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EFFECT OF OPIPRAMOL ON SEIZURE THRESHOLD SYNOPSIS FOR M. PHARM DISSERTATION SUBMITTED TO RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE BY Ms. LAKSHMI S. NAIR DEPARTMENT OF PHARMACOLOGY UNDER THE GUIDANCE OF Dr. S Jai Kumar M. Pharm. PhD Professor and H.O.D. DEPARTMENT OF PHARMACOLOGY THE OXFORD COLLEGE OF PHARMACY HONGASANDRA, BANGALORE-68 KARNATAKA 1 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA ANNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION 1. Name of the Candidate and Address a. Permanent Address LAKSHMI S. NAIR D/O K. Swaminathan H.NO :26 /204 "Krishna", Keerthi Nagar, Eroor South PO Ernakulam, Kerala b. Postal Address The Oxford College of Pharmacy , No.6/9, 1st Cross, Begur Road, Hongasandra, Bangalore-560068, Karnataka. 2. Name of the Institute The Oxford College of Pharmacy, No.6/9, 1st Cross, Begur Road, Hongasandra, Bangalore-560068, Karnataka. 3. Course of Study and Subject Master in Pharmacy [Pharmacology] 4. Date of Admission to Course 5. Title of the Topic: 11 July 2013 “ EFFECT OF OPIPRAMOL ON SEIZURE THRESHOLD” 2 6. BRIEF RESUME OF THE INTENDED WORK: 6.1 Need of study: Opipramol (Insidon,Pramolan,Ensidon,Oprimol) is an antidepressant and anxiolytic used in Germany and other European countries.[1][2] This drug has been recently introduced in India. An anxiolytic (also antipanic or antianxiety agent)[3] is a drug that inhibits anxiety. Anxiolytic medications have been used for the treatment of anxiety and its related psychological and physical symptoms. Anxiolytics are also known as minor tranquilizers.[4] Antidepressants are drugs used for the treatment of major depressive disorder and other conditions, including dysthymia, anxiety disorders, obsessive compulsive disorder, eating disorders, chronic pain, neuropathic pain and, in some cases, dysmenorrhea, snoring, migraines, attention-deficient hyperactivity disorder (ADHD), substance abuse and sleep disorders. They can be used alone or in combination with other medications. IUPAC NAME: 4-[3-(5H-dibenzazepin- 5-yl)propyl]-1-piperazine ethanol The most important classes of antidepressants are the selective serotonin reuptake inhibitor (SSRIs), serotonin–norepinephrine reuptake antidepressants (TCAs) oxidase pharmaceutical and monoamine approaches to include psychotherapy, electro-convulsive the inhibitors(SNRIs), tricyclic inhibitors (MAOIs). treatment of Non- depression therapy, acupuncture, exercise, sleep deprivation and bright light exposure.[5] 3 Opipramol acts as a high affinity sigma receptor agonist, primarily at the σ1 subtype, but also at the σ2 subtype with somewhat lower affinity.[1] It is this property which is responsible for its therapeutic benefits against anxiety and depression.[2] Opipramol also acts as a low to moderate affinity antagonist for the D2, 5HT2, H1, H2, and muscarinic acetylcholine receptors. H1 and H2 receptor antagonism account for its antihistamine effects, and muscarinic acetylcholine receptor antagonism is responsible for its anticholinergic properties.[1] Opipramol is similar in structure to tricyclic antidepressants (TCAs) but it is primarily used for the treatment of generalized anxiety disorders (GAD).[6] Generalized anxiety disorder (GAD) is an anxiety disorder that is characterized by excessive, uncontrollable and often irrational worry about everyday things that is disproportionate to the actual source of worry.[7] Anxiolytics becomes prominent after only one to two weeks of chronic administration. Upon first commencing treatment, opipramol is rather sedating in nature due to its antihistamine properties, but this effect becomes less prominent with time. Opipramol is active in several behavioural paradigms indicative of anxiolytic properties at doses (1-10 mg/kg), which are also needed to occupy sigma binding sites. Somewhat higher doses (10-20 mg/kg) are needed for "antidepressant like" effects.