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ABSTRACT

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

Certification————————————————————————– ii

Dedication—————————————————————————- iii

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

1.3—- Some previous researches on T. superba Engl. & Diels—————– 13

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

References—————————————————————————- 67

Appendix—————————————————————————– 80

 

 

CHAPTER ONE

1.1:  Introduction

 

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 gingsengGingko bilobaAtropa 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.

1.2 THE PLANT TERMINALIA SUPERB ENGL. DIELS

Taxonomy:

kingdom:             Plantae                                                                                                           Division:              Mangnoliophyta                                                                                                 Class:                   Mangnoliopsida                                                                                                      Order:                  Myrtales                                                                                                               Family:                Combretaceae                                                                                                Genius :              Terminalia                                                                                                    Species :              T. superba

Current name:             Terminalia superba

Authority:           Engl. & Diels

Common names
(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

Benin                                       AZINII

Cameroon                                AKOM

Central African Rep.               N’GANGA

Congo                                     LIMBA

Côte d’Ivoire                          FRAKE

Dem. Rep. of Congo               LIMBA

Equatorial Guinea                   AKOM

Ghana                                      OFRAM

Nigeria                                               AFARA

Nigeria                                               WHITE AFARA

Sierra Leone                            KOJAGEI

France                                     FRAKE

France                                     LIMBO

France                                     NOYER DU MAYOMBE

USA                                        KORINA

(www.ecochoice.co.uk/pdf, 2014)

 

 

 

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)

ISEKIRI         egonni

NUPE             eji

URHOBO       unwon ron

YORUBA       afaa , afara  (www.ecocrop.fao.org/ecocrop)

 

Botanical Description

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.

Ecology
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

GENERAL 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).

ETHNO-MEDICINAL USES

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:

Bark

Medicines: anti-emetics; diarrhoea, dysentery; dropsy, swellings, oedema, gout; generally healing; oral treatments; pain-killers; pregnancy, anti-aborifacients, pulmonary troubles

Phytochemistry: alkaloids

Products: dyes, stains, inks, tattoos and mordants

Root bark

Phytochemistry: tannins, astringents

Leaf

Medicines: abortifacients, ecbolics

Root

Medicines: laxatives, etc.

Phytochemistry: resins

Wood

Products: fuel and lighting; household, domestic and personal items; pulp and paper

(www.plants.jstor.org, 2013).

PHYTOCHEMISTRY

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-OβD-lucopyranoside , 2α,3β, 21β-trihydroxyolean-12-en-28-oic acid 28-OβD-glucopyranoside , 2α,3β, 29-trihydroxyolean-12-en-28-oic acid 28-OβD-glucopyranoside  and 2α,3β,23,27-tetrahydroxyolean-12-en-28-oic acid 28-OβD-glucopyranoside (Turibio et al., 2009)

 

 

Table 1: Some previous researches on T. superba 

 

 

 

 

 

 

 

 

Title Aim Result Author
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

wistar rats

 

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

T. mentagrophytes

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).

Natural Remedies

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 a2012
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 
Cassia singueana 

 

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

FLAVONOID ULCER MODEL REFERENCE
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
Silymarin Ethanol Alarcon  1992
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
 Flueggeamicrocarpa

(Leaves and

roots)

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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