Recently, extensive behavioral research has been conducted on the benztropine (BZT) analogs with the goal of developing successful therapeutics for cocaine abuse. The present study was conducted to characterize the contribution of dispositional factors in mediating the behavioral differences among the chloro BZT analogs and to identify cytochrome P450 enzymes involved in their metabolism. Bidirectional transport and efflux studies of four of the chloro BZT analogs were conducted. Screening with a panel of human and rat Supersomes was performed for 4',4''-diCl BZT. In addition, pharmacokinetic and brain distribution studies for 4'-Cl and 4',4''-diCl BZT in Sprague-Dawley rats were conducted. The permeability of the chloro analogs ranged from 8.26 to 32.23 and from 1.37 to 21.65 x 10(-6) cm/s, whereas the efflux ratios ranged from 2.1 to 6.9 and from 3.3 to 28.4 across Madin-Darby canine kidney-multidrug resistance 1 (MDCK-MDR1) and Caco-2 monolayers, respectively. The P-glycoprotein (P-gp) inhibitor verapamil reduced the efflux ratios and enhanced the absorptive transport of the chloro BZT analogs. 4',4''-diCl BZT was a substrate of human CYP2D6 and 2C19 and rat 2C11 and 3A1. The brain uptake for 4'-Cl and 4',4''-diCl BZT was comparable and higher than previously reported for cocaine (brain-to-plasma partition coefficient = 4.6-4.7 versus 2.1 for cocaine). The rank order for t(1/2) was 4',4''-diCl BZT > 4'-Cl BZT > cocaine and for steady-state volume of distribution was 4'-Cl BZT > 4',4''-diCl BZT > cocaine. In conclusion, the chloro analogs differ significantly in their clearance and duration of action, which correlates to their behavioral profiles and abuse liability. Furthermore, these results suggest that the distinctive behavioral profile of these analogs is not due to limited brain exposure.

This work discusses the physical, geochemical and mineralogical characterization of some bentonite resources in South El-Hammam area which are hosted in thick sandstone sequences belonging to the Lower Miocene Moghra Formation. Bentonite samples were characterized by microscopic, SEM, XRD and ICP-MS analyses. Bentonite resources in this study consist of montmorillonite as the main clay mineral of all the analyzed samples. Kaolinite also occurs as minor clay constituents. The identified non-clay minerals include; quartz, albite and calcite. The highest grade of the studied bentonite, contains Si/Al molecular ratio of 2, suggesting absence of detrital quartz. In contrary, the lowest grade of bentonite with alumina content of 15.06%, display Si/Al molecular ratio of 4.34, where free silica dominates over bentonite. The REE content of the Lower Miocene bentonite study area is strongly imparted by LREE signature. The very high CIA index (74.85 and 91.25) suggesting intense chemical weathering of source rock, which is supported by the presence of Ce abnormality, indicating that they were deposited under pluvial conditions.

GA2-50 is a novel N-substituted benztropine analog with improved potency and selectivity for the dopamine transporter. The pharmacokinetic and pharmacodynamic properties of GA2-50 were characterized as a part of its preclinical evaluation as a substitute medication for cocaine abuse. In vitro transport and metabolism studies as well as pharmacokinetic studies in rats were conducted. Effect of GA2-50 on the extracelluar nucleus accumbens (NAc) dopamine levels and on cocaine's induced dopamine elevation was evaluated using intracerebral microdialysis. GA2-50 showed high transcellular permeability despite being a P-glycoprotein substrate. GA2-50 was a substrate of human CYP2D6, CYP2C19, CYP2E1, rat CYP2C11, CYP2D1, CYP3A1, and CYP1A2; with low intrinsic clearance values. In vivo, GA2-50 showed high brain uptake (R(i) approximately 10), large volume of distribution (V(ss) = 37 L/kg), and long elimination half-life (t((1/2)) = 19 h). GA2-50 resulted in 1.6- and 2.7-fold dopamine elevation at the 5 and 10 mg/kg i.v. doses. Dopamine elevation induced by GA2-50 was significantly reduced, slower and longer lasting than previously observed for cocaine. GA2-50 had no significant effect on cocaine's induced dopamine elevation upon simultaneous administration. Results from the present study indicate that GA2-50 possesses several attributes sought after for a substitute medication for cocaine abuse.

Aim The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Methods Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. Results ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Conclusions Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients.

Efforts are made to record biodiversity of microflora and diazotrophs associated with the plant cover of the major agricultural development areas in north Sinai, around the El-Salam canal, a newly-constructed canal that brings Nile water westward across the Suez canal. Natural plant communities were collected from three major areas. Ectorhizosphere, endorhizosphere and phyllosphere samples were examined for total microbial population and diazotrophs. The vegetation of South Qantara (area I) is characterized by the dominance of Stipagrostis scoparia followed by Nitraria retusa, Convolvulus lanatus, Cornulaca monacantha and Filago desertorum. Rabaa-Bir El Abd (area II) is dominated by Artemisia monosperma, Panicum turgidum and Zygophyllum album. Euphorbia terracina, Oligomeris linifolia, Astragalus kahiricus, Hyoscyamus muticus and Thymelea hirsuta represent the major plants of El Ser and Al Quarir (area III). Microorganisms colonized root surfaces of all tested plants ranging from > 10 5 to 10 10 cfu g − 1 . Diazotrophs were common residents (10 10 cfu g − 1 ), invaded the root tissue and established endophytically (10 2 – 10 6 cfu g − 1 ). Fifty-one N 2 -fixing isolates were obtained. Among the 32 bacilli isolates, Bacillus polymyxa and Bacillus circulans were more common compared to Bacillus macerans. BNF Gram-negative isolates belonged to Enterobacter agglomerans, Enterobacter gergoviae, Enterobacter amnigenus, Klebsiella pneumoniae, Pseudomonas luteola, Pseudomonas cepacia, Agrobacterium radiobacter and Azospirillum spp. © 2003, Taylor & Francis Group, LLC.

