Characterization of Mefenamic Acid-Guaiacol Ester: Stability and Transport Across Caco-2 Cell Monolayers

Purpose. Prodrug of non-steroidal anti-inflammatory drugs (NSAIDs) or NSAIDs linked with guaiacol have been reported to suppress gastrointestinal (GI) toxicity or induce GI protective effect. In this study, mefenamic-guaiacol ester was synthesized and its physicochemical properties, stability, and transport across Caco-2 monolayers were investigated. Methods. Synthesis of the ester was carried out using mefenamic acid, guaiacol, N, N-dimethylaminopyridine, and N, Ndicyclohexylcarbodiimide. The hydrolysis of the ester was investigated in aqueous buffer solutions pH 1-12 as well as in Caco-2 homogenate, human plasma, and porcine liver esterase. Caco-2 cell monolayers were utilized for transport studies. Due to the high lipophilicity of the ester with a calculated logP of 6.15, bovine serum albumin (BSA, 4%) was included in the receiver compartment to obtain a good in vitro-in vivo correlation. Permeation of the ester was assessed with or without the exposure of cells to PMSF, an inhibitor of esterase. Results. The ester was stable at a wide pH range from 1-10. However, it was hydrolyzed by enzymes from porcine liver esterase and Caco-2 homogenate. With the PMSF exposure on the apical (AP) side and in the presence of 4% BSA on the basolateral (BL) side, the transported amount of the ester from AP-to-BL direction was 14.63% after 3 hr with a lag time of 23 min. The Papp for the ester was 4.72 × 10^-6 cm s^-1. Conclusion. The results from hydrolysis studies indicate that this ester is a prodrug. The Papp value suggests the moderate absorption characteristic of the compound. The accumulation of this highly lipophilic ester in Caco-2 cells is reduced in the presence of BSA.     

Development of a reservoir-type transdermal enantioselective-controlled delivery system for racemic propranolol using a molecularly imprinted polymer composite membrane

The aims of this study were to develop a transdermal patch for selective controlled delivery of the active S-enantiomer from racemic propranolol, and to evaluate its performance in vivo using Wistar rats. A molecularly imprinted polymer (MIP) thin-layer composited cellulose membrane with selectivity for S-propranolol was employed as the enantioselective-controlled release system. The effect of gel reservoir (poloxamer and chitosan) on enantioselective delivery was investigated. The chitosan gel allowed excellent selectivity for delivery of the S-propranolol enantiomer, whilst the more rheologically structured poloxamer gel formulation provided no selective release of S-propranolol. The chitosan gel exhibited high flux and had the ability to enantioselective deliver S-propranolol across excised rat skin. The results from confocal laser scanning microscopy study, carried out with the R- and S-propranolol enantiomers labeled with a 1-pyrenebutyric acid probe as fluorescent markers, suggested that the MIP composite membrane selectively regulated the release of the recognised S-enantiomer via a facilitated transport pathway through complex formation with the selective receptor sites, while the release of the R-enantiomer was via a non-selective route. The reservoir patch for enantiomer-controlled delivery of propranolol was therefore fabricated by incorporating the chitosan gel formulation containing racemic propranolol hydrochloride into the MIP composite membrane laminated backing. These patch devices were shown to exhibit the significant stereoselectivity uptake of propranolol when attached to the skin, using pharmacokinetic studies in rats. S-Propranolol enantiomer plasma concentration profiles for the transdermal patch in the in vivo study were comparable to data for the gel formulations that were applied directly to skin, and containing a single S-enantiomer of propranolol. The results demonstrate that the transdermal patch based on the MIP composite membrane-controlled release system may have potential in the enantioselective-controlled delivery of the S-isomer of racemic propranolol.     

Imogolite Reinforced Nanocomposites: Multifaceted Green Materials

This paper presents an overview on recent developments of imogolite reinforced nanocomposites, including fundamental structure, synthesis/purification of imogolite, physicochemical properties of nanocomposites and potential applications in industry. The naturally derived nanotubular material of imogolite represents a distinctive class of nanofiller for industrially significant polymer. The incompatibility between the surface properties of inorganic nanofiller and organic matrix has prompted the need to surface modify the imogolite. Early problems in increasing the binding properties of surface modifier to imogolite have been overcome by using a phosphonic acid group. Different approaches have been used to gain better control over the dispersal of nanofiller and to further improve the physicochemical properties of nanocomposites. Among these, polymer grafting, in situ synthesis of imogolite in polymer matrix, and spin-assembly are some of the promising methods that will be described herein. This imogolite reinforced nanocomposite of enhanced optical and mechanical properties, and with unique biological and electronic properties, is expected to become an important category of hybrid material that shows potential for industrial applications.     

