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					PHARMOCOLOGICAL STUDIES OF AQUEOUS EXTRACTS OF
Cyperus rotundus Linn. ON PLASMA ADIPONECTIN LEVELS AND
   GLUCOSE TOLERENCE IN DIET FED OBESE WISTAR RATS




                    SYNOPSIS FOR
                M.PHARM DISSERTATION




                   SUBMITTED TO
    RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
              BANGALORE, KARNATAKA.




                       BY
             VISHWESHWAR M DHARASHIVE
                    M. PHARM PART-I
           DEPARTMENT OF PHARMACOLOGY
           NARGUND COLLEGE OF PHARMACY
                  BANGALORE-85
                     (2009-2011)


    RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
             BANGALORE, KARNATAKA.
                                 ANNEXURE-II

     PROFORMA FOR REGISTRATION OF SUBJECTS FOR PG DISSERTATION


1.   Name of the candidate and            VISHWESHWAR MAHISHANKAR
                                          DHARASHIVE,
     address(in block letters)
                                          NARGUND COLLEGE OF PHARMACY,
                                          DATTATREYA NAGAR, II MAIN, 100FEET
                                          RING ROAD, BSK III STAGE,
                                          BANGALORE-85.




2.   Name of the institution              NARGUND COLLEGE OF PHARMACY,
                                          DATTATREYA NAGAR, II MAIN, 100FEET
                                          RING ROAD, BSK III STAGE,
                                          BANGALORE-85.

3.   Course of study and subject          MASTER OF PHARMACY IN
                                          PHARMACOLOGY



4.   Date of the admission                8th JUNE, 2009



5.   Title of the topic:


     PHARMOCOLOGICAL STUDIES OF AQUEOUS EXTRACTS OF Cyperus
     rotundus Linn. ON PLASMA ADIPONECTIN LEVELS AND GLUCOSE
     TOLERENCE IN DIET FED OBESE WISTAR RATS




                                      1
6.
     BRIEF RESUME OF INTEENDED WORK

     6.1 NEED FOR THE STUDY
             Obesity is abnormal or excessive fat accumulation that presents risk to health. The body
     mass index (BMI) of a person is 25-30 kg/m2 indicates overweight and above 30 kg/m2 represents
     obesity. World Health Organization (WHO) assigns obesity as global epidemic. WHO’s latest
     study indicate that globally in 2005, approximately 1.6 billion adults (15+) were overweight and at
     least 400 million adults were obese. Further WHO projects that by 2015 approximately 2.3 billion
     people will be overweight and more than 700 million will be obese1. Once it was considered that
     obesity was only in high income countries. But now a day, it is spread dramatically in medium and
     low income countries1.
             The epidemic of obesity is on the rise and this is probably due to increasingly sedentary
     lifestyles combined with easy availability of palatable, high fat foods. Its prevalence has shown a
     startling Increase in allage groups and in all the countries of the world during past 19 years. In
     1980, a Department of health Survey in U.K. showed that 6% of men and 8% of women were
     obese, as defined by a BMI >30 kg/m2. In 1995, 15% of men and 16.5% of women were
     obese and more than half of the adult population is now either overweight or obese. It has been
     predicted that if this trend continues to the year 2005, the prevalence of obesity among men and
     women would by then be 18 and 24% - exactly three times the target figure. There has also been
     an increase in comorbid risk factors like coronary heart disease, hypertension, various cancers
     (e.g., endometrium, ovaries, breast, colon), gall bladder disease, NIDDM, arthritis, respiratory
     disease, pregnancy complications, menstrual difficulties, varicose veins, psychological
     problems (poor self-esteem, depression, poor employment prospects).2-3
            The successful management of obesity is possible through lifestyle changes in diet and
     physical activity. But this requires extreme efforts. The market for safe and efficacious drug is
     therefore potentially huge, but currently available therapies are not having potential and these are
     associated with lot of side effects. Currently FDA approved only two drugs in US for long-term
     treatment for obesity. These are orlistat and sibutramine4.
                 Obesity is often associated with whole-body low-grade pro-inflammatory state,
     insulin resistance and a number of metabolic disturbances together defined as the metabolic



