Terminalia superba Engl. & Diels (Combretaceae), is a member of the genus Terminalia that comprises around 100 species distributed in tropical regions of the world. In Africa it is found along the coast of west and central Africa. It has different uses in traditional medicine such as antimalarial, anti-diabetic, anti-fungal, and anti-hypertensive in the areas where it is found. Most of these uses are yet to be scientifically investigated. The powdered stem bark of Terminalia superba was extracted by maceration using methanol. The crude extract was chromatographically fractionated using n-hexane, ethyl acetate, and methanol. Phytochemical analysis was conducted on the crude methanol extract, n-hexane, methanol, and ethyl acetate fractions using standard procedures. The LD50 of the crude methanol extract was determined using Lorke’s method. The phytochemical analysis showed the presence of alkaloids, saponins, glycosides, flavonoids, tannins, terpenoids, resins and reducing sugars. The crude extract, the methanol and ethyl acetate fractions were investigated for anti-ulcer activity using the ethanol, stress, and aspirin induction models. The parameters evaluated were ulcer index and percentage protective index. The data was statistically analysed. There was significant difference (p < 0.05) between the group treated with the crude extract and the control group. The microscopy showed the presence features characteristic of a bark. The anti-ulcer screening showed that the methanol extract of Terminalia superba possesses antiulcer property and its use in traditional medicine for treatment of stomach ulcer is justified.
TABLE OF CONTENTS
Title Page —————————————————————————- i
Acknowledgements —————————————————————— iv
Table of Contents——————————————————————– v
List of Tables————————————————————————- vii
List of Figures ———————————————————————– viii
Abstract —————————————————————————— ix
Chapter One————————————————————————————— 1
- Introduction————————————————————- 2
1.2 The Plant Terminalia superba——————————————- 4
1.2.1– Uses————————————————————– 9
1.4—- Ulcers——————————————————————– 17
——- 1.4.1 Pathophysiology of stomach ulcers——————————– 17
——- 1.4.2 Treatment of ulcers———————————————— 18
1.5 In vivo models used for evaluation of potential anti-gastro
———— duodenal ulcer agents—————————————————- 30
1.6—- Acute toxicity testing—————————————————- 33
Chapter Two: Materials and Methods
2.1—- Reagents and Equipments———————————————– 34
2.2—- Experimental procedure————————————————- 35
——- 2.2.1 Collection, Identification and Preparation———————— 35
——- 2.2.2 Microscopy——————————————————– 35
2.2 3 Extraction———————————————————- 35
——- 2.2.4 Preliminary phytochemical screening of powdered bark———- 36
——- 2.2.5 Acute toxicity test of crude extract——————————- 39
——- 2.2.6 Fractionation——————————————————- 40
2.2.7 EVALUATION OF ANTIULCER ACTIVITY———————————— 41
Chapter Three: Results
3.1—- Macroscopy————————————————————– 46
3.2—- Microscopy————————————————————– 48
3.3—- Phytochemical screening————————————————- 54
3.4—- Acute toxicity———————————————————— 58
3.5—- Antiulcer activity——————————————————– 59
Chapter Four: Discussion and Conclusion
4.1—- Discussion————————————————————— 64
4.2 — Conclusion————————————————————— 66
The fact that nature has bestowed us with abundant provision and resources for healing through herbs is not in doubt and cannot be over emphasized. Man has used plants as sources of food and medicine since creation. Many applications of plants as medicines are not scientifically evaluated but are based on reported success in healing/cure over time. The use of plants and plant parts for medicinal purposes can be described with different names, such as Traditional Medicine, Complimentary Alternative Medicine (CAM) but the contents are the same, natural substances.
Traditional medicine is the sum total of knowledge, skills and practices based on the theories, beliefs and experiences indigenous to different cultures that are used to maintain health, as well as to prevent, diagnose, improve or treat physical and mental illnesses…in some Asian and African countries, 80% of the population depend on traditional medicine for primary healthcare (WHO , 2008). Almost 65% of the world’s population has incorporated the value of plants as a methodology of medicinal agents into their primary modality of health care (Lanfranco, 1992).
Whether critics look at traditional medicine (complimentary alternative medicine) as folklore, trick, or manipulation and exploitation of the ignorant, the fact remains that there have been, and there are still herbs with undeniable therapeutic efficacy around us, e.g. Digitalis purpurea L. foxglove-source of the cardiac glycoside digitoxin, Papaver somniferum L. (opium poppy)-source of the drug morphine and codeine, Cinchona succirubra –source of the anti-malarial drug quinine , Artemisia annua, source of artemisinin, now one drug used as part of combination therapy (ACT) for treatment Plasmodium falciparum infection, Panax gingseng, Gingko biloba, Atropa belladonna-source of atropine, Erythroxylum coca–source of cocaine, Ephedra species–source of ephedrine, Pilocarpus jaborandi (Holmes) – source of pilocarpine Physostigma venenosum –source of physostigmine, Pacific yew tree, Taxus brevifolia source of paclitaxel (Taxol® )
What may be lacking is information on these herbs. In today’s world in which the trend is like “back to the roots” the need for evaluation of herbal materials to verify and authenticate claims of pharmacological properties and therapeutic values (claims) is a necessity. Only 0.4% of the total number of MEDLINE-listed articles for the period 1966 – 1996, refer to research concerning natural drugs and herbs (World Health Organization, 2005). Recent screening with plants has revealed many compounds like flavonoids, alkaloids, saponins, terpenoids, monoterpenoids (linalool), glycoproteins, polysaccharides, tannins, essential fatty acids, phenolic compounds and vitamins having pronounced antioxidant, antineoplastic, antiulcer, anti-inflammatory and immune stimulating potential (Dashputre and Naikwade, 2011).
