Ameliorative Potential of Aminophylline In Restrain Stress Induced Behavioural and Biochemical Alterations

This study is designed to investigate the attenuating prospective of aminophylline in immobilization stress generated behavioural changes in rats. Animals were exposed to restrain stress before being subjected to varying doses of aminophylline (1mg/kg, 2mg/kg and 4mg/kg). Behavioural changes were analyzed to assess the intensity and the degree of the stress, by estimating the changes in the exploratory behaviour, spontaneous activity and social behaviour using various paradigms. As a consequence of stress, the behavioral patterns so changed were assessed in the terms of changes in the locomotor activity, number of head dips and increased avoidance behaviour. Aminophylline (4mg/kg) modulated the stress produced changes in the behaviour and oxidative stress generated biochemical alterations in a significant manner (p<0.001). The results so obtained suggest that upon exposure to stress, animal behavioural patterns, biochemical markers levels changed and these changes wereefficiently modulated by aminophylline at therapeutic doses

RECENT ADVANCES IN ALZHEIMER'S DISEASE: CAUSES AND TREATMENT

Alzheimer's disease (AD) is a destructive neurodegenerative disorder characterized by progressive memory defeat and impairment in behavior, language, and visuospatial skills. Neuropsychiatric symptoms such as apathy, depression, aggression, agitation, sleep disruption, and psychosis are now recognized as core symptoms of AD that are expressed to varying degrees throughout the course of disease. The neuro pathological features of AD comprise extracellular senile plaques constituted of β-amyloid (Aβ) pledges, intracellular neurofibrillary tangles (NFTs), and cerebral atrophy; others include apolipoprotein E, oxidative stress, mitochondrial dysfunction and cholinergic hypothesis. Anti-amyloid therapy is available for the treatment of Alzheimer's disease, others are anticholinergic therapy, and therapy for mitochondrial dysfunction, γ-secretase inhibitors (GSI) and modulators (GSM), ð›½-secretase (BACE1) inhibitors, Glial modulating drugs includes RAGE receptor antagonists, TNF-α antagonists, neuroprotective drugs such as antioxidants, phosphodiesterase inhibitors, PPARγ agonists, and anti-tau or tau modulators like microtubule stabilizers, kinase inhibitors. This review includes discussion on neurobiological mechanisms and newly developed compounds which have lesser side effects and are proving more efficient for treatment of Alzheimer's disease.Â

Effect of obesity on lung volumes among adults

Background: Obesity has long been recognized to have significant effect on respiratory functions. Many studies have reported exponential decrease in pulmonary function test (PFT) with increasing body mass index (BMI), which is a crude indicator of obesity. Also, the relationship between BMI and PFTs varies with age, race, geographical region and the different obesity standards used. To the best of our knowledge, not many studies have been done to examine the relationship between obesity and lung volumes among adults in our region, Jammu. This cross-sectional study was carried out with the objective of evaluating the effect of obesity on lung function test in obese but otherwise healthy adults of Jammu region.Methods: This cross-sectional study was conducted in Jammu region on subjects selected randomly from different colleges in the age group of 18-40 years. The study involved 300 subjects; divided into three groups of 100 each, based on BMI into normal, overweight and obese groups. Four respiratory parameters viz. FVC (Forced Vital Capacity), FEV1 (Forced Expiratory Volume in 1 second), FEV3 (Forced Expiratory Volume in 3 seconds), and MVV (Maximum Voluntary Ventilation) were used to assess their lung functions.Results: All the respiratory parameters exhibited statistically significant decrease in obese groups as compared to normal and overweight groups.Conclusions: The present study suggests that obesity alters the respiratory physiology by producing a restrictive ventilatory pattern

Influence of active efflux transport on the distribution of targeted agents to brain tumors

University of Minnesota Ph.D. dissertation. July 2014. Major: Pharmaceutics. Advisor: William F. Elmquist. 1 computer file (PDF); xxvii, 284 pages, appendices p. 281-284.Glioblastoma multiforme (GBM) is a lethal disease of the whole brain. Despite complete surgical resection of the tumor, recurrence is inevitable and leads to patient death. Several molecularly-targeted agents have shown promising results preclinically, although clinical results have been disappointing. One plausible explanation for clinical failure of drugs is their inability to effectively target the invasive glioma cells that reside in areas away from the tumor core. These regions of the brain have an intact blood brain barrier (BBB), which through a combination of endothelial tight junctions and active efflux transporters restricts brain penetration of several drugs. The objective of this thesis was to investigate the influence of active efflux transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) on the brain distribution of molecularly targeted agents. To enhance our understanding of brain distribution with statistical certainty, we proposed a population-based analysis method to estimate variability around the brain partition coefficient (Kp). We showed that the brain distribution of sunitinib (a tyrosine-kinase inhibitor) is limited by active efflux mediated by P-gp and Bcrp at the BBB. We further demonstrated that brain distribution could be enhanced by administration of a dual P-gp/Bcrp inhibitor. To statistically ascertain the variability associated with Kp in a serial sacrifice design, we developed a pharmacokinetic model to simultaneously describe plasma and brain concentration time profile data. We further evaluated the influence of study design features such as between subject variability (BSV) and sample size at each time point on bias and precision of estimation of Kp. Our results show that bias is unaffected by the assumptions regarding the magnitude of BSV and sample size, however, precision improves with sample size.We further examined the influence of BBB on delivery and efficacy of dual PI3K/mTOR inhibitors, GNE-317 (higher BBB permeability) and GDC-0980 (restricted BBB penetration) using three glioma mouse models, GL261-luc-GFP model, GBM10 and U87. Disruption of the BBB in the tumor core resulted in higher drug concentrations for GDC-0980. However, intact BBB in the areas adjacent to the core restricted the brain concentrations of GDC-0980. Contrary to this, the brain concentrations of GNE-317 were similar in all the three regions of the brain. Furthermore, results from survival studies indicated that although both GNE-317 and GDC-0980 significantly improved survival compared to placebo, the treatment groups were not significantly different from each other. Therefore, it is important to consider that effective treatment of GBM relies not only on effective delivery across the BBB to invasive glioma cells but also on an effective drug

