vet pathol 1990 meschter 244 53

8/16/2019 Vet Pathol 1990 Meschter 244 53

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Phenyl"ta/one#nd"'ed @a%tr#' *l'er% #n ,or%e% 245

-or the f#r%t part of the #n+e%t#gat#on the morpholog#' %t"dy

16 treated and e#ght 'ontrol hor%e% 2ere "%ed. a'h hor%e #n

the treated gro"p 2a% adm#n#%tered phenyl"ta/one (Phen

B"taVet 13#4 mg<g Anthony Prod"'t% Co. Ar'ad#a CA)

#ntra+eno"%ly da#ly for "p to 4 day%. $he 'ontrol hor%e%re'e#+ed no phenyl"ta/one "t re'e#+ed 3 ml normal %al#ne

#ntra+eno"%ly da#ly #n order to %ham phenyl"ta/one

#ne't#on%.

$he p"rpo%e of the %t"dy 2a% to e&am#ne the early le%#on% of

pylor#' m"'o%al ero%#on format#on. ,or%e% 2ere e"thanat#/ed

a% follo2% 24 ho"r% after a %#ngle #ne't#on 024 ho"r%); after

t2o #ne't#on% at 24 ho"r #nter+al% 04 ho"r%); after three

#ne't#on% at 24 ho"r #nter+al% 072 ho"r%); and after fo"r

#ne't#on% at 24 ho"r #nter+al% (95 ho"r%). $2o treated hor%e%

and t2o 'ontrol hor%e% 2ere e"thanat#/ed at 24 and 72 ho"r%

and fo"r treated and t2o 'ontrol hor%e% 2ere e"thanat#/ed at

4 and 95 ho"r% for 4 'on%e'"t#+e day% follo2#ng the #n#t#al

adm#n#%trat#on of phenyl"ta/one.

$he adm#n#%trat#on of the phenyl"ta/one 2a% to m#m#'

da#ly 'l#n#'al adm#n#%trat#on of the dr"g. All hor%e% 2ere

e&am#ned morpholog#'ally and #o'hem#'ally 2h#le re'e#+#ng

phenyl"ta/one. A 'omplete and %y%temat#' ne'rop%y 2a%

performed on ea'h hor%e and repre%entat#+e t#%%"e% 2ere

reta#ned for h#%topatholog#' and "ltra%tr"'t"ral e+al"at#on. $he

%toma'h% of all hor%e% 2ere thoro"ghly and %y%temat#'ally

e&am#ned ma'ro%'op#'ally and m#'ro%'op#'ally. No le%#on%

2ere %een other than #n the pylor"%. Ba%ed on the ma'

ro%'op#' le%#on% %#te% 2ere %ele'ted for "ltra%tr"'t"ral

%e't#on#ng and #o'hem#'al a%%ay. $he ma'ro%'op#' m#'ro

%'op#' and #o'hem#'al 'hange% fo"nd #n the other organ% 2#ll

e pre%ented #n %"%e!"ent man"%'r#pt%.

-or the morpholog#' %t"dy t#%%"e% for h#%topatholog#' and"ltra%tr"'t"ral e+al"at#on #n'l"ded repre%entat#+e %e't#on% fromthe pylor#' m"'o%a. $#%%"e% 2ere f#&ed for 24 ho"r% #n 'h#lled04 C) 2#5arno+%yE% %ol"t#on emedded #n paraff#n

lo'% %e't#oned at 45 pm and %ta#ned 2#th hemato&yl#nand eo%#n.

-or the "ltra%tr"'t"ral pha%e of the morpholog#' %t"dy t2otreated hor%e% and one 'ontrol hor%e from 24& 4& 72& and 95ho"r% 2ere "%ed for perf"%#on f#&at#on. $he rema#n#ng fo"r treated hor%e% and fo"r 'ontrol hor%e% from the %t"dy 2erene'rop%#ed "t not perf"%ed. $he t#%%"e% from the%e hor%e%2ere #n'l"ded #n the h#%tolog#' pha%e. -or the p"rpo%e% of a'h#e+#ng the e%t f#&at#on po%%#le for "ltra%tr"'t"ral %t"dy #n

+#+o perf"%#on 2#th 2#5 arno+%yE% %ol"t#on 2a% performed. In +#+o perf"%#on 2h#le laor#o"% and t#me 'on%"m#ng ha% een %ho2n to prod"'e e&'ellent and rel#alef#&at#on for ele'tron m#'ro%'op#' %t"d#e% #n oth the ga%tro#nte%t#nal tra't and ner+o"% %y%tem and #% performed reg"larly onhor%e% and other %pe'#e% (>ohn C"mm#ng% Department of Anatomy Cornell *n#+er%#ty College of Veter#nary ed#'#ne Itha'a NY, per%onal 'omm"n#'at#on). $he !"al#ty of

the f#&at#on 2a% e+al"ated at the t#me of perf"%#on and ne'rop%y. @ood to e&'ellent f#&at#on 2a% 'hara'ter#/ed d"r#ngthe early pha%e of the perf"%#on y m"%'"lar fa%'#'"lat#on anda profo"nd harden#ng of the 'ar'a%% eg#nn#ng at the no%e and

pro'eed#ng 'a"dally. $he properly f#&ed g"t 2a% pale andho%el#e or leathery.

-or the perf"%#on hor%e% 2ere adm#n#%tered %od#"m hepar#n (Lyphomed ?0000 "n#t% elro%e Par IL) #ntra+e

no"%ly appro&#mately 45 m#n"te% pr#or to e"thana%#a #n order

to m#n#m#/e lood 'lott#ng and allo2 for more 'omplete

e&%ang"#nat#on. After 3 m#n"te% they 2ere then adm#n#%

tered a'eproma/#ne (Proma'e 4 mg -ort Dodge Co. -ort

Dodge IA) #ntra+eno"%ly to fa'#l#tate %edat#on and +a%od#lat#on follo2ed 10 m#n"te% later 2#th etam#ne hydro'hlo

r#de (eta%et mg Br#%tolyer% +an%+#lle IN) #ntra

+eno"%ly. Fhen the hor%e% e'ame re'"ment deep

ane%the%#a 2a% a'h#e+ed +#a %lo2 #ntra+eno"% #ne't#on 2#th

%od#"m pentoar#tal (-ort Dodge Co. -ort Dodge IA).

After deep ane%the%#a 2a% ota#ned the r#ght +entral 'he%t

2all 2a% opened form#ng a 2#ndo2 appro&#mately 2 'm y

2 'm. $he l"ng% 2ere retra'ted and the per#'ard#"m #n'#%ed.

$he r#ght a"r#'le 2a% '"t off and the left +entr#'le 'ann"lated.

Appro&#mately 2 l#ter% of phy%#olog#' %al#ne pre2armed to

ody temperat"re (appro&#mately 37 C) 2ere #nf"%ed y

mean% of an #nf"%#on p"mp (ano%tat Var#o%tat#' P"mp

ano%tat Ne2 Gor NG) "nder med#"m to moderately h#gh pre%%"re #n order to e&%ang"#nate the 'ar'a%%. It 2a% then

follo2ed y 4 to ?0 l#ter% of 2#5 arno+%yE% %ol"t#on

#nf"%ed "nder med#"m pre%%"re to a'h#e+e 2hole ody #n +#+o

f#&at#on. A %"''e%%f"l perf"%#on too appro&#mately 3

m#n"te%. Ident#'al f#&at#on te'hn#!"e% 2ere "%ed #n oth the

treated and 'ontrol hor%e%.

