A promising codrug of nicotinic acid and ibuprofen for managing dyslipidemia. I: Synthesis and in vitro evaluation

Nicotinic acid is therapeutically the optimum antihyperlipidemic agent, yet its intolerable cutaneous flushing hinders its wide clinical implication. The codrug of nicotinic acid and ibuprofen (IBP) was synthesized in the aim of overcoming the troublesome side effect of nicotinic acid by blockade of prostaglandin synthesis through released IBP, thus enhance patient’s compliance. The physico-chemical properties of codrug namely solubility, partition coefficient, and pKa were determined. Its solubility in aqueous and organic solvents was highest in 0.1?M HCl and isopropanol, respectively. The kinetics of hydrolysis of the codrug and IBP 2-hydroxyethyl ester was studied in aqueous phosphate buffer solution in pH 1.2, 6.8, and 7.4 at 70°C, 80°C, and 90°C. The hydrolysis was found to be pH dependent and followed Arrhenius equation. The half-life of codrug and IBP 2-hydroxyethyl ester at 25°C in pH 7.4 was 218 days and 3 years, respectively. In vitro enzymatic hydrolysis of codrug and IBP 2-hydroxyethyl ester was studied in human plasma and rat liver homogenate. Codrug and IBP 2-hydroxyethyl ester exhibited faster in vitro enzymatic hydrolysis than in vitro chemical hydrolysis. The pseudo-first-order rate constants were 0.0113, 0.177?min^?1 for codrug and 0.0006, 0.0569?min^?1 for IBP 2-hydroxyethyl ester in human plasma and rat liver homogenate, respectively. Thus, nicotinic acid will be rapidly released from codrug to manage dyslipidemia, followed by the later release of IBP from IBP 2-hydroxyethyl ester to alleviate nicotinic acid cutaneous flushing.     

Development of a sustained release dosage form for alpha-lipoic acid. I. Design and in vitro evaluation

The purpose of this study was the design and evaluation of a sustained release dosage form for the oral administration of alpha-lipoic acid. The cationic polymer chitosan was used in order to provide a controlled drug release based on ionic interactions with the anionic drug. The effect of such ionic interactions on the release of alpha-lipoic acid could be verified by diffusion studies. In vitro release studies with tablets (diameter: 10.0 mm; thickness: approximately 4 mm) containing 80% alpha-lipoic acid and 20% chitosan acetate showed a controlled drug release over a time period of 24 h. Raising the ratio of chitosan acetate in such delivery systems led to an even stronger retardation of drug release. In addition, permeation studies carried out in Ussing-type chambers with freshly excised intestinal mucosa from guinea pigs demonstrated no significant (p < 0.05) influence of the degree of drug ionization on its absorption behavior. The apparent permeability coefficient (Papp) for alpha-lipoic acid was determined to be 1.39 +/- 0.28 x 10(-5) cm/sec at pH 6.4 (means +/- SD). The use of a sustained delivery system for alpha-lipoic acid, which is based on ionic interactions, should therefore have no influence on the absorption behavior of the drug. The sustained release dosage forms described here might provide a constant plasma level of the drug being highly beneficial for various therapeutic reasons.     

P-glycoprotein inhibitors: synthesis and in vitro evaluation of a preactivated thiomer

