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Monograph of Brindelia ferruginea Benth.

Overview

Over the last two decades, while the health of the advanced nations has tremendously improved, many poor nations, particularly those in Africa and Asia, have experienced health decline. In addition to HIV/AIDS and the perennial problems of infectious diseases (e.g. malaria, helminthiasis and cholera), many African countries are also witnessing a huge rise in conditions such as diabetes, hypertension and cancer.

A recent report in one of the leading newspapers in Ghana highlighted the growing problem of diabetes in the country with doctors expressing grave concern about the rate of increase in diabetic cases. The report noted that apart from genetic predisposition and environmental issues, the lifestyle of Ghanaians was the major cause of the upsurge. A consultant of the hospital specifically noted the eating habits (a taste for refined sugary foods instead of fruits and vegetables), lifestyle (sedentary jobs with less exercising) and cultural practices especially where obesity was cherished and considered as a sign of affluence (www.graphicghana.info/article.asp?artid=4764) as the predisposing factors.

It is clear from this report that unless research efforts are directed towards finding cost effective solutions to such debilitating disorders, there would be long term repercussions which will impact on the economies of the rich nations. Part of this solution lies in the arsenal of medicinal plants that abound on the continent. This paper therefore highlights the therapeutic potential of one such plant belonging to the genus Bridelia that can be used in the fight against diabetes in particular.

The genus Bridelia consists of about 60 species including B. atroviridis, B. cathartica, B. ferruginea, B. micrantha, B. ovata, B. siamensis, B. tomentosa and B. tulasneama, all of which are native to Africa, Asia and Australia (Rashid 2000). Of these B. ferruginea and B. micrantha appear to have been the most studied. B. ferruginea Benth; syn bridelia leaf, belongs to the family Euphorbiaceae. Among its many vernacular names are opam fufuo, baree (Twi); flatsho (Ga-Dangme); ekpazenra (Nzema); and kirni (Hausa).

Description

B. ferruginea (Euphorbiaceae) is a subtropical medicinal plant widely used in traditional African medicine for the treatment of conditions such as rheumatic pains, headaches, gastrointestinal and urogenital disorders (Ayensu 1978, Addae-Mensah 1992). Such is the esteem in which the herb is held that the Hausas of the West African subregion believe that prophylactic use of the root decoction can prevent syphilis.

It has also been reported an application of the expressed bark is an effective antidote for the wound inflicted by arrow poison. Such wounds are treated by applying the chewed bark to the affected area followed by sucking (Ayensu 1978). Its diuretic action has also been found helpful in the treatment of gonorrhea (Addae-Mensah 1992).

B. ferruginea is a small non laticiferous scaly tree or shrub that grows to about 4 metres high. The plant often bears spines and may be slash crimson coloured. The leaves may be small to medium sized, simple, alternate, spiral or distichous, broadly elliptic and pubescent. They are also pinnately veined with entire margin and an acuminate or acute apex (GHP 1992).

Geographical distribution

B. ferruginea occurs commonly in the guinea savannah and coastal plains of Africa particularly Burkina Faso, Cote d'Ivoire, Ghana, Nigeria and Togo as well as Asia and Australia (GHP 1992, Addae-Mensah 1992).

Chemistry

The plant contains triterpenoids, lignans (deoxypodophyllotoxin, 5'-demethoxy-[beta]-peltatin-5O-[beta]-D-glucopyranoside, [beta]-peltatin, [beta]-peltatin-5-O[beta]-D-glucopyranoside) (Figs 1 and 2) (Rashid 2000, Eromosele 1998); flavonoids (quercetin, quercetrin, rutin, myricitrin, myricetin-3-O-[beta]-glucoside, ferrugin) and a biflavanol (gallocatechin-[4-O-7]-epigallocatechin) (Fig 3) (Cimanga 2001, Addae-Mensah 1992); phenols and tannins (Irobi 1994, Oliver 1960, GHP 1992).

