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Antispasmodic Activity of SJ-200 (Himcospaz): An Herbal Preparation

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SJ-200 (Himcospaz), an herbal preparation, was investigated for antispasmodic activity on gastrointestinal smooth muscles of guinea pig, rats, rabbits, and mice. SJ-200 dose- dependently inhibited acetylcholine, histamine and barium chloride-induced contraction of guinea pig ileum. It inhibited spontaneous contraction of rabbit and rat colon. Oxytocin- induced contraction of rat uterus was also inhibited. Oral administration of SJ-200 dose- dependently reduced gastric emptying in rats and intestinal transit in mice. All these findings suggest the non-specific antispasmodic activity of SJ-200 in experimental models.
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[Pharmaceutical Biology (2002): (40), 6, 416-421]
Antispasmodic Activity of SJ-200 (Himcospaz) An Herbal Preparation
M.V. Venkataranganna, S.D. Anturlikar, S. Gopumadhavan, N.S. Prakash,
Mohammed Rafiq, Girish S. Murthy and S.K. Mitra*
R&D Center, The Himalaya Drug Company, Makali, Bangalore 562 123 (India).
ABSTRACT
SJ-200 (Himcospaz), an herbal preparation, was investigated for antispasmodic activity on
gastrointestinal smooth muscles of guinea pig, rats, rabbits, and mice. SJ-200 dose-
dependently inhibited acetylcholine, histamine and barium chloride-induced contraction of
guinea pig ileum. It inhibited spontaneous contraction of rabbit and rat colon. Oxytocin-
induced contraction of rat uterus was also inhibited. Oral administration of SJ-200 dose-
dependently reduced gastric emptying in rats and intestinal transit in mice. All these findings
suggest the non-specific antispasmodic activity of SJ-200 in experimental models.
Keywords: Antispasmodic, gastric emptying, intestinal transit, irritable bowel syndrome,
SJ-200, Himcospaz.
INTRODUCTION
Functional gastrointestinal disorders (FGID) affect millions of people from all age groups
(Loe et al., 1999). Irritable bowel syndrome (IBS), dyspepsia and inflammatory bowel
disease (IBD) are the most common disorders of FGID. The symptoms of FGID can cause
discomfort, ranging from inconvenience to deep personal distress (Koloski et al., 2000).
Unfortunately no single drug has proven to be effective in treating FGID. In addition, the
search for a truly effective and safe drug to control motility disturbances in FGID continues
(Scapignato & Pelosini, 1999).
Ayurveda, an Indian system of medicine, cited several plants, which are useful against
various gastrointestinal disorders without any side effects. SJ-200 (Himcospaz), an herbal
preparation contains Zingiber officinale Roscoe, Zingiberaceae (rhizome), Apium graveolens
L., Apiaceae (fruit) and Foeniculum vulgare Mill., Apiaceae (fruit). All these plants have
been used to treat various gastrointestinal disorders like abdominal pain, flatulence and colic
(Satyavathi, 1976; Nadkarni, 1982; Vavier,1996).
In the present study we have investigated the effect of SJ-200 on various smooth muscles in
vitro, gastric emptying rate and intestinal transit rate in vivo.
MATERIALS AND METHODS
Plant materials
Apium graveolens, Foeniculum vulgare and Zingiber officinale were procured from a local
supplier and identified by Dr. Kannan, Botanist, The Himalaya Drug Company, Bangalore.
Samples were retained for reference purpose at the R & D herbarium.
Drugs
The drugs acetylcholine chloride (Ach) and histamine dihydrochloride were from Sigma
Chemical Co., St. Louis. MO. Oxytocin was from Rathi Laboratories (Hindustan Pvt. Ltd.,
Patna, India). All other chemicals were purchased from Loba Chemie, Mumbai, India.
Preparation of physiological solutions
Tyrode solution composition (mM): NaCl, 137; KCl, 2.7; CaCl2, 1.8; NaH2PO4, 0.4; MgSO4
0.25; NaHCO3, 11.9; glucose, 11.1 de Jalon solution composition (mM): NaCl, 154; KCl,
5.6; CaCl2, 0.55; NaHCO3, 6.0; glucose 2.78.