Abstract

The aim of this study was to synthesize the preactivated thiomer poly(acrylic acid)-cyteine-2-mercaptonicotinic acid (PAA-Cys-2MNA) and to evaluate its P-glycoprotein (P-gp) inhibitory properties. The thiomer (PAA-Cys) was synthesized by covalent immobilization of thiol groups on poly(acrylic acid) (PAA) with a molecular mass of 250?kDa followed by immobilization of 2-mercaptonicotinic acid (2MNA) to thiol groups via disulfide bond formation resulting in PAA-Cys-2MNA. P-gp inhibitory effect of this preactivated thiomer was evaluated on Caco-2 cells. Transports of rhodamine 123 at 37?°C with and without verapamil and at 4?°C were performed to evaluate P-gp function of cells. In total, 1571.81?±?156.18?µmol thiol groups were immobilized per gram of polymer that were in the next step by 99.88% preactivated. The enhancement ratios of P_app calculated from the ratio between P_app of rhodamine 123 in the presence of P-gp inhibitors and P_app of rhodamine 123 alone were 2.36, 2.09, and 1.84-fold in the presence of PAA-Cys-2MNA, PAA-Cys, and PAA, respectively. Because of its pronounced P-gp inhibitory effect, PAA-Cys-2MNA could be considered as promising macromolecular P-gp inhibitor for various drug delivery systems.     

The aesthetics of water and land: a promising concept for managing scarce water resources under climate change

The eastern Mediterranean faces a severe water crisis: water supply decreases due to climate change, while demand increases due to rapid population growth. The GLOWA Jordan River project generates science-based management strategies for maximizing water productivity under global climate change. We use a novel definition of water productivity as the full range of services provided by landscapes per unit blue (surface) and green (in plants and soil) water. Our combined results from climatological, ecological, economic and hydrological studies suggest that, in Israel, certain landscapes provide high returns as ecosystem services for little input of additional blue water. Specifically, cultural services such as recreation may by far exceed that of food production. Interestingly, some highly valued landscapes (e.g. rangeland) appear resistant to climate change, making them an ideal candidate for adaptive land management. Vice versa, expanding irrigated agriculture is unlikely to be sustainable under global climate change. We advocate the inclusion of a large range of ecosystem services into integrated land and water resources management. The focus on cultural services and integration of irrigation demand will lead to entirely different but productive water and land allocation schemes that may be suitable for withstanding the problems caused by climate change.     

Alginate hydrogel as a promising scaffold for dental-derived stem cells: an in vitro study

The objectives of this study were to: (1) develop an injectable and biodegradable scaffold based on oxidized alginate microbeads encapsulating periodontal ligament (PDLSCs) and gingival mesenchymal stem cells (GMSCs); and (2) investigate the stem cell viability, and osteogenic differentiation of the stem cells in vitro. Stem cells were encapsulated using alginate hydrogel. The stem cell viability, proliferation and differentiation to adipogenic and osteogenic tissues were studied. To investigate the expression of both adipogenesis and ontogenesis related genes, the RNA was extracted and RT-PCR was performed. The degradation behavior of hydrogel based on oxidized sodium alginate with different degrees of oxidation was studied in PBS at 37?°C as a function of time by monitoring the changes in weight loss. The swelling kinetics of alginate hydrogel was also investigated. The results showed that alginate is a promising candidate as a non-toxic scaffold for PDLSCs and GMSCs. It also has the ability to direct the differentiation of these stem cells to osteogenic and adipogenic tissues as compared to the control group in vitro. The encapsulated stem cells remained viable in vitro and both osteo-differentiated and adipo-differentiated after 4?weeks of culturing in the induction media. It was found that the degradation profile and swelling kinetics of alginate hydrogel strongly depends on the degree of oxidation showing its tunable chemistry and degradation rate. These findings demonstrate for the first time that immobilization of PDLSCs and GMSCs in the alginate microspheres provides a promising strategy for bone tissue engineering.     

