Plasma 15-F2t-isoprostane in idiopathic pulmonary arterial hypertension

Background

15-F_2t-isoprostane (15-F_2t-IsoP), a prostaglandin F₂-like compound, is widely recognized as a biomarker of chronic heart failure. This study investigated the potential role and prognostic significance of plasma 15-F_2t-IsoP in patients with idiopathic pulmonary arterial hypertension (IPAH).

Methods

Plasma 15-F_2t-IsoP concentrations were determined in 80 consecutive IPAH patients at the time of their first right heart catheterization, and monitored for 30 ± 12 months. The expression of 15-F_2t-IsoP protein in autopsy lung samples was determined by immunohistochemical staining.

Results

Plasma 15-F_2t-IsoP concentrations were significantly increased in patients with IPAH compared with healthy controls (91 pg/ml vs. 30 pg/ml, respectively; P < 0.001). Patients with baseline 15-F_2t-IsoP concentrations ≥ 97 pg/ml had a significantly lower survival rate than those with lower baseline concentrations (P < 0.001). During follow-up, 15-F_2t-IsoP concentrations in survivors decreased, whereas concentrations in non-surviving patients increased further (P < 0.05). Elevated concentrations of 15-F_2t-IsoP were correlated with a severity of WHO functional class, lower 6-minute walking distance and mixed venous oxygen saturation, higher mean right atrial pressure and brain natriuretic peptide. Multivariate analysis revealed that the plasma 15-F_2t-IsoP concentration was an independent factor associated with mortality. Histological studies showed that the expression of 15-F_2t-IsoP was up-regulated in remodeled pulmonary vessels.

Conclusions

An elevated plasma 15-F_2t-IsoP concentration and a further increase during follow-up may be a risk factor for higher mortality in patients with IPAH.     

Long-term benefits of aggressive treatment for primary colorectal cancer

The long-term follow up of 128 colorectal cancer patients is reported. Seventy-nine percent (101/128) of the patients had curative resections: 70 patients had radical lymphadenectomies with wide removal of tumor-adjacent nodes, and 31 patients had standard resections. The 5-year overall survival rates for Dukes' stage B and C patients and for all rectosigmoid cancer patients significantly favored radical resection (60% vs. 38%, 57% vs. 29%, respectively, P < 0.05). Tumor-free survival rates were also higher after radical lymphadenectomy but did not reach statistical significance. Eleven percent (14/128) of the patients required multiorgan resections, and/or preoperative radiation to render fixed cancers resectable, and these patients had a 10-year tumor-free survival rate of 45%, compared to zero % 5-year survival for the 27 patients who underwent palliative procedures (P < 0.01). These results confirm that many colorectal cancer patients will be cured with aggressive treatment and they support the need for a controlled trial for evaluation of lymphadenectomy for this disease. © 1996 Wiley-Liss, Inc.     

FAK regulates cardiomyocyte survival following ischemia/reperfusion

Myocyte apoptosis is central to myocardial dysfunction following ischemia/reperfusion (I/R) and during the transition from hypertrophy to heart failure. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase regulates adhesion-dependent survival signals and unopposed FAK activation has been linked to tumor development. We previously showed that conditional myocyte-specific deletion of FAK (MFKO) in the adult heart did not affect basal cardiomyocyte survival or cardiac function but led to dilated cardiomyopathy and heart failure following pressure overload. In the present study, we sought to determine if FAK functions to limit stress-induced cardiomyocyte apoptosis. We reasoned that (I/R), which stimulates robust apoptotic cell death, might uncover an important cardioprotective function for FAK. We found that depletion of FAK markedly exacerbates hypoxia/re-oxygenation-induced cardiomyocyte cell death in vitro. Moreover, deletion of FAK in the adult myocardium resulted in significant increases in I/R-induced infarct size and cardiomyocyte apoptosis with a concomitant reduction in left ventricular function. Finally, our results suggest that NF-κB signaling may play a key role in modulating FAK-dependent cardioprotection, since FAK inactivation blunted activation of the NF-κB survival signaling pathway and reduced levels of the NF-κB target genes, Bcl2 and Bcl-xl. Since the toggling between pro-survival and pro-apoptotic signals remains central to preventing irreversible damage to the heart, we conclude that targeted FAK activation may be beneficial for protecting stress-dependent cardiac remodeling.     

