Use of a water-soluble busulfan formulation--pharmacokinetic studies in a canine model

In a canine model we investigated the toxicity and pharmacokinetics of a water soluble busulfan preparation. Busulfan was dissolved in dimethylsulfoxide (DMSO) and administered either orally or intravenously in a single dose of 1 mg/kg. The application in either preparation was well tolerated. In seven dogs, peak levels in the range of 730 ng/mL to 1,000 ng/mL were measured after intravenous injection with an area under curve (AUC) of 75 ng.h/kg.mL to 146 ng.h/kg.mL. It was of note that even the oral administration of the same busulfan preparation resulted in AUC values in the same range as observed after parenteral application. The absorption rate of busulfan tablets in our model was as unpredictable as documented in clinical trials. On the basis of the present study, clinical trials using busulfan dissolved in DMSO given either intravenously or orally appear warranted. This approach should lead to predictable blood levels, reduced toxicity, and increased efficacy of busulfan-containing regimens.     

VIPER-2: a prospective, randomized single-center comparison of 2 different closure devices with a hemostatic wound dressing for closure of femoral artery access sites.

PURPOSE: To report the outcome of a prospective randomized safety and performance trial of 2 access site closure devices versus a wound dressing. METHODS: Between October 2005 and July 2006, 852 consecutive patients (605 men; mean age 67 years) undergoing diagnostic or interventional catheterization procedures thru a 5- or 6-F femoral sheath were randomized to one of the 3 closure methods: a collagen plug device (Angio-Seal), a clip (StarClose), or a wound dressing (D-Stat Dry). The efficacy of the devices was assessed, as well as the complications occurring at the puncture site during the hospital stay. The primary endpoint of the study was the cumulative incidence of access site pseudoaneurysm, major access site bleeding requiring transfusion, access site vascular surgery, or death from all causes. RESULTS: There were no significant differences in baseline characteristics between the 3 treatment groups. The primary endpoint was reached in 20 (7.1%) of 281 patients treated with D-Stat Dry and in 11 (1.9%) of 571 patients treated with the mechanical closure devices (p<0.0001). There was no significant difference among the mechanical closure devices concerning the incidence of the primary endpoint (Angio-Seal 1.1% versus StarClose 2.8%; p = 0.13). CONCLUSION: The collagen plug device had the lowest rates of major and minor access site-related complications after removal of 5- or 6-F femoral sheaths. The difference between the mechanical closure devices concerning the incidence of the primary endpoint did not reach statistical significance. The wound dressing showed significantly higher major and minor complication rates.     

Blood Transfusion in Elderly Patients with Acute Myocardial Infarction: Data from the RICO Survey

Background

Red blood cell transfusion benefit during acute myocardial infarction remains unclear in the elderly. We aimed to assess the transfusion impact on 1-year mortality in acute myocardial infarction patients aged ≥65 years, according to their age and hemoglobin nadir.

Postischemic myocardial recovery and oxidative stress status of vitamin C deficient rat hearts

OBJECTIVE: To investigate the role of vitamin C tissue content as a protective agent during myocardial ischemia-reperfusion injury, we have evaluated the postischemic functional recovery and free radical release of osteogenic disorder Shionogi (ODS) inherently scorbutic rat hearts and compared them to healthy Wistar rat hearts. METHODS: Isolated perfused hearts of ODS or Wistar rats underwent 30 min of a global total normothermic ischemia followed by 30 min of reperfusion. The lipid-soluble spin trap alpha-phenyl N-tert-butylnitrone (3 mM) was perfused upstream of the coronary bed. Functional parameters were recorded and samples of coronary effluents were analysed using electron spin resonance spectroscopy to characterise and quantify the amount of radical species released. RESULTS: From the onset of reperfusion, a large and long-lasting release of alkyl/alkoxyl radicals was detected, with a peak value of 29.0+/-3.2 nM obtained after 13 min, which was associated with a persistent contractile dysfunction. However, ODS rat hearts showed a higher myocardial recovery with lower left ventricular end diastolic pressure (44.34+/-1.74 vs. 55.03+/-1.57 mmHg for Wistar), higher recovery of rate pressure product (12.3+/-1.4 vs. 1.9+/-1.7x10(3) mmHg beats/min for Wistar) and shorter duration of contractile abnormalities during reperfusion (3.7+/-1.0 vs. 20.8+/-5.3 min for Wistar). Moreover, free radical release was identical in ODS rat hearts as compared to control Wistar rats. Ascorbic acid tissue content was significantly altered in ODS rats (31.9+/-3.3 vs. 591.0+/-54.9 mmol/g of tissue for Wistar) but superoxide dismutases, glutathion peroxidases and inducible heat shock protein 70 genes were up-regulated. CONCLUSIONS: This study shows that ascorbic-acid-deficient ODS rat hearts are more resistant to an ischemic insult than control Wistar rats, probably through the development of alternative protective defences, like the induction of heat shock proteins. These paradoxical results raise the question of the relative importance of each endogenous antioxidant in the cardiac resistance to ischemia-reperfusion injury.     

