Rachna Gupta

Improvement in long term and visuo-spatial memory following chronic pioglitazone in mouse model of Alzheimer's disease.

Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists (thiazolidinediones) are widely prescribed for the treatment of type-II diabetes mellitus. Recently, PPAR-γ agonists have shown neuroprotective effects in neurodegenerative disorders. The current study was carried out to investigate the effects of chronic administration of pioglitazone, a PPAR-γ agonist, on cognitive impairment in a mouse model of Alzheimers disease induced by scopolamine. Scopolamine was administered in a dose of 1mg/kg intraperitoneally (i.p.). Cognitive functions were assessed using step-down latency (SDL) on a passive avoidance apparatus and escape latency in Morris water maze test. Pioglitazone was also investigated for its effects on parameters of oxidative stress by measuring malondialdehyde (MDA) and reduced glutathione (GSH) levels in the brain. Scopolamine produced significant reduction in SDL and prolongation of escape latency indicating cognitive impairment in mice. Pioglitazone (20 and 40 mg/kg, i.p.), administered for 21 days, showed significant dose-dependent improvement in scopolamine-induced dysfunctions in long-term and visuo-spatial memory in passive avoidance and Morris water maze tests, respectively. Furthermore, pioglitazone significantly prevented the fall in GSH levels and elevation in brain MDA levels induced by scopolamine. These results demonstrate that pioglitazone offers protection against scopolamine-induced dysfunctions in long-term and visuo-spatial memory, possibly due to its antioxidant action, and therefore, could have a therapeutic potential in Alzheimers disease.

Effect of Mirtazapine Treatment on Serum Levels of Brain-Derived Neurotrophic Factor and Tumor Necrosis Factor-α in Patients of Major Depressive Disorder with Severe Depression

Background: This study evaluated the clinical efficacy of mirtazapine and its effect on serum brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-α (TNF-α) levels in patients of major-depressive disorder (MDD) with severe depression. Methods: Patients (aged 18-60) with MDD diagnosed by DSM-IV criteria, and Hamilton Rating Scale for Depression (HAM-D) score ≥25 were included (n = 30). Mirtazapine was given in the doses of 30 mg/day. All patients were followed up for 12 weeks for the evaluation of clinical efficacy, safety along with serum BDNF and TNF-α levels. Results: HAM-D score at the start of treatment was 30.1 ± 1.92, which significantly (p < 0.05) reduced to 13.47 ± 1.77 at 12 weeks of treatment. In responders, mean serum BDNF levels at the start of treatment were 2.32 ± 0.3 ng/ml, which significantly (p < 0.05) increased to 2.79 ± 0.33 ng/ml at 12 weeks of treatment and mean serum TNF-α levels at the start were 5.18 ± 0.67 pg/ml, which significantly decreased to 4.36 ± 0.72 pg/ml (p < 0.05) at 12 weeks of treatment. Conclusion: Our results suggest that mirtazapine is effective and well tolerated in severely depressed patients and treatment response is associated with an increase in serum BDNF and a decrease in serum TNF-α levels.

Comparison of efficacy, safety and brain derived neurotrophic factor (BDNF) levels in patients of major depressive disorder, treated with fluoxetine and desvenlafaxine

This randomized, open label, prospective, observational study compared clinical efficacy, safety alongwith plasma BDNF levels in outpatients of depression treated with fluoxetine and desvenlafaxine. Patients (aged 18-60 years) with moderate to severe major depressive disorder (MDD) diagnosed by DSM-IV criteria, and Hamilton Rating Scale for Depression (HAM-D) score ≥14, who were prescribed fluoxetine or desvenlafaxine were included (n=30 in each group). Patients were followed up for 12 weeks for evaluation of clinical efficacy, safety along with BDNF levels. In the fluoxetine group, HAM-D scores at the start of treatment was 19±4.09 which significantly (p<0.05) reduced to 9.24±3.98 at 12 weeks. In the desvenlafaxine group, HAM-D scores at the start of treatment was 18±3.75 which significantly (p<0.05) reduced to 10±3.75 at 12 weeks. The BDNF levels in the fluoxetine group were 775.32±30.38pg/ml at the start of treatment which significantly (p<0.05) increased to 850.3±24.92pg/ml at 12 weeks. The BDNF levels in the desvenlafaxine group were 760.5±28.53pg/ml at the start of treatment which significantly (p<0.05) increased to 845.8±32.82pg/ml at 12 weeks. Both the antidepressants were found to be safe and well tolerated. The efficacy and the safety profile of desvenlafaxine is comparable to fluoxetine in patients of MDD. BDNF levels were significantly increased post-treatment with both the antidepressive agents. Whether BDNF may have a prognostic value in predicting treatment response to antidepressant drugs needs to be investigated in a larger patient population.

