Atropisomerism transforming anti-cancer drug discovery

Atropisomerism is a stereochemical phenomenon that describes how groups are arranged in space as a result of their impeded rotation around a single bond. It is one of the frequently underappreciated conformational kinds of chirality. A significant role for atropisomers in drug discovery and development has been established via substantial study on the characteristics of molecules exhibiting this form of chirality. According to studies on the target selectivity of anti-cancer drugs, it was identified that atropisomers of specific compounds could be examined to modulate the selectivity of promiscuous inhibitors, which are a key target in cancer therapy. Conversely, it was discovered that these deliberate rigidifications of possible molecules along an axis of chirality gave an abundant possibility of acquiring more tailored anti-cancer action. Atropisomerism plays a significant role in altering pharmacodynamic and pharmacokinetic properties and thereby the success of any proposed drug candidate. It is thus necessary to anticipate the impact of stereogenic centres in such compounds on cancer drug development. Hence, herein we review atropisomeric anti-cancer moieties which have been investigated based on their target proteins, origin and isomerism. The insights offered herein would be extremely useful in anti-cancer drug design, pave way for new avenues to development promising potent agents to combat this life-threatening disease.     

Recruitment of hippocampal neurons to encode behavioral events in the rat: Alterations in cognitive demand and cannabinoid exposure

Successful performance by rats of a delayed‐nonmatch‐to‐sample (DNMS) task is hippocampal dependent. We have shown that neurons in hippocampus differentially encode task‐relevant events. These responses are critical for correct DNMS performance and are diminished by exogenous cannabinoids. We therefore reasoned that hippocampal neural correlates of behavior are likely shaped during learning; however, to date, no work has examined these correlates during DNMS acquisition training. Consequently, the present study assessed the emergence of hippocampal neural encoding when (i) cognitive task demands were increased through prolongation of delay intervals between sample and nonmatch phase and (ii) when animals are under cannabinoid treatment and performance is compromised. Adult, male Long‐Evans rats were trained to perform the DNMS task without delay and then implanted with multielectrode recording arrays directed to CA3 and CA1 subfields of the hippocampus. Following recovery, single units were isolated and animals divided into two treatment groups: vehicle or WIN 55,212‐2 (WIN‐2, 0.35 mg/kg). Ensemble firing was monitored during retraining in DNMS task at 0 s, and subsequently delay intervals were progressively increased to 1–10 s, 11–20 s, and 21–30 s when animals met criterion (80% correct) at each respective interval. Hippocampal CA3 and CA1 principal cells were isolated and recorded throughout treatment. Extension of the delay led to an increase in the number of task‐correlated neurons in controls. This recruitment of novel cells was reduced/prevented in the presence of WIN‐2 and was paralleled by impairment in acquisition learning at longer delay intervals. Moreover, WIN‐2 suppressed hippocampal ensemble firing during the sample (encoding) but not nonmatch phase of the DNMS task across all delays. These cannabinoid‐induced alterations in hippocampal neuronal activity may explain the observed deficits in DNMS performance. © 2009 Wiley‐Liss, Inc.     

The Provision of Complementary,Alternative, and Integrative Medicine Information and Services: a Review of World Leading Oncology Hospital Websites

Current Oncology Reports - Many cancer patients use complementary, alternative, and integrative medicine (CAIM) to improve their psychological and functional health. However, there is little known...     

Comparison of near-patient capillary glucose measurement and a risk assessment questionnaire in screening for type 2 diabetes in a high-risk population in rural India

OBJECTIVE

To assess the utility of a point-of-care (POC) capillary blood glucose measurement as compared with routine clinical parameters in predicting undiagnosed diabetes in a low-resource rural India setting.

RESEARCH DESIGN AND METHODS

Nine hundred and ninety-four participants aged >30 years and stratified by age and sex were randomly selected from 20 villages in India. A clinical questionnaire, sampling for laboratory venous fasting plasma glucose (FPG), and POC capillary blood glucose assay were performed simultaneously. Diabetes diagnosis was based on the World Health Organization (WHO) definition using FPG. The capacity of the POC glucose to predict the presence of diabetes was assessed and compared with the questionnaire using area under the receiver operating characteristic curves (AUCs).

