A Data-Mining Approach for the Quantitative Assessment of Physicochemical Properties of Molecular Compounds in the Skin Flux.

This paper aimed to provide an insight into the mechanism of transdermal penetration of drug molecules with respect to their physicochemical properties, such as solubility (S), the presence of enantiomer (ET) and logarithm of octanol-water partition coefficient (log P), molecular weight (MW), and melting point (MP). Propionic acid derivatives were evaluated for their flux through full-thickness skin excised from hairless mice upon being delivered from silicone-based pressure-sensitive adhesive (PSA) matrices in the presence or absence of various enhancers. The skin fluxes of model compounds were calculated based on the data obtained using the method engaged with the diffusion cell system. The statistical design of experiments (DoE) based on the factorial approach was used to find variables that have a significant impact on the outcomes. For the prediction of skin flux, a quantitative equation was derived using the data-mining approach on the relationship between skin permeation of model compounds (~125 mg/ml) and involved physicochemical variables. The most influential variables for the skin flux of propionic acid derivatives were the melting point (0.97) followed by the presence of enantiomer (0.95), molecular mass (0.93), log P values (0.86), and aqueous solubility (0.80). It was concluded that the skin flux of molecular compounds can be predicted based on the relationship between their physicochemical properties and the interaction with cofactors including additives and enhancers in the vehicles.

Hormone Therapy and Delivery Strategies against Cardiovascular Diseases.

This review article is aimed to delineate the potential role of hormones in the treatment and diagnosis of cardiovascular diseases with special emphasis on the nitric oxide (NO) involved mechanisms. This review will also offer an overview on current and future hormone usages, pathophysiology, clinical features, absorption mechanisms and adverse effects. The hormone therapies against cardiovascular diseases as well as their treatment strategies, delivery routes and carriers were thoroughly discussed. Ongoing and future basic and clinical research with hormone will provide important insights into efficient treatment strategies against cardiovascular diseases. It was necessary to explore advanced delivery systems, such as drug eluting stent, microneedles, nanotechnology and stem cell preconditioning, for an efficient delivery of hormones against cardiovascular diseases. The future is enlightened with the advent of novel, safer and more effective carriers for hormone delivery as well as learning how to maximize the therapeutic efficacy against cardiovascular diseases.

A cascade computer model for mocrobicide diffusivity from mucoadhesive formulations.

BACKGROUND: The cascade computer model (CCM) was designed as a machine-learning feature platform for prediction of drug diffusivity from the mucoadhesive formulations. Three basic models (the statistical regression model, the K nearest neighbor model and the modified version of the back propagation neural network) in CCM operate sequentially in close collaboration with each other, employing the estimated value obtained from the afore-positioned base model as an input value to the next-positioned base model in the cascade. The effects of various parameters on the pharmacological efficacy of a female controlled drug delivery system (FcDDS) intended for prevention of women from HIV-1 infection were evaluated using an in vitro apparatus "Simulant Vaginal System" (SVS). We used computer simulations to explicitly examine the changes in drug diffusivity from FcDDS and determine the prognostic potency of each variable for in vivo prediction of formulation efficacy. The results obtained using the CCM approach were compared with those from individual multiple regression model. RESULTS: CCM significantly lowered the percentage mean error (PME) and enhanced r(2) values as compared with those from the multiple regression models. It was noted that CCM generated the PME value of 21.82 at 48169 epoch iterations, which is significantly improved from the PME value of 29.91% at 118344 epochs by the back propagation network model. The results of this study indicated that the sequential ensemble of the classifiers allowed for an accurate prediction of the domain with significantly lowered variance and considerably reduces the time required for training phase. CONCLUSION: CCM is accurate, easy to operate, time and cost-effective, and thus, can serve as a valuable tool for prediction of drug diffusivity from mucoadhesive formulations. CCM may yield new insights into understanding how drugs are diffused from the carrier systems and exert their efficacies under various clinical conditions.

Calcium and phosphorus concentrations in native and decellularized semilunar valve tissues.