Blo'% of t#%%"e 2ere 'olle'ted from ma'ro%'op#' pylor#'

ero%#on% and from ma'ro%'op#'ally "neroded m"'o%a ada

'ent to the ero%#on%. $he f"nd"% and antr"m 2ere e&am#ned

h#%tolog#'ally "t not "ltra%tr"'t"rally. $here 2ere no ma'

ro%'op#' le%#on% %een #n the f"nd"% or antr"m.

$#%%"e for ele'tron m#'ro%'opy (pylor#' m"'o%a) 2a% f#&ed24 ho"r% #n 2#5arno+%yH% %ol"t#on 'hanged #nto 0.1 'a'odylate "ffer po%tf#&ed #n 1% o%m#"m tetro&#de #n 0.1

pho%phate "ffer 07#2 p,) dehydrated #n a graded %er#e% of ethanol and emedded #n :p"rrE% re%#n. $he m"'o%a 2a%or#ented long#t"d#nally. $he %em#th#n pon %e't#on% (1 pm)and "ltrath#n %e't#on% 03-5 nm) 2ere '"t. *ltrath#n %e't#on%2ere %ta#ned 2#th "ranyl a'etate and lead '#trate. Ap

pro&#mately 1?00 lo'% (appro&#mately 25 lo'% per hor%e)for a total of 7&5 gr#d% 2ere e&am#ned.

In the %e'ond part of the #n+e%t#gat#on the #o'hem#'al

%t"dy for the analy%#% of pylor#' m"'o%a for 5etopro%ta

gland#n - the %tale reado2n prod"'t of pro%ta'y'l#n and

pro%tagland#n fo"r treated hor%e% and t2o 'ontrol hor%e%

2ere "%ed. A% #n the morpholog#' %t"dy the treated hor%e%

2ere adm#n#%tered 13#4 mg<g phenyl"ta/one #ntra+eno"%ly da#ly for 4 day%. $he 'ontrol hor%e% re'e#+ed no

phenyl"ta/one "t re'e#+ed 3 ml normal %al#ne #ntra+e

no"%ly #n order to %ham phenyl"ta/one #ne't#on% pr#or to

e"thana%#a. $2o treated hor%e% and one 'ontrol hor%e 2ere

e"thanat#/ed at 4 ho"r% and at 95 ho"r%. Complete ne'rop

%#e% 2ere performed on the%e hor%e%. $he l#ght m#'ro%'op#'

f#nd#ng% 2ere #n'l"ded #n morpholog#' %t"dy. In the 'ontrol

and treated hor%e% m"lt#ple lo'% of t#%%"e from the pylor#'

m"'o%a of ea'h hor%e 2ere pro'e%%ed a''ord#ng to the meth

od of Fh#ttle et al.45#n preparat#on for rad#o#mm"noa%%ay.

$he %#te% %ele'ted for pro%tagland#n a%%ay 'orre%ponded to the

%#te% %ele'ted for ele'tron m#'ro%'opy #.e. ma'ro%'op#'ally

eroded and ada'ent ma'ro%'op#'ally "neroded pylor#' m"'o%a(-#g. 1).

In preparat#on for rad#o#mm"noa%%ay %ol#dpha%e t#%%"e

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645 e%'hter et al.

-#g. 1. :'hemat#' d#agram #nd#'at#ng the lo'at#on andonentat#on of ero%#on% aro"nd the pylor"%. -or othele'tron m#'ro%'opy (perf"%#on f#&ed t#%%"e) and

pro%tagland#n a%%ay ("nf#&ed t#%%"e) %mall lo'% of m"'o%a 2ere 'olle'ted from ma'ro%'op#'ally eroded (1)

and ada'ent ma'ro%'op#'ally "neroded (6) t#%%"e.

e&tra't#on 2a% a''ompl#%hed y e&tra't#ng t#%%"e %"pernatant%ol"t#on% 2#th o'tade'yl (C17) %ol#d pha%e 'ol"mn% (Appl#ed:eparat#on% Leh#gh Valley PA). -or rad#o#mm"noa%%ay for

pro%ta'y'l#n and pro%tagland#n pro%tagland#n E, and6-keto-prostaglandinF,,-iodine1-6?

rad#o#mm"noa%%ay #t% 2ere "%ed (Ne2 ngland N"'lear

Bo%ton A). $he pooled mean of pro%tagland#n 'on'entrat#on%from the 'ontrol hor%e% 2ere 'ompared to the pooled mean of the

pro%tagland#n 'on'entrat#on% of the treated hor%e% "%#ng the tte%t.

%esults

@ro%% patholog#' f#nd#ng%

$horo"gh and %y%temat#' e&am#nat#on %ho2ed thatm"'o%al le%#on% 2ere l#m#ted to the pylor#' reg#on; no

para%#te% 2ere pre%ent. At 24 and 4 ho"r% m"lt#ple#rreg"lar %mall eroded and hemorrhag#' fo'# 2ere

%'attered o+er the pylor"% of all hor%e%. $he ero%#on%2ere fa#rly %"perf#'#al #n the m"'o%a and ranged from0.2 to 0.? 'm #n d#ameter. At !2 ho"r% there 2ere m#ld

pat'hy area% of 'onge%t#on on the pylor"% of oth hor%e%.At 95 ho"r% there 2ere m"lt#ple eroded area% rang#ngfrom %mall p#npo#nt area% of 'onge%t#on to deeper moree&ten%#+e area% of ero%#on #n all hor%e%. $he ero%#on%formed a rad#at#ng or %poel#e pattern aro"nd the

pylor#' open#ng. $he%e ero%#on% 2ere deeper than tho%e%een at 24 and 4 ho"r%. $hey 2ere et2een 0.2 and 1.5'm #n 2#dth and 1 and 3 'm #n length. $hey 2ere

%ome2hat '#gar %haped and ranged et2een 4 and 16 #nn"mer rad#at#ng aro"nd the pylor#' open#ng. $here 2ereno le%#on% #n any of the 'ontrol hor%e%.

-#g. 6. Pylor#' m"'o%a 64 ho"r%; hor%e No. ,64 1.$here #% l#ft#ng off and %eparat#on of the ep#thel#"m fromthe fo+eolar 're%t% (arro2%). :mall throm# ($) are pre%ent%"a'ent to the ep#thel#"m. $here #% 'onge%t#on andhemorrhag#ng of the 'ap#llar#e% (,).

