Registration trials for specific immunotherapy in Europe: advanced guidance from the new European Medical Agency guideline.

Marketing authorization of medicinal products is granted based on results of registration trials. The European Medical Agency (EMA) has issued general and disease state-specific guidelines for the conduct of such trials. In the area of allergic diseases, there are basically two general therapeutic approaches: Drugs that mitigate the symptoms and an approach that is targeted to the root cause of the disease, the allergen-specific immunotherapy (SIT). While the 'Guideline on the Clinical Development of Medicinal Products for the Treatment of Allergic Rhino-Conjunctivitis' (CHMP/EWP/2455/02) and the 'Note for Guidance on the Clinical Investigation of Medicinal Products in the Treatment of Asthma' (CPMP/EWP/2922/01) focuses exclusively on the development of medicinal products to treat allergic symptoms, there was no guideline for SIT in the past. In consequence, the conduct of clinical trials for SIT was widely lacking a standardized approach. This created difficulties when comparing drugs and outcomes and also uncertainty to predict marketing authorization. In 2009, the EMA has issued a new guideline on the clinical development of products for SIT. Despite some white spots in some areas, the new guideline constitutes a breakthrough with regard to guidance, harmonization and transparency in the conduct of clinical trials in SIT.

Renal denervation: results of a single-center cohort study.

PURPOSE: To investigate the effect of renal denervation on office-based and 24-h ambulatory blood pressure measurements (ABPM) in a highly selective patient population with drug-resistant hypertension. MATERIALS AND METHODS: Patients with drug resistant hypertension eligible for renal denervation were included in the study population. Office blood pressure and ABPM were assessed prior to and after renal denervation. To detect procedure related renal or renal artery damage, magnetic resonance imaging (MRI) and angiography (MRA) were performed pre-interventional, one day post-interventional, and one month after renal denervation. RESULTS: Mean follow-up time between renal denervation and blood pressure re-assessment was 9.5 ±â€Š3.9 months. Between August 2011 and March 2013, 17 patients prospectively underwent renal denervation. Pre-interventional mean office blood pressure and ABPM were 177.3 ±â€Š20.3/103.8 ±â€Š20.4 mmHg and 155.2 ±â€Š20.5/93.7 ±â€Š14.5 mmHg, respectively. Post-interventional, office blood pressure was significantly reduced to 144.7 ±â€Š14.9/89.5 ±â€Š12.1 (p < 0.05). ABPM values remained unchanged (147.9 ±â€Š20.3/90.3 ±â€Š15.6, p > 0.05). The number of prescribed antihypertensive drugs was unchanged after renal denervation (4.7 ±â€Š2.0 vs. 4.2 ±â€Š1.2, p = 0.18). No renovascular complications were detected in follow-up MRI. CONCLUSION: After renal denervation, no significant decrease in ABPM was observed. These results may indicate a limited impact of renal denervation for drug resistant hypertension. KEY POINTS: • Renal denervation showed no significant effects on 24-h ambulatory blood pressure measurements. • A significant decrease in office blood pressure measurements may be explained by a potential detection bias. • Renal artery alterations were not observed on follow-up MRI scans.

Effects of combined therapy of clopidogrel and aspirin in preventing thrombus formation on mechanical heart valves in an ex vivo rabbit model.

BACKGROUND: The aim of our study was to investigate the efficacy of the combination of clopidogrel and aspirin in the prevention of thrombus formation on artificial heart valves in an experimental rabbit model as compared to anticoagulation with warfarin. METHODS: Studies were performed after oral administration of clopidogrel and aspirin in group I (n=9) for 5 days, after 5+/-2 days treatment with warfarin in group II (n=9) and without medication in group III (n=9). Leaflets from Sulzer Carbomedics bileaflet valves were placed in a flow chamber. The flow chamber was filled with blood in a continuous circulation between the carotid artery and the jugular vein. RESULTS: In group III, the flow chamber was clotted after a median of 15 min of circulation. Weight analysis before and after 1 h of perfusion showed that the median thrombus weight was 9.1 mg in group I, 14.4 mg in group II and 33.7 mg in group III. Further analysis by electron microscopy showed fewer platelets and erythrocytes on leaflets in group I than on leaflet surfaces in group II. CONCLUSION: Clopidogrel and aspirin were more effective than warfarin in preventing thrombus formation on artificial heart valve leaflets in our investigation. This rabbit model with a high dosage of clopidogrel and aspirin, and a short-time exposure of the heart valve leaflets to rabbit blood under laminar flow, should be further evaluated with respect to whether it can give information about antithrombotic regimens in patients after mechanical heart valve replacement.