[8] Although it is a member of the tricyclic antidepressants, opipramol primary mechanism of action is much different in comparison.[2] Most TCAs act as reuptake inhibitors, but opipramol does not, and instead acts as a sigma receptor agonist, among other properties.[2] Tricyclic antidepressants (TCAs), at supra therapeutic doses can induce seizures. TCAs can block GABAA receptors and decrease inhibitory neuronal signals resulting in seizures. Caution should be exercised when using these medications in patients who may be at a high risk of developing seizures or have a known diagnosis of epilepsy. If TCAs are prescribed they should be titrated slowly and patients should be monitored for adverse events. Since TCA shows seizure threshold activity ,it can be assumed that opipramol may show seizure threshold.[9] The seizure threshold is therefore an important biologic marker. [10] The seizure threshold is a tipping point in a person's brain activity where a seizure will develop. People with seizure disorders tend to have a low seizure threshold, and this can be exacerbated over time, as seizures can have the effect of exciting the brain and increasing the chances of having another 4 seizure. During a seizure, the brain experiences uncontrolled electrical activity, with neurons firing repeatedly and at random. Depending on the area of the brain involved, the patient can experience a variety of symptoms over the course of the seizure, including muscle jerks and confusion. In a person with a low seizure threshold, brain activity is naturally high, and it does not take much excitement to push the patient’s brain into a seizure. [11] Electroconvulsive therapy (ECT), formerly known as electroshock, is a standard psychiatric treatment in which seizures are electrically induced in anesthetized patients for symptom remission. Electroconvulsive therapy can differ in its application in three ways: electrode placement, frequency of treatments, and the electrical waveform of the stimulus. These three forms of application have significant differences in both adverse side effects and symptom remission. After treatment, drug therapy is usually continued, and some patients receive maintenance ECT.[12] 5 6.2 Review of Literature: Sogut, O, et al. (2012) [6] reviewed that opipramol is an antidepressant and anxiolytic drug similar in structure to tricyclic antidepressants (TCAs) but it is primarily used for the treatment of generalized anxiety disorders. Unlike many TCAs, opipramol has no reuptake-inhibiting properties. Opipramol acts as a high affinity sigma receptor agonist. Opipramol acts as a low to moderate affinity antagonist for the dopamine-2 (D2), 5-hydroxtryptamine (5-HT2), histamine 1 (H1), histamine 2 (H2), and muscarinic acetylcholine receptors accounting for its antihistamine effects, and muscarinic anticholinergic properties. Rare case of opipramol overdose case involving a 18-year-old woman, presenting in emergency department (ED) with loss of consciousness and wide complex tachycardia. A firm diagnosis of opipramol overdose was made on the basis of clinical, laboratory and electrocardiogram findings. Hueppe M , et al. (2011) [13] reported that due to its pharmacological properties, opipramol may be useful in the context of evening premedication in anaesthesiology. Opipramol may be used as a premedication in the evening prior to surgery if the primary target is an impact on the experienced quality of sleep. For this a single dosage of 100 mg opipramol is sufficient and can be recommended. Gale CK. (2002) [14] reviewed the treatment of generalised anxiety disorder (GAD).Cognitive therapy, anxiety management therapy; certain antidepressants (paroxetine, imipramine, trazodone, and opipramol), benzodiazeines and buspirone are effective treatments for GAD. Dursun H , et al. (2009) [15] stated that the activation of enzymatic and non- enzymatic antioxidant mechanisms, as well as the inhibition of some toxic oxidant mechanisms, appear to play a role in the antiulcer effect of opipramol. Boerner RJ , et al. (2003) [16] in