Journal of Ethnopharmacology PDF
Journal of Ethnopharmacology PDF
Journal of Ethnopharmacology PDF
Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep
Review
art ic l e i nf o a b s t r a c t
Article history: Ethnopharmacological relevance: The prevalence of diabetes is on a steady increase worldwide and it is
Received 15 November 2013 now identified as one of the main threats to human health in the 21st century. In Nigeria, the use of
Received in revised form herbal medicine alone or alongside prescription drugs for its management is quite common. We hereby
26 May 2014
carry out a review of medicinal plants traditionally used for diabetes management in Nigeria. Based on
Accepted 26 May 2014
the available evidence on the species' pharmacology and safety, we highlight ways in which their
Available online 12 June 2014
therapeutic potential can be properly harnessed for possible integration into the country's healthcare
Keywords: system.
Diabetes Materials and methods: Ethnobotanical information was obtained from a literature search of electronic
Nigeria databases such as Google Scholar, Pubmed and Scopus up to 2013 for publications on medicinal plants
Ethnopharmacology
used in diabetes management, in which the place of use and/or sample collection was identified as
Herb–drug interactions
Nigeria. ‘Diabetes’ and ‘Nigeria’ were used as keywords for the primary searches; and then ‘Plant name –
WHO Traditional Medicine Strategy
accepted or synonyms’, ‘Constituents’, ‘Drug interaction’ and/or ‘Toxicity’ for the secondary searches.
Results: The hypoglycemic effect of over a hundred out of the 115 plants reviewed in this paper is backed
by preclinical experimental evidence, either in vivo or in vitro. One-third of the plants have been studied
for their mechanism of action, while isolation of the bioactive constituent(s) has been accomplished for
twenty three plants.
Some plants showed specific organ toxicity, mostly nephrotoxic or hepatotoxic, with direct effects on the
levels of some liver function enzymes. Twenty eight plants have been identified as in vitro modulators
of P-glycoprotein and/or one or more of the cytochrome P450 enzymes, while eleven plants altered the levels
of phase 2 metabolic enzymes, chiefly glutathione, with the potential to alter the pharmacokinetics of
co-administered drugs.
Conclusion: This review, therefore, provides a useful resource to enable a thorough assessment of the profile
of plants used in diabetes management so as to ensure a more rational use. By anticipating potential toxicities
or possible herb–drug interactions, significant risks which would otherwise represent a burden on the
country's healthcare system can be avoided.
& 2014 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/3.0/).
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
1.1. Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
1.2. Traditional herbal medicines in diabetes management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
2. Ethno-pharmacological data collection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
2.1. Method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
Abbreviations: AAN, aristolochic acid nephropathy; ADME, absorption, distribution, metabolism and excretion; CYT P450, cytochrome P450; DPP-IV, dipeptidyl peptidase
IV; GLP1, glucagon like peptide 1; GLUT4, glucose transporter 4; GSH, glutathione; GST, glutathione-S-transferase; IDDM, insulin dependent diabetes mellitus; NIDDM, non-
insulin dependent diabetes mellitus; P-GP, P-glycoprotein; PPARγ, peroxisome proliferator activated receptor gamma; STZ, streptozotocin; WHO, World Health Organization
n
Corresponding author. Tel.: þ 44 2077535871.
E-mail addresses: [email protected] (U.F. Ezuruike), [email protected] (J.M. Prieto).
1
Tel.: þ44 2077535841.
http://dx.doi.org/10.1016/j.jep.2014.05.055
0378-8741/& 2014 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/).
858 U.F. Ezuruike, J.M. Prieto / Journal of Ethnopharmacology 155 (2014) 857–924
1. Introduction 2009; Ogbera et al., 2007, 2009). In the presence of these, the
number of prescribed drugs increases to an average of four per day
1.1. Diabetes for each patient (Enwere et al., 2006). This need for the chronic
intake of a large number of drugs with their attendant side effects
Diabetes is a chronic metabolic disorder characterized by high in addition to their high costs which is often borne by the patients
blood glucose levels. This is either as a result of insufficient themselves is the identified reason for non-adherence to therapy
endogenous insulin production by the pancreatic beta cells (other- amongst diabetic patients. As a result, patients often have recourse
wise known as type-1 diabetes); or impaired insulin secretion to alternative forms of therapy such as herbal medicines (Yusuff
and/or action (type-2 diabetes). type-1 diabetes is an autoimmune et al., 2008).
disease characterized by T-cell mediated destruction of the pan-
creatic beta cells. In type-2 diabetes, there is a gradual develop- 1.2. Traditional herbal medicines in diabetes management
ment of insulin resistance and beta cell dysfunction, strongly
associated with obesity and a sedentary lifestyle (Zimmet et al., A number of reviews on medicinal plants used in the manage-
2001). Due to a higher incidence of the risk factors, the prevalence ment of diabetes in different parts of the world (Bailey and Day,
of diabetes is increasing worldwide, but more evidently in devel- 1989; Marles and Farnsworth, 1995), as well as those used
oping countries. Current estimates indicate a 69% increase in the specifically in certain regions, such as in West Africa (Bever,
number of adults that would be affected by the disease between 1980), Central America (Andrade-Cetto and Heinrich, 2005) and
2010 and 2030, compared to 20% for developed countries (Shaw Asia (Grover et al., 2002) exist. These reviews have highlighted the
et al., 2010). dependence of a large percentage of the world population on
Administration of exogenous insulin is the treatment for all traditional medicine for diabetes management. This is also corro-
type-1 diabetic patients and for some type-2 patients who do not borated by the WHO fact sheet (No. 134), which estimates that
achieve adequate blood glucose control with oral hypoglycemic about 80% of the population in African and Asian countries rely on
drugs. Current drugs used in diabetes management can be cate- traditional medicine for their primary healthcare (WHO, 2008).
gorized into three groups. Drugs in the first group increase It also recognizes traditional medicine as ‘an accessible, affordable
endogenous insulin availability. These include the sulphonylureas and culturally acceptable form of healthcare trusted by large
such as glibenclamide, the glinides, insulin analogs, glucagon-like numbers of people, which stands out as a way of coping with
peptide 1 (GLP-1) agonists and dipeptidyl peptidase-IV (DPP-IV) the relentless rise of chronic non-communicable diseases in the
inhibitors. The first two members of this group act on the midst of soaring health-care costs and nearly universal austerity’
sulfonylurea receptor in the pancreas to promote insulin secretion. (WHO, 2013).
GLP-1 agonists and DPP-IV inhibitors on the other hand act on the Ethnobotanical surveys of plants traditionally used in diabetes
ileal cells of the small intestine. The second group of drugs management in different parts of Nigeria have been carried out
enhance the sensitivity of insulin. This includes the thiazolidine- (Abo et al., 2008; Etuk and Mohammed, 2009; Gbolade, 2009;
diones, which are agonists of the peroxisome proliferator- Soladoye et al., 2012). These medicinal plants are used either alone
activated receptor gamma (PPARγ) and the biguanide metformin. as a primary therapeutic choice, or in conjunction with conven-
The third group comprises the α-glucosidase inhibitors such as tional medicines. On an average, approximately 50% of diabetic
acarbose, which reduce the digestion of polysaccharides and their patients visiting hospitals in urban cities like Lagos and Benin have
bioavailability (Chehade and Mooradian, 2000; Sheehan, 2003). used some forms of traditional medicine during the course of their
All the existing therapies however have limited efficacy, limited disease management (unpublished results of field work conducted
tolerability and/or significant mechanism based side effects by first author). Unfortunately, clinicians are either unaware of
(Moller 2001; Rotenstein et al., 2012). their patients' herb use or the identity of the herbal product being
Despite the existing pharmacotherapy, it is still difficult to taken. To complicate matters further, herbal practitioners are
attain adequate glycemic control amongst many diabetic patients usually unwilling to divulge the identity of the constituents of
due to the progressive decline in β-cell function (Wallace and their preparations to patients. Most patients are also not interested
Matthews, 2000). In Nigeria, polytherapy with two or more in finding this out as they consider herbal preparations to be
hypoglycemic agents to achieve better glucose control is common ‘safe’; thereby making it difficult to ascertain if the herb may have
practice (Yusuff et al., 2008). There is also a high incidence of a significant contributory role to the efficacy or failure of the
diabetic complications and hyperglycemic emergencies (Gill et al., treatment.
