863693_634345504962501250
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1
SCREENING
OFANTIDIABETIC
PRESENTED BY:-
Salunkhe Pankaj ShrikantSemester 1st
M.Pharm {Pharmacolo!"
De#artment o$ Pharmacolo!
R.%.Patel collee o$ #harmac!&Shir#ur
SHRI
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2
Content :-
• History
• Definition & Classification of Diabetes
• Insulin
-Structural feature
-Mode Of Action
• Oral hypoglyceic agent -Classification & Mode of Action
• !lucose "stiation Method
• Screening techni#ues
-In $i%o
-In $itro
• eferences
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'
• DM (no)n since ages as *Madhumeha” i+e+s)eetness of disease urine in Ayur%eda by,Sushruta
• During first century !ree. physician ,Aeretausgi%es ter Diabetes as *to flo) through/
• In 01 by ,Dobson deonstrated Diabetes as bypresence of sugar in urine+
• In 0343 by ,De Mayer gi%es stateent aboutinsulin is ,the non-digesti%e part of pancreas & isletcell )as responsible for pancreatic diabetes+
• History :-
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-It is chronic etabolic disorder6 resulting froinsulin deficiency characteri7ed byhyperglyceia6 altered etabolis ofcarbohydrate6 protein 6 lipid & increases the ris.
of %ascular coplications+
-Diabetes is not a single disease6 it is
heterogeneous group of syndroe6 characteri7edby an e%aluation of 8lood !lucose caused by arelati%e deficiency of Insulin+
•Definition :- 16
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9
INSULIN LACK
HYPERGLYCEMIA KETOSIS
Glycosouria
Oso!ic "iur#sis
Loss o$ El#c!roly!#
Na%& K%& Ca%%
I'!rac#llular K% "#(l#!io'
Hy(o!#'sio'& S)oc*
Aci+osis
Loss o$ ,i#+
ca!io' i' Uri'#
"#)y+ra!io'
Hy(oosolari!y o$ .loo+
Loss o$ /a!#r
0oi!i'K#!o'ur#a
Hy(#r0#'!ila!io'
I(air#'!
o$ Glucos#
#'!ry i'
.rai'
I(air#'! o$
co'scious'#ss
I'!rac#llular
"#)y+ra!io'
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• Classification :-
0: T!#e-' ( )u*enile onset ( 'nsulinDe#en+ent Dia,etes Mellitus ;-
It occurs in nonbiased or before age '4+
Autoiune Disease of <-cell+ Autoiune
type 0A antibody destroy <-cell+ Circulating insulin is lo) or %ery lo) so
patient pro%e to .etosis+
=atient ust rely on ">ogenous insulin to
control the hyperglyceia+ Mostly Subcutaneous rout is preferred+
963663
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T!#e '' (Maturit! /nset (Non-'nsulin
+e#en+ent Dia,etes Mellitus :-
@sually occurs after age 54+ Obesity6 lac. of e>ercise
is aor ris. factor+
Moderate reduction of <-cell+
Insulin circulation is less B noral B high ay occur
hyperglyceia or hypoglyceia+
Here6 abnoralities in !lucoreceptor in <-cell so that
they respond at higher glucose concentration+
Oral hypoglyceic agent are as a part of treatent 6
e>ercise 6 dietary odification+
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0T!#e ''' ( M/DY Maturit! /nset Dia,etes in
Youn :-
In )hich dysregulation of glucose sensing or insulinsecretion is due to utation of particular gene+
Due to Horonal disorder+
reatent %aries often response to OHA
2T!#e '3 ( 4estational Dia,etes Mellitus :-!lucose intolerance associated )ith =regnancy+ It Is iportant to tight glyceic control close to
noral range during pregnancy 6because-
hyperglyceia can lead to congenital abnoralities
in fetus
reatent- controlled by diet6e>ersise
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Insulin:Structural $eature:-
High ol+ )t+ polypeptideha%ing )t+ about
?4?