Properties of solid dispersions of piroxicam in polyvinylpyrrolidone.

Solid dispersions of piroxicam were prepared with polyvinylpyrrolidone (PVP) K-17 PF and PVP K-90 by solvent method. The physical state and drug:PVP interaction of solid dispersions and physical mixtures were characterized by X-ray diffraction, Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). FTIR analysis demonstrated the presence of intermolecular hydrogen bonding between piroxicam and PVP in solid dispersions. These interactions reflected the changes in crystalline structures of piroxicam. The amorphousness within the PVP moeity might be predicted in piroxicam dispersions by the disappearance of N-H or O-H peak of piroxicam. Dissolution studies indicated a significant increase in dissolution of piroxicam when dispersed in PVP. The better results were obtained with the lower molecular weight PVP K-17 than with higher molecular weight PVP K-90. The non-amorphous solid dispersions in PVP K-17 showed almost equally fast dissolution rates to amorphous dispersions in PVP K-90. The mechanism of dissolution of solid dispersion in PVP K-90 is predominantly diffusion-controlled due to the very high viscosity of PVP K-90. Dissolution was maximum with the amorphous solid dispersions containing drug:PVP K-17 1:5 and 1:6 which showed a 40-fold increase in dissolution in 5 min as compared with pure drug. Copyright     

Studies on aging piroxicam-polyvinylpyrrolidone solid dispersions

The stabilities of X-ray amorphous solid dispersions of piroxicam and polyvinylpyrrolidone (PVP) K-17 and PVP K-30 (1:5 and 1:4), respectively, were investigated after storage for 12 months. X-ray diffraction showed that in the aged solid dispersions piroxicam remained in the amorphous state. Fourier transform infrared (FTIR) spectroscopy indicated that the interactions between drug and PVP in aged solid dispersions are similar to those in freshly prepared samples. The dissolution rates of the X-ray amorphous solid dispersions during storage for 12 months at 45 degrees C and ambient temperature were examined. Very minor decreases in dissolution rates of aged solid dispersions were found which might be due to the coarsening of the particles. Dissolutions of these amorphous solid dispersions after aging for 12 months still showed an about 40-fold increase in dissolution in 5 min compared to pure drug.     

Priority-setting for achieving universal health coverage

Governments in low- and middle-income countries are legitimizing the implementation of universal health coverage (UHC), following a United Nation’s resolution on UHC in 2012 and its reinforcement in the sustainable development goals set in 2015. UHC will differ in each country depending on country contexts and needs, as well as demand and supply in health care. Therefore, fundamental issues such as objectives, users and cost–effectiveness of UHC have been raised by policy-makers and stakeholders. While priority-setting is done on a daily basis by health authorities – implicitly or explicitly – it has not been made clear how priority-setting for UHC should be conducted. We provide justification for explicit health priority-setting and guidance to countries on how to set priorities for UHC.     

Topical anti-inflammatory and analgesic activities of standardized pomegranate rind extract in comparison with its marker compound ellagic acid in vivo

Ethnopharmacological relevance

In Chinese traditional medicine, the peels of Punica granatum L. have been used to treat traumatic hemorrhage, burn, and ulcers.

Aims of the study

This study aimed to assess the topical anti-inflammatory and analgesic activities of a standardized pomegranate rind extract (SPRE) of which ellagic acid (EA) was the major antioxidant constituent and the marker compound.

Material and methods

The topical anti-inflammatory effects of SPRE were evaluated against acute models (croton oil-induced mouse ear edema and carrageenan-induced rat paw edema) and chronic model (complete Freund's adjuvant (CFA)-induced polyarthritis). The topical analgesic activities of SPRE were investigated in the rat punctuate mechanical hyperalgesia test and in the mouse formalin test. All studies of SPRE were carried out in parallel with its marker compound EA.

