leukotrieneantagonist& inhibitor:clinicalapplicationsjkscience.org/archive/volume44/salai...
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IREVIEW ARTICLEI
Salai Guggal-Boswellia SerrataLeukotriene Antagonist & Inhibitor:Clinical Applications
hIder Gupta, Annil Mahajan, Vijay Gupta
InDamm3tion is the hall mark of various diseases
and is characterized by five symptoms; redness,
heal. pain, swelling and decreased function. These
symptoms are caused by a variety of inflammatory
mediators \\hich are listed in table I.
So far only two major principles of antiphlogistic
drug activity are available in therapy. First
compounds inhibiting the synthesis of
prostaglandin's by interfering with the cyclo
o'ygenase system (salicylic acid, etc.). Second the
gluco- corticosteroids. which finally inhibit both the
cyclo-oxygenase pathway & the lipoxygenase
path\\ay by interfering with the phospholipase. A2
-reaction (Fig. I ). However. there are number of
inflammatory diseases where increased production
of leukotrienes seems to be a reason for keeping
the inflammatory process running. Among these
diseases are: bronchial asthma, chronic inflam
malory arthritis, hepatitis, psoriasis, ulcerative
colitis and crohn's disease. In these diseases
leukotriene antagonists are the target point as far
as therapy is concerned. We briefly review the role
ofSalai Guggal as anti leukotriene and its applica
tions in different diseases.
Table. I Mediators of Inflammation
Mediator Origin Appearance Inflammationaftcl'" sumptoms
Bradykinin Plasm3 seconds Vasodilatation.increased vas-cular pennea-bility, pain
Histamine Mast Cells Seconds Vasodilatation.increasedvascular penne-ability. pain
Prostaglandins Ubiquitous Seconds Vasodilatation.pain. sensitiza-
tion againstBradykinin andhistamine
lllromboxane Thrombocytes Seconds Platelet activa-other cells tion
Hydroxy-fatty Ubiquitous Seconds Chemotactic foracids leucocytes. pain
Leucotrienes Leucocytes minutes Chemotactic forleucocytcs. in-
creased vascularpermeability
Lysosomal Leucocytes minutes Necrotic.enzymes synovial cells chemotactic
for leucocytes
Lymphokines Lymphocytes hours Necrotic-----------------------------------------------------------------------------_._-
From the Postgraduate Department of Medicine, Govt. Medical College Jammu (J&K).
Correspondence to: Dr. Inder Gupta. 8)-Below Purani MandL Jammu (J&K) India.
Vol. 4 No.4. October-December 2002 169
______________J:'J.K..S..C..J.E..N...'C...E...-------------
1EndopcrO'\ldeD-lso11lerase
Prostaglandlll D:
1
ProslaglandHI E1
1
Prostaglandm F2
Leukotriene E~
Thromboxane A~
Thromboxane EndoperO:'<lde Endopero'\ldesynthase F-reduclase E-Isomerasc
1 1
is called 'salai guggal 'when defatted cthanolic extracts of
salai guggal was introduced into the 5 - lipoxygenase test
system using calcium/calcium ionophore- stimulaled
pcritonealncutrophils of rats. it tumed oullhal Ihis extraci
significantly decreased production of LTB, and total 5
lipoxygenase products, the EC 50 being about 30 ug/ml.
Boswellic acids are the main constituents of the
ethanolic extract of the resin of Boswellia serrala.
Differenl Boswellic acids have been idcnlified including
p-Boswellic acid. a-Boswellic acid and I I-kclo -p
Boswellic acid and other acetyl forms (9-13).
Crude ethanolic extracts of the resin and or Boswcllic
acid have phannacological actions as anli-inflammatory,
inhibition of complemenl system and hcpatoprotectivc.
Studies of the boswellic acids possible effects on cyclo
oxygenase or 12- lipoxygenase activity showcd that thc)
affected neither prostaglandin synthesis nor 12
lipoxygenase activity suggesting thai this type of
pentacyclic triterpenes may inhibit only leukolricne
6-Keto prostaglandin FlO
INon-enzymatic hydrolysis
P I '1'rostacyci 111
11 1NOIl-entymauc Leukotriene C I ProsiocycllllhydrolysIs synthase synthase
1 15.6-DJHETE Leukotriene C~
5, t 2 DIHETE 1f·G Iulamyl- transferase
1Lcukotriene 04 -----Dlpeplidase
LeukOlrlenc A.j
hydrolase1
LeukOlriene Sol
1
Phospholipids1
Phospholipase A,1
l-r---------------- Arachidonic Acid --------------,1
Cyclo-oxygcllase(PGII~-Synlhase)1 -
Presteg)andin G I
-1Prostaglandinhydroperoxidose
1Prostaglandin 11:-
LlpOSlll(S) A.S
15-Lipoxygenase 5-Lipoxygenase 12-Lipo,,:ygenase1 1 1
15-Hl'ETE 5-IIPETE 12-~U)ETE
Glutat,ione Leukt;;:;;:;,;;-;-+Glutahione GlutothionePeroxidase synthase peroxidase peroxidase
~I~E LeuttrieneA, 5-~ 12-lk
5-Llpotygenase Wl!hisynthase activity _1 ----,1,---,1
w-oxldatlon -- 20·011·Lcukotnenc 8"
120-COOH-LcukOlflcnc B.j
Fig. 1 Eicosanoid llIetablic pathways
Salai Guggal is a traditional remedy in Ayurvedic medicine
used in India fora varie!) ofinflammatory diseases including
rhewllaloid arthritis. osteoarthritis & cervical spondylosis.
