Poenostavljena metoda za analiziranje nasipov, podprtih s piloti in geosintetsko ojačitvijo, ter analiza vpliva pomembnosti projektnih parametrov

A simplified method for evaluating a pile-supported embankment reinforced with geosynthetic (PGRS embankment) is proposed in this paper. The method takes into account not only the arching effect, the membrane effect of the deflected geosynthetic, and the subsoil reaction, but also the pile head settlement, which makes the method applicable for floating piles, as well as piles seated on a firm soil layer. The settlement of the subsoil surface is considered to consist of two parts: (a) the settlement of the subsoil surface equals that of the pile cap with no deformation in geosynthetic yet(b) the subsoil surface subsides along with the geosynthetic deforming, and the deflected geosynthetic being considered as catenary shaped. The formula for the maximum differential settlement between the subsoil surface and the piles is worked out by analyzing the force equilibrium of the geosynthetic and the stress-strain relationship of the geosynthetic at the edge of the pile cap. The comparison of the calculated results with the observed data and the six current analytical methods has been implemented to verify the proposed method. The influence of the tensile stiffness of the geosynthetic, compression modulus of soft soil, soft soil thickness, embankment height, internal friction angle of the embankment fill and the pile spacing on the subsoil reaction, the stress concentration ratio (SCR) and the tension of the geosynthetic are investigated using the proposed method. The influence significance of these factors has been investigated using the evaluation theory of binary variance analysis for the non-repeatability tests, which helps optimize the design of the PGRS embankment.V tem članku je predlagana poenostavljena metoda za ovrednotenje nasipa, podprtega s piloti in ojačenim z geosintetikom (PGRS nasip). Metoda upošteva poleg ločnega učinka, membranskega učinka odklonjenega geosintetika in reakcije tal, tudi posedek glave pilota. Zaradi slednjega se metoda lahko uporablja tako za viseče pilote kot tudi za pilote, ki stojijo na trdnem zemljinskem sloju. Posedek sloja zemljine pod površjem je sestavljen iz dveh delov: (a) posedka sloja zemljine pod površjem, ki je enak posedku glave pilota brez deformacij v geosintetiku(b) ugrezka sloja zemljine pod površjem zaradi deformiranja geosintetika, pri čemer je upoštevana deformirana oblika za geosintetik enaka obliki deformacije vrvi. Enačba za največji diferencialni posedek med površino podlage in piloti je dobljena s pomočjo analize ravnotežja sil geosintetika in razmerja napetost-specifična deformacija geosintetika na robu glave pilota. Za preveritev predlagane metode je bila izvedena primerjava izračunanih rezultatov z opazovanimi podatki in šestimi trenutnimi analitskimi metodami. Z uporabo predlagane metode je bil preučevan vpliv natezne togosti geosintetika, kompresijskega modula mehke zemljine, debeline mehke zemljine, višine nasipa, notranjega kota trenja nasipnega materiala in razmika pilotov na reakcijo zemljine, razmerja koncentracije napetosti (SCR) in napetosti geosintetika. Učinek teh faktorjev je bil raziskan z uporabo teorije vrednotenja binarne analize variance za neponovljive preizkuse, kar pomaga optimirati načrtovanje PGRS nasipa

Investigation of the potential pharmacokinetic and pharmaco-dynamic drug interaction between AHN 1-055, a potent benztropine analog used for cocaine abuse, and cocaine after dosing rats using intracerebral microdialysis