U.F. Ezuruike, J.M. Prieto / Journal of Ethnopharmacology 155 (2014) 857–924 859
In a systematic review of herbs and supplements clinically used from primary research papers (as indicated in Table 1). These
for glycemic control, Allium sativum, Aloe vera and Momordica are tabulated according to their accepted Latin Name (based on
charantia were the only identified plants used in Nigeria. http://www.plantlist.org). Synonyms are included for plants which
This inclusion was however based on clinical studies carried out were not identified with their accepted names in the primary
outside Nigeria (Yeh et al., 2003). This indicates the lack of research paper. For each of the identified plants, the family name,
information about the clinical use (or monitoring thereof) of common name(s), identified region of use in diabetes manage-
plants in diabetes management in Nigeria, despite widespread ment, experimental evidence of activity (where available), other
traditional use. medicinal uses, plant part(s) used, traditional method(s) of pre-
In line with the increasing importance of traditional medicine paration, identified active constituent(s), other relevant phyto-
in various healthcare systems around the world, the WHO Tradi- chemical constituents, as well as data on interaction and toxicity
tional Medicine Strategy has recently been updated. ‘The goals of studies are included [Table 1].
the strategy for the next decade (2014–2023) are to support Out of the 115 plants reviewed in this paper, only twelve of
Member States in (a) harnessing the potential contribution of them have no experimental evaluation of their blood sugar
traditional medicine to health, wellness and people-centered reducing effects, either in vivo or in vitro. In selecting studies to
health-care; and (b) promoting the safe and effective use of be included, priority was given to investigations carried out with
traditional medicine by regulating, researching and integrating samples collected in Nigeria. Certain publications were not
traditional medicine products, practitioners and practice into included if the study design of the experimental evidence
health systems where appropriate’ (WHO, 2013). was not appropriate enough for validating the effect of the plant,
Given that diabetes is now considered as one of the main such as the absence of a suitable control or the use of improper
threats to human health in the 21st century (Zimmet et al., 2001), doses. Two-thirds of the identified plants with experi-
there might be an even greater reliance by diabetic patients in mental evidence for their biological activity involved samples
Nigeria on herbal medicines used in its management. Unfortu- collected from Nigeria. For the remaining one-third, although the
nately, pharmacological and toxicological evidences validating the studies were not carried out with plant samples sourced from
safety and efficacy of these medicinal plants are not readily within Nigeria, these were still included, as the experimental
available. The objective of this paper is to collate as much as evidence could provide some information validating their use in
possible, available information about medicinal plants tradition- diabetes management, since they are widely used in Nigeria. The
ally used in diabetes management in Nigeria. In doing so, we aim ethnobotanical research carried out on Moringa oleifera provides a
to promote the rational use of these plants based on pharmaco- rationale for including information from studies carried out in
logical evidence for their therapeutic use and their toxic/interac- different countries, as some of these locally available plants could
tion profile. have been initially sourced from elsewhere (Popoola and Obembe,
2013).
In-vitro experimental studies as well as phytochemical studies
carried out on the plant species regardless of the source of
2. Ethno-pharmacological data collection the plant samples were also included. These together could
provide more insight into the biological activity(s) of the plant,
2.1. Method which would in turn help to promote a more rational use
of the plant in diabetes management, either in the presence or
Information about medicinal plants traditionally used in the absence of other co-morbidities. For completeness, reports
management of diabetes in Nigeria was obtained from published on the antioxidant properties of many of the identified plants
papers and texts on ethnobotanical studies, as well as those have been included as this has become a popular parameter
investigating the effect of plant(s) used in diabetes management, in assessing the beneficial effects of a plant in diabetes
in which the place of use and/or sample collection was identified management.
as Nigeria. A literature search of electronic databases such
as Google Scholar, Pubmed and Scopus up to 2013 was carried
out using ‘Diabetes’ and ‘Nigeria’ as keywords for the primary
searches; and then ‘Plant name – accepted or synonyms’, 3. Pharmacological evidence and its clinical implications
‘Constituents’, ‘Drug interaction’ and/or ‘Toxicity’ for the secondary
searches. 3.1. In vivo hypoglycemic activity
In order to highlight medicinal plants traditionally used in
diabetes management with the potential for integration into the Reducing blood sugar level is the classical clinical target in all
healthcare system, not all identified plants were included in this forms of diabetes. Thus, the in vivo sugar lowering effect of
paper. Only those with (1) more than one reference to its use in putative hypoglycemic plants is therefore a premise to infer their
diabetes management in Nigeria based on ethnobotanical studies potential clinical efficacy. In vivo validation also provides an
were retained; and/or (2) experimental evidence in one or more indication of the relative toxicity of the plant. Although most
diabetes experimental models validating its activity. This review is herbal medicines have a long history of traditional use, only their
therefore not exhaustive for all the plants used traditionally for experimental validation at known doses may give a clearer idea
diabetes management in Nigeria. about its safety and efficacy, in line with the objectives of the WHO
Traditional Medicine Strategy (WHO, 2013).
2.2. Results Ninety six out of the one hundred and fifteen plants here
reviewed have been evaluated in various in vivo animal models
Data for one hundred and fifteen plants traditionally used in of diabetes, mostly using alloxan and/or streptozotocin (STZ)-
diabetes management in Nigeria were obtained, either from previ- induced diabetic animals, which are the most frequently used
ously conducted ethnobotanical studies (Abo et al., 2008; Aiyeloja animal diabetes models worldwide (Fröde and Medeiros, 2008).
and Bello, 2006; Ajibesin et al., 2008; Etuk and Mohammed, 2009; These chemical agents are cytotoxic to the β-cells of the pancreatic
Gbolade, 2009; Igoli et al., 2005; Lawal et al., 2010; Ogbonnia and islets, generating a state of insulin deficiency (akin to type-1
Anyakora, 2009; Okoli et al., 2007; Olowokudejo et al., 2008); or diabetes) with subsequent hyperglycemia (Szkudelski, 2001). The
860
Table 1
Medicinal plants used in the management of diabetes in Nigeria.