their study explored Kava-Kava LI150 is well tolerated and as effective as Buspirone and Opipramol in the acute treatment of outpatients suffering from GAD. Kees F , et al. (2003) [17] investigated that in two open, randomized cross-over studies in 20 (study 1) and 18 (study II) healthy volunteers, the relative bioavailability of 50 mg opipramol-2HCl from a sugar-coated tablet was compared with an aqueous solution, and of 100 mg opipramol-2HCl from a newly developed film-coated tablet was compared with the sugar-coated tablet. The concentrations of opipramol were determined in plasma by high-performance liquid chromatography 6 (HPLC) with photometric detection. The mean dose corrected kinetic parameters of opipramol were similar after administration of all formulations. The peak concentrations of opipramol were 13-15 mg ml-1 (study I) and 28 mg ml-1 (study II). They were achieved after 3 h. The area under the plasma concentration-time curve was about 170 mg ml-1 h (study I) and about 320 mg ml-1 h (study II). The terminal plasma half-life was 11 h. Bioequivalence was proven between sugarcoated tablet and aqueous solution, and between film-coated tablet and sugar-coated tablet, respectively. Francesco Pisani , et al. (2002) [18] proved that psychotropic drugs, especially antidepressants and antipsychotics, may give rise to some concern in clinical practice because of their known ability to reduce seizure threshold and to provoke epileptic seizures. C. Edward Coffey , et al. (1995) [19] studied initial seizure threshold by means of a structured stimulus dosage titration procedure in a clinical sample of 111 depressed patients undergoing brief-pulse, constant current electroconvulsive therapy (ECT). Initial seizure threshold was approximately 60 millicoumbs (mc) (10 Joules) on average, but varied widely (6-fold) across patients. Initial seizure threshold was predicted by four variables: electrode placement (higher with bilateral), gender (higher in men), age (higher with increasing age), and dynamic impedance (inverse relationship). Use of neuroleptic medication was associated with a lower seizure threshold. 6.3 Objective of study: The objective of the proposed study is to investigate the effect of opipramol on seizure threshold. 7. MATERIALS AND METHODS: 7.1 Source of Data: Data will be obtained from CD-ram, Internet facilities, Literatures and related articles from libraries of The Oxford College of Pharmacy, NIMHANS and other Research Publications and Journals. 7 7.2 Method of Collection of Data: The data collected will be based on animal experimentation as per the parameters studied under animal model. EXPERIMENTAL MODEL Source of animals : Male Wistar Albino rats weighing between 180-200 gm are obtained from animal house of NIMHANS, Bangalore. Study site: National Institute of Mental Health and Neurosciences (NIMHANS), Department of Psychopharmacology, Bangalore. Experimental Model Male Wistar rats weighing 180-200g will be grouped into four groups (n=15). Group I (Control) : will be treated with vehicle. Group II (Treatment group) : will be treated with opipramol of dose 5mg/kg. Group III (Treatment group): will be treated with opipramol of dose 25mg/kg ( 5 times More than the first dose) Group IV (Treatment group): will be treated with opipramol of dose 50mg/kg ( 10 times More than the first dose) On first day opipramol is administered to all the group of rats orally and on the fourth day all the rats receive a 3-millicoumbs (mC) electroconvulsive shock (ECS) stimulus.[20] This process is continued by increasing the stimulus intensity by 2-mC until the rats shows seizure threshold. Statistical Analysis: All data will be expressed as mean ± SD. Student’s t-test will be performed for each experimental group. Data will be compared by analysis of variance (ANOVA) and only values with P<0.05 will be considered as significant. 