Alzheimer's disease (AD) poses a serious public health threat to the United States. Disease-modifying drugs slowing AD progression are in urgent need, but they are still unavailable. According to the amyloid cascade hypothesis, inhibition of ␤-or ␥-secretase, key enzymes for the production of amyloid ␤ (A␤), may be viable mechanisms for the treatment of AD. For the discovery of ␥-secretase inhibitors (GSIs), the APP-overexpressing Tg2576 mouse has been the preclinical model of choice, in part because of the ease of detection of A␤ species in its brain, plasma, and cerebrospinal fluid (CSF). Some biological observations and practical considerations, however, argue against the use of the Tg2576 mouse. We reasoned that an animal model would be suitable for GSI discovery if the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of a compound for A␤ lowering in this model is predictive of that in human. In this study, we assessed whether the background 129/SVE strain is a suitable preclinical pharmacology model for identifying new GSIs by evaluating the translatability of the intrinsic PK/PD relationships for brain and CSF A␤ across the Tg2576 and 129/SVE mouse and human. Using semimechanistically based PK/PD modeling, our analyses indicated that the intrinsic PK/PD relationship for brain A␤x-42 and CSF A␤x-40 in the 129/SVE mouse is indicative of that for human CSF A␤. This result, in conjunction with practical considerations, strongly suggests that the 129/SVE mouse is a suitable model for GSI discovery. Concurrently, the necessity and utilities of PK/PD modeling for rational interpretation of A␤ data are established.

The estimated prevalence of a malaria parasite, Plasmodium mexicanum, of western fence lizards, Sceloporus occidentalis, was compared using two techniques: microscopic examination of blood smears, and nested PCR amplification of the 18S small subunit rRNA gene. Two sites in northern California, USA were investigated, one with known long‐term high prevalence of the parasite (30% by blood smear scanning), and one with low prevalence (6%). The nested PCR readily detected very low‐level infections (< 1 parasite per 10 000 erythrocytes); such infections are often subpatent by normal microscopic examination. False negatives (scored as not infected after scanning the blood smear, but found infected via PCR) were rare at both sites (4% at the high‐prevalence site, 6% at the low‐prevalence site). However, a greater proportion of infections was detected only by PCR at the low‐prevalence site (50% vs. 9%). If 50% of the infections sustain very weak parasitaemia where lizards are rarely infected, this would accord with hypotheses that predict that parasites should reduce infection growth when transmission is uncommon. The study demonstrates that PCR is a powerful tool to detect very low‐level malarial infections in vertebrate hosts, including those with nucleated erythrocytes.

Reducing the generation of amyloid-␤ (A␤) in the brain via inhibition of ␤-secretase or inhibition/modulation of ␥-secretase has been pursued as a potential disease-modifying treatment for Alzheimer's disease. For the discovery and development of ␤-secretase inhibitors (BACEi), ␥-secretase inhibitors (GSI), and ␥-secretase modulators (GSM), A␤ in cerebrospinal fluid (CSF) has been presumed to be an effect biomarker for A␤ lowering in the brain. However, this presumption is challenged by the lack of quantitative understanding of the relationship between brain and CSF A␤ lowering. In this study, we strived to elucidate how the intrinsic pharmacokinetic (PK)/pharmacodynamic (PD) relationship for CSF A␤ lowering is related to that for brain A␤ through quantitative modeling of preclinical data for numerous BACEi, GSI, and GSM across multiple species. Our results indicate that the intrinsic PK/PD relationship in CSF is predictive of that in brain, at least in the postulated pharmacologically relevant range, with excellent consistency across mechanisms and species. As such, the validity of CSF A␤ as an effect biomarker for brain A␤ lowering is confirmed preclinically. Meanwhile, we have been able to reproduce the dose-dependent separation between brain and CSF effect profiles using simulations. We further discuss the implications of our findings to drug discovery and development with regard to preclinical PK/PD characterization and clinical prediction of A␤ lowering in the brain.

ABSTRACT:Previous publications suggest that interstitial fluid compound concentrations (C ISF ) best determine quantitative neurotherapeutic pharmacology relationships, although confirming large animal C ISF remains elusive. Therefore, this work primarily evaluated using respective acute dose, rat-derived unbound brain compound concentration-to-unbound plasma compound concentration ratios (C b,u / C p,u ) to project accurately dog and nonhuman primate (nhp) C b,u , a C ISF surrogate, from measured C p,u for the highly permeable non-Pglycoprotein substrates N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) and [4-chloro-5-fluoro-2-(3-methoxy-2-methyl-phenoxy)-benzyl]-methylamine (CE-

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