03-0.5 mg l(-1)), nystatin 0.83 mg l(-1) (range 0.25-4 mg l(-1)), itraconazole 0.59 mg l(-1) (range 0.03 to >8 mg l(-1)), voriconazole 6.50 mg l(-1) (range 2 to >8 mg l(-1)), ciclopiroxolamine 1.59 mg l(-1) (range 0.5-4 mg l(-1)), and amorolfine 9.19 mg l(-1) (range 1 to >16 mg l(-1)). All strains were resistant to 5-flucytosine, fluconazole (MIC >64 mg l(-1)) and caspofungin (MIC >16 mg l(-1)).     

Economic assessment of adjustable maintenance treatment with budesonide/formoterol in a single inhaler versus fixed treatment in asthma

OBJECTIVES: To compare the costs and effectiveness of adjustable maintenance dosing with budesonide/formoterol in a single inhaler versus fixed dosing in adults with asthma. METHODS: In this prospective, randomised, open-label, parallel-group, multicentre trial conducted in Germany, patients with asthma received budesonide/formoterol 160 microg/4.5 microg in a single inhaler (Symbicort Turbuhaler with two inhalations twice daily for a 4-week run-in period. Patients were then randomised to either adjustable maintenance dosing (one inhalation twice daily, stepping up to four inhalations twice daily for 1 week if asthma worsened; n=1679) or fixed dosing (two inhalations twice daily; n=1618) for 12 weeks. The primary efficacy variable was the change in health-related quality of life (HR-QOL), measured using the Asthma Quality of Life Questionnaire (standardised) during the randomised treatment period. Resource utilisation data were collected in parallel and combined with German unit costs to estimate direct and indirect costs (year 2001 values). RESULTS: Both treatment regimens were equally effective in maintaining HR-QOL and asthma control during the randomised treatment period. However, overall, patients in the adjustable maintenance dosing group took fewer daily inhalations of budesonide/formoterol than those in the fixed-dosing group (mean: 2.63 vs 3.82 inhalations; p<0.001). Adjustable maintenance dosing was associated with significantly lower asthma-related direct costs compared with fixed dosing (mean: 221 euro vs 292 euro; p<0.001). This pattern was maintained when patients were stratified into those with peak expiratory flow (PEF) of 60% to <80% predicted normal and those with PEF of>/=80% predicted normal and when total costs were considered. CONCLUSION: Adjustable maintenance dosing with budesonide/formoterol in a single inhaler maintained HR-QOL in adult patients with asthma at a significantly lower cost than fixed dosing.     

Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects

Objectives There is a clinical need for safe new oral anticoagulants. The safety, tolerability, pharmacodynamics, and pharmacokinetics of BAY 59-7939—a novel, oral, direct Factor Xa (FXa) inhibitor—were investigated in this single-center, placebo-controlled, single-blind, parallel-group, multiple-dose escalation study. Methods Healthy male subjects (aged 20–45 years, body mass index 18.6–31.4 kg/m²) received oral BAY 59-7939 (n=8 per dose regimen) or placebo (n=4 per dose regimen) on days 0 and 3–7. Dosing regimens were 5 mg once, twice (bid), or three times daily, and 10 mg, 20 mg, or 30 mg bid. Results There were no clinically relevant changes in bleeding time or other safety variables across all doses and regimens. There was no dose-related increase in the frequency or severity of adverse events with BAY 59-7939. Maximum inhibition of FXa activity occurred after approximately 3 h, and inhibition was maintained for at least 12 h for all doses. Prothrombin time, activated partial thromboplastin time, and HepTest were prolonged to a similar extent to inhibition of FXa activity for all doses. Dose-proportional pharmacokinetics ( and C_max,norm) were observed at steady state (day 7). Maximum plasma concentrations were achieved after 3–4 h. The terminal half-life of BAY 59-7939 was 5.7–9.2 h at steady state. There was no relevant accumulation at any dose. Conclusions BAY 59-7939 was safe and well tolerated across the wide dose range studied, with predictable, dose-proportional pharmacokinetics and pharmacodynamics and no relevant accumulation beyond steady state. These results support further investigation of BAY 59-7939 in phase II clinical trials.     

Chromosomal aberrations in lymphocytes of healthy subjects and risk of cancer

There is evidence that increased frequency of chromosomal aberration (CA) in peripheral blood lymphocytes is a predictor of cancer, but further data are needed to better characterize CA as marker of cancer risk. From the archives of 15 laboratories we gathered cytogenetic records of 11,834 subjects who were free of cancer at the moment of blood drawing and who underwent cytogenetic examination for preventive purposes in the Czech Republic during 1975-2000. We linked these records to the national cancer registry, revealing a total of 485 cancer cases. Subjects were classified according to the percentiles of CA distribution within each laboratory as low (0-33rd percentile), medium (34-66th percentile), and high (66-100th percentile). Subjects were further classified by occupational exposure and by subclass of CA. We found a significant association between the overall cancer incidence and the presence of chromosome-type aberrations [relative risk (RR) for high vs. low CA level = 1.24; 95% confidence interval (CI), 1.03-1.50] but not chromatid-type aberrations. Stomach cancer showed a strong association with frequency of total CA (RR = 7.79; 95% CI, 1.01-60.0). The predictivity of CA observed in subjects exposed to various classes of carcinogens did not significantly differ from the group of nonexposed subjects. This study contributes to validation of CA as a predictive marker of cancer risk, in particular, of stomach cancer; the association between CA frequency and cancer risk might be limited to chromosome-type aberrations.     

Intravenous Ketoprofen in Postoperative Pain Treatment after Major Abdominal Surgery

In recent years considerable attention has been paid to the treatment of postoperative pain, with regard to the favorable effect of adequate analgesia on patient outcome. Multimodal analgesia (e.g., opioids and nonsteroidal anti-inflammatory drugs [NSAIDs] or local anesthetics) is recommended for effective postoperative pain relief. There are few data on the use of NSAIDs in postoperative pain treatment after abdominal surgery. We conducted a randomized, double-blind, placebo-controlled study to assess the analgesic efficacy and safety of ketoprofen after major abdominal surgery. One and nine hours postoperatively patients received 100 mg of ketoprofen i.v. (n = 21) or placebo (n = 22) in addition to a pain-treatment protocol consisting of continuous infusion of tramadol 200 mg and metamizol 5 g over 24 hours with additional 25 mg i.v. tramadol in case of inadequate analgesia. Pain was assessed by numeric rating scale at rest and at deep breath 3, 6, 12, and 24 hours postoperatively and the total dose of tramadol used in the first 24 hours was recorded. Patients in the ketoprofen group had significantly lower pain scores both at rest and at deep breath, at 3 (p < 0.01), 6, and 12 hours (p < 0.05) postoperatively. The 24-hour use of tramadol was significantly lower in the ketoprofen group (p < 0.01), with less nausea and vomiting. There were no bleeding complications or other adverse events related to ketoprofen therapy. The study showed the value of short-term use of ketoprofen to improve the quality of analgesia after major abdominal surgery without significant adverse effects.Presented in part at the 9th Symposium on Intensive Care Medicine, June 24–27, 2002, Brijuni Islands, Croatia, and at the Euroanaesthsia 2004 Meeting, June 5–8, 2004, Lisbon, Portugal