,#%tolopatholog#' f#nd#ng%

$here 2ere no %#gn#f#'ant h#%tolog#' le%#on% #n the'ontrol hor%e%. At 24 ho"r% there 2a% %eparat#on of thefo+eolar 're%t ep#thel#"m and m#'rothromo%#% of the%"perf#'#al lam#na propr#a (-#g. 2". ore %e+ere le%#on%2ere 'hara'ter#/ed y %hallo2 ero%#on% of the %"perf#'#alm"'o%a and the lam#na propr#a 'onta#ned n"mero"% fo'#of ne'ro%#% (-#g. 3). Cap#llar#e% 2ere thromo%ed and'ap#llary 2all% 2ere den%e eo%#noph#l#' and d#%r"pted.$he mo%t %"perf#'#al le%#on% 'on%#%ted of +ery %hallo2ero%#on% #n+ol+#ng only the fo+eolar 're%t%. $here 2ere%"ep#thel#al 'left% and %"rfa'e rea% #n the m"'o%alep#thel#"m 2#th the ep#thel#"m of the ne' of the glandf#r%t l#ft#ng off and then peel#ng a' e&po%#ng thelam#na propr#a. Ne"troph#l% eo%#noph#l% f#r#n andder#% lay on the m"'o%al %"rfa'e of the ga%tr#' l"men.Ind#+#d"al or large raft% of %lo"ghed ep#thel#al 'ell% andf#r#no"% and 'ell"lar der#% 2ere free #n the ga%tr#'l"men. $he 'ytopla%m of the 'ol"mnar ep#thel#al 'ell%+ar#ed from darly eo%#noph#l#' to pale and f#nely+a'"olated. In many area% part#'"larly #n the deeper

port#on% of the gland% the m"'o%al ep#thel#al 'ell%'onta#ned large +e%#'"lar n"'le# and n"mero"% m#tot#'f#g"re%. In other area% "%"ally more %"perf#'#allyep#thel#al 'ell% 2ere '"o#dal to flattened %"gge%t#nge#ther attempt% to 'o+er eroded area% or







Phenyl"ta/one#nd"'ed Gastric *l'er% in $orses 247

-#g. 3. Pylor#' m"'o%a 24 ho"r%; hor%e No. $-24- 1. $here

#% %"perf#'#al %lo"gh#ng of the m"'o%al ep#thel#"m and ne"

troph#l% are %'attered thro"gho"t the m"'o%a. Cap#llary 2all%

are hyal#n#/ed (arro2%) and there #% per#+a%'"lar leaage and

thromo%#% ($).

-#g. 4# Pylor#' m"'o%a 4 ho"r%; hor%e No. $-4-2# $here

#% more e&ten%#+e %lo"gh#ng and ero%#on of the m"'o%a and

#nf#ltrat#on 2#th ne"troph#l%. :lo"ghed ep#thel#"m and der#%

are pre%ent on the %"rf&e. $here #% more e&ten%#+e damage to

'ap#llary 2all% thromo%#% ($) and ne'ro%#%.

ep#thel#al atrophy. $he m"'o%al lam#na propr#a %" a'ent to the ero%#on% 2a% edemato"% 2#th engorged

'ap#llary loop% that often 'onta#ned %mall throm# andmarg#nated ne"troph#l% and eo%#noph#l%. &tra+a%atederythro'yte% ne"troph#l% and engorged 'ap#llar#e%2ere pre%ent #n the deeper lam#na propr#a.

pon %em#th#n %e't#on% re+ealed a m#'ro+a%'"lar le%#on #n the %"perf#'#al m"'o%a. $he m#'ro+a%'"lar le%#on 2a% "%"ally %"a'ent to the %"ep#thel#al 'left%.$he 'ap#llary 2all% 2ere hyal#n#/ed and there 2a% d#%r"pt#on of the%e +e%%el 2all%. N"mero"% %mall f#r#nthrom# 2ere pre%ent. $he m#'ro+a%'"lar le%#on 2a%'onf#ned to the mo%t %"perf#'#al %"ep#thel#al reg#onand often appeared 2here there 2a% l#ttle ep#thel#al or #nter%t#t#al #n"ry.

After 48 ho"r% the m"'o%al le%#on% 2ere %#m#lar tothe%e de%'r#ed at 24 ho"r% e&'ept that the ero%#on%2ere often larger deeper and more %e+ere. $he m#'ro+a%'"lar le%#on pre%ent at 24 ho"r% 2a% more prom#nent and %e+ere at 48 ho"r% 2#th prono"n'ed th#'en#ng d#lat#on #n'rea%ed den%#ty and often d#%r"pt#onof the 2all% of %mall +e%%el% and 'ap#llar#e%. $he+e%%el% 'onta#ned f#r#n 'ell"lar der#% and %mallthrom# (-#g. 4). In the m"%'"lar#% m"'o%a and%"m"'o%a "nderly#ng ero%#on% many arter#al 2all%2ere d#%r"pted. Large n"mer% of ne"troph#l% andmonon"'lear 'ell% 2ere pre%ent oth 2#th#n the%e+e%%el 2all% and per#+a%'"larly. $#%%"e not a%%o'#ated2#th eroded area% 2a% h#%tolog#'ally normal.

At 72 ho"r% the pylor#' m"'o%al le%#on% 2ere l#m#ted

to a pat'hy m"'o%al 'onge%t#on. No ero%#on% 2ere %een.After 95 ho"r% the h#%tolog#' le%#on% 2ere %#m#lar

"t more %e+ere and e&ten%#+e than tho%e #n the 48ho"r gro"p. Deep m"'o%al ero%#on% e&tended to "td#d not penetrate the m"%'"lar#% m"'o%a. $here 2a%%e+ere ne"troph#l#' #nf#ltrat#on and ne'ro%#% of them"'o%a. $he m#'ro+a%'"lar le%#on% 2ere more %e+ereand e&ten%#+e than tho%e %een at 48 ho"r%. $here 2a%%e+ere hemorrhage and thromo%#% of the m"'o%a.

6ltrastructural f#nd#ng%

No "ltra%tr"'t"ral le%#on% 2ere %een #n the 'ontrolhor%e%. After 24 ho"r% #n the ma'ro%'op#'ally "neroded

pylor"% ada'ent to eroded m"'o%a there 2ere 2ell pre%er+ed gland% 'on%#%t#ng of 'ol"mnar ep#thel#al 'ell%'onta#n#ng m"'"% gran"le% and o''a%#onal endo'r#ne'ell%. $he m"'"% %e'ret#ng entero'yte% 'onta#ned amoderate n"mer of ap#'ally lo'ated %e'retory gran"le%;n"mero"% 2ellformed m#'ro+#ll#; n"mero"% 2elldef#ned m#to'hondr#a; and a"ndant ro"gh endopla%m#'ret#'"l"m. $he #nter%t#t#"m 'onta#ned f#rola%t% loo%e

'ollagen and a fe2 #n'on%p#'"o"% normal 'ap#llar#e%.

O''a%#onally %mall arter#e% 2#th %2ollen endothel#"mand 'on+ol"ted n"'le# 2ere %een.

