AStudy on Effect of Losartanon the Pharmacokinetic and Antidepressant Activity of Sertraline

M. PHARM DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE

BY

Mr. JEEVAN DEEP KANDELB.Pharm.

UNDER THE GUIDANCE OF

Dr. SHIVAKUMAR SWAMY M.Pharm., Ph. D.

Principal & HOD

MALLIGE COLLEGE OF PHARMACY, BANGALORE.

MALLIGE COLLEGE OF PHARMACY

#71 SILVEPURA,BANGALORE 90

Rajiv Gandhi University of Health Sciences,

Karnataka, Bangalore.

Annexure – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

01 / Name and Address of the Candidate / Jeevan Deep Kandel.
S/O Panchhi Raj Kandel
Tulsipur-9, Doghare, Dang, Rapti zone, Nepal
02 / Name of the Institution / Mallige College of Pharmacy
#71 Silvepura,
Post : Chikkabanavara
Bangalore 90
03 / Course of the Study Branch / M.Pharm (Pharmacology)
04 / Date of Admission to course / 07/01/2013
05 / Title of the Topic / Study on effect of pantoprazole on the pharmacokinetics and antidepressant activity of sertraline.
06 / Brief resume of the intended work
6.1. Need for the Study / Enclosure – I
6.2. Review of the Literature / Enclosure – II
6.3. Objective of the Study / Enclosure – III
07 / Materials and Methods
7.1. Source of data / Enclosure – IV
7.2. Methods of collection of data / Enclosure – V
7.3. Does the study require any Investigations on animals?
If yes give details / Enclosure – VI
7.4. Has ethical clearance been obtained from your institutionin case of 7.3 / Yes
08 / List of References / Enclosure – VII
09 / Signature of the Candidate / (Jeevan Deep Kandel)
10 / Remarks of the Guide / The present research work is original and not published in any of the journals with best of my knowledge upon extensive literature review. This work will be carried out in the Pharmacology laboratory by Mr. Jeevan Deep Kandelunder my supervision.
11 / Name and Designation of
(in Block Letters)
11.1. Guide
11.2.Signature
11.3.Co-Guide (if any)
11.4.Signature
11.5. Head of the Department
11.6.Signature / Dr. SHIVA KUMARSWAMYM. Pharm., Ph.D.
Principal & HOD
Mallige College of Pharmacy,
Bangalore, Karnataka.
Dr. SHIVAKUMAR SWAMYM. Pharm., Ph. D.
Principal & HOD
Mallige College of Pharmacy,
Bangalore, Karnataka
12 / Remarks of the Principal
12.1. Signature / The present study is permitted to perform in the Pharmacology laboratory of our institution and the study protocol has been approved by IAEC.
(Dr. Shivakumar Swamy)

1

ENCLOSURE- I

06. Brief resume of the intended work

Introduction

Drug-Drug Interaction

Drug interaction is the modification of the effect of a drug when administered with another drug. The effect may be an increase or a decrease in the action of either substance, or it may be an adverse effect that is not normally associated with either drug. The particular interaction may be the result of a chemical-physical incompatibility of the two drugs or a change in the rate of absorption or the quantity absorbed in the body, the binding ability of either drug, or an alteration in the ability of receptor sites and cell membranes to bind either drug. Most adverse drug-drug interactions are either pharmacodynamic or pharmacokinetic in nature1.

Drugs besides their beneficial effects may also induce illness and death. Whenever two or more drugs are being taken, there is a chance of interaction. Drug-drug interactions can alter patient’s response to therapy. The net result may be enhanced or diminished effects of one or both of the drugs or the appearance of a new effect which is not seen with either drug alone. The possibility of drug interactions increases as the number of drugs being taken increases. Therefore, patients who take several drugs are at the greatest risk for interactions. The concept of drug interaction is also extended to include; drug-drug interaction, drug-food interaction, drug-herbal interaction, drug-laboratory test interaction and drug-condition interaction2

There are different mechanisms by which drugs interact with each other, and most of them can be divided into two general categories and they are pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic drug-drug interactions can occur at the level of absorption, distribution, or clearance of the affected agent which will ultimately alter the concentration and duration of the drug available at the receptor sites. The most important pharmacokinetic interactions are those involving cytochrome P450 isoenzymes in hepatic metabolism.There are more than 50 CYP450 enzymes, but the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 enzymes metabolize 90 percent of drugs3-4.