Natural products serve in various capacities as drugs and starting materials for drugs. Review of all approved agents during the time frame of more than 25 years from 01/1981 to 06/2006 for all diseases worldwide and from 1950 (earliest so far identified) to 06/2006 for all approved antitumor drugs worldwide reveals the utility of natural products as sources of novel structures, but not necessarily the final drug entity (Newman and Cragg, 2007). Out of 255 drugs which are considered as basic and essential by the World Health Organization (WHO), 11% are obtained from plants and a number of synthetic drugs are also obtained from natural precursors (World Health Organization, 2005). The evaluation and assessment of phytochemical properties of a plant has standard and established methods which may vary slightly but have the same basic chemical principles. Phytochemical evaluation involves mainly the tests for secondary metabolites-alkaloids, glycosides, steroids, flavonoids, tannins, saponins, proteins, carbohydrates, fats and oils.
Phytochemical evaluation will be incomplete or ineffective if the various constituents present in an extraction liquor are not separated from one another. Among the separation techniques available and/or practiced, chromatography is the most common, easiest, and cheapest.
For further characterization advanced techniques like HPLC, Two-Dimensional Chromatography, Gel Electrophoresis Chromatography, GC/MS, LC/IR, LC/Nmr, 2D Nmr, Tandem MS etc. are employed. With developments in analytical chemistry and its principles- extraction techniques, separation techniques, purification techniques, isolation and characterization techniques, more plants have been deeply evaluated for pharmacological and therapeutic properties. Some have been re-evaluated for properties that have not been investigated before, with some positive and justifiable results.
A woman was interview on the Network Service of Radio Nigeria, 7’0 clock news, on 4th February 2013 (World Cancer Day 2013). She said that she was diagnosed of cancer and went to traditional health practitioners. Her case worsened and complicated and by the time she sought conventional healthcare the cancer had spread. Whatever she was given may be active against another ailment, or may have no pharmacological activity at all, or may even be carcinogenic. This is not to say that there are no natural anticancer drugs. This is one case in support for the call for investigation and standardization of herbal products in the country. There is the urgent need for scientific investigation of the ingredients of our traditional medicine system to determine their pharmacologically active constituents, hence, therapeutic applications, their efficacy or lack of it, as well as their safety. The aim of this research is to investigate the phytochemical properties and anti-ulcer activity of the methanol extract of the stem bark of Terminalia superb Engl. & Diels (Family Combretaceae). The result of this research will strengthen or discourage the use of Terminalia superba in the treatment of stomach ulcers and add to available knowledge data base on our plants.
Available literature was searched for current and relevant information on the plant Terminalia superb Engl. & Diels, recent researches on it, researches on antiulcer activity of other plants, techniques and principles of methods to be involved in the research (for example methods of ulcer induction, methods of extraction of medicinal actives from plants, etc.). This search in as much as it tried to be extensive and desired to be exhaustive, does claim to have assessed all materials available.
