Similar Systemic Effects Research Articles

Non-clinical safety assessment of single and repeated administration of gE/AS01 zoster vaccine in rabbits.

HZ/su is an investigational recombinant subunit vaccine for the prevention of shingles, a disease resulting from the reactivation of varicella zoster virus. The vaccine is composed of recombinant varicella zoster virus glycoprotein E (gE), and liposome-based Adjuvant System AS01. To evaluate the potential local and systemic effects of this vaccine, three studies were performed in rabbits. In the first two studies, rabbits received a single intramuscular (IM; study 1) or subcutaneous (SC; study 2) dose of gE/AS01, AS01 alone (in study 2 only) or saline, and the local tolerance was evaluated up to 3 days after administration. Under these conditions, only local inflammatory reactions at the injection sites were detected by microscopic evaluation. In the third study, gE/AS01, AS01 alone or saline, were injected SC or IM on four occasions at 2 week intervals. General health status, local tolerance, ophthalmology, haematology and blood chemistry parameters were monitored. Macroscopic and microscopic evaluations were performed after termination of the study. The only treatment-related changes included a transient increase in neutrophils, C-reactive protein and fibrinogen levels and microscopic signs of inflammation at the injection sites, which are expected observations related to the elicited inflammatory reaction. The SC and IM routes of administration produced similar systemic effects. However, microscopic findings at the injection sites differed. One month after the last injection, recovery was complete in all groups. In conclusion, the single and repeated SC and IM administration of the gE/AS01 vaccine were locally and systemically well-tolerated in rabbits and support the clinical development of the vaccine. Copyright © 2016 John Wiley & Sons, Ltd.

Particulate nature of inhaled zinc oxide nanoparticles determines systemic effects and mechanisms of pulmonary inflammation in mice

Inhalation of zinc oxide nanoparticles (ZnONP) has potential health impact. Because zinc ion may involve in the toxicity of ZnONP, we compared adverse effects of inhaled aerosolized ZnONP and zinc nitrate in mice. Aerosolized ZnONP and zinc nitrate were well-dispersed in the inhalation chamber. Inhalation of 0.86 mg/m3 ZnONP or 1.98 mg/m3 zinc nitrate for 5 h caused acute inflammation mainly at bronchioloalveolar junctions of lungs at 24-h post-exposure. Inhalation of ZnONP or zinc nitrate increased metallothionein expression in the epithelial cells of brochioloalveolar junction. While the effects on cytokines secretion in bronchoalveolar lavage were similar between ZnONP and zinc nitrate, only ZnONP increased lactate dehydrogenase activity. However, repeated exposure to 0.86 mg/m3 ZnONP 5 h/day for 5 days failed to cause a similar adverse effect. Either single or repeated exposure to 0.86 mg/m3 ZnONP increased activities of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and creatine phosphokinase in blood. In contrast, exposure to zinc nitrate had no similar systemic effects. In human bronchial epithelial cells, ZnONP-induced interleukin-8 secretion was partially prevented by co-treatment with the Toll-like receptor 4 (TLR4) inhibitor. Furthermore, ZnONP-induced pulmonary inflammation was greater in wild-type mice than in TLR4-deficent mice. It appears that ZnONP-induced acute pulmonary inflammation partially depended on TLR4. In summary, we demonstrated the dose-responsive effects for inhalation of ZnONP and zinc nitrate in mice. The threshold of cytokines induction for inhalation of ZnONP for 5 h was 0.43 mg/m3. The particulate characters of ZnONP might contribute to the systemic adverse effects and shall be evaluated for assessing its health impact in humans.

Assessing Relative Bioactivity of Chemical Substances Using Quantitative Molecular Network Topology Analysis

Structurally different chemical substances may cause similar systemic effects in mammalian cells. It is therefore necessary to go beyond structural comparisons to quantify similarity in terms of their bioactivities. In this work, we introduce a generic methodology to achieve this on the basis of Network Biology principles and using publicly available molecular network topology information. An implementation of this method, denoted QuantMap, is outlined and applied to antidiabetic drugs, NSAIDs, 17β-estradiol, and 12 substances known to disrupt estrogenic pathways. The similarity of any pair of compounds is derived from topological comparison of intracellular protein networks, directly and indirectly associated with the respective query chemicals, via a straightforward pairwise comparison of ranked proteins. Although output derived from straightforward chemical/structural similarity analysis provided some guidance on bioactivity, QuantMap produced substance interrelationships that align well with reports on their respective perturbation properties. We believe that QuantMap has potential to provide substantial assistance to drug repositioning, pharmacology evaluation, and toxicology risk assessment.