                                                 2
syndrome. In the search for mechanisms that help explain the link between obesity, insulin
resistance, and metabolic complications, it has been suggested that endocrine substances produced
by adipose tissue (adipocytokines) might play a role. Adiponectin is a 30 kDa plasma protein
secreted by mature adipocytes5 representing 0.01% of total plasma proteins6. Plasma adiponectin
levels have been shown to be reduced in type 2 diabetic patients7, insulin-resistant subjects8, obese
individuals6, as well as in coronary heart disease patients7. These findings suggest that adiponectin
has insulin-sensitizing and anti-atherosclerotic effects9. In human plasma, adiponectin circulates in
distinct multimeric complexes forming trimeric low molecular weight (LMW), hexameric medium
molecular weight (MMW), and oligomeric high molecular weight (HMW) complexes. However,
using different analytical methods, some authors distinguished only two adiponectin isoforms:
LMW and HMW8,10,12,13,2 . Adiponectin cellsurface receptors (AdipoR1, AdipoR2) are expressed
in muscle, liver, and adipose tissue14,15. In mouse myocytes and hepatocytes, adiponectin
stimulates phosphorylation and the activation of 50-AMP-activated protein kinase16, a key
regulatory enzyme in glucose and lipid metabolism, inducing glucose uptake and fatty acid
oxidation in muscle16, 17 and reducing hepatic gluconeogenesis18. Activation of different cellular
transduction pathways seems to be specific for different multimeric complexes in different
organs19, 20. Previous investigations revealed that plasma HMW adiponectin levels are positively
associated with insulin sensitivity indices12,21,13,22,23 and plasma highdensity lipoprotein cholesterol
(HDL C), while negatively associated with body mass index (BMI) and central body fat mass (11).
Mutations in the adiponectin gene associated with impaired formation of HMW complexes have
been phenotypically connected with hypoadiponectinemia and type 2 diabetes in humans20.
       . Adiponectin is 30 kDa plasma protein secreted by mature adipocytes. Plasma adiponectin
level are decreased in type 2 diabetes mellitus patients, obese individuals, and in coronary heart
disease patients. This suggest that adiponectin – insulin sensitizing and antiatherosclerotic effects.
Plasma adiponectin levels are positively associated with insulin sensitivity indices and plasma
high density lipoproteins (HDL), and plasma high density lipoprotein cholesterol (HDLC), while
negatively associated with body mass index and central body fat mass. Mutation associated with
adiponectin gene may lead impaired formation high molecular weight adiponectin and individual
suffer from type 2 diabetes mellitus10.
         From the literature survey it can be understood that an explorative investigation is
necessary to treat obesity and the obesity related metabolic syndrome such as diabetes mellitus.



                                             3
Cyperous rotundus tuber extracts are suggested to be effective in reducing the body weight.Hence
an explorative investigation of aqueous extracts of C.rotundus on obesity and glucose tolerance
and the present study is envisaged.
6.2 REVIEW OF LITERATURE:
Plant description:
     In the traditional system, it was used both in its fresh and dry form. It is also mentioned in
literature pertaining to Arabian and Persian medicines. It was known to heal ulcers and sores.
Dioscorides mentions its use as a diuretic in the treatment of ulcers, as an emmenagogue and an
ingredient in warm plasters. It was used as a perfume and an aromatic. It grows throughout
India33.


Scientific name: Cyoerus rotundus
Family : Cyperaceae
Genus : Cyperus
Species : rotundus
Synonyms : Musta


Botanical Description:
This grass like herb is found in South India. It has tubers roots or rhizomes that are fragment. It
has been mentioned in “Sahasrayoga”, prennial herb with long rhizomes, sometimes tuberous
,culms up to 60 cm tall; leaves 2-6 cm wide; spikes ovate, on rays to 6 cm long; spikletes linear,
1-2 cm long, 12-30 flowered, the rachilla winged; scales purplish, carinate, obtuse; achene sub-
obvoid, trigonal, 1.5 mm long, black, minutely papillate36.


