Development of Novel In Silico Model to Predict Corneal Permeability for Congeneric Drugs: A QSPR Approach

This study was undertaken to determine in vivo permeability coefficients for fluoroquinolones and to assess its correlation with the permeability derived using reported models in the literature. Further, the aim was to develop novel QSPR model to predict corneal permeability for fluoroquinolones and test its suitability on other training sets. The in vivo permeability coefficient was determined using cassette dosing (N-in-One) approach for nine fluoroquinolones (norfloxacin, ciprofloxacin, lomefloxacin, ofloxacin, levofloxacin, sparfloxacin, pefloxacin, gatifloxacin, and moxifloxacin) in rabbits. The correlation between corneal permeability derived using in vivo studies with that derived from reported models was determined. Novel QSPR-based model was developed using in vivo corneal permeability along with other molecular descriptors. The suitability of developed model was tested on β-blockers (n = 15). The model showed better prediction of corneal permeability for fluoroquinolones (r2 > 0.9) as well as β-blockers (r2 > 0.6). The newly developed QSPR model based upon in vivo generated data was found suitable to predict corneal permeability for fluoroquinolones as well as other sets of compounds

Screening of antiangiogenic potential of twenty two marine invertebrate extracts of phylum Mollusca from South East Coast of India

ABSTRACTObjectiveTo evaluate the antiangiogenic potential of twenty two marine invertebrate species of Phylum Mollusca from south east coast of India.MethodsLive specimens of molluscan species were collected and their methanolic extracts were evaluated for preliminary antiangiogenic activity using the in ovo chick chorio-allantoic membrane assay. The extracts were further evaluated for in vivo antiangiogenic activity using chemical cautery induced corneal neovascularization assay in rats and oxygen induced retinopathy assay in rat pups.ResultsIn the chick chorio-allantoic membrane assay, four methanolic extracts of marine molluscan species viz. Meretrix meretrix, Meretrix casta, Telescopium telescopium and Bursa crumena methanolic extracts exhibited noticeable antiangiogenic activity at the tested concentration of 200 μg whereby they significantly inhibited the VEGF induced proliferation of new blood vessels. Among these four extracts, the methanolic extract of Meretrix casta exhibited relatively higher degree of antiangiogenic activity with an inhibitiory percentage (64.63%) of the VEGF induced neovascularization followed by the methanolic extracts of Telescopium telescopium (62.02%), Bursa crumena (60.48%) and Meretrix meretrix (47.01%). These four methanolic extracts were further evaluated for in vivo antiangiogenic activity whereby the methanolic extract of Telescopium telescopium exhibited most noticeable inhibition (42.58%) of the corneal neovascularization in rats in comparison to the sham treated group, and also exhibited most noticeable inhibition (31.31%) of the oxygen induced retinal neovascularization in rat pups in comparison to the hyperoxia group that was observed for considerable retinal neovascularization.ConclusionsThe significant antiangiogenic activity evinced by the extract of Telescopium telescopium merits further investigation for ocular neovascular diseases

Circulating biomarkers in glaucoma, age-related macular degeneration, and diabetic retinopathy

Biomarkers to predict the altering physiological conditions over the period leading toward the ocular disorders are of major importance in therapeutics. Isolation and validation of the biomarkers specific to ocular diseases are a challenging task. Glaucoma is a neurodegenerative disease of the eye where the correlation of biomarkers in circulating fluid may be made specific for the eye. However, conditions such as wet age-related macular degeneration (AMD) and proliferative diabetic retinopathy (DR), circulating biomarkers might be having some degree of overlap with other conditions like cancer where a common factor such as angiogenesis is involved. Diabetes, a systemic disorder affecting the target organs such as eye, kidney, heart, and nervous system can be predicted using common circulating biomarkers. However, these markers need to be validated along with various stages of disease progression to enable the possibility of targeted pharmacological interventions apart from good glycemic control alone. This review compiles the attempts made to correlate such circulating biomarkers in the ocular conditions such as glaucoma, AMD, and DR in the search for a surrogate marker for diagnostic and prognostic value. To make biomarkers for the common convenience, genetic markers are excluded from this review

Evaluation of anti-leishmanial activity of selected Indian plants known to have antimicrobial properties

The severe toxicity, exorbitant cost and the emerging resistance of Leishmania spp. against most of the currently used drugs led to the urgent need for exploiting our traditional Ayurvedic knowledge to treat visceral leishmaniasis. The aim of this study was to evaluate the in vitro anti-leishmanial activity of various extracts from ten traditionally used Indian medicinal plants. The methanolic extract from only two plants, Withania somnifera Dunal (ashwagandha) and Allium sativum Linn. (garlic), showed appreciable activity against Leishmania donovani. Further active compounds from these two plants were isolated and purified based on bioactivity-guided fractionation. HPLC-purified fraction A6 of ashwagandha and G3 of garlic showed consistently high activity with 50% inhibitory concentration (IC50) of 12.5 +/- 4 and 18.6 +/- 3 mu g/ml against promastigotes whereas IC50 of 9.5 +/- 3 and 13.5 +/- 2 mu g/ml against amastigote form, respectively. The fraction A6 of ashwagandha was identified as withaferin A while fraction G3 of garlic is yet to be identified, and the work is in progress. Cytotoxic effects of the promising fractions and compounds were further evaluated in the murine macrophage (J774G8) model and were found to be safe. These compounds showed negligible cytotoxicity against J774G8 macrophages. The results indicate that fraction A6 of ashwagandha and fraction G3 of garlic might be potential sources of new anti-leishmanial compounds. The in vivo efficacy study and further optimization of these active compounds are in progress

