LeukotrieneAntagonist& Inhibitor:ClinicalApplicationsjkscience.org/archive/volume44/Salai Guggal-clinical... · 2009-11-27 · diseases are: bronchial asthma, chronic inflam malory

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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