Plant chemicals:
The C. rotundus have been reported to contain oils, alkaloids, glycosides, saponins, flavonoids,
tannins, starch and carbohydrates. It also contains proteins and traces of Mg, V, Cr, Mn and Co.
The rhizome oils of C. rotundus from India were reported to have α-copaene (11.4-12.1%),
cyperene (8.4-11.7%), valerenal (8.7-9.8%), caryophyllene oxide (7.8-9.7%) and trans-
pinocarveol (5.2-7.4%), some of which were absent in the species from other countries. The
essential oil of C. rotundus from Germany, and found the oil to be dominated by cyprotene, α-



                                           4
copaene, cyperene, α-selinene, rotundene, cadalene and nootkatene, among others35.
         Ngamrojanavanich et al.,(2006)           reported the inhibitory effect of hexane extract of
cyperus rotundus and other medicinal on Na+K+ ATPase pump.The hexane extract of C.rotundus
and Orthosiphon aristatus showed high potent inhibitory activity on crud e enzyme Na+,k+-
ATPase from rat brain.41
         Uddin et al ,(2006) observed the antidiarrhoeal activity of C.rotundus.The methanol
extract of c.rotundus rhizome ,given orally at the doses of 250 and 500 mg/kg body weigh,showed
significant antidiarrhoeal activity in castor oil induced diarrhoea in mice.among the fractions
,tested at 250mg/kg ,the petroleum ether fraction and residuai methano fraction were found to
retain the activity,the lattrr being more active as compared to the control.The ethyl acetate fraction
did not show any antidiarrhoeal activity.42
         Natarajan et al.(2006) reported the antioxidant activity of C.rotundus and other medicinal
plant against free radical induction.A combination of speacies (piper nigram,p.longum and
zingiber officinale) herbs(C.rotundus and plumbago zeylanicam) and salts makes up Amrita bindu
. These result reveal that Amrita bindu , a salt –spice-herbal mixture exerts a promising antioxidant
potential againsts free radical induced oxidative damage.43
         Duarte et al.,(2005) reported the anti-candida activity of C.rotundus .44           .
         Jagtap et al.,(2004) observed the effect of polyherbal formulation containing C.rotundus
on experimental models of inflammatory bowel disease. The formulation showed significant
inhibitory activity against inflammatory bowl disease induced in these experimental animal
models. The activity was comparable with the standard drug prednisolone. The results obtained
established the efficacy of this poly herbal formulation against inflammatory bowel diseases.45
         Haung and Peng(2003) observed the advances in the study of chemical constituents and
pharmacology of C.rotundus L.46
         Bamgbose et al. (2003) studied the utilization of tigernut ( C. rotundus, L.) meal in diets
for cockerel starters. The effect of feeding graded levels of tigernut meal (TGN) as a replacement
for the maize in the diets of cockerel starters on carcass characteristics and economics of feed
conversion was assessed for 70 days. Tigernut replaced maize at 0 %, 33.33%, 66.67% and 100%
levels. A total of 120 day-old chicks were randomly allotted to four experimental diets such that
each dietary treatment had three replicates of ten birds. Inclusion of TGN at 33.33% in cockerel
diets supported better carcass yield in terms of high plucked, eviscerated, drumstick, thigh, neck,



                                              5
wings, heads, shanks, livers, hearts and lungs weights without significance differences (P>0.05) in
values obtained. However, there were significant difference (P<0.05) in values obtained. However,
there were significant difference (P<0.05) in back, breast, abdominal fat, gizzard, spleen, kidney
and intestinal weights and lengths. Inclusion of        TGN 100% level significantly depressed
parameters assessed. The optimum replacement level of maize with TGN was 33.33% as this gave
no significant reduction in carcass yield of the birds but a significant reduction in the cost of feed
consumed. It required a feed cost of 0.31 US dollars to produce one kilogram weight gain on diet 2
(33.33%). Inclusion of TGN in the diet resulted in feed cost saving of 4.88% (D2), 8.17 (D3) and
8.90% (D4) respectively.47
        Ha et al. (2002) studied the four sesquiterpenes, beta-selinene, isocurcumenol, mootkatone
and aristolone and one triterpene, oleanolic acid were isolated from the ethyl acetate fraction of the
rhizomes of C. rotundus      and tested for their ability to modulate gamma- aminobutyric acid
(GABA(A)-benzodiazepine receptor function by radioligand binding assays using rat cerebro
cortical membranes. Among these compounds, only isocurunenol, one of the newly identified
constituents of this plants, was found to inhibit (3H)Ro15-1788 binding and enhance
(3H)flunitrazepam binding in the presence of GABA. These results suggest that isocurcunenol
may serve as a benzodiazepine receptor agonist and allosterically modulate               GABAargic
neurotransimission via enhansiment of endegenous receptor ligand binding.48
         Seo et al. (2001) studied that rhizomes of C. rotundus have been used in oriental
traditional medicines for the treatment of stomach and bowel disorders, and inflammatory
diseases. Nitric oxide and super oxide are are important mediators in the pathogenesis
inflammatory diseases. This study was undertaken to addresses weather the methanol extracts of
rhizomes of C. rotundus could modulate NO and O-2 productions by murine macrophsge cell line,
RAW 264.7 cells. The MeOH extract of rhizomes of C. rotundus showed the inhibition of NO
production in a dose-dependent manner by RAW 264.7 cells stimulated with interferon-gama plus
lipopolysaccharides. The inhibition ofNO production by the extract was due to the suppresssion of
iNOS protein, as well as iNOS mRNA expression, determined by western and northen blotting
analysis, respectively. In addition the MeO Of O2- by phorbol ester-stimulated RAW 264.7 cells in
dose- and time – dependent manners. Collectively, these results suggested that the MeOH extract
of rhizomes of C. rotundus could be developed as anti-inflammatory candidate for the treatment of
inflammatory diseases mediated by overproduction of NO and O2-.49