Aino acid lin.ages 0 aa
arranged in 2 chain+
A chain -acidic E 20 aa
8 chain -basic -- '4 aa
C Epeptide lin.age connectto A & 8 chain+
2 disulphide bond are
lin.ed in both aa+
6961
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# OA of Insulin:-
2 23 3
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/ral h!#ol!cemic aent Classification :- 1 'nsulin secretaous E they proote the insulin
release fro <-cell of pancreas+e+g++ Sulfonylurea ;- Tolbutamide,Acetohexamide
'nsulin sensiti5er E
Fi: it increases insulin upta.e & utili7ation by target
tissue+ e+g+hia7olidinediones;-osiglitazone,Pioglitazone
Fii: it reduces hepatic glucose output6 largely byinhibiting hepatic gluconeogenesis
e+g+ 8iguanides ; - Metfomin,Phetformin0 6-4l!cosi+ase inhi,itor E they act by delaying the
digestion of carbohydrate thereby decreasingglucose absorption
e+g+ Acarbose, Miglitol
163
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04 20
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Screenin! Tec"niue
In %i%o
- Cheical Induced Diabetes
i: Allo>an induced Diabetes
ii: Strepto7otocin induced Diabetes
iii: ?-SG Induced diabetes
- $iral Induced diabetes
- !enetically diabetic anial - Assay of Insulin
i: 8lood sugar lo)ering effect in abbit
ii: Hypoglyceic Sei7ures in ice
iii: 8lood Sugar deterination in ice
- 8lood !lucose lo)ering acti%ity of Antidiabetic Drugs
i: In abbits ii: In ats
- "uglyceic Clap techni#ue
- Inhibition of !lucose absorption in %i%o
04620
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In $itro
-Isolated at pancreas2
-Isolated Diaphrag of rat
' 5
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09
Glucos# Es!ia!io' M#!)o+
• 4lucose /7i+ase metho+-1
!lucose is o>idi7ed in !luconic Acid by glucose o>idi7e+
he hydrogen pero>ide liberated is reduced by pero>ides &O>ygen transferred to an accepter6 )hich is colour less in
the reduced for but coloured in o>idi7ed for+
• 4lucometer-
•$rine analysis-
Gualitati%e6Cheap6Con%enient+ 8enedict eagent are
used+ but Diagnosis cant based- ay sho) false %e6
false-%e
'6566
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01
• 8e7okinase en5!me metho+--9
he procedure is a fluoroetric rate ethod easuring
the foration of AD=H cataly7ed by iobili7ed glucose-9-
phosphate dehydrogenase and he>o.inase held )ithin a tinystirrer+ he en7ye stirrer is stable for at least t)o onths and
can be used o%er eight-hundred assays )ithout any loss of
acti%ity+
• 4l!cos!late+ 8aemolo,in 8,1c0
Measureent of blood glucose le%el in diabetic suffer
fro %ariation due to dietary inta.e of pre%ious day+ Jong ter
obecti%e assessent degree of diabetic control is better done
by easureent of glycosylated haeoglobin HbA0c6a inor
haeoglobin coponent present in noral person+ his isbecause non-en7yatic glycosylation of haeoglobin ta.es
place o%er 024 days+ his gi%es an estiated of diabetic
control for the =receding 9-04 days+
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0?
