The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

A CT-free, intra-operative planning and navigation system for minimally invasive anterior spinal surgery - an accuracy study.

OBJECTIVE: A comprehensive study was performed to evaluate the accuracy of a newly developed CT-free, intra-operative planning and navigation system for anterior spine surgery. MATERIALS AND METHODS: Instruments and an image intensifier were tracked using the SurgiGATE navigation system. A laboratory study was performed on 27 plastic vertebrae. Fiducial markers were implanted in the vertebrae for accuracy evaluation purposes, and a dynamic reference base was placed on the vertebrae to establish a patient coordinate system (P-COS). Two fluoroscopic images were used for intra-operative planning. The graft bed plan was recorded in P-COS, followed by surgical formation of the graft bed, which was visualized. To evaluate the accuracy, the vertebrae were scanned with CT, and the markers were used to calculate an accurate paired-point registered transformation between the CT coordinate system and P-COS. RESULTS: Using the new SPO module, accurate planning and navigation of a resection of the vertebral body is possible using two fluoroscopic images. The overall mean error between the planned resection volume and the actual resection was 0.98 mm. In addition, the module can serve as an educational tool for training spine surgeons. CONCLUSIONS: The new fluoroscopy-based system can be used safely for accurate performance of anterior resection during spondylodesis. New methods for safe and accurate registration during anterior spine surgery need to be developed.     

A Chinese adolescent girl with Fechtner-like syndrome

We describe a 15-y-old girl with Fechtner-like syndrome, who is the first Chinese reported to have this rare syndrome. She presented with left homonymous hemianopia and neuroimaging revealed haemorrhage in both parietal and occipital lobes. Peripheral blood smear showed macrothrombocytopenia and intracytoplasmic inclusion bodies inside leucocytes. Thrombocytopenia and proteinuria responded to intravenous immunoglobulin and pulsed methylprednisolone. This case illustrates that life-threatening haemorrhage can occur in patients with Fechtner syndrome. Although there was no effective treatment reported in the literature, high dose steroid and immunoglobulin seemed to be useful in our patient. Our patient also had nephritic-nephrotic syndrome with renal insufficiency, which is unusual in adolescent female patients.     

Selective unresponsiveness of pancreatic beta-cells to acute sulfonylurea stimulation during sulfonylurea therapy in NIDDM

Patients with non-insulin-dependent diabetes mellitus (NIDDM) who have chronic hyperglycemia lose acute incremental insulin responses to glucose but are able to briskly respond to other beta-cell secretagogues. To investigate whether this is a defect specific for glucose or represents a more general phenomenon, we measured the insulin responses to acute intravenous tolbutamide in 10 obese patients with NIDDM both before and during sulfonylurea therapy with tolazamide. Comparable glycemia was achieved with oral dextrose 2 h before intravenous testing. To assess beta-cell responsiveness to a nonsulfonylurea secretagogue, 1 mg glucagon was administered intravenously during tolazamide therapy. In seven patients, the mean peak insulin increment 5 or 10 min after intravenous tolbutamide was 54 +/- 11 microU/ml when not receiving tolazamide (0.14 +/- 1.3 microU/ml) with tolazamide (P less than .001), even though serum insulin responded rapidly to intravenous glucagon. In four patients tested for reversibility of their refractoriness to intravenous tolbutamide during chronic tolazamide therapy, the mean peak insulin increment 1 wk after discontinuing tolazamide was 79 +/- 22 microU/ml. A relatively rapid development of refractoriness was documented in four patients who were tested only 12 h after beginning tolazamide therapy; the mean peak insulin increments 5-10 min after intravenous tolbutamide were undetectable (-0.5 microU/ml), yet responses to intravenous glucagon were evident. In these NIDDM patients, exposure of pancreatic beta-cells to sustained levels of sulfonylureas induces a reversible state of refractoriness to acute stimulation with sufonylureas but not to another secretagogue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sauerstoff tragende L?sungen verbessern die Gewebeoxygenation im quergestreiften Hautmuskel nach kritischer Isch?miezeit

Zusammenfassung Fragestellung. Ziel der vorliegenden Untersuchung war, die Effekte der Sauerstoff tragenden freien H?moglobinl?sung (Diaspirin-crosslinked-H?moglobin, DCLHb) auf die kapillare Perfusion sowie die Oxygenation im quergestreiften Hautmuskelgewebe nach kritischer Isch?miezeit und nachfolgender Reperfusion zu analysieren. Material und Methode. Die kapillare Gewebeperfusion wurde anhand der funktionellen Kapillardichte im Hautmuskel des syrischen Goldhamsters quantitativ vor der Induktion einer 4-stündigen Isch?mie sowie nach 0,5 h, 2 h und 24 h Reperfusion mittels intravitaler Fluoreszenzmikroskopie erfasst (n=8 pro Versuchsgruppe). In separaten Tieren wurde nach demselben Versuchsansatz mit der Mehrdrahtoberfl?chenelektrode (MDO, Eschweiler, Kiel) die Gewebeoxygenation gemessen (n=8 pro Versuchsgruppe). Die Tiere der Testgruppe (n=8) erhielten 15 min vor der Reperfusion eine Kurzinfusion von 5 ml/kg KG DCLHb (Diaspirin-crosslinked-H?moglobin, 10 g/dl, Baxter, IL, USA). Die Kontrolltiere (n=8) erhielten ?quivalente Dosen einer isotonen Kochsalzl?sung (Braun, Melsungen). Ergebnisse. Die funktionelle Kapillardichte als Ma? für die L?nge von erythrozytenperfundierten Kapillaren pro Beobachtungsfeld war bei den Kontrolltieren in der Reperfusionsphase dramatisch vermindert, w?hrend bei den mit DCLHb behandelten Tieren signifikant h?here Werte nachweisbar waren (p<0,05). Diese Beobachtung spiegelte sich in einer vollst?ndigen Erholung des Gewebe-pO₂ bei den Behandlungstieren wider, was in Kontrolltieren nicht erreicht wurde. Schlussfolgerungen. Die Ergebnisse dieser Studie zeigen, dass die Sauerstoff tragende L?sung DCLHb nach kritischer Isch?mie und Reperfusion die nutritive Perfusion und Gewebeoxygenation gegenüber kristalloiden L?sungen verbessert. Die Anwendung derartiger L?sungen scheint unter den klinischen Bedingungen einer kritischen Isch?mie daher als viel versprechender adjuvanter therapeutischer Ansatz. Electronic Publication