Pre-B cell colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity

Pre-B cell colony-enhancing factor (PBEF), also known as visfatin, is a highly conserved, 52-kDa protein found in living species from bacteria to humans. Originally a curiosity identified serendipitously in microarray studies but having no obvious functional importance, PBEF has now been shown to exert three distinct activities of central importance to cellular energetics and innate immunity. Within the cell, PBEF functions as a nicotinamide phosphoribosyl transferase, the rate-limiting step in a salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. By virtue of this role, it can regulate cellular levels of NAD and so impact not only cellular energetics but also NAD-dependent enzymes such as sirtuins. Although it lacks a signal peptide, PBEF is released by a variety of cells, and elevated levels can be found in the systemic circulation of patients with a variety of inflammatory diseases. As an extracellular cytokine, PBEF can induce the cellular expression of inflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6. Finally, PBEF has been shown to be an adipokine expressed by fat cells that exerts a number of insulin mimetic and antagonistic effects. PBEF expression is up-regulated in a variety of acute and chronic inflammatory diseases including sepsis, acute lung injury, rheumatoid arthritis, inflammatory bowel disease, and myocardial infarction and plays a key role in the persistence of inflammation through its capacity to inhibit neutrophil apoptosis. This review summarizes the admittedly incomplete body of emerging knowledge about a remarkable new mediator of innate immunity.     

Peroxisome proliferator-activated receptor-alpha agonist treatment in a transgenic model of type 2 diabetes reverses the lipotoxic state and improves glucose homeostasis

Abnormalities in insulin action are the characteristics of type 2 diabetes. Dominant-negative muscle-specific IGF-I receptor (MKR) mice exhibit elevated lipid levels at an early age and eventually develop type 2 diabetes. To evaluate the role of elevated lipids in the progression of the diabetic state, MKR mice were treated with WY14,643, a peroxisome proliferator-activated receptor (PPAR)-alpha agonist. WY14,643 treatment markedly reduced serum fatty acid and triglyceride levels within a few days, as well as muscle triglyceride levels, and subsequently normalized glucose and insulin levels in MKR mice. Hyperinsulinemic-euglycemic clamp analysis showed that WY14,643 treatment enhanced muscle and adipose tissue glucose uptake by improving whole-body insulin sensitivity. Insulin suppression of endogenous glucose production by the liver of MKR mice was also improved. The expression of genes involved in fatty acid oxidation was increased in liver and skeletal muscle, whereas gene expression levels of hepatic gluconeogenic enzymes were decreased in WY14,643-treated MKR mice. WY14,643 treatment also improved the pattern of glucose-stimulated insulin secretion from the perfused pancreata of MKR mice and reduced the beta-cell mass. Taken together, these findings suggest that the reduction in circulating or intracellular lipids by activation of PPAR-alpha improved insulin sensitivity and the diabetic condition of MKR mice.     

Hyperosmolarity enhances the lung capillary barrier

Although capillary barrier deterioration underlies major inflammatory lung pathology, barrier-enhancing strategies are not available. To consider hyperosmolar therapy as a possible strategy, we gave 15-minute infusions of hyperosmolar sucrose in lung venular capillaries imaged in real time. Surprisingly, this treatment enhanced the capillary barrier, as indicated by quantification of the capillary hydraulic conductivity. The barrier enhancement was sufficient to block the injurious effects of thrombin, TNF-alpha, and H2O2 in single capillaries, and of intratracheal acid instillation in the whole lung. Capillary immunofluorescence indicated that the hyperosmolar infusion markedly augmented actin filament formation and E-cadherin expression at the endothelial cell periphery. The actin-depolymerizing agent latrunculin B abrogated the hyperosmolar barrier enhancement as well as the actin filament formation, suggesting a role for actin in the barrier response. Furthermore, hyperosmolar infusion blocked TNF-alpha-induced P-selectin expression in an actin-dependent manner. Our results provide the first evidence to our knowledge that in lung capillaries, hyperosmolarity remodels the endothelial barrier and the actin cytoskeleton to enhance barrier properties and block proinflammatory secretory processes. Hyperosmolar therapy may be beneficial in lung inflammatory disease.     