kingdom: Plantae Division: Mangnoliophyta Class: Mangnoliopsida Order: Myrtales Family: Combretaceae Genius : Terminalia Species : T. superba
Current name: Terminalia superba
Authority: Engl. & Diels
(English) : Black korina, limba, white afara
(French) : Frakè, limba
(German) : Limba
(Spanish) : Akom
(Swahili) : Mwalambe
(Trade name) : Korina, limba
(Yoruba) : Afa, afara : (www.worldagroforestrycentre.org, 2013)
Synonym(s) Terminalia altissima A. Chev (http://www.plantnames.unimelb.edu.au/new/Sorting/Terminalia.html, 2013
Origin and geographic distribution
Terminalia superba is a tree of about 30-50 m high. It is a member of the genus Terminalia that comprises around 100 species distributed in tropical regions of the worldwide (Victor et al, 2010). In Africa it is found in West and Central Africa, from Guinea Bissau east to DR Congo and south to Cabinda (Angola) (Kimpouni, 2009) In Nigeria it is Indigenous to Cross River State (Burkill., 1985)
Figure 1: T. superba Tree ( Magnification = 1.0)
MAIN LOCAL NAMES
Countries Local Names
Central African Rep. N’GANGA
Côte d’Ivoire FRAKE
Dem. Rep. of Congo LIMBA
Equatorial Guinea AKOM
Nigeria WHITE AFARA
Sierra Leone KOJAGEI
France NOYER DU MAYOMBE
Nigerian Vernacular Names
EDO ẹ̀ghọẹ̀n-nófūá, nófūó: white; referring to the flaking bark
EFIK àfia étò = white tree
IGALA uji-oko (H-Hansen)
IGBO èdò (auctt.) èdò ọ́chá = white edo (Amufu)ojiloko (Nkalagu) ojiroko (Owerri) èdò ọ́chá = white edo (Egbema) apaụpaụ tịín (Tiemo)
URHOBO unwon ron
YORUBA afaa , afara (www.ecocrop.fao.org/ecocrop)
Terminalia superba is a large tree, up to 50 m tall and 5 m in girth, bole cylindrical, long and straight with large, flat buttresses, 6 m above the soil surface; crown open, generally flattened, consisting of a few whorled branches, leaves simple, alternate, in tufts at the ends of the branches. Bark fairly smooth, greying, flaking off in small patches; slash yellow, bark surface smooth and grey in young trees, but shallowly grooved and with elongated, brownish grey scales, inner bark soft-fibrous, pale yellow (Kimpouni, 2009 ). Root system frequently fairly shallow, and as the tree ages the taproot disappears. Buttresses, from which descending roots arise at some distance from the trunk, then support the tree. Leaves simple, alternate, in tufts at the ends of the branches; deciduous, leaving pronounced scars on twigs when shed. Petiole 3-7 cm long, flattened above, with a pair of sub-opposite glands below the blade; lamina glabrous, obovate , 6-12 x 2.5-7 cm, with a short acuminate apex. Nerves 6-8 pairs; secondary reticulation inconspicuous. Inflorescence a 7-18-cm, laxly flowered spike, peduncle densely pubescent; flowers sessile, small, s greenish-white; calyx tube saucer shaped, with 5 short triangular lobes. Petals absent. Stamens usually twice the number of calyx lobes (usually 10), in 2 whorls, glabrous; filaments a little longer than calyx; intra-staminal disc annular, flattened, 0.3 mm thick; densely woolly pubescent. Fruit a small, transversely winged, sessile, golden-brown smooth nut, 1.5-2.5 x 4-7 cm (including the wings). Nut without the wing about 1.5 x 2 cm when mature, usually containing 1 seed. The generic name comes from the Latin ‘terminalis’ (ending), and refers to the habit of the leaves being crowded at the ends of the shoots (Burkill, 1985). Some of the above botanical descriptions are shown in Fig.3 to Fig. 4 below.
Terminalia superba is most common in moist semi-deciduous forest, but can also be found in evergreen forest. It occurs up to 1000 m altitude. It is most common in disturbed forest. It is found in regions with an annual rainfall of (1000–) 1400–3000 (–3500) mm and a dry season up to 4 months, and mean annual temperatures of 23–27°C. Terminalia superb prefers well-drained, fertile, alluvial soils with pH of about 6.0, but it tolerates a wide range of soil types, from sandy to clayey-loamy and lateritic. It does not tolerate prolonged water logging, but withstands occasional flooding (Richter and Dallwitz, 2000).
1. 2. 1 USES
The wood, usually traded as ‘limba’, ‘afara’, ‘ofram’ or ‘fraké’, is valued for interior joinery, door posts and panels, mouldings, furniture, office-fittings, crates, matches, and particularly for veneer and plywood. It is suitable for light construction, light flooring, ship building, interior trim, vehicle bodies, sporting goods, toys, novelties, musical instruments, food containers, vats, turnery, hardboard, particle board and pulpwood. It is used locally for temporary house construction, planks, roof shingles, canoes, paddles, coffins, boxes and domestic utensils. It is suitable for paper making, although the paper is of moderate quality. The wood is also used as firewood and for charcoal production. A yellow dye is present in the bark; it is used traditionally to dye fibres for matting and basketry. The bark is also used for dyeing textiles blackish. In Côte d’Ivoire Terminalia superba is occasionally used as a shade tree in cocoa and coffee plantations, and in DR Congo it is used as shade tree in coffee, cocoa and banana plantations (Kimpouni, 2009).
Bark decoctions and macerations are used in traditional medicine to treat wounds, sores, haemorrhoids, diarrhoea, dysentery, malaria, vomiting, gingivitis, bronchitis, aphthae, swellings and ovarian troubles, and as an expectorant and anodyne. The leaves serve as diuretic and roots as laxative (Richter and Dallwitz, 2009). Terminalia superba is generally used in traditional medicine to treat bacterial, fungal and viral infections. The bark of this plant is used to eradicate intestinal worms and treat gastrointestinal disorders such as enteritis, abdominal pain, diarrhoea, fever, headache, conjunctivitis. In the Southwest of Côte d’Ivoire the bark of T. superba, called “tree of malaria”, (Orewa et al 2009). In Cameroon it is locally used in the treatment of various ailments, including diabetes mellitus, gastroenteritis, female infertility and abdominal pains (Adjanohoun et al., 1996).
