Cytological features of a lymphoepithelial cyst of the salivary gland with application of the second edition of Milan System for Reporting Salivary Gland Cytopathology.

Lymphoepithelial cysts (LECs) of the salivary glands are relatively rare, benign cystic lesions. Characteristic histopathological features of LEC include presence of well-circumscribed unilocular cysts surrounded by dense lymphoid tissue with lymphoid follicles. These cysts are lined by a combination of squamous, ciliated, columnar and mucous epithelia. Fine-needle aspiration (FNA) cytology is the standard preoperative diagnostic procedure for salivary gland lesions. Although the cytological diagnosis of cystic salivary gland lesions is difficult, the use of Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) in the cytodiagnosis of cystic salivary gland lesions has been reported. However, only a few studies have described the cytological features of LEC. To the best of our knowledge, the present study reviewed the cytological features of a case series of LEC and evaluated the application of MSRSGC for the first time. This retrospective study included 13 patients with LEC of the salivary glands who underwent pre-operative FNA followed by surgical resection of the cyst. All the lesions were present in the parotid gland. Cytological analysis revealed no epithelial cell component in eight patients (62.5%) along with a proteinaceous background containing lymphocytes and/or foamy cells. Non-keratinising squamous epithelium was observed in three patients. Amylase crystalloids were noted in two patients. None of the patients were cytodiagnosed with LEC. Eight, three, one and one patients were categorised as MSRSGC I, II, III, and IVa, respectively. The results of the present study demonstrated that cytodiagnosis of LEC was difficult due to the absence of epithelial component in 62.5% of the specimens. However, evaluation of its benignity was not difficult. Thus, it can be summarized that MSRSGC may be useful for cytological evaluation of LECs.

Evaluation of Using Dogs to Predict Fraction of Oral Dose Absorbed in Humans for Poorly Water-Soluble Drugs.

Dogs have been widely used to study the oral absorption of a drug in drug discovery. However, there has been no quantitative validation of using dogs to predict the fraction of oral dose absorbed (Fa) in humans (Fah) for poorly water-soluble drugs. Here, we report the results of using dogs for quantitative Fah prediction, focusing on poorly water-soluble free acid and neutral drugs. The Fa values of 4 acidic and 1 neutral proprietary compounds were measured in humans and dogs. Extensive literature survey was also performed to increase the number of Fa data. Fah and Fa in dogs (Fad) were then compared at equivalent body weight-normalized doses. In the case of neutral compounds, Fad was found to be similar to Fah. In the case of acidic compounds, Fad significantly overestimated Fah in most cases. A difference in intestinal pH was suggested as the main reason for this discrepancy. In conclusion, the use of dogs would not be appropriate to predict Fah for acidic compounds, but more work is required to know about neutral compounds.

Enhanced oral delivery of alendronate by sucrose fatty acids esters in rats and their absorption-enhancing mechanisms.

Oral delivery is the most fascinating route for interminable drug remedy. However, the intestinal absorption of alendronate (ALN), a bisphosphonate drug after oral administration is very poor. Absorption enhancers, which help to achieve the efficiency-safety balance, are considered one of the most promising agents for the improvement the intestinal absorption of drugs. In the current study, we focused on using sucrose fatty acid esters (SEs) as promising absorption enhancers to enhance the intestinal absorption of alendronate using an in situ closed-loop method in rats. The intestinal absorption of alendronate was significantly enhanced in the presence of SEs, especially L-1695. In addition, no considerable increase was observed in the activity of lactate dehydrogenase (LDH) or in protein release from the intestinal epithelium in the presence of sugar esters at concentrations equivalent to or lower than 1.0% (w/v), suggesting that these compounds are safe. Furthermore, mechanistic studies revealed increased membrane fluidity and loosening of the tight junctions (TJs) might be the underlying mechanism by which SEs improve the intestinal intake of alendronate, via transcellular and paracellular routes, respectively. These findings suggest that SEs are effective absorption enhancers for improving the intestinal absorption of alendronate, without causing serious damage to the enteric epithelium.

Quadrantal macular retinal thickness changes in strabismus subjects with abnormal binocular vision development.