RESULTS

The AUC for POC glucose alone in predicting diabetes was 0.869 (95% CI 0.810–0.929). This was significantly better (P < 0.001 for AUC comparison) than the models based upon clinical variables alone (AUC for the best clinical model including age, BMI, hypertension, waist circumference: 0.694 [95% CI 0.621–0.766]). POC glucose appropriately reclassified the risk of up to one-third of participants ranked according to the clinical models. Adding the clinical variables to the POC glucose assay did not significantly improve the discriminatory capability beyond that achieved with the POC glucose measurement alone (all P > 0.37).

CONCLUSIONS

POC glucose testing appears to be a simple and reliable tool for identifying undiagnosed diabetes in a high-risk, resource-poor rural population. However, studies evaluating the cost effectiveness of introducing POC glucose testing are needed prior to widespread implementation.The prevalence of type 2 diabetes is rapidly increasing around the world (1). Developing countries are facing the largest increases both in absolute and relative terms (1). It is predicted that this will have devastating consequences on the economies and health systems of these countries. Successful prevention and early management of diabetes is therefore a major health priority (1,2).In many regions, up to 50% of people with diabetes remain undiagnosed (1,3,4). Failure to improve these levels of detection will mean that the opportunity to improve health outcomes with early intervention will be lost. Early treatment with successful glucose control significantly reduces the morbidity and mortality associated with diabetes (5,6). Earlier detection of diabetes also allows for the implementation of other treatments that reduce the vascular complications of diabetes (5,6).Universal screening for diabetes is not currently recommended due to a lack of good evidence for an accurate test. However, targeted screening is advocated in certain ethnic groups deemed at increased risk of diabetes (2). For some ethnic groups, implementation of targeted screening may require the entire population to be screened. This applies for instance to Asian Indian populations, which are at greater risk of developing diabetes (7) and have a high prevalence of diabetes both in urban (4) and rural settings (3). However to successfully apply screening to such populations requires accurate, safe, and low-cost diagnostic strategies that are easy to implement (8).In resource-poor settings, clinical variables–based risk assessment questionnaires or point-of-care (POC) glucose analysis may be reasonable screening tools (9). Both require little expertise and allow an individual''s risk of having undiagnosed diabetes to be immediately determined so that only those at high risk require a confirmatory diagnostic test. However, the value of risk assessment questionnaires (9–13) and POC glucose analysis (14–16) in resource-poor settings remains unclear. Additionally the performance of these different screening methods has not been compared in rural Asian Indian populations.The aim of this study was to quantify and compare the accuracy of strategies based on POC glucose, clinical variables, and the combination of both in predicting undiagnosed diabetes in an asymptomatic, resource-poor rural Asian Indian population.     

Cannabinoids alter spontaneous firing,bursting, and cell synchrony of hippocampal principal cells

Both natural and synthetic cannabinoid receptor (e.g., CB1) agonists such as Δ⁹‐THC, WIN 55,212‐2 (WIN‐2), and HU‐210 disrupt spatial cognition presumably through the inhibition of synchrony of hippocampal ensemble firing to task‐related events. Although the CB1 receptor agonist CP 55,940 also disrupts the synchronous firing of hippocampal neurons, it does not seem to affect the average firing rate. This difference is not readily explained by the chemical structure and pharmacology of the different compounds thus warranting a more detailed examination into (i) how other cannabinoids affect the spontaneous firing, bursting, and cell synchrony of hippocampal principal cells located in CA3 and CA1 subfields, and (ii) whether these effects are indeed mediated through CB1 receptors, which will be explored by the selective antagonist AM‐251. Male Long‐Evans rats surgically implanted with multielectrode arrays to hippocampal CA3 and CA1 were anesthetized and principal cells discharging at 0.25–6.0 Hz were isolated and “tracked” following the systemic administration of Tween‐80, Δ⁹‐THC (1 or 3 mg/kg) or WIN‐2 (1 mg/kg) or HU‐210 (100 μg/kg), and 1.5 mg/kg AM‐281. All cannabinoids except for 1 mg/kg Δ⁹‐THC reliably reduced average firing rates and altered “burst” characteristics, which were reversible with AM‐281 for Δ⁹‐THC and WIN‐2 but not for HU‐210. In addition, all cannabinoids disrupted intrasubfield and intersubfield ensemble synchrony of pyramidal cells, which is an effect insensitive to AM‐281 and thus unlikely to be CB1 mediated. We consider these cannabinoid effects on spike timing and firing/bursting of principal hippocampal neurons carried by CB1 and non‐CB1 receptors to be physiological underpinnings of the cognitive impairments inherent to cannabinoid exposure. © 2010 Wiley‐Liss, Inc.     