Preparation and standardization of SJ-200
Dried and powdered materials of Zingiber officinale, Apium graveolens and Foeniculum
vulgare in the ratio of 1:1:1 were mixed and 100 g powder was refluxed with 500 ml
chloroform at 70°C for 6 h. After filtration the chloroform was evaporated in a vacuum
evaporator. The extract thus obtained was taken for the standardization and pharmacological
studies. The yield of the extract was 10% of total dried material.
Ten microlitres of 1% v/v solution of SJ-200 in
chloroform was injected into a 20 M stainless-
steel column filled with 10% carbowax. Nitrogen
was used as the carrier gas at 30 ml per min and
a flame ionization detector was used. The
temperature of the oven, injector and detector
were 220, 230 and 250oC respectively. The
chromatogram was recorded with the help of
Aimil chromatography data station. A fingerprint
chromatogram of SJ-200 is presented in Fig. 1.
F
igure 1. Gas chromatogram of SJ-200
Experimental animals
Swiss albino mice, albino rats (Wistar strain),
New Zealand white rabbits and guinea pigs were
housed in an air-conditioned area at 25 ± 2oC
with 12:12 h light and dark cycle. They were
maintained on synthetic pelleted feed (Lipton
India Ltd., Mumbai, India) and water ad libitum.
Animals for organ bath studies
Male and female Wistar rats (160-200 g b.wt.) and male guinea pig (300-350 g b.wt.) after 24
h fasting were killed by stunning and bleeding. Ileum, colon or uterus were removed and
suspended under a constant tension of 1 g in 15 ml organ baths containing Tyrode at 37°C
(Ulrike et al., 1997; Parry et al.,1996). Before the experimental procedures the organs were
allowed a 30-40 min equilibration period with changes of medium at every 5 min. SJ-200 was
dissolved in 0.5% DMSO. 200 µl diluted SJ-200 was used as the maximum volume in the
baths, at which volume there was no solvent effect. During the experimental phase SJ-200
was added to the bath and after 1 min incubation period the agonist was added. Contractions
were recorded using isotonic transducer connected to a polyrite (Model 201, Recorders and
Medicare, India).
Isolated rat colon and uterus
A portion (2.5 cm) of colon (n=6) was washed and suspended in aerated tyrode solution at
37°C. The uterus (n=6) from an estradiol-treated female rat (10 µg/kg s.c. 48 h before
experiment) was isolated and suspended in de Jalon solution (Blazquez et al.,1995).
Isolated guinea pig ileum and rabbit colon
A portion of 2.5 cm guinea pig ileum (n=6) and rabbit colon (n=3) was suspended in aerated
Tyrode solution at 37°C.
Effect of drugs
Dose response curves or isolated concentrations were performed with Ach (10-8-10-4 M),
Oxytocin (2 mIU/ml) histamine 10-8-10-4 M and barium chloride (10-3–10-1 M) in the
presence or absence of SJ-200. The effect of SJ-200 on normal motility of rat and rabbit
colon was evaluated without agonists.
Effect of SJ-200 on gastric transit rate in rats
Wistar strain rats of either sex weighing between 180-200 b.wt. were used for the study.
Twenty -four overnight fasted rats were divided into 4 groups of 6 each. Group I served as
control and received vehicle alone. Group II, III and IV received SJ-200 at a dose of 50, 100
and 200 mg/kg p.o. in 0.5% DMSO. After 30 min all the rats received 1.5 ml of test
meal/animal, which contains 50 mg of phenol red in 100 ml of 1.5% w/v aqueous
methylcellulose. Twenty minutes after administration of the test meal, the rats were
euthanised under ether anesthesia. The stomach was dissected out by opening the abdominal
cavity after clamping the cardiac and pyloric ends. The stomach was rinsed in physiological
saline and placed into 100 ml 0.1 NaOH and cut into small pieces and then homogenized. The
homogenized suspension was allowed to settle for 60 min at room temperature. Five milliliter
of supernatant was pipetted out into a test tube to which 0.5 ml of 20% w/v
trichloroaceticacid (TCA) was then added and centrifuged at 2800 rpm for 20 min. To the
supernatant 4 ml of 0.5N NaOH was added and absorbance was measured
spectrophotometrically at 560 nm. For the standard concentration, phenol red recovered from
the stomach of rats sacrificed immediately following oral administration was considered
(Tache et al., 1987).