Salai guggal is Ihe gumresin of Boswellia sen'ata Roxb.
The main constituents ofthe gwn resin are boswellic acids
and other compounds such as volatile oils, terpinols,
arabillosa, xylose, galactose, uronic acids, ~-sicosterin andphlobaphenes. Boswellic acids are also a constituent ofthe
gWll resin of Boswellia cal1erti Birdw, also known as
OlibanlU11. The known phannacological effects ofOlibanum
are anti-inflammalOl), analgesic, immunosuppressive,
hepatoproteclive and antimicrobic (1,2). The gum resin of
Boswellia sen'ala & Boswellia carterti is also widely used
as incense forreligious ceremonies. Salai guggal & boswellic
acids have been shown to possess anti-in:fIanU11atory activity
in a variety ofanimal's models (3-5).
Boswellic Acids
The resin of Boswellia serrata is used in India for the
treatment ofchronic inflanunatory arthritis. The raw product
170 Vol. 4 o. -l, October-December 2002
--------------6-. JK SCIENCE
s) nthesis. Boswcllic acids are speci fically non-redox
inhibitors of 5- lipoxygenase (I -1-23).
Clinical Applications
Rheumatoid Arthritis & Osteoarthritis:
In the traditional Ayurvedic medicine ofTndia the use ofSalai guggal is very common to treat inflammatory
disease including chronic polyarthritis especially
rheLUnatoid artIlI;tis and osteoa,th,;tis. Many preparations
like S-compound Sallaki. I-l I5 etc. are available in the
market lor the treatment of these inflaJlllllatory and
degenerative diseases (24-28).
Inflammatory Bowel Diseases
u. Llcerali\'e colitis is achronic inOammatOly disease with
remissions and exacerbations affecting principally the
rectal mucosa. the left colon but in many instances the
entire colon. It is characterized by rectal bleeding and
dianhea appearing principally.
Illough the aetiology of this disease is complex, it has
been repOlted that the inflammatOlY process is associatcd
with cxtensi\'e Icukac) Ie infiltration & increased
lOllllation ofleukotrienes. Drug therapy so far is mainlylimited to ~le use ofslilrasalazine or otiler aJninosalicylates
and corticosteroids but they are weak inhibitors of
lellkotrienes production & cellular interleuk.in-I release
and dose dependent modifiers of prostaglandin profile.
all of\\hich might affect the inflaJ11lllatoty response in
inflallllllalOly bowel diseases.
Bos\\ellia selTata blocked leukotriene biosyntlhesis in
neutrophilic graJlUlocytes, being direct non-redox and non
competitive inhibitors of 5 - lipoxygenasc - Gupta el. al.
(29) ha\ e for ti,e first time demonstrated the lise ofBoswellia
serrata in ulccrati\'c colitis.
b. Crohns Disease is also a chronic innammatory
disease WiUl remission and exacerbations. Leukotrienes
(LTB,) are major chemotactic factors in such patients and
large 31nOlUlts of leukou'ienes aJ'e fowld Ul the mucosa of
patients with Crohns disease. Gerhardt ef al (30) had
eonfinned Ul their sludies that tilerapy witlh Boswellia sen'ata
is not inferior to mesalzine in Crohns disease. Considering
Vol. 4 0.4. October-December 2002
both safet) and efficacy or Bos\\ellia serrata extract it
appears to be superior over mcsalal.ine in tCll11S ofa benefitrisk evaluation.
Bl'Ollehial Asthma
It is a chronic inOammatOl") condition characteriLcd b)
bronchial hypercsponsivcl1css and reversible ain\ay
obstruction, A wide range of compounds mediate these
proccsses. Leukotricnes were identi fied as products of
arachidonic acid metabolism and as innammatol)' mediators
in the late 1970. Prior to this their existence \\as recognized
as the slow-reacting substances oranaphylaxis (SRS-i\) a
tenn coined b) Feldberg and kelJa\\a) in 1938. In 19-10.
Kcllav;ay and Trcthc\\ie suggested a role of SRS-/\ in
asthma but it was not until 40 years later that it bc<:amc
clear that SRS-A consisted of the Ieukou·ienes. Besides
causing chemotaxis, chemokinesis. synthesis ofsuperoxidcradicals and release oflysosomal enzymes by phagoc) tes
leukotrienes cause (a) broncho-constriction (b) mucosal
oedema (c) increased mucus secretion and (d) an
innan1lllatOlY ccllular infilu·atc rich in eosinophils (31--1 1).
