Discovery of phthalimide derivatives as novel inhibitors of a soluble epoxide hydrolase

Soluble epoxide hydrolase (sEH) inhibitors are effective in reducing blood pressure, inflammation, and pain in a number of mammalian disease models. As most classical urea-based sEH inhibitors suffer from poor solubility and pharmacokinetic properties, the development of novel sEH inhibitors with an improved pharmacokinetic specification has received a great deal of attention. In this study, a series of amide-based sEH inhibitors bearing a phthalimide ring as the novel secondary pharmacophore (P₂) was designed, synthesized, and evaluated. Docking results illustrated that the amide group as the primary pharmacophore (P₁) was placed at a suitable distance from the three key amino acids (Tyr383, Tyr466, and Asp335) for an effective hydrogen bonding. In agreement with these findings, most of the newly synthesized compounds demonstrated moderate to high sEH inhibitory activities, relative to 12-(3-adamantan-1-yl-ureido)dodecanoic acid as the reference standard. Compound 12e with a 4-methoxybenzoyl substituent exhibited the highest sEH inhibitory activity, with an IC₅₀ value of 1.06 nM. Moreover, the ADME properties of the compounds were evaluated in silico, and the results revealed appropriate predictions.     

Adolescent depression and adult labor market marginalization: a longitudinal cohort study

European Child & Adolescent Psychiatry - Adolescent depression is linked to adult ill-health and functional impairment, but recent research suggests that individual/contextual factors might...     

Intradermal Delivery of a Near-Infrared Photosensitizer Using Dissolving Microneedle Arrays

Nodular basal cell carcinoma is a deep skin lesion and one of the most common cancers. Conventional photodynamic therapy is limited to treatment of superficial skin lesions. The parenteral administration of near-IR preformed photosensitizers suffers from poor selectivity and may result in prolonged skin photosensitivity. Microneedles (MNs) can provide localized drug delivery to skin lesions. Intradermal delivery of the preformed near-IR photosensitizer; 5,10,15,20-tetrakis(2,6-difluoro-3-N-methylsulfamoylphenyl bacteriochlorin (Redaporfin?) using dissolving MN was successful in vitro and in vivo. MN demonstrated complete dissolution 30 min after skin application and showed sufficient mechanical strength to penetrate the skin to a depth of 450 μm. In vitro deposition studies illustrated that the drug was delivered and detected down to 5 mm in skin. In vivo biodistribution studies in athymic nude mice Crl:NU(NCr)-Foxn1^nu showed both fast initial release and localized drug delivery. The MN-treated mice showed a progressive decrease in the fluorescence intensity at the application site over the 7-day experiment period, with the highest and lowest fluorescence intensities measured being 9.2 × 10¹⁰ ± 2.5 × 10¹⁰ and 3.8 × 10⁹ ± 1.6 × 10⁹ p/s, respectively. By day 7, there was some migration of fluorescence away from the site of initial MN application. However, the majority of the body surfaces showed fluorescence levels that were comparable to those seen in the negative control group. This work suggests utility for polymeric MN arrays in minimally invasive intradermal delivery to enhance photodynamic therapy of deep skin lesions.     

N-acetyl cysteine in prevention of amphotericin- induced electrolytes imbalances: a randomized,double-blinded,placebo-controlled,clinical trial

Purpose

The aim of this study was to evaluate the effectiveness of oral n-acetyl cysteine, as a potential nephroprotective agent, in preventing and/or attenuating amphotericin B-induced electrolytes imbalances.