[FIGURE 1 OMITTED]

Parts used

Stem bark, root bark, leaf.

Traditional uses

B. ferruginea is widely used in traditional African medicine to treat a range of diseases (Cimanga 2001, Ayensu 1978). Extracts of the plant are used as an oral hypoglycemic (antidiabetic) (Oliver-Bever 1986) and antihypertensive. They are also used as a mouthwash and remedy for oral thrush in western Nigeria, whilst in northern Nigeria the bark is used for the treatment of infections generated by the wounds of poisoned arrow (Irobi 1994, Ayensu 1978), and for roundworm, cystitis and dysentery (Oliver-Bever 1960, Ayensu 1978).

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

The root decoction is diuretic (GHP 1992) and is used in the folk medicine of Cote d'Ivoire and Togo to treat gonorrhea. Besides its use as an antidote for arrow poison, the Togolese also use the plant to treat disorders of the skin, intestine and bladder (Addae-Mensah 1992). The Hausas of Ghana believe that the leaf decoction and the stem bark provide prophylactic immunity to syphilis (Addae-Mensah 1992).

A leaf decoction is used as an antidiabetic, purgative and vermifuge (Cimanga 1999, De Bruyne 1997), the extract being employed in the treatment of roundworms (Hutchings 1996). A stem bark decoction is used to treat diarrhea, dysentery, gastrointestinal (GIT) and gynaecological disorders (including sterility) and rheumatic pains (Ayensu 1978). According to Addae-Mensah (1992) an enema or tea of the pulped bark is an effective remedy for dysentery and diarrhoea, fevers, headaches, stiffness and rheumatic pains and as a local application for treating edemas. The plant has also been used in the local textile industry in Ghana as a source of dye for the traditional "adinkra" cloth (Irvine 1961, Addae-Mensah 1992, Addae-Mensah 1985).

Pharmacological studies

Among all its effects the plant's antidiabetic properties have received the most attention. At the Centre for Research into Plant Medicine (CRPM) in Ghana, B. ferruginea and Indigofera arrecta have reportedly been used to successfully treat maturity onset diabetes (Addae-Mensah 1992).

Antidiabetic activity

Researchers in Ghana and Nigeria have carried out numerous investigations into the hypoglycemic effects of B. ferruginea. In a small scale study reported by Iwu in 1983, the blood sugar levels of eight out of ten patients orally administered a daily decoction of the leaves of the plant were said to have been reduced from 230 mg% to 120 mg% and remained at this level for eight weeks. In addition aqueous extracts of the leaves were able to normalise the fasting blood glucose (FBS) levels of patients with maturity onset diabetes. After two weeks of treatment it was further noticed that the extracts helped in eliminating glycosuria even in cases of established ketosis (Iwu 1993).

Several animal studies have shown that the leaf extracts possess hypoglycemic effects but are less effective in alloxan induced diabetes. However when the extracts were administered an hour before intravenous administration of alloxan, the expected rise in blood sugar levels was inhibited (Githens 1949, Iwu 1986).

The efficacy of B. ferruginea as a potential antidiabetic is clearly illustrated by two cases reported by Addae-Mensah (1992) in an inaugural address delivered at the University of Ghana. In the first of these cases, a 49 year old female diabetic patient with an FBS level of 242 mg% who had been receiving a 44 unit dose of insulin intravenously for two years, was reported to have had her FBS level dramatically reduced to about 120 mg% after 12 weeks of treatment with a leaf decoction of B. ferruginea (Addae-Mensah 1992).

In the second case, a 45 year old woman presented with hypertension at the CRPM in Ghana but had diabetes diagnosed on routine examination with an FBS level of 370 mg%. On immediate administration of B. ferruginea therapy her FBS level reduced to 250 mg% after one week and continued to fall until it normalised after 11 weeks. Interestingly, although no medication was prescribed for her hypertension, her blood pressure fell from 180/90 to 140/90 during the treatment period (Addae-Mensah 1992, Ampofo 1977). It is worth noting that the two patients were subsequently followed for several months and no change in their FBS was noted.