• 4lucose Tolerance Test 4TT- 0&2&9
Kasting 8lood glucose le%el is first deterined & then
blood glucose le%el are sapled inutes to hour after an
oral dose of glucoseF1g in '44 l )ater: + 8lood and
urine saple are collected at half hourly inter%al+
i i
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03
I' 4i0o Scr##'i'
F1 llo7an in+uce+ +ia,etes:-
=urpose E
Induction of diabetes using cheical allo>an+ In Most
species riphasic tie course is obser%ed+ FInitial rise of glucose is
follo)ed by decrease6due to depletion of islets fro insulin6again
follo)ed by sustain increase of blood glucose:+
nimal abbits ats 8eagle dogs
;eiht 2+4-'+ .g 04-244 g 0-24 .g
Route "ar %ein subcutaneously Intra%enously
Dose 04 gB.g 044-01 gB.g 94 gB.g
=rocedure- ' !roup are selected as FControl6 Standard6est :
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• "%aluation
@se any suitable ethod for collection of blood+ and
estiation of blood glucose le%el+
Copare the result of test )ith standard and control+
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Stre#to5otacin in+uce+ +ia,etes:-
=urpose E
Induction of diabetogenic acti%ity of antibioticstrepto7otacin+ he copound turned out cytoto>ic to <-cellof pancreas+
Initially blood glucose increases up to 04-244 g L6 9-?hour after insulin increase up to 5 ties Fhypoglyceicphase: after 25-5? hyperglyceia up to ?44 gL+
=rocedure-
Male istar at E 04-244 g
!roup E est6 Standard6 Control
SN+ Dose E 94 gB.g intra%enously
"%aluation
@se any suitable ethod for collection of blood+ andestiation of blood glucose le%el+
Copare the result of test )ith standard and control+
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0 /ther Dia,etoenic com#oun+ in+uce+ +ia,etes:-
=urpose E
Se%eral other copound to induce syptos of diabetesandBor obesity+ hese copound also sho)s triphasicglyceic reaction+
=rocedure-
Anial E Cats 6abbits 6!olden Hasters 6Mice
!roup E est6 Standard6 Control
Cheical E Dithi7one ?-SG F?-p-toluene-sulfonylaino-#uinoline:
?-8SG F?-ben7ene-sulfanylaino-#uinoline:
Dose E 54-044 gB.g intra%enously
"%aluation @se any suitable ethod for collection of blood+ and
estiation of blood glucose le%el+
Copare the result of test )ith standard and control+
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2'
2 3irus in+uce+ Dia,etes ;-
=rinciple-
-It causes type-I diabetes ellitus+
-he D-%ariant of Encephalomyocarditis %irus F"MC-D:selecti%ely infects and destroys pancreatic <-cell +
-Islet cell destruction )as associated )ith chronic isletcell inflaation6 ele%ation of islet cell antibody6 andprolonged presence of %iral A in the pancreas+
9 4eneticall! +ia,etic animal :-
88 at-
8io 8reeding rat is a odel of spontaneous diabetesassociated )ith insulin deficiency due to autoiune
destruction of pancreatic beta cell+
"8B(O8 at-
Spontaneous hyperglyceia6 glycocosourea ha%e beenobser%ed in aged ale of istar Strain+
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DK BA-KA at-
Coonly referred to as the fatty rat6 is a genetically obese6hyperglyceic rat established by transfer of fatty gene froNuc.er rat to )istar (yoto rat+
OD Mice-
OD ice is a odel of ype-I diabetes
OD ice De%elop diabetes bet)een 044 and 244 days of
age+ As )ell as rapid )eight loss6 polyuria6 se%ere !lucosuria+
OD ice caused by specific -cell ediated6 destruction ofinsulin producing beta cell+
Chinese Haster E FCrecetulus griseus) he no+ of pancreatic islet )as decreased 6 and the cell of the
reaining islet )as decreased and other cell )ere abnoral+
8SJ of diabetic haster )ere ele%ated fro noral of004gL up to 944 gL+
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2
OD Mice 8io 8reeding rat
Chinese Haster E FCrecetulus griseous)
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ssa! o$ 'nsulin
8lood sugar lo)ering effect in abbits-
=urpose- A biological assay of insulin preparation in coparison
)ith a suitable standard using the blood sugar lo)ering
effect in rabbits+
=rocedure- 9 rabbit in each group+ )t+at least 0+?.g 25 h before test rabbit is pro%ided )ith food ad libidum.
During test food !ater !ithheld until blood sam"le ta#en.