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
1 Abelmoschus Malvaceae Okro/Okra; Ila (Y); SW, SS 100 and 200 mg/kg of the Infections, Immune- Fruit, Seed Decoction, β-1,3-D-glucans (Sheu and Water soluble fraction
esculentus (L.) Lady's fingers Okweje (I); seed and peel powder modulatory, Fevers, Maceration Lai, 2012); Hydroxy of the fruits decreased
Moench Kubewa (H) decreased blood glucose in Spasms, Gonorrhoea, food cinnamic derivatives, oral metformin
STZ induced diabetic rats Dysentry vegetable Oligomeric catechins, absorption in-vivo
(Sabitha et al., 2011)§; Isorhamnetin glycosides, (Khatun et al., 2011)
Antioxidant effects of the Quercetin, Myricetin and
aqueous extract of the leaves Kaempferol and their
(Tsumbu et al., 2011) glycosides (Arapitsas,
2008); Abelesculin (Kondo
and Yoshikawa, 2007);
Rhamnogalacturonans
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
861
862
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
863
864
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
glycosides, Catechin,
Chlorogenic acid,
Argentinine, kaempferol
and its glycosides
(Nawwar et al., 2012)
17 Annona Annonaceae Wild custard Uburu ocha SS, NC, 100 mg/kg of the aqueous Anti-parasitic, Anti- Stem-bark, Decoction Acetogenins (Carmen Stem bark extract
senegalensis Pers. apple (I), Abo (Y), NW, SW extract of a herbal bacterial, Tumours, Root, Leaves Zafra-Polo et al., 1998); inhibited P-gp mediated
Gwander-daji preparation ADD-199 Erectile dysfunction, Roemerine, Isocorydine, Rh-123 efflux (Ezuruike
(H), Ogoganto containing the roots of Wound-healing, Snake 8,8-Bisdihydrosiringenin, et al., 2012); Roemerine
(Es), Annona senegalesis and three bites, Convulsions, Syringaresinol (You et al., interacts with P-gp and
Ndaweewu other plants decreased Hemorrhage 1995); Kaurane enhances vinblastine
(F) plasma glucose and increased diterpenes, Quercetin, cytotoxicity (You et al.,
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
865
866
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
Piliostigma well as improved serum lipid the stem bark acid, Labd-13-en-8-0l-19- of the monolayer and
thonningii profile in alloxan-induced decreased blood oic acid (Baratta et al., the secretory transport
diabetic rats (Ojezele and glucose levels in 1999); Quercetin, of Cyclosporin A (CsA)
Abatan, 2011) alloxan-induced Quercitrin, C-methyl indicating possible
diabetic rats dose- quercetin ethers, C-methyl inhibition of P-gp
dependently kaempferol ethers, (Deferme et al., 2003)
(Asuzu and Piliostigmin (Ibewuike et
Nwaehujor, 2013) al., 1997); Kaurane
diterpenes (Martin et al.,
1997); Griffonilide,
Rhamnetin, Carotenoids
(Okwute et al., 1986)
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
867
868
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
34 Bryophyllum Crassulaceae Africa never Ewe abamoda SW 400 mg/kg of the aqueous Hypertension, Leaves, Juice extract Syringic acid, Caffeic acid, Risk of cardiac glycoside
pinnatum (Lam.) die, Life plant, (Y) extract of the fresh leaves Analgesic, Flower 4-hydroxy-3-methoxy poisoning due to the
Oken Resurrection produced hypoglycaemia in Inflammation, Wound cinnamic acid, 4-hydroxy bufadienolides
plant both normal and STZ- ulcers, Anti-parasitic, benzoic acid, Hydroxy Bryotoxin A, B, C
induced diabetic rats Insect bites, Anti-cancer, cinnamic acid, P-coumaric (McKenzie et al., 1987);
(Ojewole, 2005); Cough, Diarrhoea, acid, Protocatechuic acid, Significant decrease in
Hypoglycemic effect of Sedative, Diuretic, Anti- Phosphoenolpyruvate, serum ALT levels in rats
500 mg/kg aqueous extract of microbial, Convulsions Ferulic acid, Astragalin, after daily oral dosing of
the leaves in normal fasted Friedelin, Luteolin, 2 g/kg aqueous extract
glucose-loaded and STZ- Quercetin glycosides, of the leaves (Ozolua et
induced diabetic rats Epigallocatechin-3-O- al., 2010)
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
36 Capsicum annum Solanaceae Chilli, Bird Ata or Ata SW, SE Alpha glucosidase and α- Analgesic, Fruit Decoction Capsaicinoids
L., Syn: Capsicum pepper wewe (Y), amylase inhibitory activities Antimicrobial, (Schweiggert et al., 2006);
frutescens L. Ose (I), and antioxidant effects (Oboh Inflammation, Myricetin, Kaempferol,
Barkono (H), et al., 2011; Kwon et al., Hemorrhoids, Fevers, Apigenin, Luteolin,
Asin (Es) 2007); Incorporation of 2% of Dysentry, Malaria, Quercetin (Miean and
the fruit powder in a high fat Carminative, Stimulant Mohamed, 2001); CAY-1
diet given to STZ-induced (Stergiopoulou et al.,
diabetic rats increased serum 2008); Alpha tocopherol
insulin levels (Islam and (Ching and Mohamed,
Choi, 2008)§; 100 mg/l fruit 2001); Ortho hydroxyl
extracts possessed PPAR N-benzyl 16-Methyl 11,14-
alpha and gamma agonistic diene octadecamide, 9, 12-
869
870
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
871
872
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
arabinopyranosides of
vitexin and isovitexin
(Veitch and Grayer, 2011);
Bergamottin, Limettin,
Bergapten, 5-geranyloxy-
7-methoxycoumarin,
Isopimpinellin, 3-methyl-
1,2-cyclopentadione,
1-methoxy-cyclohexene,
Corylone, Umbelliferone,
5,8-dimethoxypsoralen,
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
873
874
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
Dihydrophilonotisflavone,
Catalposide, Obtusoside,
Picrosides, Quercitrin,
Coumarin, Cimifugin,
(Abu-Reidah et al., 2013)
48 Cola acuminata Malvaceae Kolanut Obi agada (Y), SW Antioxidant effects (Atawodi Stimulant, Appetite Nuts, Stem- Decoction, Procyanidin B1 and B2,
(P.Beauv.) Schott Orji (I) et al., 2007) 500 mg/kg of the suppressants, bark, Leaves Juice extract Catechin, Epicatechin,
and Endl. methanol extract of the stem Aphrodisiac, Respiratory Caffeine (Atawodi et al.,
bark decreased blood glucose infections, 2007); Theobromine
levels in alloxan induced Hypertension, Anti- (Niemenak et al., 2008);
diabetic rats after 21 days parasitic Chlorogenic, Quinnic and
(Adediwura et al., 2011) Tannic acids (Odebode,
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
875
Salicyaldehyde, Luteolin
Table 1 (continued )
876
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
55 Daniellia oliveri Leguminosae African balsam Iya (Y), Maje SE, NE 100, 200 and 400 mg/kg Analgesic, Root, Leaves, Maceration Daniellic acid, Oliveric acid
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
877
878
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
activity of glucose problems, Chewing extract of the stem Aromadendrene and its
metabolizing enzymes stick, Laxative, Ulcer, and leaves in hydrate, α-Humulene,
(Ugochukwu and Babady, Analgesic, Fevers glucose loaded rats δ-Cadinene, Germacrene,
2003) as well as the α- and γ-Eudesmol, (E)-
Hypoglycaemic effect of In vitro glucose Phytol, Methyl palmitate
100 mg/kg of the methanol stimulating effects (Edet et al., 2005); 3-O-[6-
extract in alloxan-induced in INS-1 cells led to deoxy-3-O-methyl-β-D-
diabetic mice (Ogundipe et the isolation of α- allopyranosyl-(1-4)-β-D-
al., 2003) and β-amyrin canaropyranosyl-17β-
Antioxidant effects (Fasakin cinnamate, lupenyl mardenin and 3-O-[6-
et al., 2011; Ugochukwu and cinnamate and deoxy-3-O-methyl-β-D-
Babady, 2002) lupenyl acetate as allopyranosyl-(1-4)-β-D-
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
879
880
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
