The aim of the present study was to evaluate the Antiulcer activity of Boswelia ovalifolita on Aspirin+Pyloric ligation in rat model
To compare the influence of Omeprazole (30 mg/kg) & Boswelia ovalifolita on free acidity with normal saline. To compare the influence of Omeprazole (30 mg/kg) & Boswelia ovalifolita on total acidity with normal saline. To compare the influence of Omeprazole (30 mg/kg) & Boswelia ovalifolita on ulcer index with normal saline.
2
INTRODUCTION Manki nd has l i ved wi th pept i c ul cers si nce anci ent ti mes. Perhaps the f i rst descri pt i on of thi s mal ady i s the one i nscri bed on the pi l l ars of the templ e of Aescul api us at Epi daurus f rom around the f ourth century B.C.: A man wi th an ul cer i n hi s stomach. He i ncubated and saw a vi si on; the god seemed to order hi s f ol l owers to sei ze and hol d hi m, that he mi ght i nci se hi s stomach. So he f l ed, but they caught and ti ed hi m to the doorknocker. Then Askl epi os opened hi s stomach, cut out the ul cer, sewed hi m up agai n, and l oosed hi s bonds. 1 Pepti c ul cer and rel ated aci d pept i c di seases af f ect up to 10 percent of the popul at i on wi th suf f i ci ent severi t y to prompt vi cti ms t o seek medi cal att enti on. The most si gni f i cant di sorders requi ri ng medi cal at tenti on are Pepti c ul cer and gast ro esophageal ref l ux di sease. 2
Diagram of Peptic Ulcer 3
3
Ul cers occur as a resul t of an i nf l ammati on of the stomach l i ni ng cal l ed gast ri ti s (when i t i s the duodenum t hat gets i nf l amed, the condi ti on i s cal l ed duodeni ti s).
The most uni f orm i ndex of the i nci dence of ul cers was exami ned by Jenni ngs
(1940). Hi s i nterpretat i on suggested that duri ng thi s
peri od there had been three observabl e syndromes: perf orati ons
of acute gast ri c ul cers i n young women; perf orati ons of duodenal
ul cers i n young and mi ddl e- aged men; and perf orati ons of gast ri c
ul cers i n ol der men.
Perf orati ons began to be noted wi t h i ncreasi ng f requency at
the begi nni ng of the 19th century. The common perf orati ons of today made an appearance onl y at
the begi nni ng of the 20th century; these are j uxta- pyl ori c ul cers
occurri ng mai nl y i n young and mi ddl e-aged men. 4 However the i nci dence of these t ypes of ul cer had begun to decl i ne because of the sharp ri se i n morbi di t y
and mortal i t y duri ng thi s century, due to pept i c ul cer, part i cul arl y
of the duodenum, has earned i t sel f a pl ace as one of the di seases
of ci vi l i zat i on. 5
The f ol l owi ng stat i sti cs rel ate to the preval ence of Pepti c Ul cer : 6, 7, 8, 9
COUNTRY/REGION PREVALENCE POPULATION ESTIMATED USED USA 5,398,077 293,655,405 Uni ted Ki ngdom 1,107,917 60,270,708 Chi na 23,875,874 1,298,847,624 India 19,578,503 1,065,070,607
4
Pepti c ul cer i s di agnosed i n 2.03% of workers engaged i n the engi neeri ng i ndust ry and 1.82% of those worki ng at the chemi cal pl ant. 10
A pepti c ul cer i s erosi on i n the l i ni ng of the stomach or duodenum (the f i rst part of the smal l i ntesti ne). The word pepti c ref ers to pepsi n, a stomach enzyme that breaks down protei ns. If a pept i c ul cer i s l ocated i n the stomach i t i s cal l ed a gastri c ul cer. Smal l ul cers may not cause any symptoms. Large ul cers can cause seri ous bl eedi ng. Most ul cers occur i n the f i rst l ayer of the i nner l i ni ng. A hol e that goes al l the way through i s cal l ed a perf orati on of the i ntesti nal l i ni ng. A perf orat i on i s a medi cal emergency. 11 Peptic ulcer resul ts f rom l esi ons i n the gastri c or duodenal mucosa caused or exacerbated by gastric acid and pepsin, or as the resul t of a confrontati on between acid aggression and mucosal defense. 12
Can l i f est yl e changes & di etary changes hel p?
Aspi ri n and rel at ed drugs (non-st eroi dal ant i -i nf l ammatory drugs), 13 al cohol , 14 cof f ee 15 (i ncl udi ng decaf ), and tea 16 can aggravate or i nterf ere wi th the heal i ng of pepti c ul cers. Smoki ng i s al so known to sl ow ul cer heal i ng 17 Peopl e wi th ul cers have been reported to eat more sugar than peopl e wi thout ul cers 18 ,
though thi s l i nk may onl y occur i n those wi th a geneti c suscepti bi l i ty toward ul cer f ormati on. 19
Sugar has al so been reported to i ncrease stomach aci di t y 20 ,
whi ch coul d aggravate ul cer symptoms. 21 Sal t i s a stomach and i ntesti nal i rri tant. Hi gher i ntakes of sal t have been l i nked to hi gher ri sk of stomach ul cer. 22 As a resul t of these reports, some doctors suggest that peopl e wi th ul cers shoul d rest ri ct the use of both sugar and sal t , al though the benef i t of such di etary changes remai ns unknown. 5
Vi tami n A i s needed to heal the l i ni ngs (cal l ed mucous membranes) of the stomach and i ntesti nes. Zi nc i s al so needed f or the repai r of damaged ti ssue and has prot ected agai nst stomach ul cerati on i n ani mal studi es. 23
Gl utami ne, an ami no aci d, i s the pri nci pal source of energy f or cel l s that l i ne the smal l i nt esti ne and stomach. 24 Gl utami ne has al so prevented stress ul cers tri ggered by severe burns i n another prel i mi nary study. 25
Management of Peptic Ulcer: Successf ul management of pepti c ul cer i s done by reduction of gastric acid secretion whi ch i ncl udes H 2 anti hi stami nes such as ci meti di ne, rani ti di ne, f amoti di ne, roxati di ne and l oxati di ne, proton pump i nhi bi tors such as omeprazol e, l ansoprazol e, pantoprazol e, rabeprazol and esmoprazol e, and anti chol i nergi cs such as pi renzepi ne, propanthel i ne and oxyphenoni um as wel l as prostagl andi n anal ogues such as mi soprostol , enprost i l and ri oprost i l . Another pathway f or the cont rol and treatment of pept i c ul cer i s by Neutralization of gastric aci d (Antaci ds) whi ch i ncl udes Systemi c antaci ds l i ke sodi um bi carbonate, sodi um ci t rate and Nonsystemi c antaci ds l i ke magnesi um hydroxi de, magnesi um tri si l i cate, al umi ni um hydroxi de gel , magal drate, cal ci um carbonate. Other cl asses i ncl udes Ulcer protecti ves such as sucral f ate, col l oi dal bi smuth subci t rate(CBS), Ulcer heal ing drugs such as carbenoxol one sodi um and Anti - Helicobacter pyl ori drugs l i ke amoxi ci l l i n, cl ari thromyci n, metroni dazol e, ti ni dazol e and tet racycl i ne. 26
Herbs Helpful in Anti ulcer Therapy: 27, 28, 29, 30
Fortunatel y, there are vari ous pl ant -ori gi nated "gastroprotectors" wi th di f f erent composi ti on that have been used i n cl i ni cal and f ol k medi ci ne f or many countri es due to thei r benef i ci al ef f ects on the mucosa 6
of GIT. Many years ago, researchers reported that cabbage j ui ce accel erated heal i ng of pepti c ul cers. Dri nki ng a quart of cabbage j ui ce per day was necessary f or symptom rel i ef i n some report s. In Chi na and Japan, pol yphenol extracts such as Sopharadi n ext racts, contai ni ng f l avonoi ds and i ts syntheti c f l avonoi d deri vati ve known as Sol on are wi del y empl oyed i n pepti c ul cer therapy and al so as f ood addi ti ves and nutri t i onal suppl ements, mai nl y because of thei r st rong i nhi bi ti on of prostagl andi n (PG) metabol i sm and vasoconst ri ct i ve l eukot ri enes i nhi bi ti on. It enhances heal i ng of chroni c gastri c and duodenal ul cers i nduced by aceti c aci d and that i t acts probabl y through the i ncrease i n mucosal PG content probabl y due to i nhi bi t i on of 15-OH-PG dehydrogenase, a PG hydrol yzi ng enzyme. Thi s study provi des an evi dence that extr acts ori gi nat i ng f rom the pl ant s used i n anci ent herbal medi ci ne appear t o contai n hi ghl y ef f ecti ve, but l i t tl e studi ed i n humans compounds, most l i kel y f l avonoi ds, t hat are capabl e of protecti ng the gast ri c mucosa f rom necroti zi ng substances and possi bl e usef ul i n the therapy of acute and chroni c gast ri c ul cerati ons. Among pl ant ant i ul cer drugs, onl y Sol on i s now wi del y used i n gast ri ti s and pepti c ul cer therapy i n certai n countri es. Astragal us (Ast ragal us membranaceus) Amaranth Barberry (Berberi s vul gar i s) Bari i l ayachi ( El ett ari a cardamomum and Amomum subul atum) Banana (Musa paradi si acal ) Bi l berry (Vacci ni um myrti l l us) Bl ack berry Cal endul a Cat' s Cl aw (Uncari a tomentosa) Chamomi l e (Mat ri cari a recut i ta) Comf rey 7
Corydal i s Cranberry (Vacci ni um spp) Dong Quai (Angel i ca si nensi s) Garl i c (Al l i um sati vum) Grapef rui t (Ci t rus paradi si ) Li cori ce (Gl ycyrrhi za gl abra) Marshmal l ow Root (Al thaea off i ci nal i s) Pi stachi a l ent i scus, Pl antai n Sl i ppery el m ( Ul mus ful va) Sol on Symcl i si a scabri da Tea root extract ( Camel l i a si nensi s) Turmeri c (Curcuma l onga) REVIEW OF LITERATURE An ulcer i s an open sore, or l esi on, usual l y f ound on the ski n or mucous membrane areas of the body. An ul cer i n the l i ni ng of the stomach or duodenum, where hydrochl ori c aci d and the di gest i ve enzyme cal l ed pepsi n are present , i s cal l ed a pepti c ul cer. Pept i c ul cers occur when the mucous l i ni ng of the stomach or duodenum i s not suf f i ci ent to protect them agai nst the corrosi ve act i on of stomach aci d, pepsi n, or other aggressi ve substances. 1
Major Forms of Peptic Ulcers
Gastric ulcer Duodenal Ulcer 8
GASTRIC ULCER: 2, 3
Numerous pathophysi ol ogi c def ects have al so been i denti f i ed i n gast ri c ul cer di sease but not al l of these f actors are present i n each pati ent. These def ects i ncl ude decreased aci d secreti on, decreased pari etal cel l mass and back-di f f usi on of aci d. Many pati ent s wi th chroni c gast ri c ul cers have associ ated gastri ti s. There may be i ncreased concentr at i on of bi l e aci ds and pancreati c j ui ce i n the stomach as a resul t of duodenogastri c ref l ux. Bi l i ary ref l ux through the pyl orus i s al so a common f i ndi ng i n pati ents wi th gastri c ul cers, and i t has been suggest ed t hat t he combi nat i on of bi l e and aci d may be part i cul arl y damagi ng t o t he mucosa, probabl y by causi ng back-di f f usi on of hydrogen i ons i nt o i t and t hus di srupt i ng i nt racel l ul ar organel l es. Del ayed gast ri c empt yi ng has al so been i dent i f i ed i n some pat i ent s wi t h gast ri c ul cers, and t hi s may accent uat e t he rel ease of gast ri n and t he secret i on of hydrochl ori c aci d. I t has yet t o be det ermi ned whet her del ayed gast ri c empt yi ng i s t he cause or secondary ef f ect of gast ri c ul cer di sease. However, as a resul t of back-di f f usi on of aci d, t he act ual concent rat i on of aci d i n t he gast ri c l umen may be underest i mat ed. Hypergast ri nemi a and hyperchl oremi a are not commonl y t hought t o be associ at ed wi t h gast ri c ul cers. The pressure of t he pyl ori c sphi nct er may be i nappropri at el y decreased under basal condi t i ons and may f ai l t o respond normal l y t o aci d or f at i n t he duodenum, t hereby predi sposi ng t o duodenogast ri c ref l ux l ess common t han duodenal ul cers. Most common changes are seen al ong t he l esser curvat ure and pyl ori c ant rum. I t i s grossl y si mi l ar t o duodenal ul cer and hi st ol ogi cal l y i ndi st i ngui shabl e f rom duodenal ul cer. Cl i ni cal features i ncl udes f ood pai n pat t ern, no ni ght pai n, haemat emesi s more common, si gni f i cant l oss of wei ght , pat i ent s choose bl and di et devoi d of f ri ed f oods, curri es et c. , deep t enderness i n t he mi dl i ne i n epi gast ri um, no seasonal vari at i on, more of t en i n l abori ng groups. Abdomi nal di scomf ort - t hi s i s t he pri mary sympt om usual l y chroni c and ongoi ng, 9
