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Preclinical Evaluation (preclinical + evaluation)
Selected AbstractsPreclinical Evaluation of Riluzole: Assessments of Ethanol Self-Administration and Ethanol Withdrawal SymptomsALCOHOLISM, Issue 8 2009Joyce Besheer Background:, Many of the neurobehavioral effects of ethanol are mediated by inhibition of excitatory N -methyl- d -aspartate (NMDA) and enhancement of inhibitory ,-amino-butyric-acid (GABA) receptor systems. There is growing interest in drugs that alter these systems as potential medications for problems associated with alcoholism. The drug riluzole, approved for treatment of amyotrophic lateral sclerosis (ALS), inhibits NMDA and enhances GABAA receptor system activity. This study was designed to determine the preclinical efficacy of riluzole to modulate ethanol self-administration and withdrawal. Methods:, Male C57BL/6J mice were trained to lever press on a concurrent fixed-ratio 1 schedule of ethanol (10% v/v) versus water reinforcement during daily 16-hour sessions. Riluzole (1 to 40 mg/kg, IP) was evaluated on ethanol self-administration after acute and chronic (2 week) treatment. To determine if riluzole influences ethanol withdrawal-associated seizures, mice were fed an ethanol-containing or control liquid diet for 18 days. The effects of a single injection of riluzole (30 mg/kg) were examined on handling-induced convulsions after ethanol withdrawal. Results:, Acute riluzole (30 and 40 mg/kg) reduced ethanol self-administration during the first 4 hours of the session, which corresponds to the known pharmacokinetics of this drug. Ethanol self-administration was also reduced by riluzole after chronic treatment. Riluzole (30 mg/kg) significantly decreased the severity of ethanol-induced convulsions 2 hours after ethanol withdrawal. Conclusions:, These results demonstrate that riluzole decreases ethanol self-administration and may reduce ethanol withdrawal severity in mice. Thus, riluzole may have utility in the treatment of problems associated with alcoholism. [source] Preclinical evaluation of tolerance induction protocols and islet transplantation in non-human primatesIMMUNOLOGICAL REVIEWS, Issue 1 2001Sean P. Montgomery Summary: Non-human primate studies of tolerance induction strategies in solid organ transplantation represent a critical bridge between studies in rodents and humans. Our work demonstrates that strategies involving the blockade of co-stimulatory molecules, especially the CD40,CD154 pathway, have great potential for clinical adaptation. While the combination of anti-CD154 antibody with blockade of the CD28 pathway reduced donor antibody production, graft survival was not significantly improved over that achieved with anti-CD154 antibody alone. Moreover, although long courses of steroids seem to interfere with this approach, it may be possible to combine blockade of the CD40,CD154 pathway with other conventional immunosuppressants without sacrificing efficacy. This is a key issue for reducing the risk associated with eventual clinical trials. Work in the non-human primate islet transplant model demonstrates that viable islets can be recovered, isolated and infused in a reliable fashion. It also confirms the efficacy of a steroid sparing approach to immunosuppression for islet transplantation. These data have been expanded to the kidney allograft model, setting the stage for kidney islet transplantation studies. Overall, tolerance induction and islet transplant studies in non-human primates permit the preclinical screening of promising immunomodulatory approaches developed in rodents and reduce the inherent uncertainties associated with adapting new regimens to the clinic. [source] Preclinical evaluation of carcinoembryonic cell adhesion molecule (CEACAM) 6 as potential therapy target for pancreatic adenocarcinoma,THE JOURNAL OF PATHOLOGY, Issue 3 2009Laura A Strickland Abstract Despite the availability of new targeted therapies, ductal pancreatic adenocarcinoma continues to carry a poor prognosis. Carcinoembryonic antigen-related cell adhesion molecule (CEACAM)6 has been reported as a potential biomarker and therapy target for this malignancy. We have evaluated CEACAM6 as a potential therapy target, using an antibody,drug conjugate (ADC). Expression of CEACAM6 in pancreatic adenocarcinomas was determined using