An inhibitory anti-factor IX antibody effectively reduces thrombus formation in a rat model of venous thrombosis

An inhibitory anti-factor IX/IXa antibody (BC2) has been investigated as an anti-thrombotic agent in a rat venous thrombosis model. The treatment of rats post-injury with a single bolus dose of BC2 (3 mg/kg, i.v.) resulted in an approximately 4 fold reduction in venous thrombus mass (P = 0.043). This efficacy was matched by a minimal (<2.5 fold) prolongation of the aPTT and had no effect on the prothrombin time (PT). Heparin by comparison, given as a bolus followed by continuous infusion, at doses comparable in efficacy at reducing thrombus formation, prolonged the aPTT >50 fold. These results demonstrate that the anti-factor IX/IXa antibody (BC2), when compared to heparin, can effectively reduce venous thrombosis with less disruptive consequences on blood clotting.     

Estimation of the biophase concentration of noradrenaline at presynaptic α2-adrenoceptors in brain slices

Summary The aim of the present study was to determine the local concentrations of noradrenaline existing at presynaptic ₂-adrenoceptors during electrical pulse train stimulation of brain slices at different frequencies. The experiments are based on the assumption that the concentration of released noradrenaline at the ₂-adrenoceptors exerting a certain autoinhibition should be equal to the concentration of exogenous noradrenaline causing the same inhibition under conditions in which any influence of the released transmitter is excluded. In order to avoid autoinhibition, hippocampus and cortex slices of the rabbit and the rat, prelabelled with [³H]noradrenaline and superfused in presence of an uptake inhibitor, were electrically stimulated using 4 pulses delivered at 100 Hz (POP stimulation). Exogenous noradrenaline diminished the overflow of tritium elicited by POP stimulation in a concentration-dependent manner. In rabbit brain tissues the EC₅₀ value and maximum inhibition of noradrenaline release were found to be approximately 6 nmol/l and more than 95%, respectively, whereas in rat tissues the corresponding values were between 20 and 30 nmol/l and approximately 90%. When electrical stimulation was performed with trains of 36 pulses delivered at 0.1, 0.3 or 3 Hz in absence or presence of an uptake inhibitor, the ₂-adrenoceptor antagonist yohimbine (1 or 10 mol/l) enhanced the evoked tritium overflow in a manner which was dependent on the frequency of stimulation and on blockade of the re-uptake mechanism. The facilitatory effects of yohimbine reflected an extent of autoinhibition which was between 53% (36 pulses/0.1 Hz, no uptake inhibitor) and 85% (36 pulses/3 Hz, uptake inhibitor present) in rabbit and between 16% (36 pulses/0.3 Hz, no uptake inhibitor) and 71% (36 pulses/3 Hz, uptake inhibitor present) in rat brain slices. Accordingly, the corresponding estimated biophase concentrations of noradrenaline were generally higher in rat than in rabbit tissues (they were between 32.5 and 74.5 or 5.1 and 51.6 nmol/l in the presence or absence of an uptake inhibitor, respectively, in the rat, and between 15 and 23.1 or 6.1 and 18.6 nmol/l in the rabbit). The observed frequency dependence of the effect of re-uptake blockade on the calculated biophase concentrations of noradrenaline would be compatible with the idea of a dependence of the effectiveness of the re-uptake mechanism on the firing rate of the neurone in being more effective at lower frequencies. Moreover, the stikingly low biophase concentrations of noradrenaline suggest that also in brain tissue noradrenaline causes lateral inhibition of release as has recently been shown for guinea-pig vas deferens. Send offprint requests to C. Allgaier at the above address     

Hypoxia and cyanosis in alpha-1-antitrypsin deficiency. Cirrhosis as an unusual etiologic factor

A patient with type PiZZ alpha-1-antitrypsin deficiency was found to have severe hypoxia despite normal pulmonary function testing and a normal chest radiograph. A nuclear medicine ventilation-perfusion study revealed a right-to-left shunt. Computed tomography showed minimal bleb formation, no diffuse changes, and hepatic changes of cirrhosis with portal hypertension. No nodular pulmonary masses or enlarged peripheral pulmonary vessels were found. The diagnosis of diffuse intrapulmonic arteriovenous shunts ("pulmonary spiders of cirrhosis") was suggested and then confirmed with a dynamic radionuclide flow study.     