t he di scomf ort has part i cul ar charact eri st i c pat t erns: abdomi nal pai n af t er a meal usual l y 2-3 hours l at er, abdomi nal pai n on empt y st omach, abdomi nal pai n rel i eved by f ood, abdomi nal pai n rel i eved by ant aci ds, poor appet i t e, bl oat i ng, bel chi ng, nausea, vomi t i ng, gast roi nt est i nal bl eedi ng - a very seri ous sympt om requi ri ng i mmedi at e medi cal at t ent i on; caused by a bl eedi ng ul cers, i t s sympt oms may i ncl ude: vomi t wi t h cof f ee grounds consi st ency, bl ood i n st ool , bl ack st ool . Emergency Symptoms 4
Sharp, sudden, persi stent stomach pai n Bl oody or bl ack stool s Bl oody vomi t or vomi t that l ooks l i ke coff ee grounds Perf orati on--when the ul cer burrows through the stomach or duodenal wal l . Bl eedi ng--when aci d or the ul cer breaks a bl ood vessel . Obstructi on--when the ul cer bl ocks the path of f ood tryi ng to l eave the stomach DUODENAL ULCER: 2, 3
A number of pathophysi ol ogi c def ects have been i denti f i ed i n some pati ents wi th duodenal ul cer di sease. These i ncl ude i ncreased pari etal cel l mass (l eadi ng to i ncreased maxi mal and peak aci d output); i ncreased sensi t i vi t y of the pari etal cel l s to gast ri n and other secretagogues; i ncreased secretory dri ve; decreased aci d-i nduced i nhi bi t i on of meal - sti mul ated gast ri n rel ease; and i ncreased gast ri c emptyi ng (l eadi ng to i ncreased duodenal aci d and pepsi n l oads). Apart f rom an i ncreased pari etal cel l popul ati on (and possi bl y G-cel l hyperpl asi a), the gastri c 10
mucosa i s hi stol ogi cal l y normal i n duodenal ul cer. By contrast, i n gast ri c ul cer the nonpari et al mucosal area i s usual l y i ncreased, especi al l y on the l esser curvature, and there i s of ten some degree of hi stol ogi cal l y demonstrabl e gastri ti s. It i s f our ti mes more common than gastri c ul cers. It starts at an age 25-50 years. Most commonl y as a resul t of H. pyl ori i nf ecti ons. Other f actors l eadi ng to hypersecreti on of aci d-pepsi n, associ ati on wi th al cohol i c ci rrhosi s, t obacco, hyperparat hyroi di sm, chroni c pancreati ti s, bl ood group O, genet i c f actors. Protect i ve gastri c mucus barri er may be damaged. Cli nical features i ncl udes common ni ght pai n , no vomi t i ng, mel aena more common than haematemesi s, no l oss of wei ght, no parti cul ar choi ce of di et, deep tenderness i n the ri ght hypochonri um, marked seasonal vari at i on occurs more commonl y i n peopl e at greater stress, commonl y hemorrhage, perf orati on, somet i mes obstruct i on, mal i gnant transf ormati on never occurs. Abdomi nal Discomfort Symptoms of Peptic Ulcer 4
A dul l , gnawi ng ache. Comes and goes f or several days or weeks. Occurs 2 to 3 hours af ter a meal . Occurs i n the mi ddl e of the ni ght (when the stomach i s empty). Rel i eved by f ood. Rel i eved by antaci d medi cati ons. STOMACH: The stomach i s t ypi cal l y a J shaped enl argement of the GI tract di rect l y i nf eri or to the di aphragm i n the epi gastri c, umbi l i cal , and l ef t hypochondri ac regi ons of the abdomen. 5
11
Gastri c j ui ce i s a mi xt ure of secreti ons of pepti c cel l s, mucous secret i ng cel l s, surf ace epi thel i al cel l s and so on. The composi ti on of gastri c j ui ce i s not constant; i n the same person, someti mes the HCl concentrat i on i s hi gher somet i mes l ower - and so on. About 99.5% of the gastri c j ui ce i s water, rest i s sol i d. There are 2 ki nds of sol i ds: 1) Inorganic compounds: HCl and Bi carbonates. 2) Organic compounds: Mucus, Enzymes and Intri nsi c f actor.
HCl i s necessary f or conversi on of pepsi nogen to pepsi n. It st i mul ates secret i on of some GI hormone, act s as bacteri ostati c. Pepsi nogen i s converted i nto pepsi n, provi ded the gastri c j ui ce i s suf f i ci entl y aci di c. In the presence of HCl , pepsi n i s very acti ve and di gests f ood protei n.
Mucus protect s the gastri c mucosa mechani cal l y f rom bei ng i nj ured by the corrosi ve ef f ects of f ood, together wi t h the HCO 3 - of the gast ri c j ui ce; i t consti tutes the mucosal barri er, whi ch prevents the auto di gesti on of the gast ri c mucosa i t sel f by the aci d pepsi n mi xture (APM). Bi carbonate act together wi th the gastri c mucus to prevent auto di gesti on of the stomach. The Intri nsi c f actor, IF i s needed f or the absorpt i on of oral l y i ngested vi tami n B 12 . 6
12
Anatomy of the Stomach 7
The stomach has four mai n regi ons: The cardi a, f undus, body, and pyl orus.The cardia surrounds the superi or openi ng of the stomach. The rounded porti on superi or to the l ef t of the cardi a i s the fundus. Inf eri or to the f undus i s the l arge central port i on of the stomach, cal l ed the body. The regi on of the stomach that connects to the duodenum i s the pyl orus: i t has two parts, the pyl ori c ant rum whi ch connects to the body of the stomach, and the pyl ori c canal , whi ch l eads i nto the duodenum. When the stomach i s empt y, the mucosa l i es i n l arge f ol ds, cal l ed rugae that can be seen wi th the unai ded eye. The pyl orus communi cates wi th the duodenum of the smal l i ntest i ne vi a a sphi ncter cal l ed the pyl ori c sphi ncter. The concave medi al border of the stomach i s cal l ed the l esser curvature, and the convex l ateral border i s cal l ed the greater curvature. 8
1.Serosa 2.Tel asubserosa 3.Muscul ari s 4.Obl i que f i bers of muscl e wal l 5. Ci rcul ar muscl e l ayer 6. Longi tudi nal muscl e l ayer 7. Submucosa 8. Lami na muscul ari s Mucosae 9. Mucosa 10. Lami na propri a 11. Epi thel i um 12. Gastri c gl ands 13. Gastri c pi ts 14. Vi l l ous f ol ds
13
15. Gastri c areas (gast ri c surf ace) Fi gure of Stomach Layers 7
The stomach wal l i s composed of the same f our basi c l ayers as the rest of the GI tract, wi th certai n modi f i cat i ons. The surf ace of the mucosa i s a l ayer of si mpl e col umnar epi thel i al cel l s cal l ed surf ace mucous cel l s. The mucosa contai ns a l ami na propri a and a muscul ari s mucosae. Epi thel i al cel l s extends down i nto the l ami na propri a, where they f orm col umns of secretary cel l s cal l ed gastri c gl ands t hat l i ne many narrow channel s cal l ed gast ri c pi ts. Secret i ons f rom several gast ri c gl ands f l ow i nto each gast ri c pi t and then i nto t he l umen of the stomach. The gastri c glands contai n three t ypes of exocri ne gl and cel l s t hat secrete thei r products i nto the stomach l umen: mucous neck cells, chief cells, and parietal cells. Both surface mucous cells and mucous neck cells secrete mucus. Parietal cells produce intri nsic factor, whi ch i s needed f or absorpti on of vi tami n B 12, and hydrochl oric aci d. The chief cells secrete pepsinogen and gast ri c l i pase. The secret i ons of the mucous cel l s, chi ef cel l s, and pari etal cel l s f orm gastri c j ui ce, whi ch total s 2000 - 3000 mL per day. In addi t i on, gastric glands i nclude a t ype of enteroendocri ne cel l s, the G cells, whi ch i s l ocated mai nl y i n the pyl ori c antrum and secretes the hormone gastri n i nto the bl oodstream. 8
PROCESS OF DIGESTION: a) Mechanical Di gestion: Several mi nutes af ter f ood enters the stomach, gentl e, ri ppl i ng, peri stal t i c movements cal l ed mi xi ng waves pass over the stomach every 15 to 25 seconds. These waves macerate f ood, mi x i t wi th secret i ons of gast ri c gl ands, and reduce i t to a soupy l i qui d cal l ed chyme. Few mi xi ng waves are observed i n the f undus, whi ch pri mari l y has a storage f unct i on. 14
As di gesti on proceeds i n the stomach, more vi gorous mi xi ng waves begi n at the body of the stomach and i ntensi f y as t hey reach the pyl orus. The pyl ori c sphi ncter normal l y remai ns al most, but not compl etel y, cl osed. As f ood reaches the pyl orus, each mi xi ng wave f orces several mi l l i l i ters of chyme i nto the duodenum through the pyl ori c sphi ncter. Most of the chyme i s f orced back i nto the body of the stomach, where mi xi ng cont i nues. The next wave pushes the chyme f orward agai n and f orces a l i tt l e more i nto the duodenum. These f orward and backward movements of the gastri c contents are responsi bl e f or most mi xi ng i n the body. Foods may remai n i n the f undus f or about an hour wi thout becomi ng mi xed wi th gastri c j ui ce. Duri ng thi s t i me, di gest i on by sal i vary amyl ase conti nues. Soon, however, the churni ng act i on mi xes chyme wi th aci di c gast ri c j ui ce, i nacti vat i ng sal i vary amyl ase and acti vat i ng l i ngual l i pase, whi ch starts to di gest tri gl yceri des i nto f atty aci ds and di gl yceri des.
b) Chemical Di gesti on: Even through pari etal cel l s secrete hydrogen i ons (H +) and chl ori de i ons (Cl - ) separatel y i nto the stomach l umen; the net eff ect i s secret i on of hydrochl ori c aci d (HCl ). Proton pumps powered by H + / K + ATPase acti vel y t ransport H + i nto the l umen whi l e bri ngi ng potassi um i ons (K + ) i nto the cel l s. At t he same ti me Cl - and K + di f f use out t hrough Cl - and K + channel s i n the api cal membrane. The enzyme carbonic anhydrase, whi ch i s especi al l y pl enti f ul i n pari etal cel l s, catal yzes the f ormati on of carboni c aci d f rom water and carbon di oxi de. As carboni c aci d di ssoci ates, i t provi des a ready source of H + f or
the proton pumps but al so generates bi carbonate i ons (HCO 3 - ). As HCO 3 - bui l ds up i n the cytosol , i t exi ts t he pari etal cel l i n exchange f or Cl - vi a Cl - /HCO 3 - anti porters i n the basol ateral membrane. HCO 3 - di f f uses i nto nearby bl ood capi l l ari es. Thi s al kal i ne ti de of bi carbonate i ons enteri ng the 15
bl oodstream af ter a meal may be l arge enough to sl i ghtl y el evate bl ood pH and make uri ne more al kal i ne.