Spirocurcasone, Ellagic
acid, Jatrophalactam,
Jatrogrossidione
derivatives, β-amyrin,
Jatrophalactone, Caffeoyl
aldehyde, Syringaldehyde,
Jatrophadiketone, Uracil,
β-sitosterol, Jatrophalone,
Taraxasterol, Stigmasterol,
Daucasterol, Pyrrolidine,
Curcamide, Tomentin,
Coumarin compounds
881
882
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
70 Lawsonia Lythraceae Henna plant, Laali (Y), Lelle SW Alpha glucosidase inhibitory Wound infection, Anti- Leaves Decoction Lawsone and gallic β-Sitosterol glucoside, Administration of
inermis L. Mehndi, (H) effects of the ethanol extract microbial, Anti- acid isolated from Gallic acid, Coumarins, henna leaf extract to
Egyptian's of the leaves (Prashanth et parasitic, Jaundice, the ethanol extract Xanthones, Lawsoniaside, mice for 21days
priest al., 2001)§ Increased activity Nervous disorder, of the aerial parts Lalioside, Luteolin resulted in increased
of in-vivo antioxidant Arthritis, Analgesic, inhibited the glucosides, 1,2-dihydroxy- activity of cytochrome
enzymes (Dasgupta et al., Ulcers, Diarrhea, Anti- formation of 4-glucosyloxy b5 reductase enzyme
2003)§ Daily administration pyretic, Hepato- glycated protein naphthalene (Takeda and and the phase
of graded doses (100– protective, Leucorrhoea, In vitro (Sultana et Fatope, 1988); Vomifoliol, 2 enzymes GST and DDT
800 mg/kg) of the ethanol Excessive ejaculation, al., 2009) Lawsonicin, Lawsonadeem (Dasgupta et al., 2003)
extract of the leaves for Emmenagog, Skin (Siddiqui et al., 2003); Topical application to
2 weeks decreased blood diseases, STDs, Isoplumbagin, Hexenol, skin lesions in G6PD
sugar levels in alloxan- Abortifacient, Sickle cell, Linalool, β-Ionone, α- and deficient patients
induced diabetic rats Tumours, Tuberculosis, γ-Terpineol, Terpinolene, resulted in hemolytic
(Inawati and Winarno, Splenomegaly, δ-3-Carene, Benzaldehyde, anemia (Kök et al.,
2008)§ In vitro antioxidant Menorrhagia Isocaryophyllene, Methyl 2004)
effects of isolated salicylate, Naphthalene,
constituents of the plant Eugenol, Germacrene D,
(Hsouna et al., 2011)§ Farnesene, Bisabolene, β-
Elemene, Isophytol, δ-
Cadinene, Cadalene,
Geranyl isobutyrate,
Methyl cinnamate
(Oyedeji et al., 2005);
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
Mannitol, Hennatannic
acid, Lawsone (2-hydroxy
1,4-naphtoquinone),
Behenic, Oleic, Linolenic,
Arachidic, Palmitic and
Stearic acids, Laxanthone I,
II and III, Apigenin
glycosides, Stigmasterol,
Acacetin, Cosmosiin, p-
Coumaric acid, Fraxetin,
Hennadiol, Scopoletin,
Esculetin, Apiin, Lupeol,
883
884
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
2005); 3β,7β-dihydroxyl-
cucurbita-5,23,25-trien-
19-al, Kaempferol-3-O-β-
D-glucopyranoside
(Odeleye et al., 2009)
75 Mondia whiteii Apocynaceae White ginger, Isirigun SW Aqueous extract of the roots Infertility, Erectile Stem, Root Infusion, Isovanillin, 2-hydroxy-4-
(Hook.f.) Skeels African ginger orAghuma did not show any inhibition dysfunction, Malaria, Decoction methoxy benzaldehyde
orGbolo- against pancreatic alpha Gonorrhea, Anti- and its -2-O-β-D-
gbolo (Y) amylase and lipase enzymes parasitic, Anti- glucopyranose-(1-6)-O-
(Etoundi et al., 2010)§ depressant, Anti- β-D-xylopyranoside
spasmodic, (Koorbanally et al., 2000);
Hemorrhoids, Propacin, 5-methoxy
Inflammation, Memory propacin,
885
hydroxyadoxoside, 6β,7β-
epoxy-8-epi-splendoside,
886
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
Borreriagenin, Deacetyl
asperuloside, Dehydro
methoxygaertneroside,
5,15-dimethyl morindol,
Alizarin-1-methyl ether,
Anthragallol-1,3-dimethyl
ether, Anthragallol-2-
methyl ether, 6-hydroxy-
anthragallol-1,3-dimethyl
ether, Morindone-5-
methyl ether,
Asuperlosidic acid,
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
rhamnopyranosyl)benzyl]
carbamate, Methyl N-4-
[(α-L-rhamnopyranosyl)
benzy] carbamate, O-[20 -
hydroxy-30 -2″-heptenyl
oxy)]-propyl undecanoate,
methyl p-
hydroxybenzoate,
Moringine, Moringinine
(Anwar et al., 2007)
79 Morus alba L. Moraceae White Alpha glucosidase inhibitory Anti-helminthic, Leaves, Fruit, Infusion, Morusin, Isomorusin, A sodium chloride
mulberry effects of the aqueous extract Laxative, Emollient, Bark Decoction, Compound A (Taro et al., extract of the leaves
887
diabetic rats and Antioxidant (Dineshkumar et Bismahane, 8,10-
888
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
82 Ocimum Lamiaceae Scent leaf, Nchonwu (I), SE, SS, 200 mg/kg aqueous extract of Diarrhoea, Malaria, Leaves Infusion, Oleanolic acid (Njoku et Aqueous and ethanol
gratissimum L. African basil, Efirin (Y), SWa, NW the leaves improved glucose Anti-microbial, Anti- Food al., 1997); Xanthomicrol, extract of the leaves
Mint Daidoya (H) tolerance in normal and parasitic, Anxiolytic, vegetable Cirsimaritin, Rutin, caused dose-dependent
neonatal STZ-induced Analgesic, Kaempferol 3-O- (400–3200 mg/kg)
diabetic rats (Oguanobi et al., Inflammation, Wound rutinoside, Luteolin 5-O- increase in AST and ALT
2012) In vitro antioxidant healing, Cold symptoms, and 7-O-glucosides, enzyme levels, markers
effects (Akinmoladun et al., Hemorrhoids, Insect Vicenin-2, Isothymusin, of hepatotoxicity
2010) (Awah and Verla 2010) repellent, Anti- Apigenin 7-O-glucoside, (Ajibade et al., 2012;
400 mg/kg methanol extract helminthic, Infant colic Vitexin, Isovitexin, Onaolapo and
of the leaves decreased blood Quercetin 3-O-glucoside Onaolapo, 2012)
glucose levels in normal and (Grayer et al., 2000);
alloxan-induced diabetic rats Thymol, Eugenol, Luteolin,
889
890
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
thiazole, Trimethyl
pyrazole, (Ouoba et al.,
2005); Ferulic acid,
Isoferuloyl alkanoyl
glycerol, Feruloyl
lignoceryl glycerol, Lupeol,
Epicatechin-3-O-gallate,
Epigallocatechin-3-O-
gallate, 4-O-methyl-epi-
gallocatechin,
Epigallocatechin (Tringali
et al., 2000)
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
Picralima nitida Mkpokiri or SW, SE, kg) of the methanol extract of Jaundice, Pneumonia, Stem-bark, chloroform extract Melinosime, Akuammine, produced hepato-toxic
(Stapf) T.Durand Otosu (I) NW, NC, the leaves in normal and AsthmaTrypanosomiasis Seeds, Root, of the seeds Picracine, Akuammidine, effects characterized by
and H.Durand SS alloxan-induced diabetic rats Fruit rind stimulated glucose Picra-phylline, necrotic damage
(Okonta and Aguwa, 2007) uptake in 3T3-L1 Akuammigine, congestion of hepatic
300 mg/kg hydro-ethanol adipocytes (Shittu Akuammicine (Oliver- blood vessels (Fakeye et
extract of the leaves et al., 2010) Bever, 1986); Alstonine, al., 2004) Methanol
decreased blood glucose Picranitidine, Picratidine, extract of the fruit rind
levels in STZ-induced Picraline, ψ-akuammigine administered daily for
diabetic mice and In vitro (Okunji et al., 2005); 10- 6 weeks elevated AST,
antioxidant effects (Teugwa deoxyakuammine, ALT and GSH levels in
et al., 2013b)§ Burnamine (Shittu et al., rats (Kouitcheu Mabeku
2010); Coumesan et al., 2008)
891
892
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
perbenzoates, Tetra-O-
benzoy-fructo furanoside
(Abreu et al., 2001);
Betulinic acid (Yinusa et
al., 2012)
90 Scoparia dulcis L. Plantaginaceae Sweet Roma-fada NC Administration of the Anti-infective, HIV, Leaves, Infusion, Scoparol (30 -O-methyl
broomweed (H), Aiya (I), aqueous extract of the leaves Abortifacient, Sickle cell, Whole plant Decoction luteolin), Scoparoside