BACKGROUND AND AIM OF THE STUDY: Native, allograft, xenograft and bioprosthetic semilunar valves are all susceptible to calcific degeneration. However, intrinsic differences in baseline calcium and phosphorus tissue concentrations within mammalian normal valve structural components (e.g., cusps, sinus, vessel wall) additionally subdivided by tripartite regions (e.g., right-, left- and non-coronary leaflets) have never been systematically measured and reported. It was originally hypothesized that variations in normative tissue concentrations of calcium and phosphorus may correspond to subsequent clinical patterns of acquired dystrophic calcification; decellularization was also expected to reduce the tissue concentrations of these elements. METHODS: Native semilunar valves were freshly harvested from 12 juvenile sheep. Half of the valves were decellularized (six aortic and six pulmonary), while the other valves were flash-frozen at -80 degrees C within minutes of euthanasia as native valves. Elemental calcium and phosphorus concentrations were measured in the great vessels, sinus walls and cusps using inductively coupled plasma optical emission spectrometry (ICP-OES), and analyzed with non-parametric statistical tests. RESULTS: Calcium concentrations (microg/mg tissue; median (range) were similar in aortic native cusps (0.37 (0.21)), sinus walls (0.37 (0.09)) and aorta (0.37 (0.08)) (p = 0.8298). Pulmonary calcium concentrations were similar in cusps, but 10-25% higher in the native sinus (p = 0.0018) and pulmonary artery (p < 0.0001) compared to analogous aortic structures. All cusps had higher phosphorus concentrations than their respective conduit tissues. No tripartite regional variations were observed. Decellularization did not reduce the calcium content of cusps, but removed 50-55% of vessel and sinus wall calcium. However, up to 85% of phosphorus was removed from all valve tissues (p < 0.001). CONCLUSION: There were no significant differences in normal tissue concentrations of calcium between aortic valve functional structures, and no semilunar tripartite regional differences in either semilunar valve complex. Thus, the distribution of baseline tissue calcium content of healthy young valves is not inherently predictive of selective or asymmetric anatomical patterns of valve degenerative calcification. Native semilunar cusps contain the highest phosphorus concentrations. Decellularization reduces all elemental concentrations except for cuspal calcium.

Pulmonary arterioplasty with decellularized allogeneic patches.

BACKGROUND: Decellularized allogeneic nonvalved pulmonary artery patches for arterioplasty are a relatively new option compared with cryopreserved allogeneic, crosslinked xenogeneic bioprosthetic or synthetic materials. This study examines the midterm experience with a new decellularized allogeneic patch for congenital cardiac reconstructions. METHODS: For this prospective postmarket approval, nonrandomized, inclusive observational study, we collected data on a consecutive cohort of 108 patients with cardiovascular reconstructions using 120 decellularized allogeneic pulmonary artery patches (MatrACELL; LifeNet Health, Inc, Virginia Beach, VA) between September 2009 and December 2012. One hundred of the patches were used for pulmonary arterioplasties. Two patients were lost early to follow-up and excluded from subsequent survival and durability analyses. Data included demographics, surgical outcomes, subsequent reoperations, and catheter reinterventions. These variables were also collected for an immediately preceding retrospective consecutive cohort of 100 patients with 101 pulmonary arterioplasty patches who received classical cryopreserved pulmonary artery allografts (n=59 patches and patients) or synthetic materials (n=41 patients with 42 patches) for pulmonary arterioplasties between 2006 and 2009. RESULTS: In 106 patients with 118 decellularized patches, there were no device-related serious adverse events, no device failures, and no evidence of calcifications on chest roentgenograms. In contrast, the prior comparative pulmonary arterioplasty cohort of 100 patients experienced an overall 14.0% patch failure rate requiring device-related reoperations (p<0.0001) at mean duration of 194±104 days (range, 25 to 477 days). CONCLUSIONS: The intermediate-term data obtained in this study suggest favorable performance by decellularized pulmonary artery patches, with no material failures or reoperations provoked by device failure.

Computational analysis and predictive modeling of polymorph descriptors.

BACKGROUND: A computation approach based on integrating high throughput binding affinity comparison and binding descriptor classifications was utilized to establish the correlation among substrate properties and their affinity to Breast Cancer Resistant Protein (BCRP). The uptake rates of Mitoxantrone in the presence of various substrates were evaluated as an in vitro screening index for comparison of their binding affinity to BCRP.The effects of chemical properties of various chemotherapeutics, such as antiviral, antibiotic, calcium channel blockers, anticancer and antifungal agents, on their affinity to BCRP, were evaluated using HEK (human embryonic kidney) cells in which 3 polymorphs, namely 482R (wild type) and two mutants (482G and 482T) of BCRP, have been identified. The quantitative structure activity relationship (QSAR) model was developed using the sequential approaches of Austin Model 1 (AM1), CODESSA program, heuristic method (HM) and multiple linear regression (MLR) to establish the relationship between structural specificity of BCRP substrates and their uptake rates by BCRP polymorphs. RESULTS: The BCRP mutations may induce conformational changes as manifested by the altered uptake rates of Mitoxantrone by BCRP in the presence of other competitive binding substrates that have a varying degree of affinities toward BCRP efflux. This study also revealed that the binding affinity of test substrates to each polymorph was affected by varying descriptors, such as constitutional, topological, geometrical, electrostatic, thermodynamic, and quantum chemical descriptors. CONCLUSION: Descriptors involved with the net surface charge and energy level of substrates seem to be the common integral factors for defining binding specificity of selected substrates to BCRP polymorph. The reproducible outcomes and validation process further supported the accuracy of the computational model in assessing the correlation among descriptors involved with substrate affinity to BCRP polymorph. A quantitative computation approach will provide important structural insight into optimal designing of new chemotherapeutic agents with improved pharmacological efficacies.

Optimization of cardiovascular stent against restenosis: factorial design-based statistical analysis of polymer coating conditions.