Neurobehavioral effects of liraglutide and sitagliptin in experimental models.

Glucagon-like peptide (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors are two currently approved therapies for type 2 diabetes mellitus (T2DM). Present study evaluated the effect of liraglutide (a long-acting GLP-1 agonist) and sitagliptin (a DPP-4 inhibitor) on nociception, anxiety, depression-like behavior and cognition in rats or mice. Nociception was assessed using tail-flick test; anxiety-behavior in open-field test and elevated plus maze (EPM) test while depression-like behavior was evaluated in forced swim test (FST) and tail-suspension test (TST). Cognition was assessed in EPM and Morris water maze (MWM) following memory deficit induced by pentylenetetrazole (PTZ) or scopolamine. In tail-flick test sitagliptin (6 mg/kg) produced transient nociceptive effect. Liraglutide (200 µg/kg) reduced peripheral square crossings by rats in open field test as well as reduced closed arm entries in the EPM, indicating a decline in exploratory behavior. In FST and TST models for depression, the duration of immobility with sitagliptin (6 mg/kg) was reduced significantly in comparison to control group suggesting its antidepressant effect. Liraglutide did not show any antidepressant action. In EPM test for cognition, liraglutide and sitagliptin ameliorated the increase in transfer latency caused by PTZ in a dose-dependent manner. In MWM liraglutide and sitagliptin prevented the scopolamine-induced increase of the escape latency. This study shows that sitagliptin has mild antinociceptive effect and anti-depressant effect in the animal models of depression while liraglutide did not have such an effect. Liraglutide showed anxiogenic effects in the animal models. Both liraglutide and sitagliptin produced cognitive improvement in the animal models.

Randomized controlled pilot trial of nifedipine as oral therapy vs topical application in the treatment of fissure-in-ano

BACKGROUND Fissure-in-ano is a common condition that leads to pain and affects quality of life. Sphincterotomy remains the gold standard, but it may lead to troublesome incontinence in some patients. To overcome this problem, numerous pharmacologic therapies have been tested with varying outcomes. The investigators compared the effect of the addition of oral and topical nifedipine to conservative measures in the treatment of patients with fissure-in-ano. METHODS Ninety patients with fissure-in-ano, randomized into 3 groups of 30 each, were included in the study. Group I received conventional treatment, group II received oral nifedipine and conventional treatment, and group III received topical nifedipine along with conventional treatment. Patients were followed for 8 weeks for pain relief (assessed using a visual analogue scale) and healing to evaluate the effect of treatment. RESULTS Pain relief was significantly better in the group III at 3 weeks and 2 months compared with group I (P < .05). Groups II and III were comparable in terms of pain relief. Healing rates were significantly better in group II (P = .03) and group III (P = .00) compared with group I, but groups II and III were found to be comparable. Adverse effects were most commonly reported by group II patients, but these were not significantly higher than in other 2 groups. CONCLUSIONS We recommend the addition of either oral or topical nifedipine to conservative measures to significantly improve pain relief and healing rates in patients with fissure-in-ano.