Mesen- for 45 days produced a dose InflammationAnalgesic, (glycosyl scopanol),
mesen gogoro dependent (150–450 mg/kg) Anti-tumour, Bronchitis, Amellin (Oliver-Bever,
(Y)Ndiyang decrease in glucose levels Hypertension, Gastric 1986); Scoparic acid A, B
(Ef) after an OGTT; as well as a disorders, Sedative and C, Scopadulcic acid A
Bibimbelemo hypoglycaemic effect in and B (Hayashi et al., 1988)
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
methoxyxanthone),
2-hydroxy-1,7-dimethoxy
xanthone, 1,6-dihydroxy
xanthone, 6-methoxy
salicylic acid and its
methyl ester, β-D-(6-
sinapoyl)-
glucopyranoside, β-D-(3-
sinapoyl)-fructofuranosyl-
α-D-(6-sinapoyl)-gluco
pyranoside (Meli Lannang
893
894
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
3-O-β-D-glucopyranoside,
Luteolin, Chrysoeriol-7-O-
and Rhamnetin-3-O- (2″-
O-β-D-manno pyranosyl)-
β-D-allopyranoside, Aloe-
emodin and its 8-O-β-
glucoside, Chrysophanol,
Rhein, Physcion and its 1-
O-glucoside, Alquinone,
Isochrysophanol, Adenine,
1,3,8-trihydroxy-2-methyl
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
895
896
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
897
898
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
899
900
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
Imperatorin, Mangiferin,
Quercetin, Palmitic and
Linoleic acid triglycerides
(Morelli et al., 2006);
Syringic acid, Gluco-
syringic acid, Salicylic acid,
Protocatechuic acid and its
methyl ester, Caffeic acid,
Hexatriacontanoic acid,
Pentadecanoic acid,
Hexadecanoic acid, Maleic
acid, Heptadecanoic acid,
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
901
902
Table 1 (continued )
S/ Plant name Family Common Local Region of Experimental evidence for Other medicinal uses Plant part Traditional Identified active Other relevant Interaction/toxicity
no. name Nigerian use for its use in diabetes (s) used preparation constituent(s) phytoconstituents studies
name(s)* diabetes# management method identified in the plant
methoxy phenyl)-N-2-
[4-hydroxy
phenylethyl]-2-
propenamide, E-3-
(3,4-dihydroxyphenyl)-
N-2-[4-hydroxyphenyl-
ethyl]-2-propenamide,
Grossamide,
Demethylgrossamide,
Cannabisin B and D
(Lajide et al., 1995); 7α-
hydroxy trachyloban-
n
Bi-Bini, Ef-Efik, Es-Esan, F-Fulani, H-Hausa, I-Ibo, Ib-Ibibio, Id-Idoma, Ig-Igala, Ige-Igede, Ij-Ijaw, Nu-Nupe, Ti-Tiv, and Y-Yoruba.
#
NC ¼North central, NE¼ North east, NW ¼North west, SE ¼South east, SS ¼ South south, and SW ¼ South west.
§
Experimental evidence involving plant samples not collected from within Nigeria.
U.F. Ezuruike, J.M. Prieto / Journal of Ethnopharmacology 155 (2014) 857–924 903
other in vivo models used include spontaneous diabetic animal 3.2. In vitro pharmacological evidence
models obtained as a result of one or more genetic mutations such
as obese zucker fatty rats, db/db mice and KK-Ay mice; as well as It is recommended that in vitro experiments are carried out to
the use of high glucose or fructose-fed animals. This latter group ascertain the mechanism of action for the plant. Certain plants
simulate the development of diabetes from insulin resistance produce their hypoglycemic effects as a side effect of their in vivo
better as is more commonly found in patients with type-2 diabetes toxicity (Marles and Farnsworth, 1995). There is also the risk that
(Srinivasan and Ramarao, 2007). the hypoglycemic effect is being mediated – at least in part –
Although most plants were only evaluated experimentally in a through an unwanted physical mechanism, rather than a physio-
type-1 diabetes model, some of these have been shown to be logical one, such as was observed with Gymnema sylvestre (Retz.)
effective hypoglycemic agents in type-2 diabetes patients, such as R. Br. Ex Sm (Persaud et al., 1999). This immediately eliminates the
extracts of Bridelia ferruginea Benth. Daily administration of 15 mg potential use of such a plant as a therapeutic hypoglycemic
of the leaves as an infusion to type-2 diabetic patients previously agent. In addition, due to the ethical considerations surrounding
on insulin injections for eight weeks resulted in a significant animal use (Festing and Wilkinson, 2007), it is advised that
decrease in their blood sugar levels (Iwu, 1983). validation experiments are ‘replaced’ with non-animal models
Only two out of the 96 plant species were ineffective in the where possible.
in vivo experimental model of study, namely Zea mays L. (Suzuki Over one-third of the plants in our review have been studied
et al., 2005) and Cucumeropsis mannii Naudin (Teugwa et al.). for in vitro in models that could possibly explain some or all of
Despite its identified in in vitro PPARα and γ agonist activities their mechanism of action. Twenty-nine plants have inhibitory
and α-glucosidase inhibitory effects (Lee et al., 2010), extracts of effects against either α-amylase or α-glucosidase enzymes; five
Zea mays failed to produce a significant hypoglycemic effect plants have agonist activity on the PPARγ receptor, whose activa-
in vivo (Rau et al., 2006). This could possibly be as a result of the tion enhances glucose metabolism; four plants increase insulin
absence of the bioactive constituent(s) responsible for the release from pancreatic cells; five plants increase glucose uptake
hypoglycemic effect in the sample used for the in vivo study. in muscles or liver; while two plants increased the expression of
The absence of an in-vivo hypoglycemic effect would however the glucose transporter GLUT4, which in turn increases glucose
not ‘eliminate’ its use in the clinical management of diabetes, uptake into muscles and adipose tissues. Two plants were identi-
which also takes into account co-morbid conditions. In this fied as potential DPP-IV inhibitors, while six plants were identified
regard, Zea mays could also provide protection against diabetic as aldose reductase inhibitors (Fig. 1).
nephropathy, as it has been shown to improve kidney para- In vitro experiments are often designed to ‘reflect’ the mechanism
meters in vivo (Suzuki et al., 2005). of existing drugs used in diabetes management. Plants that possess
In the case of Cucumeropsis mannii, its traditional use involves alpha amylase or alpha glucosidase inhibitory effects reflect the
the ingestion of its ashes or its juice (Gbolade, 2009). This may action of acarbose, PPARγ agonist activity reflect the thiazolidine-
indicate that its use is based on its oligo-elements and/or vitamins. diones, while aldose reductase inhibitors are potential agents for
In fact the supplementation of elements such as chromium, preventing diabetic complications like the drug epalrestat. Thus with
magnesium and vanadium is actively explored in the treatment this identified mechanisms, researchers and healthcare professional
of diabetes (Anderson et al., 1997; Halberstam et al., 1996; alike can immediately identify the potential therapeutic benefit of
Rodríguez-Morán and Guerrero-Romero, 2003); some of which the plant. This information could contribute to a more rational
have been identified in the seeds of Cucumeropsis mannii (Badifu therapeutic regimen for diabetes patients, possibly benefitting from
and Ogunsua, 1991). a synergistic effect with herbal remedies.
Fig. 1. Proposed molecular mechanisms of hypoglycemic effects for species studied so far.