In an attempt to uncover the compounds responsible for the plant's hypoglycemic effects, the flavonoids of B. ferruginea, including quercetin, quercetrin, rutin, myricitrin, myricetin-3-O-[beta]-glucoside, ferrugin and a biflavanol gallocatechin-[4-O-7]-epigallocatechin, have been extensively investigated. Onunkwo and his co-workers (1996) have shown that the flavonoid rutin has hypoglycemic activity with the ability to lower blood sugar levels of fasted rabbits (Addae-Mensah 1989). Studies carried out by Addae-Mensah's group showed that the crude extract as well as pure rutin (10 mg/kg os), lowered the fasting blood sugar of New Zealand white rabbits by up to 20% within 30 minutes of administration, and a maximum of 35% within 90 minutes, being maintained for up to 3 hours. The extracts were said to be more effective than the normal dose of glibenclamide (euglucon) (0.13 mg/kg) and compared well with a 10 mg/kg dose of the same drug (i.e. 100 times the normal human dose) but were less effective than insulin. However the rutin containing extract was able to inhibit artificially induced (5% dextrose) acute hyperglycemia, an effect reported to be statistically very similar to that of insulin (Addae-Mensah 1989).

A number of studies have shown that diets rich in bioflavonoids such as quercetrin can delay the development of cataracts in experimental rats by their ability to antagonise the activity of aldose reductase (Chaundry 1983, Addae-Mensah 1992).

Antimicrobial and antispasmodic effects

Studies carried out by various workers in the field have shown B. ferruginea to be antimicrobial, anti-HIV and antispasmodic (Cimanga 1999, Akinpelu 2000, Muanza 1995, Onoruvwe 2001). The biflavanol and the quinic acid derivatives have been shown to inhibit the complement system (Cimanga 1999, Stryer 1995).

Antiviral properties of flavonoids of B. ferruginea

The flavonoids quercetin, quercitrin and rutin have all been found to have antiviral effects against coxsackie, Herpes simplex, measles, parainfluenza and polio viruses. Methyl quercetin for instance, has been found to be 10 (7) times more effective in inhibiting the growth of poliovirus in tissue cultures than the other flavonoids, at very dilute concentrations. Consumption of quercetrin containing diet prior to rabies infection is said to offer prophylactic protection (Addae-Mensah 1992).

Antibacterial and antifungal effects

The ethyl acetate, hexane and methanol extracts of B. ferruginea leaves have all been shown to be effective against Bacillus subtilis, Escherichia coli, Pseudomonas frutescens, Staphylococcus aureus and Streptococcus faecalis (Talla 2002). The aqueous and ethanolic extracts of powdered B. ferruginea bark (5 mg/mL concentration) were found to exhibit antifungal activity against Candida albicans and antibacterial activity against E. coli, Klebsiella spp, Proteus vulgaris, P. mirabilis Staphylococcus aureus, S. epidermidis, Streptococcus lactis and S. pyogenes (Irobi 1994).

Anti-inflammatory and free radical scavenging effects

In vitro evaluation of the flavonoids of B. ferruginea showed that methylquercetin, myricetin, methylmyricetin (ferrugin) and quercetin 3-O-glucoside have xanthine oxidase inhibiting and superoxide scavenging activity at very low (micromolar) concentrations (Cimanga 2001). These actions coupled with the ability of bioflavonoids to cross link collagen fibres and reinforce connective tissue matrix probably explain the traditional use of the herb's stem bark for the treatment of rheumatic pains and gout (Gabor 1986, Cimanga 2001). Methylation of the hydroxyl functionality at C-3 and in rings A and B of the flavonoid nucleus (Fig 4) is reported to suppress the xanthine oxidase inhibitory activity.

