Rajivgandhiuniversity of Health Scienceskarnataka, Bengaluru

RajivGandhiUniversity of Health SciencesKarnataka, Bengaluru

“STUDIES ON THE PHARMACODYNAMIC AND PHARMACOKINETIC INTERACTIONS BETWEEN BIOFLAVONOIDS AND CALCIUM CHANNEL BLOCKERS”

A Protocol submitted to Rajiv Gandhi University of Health Sciences Karnataka, Bengaluru

In partial fulfillment of the requirement for the award of

MASTER OF PHARMACY

PHARMACOLOGY

O.PRIYANKA

Department of Pharmacology,

NationalCollege of Pharmacy,

Balraj-Urs Road,

Shimoga-577 201

Karnataka-INDIA

RajivGandhiUniversity of Health Sciences, Karnataka, Bengaluru

Annexure – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

01 / Name and Address of the Candidate / O.PRIYANKA,
D/O O.APPALARAJU,
DOOR NO. 30/5/35,
KRISHNA GARDENS,
DABA GARDENS,
VISHAKAPATNAM, A.P-530020
02 / Name of the Institution / NATIONAL COLLEGE OF PHARMACY, BALRAJ-URS ROAD,
SHIMOGA-577201,
KARNATAKA, INDIA
03 / Course of the Study
Branch / M. Pharm. (Pharmacology)
04 / Date of Admission to course / 15-11-2010
05 / Title of the Topic / STUDIES ON THE PHARMACODYNAMIC AND PHARMACOKINETIC INTERACTIONS BETWEEN BIOFLAVONOIDS AND CALCIUM CHANNEL BLOCKERS
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. / Enclosure – VI-A
08 /

List of References (About 4 – 6)

/ Enclosure – VII
09 /

Signature of the Candidate

10 /

Remarks of the Guide

/ The present research work is original and not published in any of the Journals. This work can be carried out in our Pharmacology Department laboratory.
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.I.J. KUPPAST M.PHARM,Ph.D,FIC.
PROFESSOR
DEPARTMENT OF PHARMACOLOGY,
NATIONALCOLLEGE OF PHARMACY,
SHIMOGA-577201
KARNATAKA, INDIA
N.A.
N.A.
Dr. K.L.MANKANI M.Sc.,Ph.D
HEAD OF THE DEPARTMENT,
DEPARTMENT OF PHARMACOLOGY,
NATIONALCOLLEGE OF PHARMACY,
SHIMOGA-577201
KARNATAKA, INDIA
12 /

Remarks of the Principal

12.1. Signature / The present study is permitted to perform in the Pharmacology Department laboratory of our Institution and the study protocol has been approved by IAEC.
Principal

Enclosure – I

Brief resume of intended work:

Need for study:

Herbs have been used for medicinal purposes since the beginning of recorded time. Although most people in the United States believe that herbs are harmless plants, about one third of our drugs (including digitalis, morphine, atropine, and several chemotherapeutic agents) were developed from plants1.

Most of the plants contain bioflavonoids as major active constituents. Flavonoids or bioflavonoids (from the Latin word flavus meaning yellow), also collectively known as Vitamin P and citrin3are a class of plant secondary metabolites or yellow pigments having a structure similar to that of flavones4.

Flavonoids commonly interact with most of the drugs and they claim to have effect on CVS and blood vessels. Therefore, when bioflavonoids are taken concurrently with antihypertensive drugs, interactions are possible1.

When herbal therapies and drugs are used together, they can interact in our body, causing changes in the way the herbs and/or drugs function. Such changes are called drug-herb interactions. They can be beneficial or harmful, depending on type of interactions2.

Flavonoids have been used as effective constituents of several pharmaceuticals used for treatment of capillary fragility and phlebosclerosis. The activities of certain flavonoids inhibit capillary permeability5-8.Flavanoid namely Rutin inhibits platelet aggregation, as well as decreasing capillary permeability, making the blood thinner and improving circulation9.Cordio dichotomaForst.f.Fruits belonging to the family Boraginaceae is medium sized tree with a short, usually crooked trunk of 3-4ft. in grith10, containing bioflavonoids have been selected for its interaction with anti-hypertensives like calcium channel blockers in the study.