904 U.F. Ezuruike, J.M. Prieto / Journal of Ethnopharmacology 155 (2014) 857–924
The disadvantage of the molecular approach for experimental fractionation or in silico studies as the bioactive constituents
validation of plant activity is that the biological assays only explore responsible for some or all of the plants' beneficial effects in
known targets and do not take into account extracts that might be diabetes. Some of these constituents are species-specific such as
acting on unknown targets, possibly through innovative mechan- the alkaloid mahanimbine from Murraya koenigii (L.) Spreng
isms. In addition, herbal medicines are often complex mixtures (Dineshkumar et al., 2010), while others are known to be present
of various phytochemicals which work synergistically to achieve a in many plants like the alkaloid trigonelline, which is responsible
desired therapeutic outcome (Campbell-Tofte et al., 2012). In such for the hypoglycemic effect of Abrus precatorius L. (Monago and
cases, a single end-point in vitro biological assay will not be Nwodo, 2010) and Trigonella foenum-graecum L. (fenugreek), a
sufficient in evaluating the clinical effect of the plant. For plant whose use in diabetes management is popular across India
instance, the methanol extract of the root and stem of Gongronema and Europe (Bailey and Day, 1989). We hereby classify these
latifolium Benth. produced a greater anti-hyperglycemic effect in compounds according to similar chemical features (which may
glucose loaded rats than each of its fractions, indicating a syner- not necessarily refer to similar biosynthetic pathways) as follows:
gistic effect of its constituents possibly acting through different compounds containing nitrogen (1–9) (Fig. 2), terpenes (10–16)
molecular mechanisms (Adebajo et al., 2013). (Fig. 3), phenolic compounds (17–33) (Figs. 4 and 5), and com-
There is also a holistic approach in the herbal management of pounds containing hydroxyl groups including sugars (34–40)
diabetes such that plants which are not hypoglycemic themselves (Fig. 6).
may be included in multi-component preparations because of
their benefits in co-morbid conditions. Thus, in vitro studies might
not immediately indicate the beneficial effect of the plant. A good 3.3.1. Nitrogen containing compounds
example is the use of the aphrodisiac plant Mondia whiteii (Hook. A number of alkaloidal and non-alkaloidal active principles
f.) Skeels (Quasie et al., 2010). Despite not showing in vitro from plants used in diabetes management have been reported.
hypoglycemic effect (Etoundi et al., 2010), it is commonly included Some of these were isolated from samples not collected from
in multi-component preparations for diabetes management in Nigeria such as hypoglycin A (1) and B (2) – from the fruit of
men since erectile dysfunction is a common complication of the Blighia sapida K.D.Koenig. (Chen et al., 1957). Murraya koenigii
illness (personal communication during field work). This however leaves are also used traditionally in Indian Ayurvedic system to
does not preclude any in vivo activity which is yet to be evaluated. treat diabetes. Mahanimbine (5) isolated from the Indian plant
samples decreased blood glucose levels in STZ-induced diabetic
rats and also produced a dose-dependent α-amylase and
3.3. Bioactive compounds α-glucosidase inhibitory effect (Dineshkumar et al., 2010). Its
cellular mechanism of action is also thought to be mediated by
Over forty compounds from twenty three of the reviewed an increase in glucose utilization (Dinesh Kumar et al., 2013).
plants have been identified, either through an activity guided Paradoxically, this and other related carbazole alkaloids isolated
Akuammicine(3)
Picralima nitida
Hypoglycin A (1) & Hypoglycin B (2)
Blighia sapida
Trigonelline (4)
Abrus precatorius
Mahanimbine (5) Ajmaline (6)
Murraya koenigii
& Isosandwichine (7)
Rauvolfiavomitoria
3-β-D-glucopyranosyl-1-hydroxy-6(E)-
tetradecene-8,10,12-triyne (10)
& 2-β-D-glucopyranosyl-1-hydroxy-6(E)-
tetradecene-7,9,11-triyne (11)
Bidens pilosa
Myrcene (12)
Geraniol (14)
Cymbopogon citrallatus
Kolaviron (17) –
Mixture of GB1 (R1=H, R2=H),
GB2 (R1=OH, R2=H)
Damnacanthol -3 -O- β-D-primeveroside ( 18) (R=OCH )
& kolaflavanone (R1=OH, R2=Me)
Lucidin-3-O-β-D-primeveroside(19) (R=OH ).
Garcinia kola
Morinda citrifolia
Lawsone (20)
Lawsonia inermis
Isoscutellarein (28)
Bixa orellana
from plant samples from Nigeria decreased the glucose-mediated would most likely be contributing to their blood glucose lowering
insulin release from INS-1 cells when compared to control, even activity. Ajmaline (6) and isosandwichine (7) from Rauvolfia
though the amount of glucose released was dose dependent. vomitoria Afzel. were identified as DPP-IV inhibitors using an in
This effect may however be explained by their known in vitro silico approach (Guasch et al., 2012).
cytotoxicity (Adebajo et al., 2005). Garlic and onions are commonly used as part of the diet in
The alkaloid trigonelline (4) isolated from the seeds of Abrus many Nigerian households and the hypoglycemic effect of
precatorius (L.) collected from the eastern part of Nigeria decreased plant samples collected from Nigeria has also been studied
blood glucose levels in alloxan-induced diabetic rats as well (Eyo et al., 2011). This hypoglycemic effect is possibly due to the
as reduced the activity of glucose-6-phosphatase and glycogen presence of S-methylcysteine sulfoxide (8) (SMCS) in onions
phosphorylase, two enzymes important for glucose production and S-allylcysteine sulfoxide (9) (SACS) in garlic, which have
(Monago and Nwodo, 2010). Akuammicine (3) isolated from the been isolated from Indian plant samples and have been shown
chloroform extract of the seeds of Picralima nitida (Stapf) T.Durand to improve glucose tolerance in alloxan-induced diabetic rats
and H.Durand stimulated glucose uptake in 3T3-L1 adipocytes (Sheela et al., 1995). Clinical studies in humans have shown that
(Shittu et al., 2010). It is also present in plants of the genus Alstonia the supplementation of garlic to diabetic patients in combination
such as Alstonia boonei De Wild. and Alstonia Congensis Engl. and with hypoglycemic drugs improves glycemic control in addition to
U.F. Ezuruike, J.M. Prieto / Journal of Ethnopharmacology 155 (2014) 857–924 907
the reduction of cardiovascular risk (Sobenin et al., 2008). showed potent maltase inhibitory effects in vivo (Matsui et al.,
Although they both contain nitrogen, SMCS and SACS are primarily 2002), while ellagic acid (26) and 3,5-dicaffeoylquinic acid (27)
classed as sulfur containing compounds. isolated from the hot water extract of the leaves showed potent
aldose reductase inhibitory effects (Terashima et al., 1991). Law-
sone (20) (a naphtoquinone) and gallic acid (21) isolated from the
3.3.2. Terpenes
ethanol extract of the aerial parts of Lawsonia inermis L. inhibited
A number of terpenes have been isolated as bioactive consti-
the formation of advanced glycated end products in vitro (Sultana
tuents in plants used for diabetes management (Fig. 3). The leaves
et al., 2009). Some methoxy phenyl derivatives (22–25) isolated
of Gongronema latifolium, otherwise known as ‘utazi’ or ‘madu-
from the rhizomes of Zingiber officinale Roscoe have been identi-
maro’ in Ibo and Yoruba respectively is commonly used as a food
fied as aldose reductase inhibitors both in vitro and in vivo,
vegetable and is widely recognized for its traditional use in
suppressing sorbitol accumulation in human erythrocytes as well
diabetes management. Lupenyl cinnamate (15), lupenyl acetate
as lens galactitol accumulation in 30% galactose-fed rats (Kato
and α- and β-amyrin cinnamates (16) isolated from the combined
et al., 2006).
root and stems of locally obtained samples have recently been
Several isolated flavonoids have also been identified as bioac-
identified as the bioactive compounds, possessing both anti-
tive constituents. Isoscutellarein (8-hydroxy apigenin) (28) is a
hyperglycemic effects in glucose-fasted rats as well as insulin
flavonoid isolated from the hot water extract of the leaves of Bixa
stimulating effects in INS-1 cells (Adebajo et al., 2013).