Disparities between prescribing of secondary prevention therapies for stroke and coronary artery disease in general practice

Background Extensive evidence exists regarding the effectiveness of secondary prevention measures in patients with cardiovascular disease. Aim We aimed to examine the management and risk perceptions of cardiovascular events in people with established cardiovascular disease. Methods We analyzed data on 1453 patients, ≥55 year old, with a history of cardiovascular disease, from the Australian Hypertension and Absolute Risk Study. Results Compared with those 533 patients with stroke/transient ischemic attack, the 743 patients with coronary artery disease were twice as likely to have been prescribed secondary prevention therapies even after adjustment for potential confounding variables (adjusted relative risks 1·85; 95% confidence interval 1·56-2·19, 42% vs. 73% for use of the combination of blood pressure-lowering, lipid-lowering and antiplatelet therapies) and to have better control of lipid and blood pressure levels. General practitioners estimated that only 27% of patients with stroke/transient ischemic attack - 38% of those with coronary artery disease and 41% of those with both conditions - were at a high risk (≥15%) of a recurrent event. Patients similarly underestimated their risk of recurrent cardiovascular events, with only 8% of stroke/transient ischemic attack, 11% of coronary and 15% of combination disease patients rating themselves at 'high' or 'very-high' risk. Conclusions This study reaffirms the large treatment gap in the uptake of secondary prevention for cardiovascular disease in primary care settings, being much greater for patients with cerebral compared with cardiac cardiovascular disease. This appears to be related to differential perceptions of cardiovascular risk across different vascular territories in both patients and doctors.     

Perindopril-based blood pressure-lowering therapy reduces amino-terminal-pro-B-type natriuretic peptide in individuals with cerebrovascular disease

OBJECTIVE: The plasma amino-terminal-pro-B-type natriuretic peptide (NT-proBNP) level predicted congestive heart failure, myocardial infarction, and ischaemic stroke in participants of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a placebo-controlled study of the effects of blood pressure lowering on cardiovascular events among individuals with cerebrovascular disease. Active treatment comprised a flexible regimen based on perindopril, with the addition of indapamide at the discretion of treating physicians. Active treatment reduced cardiovascular events, and we therefore investigated whether active treatment modified NT-proBNP and other cardiovascular risk factors. METHODS: We measured NT-proBNP and other cardiovascular risk factors at randomization and after 13 months of therapy in a subset of 357 PROGRESS participants. RESULTS: Baseline systolic and pulse pressures were higher in individuals with elevated baseline NT-proBNP levels. In comparison with placebo, active treatment reduced the blood pressure and NT-proBNP levels, and increased renin levels. Reduction of NT-proBNP levels by active treatment was most evident in individuals with baseline NT-proBNP levels in the highest quarter (> 26 pmol/l), with a median reduction of 16 pmol/l (interquartile range 0-51 pmol/l, P = 0.004), corresponding to a median decrease of 39% (interquartile range 0-69%). Active treatment reduced blood pressure similarly for individuals in each of the four quarters of baseline NT-proBNP. Active therapy had no effect on plasma lipid, C-reactive protein, homocysteine, or soluble vascular cell adhesion molecule 1 levels. CONCLUSION: We conclude that plasma NT-proBNP level, in addition to predicting cardiovascular risk, may provide a measure of risk reduction by blood pressure-lowering therapy.