[FIGURE 4 OMITTED]

B. ferruginea has also shown significant activity in both the acute and chronic phases of inflammation. When the aqueous extract of the stem bark was investigated for anti-inflammatory activity using carrageenan induced paw edema in rats and mice and the cotton pellet granuloma method, it was observed that the extract dose dependently (10-80 mg/kg po) caused a significant inhibition of the carrageenan induced rat paw edema, with an [ID.sub.50] value of 36 mg/kg, but the activity diminished in the mouse paw edema. In addition the extract suppressed the granulomatous tissue formation characteristic of chronic inflammation (Olajide 1999).

It has been found that quercetin and rutin as well as other flavonoids can inhibit platelet aggregation and contraction of isolated rat aorta, hence the purported antithrombotic and antiatherosclerotic properties (Beretz 1980). Evaluation of six African medicinal plants including Azadiracta indica, B. ferruginea, Commiphora molmol, Garcinia kola and Curcuma longa for their activity on experimental thrombosis in mice, demonstrated that the extracts of all these plants have significant antithrombotic effect (Olumayokun 1999).

Ofgba et al (1998) have also shown that the aqueous stem bark extract has the ability to elevate levels of serum alanine aminotransferase (GPT), aspartate aminotransferase (GOT), alkaline phosphatase (ALP), [K.sup.+], total bilirubin, creatinine, high density lipoprotein (HDL) cholesterol, urea nitrogen (BUN) (p<0.001) and decrease in serum Na+, Cl-, C[O.sub.22+] (p<0.01, 0.001) in rats. However the levels of serum triglyceride, uric acid, phosphate and total protein appeared to remain the same when compared with the control (Ofogba 1998).

A study carried out by Olajide, Okpako and Makinde (2003), which investigated the anti-inflammatory activity of the aqueous extract of the stem bark of B. ferruginea in models which are mediated by tumour necrosis factor alpha (TN[F.sub.[alpha]]), demonstrated that the effect was possibly mediated through the down regulation of TN[F.sub.[alpha]].

The effect of the plant extract on lipopolysaccharide (LPS) induced septic shock and vascular permeability on the dorsal part of mice skin, measured by the number of deaths and the serum levels of alanine and aspartate aminotransferases after intraperitoneal injection of LPS (1 [micro]gkg) into D-galactosamine-primed mice and the local accumulation of Evan's blue after subcutaneous injection of LPS respectively, showed that pre-treatment with about 10-80 mg/kg of the extract inhibited the septic shock syndrome in mice in a dose dependent manner, with an 80 mg/kg dose found to be as effective as 100 mg/kg of the drug pentoxifylline. The same dosage range of the extract (10-80 mg/kg) also reduced LPS-induced dye leakage in the skin of mice.

Neuromuscular activity

Onoruvwe et al (1994, 2001) have reported that the neuromuscular activity of the extracts from stem bark and leaves of B. ferruginea may account for the anthelmintic use of the extracts against roundworms. Investigation of the effects of the ethanolic leaf and stem bark extracts of the plant on purinergic neurotransmission in the rat bladder showed that the extract enhanced the exogenous adenosine 5-triphosphate-induced bladder contraction but depressed KCl-induced contractions in a dose dependent manner.

On the other hand the leaf extract appeared to block purinergic neurotransmission since it did not affect KCl-induced contractions (Onoruvwe 2001).

Cytotoxic and cytostatic activities

There have been no reported adverse effects of B. ferruginea, but a bioassay guided fractionation of an extract showed that the compounds 5'demethoxy-[beta]-peltatin-5-O-[beta]-D- glucopyranoside and [beta]-peltatin-5-[beta]-6-D-glucopyranoside have cytotoxic and cytostatic activity in the NCI's 60 cell antitumour screen (Rashid 2000). While this may be seen as a possible toxic effect particularly when used in excessive doses, the potential in inhibiting tumour growth cannot be underestimated.

