In vivo antimuscarinic actions of the third generation antihistaminergic agent, desloratadine

BACKGROUND: Muscarinic receptor mediated adverse effects, such as sedation and xerostomia, significantly hinder the therapeutic usefulness of first generation antihistamines. Therefore, second and third generation antihistamines which effectively antagonize the H(1 )receptor without significant affinity for muscarinic receptors have been developed. However, both in vitro and in vivo experimentation indicates that the third generation antihistamine, desloratadine, antagonizes muscarinic receptors. To fully examine the in vivo antimuscarinic efficacy of desloratadine, two murine and two rat models were utilized. The murine models sought to determine the efficacy of desloratadine to antagonize muscarinic agonist induced salivation, lacrimation, and tremor. Desloratadine's effect on the cardiovascular system was explored in both rodent models. RESULTS: In the pithed rat, both desloratadine (1.0 mg/kg, i.v.) and the muscarinic M(2 )selective antagonist, methoctramine (0.5 mg/kg, i.v.), inhibited negative inotropic (left ventricular dP/dt) effects caused by oxotremorine, a nonselective muscarinic agonist (p < 0.05). Negative chronotropic effects caused by oxotremorine were inhibited by desloratadine, methoctramine, and the muscarinic M(3 )selective antagonist, 4-DAMP (1.0 mg/kg, i.v.). A late positive inotropic event observed after the initial decrease was inhibited by all three test compounds with desloratadine and 4-DAMP being the most efficacious. In the conscious animal, inhibition of baroreflex-mediated bradycardia was evaluated. Unlike atropine (0.5 mg/kg, i.v.), desloratadine did not alter this bradycardia. The antimuscarinic action of desloratadine on salivation, lacrimation, and tremor was also explored. In urethane-anesthetized (1.5 g/kg, i.p.) male ICR mice (25–35 g) desloratadine (1.0, 5.0 mg/kg) did not inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, unlike atropine (0.5 mg/kg) and 4-DAMP (1.0 mg/kg). In conscious mice, desloratadine failed to inhibit oxotremorine-induced (0.5 mg/kg, s.c.) salivation, lacrimation, and tremor. However, desloratadine did inhibit oxotremorine-induced tremor in phenylephrine pretreated animals. CONCLUSION: The presented data demonstrate that the third generation antihistamine, desloratadine, does not significantly antagonize peripheral muscarinic receptors mediating salivation and lacrimation, therefore, xerostomia and dry eyes should not be observed with therapeutic use of desloratadine. Our data also indicate when administered to a patient with a compromised blood-brain barrier, desloratadine may cause sedation. Patients with compromised cardiovascular systems should be closely monitored when administered desloratadine based on our results that desloratadine has the ability to interfere with normal cardiovascular function mediated by muscarinic receptors

Relationships between gas-liquid interfacial surface area, liquid saturation, and light transmission in variably saturated porous media

Liquid saturation and gas-liquid interfacial area are important parameters for evaluating the transport and fate of contaminants in unsaturated subsurface environments. Recent findings indicate that interfacial surface area controls the relative degree of transmitted light in laboratory systems containing translucent porous media. Equations are derived to estimate the specific gas-liquid interfacial area from the area under the primary-drainage branch of the S[subscript eff]-h characteristic curve as parameterized using common water retention functions. The total area under the curve provides the maximum available specific gas-liquid interfacial area available at residual saturation, which can be incorporated into the relationship to determine the gas-liquid interfacial area at intermediate degrees of saturation via light transmission. Experimental results, and analysis of external data sets, support these findings. Closed-form relationships are presented as enhancements to a recent method for determination of liquid saturations above residual using light transmission. A physically based model is developed and tested for the quantification of liquid contents below residual saturation.Keywords: gas-liquid interfacial surface area, light transmission, liquid saturation, residual saturation, characteristic curve, unsaturated porous medi

Impact of microbial growth on water flow and solute transport in unsaturated porous media