The clinical significance of a specific drug-drug interaction depends on the degree of accumulation of the substrate and the therapeutic window of the substrate5. Pharmacodynamics interaction is due to interaction between agonist and antagonist at drug receptors. It is seen when two drugs have additive, synergistic or antagonist pharmacological effects. Either type of drug interaction can result in desired or undesired effects in some individuals.

Drug-drug interactions among widely and chronically prescribed medications are a relevant health issue in clinical practice. Drug-drug interactions may lead to adverse drug reactions that can be severe enough to require hospitalization6.

However, combinations of potentially interacting drugs do not necessarily result in adverse clinical manifestations, if they are knowingly prescribed and properly managed. Pharmacokinetic drug interactions in particular are often manageable, and their risk may be lessened by dose adjustment7. Otherwise, the burden of drug-drug interaction, in terms of patient's safety, may be reduced by preventing concomitant use of potentially interacting drugs and, whenever possible, by replacing drugs at interaction risk with effective but safer alternative medications belonging to the same drug class.

6.1 Need for Study

Hypertension is a condition which affects large population in the society. It is emerged as an major public health problem in India and many other developing countries8. Increasing hypertension in India and other developing countries has been related to sedentary lifestyle, excess dietary salt, calorie and alcohol intake, increasing generalized and central obesity and stress of migration and urbanization9.

Thirty five percentage of the patient with pulmonary hypertension suffered from mental depression with the most being major depressive disorder (15.9%) and panic disorder (10.4%). The prevalence of mental disorder in patient with pulmonary hypertension increased significantly with functional impairment, from 17.7% to 61.9%. Only 24.1% of patient with pulmonary hypertension with mental disorder were receiving psychological or psychotherapeutic treatment. 35% of the population is suffering from both hypertension and mental depression respectively. There is compulsion that 35% of the population has to use the antihypertensive and antidepressants simultaneously for a long period of time to maintain their health10.

The mental depression is one of the major disorders in the modern era affecting large population. Depression is characterized by symptoms like sad mood, loss of interest and pleasure, low energy, worthlessness, guilt, psychomotor retardation or agitation, change in appetite or sleep, melancholia, suicidal thoughts etc. antidepressants are used to elevate mood in depressive illness5.

Depression affects over 120 million people worldwide. It can interfere with a person's ability to work, make relationships difficult, and destroy quality of life. In severe cases it leads to suicide, causing 850,000 deaths a year11. Indians are the world's most depressed people with nearly 36 per cent suffering from Major Depressive Episode (MDE). Depressive disorder affects approximately 18.8 million American adults or about 9.5% of the U.S population age 18 and older12. Depression will be the second largest killer after heart disease by 2020-studies show depression is a contributory factor to fatal coronary disease13.

The two drugs selected for the present study are losartan and sertraline used in hypertension and depression respectively. Since both the drugs are administered for longer duration and metabolized by the common enzymes CYP2C9, there could be significant drug interaction which may be harmful to the patient. Hence the present study has been taken up to evaluate extent of pharmacokinetic and pharmacodynamic interaction and also to predict the mechanism of interaction.

ENCLOSURE: II

6.2 REVIEW OF LITERATURE

Atherton and co-workers reported the study on rat for the losartan interaction with renal lithium excretion and concluded that losartan when given orally in the rat at a dose of 10 mg/ kg/ day over 5 days does not modify the renal lithium handling. They suggest that blockade of the angiotensin II receptor does not interfere at proximal tubular site14.