Effect of SJ-200 in intestinal transit time in mice
Twenty-four Swiss albino mice weighing 25-28 g were fasted overnight and divided into four
groups of 6 each. Group I served as control, which received vehicle alone. Group II, III and
IV received SJ-200 at a dose of 50, 100 and 200 mg/kg p.o. in 0.5% DMSO. After 30 min all
the mice received charcoal meal (1.0% charcoal in 1.5% tragacanth) at a dose of 0.1
ml/animal. Twenty minutes after administration of the charcoal meal, the intestine was
removed. The total length of the intestine, from duodenal end to the cecum, and the distance
travelled by the charcoal were recorded and the percentage of charcoal movement was
calculated (Hamada et al., 1999).
Statistical Analysis
Data were expressed as Mean ± SEM. Significance was assessed by Student’s ‘t’ test or
ANOVA followed by Dunnet’s test. The minimum level of significance was fixed at p<0.05.
RESULTS
Effect of SJ-200 on spontaneous motility of rat and rabbit colon
SJ-200 at a concentration of 40-80 µg/ml dose-dependently inhibited spontaneous contraction
of rat and rabbit colon. A dose of 80 µg/ml of bath concentration completely blocked
spontaneous contraction (Figs. 2 and 3).
F
igure 2. Effect of SJ-200 on normal motility of rat colon.
F
igure 3. Effect of SJ-200 on normal motility of rabbit colon.
Effect of SJ-200 on agonist-induced
contraction
Acetylcholine and histamine (10-8-10-4
M) induced dose-dependent contraction
of guinea pig ileum. Exposure (60 sec)
of the ileum to SJ-200 (40-80 µg/ml)
reduced the contractile response of
acetylcholine and histamine (10-4 M) in
a dose-dependent manner (Fig. 4).
SJ-200 at a dose of 80 µg/ml almost
completely blocked the barium
chloride-induced contraction of guinea
pig ileum (Fig. 5). The incubation of
F
igure 4. Effect of SJ-200 on acetylcholine- and histamine-
induced contractions of guinea pig ileum
the isolated rat uterus with SJ-200 (80 µg/ml) resulted in significant inhibition of the
oxytocin-induced contractile response (Fig. 6).
F
igure 5. Effect of SJ-200 on barium chloride (BaCl2)-induced contractions of guinea pig ileum.
F
igure 6. Effect of SJ-200 on oxytocin (OXT)-induced contractions of rat uterus.
Effect of SJ-200 on gastric
emptying rate (GER) and intestinal
transit time (ITT)
SJ-200 (50-200 mg/kg b.wt) dose-
dependently reduced gastric emptying
and intestinal transit in rat and mice
respectively. The effects on both
parameters were significant at a dose
of 100 and 200 mg/kg b. wt. p.o. of
SJ-200 (Fig. 7).
F
igure 7. Effect of SJ-200 on gastric emptying in rats
DISCUSSION
The present study shows that SJ-200
reduces spontaneous motility of rat
and rabbit colon. The absence of
contractile activity of the drug itself
on various smooth muscle
preparations shows the lack of
agonistic activity on muscaranic,
histaminergic and oxytocin receptors.
The results obtained on isolated
smooth muscle show the inhibition of
histamine, acetylcholine, oxytocin
and barium chloride-induced contractions.
F
igure 8. Effect of SJ-200 on intestinal transit in mice
Binding of Ach to muscarinic receptors or histamine to H1 receptor in smooth muscles results
in opening of receptor operated channels, thereby allowing sodium influx, which causes a
depolarization of the cell membrane. This depolarization opens voltage dependent calcium
channels and calcium ions enter the cell to induce the release of calcium from the
sarcoplasmic reticulum. The cytosolic calcium thus binds to calmodulin, which results in
contraction (Balton, 1979; Rojas et al., 1996).
Since these spasmogens have different modes of action, the antagonism elicited by SJ-200
indicates that it might be acting at a common step in the contraction mechanism elicited by
these agonists. The antagonism displayed was concentration dependent. Since acetylcholine,
histamine, oxytocin and barium chloride effects were altered by the SJ-200, it seems to be
non-specific antagonism. Earlier research works on the extracts of individual ingredients of
Zingiber officinale, Apium graveolens and Foeniculum vulgare were credited for their
antispasmodic activity. Zingiber officinale is proven to be effective in inhibiting the gastric
and intestinal motility in mice and also found to inhibit the colonic motility in rats (Tulimat et
al., 2001; Wu et al., 1994). The spasmolytic activity of Zingiber officinale could be attributed
to gingerol, an active constituent that was found to inhibit prostaglandin biosynthesis and
seratonergic activity (Harborne et al., 1999). Apigenin, an active constituent of Apium
graveolens, was reported to inhibit norepinephrine-induced contractions of rat aortic
preparations in a dose-dependent manner (Ko et al., 1991). The essential oils of Foeniculum
vulgare are reported to exhibit antispasmodic effect in rat uterus preparation. (Ostad et al.,
2001; Neuhas-Carlisle et al., 1993; Forster et al., 1980). The combination of these active
constituents could be responsible for the observed antispasmodic effect of SJ-200.