A novel analytical method was developed that permitted real-time, noninvasive measurements of microbial growth and associated changes in hydrodynamic properties in porous media under unsaturated flowing conditions. Salicylate-induced, lux gene-based bioluminescence was used to quantify the temporal and spatial development of colonization over a 7-day time course. Water contents were determined daily by measuring light transmission through the system. Hydraulic flow paths were determined daily by pulsing a bromophenol blue dye solution through the colonized region of the sand. Bacterial growth and accumulation had a significant impact on the hydraulic properties of the porous media. Microbial colonization caused localized drying within the colonized zone, with decreases in saturation approaching 50% of antecedent values, and a 25% lowering of the capillary fringe height. Flow was retarded within the colonized zone and diverted around it concurrent with the expansion of the colonized zone between days 3 and 6. The location of horizontal dispersion corresponded with the cell densities of 1–3 × 10⁹ cells g⁻¹ dry sand. The apparent solute velocity through the colonized region was reduced from 0.41 cm min⁻¹ (R² = 0.99) to 0.25 cm min⁻¹ (R² = 0.99) by the sixth day of the experiment, associated with population densities that would occupy approximately 7% of the available pore space within the colonized region. Changes in the extent of colonization occurred over the course of the experiment, including upward migration against flow. The distribution of cells was not determined by water flow alone, but rather by a dynamic interaction between water flow and microbial growth. This experimental system provides rich data sets for the testing of conceptualizations expressed through numerical modeling.Keywords: Bacteria in the subsurface, Vadose zone, Bacteria in porous medi

Noninvasive Quantitative Measurement of Bacterial Growth in Porous Media under Unsaturated-Flow Conditions

Glucose-dependent growth of the luxCDABE reporter bacterium Pseudomonas fluorescens HK44 was monitored noninvasively in quartz sand under unsaturated-flow conditions within a 45- by 56- by 1-cm two-dimensional light transmission chamber. The spatial and temporal development of growth were mapped daily over 7 days by quantifying salicylate-induced bioluminescence. A nonlinear model relating the rate of increase in light emission after salicylate exposure to microbial density successfully predicted growth over 4 orders of magnitude (r² = 0.95). Total model-predicted growth agreed with growth calculated from the mass balance of the system by using previously established growth parameters of HK44 (predicted, 1.2 × 10¹² cells; calculated, 1.7 × 10¹² cells). Colonization expanded in all directions from the inoculation region, including upward migration against the liquid flow. Both the daily rate of expansion of the colonized zone and the population density of the first day's growth in each newly colonized region remained relatively constant throughout the experiment. Nonetheless, substantial growth continued to occur on subsequent days in the older regions of the colonized zone. The proportion of daily potential growth that remained within the chamber declined progressively between days 2 and 7 (from 97 to 13%). A densely populated, anoxic region developed in the interior of the colonized zone even though the sand was unsaturated and fresh growth medium continued to flow through the colonized zone. These data illustrate the potential of a light transmission chamber, bioluminescent bacteria, and sensitive digital camera technology to noninvasively study real-time hydrology-microbiology interactions associated with unsaturated flow in porous media

Uranium Contamination in the Subsurface Beneath the 300 Area, Hanford Site, Washington

This report provides a description of uranium contamination in the subsurface at the Hanford Site's 300 Area. The principal focus is a persistence plume in groundwater, which has not attenuated as predicted by earlier remedial investigations. Included in the report are chapters on current conditions, hydrogeologic framework, groundwater flow modeling, and geochemical considerations. The report is intended to describe what is known or inferred about the uranium contamination for the purpose of making remedial action decisions

Total Cardiovascular and Limb Events and the Impact of Polyvascular Disease in Chronic Symptomatic Peripheral Artery Disease.

Background Peripheral artery disease (PAD) is associated with heightened risk for major adverse cardiovascular and limb events, but data on the burden of risk for total (first and potentially subsequent) events, and the association with polyvascular disease, are limited. This post hoc analysis of the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial evaluated total cardiovascular and limb events among patients with symptomatic PAD, overall and by number of symptomatic vascular territories. Methods and Results In the EUCLID trial, patients with symptomatic PAD (lower extremity revascularization >30 days before randomization or ankle-brachial index ≤0.80) were randomized to treatment with ticagrelor or clopidogrel. Relative effects on total events (cardiovascular death; nonfatal myocardial infarction and ischemic stroke; acute limb ischemia, unstable angina, and transient ischemic attack requiring hospitalization; coronary, carotid, and peripheral revascularization procedures; and amputation for symptomatic PAD) were summarized by hazard ratios (HRs), whereas absolute risks were estimated by incidence rates and mean cumulative functions. Among 13 885 randomized patients, 7600 total cardiovascular and limb events occurred during a median 2.7 years of follow-up, translating to 60.0 and 62.5 events per 100 patients through 3 years for the ticagrelor and clopidogrel groups, respectively (HR, 0.96; 95% CI, 0.89-1.03; P=0.27). Among 1393 patients with disease in 3 vascular territories, event accrual rates through 3 years for the ticagrelor and clopidogrel groups were 87.3 and 97.7 events per 100 patients, respectively. Absolute risk reductions for ticagrelor relative to clopidogrel at 3 years were -0.2, 6.7, and 10.3 events per 100 patients for 1, 2, and 3 affected vascular territories, respectively (Pinteraction=0.09). Conclusions Patients with symptomatic PAD have nearly double the number of total events than first events, with rates reflecting the number of affected vascular territories. These findings highlight the clinical relevance of quantifying disease burden in terms of total events and the need for long-term preventive treatments in high-risk patient populations. Registration URL: https://clinicaltrials.gov/; Unique identifier: NCT01732822

