BACKGROUND: ANA773 is an oral prodrug of a small-molecule toll-like receptor (TLR)7 agonist. Preclinical and healthy volunteer clinical studies with ANA773 have demonstrated induction of endogenous ...interferon-α) (IFN-α) of multiple subtypes, which supports the potential utility in the treatment of chronic hepatitis C virus (HCV) infection. AIM: To examine safety, tolerability, pharmacodynamics, pharmacokinetics and antiviral activity of ANA773. METHODS: ANA773 was investigated in a double-blind, placebo-controlled study in 34 patients chronically infected with HCV of any genotype. Patients were treatment-naïve or had relapsed following previous interferon-based treatment. This dose escalation study was composed of four dose groups (800, 1200, 1600 and 2000 mg). In each group, 6-8 patients received ANA773 and 2 received placebo. Patients were dosed with ANA773 every-other-day for either 28 days (800, 1200 or 1600 mg) or 10 days (2000 mg). RESULTS: Mild to moderate adverse events were reported, with an increase in frequency and intensity with increasing dose. No serious AEs were reported and there were no early discontinuations. There were dose-related increases in various markers of IFN-α response. The mean maximum change in serum HCV RNA level from baseline was -0.34, -0.29, -0.40, -0.97 and -1.26 log10). in the placebo, 800, 1200, 1600 and 2000 mg cohorts, respectively. At the 2000 mg dose, ANA773 significantly (p=0.037) reduced serum HCV RNA levels (range: 0.14 to -3.10 log10). CONCLUSIONS: ANA773 was generally well tolerated and resulted in a dose-related IFN-dependent response leading to a significant decrease in serum HCV RNA levels in the 2000 mg dose group.
We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control ...individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10−5 and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10−3: an SNP in ATM (rs1801516, overall P = 3.4 × 10−9), an SNP in MX2 (rs45430, P = 2.9 × 10−9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10−10). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10−7 under a fixed-effects model and P = 1.2 × 10−3 under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.
Computer modeling studies have been carried out on three nonnucleoside inhibitors complexed with human immunodeficiency virus type 1 (HIV‐1) reverse transcriptase (RT), using crystal coordinate data ...from a subset of the protein surrounding the binding pocket region. Results from the minimizations of solvated complexes of 2‐cyclopropyl‐4‐methyl‐5,11‐dihydro‐5H‐dipyrido3,2‐b :2′,3′‐e1,4diazepin‐6‐one (nevirapine), α‐anilino‐2, 6‐dibromophenylacetamide (α‐APA), and 8‐chloro‐tetrahydro‐imidazo(4,5,1‐jk)(1,4)‐benzodiazepin‐2(1H)‐thione (TIBO) show that all three inhibitors maintain a very similar conformational shape, roughly overlay each other in the binding pocket, and appear to function as π‐electron donors to aromatic side‐chain residues surrounding the pocket. However, side‐chain residues adapt to each bound inhibitor in a highly specific manner, closing down around the surface of the drug to make tight van der Waals contacts. Consequently, the results from the calculated minimizations reveal that only when the inhibitors are modeled in a site constructed from coordinate data obtained from their particular RT complex can the calculated binding energies be relied upon to predict the correct orientation of the drug in the pocket. In the correct site, these binding energies correlate with EC50 values determined for all three inhibitors in our laboratory. Analysis of the components of the binding energy reveals that, for all three inhibitors, solvation of the drug is endothermic, but solvation of the protein is exothermic, and the sum favors complex formation. In general, the protein is energetically more stable and the drug less stable in their complexes as compared to the reactant conformations. For all three inhibitors, interaction with the protein in the complex is highly favorable. Interactions of the inhibitors with individual residues correlate with crystallographic and site‐specific mutational data. π‐Stacking interactions are important in binding and correlate with drug HOMO RHF/6–31G* energies. Modeling results are discussed with respect to the mechanism of complex formation and the design of nonnucleoside inhibitors that will be more effective against mutants of HIV‐1 RT that are resistant to the currently available drugs.