!roup Inection
0 Standard sol+ 2
2 Standard sol+ 0
' Assay sol+ 2
5 Assay sol+ 0
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"%aluation E
Calculate the response of each rabbit to each inection+
Kro the su of t)o 8SJ %alues substrate its response
to standard solution 0 & fro standard solution 2+
!roup Differences Indi%idualresponse
otalresponse
0 Std+sol+2-assay sol+0 P0 0
2 Assay sol+2-std+sol+0 P2 2
' Assay sol+2-std+sol+0 P' '
5 Std+sol+2-assay sol+0 P5 5
@S=
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2?
< 8!#ol!cemic sei5ure in mice1=&-0
=urpose-
)in crosso%er ethod for bioassay of Insulin usingblood glucose le%el in ice+
=rocedure-
Anial - S)iss albino F)t+ 24 Q 2 g:
!roup - 5 !roup Feach R04 anial :
Solution - Standard F 2 diluting )ith 4+3L acl6 =H-2+5:
est F 2 diluting )ith 4+3L acl6 =H-2+5:
on fasting ice are used+ F s+c+rout:
"%aluation-
he ice are obser%ed for 0+ hour+
he no+ of ice are recorded that are dead6 con%ulse+
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< Bloo+ Suar +etermination in mice
=urpose-
8iological assay of Insulin using hypoglyceic sei7ures inice+
=rocedure-
Anial - 39 ice of either se> F)t+ 24 Q g:
!roup - 5 !roup
Solution - Standard F diluting )ith 4+3L acl6 =H-2+5:
est F diluting )ith 4+3L acl6 =H-2+5:
Mice depri%ed food 2-24 hour iediately preceding test
"ach of prepared sol+4+0 lB04g inected s+c+
ot less than 2+ h later6 each sol+ Adinistered to secondgroup+
"%aluation- ">actly 2+ h later6 a saple of 4 l of blood is ta.en
fro orbital %enous sinus of each ice+
8SJ is deterine+ =otency is calculated by t)in-cross-o%er
assay
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'4
Bloo+ lucose lo>erin acti*it! o$ anti+ia,etic +ru
$ Bloo+ lucose lo>erin acti*it! in Ra,,it
=urpose-
abbit has been used since any year for standardi7ation ofinsulin+
=rocedure-
!roups Fstd+6 test6 control: rabbits of either se> F'+4-5+ .g:
Anial .ept on oral diet+ Oral glucose lo)ering agent are
applied by ga%ages in 0 lB.g of 4+5L starch suspension or i+%+in solution+ se%eral dose are gi%en to different groups+ controlgroup recei%e %ehicle only+
"%aluation-
8y puncturing of ear %ein6 blood 04 l is )ithdra)niediately and 06 26 '6 56 6 256 5?6 & 12 hours+
8SJ is deterine+
A%erage blood sugar %alues are plotted %erse tie for eachdosage
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'0
$ Bloo+ lucose lo>erin acti*it! in Rats%
=urpose-
ats are used for screening as )ell as for #uantitati%e
e%aluation of blood glucose lo)ering agent+
=rocedure-
Male istar rats F0?4-254 g: are .ept on standard diet +
!roups of 5-1 non-fasted anial are treated orally or
intraperitoneally )ith %arious doses+
Control group recei%e only %ehicle+
"%aluation-
8lood is )ithdra)n 04 l fro tip of tail iediately beforeand 06 26 '6 6 256 5? hours+
8SJ is deterine+
A%erage blood sugar %alues are plotted %erse tie for each
dosage
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'2
Eul!cemic %lam# Techni?ue;-
=urpose-
@seful ethod of #uantifying in &i&o insulin sensiti%ity inhuan+ In this techni#ue a %ariable glucose is deli%ered toaintain euglyceia during insulin infusion+
=rocedure- -Male istar rats F04-244 g : are fasted o%ernight+
-Anaestheti7ed )ith =entobarbital F 54 gB.g6 i+p+ :
-Catheters are inserted into ugular %ein for blood collectionand a feoral %ein for insulin and glucose infusion+
-Insulin infusion rates6 9 and '4 @B.gBin+ -!lucose infusion rate is adusted so as to aintain 8SJ at