The uses of the different parts of the plant can be summarized as follows:
Medicines: anti-emetics; diarrhoea, dysentery; dropsy, swellings, oedema, gout; generally healing; oral treatments; pain-killers; pregnancy, anti-aborifacients, pulmonary troubles
Products: dyes, stains, inks, tattoos and mordants
Phytochemistry: tannins, astringents
Medicines: abortifacients, ecbolics
Medicines: laxatives, etc.
Products: fuel and lighting; household, domestic and personal items; pulp and paper
The phytochemical screening revealed the presence of polyterpens, polyphenols, flavonoids, tannins catechic, alkaloids and saponins (Kouakou et al., 2013).
Previous works revealed presence of compounds that have been characterised. Two compounds isolated following bio-assay guided fractionation namely 3,4′-di-O-methylellagic acid 3′-O-β-D-xylopyranoside and 4′-O-galloy-3,3′-di-O-methylellagic acid 4-O-β-D-xylopyranoside (Kuete et al., 2010). Methanol extract of the stem bark of Terminalia superba led to the isolation of four new triterpene glucosides ( which were characterized as 2α,3β-dihydroxyolean-12-en-28-oic acid 28-O–β–D-lucopyranoside , 2α,3β, 21β-trihydroxyolean-12-en-28-oic acid 28-O–β–D-glucopyranoside , 2α,3β, 29-trihydroxyolean-12-en-28-oic acid 28-O–β–D-glucopyranoside and 2α,3β,23,27-tetrahydroxyolean-12-en-28-oic acid 28-O–β–D-glucopyranoside (Turibio et al., 2009)
|1||Acute toxicity and anti-ulcerogenic activity of an aqueous extract from the stem bark of Terminalia superba Engl. and Diels (Combretaceae)||This study was aimed to evaluate the acute toxicity and gastric anti-ulcer activity of an aqueous extract of Terminalia superba||These results suggested that the preventive anti-ulcer activity of AETs may be due to a cytoprotective effect.||Kouakou et al., 2013|
|2||Phytochemical constituents and antidiarrheal effectsof the aqueous extract of Terminalia superba leaves on
|In this research,aqueous extract of T. superba leaves was investigated for the treatment of diarrhoea in wistar rats.||The data in the presentstudy indicate that the aqueous extract of T. superba leaves possessed antidiarrheal properties||Bamisaye et al.,2013|
|3||Antifungal activity of the aqueous and hydro-alcoholic extracts of T. superba Engl. on the in vitro growth of clinical isolates of pathogenic fungi||To locate the true potential anti-microbial in general, but especially anti-fungal extracts of T. superba on the in- vitro growth of C. albicans, A. fumigatus, C. neoformans and
|Aqueous extracts and hydro-alcoholic extract of T. superba have a dose-dependent fungicidal activity against clinical fungal isolates used||Ahon et al., 2011|
|4||The aqueous extract of Terminalia superba (Combretaceae) prevents glucose-induced hypertension in rats.||To Investigate the hypotensive and the antihypertensive effects of the aqueous extract of the stem bark of Terminalia superba.||The aqueous extract of the stem bark of T. superbaexhibits hypotensive and anti-hypertensive properties||Tom et al., 2011|
|5||Protective role of Terminalia superba Ethyl Aetate against Oxidative Stress Type 2 Diabetes||Investigation of the protective role of Terminalia superbaethyl acetate extract against streptozotocin-nicotinamide induced type 2 diabetes.
|The results suggest that, ethyl acetate extract of T. superba lower blood glucose and hyperlipidemia, prevent oxidative stress and reduce blood pressure in diabetic conditions.||Ngueguim et al., 2011|
|5||Antimycobacterial, antibacterial and antifungal activities of Terminalia superba (Combretaceae)||To evaluate the methanol extract from the stem bark of Terminalia superba (TSB), fractions (TSB1–7) for antimicrobial activity||Provide promising baseline information for the potential use of the crude extract fromT. superba, in the treatment of tuberculosis, bacterial and fungal infections||Kuete et al., 2010|
|7||Anti-diabetic activity of methanol/methylenechloride extract of Terminalia superba leaves on streptozotocin-induced diabetes in rats||The present study was undertaken to investigate the anti-hyperglycemia effect of the methanol/methylenechloride extract of Terminalia superba leaf||Terminalia superba leaf extract possess antidiabeticproperties||Padmashree et al., 2010|
|8||in vivo assessment of hypoglycaemic and antioxidant activities of aqueous extract of Terminalia superba in alloxan-diabetic rats||To investigate the possible actions of aqueous extract of the roots of Terminalia superba on glucose homeostasis and on MDA, SOD and catalase homolysate of diabetes rats||This extract demonstrates significant hypoglycaemic effect thus reduces the antioxidant parameters in alloxan-induced diabetes rats||Momo and Oben 2009|
|9||Antioxidant properties and α-amylase Inhibition of Terminalia superba, Albiziz sp., Cola odorata and Harunga madagascarensis used in the management of diabetes||The evaluations of the antioxidant potential and α-amylase inhibitory activity of these extracts were also carried out||For all the plants tested, at least one extract inhibited the activity of α-amylase. The most effective was the hydroethanolic extract of T. superba.||Momo et al., 2009|