European regulatory agenices should employ full time statisticians

No abstract available

Association of Heart Failure With Outcomes Among Patients With Peripheral Artery Disease: Insights From EUCLID.

Background Peripheral artery disease (PAD) and heart failure (HF) are each independently associated with poor outcomes. Risk factors associated with new-onset HF in patients with primary PAD are unknown. Furthermore, how the presence of HF is associated with outcomes in patients with PAD is unknown. Methods and Results This analysis examined risk relationships of HF on outcomes in patients with symptomatic PAD randomized to ticagrelor or clopidogrel as part of the EUCLID (Examining Use of Ticagrelor in Peripheral Arterial Disease) trial. Patients were stratified based on presence of HF at enrollment. Cox models were used to determine the association of HF with outcomes. A separate Cox model was used to identify risk factors associated with development of HF during follow-up. Patients with PAD and HF had over twice the rate of concomitant coronary artery disease as those without HF. Patients with PAD and HF had significantly increased risk of major adverse cardiovascular events (hazard ratio [HR], 1.31; 95% CI, 1.13-1.51) and all-cause mortality (HR, 1.39; 95% CI, 1.19-1.63). In patients with PAD, the presence of HF was associated with significantly less bleeding (HR, 0.65; 95% CI, 0.45-0.96). Characteristics associated with HF development included age ≥66 (HR, 1.29; 95% CI, 1.18-1.40 per 5 years), diabetes mellitus (HR, 1.85; 95% CI, 1.41-2.43), and weight (bidirectionally associated, ≥76 kg, HR, 0.77; 95% CI, 0.64-0.93; <76 kg, HR, 1.12; 95% CI, 1.07-1.16). Conclusions Patients with PAD and HF have a high rate of coronary artery disease with a high risk for major adverse cardiovascular events and death. These data support the possible need for aggressive treatment of (recurrent) atherosclerotic disease in PAD, especially patients with HF

Analysis of vadose zone inhomogeneity toward distinguishing recharge rates: Solving the nonlinear interface problem with Newton method

Citation: Steward, D. R. (2016). Analysis of vadose zone inhomogeneity toward distinguishing recharge rates: Solving the nonlinear interface problem with Newton method. Water Resources Research, 52(11), 8756-8774. doi:10.1002/2016wr019222Recharge from surface to groundwater is an important component of the hydrological cycle, yet its rate is difficult to quantify. Percolation through two-dimensional circular inhomogeneities in the vadose zone is studied where one soil type is embedded within a uniform background, and nonlinear interface conditions in the quasilinear formulation are solved using Newton's method with the Analytic Element Method. This numerical laboratory identifies detectable variations in pathline and pressure head distributions that manifest due to a shift in recharge rate through in a heterogeneous media. Pathlines either diverge about or converge through coarser and finer grained materials with inverse patterns forming across lower and upper elevations; however, pathline geometry is not significantly altered by recharge. Analysis of pressure head in lower regions near groundwater identifies a new phenomenon: its distribution is not significantly impacted by an inhomogeneity soil type, nor by its placement nor by recharge rate. Another revelation is that pressure head for coarser grained inhomogeneities in upper regions is completely controlled by geometry and conductivity contrasts; a shift in recharge generates a difference Dp that becomes an additive constant with the same value throughout this region. In contrast, shifts in recharge for finer grained inhomogeneities reveal patterns with abrupt variations across their interfaces. Consequently, measurements aimed at detecting shifts in recharge in a heterogeneous vadose zone by deciphering the corresponding patterns of change in pressure head should focus on finer grained inclusions well above a groundwater table