The strongl y aci di c f l ui d of the stomach ki l l s many mi crobes i n f ood, and HCl part i al l y denatures protei ns i n f ood and sti mul ates the secret i on of hormones that promote the f l ow of bi l e and pancreati c j ui ce. Enzymat i c di gest i on of protei ns al so begi ns i n the stomach. The onl y proteol yt i c enzyme i n t he stomach i s pepsi n, whi ch i s secreted by chi ef cel l s. Because pepsi n breaks certai n pepti de bonds bet ween the ami no aci ds maki ng up protei ns, a protei n chai n of many ami no aci ds i s broken down i nto smal l er pept i de f ragments. Pepsi n i s most eff ecti ve i n the very aci di c envi ronment of the stomach (pH 2): i t becomes i nacti ve at hi gher pH. Another enzyme of the stomach i s gastri c l i pase, whi ch spl i ts the short chai n tri gl yceri des i n f at mol ecul es f ound i n mi l k i nto f att y aci ds and monogl yceri des. Thi s enzyme, whi ch has a l i mi ted rol e i n the adul t stomach, operates best at pH of 5-6. More i mportant than ei ther l i ngual l i pase or gast ri c l i pase i s pancreat i c l i pase, an enzyme secreted by the pancrease i n to the smal l i ntest i ne. Onl y a smal l amount of absorpti on occurs i n the stomach because i ts epi thel i al cel l s are i mpermeabl e to most materi al s. However, mucous cel l s of the stomach absorb some water, i ons, and short -chai n f att y aci ds, as wel l as certai n drugs. Regulati on of Gastric Secretion and Motili ty:
Both neural and hormonal mechani sms cont rol the secreti on of gast ri c j ui ce and the contracti on of smooth muscl e i n the stomach wal l . Events i n the gast ri c di gesti on occur i n three overl appi ng phases: The cephalic, gastric, and intesti nal phases.
16
1- Cephalic Phase: The cephal i c phase of gastri c di gesti on consi sts of ref l exes i ni t i ated by sensory receptors i n the head. Even bef ore f ood enters the stomach, the si ght, smel l , t aste or thought of f ood i ni ti ates thi s ref l ex. The cerebral cortex and the f eedi ng center i n the hypothal amus send nerve i mpul ses to the medul l a obl ongata. The medul l a then transmi ts i mpul ses to parasympatheti c pregangl i oni c neurons i n the vagus nerves, whi ch sti mul ates parasympatheti c post gangl i oni c neurons i n the submucosal pl exus. In turn, i mpul ses f rom parasympathet i c postgangl i oni c neurons sti mul ate t he gastri c gl ands to secrete pepsi nogen, hydrochl ori c aci d, and mucus i nto stomach chyme, and gast ri n i nto the bl ood. Impul ses f rom parasympatheti c neurons al so i ncrease stomach moti l i t y. Emot i ons such as anger, f ear, and anxi et y may sl ow di gesti on i n the stomach because they sti mul ate the sympatheti c nervous system, whi ch i nhi bi ts gast ri c act i vi t y.
2- Gastric Phase: Once f ood reaches the stomach, sensory receptors i n the stomach i ni t i ate bot h neural and hormonal mechani sms to ensure that gast ri c secret i on and mot i l i t y cont i nue. Thi s i s the gast ri c phase of gast ri c di gesti on. Food of any ki nd di stends the stomach and sti mul ates stret ch receptors i n i ts wal l s. Chemoreceptors i n the st omach moni tor the pH of the stomach chyme. When the stomach wal l s are di stended or pH i ncreases because protei ns have entered the stomach and buff ered some of the stomach aci d, the stret ch receptors and chemoreceptor are acti vated, and a neural negat i ve f eedback l oop i s set i n moti on. From the stretch receptors and chemoreceptors, nerve i mpul ses propagat e to the submucosal pl exus, where they acti vate parasympatheti c and enteri c neurons. The resul t i ng nerve i mpul ses cause waves of peri stal si s and cont i nue to sti mul at e the f l ow of gastri c j ui ce f rom pari etal cel l s, chi ef cel l s, and mucous cel l s. 17
The peri stal t i c waves mi x the f ood wi th gast ri c j ui ce, and when the waves become strong enough, a smal l quant i t y of chyme about 10 - 15mL squi rts past the pyl ori c sphi nct er i nto the duodenum. As the pH of the stomach chyme becomes more aci di c agai n and the stomach wal l s are l ess di st ended because chyme has passed i nto the smal l i ntest i ne, thi s negati ve f eedback cycl e suppresses secret i on of gast ri c j ui ce.
Hormonal negat i ve f eedback al so regul ates gast ri c secret i on duri ng the gast ri c phase. Part i al l y di gested protei ns buf f er H + thus i ncreasi ng pH, and i ngested f ood di stends the stomach. Chemoreceptors and stret ch receptors moni tori ng these changes st i mul ate parasympatheti c neurons to rel ease acet yl chol i ne. In turns, acetyl chol i ne st i mul ates secret i on of the hormone gast ri n by G cel l s, enteroendocri ne cel l s i n the mucosa of the pyl ori c antrum. Gastri n enters the bl oodst ream and f i nal l y reaches i ts target cel l s, the gast ri c gl ands. Gastri n sti mul ates growth of the gast ri c gl ands and secreti on of l arge amount of gastri c j ui ce. It al so strengthens cont racti on of the l ower esophageal sphi ncter, i ncreases moti l i t y of the stomach, and rel axes the pyl ori c and i l eocecal sphi ncters. Gastri n secret i on i s i nhi bi ted when the pH of the gastri c j ui ce drops bel ow 2.0 and i s sti mul ated when the pH ri ses. Thi s negati ve f eedback mechani sm hel ps provi de an opt i mal l ow pH f or the f uncti oni ng of pepsi n, the ki l l i ng of mi crobes, and the denaturi ng of the protei ns i n the stomach. Acet yl chol i ne (Ach) rel eased by parasympatheti c neurons and gast ri n secreted by G cel l s st i mul ate pari etal cel l s to secrets more HCl i n t he presence of hi st ami ne. In other words, hi stami ne, a paracri ne substance that i s rel eased by mast cel l s i n the l ami na propri a and acts on nearby pari etal cel l s, act synergi st i cal l y wi th acet yl chol i ne and gastri n to enhance thei r ef f ects. Receptors f or al l three substances are present i n the pl asma 18
membrane of pari etal cel l s. The hi stami ne recept ors on pari etal cel l s are cal l ed H 2 receptors; they medi at e di ff erent responses than do the H 1 receptors i nvol ved i n al l ergi c responses. 3- Intestinal Phase: The i ntesti nal phase of gastri c di gest i on i s due to act i vati on of receptors i n the smal l i ntest i ne. Whereas ref l exes i ni ti ated duri ng the cephal i c and gast ri c phases st i mul at e stomach secretary act i vi t y and moti l i t y, those occurri ng duri ng the i ntest i nal phase have i nhi bi tory eff ects that sl ow the exi t of chyme f rom the stomach and prevent overl oadi ng of the duodenum wi th more chyme than i t can handl e. In addi ti on, responses occurri ng duri ng the i ntest i nal phase promote the conti nued di gesti on of f oods that have reached the smal l i ntest i ne. When chyme contai ni ng f att y aci ds and gl ucose l eaves the stomach and enters the smal l i ntest i ne, i t t ri ggers enteroendocri ne cel l s i n the smal l i ntest i nal mucosa to rel ease i nto the bl ood t wo hormones that aff ect the stomach secret i n and chol ecystoki ni n or CCK. Wi th respect to the stomach, secret i n mai nl y decreases gastri c secreti on, whereas CCK mai nl y i nhi bi ts stomach emptyi ng. Both hormones have other i mportant ef f ects on the pancrease, l i ver, and gal l bl adder that cont ri bute to the regul ati on of di gest i ve processes. 9
19
Regulati on of Gastric Secretion 10
CAUSES OF PEPTI C ULCER: When the stomach' s natural protect i ons f rom the damagi ng ef f ects of di gesti ve j ui ces i ncl udi ng aci d and pepsi n [an enzyme that hel ps 20
breakdown protei n] stop worki ng or the aci d product i on i s too overwhel mi ng f or t hese protect i ve def enses to work properl y, you can get an ul cer. There are a f ew di f f erent ways thi s happens. 11
Helicobacter pyl ori (H. pyl ori ): Hel i cobacter pyl ori i s a spi ral -shaped Gram-negati ve bacteri um that col oni zes the stomach i n about 50% of al l humans. Hel i cobacter pyl ori i s uni quel y adapted to survi val i n the hosti l e envi ronment of stomach. It at taches to the surf ace epi thel i um beneath the mucus, has hi gh urease acti vi t y produces ammoni a whi ch mai ntai ns a neut ral mi croenvi ronment around the bacteri a, and promotes back di f fusi on of H + i ons. It i s now accepted as an i mportant contri butor to the causat i on of chroni c gastri t i s, dyspepsi a, pept i c ul cer, gast ri c l ymphoma and gast ri c carci noma. The presence of Hel i cobacter pyl ori i s al ways associ ated wi th an i nf l ammati on of the underl yi ng gast ri c mucosa as evi denced by an i nf i l trat i on of i nf l ammatory cel l s. The chroni c i nf ecti on i s i ni ti ated i n the l ower part of the stomach (ant rum) such ul cers are more common i n t he duodenum than i n the stomach i tsel f . Severe compl i cat i ons i ncl ude bl eedi ng and perf orati on. The current vi ew i s that the chroni c i nf l ammati on i n the di stal part of the stomach caused by Hel i cobacter pyl ori i nf ecti on resul ts i n an i ncreased aci d product i on f rom the non-i nf ected upper corpus regi on of the stomach. Thi s wi l l predi spose f or ul cer devel opment i n the more vul nerabl e duodenum. Hel i cobacter pyl ori i nf ecti on starts wi t h a neutrophi l i c gastri ti s l asti ng 7-10 days whi ch i s usual l y asymptomati c. Once establ i shed, H. pyl ori general l y persi st s f or the l i f e of the host. Upto 90% pat i ents of duodenal and gast ri c ul cer have tested posi ti ve f or H. pyl ori .
