preparations A success journey for STW 5 in gastrointestinal disorders Mohamed T Khayyal Faculty of Pharmacy Cairo University Herbal Remedies used by the Ancient Egyptians Acacia acacia ID: 544137
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Slide1
The necessity of providing evidence for the therapeutic effectivity of herbal preparations A success journey for STW 5 in gastro-intestinal disorders.
Mohamed T. Khayyal
Faculty of Pharmacy, Cairo UniversitySlide2
Herbal Remedies used by the
Ancient Egyptians
Acacia
(acacia
nilotica
) :
vermifuge
, eases
diarrhoea
and internal bleeding, also used to treat skin diseases.
Aloe
vera
: worms, relieves headaches, soothes chest pains, burns, ulcers and for skin disease and allergies.
Basil
(
ocimum
basilicum
)
: excellent for heart.
Balsam Apple (
malus
sylvestris
) :
laxative, skin allergies, headaches, gums and teeth, for asthma, liver stimulant, digestion.
Bayberry
(
Myrica
cerifera
)
:
stops
diarrhoea
, ulcers,
haemorrhoids
.
Liquorice
(
Glycyrrhiza
glabra
):
laxative
, expels phlegm, liver, pancreas and
chest
respiratory problems.
Fenugreek (
Trigonella
foenumgraecum
): respiratory disorders, cleanses the stomach, calms the liver, soothes pancreas, reduces swelling.
Caraway
(
Carum
carvi
): flatulence
, digestive, breath freshener. Slide3Slide4
Herbal CombinationsEarly in the history of use of medicinal agents, it was realized that the presence of one herb may alter the effect of the other when they are co-administered.The combined effect, either complementary or antagonistic, would be manifested in the clinical
outcome.
* Herb-Herb Combination for Therapeutic Enhancement and Advancement: Theory, Practice and Future Perspectives
Chun-Tao Che, Zhi Jun Wang, Moses Sing Sum Chow and Christopher Wai Kei Lam
Molecules
2013,
18
, 5125-5141Slide5
Need for evidence based medicineMany herbal medicines have been developed empirically and their therapeutic usefulness proven clinically.Developing models for human disease conditions helps to establish evidence of mechanisms of action and therapeutic usefulness.Evidence increases credibility for both patients and physicians.
Synergism between academia and industry mandatorySlide6
Shown clinically/experimentally to be a multi-target preparation for gastrointestinal disorders, such as:Ulcers (anti-inflammatory & ↓
hyperacidity)
1
Functional
dyspepsia
2
Irritable bowel
syndrome
3
DSS induced colitis4(1) Khayyal MT et al. (2006), Phytomedicine. 2006;13 Suppl 5:56-66. (2) Schmulson MJ (2008) Nature clinical practice gastroenterology & hepatology, 5, 136-137.(3) Madisch A et al. (2004) Aliment Pharmacol Ther, 19: 271-279. (4) Wadie,W. et al. (2012) Int J Colorectal Dis. 2012 Nov;27(11):1445-53.
STW5 (Iberogast
®
) Slide7
STW 5 (Iberogast®, Steigerwald, Germany)Slide8
Anti-ulcerogenic activityin Pyloric – ligated ratsSlide9
Anti-ulcerogenic effect of STW5 & componentsSlide10
Effect of STW5 & components on gastric aciditySlide11
Effect of STW5 & components on gastric mucinSlide12
Effect of STW5 & components on PGE2 in gastric juice Slide13
Effect of STW5 & components on LTD4 in gastric juiceSlide14
ConclusionsIndividual components exert effects in their own right on various parameters relevant to gastric ulcers.Combined effect as STW 5 gives evidence to its beneficial activitySlide15
Novel mechanisms underlying the effectiveness of STW 5 in functional dyspepsia.Slide16
IntroductionFunctional dyspepsia often correlated with subjection to stress at some stage in life.
Clinical evidence suggests that stress in early life followed by stress in adulthood could lead to functional dyspepsia (FD)
1,2,
involving derangement in gastric function.
Present study assesses the value of a novel developed stress model for determining mechanisms involved in the effectiveness of STW 5 in FD.