PURPOSE: To investigate retinal morphological changes in strabismus patients with abnormal binocular vision development by comparing differences in quadrantal macular retinal thickness. METHODS: Six strabismus patients (6 dominant and 5 non-dominant eyes) with abnormal binocular vision (mean age 22 years), and 11 control subjects (11 dominant and 11 non-dominant eyes) (mean age 21 years) were enrolled. Macular retinal thickness measurements were performed by optical coherence tomography, with total macular retinal (TMR) and ganglion cell complex (GCC) thicknesses measured in 3- and 6-mm regions in each quadrant. Measurement values were then used to determine quadrant ratios. RESULTS: Compared to the dominant eyes of the controls, the superior/inferior (S/I) ratio of the TMR thickness and GCC thickness in the 3-mm region was significantly lower in the dominant eyes of the strabismus group (P < 0.05, each). The superior temporal/inferior temporal (ST/IT) ratio of the GCC thickness in the dominant eyes of the strabismus group was also significantly lower (P < 0.01). CONCLUSIONS: Dominant eyes of the strabismus group with abnormal binocular vision development exhibited thinner superior temporal GCC thicknesses in the 3-mm region. Retinal ganglion cells in this region might be affected by efferent neural degeneration that originates in the visual pathway responsible for adaptations to the visual experience.

Structure-activity study of L-amino acid-based N-type calcium channel blockers.

Synthesis and structure-activity relationship (SAR) study of L-amino acid-based N-type calcium channel blockers are described. The compounds synthesized were evaluated for inhibitory activity against both N-type and L-type calcium channels focusing on selectivity to reduce cardiovascular side effects due to blocking of L-type calcium channels. In the course of screening of our compound library, N-(t-butoxycarbonyl)-L-aspartic acid derivative 1a was identified as an initial lead compound for a new series of N-type calcium channel blockers, which inhibited calcium influx into IMR-32 human neuroblastoma cells with an IC(50) of 3.4 microM. Compound 1a also exhibited blockade of N-type calcium channel current in electrophysiological experiment using IMR-32 cells (34% inhibition at 10 microM, n=3). As a consequence of conversion of amino acid residue of 1a, compound 12a, that include N-(t-butoxycarbonyl)-L-cysteine, was found to be a potent N-type calcium channel blocker with an IC(50) of 0.61 microM. Thus, L-cysteine was selected as a potential structural motif for further modification. Optimization of C- and N-terminals of L-cysteine using S-cyclohexylmethyl-L-cysteine as a central scaffold led to potent and selective N-type calcium channel blocker 21f, which showed improved inhibitory potency (IC(50) 0.12 microM) and 12-fold selectivity for N-type calcium channels over L-type channels.

L-Cysteine based N-type calcium channel blockers: structure-activity relationships of the C-terminal lipophilic moiety, and oral analgesic efficacy in rat pain models.

This study was performed to determine the structure-activity relationships (SAR) of L-cysteine based N-type calcium channel blockers. Basic nitrogen was introduced into the C-terminal lipophilic moiety of L-cysteine with a view toward improvement of its physicochemical properties. L-Cysteine derivative 9 was found to be a potent and selective N-type calcium channel blocker with IC(50) of 0.33 microM in calcium influx assay using IMR-32 cells and was 15-fold selective for N-type calcium channels over L-type channels. Compound 9 showed improved oral analgesic efficacy in the rat formalin induced pain model and the rat chronic constriction injury (CCI) model, which is one of the most reliable models of chronic neuropathic pain, without any significant effect on blood pressure or neurological behavior.

Structure-activity study of L-cysteine-based N-type calcium channel blockers: optimization of N- and C-terminal substituents.

Synthesis and structure-activity relationship (SAR) studies of L-cysteine-based N-type calcium channel blockers are described. In the course of exploring SAR of the N- and C-terminal substituents, the L-cysteine derivative was found to be a potent N-type calcium channel blocker with an IC(50) value of 0.14 microM on IMR-32 assay. Compound showed 12-fold selectivity for N-type over L-type calcium channels on AtT-20 assay.