immunohistochemistry on tissue microarrays. The expression pattern in granulocytes and granulocytic precursors was measured by flow cytometry. Murine xenograft and non-human primate models served to evaluate efficacy and safety, respectively. Robust expression of CEACAM6 was found in > 90% of invasive pancreatic adenocarcinomas as well as in intraepithelial neoplastic lesions. In the granulocytic lineage, CEACAM6 was expressed at all stages of granulocytic maturation except for the early lineage-committed precursor cell. The anti-CEACAM6 ADC showed efficacy against established CEACAM6-expressing tumours. In non-human primates, antigen-dependent toxicity of the ADC consisted of dose-dependent and reversible depletion of granulocytes and their precursors. This was associated with preferential and rapid localization of the antibody in bone marrow, as determined by sequential in vivo PET imaging of the radiolabelled anti-CEACAM6. Localization of the radiolabelled tracer could be attenuated by predosing with unlabelled antibody confirming specific accumulation in this compartment. Based on the expression pattern in normal and malignant pancreatic tissues, efficacy against established tumours and limited and reversible bone marrow toxicity, we propose that CEACAM6 should be considered for an ADC-based therapy approach against pancreatic adenocarcinomas and possibly other CEACAM6-positive neoplasms. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] 1,026 Experimental treatments in acute strokeANNALS OF NEUROLOGY, Issue 3 2006Victoria E. O'Collins B.Sci Objective Preclinical evaluation of neuroprotectants fostered high expectations of clinical efficacy. When not matched, the question arises whether experiments are poor indicators of clinical outcome or whether the best drugs were not taken forward to clinical trial. Therefore, we endeavored to contrast experimental efficacy and scope of testing of drugs used clinically and those tested only experimentally. Methods We identified neuroprotectants and reports of experimental efficacy via a systematic search. Controlled in vivo and in vitro experiments using functional or histological end points were selected for analysis. Relationships between outcome, drug mechanism, scope of testing, and clinical trial status were assessed statistically. Results There was no evidence that drugs used clinically (114 drugs) were more effective experimentally than those tested only in animal models (912 drugs), for example, improvement in focal models averaged 31.3 ± 16.7% versus 24.4 ± 32.9%, p > 0.05, respectively. Scope of testing using Stroke Therapy Academic Industry Roundtable (STAIR) criteria was highly variable, and no relationship was found between mechanism and efficacy. Interpretation The results question whether the most efficacious drugs are being selected for stroke clinical trials. This may partially explain the slow progress in developing treatments. Greater rigor in the conduct, reporting, and analysis of animal data will improve the transition of scientific advances from bench to bedside. Ann Neurol 2006 [source] Preclinical evaluation of antisense bcl -2 as a chemosensitizer for patients with gastric carcinomaCANCER, Issue 10 2004Ph.D., Ryungsa Kim M.D. Abstract BACKGROUND Because bcl -2 is a critical factor for anticancer drug-induced apoptosis, the authors conducted a preclinical evaluation of antisense (AS) bcl -2 as an enhancer of the chemotherapeutic effect in the treatment of patietns with gastric carcinoma. METHODS AS bcl -2 was used with 18-mer phosphorothiated oligonucleotides in the MKN-45 gastric carcinoma cell line. Drug sensitivity in vitro was evaluated using the methyl-thiazoldiphenyl tetrazolium assay, and antitumor effects in vivo were evaluated using the nude mouse xenograft. Apoptosis was determined with the terminal deoxyuridine triphosphate nick-end labeling assay. AS bcl -2 in vitro was treated with lipofectin, whereas it was administered intraperitoneally for 6 consecutive days twice every 2 weeks in vivo. Anticancer drugs were administered intraperitoneally four times per week. RESULTS bcl -2 was down-regulated to 60% of its initial value after treatment with 1.0 ,M AS bcl -2 compared with the controls of random and mismatched oligonucleotides. Drug sensitivity to doxorubicin, cisplatin, and paclitaxel (TXL) was increased 3,4-fold