Irritable bowel syndrome is the most common functional disorder, which is characterized by
a combination of abdominal pain and altered bowel function affecting primarily the mid and
lower gut (Vasllo et al., 1992). As a consequence drugs affecting gastrointestinal motility
have been widely employed with the aim of correcting the major IBS manifestation i.e. pain
and altered bowel function (Scapignato & Pelosini, 1999). The present study reveals that SJ-
200 dose-dependently decreased gastric emptying and intestinal transit, which indicates
inhibition of gastro-intestinal motility in vivo. The in vivo observations were also correlating
with in vitro studies. All these findings suggest that SJ-200 is having non-specific
antispasmodic activity, which can be used in the treatment of various non-specific spasm
disorders.
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Up to 35% of the world population suffer from functional gastrointestinal disorders (FGD), accounting for about 40% of gastroenterologic and 12% of primary care practice. Society incurs high costs from FGD morbidity in terms of medical workups and absenteeism from work. FGD are characterized by chronic and recurrent symptoms of the gastrointestinal (GI) tract without detectable structural or biochemical abnormalities. In the absence of universal biologic markers, the diagnosis is based on consensus symptom criteria (1). This chapter reviews current knowledge of the pathophysiology and provides a practical approach to patients with functional dyspepsia and irritable bowel syndrome, 2 of the most common functional GI syndromes.
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The present study evaluates the central nervous system action of rat corticotropin-releasing factor (CRF) on gastric emptying of a liquid meal in conscious rats using the phenol red method. Intracisternal injection of CRF (63-210 pmol) dose-dependently inhibited gastric emptying of a liquid meal by 37-80%. Peptide action was rapid in onset, long acting, and not mimicked by intracisternal injection of growth hormone-releasing factor. Intracisternal CRF-induced inhibition of gastric emptying was reversed by subdiaphragmatic vagotomy but not by naloxone pretreatment or adrenalectomy. Intravenous injection of CRF (21-630 pmol) also dose-dependently inhibited gastric emptying. CRF antiserum blocked the effect of intravenous but not of intracisternal injection of CRF (63 pmol). These results demonstrated that CRF injected in a picomole amount into the cerebrospinal fluid acts within the brain to inhibit gastric emptying of a liquid meal through vagal-dependent pathways.
Article
This review is concerned with the mechanisms by which substances, many of them neurotransmitters, produce their effects on smooth muscle cells. It is concerned primarily with those that exert effects within seconds of their application to the muscle - effects most easily studied in vitro with the smooth muscle cells bathed in physiological salt solutions. Those substances, such as hormones or other trophic agents, that have a long-term effect are not considered here. An examination is presented of the strength of the experimental support for some simple concepts about how stimulant or inhibitory chemicals affect the contractility of smooth muscle. This review concentrates particularly on the effects of drugs, and substances found naturally in the body, on the permeability of the smooth muscle cell membrane and how these changes might increase or decrease tension in the contractile proteins.
Article
The effect of apigenin, isolated from Apium graveolens, on the contraction of rat thoracic aorta was studied. Apigenin inhibited the contraction of aortic rings caused by cumulative concentrations of calcium (0.03-3 mM) in high potassium (60 mM) medium, with an IC50 of about 48 microM. After pretreatment it also inhibited norepinephrine (NE, 3 microM)-induced phasic and tonic contraction in a concentration (35-140 microM)-dependent manner with an IC50 of 63 microM. At the plateau of NE-induced tonic contraction, addition of apigenin caused relaxation. This relaxing effect of apigenin was not antagonized by indomethacin (20 microM) or methylene blue (50 microM), and still existed in endothelial denuded rat aorta or in the presence of nifedipine (2-100 microM). Neither cAMP nor cGMP levels were changed by apigenin. Both the formation of inositol monophosphate caused by NE and the phasic contraction induced by caffeine in the Ca(2+)-free solution were unaffected by apigenin. 45Ca2+ influx caused by either NE or K+ was inhibited by apigenin concentration-dependently. It is concluded that apigenin relaxes rat thoracic aorta mainly by suppressing the Ca2+ influx through both voltage- and receptor-operated calcium channels.