Assessment of anti-CarP antibodies, disease activity and quality of life in rheumatoid arthritis patients on conventional and biological disease-modifying antirheumatic drugs

Objective Good biomarkers are important to guide decisions in the clinical management of rheumatoid arthritis (RA). RA patients harbor antibodies directed against carbamylated proteins which may predict joint damage. This study investigated whether antibodies against carbamylated proteins (anti-CarP) may serve as surrogate prognostic markers. Material and methods Fifty-three patients with a diagnosis of rheumatoid arthritis according to ACR 1987 criteria were included. Blood samples were analyzed for CarP antibody levels using the ELISA method. Quality of life (QoL) was assessed by the WHO SF-36 questionnaire, and disease activity was assessed using the DAS28 calculator. Newly diagnosed patients were assessed at the first visit and at 12 weeks of treatment, while a single assessment was made for patients already on maintenance therapy. Results Out of 53 patients, 22 had titers of anti-CarP above the cut-off range and considered as positive for anti-CarP antibodies. Anti-CarP antibody serum level was significantly higher in patients with deformity of joints and with erosions in comparison to those without any destructive changes (p < 0.05). There was a weak positive correlation between anti-CarP and DAS 28 (p > 0.05). Also there was a weak negative correlation in all domains of quality of life with anti-CarP antibody titers (p > 0.05). There was no significant correlation between titers of anti-CarP antibodies and presence or absence of rheumatoid factor. Conclusions Serum levels of anti-CarP antibodies in RA patients with joint erosions/deformities were much higher than in those without any joint damage. Anti-CarP antibodies may have good prognostic value in RA patients with erosions. Disease activity and QoL of RA patients improved during treatment, but no correlation was found between DAS 28/QoL and anti-CarP antibody serum levels.

Chronic administration of modafinil induces hyperalgesia in mice: reversal by L-NG-nitro-arginine methyl ester and 7-nitroindazole.

Modafinil [2-((diphenylmethyl) sulfinyl) acetamide] is a central nervous system stimulant. It has received considerable attention as a potential psychotropic agent in several psychiatric disorders. The current study was carried out to investigate the effect of modafinil after acute administration on animal models of pain in mice. Also, this study evaluated the effect of L-NG-nitroarginine methyl ester (L-NAME), 7-nitroindazole (7-NI) and naloxone following chronic administration of modafinil. Modafinil was administered in the doses of 50, 100 or 200 mg/kg once in acute study and it showed significantly increased tail-flick latency (tfl) and paw-licking latency. In formalin test modafinil (100 mg/kg) significantly reduced licking/biting time in both early and late phases in comparison to control. In chronic study, modafinil 100 mg/kg administered for 10 days, produced a progressive decrease in the reaction time (i.e., tfl/paw-licking latency) in comparison to day 1 values which started building up from day 4 and fully established at day 6, indicating hyperalgesic response. Prior administration of 7-NI (on day 7) and L-NAME (on day 10) prevented the hyperalgesic response while naloxone on day 10 did not have a significant effect on modafinil-induced hyperalgesia. These results demonstrate that modafinil has a potential role in pain as it exhibited antinociceptive effect after acute administration in a dose-dependent manner and on chronic administration it caused hyperalgesia. This hyperalgesia is reversed by nitric oxide synthase inhibitors, suggesting the possibility of involvement of nitric oxide pathway. Further studies are required to evaluate the role of modafinil in clinical pain.

Effect of Agomelatine and Fluoxetine on HAM-D Score, Serum Brain-Derived Neurotrophic Factor, and Tumor Necrosis Factor-α Level in Patients With Major Depressive Disorder With Severe Depression