when used in combination with AS bcl -2, which was determined with 50% inhibitory concentration values, compared with the control group. Increased drug sensitivity was associated with apoptosis, which increased in Bax and poly-adenosine diphosphate (ADP-ribose) polymerase and decreased in phosphorylated Akt (pAkt). The antitumor effect of cisplatin and TXL in vivo was enhanced significantly in combination with AS bcl -2. Down-regulation of bcl -2 was observed on Day 4 after the treatment with AS bcl -2. CONCLUSIONS Combination treatment with AS bcl -2 and anticancer drugs, including cisplatin and TXL, may be a new strategy for enhancing chemotherapeutic effects in the treatment of gastric carcinoma. Cancer 2004. © 2004 American Cancer Society. [source] Electrophoretically mediated microanalysis for the evaluation of interspecies variation in cholinesterase metabolismELECTROPHORESIS, Issue 14 2010Joana Moura Abstract This study describes an electrophoretically mediated microanalysis method, suitable for the preclinical evaluation of the hydrolysis of ester drugs by the serum of different animals and for further characterization of human,animal correlation. Dog, cat, cow, horse, sheep, rat and human serum were diluted (25%) in the appropriate buffer and replaced the enzyme solution usually used in electrophoretically mediated microanalysis methods for the study of enzyme kinetics. They were then compared in terms of the ability to hydrolyze acetylthiocholine and butyrylthiocholine (0.25,mM) by in-capillary reaction. Human serum afforded the highest conversion rates (52% butyryltiocholine and 34% acetylthiocholine) followed by horse (31 and 35%), dog (26 and 24%), cat (22 and 14%), rat (11 and 15%) and sheep (8 and 8%). Hydrolysis by bovine serum was negligible. The method is fast (under 8,min including rinsing steps), sensitive (under 25,,M substrate could be quantified) and repeatable (RSD,2%), only requiring minute amounts of sample. [source] Growth inhibition of orthotopic anaplastic thyroid carcinoma xenografts in nude mice by PTK787/ZK222584 and CPT-11HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 5 2006Seungwon Kim MD Abstract Background. A preclinical evaluation of CPT-1 (Camptosar, irinotecan) and PTK787/ZK222584, a vascular endothelial growth factor receptor (VEGFR-2) tyrosine kinase inhibitor, as therapeutic agents against anaplastic thyroid carcinoma (ATC) was performed in vitro and in an orthotopic model of ATC in nude mice. Methods. The cytotoxic and cytostatic effects of CPT-11 on ATC cell lines were evaluated. The antitumor effects of CPT-11 in combination with PTK787/ZK222584 on orthotopic ATC xenografts in nude mice were also studied. Results. CPT-11 demonstrated significant antiproliferative effects on ATC cell lines. In vivo, PTK787/ZK222584, CPT-11, and the two agents together produced 61%, 82%, and 89% decrease in tumor growth, respectively. The differences in tumor volume between CPT-11 and CPT-11 + PTK787/ZK222584 groups were not statistically significant. PTK787/ZK222584 inhibited the phosphorylation of VEGFR-2 on tumor endothelium and decrease the tumor microvessel density. Conclusions. The camptothecin class of chemotherapeutic agents and antiangiogenic agents such as PTK787/ZK222584 warrant further study as novel therapeutic agents against ATC. © 2005 Wiley Periodicals, Inc. Head Neck27: 389,399, 2006 [source] A celecoxib derivative inhibits focal adhesion signaling and induces caspase-8-dependent apoptosis in human acute myeloid leukemia cellsINTERNATIONAL JOURNAL OF CANCER, Issue 1 2008Isolda Casanova Abstract Most acute myeloid leukemias (AMLs), including those with c-Kit or FLT3 mutations, show enhanced anchorage independent growth associated with constitutive activation of focal adhesion proteins. Moreover, these alterations increase cell survival, inhibit apoptosis and are associated with poor prognosis and resistance to chemotherapy. Therefore, the induction of apoptosis by selective inhibition of focal adhesion signaling may represent a novel anti-AML therapy. Here, we have evaluated the antitumor effect and the mechanism of action of celecoxib and E7123, a non-Cox-2 inhibitor derivative, in a panel of human AML cell lines and bone marrow mononuclear cells from AML patients. Both compounds induce cell death by inhibiting focal adhesion signaling through