ANTIDEPRESSANT ACTIVITY OF AQUEOUS EXTRACTS OF FRUITS OF TERMINALIA CHEBULA AND PHYLLANTHUS EMBLICA IN BEHAVIOURAL MODELS OF DEPRESSION: INVOLVEMENT OF MONOAMINERGIC SYSTEM

Objectives: Terminalia chebula (TCh) and Phyllanthus emblica (PE) posses wide range of central nervous system activity. This study was conducted to investigate the antidepressant activity and mechanism action of aqueous extract of TCh & PE using forced swimming test (FST) and tail suspension test (TST). Methods: Aqueous extracts of TCh (390, 780 & 1560mg/kg) and PE (390, 780, 1560 & 3120 mg/kg) were administered for seven days to mice and immobility time was measured in FST & TST. Extracts were administered for 14 days and immobility time was measured in chronic FST. The mechanisms of antidepressant effect of TCh and PE were studied using prazosin (1mg/kg), levosulpiride (20mg/kg) and p-CPA (300mg/kg) in TST. Results: In FST, 780 & 1560 mg/kg of TCh and 1560 & 3120 mg/kg of PE reduced immobility time while in TST, 1560 mg/kg of TCh and 3120 mg/kg of PE decreased immobility significantly compared to control. In chronic FST, only 780 & 1560 mg/kg of TCh showed significant reduction. Antidepressant effect of TCh was reversed by prazosin while antidepressant effect of PE was reversed by prazosin and levosulpiride significantly in TST. Conclusions: The aqueous extracts of TCh and PE possess antidepressant activity at higher doses. This effect was possibly mediated through mono aminergic pathways

Celastrus paniculatus and memantine prevent alcohol dependence and improve decision making in alcohol dependent C57BL6 mice

Background: Alcohol use disorder poses a huge burden with only a handful of approved drugs. AUD is associated with impaired decision-making that leads to compulsive drinking despite negative consequences. A drug that decreases alcohol consumption as well as improves decision-making may thus prove more useful. This study was planned to evaluate the effect of two drugs, Celastrus paniculatus and memantine on alcohol preference and decision impairment in alcohol-dependent mice. Methods: In part 1, the effect of both the study drugs on alcohol consumption was studied using intermittent access model in 70 male C57BL6 mice. In part 2, effect of drugs on decision making was studied using the rodent version of Iowa gambling task. Mice were divided in seven study groups: Group 1-3: Celastrus paniculatus (140, 280, and 560 mg/kg), Group 4: memantine (25 mg/kg), Group 5: vehicle control 1 (Milk), Group 6: vehicle control 2 (normal saline) and Group 7: naltrexone(1mg/kg). Results: Percentage alcohol preference was lower in test groups i.e., Celastrus paniculatus at medium (40.90±15.18%) and high doses (31.79±7.46%) vs. milk (82.74±8.53%; p<0.05); and in memantine group (36.28±10.99%) vs. normal saline (83.27±5.51%; p<0.05). The results were not significantly different to Naltrexone (19.70±6.90%). Percentage preference to disadvantageous arms was also lower in Celastrus paniculatus, at medium (50.52±1.92%) and high doses (48.11±2.43%) compared to milk (54.47±2.73%; p<0.05) and memantine (47.45±1.67%) compared to normal saline (54.00±2.73%; p<0.05), indicating better decision-making ability in the test groups. The findings were comparable to Naltrexone group (45.43±2.52%). Conclusions: These results indicate that Celastrus paniculatus and memantine reduce alcohol consumption and improve decision making in alcohol-dependent mice

Ethics Committees in India: Past, present and future

Following watershed amendments in Schedule Y India's star rose rather rapidly on the clinical research (especially clinical trials) horizon. Just as dramatic was the fall of this empire. At the centre of these events has been the participant and indirectly, the Ethics Committee (EC) that is established primarily to protect this individual. This paper traces the evolution of the concept of ECs in India, examines the current state of these committees in the country and suggests the way forward. The Past: The requirement for an EC to oversee clinical research was first made in the ICMR Policy Statement for Ethics published in 1980 and then again in the Schedule Y (1988). Later, both the Amended Schedule Y (2005) assigned regulatory responsibility on the EC and the ICMR Guidelines (2006) described the functioning of ECs. Several challenges including inadequate formal training, contribution from non-technical members, administrative support as well no SOPs and a heavy workload were identified. In the absence of regulatory oversight of ECs, the introduction of the Clinical Trial Registry - India (CTRI) and self-regulation through voluntary accreditation programs brought a measure of accountability and transparency. The Present: A slew of regulatory reforms led to more than 1000 ECs to be registered with CDSCO although the actual impact on participants' protection and safety of these new regulations still remains to be seen. Way Forward: A method to oversee all ECs, improved functioning of ECs including on site monitoring, central ECs for multicentric studies, the development of metrics to assess the ability of ECs to protect the participant are other ideas for the future. Conclusions: Although ECs in India have evolved from being mere rubber stamps for approval of protocols to efficiently functioning accredited ECs, yet there is much to be done for and by Ethics Committees

Effect of combination of Phyllanthus emblica, Tinospora cordifolia, and Ocimum sanctum on spatial learning and memory in rats