|10||α-Glucosidase inhibitory constituents from stem bark of Terminalia superba (Combretaceae)||To identifyα-glucosidase inhibitory constituents from stem bark of Terminalia superba||All the isolated compounds were evaluated for their glycosidase inhibition activities. Gallic acid and methyl gallate showed significant α-glucosidase inhibition activity.||Wansi et al., 2007|
|11||Antimicrobial Pentacyclic Triterpenoids from Terminalia superba||Antibacterial bioassay-guided fractionation of the methanol extract of the stem bark of Terminalia superba||The isolation and characterization of four new triterpene glucosides||Tabopda et al., 2009|
|12||Analgesic Activities of the Stem Bark Extract of Terminalia superbaEngl and Diels (Combretacea)||To evaluate the analgesic activities of the extractobtained from this plant by in-vivo screening methods||n-BuOH fraction of T. superba stem bark could be beneficial in the management of pain||Dongmo et al., 2006|
Other members of the Terminalia species have also been shown to possess anti-ulcer roperties. T. chebula showed reduction in lesion index, total affected area and percentage of lesion in comparison with control groups in the aspirin, ethanol and cold restraint stress-induced ulcer models. The T. chebula extract increased mucus production in aspirin and ethanol-induced ulcer models and showed anti-secretory activity in pylorus ligated model leading to a reduction in the gastric juice volume, free acidity, total acidity, and significantly increased gastric pH (Sharma et al., 2011. Raju. et al 2009). In pyloric ligation induced ulcer model, oral administration of ethanolic extract of T. catappa in two different doses showed significant reduction in ulcer index, gastric volume, free acidity, total acidity and PH as compared to the control group. (Bharath et al., 2014), Terminalia pallida Brandis has also been demonstrated to possess anti-ulcer activity (Gupta et al., 2005).
1 .4 ULCERS
1.4.1 PATHOPHYSIOLOGY OF STOMACH ULCERS
Pathophysiology of ulcer is due to an imbalance between aggressive factors (acid, pepsin, H. pylori and NSAID’s) and local mucosal defensive factors (mucus bicarbonate, blood flow and prostaglandins). (Walker and Whittlesea, 2012). The underlying pathophysiology associated with H. pylori infection involves the production of cytotoxin associated gene A (cag A) proteins and vacuolating cytotoxins such as vac. A which activate the inflammatory cascade (Maury et al., 2012). Alcohol causes secretion of gastric juice and decrease mucosal resistance due to which protein content of gastric juice is significantly increased by ethanol (Maity et al., 2003). Ethanol readily penetrates the gastric mucosa due to its ability to solubilize the protective mucous and expose the mucosa to the proteolytic and hydrolytic actions of hydrochloric acid and pepsin, causing damage to the membrane. Moreover, alcohol stimulates acid secretion and reduces blood flow leading to micro vascular injuries, through disruption of the vascular endothelium and facilitating vascular permeability; it also increases activity of xanthine oxidase (Sener et al., 2004). NSAIDs inhibits the PG synthesis of gastric mucosa, PG gives cytoprotection. Enhancement of leukotriene synthesis, exhibits damage effect. Aspirin also inhibit gastric peroxidase and may increase mucosal H2O2 and hydroxyl ions level to cause oxidative mucosal damage (Datta et al., 2002). Stress can arise from prolonged anxiety, tension, and emotion, severe physical discomfort, haemorrhage and surgical shock, burns and trauma, thereby resulting in severe gastric ulceration. Recently research has shown that resistant cold stress causes severe haemorrhage ulcer through derangement of the mucosal antioxidant enzyme such as super oxide, dismutase and peroxides. This is the stress condition arising mainly from physiology discomfort and the mechanism of ulceration caused in this case should be different from ulcer caused due to other factors. The stress generate highly reactive OH– radicals that causes oxidative damage of the gastric mucosa (Udaya et al., 1999).
Recently oxidative free radicals have been implicated in mediating NSAID, H. Pylori, ethanol, and cold restraint stress induced gastric injury (Huilgol and Jamadar, 2013). Stress has also been found to decrease the quality and amount of mucus adhering to the gastric mucosa. It has been suggested that, in conditions of emotional tension, there is not only a greater destruction of mucus and decreased synthesis of its components, but also a quality change that affects the translation, acylation, and glycosylation of the ribosomal peptides (Peters and Richardson, 1983).
1.4.2 TREATMENT OF ULCERS
Treatment of endoscopically proven uncomplicated peptic ulcer disease has changed dramatically in recent years. Curing of H. pylori infection and discontinuation of NSAIDS are key elements for the successful management of peptic ulcer disease (Maury et al., 2012)
Antiulcer agents can be grouped into the following pharmacological classes;
Histamin H2-Receptor Antagonists e.g. cimtetidine, ranitidine, famotidine, nizatidine.