Kaukonen and co-workers conducted a research on the effect of fluconazole or itraconazole on metabolism of losatan to E-3174 and found that fluconazole but not itraconazole decreases the metabolism of losartan to E-3174. fluconazole caused only a significant increase in the AUC and t1/2 of the unchanged losartan15.

A number of studies have reported that the coadministration of sertraline with TCA can increase the plasma concentrations of desipramine, imipramine and nortriptyline. The plasma levels of a co-administered CYP2D6 substrate can be increased by an average of 19% following administration of sertraline at 50 mg/day. The observation shows the increases in the plasma concentration of TCAs only weak inhibition of this system16.

Pinninti and co-workers reported evidence for significantinhibition of clozapine’s metabolism by sertraline.Under 600 mg clozapine and 300 mg sertraline, the serumconcentration of clozapine was 1300 ng/mL, and it decreasedby 40% after discontinuation of sertraline . A similar observation was described byChong and co-workers, who found that in a patienttaking 175 mg clozapine, there was a 2.1-fold increase inclozapine serum concentration after addition of 50 mg sertraline,which disappeared after discontinuation of theSSRI17.

A recent study in 11 patients with schizophrenia or schizoaffective disorder stabilized on risperidone therapy (4–6 mg/day) has demonstrated that an 8-week co-medication with sertraline, 50–100 mg/day, did not change significantly steady-state plasma concentrations of risperidone active fraction. However, in the two patients receiving the highest dose of sertraline, 150 mg/day, at week 8 total plasma risperidone concentrations were increased by 36% and 52%, respectively, as compared to baseline values, presumably because of a dose-dependent inhibition of CYP2D6-mediated 9-hydroxylation of risperidone18.

When sertraline was administered to patients maintained on methadone (a CYP3A4 substrate), a transient increase in methadone serum levels over the first 6 weeks of treatment was observed16.

Sertraline has linear pharmacokinetics so that increases in dose lead to proportional increases in drug concentration. The half-life of sertraline is about 26 hr so that it reaches a steady state in one week, according to the product monograph.Hypoglycemia associated with sertraline and co administration of oral hypoglycemics belonging to the sulphonylurea derivatives has rarely been reported19.

ENCLOSURE:III

6.3 OBJECTIVE OF THE STUDY

  • To study the effect oflosartan on pharmacokinetic parameters of sertraline in healthy albino rabbits.
  • To study the possible interactions oflosartan on anti-depressant activity of sertraline in healthy albino wistar rats and albino mice.
  • To suggest the alterations in the dose and frequency of administration of sertraline, if necessary.

ENCLOSURE: IV

7. Materials and method:

7.1 Source of data

The work is aimed to generate data from the experiments to be conducted at pharmacology laboratory of our institution.

Animals

Adult male wistar rats and rabbits will be used for this purpose. The animal will be obtained from animal house of Mallige College of Pharmacy. Animal clearance will be obtained from institutional animal ethical committee for experimental purpose. They will be maintained under laboratory condition with controlled environment of temperature, humidity as per committee for the purpose of control and supervision of experiments on animal (CPCSEA) guidelines. They will be provided with standard diet and water ad libitum.

Drugs

Losartan and sertraline receive as a gift sample from manufacturers will be used in this study, all other chemicals used will be of analytical grade.

ENCLOSURE: V

7.2 Method of collection of data

A. Study of effect of losartan on pharmacokinetic parameters of sertraline in albino rabbits.

The four healthy albino male rabbits will be treated with sertraline (20mg/kg, p.o).The concentration of the sertraline in blood at different time interval 0, 2, 4, 8, 12, 16, 24will be measured byHPLC method22.In this method, the estimation of sertraline will be carried out using a reversed phase C18 column(Grace smart RP-18), mobile phase (Acetonitrile/0.25 M potassium phosphate (pH2.7) 30:70v/v) and UVdetection at a wavelength of 235 nm. Flow rate maintained at 1.0 ml/min.