Methods

During a one year period, patients were to receive conventional amphotericin b for any indication for at least one week and were randomly allocated to receive either placebo or 600 mg oral n-acetyl cysteine twice daily during the treatment course of amphotericin b. Demographic and clinical data of the study population were gathered. Different aspects of amphotericin b nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, renal magnesium and potassium wasting were assessed. Each patient was monitored for any adverse reaction to n-acetyl cysteine. Sixteen and 14 patients in the n-acetyl cysteine and placebo groups completed the study, 3incidences of hypokalemia (75 % versus 70 %; P?=?0.724) and hypomagnesemia (30 % versus 20 %; P?=?0.468) did not differ significantly between placebo and NAC groups, respectively. Although the rate of AmB nephrotoxicity was higher in the placebo than in the NAC group (60 % versus 40 %), this difference was not statistically significant (P?=?0.209) even after adjusting for probable associated factors of amphotericin b nephrotoxicity (P?=?0.206). The incidence as well as time of onset of electrolyte abnormalities also did not differ significantly between placebo and n-acetyl cysteine groups. About 44 % of n-acetyl cysteine recipients experienced new onset nausea and a mild unpleasant taste during the study.

Conclusion

Oral n-acetyl cysteine during the amphotericin B treatment course was not significantly effective in preventing or mitigating different features of its nephrotoxicity including decrease of glomerular filtration rate, hypokalemia, hypomagnesemia, and renal potassium as well as magnesium wasting.     

Overweight and Obesity among Women by Economic Stratum in Urban India

Using data of the third round of the National Family Health Survey (NFHS) 2005-2006, this study examined the prevalence of overweight and obesity among women from different economic strata in urban India. The study used a separate wealth index for urban India constructed using principal components analysis (PCA). The result shows that prevalence of overweight and obesity is very high in urban areas, more noticeably among the non-poor households. Furthermore, overweight and obesity increase with age, education, and parity of women. The results of multinomial logistic regression show that non-poor women are about 2 and 3 times more at risk of being overweight and obese respectively. Marital status and media exposure are the other covariates associated positively with overweight and obesity. Thus, the growing demand which now appears before the Government or urban health planners is to address this rising urban epidemic with equal importance as given to other issues in the past.Key words: Body mass index, Economic status, Urban women, India     

Father involvement with three-to-four-year olds at home: giving fathers a chance

This study examined fathers' perceptions regarding their home-based activities (HBA) and the influence of fathers' demographic characteristics on their perceptions and practices at home. A total of 396 fathers completed a survey questionnaire describing their demographic information, perceptions and their practices regarding their involvement in HBA. Results indicated that fathers have moderate level of practice concerning their HBA, yet they have low perception of their actual practice at HBA. In addition, there was a statistical significance in HBA due to fathers' age, educational level and specialisation which had an influence on their perceptions as well. Recommendations and implications of future research were discussed.     

Photocatalysis of nanocomposite titania–natural silica as antibacterial against Staphylococcus aureus and Pseudomonas aeruginosa

The entries of pathogenic bacteria into the human body remain a severe problem to health that can be prevented using antibacterial agents. Meanwhile, the photocatalytic technique using semiconductor nanocomposite TiO₂–SiO₂ has great potential as an antibacterial method. In order to utilize natural resources, SiO₂ supporting materials are obtained from the extraction of beach sand due to the high silica content. Therefore, this study aims to synthesize a nanocomposite of TiO₂ with SiO₂ extracted from beach sand as an antibacterial agent against Staphylococcus aureus and Pseudomonas aeruginosa. The antibacterial activity test used the dilution and optical density method. Based on XRD analysis, the crystals of TiO₂ in the synthesized composites showed a more dominant anatase structure. Furthermore, Ti–O–Si bonds were identified from the IR spectrum, which showed the interaction between TiO₂ and SiO₂. In addition, SEM-EDX results showed agglomerated spherical particles with a TiO₂–SiO₂ nanocomposite particle size of 40–107 nm. The best antibacterial activity was demonstrated by the 1 : 0.5 TiO₂–SiO₂ nanocomposite, with inactivation percentages of S. aureus and P. aeruginosa of 98.69% and 97.44%, respectively.

TiO₂ material is composited with silica obtained from natural sand with indirect sonochemistry method. The addition of SiO₂ increase the photocatalyst activity of TiO₂ as an antibacterial against S. aureus and P. aeruginosa.