ANITINERARY TO ACCESS THE COLON

Although oral delivery has become a widely accepted route of administration of therapeutic drugs, the gastrointestinal tract presents several formidable barriers to drug delivery. The delivery of drugs to the colon has a number of important implications in the field of pharmacotherapy. Drugs that are destroyed by the acidic environment of the stomach or metabolized by pancreatic enzymes are only slightly absorbed in the colon. Targeted delivery of drugs to the colon has attracted much interest recently for local treatment of a variety of colonic diseases such as irritable bowel syndrome (IBS), colorectal cancer and inflammatory bowel diseases (IBD), which includes both ulcerative colitis and crohn's disease. The colon is also receiving significant attention as a portal for the entry of drugs into the systemic circulation. A variety of delivery strategies and systems have been proposed for colonic targeting.This article shall review the diversestrategies used to target the drug to the colon.The various features of different approaches allowing locally restricted drug delivery to the inflamed colon are discussed including the main physiological issues and histological changes of the colon as its cancer develops

Escitalopram induced syndrome of inappropriate antidiuretic hormone in elderly: an interesting scenario

Selective serotonin reuptake inhibitors (SSRI) are the first line drugs used in the treatment of endogenous depression. Though clinically well tolerated in elderly, hyponatremia is one of the recognized side effects and its pathophysiology may be linked to syndrome of inappropriate antidiuretic hormone (SIADH). This side effect of SSRIs is a serious one since it can cause death also, if not diagnosed at the onset.  This is an interesting case of an elderly patient who developed hyponatremia which further related to SIADH induced by escitalopram, an SSRI.  The patient had symptomatic improvement in depression within one month but symptoms of hyponatremia appeared and then deteriorated again. Severe hyponatremia, serum hypo-osmolality, urine osmolality, and measurable levels of plasma antidiuretic hormone suggested SIADH. The hyponatremia improved after stoppage of the offending drug along with conservative medical therapy in hospital.  Clinicians should be aware of this uncommon but significant side effect of escitalopram and monitor high-risk patients for the development of SIADH

Evaluation of efficacy and tolerability of nitrofurantoin versus ciprofloxacin in patients of urinary tract infection: a comparative study

Background: UTIs are one of the most common infectious diseases encountered in out-patient departments on day to day basis. Nitrofurantoin and Ciprofloxacin are most commonly used antibiotics in the treatment of UTI. The present study was done to compare the efficacy and tolerability of nitrofurantoin and ciprofloxacin in patients of urinary tract infection.Methods: This prospective, open, randomized, parallel group, comparative study was conducted on 60 patients presenting with acute/uncomplicated or recurrent urinary tract infection in the outpatient Department of Urology, Rajindra Hospital attached to Govt. Medical College, Patiala, Punjab. They were divided into two groups, Group I and Group II of 30 cases each. Group I patients were put on Nitrofurantoin and Group II patients were put on Ciprofloxacin. Initially 100 patients were enrolled but only those who showed growth of uropathogens on baseline urine culture or those who completed the treatment were included in the study. The primary outcome measure was microbiological eradication on post treatment urine culture.Results: The age range of the patients in Group I and Group II was 19 to 68 years (43.40±14.58 years) and 20-60 years (39.77±13.49 years) respectively. The total no. of males and females who participated in this study were 32 (53.33%) and 28 (46.66%) respectively. The most common uropathogen associated with uncomplicated UTI was E. coli (80%), other organisms detected were Klebsiella species (16.67%), Staphylococcus aureus (3.33%) and Providencia (3.33%). Post treatment urine culture results showed significant difference between two groups, 5 patients (16.67 %) in case of Group I and 14 patients (46.67%) in case of Group II showed growth of micro-organisms post treatment. P-value comes out to be 0.017 which is significant.Conclusions: In this era of super bugs, nitrofurantoin is more efficacious than ciprofloxacin in the treatment of UTI. E. coli was found to be major organism causing UTI. Ciprofloxacin is less effective due to increasing antibiotic resistance among uropathogens. Both the drugs were well tolerated, no major significant adverse effects were encountered

Enhancing biopharmaceutical performance of an anticancer drug by long chain PUFA based self-nanoemulsifying lipidic nanomicellar system.