Results

SPRE (5%, 2.5%, and 1%, w/w) and the equivalent EA (0.65%, 0.325%, and 0.13%, w/w) dose-dependently reduced the croton oil-induced mouse ear edema with a maximal inhibition of 86.30% and 80.82%, respectively. SPRE dose-dependently attenuated the inflammatory responses in the carrageenan-induced rat paw edema and in the CFA-induced polyarthritis but the equivalent EA were effective only at the doses of 0.65% and 0.325%. Both SPRE (5%) and EA (0.65%) showed significant topical analgesic activities in the rat punctuate mechanical hyperalgesia test and in the mouse formalin test.

Conclusions

SPRE was more active as an anti-inflammatory agent than EA. The anti-inflammatory and analgesic effects of SPRE were achieved through inhibiting the leukocyte infiltration and modulating the pro-inflammatory cytokines IL-β and TNF-α. These results clearly demonstrated that SPRE is a promising phytomedicine that could find use in the treatment of inflammatory diseases.     

Effect of single-session dual-tDCS before physical therapy on lower-limb performance in sub-acute stroke patients: A randomized sham-controlled crossover study

Anodal stimulation increases cortical excitably, whereas cathodal stimulation decreases cortical excitability. Dual transcranial direct current stimulation (tDCS; anodal over the lesioned hemisphere, cathodal over the non-lesioned hemisphere) was found to enhance motor learning. The corresponding tDCS-induced changes were reported to reduce the inhibition exerted by the unaffected hemisphere on the affected hemisphere and restore the normal balance of the interhemispheric inhibition. Most studies were devoted to the possible modification of upper-limb motor function after tDCS; however, almost no study has demonstrated its effects on lower-limb function and gait, which are also commonly disordered in stroke patients with motor deficits. In this randomized sham-controlled crossover study, we included 19 patients with sub-acute stroke. Participants were randomly allocated to receive real or sham dual-tDCS followed by conventional physical therapy with an intervention interval of at least 1 week. Dual-tDCS was applied over the lower-limb M1 at 2-mA intensity for 20 min. Lower-limb performance was assessed by the Timed Up and Go (TUG) and Five-Times-Sit-To-Stand (FTSTS) tests and muscle strength was assessed by peak knee torque of extension. We found a significant increase in time to perform the FTSST for the real group, with improvements significantly greater than for the sham group; the TUG score was significantly increased but not higher than for the sham group. An after-effect on FTSTS was found at approximately 1 week after the real intervention. Muscle strength was unchanged in both limbs for both real and sham groups. Our results suggest that a single session of dual-tDCS before conventional physical therapy could improve sit-to-stand performance, which appeared to be improved over conventional physical therapy alone. However, strength performance was not increased after the combination treatment.     

Composite membrane of bacterially-derived cellulose and molecularly imprinted polymer for use as a transdermal enantioselective controlled-release system of racemic propranolol.

A composite membrane for transdermal delivery of S-propranolol enantiomer was developed based on the controlled pore functionalization of bacterial cellulose membranes using a molecularly imprinted polymer (MIP) layer synthesis. The reactive pore-filling of an asymmetric porous cellulose membrane with a MIP thin-layer was effected using a silanized coupler as an additional anchor for the MIP. MIP thin-layers with specific binding sites for S-propranolol were synthesized by copolymerization of methacrylic acid with a cross-linker, ethylene glycol dimethacrylate in the presence of S-propranolol as the template molecule and the latter was subsequently extracted. Selective transport of S-propranolol through the MIP composite membrane was obtained, although this was determined mostly by the parent cellulose membrane with some ancillary contributory effect from the MIP layer. In addition, an enantioselectivity in the transport of propranolol prodrug enantiomers was found, suggesting that the shape and functional groups orientation, which are similar to that of the print molecule were essential for enantiomeric recognition of the MIP composite membrane. The enantioselectivity of S-MIP membranes was also shown when the release of propranolol enantiomers was studied in vitro using rat skin, with racemic propranolol contained in the donor compartment. The composite membrane of bacterially-derived cellulose and molecularly imprinted polymer may have great potential for use as a transdermal enantioselective controlled-release system for racemic propranolol.