Bioavailability of repeated oral administration of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase in healthy volunteers.

BACKGROUND: MDL 100,240 (pyrido[2,1-a] [2]benzazepine-4-carboxylic acid,7-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8, 12b-octahydro-6-oxo, [4S-[4alpha,7alpha(R(*)),12bbeta]]-) is a molecule possessing an inhibiting ability on both angiotensin converting enzyme (ACE) and neutral endopeptidase, the enzyme responsible for atrial natriuretic peptide (ANP) degradation. Such a dual mechanism of action presents a potential clinical interest for the treatment of hypertension and congestive heart failure. OBJECTIVES: To evaluate the bioavailability of MDL 100,240 and its accumulation over repeated oral administration, using ACE inhibition as a surrogate for plasma drug level and determining its profile after oral and i.v. administration. METHODS: First, in an open, one-period, single-dose study, the ACE inhibition profile was characterised following a 12.5 mg MDL 100,240 i.v. infusion. Second, in a three-group, parallel, randomised, double-blind study, each group of four subjects received q.d., over 8 days, 2.5, 10 or 20 mg of MDL 100,240 orally. The ACE inhibition profile was determined on day 1 and day 8. Trough plasma ACE was measured on days 2, 3 and 4. The recovery of ACE activity was monitored up to 72 h after the last dose of MDL 100,240. RESULTS: ACE inhibition profile was similar on day 1 and day 8, and trough inhibition remained unchanged after the 8 days of treatment with 10 mg or 20 mg. Following repeated 2.5-mg ingestion, trough inhibition increased from 33% to 44% after the eighth dose. The oral bioavailability of MDL 100,240 was estimated at 85%, not statistically different from 100%. The accumulation ratio at steady state was estimated at 112%. Expressing the accumulation ratio in terms of half-life, a t(1/2) of 0.31 days or 7. 5 h was estimated. CONCLUSION: MDL 100,240 (oral solution) has a good bioavailability, as estimated by ACE inhibition, and no drug accumulation seems to occur over 8 days with the 10-mg and 20-mg doses, but a slight rise in the trough level is observed with the 2. 5-mg dose.

Delayed priming promotes CNS regeneration post-rhizotomy in Neurocan and Brevican-deficient mice.

A wealth of literature has provided evidence that reactive tissue at the site of CNS injury is rich in chondroitin sulfate proteoglycans which may contribute to the non-permissive nature of the CNS. We have recently demonstrated using a murine model of human brachial plexus injury that the chondroitin sulfate proteoglycans Neurocan and Brevican are differentially expressed by two subsets of astrocytes in the spinal cord dorsal root entry zone (DREZ) following dorsal root lesion (Beggah et al., Neuroscience 133: 749-762, 2005). However, direct evidence for a growth-inhibitory role of these proteoglycans in vivo is still lacking. We therefore performed dorsal root lesion (rhizotomy) in mice deficient in both Neurocan and Brevican. Rhizotomy in these animals resulted in no significant increase in the number of sensory fibres regenerating through the DREZ compared to genetically matched controls. Likewise, a conditioning peripheral nerve lesion prior to rhizotomy, which increases the intrinsic growth capacity of sensory neurons, enhanced growth to the same extent in transgenic and control mice, indicating that absence of these proteoglycans alone is not sufficient to further promote entry into the spinal cord. In contrast, when priming of the median nerve was performed at a clinically relevant time, i.e. 7 weeks post-rhizotomy, the growth of a subpopulation of sensory axons across the DREZ was facilitated in Neurocan/Brevican-deficient, but not in control animals. This demonstrates for the first time that (i) Neurocan and/or Brevican contribute to the non-permissive environment of the DREZ several weeks after lesion and that (ii) delayed stimulation of the growth program of sensory neurons can facilitate regeneration across the DREZ provided its growth-inhibitory properties are attenuated. Post-injury enhancement of the intrinsic growth capacity of sensory neurons combined with removal of inhibitory chondroitin sulfate proteoglycans may therefore help to restore sensory function and thus attenuate the chronic pain resulting from human brachial plexus injury.

[Volterra. Museo etrusco Guarnacci]

Référence bibliographique : Weigert, 749

Peri-operative management of antiplatelet therapy in patients with coronary artery disease. Joint position paper by members of the working group on Perioperative Haemostasis of the Society on Thrombosis and Haemostasis Research (GTH), the working group on Perioperative Coagulation of the Austrian Society for Anesthesiology, Resuscitation and Intensive Care (ÖGARI) and the Working Group Thrombosis of the European Society for Cardiology (ESC).