Formulation, Antimicrobial and Toxicity Evaluation of Bioceramic based Ofloxacin Loaded Biodegradable Microspheres for Periodontal Infection

In the present study an attempt has been made to load Poly (Lactic-Co-glycolic acid) microspheres with hydroxyapatite (HA) and ofloxacin and propose the composite microspheres to be used as local drug delivery system with the drug releasing capability for periodontitis treatment. A modified single emulsion method has been used for the preparation of microspheres. Experiments were conducted to optimize the formulation by RSM-Box-Behnken Method, which is an independent quadratic design involving three or four independent variables against a pre determined set of dependant parameters. The particle size of composite microspheres was analyzed and the average size was found to be 22.05 μm. Photomicrographs and scanning electron micrographs showed that the composite microspheres are spherical in shape and porous in nature. The microbiological activity of optimized formulation was evaluated using strain: S. aureus-ATCC- 29213 and E. coli-ATCC-25922. In vivo/in situ toxicity evaluation of the formulation was assessed by MTT assay and the formulation was found to be biocompatible.     

Formulation optimization and in vitro characterization of sertraline loaded self-nanoemulsifying drug delivery system (SNEDDS) for oral administration

Sertraline is a selective serotonin reuptake inhibitors used as major therapeutic advances in psychiatry and is drug of choice for treatment of major depressive disorders. The drug (free base) encounters problem of poor aqueous solubility and vulnerability to enzymatic degradation in liver. The hydrochloride salts of free base revert back to its original form in gastrointestinal tract leading to slow/poor absorption. In the current study, sertraline loaded self-nanoemulsifying drug delivery systems (SNEDDS) were prepared in an attempt to circumvent the problems associated with poor aqueous solubility, vulnerability to enzymatic degradation in liver and to sort out the problems associated with salt formation. Preliminary screening was carried out to select proper ingredient combinations. Ternary phase diagrams were then constructed and an optimum system was designated. Formulations selected were then compared for optimization. The systems were assessed for robustness, globule size, cloud point, percentage transmittance, surface morphology and drug release. An optimum system composed of oil (25.42?%), surfactant (49.72?%), and co-surfactant (24.86?%). It possessed a mean globule size, cloud point and percentage transmittance of 63.5?nm, 90?°C and 82.43?%, respectively. Transmission electron microscopy demonstrated spherical particle morphology. The drug release from the selected formulation was significantly higher than other SNEDDS and drug suspension as well. Optimized formulation was subjected to stability studies at different temperature and relative humidity and was found to be stable. No significant variations were observed in the formulation over a period of 3?months at accelerated conditions.     

The emerging role of P-glycoprotein inhibitors in drug delivery: a patent review

INTRODUCTION: The ATP-binding cassette superfamily contains membrane transporter proteins that transport a wide range of diverse compounds across cellular membranes. The P-glycoprotein (P-gp) is an important member of this family and a multi-specific drug efflux transporter that plays a significant role in governing the bioavailability of many clinically active drugs. The inhibition of this efflux transporter by various P-gp inhibitors forms a distinctive approach in improving bioavailability and conquering drug resistance. Most P-gp inhibitors exhibit limitations associated with their safety and unwanted pharmacokinetic interactions, thereby restraining their clinical applicability. AREAS COVERED: This review explores the investigations on the feasibility and applicability of various classes of P-gp inhibitors as described in recent patents for enhanced drug delivery. EXPERT OPINION: Several candidates presently under development look promising as P-gp inhibitors, e.g., tariquidar and elacridar. Pharmaceutical excipients currently constitute the most promising class of P-gp inhibitors and are considered safe and pharmaceutically acceptable for use in formulations. In addition, lipid-based excipients and thiolated polymers play an active role in affecting P-gp-mediated transport not only by altering the membrane fluidity or ATPase activity but by down regulating P-gp expression. An additional overture such as the prodrug derivatization of P-gp substrates is a feasible approach to bypass P-gp-mediated efflux.