21
Role of H pylori i n Peptic Ulcer 12
22
Non-Steroi dal Anti -Inflammatory Drugs (NSAI Ds) : Ongoi ng use of thi s cl ass of medi cati ons i s the second most common cause of ul cers. These drugs (whi ch i ncl ude aspi ri n, i buprof en, naproxen, di cl of enac, tol meti n, pi roxi cam, f enoprof en, i ndomethaci n, oxaprozi n, ketoprof en, sul i ndac, nabumet one, etodol ac, and salicyl ates) are aci di c and they bl ock prostagl andi ns, substances i n the stomach that hel p mai ntai n bl ood f l ow and prot ect the area f rom i nj ury. Some of the speci f i c drugs l i sted are more l i kel y to produce ul cers than others. 14
Zolli ngerEll ison Syndrome: The Zol l i nger -El l i son (ZE) syndrome i s characteri zed by autonomous gast ri n product i on by an adenoma or adenocarci noma of the pancreas or duodenum. The Zol l i nger -El l i son syndrome i s di sti ngui shed f rom pepti c ul cer di sease by the demonstrati on of f asti ng hypergast ri nemi a. There are many causes of f asti ng hypergast ri nemi a (gast ri t i s, vagotomy and pyl oropl ast y, the short bowel syndrome, rheumatoi d arthri t i s, retai ned antrum, G-cel l hyperpl asi a), but onl y t wo condi t i ons - at rophi c gast ri ti s and renal f ai l ure - are associ ated wi th gast ri n l evel s i ncreased several ti mes above the upper l i mi t of the normal range. However, i n a pati ent wi th pepti c ul cer di sease and hypergast ri nemi a, i t i s i mport ant to excl ude the Zol l i nger-El l i son syndrome. The Zol l i nger -El l i son syndrome ari ses f rom a gastri noma, a tumor i n the pancreas. Thi s may be a l ocal i zed or di f f use tumor. The presence of hypergast ri nemi a l eads to hypersecret i on; whi l e the maxi mal aci d output may be i ncreased, the maj or def ect i s basal hypergast ri nemi a and a marked i ncrease i n the basal aci d output. The pati ent wi l l have aggressi ve pept i c ul cer di sease wi th ul cerati on i n unusual si tes, or mul ti pl e ul cers that f ai l to heal on medi cal therapy. Hypertrophi c gast ri c f ol ds and di arrhea may be promi nent f eatures. 15
Heredi tary Factors: Heredi tary f actors are i mportant i n the pathogenesi s of pepti c ul cer di sease, as suggested by a hi gher 23
preval ence of pepti c ul cer di sease i n certai n geneti c syndromes. A number of f ami l i al aggregat i ons have been noted i n pati ents wi th pept i c ul cer di sease. These i ncl ude hyperpepsi nogenemi a 1, normal pepsi nogenemi a 1, antral G-cel l hyperf uncti on, rapi d gastri c empt yi ng, chi l dhood duodenal ul cer and i mmunol ogi c f orms of pepti c ul cer di sease. Heredi t y al so pl ays a rol e i n the devel opment of ul cerati on and i s associ at ed wi th the syndrome of mul ti pl e endocri ne adenomatosi s 1 (adenomas of the pancreas, pi tui tary and parathyroi d). Parents, si bl i ngs and chi l dren of ul cer pati ent s are more l i kel y to have pepti c ul cer di sease than control i ndi vi dual s. There i s greater concordance f or ul cer di sease i n i denti cal than i n f raternal t wi ns. Hyperpepsi nogenemi a 1 appears to be an autosomal domi nant trai t. There i s i ncreasi ng evi dence to suggest that f ami l i al pepti c ul cer di sease i s rel ated to Hel i cobacter pyl ori c i nf ecti on amongst f ami l y members. 16
Male Sex: There i s greater concordance f or ul cer di sease i n mal es than f emal es, i n duodenal ul cer the rati o of occurrence i n mal es than f emal es i s (4: 1), and f or gast ri c ul cer the rat i o i s (3.5: 1). 17
First Degree Relati ve with Duodenal Ulcer: Genet i c predi sposi t i on appears to be i mportant; f i rst -degree rel at i ves of duodenal ul cer pati ents have about 3 t i mes the general popul at i on' s ri sk of devel opi ng duodenal ul cer. 18
Elevated Pepsinogen Levels: The rel at i on of the serum pepsi nogen concentrat i on to the l ocat i on of gast ri c ul cers and chroni ci t y of pepti c
ul cers i s as f ol l ows - the mean pepsi nogen concentrat i on i s si gni f i cant l y hi gher i n
mal es than i n f emal es. In
mal e pati ents wi th ul cers i n the duodenum, antrum, or
angul us porti on, the mean serum pepsi nogen concentrati on i s si gni f i cantl y hi gher than i n the normal mal es but i n
pat i ents wi th an ul cer i n t he upper body i t i s si mi l ar to 24
control
val ues. Men wi th acti ve or heal i ng ul cers showed a si gni f i cant l y
hi gher serum pepsi nogen concent rat i on than those wi th scarred l esi ons when the abnormal i ty i s l ocated i n ei ther the upper body or i n the angul us
port i on. For f emal e pati ents, t he resul ts are si mi l ar. These
resul ts suggest that serum pepsi nogen concentrat i ons ref l ect the stages of
acti vi t y of pepti c ul cer i n humans. 19
HLA-B5: Some bl ood groups are associ ated wi th i ncreased ri sk of duodenal ul cer, and HLA-B5 ant i gen appears to be i ncreased among whi te mal es wi th duodenal ul cer. 18
Cigarette Smoking: Smoki ng i s associ ated wi th a hi gher preval ence of pepti c ul cer di sease and may be associ ated wi th i mpai red heal i ng of duodenal and gast ri c ul cer di sease. Al so, deat h rat es f rom pept i c ul cer di sease are hi gher i n i ndi vi dual s who smoke. Smoki ng i ncreases a person' s ri sk of getti ng an ul cer because the ni coti ne i n ci garettes causes the stomach to produce more aci d. Ci garette smoki ng i ncreases both the i nci dence and rel apse rate of pepti c ul cer di seases and al so del ays ul cer heal i ng. 20
Al coholic Cirrhosis: Ul cers are more common i n peopl e who have ci rrhosi s of the l i ver. Si nce ci rrhosi s of the l i ver i s associ ated wi th al cohol consumpt i on, al cohol reducti on may work as a prevent i ve measure to reduce the ri sk of pepti c ul cer. Al so al cohol i s thought to sl ow wound heal i ng i ncreasi ng the ri sk bl eedi ng ul cers. Consumpti on of al cohol si gni f i cantl y i ncreases the ri sk of gastri c ul cers. 21
Stress: Stress ul cers are usual l y occurs i n the context of a maj or systemi c or CNS i l l ness or trauma. The eti ol ogy i nvol ves aci d as wel l as mucosal i schemi a. But thi s usual l y onl y happens i n si tuati ons when i l l ness i nvol vi ng severe emoti onal or physi cal st ress i s i nvol ved. Ul cers 25
occur because of uncontrol l ed i ncreased aci d producti on i n the stomach and changes i n a person' s i mmune system (the body system that f i ghts i nf ecti on). Wi th any i l l ness where the body' s abi l i t y to heal i s chal l enged (such as when a person has been burned badl y i n a f i re), there i s a ri sk f or devel opi ng ul cers. 22, 23
COX-2 I nhi bi tors: The Cycl o-oxygenase-2 (COX-2) i nhi bi tors exert thei r therapeut i c eff ect by i nhi bi t i ng the product i on of prostagl andi ns i nvol ved i n i nf l ammati on. At therapeuti c doses they have l i t tl e or no i nhi bi tory ef f ect on cycl o-oxygenase-1, whi ch i s expressed i n many ti ssues and i s necessary f or the product i on of prostagl andi ns that protect the mucosa of the upper gastroi ntesti nal tract. It i s theref ore expected that COX-2 i nhi bi tors wi l l have reduced gastro duodenal toxi ci t y compared wi th convent i onal NSAIDs. Cycl o-oxygenase-2 (COX- 2) i nhi bi tors cause gast ro duodenal ul cerat i on and subsequent compl i cat i ons. The ri sk, however, i s hal ved compared wi th conventi onal non-steroi dal anti -i nf l ammatory agents (NSAIDs). COX-2 i nhi bi tors, l i ke NSAIDs, may exacerbate i nf l ammatory bowel di sease and cause i ntesti nal st ri ctures. 24
COPD: Gastroi ntesti nal symptoms coul d be rel ated to the hi gh i nci dence of pepti c ul cer di sease i n pati ents wi th Chroni c obstructi ve pul monary di seases (COPD), to abdomi nal di scomfort caused by bronchodi l ator drugs or corti costeroi ds, or to earl y sat i et y caused by f l attened di aphragm or ai r swal l owi ng 25 .