Hypertension (HTN) is elevated blood pressure. Conventional anti-hypertensive drugs are usually associated with many side effects. About 75 to 80% of the world population use herbal medicines, mainly in developing countries, for primary health care because of their better acceptability with human body and lesser side effects11.

In the present study bioflavanoids needs to be coupled with selective antihypertensive drugs like calcium channel blockers and more scientific research needs to be done to verify the effectiveness, and elucidate the safety profile of such herbal remedies for their antihypertensive potential.

Calcium channel blockers are the first line drugs in the treatment of hypertension. Hence it is claimed to study the calcium channel blockers in the present study.

Calcium is necessary for excitation-contraction coupling in both skeletal and smooth muscles. Skeletal muscles have contractile activity whereas cardiac and vascular smooth muscles contraction depends on extra cellular calcium concentration.

Mechanism of action of calcium channel blockers:

Calcium channel blockers mainly act by inhibiting the entry of calcium from L channel into myocardial and vascular smooth muscles thus decreasing the availability of intracellular calcium.

Pharmacodynamics actions of calcium channel blockers on peripheral blood vessels:Calcium channel blocker relaxes the vascular smooth muscles in systemic as well as pulmonary arterial circulation.They decrease vascular resistance and B.P in both pulmonary and systemic circulation12-13.

Number of studies has been reported on calcium channel blockers and bioflavonoids. However the interactions between bioflavonoids and calcium channel blockers have not been documented in scientific literature. Hence the present study is aimed at investigation of pharmacodynamic and pharmacokinetic interactions between bioflavonoids and anti-hypertensive drugs like calcium channel blocker.

Enclosure – II

6.2 Review of Literature:

1)The Bioflavonoid Galangin Blocks Aryl Hydrocarbon Receptor Activation and Polycyclic Aromatic Hydrocarbon14.

2)Mechanisms for the Inhibition of DNA Methyltransferases by Tea Catechins and Bioflavonoids15.

3)Bioflavonoids- Their pharmacokinetic interaction with cytochrome P450 isozymes and P-glycoprotein16.

4)Interaction of calcium channel blockers (CCB’s) with Noradrenaline and Terbutalin on isolated right ventricle from normal and diseased rats17.

5)Bioflavonoids Classification, Pharmacological, Biochemical Effects and Therapeutic Potential18.

6)Cardiac effects of calcium channel blockers in human volunteers19.

Enclosure – III

6.3 Objectives of present study:

1)The present studyis planned to investigate the Pharmacodynamic and Pharmacokinetic Interactions between Bioflavonoids and Calcium Channel Blockers in rats.

2)In view of this some of the flavonoids have been isolated from selected plant fruits.

3)The isolated flavonoids from the plant subjected to phytochemical analysis, TLC, Column chromatography and elucidation of structures by spectral analysis.

4)The selective calcium channel blockers will be obtained from the market.

5)The identified flavonoids and selected calcium channel blockers are subjected for pharmacokinetic and pharmcodynamic study.

6)This study shows drug- herb interaction.

Enclosure – IV

Materials and methods:

7.1 Source of data:

The required data will be obtained from:

Electronic data (Internet).

Online Journals
Wikipedia.in
Google

2. Published research papers.

3. Review and research articles from Journals.

4. Library, National College of Pharmacy, Shimoga.

Enclosure – V

7.2Methods of collection of data:

1)In the present study flavonoids will be isolated from Cordia dichotoma Forst.f fruit and used for the study.

2)The plant will be identified and authenticated with the help of botanist.

3)Plants are collected and subjected for extraction and fractionation.

4)Fractionated compound will be subjected to phytochemical analysis, TLC, Column chromatography and elucidation of structures by spectral analysis.

5)Procurement of calcium channel blockers like Verapamil, Nifedipine and Amlodipine from local market.

6)The identified flavonoids and selected calcium channel blockers are subjected for pharmacokinetic and pharmcodynamic study.

7)Results are analysed by ANOVA test.

Enclosure – VI

7.3 Does the study require any investigation or intervention to be conducted on patients or other humans/animals?

As per the standard procedure, to study pharmacodynamic and pharmacokinetic interactions between bioflavonoids and calcium channel blockerswill be carried out on the wistar albino rats.

Enclosure – VI-A

7.4 Has ethical clearance been obtained from your Institution?

Ethical clearance is provided by the Institution.

Clearance number: NCP/IAEC/CL/24/05/2011-12.