                                            6
          Hsieh et al. (2000) investigated the ameliorating effects of the cognitive-enhancing
Chinese herbs administrated orally for 1 week-panax ginseng (pg), panax notoginseng (PNG),
Dioscorea opposite (DO). Gastrodia elata (GF), salvia miltiorrhiza (SM), acorus gramineus (AG),
coptis chinensis (CC), Polygonum multiflorum(pm), cyperus rotundus (CR) and psoralea
corylifolia(PC)-on the scopolamine(SCOP)-induced amnesia by using passive avoidance task in
rats.Often Chinese herbs,only PG,PNG,GE and CC prolonged SCOP-shortened step-through
latency(STL).these results revealed that PG,PNG,GE and CC administered orally for 1 week
improved the SCOP-induced learning and memory deficit in rats.50
          Jeong et al.(2000) observed Rotendines A(1),B(2),and C(3) the novel sesquiterpene
alkaloids with an unpresident carbon skeleton, were isolated from the rhizomes of C.rotendes. the
structure of 1-3 were elucidated by spectral and chemical methods.51
          Bamgbos et al(1997)observed the effect of feeding tagenut(C.rotundus L)meal on the
performance of rabbits.52
          Thebtaranonth et     al.(1995) performed activity –guided investigation of C.rotendus
tubers led to the isolation of pactchoulenone,cariyophyllene-alpha-oxide,10,12-paraoxycalamene
and 4,7-di methyl-1-tetralone.The anti-malarial activity of these compounds are in the range of
EC50 10(-4)-10(-6) M,with the novel edoperoxide sesquiterpene ,10,12-peroxy calamenene,
exhibiting the strongest effect at EC50 2.33 10(-6) M.53
          Xue    et   al.(1994)   reported   the   effect   of   the   combination   of   Astragalus
membranaceus(fisch) Bge. (AM), Angelica sinensis (oliv.) Diels (TAS) , Cyperus rotundus L,
(CR), Ligusticum chuangxiong hort (LC) and peaonia veitchii Lynch (PV) on the
hemorrhcological changes in “blood stagnating” rats.54
          Xue et al.(1994) built the “blood stagnating” rat model with adrenalin and cold
stimulation. Its hemorrhcological character was an increase in the viscosity , thickness of blood
and its liability to coagulate . the experimental result showed that AM and TAS could decrease the
whole blood specific viscosity, but at the same time increase the plasma specific viscosity. the Qi-
regulating drug CR and two blood activating drug LC and PV could improve the hemorrhcological
changes in “blood stagnated” rats .the combination of qi- regulating drugs and blood-activating
drugs had more favorable effect.55
        Study on analgesic effect of C.stoloniferus Retz, was reported by VU and Mai (1994). The
decocts of rhizomes of C.rotundus and C.stoloniferus and total alkaloids and essential oil from C.