Corticosteroids: Gl ucocort i coi ds i ncrease the secreti on of hydrochl ori c aci d, pepsi nogen and pancreat i c trypsi nogen. They i ncrease both basal and nocturnal gastri c secret i on. They decrease the 26
resi stance of gastri c mucosa to the i rri tant act i on of the gastri c secret i ons, and produce or aggravate gast ri c ul cerati on. They are ul cerogeni c, the ri sk i s doubl ed, bl eedi ng and si l ent perf orati on of ul cers may occur. 26
Other causes of ul cers are condi ti ons that can resul t i n di rect damage t o the wal l of the stomach or duodenum such as radi at i on t herapy, burns, and physi cal i nj ury. AGGRESSIVE AND DEFENSIVE FACTORS OF THE GASTROINTESTINAL TRACT 27
Pepti c ul cer i s preci pi tated by an i mbal ance of the aggressi ve and def ensi ve f actors of the GI tract. AGGRESSIVE FACTORS DEFENSIVE FACTORS Gastri c aci d Mucus Pepsi n Bi carbonate Bi l e Prostagl andi ns Acet yl chol i ne Phosphol i pi d membrane Hi stami ne Cel l ul ar repai r and mi grati on Gastri n Mucosal bl ood f l ow Medi cati ons Hel i cobacter pyl ori FACTORS PROMOTING HEALI NG OF ULCER: Ul cer heal i ng i s a compl ex and t i ghtl y regul ated process of f i l l i ng the mucosal def ect wi t h prol i f erati ng and mi grat i ng epi thel i al and connecti ve ti ssue cel l s. Thi s process i ncl udes the re-establ i shment of the conti nuous surf ace epi thel i al l ayer, gl andul ar epi thel i al st ructures, mi crovessel s and connecti ve t i ssue wi thi n the scar. Epi thel i al cel l s i n t he mucosa of the ul cer margi n prol i f erate and mi grate onto the granul at i on ti ssue to re - 27
epi thel i al i ze the ul cer. Growth f actors, such as epi dermal growth f acto r (EGF), basi c f i brobl ast growth f actor (bFGF), t ri f ol i at e pepti des (TP), pl atel et deri ved growth f actor (PDGF) and other cytoki nes produced l ocal l y by regenerati ng cel l s, control re-epi thel i al i zat i on and the reconst ruct i on of gl andul ar structures. These growth f act ors, most notabl y EGF, t ri gger epi thel i al cel l prol i f erati on vi a si gnal transducti on pathways i nvol vi ng EGF-R- MAP (Erk1/Erk2) ki nases. Granul at i on ti ssue, whi ch devel ops at the ul cer base, consi st s of f i brobl asts, macrophages and prol i f erati ng endot hel i al cel l s, whi ch f orm mi crovessel s under the control of angi ogeni c growth f actors. These growth f actors [bFGF, vascul ar endothel i al growt h f actor (VEGF) and angi opoi eti ns] promote angi ogenesi s--capi l l ary vessel f ormati on--thereby al l owi ng f or the reconst ruct i on of mi crovascul ature i n t he mucosal scar, whi ch i s essenti al f or del i very of oxygen and nut ri ent s to the heal i ng si te. The pri mary tri gger to acti vate expressi on of angi ogeni c growth f actors and thei r receptors appears to be hypoxi a. Duri ng ul cer heal i ng expressi on of growth f actor genes i s t i ghtl y regul ated i n a temporal l y and spat i al l y ordered manner. 28 NATURAL REMEDI ES: 29, 30
Herbs may cause si de ef f ects or i nteract wi th medi cati ons. They shoul d, theref ore, be used wi th caut i on and onl y under the gui dance of a prof essi onal l y trai ned and qual i f i ed herbal i st. Wi th that sai d, there are many herbs, some of whi ch are descri bed bel ow, that may be recommended by an herbal speci al i st f or pepti c ul cers. Amaranth: It resul ts i n gastroprotect i on agai nst 100% ethanol and i t s f avorabl e ef f ect coul d be reversed by the pretreatment wi th neurotoxi c dose of capsai ci n t hat i s known to cause f uncti onal abl ati on of sensory aff erent nerves and rel ease of Gastroprotect i ve sensory neuropept i des such as cal ci toni n - gene rel ated pepti de (CGRP) . Based on the resul ts we can specul ate that Amaranth acts on gast ri c mucosa to sti mul ate af f erent nerves and i ncrease i n gast ri c mi croci rcul ati on. 28
Astragalus (Ast ragal us membranaceus): used t radi t i onal l y to t reat stomach ul cers. Barberry (Berberi s vul gari s): Thi s herb contai ns act i ve substances cal l ed berberi ne al kal oi ds. These substances have been shown to combat i nf ecti on and bacteri a. For t hi s reason, barberry i s used to ease i nf l ammati on and i nf ecti on of the gast roi ntest i nal t ract. Barberry has al so been used tradi t i onal l y to i mprove appeti te. Bari ilayachi (El et tari a cardamomum and Amomum Subul atum): Gastro protect i ve ef f ect of both drugs may be due to a decrease i n gast ri c moti l i t y. 31 They cause rel axat i on of ci rcul ar muscl es whi ch may protect gast ri c mucosa through f l atteni ng of the f ol ds. Thi s wi l l i ncrease the mucosal area exposed to narcot i zi ng agents and rel ease the vol ume of gast ri c agent s on rugal crest. Such acti on has been postul at ed to pl ay a rol e i n cytoprotecti ve ef f ect of prostagl andi ns. 32
Black berry: One of the most i nteresti ng substances that has been obtai ned f rom chi l l y peppers and present i n spi cy pl ants such as gi nger or bl ack pepper i s capsai ci n. Thi s substance acts on sensory neurons to sti mul ate thei r membrane receptors, predomi nantl y vani l oi d (VR) -1 receptors, and rel ease vari ous ki ni ns such as CGRP and substance P. When appl i ed i n l arge dose capsai ci n dest roys sel ecti vel y C-f i ber neuronal endi ngs l eadi ng to i nact i vat i on of sensory nerves and the l oss of al l ref l exes i n whi ch these nerves are i nvol ved. In smal l er dose, capsai ci n i s the potent gast roprotecti ve agent and sti mul ant of gastri c mi croci rcul ati on. 33
Bilberry (Vacci ni um myrti l l us): Vacci ni um Myrt i l l us has a protect i ve i nf l uence on the st omach and i s used to treat pept i c ul cers. Bi l berry tea i s admi ni stered to treat stomach probl ems and soothe the di gesti ve tract. The herb i s ri ch i n tanni ns (7%), and pect i n. Tanni ns have both 29
anti -i nf l ammatory and astri ngent pr operti es whi ch are usef ul i n treat i ng aci d i ndi gesti on. Bi l berry i s hi gh i n the bi of l avonoi d compl ex anthocyanosi des. Anthocyanosi des i nhi bi t hi stami ne (whi ch i n turn reduces aci ds i n the stomach), i nf l ammatory prostagl andi ns, l eukot ri enes, and enzymes. Studi es i n rat s have f ound that anthocyani di ns (an anti oxi dant ) f rom bi l berry f rui t s hel p prevent stomach ul cers rel ated to a vari ety of f actors i ncl udi ng stress, medi cati ons, and al cohol . 34
Cat' s Claw (Uncari a tomentosa): The bark and root of thi s herb have been used among i ndi genous peopl e of the rai nf orest f or centuri es to treat a vari et y of heal th probl ems i ncl udi ng ul cers and other gast roi ntest i nal di sorders. The benef i ts of thi s herb may be due to i ts abi l i t y to reduce i nf l ammati on.
Chamomile (Matri cari a recut i ta): Chamomi l e (Matri cari a recut i ta) i s an herb that has been used tradi ti onal l y as a mi l d sedat i ve to rel i eve anxi et y and i n t reati ng di gest i ve di sorders i ncl udi ng pepti c ul cers. Chamomi l e al so may be eff ecti ve i n rel i evi ng i nf l amed or i rri tated mucous membranes of the di gest i ve tract and i n promoti ng di gesti on. Chamomi l e has a soothi ng act i on on the di gesti ve syst em. Its gent l e soothi ng act i on i s benef i ci al i n di gesti ve di sorders l i ke i ndi gesti on, aci di t y and pepti c ul cers. It i s al so hi gh i n the f l avonoi d api geni n another f l avonoi d t hat has i nhi bi ted growth of H. pyl ori i n test tubes. 35
Cranberry (Vacci ni um spp): May have properti es that hel p prevent Hel i cobactor pyl ori i nf ecti on. Dong Quai (Angel i ca si nensi s): Ani mal studi es suggest that dong quai may soothe ul cers, but studi es i n peopl e are needed bef ore a def i ni t i ve concl usi on can be drawn. 30
Garlic (Al l i um sat i vum): some studi es suggest that hi gh amounts of garl i c may protect agai nst stomach cancer, whi ch i s a potent i al compl i cat i on of H. pyl ori pept i c ul cers. Thi s i s cont roversi al , however, and hi gh amounts of garl i c may i n f act cause gast roi ntesti nal di st ress. Grapefrui t (Ci t rus paradi si ): Nari ngeni n, the bi oact i ve component of GSE, (grapef rui t seeds-ext ract ) showed gastroprotect i ve acti vi t y due to i ncrease expressi on of prostagl andi ns bi osynthesi s. Present studi es wi th GSE conf i rmed that i n vi t ro GSE i s hi ghl y anti bacteri al and anti f ungal agent , i t i s a potent ant i -H. pyl ori substance and exerts prof ound gast roprotecti on.
Licorice (Gl ycyrrhi za gl abra): Li cori ce root has a l ong hi stor y of use f or soothi ng i nf l amed and i nj ured mucous membranes i n the di gest i ve tract. Li cori ce may protect the stomach and duodenum by i ncreasi ng producti on of muci n, a substance t hat protect s the l i ni ng of these organs agai nst stomach aci d and other harmf ul substances. Accordi ng to l aboratory research, f l avonoi ds i n l i cori ce may al so i nhi bi t growth of H. pyl ori . Carbenoxol one, a popul ar drug f or treat i ng pepti c ul cers, i s a semi synthet i c deri vati ve of gl ycyrrhi zi n, devel oped over 30 years ago. The mechani sm underl yi ng the anti ul cer ef f ects of l i cori ce appears to i nvol ve the abi l i t y of GL and GA (gl ycyrrhet i ni c aci da part i al l y hydrol yzed f orm of gl ycyrrhi zi n to i nhi bi t the enzymes 15- hydroxyprostagl andi n dehydrogenase and D-13-prostagl andi n reductase, whi ch i nacti vates the prot ecti ve prostagl andi ns (PG) i n the gast ri c mucosa. 36, 37
Marshmallow Root (Al thaea offi ci nal i s): For decades, marshmal l ow has been used i n fol k medi ci ne to hel p cure gastri c ul cers. The roots of the marshmal l ow contai n muci l age, a gel at i nous subst ance f ound i n 31
pl ants. When i t comes i nto contact wi th water, thi s muci l age swel l s, f ormi ng a sof t, prot ecti ve gel . Thi s i s bel i eved to provi de a protect i ve barri er agai nst i rri t ati ng substances that may aggravate ul cers. 38
Slippery el m (Ul mus ful va): Al though there has been l i ttl e sci enti f i c research on sl i ppery el m, i t has a l ong hi story of use based on c l i ni cal experi ence. Gastri ti s (stomach i nf l ammati on) and pepti c ul cer are among the condi ti ons that seem to respond wel l to sl i ppery el m. Symclisia scabri da: It possesses Ant i ul cer propert y. The f l avanod and al kal oi dal f acti ons of thi s pl ant decrease the number of neutrophi l s usi ng smears f rom the erosi ons made on the gastroi ntest i nal l umen. 39