An increasing number of patients suffering from cardiovascular disease, especially coronary artery disease (CAD), are treated with aspirin and/or clopidogrel for the prevention of major adverse events. Unfortunately, there are no specific, widely accepted recommendations for the perioperative management of patients receiving antiplatelet therapy. Therefore, members of the Perioperative Haemostasis Group of the Society on Thrombosis and Haemostasis Research (GTH), the Perioperative Coagulation Group of the Austrian Society for Anesthesiology, Reanimation and Intensive Care (ÖGARI) and the Working Group Thrombosis of the European Society of Cardiology (ESC) have created this consensus position paper to provide clear recommendations on the perioperative use of anti-platelet agents (specifically with semi-urgent and urgent surgery), strongly supporting a multidisciplinary approach to optimize the treatment of individual patients with coronary artery disease who need major cardiac and non-cardiac surgery. With planned surgery, drug eluting stents (DES) should not be used unless surgery can be delayed for ≥12 months after DES implantation. If surgery cannot be delayed, surgical revascularisation, bare-metal stents or pure balloon angioplasty should be considered. During ongoing antiplatelet therapy, elective surgery should be delayed for the recommended duration of treatment. In patients with semi-urgent surgery, the decision to prematurely stop one or both antiplatelet agents (at least 5 days pre-operatively) has to be taken after multidisciplinary consultation, evaluating the individual thrombotic and bleeding risk. Urgently needed surgery has to take place under full antiplatelet therapy despite the increased bleeding risk. A multidisciplinary approach for optimal antithrombotic and haemostatic patient management is thus mandatory.

On-pump fibrillating heart mitral valve replacement with the SAPIEN? XT transcatheter heart valve.

In some high-risk patients, standard mitral valve replacement can represent a challenging procedure, requiring a risky extensive decalcification of the annulus. In particular, high-risk redo patients and patients with a previously implanted transcatheter aortic valve, who develop calcific mitral disease, would benefit from the development of new, minimally invasive, transcatheter or hybrid techniques for mitral valve replacement. In particular, mixing transcatheter valve therapies and well-established minimally invasive techniques for mitral replacement or repair can help in decreasing the surgical risk and the technical complexity. Thus, placing transcatheter, balloon-expandable Sapien? XT stent-valves in calcified, degenerated mitral valves through a right thoracotomy, a left atriotomy and on an on-pump fibrillating heart, represents an attractive alternative to standard surgery in redo patients, in patients with concomitant transcatheter aortic stent-valves in place and in patients with a high-risk profile. We describe this hybrid technique in detail.

Automatic quality assessment in structural brain magnetic resonance imaging

MRI has evolved into an important diagnostic technique in medical imaging. However, reliability of the derived diagnosis can be degraded by artifacts, which challenge both radiologists and automatic computer-aided diagnosis. This work proposes a fully-automatic method for measuring image quality of three-dimensional (3D) structural MRI. Quality measures are derived by analyzing the air background of magnitude images and are capable of detecting image degradation from several sources, including bulk motion, residual magnetization from incomplete spoiling, blurring, and ghosting. The method has been validated on 749 3D T(1)-weighted 1.5T and 3T head scans acquired at 36 Alzheimer's Disease Neuroimaging Initiative (ADNI) study sites operating with various software and hardware combinations. Results are compared against qualitative grades assigned by the ADNI quality control center (taken as the reference standard). The derived quality indices are independent of the MRI system used and agree with the reference standard quality ratings with high sensitivity and specificity (>85%). The proposed procedures for quality assessment could be of great value for both research and routine clinical imaging. It could greatly improve workflow through its ability to rule out the need for a repeat scan while the patient is still in the magnet bore.

Recovery of rotators strength after latarjet surgery.

The purposes of this study were to prospectively determine changes in rotator cuff strength before and after surgical shoulder stabilization by Bristow-Latarjet procedure and to better estimate time needed for rotator cuff strength recovery. 20 patients with recurrent anterior posttraumatic shoulder dislocation underwent internal (IR) and external (ER) rotator isokinetic evaluation before and 3, 6 and 21 months after Bristow-Latarjet surgery. In a seated position with 45° of shoulder abduction in the scapular plane, both shoulders were evaluated concentrically with a Con-Trex® isokinetic dynamometer at 180°∙s - 1, 120°∙s - 1 and 60°∙s - 1. 3 months post-surgery, IR and ER strength of the operated shoulder were significantly lower than before surgery ( - 28±20% for IR, - 17±17% for ER) (P<0.05). At 6 and 21 months post-surgery, IR and ER strength were comparable to strength before surgery; strength recovery is seen at 6 months post-surgery with long-term maintenance at 21 months. Given the weakness 3 months post-surgery, return to sports (including overhead and contact sports) should be discussed, and 6 months post-surgery may be a better point for an athlete to resume practicing sports. Isokinetic rotator cuff strength evaluation appears to be relevant in helping to determine the need of continuing strength rehabilitation. Pre-surgical evaluation contributes to the relevance of later comparisons.

