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By Z. Mazin. South Carolina State University.

In studies directly comparing clozapine the dose (112) xalatan 2.5 ml low cost. Nevertheless buy cheap xalatan 2.5 ml line, Volavka and colleagues (113) (450 mg/day) and haloperidol (5 mg/day), there was a rever- (1995) showed that antipsychotic efficacy of haloperidol sal of receptor occupancy producing high D blockade with increases with plasma levels up to 12 ng/mL, plasma levels 2 haloperidol and high 5HT blockade with clozapine. In- that would predict almost completely saturated D2 receptors 2A deed PET imaging has been an important approach for according to the Kapur and associates (1997) data (112). Risperidone has been shown to block40% to 60% with haloperidol plasma levels up to 15 ng/mL and almost of D receptors at only 1 mg (104) with even higher 5HT complete D2R occupancy saturation with haloperidol 2 2A receptor occupancy. Indeed, in patients with schizophrenia, plasma levels above 15 to 20 ng/mL (100). These differences oral dose of 6 mg risperidone, 75% to 80% of D2Rs and could be explained partly by the differences in radioligands 78% to 88% of 5HT2Areceptors are occupied (106). Further research by other investi- levels of risperidone correlate with D2R occupancy (107). The probability of acute dyskinesias is directly pro- of olanzapine (10 to 20 mg/kg) produce 71% to 80% D2R portional to the proportion of D2Rs occupied by the drug occupancy. These doses usually do not result in the adverse (99,110,115). Furthermore, receptor imaging demonstrates Chapter 34: Proof of Concept 465 a lower degree of D2 receptor occupancy during treatment most well developed area is in helping target rational drug with atypical neuroleptics. For example, PET has been used dosing as in the neuroleptic studies described in the preced- to obtain the minimal effective dose of risperidone. The second is the elucidation of the biodistribution of high D2R occupancy associated with 6 mg or more risperi- the drug by radiolabeling the drug or a derivative of the done daily suggests a high riskof acute dyskinesias. Examples of this application include the characteriza- other hand, 4 mg risperidone daily results in 70% to 80% tion of MDL, which is the first selective 5HT2A antagonist D2R occupancy and a lesser riskof acute dyskinesias (116). MDL has been ra- An additional role for occupancy studies in drug develop- diolabeled with [11C] in an isotopic form such that a stable ment takes the form of the interpretation of the time course carbon atom (atomic number 12C) is substituted with a of receptor occupancy following a single drug dose. Such radioactive atom (11C) without a change in the pharmacol- studies help determine the appropriate dosing regimen for ogy or chemistry. This procedure facilitates characterization future trials, such as once or twice a day dosing. For exam- of the biodistribution and washout characteristics of the ple, 70% to 90% of 5HT2A receptors are occupied during agent (117). One example of this is in the development results suggest that a 20-mg dose may be administered once of drugs for cocaine abuse. Unlike neuroleptics and antide- daily, whereas a 10-mg dose requires administration twice pressants, drugs developed to inhibit the action of cocaine a day. Thus, occupancy studies constitute surrogate markers have failed clinical trials. Although cocaine has been shown for the outcome variable and frequency of drug administra- to affect multiple neurotransmitter systems, current research tion. Another use of occupancy studies is the correlation of efforts to develop effective treatment for cocaine depen- D R occupancy with plasma levels of neuroleptics. Cocaine is hypothe- 2 approach has been successfully applied to estimate D R oc- sized to produce euphoria by increasing the intrasynaptic 2 cupancy by haloperidol in patients with low doses of halo- concentration of dopamine. These preliminary results can be refined in the dopamine transporter (DAT); therefore, contemporary future research with larger sample sizes. One example of po- These imaging methods also have a role to determine in tential treatments for cocaine dependence is the develop- vivo occupancy of new neuroleptics with multiple sites for ment of GBR12909 (GBR), a potent DAT inhibitor. The studies probably have their pharmaceutical, originally developed in Europe as an anti- greatest role in giving approximate dosage estimates for fu- depressant, has found a potential new application as a proto- ture clinical trials. Prior studies have shown that IV infusion of GBR to Rhesus monkeys selectively reduced (1 mg/kg) and eliminated (3 mg/kg) cocaine self- Other Roles for Neuroreceptor Imaging administration (119). Villemagne and colleagues (120) in Drug Development tested the hypothesis that doses of GBR, which reduce self- Four major areas in which neuroreceptor imaging can assist administration, also produce significant occupation of in drug development are listed in Table 34. Doses of 1, 3, and 10 mg/kg demonstrated occupancy of 26%, 53%, and 72%, respectively, in Papio anubis ba- boons (Figs. These data suggest that doses that suppress cocaine administration also provide high occu- pancy of the DAT. COMPONENTS OF THE DRUG DEVELOPMENT PROCESS ACCOMPLISHED BY esis that elevations of mesolimbic DA mediate the addictive NEURORECEPTOR IMAGING and reinforcing effects of methamphetamine and amphet- amine. In vivo rodent microdialysis has demonstrated that Rational drug dosing GBR attenuates cocaine and amphetamine induced in- Biodistribution of drug bound to radiolabels 11C and 18F for PET creases in mesolimbic DA. Utilizing PET scans of a continu- 123 99m 11 I and Tc for SPECT ous infusion of [ C]raclopride in baboons, Villemagne and Therapeutic rationale for drug utilization colleagues (120a) also showed that GBR attenuates amphet- Mechanism of drug action amine induced striatal DA release by 74% (Figs. Thus, GBR is a potentially effective agent to treat computed tomography. This experi- 466 Neuropsychopharmacology: The Fifth Generation of Progress 1 mg/kg Saline 3 mg/kg GBR 12909 1 mg/kg 10 mg/kg FIGURE 34. These images illustrate the binding of [11C]raclo- FIGURE 34.