p130Cas, FAK and c-Src, leading to caspase-8 dependent apoptosis. This mechanism of action differs from that of classical cytotoxic drugs or of other targeted therapies, and is amenable to rational drug development. Therefore, both drugs could be developed as AML therapeutics; nevertheless, E7123 shows more activity than celecoxib against AML cells, and may not present its Cox-2 dependent cardiovascular toxicity. Finally, our results support the evaluation of celecoxib in AML patients, and the preclinical evaluation of E7123, before its possible clinical testing. © 2008 Wiley-Liss, Inc. [source] The novel N -substituted benztropine analog GA2-50 possesses pharmacokinetic and pharmacodynamic profiles favorable for a candidate substitute medication for cocaine abuseJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2008Ahmed A. Othman Abstract 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 (Ri,,,10), large volume of distribution (Vss,=,37 L/kg), and long elimination half-life (t½,=,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. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci [source] DNA minor groove binders as potential antitumor and antimicrobial agentsMEDICINAL RESEARCH REVIEWS, Issue 4 2004Pier Giovanni Baraldi Abstract DNA minor groove binders constitute an important class of derivatives in anticancer therapy. Some of these compounds form noncovalent complexes with DNA (e.g., distamycin A, Hoechst 33258, and pentamidine) while others DNA-binding compounds (such as CC-1065) cause cleavages in the DNA backbone. In this article, we have reviewed the minor groove binders currently in preclinical evaluation in the last years. Diarylamidines such as DAPI, berenil, and pentamidine; bis-benzimidazoles such as Hoechst 33258; ecteinascidins, pyrrololo [2,1- c]-[1,4]-benzodiazepines (PBDs), CC-1065, and distamycins are the classes discussed in this review article. A special section has been dedicated to hybrid molecules resulted by the combination of two minor groove binders, especially for derivatives of naturally occurring antitumor agents, such as anthramycin or the alkylating unit of the antibiotic CC-1065, and distamycin frames. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 4, 475,528, 2004 [source] Pharmacokinetic measurements of IDN 5390 using electrospray ionization tandem mass spectrometry: structure characterization and quantification in dog plasmaRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 24 2005Liguo Song In this report, electrospray ionization tandem mass spectrometry (ESI-MS/MS) for a pharmacokinetic study of IDN 5390, a novel C- seco taxane derivative, which is under preclinical evaluation, has been investigated. Our results showed that IDN 5390 and other taxanes including paclitaxel and IDN 5109 could ionize well in not only positive-, but also in negative-ion mode. Under collision-induced dissociation (CID) conditions, these compounds could fragment into similar M- (molecular), T- (taxane ring) and S- (side chain) series ions. In positive-ion ESI, the formation of both T- and S-series ions involved the breaking of the C-13 ester bond. In negative-ion ESI, however, while the formation mechanism of S-series ions remained the same, the breaking of the C-1, carboxylic ester bond resulted in T-series ions. At optimum collision energy (CE) values, M-, T- and S-series ions of IDN 5390 in both positive- and negative-ion ESI-MS/MS spectra had good intensity. This phenomenon makes both positive- and negative-ion ESI-MS/MS good methods for IDN 5390 metabolite structural characterization, i.e. to reveal the location of modification groups in IDN 5390 metabolites versus IDN 5390 either on the side chain or the taxane ring. A liquid chromatography (LC)/ESI-MS/MS method using the multiple-reaction monitoring (MRM) technique was thereafter developed to quantify IDN 5390 in dog plasma using paclitaxel as internal standard. The method was validated using a concentration range between 5 and 1000,ng/mL and had a limit of detection of 1,ng/mL. The inter-day %CV (%coefficient of variation) of the calibration standards ranged between 4.36 and 9.64%, the intra-day %CV of the calibration standards between 0.61 and 13.44%, and the mean % accuracy of the quality control samples at the low, middle and high end of the concentration curves were 12.5, 6.8 and 