Euglycemic Infusion of Insulin Detemir Compared With Human Insulin Appears to Increase Direct Current Brain Potential Response and Reduces Food Intake While Inducing Similar Systemic Effects

OBJECTIVEIn the treatment of diabetic patients, the long-acting insulin analog insulin detemir is less prone to induce weight gain than other insulin formulations. Assuming that because of its pharmacologic properties, detemir displays stronger central nervous anorexigenic efficacy than human insulin, we compared acute effects of human insulin and detemir on electroencephalography (EEG) measures and food intake.RESEARCH DESIGN AND METHODSFrontocortical EEG direct current (DC) potentials were recorded in 15 healthy men during two hyperinsulinemic-euglycemic clamps that included an insulin bolus injection (human insulin, 17.75 mU/kg body wt; detemir, 90 mU/kg body wt) followed by a steady 90-min infusion (1.0 vs. 2.0 mU · kg−1 · min−1). A higher dosage was chosen for detemir to compensate for its delay in impact relative to human insulin and to elicit similar systemic effects. At 20 min after infusion, subjects were allowed to eat ad libitum from a test buffet.RESULTSMean glucose infusions to maintain euglycemia (P > 0.93) and blood glucose concentrations (P > 0.34) did not differ between conditions. Detemir infusion induced a negative DC-potential shift, averaging −372.2 μV from 21 to 90 min that was not observed during human insulin infusion (146.5 μV, P = 0.02). Detemir, in comparison with human insulin, reduced subsequent food intake by 303 kcal (1,257 vs. 1,560, P < 0.04).CONCLUSIONSWhile inducing comparable peripheral effects, detemir exerts stronger acute effects on brain functions than human insulin and triggers a relative decrease in food consumption, suggesting an enhanced anorexigenic impact of detemir compared with human insulin on central nervous networks that control nutrient uptake.

Levosimendan is superior to milrinone and dobutamine in selectively increasing microvascular gastric mucosal oxygenation in dogs*

The effect of levosimendan, a novel inotropic vasodilator (inodilator), on the microvascular gastric mucosal hemoglobin oxygenation (muHbo(2)) is unknown. A possible effect could thereby be selective for the splanchnic region or could primarily reflect changes in systemic oxygen transport (Do(2)) and/or oxygen consumption (Vo(2). We compared systemic and regional effects of levosimendan with those of established inotropes, milrinone and dobutamine. Laboratory experiment. University animal research laboratory of experimental anesthesiology. Chronically instrumented dogs with flow probes for cardiac output measurement. Anesthetized, mechanically ventilated dogs (each group n = 6) on different days randomly received levosimendan (10 microg.kg, followed by four infusion steps: 0.125-1.0 microg.kg.min), milrinone (5.0 microg.kg, followed by 1.25-10 microg.kg.min), or dobutamine (2.5-10.0 microg.kg.min). Since these drugs may modify regional or systemic responses to fluid load, an additional predefined volume challenge was subsequently performed with hydroxyethyl starch 6% (10 mL.kg). We measured muHbo(2) (reflectance spectrophotometry), Do(2), Vo(2), and systemic hemodynamics. Levosimendan significantly increased muHbo(2) from baseline (approximately 55% for all groups) to 64 +/- 4% and further to 69 +/- 2% with volume challenge (mean +/- sem). At the systemic level, levosimendan alone only slightly increased Do(2) at a Vo(2). Milrinone elicited similar systemic effects (Do(2), Vo(2), hemodynamics) but failed to increase muHbo(2). Dobutamine, conversely, increased muHbo(2) to a similar extent as levosimendan; however, this was accompanied by marked increases in Do(2) and Vo(2). The gastric mucosa selectivity of these interventions, expressed as slope of the muHbo(2)/Do2 relation, was highest for levosimendan (+1.89 and +1.14, without and with volume challenge), compared with milrinone (+0.45 and + 0.47) and dobutamine (+0.48 and + 0.33). Levosimendan is superior to milrinone (no significant regional effects) and dobutamine (marked systemic effects) in increasing gastric mucosal oxygenation selectively (i.e., at only moderately increased Do(2) and stable Vo(2). If our experimental data apply to the clinical setting, levosimendan may serve as an option to selectively increase gastrointestinal mucosa oxygenation in patients at risk to develop splanchnic ischemia.