聚环氧琥珀酸合成及阻垢率测量方法改进

聚环氧琥珀酸(PESA)是一种国际上公认的绿色阻垢剂。重点分析了反应体系pH值、温度和时间等PESA合成过程中的主要工艺参数对产品阻垢性能的影响。实验结果表明,环氧化过程pH值对中间体产率影响显著,聚合反应过程中体系的温度和反应时间存在关联性。将镁离子与铬黑T作为复合指示剂来指示阻垢率测量终点颜色变化,使滴定终点从紫红色到蓝色的跃迁明显,提高了滴定终点敏锐度。此方法具有较高的精密度和准确度,测定相对标准偏差RSD%<1%,加标回收率在99.5%～100.5%之间。采用此方法对中试样品进行检测,在用量为2.0×10-5的情况下,其10h阻垢性能均在95%以上。     

Comparison of D.C. and A.C. techniques for the evaluation of inhibitor efficiency in acid corrosion

Five different techniques (analytical determination of dissolved iron, Tafel line extrapolation, linear polarization method, impedance and Faradaic distortion measurements) were used for the evaluation of the inhibiting efficiency of N-decyl-3-hydroxypyridine bromide in 1 M hydrochloric acid solutions. The results obtained with the different methods were found to agree satisfactorily. High inhibiting efficiency value was obtained at 1× 10^?4Mdm^?3 concentration.     

Directly compressed mini matrix tablets containing ibuprofen: preparation and evaluation of sustained release

Directly compressed mini tablets were produced containing either hydroxypropylmethylcellulose (HPMC) or ethylcellulose (EC) as release controlling agent. The dynamics of water uptake and erosion degree of polymer were investigated. By changing the polymer concentration, the ibuprofen release was modified. In identical quantities, EC produced a greater sustaining release effect than HPMC. Different grades of viscosity of HPMC did not modify ibuprofen release. For EC formulations, the contribution of diffusion was predominant in the ibuprofen release process. For HPMC preparations, the drug release approached zero-order during a period of 8 h. For comparative purposes, tablets with 10 mm diameter were produced.     

Preparation, characterization, and evaluation of liposomal ferulic acid in vitro and in vivo

In the present study, various gradients were evaluated for efficient loading of weak acid into liposomes. Several salt gradients showed efficient loading of ferulic acid (FA) into liposomes and the optimized conditions were established in calcium acetate gradient method to obtain 80.2 +/- 5.2% entrapment efficiency (EE). Unilamellar vesicles were observed in micrographs and liposomal FA showed good stability. 80% of FA was released from liposomes within 5 h in vitro. There is a novel finding in this study: that drugs could be entrapped with a high solubility in the intraliposomal buffer in contrast to the low solubility in the extraliposomal buffer. The results of body distribution in rats indicated that liposomes could improve the body distribution of FA. For FA liposome, the concentration of FA in brain was two-fold higher than that of free FA. Liposomal FA was a promising approach to improve the body distribution of FA.     

Characterization and in vitro evaluation of an acid resistant nanosized dental eggshell-titanium dioxide material

This paper reports on novel nanosized acid resistant material base on the modification of eggshell powder and titanium dioxide (TiO₂-EB) for enamel remineralization. The TiO₂-EB was prepared by ball milling eggshell powder and titanium dioxide. Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Scanning Electron Microscope (SEM), Transmission Electron Microscopy (TEM), and ImageJ were used to characterise TiO₂-EB. A computation model using Material Studio Software was used to explain the mechanism of TiO₂-EB interaction. In addition, the acid resistant of TiO₂-EB was evaluated by comparison using three commercial toothpaste. The mean pressure value (kPa/s) was measured using a pressure sensor. The FTIR, XRD analysis confirmed the surface modification of TiO₂-EB. The SEM image revealed that pure TiO₂ particles are spread on the surface of eggshell powder. The TEM image revealed spherical particles in TiO₂-EB. The ImageJ showed the average particle size of TiO₂-EB to be 13 nm. In addition, the commercial toothpastes doped with TiO₂-EB showed an improved acid resistant. The salient features of this study indicate that TiO₂-EB will effectively remineralized enamel lesions while offering better protective covering to the enamel.     