Anti-Ieukotriene drugs either inhibit the S) mhesis or
leukotricncs {l'om arachidonic aciel (e.g. zilclilon. MK-886.
BAYX 1005) or act as leuk.otriene receptor antagonisls(e.g.
zafirlukast, ICI20-l, 219: montelukast. MKO-l76. pranlukast.
imlukast). The glUll resin ofBoswellia seralta (salai guggal)
was shoml to block leukotrienes bios) nthesis due 10 the
action of genuine bos\vcllic acids constilUcnts. I-.:..C10
boswellic acid (i.e. AKBA-acctyl: II-Keto-~-l3os\\cllicacid)
are orally. actiye direct non-redox and noncompetiti\'(~
inhibitors of5-lipoxygenase( 19).
Gupta el. al. (36) have sho\\ll that Boswellia serrata
induces remission in patients \\ ith bronchial asthma.
Improvement of the disease is evident h) disappearancc or
physical symptoms and increasc in FEVI, I've and PI:FR
as well as decrease in eosinophilic count 'nd ESR.
Peritumoral Brain Oedema
Boswellia seratta containing A KBA and KBA pro\ idcd
promising result in reducing peritlulloral brain oedema in
patients with maligl1fUlt glioblastomas along \\~th adecreased
1 71
,JK SCIENCE----------------oJurinal) lcukotricllc ~xcrcliol1. Ilcldt el. al. !lm"e showil
c: stcin: I Icukotriencs as potcntial mcdiators of the
perilllllloral brain oedema in astrocytoma patients while
l30kcr "I. ,,/ rcportcd \\nndcrful effects in thcrap: of
malignant gl ioma. II ighcr dose ol'drugs in grams arc gi '"en
in reducing intracranial prcssul'l".' in head injuries (-l2-45).
Psoriasis
Psoriasis is another disease charaC1CI;zed b) cxtensi, c
ICllhoc~ lc inlillratiol1 albeit into the skin rather than the rectal
lllllcosa. f\, lcasurcll1cnts haye bc.::cll made lor the presence
of \ ariolls chl..:ll1otactic agents ill psoriatic lesions and the
pn,:scllcc of! I B-t like imll1unnorcaCliye material has been
(kscrihcll. 1l1crc hm c also heen suggestions that existing
drugs ll1a~ act h) inhibiting the production ofleukou-icnes.
Clinil.:al trials ha\'c beel1 carried out \\ ith both /.ilcuton
(illpicall: and s: stcmalicall: ) and MK-886. Thcsc agcnls
\\ cn.: Illlllld 110tlo (..!encase the amount ofLrR.J like material
1()LIlld in psoriatic skin Ic~ions indicating that this material is
not dcri\ ed through thc action of thc 5-lipoxygenasc
path\\ a) s( ~6)" M~lIl) studies are showing good results of
bo;.;\\cllil.: al.:ids inlhe lrealmC'1lt of'psoriasis(47).
Chronic Colits
Chronic 11l)l1spcci lie colitis is a common disease
characterizcd b) \"ague lo\\cr abdominal pain bleeding per
rectum \\ ith diarrhea and palpable tender descending as
\Veil a, sigmoid colon (48-50). This disease is secn in young
and middle aged persons and may be a ,·m;ation ofulcerati\"e
colitis. Gupta el. al. (2~) haye ShO\\'1"l promising results \\ith
13os\\cllia seratW in chronic colitis.
C lomcl'uloncph ritis
LClIhotricncs mediate the alterations in renal
halmod;. namic and glomerular filtration, which occur in <I
\"ariet) of nephritis including nephrotoxic serum nephritis.
murine lupus and passi\c lie: man nephritis. A cOITciation
bel\\een ncutrophil infiltration and glomerual LTI3.synthesis
has bccn delincd. CyslcinyllcukOlrienes playa role in the
pathogenesis and progression ofglomerulonephritis not only
through cflects on renal blood flow and filtration but also
through prolileralive changes in response to both LTC.and
LTD.nnd in \'ivo inhibition ofLT biosyl1lhesis in nephritic
rats \\ ilh MK-886 b) IJrC\ cnling glomerular cell proli feration
172
(II ).Man)' studies arc undcma: \\ hich sho\\ that gum resin
ofl3oswellia scn'llta is \CI) cflecti\c in ncphritis paticnts(47).
Other Diseases
Animal studies hm c ShO\\ll that Bos\\dlia Sl.:rrata is
effCCli\c in lreatment ordrug induced hepatitis and ILlpoid
hepatitis. Clinical trials arc being conducted for lhe cnCCIS
ofBoswellic acid in thesc diseases(50.51).
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173