Solon: Sopharadi n ext racts, contai ni ng f l avonoi ds and i tssynthet i c f l avonoi d deri vat i ve known as Sol on are wi del y empl oyed i n pept i c ul cer therapy and al so as f ood addi ti ves and nutri ti onal suppl ements, mai nl y because of thei r strong i nhi bi t i on of prost agl andi n (PG) metabol i sm and vasoconst ri cti ve l eukotri ene i nhi bi t i on. i t enhances heal i ng of chroni c gast ri c and duodenal ul cers i nduced by aceti c aci d and that i t acts probabl y through the i ncrease i n mucosal PG content probabl y due to i nhi bi ti on of 15-OH-PG dehydrogenase, a PG hydrol yzi ng enzyme. Tea root extract (Camel l i a si nensi s): Tea root ext ract mi ght pri marl y decrease the l eakage of pl asma protei ns i nto the gastri c j ui ce wi th strengtheni ng of the mucosal barri er and i ncrease i n i t s resi stance to the damagi ng ef f ect of ethanol i nduced ul cer. 40
Turmeric (Curcuma l onga): Const i tuents of Curcuma l onga exert several protecti ve eff ects on the gast roi ntest i nal t ract. A sal t of curcumi n, sodi um curcumi nate, was f ound to i nhi bi t i nt esti nal spasm, and p-tol ymethyl carbi nol , a turmeri c component, was f ound capabl e of 32
i ncreasi ng gastri n, secreti n, bi carbonate, and pancreat i c enzyme secret i on. Turmeri c has al so been shown i n rats t o i nhi bi t ul cer f ormati on caused by st ress, al cohol , i ndomethaci n, pyl ori c l i gati on, and reserpi ne. Thi s study demonstrated turmeri c ext ract si gni f i cantl y i ncreased the gastri c wal l mucus i n rat s subj ect ed to these gast roi ntest i nal i nsul ts. Ani mal studi es i ndi cate that certai n i ndi vi dual herbal ext racts as wel l as a combi nati on of these extracts may hel p heal ul cers. More studi es are needed, however, to know whether t hese i ndi vi dual herbs or a parti cul ar combi nati on of them woul d hel p peopl e. 41, 42
The combi nati on preparati on used i n t hese ani mal studi es i ncl uded: Angel i ca (Angel i ca archangel i ca) German chamomi l e (Mat ri cari a recut i t a) Lemon bal m (Mel i ssa offi ci nal i s) Li cori ce (Gl ycyrrhi za gl abra) Mi l k thi st l e (Si l ybum mari anum) Peppermi nt (Mentha x pi peri ta) Cal endul a (Cal endul a offi ci nal i s) - used i n the Uni ted St ates duri ng the 19th century to treat stomach ul cers Capsai ci n - the act i ve i ngredi ent i n cayenne ( Capsi cum frutescens/Capsi cum spp) Marshmal l ow ( Al thea offi ci nal i s) HOMEOPATHY: Al though f ew studi es have exami ned the eff ecti veness of speci f i c homeopathi c therapi es, prof essi onal homeopaths may consi der the f ol l owi ng remedi es f or the treatment of ul cers or i t s symptoms, based on thei r knowl edge and experi ence. Bef ore prescri bi ng a remedy, homeopaths take i nto account your consti tut i onal t ype. A consti tut i onal 33
type i s def i ned as your physi cal , emoti onal , and psychol ogi cal makeup. An experi enced homeopath assesses al l of these f actors when determi ni ng the most appropri ate treatment f or you i ndi vi dual l y. For the treatment of ul cers, even i f you do seek homeopathi c remedi es as adj unct i ve care, conventi onal treat ment recommendati ons must be f ol l owed. Argentum ni t ri cum f or abdomi nal bl oat i ng wi t h bel chi ng and pai n. Arseni cum al bum f or ul cers wi th i ntense burni ng pai ns and nausea; especi al l y f or peopl e who cannot bear the si ght or smel l of f ood and are thi rst y. Kal i bi chromi cum f or burni ng or shooti ng abdomi nal pai n that i s worse i n the wee hours of the morni ng (that i s, af ter mi dni ght). Lycopodi um f or bl oati ng af ter eat i ng wi th burni ng that l asts f or hours; especi al l y f or peopl e who f eel hungry soon af ter eati ng and wake hungry. Ni t ri c aci d f or sharp, shooti ng pai n that worsens at ni ght and i s accompani ed by f eel i ngs of hopel essness and even f ear of dyi ng. Nux vomi ca f or di gesti ve di sturbances (i ncl udi ng heartburn and i ndi gest i on) that worsens af ter eati ng; part i cul arl y f or those who crave al cohol , cof fee, and tobacco. Phosphorus f or burni ng stomach pai n that worsens at ni ght; those f or whom thi s remedy i s appropri ate tend to f eel very thi rst y, cravi ng col d beverages. Pul sat i l l a f or sympt oms that vary a l ot (that i s, change abruptl y) and pai n that gets worse f rom f att y f oods; appropri ate peopl e are di st i nctl y not thi rst y. ACUPUNCTURE Acupuncture has been used t radi t i onal l y f or a vari et y of condi ti ons rel ated to the gast roi ntesti nal tract, i ncl udi ng pepti c ul cers. A growi ng body of sci enti f i c evi dence suggest s t hat acupuncture can hel p reduce 34
pai n associ ated wi th endoscopy (the procedure used, as descri bed earl i er, to make a di agnosi s of ul cer or to treat i ts compl i cati ons. ) APPROACHES FOR THE TREATMENT OF PEPTIC ULCER 1) Reduction of Gastric Acid Secretion 43, 44, 45
a) H 2 Anti histamines: The H 2 antagoni sts exhi bi t competi ti ve i nhi bi t i on at the pari etal cel l H 2 receptors, and suppress basal and meal - st i mul ated aci d secreti on i n a l i near, dose dependent manner. They are hi ghl y sel ect i ve and do not aff ect H 1 or H 3 receptors. The vol ume of gastri c secret i on and concentrati on of pepsi n are al so reduced. H 2 antagoni sts reduce aci d secret i on st i mul ated by hi stami ne as wel l as gastri n and chol i nomi met i c agents through t wo mechani sms. Fi rst, hi stami ne rel eased f rom ECL cel l s by gast ri n or vagal sti mul at i on i s bl ocked f rom bi ndi ng to the pari etal cel l by gastri n or acet yl chol i ne resul ts i n di mi ni shed aci d secret i on i n the presence of H 2 recept or bl ockade. It appears that reduced pari etal cel l cycl i c AMP l evel s attenuate the i ntracel l ul ar act i vat i on of protei n ki nases by gast ri n or acetyl chol i ne.
Cimetidi ne: Ci met i di ne contai ns an i mi dazol e ri ng. It reduces f asti ng and st i mul ated aci d and pepsi n secret i on by competi tevel y antagoni si ng the acti on of hi stami ne on H 2 receptors. It i s very eff ecti ve i n promoti ng heal i ng of gastri c and pepti c ul cer. Rani tidi ne: Int roduced subsequent to ci met i di ne as a noni mi dazol e (has a f uran ri ng). I t i s about 5 t i mes more potent than ci meti di ne. Famotidi ne: A thi azol e ri ng contai ni ng H 2 bl ocker whi ch bi nds ti ghtl y to the H 2 receptors and exi hi bi t l onger durat i on of acti on. It i s 5-8 ti mes more pot ent than rani t i di ne. 35
Roxatidi ne and Loxati dine are other exampl es of thi s cl ass. b) Proton Pump Inhibitors: The most ef fecti ve suppressors of gastri c aci d secreti on undoubtedl y are H + /K + ATPase (proton pump) i nhi bi tors. They are - pyri dyl methyl sul f i nyl benzi mi dazol e wi th di f f erent substi tut i ons on t he pyri di ne or t he benzi mi dazol e groups; thei r pharmacol ogi cal propert i es are si mi l ar. Proton pump i nhi bi tors are prodrugs, requi ri ng acti vati on i n an aci d envi ronment. These agents enter the pari etal cel l s, f rom the bl ood and, because of thei r weak basi c nature, accumul ate i n the aci di c secretory canal i cul i of the pari etal cel l s, where they are act i vated by a proton catal yzed process that resul t s i n the f ormati on of a thi ophi l i c sul f enami d or sul f eni c aci d. Thi s acti vated f orm reacts by coval ent bi ndi ng wi th the sul f hydryl group of cystei nes f rom the ext racel l ul ar domai n of the H + /K + ATPase. Bi ndi ng to cystei ne 813, i n parti cul ar . Is essenti al f or i nhi bi t i on of aci d producti on, whi ch i s i rreversi bl e f or t hat pump mol ecul e. Proton pump i nhi bi tors have prof ound eff ects on aci d product i on. Omeprazole: It i s the protot ype member of substi tuted benzi mi dazol es.It i s a powerf ul i nhi bi tor of gast ri c aci d; can total l y abol i sh HCl secret i on, both resti ng as wel l as st i mul ated by any of the secretogagues, wi thout much eff ect on pepsi n, i ntri nsi c f actor, j ui ce vol ume and gastri c mot i l i t y. Omeprazol e i s i nacti ve at neutral pH, but at pH<5 rearranges t wo charged cati oni c f orms (a sul pheni c aci d and a sul phi nami de conf i gurat i ons) that react coval entl y wi th SH groups of the H + /K + ATPase enzyme and i nacti vates i t i rreversi bl y, especi al l y when t wo mol ecul es of omeprazol e react wi th one mol ecul e of the enzyme. Af ter di ff usi ng i nto the pari etal cel l s f rom bl ood i t gets concentrated i n t he aci di c pH of the canal i cul i because the charged f orms generated there at the aci di c pH are unabl e to di f f use back. Moreover i t gets ti ght l y bound to t he enzyme. 36
Aci d secreti on resumes onl y when new H + /K + ATPase mol ecul es are synthesi zed. It al so i nhi bi ts gastri c mucosal carboni c anhydrase. Lansoprazole: It i s more potent than omeprazol e but si mi l ar i n propert i es. Inhi bi ti on of H + /K + ATPase by l ansoprazol e i s partl y reversi bl e. i t has been shown to have greater i nhi bi tory ef f ect on Hel i cobactor pyl ori than omeprazol e.
Pantoprazole, Rabeprazole and Esmoeprazole are the other exampl es of thi s cl ass.
c) Anticholinergics: Anti chol i nergi c drugs reduce the i nter and post prandi al secret i on of gast ri c j ui ce, si nce these phases are part i al l y under chol i nergi c control . They reduce basal aci d secreti on by about 50% and histamine and gastri n - i nduced secreti on by 40%. They do not reduce f ood sti mul ated secret i on. They i nhi bi t gast ri c moti l i t y and prol ong the gastri c emptyi ng ti me.
Pirenzepine: Thi s drug has sel ect i ve anti muscari ni c acti on on M 1
muscarni c receptors i n the stomach. Propantheline and Oxyphenoni um are the other exampl es of thi s cl ass.
d) Prostaglandi n Analogues: Prostagl andi ns such as PGE 2 and PGI 2 are the maj or prostagl andi ns synthesi zed by the gast ri c mucosa; they i nhi bi t aci d product i on by bi ndi ng to the EP 3 receptor on pari etal cel l s. Prostagl andi n bi ndi ng to the receptor resul t s i n i nhi bi t i on of adenyl yl cycl ase and decreased l evel s of i nt racel l ul ar cycl i c AMP. PGE 2 also can prevent gast ri c i nj ury by i ts so-cal l ed cytoprotecti ve eff ects, whi ch i ncl udes st i mul ati on of secreti on of muci n and bi carbonate and 37
i mprovement i n mucosal bl ood f l ow; however, aci d suppressi on appears to be i ts more cri t i cal ef f ect. Misoprostol: Mi soprostol has both aci d i nhi bi tory and mucosal protect i ve propert i es. It i s bel i eved to sti mul ate mucus and bi carbonate secreti on and enhance mucosal bl ood f l ow. In addi ti on, i t bi nds to a prostagl andi n receptor on pari etal cel l s, reduci ng hi stami ne st i mul ated cycl i c AMP product i on and causi ng modest aci d i nhi bi ti on. Prostagl andi ns have a vari et y of other act i ons, i ncl udi ng sti mul ati on of i ntest i nal el ectrol yte and f l ui d secret i on, i ntest i nal moti l i t y and uteri ne contracti ons.
