Pharmacokinetic properties of MH84, a γ-secretase modulator with PPARγ agonistic activity.

Alzheimer's disease (AD) is the most common cause of dementia. Since no causative treatment is available, new therapeutic options are utmost needed. Several pirinixic acid derivatives, including MH84 (2-((4,6-bis(4-(trifluoromethyl)phenethoxy)pyrimidin-2-yl)thio)hexanoic acid), have shown promising in vitro results as γ-secretase modulators as well as PPARγ activators as potential pharmacological compounds against AD. Using a newly developed and validated sensitive LC-MS (APCI-qTOF mass analyzer) method, the pharmacokinetic and long-term accumulating properties as well as the blood-brain-barrier permeability of MH84 were evaluated in a preclinical animal study. MH84 was administered to mice by oral gavage with a dose of 12 mg/kg. Nine time points from 0.5 to 48 h with 6 animals per point were investigated. Additionally 6 animals were fed daily, for 21 days with an identical dose to determine possible long-term accumulation in plasma and brain tissue. The sample preparation was performed by a liquid-liquid extraction on Extrelut(®) columns whereas the LC separation was operated on a MulthoHigh 100 RP 18-5 µ column (125 × 4 mm) using an isocratic mobile phase of formic acid (0.1% (v/v))-methanol mixture (11:89 (v/v)) at a flow rate of 1 ml/min. The validation confirmed the new LC-MS method to be precise, accurate and reliable. After oral application, Cmax and Tmax of unmetabolized MH84 was determined to be 10.90 µg/ml and 3h in plasma. In brain tissue a constant level of 300 to maximum 320.64 ng/g was found after 1.5-6h. Daily gavage for 21 days did not lead to a long-term drug accumulation in the brain. The efficacy of the obtained MH84 levels needs to be investigated in further preclinical pharmacodynamic animal studies.

Advances in personalized medicine - medicinal chemistry and pharmacology of vemurafenib and ivacaftor.

Pharmacogenomics offers an entrance in the field of personalized medicine. This form of adapted therapy is going to be the future concerning the reduction of side effects and efficacy of the treatment of severe diseases. Vemurafenib and Ivacaftor are the first FDA approved drugs specially addressing mutated proteins. Both substances showed promising results in all clinical trials combined with relatively mild side effects by vemurafenib and placebo-like side effects by ivacaftor. The efficacy in addressing the specific mutation of each compound was confirmed in preclinical and clinical development.

Aortic valve prosthesis tracking for transapical aortic valve implantation.

PURPOSE: Transapical aortic valve implantation (TA-AVI) is a new minimally invasive surgical treatment of aortic stenosis for high-risk patients. The placement of aortic valve prosthesis (AVP) is performed under 2D X-ray fluoroscopic guidance. Difficult clinical complications can arise if the implanted valve is misplaced. Therefore, we present a method to track the AVP in 2D X-ray fluoroscopic images in order to improve the accuracy of the TA-AVI. METHODS: The proposed tracking method includes the template matching approach to estimate the position of AVP and a shape model of the prosthesis to extract the corner points of the AVP in each image of sequence. To start the AVP tracking procedure, an initialization step is performed by manually defining the corner points of the prosthesis in the first image of sequence to provide the required algorithm parameters such as the AVP model parameters. RESULTS: We evaluated the AVP tracking method on six 2D intra-operative fluoroscopic image sequences. The results of automatic AVP localization agree well with manually defined AVP positions. The maximum localization errors of tracked prosthesis are less than 1 mm and within the clinical accepted range. CONCLUSIONS: For assisting the TA-AVI, a method for tracking the AVP in 2D X-ray fluoroscopic image sequences has been developed. Our AVP tracking method is a first step toward automatic optimal placement of the AVP during the TA-AVI.

Late perforation of a right ventricular pacing lead: a potentially dangerous complication.

Four days after uncomplicated implantation of a two-chamber pacemaker and a normal postoperative course, a patient was referred to our hospital with left-sided hemothorax and early hemorrhagic shock. Chest X-ray and CT scan were suspicious of a right ventricular lead perforation with additional pericardial and pleural injury. Immediate surgery was performed via a lateral thoracotomy and the perforation was repaired via direct suture. An epimyocardial ventricular lead was implanted simultaneously. The patient made an uneventful recovery.

[The audio-visually determined reaction evaluation test (A-V-R test) (a hearing test for infants and small children)]. / Der auditiv-visuell gerichtete Reaktionsprüfungstest (A-V-R-Test) (Ein Hörtest für Säuglinge und Kleinkinder).

The A-V-R-test is accomplished in a free sound field, either with a play audio-metric table (clinical use) or with a textile paravent (practice). The main effort of this reactiontest is the auditive-visual determination. The examiner provokes the auditive readiness with a supraliminal impulse, which prepares the starting position for offering an acoustic test impulse in a low signal strength on the left or right side. If the test is realized with the textile paravent, frequency and intensity proved music instruments or other sound producing objects (bunch of keys, Ewing-rattle, etc.) are offered to the child. If the A-V-R-test is accomplished with the play-audio-metric table, the tester presents a frequency specific narrow band noise to the examinee. Only the turn of the infant's head towards the source of the sound is evaluated. Infants older than 2 years may show specific reactions, depending on the stage of their development.