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Articles by J Kwan
Total Records ( 3 ) for J Kwan
  X Liu , O Vilenski , J Kwan , S Apparsundaram and R. Weikert
 

It is a commonly accepted hypothesis that central nervous system (CNS) activity is determined by the unbound brain drug concentration. However, limited experimental data are available in the literature to support this hypothesis. The objective of this study was to test this hypothesis by examining the relationship between in vitro binding affinity (KI) and in vivo activity quantified as the drug concentration occupying 50% of the transporters (OC50) for 18 serotonin (SERT) and dopamine transporter (DAT) inhibitors. In vivo rat OC50 was determined by autoradiography using [3H]N,N-dimethyl-2,2-amino-4-cyanophenylthiobenzylamine and [3H](–)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane-1,5-napthalenedisulfonate (WIN35,428) as the ligands to assess SERT and DAT occupancy, respectively. The unbound brain concentrations were calculated from total brain concentrations and the unbound brain fraction, which was determined by the brain homogenate method. The in vivo total brain SERT and DAT OC50 values (mean ± S.D.) were 408 ± 368- and 410 ± 395-fold greater than the KI values, respectively. In contrast, the in vivo unbound brain SERT and DAT OC50 values were only 3.3 ± 2.1- and 4.1 ± 4.0-fold different from the KI values. Therefore, prediction of the biophase drug concentration by using the unbound brain concentration rather than the total brain concentration results in an approximately 100-fold improvement for the accuracy. In the present study, a 10-fold improvement was also observed by using the unbound plasma concentration rather than the total plasma concentration to predict the biophase concentration in the brain. This study supports the hypothesis that CNS activity is more accurately determined by the unbound brain drug concentration and not by the total brain drug concentration.

  X Liu , O Vilenski , J Kwan , S Apparsundaram and R. Weikert
 

It is a commonly accepted hypothesis that central nervous system (CNS) activity is determined by the unbound brain drug concentration. However, limited experimental data are available in the literature to support this hypothesis. The objective of this study was to test this hypothesis by examining the relationship between in vitro binding affinity (KI) and in vivo activity quantified as the drug concentration occupying 50% of the transporters (OC50) for 18 serotonin (SERT) and dopamine transporter (DAT) inhibitors. In vivo rat OC50 was determined by autoradiography using [3H]N,N-dimethyl-2,2-amino-4-cyanophenylthiobenzylamine and [3H](–)-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane-1,5-napthalenedisulfonate (WIN35,428) as the ligands to assess SERT and DAT occupancy, respectively. The unbound brain concentrations were calculated from total brain concentrations and the unbound brain fraction, which was determined by the brain homogenate method. The in vivo total brain SERT and DAT OC50 values (mean ± S.D.) were 408 ± 368- and 410 ± 395-fold greater than the KI values, respectively. In contrast, the in vivo unbound brain SERT and DAT OC50 values were only 3.3 ± 2.1- and 4.1 ± 4.0-fold different from the KI values. Therefore, prediction of the biophase drug concentration by using the unbound brain concentration rather than the total brain concentration results in an approximately 100-fold improvement for the accuracy. In the present study, a 10-fold improvement was also observed by using the unbound plasma concentration rather than the total plasma concentration to predict the biophase concentration in the brain. This study supports the hypothesis that CNS activity is more accurately determined by the unbound brain drug concentration and not by the total brain drug concentration.

  C. M Lu , J Kwan , A Baumgartner , J. F Weier , M Wang , T Escudero , S Munne , H. F Zitzelsberger and H. U. G. Weier
 

Structural chromosome aberrations are hallmarks of many human genetic diseases. The precise mapping of translocation breakpoints in tumors is important for identification of genes with altered levels of expression, prediction of tumor progression, therapy response, or length of disease-free survival, as well as the preparation of probes for detection of tumor cells in peripheral blood. Similarly, in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) for carriers of balanced, reciprocal translocations benefit from accurate breakpoint maps in the preparation of patient-specific DNA probes followed by a selection of normal or balanced oocytes or embryos. We expedited the process of breakpoint mapping and preparation of case-specific probes by utilizing physically mapped bacterial artificial chromosome clones. Historically, breakpoint mapping is based on the definition of the smallest interval between proximal and distal probes. Thus, many of the DNA probes prepared for multiclone and multicolor mapping experiments do not generate additional information. Our pooling protocol, described here with examples from thyroid cancer research and PGD, accelerates the delineation of translocation breakpoints without sacrificing resolution. The turnaround time from clone selection to mapping results using tumor or IVF patient samples can be as short as 3 to 4 days. (J Histochem Cytochem 57:587–597, 2009)

 
 
 
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