The aim of this study was to develop polyunsaturated fatty acid (PUFA) long chain glyceride (LCG) enriched self-nanoemulsifying lipidic nanomicelles systems (SNELS) for augmenting lymphatic uptake and enhancing oral bioavailability of docetaxel and compare its biopharmaceutical performance with a medium-chain fatty acid glyceride (MCG) SNELS. Equilibrium solubility and pseudo ternary phase studies facilitated the selection of suitable LCG and MCG. The critical material attributes (CMAs) and critical process parameters (CPPs) were earmarked using Placket-Burman Design (PBD) and Fractional Factorial Design (FFD) for LCG- and MCG-SNELS respectively, and nano micelles were subsequently optimized using I- and D-optimal designs. Desirability function unearthed the optimized SNELS with Temul 85% and Perm45min >75%. The SNELS demonstrated efficient biocompatibility and energy dependent cellular uptake, reduced P-gp efflux and increased permeability using bi-directional Caco-2 model. Optimal PUFA enriched LCG-SNELS exhibited distinctly superior permeability and absorption parameters during ex vivo permeation, in situ single pass intestinal perfusion, lymphatic uptake and in vivo pharmacokinetic studies over MCG-SNELS. [Abstract copyright: Copyright © 2017. Published by Elsevier B.V.

Clathrin-mediated endocytic uptake of PUFA enriched self-nanoemulsifying lipidic systems (SNELS) of an anticancer drug against triple negative cancer and DMBA induced preclinical tumor model

The current studies envisage unravelling the underlying cellular internalisation mechanism of the systematically developed docetaxel (DTH) polyunsaturated fatty acid (PUFA) enriched self-nanoemulsifying lipidic micellar systems (SNELS). The concentration-, time- and cytotoxicity-related effects of DTH-SNELS on triple negative breast cancer (TNBC) MDA-MB-231 and non-TNBC MCF-7 cell lines were assessed through Presto-blue assay. Subsequently, rhodamine-123 (Rh-123) loaded SNELS were employed for evaluating their internalisation through flow cytometry and fluorescence microscopy, establishing it to be “clathrin-mediated” endocytic pathway. Apoptosis assay (65% cell death) and cell cycle distribution (47% inhibition at G2/M phase) further corroborated the cytotoxicity of DTH-SNELS towards cancerous cells. Biodistribution, histopathology and haematology studies indicated insignificant toxicity of the optimized formulation on vital organs. Preclinical anticancer efficacy studies using 7,12-dimethylbenzantracene (DMBA)-induced model construed significant reduction in breast tumor-volume. Overall, extensive in vitro and in vivo studies indicated the intracellular localization and cytotoxicity, suggesting DTH-SNELS as promising delivery systems for breast tumor therapeutics including TNBC

Enhancing Biopharmaceutical Attributes of Phospholipid Complex-loaded Nanostructured Lipidic Carriers of Mangiferin: Systematic Development, Characterization and Evaluation

Mangiferin (Mgf), largely expressed out from the leaves and stem bark of Mango, is a potent antioxidant. However, its in vivo activity gets tremendously reduced owing to poor aqueous solubility and inconsistent gastrointestinal absorption, high hepatic first-pass metabolism and high P-gp efflux. The current research work, therefore, was undertaken to overcome the biopharmaceutical hiccups by developing the Mgf-phospholipid complex (PLCs) loaded in nanostructured lipidic carriers (NLCs). The PLCs and NLCs were prepared using refluxing, solvent evaporation and hot emulsification technique, respectively with various molar ratios of Mgf and Phospholipon 90 G, i.e., 1:1; 1:2; and 1:3. The complex was evaluated for various physicochemical parameters like drug content (96.57%), aqueous solubility (25-fold improved) and oil-water partition coefficient (10-fold enhanced). Diverse studies on the prepared complex using FTIR, DSC, PXRD and SEM studies ratified the formation of PLCs at 1:1 ratio. The PLCs were further incorporated onto NLCs, which were systematically optimized employing a face centered cubic design (FCCD), while evaluating for particle size, zeta potential, encapsulation efficiency and in vitro drug release as the CQAs. Caco-2 cell line indicated insignificant cytotoxicity, and P-gp efflux, bi-directional permeability model and in situ perfusion studies specified enhanced intestinal permeation parameters. In vivo pharmacokinetic studies revealed notable increase in the values of Cmax (4.7-fold) and AUC (2.1-fold), respectively, from PLCs-loaded NLCs vis-à-vis Mgf solution. In a nutshell, the promising results observed from the present research work signified boosted biopharmaceutical potential of the optimized PLCs-loaded NLCs for potentially augmenting the therapeutic efficacy of Mgf