1
Kim HI et al. J Korean Med Sci 2013;28:431-7;
2
Monnikes H et al. Dig Dis 2001;19:201-11Slide17
Assessment of stress in animal models: Plasma CRFNeonatal maternal stress (NMS)Weanling
Wistar
rats
exposed
to
(NMS) by removing pups from mother cage for 3 h/day from postnatal day 2 till 21 then weaned
.
Restraint
stress (RS)
Adult Wistar rats subjected (RS) by confining them restrained in tightly fitting ventilated Perspex cylinders 90 min/day for 1 week.Plasma CRF measured 24h after last subjection to stress Slide18
Stress induces ↑ plasma CRF, normalization by STW 5Slide19
Sequential model: NMS/RSWeanling rats exposed to NMS
then weaned. Once adult, subjected to
RS for 1
week.
STW
5 (
Iberogast
®
Steigerwald
, Darmstadt, Germany) was administered orally at 2 dose levels (2 and 5 ml/Kg) for 1 week before and during exposure to RS.Experimentation started 24 h after last restraining session.Slide20
Parameters studiedGastric emptying using a phenol red meal*
.
Corticosterone and ghrelin in plasma
S
tomach
fundus strips
tested ex-vivo for sensitivity
towards carbachol, KCl, serotonin and adrenaline.
Duodenal homogenates
examined using qPCR for expression of some signalling and tight junction proteins, including CSE, RelA, Nrf-2, ZO-1, occludin. * Scarpignato C, et al. Arch Int Pharmacodyn Ther1980; 246: 286-94Slide21
Gastric emptying inhibited by model but normalized by STW5Slide22
Plasma corticosterone ↑model tended to be normalized
by STW5Slide23
Plasma ghrelin raised by model hardly
affected by STW5Slide24
Stress induced ↓ fundus sensitivity to carbachol/amelioration by STW5Slide25
Stress induced ↓ fundus sensitivity to KCl amelioration by STW5Slide26
Stress induced ↓ fundus sensitivity to serotonin / improvement by STW5Slide27
Stress induced ↓ fundus sensitivity to adrenaline improvement by STW5Slide28
Stress ↓duodenal ZO1, RelA, Nrf2 & ↑Occludin, CSE expression/ partial improvement by STW5Slide29
Summary & ConclusionsStress model led to marked delay in gastric emptying, raised plasma level of active ghrelin and corticosterone, but reduced expression of Nrf-2 and ZO-1 and
raised
occludin
in duodenal homogenates: changes normalized by STW5
.
Stress
markedly reduced gastric fundus sensitivity of parasympathetic, sympathetic and serotonergic
receptors.
Since
deranged gastric functions (emptying, fundus sensitivity) are among symptoms of FD, present findings help to elucidate mechanisms underlying therapeutic usefulness of STW 5 in that condition.Sequential stress offers a new model for studying agents with potential usefulness in FD Slide30
Novel Therapeutic Potential for STW 5: Prophylactic Measure against Intestinal Mucositis induced by RadiationSlide31
BackgroundExposure to radiotherapy often leads to mucositis of intestinal epithelium, possibly as a result of release of ROS and induction of apoptosis. This severely limits continuation of treatment.Treatment of mucositis usually carried out with agents with anti-inflammatory properties. So far, no standard medication has proved effective in preventing mucositis.
STW 5 was studied for its potential usefulness.Slide32
Induction & Assessment of MucositisMale Wistar rats exposed to whole body gamma radiation levels of 4, 6 and 8 Gy from Cs 137 source.
Animals sacrificed 3 days after exposure, segments of intestine examined histologically.
Intestinal homogenates and serum examined for parameters of apoptosis, inflammation and oxidative stress.Slide33
Rats were divided into the following groups
Non-irradiated control
Acute Irradiated
4
Gy
6
Gy
8
Gy
STW 5 + 8
Gy
STW 5
(2, 5 or 10
ml/kg)
orally for 5 days before and 2 days after radiation exposure. Rats sacrificed one day later.
Experimental DesignSlide34
At SacrificeSegments of small intestine examined histologically.