[Pulmonary hypertension in end-stage renal disease: three case reports]. / Pulmonale Hypertonie bei terminaler Niereninsuffizienz: Drei Kasuistiken.

HISTORY: Within three months, three patients with end-stage renal disease presented for evaluation of pulmonary hypertension (PH): a 72-year-old woman (case 1), a 67-year-old patient (case 2) and a 75-year-old patient (case 3), each with increasing dyspnea (WHO functional class III). INVESTIGATIONS: In all three cases, there was echocardiographic evidence of right heart failure; right heart catheterization was completed before and after dialysis. In case 1, we found a postcapillary PH (PH group 2 - PH with left heart diseases/diastolic dysfunction). Case 2 also showed a postcapillary PH and a high cardiac output of 9.7 l/min. In case 3, unmasked after dialysis, a precapillary, pulmonary arterial hypertension (PAH - group 1) was detected. TREATMENT AND COURSE: In patient 1, no relevant improvement of symptoms was observed, despite optimized cardiac therapy. There was a significant clinical improvement in patient 2 after surgical reduction of the arteriovenous shunt. In patient 3, relevant clinical and hemodynamic improvement was seen under treatment with bosentan. CONCLUSION: These cases confirm the role of right heart catheterization in the differential diagnosis of unclear PH in patients with end-stage renal failure. Moreover, the three cases point to three different causes. Specific therapies can result in significant symptomatic improvement.

The determination of the DNA base composition in 19 species of adriatic sponges with high-pressure liquid cation-exchange chromatography.

The (adenine+thymine)/(guanine+cytosine) base ratios of 19 species of adriatic sponges have been determined by high-pressure liquid cation-exchange chromatography. The base ratios vary from 1.49 (Mycale massa) to 0.63 (Hippospongia communis) according to an (A+T) content of 59.7 and 38.6 mol%, respectively. The DNAs of sponges of the order Keratosa showed marked differences in their (A+T) contents (39.5 to 58.8 mol%) whereas those of Tetractinellida and Halichondrina were nearly identical (39.3 to 40.8 and 49.5 to 49.8 mol%, respectively). The 5-methylcytosine (5MC) content was determined in 8 sponge DNAs by a semiquantitative method. The values differed from 0.8 to 2.2 mol% of 5MC.

Effects of isoflurane on the DNase I activity in an isolated enzyme preparation and on the DNase I-G actin complex.

Effects of isoflurane on the DNase I activity in an isolated enzyme preparation and in the DNase I-globular (G) actin complex were investigated. DNase I, DNase I-G actin complex, and G actin were exposed to various (0.2-4.0 vol%) isoflurane concentrations for 180 min. Thereafter, DNase I activity was determined. DNase I activity was inhibited in relation to time and concentration of isoflurane exposure. At concentrations ranging from 0.2 to 1.0 vol% of isoflurane inactive DNase I was activated in the DNase I-G actin complex. The DNase I inhibitor G actin showed a reduced capability to inhibit DNase I following isoflurane exposure. Albumin can inhibit the DNase I inactivation possibly by competition in the reactions between DNase I/albumin and isoflurane. After exposure to isoflurane the absorption maximum of DNase I was identical with the absorption maximum of heat-denatured DNase I. The results suggest a mechanism by which isoflurane may affect DNA in an indirect way at concentrations to which the patient is exposed during clinical anesthesia.

[Analgesia and sedation in neurosurgical intensive care patients]. / Analgosedierung bei neurochirurgischen Intensivpatienten.

Different concepts for analgosedation of neurosurgical patients are recommended during postoperative ventilation. In 30 neurosurgical patients (2 groups of 15 patients), we studied a continuous i.v. application of alfentanil (Rapifen) and midazolam (Dormicum) compared to an application of continuously given alfentanil with discontinuously given midazolam. A good analgosedation (i.e. sufficient sedation with good neurological judgement) was more frequently achieved (8/15 patients) by continuous application of both substances (alfentanil 0.023 mg/kg b.w./h, midazolam 0.10 mg/kg b.w./h), compared to discontinuous application of midazolam (4.5/15 patients; alfentanil 0.028 mg/kg b.w./h, midazolam 0.13 mg/kg b.w./h). No differences in extubation times were observed. We conclude from our results that a continuous application of both substances is superior to a discontinuous application of midazolam with continuously given alfentanil. A lower dosage of each substance is necessary to maintain a better state of analgosedation.