Background: There has been a steady rise in number of patients suffering from dementia including dementia associated with Alzheimer′s disease. Effective treatment of Alzheimer′s disease dementia is an unmet medical need. Objective: To evaluate effects of formulation containing combination of Phyllanthus emblica (Pe) and Tinospora cordifolia (Tc) with and without Ocimum sanctum (Os) on learning and memory performance of normal and memory impaired rats in complex maze and compare with effects of Tinospora cordifolia and Phyllanthus emblica alone. Materials and Methods: Wistar rats; either sex (100-150 g) were divided in seven groups Control, Piracetam, Rivastigmine, Tc, Pe, Formulation 1 (Tc + Pe), and Formulation 2 (Tc + Pe + Os).The study was divided in four parts: In part 1 memory enhancement was tested in normal rats. In part 2, 3, and 4 the effects of drugs were tested in Scopolamine-, Diazepam-, and Cyclosporine-induced amnesia. Hebb-Williams maze was used to test for learning and memory. Time required to trace food and number of errors in maze were noted. Results: In normal rats, all test drugs showed significant reduction in time required to trace the food and number of errors after 24 h compared with vehicle control. Formulations 1 and 2 reduced the time required to trace food and number of errors and the results were comparable with positive control groups and comparators Tc and Pe. Formulations 1 and 2 reversed amnesia produced by Scopolamine, Diazepam, and Cyclosporine when compared with vehicle control and showed comparable results with those of positive control groups and comparators Tc and Pe. Conclusion: Formulations 1 and 2 demonstrated nootropic activity and both the formulations showed comparable nootropic activity with that of Tc and Pe alone

Effect of Saraswatarishta in animal models of behavior despair

Background: Saraswatarishta (SA) is a herbo-mineral formulation consisting of 18 plants some of which are Medhyarasayanas. It has been claimed to be useful in treating central nervous system disorders. Objective: To evaluate antidepressant effect of ′Saraswatarishta′(SA) alone and in combination with imipramine and fluoxetine in animal models of depression. Materials and Methods: After obtaining IAEC permission, 144 rats (n = 36/part) were randomized into 6 groups- Group 1: Distilled water (1 mL), Group 2: Imipramine (30 mg/kg), Group 3: Fluoxetine (10 mg/kg), Group 4: SA (1.8 mL/kg), Group 5: Imipramine + SA, Group 6: Fluoxetine + SA. Effects of study drugs were evaluated in forced swim test (FST) with single exposure to FST (Part 1) and repeated exposure for 14 days (Part 2). In Part 3, reserpine was used with FST and effects of study drugs were evaluated against single exposure to FST. Same model was used with repeated exposures to FST (Part 4). In each part, rats were subjected to open field test (OFT) for 5 min prior to final FST. The variables measured: Immobility time in FST; line crossing, rearing and defecation in the OFT. Results: In all four parts, individual drugs and combinations thereof produced significant decrease in immobility time as compared to control, and extent of decrease was comparable amongst these groups. However, values for combination of fluoxetine with SA group were found to be lesser than that for individual agents in Parts 2 and 3. Combination of SA with imipramine did not enhance its anti-depressant effect in any of the parts. OFT findings did not vary significantly amongst the study groups. Conclusion: Decreased immobility in FST and absence of generalized stimulation or depression of motor activity in OFT point towards potential antidepressant effect of Saraswatarishta. Its co-administration with fluoxetine showed more promising effects

A study to assess completeness of project application forms submitted to Institutional Ethics Committees (IEC) of a tertiary care hospital

Objectives: To review Ethics Committee (EC) application forms and to find out similarities and differences in content of five ECs forms in India. Materials and Methods: The completeness of EC application forms was assessed on the following themes: title, study team, sponsor responsibility, scientific aspects, patient safety, regulatory permissions, Informed consent process from 2008-2009. Application forms (available online) of 5 ECs were studied and compared. Results: A total of 445 application forms were analyzed, 382 were academic, 63 were sponsored. The common deficiencies in academic studies were inappropriate titles (25.13%), lack of budget details (90%). More than 95% studies had not mentioned the method of recruitment. The issue of vulnerability was not marked in more than 50% of studies. Compensation for participation/injury was poorly stated in academic (99%) studies. Among industry sponsored studies, 98% were compliant with regulatory permissions and 41% were CTRI registered. The information pertaining to Informed Consent was mentioned in all forms. Comparative analysis of application forms of 5 ECs showed that the requirements for submission were similar except 1-2 ECs asked for additional information like percentage of time allotted by investigator for studies, GCP training of study team, certification by investigator regarding accuracy of local versions of Informed consent. Conclusion: Our study recommends that increased awareness and vigilance by investigators of academic studies regarding submission of applications to EC will increase efficiency and speed of review process. A common application form for all ECs across India would be an important step to achieve uniformity in functioning of ethics committees

Effect of Jyotiṣmatī seed oil on spatial and fear memory using scopolamine induced amnesia in mice

Background: Treatment of memory impairment associated with dementia such as Alzheimer′s disease is still inadequate and requires development of new drugs. Objective: The objective was to evaluate the memory enhancing effect of Celastrus paniculatus seed oil. Materials and Methods: C. paniculatus seed oil was mixed with equal amount of pure ghee and administered orally to mice in the dose of 200 mg/kg/day. Piracetam was used as a standard nootropic. Elevated plus maze and passive avoidance tests were used as a models to test spatial and fear memory respectively. Scopolamine (3 mg/kg, i.p.), was used as an amnestic agent. Results: Mice receiving C. paniculatus showed significant memory enhancement as compared to scopolamine group. The effect of C. paniculatus and combination of C. paniculatus with piracetam was comparable to that with piracetam alone. Conclusion: The present study demonstrates that C. paniculatus seed oil has memory enhancing effect and hence can be developed as a potential drug in the treatment of dementia