In other ma'ro%'op#'ally "neroded area% ho2e+erthere 2ere m"'"% %e'ret#ng entero'yte% 2#th loo%e +a'"olated 'ytopla%m %2ollen m#to'hondr#a d#lated en








248 Mesch#ter et al.

ig# 5# le'tron m#'rograph 24 ho"r%; hor%e /o# $- 24-1.$he gland"lar ep#thel#"m (@) #% flattened and there are%2ollen m#to'hondr#a (m) and a 'ytopla%m#' le. $he en

dothel#"m (C) of a %mall +e%%el #% %2ollen and 'learedred"'#ng the +e%%el l"men d#ameter. rythro'yte% (r)eo%#noph#1 (e) and a ne"troph#l (n) are free #n the#nter%t#t#"m. Note the gland"lar l"men (@L). Bar # ? pm.

dopla%m#' ret#'"l"m and @olg# 'omple&. $he ado#n#ng #nter%t#t#"m 2a% loo%e and edemato"%. In many'ap#llar#e% and %mall +e%%el% the endothel#"m 2a%%2ollen and +a'"olated red"'#ng the d#ameter% of the'ap#llary l"m#na. Ve%%el% 2ere engorged there 2a%e&tra+a%at#on of erythro'yte% and platelet ma%%e% adhered to 'ap#llary 2all%.

In ma'ro%'op#'ally eroded area% 'ap#llary and %mall+e%%el endothel#"m and per#'yte and %mooth m"%'le 'ell'ytopla%m 2ere often %e+erely %2ollen. $he 'ytopla%mof the m"'"% %e'ret#ng entero'yte%2a% 'lear and %2ollenand 'onta#ned only a +ery fe2 organelle%. Ne"troph#l%and platelet% adhered to the endothel#al 'ell %"rfa'e. $hel"m#na of many %mall arter#e% 2ere o%tr"'ted y%2ollen endothel#al 'ell% (-#g. ?). In %ome +e%%el% theendothel#"m 2a% 'ompletely ne'rot#' and ly%ed and the+e%%el l"m#na 'onta#ned 'ell"lar der#% and f#r#n (-#g.

5). $he a%ement memrane #ntegr#ty 2a% lo%t and thememrane 2a% fre!"ently %pl#t or

ig# # le'tron m#'rograph 24 ho"r%; hor%e /o# $-24-

1. $here #% a"ndant ne'rot#' der#% (). An erytho'yte(R) 'onta't% the a%ement memrane (m). Bar # ? pm.

lam#nated. F#th#n the #nter%t#t#"m 2ere n"mero"%erythro'yte% eo%#noph#l% ne"troph#l% and f#r#n. $he'ytopla%m of f#rola%t% often 2a% 'lear and %l#ghtly%2ollen and the #nter%t#t#"m 2a% loo%e and

+a'"olated. In neary gland% 'hange% #n theep#thel#"m +ar#ed from 'ol"mnar to flattened (-#g. 5),and there 2a% %2ell#ng and 'lear#ng of 'ytopla%m 2#thd#lated endopla%m#' ret#'"l"m and %2ollenm#to'hondr#a. #'ro+#ll# 2ere %par%e and %hort andmemrane'o+ered 'ytopla%m#' le% often protr"ded#nto the gland l"men. $#ght "n't#on% 2ere #nta't

et2een entero'yte%. any entero'yte% 2h#'h 2eredepleted of m"'"% gran"le% 'onta#ned memrano"%2horl% or lamellar od#e% 2#th#n oth the 'ytopla%mand m#to'hondr#a.. #to'hondr#a 2ere often %2ollen2#th d#%r"pted 'r#%tae and o''a%#onally 'onta#ned dar gran"lar mater#al #nterpreted a% pre'#p#tated 'al'#"m.

N"mero"% %"ep#thel#al 'left% 2ere pre%ent. F#th#nmany 'ol"mnar ep#thel#al 'ell% 2ere n"mero"% a%ally lo'ated +a'"olar %pa'e% %eparat#ngtheep#thel#al 'ell% from the a%ement memrane.

After 48 ho"r% the "ltra%tr"'t"ral le%#on% 2ere %#m#lar to tho%e %een at 24 ho"r% e&'ept that tho%e at 48ho"r% 2ere more %e+ere and e&ten%#+e than tho%e at24 ho"r%. After 72 ho"r% the le%#on% 2ere +ery m#n#mal; 'ell"lar %2ell#ng of ep#thel#al and endothel#al'ell% m#ld edema of the lam#na propr#a and +a%'"lar 'onge%t#on 2ere o%er+ed. *ltra%tr"'t"ral le%#on% o%er+ed at 95 ho"r% 2ere %#m#lar to tho%e %een at 48ho"r% "t 2ere more %e+ere. $here 2a% al%o %e+ere

ne'ro%#% of the lam#na propr#a.







Phenylbutazone-induced'astric 6lcers in $orses 248

Table 1# Pylor#' m"'o%al 'on'entrat#on of pro%tagland#n (ng<mg t#%%"e) and m#'ro%'op#' pylon' m"'o%al le%#on% #n

hor%e% treated at 64ho"r #nter+al% 2#th phenyl"ta/one.

$orse Prostacyclin Prostaglandin E& Microscopic Pyloric

/u"ber9 !ite ,ne site T:,

x#

!EM;< !ite ,ne !ite T=o X # !EM> Mucosal )esions

C04701 17.8 15.5 18.5? f 0.84 1.?9 1.50 1.50 f 0.003 No %#gn#f#'ant le%#on%

C09506 13.73 ?1.4 36.5 f 13.69 1.?? 4.30 6.93 f 0.98 No %#gn#f#'ant le%#on%,471 ?3.6 63.1 37.1? f 1?.18 1.74 3.48 6.?? f 0.55 #ld m"lt#fo'al ero%#on%,476 68.9 63.4 6?.5? f 1.?9 3.06 3.90 3.45 f 6.4? #ld m"lt#fo'al ero%#on%,951 15.7 ?.5 11.60 f 3.95 0.75 0.?9 0.83 k 0.31 Large m"lt#fo'al ero%#on%,956 48.8 99.9 83.7 f 17.4? 6.59 3.30 6.?? f 0.66 #ld m"lt#fo'al ero%#on%

$ There =as no significant difference (P #1? bet=een pyloric "ucosal prostacyclin and prostaglandin E& concentrations in control and treated horses#

t $orses =ere ad"inistered 13#4 "d@g of phenylbutazone intraAenously# ollo=ing t=o inBections 04 hours?& three horses =ere

euthanatized 0t=o treated and one control? and then follo=ing four inBections 08 hours?& three horses 0t=o treated and one control? =ere euthanatized $# T=o bloc@sof "ucosa =ere collected at each site#

!tandard error of the "ean#

Prostaglandin assays

$he effe't% of phenyl"ta/one on pylor#' m"'o%al pro%tagland#n 'on'entrat#on% are pre%ented #n $ale 1.In the pylor#' m"'o%a pro%ta'y'l#n 2a% the predom#nant pro%tagland#n. $here 2a% no %tat#%t#'ally %#gn#f#'ant d#fferen'e et2een the pro%tagland#n 'on'entrat#on% #n the treated and 'ontrol an#mal%. $here 2a%l#ttle 'orrelat#on et2een pro%ta'y'l#n and pro%tagland#n 'on'entrat#on% and the pre%en'e of pylor#' ero%#on%.

iscussionPhenyl"ta/one #% to&#' to ad"lt hor%e% 2hen ad

m#n#%tered #ntra+eno"%ly at do%e% of 13.45 mg<g da#ly. $h#% do%e #% ?0 larger than the '"rrently re'ommended ma&#mal do%e of 7.7 mg<g of ody 2e#ghtda#ly.

a'ro%'op#' le%#on% 2ere pre%ent #n all hor%e% at64 48 and 95 ho"r%. "'o%al 'onge%t#on "t notero%#on 2a% %een at 86 ho"r%. $h#% #% proaly d"e tothe %mall gro"p %#/e the lo2 do%e adm#n#%tered and#nd#+#d"al +ar#at#on. All hor%e% 2ere %"e'ted to atotal ne'rop%y and the 86 ho"r hor%e% a% 2ell a% the

other hor%e% d#%played ma'ro%'op#' le%#on% #n thed"oden"m 'olon and #dney. $he%e f#nd#ng% 2#ll e#n'orporated #nto %"%e!"ent man"%'r#pt%.