7.3 Does the study require any investigation or interventions to be conducted on patients or the human or animals? If so please describe briefly: YES 8 Study requires investigation on animals. The effects of the drug will be studied on various parameters using rats as experimental animal model. 7.4 Has ethical clearance been obtained from your institute Ethical Committee approval letter is enclosed. 8. List of References: 1. Moller HJ, Volz HP, Reimann IW and Stoll KD. Opipramol for the treatment of generalized anxiety disorder: a placebo-controlled trial including an alprazolamtreated group. Journal of Clinical Psychopharmacology 2001; 21(1): 59–65. 2. Muller WE, Siebert B, Holoubek G and Gentsch C. Neuropharmacology of the anxiolytic drug opipramol, a sigma site ligand. Pharmacopsychiatry 2004; 37(3): 189– 197. 3. “Antianxiety agent” at Dorland's Medical Dictionary. 4. “Anxiolytic (tranquilizer)”.Memidex (WordNet) Dictionary/Thesaurus. Retrieved 2010-12-02. 5. http://www.cet.org/eng/Therapy_ExposureRisks_ENG.html 6. Sogut O, Kaya H, Gokdemir MT, SezenY , et al. Opipramol overdose presented with wide-complex tachycardia to the emergency department. Hong Kong Journal of Emergency Medicine 2012; 19(2): 121-125. 7. Torpy JM, Burke AE and Golub RM. Generalized Anxiety Disorder. JAMA 2011; 305(5): 522–522. 8. Muller WE, Siebert B, Holoubek G and Gentsch C. Neuropharmacology of the anxiolytic drug opipramol, a sigma site ligand. Pharmacopsychiatry 2004; 37(3): 189197. 9. Oh CY and Bainbridge J. Lowering the Seizure Threshold Associated with Antidepressants, Stimulants, Antipsychotics, and Others. Ment Health Clin 2012; 2(5): 21. 10. Kurinji S and Andrade C. ECS seizure threshold: normal variations, and kindling effects of subconvulsive stimuli. J ECT 2003; 19(1): 31-37. 11. http://www.wisegeek.com/what-is-a-seizure-threshold.htm 12. Rudorfer, MV, Henry, ME and Sackeim, HA. Electroconvulsive therapy. Psychiatry 2003; 2: 1865–1901. 9 13. Hueppe M, Hartge D, Stoll KD, Ros A, et al. Opipramol improves subjective quality of sleep the night prior to surgery: confirmatory testing of a double-blind, randomized clinical trial. Neuropsychobiology 2011; 64(1): 24-31. 14. Gale CK. The treatment of generalised anxiety disorder: A systematic review. Panminerva Med 2002; 44(4): 283-286. 15. Dursun H, Albayrak F, Bilici M, Koc F, et al. Gastroprotective and antioxidant effects of opipramol on indomethacin-induced ulcers in rats. Yakugaku Zasshi 2009; 129(7): 861-869. 16. Boerner RJ, Sommer H, Berger W, Kuhn U, et al. Kava-Kava extract LI 150 is as effective as Opipramol and Buspirone in Generalised Anxiety Disorder--an 8-week randomized, double-blind multi-centre clinical trial in 129 out-patients. Phytomedicine 2003; 10(4): 38-49. 17. Kees F, Jehkul A, Bucher M, Mair G, et al. Bioavailability of opipramol from a filmcoated tablet, a sugar-coated tablet and an aqueous solution in healthy volunteers. Arzneimittelforschung 2003; 53(2): 87-92. 18. Francesco Pisani, Giancarla Oteri, Cinzia Costa, Giorgio Di Raimondo, et al. Effects of Psychotropic Drugs on Seizure Threshold. Drug Saf 2002; 25(2): 91-110. 19. C. Edward Coffeya, Joseph Luckec, Richard D. Weinerd, Andrew D. Krystald, et al. Seizure threshold in electroconvulsive therapy: I. Initial seizure threshold. Biological Psychiatry 1995; 37(10): 713–720. 20. Andrade C, Akki A, Nandakumar N and Chandra JS. Confirmation of whole-brain kindling with repeated sub threshold electroconvulsive shocks: a controlled study. J ECT 2003; 19(2): 81-83. 10 9. SIGNATURE OF THE CANDIDATE: [LAKSHMI S.NAIR] 10. REMARKS OF THE GUIDE: 11. 11.1 Name and Designation of Guide Recommended Dr.S. Jai Kumar Professor and HOD Department of Pharmacology. The Oxford College of Pharmacy, Hongasandra, Bangalore-68. 11.2 Signature 11.3 Head of the Department Dr. S. Jai Kumar Professor and HOD Department of Pharmacology The Oxford College of Pharmacy, Hongasandra, Bangalore-68. 11.4 12. 12.1 12.2 Signature Remarks of the Principal Forwarded to University for scrutiny Signature Dr.Padmaa M. Paarakh Principal The Oxford college of Pharmacy, Hongasandra, Bangalore-68. 11