Intestinal
homogenates and serum
samples
used to
assess
relevant parameters
for:
a) mucosal damage and apoptosis b) inflammation c) oxidative stress. Slide35
Histological ResultsSlide36
STW 5 inhibits radiation induced histological changes dose-dependently
normal
8
Gy
: shortened
villi, activated mucous glands, apoptotic bodies.
STW 5 (2 ml/kg):Short villi, activation of
muc
. glands, inflam. cell infiltration
STW 5 (5ml/kg):
Epith
.
denudation
, few
inflam.cell
infilt
.
activation
of
muc
. glands.
STW 5 (10 ml/kg):
very few
histological
changesSlide37
Semi-quantitative histological assessment of intestinal damageA total score for each proximal jejunal specimen was derived from the sum of scores for 9 histological criteria.
1) number of apoptotic bodies
2) villus fusion and stunting (atrophy)
3) epithelial denudation and erosion
4 ) activation of glandular epithelium
5) reduction in goblet cell number
6) activation of nuclei of enterocytes
7) inflammatory cell infiltration 8) oedema 9) haemorrhage in lamina propria Each histological variable was scored from 0 (normal) to 3 (maximal damage) for each rat intestine. Slide38
Acute irradiation induced intestinal mucosal damageSlide39
STW 5 dose dependently suppresses radiation-induced mucosal damageSlide40
Concluding RemarksAcute exposure to radiation dose levels of 4, 6, and 8 Gy produced graded extents of intestinal mucositis as judged by light and
elecron
microscopy with evidence of apoptotic cells with the highest exposure level.
STW 5 in a dose of 10 ml/kg was most effective in reducing the severity of degenerative changes observed after acute irradiation. Slide41
Markers for Mucosal Damage LDH in serumDiamine oxidase
in serum
TNF
α
in intestinal homogenatesSlide42
Radiation induces release of LDH in serum
Significantly different at P
≤
0.05 from control group (*)Slide43
STW 5 protects against rise in LDH in SerumSlide44
Significantly different at P≤0.05 from control group (*) or from irradiated group (#)
STW 5 suppresses radiation induced rise in serum diamine oxidase (DAO)Slide45
Significantly different at P≤0.05 from control group (*) or from irradiated group (#)
STW 5 suppresses radiation induced rise in intestinal TNF-
αSlide46
Apoptotic markers- Cytosolic calcium
content
-
Mitochondrial
cytochrome c
(pro-apoptotic protein)
- Mitochondrial B-cell lymphoma-2 (Bcl-2) (anti-apoptotic protein)- Mitochondrial respiratory chain complex I activity. Slide47
Radiation induces release of cytosolic Calcium in Intestinal Tissue
Significantly different at P
≤
0.05 from control group (*)Slide48
STW 5 prevents radiation induced rise of cytosolic CalciumSlide49
STW 5 supresses radiation induced depletion in mitochondrial cytochrome c
Significantly different at P
≤
0.05 from control group (*) or from irradiated group (#)Slide50
Significantly different at P≤0.05 from control group (*) or from irradiated group (#)
STW 5 supresses radiation induced depletion in mitochondrial Bcl-2Slide51
Significantly different at P≤0.05 from control group (*) or from irradiated group (#)
STW 5 supresses radiation induced depletion in mitochondrial complex ISlide52
Oxidative stress biomarkersReduced glutathione (GSH) content in intestinal homogenate
Malondialdehyde
(MDA)
content in intestinal homogenateSlide53
Significantly different at P≤0.05 from control group (*) or from irradiated group (#)
STW 5 suppresses radiation induced depletion in intestinal GSHSlide54
Significantly different at P≤0.05 from control group (*) or from irradiated group (#)
STW 5 suppresses radiation induced rise in intestinal MDASlide55
Summary & Conclusions STW 5 protected to a large extent in a dose dependent manner against histological changes induced by gamma radiation and counteracted to different extents the derangement in all the relevant parameters measured suggesting that it may be useful as an adjuvant during radiotherapy to reduce the tendency to develop radiation enteritis.Slide56
Effects of STW 5 and STW 5-II in dextran sodium sulfate-induced colitisSlide57
How does STW 5-II differ from STW 5
Iberis amara
15%
tonicising
anti-inflammatory
Liquorice
10%
spasmolytic
anti-inflammatory
Lemon balm
15%
spasmolytic
anti-inflammatory
Chamomille
30
%
spasmolytic
anti-inflammatory
Caraway
20
%
spasmolytic
bacteriostatic
Peppermint
10%
spasmolytic,
anti-emeticSlide58
Inflammatory Bowel Disease (IBD)1. Crohn‘s Disease: STW 5 found effective in TNBS induced colitis. Abdel-Aziz H, Wadie W, Abdallah DM, Vinson B, Kelber O, Weiser D, Khayyal
MT.