Conclusion

The aforementioned studies reveal that B. ferruginea has potent phytopharmacological properties that can be exploited to help in the management of diabetes, a condition which appears to pose a serious health challenge to some impoverished African communities in particular. Obviously it cannot be guaranteed that the efficacy of a herb demonstrated in both in vitro and in vivo studies can be replicated in human clinical trials. However in the case of B. ferruginea the existing scientific evidence seems to suggest that it has most of the medicinal properties that the traditional healers of Africa have over centuries attributed to it.

What is therefore needed is a large scale properly conducted clinical trial to justify its adoption into the materia medica of the world.

References

Addae-Mensah I, Achenbach H. 1985. Terpenoids and flavonoids of Bridelia ferruginea. Phytochem 24;1817-19.

Addae-Mensah I, Munenge RW. 1989. Quercetin-3-neohesperidose (rutin) and other flavonoids as the active hypoglyeaemic agents in Bridelia ferruginea. Fitoterapia IX:4;359-62.

Addae-Mensah I. 1992. Towards a rational scientific basis for herbal medicine: A phytochemist's two-decade contribution. Accra: Ghana Universities Press.

Akinpelu DA, Olorunmola FO. 2000. Antimicrobial Activity of Bridelia ferruginea fruit. Fitoterapia 71 ;75-6.

Ampofo O. 1977. Some Clinical Observations on the treatment of selected diseases by herbal preparations. Paper presented at the International Conference on Medicinal Plant Research, University of Ife, Nigeria.

Asare GE. Diabetes cases on the rise. http://www.graphicghana.info/article.asp?artid=4764. Accessed 11 Mar 2005.

Ayensu ES. 1978. Medicinal Plants of West Africa. Michigan: Reference Publication Inc.

Beretz A, Stoclet JC, Anton R. 1980. Flavonoid inhibition of aggregation and secretion of washed human platelets: structure activity relationships. Planta Med 39:3;240.

Chaundry PS, Cambera J, Juliana HR, Varma SD. 1983. Inhibition of human lens aldose reductase by flavonoids, sulindac and indomethacin. Biochem Pharmacol 32; 1995-8.

Cimanga K, Ying L, de Bruyne T, Apers S, Pieters L, Totte J et al. 1999. Complement-inhibiting constituents of Bridelia ferruginea stem bark. Planta Med 65;213-17.

Cimanga K, Ying L, de Bruyne T, Apers S, Cos P, Hermans et al. 2001. Radical scavenging and xanthine oxidase inhibitory activity of phenolic compounds from Bridelia ferruginea stem bark. J Pharm & Pharmacol 53:5;757-61.

De Bruyne T, Cimanga K, Pieters L, Claeys M, Dommisse R, Vlietinck A. 1997. Gallocatechin(4'[right arrow]O[right arrow]7)-epigallocatechin, a new bioflavonoid isolated from Bridelia ferruginea. Nat Prod Lett 11;47-52.

Gabor M. 1986. Anti-inflammatory and anti-allergic properties of flavonoids. Prog Clin & Biol Res 213;471-80.

Ghana Herbal Pharmacopoeia (GHP). 1992. Bridelia leaf. Ghana: The Advent Press.

Githens TS. 1949. Drug Plants of Africa. Pennsylvania: University of Pennsylvania Press.

Hutchings A, Scott AH, Lewis G, Cunningham A. 1996. Zulu Medicinal Plants, An Inventory. Cape Town: University of Natal Press.

Irobi ON, Moo-Young M, Anderson WA, Daramola SO. 1994. Antimicrobial activity of bark extracts of Bridelia ferruginea (Euphorbiaceae). J Ethnopharmacol 43:3; 185-90.

Irvine FR. 1961. Woody Plants of Ghana. London: Oxford University Press.

Iwu MM. 1980. Antidiabetic Properties of Bridelia ferruginea leaves. Planta Med 39;247.

Iwu MM. 1983. The hypoglycaemic properties of Bridelia ferruginea. Fitoterapia 54;243-8.

Iwu MM. 1986. African Ethnomedicine. Enugu, Nigeria: USP Press.

Iwu MM. 1993. Handbook of African Medicinal Plants. Florida: CRC Press.