The objective of this study was to optimize the physicodynamic conditions of polymeric system as a coating substrate for drug eluting stents against restenosis. As Nitric Oxide (NO) has multifunctional activities, such as regulating blood flow and pressure, and influencing thrombus formation, a continuous and spatiotemporal delivery of NO loaded in the polymer based nanoparticles could be a viable option to reduce and prevent restenosis. To identify the most suitable carrier for S-Nitrosoglutathione (GSNO), a NO prodrug, stents were coated with various polymers, such as poly (lactic-co-glycolic acid) (PLGA), polyethylene glycol (PEG) and polycaprolactone (PCL), using solvent evaporation technique. Full factorial design was used to evaluate the effects of the formulation variables in polymer-based stent coatings on the GSNO release rate and weight loss rate. The least square regression model was used for data analysis in the optimization process. The polymer-coated stents were further assessed with Differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy analysis (FTIR), Scanning electron microscopy (SEM) images and platelet adhesion studies. Stents coated with PCL matrix displayed more sustained and controlled drug release profiles than those coated with PLGA and PEG. Stents coated with PCL matrix showed the least platelet adhesion rate. Subsequently, stents coated with PCL matrix were subjected to the further optimization processes for improvement of surface morphology and enhancement of the drug release duration. The results of this study demonstrated that PCL matrix containing GSNO is a promising system for stent surface coating against restenosis.

Advanced polymeric matrix for valvular complications.

Poly(L-lactic acid) (PLLA) matrix systems incorporated with poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) containing nitric oxide (NO) donors (DETA NONOate) were developed for prevention of heart valve complications through sustained and controlled release of NO. PLLA matrices were prepared using the salt leaching method and the properties and drug release profiles were characterized. For assessment of the effects of PLLA systems on the pharmacological responses and cytotoxicity, various factors, such as calcium content, alkaline phosphatase (ALP) activity, cyclic guanosine monophosphate (cGMP) expression, intercellular adhesion molecule (ICAM-1) expression and cell viability of porcine aortic valve interstitial cells (PAVICs), were evaluated. PLLA matrices embedded with PLGA- NPs demonstrated its usefulness in alleviating the calcification rate of the VICs. The cGMP levels under osteoblastic conditions significantly increased, supporting that anticalcification activity of NO is mediated through NO-cGMP signaling pathway. The level of ICAM-1 expression in cells exposed to NO was lowered, suggesting that NO has an inhibitory activity against tissue inflammation. NO releases from PLLA matrix embedded with PLGA NPs prevented valvular calcification and inflammation without causing any cytotoxic activities. PLLA matrix system loaded with NPs containing NO donors could provide a new platform for sustained and controlled delivery of NO, significantly reducing valvular complications.

Effects of dialdehyde starch on calcification of collagen matrix.

Dialdehyde starch (DAS), a polymeric aldehyde derived from naturally occurring polysaccharide, was used as an additive to the collagen (COL) matrix in an effort to improve its physical and biological properties. The effects of DAS on the thermal stability of COL were characterized by differential scanning calorimetry. The conformational changes in COL were characterized by resistance to protease degradation assay, residual amine analysis, and Fourier-transform infrared spectroscopy. To assess biocompatibility enhancement, the calcium content in porcine aortic valve interstitial cells (PAVICs) on exposure to cardiovascular stents coated with DAS-stabilized COL was examined using atomic absorption spectroscopy. Thermal stability of DAS-stabilized COL was affected by DAS in a concentration dependent manner, reaching maximum at the saturation concentration (DAS:COL = 1:120) and decreasing the thermal stability at the concentrations above saturation. In the long-term exposure condition (21 days), stents coated with DAS at the lowest concentration significantly reduced the calcification rate of PAVIC, when compared with bare stent (p = 0.001). DAS appears to be an efficient additive to the COL matrix in improving its physical and biological properties. Further optimization process is needed for the suitable crosslinking conditions of DAS, which subsequently enhances thermal strength and anticalcification activities of COL matrix.

In vivo evaluation of vaginal films for mucosal delivery of nitric oxide.

Nitric oxide (NO)-releasing vaginal films were developed and evaluated as a potential advanced treatment option for female sexual arousal disorder (FSAD). The polymeric films containing s-nitrosoglutathione (GSNO), an endogenous NO donor, were prepared using the reduced-pressure drying method. The surface morphology, thermal/mechanical properties, stability, loading efficiency and physicodynamic properties were characterized and the pharmacological activities were evaluated through in vitro and in vivo studies. The GSNO films were homogeneous and transparent, and showed suitable mucoadhesiveness and mechanical properties. The release profiles of NO from the GSNO films followed the first-order kinetic pattern and NO activated the NO-cGMP signaling pathway in vaginal cells. The GSNO films significantly enhanced the duration of action of GSNO and vagina blood perfusion in the rat model without causing any cytotoxic effects. The NO-releasing vaginal films might be used as a promising treatment device against FSAD.