                                             7
stoloniferus showed analgesic effect in the acetic acid writhing test . the oral LD50 of essential oil
of C.stoloniferus in mice was 12.1 ml./Kg.56
        Shinde et al.1988 reported the effect of Nagarmotha (C rotundus Linn) on reserpine
induced emesis in pigeons.57
       Biologically active substances in subterranean parts of purple nutssedge is reported by
Friedman and Horowitz 1971 as the growth of barley( hordeum disichon var eszperanza) seedlings
in nutrient solution was reduced by purple nutsedge (cyperus otundus) plants growing in
connected vials and by addition of ethanol extract of purple nutsedge, aqueous and ethanol extract
from subterranean parts of purple nutsedge red seed the germination and root elongation of barley.
Stimulations of barley root elongation were obtained with diluted aqueous extract the germination
of barley, mustard( brassica nigra var Alsace,) and cotton (Gossypium hirsutum var acala 1517)
was reduced in soil which had been infested previously with purple nutsedge. Radical elongation
of barley was inhibited by ethanol extract of soil previously infested. Chromatographic studies
indicated that the inhibitors are phenolic substances.58
     Gupta et al.(1971) performed pharmacological studies to isolate the active constituents from
c. rotundus possessing anti inflammatory, antipyretic and analgesic activities.59
       Lee et al.(1970) characterized ferredoxin from nutsedge, c.rotundus L, and other species
with a high photosynthetic capacity. Singh et al.(1970) investigated pharmacological activites of
C.rotundus.60
       Akperoekova and abdullaev (1966) reported the diuretic effect of drug from and galenicals
from the roots of cyperus rotundus growing in azerbaidzhan. The chemical composition of dry
roots was as follows: alkaloids 0.21-0.24, heart glycosides 0.62-0.74 flavonoids 1.25, polyphenolic
compounds 1.62, saccharides before hydrolysis 13.22, saccharides after hydrolysis 14.4, starch
9.2, pectins 3.72, ethereal oils 1.06, lipid compounds 2.98, resins 4.21, total acidity expressed as
malic acid3.25% and vitamin c 8.8mg%. the water extract were nontoxic for white mice; the LD50
of the alcohol extract (2:1) was determined as 90g/kg. both the drug form and galenicals increased
diuresis was induced by administration of resins, alkaloids(39.6) polyphenolic compounds,
flavonoids and ethereal oils and glycosides(11.6%) list and horhammer,(1969-1979).61
        Indira et al. (1956) reported the occurrence of estrogenic substance in plants. L. estrogenic
activity of cyperus rotundus. The oil of c. rotundus exhibits low order estrogenic activity. The
hydrocarbon fraction is more active than other fractional distillates, but none of the components



                                            8
was found as active as the oil. The probability of these compounds being proestrogens is indicated
by the ratio of systemically active to locally effective concentration. No correlation exists between
antibacterial activity and estrogenic potency of the oil and its fraction.62


6.3 OBJECTIVE OF THE STUDY
1. Preparation of cyperus rotundus aqueous extracts
2. To evaluate the effect of aqueous extracts of C.rotundus on pancreatic lipase activity.
3. To induce Cafeteria diet / High fat diet fed obesity in Wistar rats of either sex and evaluate the
   effect of aqueous extracts of C.rotundus against weight gain / loss and effects of the extracts
   on adipositic fat deposition.
4. To evaluate the effect of aqueous extracts of C.rotundus on glucose tolerance levels in obese
   wistar rats.
5. To evaluate the effect of aqueous extracts of C.rotundus on the Adepokine ie., Adiponectin
   levels in obese diabetic rats.


MATERIAL AND METHODS

7.1 Source Of Data :
       Whole work is planned to generate data from laboratory studies i.e. experiments are
performed as described in references. Experimental studies in journals and in text books available
with college and various institutions.
Web sites: http:// www.sciencedirect.com
             http:// www.pubmed.com
             http:// www.google.com
             http:// www.ijp-online.com
             http://www.himalayahealthcare.com
             http://www.who.int




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7.2 METHODOLOGY :

