Facile access to new C-glycosides and C-glycoside scaffolds incorporating functionalised aromatic moieties

The tandem ene/intramolecular Sakurai cyclisation (IMSC) reaction has been successfully applied to thesynthesis of a range of C-glycosides, with key intermediates offering opportunities for functionalisation ofthe glycon moiety. To demonstrate the versatility of the approach to access the 2-deoxy-C-glycoside series,we synthesised diastereomerically pure C-glucoside and galactoside derivatives incorporating functionalisedaromatic, heteroaromatic and bicyclic aromatic moieties, in addition to the C-homologue of(±)-b-2-deoxy-glucose 6-phosphate.

In vitro bioassay investigations of the endocrine disrupting potential of steviol glycosides and their metabolite steviol, components of the natural sweetener Stevia

The food industry is moving towards the use of natural sweeteners such as those produced by Stevia rebaudiana due to the number of health and safety concerns surrounding artificial sweeteners. Despite the fact that these sweeteners are natural; they cannot be assumed safe. Steviol glycosides have a steroidal structure and therefore may have the potential to act as an endocrine disruptor in the body. Reporter gene assays (RGAs), H295R steroidogenesis assay and Ca(2+) fluorimetry based assays using human sperm cells have been used to assess the endocrine disrupting potential of two steviol glycosides: stevioside and rebaudioside A, and their metabolite steviol. A decrease in transcriptional activity of the progestagen receptor was seen following treatment with 25,000 ng/ml steviol in the presence of progesterone (157 ng/ml) resulting in a 31% decrease in progestagen response (p=<0.01). At the level of steroidogenesis, the metabolite steviol (500-25,000 ng/ml) increased progesterone production significantly by 2.3 fold when exposed to 10,000 ng/ml (p=<0.05) and 5 fold when exposed to 25,000 ng/ml (p=<0.001). Additionally, steviol was found to induce an agonistic response on CatSper, a progesterone receptor of sperm, causing a rapid influx of Ca(2+). The response was fully inhibited using a specific CatSper inhibitor. These findings highlight the potential for steviol to act as a potential endocrine disruptor.

Differential Pharmacokinetics of Digoxin in Elderly Patients

Digoxin remains one of the most commonly prescribed of all cardiac medications. The main indications for digoxin usage include atrial fibrillation and heart failure; both these conditions are more prevalent in older patients. Given the aging population and the increasing incidence of heart failure we would expect prescribing of digoxin to remain as frequent or to even increase in older patients. Older patients are also more likely to develop toxicity and diagnosis of digoxin toxicity can be difficult in this group. Numerous components contribute to the development of toxicity in older patients, ranging from aging-related changes in renal function or body mass to polypharmacy and possible interactions with digoxin. It is therefore important to understand how the pharmacokinetics of digoxin may be altered in the older population. Application of basic pharmacological principles may be helpful in anticipating these problems. This review describes the pharmacokinetics of digoxin, the changes in pharmacokinetics with increasing age and how concomitant disease states or drug interactions may affect the pharmacokinetics of digoxin. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin toxicity, especially in the elderly population.
For over 200 years debate has raged regarding the use of digitalis glycosides in cardiac disease. At present digoxin is the most commonly prescribed digitalis compound. This review describes the pharmacokinetics of digoxin and in particular how they are altered with increasing age. When considering the elderly population it is important to recognise the heterogeneity of response in this group, therefore there are no rules, with regards to prescribing, that can apply to the entire elderly population.