Pylor#' ero%#on% 2ere pre%ent after 64 ho"r%. $he p"rpo%e of th#% %t"dy 2a% to e+al"ate the +ery earl#e%tm"'o%al le%#on% o''"rr#ng #n order to e+al"ate the

pathogene%#% of phenyl"ta/one#nd"'ed ero%#on format#on. It appear% that ero%#on% de+elop f#r%t #n the

pylor"%. In other % t " d # e = =deep>= =and= largee+en perforat#ng "l'er% ha+e een %een. In the%e %t"d#e%m"'h h#gher do%e% and longer adm#n#%trat#on of phenyl"ta/one 2ere g#+en. $he lo2er da#ly do%age #n th#%%t"dy 2a% "%ed oth to m#m#' 'l#n#'al adm#n#%trat#on and

to 'a"%e le%% %e+ere le%#on% that 'o"ld e e+al"ated

#n a more deta#led 2ay than large flor#d le%#on%. In#t#allym"lt#fo'al p#npo#nt pylor#' ero%#on% o''"rred 2h#'h then#n'rea%ed #n %e+er#ty o+er t#me. ,#%tolog#'ally

progre%%#+e m#'ro+a%'"lar damage and m"'o%al ep#thel#aldamage re%"lted #n de%tr"'t#on and %lo"gh#ng of the%"perf#'#al m"'o%a. $he pr#mary "ltra%tr"'t"ral le%#on 2a%m#'ro+a%'"lar damage that 'a"%ed hemodynam#'derangement% m#'rohemorrhage m#'rothromo%#% and%"%e!"ent m"'o%al #%'hem#a 2h#'h therey led toero%#on%. $he m#'ro+a%'"lar le%#on o''"rred e#ther#ndependently of ep#thel#al #n"ry or pre'eded ep#thel#al#n"ry and 2a% 'omparat#+ely more %e+ere than theep#thel#al #n"ry. $he le%#on 2a% 'hara'ter#/ed yendothel#al %2ell#ng that progre%%ed to ne'ro%#% and ly%#%of the +e%%el 2all% of %mall arter#ole% 'ap#llar#e% and%mall +en"le%. $he%e %2ollen +e%%el% o''l"ded lood%"pply 2h#'h led to a lo2flo2 %tate 2#th retrograde%lo2#ng and %l"dg#ng of the 'ap#llary lood flo2."'o%al #%'hem#a and ne'ro%#% 2#th %"%e!"ent ero%#onfollo2ed. $he ne'rot#' and ly%ed endothel#al 'ell%re%"lted #n a lo%% of #ntegr#ty of the m#'ro+a%'"lat"rem#'rohemorrhage thromo%#% and de%tr"'t#on of them"'o%a. :#m#lar m#'ro+a%'"lar le%#on% ha+e een

de%'r#ed #n the %toma'h of ethanol3%4I and a%p#r#ntreated ratJJJJJJJ and #ndometha'#ntreated

p#g%.67#'ro+a%'"lar le%#on% ha+e een o%er+ed 2#th#n1? m#n"te% of adm#n#%trat#on of 'erta#n non%tero#dalant##nflammatory dr"gJ.JJJJ $he%e #n+e%t#gator%'on'l"ded that m#'ro+a%'"lar damage 2#th fo'al #%'hem#a#% the #n#t#al le%#on #n non%tero#dal ant##nflammatorydr"g#nd"'ed ga%tr#' ero%#on%. $h#% #% 'ompat#le 2#th2hat 2a% o%er+ed #n th#% %t"dy and #t #% 'on'l"ded that

phenyl"ta/one 'a"%e% a d#re't to&#' #n"ry to ga%tr#'m"'o%al ep#thel#"m. #'ro+a%'"lar le%#on% 2ereo%er+ed #n eroded m"'o%a and 2ere pre%ent m"lt#fo'ally

#n ada'ent "neroded m"'o%a. $h#% ha% een o%er+ed "tnot e&pla#ned #n other








25 Meschter et al#

$he le%#on% #n "neroded area% proaly repre%ent pro

dromal 'hange%. Non%tero#dal ant##nflammatory dr"g% red"'e the lood

flo2 #n the %toma'h po%%#ly y 'a"%#ng +a%o'on%tr#'t#on

d"e to pro%tagland#n # n h # # t # = n . Retro===grade'onge%t#on 'a"%e% r"pt"re of 'ap#llar#e% and m#

'rohemorrhage of the m#d m"'=%a .Altho"gh= %ome

m#'rohemorrhage of the m#dm"'o%a 2a% o%er+ed #n one

treated hor%e the "ltra%tr"'t"ral f#nd#ng% #n th#% %t"dy

#nd#'ate that endothel#al %2ell#ng and damage rather that

+a%o'on%tr#'t#on of the m#'ro+a%'"lat"re o''"r%. $he

endothel#al le%#on% do not re%emle tho%e %een #n e#ther

#nfar't#on or reperf"%#on #n"ry of 'olon#' m"'o%a (D#ane

Cra#g per%onal 'omm"n#'at#on). $he m#'rohemorrhage #%

a%%o'#ated 2#th leaage from damaged +e%%el% rather than

leaage d"e to a' pre%%"re from +a%o'on%tr#'t#on.

@a%tr#' le%#on% de+eloped f#r%t #n the pylor"% 2herethe le%#on% 2ere arranged #n %poel#e ray% aro"ndthe '#r'"mferen'e of the pylor"%. :#m#lar d#%tr#"t#on%of pylor#' ero%#on ha+e een de='r#ed.=K"%'"lar 'ontra't#on aro"nd the pylor"% 'ontr#"te% to thed#%tr#"t#on of the%e le%#onJ.JJJJJ Phenyl"ta/one#n'rea%e% ga%tr#' 'ontra't#l#ty and hemorrhage o''"r%at %#te% of m"'o%al 'ompre%%#on.6oIn the hor%e'ontra't#+e per#%talt#' a't#on% of the pylor"% 'o"ld

prod"'e 'ompre%%#on and a lo'al red"'t#on #n'#r'"lat#on. I%'hem#a of the m"'o%a 'o"pled 2#thendothel#al damage 'o"ld lead to the d#%tr#"t#on of

ero%#on% rad#at#ng aro"nd the pylor#' open#ng.In th#% %t"dy a% 2ell a% #n %e+eral other%

phenyl"ta/one0or other non%tero#dal ant##nflammatory dr"gJJJJJJJ 2ere g#+en parenterally and m"'o%al ero%#on% de+eloped #nd#'at#ng that ero%#on% donot ne'e%%ar#ly de+elop e'a"%e of the d#re't 'onta't of

phenyl"ta/one or other non%tero#dal ant##nflammatory dr"g% 2#th the ga%tr#' m"'o%a. Be'a"%e of #t%lo2 pA phenyl"ta/one a''"m"late% #n a'#d#' en+#ronment% %"'h a% the %toma'h and renal med"lla. It#% l#ely that the m#'rodoma#n of the ga%tr#' m"'o%al'ap#llary endothel#"m #% the #n#t#al t#%%"e #n the %toma'h 2#th 2h#'h phenyl"ta/one #ntera't%. In"ry to the'ap#llary endothel#"m then 2o"ld lead to the de+elopment of m"'o%al ero%#on%. In the 'a%e of other orallyadm#n#%tered non%tero#dal ant##nflammatory dr"g%65or ethan01=K+ery early endothel#al 'ell #n"ry #% al%oo%er+ed #nd#'at#ng that endothel#al #n"ry #% an #m

portant 'omponent of "l'erogene%#% 2hether the%e "l'erogen#' agent% are adm#n#%tered parenterally or orally.