9.6%, respectively. Copyright © 2005 John Wiley & Sons, Ltd. [source] Limitations of the Human-PBL-SCID Mouse Model for Vaginal Transmission of HIV-1AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 5 2007Osmond J. D'Cruz Problem SCID mice reconstituted with human peripheral blood lymphocytes (PBL) are amenable to vaginal transmission of HIV-1. We investigated the effectiveness of this model to establish systemic HIV-1 infection. Method of study Eighty progesterone-primed C.B-17 SCID mice were reconstituted with human-PBLs and intravaginally inoculated with CCR5 HIV-1 (BaL or 92BR09) infected human-PBLs in the presence of human semen. After two weeks, viral RNA load in spleen, peritoneal lavage (PL), and serum was quantitated by the nucleic acid sequence-based amplification method. Results In five independent experiments, spleen from 8/60 (13.3%), PL from 7/60 (11.6%), and serum from 16/56 (28.5%) mice were positive for BaL HIV-1 infection. Similarly, spleen from 4/20 (20%), PL from 1/20 (5%) and serum from 5/20 (25%) mice vaginally inoculated with 92BR09-infected human-PBLs were positive for HIV-1. A one-sided power analysis using normal approximation revealed that at 5% significance level, the overall response rate need to increase form 0.29 to 0.9 and 80% of the control groups needs to achieve a response rate between 6/10 and 9/10 to make the assay feasible. Conclusion The incidence of vaginal transmission of CCR5 HIV-1 in the human-PBL-SCID mouse was low and variable, which constitutes a major disadvantage for preclinical evaluation of vaginal microbicides. [source] The PediPump: A Versatile, Implantable Pediatric Ventricular Assist Device,Update IVARTIFICIAL ORGANS, Issue 11 2009Brian W. Duncan Abstract Cleveland Clinic's PediPump (Cleveland, OH, USA) is a ventricular assist device designed for the support of pediatric patients. The PediPump is a mixed-flow ventricular assist device with a magnetically suspended impeller measuring 10.5 mm in diameter by 64.5 mm in length. Progress and achievements for the PediPump program are considered according to the development project's three primary objectives: Basic engineering: along with size reductions, substantial design improvements have been incorporated in each design iteration including the motor, magnetic bearings, axial touch points, and heat transfer path; Anatomic modeling and device fitting studies: Techniques based on computed tomography and magnetic resonance imaging have been developed to create three-dimensional anatomic-modeling and device-fitting tools to facilitate device implantation and to assist in preoperative planning. For in vivo testing, to date, six acute (6-h duration) and nine chronic (30-day target duration) implantations have been performed in sheep; the implantation of the PediPump appears to be relatively easy with excellent hemodynamic performance and minimal hemolysis during support. Cleveland Clinic's PediPump program supported by the National Heart, Lung and Blood Institute's Pediatric Circulatory Support Program has led to the development of a pediatric ventricular assist device that has satisfactory performance in preclinical evaluation and appears to be ready to support a program of clinical testing. [source] Effects of Liposome-Encapsulated Hemoglobin on Human Immune System: Evaluation in Immunodeficient Mice Reconstituted With Human Cord Blood Stem CellsARTIFICIAL ORGANS, Issue 2 2009Akira T. Kawaguchi Abstract As preclinical evaluation in animals does not necessarily portray human responses, liposome-encapsulated hemoglobin (LEH), an artificial oxygen carrier, was tested in immunodeficient mice reconstituted with human hematopoietic stem cells (cord blood-transfused NOD/SCID/IL-2R,null[CB-NOG] mice). Changes in immunocompetent T-cell and B-cell composition in peripheral blood, spleen, and bone marrow were examined 2 and 7 days after 10 mL/kg of intravenous administration of LEH, empty liposome (EL), or saline using immunohistochemical and flow cytometrical techniques in wild-type mice and CB-NOG mice. Responses to intraperitoneal administration of toxic shock syndrome toxin-1 (TSST-1) under the absence or presence of LEH (10 mL/kg) were also determined 4 h and 3 days later in terms of lymphocyte composition and IL-2 plasma level in wild-type as well as CB-NOG mice. When liposome (LEH or EL) was administered to wild-type