In the second part of experiment, losartan (10 mg/kg, p.o) will be administered to the same group of animals once daily for one week after the gap of 15 days. On the 8th day, the sertraline (20mg/kg, p.o.) will be administered and the concentration of sertralineat different time interval will be measured in serum. The data obtained will be subjected to Ramkinsoftware to obtain the following parameters (doses of two drugs have selected depending on previous experimental studies on animals).

  • tmax (Time of peak plasma concentration)
  • t1/2 (Terminal half life)
  • Cmax (Peak plasma concentration)
  • AUC (Area under curve)
  • AUMC(Area under movement curve)
  • MRT (Mean residential time)

B.Effect of omeprazole treatment on anti-depressant activity of sertraline

The effect of omeprazole treatment on anti-depressant activity of sertraline will be studied using two animal models:

  1. Despair swim test in rats.
  2. Tail suspension in mice.

I. Despair swim test in rats20

Six male albino rats weighing between 160-180g will be selected and forced to swim inside in a vertical plexiglas cylinder (height:40cm, diameter:18cm, containing 15cm of water maintained at 25oC) and total duration of immobility will be measured during a 5 min test. An animal will be judged to immobile whenever it remains floating passively in the water in a slightly hunched but up right position, its nose just above the surface.

The rats will be administered with sertraline (20mg/kg, p.o.) and the duration of immobility will be recorded at different time interval 0, 2, 4, 8, 12, 16, 24hr. In the next phase of experiment, same group of animals will be administered after the gap of 15 days with losartan (4mg/kg, p.o) daily once for one week. On the 8th day, sertraline (20mg/kg, p.o.) will be administered and the test will be repeated.

II. Tail suspension in mice

Male Swiss albino mice weighing between 18-22 g will be selected and suspended on the edge of table 50cm above the floor by adhesive tape placed approximately 1cm from tip of the table and total duration of immobility will be measured during a 6min test. An animal will be judged to be immobile when it did not show any movement of body and hanged passively.

Six albino mice weighing between 18-22 g will be selected and administrated with sertraline (10mg/kg, p.o) andtotal duration of immobility will be measured during a 6min test. After the gap of 15 days, the same animals will be treated with losartan (30mg/kg, p.o) once daily for one week. On 8thday sertraline (10mg/kg, p.o) will be administered and the test will be repeated.

Experimental design

SL.NO. / METHODS / NO. OF ANIMALS
I. / Pharmacokinetic study / 4 Albino rabbits.
II.
1.
2. / Pharmacodynamic study
(Anti-depressant)
Despair swim test in rats.
Tail suspension in mice / 6 Male Albino wistar rats.
6 Male Albino mice.

Statistical analysis:

Data will be reported as mean ± SEM and Annova one way tests will be used for the level of significance.

Enclosure VI

1.Does the study require any investigation or interventions to be conducted on patients or other humans and animals? If so please describe briefly.

The proposed study requires the investigation on albino mice,albino rats and rabbits for thepharmacokinetic and anti-depressant activity.

2. Has ethical clearance been obtained from your institution in case of 1?

The present study protocol will be approved from Institutional Animal EthicalCommittee (IAEC).

ENCLOSURE: VII

REFERENCES

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  2. Sharma HL SK, editor. Principle of Pharmacology. Hyderabad: Parasb medical publisher; 2007.
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  5. Goodman, Gilman's The pharmacological Basis of TherapeuticsThe Pharmacological Basis of Therapeutics. New York: McGraw Hill; 2011.
  6. Enderle C, Muller W, Grass U. Drug interaction:omeprazole and Phenprocoumon. 2001;1:2.
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  8. Yusuf S, Reddy KS, Ounpuu S, Anand S. Global burden of cardiovascular diseases Part I. 2001;104(2746-53).
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