orellana L., which was identified as an aldose reductase inhibitor
Foetidin from the whole plant and the unripe fruits of Momor-
(Terashima et al., 1991). Rutin (29) and quercetin (30) were
dica foetida collected in Nigeria also decreased blood glucose levels
isolated from the leaves of Bauhinia monandra Kurz as the anti-
of normal fasted, but not alloxan-induced rats at only 1 mg/kg
hyperglycemic constituents in alloxan-induced diabetic rats (Alade
(Marquis et al., 1977). Acetylenic glucosides (10) and (11) from
et al., 2011, 2012). A bioassay guided fractionation of the stem bark
Bidens pilosa decreased blood glucose in the murine type 2 diabetes
of Cassia fistula L. led to the identification of catechin (33) as the
model C57BL/Ks-db/db mice (Ubillas et al., 2000), and inhibited the
bioactive agent. It decreased plasma glucose levels in STZ-induced
spontaneous development of diabetes in non-obese diabetic
diabetic rats, with direct effects on glucose metabolizing enzymes
(NOD) mice by modulating the differentiation of T-helper cells
and expression of the glucose transporter GLUT4 (Daisy et al.,
(Chang et al., 2004).
2010). Fractionation of the methanol extract of the leaves of Senna
The monoterpenes myrcene (12), citral (13) and geraniol (14)
alata (L.) Roxb. (syn- Cassia alata), which showed potent α-
found in Cymbopogon citratus were identified as aldose reductase
glucosidase inhibitory effects, identified kaempferol gentiobioside
inhibitors using in-silico docking methods (Vyshali et al., 2011).
(31) and kaempferol (32) as the bioactive compounds (Varghese et
They are also components of the essential oil of many medicinal
al., 2013). Increased translocation of GLUT4 receptors to the
plants used in Nigeria as shown in Table 1. This preliminary
plasma membrane of L6 myotubes was also observed with a
information warrants further in vitro and in vivo studies involving
flavonoid-rich fraction of Scoparia dulcis L. (Beh et al., 2010),
plant samples from Nigeria previously shown to contain these
although the bioactive constituent(s) was not identified.
compounds, given that the beneficial effect of the essential oil of
The presence of aromatic hydroxyl groups in the benzo-γ-
Cymbopogon citratus containing high amounts of these monoter-
pyran structure of flavonoids is associated with its antioxidant
penes has now been validated in vivo in experimentally induced
properties, particularly its free radical scavenging effects. These
type-2 diabetic rats (Bharti et al., 2013).
properties have been shown to protect pancreatic islet cells from
oxidative stress as well as help in the regeneration of β-cells as
3.3.3. Phenolic compounds shown with epicatechin found in green tea (Sabu et al., 2002) and
A wide range of phenolic compounds have been identified quercetin (Coskun et al., 2005). More importantly, they can
as active principle(s) in some of the plants here reviewed. prevent the formation of advanced glycated end products (AGEs)
Anthraquinone glycosides from Morinda citrifolia L, namely dam- and other diabetic complications associated with high oxidative
nacanthol-3-O-β-D-primeveroside (18) and lucidin 3-O-β-D-prime- stress conditions such as artherosclerosis, nephropathy, neuropa-
veroside (19), decreased blood glucose levels in STZ-induced thy, retinopathy and erectile dysfunction (Rahimi et al., 2005).
diabetic mice at 100 mg/kg (Kamiya et al., 2008). Incidentally, this Thus, the presence of quercetin and epicatechin as well as other
plant is not native to Nigeria and is not known to grow in Nigeria. potent antioxidant flavonoids in a wide range of plants such as
However, the use of a registered herbal product of the juice Irvingia gabonensis, Khaya senegalensis, Mangifera indica, Securi-
extract, Tahitian noni juices (TNJ) is quite popular in Nigeria for daca longipedunculata and Ocimum gratissimum, will contribute to
various ailments including diabetes. Administration of 1 ml/ – and in some cases may be the basis for – their use in the holistic
150 mg body weight of the rats twice daily for four weeks prior management of diabetes which includes the prevention of diabetic
to and after the induction of diabetes with alloxan resulted in complications.
significant decrease in blood sugar levels, indicating a prophylactic Other flavonoids have also been shown to directly affect
effect of the extract against alloxan-induced diabetes (Horsfal et specific therapeutic targets in diabetes. For instance, supplemen-
al., 2008). The presence of these phenolic compounds in the tation of mice diet with naringin or hesperidin modulated the
marketed product has however not been confirmed. activity of glucose metabolizing enzymes, with an increase in
Kolaviron (17) is a mixture of flavanones isolated from the hepatic glucokinase activity and decrease in hepatic glucose-6-
acetone extract of the edible nuts of Garcinia kola Heckel (bitter phosphatase activity in diabetic db/db mice (Jung et al., 2004) and
kola), which is valued in most parts of West Africa. It decreased GK type-2 diabetic rats (Akiyama et al., 2009). These two flavo-
blood sugar levels in normal and alloxan induced diabetic mice at noids are constituents of all citrus fruits and have also been
a dose of 100 mg/kg, as well as inhibited rat lens aldose reductase identified in Senna alata (Hennebelle et al., 2009) and Rauvolfia
(RLAR) activity (Iwu et al., 1990a). vomitoria (Campbell-Tofte et al., 2011) and as such may account for
Other phenolic compounds have been identified as bioactive some of their effects. Myricetin is another flavonoid that has
constituents but not from plant samples collected in Nigeria. shown direct beneficial effects in diabetes through enhanced
A diacylated anthocyanin peonidin 3-O-[2-O-(6-O-E-feruloyl-β- glycogen metabolism (Ong and Khoo, 2000) and improved insulin
D-glucopyranosyl)-6-O-E-caffeoyl-β-D-glucopyranoside]-5-O-β-D- sensitivity (Liu et al., 2007). It has been identified in some of the
glucopyranoside isolated from the root of Ipomoea batatas (L.) Poir. plants either in its aglycone form or as a glycoside. These are the
908 U.F. Ezuruike, J.M. Prieto / Journal of Ethnopharmacology 155 (2014) 857–924
Allium species, Aloe vera, Azadirachta indica, Citrus species, Carica appropriate conclusions that will act as guidelines for their clinical
papaya, Bryophyllum pinnatum, Cassia sieberiana, Chrysophyllum use cannot be drawn.
albidum, Ipomoea batatas and Bridelia ferruginea. A good knowledge of the traditional use of these plants based
on ethnobotanical studies is very important in the design of a good
clinical study. This is especially important for plants which are
3.3.4. Hydroxylated compounds including sugars used as mixtures, as the individual components may be working
Some other non-phenolic hydroxylated cyclic compounds have synergistically to produce the overall desired effect. An example is
been isolated and identified as bioactive agents. These include the the synergistic effect produced by a decoction mix of the leaves
gingerols (34–36) from Zingiber officinale, which were shown to of Gongronema latifolium, Ocimum gratissimum and Vernonia
enhance glucose uptake into muscles as a result of a direct amygdalina in modulating baseline blood glucose levels, which
increase in the expression of the GLUT4 receptor (Li et al., 2012). was not observed with the individual plants (Ejike et al., 2013).
An inositol derivative, D-3-O-methyl chiroinositol (37) isolated Given that many of these herbal remedies are currently being
from the methanol extract of the stem bark of Bauhinia thonningii taken by diabetic patients alongside their prescription medicines,
Schum. produced a dose-dependent decrease in blood glucose a concerted effort between clinicians and researchers would be an
levels in alloxan-induced diabetic rats (Asuzu and Nwaehujor, ideal way to recruit patients to such studies.