Processing of ultrasonic array signals for characterizing defects. Part I: signal synthesis

This work presents a novel procedure to characterize damage using an array of ultrasonic measurements in a generalized model-based inversion scheme, which integrates the complete information recorded from the measurements. In the past, we proposed some idealized nondestructive evaluation test methods with emphasis on the numerical results, but it is necessary to develop the techniques in greater detail in order to apply the techniques to real conditions. Our detection principle is based on the measurement and inversion of frequency-domain data combined with a reduced set of output parameters. The approach is developed and tested for the case of an aluminum specimen with a synthetic array of point contact ultrasonic transmitters and receivers. The first part of this two-part paper is focused on numerical synthesis of the experimental measurements using the boundary element method for a general ultrasonic propagation model. This part also deals with the deconvolution by comparing the data measured from the damaged and undamaged specimens. The deconvolution technique allows us to calibrate the data by taking into account the uncertainties due to mechanical properties, input signal, and other coherent noise. The second part of the paper presents the inversion of the measurements to obtain the parameters and ultimately to predict the position and size of the real defect.     

A novel mixed polymeric micelle for co-delivery of paclitaxel and retinoic acid and overcoming multidrug resistance: synthesis,characterization, cytotoxicity,and pharmacokinetic evaluation

In the current study, retinoic acid (RA) was conjugated to Pluronic F127 (PF127) through an esterification process. Mixed micelles were formed with tocopheryl polyethylene glycol 1000 (TPGS) for co-delivery of paclitaxel (PTX) and RA to the cancer cells. Mixed micelles of RA-PF127 and TPGS in different weight ratios (10:0, 7:3, 5:5, 3:7, 0:10 w/w) were prepared and physicochemical properties including, particle size, zeta potential, critical micelle concentration (CMC), drug loading content, entrapment efficiency, drug release, cellular uptake and in vitro cytotoxicity, were investigated in details. Furthermore, the pharmacokinetics of PTX-loaded optimized mixed micelles were evaluated in Sprague-Dawley rats and compared with Stragen^® (PTX in Cremophor EL^®). Particle sizes and zeta potentials of the drug-loaded micelles were in the range of 102.6–223.5?nm and ?5.3 to ?9.6?mV, respectively. The 7:3 and 5:5 micellar combinations had lower CMC values (0.034–0.042?mg/mL) than 0:10 (0.124?mg/mL). The entrapment efficiencies of 10:0, 7:3, and 5:5 were 53.4?±?9.3%, 61.3?±?0.5%, and 78.7?±?1.66%, respectively. The release rates of PTX from 7:3 and 5:5 mixed micelles were significantly slower than other formulations. Cytotoxicity assay demonstrated increased cytotoxic activity of PTX-loaded mixed micelles compared to free PTX. The V_d and t_1/2ß of PTX-loaded RA-PF127/TPGS (7:3) were increased by 2.61- and 1.27-fold, respectively, while the plasma area under the curve (AUC) of the micelles was 2.03-fold lower than those of Stragen^®. Therefore, these novel mixed micelles could be effectively used for delivery of PTX and RA to the cancer cells. Moreover, TPGS as part of micelle composition could enhance the therapeutic effect of PTX and reduce side effects.     

Graphene: A promising candidate for charge regulation in high-performance lithium-ion batteries

The development of rechargeable lithium-ion batteries (LIBs) is being driven by the ever-increasing demand for high energy density and excellent rate performance. Charge transfer kinetics and polarization theory, considered as basic principles for charge regulation in the LIBs, indicate that the rapid transfer of both electrons and ions is vital to the electrochemical reaction process. Graphene, a promising candidate for charge regulation in high-performance LIBs, has received extensive investigations due to its excellent carrier mobility, large specific surface area and structure tunability, etc. Recent progresses on the structural design and interfacial modification of graphene to regulate the charge transport in LIBs have been summarized. Besides, the structure-performance relationships between the structure of the graphene and its dedicated applications for LIBs have also been clarified in detail. Taking graphene as a typical example to explore the mechanism of charge regulation will outline ways to further understand and improve carbon-based nanomaterials towards the next generation of electrochemical energy storage devices.