Proton Pump Inhibitors e g. Omeprazole, Lansoprazole, Rabeprazole, Pentoprazole
Cytopretective Agents e.g. Sucralfate, Bismuth chelate
Prostaglandine analogoues e.g. Misoprostol
Antacids e.g. Magnesium trisilicate, Aluminium hydroxide gel
Antibiotics e.g. Amoxycillin, Clarithromycin, Metronidaziole
Muscarinic receptor Blockers e.g. Pirezepine, and Telenzepine
These drugs are broadly classified into two, those that decrease or counter acid pepsin secretion and those that afford cytoprotection by virtue of their effects on mucosal defensive factors. These drugs act by different mechanisms. Most of the commonly used drugs such as H2-blockers (ranitidine, famotidine etc.), M1-blockers (pirenzepine, telenzepine etc), proton pump inhibitors (omeprazole, lansaprazole etc), decrease secretion of acid while, drugs like sucralfate and carbenoxolone promote mucosal defence. It is now assumed that these drugs ultimately balance the aggressive factors (acid, pepsin, H. pylori, bile salts) and defensive factors (mucin secretion, cellular mucus, bicarbonate secretion, mucosal blood flow and cell turnover). (Goel and Bhattacharya, 2002). The standard first-line therapy is a one week “triple therapy” consisting of proton pump inhibitors such as omeprazole and the antibiotics clarithromycin and amoxicillin. In Helicobacter Pylori Infection a typical regime is lansoprazole 30 mg + amoxicillin 1 g + clarithromycin 500 mg PO q12hr for 10-14 days. Dual therapy (clarithromycin-resistant): lansoprazole 30 mg + amoxicillin 1 g PO q8hr for 14 days. Penicillin allergy: lansoprazole 30 mg + clarithromycin 500 mg + metronidazole 500 mg q12hr for 10-14 days (emedicine.medscape.com, 2014).
REVIEW OF PLANT-DERIVED ANTI-ULCER AGENTS
Recent screening of plants has revealed many compounds like flavonoids, alkaloids, saponins, terpenoids, monoterpenoids (linalool), glycoproteins, polysaccharides, tannins, essential fatty acids, phenolic compounds with antiulcer properties (Neetesh et al., 2010).
Fresh cabbage juice is an excellent ulcer treatment. It produces an amino acid that increases blood flow to the lining of the stomach. Honey has been used for hundreds of years as a topical preparation to promote the healing of wounds. When ingested, it heals and strengthens the stomach lining and kills harmful bacteria. Unripe plantains promote strong stomach linings by producing a mucoid substance that coats the stomach lining, giving it protection against acids. Bananas offer protection in the same manner. Eating a diet that is fibre-rich is an added ulcer protection. ((African traditional herbal clinic, 2013) Fruits, vegetables, legumes and whole grains produce substance, which help to protect the stomach lining (Borrelli and Izzo, 2000). Among herbal drugs, liquorice, aloe gel and capsicum (chilli) have been used extensively and their clinical efficacy documented. Also, ethno-medical systems employ several plant extracts for the treatment of peptic ulcer. (African traditional herbal clinic, 2013)
Botanical compounds with anti-ulcer activity include flavonoids (i.e. quercetin, naringin, silymarin, anthocyanosides, sophoradin derivatives), saponins (i.e. from Panax japonicus and Kochia scoparia), tannins (i.e. from Linderae umbellatae), gums and mucilages (i.e. gum guar and myrrh). (Borrelli and Izzo, 2000).
TABLE 2: REVIEW OF SOME RECENT ANTI-ULCER RESEARCHES INVOLVING OTHER PLANTS
|Plant||Plant part||Extract||Ulcer Model||Reference|
|Cayratia trifolia L. (MECT) (Vitaceae)||Leaves||petroleum ether and hydro-alcohol (30:70)||Pylorus ligation and ethanol||Gupta et al.,2012|
|Emblica officinalis Gaertn., syn: Phyllanthus emblica (Euphorbiaceae),
|Fruit||Ethanol||Pylorus ligation, indomethacin, hypothermic restraint stress and necrotizing agents (80% ethanol, 0.2 M NaOH and 25% NaCl).||Al-Rehaily et al., 2002
|Nigella sativa LinnFamily: Ranunculaceae||Seed||Alcoholic||Pylor ligation and aspirin||Rajkapoor et al.,2002|
|Abutilon indicum L. (Family: Malvaceae),||Leaves||ethanolic extract||Pylorus ligatIion and ethanol||Dashputre et al.,2011|
|Capsicum frutescenes||Fruit||ethanolic||aspirin||Dass , et al.,2008|
|Mimosa pudica , (Fabaceae),||leaves||Methanolic, chloroform and diethel ether extracts||Aspirin, Alcohol and pyloric ligation model||Vinothapooshan and K Sundar 2011|
|Aegle marmelos||Fruit seed||Methanolic and aqueous||Indomethacin induced ulceration, stressed induced ulceration and pylorus ligation||Ganesh et al, 2011
|Picrasma quassioides (D. Don) Bennettfamily Simaroubaceae||Whole plant||Aqueous Extract||Aspirin-pylorus ligation, HCl-ethanol, water immersion-stress|| Hwisa et al., 2013
|Garcinia kolaFamily: Guttifera.