Epidemiologie der chronisch venösen Insuffizienz--Schweizer Befragung liefert überraschende Ergebnisse [Epidemiology of chronic venous insufficiency--Swiss survey with surprising results]

Lower limb chronic venous insufficiency (CVI) is one of the most common diseases in western world adults with considerable socio-economic impact. Varicose veins of the legs are caused by a number of factors. Current data suggest that both lifestyle and environmental factors play a role in varicose vein occurrence. Nevertheless, environmental factors seem to play greater role than previously thought. This was also observed in a Swiss survey of 1099 participants carried out during summer 2008 in 40 different Swiss pharmacies.

Langattoman Internet-puhelupalvelun tarjoaminen

Langattomalla Internetpuhelupalvelulla tarkoitetaan Internet-puheluiden (Voice over Internet Protocol, VoIP) siirtoa langattoman tiedonsiirtoverkon ylitse. Tälläisia langattomia verkkoja voivat olla esimerkiksi langattomat lähiverkot, WiMAX-verkot tai 450 megahertsin (MHz) taajuusalueella toimivat tiedonsiirtoverkot. VoIP-yhteyden toiminta voidaan jakaa kolmeen eri toiminta-alueeseen: yhteydenmuodostusprotokollaan, äänen koodaukseen sekä siirtotiehen. Yhteydenmuodostusprotokollia ovat esimerkiksi SIP (Session Initiation Protocol) sekä H.323. Yhteydenmuodostusprotokollantehtävänä on muodostaa yhteys käyttäjien välille sekä sopia yhteydessäkäytettävistä ominaisuuksista. Äänen koodauksessa ääni pakataan paketteihin, joita lähetetään siirtotietä pitkin eri käyttäjien välillä. Normaalissa Internetpuheluyhteydessä siirtotienä käytetään langallisia siirtoteitä. Tässä työssä on keskitytty langattomiin siirtoteihin ja niidentuomiin haasteisiin, kuten yhteyden luotettavuuteen ja laatuun, yhteyskapasiteetin riittävyyteen sekä siirtymiseen saman verkon eri tukiasemien sekä eri verkkojen välillä. Työssä rakennettiin yksinkertainen, mutta toimiva langaton Internetpuhelujärjestelmä sekä verrattiin sen ominaisuuksia normaaliin Internetpuhelujärjestelmään. Järjestelmää koekäytettiin oikeassa toimintatilanteessa varsinaisen puhelinjärjestelmän rinnalla tavallisessa toimistoympäristössä. Testaustulosten ja käyttäjäkokemusten perusteella on periaatteessa mahdollista rakentaa yksinkertainen langaton Internetpuhelujärjestelmä ja käyttää sitä puhelupalveluiden tarjoamiseen. Palvelun tarjoaminen vaatii kuitenkin vielä tiettyjen viestintäviraston määräysten täyttämistä ennen tuotantokäyttöön ottamista.

Comparison of central macular thickness (CMT) measurement between time domain and spectral domain (SD) optical coherence tomography (OCT) and reproducibility of SD OCT in active neovascular AMD

Purpose: To evaluate the reproducibility of Cirrus-SD OCT measurements and to compare central macular thickness (CMT) measurements between TD-Stratus and SD-Cirrus OCT in patients with active exudative AMD. Methods: Consecutive case series of patients with active exudative AMD seen in the Medical Retina Department. Patients underwent 1 scan with Stratus (macular thickness map protocol) and 5 scans with Cirrus (Macular Cube protocol) at the same visit by the same experienced examiner. To be included, patients best-corrected visual acuity (BCVA) had to be >20/200 while all scans had to be of sufficient quality, well-centered and at least one Cirrus scan with CMT >300 microns. The repeatability of the SD Cirrus was estimated by using all 5 CMT measurements and the mean of the Cirrus measurements was compared with the CMT obtained by TD Stratus. Results: Cirrus OCT demonstrated high intraobserver repeatability at the central foveal region (ICC 96%). The mean of the CMT measurements was 321microns for Stratus and 387 microns for Cirrus. The average difference was 65m (SD=30). The coefficient of concordance between Stratus and Cirrus CMT measurements was rho=0,749 with a high precision and a moderate accuracy. The equation of the line of regression between Stratus and meanCirrus is given by the following: M_stratus = 0,848 x m_cirrus - 4,496 (1).Conclusions: The Cirrus macular cube protocol allows reproducible CMT measurements in patients with active exudative AMD. In cases of upgrading from TD to SD use and vice versa, there is the possibility to predict the measurements by using the equation (1). These real life data and conclusions can help in improving our clinical management of patients with neovascular AMD.