     

Ocular drug metabolism of the bioactivating antioxidant N-acetylcarnosine for vision in ophthalmic prodrug and codrug design and delivery

The basic idea in this study relates to the interesting research problem to employ with the knowledgeable pharmacy staff N-acetylcarnosine (NAC) in the developed suitable compounded prodrug ophthalmic preparations, which are currently used for the treatment of cataract and have antioxidant effect, in order to provide the molecular support to one of the most popular beliefs of the growing market for the treatment of senile cataract in patients and animals with efficacious NAC drug formulations worldwide patented by the author. This work presents the progress in ocular NAC prodrug and codrug design and delivery in light of revealed ocular metabolic activities. There is a considerable interest in the ophthalmic codrug design including NAC prodrug based on the strategies to improve ophthalmic drug delivery of the active peptide principal L-carnosine through the sustained intraocular metabolic activation of a dipeptide while making it resistant to enzymatic hydrolysis. Novel approaches to ocular NAC drug delivery, developed by Innovative Vision Products, Inc. (IVP), aim at enhancing the drug bioavailability by ensuring a prolonged retention of the medication in the eye, and/or by facilitating transcorneal penetration. IVP team studied the effects of lubricant eye drops designed as 1% NAC prodrug of L-carnosine containing a mucoadhesive cellulose-based and corneal absorption promoters in a drug delivery system. The predicted responses of the corneal and conjunctival penetrations to the synergistic promoters are useful in controlling the extent and pathway of the ocular and systemic absorptions of instilled NAC prodrug in designed ophthalmic formulations thereof. Utility of peptidase enzyme inhibitors in the codrug formulation to modulate the transport and metabolism of NAC prodrug appears to be a promising strategy for enhancing dipeptide drug transport across the cornea. The developed and officially CE mark registered by IVP NAC prodrug and codrug lubricating eye drop systems (including principal regulatory registered eye drops design and lubricating eye drops marketed under numerous brand labels), increase the intraocular uptake of the active principle L-carnosine from its ophthalmic carrier NAC in the aqueous humor and the permeability of a drug into the eye, and so enhance the ocular bioavailability, bioactivating universal antioxidant, and anti-cataract efficacy (in human and in canine eyes) of the developed NAC eye drops.     

In vitro evaluation of spray-dried mucoadhesive micropheres for nasal administration.

Microspheres of disodium cromoglycate (DSCG) were prepared with either polyacrylic acid (Carbopol 934) or sodium carboxymethylcellulose (NaCMC) by the spray-drying technique. The arithmetic mean diameter of the spraydried particles ranged from 3.2 to 5.7 microns. The plain DSCG particles and the microspheres containing NaCMC were spherical and had a smooth surface, whereas the microspheres containing Carbopol 934 were more irregular and partly shrunken. The dissolution rate of the plain DSCG was prolonged when the drug was incorporated with the polymers. The more polymer the microspheres contained the slower the drug release rate. The in vitro mucoadhesion test showed that the plain DSCG was nearly as mucoadhesive as the the plain polymers. The microspheres of DSCG with either of the polymers were, however, clearly more mucoadhesive than the plain starting materials. The adsorption isotherms showed the hygroscopic nature of the polymers and DSCG. The hydration of the microspheres increased as a function of the drug content.     

Combustion synthesis of advanced materials: Part I. Reaction parameters

An explanation of combustion (self propagating high temperature) synthesis (SHS) is given together with a historical perspective of the examination of such exothermic reactions. The application of thermochemical functions has been used to predict theoretically the maximum adiabatic temperature, T_ad. This, combined with a knowledge of the ignition temperature, T_ig, and the actual combustion temperature, T_c, has been used to determine the heat loss from the SHS reaction and the amount of heat needed to raise the adjacent, cold, reactant layer to the ignition temperature in order to maintain the self sustaining nature of the propagating mode of the reaction. The pertinent reaction parameters that control self propagating high temperature (combustion) synthesis reactions have been examined. These include: reactant particle size and shape; powder mixing and compaction; green density; reaction stoichiometry; impurities; volatiles and diluents; reaction environment; mode and technique of ignition; heating rate; and the effect of these parameters on the generation of heat, exothermicity and control of the SHS reaction.     