|seeds,||Methanolic||Ethanol,||Ige et al, 2012|
|Entandrophragma utile||Bark||Aqueous||Aspirin, immobilization, cold-restraint, histamine-induced, pylorus ligation, necrotizing substances||John et al 2012|
|Cayratia trifolia||methanolic||pyloric ligated and ethanol||Jyoti , et al 2012|
|Tinospora cordifolia||wholeplant||Alcoholic extract,||Pyloric ligation, ibuprofen and cold restraint||Bairy et al.2001|
|Falcaria vulgarisFamily :Umbelliferae||leaves and stems||Ethanolic extract||Ethanol||Khazaei et al, 2006|
|Barleria prionitis LinnFamily Acanthaceae)||Leaves||Methanol||Ethanol and Indomethacin||Manjusha et al,2013|
|Morinda citrifolia Linn Rubiaceae,||Fruit||Ethyl acetate||Ethanol,A spirin and Pyloric ligation, Cysteamine HCl,||Muralidharan and Srikanth, 2009|
|Carpolobia lutea (polygalaceae) G. Don||leaf||Ethanol||Indomethacin, Ethanol, Reserpine in 0.5% Acetic acid, Stress, Serotonin and Diethylthiocarbamate||Nwidu and Nwafor, 2009|
|Leaves||Methanol||Indomethacin|| Ode, 2011
|Hibiscus cannabinusFamily: Malvaceae,
|Leaves||methanolic||Pylorus ligation and Indomethacin||Silambujanaki et al 2010
|Falcaria vulgarisFamily: Umbelliferae||leaves and stems||hydro alcoholic||ethanol (50%)||Khazaei, and Salehi 2006.|
|Aloe vera||Leaf gel||Etanolic extract||Indomethacin and Ethanol||Subramanian et al., 2007
|Bauhinia racemosa||fruit powder||aqueous extract||Paracetamol||Borikar et al 2009|
|“Parsley” Petroselinum crispum,||Aerial parts||Ethanolic||Pyloric ligation, hypothermic- restraint- stress,||Al-Howiriny et al, 2003|
|Aspilia africana C.D. Adams, (Compositae)||Leaf||Aqueous||Ehanol, indomethacin and aspirin||Ubaka et al., 2010|
|Croton zambesicus Muell Arg. (Euphorbiaceace) (syn C. amabilis Muell. Arg. C. gratissimus Burch)||leaf||ethanolic||indomethacin, ethanol and histamine||Okokon et al, 2011.|
|Boswellia serrata (Family Bursera-ceae)||bark||Ppetroleum ether (250mg/kg) and aqueous extracts||aspirin||Zeeyauddin , 2011|
|Moringa oleifera Lam (Moringaceae)||leaves and fruits||acetone extractand methanol extract||Ethanol, Cold restraint stress, indomethacin, Pylorus ligation,||Devaraj et al.., 2007|
|Momordica charantia L.-(cucurbitaceae)||Fruits||olive oil extract||indomethacin||DENG‹Z and Nesrin ,2005|
|Barleria prionitis L. Family Acanthaceae||Leaves||methanolic||ethanol and indomethacin||Manjusha et al, 2013|
|Kigelia africana, Nauclea latifolia and Staudtia stipitata||Leaves||Ethanolic extracts||aspirin||Orole et al., 2013.|
|Ginger (Zingiber officinale)||Ginger powder||Aqueous||aspirin||Wang et al. 2011|
|Etandrophagma utile||fresh bark||aqueous||Ethanol or histamine||John et al 2012|
|Aegle marmelos (AM), family: Rutaceae||fruits||aqueous||Aspirin||Das and Roy 2012|
Researches have been done on plants with antiulcer effect, some such researches are reported Table 3-4. Some even extending to identification of chemical groups responsible for activity, table 6 below,
TABLE 3: SOME PLANTS CONTAINING TANNINS WITH ANTI-ULCER ACTIVITY
|Botanical name||Part plant||Ulcer model||Reference|
|Calliandra portoticensis||Leaves||Stress, pylorus ligated, E. coli||Aguwa and Lawal 1988|
|Entandrophragma utile||Bark||Ethanol||John and Onabanjo,1990|
|Linderae umbellatae||Stem||Stress||Ezaki et al.,1985|
|Mallotus japonicas||Bark||(Clinical study)||Saijo et al., 1989|
|Rhigiocarya racemifera||Leaves||Indomethacin, reserpine, serotonin||Aguwa, 1985,|
|Veronica officinalis||Aerial parts||Indomethacin, reserpine||Scarlat et al 1985|
TABLE 4: SOME PLANTS CONTAINING FLAVONOIDS WITH ANTI-ULCER ACTIVITY
|Anthocyanosides||Pylorus-ligated, Reserpine, Phenylbutazone||Magistretti et al 1998|
|Catechin||Stress||Lorenz et al., 1975|
|Genistin||Phenylbutazone, Serotinine, Pylorus-ligated,Stress, Reserpin||Rainova et al., 1988|
|Hypolaetin-8-glucoside||Stress, Ethanol, Acetylsalicylic acid||Alcaraza and Hoult, 1985|
|Kaempferol||Ethanol||Izzo et al., 1994|
|Leucocyanidin||Aspirin||Lewis et al., 1999|
|Luteolin-7-glycoside||Pylorus-ligated, Stress, Reserpine, Phenylbutazone, Serotinin||Rainova et al., 1988|
|5-Methoxyflavone||Indomethacin||Blank et al., 1997|