Z.Gastroenterol
. 2008, 46, 362
2. Ulcerative Colitis: STW 5 found effective in DSS induced colitis.
Wadie
W, Abdel-Aziz H, Zaki HF, Kelber O, Weiser D, Khayyal MT (2012) Int.J.Colorectal Dis. 27, 1445 – 1453Slide59
Experimental DesignMale Wistar
rats (n=7-9) administered 5%
Dextran Sodium
Sufate
(DSS)
in drinking water. Lesions in the colon develop within 7 days
.
Drugs
given orally for 1 week before starting adding DSS in the drinking water and continued for a further week. Rats sacrificed. Colon length and weight recorded. The colon was cut longitudinally into 2 segments. One was examined histologically, and the other homogenized
and tested for various relevant parameters.Slide60
STW5 improved abnormal body weight changes. Slide61
STW 5 II prevents body weight lossSlide62
STW5
prevents DSS induced colon shortening.Slide63
STW 5 II tends to prevent colon shorteningSlide64
STW5
protects
against increase in colon weight
(
oedema
formation).Slide65
STW 5 II protects against rise in colon mass indexSlide66
STW5 guards against rise in myeloperoxidase activity induced by DSS (measure of neutrophilic infiltration).Slide67
STW 5 II prevents rise in MPOSlide68
STW 5 prevents
DSS induced
decrease in glutathione
levels.Slide69
STW 5 II prevents DSS induced fall in GSH levelsSlide70
STW5 largely
prevents DSS induced fall
in glutathione
peroxidaseSlide71
STW 5 II protects against DSS induced fall in GPxSlide72
STW5 completely
prevents DSS induced reduction of
SOD
levels
.Slide73
STW 5 II prevents DSS induced fall in colonic SOD levelsSlide74
STW5 completely
protects against DSS induced
rise in
TNF-
α
.Slide75
Histological ExaminationDSS induced following changes:marked necrosis of the
epithelium
intra-luminal
accumulation of mucous
exudates
sub-mucosal oedema
massive
inflammatory cell infiltration in the lamina
propria
and sub-mucosa. The infiltrated inflammatory cells included polymorphonuclear leucocytes, lymphocytes and plasma cells.Treatment with either STW 5 or STW 5 II largely prevented the above changesSlide76
Histology Scores after treatment with STW 5 or STW 5 IISlide77
Conclusions IDSS induced marked colitis, as evidenced by changes in both histological and biochemical parameters. Earlier studies showed that treatment with either STW 5 or sulfasalazine was effective in preventing such changes
(Abdel-Aziz H et al. Gastroenterology 2011; 14: S-
608
).
STW 5 II was developed to contain only 6 of the original components of STW 5 but with modified concentrations.
Present findings show that STW 5 II in a dose of 2 ml/kg was as effective as STW 5 in protecting against DSS-induced changes in both histological and biochemical parameters.
.
Slide78
Conclusions IIThe results point to the good anti-oxidant and anti-inflammatory properties of STW 5 II, imaging those of STW 5.
This
lends support to its potential therapeutic usefulness in inflammatory conditions of the GIT,
such as
ulcerative colitis.Slide79
Final concluding remarksExperimental models help to establish credibility for therapeutic usefulness of herbal combinations for both patients and physicians.The models may help to develop novel therapeutic applications for established preparations.
Close interaction between academia and industry is imperative for better development of herbal medications.Slide80
Thank you for your kind attention
STW 5-II
STW5