Purpose. AHN 1-055, a benztropine (BZT) analog, binds with high affinity to the dopamine transporter (DAT), possesses behavioral, pharmacokinetic (PK) and brain microdialysate dopamine (DA) profiles distinct from cocaine. Accordingly, the objectives of this study were to evaluate the pharmacokinetics and dopamine release of AHN 1-055, in the presence of cocaine. Methods. Male Sprague Dawley rats (~300 g) were administered 5 mg/kg of AHN 1-055 and cocaine i.v. and blood and brain samples were collected over 36 h. In addition, dialysis probes were stereotaxically implanted into the nucleus accumbens and extracellular fluid (ECF) DA levels were measured. PK and PD models were used to describe the relationship between the AHN 1-055, cocaine and DA levels. Results. No significant (p50.05) differences were found in the PK parameters of AHN 1-055 alone (Vdss=18.7 l/kg, Cl=1.8 l/h/kg and t₁/₂=7.69 h) or AHN 1-055 with cocaine (Vdss=17.4 l/kg, Cl=1.9 l/h/kg and t₁/₂=6.82 h). The brain-to-plasma (B/P) ratios (B/PAHN ₁₋₀₅₅=4.8 vs B/Pwith cocaine=4.4) and half-lives (t₁/₂(AHN ₁₋₀₅₅)=6.2 h vs t₁/₂(cocaine)=5.6 h for AHN 1-055 alone and with cocaine were comparable. AHN 1-055 DA profiles were significantly different after co-administration with cocaine. There were no differences in the IC₅₀ for AHN 1-055, with cocaine, however, the IC₅₀ for cocaine was significantly reduced with AHN 1-055. Conclusions. The PK parameters of AHN 1-055 were not changed, however, the effect on DA levels was affected when cocaine was administered with AHNDA profile is affected when dosed with cocaine. This latter effect is a desirable attribute in the development of a medication as a potential substitute therapeutic medication for the treatment of cocaine abuse.12 page(s

Pharmacodynamic Assessment of the Benztropine Analogues AHN-1055 and AHN-2005 Using Intracerebral Microdialysis to Evaluate Brain Dopamine Levels and Pharmacokinetic/Pharmacodynamic Modeling

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N-Substituted Benztropine Analogs: Selective Dopamine Transporter Ligands with a Fast Onset of Action and Minimal Cocaine-Like Behavioral Effects

Previous studies suggested that differences between the behavioral effects of cocaine and analogs of benztropine were related to the relatively slow onset of action of the latter compounds. Several N-substituted benztropine analogs with a relatively fast onset of effects were studied to assess whether a fast onset of effects would render the effects more similar to those of cocaine. Only one of the compounds increased locomotor activity, and the increases were modest compared with those of 10 to 20 mg/kg cocaine. In rats trained to discriminate 10 mg/kg cocaine from saline none of the compounds produced more than 40% cocaine-like responds up to 2 h after injection. None of the compounds produced place-conditioning when examined up to 90 min after injection, indicating minimal abuse liability. The compounds had 5.6 to 30 nM affinities at the dopamine transporter (DAT), with uniformly lower affinities at norepinephrine and serotonin transporters (from 490-4600 and 1420–7350 nM, respectively). Affinities at muscarinic M1 receptors were from 100- to 300-fold lower than DAT affinities, suggesting minimal contribution of those sites to the behavioral effects of the compounds. Affinities at histaminic H1 sites were from 11- to 43-fold lower than those for the DAT. The compounds also had affinity for sigma, 5-hydroxytryptamine1 (5-HT1), and 5-HT2 receptors that may have contributed to their behavioral effects. Together, the results indicate that a slow onset of action is not a necessary condition for reduced cocaine-like effects of atypical DAT ligands and suggest several mechanisms that may contribute to the reduced cocaine-like efficacy of these compounds

Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors.

Cocaine exerts its stimulatory effect by inhibiting the dopamine transporter (DAT). However, novel benztropine- and rimcazole-based inhibitors show reduced stimulant effects compared with cocaine, despite higher affinity and selectivity for DAT. To in-vestigate possible mechanisms, we compared the subjective effects of different inhibitors with their molecular mode of in-teraction at the DAT. We determined how different inhibitors affected accessibility of the sulfhydryl-reactive reagent [2-(tri-methylammonium)ethyl]-methanethiosulfonate to an inserted cysteine (I159C), which is accessible when the extracellular transporter gate is open but inaccessible when it is closed. The data indicated that cocaine analogs bind an open conforma-tion, whereas benztropine and rimcazole analogs bind a closed conformation. Next, we investigated the changes in inhibitio