or CB-NOG mice, the composition of B-cells and T-cells in the spleen or peripheral blood failed to show any consistent or significant changes. The responses to a bacterial antigen (TSST-1) measured by IL-2 production were comparable regardless of the presence or absence of LEH in wild-type as well as in CB-NOG mice. Cellularity, distribution, and maturation of these human cells in peripheral blood, spleen, and bone marrow were comparable among the groups. The results suggest that simple LEH administration may not change immune cellularity, and LEH presence may not largely affect the early T-cell response to bacterial enterotoxins in murine as well as in reconstituted human immune systems. [source] Preclinical evaluation of antisense bcl -2 as a chemosensitizer for patients with gastric carcinomaCANCER, Issue 10 2004Ph.D., Ryungsa Kim M.D. Abstract BACKGROUND Because bcl -2 is a critical factor for anticancer drug-induced apoptosis, the authors conducted a preclinical evaluation of antisense (AS) bcl -2 as an enhancer of the chemotherapeutic effect in the treatment of patietns with gastric carcinoma. METHODS AS bcl -2 was used with 18-mer phosphorothiated oligonucleotides in the MKN-45 gastric carcinoma cell line. Drug sensitivity in vitro was evaluated using the methyl-thiazoldiphenyl tetrazolium assay, and antitumor effects in vivo were evaluated using the nude mouse xenograft. Apoptosis was determined with the terminal deoxyuridine triphosphate nick-end labeling assay. AS bcl -2 in vitro was treated with lipofectin, whereas it was administered intraperitoneally for 6 consecutive days twice every 2 weeks in vivo. Anticancer drugs were administered intraperitoneally four times per week. RESULTS bcl -2 was down-regulated to 60% of its initial value after treatment with 1.0 ,M AS bcl -2 compared with the controls of random and mismatched oligonucleotides. Drug sensitivity to doxorubicin, cisplatin, and paclitaxel (TXL) was increased 3,4-fold when used in combination with AS bcl -2, which was determined with 50% inhibitory concentration values, compared with the control group. Increased drug sensitivity was associated with apoptosis, which increased in Bax and poly-adenosine diphosphate (ADP-ribose) polymerase and decreased in phosphorylated Akt (pAkt). The antitumor effect of cisplatin and TXL in vivo was enhanced significantly in combination with AS bcl -2. Down-regulation of bcl -2 was observed on Day 4 after the treatment with AS bcl -2. CONCLUSIONS Combination treatment with AS bcl -2 and anticancer drugs, including cisplatin and TXL, may be a new strategy for enhancing chemotherapeutic effects in the treatment of gastric carcinoma. Cancer 2004. © 2004 American Cancer Society. [source] Pharmacokinetic modelling of blood,brain barrier transport of escitalopram in ratsBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 7 2007Christoffer Bundgaard Abstract This study examined the pharmacokinetics and distribution of escitalopram in the brain extracellular fluid in rats by the concurrent use of intracerebral microdialysis and serial blood sampling. Following three constant intravenous infusions, drug concentrations in the hippocampus and plasma were monitored for 6 h. To estimate the integrated pharmacokinetics and intercompartmental transport parameters, including blood,brain barrier (BBB) transport over the entire dose range, unbound brain and plasma escitalopram concentration data from all doses were simultaneously analysed using compartmental modelling. The pharmacokinetic analysis revealed that systemic clearance decreased as a function of dose, which was incorporated in the integrated model. Escitalopram was rapidly and extensively transported across the BBB and distributed into the brain extracellular fluid. The modelling resulted in an estimated influx clearance into the brain of 535 µl/min/g brain, resulting in an unbound brain-to-plasma AUC ratio of 0.8 independent of escitalopram dose. The model may be applied for preclinical evaluations or predictions of escitalopram concentration-time courses in plasma as well as at the target site in the CNS for various dosing scenarios. In addition, this modelling approach may also be valuable for studying BBB transport characteristics for other psychotropic agents. Copyright © 2007 John Wiley & Sons, Ltd. [source] | |||||||||||||||||||||||||