ABT-102 is a selective TRPV1 antagonist designed for treatment of nociceptive pain. The objective of this study was to characterize the bioavailability and the food effect of 2 solid-dispersion (melt-extrusion [Meltrex] and spray-dried) tablet formulations of ABT-102 relative to the solution formulation used in initial clinical trials. The study followed a 2-part, single-dose (2-mg), open-label, randomized, 3-period, crossover design in 24 healthy adults, where in each study part, 1 of the 2 solid-dispersion formulations (under fasting and nonfasting conditions) was compared to the solution formulation (under nonfasting conditions). Under nonfasting conditions, the melt-extrusion and spray-dried formulations had 53% and 87% higher Cmax and 42% and 70% higher AUC∞ than the solution formulation, respectively. The 2 solid-dispersion formulations provided comparable absolute ABT-102 exposures (mean ± SD AUC∞ of 116 ± 35 ng·h/mL [melt-extrusion] and 112 ± 55 ng·h/mL [spray-dried]). There was no effect of food (high-fat/high-calorie breakfast) on the bioavailability of the melt-extrusion formulation with the fasting and nonfasting regimens meeting bioequivalence. Food increased Cmax and AUC∞ central values of the spray-dried formulation by an estimated 11% and 17%, respectively. Based on the results of the study, the melt-extrusion formulation of ABT-102 was selected to replace the solution formulation for subsequent clinical development.

A mathematical model has been reviewed and used to simulate retention of beryllium ions on flow-through fixed bed reactor of Amb-IR-120. The interlinked effects of structural parameters, kinetics, hydrodynamic and operating conditions have been incorporated in the mathematical model.

Oral levodopa-carbidopa (LC-oral) treatment in advanced Parkinson's disease (PD) is associated with motor complications due to large fluctuations in levodopa plasma concentrations. Levodopa–carbidopa intestinal gel (LCIG) provides individualized continuous levodopa–carbidopa delivery through intrajejunal infusion. This study evaluated the pharmacokinetics, safety, and efficacy of LCIG relative to LC-oral in Japanese subjects with advanced PD.

The parsing of Arabic sentence is a necessary prerequisite for many natural language processing applications such as machine translation and information retrieval. In this paper we report our attempt to develop an efficient chart parser for Analyzing Modern Standard Arabic (MSA) sentence. From a practical point of view, the parser is able to satisfy syntactic constraints reducing parsing ambiguity. Lexical semantic features are also used to disambiguate the sentence structure. We explain also an Arabic morphological analyzer based on ATN technique. Both the Arabic parser and the Arabic morphological analyzer are implemented in Prolog. The linguistic rules were acquired from a set of sentences from MSA sentence in the Agriculture domain.

BACKGROUND AND OBJECTIVE: Daclizumab is a humanized monoclonal antibody that blocks the α-subunit of the interleukin-2 receptor with demonstrated benefits in the treatment of multiple sclerosis. The present work aimed to characterize the pharmacokinetics of daclizumab high-yield process (HYP) in healthy volunteers.

METHODS: Three double-blind, randomized, placebo-controlled, phase I studies evaluated the pharmacokinetics of daclizumab HYP in healthy volunteers following single subcutaneous administration (50, 150, or 300 mg), multiple subcutaneous administrations (100 or 200 mg biweekly with a 200 mg loading dose), or single intravenous administration (200 or 400 mg). Measurable serum concentrations (n = 925) from 70 subjects treated with daclizumab HYP in the three studies were analyzed using non-linear mixed-effects modeling.

RESULTS: A two-compartment model with a first-order absorption and elimination adequately described daclizumab HYP pharmacokinetics. Daclizumab HYP clearance, inter-compartmental clearance, and central and peripheral volumes of distribution were 10 mL/h, 44 mL/h, 3.89 L, and 2.52 L, respectively, scaled by [bodyweight (kg)/70] with 0.54 and 0.64 exponents for clearance and volume parameters, respectively. Lag-time, mean absorption time, and absolute bioavailability (100-300 mg) for subcutaneous administration were 2 h, 4.6 days, and 84 %, respectively. Bodyweight explained only ~20 % of daclizumab HYP pharmacokinetic variability. With this limited dataset, sex, age, race, or presence of antibodies did not correlate with daclizumab HYP clearance. The estimated effective half-life was 21-25 days. The developed model was robust in bootstrap evaluation and predicted the data adequately in stochastic simulations.

CONCLUSIONS: Daclizumab HYP is characterized by slow clearance, linear pharmacokinetics (at doses ≥100 mg), high subcutaneous bioavailability, and a half-life suitable for monthly administration.

The introduction of 3-dimensional (3D) volumetric technology and the massive amount of information that can be obtained from it compels the introduction of new methods and new technology for orthodontic diagnosis and treatment planning. In this article, methods and tools are introduced for managing 3D images of orthodontic patients. These tools enable the creation of a virtual model and automatic localization of landmarks on the 3D volumes. They allow the user to isolate a targeted region such as the mandible or the maxilla, manipulate it, and then reattach it to the 3D model. For an integrated protocol, these procedures are followed by registration of the 3D volumes to evaluate the amount of work accomplished. This paves the way for the prospective treatment analysis approach, analysis of the end result, subtraction analysis, and treatment analysis.