The synthesis and SAR of tolylamines with 5-HT
6 receptor antagonist activity is presented. The amine, core aromatic, peripheral aromatic, and ether linker moieties of HTS hit
1 were modulated and ...the effect on potency at 5-HT
6 examined. Tolylpiperidine ether
9h was found to possess desirable pharmacokinetic (PK) properties, and was also shown to enhance cognition in the rat novel object recognition paradigm.
BACKGROUND Knowledge of the evolution of cognitive deficits in Alzheimer disease is important for our understanding of disease progression. Previous reports, however, have either lacked detail or ...have not covered the presymptomatic stages. OBJECTIVE To delineate the onset and progression of clinical and neuropsychological abnormalities in familial Alzheimer disease. METHODS Nineteen subjects with familial Alzheimer disease underwent serial clinical and neuropsychological assessments. Eight of these had undergone presymptomatic assessments. The follow-up period was 1 to 10 years (mean, 5 years). The relative timing of the occurrence of 3 markers of disease onset and progression (onset of symptoms, Mini-Mental State Examination score ≤ 24, and impaired scores on a range of neuropsychological tests) were compared using the binomial exact test. RESULTS Neurological abnormalities were not prominent, although myoclonus appeared early in some. Mini-Mental State Examination score was not sensitive to early disease. Memory and general intelligence deficits appeared at an earlier stage, in some patients when presymptomatic. Perceptual, naming, and especially spelling skills were preserved to a late stage. CONCLUSION Familial Alzheimer disease may have a long prodromal phase of several years with subtle deficits initially of general intelligence and memory, while spelling, naming, and perception are relatively preserved until a late stage.Arch Neurol. 2004;61:1743-1748-->
We show that hard encounters in the central regions of globular clusters embedded in dark matter (DM) haloes necessarily lead to the formation of gravitationally-bound stellar envelopes that extend ...far beyond the nominal tidal radius of the system. Using statistical arguments and numerical techniques we derive the equilibrium distribution function of stars ejected from the centre of a non-divergent spherical potential. Independently of the velocity distribution with which stars are ejected, GC envelopes have density profiles that approach asymptotically \(\rho\sim r^{-4}\) at large distances and become isothermal towards the centre. Adding a DM halo component leaves two clear-cut observational signatures: (i) a flattening, or slightly increase of the projected velocity dispersion profile at large distances, and (ii) an outer surface density profile that is systematically shallower than in models with no dark matter.
BACKGROUND Three affected individuals are described from a small English kindred with early-onset autosomal dominant familial Alzheimer disease (FAD) caused by a leucine-to-valine change at codon 153 ...(L153V) of the presenilin 1 (PSEN1) gene. METHODS Clinical information on the pedigree was collected directly from family members and from hospital records. Samples of DNA were screened by means of direct sequencing of all coding exons of PSEN1. One patient underwent neuropathological examination. RESULTS Mean age at onset of symptoms was 35.3 years (95% confidence interval CI, 34.6-36.0 years); at death, 44.0 years (95% CI, 39.1-48.9 years). Mean duration of illness was 8.3 years (95% CI, 4.7-11.9 years). Myoclonus was a late feature in 1 patient; seizures were not reported in any subjects. Spastic paraparesis and extrapyramidal signs were absent. The neuropsychometric profile of 1 patient showed relatively preserved naming skills in the setting of global cognitive deficits. Results of neuropathological examination demonstrated the signature lesions of Alzheimer disease and the presence of occasional cortical Lewy bodies. CONCLUSIONS The PSEN1 L153V mutation lies in the main mutation cluster of PSEN1 in the second transmembrane domain. It causes early-onset FAD with clinical features similar to those of other reported FAD pedigrees.Arch Neurol. 2001;58:953-958-->
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