Virgin Olive Oil: Losses of Antioxidant Polar Phenolic Compounds due to Storage, Packaging, and Culinary Uses

Virgin olive oil is a high quality natural product obtained only by physical means. In addition to triacylglycerols it contains nutritionally important polar and non-polar antioxidant phenols and other bioactive ingredients. The polar fraction is a complex mixture of phenolic acids, simple phenols, derivatives of the glycosides oleuropein and ligstroside, lignans, and flavonoids. These compounds contribute significantly to the stability, flavor, and biological value of virgin olive. In the various stages of production, during storage and in the culinary uses, polar phenols and other valuable bioactive ingredients may be damaged. Oxidation, photo-oxidation, enzymic hydrolysis and heating at frying temperatures have a serious adverse effect. Due to the biological importance of the oil and its unique character, analytical methods have been developed to evaluate antioxidant activity or analyse complex phenol mixtures. These are based on radical scavenging assays and chromatographic techniques. Hyphenated methods are also used including liquid chromatography-mass spectrometry and liquid chromatography-nuclear magnetic resonance spectroscopy.

Triterpenoids from Pulsatilla chinensis

A new lupane type triterpenic acid, pulsatillic acid, and two new lupane type triterpenoid glycosides, pulsatilloside A and B, along with the known 23-hydroxybetulinic acid were isolated from the roots of Pulsatilla chinensis. Their structures were characterized as 3-oxo-23-hydroxy-lup-20(29)-en-28-oic acid, 3 beta, 23-dihydroxy-lup-20(29)-en-28-oic acid 3-O-alpha-L-arabinopyranoside and 3 beta, 23-dihydroxy-lup-20(29)-en-28-oic acid 28-O-beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranoside on the basis of hydrolysis and spectral evidence including two-dimensional relay HOHAHA, one-dimensional multiple relay COSY and ROESY NMR techniques. Pulsatillic acid exhibited cytotoxic activities against P-388, Lewis lung carcinoma and human large-cell lung carcinoma.

Digoxin use after diagnosis of breast cancer and survival: a population-based cohort study

Digoxin has been shown to have an estrogenic effect and is associated with increased risk of gynecomastia and estrogen-sensitive cancers such as breast and uterus cancer. These findings, particularly recent observations of increased breast cancer risk, raise questions about the safety of digoxin use in breast cancer patients. Therefore, we investigated whether digoxin use after breast cancer diagnosis increased the risk of breast cancer-specific mortality in breast cancer patients. A cohort of 17,842 breast cancer patients newly diagnosed from 1998 to 2009 was identified from English cancer registries (from the National Cancer Data Repository). This cohort was linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify breast cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95 % confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and breast cancer-specific and all-cause mortality. In 17,842 breast cancer patients, there were 2219 breast cancer-specific deaths. Digoxin users appeared to have increased breast cancer-specific mortality compared with non-users (HR 1.73; 95 % CI 1.39–2.15) but this association was entirely attenuated after adjustment for potential confounders (adjusted HR 0.91; 95 % CI 0.72–1.14). In this large population-based breast cancer cohort study, there was little evidence of an increase in breast cancer-specific mortality with digoxin use after diagnosis. These results provide some reassurance that digoxin use is safe in breast cancer patients.

Digoxin use after diagnosis of prostate cancer and survival: a population-based cohort study

PURPOSE:
Preclinical studies have shown that digoxin exerts anticancer effects on different cancer cell lines including prostate cancer. A recent observational study has shown that digoxin use was associated with a 25% reduction in prostate cancer risk. The aim of this study was to investigate whether digoxin use after diagnosis of prostate cancer was associated with decreased prostate cancer-specific mortality.
METHODS:
A cohort of 13 134 patients with prostate cancer newly diagnosed from 1998 to 2009 was identified from English cancer registries and linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify 2010 prostate cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated for the association between post-diagnostic exposure to digoxin and prostate cancer-specific mortality.
RESULTS:
Overall, 701 (5%) patients with prostate cancer used digoxin after diagnosis. Digoxin use was associated with an increase in prostate cancer-specific mortality before adjustment (HR = 1.59; 95% CI 1.32-1.91), but after adjustment for confounders, the association was attenuated (adjusted HR = 1.13; 95% CI 0.93-1.37) and there was no evidence of a dose response.
CONCLUSIONS:
In this large population-based prostate cancer cohort, there was no evidence of a reduction in prostate cancer-specific mortality with digoxin use after diagnosis.