Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones.

In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs from previously reported COX-2, 15-LOX and PPARγ ligands. Challenging our design with pre-synthetic docking experiments on PPARγ showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARγ agonist, potent COX-2 antagonist (nanomolar IC50 values) and moderate 15-LOX inhibitor (micromolar IC50 values). We envisioned such outcome as a prototypical balanced modulation of the 3 inflammatory targets. In vitro glucose uptake assay defined six compounds as insulin-sensitive and the other two as insulin-independent glucose uptake enhancers. Also, they were able to induce PPARγ nuclear translocation in immunohistochemical analysis. Their anti-inflammatory potential has been translated to effective inhibition of monocyte to macrophage differentiation, suppression of LPS-induced inflammatory cytokine production in macrophages, as well as significant in vivo anti-inflammatory activity. Ligand co-crystallized PPARγ X-ray of one of MTDLs has identified new clues that could serve as structural basis for its partial agonism. Docking of the most active compounds into COX-2 and 15-LOX active sites, pinpointed favorable binding patterns, similar to those of the co-crystallized ligands. Finally, in silico assessment of pharmacokinetics, physicochemical properties, drug-likeness and ligand efficiency indices was performed. Hence, we anticipate that the prominent biological profile of such series will rationalize relevant anti-inflammatory drug development endeavors.

Structural and Dynamic Elucidation of a Non-acid PPARγ Partial Agonist: SR1988.

Targeting peroxisome proliferator-activated receptor γ (PPARγ) by synthetic compounds has been shown to elicit insulin sensitising properties in type 2 diabetics. Treatment with a class of these compounds, the thiazolidinediones (TZDs), has shown adverse side effects such as weight gain, fluid retention, and congestive heart failure. This is due to their full agonist properties on the receptor, where a number of genes are upregulated beyond normal physiological levels. Lessened transactivation of PPARγ by partial agonists has proved beneficial in terms of reducing side effects, while still maintaining insulin sensitising properties. However, some partial agonists have been associated with unfavourable pharmacokinetic profiles due to their acidic moieties, often causing partitioning to the liver. Here we present SR1988, a new partial agonist with favourable non-acid chemical properties. We used a combination of X-ray crystallography and hydrogen/deuterium exchange (HDX) to elucidate the structural basis for reduced activation of PPARγ by SR1988. This structural analysis reveals a mechanism that decreases stabilisation of the AF2 coactivator binding surface by the ligand.

Sensorized guidewires with MEMS tri-axial force sensor for minimally invasive surgical applications.

This paper describes the design of a tri-axial microelectromechanical force sensor (FS) that can be mounted on the tip of the guidewire. Piezoresistive silicon nanowires (SiNW) are embedded into a cross cantilever design with a manoeuvrable stylus to allow the detection of force in all directions. The electrical resistance changes in the four SiNWs are used to decode an arbitrary force applied onto the FS. The sensitivity of the device can be improved by two orders of magnitude compared to bulk Si thanks to the giant piezoresistive effects offered by the SiNW. Robustness of the FS is improved due to the novel design by incorporating a mechanical stopper at the tip of the stylus. Finite element analysis (FEM) analysis was used in designing the FS.

Hip fractures in the elderly: the impact of comorbid illnesses on hospitalisation costs.

INTRODUCTION: Hip fractures in the elderly are associated with multiple comorbidities. MATERIALS AND METHODS: We prospectively surveyed and went through all relevant medical records of 70 consecutive patients admitted to Singapore General Hospital following either a cervical or intertrochanteric femoral fracture from late February to May 2004. The total hospitalisation cost for each patient was calculated based on the costs of inpatient care up to the point of discharge. Regression modeling was performed on the 7 commonest age-related conditions (based on our data), to determine the impact of each comorbidity on total costs. RESULTS: The average age of the cohort was 77.24 years. The median length of stay was 13.6 days. In patients without comorbidities, the mean hospitalisation cost was S$9,347.5 +/- 1719.6. With the presence of comorbidities, the mean cost increased to S$11,502.3 +/- 6024.3. In univariate modeling, dementia added the largest amount to total costs [S$5,398; 95% confidence interval (CI), S$1273 to S$9523; P <0.05]. The presence of diabetes (S$758; 95% CI, S$2,051 to S$3,566), hypertension (S$644; 95% CI, S$1,986 to S$3,274) and osteoarthritis (S$915; 95% CI, S$3,721 to S$1,891) did not significantly add to total costs. When controlled for multiple comorbidities, dementia retained its significance in adding to total costs (S$6,178; 95% CI, S$1,795 to S$10,562; P = 0.006). CONCLUSION AND DISCUSSION: Hip fracture patients with comorbidities incurred higher hospitalisation costs. Cost-containment strategies in hip fracture patients should not only examine the number of comorbidities but also the type of disease.

Characteristics of treated hypertension in incident hemodialysis and peritoneal dialysis patients.

BACKGROUND: The treatment of hypertension in dialysis patients is prevalent and poorly characterized. beta-Blockers and calcium channel blockers (CCBs) have been associated with reduced all-cause and cardiovascular mortality. This study describes the treatment of hypertension and assesses the association between mortality and class of antihypertensive medication among a cohort of dialysis patients. METHODS: The US Renal Data System (USRDS) Dialysis Morbidity and Mortality Study Wave II cohort was analyzed. A total of 2,877 patients initiating hemodialysis or peritoneal dialysis in 1996 or 1997 and treated with antihypertensives were included in this analysis. Vital status was followed until November 2000. RESULTS: Calcium channel blockers were prescribed to 70.3% of patients. Only 31.5% and 27.0% of patients with cardiovascular disease were prescribed angiotensin-converting enzyme inhibitors and beta-blockers, respectively. Mono-, double-, triple-, and more than triple-therapy were reported in 48.0%, 36.1%, 13.2%, and 2.7% of the cohort, respectively. In multivariable, fully adjusted models, no individual class of antihypertensives was associated with changes in all-cause mortality. In all patients, nondihydropyridine CCBs (non-DHP CCBs) were associated with a reduced risk of cardiovascular death (hazard ratio, 0.78; 95% confidence interval, 0.62 to 0.97) and among end-stage renal disease patients with preexisting cardiovascular disease, dihydropyridine CCBs (DHP CCBs) and non-DHP CCBs were associated with reduced risk of all-cause and cardiovascular mortality. CONCLUSION: Calcium channel blocker use is widespread among hypertensive dialysis patients. Antihypertensive prescription patterns suggest a lack of consensus regarding treatment of hypertension. Multivariable analysis of associations between antihypertensive class and mortality reveals results of uncertain clinical significance. Hypertension treatment trials in dialysis patients should be performed to appropriately inform treatment decisions.