$he format#on of %"ep#thel#al 'left% 2a% o%er+ed'on'"rrently 2#th the m#'ro+a%'"lar 'hange%. $h#% le%#on pre'eded m"'o%al ero%#on and %lo"gh#ng. Cleft%2ere generally a%%o'#ated 2#th %"a'ent damaged 'ap

#llar#e%. :"ep#thel#al 'left% are 'on%#dered 'hara'ter

#%t#' of and are #n#t#ally #nd#'at#+e of #%'hem#' %mall and

large #nte%t#nal damage.61%444?:#m#lar 'left% #n the

ga%tr#' m"'o%a 2o"ld al%o e #nd#'at#+e of #%'hem#' or

lo2flo2 #n"ry. It 2a% theor#/ed that 'left% de+eloped a%

a re%"lt of the a''"m"lat#on of edema fl"#d et2een theep#thel#al 'ell% and lam#na p r = p r # a:"%e!"ent.==

2or %"gge%t% that the 'left format#on o''"r% a% a re%"lt

of the format#on of to&#' free rad#'al% generated d"r#ng

lo2flo2 or reperf"%#on = t a t e % . =$heK= M

generat#on== of %"pero&#de rad#'al% may a''o"nt for

'left format#on and ep#thel#al %lo"gh#ng y degrad#ng

hyal"ron#' a'#d the pr#mary 'omponent of the ep#thel#al

a%ement mem=ane . =$he.K= %"pero&#de rad#'al% al%o

damage 'ell"lar 'omponent% %"'h a% m#to'hondr#a1 and

'ell"lar memrane% y l#p#d pero&#dat#on.

@eneral#/ed damage to the m"'"% %e'ret#ng enter

o'yte% #n'l"d#ng d#%'harge of the m"'"% gran"le m#to'hondr#al #n"ry format#on of lamellar od#e% andm#'ro+#ll"% #n"ry %een #n th#% %t"dy and el=e2here=

proaly repre%ent% d#re't to&#' #n"ry to the 'ol"mnarep#thel#al 'ell y phenyl"ta/one. Phenyl"ta/one and%ome %al#'ylate% ha+e een %ho2n to #n'rea%e ap#'al%hedd#ng of ep#thel#al 'ell% 2#tho"t #n'rea%#ng the rene2al rate17 to de'rea%e m"'#n prod"'t#on17damage

par#etal 'ell%6K and to a''elerate ga%tr#' ap#'al gran"lea% 2a% %een #n th#% %t"dy. $he%e fa'tor%

al%o 'ontr#"te to m"'o%al ero%#on.Altho"gh phenyl"ta/one #% 'ommonly 'on%#dered

a pro%tagland#n or 'y'loo&ygena%e th#% %t"dy

#nd#'ate% that phenyl"ta/one may damage 'ell%thro"gh nonpro%tagland#n med#ated path2ay%. Phenyl"ta/one e&ert% n"mero"% nonpro%tagland#n med#ated effe't% #n'l"d#ng a +ar#ety of to&#'effe't%K56?3746 and en/yme #nh##tory $he%e effe't%may re%"lt #n damage to energyprod"'#ng path2ay% o&#dat#+e pho%phorylat#on and #o'hem#'al path2ay% that"%e the m#to'hondr#a %"'h a% the reK% 'y'le. De

plet#on of adeno%#ne tr#pho%phate lead#ng to a red"'t#on #n energy potent#al and #nh##t#on of #o'hem#'al

path2ay% 2o"ld lead to 'ell"lar %2ell#ng and a''o"ntfor %ome of the "ltra%tr"'t"ral le%#on% o%er+ed part#'"larly the 'ell damage and %2ell#ng. It ha% een demon%trated that the metaol#%m of phenyl"ta/one re%"lt%#n the prod"'t#on of to&#' o&ygen %pe'#e%.3L$hegenerat#on of free rad#'al% 'a"%e% lo'al t#%%"e damageand 'ontr#"te% to the to&#' effe't% of the dr"g.31

$he pylor#' m"'o%a 2a% a%%ayed y rad#o#mm"noa%%ay for the t2o predom#nant ga%tr#' pro%tagland#n%

pro%ta'y'l#n and pro%tagland#n . In the pylor#' m"'o%aof the hor%e a% #n other %pe'#eJJJJJ pro%ta'y'l#n 2a%fo"nd to e the predom#nant pro%tagland#n. A% there 2a%no %tat#%t#'al d#fferen'e#n m"'o%al pro%tagland#n'on'entrat#on% et2een 'ontrol and treated hor%e% #t #%'on'l"ded that phenyl"ta/one may not 'a"%e a

red"'t#on #n m"'o%al pro%tagland#n 'on'en







Phenyl"ta/one#nd"'ed @a%tr#' *l'er% in ,or%e% 25 1

trat#on after 95 ho"r% of treatment. 'orrelat#on e effe't of phenyl"ta/one on the ga%tr#' m"'o%a. - %e'0

t2een the de+elopment of ga%tr#' ero%#on a%%o'#ated ond e&planat#on #% that there may e an early phenyl"02#th phenyl"ta/one adm#n#%trat#on and alterat#on% #n ta/one#nd"'ed pro%tagland#n red"'t#on "t m"'o%althe 'on'entrat#on of pro%tagland#n #n the pylor#' m" pro%tagland#n 'on'entrat#on% e#ther then "ndergo a

'o%a doe% not %eem to e&#%t a%ed on the data pre%ent. 'ompen%atory #n'rea%e45or are o%'"red y the #nten%e$h#% #% #n 'onfl#'t 2#th %ome report%674547"t #n agree #nflammatory 'ell #nf#ltrat#on. -#nally the gro"p of ment 2#th other=.3.1?.6769.4145 hor%e% a%%ayed 2a% %mall ( n # 4)and may not e 'om