No modulatory effect of neurokinin-1 receptor antagonists on serotonin uptake in human and rat brain synaptosomes

Some studies have demonstrated antidepressant activity of neurokinin-1-receptor antagonists (NK-1-RA) in major depressive disorder. However, the underlying mechanisms of this antidepressant effect are largely unknown. Preclinical studies in rats and mice have suggested that NK-1-RA do increase the neuronal release of serotonin (5-HT). This, however, seems to be compensated by an increased 5-HT reuptake, indicating that NK-1-RA have no inhibitory effect on the 5-HT transporter in rodents. Given the possibility that modulation of neurotransmitter release and reuptake may differ between species, with major differences found between rodents and humans, we investigated for the first time the possible modulatory effect of NK-1-RA on 5-HT uptake in human brain synaptosomes and compared it with the situation in rat cortex. We found that the specific human NK-1-RA L-733060, in contrast to the SSRI fluvoxamine (IC₅₀ = 10^− 7.96 M) did not inhibit 5-HT uptake in human brain synaptosomes and did not modulate fluvoxamine-induced 5-HT uptake inhibition at 1 μM. Furthermore, substance P as well as Sar⁹Met(O₂)¹¹SP, as the major agonists at the NK-1-R, did not modulate 5-HT uptake in human brain synaptosomes. Similar results were found in rat cortex synaptosomes by using the rat-specific NK-1-RA WIN51708. These results show that in humans, as in rodents, inhibition of the 5-HT transporter is probably not the underlying mechanism of the assumed antidepressant activity of NK-1-RA.     

Protective effect of a PAF-acether antagonist, BN 52021, in trichothecene toxicosis

Trichothecenes are mycotoxins which produce lethal toxicosis in humans and animals, yet no adequate therapeutic regimen has been developed. This study provides evidence that the selective platelet activating factor (PAF) antagonist, BN 52021 (5-15 mg/kg i.v.) can prolong the survival of conscious rats exposed to a highly lethal T-2 toxicosis. These data also suggest that PAF is an important mediator of this unique toxicosis.     

Evidence-based practice for acute low back pain in primary care: patient outcomes and cost of care

Provider adherence with clinical practice guidelines (CPGs) for acute low back pain (LBP) and its impact on clinical outcomes and cost are controversial. A panel and cross-sectional design was used to determine the rate of provider adherence to the Department of Defense/Veteran's Administration CPG for Acute LBP which included ergonomic and psychosocial intervention. The relationship among adherent care, patient satisfaction, general health, functional outcome, and cost was examined. Direct health services and patient survey data 1 year before and 3 years following guideline implementation were analyzed. The sample consisted of 15,789 LBP cases (CPG) and 14,409 upper extremity cases used as controls (no CPG). Ten to 40% of LBP cases received CPG-adherent care across the 4 years. No differences were found between LBP and upper extremity diagnoses groups in the rates of change in the four outcomes over years. Multivariable regression analyses controlling for demographic variables and perceived health indicated that CPG adherence was related to better functional outcomes, Odds ratio (OR)=1.45 [95% CI=1.31-1.60] and lower healthcare costs (beta=-230.15, p<0.001). Cases receiving more adherent care also reported higher levels of patient satisfaction (beta=0.09, p<0.05) and general health, OR=1.44 [95% CI=1.29-1.60]. Higher levels of adherent care which included efforts to address both ergonomic and psychosocial factors in the course of acute back pain were related to better clinical outcomes and lower costs.