Enprostil and Ri oprostil are the other exampl es of thi s cl ass. 2) Neutralization of Gastric Acid (Antaci ds) 46
Antaci ds are weak bases that react wi th gastri c hydrochl ori c aci d to f orm sal t and water. The antaci ds di mi ni sh the quanti t y of f ree hydrochl ori c aci d by three mechani sms. Di rect neutral i zat i on of pref ormed aci d, thereby el evat i ng the gast ri c pH to about 4.0 whi ch are not strong enough to damage the mucosal l ayer. The other mechani sm i s buf f eri ng of pref ormed aci d, by agents l i ke magnesi um tri si l i cate and sodi um ci t rate. The thi rd mechani sm i s the adsorpti on of hydrogen i ons pl us adsorpti on of adsorpti on and i nacti vat i on of pepsi n as brought about by al umi ni um antaci ds and i on exchange resi ns. a) Systemic: Sodium bicarbonate: It react s rapi dl y wi th HCl to produce carbon di oxi de and NaCl . Formati on of carbon di oxi de resul t s i n gast ri c di stent i on and bel chi ng. Unreacted al kal i i s rapi dl y absorbed, potenti al l y causi ng metabol i c al kal osi s when gi ven i n hi gh doses or to pati ent s wi th renal i nsuf f i ci ency. Sodi um chl ori de absorpti on may exacerbate f l ui d secret i on i n pati ents wi th heart f ai l ure, hypertensi on and renal i nsuf f i ci ency. 38
b) Nonsystemic : Magnesi um hydroxide and Al umi nium hydroxide: Formul at i on contai ni ng magnesi um hydroxi de and al umi ni um hydroxi de react sl owl y wi th HCl to f orm magnesi um chl ori de or al umi ni um chl ori de and water. Because no gas i s generated, bel chi ng does not occur. Metabol i c al kal osi s i s al so uncommon because of the eff i ci ency of the neutral i zat i on react i on. Because unabsorbed magnesi um sal ts may cause an osmoti c di arrhea and al umi ni um sal ts may cause consti pat i on, these agent s are commonl y admi ni stered together i n propri etary f ormul ati ons. To mi ni mi ze the i mpact upon bowel f uncti on. Both al umi ni um and magnesi um are absorbed and excreted by the ki dney. Hence, pati ents wi th renal i nsuf f i ci ency shoul d not take these agents l ong term.
Magnesi um trisili cate, Magal drate and Calcium carbonate are the other exampl es of thi s cl ass.
3) Ulcer Protecti ves: 47, 48
The gastroduodenal mucosa has evol ved a number of def ense mechani sms to protect i tsel f agai nst the noxi ous ef f ects of aci d and pepsi n. Both mucus and epi thel i al cel l -cel l ti ght j uncti on rest ri ct back di f f usi on of aci d and pepsi n. Epi thel i al bi carbonate secreti on establ i shes a pH gradi ent wi th i n the mucus l ayer i n whi ch the pH ranges f rom 7 at the mucosal surf ace to 1-2 i n the gast ri c l umen. Bl ood f l ow carri es bi carbonate and vi tal nutri ent s to surf ace cel l s. Areas of i nj ured epi thel i um are qui ckl y repai red by resti tuti on, a process i n whi ch mi grati on of cel l s f rom gl and neck cel l s seal s smal l erosi ons to establ i sh i ntact epi thel i um. Mucosal prostagl andi ns appear to be i mportant i n st i mul ati ng mucus and bi carbonate secreti on and mucosal bl ood f l ow. A number of agents that potenti ate these mucosal 39
def ensi ve mechani sms are avai l abl e f or the prevent i on and treatment of aci d-pepti c di sorders.
Sucralfate: In the presence of aci d i nduced damage, pepsi n- medi ated hydrol ysi s of mucosal prot ei ns contri butes t o mucosal erosi on and ul cerati ons. Thi s process can be i nhi bi ted by sul f ated pol ysacchari des. Sucral f ate consi st s of the octasul f ate of sucrose to whi ch al umi ni um hydroxi de has been added. In an aci d envi ronment (pH > 4), i t undergoes extensi ve cross-l i nki ng and pol ymeri zat i on to produce a vi scous, sti cky gel that adheres strongl y to epi thel i al cel l s and even more st rongl y to ul cer craters f or as l ong as 6 hours af ter a si ngl e dose. In addi t i on to i nhi bi ti on of hydrol ysi s of mucosal protei ns by pepsi n, sucral f ate may have addi ti onal cyt oprotect i ve eff ects, i ncl udi ng sti mul at i on of l ocal producti on of prostagl andi n and epi dermal growth f actor (EGF). Sucral f ate al so bi nds bi l e sal ts, accounti ng f or i ts use i n some pati ents wi th esophagi t i s i n whom ref l ux of bi l e i s thought by some to pl ay a rol e i n pathogenesi s.
Coll oidal bismuth subcitrate (CBS): It i s a col l oi dal bi smuth compound, i t i ncreases the secret i on of mucus and bi carbonate through st i mul at i on of mucosal PGE 2 producti on. CBS and mucus f orms a gl ycoprotei n bi compl ex whi ch coats the ul cer and acts as a di ff usi on barri er to HCl . It detaches Hel i cobactor pyl ori f rom the surf ace of mucosa and di rectl y ki l l s thi s organi sm i nvol ved i n causati on of ul cer and rel apses.
4) Ulcer Heali ng Drugs: 49, 50
Carbenoxol one sodium: It i s a steroi d l i ke t ri terpenoi d gl ycyrrheti ni c aci d (f ound i n l i quori ce root), whi ch was f ound to 40
promote heal i ng of gastri c ul cer wi t hout al teri ng the vol ume or aci di t y of gastri c j ui ce. It s most i mport ant acti on i s augmentati on of mucus product i on, speci al l y the vi sci d mucus that remai ns adherent to the gastri c mucosa. Other act i ons are prol ongat i on of l i f e span of gastri c epi thel i al cel l s, preventi on of bi l e ref l ux and sl owi ng of PG degradati on i n gastri c mucosa.
5) Anti H.pylori Drugs: For H. pyl ori associ ated ul cers, there are t wo therapeuti c goal s: heal the ul cer and eradi cate the organi sm. The most eff ecti ve regi mens f or H. pyl ori eradi cati on are combi nati on s of t wo ant i bi ot i cs and a proton pump i nhi bi tor. Proton pump i nhi bi tors promote eradi cati on of H. pyl ori through several mechani sms; di rect anti mi crobi al properti es (mi nor) and by- rai si ng i ntragast ri c pH l oweri ng the mi ni mal i nhi bi tory concentrat i ons of anti bi ot i cs agai nst H. pyl ori . Amoxici llin, Clarithromyci n, Metronidazole, Tini dazole, and Tetracycli ne are t he exampl es of thi s cl ass.
41
Therapeutic I nterventi on i n a Pathophysiol ogic Scheme 51
42
SCREENING METHODS FOR ANTIULCER ACTIVITY 52
1) Pylorus li gati on in rat (SHAY rat): A si mpl e and rel i abl e method f or producti on of gast ri c ul cerati on i n the rat based on l i gature of the pyl orus, the ul cerat i on i s caused by accumul ati on of aci di c gastri c j ui ce i n the stomach. Ul cer i ndex and aci di t y of the gast ri c content of treated ani mal s are compared wi th control s. Usi ng vari ous doses, dose - response curves can be establ i shed f or ul cer f ormati on and gastri c aci d secret i on. Procedure: Femal e Wi star rat s wei ghi ng 150-170 g are starved f or 48 hours havi ng access to dri nki ng water ad l i bi tum. Duri ng thi s ti me they are housed si ngl e i n cages wi th rai sed bottoms of wi de wi re mesh i n order to avoi d canni bal i sm and coprophagy. Ten ani mal s are used per dose and as cont rol s. Under ether anesthesi a a mi dl i ne abdomi nal i nci si on i s made. The pyl orus i s l i gated, care bei ng exerci sed that nei ther damage to the bl ood suppl y nor the pyl orus occurs. Graspi ng the stomach wi th i nst ruments i s t o be meti cul ousl y avoi ded; el se ul cerati on wi l l i nvari abl y devel op at such poi nts. The abdomi nal wal l i s cl osed by sutures. The test compounds are gi ven ei ther oral l y by gavage or i nj ected subcutaneousl y. The ani mal s are pl aced f or 19 hours i n pl asti c cyl i nders wi th an i nner di ameter of 45 mm bei ng cl osed on both ends by wi re mesh. Af terwards, the ani mal s are sacri f i ced i n CO 2 anesthesi a. The abdomen i s opened and a l i gature i s pl aced around the esophagus cl ose to the di aphragm. The stomach i s removed, and the contents are drai ned i n a centri f uge tube. Al ong the greater curvature the stomach i s opened and pi nned on a cork pl ate. The mucosa i s exami ned wi th a stereomi croscope. ` 43
2) Stress ulcer through immobi lizati on stress: Psychogeni c f actors, such as st ress, pl ay a maj or rol e i n the pathogenesi s of gast ri c ul cers i n man. The experi mental model resembl es the psychogeni c f actors i n the pathogenesi s of gast ri c ul cers i n pati ent s. Theref ore, i t i s not surpri si ng that not onl y antaci ds, anti chol i nergi cs, H 2 antagoni st s, proton pump i nhi bi t ors, but al so psychot ropi c drugs, l i ke neurol epti cs have been f ound to be eff ecti ve i n thi s test.