Evidence suggests that neurotrophic factors, inflammatory markers, and circadian rhythm dysfunctions could be involved in pathophysiology of major depressive disorder. This study evaluated the efficacy and tolerability of agomelatine, a melatonergic drug, and fluoxetine (positive comparator) and their effect on serum brain‐derived neurotrophic factor (BDNF) and tumor necrosis factor (TNF)‐α level in patients having major depressive disorder with severe depression. In the present study, we chose TNF‐α and BDNF because reduction of TNF‐α and rise in BDNF levels are linked with improvement in major depressive disorder. Patients with Hamilton Rating Scale for Depression (HAM‐D) score ≥25 were treated with agomelatine or fluoxetine and followed up for 12 weeks. In the agomelatine group, the HAM‐D score, BDNF level, and TNF‐α level at the start of treatment were 31.1 ± 1.88 ng/mL, 2.44 ± 0.38 ng/mL, and 512.5 ± 86.2 pg/mL, respectively, which significantly changed to 13.67 ± 2.22 ng/mL, 2.87 ± 0.44 ng/mL, and 391.64 ± 104.8 pg/mL, respectively (P < .05 for all 3 measures), at 12 weeks. In the fluoxetine group, the HAM‐D score, BDNF level, and TNF‐α level at the start of treatment were 30.83 ± 2.60 ng/mL, 2.54 ± 0.37 ng/mL, and 554.14 ± 46.8 pg/mL, respectively, which significantly changed to 13.67 ± 1.79 ng/mL, 3.07 ± 0.33 ng/mL, and 484.15 ± 49.9 pg/mL, respectively (P < .05 for all 3 measures) at 12 weeks. The BDNF level was significantly increased posttreatment with both drugs, and TNF‐α level fell significantly more with agomelatine compared to fluoxetine. Thus, chronic neuroinflammatory biomarkers contribute to circuitry dysregulation in depression. Trophic factors repair dysfunctional circuits in depression. Both treatments were found to be safe and well tolerated.

Correlation of long-term glycemic control as measured by glycated hemoglobin with serum angiopoietin-like 6 protein levels in type 2 diabetes mellitus patients

AIMS: Angiopoietin-like growth factors (ANGPTLs) regulate glucose, lipid homeostasis, and insulin sensitivity. This study aimed to find whether long-term glycemic control (glycated hemoglobin [HbA1c]) has any correlation with serum ANGPTL6 levels in patients of type 2 diabetes mellitus. MATERIALS AND METHODS: It was an open-label, observational, prospective clinical study. Sixty-five participants (41 diabetic patients receiving daily dose of oral metformin for a minimum of 3 months and 24 matched controls) completed the study. A single venous blood sample was taken from each participant to determine serum HbA1c and serum ANGPTL6 levels. Comparison of serum ANGPTL6 levels according to the HbA1c levels, in groups A, B, and C ranging from 6.5%–8%, 8.1%–9.5%, and >9.5%, respectively, was done using Kruskal–Wallis H-test followed by pairwise comparisons. RESULTS: Serum HbA1c and serum ANGPTL6 levels were raised significantly (P < 0.05) in diabetic patients when compared with control participants. A positive correlation was observed between serum HbA1c and serum ANGPTL6 levels (r = 0.88, 95% confidence interval 0.81, 0.92). Mean ANGPTL6 level for Group A (n = 20) was 394.3 pg/ml, for Group B (n = 8) 692.8 pg/ml, and for Group C (n = 13) 896.2 pg/ml. CONCLUSIONS: Serum ANGPTL6 levels were significantly higher in type 2 diabetic patients in comparison with healthy controls. Poor glycemic control in diabetes mellitus as reflected by higher serum HbA1c levels is associated with raised serum ANGPTL6 levels.

Comparison of Aqueous Humour Concentration after Single High Dose Versus Multiple Administration of Topical Moxifloxacin in Rabbits

For the prevention of postoperative ocular infections prophylactic topical antibiotics are routinely used. Studies evaluating comparative difference between single dose versus multiple dose administration on aqueous humour concentration of moxifloxacin are lacking. This study compared the aqueous humour concentration of moxifloxacin following its topical administration in rabbit eyes with two dose regimens. Twelve albino rabbits were divided into two groups. In group-1, two drops were administered thrice (total six drops) at 2 min intervals, in both the eyes; in group-2, two drops of moxifloxacin were administered three times a day for three days and also two h before aqueous humour collection i.e. on fourth day. Mean aqueous humour concentrations were calculated and compared using Students ‘t’ test and P<0.05 was considered significant. Moxifloxacin concentration in aqueous humour in group-1 was 23.79 μg/ml and in group-2 was 42.08 μg/ml. Both dosing regimens produced substantially higher aqueous concentrations than the known minimum inhibitory concentration for most bacteria. Moxifloxacin concentration in aqueous humour with multiple instillations is significantly higher than single instillation (P<0.05), which is adequate to cover ciprofloxacin-resistant gram-negative bacteria. Repeated topical moxifloxacin administration achieved significantly higher aqueous humour concentrations than single administration.