Antifertility Activity of Stems of Plumbago rosea in Female Albino Rats

In the present study, Plumbago rosea Linn. (Plumbaginaceae), one of the folk medicinal plants commonly used as an antifertility agent, was evaluated for its antifertility effect. Five successive solvent extracts, petroleum ether, chloroform, acetone, ethanol, and water extracts, of the stems of P. rosea were studied on estrous cycle at two dose levels, 200 and 400 mg/kg respectively. Of these, the acetone extract was found to be most effective in interrupting the normal estrous cycle of rats (p < 0.05) (p < 0.01). The rats exhibited prolonged diestrous stage of the estrous cycle with consequent temporary inhibition of ovulation. The antiovulatory activity was reversible on withdrawal of the extract. The effective acetone extract was further studied on estrogenic functionality in rats. The acetone extract showed significant estrogenic and antiestrogenic activity (p < 0.05) (p < 0.001). Histological studies of the uteri further confirmed the estrogenic activity of acetone extract. The results indicated the antifertility activity of stems of Plumbago rosea in female Wistar rats.     

2-ABT-S-oxide detoxification by glutathione S-transferases A1-1, M1-1 and P1-1: Implications for toxicity associated with zileuton

1. Zileuton, an agent which targets the leukotriene pathway through inhibition of 5-lipoxygenase (5-LO), was approved for the treatment of asthma in 1997. Shortly after its release, its use was restricted due to the observation of hepatotoxicity in patients.

2. Previous research from the authors’ laboratory demonstrated the formation of the reactive metabolite, 2-ABT-S-oxide (M1) from zileuton, and has identified a mercapturate of 2-ABT, C1, in the urine of rats dosed with zileuton. The reaction between M1 and glutathione (GSH) has been established in vitro; however, the potential for catalysis by glutathione transferases (GSTs) was not addressed.

3. The work presented here outlines a role for GSTs in the detoxification of M1. Non-enzymatic conjugation studies with M1 and GSH in control experiments led to a t_1/2 of 6.4 ± 0.4 h at pH 6.5. This rate was accelerated in the presence of GSTA1-1, GSTM1-1 and GSTP1-1 providing t_1/2 values of 2.6 ± 0.1, 0.53 ± 0.02, and 0.3 ± 0.04 h, respectively, at pH 6.5.

4. The inhibition of various GST enzymes was also studied. Results show that M1 inhibits GSTM1-1 and GSTP1-1 to a greater extent as compared with GSTA1-1. In the case of GSTA1-1, the inhibition was observed to be reversible, whereas M1 inhibition of GSTM1-1 and GSTP1-1 was found to be irreversible under identical conditions.

5. GSTM1-1 is present in liver and thus the finding of the alkylation and potential irreversible inactivation of this isoform in vivo could contribute to an understanding of the hepatotoxicity associated with zileuton.

     

Drug-drug interaction between voriconazole and oral hypoglycemic agents in diabetic rats

Objective:

The objective was to study the of drug-drug interaction between voriconazole and oral hypoglycemic agents in normal and alloxan induced diabetic rats.

Materials and Methods:

The study was designed in two phases. In the first phase, influence of glibenclamide (0.45 mg/kg, p.o.) and pioglitazone (2.7 mg/kg, p.o. once daily) on blood glucose levels in normoglycemic rats was studied and then influence of voriconazole (18 mg/kg, p.o. twice daily.) pre-treatment on the hypoglycemic activity studied. Simultaneously the influence of voriconazole treatment for seven consecutive days (per se effect) on blood glucose levels was also studied in normoglycemic rats. In the second phase of the study alloxan-induced diabetic rats were used to find out the influence of voriconazole pre-treatment on glibenclamide and pioglitazone induced hypoglycemic effect in pathophysiological condition. Blood samples were collected from retro orbital plexus at regular intervals of 0.0, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 18.0 and 24.0 h after drug treatment. All the blood samples were analyzed for plasma glucose by glucose oxidase peroxidase method (GOD/POD).

Results:

The therapeutic dose of voriconazole potentiates the hypoglycemic activity of glibenclamide and pioglitazone both in normoglycemic and diabetic rats respectively.

Conclusion:

The results indicate that the dose of oral hypoglycemic agents needs to be adjusted if co-administered with voriconazole.KEY WORDS: Drug-drug interaction, glibenclamide, hypoglycemic, pioglitazone, voriconazole     

Solid Surface Chemical and Physical Effects on the Adsorption of Recombinant Factor VIII

The adsorption of a recombinant Factor VIII to silica surfaces coated to present different hydrophilic/hydrophobic, electrostatic and steric characteristics was monitored in situ, with ellipsometry. rFVIII adsorption affinity was high for hydrophobic surfaces and hydrophilic, charged surfaces. A lower affinity was recorded between rFVIII and a neutral hydrophilic surface, with substantial reduction in rFVIII adsorption to electronically neutral surfaces presenting pendant poly[ethylene oxide] chains. We conclude that steric repulsion is a requirement for minimizing rFVIII adsorption at solid surfaces.     