Muanza DN, Euler KL, Williams L, Newman DJ. 1985. Screening for anti-HIV activities of nine medicinal plants from Zaire. Int J Pharmacog 33;98-106.

Ofogba CJ, Agbomo FU, Abdul-Kareem FB, Abaelu AM, Alatishe K. 1998. Effect of Bridelia ferruginea stem bark on blood chemistry and histology of some organs in rats. Nig J Nat Prod & Med 2;26-8.

Olajide OA, Makinde JM, Awe SO. 1999. Effects of the aqueous extract of Bridelia ferruginea stem bark on carrageenan-induced oedema and granuloma tissue formation in rats and mice. J Ethnopharmacol 66:1;113-17.

Olajide OA, Okpako DT, Makinde JM. 2003. Anti-inflammatory properties of Bridelia ferruginea stem bark. Inhibition of lipopolysaccaride-induced septic shock and vascular permeability. J Ethnopharmacol 88:2-3;221-4.

Oliver-Bever B. 1960. Medicinal Plants of Nigeria. Nigerian College of Arts, Science and Technology.

Oliver-Bever B. 1986. Medicinal Plants in Tropical West Africa. Cambridge University Press.

Oliver-Bever B, Zahnd GR. 1979. Plants with oral hypoglycaemic action. J Crude Drug Res 17; 139-96.

Olumayokun AO. 1999. Investigation of the effects of selected medicinal plants on experimental thrombosis. Phytotherapy Res 13:3;231-2.

Onoruvwe O, Olayinka AO, Lot TY, Udoh FV. 1994. Effects of stem bark and leaf extracts of Bridelia ferruginea on skeletal muscle. Phytother Res 8;38-41.

Onoruvwe O, Olayinka AO, Lot TY, Udoh FV. 2001. Effects of stem bark and leaf extracts of Bridelia ferruginea on rat bladder smooth muscle. Fitoterapia 72:3;230-5.

Onunkwo GC, Akah PA, Udeala OK. 1996. Studies on Bridelia ferruginea (1). Stability and hypoglycaemic actions of the leaf extract tablets. Phytother Res 10;418-20.

Rashid MA, Gustafson KR, Cardellina JH, Boyd MR. 2000. A new podophyllotoxin derivative from Bridelia ferruginea. Nat Prod Lett 14:4;285-92.

Stryer L. 1995. Biochemistry. New York: WH Freeman & Co.

Talla E, Djamen D, Djoulde D, Tatsadjeu L, Tantoh D, Mbafor JT, Fomum ZT. 2002. Antimicrobial activity of Bridelia ferruginea leaves extracts. Fitoterapia 73:4;343-5.

Kofi Busia PhD, BSc (Hons) Chem; MRSC Cchem, BSc (Hons) Herb Med; PGCert HE

Senior Lecturer, Dept of Herbal Medicine, School of Health and Social Sciences

Middlesex University, Queensway, Enfield Middlesex, EN3 4SF UK

Tel: 0208 411 5277/07990 764 850

Fax: 0208 411 6774

Email: K.Busia@ mdx.ac.uk/Kofi_Busia@hotmail.com

Currently a Senior Lecturer in the Dept of Chemistry at the University of Ghana, Kofi was until August 2005, a Senior Lecturer in Pharmacognosy, Herbal Pharmacy and Herbal Pharmacology at Middlesex University in the UK. He is a UK trained medical herbalist, medical scientist and chartered chemist with rare expertise in plant medicine, plant chemistry, herbal pharmacology and pharmacy. An able and experienced teacher, researcher and practitioner, he has written extensively on topical subjects in herbal medicine and health generally. He aims to promote high quality herbal medicine in Ghana through his practice, lectures, seminars and health education classes.
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Title Annotation:Global dispensary
Author:Busia, Kofi
Publication:Australian Journal of Medical Herbalism
Geographic Code:8AUST
Date:Dec 22, 2006
Words:3456
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