Enclosure – VII

List of References:

1)Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States: results of a follow-up national survey. JAMA, 1998. 280: p.1569-1575.

2)Eisenberg DM and Kaptchuk TJ. The Risk-benefit profile of commonly used herbal therapies: ginko, st.John’s Wort, Ginseng, Eichinacea, Saw Palmetto and Kava. Annals of internal medicine, 2002. 136: p.42-53.

3)Vitamin P, dictionary results,

4)Flavonoids (isofloavnoids and neoflavonoids), Compendium of chemical terminology.

5)Felicia V S, Najla G,Ann P C,Madeleine M and Keneeth K C,“Inhibition of Human Breast cancer cell proliferation anddelay of mammary tumorigenisis by flavonoids and citrusjuices”, Nutrition and Cancer; 1996, 26:167-181.

6)Catherine C,Malc S, Esther H L,Vadimir A,Krutorslaikh,etal. “Lack of tumour-Promoting effects of flavonoids: studieson rat liver preneostatic foci and on In vivo and In vitro gapjunctional inter cellular communication”, Nutrition and Cancer; 1996,26:251-263.

7)Paul P, Ritra J,Ritva S, Mackku H, Lyly T, EeroP andArpo A,“Dietary flavonoids and the risk of lung cancer and othermalignant neoplasms”, American Journal of Epidemiology; 1997,146:223-230.

8)Fritz B,Tobias S,Albrecht K,Chaelotte B,Kent C, et al.“Selected novel flavones inhibit the DNA binding or the DNAreligation step of eukaryotic topoisomerase-I”,Journal of Biological Chemistry;1996, 271:2262-2270.

9)Navarro-Núñez et al. "Apigenin Inhibits Platelet Adhesion and Thrombus Formation and Synergizes with Aspirin in the Suppression of the Arachidonic Acid Pathway", Jounal of Agricultural and Food Chemisry; 2008, 56 (9): 2970–2976.

10)The Wealth of India, A Dictionary of Indian Raw Materials and Industrial Products-Raw Materials Series, Publication and Information Directorate, CSIR, New Delhi, vol.2, 1950. p. 346-348.

11)Tabassum N and Ahmad F,“Role of natural herbs in the treatment of hypertension”, Pharmacognosy Review; 2011, 5:30-40.

12)Satoskar R S, Bandarkar S D, Nirmala N Rege, Pharmacology and Pharmacotherapeutics, Popular Publications, 19th Edition, p.395-397.

13)Tripathi K D, Essentials of Medical Pharmacology, Jaypee Brothers Medical Publishers, New Delhi 5th Edition, p.493-498.

14)Shafat A Quadri, Ariful N Qadri, Mark E, Hahn, Koren K Mann, David H, and Sherr, “The Bioflavonoid Galangin Blocks Aryl Hydrocarbon Receptor Activation and Polycyclic Aromatic Hydrocarbon”, Journal of Molecular Pharmacology; 2000, 58(3): 515-525.

15)Won Jun Lee, Joong-Youn Shim and Bao Ting Zhu,“Mechanisms for the Inhibition of DNA Methyltransferases by Tea Catechins and Bioflavonoids”,Journal of Molecular Pharmacology; 2005, 68(4): 1018-1030.

16)Sripal Reddy M, Raj Narayana K, Chaluvadi M R and Krishna D R,“Bioflavonoids- Their pharmacokinetic interaction with cytochrome P450 isozymes and P-glycoprotein”, Indian Journal of Pharmaceutical Sciences; 2001, 63(3): 187-195.

17)Praveen Bhugra andGulati O D,“Interaction of calcium channel blockers (CCB’s) with Noradrenaline and Terbutalin on isolated right ventricle from normal and diseased rats”, Indian Journal of Pharmacology; 1998, 30: 82-88.

18)Raj Narayana K, Sripal Reddy M, Chaluvadi M R and Krishna D R,“Bioflavonoids Classification, Pharmacological, Biochemical Effects and Therapeutic Potential”, Indian Journal of Pharmacology; 2001, 33: 02-16.

19)Sharma P, Kulshreshtha S, Sharma A L, Srivastava R K and Jain V K, “Cardiac effects of calcium channel blockers in human volunteers”,Indian Journal of Pharmacology; 1992, 24: 223-226.