Pharmacophore modeling and 3D QSAR analysis of isothiazolidinedione derivatives as PTP1B inhibitors

The article describes the development of a robust pharmacophore model and investigation of structure activity relationship analysis of 56 isothiazolidinedione derivatives reported as PTP1B inhibitors. A six-point pharmacophore model consisting of four aromatic rings (R), one hydrogen bond donor (D) and one hydrogen bond acceptor (A) with discrete geometries as pharmacophoric features was developed and the generated pharmacophore model was used to derive a predictive 3D QSAR model for the studied dataset. The obtained 3D QSAR model has an excellent correlation coefficient value (r ² = 0.98) along with good statistical significance as shown by a high Fisher ratio (F = 428.60). The model also exhibits good predictive power confirmed by the high value of cross-validated correlation coefficient (q ² = 0.62). The QSAR model suggests that hydrophobic aromatic character is crucial for the PTP1B inhibitory activity at the R-15 site.     

Molecular modeling and synthesis of ZINC02765569 derivatives as protein tyrosine phosphatase 1B inhibitors: lead optimization study

This article describes design, synthesis, and molecular modeling studies of the ZINC02765569 derivatives as potent protein tyrosine phosphatase 1B (PTP1B) inhibitors, which was previously reported as a vHTS hit (ZINC02765569) by our laboratory. Ten compounds were synthesized and characterized by IR, MASS, and NMR followed by in vitro screening for PTP1B inhibition and glucose uptake in skeletal muscle L6 myotubes. The most potent compound 3j shows 66.4 % in vitro PTP1B inhibition and 39.6 % increase in glucose uptake. Glide was used to study the nature of interactions governing binding of designed molecules with active site of the PTP1B enzyme.     

Altered Mucins (MUC) Trafficking in Benign and Malignant Conditions

Mucins are high molecular weight O-glycoproteins that are predominantly expressed at the apical surface of epithelial cells and have wide range of functions. The functional diversity is attributed to their structure that comprises of a peptide chain with unique domains and multiple carbohydrate moieties added during posttranslational modifications. Tumor cells aberrantly overexpress mucins, and thereby promote proliferation, differentiation, motility, invasion and metastasis. Along with their aberrant expression, accumulating evidence suggest the critical role of altered subcellular localization of mucins under pathological conditions due to altered endocytic processes. The mislocalization of mucins and their interactions result in change in the density and activity of important cell membrane proteins (like, receptor tyrosine kinases) to facilitate various signaling, which help cancer cells to proliferate, survive and progress to more aggressive phenotype. In this review article, we summarize studies on mucins trafficking and provide a perspective on its importance to pathological conditions and to answer critical questions including its use for therapeutic interventions.     

Ocular Morbidity among Street Children in Kathmandu Valley

Purpose: Prevalence of ocular morbidity among street children is largely unknown. The present study was carried out to determine the prevalence of ocular morbidity among street children in the Kathmandu Valley.

Methods: A cross-sectional study consisting of an eye examination program among 569 street children aged younger than 18 years was conducted from March 2013 to February 2014. Children were included from 11 safe houses of 6 non-governmental organizations and an independent eye camp. Eye examination included visual acuity testing, anterior segment and posterior segment examination, retinoscopy and refraction, cover test, convergence, accommodation and color vision tests. Chi-square test was used to analyze the association of ocular morbidity with age, sex and living conditions.

Results: The majority of children (43.8%) were in the age group of 12–15 years, and the male to female ratio was 3.9:1. Uncorrected and best-corrected visual acuity ≥6/9 in at least one eye was found in 89.8% and 98.4% of children, respectively. Total ocular morbidity was observed at 31.6%. The most common types of ocular morbidity were conjunctivitis (11.0%) and refractive error (11.6%). Ocular morbidity was more common in children over 15 years of age (40.9%; p?<?0.01; odds ratio 1.8).

Conclusions: Ocular infection and refractive error represent the most common ocular morbidities in street children in the Kathmandu Valley.     

The perceived personality traits of adults with digitally induced large angle strabismus and the impact of its correction

Purpose:

To ascertain the effect of digitally induced large angle strabismus and its correction on social bias against strabismic adults.

Subjects and Methods:

This prospective, observational study included 10 orthotropic subjects whose face photographs were digitally altered to produce esotropia, exotropia, and hypertropia. Three batches of non-medical professionals, each consisting of 14 subjects, adjudged personality traits of the altered face photographs on a 10-item questionnaire. The same evaluators effected the appraisal of the orthotropic photographs. The personality score of the strabismic photograph of a subject was compared with its own orthotropic photograph.

Subjects and Methods:

This prospective, observational study included 10 orthotropic subjects whose face photographs were digitally altered to produce esotropia, exotropia, and hypertropia. Three batches of non-medical professionals, each consisting of 14 subjects, adjudged personality traits of the altered face photographs on a 10-item questionnaire. The same evaluators effected the appraisal of the orthotropic photographs. The personality score of the strabismic photograph of a subject was compared with its own orthotropic photograph.

Results:

The 10 subjects whose photographs were digitally modified were of the same age (21 years) and had equal gender distribution. The evaluation of the photographs was performed by 42 evaluators aged 38.3 ± 14.9 years, of whom 21 were males. Different personality traits were rated negatively in the strabismic photographs. The statistically significant negative impact was apparent on more number of personality traits for esotropia (7 out of 10) as compared to exotropia (4 out of 10) or hypertropia (3 out of 10). Rating of the strabismic photographs was significantly lower by female evaluators (P = 0.006). However, there was no difference whether the subject evaluating the photograph of the strabismic individual was of the same gender or the opposite gender. Internal consistency of the questionnaire was excellent (Cronbach''s Alpha = 0.81).

Conclusion:

There was a significant negative impact of strabismus on the perceived personality traits of the digitally altered face photographs of the adults when compared to their orthotropic photograph.