$here 2a% 'on%#derale +ar#at#on #n the m"'o%al pletely repre%entat#+e; ho2e+er #n %t"d#e% 2#th 'at% ( n%#teto%#te 'on'entrat#on% of pro%tagland#n 2#th#n #n # 6 )"%#ng the %ame te'hn#!"e% employed #n th#% %t"dyd#+#d"al hor%e% and et2een hor%e%. $h#% ha% al%o een profo"nd de'rea%e% #n pro%tagland#n 'on'entrat#on%%een #n the d"oden"m and 'olon of phenyl"ta/one 2ere %een #n all a%p#r#ntreated 'at%.47treated hor%e% (Carol L. e%'hter "np"l#%hed re It #% 'on'l"ded therefore that phenyl"ta/one#n%"lt%). F#th#n the 'orte& and pel+#% of the #dney ho2 d"'ed ga%tr#' ero%#on% #n hor%e% are pr#mar#ly d"e to

e+er pro%tagland#n 'on'entrat#on% appear to e fa#rly a d#re't to&#' effe't of the dr"g on the endothel#"m and

"n#form (Carol )# e%'hter "np"l#%hed re%"lt%). L#t m"'o%a and that the de+elopment of ero%#on% #% not tle#% no2n ao"t the eha+#or of the ga%tr#'<pylor#' med#ated ent#rely y pro%tagland#n red"'t#on. m#'rodoma#n

of the hor%e or other %pe'#e% for thatmatter. $he rea%on for the +ar#at#on #n m"'o%al pro% -c@no=ledge"entstagland#n 'on'entrat#on% #% not no2n. It may e a $he a"thor than% r. >. Barato and r. . Blan for

refle't#on of an #ntr#n%#'ally "ne+en d#%tr#"t#on of the#r photograph#' e&pert#%e and %. >. -o& Da+#d%on for

pro%tagland#n 2#th#n the m"'o%a. :e'ondly #t may eher ed#tor#al a%%#%tan'e.

a refle't#on of a +ar#at#on #n the m#'roperf"%#on of them"'o%a. It 2a% noted #n the morpholog#' %t"dy that %eferences"ltra%tr"'t"ral le%#on% 2ere %een m"lt#fo'ally #n ma'

1 Bem%ford R@ Fell% D#&on - @a%tr#' ep#thel#alro%'op#'ally "naffe'ted pylor#' m"'o%a and that theremay e %ome 'orrelat#on et2een the "ne+en d#%tr# m"'"%a den%#tometr#' h#%to'hem#'al %t"dy of a%p#r#n

"t#on of "ltra%tr"'t"ral le%#on% and "ne+en d#%tr#" #nd"'ed damage #n the rat. Br > &p Pathol 556833197?

t#on of pro%tagland#n 'on'entrat#on%.6 Br"ne @raf P Ra#n%ford D A pharma'o#net#'

$he relat#on%h#p et2een pro%tagland#n prod"'t#on approa'h to the "nder%tand#ng of therape"t#' effe't% andand ero%#on or "l'er format#on #% not ent#rely "nder %#deeffe't% of %al#'y'late%. In: :ympo%#"m on A%p#r#n%tood. :ome %t"d#e% demon%trate that eroded ga%tr#' and Related Dr"g% A't#on% and *%e%( ed. Ra#n%ford D(

m"'o%a from an#mal% treated 2#th non%tero#dal ant# Br"ne +& and Fh#llho"%e F pp. 33?7. B#rha"%er

#nflammatory dr"g% ha% a profo"nd red"'t#on #n m" Verlag Ba%al 1988'o%al pro%ta'y'l#n and pro%tagland#n E2#2&4&4$here 3 Coll#er ,O 'Donald@#%on F> :aeed :A :t#m"

are other %t"d#e% that #nd#'ate( a% 2a% %een #n th#% %t"dy( lat#on of pro%tagland#n #o%ynthe%#% y 'ap%#a'#n etha

that there al2ay% may not e a d#re't 'orrelat#on e nol and tyram#ne. Lan'et 1806 198?

t2een ga%tr#' ero%#on% m"'o%al pro%tagland#n le+el% 4 Coll#n% L@ $yler D &per#mentally #nd"'ed phenyl

and non%tero#dal ant##nflammatory dr"g% adm#n#%tra "ta/one to&#'o%#% #n pon#e% de%'r#pt#on of the %yndromeand #t% pre+ent#on 2#th %ynthet#' pro%tagland#n 6. Am

t#on.3>?(67(69(41$he.45adm#n#%trat#on of e&ogeno"% pro%0> Vet Re% 45150?151? 197?

tagland#n% pre+ent% ero%#on d"e to phenyl=ta/one= ? Dalh#nden C -ehr > Re'eptord#re'ted #nh##t#on of

and other non%tero#dal ant##nflammatory dr"gJJJJJJ 'hemota't#' fa'tor#nd"'ed ne"troph#l hypera't#+#ty y34 ne'rot#/#ng agent%34 and other no& pyra/olon der#+at#+e%. > Cl#n In+e%t 5577479 1 1970#o"% % " % t a n ' e =y==a't#ng(== a% 'ytoprote't#+e agent%. 5 Del ae%tro R- $har ,, Bor , Planer Afor%

$he me'han#%m of 'ytoprote't#on #% not "nder%tood -ree rad#'al% a% med#ator% of t#%%"e #n"ry. A'ta

"t #t #% not ne'e%%ar#ly a%%o'#ated 2#th pro%tagland#n Phy%#olog#'a :'and 49643?8 1970

r e p l a = e m e n t . = = = = = = 8 @raf P @latt Br"ne A'#d non%tero#dal ant##n

It 2a% e&pe'ted that phenyl"ta/one 2o"ld ha+e flammatory dr"g% a''"m"late #n #nflamed t#%%"e. &per0

%trongly %"ppre%%ed pro%tagland#n le+el% thro"gho"t the #ent#a 319?19?3 198?

ga%tro#nte%t#nal tra't a% #t ha% 2#th other non%tero#dal 7 @"n%on D :oma L R Renal pap#llary ne'ro%#% #n hor%e%after phenyl"ta/one and 2ater depr#+at#on. Vet Pathol

ant##nflammatory dr"g% #n other %pe'#eJ.JJJJJJ $here60=503510 1973

are %e+eral po%%#le e&planat#on% 2hy pro%tagland#n%9 @"th P, A%p#r#n and related 'ompo"nd #n"ry of the

2ere not %"ppre%%ed. One #% that there may not e a ga%tro#nte%t#nal tra't. $o&#'olog#' Patholog#%t% VI Inter

%trong 'orrelat#on et2een m"'o%al pro%tagland#n 'on nat#onal :ympo%#"m Pro'eed#ng%( )ay 3 10>"ne 3& Ph#la0'entrat#on% and ero%#on format#on and that ero%#on delph#a PA 1978

format#on #% #n%tead pr#mar#ly d"e to a d#re't to&#' 10 ,#gg#n% A> $he #ology pathophy%#ology and 'ontrol








6?6 e%'hter et al.

of e#'o%ano#d% of #nflammat#on. > Vet Pharma'ol $her7l17 197?

11 ,#gg#n% A> Lee% P $he a'"te #nflammatory pro'e%%ara'h#don#' a'#d metaol#te% and the mode of a't#on of

ant##nflammatory dr"g%. !"#ne Vet > 15 15318? 1974 16alyanp"r :@ Poh"an# !& Na# :R :heth * :t"dy of #o'hem#'al effe't% of ant##nflammatory dr"g% on 'arrageen#n#nd"'ed oedema and 'otton pellet gran"loma.