basal le%el
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''
"%aluation-
8lood glucose conc+ are deterined fro saple collection at-in inter%al during the 34 in clap techni#ue+
he glucose etabolic clearance rate is obtained by di%idingglucose infusing rate by steady state blood glucoseinfusion rate
"uglyceic clap echni#ue
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< 'nhi,ition o$ 4lucose a,sor#tion in 3i*o-
=urpose-
he inhibition of glucose absorption deterined by blood
glucose after adinistration of starch or disaccharides+
=rocedure-
- Male istar rat F04-244g: .ept on standard diet6 free
access to tap )ater+
-09 hour prior to e>perient food is )ithdra)n but not )ater
-2+ gB.g Starch recei%e by stoach tube for control group &
)ith %arious dose α-aylase inhibitor in test group
-After6 046 246 '46 946 024 & 254 in6 blood is )ithdra)n and
deterined blood glucose+
-he anial are sacrificed after these inter%al & residual
starch in stoach 6 intestine is deterined+
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"%aluation-
he %alues of starch content in stoach & intestine as
)ell as blood glucose 6 seru insulin %alues are
copared bet control and treated anial+
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'9
< 'solate+ Rat Pancreas:- -
=urpose-
@sed for studying the effect of drug on Insulin6 glucagons6
soatostatin secretion+
=rocedure-
Adult istar rat F04-244 g: are fed ad libitum .
=ancreas are reo%ed under =entobarbital F4 gB.g i+p+:
hrough a portal %ein canula (rebs-ringer bicarbonate buffer
)ith 2L bo%ine albuin & + ol+Bl glucose is perfuse at
rate of 0+1 lBin+ at pressure 044Hg+
=erfusate is collected e%ery in+ for '4 in+ after first in+
test drug added till 0 in+ ne>t 09-'4 in glucose is perfuse
I' 4i!ro Scr##'i'
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'1
"%aluation
Insulin6 !lycogen6 Soatostatin are estiated usingadioiunoassay+
he effect of test drug on horone secretion of pancreasin response to ele%ated glucose le%el is copared )iththe control+
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'?
'solate+ +ia#hram o$ rat-
=urpose-
Deterination of Insulin based on the stiulation of glucose
upta.e by the isolated diaphrag fro rat +
=rocedure E
-Anial - Male Sprague Da)ley F14-044 g:
-Anial sacrificed during anesthesia and diaphrag arecarefully reo%ed6 spred out and di%ided into t)o e#ualpieces
-Hei diaphrag are incubated in (rebs buffer solution )ithcarbogen )ith M glucose6 insulin or copound to betested+
-After '4 in+ heidiphrag are blotted on tissue6 grounded onporcelin ortar pestle chilled )ith li#uid nitrogen
-After 5 hour at -244C Saple centrifuged 2444g for 04 in+
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'3
23=reparation of Diaphrag
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"%aluation-
he concentration dependent of T @-05 CU glucose upta.e
and con%ersion into glycogen and concentration by insulin orinsulin ietic copound are deterined+
•R#$#r#'c#s:
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•R#$#r#'c#s:-
0: Dr +Shi%ai =+ !a)ade+ Ho) and hats Of
=haracology+ irali =ublication6033 0st ;2'0-2'2
2: Dr+Mohd+ Asla6Dr+Surender Singh+ esearchMethodology and Statistics in =haracology+
Acadee publication624490st ;09?-012
': Cortan6(uar6collins+obbins =athology 8asic of
Disease +Harcourt Asia Jtd+ 24449th
;305: Harsh Mohan+ e>tboo. of =athology + Vaypee
8rothers 62449th ?5'6?'