|Myricetin3-0-D-Galactoside||Stress, Pylorous-ligated, Ethanol||Reyes et al., 1996|
|Naringin||Ethanol, Stress, Pylorous ligation||Martin et al 1993|
|Quercertin||Stress, Ethanol, Reserpin||Izzo et a.,l 1994|
|Rutin||Stress||Izzo et al., 1994|
|Ternatin||Ethanol, Indomethacin, Stress||Rao et al., 1997|
|Vexibinol||HCL, Ethanol||Yamahara et al 1990|
TABLE 5: SOME PLANTS CONTAINING SAPONINS WITH ANTI-ULCER ACTIVITY
|Botanical Name||Part Plant||Ulcer Model||Reference|
|Calendula officinalis||Rhizome||Caffeine-arsenic, butadiene,pylorus-ligated||Iatsyno et al., 1978|
|Calliandra portoticensis||Leaves||Stress, pylorus ligated, E. coli||Aguwa and Lawal 1988|
|Kochia scoparia||Fruit||Ethanol, indomethacin||Mastuda et al., 1998|
|Panax binnatifidus||Rhizome||Psychological stress||Nguyen et al., 1996;|
|Panax japonicus||Rhizome||Stress, HCL||Yamahara et al., 1987|
|Pyrenacantha stauditii||Leaves||Indomethacin, serotonin, stress||Aguwa and Okunji 1986|
|Rhigiocarya racemifera||Leaves||Indomethacin, reserpine, serotonin||Aguwa, 1985|
|Spartium junceum||Flowers||Ethanol||Yesilada and Takaishi, 1999|
|Veronica officinalis||Aerial parts||Indomethacin, reserpine||Scarlat et a l, 1985|
TABLE 6: SOME ACTIVE CONSTITUENTS ISOLATED FROM PLANT (GOEL AND SAIRAMANTI, 2002)
|Plants and plant part||Active Constituents||Models|
|Tectona grandis Linn (Trunk bark and wood chips||Lapachol||IS-ASP-induced GU in rats and HIST- induced DU in rats and GP repectively|
|Rhamnus procumbens (Whole plant)||Kaempferol||PL-, ethanol, IS- and CRS- induced GU in rats and HIST- induced GU and DU in GP.|
|Rhamnus triquerta Wall (Whole plant)||Emodin||RS-, PL- and IS- induced GU in rats|
|Datura fastuosa (Leaves)||Withafstuosin E||CRS-, PL- and ASP-induced GU in rats|
|Bergenin/norbergenin||PL- and ASP- induced GU in rats and CRS- induced GU in rats and GP.|
|Azadirachta indica||Nimbidin||ASP-, prednisolone-, indomethacin-, serotonin stress- and acetic acid induced GU in rats. HIST- induced DU in GP. CYS- induced DU in rats|
|Ocimum basilum||Fixed oil||ASP-, indomethacin-,ethanol, HIST-,reserpine-, Serotonin-, PL- and stress-inducedGU in rats|
|Bacopa monniera (Whole plant)||Standardized extract of bacoside A (35%)||CRS-, ethanol, ASP- and PL- induced GU in rats|
ASP-aspirin; ce-chloroform; CRS-cold restraint stress; CYS-cysteamine; DU-duodenal ulcer; GP-guinea pig; GU-gastric ulcer; HIST-histamine; IS-immobilization stress; PL-pylorus ligation; RS-restraint stress;
1.5 IN VIVO MODELS USED FOR EVALUATION OF POTENTIAL ANTI-GASTRO DUODENAL ULCER ACTIVITY
Animal models represent an attempt to imitate the pathologies associated with human disease states in a preclinical setting. In using animal models, it is therefore important to create a test system that allows the basic mechanism of pathology to be systemically manipulated so as to obtain a better understanding of its biological basis. An important issue in this regard is to construct validity-the degree to which the model corresponds to the clinical state in humans. So, in general, experimentally induced gastric and duodenal ulcers should resemble the appearance, complications, development, and mode of healing to humans.
The rat stomach shows an obvious division into two parts: the upper non-secretory portion rumen and the lower glandular secretory portion which is analogous to the body of the stomach in man both anatomically and functionally. The rat being omnivorous resembles man nutritionally (Lahiri and Plit, 2012). Peptic ulcers can be induced by physiological, pharmacological or surgical manipulations in several animal species. However, most experiments in peptic ulcer studies are carried out in rodents. For preventive models, it is advisable to compare the potential drug or test material with cyto-protectant reference drugs such as misoprostol and sucralfate that are known to prevent peptic ulcers. The case of healing, or curative studies, the use of histamine receptor antagonists such as cimetidine or ranitidine, and proton-pump inhibitors such as omeprazole, is recommended as reference drugs (Adinortey et al., 2013).
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