Electromagnetic Field Stimulation Attenuates Phasic Nociception after Complete Spinal Cord Injury in Rats

Traumatic spinal cord injury (SCI) is one of the most incapacitating pathologies, leading to huge rehabilitation challenges besides a social-economic burden on SCI patients and their families. There is no complete curative treatment available so far. Non-invasive and patient-friendly use of extremely low-frequency electromagnetic field stimulation (EMF) has emerged as a therapeutic and rehabilitation option. In this study, we tested whole-body EMF stimulation on thoracic complete SCI-induced nociception including sensorimotor deficits in rats. The EMF application significantly attenuated hyperalgesia and allodynia to thermal, electrical, and chemical stimuli from 6 weeks onwards as well as restoration of spinal reflexes, viz., H-reflex and nociceptive flexion reflex at the study endpoint (week 8). Besides, massively increased glutamate at the SCI injury site was observed in SCI rats with no treatment, which was also attenuated significantly by EMF stimulation. Spinal cord histology of the injury area showed a decrease in lesion volume and glial population in the EMF-stimulated rats. These findings indicate the beneficial role of EMF stimulation after thoracic complete SCI in adult male rats and, thereby, a beneficial patient-friendly rehabilitation tool

Anti-tumor studies with extracts of <i>Calotropis procera</i> (Ait.) R.Br. root employing Hep2 cells and their possible mechanism of action

343-348Anti-tumor potential of root extracts of Calotropis procera : methanolic extract (CM), hexane extract (CH), aqueous extract (CW) and ethylacetate extract (CE) and its possible mechanism against Hep2 cancer cells has been investigated. Cellular proliferation activities were assayed by tetrazolium bromide (MTT) colorimetry. Morphological changes of cancer cells were observed under inverted microscope and cell cycle parameters were determined by flow cytometry following propidium iodide staining. Treatment with the extracts at various doses of 1, 5, 10 and 25 µg/ml revealed that CM, CH and CE possessed cytotoxicity, whereas CW did not have cytotoxic effect. CE (10 µg/ml) showed strongest cytotoxic effect (96.3%) on Hep2 at 48 hr following treatment, whereas CM and CH showed cytotoxicity of 72.7 and 60.5%, respectively. Extract-treated cells exhibited typical morphological changes of apoptosis. Results of flow cytometric analysis clearly demonstrated that root extracts initiated apoptosis of Hep2 cells through cell cycle arrest at S phase, thus preventing cells from entering G2/M phase. Results of the study indicate that the root extracts of C. procera inhibit the proliferation of Hep2 cells via apoptotic and cell cycle disruption based mechanisms. </span

An experimental study to evaluate safety/toxicity of intravitreal natalizumab

Purpose: The purpose of this prospective experimental study was to evaluate the safety/toxicity of α4β1 integrin blockade in rabbit retina using its monoclonal antibody (Natalizumab). Methods: Twelve New Zealand albino rabbits were divided into three groups (n = 4). Unilateral intravitreal injections of three different concentrations of natalizumab were performed in every rabbit of each group (Group A: 0.625 mg, Group B: 1.25 mg, and Group C: 2.5 mg). Baseline electroretinogram (ERG) and fundus photography were performed prior to injection. At days 1, 7, and 21 postinjection, ERG and fundus photography of each eye were performed. At last follow-up, Group C animals with highest drug concentration were sacrificed and the enucleated eyes were evaluated for retinal toxicity using transmission electron microscopy (TEM). Results: No difference in ERG responses was observed in eyes injected with low and intermediate concentration of natalizumab between day 0 and day 21. Furthermore, rabbits injected intravitreally with highest dose showed reduction in amplitude of “a” wave (P = 0.0017) and a reduction in amplitude of “b” wave of ERG at day 21 (P = 0.0117). TEM revealed changes in the outer plexiform layer and inner nuclear layer, suggestive of toxicity primarily to the photoreceptor synaptic terminals and bipolar cells. Conclusion: Low-dose (0.625 mg) and intermediate-dose (1.25 mg) intravitreal injection of natalizumab appears safe for rabbit retina. However, functional and anatomical changes were observed in rabbit retina following a high-dose (2.5 mg) intravitreal injection of a monoclonal antibody blocking α4β1 integrin

Rat bone marrow stromal cell transplantation ameliorates complete spinal cord injury induced sensorimotor dysfunctions and associated neurotransmitters

535-546Traumatic spinal cord injury (SCI) leads to sensorimotor dysfunction with significant impact on the patient and their family’s quality of life, social, and economic status. There is no complete restorative treatment so far. Bone marrow stromal cells (BMSCs) have anti-inflammatory and neuroprotective effects and recently emerged as a therapeutic candidate for SCI repair. Here, we examined the role of rat BMSCs transplantation on thoracic (T11) complete SCI induced dysfunctions, namely hyperalgesia, allodynia, locomotion, spinal reflexes, and spinal neurotransmitters in rats. Pre-labelled BMSCs were injected on day 9 after SCI locally. We observed that BMSCs transplantation facilitate locomotor recovery (week 2-8) and attenuated hyperalgesia and allodynia to varying sensory stimuli (week 6-8) after SCI. In addition, spinal reflexes and neurotransmitters were affected significantly by complete SCI, which were partially restored by BMSCs transplantation. Histological analyses also revealed the presence of BMSCs at the injury site and appear to fill the lesion cavities, thereby significantly reducing the lesion volume. Our data shows the beneficial effects of BMSCs transplantation on complete SCI-induced sensorimotor functional deficits in rats