: (+D+ripathi+ "ssential of edical =haracology+
Vaypee 8rothers +6244'th
;'?4-'?19: H+=+ ang6 M+M+Dale6 V+M+itter6 =+(+Moore
+=haracology+ Churchill Ji%ingstone+244'th;2'9-
20+
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5'
1: K+S+(+8arar+ "ssential of =haracotherapeutics+S+Chand62443th ;'54-'53
?: Arthur C+ !uyton6ohn "+hall6 e>tboo. of Medical=hysiology +Harcourt 8race & Copany6033?3th ;3?2
3: ichard D+Ho)land6 Mary V+ Myce.+ JippincottsIllustrated re%ie)s6 =haracology6 Jippincot )illias &il.ins62442'rd edition;2?0-2?3
04: H+ !erhard $ogel + Drug Disco%ery and "%aluation=haracological assay+springer+24422nd;Chapter-.+;351-0422
00: he @nited states =haracopeias 6 Asian edition6 @S=-2?6244F020:;22?1
02: +aghuraulu6 (+Madha%an air & S+(alynasundara + A Manual of Jaboratory echni#ues6national institute of utrition6ICM6Hydrabad6244'2nd 04'-045
0': Anne augh6 Allison !rant6 oss & illisons6Anatoy And physiology in Health & Illness+ Churchill6 2440 3th;22 6 2'62'1
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05: S+8hard)a et+al6 Antihyperglyceic acti%ity of a#+">tract of lea%es of cocculus hirsutus' J+: in allo>aninduced diabetic ice6 Indian ournal of =haracology6
feb+2449'?;53-'+0: =+D +Doeni et+al+6Hypoglyceic effect of methylene
chloride root e>tract of ceiba "entandra in noral andDiabetic rat6 Indian ournal of =haracology6 Vune 2449 '? ; 035-031
09: Sh)eta !uptaet+al6 Antidiabetic 6antihypercholesterolae-
-ic and antio>idant effect of occium santum FJ: seedoil6 Indian ournal of ">periental 8iology6april-244955;'42-'45+
01: $enugopal =+ Menon et+al+ Antidiabetic & Antihyperlipidaeic effect of alcoholic syzium cumini seed inallo>an induced diabetic rat 6 Vournal of "thnopharacology 62445630243-20'
0?: = Orti7 Andrade et al Antidiabetic effect on
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0?: =++Orti7 Andrade et+al+ Antidiabetic effect on
allo>ianis7ed and noroglyceic rat of Tournefortia
harrt!egiana.Vournal of "thno pharacology 6 2446
040 ;'1-52
03: S+Helata et+al+ "ffect of a#+e>tract of fruit of ithania
caagulens on glucose utili7ation by rat
Heidiaphrag+Indian Vournal of atural
=roduct20F2:; 24-22
24: aanarayana (6 et+al+6Antidiabetic6antihyperlipideic
and Kree radical sca%enging acti%ities of Ayur%edic
Medicine6 Indian Drug6 March 2442'1F':;0'4-0'0
20: Alan !+ 8a>terW6 o)ena C+ Duc.)orth6 Models of
type0 Fautoiune: diabetes Coparati%e !enoics
Centre6 Vaes Coo. @ni%ersity6 Australia Drug
Disco%ery oday; Disease Models $ol+ 06 o+ 5
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22+ oel So)ar06 Xian ping Kang26 !ary
S)eeney26WDrug Disco%ery oday; Disease Models
$ol+ 26 o+ ' 244;0?0-0??
2'+ Dr+ Jibor $elise. +6Hypoglyceic Sei7uresInstitution; Albert "instein College of Medicine at
Peshi%a @ni%ersity Mentor ; 8y (a Jai =oon
24. www.diabetescare.com
25. www.americanassociationofdiabetis.com26. www.hopkinsmedicine.org
27. www.diabetis.diabetiso!rnal.com"
2#. www.t!b!les.com"..."mice$#nod$sept.2%%4.pg
2&. '.(.).*erry. *harmacological E+periment,s on
solated preparation E./.0. (i1ingstone &7%32 nd 3
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