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1.  Evaluation of an Innovative Population Pharmacokinetic-Based Design for Behavioral Pharmacodynamic Endpoints 
The AAPS Journal  2012;14(4):657-663.
Pre-clinical behavioral pharmacology studies supporting indications like analgesia typically consist of at least three different studies; dose-finding, duration of effect, and tolerance-development studies. Pharmacokinetic (PK) plasma samples are generally taken from a parallel group of animals to avoid disruption of the behavioral pharmacodynamic (PD) endpoint. Our objective was to investigate if pre-clinical behavioral pharmacology studies in rats could be performed effectively by combining three studies into a single experimental design and using sparse PK sampling in the same animals as for PD. A refined dosing strategy was applied for a muscarinic agonist, AZD6088, using the rat spinal nerve ligation heat hyperalgesia model. PD measurements were performed on day 1, 3, 5 and 8. Two PK samples per day were taken day 2 and 4. In a separate control group, PD measurements were performed on rats without PK sampling. Data was analyzed using a population approach in NONMEM. The animals produced a consistent and reproducible response irrespective of day of testing suggesting that blood sampling on alternate days did not interfere with the PD responses. A direct concentration–effect relationship with good precision was established and no tolerance development was observed. The new design combining three studies into one and eliminating a satellite PK group realized substantial savings compared to the old design; animal use was reduced by 58% and time required to generate results was reduced by 55%. The design described here delivers substantial savings in animal lives, time, and money whilst still delivering a good quality and precise description of the PKPD relationship.
doi:10.1208/s12248-012-9380-3
PMCID: PMC3475849  PMID: 22711220
3Rs; analgesia; muscarinic; PKPD
2.  Blocking spinal CCR2 with AZ889 reversed hyperalgesia in a model of neuropathic pain 
Molecular Pain  2010;6:90.
Background
The CCR2/CCL2 system has been identified as a regulator in the pathogenesis of neuropathy-induced pain. However, CCR2 target validation in analgesia and the mechanism underlying antinociception produced by CCR2 antagonists remains poorly understood. In this study, in vitro and in vivo pharmacological approaches using a novel CCR2 antagonist, AZ889, strengthened the hypothesis of a CCR2 contribution to neuropathic pain and provided confidence over the possibilities to treat neuropathic pain with CCR2 antagonists.
Results
We provided evidence that dorsal root ganglia (DRG) cells harvested from CCI animals responded to stimulation by CCL2 with a concentration-dependent calcium rise involving PLC-dependent internal stores. This response was associated with an increase in evoked neuronal action potentials suggesting these cells were sensitive to CCR2 signalling. Importantly, treatment with AZ889 abolished CCL2-evoked excitation confirming that this activity is CCR2-mediated. Neuronal and non-neuronal cells in the spinal cord were also excited by CCL2 applications indicating an important role of spinal CCR2 in neuropathic pain. We next showed that in vivo spinal intrathecal injection of AZ889 produced dose-dependent analgesia in CCI rats. Additionally, application of AZ889 to the exposed spinal cord inhibited evoked neuronal activity and confirmed that CCR2-mediated analgesia involved predominantly the spinal cord. Furthermore, AZ889 abolished NMDA-dependent wind-up of spinal withdrawal reflex pathway in neuropathic animals giving insight into the spinal mechanism underlying the analgesic properties of AZ889.
Conclusions
Overall, this study strengthens the important role of CCR2 in neuropathic pain and highlights feasibility that interfering on this mechanism at the spinal level with a selective antagonist can provide new analgesia opportunities.
doi:10.1186/1744-8069-6-90
PMCID: PMC3009975  PMID: 21143971
3.  MRI-GUIDED HDR PROSTATE BRACHYTHERAPY IN STANDARD 1.5T SCANNER 
Purpose:
Magnetic resonance imaging (MRI) provides superior visualization of the prostate and surrounding anatomy, making it the modality of choice for imaging the prostate gland. This pilot study was performed to determine the feasibility and dosimetric quality achieved when placing high-dose-rate prostate brachytherapy catheters under MRI guidance in a standard “closed-bore” 1.5T scanner.
Methods and Materials:
Patients with intermediate-risk and high-risk localized prostate cancer received MRI-guided high-dose-rate brachytherapy boosts before and after a course of external beam radiotherapy. Using a custom visualization and targeting program, the brachytherapy catheters were placed and adjusted under MRI guidance until satisfactory implant geometry was achieved. Inverse treatment planning was performed using high-resolution T2-weighted MRI.
Results:
Ten brachytherapy procedures were performed on 5 patients. The median percentage of volume receiving 100% of prescribed minimal peripheral dose (V100) achieved was 94% (mean, 92%; 95% confidence interval, 89–95%). The urethral V125 ranged from 0% to 18% (median, 5%), and the rectal V75 ranged from 0% to 3.1% (median, 0.3%). In all cases, lesions highly suspicious for malignancy could be visualized on the procedural MRI, and extracapsular disease was identified in 2 patients.
Conclusion:
High-dose-rate prostate brachytherapy in a standard 1.5T MRI scanner is feasible and achieves favorable dosimetry within a reasonable period with high-quality image guidance. Although the procedure was well tolerated in the acute setting, additional follow-up is required to determine the long-term safety and efficacy of this approach.
doi:10.1016/j.ijrobp.2004.01.016
PMCID: PMC2396328  PMID: 15275727
Prostate cancer; Brachytherapy; MRI; Image guidance

Results 1-3 (3)