Thermooptical processes in mirror-lens objectives. I. Scheme for synthesis of a thermostable telescope

Special features of the designing of a thermostable telescope are discussed on the example of the objective for the narrow-angle television camera of the Vega spacecraft.Translated from Inzhenerno-Fizicheskii Zhurnal, Vol. 52, No. 5, pp. 827–833, May, 1987.     

Microemulsions as vehicles for topical administration of voriconazole: formulation and in vitro evaluation

This work was undertaken to investigate microemulsion (ME) as a topical delivery system for the poorly water-soluble voriconazole. Different ME components were selected for the preparation of plain ME systems with suitable rheological properties for topical use. Two permeation enhancers were incorporated, namely sodium deoxycholate or oleic acid. Drug-loaded MEs were evaluated for their physical appearance, pH, rheological properties and in vitro permeation studies using guinea pig skin. MEs based on polyoxyethylene(10)oleyl ether (Brij 97) as the surfactant showed pseudoplastic flow with thixotropic behavior and were loaded with voriconazole. Jojoba oil-based MEs successfully prolonged voriconazole release up to 4?h. No significant changes in physical or rheological properties were recorded on storage for 12 months at ambient conditions. The presence of permeation enhancers favored transdermal rather than dermal delivery. Sodium deoxycholate was more effective than oleic acid for enhancing the voriconazole permeation. Voriconazole-loaded MEs, with and without enhancers, showed significantly better antifungal activity against Candida albicans than voriconazole supersaturated solution. In conclusion, the studied ME formulae could be promising vehicles for topical delivery of voriconazole.     

A comprehensive design and rating study of evaporative coolers and condensers. Part I. Performance evaluation

The mathematical models of evaporative fluid coolers and evaporative condensers are studied in detail to perform a comprehensive design and rating analysis. The mathematical models are validated using experimental as well as numerical data reported in the literature. These models are integrated with the fouling model presented in an earlier paper, using the experimental data on tube fouling. In this paper, we use the fouling model to investigate the risk based thermal performance of these evaporative heat exchangers. It is demonstrated that thermal effectiveness of the evaporative heat exchangers degrades significantly with time indicating that, for a low risk level (p=0.01), there is about 66.7% decrease in effectiveness for the given fouling model. Furthermore, it is noted that there is about 4.7% increase in outlet process fluid temperature of the evaporative fluid cooler. Also, a parametric study is performed to evaluate the effect of elevation and mass flow rate ratio on typical performance parameters such as effectiveness for rating calculations while surface area for design calculations.     

Lonidamine solid dispersions: in vitro and in vivo evaluation

Solid dispersions of lonidamine in PEG 4000 and PVP K 29/32 were prepared by the spray-drying method. Then, the binary systems were studied and characterized using differential scanning calorimetry, hot stage microscopy, and x-ray diffractometry. In vitro dissolution studies of the solid dispersed powders were performed to verify if any lonidamine dissolution rate or water solubility improvement occurred. In vivo tests were carried out on the solid dispersions and on the cyclodextrin inclusion complexes to verify if this lonidamine water solubility increase was really able to improve the in vivo drug plasma levels. Drug water solubility was increased by the solid dispersion formation, and the extent of increase depended on the polymer content of the powder. The greater increase of solubility corresponded to the highest content of polymer. Both the solid dispersions and the cyclodextrin complexes were able to improve the in vivo bioavailability of the lonidamine when administered per os. Particularly, the AUC of the drug plasma levels was increased from 1.5 to 1.9-fold depending on the type of carrier.