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.     

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.     

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.     

Effects of glucam P-20, vanillin, and fixolide on mosquito repellency of citronella oil lotions

The objective of this study was to investigate the effects of three fragrance fixatives, Glucam P-20, Vanillin, and Fixolide, on the mosquito repellent property of citronella oil lotions. In the current study, two formulae (A and B) of oil-in-water citronella oil lotions were formulated using different ingredients (emulsifiers [Cremophors or Emulwax], stiffening agents, and emollients). Citronella oil was used at 10% wt:wt. The weight ratios tested between citronella oil and each fixative were 1:0.25, 1:0.5, and 1:1. Overall, 20 formulations, including one with no fixatives for both A and B, were produced, A1-A10 and B1-B10. The repellent activities of these 20 lotions against Aedes aegypti (L.) were tested using a human-bait technique. The types and concentrations of fixatives as well as the compositions of the formulations did affect the protection time of the citronella oil lotions. The lotion containing Emulwax and 5% vanillin (B6) was the most effective repellent. It provided the longest protection time of 4.8 h, which exceeded the minimum requirement of 2 h set by the National Institute of Health, Thailand. The shortest protection time (1 h) was observed in the lotion containing Emulwax and 2.5% Glucam P-20 (B2). It could be concluded that the tested fixatives affected the repellent activity of the citronella oil lotions.     

Thyroid hormone increases mRNA and protein expression of Na+-K+-ATPase alpha2 and beta1 subunits in human skeletal muscles

CONTEXT: Thyroid hormone regulates specific Na+-K+-ATPase isoforms in rodent skeletal muscles. No study has examined this relationship in human tissues. OBJECTIVE: This study investigated the effect of hyperthyroid status on the expression of the alpha- and beta-subunits of the Na+-K+-ATPase. DESIGN: The vastus lateralis muscles from eight hyperthyroid patients were biopsied before and after treatment. Ten age-matched euthyroid subjects served as controls. RESULTS: In hyperthyroid patients, the average T3 level was three times higher in pretreatment compared with posttreatment (262 +/- 75 vs. 86 +/- 21 ng/dl, P = 0.001). The relative mRNA expression of the alpha2, but not alpha1 or alpha3, subunit was increased approximately 3-fold in pretreatment (2.98 +/- 0.52 vs. 0.95 +/- 0.40, P < 0.01), whereas that of beta1, not beta2 or beta3, subunit was increased approximately 2.8-fold in pretreatment (2.83 +/- 0.38 vs. 1.10 +/- 0.27, P < 0.01). The relative mRNA expression of the alpha2 and beta1 subunits was positively correlated with the serum T3 (r = 0.75, P = 0.001 and r = 0.66, P = 0.003, respectively). Immunohistochemistry studies revealed an increase in protein abundance of the alpha2 and beta1, but not alpha1 or beta2, subunits in the plasma membrane of muscle fibers of hyperthyroid patients, which decreased after treatment. CONCLUSIONS: This provides the first evidence that, in human skeletal muscles, thyroid hormone up-regulates the Na+-K+-ATPase protein expression at least, in part, at mRNA level, and the alpha2 and beta1 subunits play the important role in this regulation.     

Wound healing activities of standardized pomegranate rind extract and its major antioxidant ellagic acid in rat dermal wounds

The in vivo wound healing potential of a standardized pomegranate rind extract (SPRE) and its major antioxidant constituent, ellagic acid (EA, 13 %, w/w), were investigated in three rat dermal wound models. It was found that both SPRE (5 and 2.5 %) and its equivalent amount of EA (0.65 and 0.325 %) increased the tensile strength of the incision wound by a maximum of 35.43 and 31.82 %, respectively. SPRE at 5 and 2.5 % accelerated wound contraction of the excision wound and the burn wound, while EA was effective only at 0.65 % in these two wound models. Further assays revealed that SPRE enhanced the synthesis of collagen by a maximum of 21.83 mg/g and inhibited neutrophil infiltration dose-dependently, while EA was not effective in increasing collagen accumulation and its inhibitory effect on neutrophil infiltration was milder. These results indicated that SPRE is a promising phytopharmaceutical effective in facilitating the healing of wounds and is superior to its marker compound EA.     

Topical Anti‐inflammatory Potential of Standardized Pomegranate Rind Extract and Ellagic Acid in Contact Dermatitis

The present study evaluated the topical anti‐inflammatory potential of a standardized pomegranate rind extracts (SPRE) in parallel with its marker compound ellagic acid (EA, 13% w/w) against a mouse model of contact dermatitis. In the phenol‐induced mouse ear edema, topical application of SPRE (5, 2.5, and 1 mg/ear) and EA (0.65, 0.325, and 0.13 mg/ear, equivalent to its content in SPRE) dose‐dependently reduced the ear edema with the maximal inhibition of 79.12% and 73.63%, respectively. Triamcinolone (0.1 mg/ear) and diclofenac (1 mg/ear) as reference drugs inhibited the edema by 73.63% and 37.91%. Myeloperoxidase (MPO) activity in the mouse ear was also decreased by SPRE and EA up to 69.68% and 68.79%, respectively. Triamcinolone and diclofenac decreased the MPO activity by 76.66% and 80.14% similarly. The results indicated that topical application of SPRE and EA is promising for use in the treatment of inflammatory skin disorders. Copyright © 2013 John Wiley & Sons, Ltd.