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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”
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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
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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]
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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.
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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
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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.
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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.
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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.
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