Procedure: Groups of 10 f emal e Wi star rats per dose of test drug and f or control s wei ghi ng 150-170 g are used. Food and water are wi thdrawn 24 hours bef ore the experi ment. Af ter oral or subcutaneous admi ni st rati on of the test compound or the pl acebo sol uti on the ani mal s ext remi ti es are f i xed together and the ani mal s are wrapped i n wi re gauze. They are hori zontal l y suspended i n the dark at 20 o C f or 24 hours and f i nal l y sacri f i ced i n CO 2 anesthesi a. The stomach i s removed, f i xed on a cork pl ate and the number and the severi t y of ul cers i s regi stered wi th a stereo-mi croscope. 3) Stress ulcers by cold water immersion: Cool i ng of rats i n water duri ng the rest rai nt peri od accel erates the occurrence of gastri c ul cers and shortens the ti me of necessary i mmobi l i zati on. Procedure: Groups of 8 - 10 Wi star rats wei ghi ng 150-200 g are used. Af ter oral admi ni st rati on of the test compound, the rat s are pl aced vert i cal l y i ndi vi dual restrai nt cages i n water at 22 o C f or 1 hour. Then, they are removed, dri ed and i nj ected i ntravenousl y vi a the tai l vei n wi th 30 mg/Kg Evans bl ue. Ten mi nutes l ater, they are sacri f i ced i n CO 2
anesthesi a and thei r stomachs removed. Formol - sal i ne (2%v/ v) i s 44
then i nj ected i nto the total l y l i gated stomachs f or storage overni ght. The next day, the stomachs are opened al ong the greater curvature, washed i n warm water, and exami ned under a 3-f ol d magni f i er. 4) Indomethaci n i nduced ulcers in rats: Nonsteroi dal ant i - i nf l ammatory agent s, l i ke i ndomethaci n and acet yl sal i cyl i c aci d, i nduce gastri c l esi ons i n men and i n experi mental ani mal s by i nhi bi t i on of gast ri c cycl o oxygenase resul t i ng i n l ess f ormati on of prostacycl i n, the predomi nant prostanoi d produced i n the gast ri c mucosa. Procedure: Groups of 8 - 10 Wi star rat s wei ghi ng 150 - 200 g are used. The test drugs are admi ni stered oral l y i n 0.1 % Tween 80 sol uti on 10 mi nutes pri or to oral i ndomethaci n i n a dose of 20 mg/kg (4 mg/mL di ssol ved i n 0.1 % Tween 80 sol uti on). Si x hours l ater, the rats are sacri f i ced i n CO 2 anesthesi a and thei r stomachs removed. Formol - sal i ne (2%v/ v) i s then i nj ected i nto the total l y l i gated stomachs f or storage overni ght . The next day, the stomachs are opened al ong the greater curvature, washed i n warm water, and exami ned under a 3-f ol d magni f i er. 5) Ethanol induced mucosal damage in rats (Cytoprotecti ve acti vity) Intragast ri c appl i cati on of absol ute ethanol i s a reproduci bl e method to produce gast ri c l esi ons i n experi ment al ani mal s. These l esi ons can be at l east part i al l y i nhi bi ted by vari ous drugs, such as prostagl andi ns. The protecti ve ef f ect agai nst vari ous i rri tants has been cal l ed cytoprotecti ve act i vi t y. Procedure: Mal e Wi star rats wei ghi ng 250 - 300 g are depri ved of f ood 18 hours pri or to t he experi ment but are al l owed f ree access to water. Duri ng thi s t i me they are kept i n restrai ni ng cages to prevent 45
coprophagy. The rats are admi ni stered ei ther are appropri ate vehi cl e or the cytoprotecti ve drugs, f or exampl e a prostanoi d, i nt ragast ri cal l y 30 mi nutes pri or to admi ni st rati on of 1 mL absol ute ethanol . Unt reated ani mal s are i ncl uded as control s. One hour af ter admi ni st r ati on of ethanol , the ani mal s are sacri f i ced i n CO 2 anesthesi a and thei r stomachs exerci sed, cut al ong the greater curvature, and gent l y ri nsed under tap water. The stomachs are stretched on a pi ece of f oam core mat, mucosal si te up. The subj ecti ve scores of the treated ti ssues are recorded. 6) Subacute gastri c ulcer in rats Thi s i s a method f or produci ng standard subacute gast ri c ul cers i n rats and f or the quanti t ati ve eval uati on of the heal i ng process. Procedure: Femal e Wi star rat s wei ghi ng 120-150 g are f asted f or 24 hours havi ng access to water ad l i bi tum i n cages wi th wi re si eves at the bottom. The rats are anestheti zed wi th ether and a pol yethyl ene catheter i ncl udi ng a f i ne steel wi re wi th a needl e ti p (1.2 mm di ameter) at the l ower end i s oral l y i nser ted i nt o the stomach. Af ter the cannul a reaches the gast ri c wal l , the upper end of the steel wi re i s pressed i n a def i ni ti ve manner, so as to puncture t he gast ri c wal l . Each rat i s kept i n the same posi ti on duri ng the i nterventi on i n order to l ocal i ze the puncture at nearl y the same regi on of the gl andul ar part of the stomach. The test substances are admi ni stered oral l y, 30 mi nutes pri or or 24 hours af ter puncture. Free access to f ood and wat er i s provi ded f rom 2 hours up to the end of the experi ment. Each group consi sts of 8 - 15 rats. The ani mal s are sacri f i ced by overdose of ether at def i ni ti ve ti me i nterval s af ter puncture. The st omach i s di ssected and opened al ong the l esser curvature, extensi vel y ri nsed i n tap wat er and f i xed to the end of a pol yethyl ene tube of 10 mm di ameter (pl asti c ti p of an automati c pi pette) i n a posi ti on wi th the punched ul cer i n the center. The end of the tube wi th the gastri c wal l i s suspended i n a beaker 46
contai ni ng physi ol ogi cal sal i ne, and the pressure i n the tube i s gradual l y i ncreased wi th a val ved rubber bal l connected to the other end of the tube. The thi rd part of the system i s a tonometer cal i brated up to 1 bar. The val ue of tensi on at whi ch bubbl es appear at the ul cerous gastri c wal l i s noted. Thi s val ue i s termed as t ensi l e st rength and can be expressed i n mm Hg.
DISTRIBUTION Boswellia ovalifoliolata is a narrow endemic and endangered plant from the hot spots of Indias Tirupati-Tirumala-Nallamalai hills, belongs to the family Burseraceae, and is vernacularly known as konda guggilum in Telugu.This medium-sized deciduous tree is narrowly distributed on the foothills of the eastern parts of the Tirumala hills up to an altitude of about 300 meters. The plant flowers from December to February and the fruits appear between April and June. Leaf fall occurs from December to February and new foliage appears in April to May. The plant trunk secretes oleoresin, a secondary metabolite that is a pale yellow liquid and hardens on exposure. Amyrins are the chief constituents of this gum together with resin acids and volatile acids. The tribals of the Tirumala hills (Lambadi, Sugali and Nakkala) and the local healers of surrounding villages use the gum extensively to cure a number of diseases. They make deep incisions on the main trunk to extract the gum but unknowingly cause damage to immature plants, leading to the depletion of the plant in its natural habitat. It has now become endangered and is listed in the CITES red data book under medicinal plants. 2.3 USES: The gum and fresh leaf juice are used for mouth and throat ulcers. Shade- dried gum is powdered, dissolved in water, mixed with curd and given orally to cure amoebic dysentery. The gum powder mixed with sour milk is taken on an empty stomach for stomach ulcers and, mixed with the plant Pedalium murex, is made into paste and applied on the affected parts of the body to cure hydrocoele. A decoction of the stem bark is used for joint or rheumatic pains [53]
49
EARLIER WORK DONE Only a few works have been carried on various activities of Boswellia ovalifoliolata till now. They are as follows: Savitramma et al [54] studied that fresh leaf juice of the plant prevented throat ulcers. Ankanna et al [55] reported the production of highly dispersed biogenic silver nano particles from the bark. Chandrasekhar et al [56] developed a protocol of in vitro micro propagation using cotyledonary nodal explants on Murashige and Skoog modified medium (MS). Nagaraju et al [57] studied that decoction of the stem bark 10 25 mL per day reduces rheumatic pains. Lakshmi niranjan reddy et al [58] produced two new macrocyclic diaryl ether heptanoids and established their structures. This class of diaryl heptanoids exhibits a broad range of potent biological activities that include anti- inflammatory, antihepatotoxic, antifungal, antibacterial, and related effects. Venkata ratnam et al [59] evaluated the antimicrobial effects properties of petroleum ether, ethyl acetate and ethanol leaf extracts of Boswellia ovalifoliolata against two Gram positive, three Gram negative bacteria and yeast. The ethyl acetate and ethanol extracts exhibited significant inhibition zones against the test pathogens.
50
RESULTS Acute toxicity studies: The acute toxicity studies of the ethanolic leaf extract of Boswelia ovalifoliata was found to be non-lethal up to dose of 2000 mg /kg body weight of the animals so that 1\5th and 1\10th (i.e. 400 mg/kg and 200 mg/kg orally) was selected for the further investigations. Phytochemical Tests: The Ethanolic extract of Boswelia ovalifoliata) was subjected for the qualitative preliminary phytochemical identifications by the standard methods..The various chemical tests were carried out for the detection of Triterpenoids, Flavonoids, Saponins, Tannins and sterols and alkaloid Table No: 2 Details of qualitative Phytochemical Tests
Tests
Ethanolic extract
Tests for sterols 1. Test solution+Conc.H 2 SO 4
2. Salkowskis test 3. Liebermann Burchards test Test for Glycosides 1. Baljets test 2. keller-killiani test 3. Bromine water test 4. Legals test Test for Saponins 1. Foam test
+ + + - - - -
+ 51
2. Haemolysis Test
Test for carbohydrates 1. Molischs test 2. Barfoeds test 3. Benedicts test Test for Alkaloids 1. Mayers test 2. Wagners test 3. Dragondroffs test 4. Hagers test Test for Flavonoids 1. Ferric chloride test 2. Schinoda test 3. Zn-HCL reduction test 4. Alkaline reagent test 5. Lead acetate test Test for Tannins 1. Ferric chloride test 2. Gelatin test Test for Protiens 1. Millons test 2. Xanthoprotic test 3. Ninhydrin test Test for Fixed oils and fats 1. Spot test Test for gums and Mucilages 1.Swelling test 2. Molischs test Test for Triterpenes +
+ + + + + + +
+ + + + +
+ +
+ + -
+
_ +
52
1. Salkowskis test 2. Leibermann Burchard test
+ +
+ Indicates positive (present) -Indicates Negative (absent) Aspirin+Pyloric ligation: The effect of the ethanolic extract on Aspirin + pyloric ligation induced ulceration was studied and the results reduced the free acidity produced by Aspirin + pyloric ligation with a volume of 26.83 + 1.02 and 19.5 + 0.62 with the dose of 200 and 400 mg/kg respectively in comparison to control, Omeprazole as reference standard drug was shown free acidity of 16.67+ 0.67. The effect of the ethanolic extract on Aspirin + pyloric ligation induced ulceration was studied and the results reduced the total acidity produced by Aspirin + pyloric ligation with a volume of 60.51.46 and 461.13 with the dose of 200 and 400 mg/kg respectively in comparison to control, Omeprazole as reference standard drug was shown total acidity of 42.161.02. The effect of the ethanolic extract on Aspirin + pyloric ligation induced ulceration was studied and the results reduced the ulceration produced by Aspirin + pyloric ligation with a ulcer index of 2.780.23 and 1.970.13with the dose of 200 and 400 mg/kg respectively in comparison to control, Omeprazole as reference standard drug was shown reduction of ulcer 1.970.13.
53
Table No: 3 Effect of Free Acidity on Aspirin + Pyloric ligation
Results are expressed as Mean SEM Significant at *** P<0.001, n=6 Compared with control group S.No Control Omeprazol e (30 mg/ kg) EBO (200mg/kg) EBO (400mg/kg) 1 28 15 23 18 2 31 19 28 20 3 26 18 30 22 4 36 15 28 20 5 31 16 27 19 6 35 17 25 18 Mean + SEM 31.2+ 1.59
16.67 + 0.67 ***
26.831.02 *
19.5 + 0.62 *** 54
Free acidity c o n t r o l o m e p r a z o l e E B O
2 0 0 m g / k g E B O
4 0 0 m g / k g 0 10 20 30 40 control omeprazole EBO 200mg/kg EBO 400mg/kg Groups F r e e
a c i d
v o l u m e
m E q / 1 0 0 g
Table No: 4 Effect of Total Acidity on Aspirin + Pyloric ligation
Results are expressed as Mean SEM Significant at *** P<0.001, n=6 Compared with control group. Total acidity c o n t r o l o m e p r a z o l e E B O
2 0 0 m g / k g E B O
4 0 0 m g / k g 0 20 40 60 80 100 control omeprazole EBO 200mg/kg EBO 400mg/kg Groups T o t a l
a c i d
v o l u m e
m E q / 1 0 0 g
Table No: 5 Effect of Ulcer Index on Aspirin + Pyloric ligation
Results are expressed as Mean SEM Significant at ** P<0.05, n=6 S.No Control Omeprazol e (30 mg/ kg) EBO (200mg/kg) EBO (400mg/kg) 1 4 2 3 1.5 2 4.5 2.5 2.5 2 3 3 1.5 2 2.5 4 3.5 1 3.5 2 5 2.5 2.2 3.2 1.8 6 2 0.5 2.5 2 Mean + SEM 3.250.38 1.620.31 **
2.780.23 1.970.13 ** 56
Compared with control group
Table No: 6 Percentage protections of ulcers Treatment Mean Ulcer Index % Protection Control 3.250.38 __ Omeprazole (30 mg/kg) 1.620.31 50.15 EBO (200 mg/kg) 2.780.23 14.46 EBO (400 mg/kg) 1.970.13 39.38
Ulcer index c o n t r o l o m e p r a z o l e
3 0
m g / k g E B O
2 0 0 m g / k g E B O
4 0 0 m g / k g 0 1 2 3 4 5 control omeprazole 30 mg/kg EBO 200mg/kg EBO 400mg/kg Groups M e a n
u l c e r
i n d e x 57
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