In silico ADME prediction: data, models, facts and myths

A critical review of a very recent work in the field of in silico ADME prediction is presented with emphasis on the work published during the period 2000-2002, and several other review articles are mentioned in order to offer a broader view of the field. We find that not much progress has been made in developing robust and predictive models, and that the lack of accurate data, together with the use of questionable modeling end-points, has greatly hindered the real progress in defining generally applicable models. Due to the largely empirical nature of QSAR/QSPR approaches, general and truly predictive models for complex phenomena, such as absorption and clearance, may still be chimeric. The development of local models for use within focused chemical series may be the most appropriate way of utilizing in silico ADME predictions, once experience and data have been gained on a given project and/or structural class.     

ADMET in silico modelling: towards prediction paradise?

Following studies in the late 1990s that indicated that poor pharmacokinetics and toxicity were important causes of costly late-stage failures in drug development, it has become widely appreciated that these areas should be considered as early as possible in the drug discovery process. However, in recent years, combinatorial chemistry and high-throughput screening have significantly increased the number of compounds for which early data on absorption, distribution, metabolism, excretion (ADME) and toxicity (T) are needed, which has in turn driven the development of a variety of medium and high-throughput in vitro ADMET screens. Here, we describe how in silico approaches will further increase our ability to predict and model the most relevant pharmacokinetic, metabolic and toxicity endpoints, thereby accelerating the drug discovery process.     

Discrimination of functionally referential calls by laboratory-housed rhesus macaques: implications for neuroethological studies

Prior to examining the neural correlates of auditory cognition with ethologically relevant stimuli, it is first necessary to establish that laboratory-housed animals respond to these stimuli with species-typical responses. Here, we report the results of experiments on laboratory-housed rhesus monkeys using both species-typical vocalizations and band-pass noise. Paralleling the approach used in field studies of this species, we used a habituation-discrimination paradigm in which auditory stimuli were presented and a monkey's orienting responses to the stimuli were quantified. In parallel with the results obtained in field studies, we found that laboratory-housed rhesus classified species-typical vocalizations according to their putative referent properties as opposed to similarities in their acoustic morphology. In control experiments, monkeys oriented to band-pass noise but did not categorize differences in the spectral composition of the noise stimuli. These findings support the hypothesis that laboratory-housed rhesus classify, in the absence of training, species-typical vocalizations in a manner comparable to rhesus monkeys living under more natural conditions. As such, species-typical vocalizations are an appropriate and necessary class of stimuli in experiments that explore the neural correlates of auditory cognition in rhesus monkeys from a neuroethological perspective.     

Update on D-ala-peptide T-amide (DAPTA): a viral entry inhibitor that blocks CCR5 chemokine receptors

Peptide T, named for its high threonine content (ASTTTNYT), was derived by a database search which assumed that a relevant receptor binding epitope within env (gp120) would have sequence homology to a known signaling peptide. Binding of radiolabeled gp120 to brain membranes was displaced by peptide T and three octapeptide analogs (including "DAPTA", Dala1-peptide T-amide, the protease-resistant analog now in Phase II clinical trials) with the same potency that these four octapeptides blocked infectivity of an early passage patient isolate. This 1986 report was controversial due to a number of laboratories' failure to find peptide T antiviral effects; we now know that peptide T is a potent HIV entry inhibitor selectively targeting CCR5 receptors with minimal effects on the X4 tropic lab adapted virus exclusively in use at that time. Early clinical trials, which demonstrated lack of toxicity and focused on neurological and neurocognitive benefits, are reviewed and data from a small ongoing Phase II trial--the first to assess peptide T's antiviral effects--are presented. Studies using infectivity, receptor binding, chemotaxis, and blockade of gp120-induced neurotoxicity in vitro and in vivo are reviewed, discussed and presented here. Peptide T and analogs of its core pentapeptide, present near the V2 stem of numerous gp120 isolates, are potent ligands for CCR5. Clinical data showing peptide T's immunomodulation of plasma cytokine levels and increases in the percentage of IFNgamma secreting CD8+ T cells in patients with HIV disease are presented and suggests additional therapeutic mechanisms via regulation of specific immunity.     