B#omed Pharma'other 18898703 195713 Land% F $he #o%ynthe%#% and metaol#%m of pro%

tagland#n%. Ann Re+ Phy%#ol41533546 198914 Le+#n RI Fel%er BB ar'"% A> >affe A Pro%ta

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N#hoff Bo%ton A 19741? L#g"m%y @ro%%man I a"ffman @ L ndog

eno"% ga%tr#' m"'o%al pro%tagland#n% the#r role #n m"'o%al #ntegr#ty. Am > Phy%#ol646@338@341 1976

15 L#o+%y @r#mo+a > Dlaa' A ,ondl# > :metana orpholog#' 'hange% #n n"'leol# of lympho'yte% andthe#r #nfl"en'#ng y tr#metha/one phenyl"ta/one #ndometha'#n and 5mer'aptop"r#ne #n al#no rat% 2#thad"+ant#nd"'ed d#%ea%e. Na"nyn :'hm#edeerg% Ar'hPharma'ol685 17 11 75 1983

18 a'ay RJ,-ren'h $F Ng"yen ,$ ayhe2 I@ ffe't% of large do%e% of phenyl"ta/one adm#n#%trat#on tohor%e%. Am > Vet Re% 44884870 1973

17 a& eng"y A Infl"en'e of a%p#r#n and phenyl "ta/one on the rate of t"rno+er of ga%tr#' m"'o%al'ell%. D#ge%t#on 65886 1959

19 'Cord > -ree rad#'al% and #nflammat#on prote't#on

of %yno+#al fl"#d y %"pero&#de d#%m"ta%e. :'#en'e 17?

?69?31 198460 er%erea" FA ,#n'hey > :ynerg#%m et2een a'#d

and ga%tr#' 'ontra't#le a't#+#ty #n the gene%#% of "l'erat#on and hemorrhage #n phenyl"ta/onetreatedrat%. :"rgery 90?15?66 1971

61 e%'hter CL ayl#n @A +roo@ L Va%'"lar pathology #n phenyl"ta/one #nto&#'ated hor%e%. Cornell Vet 84 676698 1974

66 #ller $A $he prote't#+e effe't% of pro%tagland#n%aga#n%t ga%tr#' m"'o%al damage '"rrent no2ledgeand propo%ed me'han#%m%. Am > Phy%#ol64?@50143569 1973

63 on'ada !& -err#era C, Vane >R B#oa%%ay of pro%tagland#n% and #olog#'ally a't#+e %"%tan'e% der#+ed

from ara'h#don#' a'#d. Ad+ Pro%tagland#n$hromo&ane Re% ? 6 1 1635 1971

64 Par% DA B"lly @B @ranger DN ,am#lton :R'Cord > I%'hem#' #n"ry to the 'at %mall #nte%t#nerole of %"pero&#de rad#'al%. @a%troenterology 7691?1976

6? Per#an#n A Laro $ ,a#m > Chemo#net#' a't#+#ty of N-

Formyl-Metionyl-!e"#yl-$enylalanine on

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B#o'hem Pharma'ol3130813085 1976

65 Ra#n%ford D le'tron m#'ro%'op#' o%er+at#on% on theeffe't% of orally adm#n#%tered a%p#r#n and a%p#r#n

#'aronate m#&t"re% on the de+elopment of ga%tr#'

m"'o%al damage #n the rat. @"t 15?14?61 198?

68 Ra#n%ford D Br"ne :ele't#+e 'ytoto&#' a't#on% of a%p#r#n on par#etal 'ell% a pr#n'#pal fa'tor #n the early%tage% of a%p#r#n#nd"'ed ga%tr#' damage. Ar'h $o&#'ol401431?0 1987

67 Ra#n%ford D F#ll#% C Relat#on%h#p% of ga%tr#' m"'o%al damage #nd"'ed #n p#g% y ant##nflammatorydr"g% to the#r effe't% on pro%tagland#n prod"'t#on. D#gD#% :'# 68564534 1976

69 Ra#n%ford D F#ll#% C Faler :A Ro#n% P @le'tron m#'ro%'op#' o%er+at#on% 'ompar#ng thega%tr#' m"'o%al damage #nd"'ed #n rat% and p#g% y

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30 Read F Renal med"llary 're%t ne'ro%#% a%%o'#ated2#th phenyl"ta/one therapy #n hor%e%. Vet Pathol 60556559 1973

3 1 Reed @A @r#ff#n 10 l#ng $ Ina't#+at#on of pro%ta

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36 Roert A :to2e D- Ne/am#% > - Pre+ent#on of d"odenal "l'er% y adm#n#%trat#on of pro%tagland#n 6.:'and > @a%troenterol530330? 198 1

33 Roert A :'h"lt/ >R Ne/am#% > @a%tr#' ant#%e'retory and ant#"l'er propert#e% of P@ 1?methyl P@and 1515d#methyl P@. Intra+eno"% oral and #ntra

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34 Roert A, Ne/am#% > Lan'a%ter C @a%tr#' 'ytoprote't#+e property of pro%tagland#n%. @a%troenterology86 1161 1988

3? Roert A Ne/am#% > Lan'a%ter C ,an'har A> Cy

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38 :hr#+er DA Do+e PA Fh#te CB :andor A Ro%enthall A prof#le of the ga%tro#nte%t#nal to&#'#ty of a%p#r#n#ndometha'#n o&apro/#n phenyl"ta/one and fent#a/a'#n arthr#t#' and Le2#% Normal rat%. $o&#'ol Appl Pharma'ol468?73 1988

37 :m#th R> od"lat#on of phago'yto%#% y and ly%o%omal

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40 :tra"%% RR Benoy BP :arra A> ffe't% of phenyl "ta/one on phago'yto%#% and #ntra'ell"lar #ll#ng yg"#nea p#g polymorphon"'lear le"o'yte%. > Ba'ter#ol95

19761990 19574 1 :/ao !& $r#er >: Bro2n A: :'hnoor > arly +a%'"lar

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46 $argo+n# , @l"/man B Coleon# A, N#epomn#%/'/e , ffe't% of phenyl"ta/one on thyro#d #od#ne







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80 1970

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45 Fh#ttle B>R $emporal relat#on%h#p et2een 'y'loo&ygena%e #nh##t#on a% mea%"red y pro%ta'y'l#n #o%ynthe%#% and the ga%tro#nte%t#nal damage #nd"'ed y #ndometha'#n #n the rat. @a%troenterology 709497 1971

48 Fh#ttle B> Vane >R A #o'hem#'al a%#% for ga%tro#nte%t#nal to&#'#ty of non%tero#dal ant##nflammatorydr"g%. Ar'h $o&#'ol :"ppl831?366 1974

47 Fh#ttle B> ,an%en D :almon > A @a%tr#' "l'er format#on and 'y'loo&ygena%e#nh##t#on #n 'at antr"m follo2% parented adm#n#%trat#on of a%p#r#n "t not %al#'ylate. "r > Pharma'ol1151?3151 197?

Re!"e%t repr#nt% from Dr. C. e%'hter Amer#'an ,ealth -o"ndat#on Re%ear'h An#mal -a'#l#ty One Dana Road Valhalla

NY 10?9? 06!?#






vet pathol 1990 meschter 244 53

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