I. SCREENING OF ANTIOBESITY ACTIVITY

IN VITRO SCREENING

Measurement of pancreatic lipase activity.
Lipase activity is determined by measuring the rate of release of oleic acid from triolein. Briefly, a
suspension of triolein (80 mg), phosphatidylcholine (10 mg) and taurocholic acid (5 mg) in 9 mL
of 0.1 mol/L N-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid buffer (pH 7.0)
containing 0.1 mol/L NaCl was sonicated for 5 min. This sonicated substrate suspension (0.1 mL)
was incubated with 0.05 mL (10 U) of pancreatic lipase and 0.1 mL of various concentrations of
sample solutions for 30 min at 37°C in a final volume of 0.25 mL. The amount of oleic acid
released was determined by the method of Zapf et al. (1981) with a slight modification (Tsujita
and Okuda 1983). The incubation mixture was added to 3.0-mL aliquots of a 1:1 (v/v) mixture of
chloroform and n-heptane containing 2% (v/v) methanol and extracted by shaking the tubes
horizontally for 10 min in a shaker. The mixture was centrifuged at 2000 3 g for 10 min, and the
upper aqueous phase was removed by suction. Copper reagent (1.0 mL) was then added to the
lower organic phase. The tube was shaken for 10 min, the mixture was centrifuged at 2000 3 g for
10 min and 0.5 mL of the upper organic phase, which contained copper salts of the extracted free
fatty acids, was treated with 0.5 mL of 1 g/L bathocuproine in chloroform containing 0.5 g/L
hydroxyanisole. The absorbance was then measured at 480 nm. Lipase activity was expressed as
moles of oleic acid released per liter of reaction mixture per hour.63

IN VIVO SCREENING:
Animals: Either sex Wistar rats (80 to 120 g)
No of animals: 30
Housing: 5 / cage, 12 hrs light/dark cycle
Temperature: 22±20c
Food: pellet chow and water.
I1.Diet induced obesity
Following groups will be made
Group 01: control
Group 02: Cyperus rotundus


                                             10
Group 03: cafeteria diet
Group 04: cafeteria diet + Cyperus rotundus extract
Group 05: cafeteria diet + streptozocin
Group 06: cafeteria diet + streptozocin + C. rotundus


Parameters tested with procedure:
1. Body weight: The body weight (g) was recorded on day 1 and then on alternate days for 40
days in each group.
2. Body temperature: The body temperature was recorded on day 39 using rectal telethermometer
before and after drug administration at 30, 60, 90, 120 and 180 min with a contact time of 1
minute.
3. Locomotor activity: It was recorded on day 40 using open field behaviour test apparatus and
30 min after drug administration to treatment groups. The apparatus consisted of a circular
wooden arena of 75 cm diameter and wall with a height of 25 cm. Open field test was performed
by placing the rat in the center circle and recording the ambulatory activity, the frequency of
rearing and grooming for a 5 min test period.
4. Organ weight: The animals were sacrificed by cervical dislocation and then different organs
(kidney, liver, heart, spleen) and fat pads (mesenteric, left and right perirenal and uterine fat pads)
were removed and weighed.
5. Biochemical parameters:
Glucose, Total cholesterol, Triglyceride level, LDL, HDL, Glucose tolerance test. Adeponectin by
Elisa.


7.3 STASTICAL ANALYSIS
The mean values ±SEM will be calculated for each parameter. The data was analyzed using one-
way analysis of variance (ANOVA).


7.4 Does the study require any investigation to be conducted on patients or other humans or
animals? If so please describe briefly.
Yes, The above study requires investigation on animals. The study may involve sacrifice of
animals at the end of the studies to measure end point indicators.



                                            11
7.5 Has ethical clearance been obtained from your institution in case of 7.3?
Application has been submitted to “Institutional Animal Ethics Committee” Nargund College of
Pharmacy, Bangalore. Clearance certificate as and when granted by the IAEC will be submitted to
the university.




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   American Society for Nutritional Sciences. 24 July 2000; 2760-2764




                                      18
9.    SIGNATURE OF THE CANDIDATE

                                        VISHWESHWAR M DHARASHIVE


10.   REMARKS OF THE GUIDE                         RECOMMENDED




11.   NAME AND DESIGNATION



      11.1 NAME OF THE GUIDE                   PROF. RAJEEV HIREMATH
                                            NARGUND COLLEGE OF PHARMACY
                                                   BANGALORE-85


      11.2 SIGNATURE


      11.3 CO-GUIDE (IF ANY)                           ------

                                        .
      11.4 SIGNATURE


                                              Mr. H.J.HRISHIKESHAVAN PhD
      11.5 HEAD OF THE
                                                  PROFESSOR AND HEAD
           DEPARTMENT
                                                DEPT. OF PHARMACOLOGY
                                            NARGUND COLLEGE OF PHARMACY,
                                                      BANGALORE-85


      11.6 SIGNATURE



12.   12.1 REMARKS OF THE                          RECOMMENDED
         CHAIRMAN & PRINCIPAL



      12.2 SIGNATURE

                                   19
20

				
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