Australian women's experiences of living with hepatitis C virus: results from a cross-sectional survey

BACKGROUND: Of the estimated 160000 Australians currently infected with the hepatitis C virus (HCV), over one-third are women and very few have received clinical treatment, with most managing their illness in non-specialist settings. Little is known about the experiences of women living with HCV in the general community. The present study provides the results from the first comprehensive social survey of Australian women's experiences of living with HCV. METHODS: In 2000, a questionnaire was administered to a largely non-clinical sample of women with HCV (n = 462) living in the state of Victoria and the Australian Capital Territory, Australia. The questionnaire was self-administered with a return rate of 75%. The mean age was 35 years and 83% were 'current' or 'past' injecting drug users. The mean time since diagnosis was 4.6 years (SD = 4.0) and the mean time since infection was 10.5 years (SD = 8.2). RESULTS: Fifty-eight percent of women reported experiencing symptoms related to their HCV, the most common being tiredness (78%) and nausea (44%). Of the sample, 56% currently saw a doctor for their HCV, and while 52% had ever been referred to a specialist, only 17% of the total sample had ever begun interferon-based combination or monotherapy. Forty-eight percent of women reported experiencing less favorable treatment by a health professional because of their HCV. Age-related self-assessed health status was significantly lower than Australian norms, as were SF-12 physical and mental health scores. The SF-12 physical and mental health scores were highly correlated, indicating a significant physical and mental health burden associated with HCV. CONCLUSION: The social, physical and mental health needs of women living with HCV are considerable. Most women had not accessed specialist treatment and the response of the primary health care system to HCV-related women's health issues requires improvement.     

Channelized hotelling and human observer correlation for lesion detection in hepatic SPECT imaging.

Mathematic "model" observers that predict human performance are of interest in medical imaging as substitutes in psychophysical studies. We have examined the correlations between human observers and several forms of the channelized Hotelling observer (CHO) for a tumor detection task with simulated SPECT liver images that were used to study the effects of scatter and scatter correction on detection. METHODS: A receiver operating characteristic (ROC) study was devised to investigate the relative value of a scatter-subtraction strategy in SPECT imaging. The study used simulated images of the biodistribution of 99mTc-labeled FO23C5 anticarcinoembryonic antigen antibodies within the liver. Projection data for 3 separate tumor locations and 5 strategies for handling scatter were obtained using Monte Carlo software applied to an anthropomorphic phantom. The strategies were (a) perfect scatter rejection, (b) no scatter correction, (c) no scatter correction under an assumption of an elevated amount of scatter, (d) an energy-spectrum-based scatter compensation of the normal-scatter case (b), and (e) similar scatter compensation for the elevated-scatter case (c). Image reconstruction approximated current clinical procedures at the University of Massachusetts Medical School. Human performance for each combination of location and strategy was based on averaging the areas under the ROC curve for 7 individuals. A set of 15 signal-to-noise ratios (SNRs) was derived from these averages for comparison with SNRs for CHO models featuring constant-Q and difference-of-gaussian (DOG) filters. RESULTS: The Spearman rank correlation coefficient was 0.92 (P = 0.000001) when comparing task performances for the average human and a constant-Q CHO using 4 square-profile channels. For the DOG version of the CHO, comparison with the average human found a coefficient of 0.84 (P = 0.00005). CONCLUSION: The significant positive correlations found between the rankings of the average human observer and the CHOs for our detection task indicate that a channelized model observer could eventually serve as a replacement for human observers. The specific CHO models we have used are best suited to screen for significant differences between strategies before a human psychophysical study.     

家庭足温监测可减少高危糖尿病患者足部并发症——在家中进行红外线足温监测对于有高危因素的糖尿病患者是否可预防足部并发症？

设计：随机对照试验。分配：隐匿。双盲：非双盲。随访时间：6个月。地点：得克萨斯州圣安东尼奥，得克萨斯大学健康科学中心糖尿病足高危患者诊所。患者：85例糖尿病患者（诊断依据世界卫生组织标准），年龄18～80岁（中位年龄55岁，男