EADING THEORIES ON THE PATHOphysiology of Alzheimer disease (AD) implicate overproduction of amyloid-␤ (A␤), particularly 42 amino acid peptide A␤ 42 . [1][2][3] Compounds modulating ␥-secretase enzyme cleaving ␤-amyloid precursor protein (APP) to release various forms of A␤ are candidates for treatment of AD. One such compound is tarenflurbil (formerly R-flurbiprofen), a selective A␤ 42lowering agent that has been shown in vitro and in vivo to modulate ␥secretase activity and reduce A␤ 42 production in favor of shorter less toxic forms of A␤ (eg, A␤ 38 and A␤ 37 ). 4,5 In mouse models of AD, tarenflurbil prevents learning and memory deficits and reduces A␤ 42 brain concentrations. 4,6 A phase 2 trial of tarenflurbil suggested that patients with mild AD and moderate AD responded differently to treatment, that patients with mild AD had a dose-related slower rate of decline than those treated with placebo, and that the drug was well tolerated with few adverse effects. 7 On the basis of these results, a large phase 3, randomized, placebo-controlled trial of tarenflurbil was conducted in patients with mild AD. METHODS Study DesignA randomized, double-blind, 2-group parallel study was conducted to com-pare tarenflurbil with placebo for 18 months involving 133 participating trial sites. Written informed consent was obtained from participants, their legally authorized representatives, or both. The See also pp 2565 and 2593.

Powassan virus (POWV) disease is a rare human disease caused by a tick-borne encephalitis group flavivirus maintained in a transmission cycle between Ixodes cookei and other ixodid ticks and small and medium-sized mammals. During 1958-1998, only 27 POWV disease cases (mostly Powassan encephalitis) were reported from eastern Canada and the northeastern United States (average, 0.7 cases per year). During 1999-2005, nine cases (described herein) of serologically confirmed POWV disease were reported in the United States (average, 1.3 cases per year): four from Maine, two from New York, and one each from Michigan, Vermont, and Wisconsin. The Michigan and Wisconsin cases are the first ever reported from the north-central United States. Of these nine patients, 5 (56%) were men, the median age was 69 years (range: 25-91 years), and 6 (67%) had onset during May-July. All but one patient developed encephalitis with acute onset of profound muscle weakness, confusion, and other severe neurologic signs. In one case, no neurologic symptoms were present but the presence of pleocytosis, an elevated cerebrospinal fluid (CSF) protein concentration, and POWV-specific immunoglobulin M in CSF suggested neuroinvasion. All patients recovered from their acute disease, but most had long-term neurologic sequelae. Periresidential ecologic investigations were performed in three cases, including tests of local mammals and ticks for evidence of POWV infection. Woodchucks (Marmota monax), striped skunks (Mephitis mephitis), and a raccoon (Procyon lotor) collected at two of the Maine case-patients' residences had neutralizing antibody titers to POWV. I. cookei were found on woodchucks and skunks and questing in grassy areas of one of these residences; all were negative for POWV. Although POWV disease is rare, it is probably under-recognized, and it causes significant morbidity, and thus is an additional tick-borne emerging infectious disease entity. Because no vaccine or specific therapy is available, the basis of prevention is personal protection from ticks (or "tick hygiene") and reduced exposure to peridomestic wild mammals.

Abstract.Tafenoquine is an 8-aminoquinoline under investigation for the prevention of relapse in Plasmodium vivax malaria. This open-label, dose-escalation study assessed quantitatively the hemolytic risk with tafenoquine in female healthy volunteers heterozygous for the Mahidol487A glucose-6-phosphate dehydrogenase (G6PD)-deficient variant versus G6PD-normal females, and with reference to primaquine. Six G6PD-heterozygous subjects (G6PD enzyme activity 40–60% of normal) and six G6PD-normal subjects per treatment group received single-dose tafenoquine (100, 200, or 300 mg) or primaquine (15 mg × 14 days). All participants had pretreatment hemoglobin levels ≥ 12.0 g/dL. Tafenoquine dose escalation stopped when hemoglobin decreased by ≥ 2.5 g/dL (or hematocrit decline ≥ 7.5%) versus pretreatment values in ≥ 3/6 subjects. A dose–response was evident in G6PD-heterozygous subjects (N = 15) receiving tafenoquine for the maximum decrease in hemoglobin versus pretreatment values. Hemoglobin declines were similar for tafenoquine 300 mg (−2.65 to −2.95 g/dL [N = 3]) and primaquine (−1.25 to −3.0 g/dL [N = 5]). Two further cohorts of G6PD-heterozygous subjects with G6PD enzyme levels 61–80% (N = 2) and > 80% (N = 5) of the site median normal received tafenoquine 200 mg; hemolysis was less pronounced at higher G6PD enzyme activities. Tafenoquine hemolytic potential was dose dependent, and hemolysis was greater in G6PD-heterozygous females with lower G6PD enzyme activity levels. Single-dose tafenoquine 300 mg did not appear to increase the severity of hemolysis versus primaquine 15 mg × 14 days.

A B S T R A C T PurposeThis study was conducted to characterize the effect of food on the relative bioavailability of lapatinib. Patients and MethodsA single 1,500-mg, oral dose of lapatinib was administered to 27 patients with advanced solid tumors on each of three occasions that were 1 week apart, in random order: after an overnight fast, with a low-fat breakfast, and with a high-fat breakfast. ResultsThe low-fat breakfast produced mean increases in lapatinib area under the concentration-time curve (AUC) of 167% (2.67-fold) and maximum concentration (C max ) of 142% (2.42-fold). The high-fat breakfast produced mean increases in lapatinib AUC of 325% (4.25-fold) and C max of 203% (3.03-fold) compared with the fasted state. Increased bioavailability in the fed state did not significantly decrease relative variability. Therefore, absolute variability in systemic exposure was increased. ConclusionThese large increases in lapatinib bioavailability and absolute variability support the recommendation for dosing in the fasted state to achieve consistent therapeutic exposure. Prescribers and patients should consider the potential consequences of toxicity or diminished efficacy that might result from dosing without regard to variations in diet.