Eachmultispectral data set yields labeled maps of tissue neuropathologic changes: type order 2.5 ml xalatan otc, three-dimensional (3D) brain region purchase 2.5 ml xalatan amex, and cortical topology. MRI simulator for validation of segmentation algorithms Illustrative example applications of some of these capabil- (MRISIM). Correction for coil-dependent 3D intensity nonuniform- ities are described at the end of the chapter. Within-subject registration of different sequence volumes (MINCTRACC). Fully automated 3D classification of gray/white/CSF tis- Within the BIC image analysis pipeline, MRI data are pro- sue classes (INSECT). To manage the flow Fully automated 3D extraction of gray/CSF and gray/ of MRI data through the pipeline, we have developed PCS white cortical interfaces (MSD, ASP). Each processing stage in the pipeline is performed by a single command. PCS allows the user to specify this command with its options, input Stereotaxic Image Format—MINC and output files, and dependencies on other stages in the A fundamental aspect of this pipeline environment and its pipeline using a simple script language. Efficient coarse- interaction with other sites within ICBM is the MINC grain parallelism is achieved by distributing the individual image format for intersite data communication. PCS monitors the sta- (Medical Image Net CDF), developed at the MNI by Peter tus of each job and submits a new job when the prerequisites Neelin, is a multidimensional, multimodality image file for- for submission have been satisfied (typically the completion mat that supports stereotaxic coordinate representation. This simplifies stereotaxic analysis of MRI data ensem- Nonuniformity—N3 bles collected with different voxel dimensions. A major problem for automated MRI image segmentation is the slowly varying change in signal intensity over the MRI Simulation—MRISIM image, caused principally by nonuniformities in the radio- To assist in the evaluation of these segmentation tools, we frequency field (Fig. Apparent signal from any one created an average MRI data set of a single young normal tissue type is therefore different from one brain area to an- male, by repeated MRI scanning followed by linear align- other, confusing automated segmentation algorithms that ment of all volumes. A total of 27 separate MRI scans were assume constant signal for one tissue type. The improved signal-to-noise ratio (SNR) in the oped a fully automated 3D technique for inhomogeneity composite MRI, termed ICBM27, produces a high-defini- correction, modeling inhomogeneity as the convolution of tion data set (37), suitable for brain atlas construction, vali- the true MRI intensity histogram with a blurring kernel. The method is applicable syncracies of a single brain, it is not intended for use as a to any pulse sequence, field strength, and scanner (66,67). Such maps of ANIMAL (see below), constrained to a six-parameter are generated by algorithms like INSECT or ANIMAL (see (three rotation, three translation) rigid-body transformation below) applied to a high-SNR data set. Noise Stereotaxic Transformation—MRITOTAL is modeled from first principles rather than by adding some parametric (e. MRISIM has been used in validation stud- parameter linear [three rotation, three translation, three ies for correction of MRI intensity nonuniformity (67) and scale, (15)] transformation to match the image volume to tissue classification (84). It has been used to create a database a master data set already resident in stereotaxic space. The of 108 simulate MRI images [3 slice thicknesses 3 tissue master data set therefore defines the gross dimensions and contrasts (T1/T2/PD) 3 noise levels 4 levels of radio- orientation of stereotaxic space. MRI image before (left) and after (mid- dle) correction for nonuniformity field (right), estimated using N3. Note the increased uniformity of white matter regions. The algo- 305 normal subjects, sampled on a 1-mm voxel grid (24), rithm operates upon multispectral (typically T1-, T2-, PD- as that master data set. In a series of preprocessing steps, each ICBM305, has been circulated to over 100 international MRI data set is corrected for intensity nonuniformity (67), sites and defines the stereotaxic space for the SPM statistical interslice normalization, and intersubject intensity normal- package. That data set was derived from T1-weighted data ization (Fig. Stereotaxic transformation is then per- with 2-mm-thick slice data. An artificial neural network (ANN) classifier superseded by a composite data set derived from 1-mm- with one hidden layer is used to assign each voxel to a tissue thick data collected within the ICBM project (see below). The algorithm also employs tissue likelihood, based more anatomic detail than the original ICBM305, was on the spatial location of the voxel in stereotaxic space, as nevertheless mapped into the space of the ICBM305 using orthogonal prior information to constrain the feature-space the nine-parameter MRITOTAL and is therefore a deriva- assignment. For example, periorbital fat exhibits a similar tive of that first data set. Spatial masks expressing the normal distribution of tissue Tissue Classification—INSECT classes in the population (see Fig. Classification withand without correction for intensity nonuniformity: tissue classi- fication withINSECT withand without correction for nonuniformity using N3. An idealized 3D digital phantom was created from by segmentation of a high–signal-to-noise ratio (SNR) data set (17, 37). The initial phantom data (top left) contains three classes: cerebrospinal fluid (CSF) (black), gray matter (dark gray), and white matter (light gray).