Predictive value of myocardial tomoscintigraphy in asymptomatic diabetic patients after percutaneous coronary intervention

Objective: This study was designed to assess the prognostic value of myocardial tomoscintigraphy perfusion imaging after percutaneous coronary intervention (PCI) in asymptomatic diabetic patients. Methods: One hundred and fourteen diabetic patients were followed up during 27±16 (mean±SD) months after the myocardial tomoscintigraphy. PCI-related events were studied after myocardial tomoscintigraphy stress testing and included major cardiac events (MACE) (cardiovascular death, myocardial infarction) and revascularization (bypass surgery or new PCI). Stress myocardial tomoscintigraphy imaging was performed 5±5 months after PCI and ischemia was considered as present if at least 2 contiguous segments were showing reversible defects. Results: Persistent silent ischemia was found in 49/114 (43%) patients. No difference was observed between the two groups for MACE: four among the 65 (6%) non ischemic patients versus 2 among the 49 (4%) ischemic patients (NS). In contrast, 15 (31%) among the ischemic patients and 4 (6%) among the non ischemic patients underwent iterative revascularization (p<0.01). The relative risk of revascularization for patients with significant ischemia was 5.5 versus non ischemic patients (p<0.001). Conclusion: After PCI, in asymptomatic diabetic patients followed by myocardial tomoscintigraphy a high frequency of persistent silent ischemia was found and associated with a high risk for repeat interventional procedure, although no increase in major cardiac events was observed.     

Magnetic resonance imaging early after acute myocardial infarction. A visual analysis of myocardial perfusion based on a 17 segment model

Magnetic resonance imaging allows an accurate calculation of the left ventricular ejection fraction and left ventricular volumes. Additionally, it makes possible to assess myocardial perfusion after gadolinium chelate injection. Late after the injection, the presence of a myocardial hyper-enhancement can be visualized. The present study has used the 17 segment standardized nomenclature for tomographic imaging of the heart as recommended for all cardiac imaging modalities. Sixty nine patients were studied after a revascularised myocardial infarction. All patients had Timi grade 3 flow in the infarct-related artery after therapy. Regional and global function was studied using cine MR short axis slices. The gadolinium chelate first pass was scored using a 5 level scale reflecting the transmural extent of the segmental myocardial enhancement. The delayed enhancement due to gadolinium accumulation in the myocardium 10 min post injection was scored in the same manner. Left ventricular ejection fraction was 51 +/- 13%. Segmental thickening parameters (systolic thickness, absolute thickening and relative thickening) appeared statistically related to the hypoperfusion and delayed enhancement scores. Absolute myocardial thickening varied from 4.8 +/- 2.7 mm in the myocardial segments free of any delayed enhancement to 2.4 +/- 2.1 mm in segments presenting with a transmural extent of the delayed hyper-enhancement. Scores obtained after gadolinium injection were also well correlated with the global left ventricular function (r = 0.65, p < 0.01 for late enhancement). Magnetic resonance imaging of the heart allows a precise characterisation of revascularised myocardium which makes this technique very attractive for evaluating the treatments designed to improve myocardial microperfusion.     

Quality assurance for the diagnostics of viral diseases to enhance the emergency preparedness in Europe

The threat posed by emerging and re-emerging communicable diseases and, more recently, by the intentional release of infectious agents in a susceptible population, has been receiving considerable attention at the national and international levels. Public health efforts to strengthen disease detection, surveillance and control have been intensified. However, clinicians and clinical microbiology laboratories play an important role in the early detection of disease, the identification of the putative agent, and notification of the appropriate authorities. To be effective in this role, laboratories must be specially prepared to handle viral agents safely, and need, among other things, the appropriate rapid and sensitive diagnostic tests. In 1998 the European Network for Diagnostics of 'Imported' Viral Diseases (ENIVD) was established. ENIVD presently comprises, as permanent members, 44 expert laboratories in 21 European Union (EU) member states and 4 non-EU countries and is one of the networks on infectious diseases funded by the European Commission. ENIVD fulfils many of the important tasks required for the surveillance and control of imported, rare and emerging viral infections such as the exchange of expertise and the organisation of external quality assurance (EQA) programmes, both of which are needed to improve diagnostics. Here, we summarise the data generated by recent EQA activities focussed on the diagnostics of infections with hantavirus, dengue virus, filovirus, Lassa virus, orthopox virus and the SARS-coronavirus (SARS-CoV). These were carried out between 1999 and 2004 and involved 93 laboratories from 41 countries, including laboratories from additional countries outside of Europe. Particularly the EU-candidate countries and Eastern neighbouring countries will be invited to join the network in the near future. A public website is available at http://www.enivd.de.