Differential Regulation of Ventricular Adrenomedullin and Atrial Natriuretic Peptide Gene Expression in Pressure and Volume Overload in the Rat

1. Adrenomedullin is a recently discovered vasodilating and natriuretic peptide whose physiological and pathophysiological roles remain to be established. Like atrial natiuretic peptide adrenomedullin is expressed in the left ventricle. Ventricular expression of atrial natriuretic peptide is known to be markedly increased by volume or pressure overload. In this study we investigated whether ventricular expression of adrenomedullin is similarly stimulated under such conditions. 2. Ventricular adrenomedullin and atrial natriuretic peptide mRNA levels as well as those of a loading control mRNA (glyceraldehyde-3-phosphate dehydrogenase) were quantified by Northern blot analysis in (a) rats with severe post-infarction heart failure induced by left coronary ligation at 30 days post-surgery and (b) in rats with pressure-related cardiac hypertrophy induced by aortic banding at several time points (0.5, 1 and 4 h, and 1, 4, 7 and 28 days) after surgery. Levels were compared with those in matched sham-operated controls. 3. The mRNA level of atrial natriuretic peptide was markedly increased (8-10-fold) in the left ventricle of animals with post-infarction heart failure. In contrast, there was only a modest (40%) increase in the level of adrenomedullin mRNA. In rats with pressure-induced cardiac hypertrophy the ventricular level of atrial natriuretic peptide mRNA was again markedly increased (maximum 10-fold). The increase was first noticeable at 24 h post-banding and persisted until 28 days. In contrast, there was no change in adrenomedullin mRNA level compared with sham-operated rats at any time point. 4. Despite having similar systemic effects, the expression of adrenomedullin and atrial natriuretic peptide in the left ventricle is differently regulated. The findings imply distinct roles for the two peptides. The results do not support an important role for ventricular adrenomedullin expression in the remodelling process that occurs during the development of cardiac hypertrophy but suggest that ventricular adrenomedullin participates in the local and/or systemic response to heart failure.

Consistency of UK Pension Fund Investment Performance

Transition matrix techniques are used to relate the past and present performance of pension fund portfolios. In particular, funds are ranked to study the tendency of portfolios to remain in the same quartile of the ranking as they were in the previous period. For raw returns, funds in both of the top quartiles are found to be more likely to remain in the same quartile than would be expected by chance. This result can be taken as limited evidence for the consistency of performance. Similar systemic effects are observed on a risk‐adjusted basis. There appears to be clear evidence that some fund managers can offer a degree of consistent good performance.

Effect of Tertatolol on Glomerular Hemodynamics in the Normal Munich-Wistar Rat

Administration of beta-blockers is frequently associated with decreases in both renal plasma flow and glomerular filtration rate (GFR). Tertatolol, a new non-selective beta-blocker, has demonstrated similar systemic effects to other conventional beta-blockers, but tertatolol produces increases in both renal plasma flow and glomerular filtration rate. To evaluate the renal hemodynamic mechanism responsible for the increase in GFR, micropuncture experiments were performed in normal Munich-Wistar rats. Intravenous injection of tertatolol produced a significant increase in GFR and urinary sodium excretion in spite of a decrease in systemic blood pressure. Single nephron glomerular filtration rate was significantly increased due to an increase in single nephron plasma flow related to parallel afferent and efferent arteriolar dilatation. No significant changes in glomerular hydrostatic pressure, transcapillary hydrostatic pressure gradient or the ultrafiltration coefficient were demonstrated with tertatolol. The capacity of tertatolol to increase glomerular filtration rate and to promote sodium excretion without modifying critical glomerular pressures makes this agent a highly attractive antihypertensive drug.

Systemic activity of a juvenile hormone analog.

The peptidic analog of insect juvenile hormone, ethyl pivaloyl-L-alanyl-p-aminobenzoate with enormous biological activity on the red cotton bug, Dysdercus cingulatus, has pronounced systemic effect in sunflower plants. The compound is absorbed by the plant tissues and appears to be translocated throughout the plant system in active form. There is some evidence that juvenile hormone analogs of other types also have similar systemic effects. The discovery of systemic action should aid in the possible utilization of juvenile hormone analogs in insect control programs.