Article
The inherent variability of symptoms and motor abnormalities in patients with the irritable bowel syndrome has hampered the demonstration of motor abnormalities that could underlie symptoms. The aim in the current study was to evaluate whether altered regional capacitance or transit of solid residue through the unprepared human gut were factors in the diarrhea of patients with the irritable bowel syndrome. In 10 such patients and in 5 healthy controls, gastric and small bowel transits were evaluated scintigraphically by means of a mixed meal containing 99mTc-labeled resin pellets. Regional colonic transit was quantitated by 111In-labeled pellets delivered to the ileocecal region by a pH-sensitive, methacrylate-coated capsule. Symptomatic patients did not have significantly altered gastric or small bowel transits, but colonic transit was accelerated in 7 of 10 persons with the irritable bowel syndrome (P less than 0.02), in the proximal colon of five patients and in the left colon of two patients. The 24-hour stool weight was positively correlated with the rate at which solid residue emptied from the ascending and transverse colons (r = 0.78; P less than 0.01). There was also an inverse relationship between emptying rates and maximal volumes accommodated by the proximal colon (r = -0.58; P less than 0.05), although the maximum volume of the proximal colon was not significantly different in patients and healthy subjects. Thus, accelerated transit through the proximal colon is a factor in the pathophysiology of the irritable bowel syndrome and influences the stool weight of such patients. The capacitance of the proximal colon presumably influences its storage capacity and, hence, the rate at which it empties.
Article
The antispasmodic activity of 2.5 and 10.0 ml/l of alcoholic extracts of Melissa officinalis, Rosmarinus officinalis, Mentha piperita, Matricaria chamomilla, Foeniculum vulgare, Carum carvi and Citrus aurantium prepared from 1 part of the plant and 3.5 parts of ethanol (31 % w/w) was tested employing the guinea pig ileum and using acetylcholine and histamine as spasmogens. Most of the extracts shifted the dose response curves of acetylcholine and histamine to the right in a dose dependent manner. Extracts from Carum carvi, Mentha piperita, Citrus aurantium and Matricaria chamomilla showed a significant rise of the DE50 of cetylcholine-induced contractions and a significant decrease of the maximal possible contractility. In histamine-induced contractions, all plant extracts except Extractum Melissae exhibited a significant increase of the DE50, and all extracts used here decreased the maximal possible contractility produced by histamine. The alcoholic extract of Mentha piperita was most effective when tested with acetylcholine and the extract of Citrus auran-tium was most active when tested with histamine. Melissa officinalis did not show significant antispasmodic activity. When the antispasmodic activities of the most effective plant extracts were compared with the activity of atropine, it was evident that their effects were less than that of the usual therapeutic dosage of atropine in man. The most pronounced effects with 10 ml/l Extractum Citrus aurantii and 10 ml/l Extractum Menthae piperitae correspond to the effect of 0.07 resp. 0.13 mg atropine.
Article
The diethylether extract from Thymus leptophyllus was found to be more active on uterine smooth muscle than on aorta strips. Rat uterus experiments with and without extracellular calcium, yielded similar IC50 values. A nonspecific mechanism for the relaxant activity can therefore be postulated. In rat aorta and in the presence of extracellular calcium the extract inhibited the contractile response induced by K+ depolarizing solution and had a less inhibitory effect on noradrenaline (NA) contraction. In a Ca(2+)-free solution the extract strongly reduced the Ca(2+)-release induced by NA, but it did not affect the transient contraction caused by caffeine (CAF).
Article
The experimental research has shown that neither pinellia processed by ginger juice and alum nor pinellia boiled by ginger juice have any marked influence on the secretion of PGE2 in rat gastric juice, or on the activity of gastric proteinase in rats. Both the processed products of pinellia can obviously inhibit the gastric and intestinal motility in mice. Raw pinellia can strongly inhibit the secretion of PGE2, gastric acidity and gastric proteinase in rats, but acts not so heavily on their gastric secretion and appears rather harmful to the gastric mucosa in rats. Raw pinellia can also obviously accelerate the gastric and intestinal motility in rats.