2013). To ensure the reliability of conclusions drawn from any clinical
Finally, a number of benzyl derivatives including carbamates study, they should always involve proper planning with appro-
and thiocarbamates have been isolated from fractions of the priate controls and ought to be conducted within a reasonable
methanol extract of the fruits of Moringa oleifera Lam. These time frame, in line with the guidelines of the Declaration of
compounds have been shown to possess insulin secretory effects, Helsinki. In addition, the recommendations for reporting rando-
stimulating Z 15 ng insulin/mg protein in pancreatic INS-1 cells at mized clinical trials, as defined in the ‘Consolidated Standards
100 ppm. Some of these compounds were identified as 1-O-phenyl of Reporting Randomized Clinical Trials (CONSORT) statement’
α-L-rhamnopyranoside (38), methyl N-{4-[(α-L-rhamnopyranosyl) (Schulz et al., 2010) should also be followed. Nonetheless,
benzyl]}carbamate (39), and methyl N-{4-[(40 -O-acetyl-α-L-rham- this relatively high ‘success’ rate amongst the various studies
nopyranosyl)benzyl]}carbamate (40). conducted highlights the potential of harnessing ethnobotanical
Many plant secondary metabolites have been associated with information in enhancing patient therapy.
specific beneficial effects in diabetes, which might account for the
therapeutic effect of the herbal drug (Qi et al., 2010; Singh et al.,
2013). Thus, apart from a bioguided fractionation, the biologically
active agent of a plant can also be inferred by evaluating the 4. Toxicological evidence and considerations
phytochemical constituents that have previously been isolated.
These can thereafter be confirmed in specific pharmacologic The administration of whole plant extracts or fractions con-
experiments. sisting of a myriad of compounds, can elicit different biological
effects in the body, some of which may be harmful toxic effects.
Sometimes, these toxic effects are only associated with certain
3.4. Clinical studies parts of the plant. For example, the leaves of Senna occidentalis
have hepatoprotective effects and are used traditionally for the
The validation of biologically active plants in randomized, treatment of liver disorders (Jafri et al., 1999). However, ingestion
placebo-controlled clinical trials involving human subjects is a of toxins found in the seeds (beans) is thought to be the probable
necessary step towards the possible integration of traditional cause of acute hepato-myoencephalopathy (HMP) in children
herbal products into health systems. For these purposes, isolation (Vashishtha et al., 2009). This risk of toxicity associated with the
of the active constituent may not be necessary. The European use of herbal products is one of the main reasons for the hesitance
Directive of Traditional Herbal Medicinal Products is an example of amongst healthcare practitioners towards promoting their inte-
how reports of traditional use and a sound safety profile are gration into healthcare systems.
enough to regulate herbal medicines (Cox and Roche, 2004). Adequate knowledge about the traditional use of such plants is
However, knowing the identity of the active principle would be very necessary as this often helps to forestall the ingestion of such
ideal in order to ensure a better quality control and perhaps a toxic plants or plant parts. Sometimes the toxic component may
more defined dosage. have been identified such as abrin, a toxic protein found in the
Fourteen of the plants reviewed in this paper have been seeds of Abrus pecatorius, with an estimated human fatal dose of
clinically evaluated in human subjects, either singly or in combi- 0.1–1 mg/kg (Kirsten et al., 2003). In rare cases, the hypoglycemic
nation. These are Bridelia ferruginea, Citrus aurantium, Gongronema agent in the plant could also be the toxic agent, such as with
latifolium, Ocimum gratissimum, Rauvolfia vomitoria, Vernonia hypoglycin from Blighia sapida (Sherratt, 1986). Thus, the thera-
amygdalina, Carica papaya, Curcuma longa, Ipomoea batatas, Irvin- peutic use of such a plants as whole extracts is therefore not
gia gabonensis, Gymnema sylvestre, Phyllanthus amarus and Sola- recommended.
num aethiopicum (Table 1), of which the first six involved plant Various plants in Table 1 have been associated with specific
samples collected from Nigeria. Only Phyllanthus amarus did not organ toxicity. Examples include the nephrotoxic effects of Alstonia
produce the desired clinical effect (Moshi et al., 2001). congensis, Aristolochia spp., Cassia sieberiana, Ficus exasperata,
Most of the clinical studies were not randomized, controlled Securidaca longipedunculata and the hepatotoxic effects of Cassia
trials but preliminary studies evaluating the therapeutic effect sieberiana, Ficus exasperata, Morinda citrifolia, Picralima nitida and
of the plant in human subjects. Exceptions to these were those Senna occidentalis. The hepatotoxic effects of some extracts such as
carried out on Rauvolfia vomitoria and Citrus aurantium (Campbell- Ocimum gratissimum and Sphenocentrum jollyanum are directly
Tofte et al., 2011), Irvingia gabonensis (Ngondi et al., 2009) and linked to their effect on the liver function enzymes. The cardio-
Ipomoea batatas (Ludvik et al., 2004). Similarly, a meta-analysis by toxic and neurotoxic effects of some other extracts have also been
Leung et al. (2009) of all clinical studies carried out on Momordica identified. Sometimes, these toxic effects are only seen at high
charantia identified flaws in their study design, despite the extract doses, which would therefore not preclude their continued use
consistently producing a hypoglycemic effect. As a result, as medicinal plants so long as there is appropriate information
U.F. Ezuruike, J.M. Prieto / Journal of Ethnopharmacology 155 (2014) 857–924 909
about the safe dose ranges. The use of other more toxic plants A synergistic effect should however not be assumed. It is
would however need to be completely discontinued. sometimes advisable for patients not to take drugs alongside their
A thorough analysis of the plant's extracts as well as identified herbal products due to negative drug interactions that may occur.
phytochemical constituents with respect to their safety/toxicity For instance, the water soluble fraction of okra fruits has been
profile particularly in humans can ensure a critical assessment of shown to decrease the absorption of metformin (Khatun et al.,
its therapeutic potential. Previously, coumarins which are a 2011). Although both would otherwise be beneficial in diabetes
component of a wide range of plants were identified as hepato- management, taken together would result in a decrease in the
toxic based on various studies carried out in rodents. However, therapeutic concentration of metformin, which in turn may not
further studies have showed that certain animal species are bring about the desired hypoglycemic effect in the patient.
resistant to coumarin-induced toxicity. The 7-hydroxylation meta- Constituents of medicinal plants also undergo the four main
bolic pathway is the most favored in humans leading to the pharmacokinetic processes of absorption, distribution, metabolism
formation of non-toxic metabolites, whereas in rats the most and elimination (ADME). There is therefore the possibility of an
favored pathway is a 3,4-epoxidation leading to the formation of interaction with one of the different ADME parameters by the
toxic metabolites. Knowledge of this and a quantitative health risk herb, which could invariably affect the fate/bioavailability of a co-
assessment have now confirmed its safety in humans (Felter et al., administered drug and possibly, the resulting therapeutic benefit
2006; Lake, 1999). (s). This is known as a ‘pharmacokinetic interaction’.
Evaluation of medicinal plants for potential herb–drug interac- Out of the one hundred and fifteen plants reviewed in this
tions is equally as important as its evaluation for efficacy paper, over thirty of them have shown in vitro and/or in vivo
and safety. Two types of herb–drug interactions exist: pharmaco- modulation of the activity of one or more of these ADME para-
dynamic interactions and pharmacokinetic interactions. If a herbal meters (Fig. 7). Some of these interactions were on absorption,
plant alters the expected pharmacological effect of a drug as a either by modulating the effect of P-glycoprotein (P-gp), an
result of its biochemical or physiological effect on intestinal efflux transporter, or by direct effects on the intestinal
the body, this is known as a ‘pharmacodynamic interaction’. tight junctions. Other pharmacokinetic interactions were on
If the herb and the drug are both expected to produce the same metabolism, by interacting with one or more cytochrome P450
pharmacological effect, there may be an increased therapeutic enzymes responsible for phase 1 metabolism or either of the
effect produced with their co-administration. This knowledge can phase 2 metabolic enzymes (Table 1).
be harnessed towards producing a synergistic effect between the The role of P-gp in the intestinal epithelium is the extrusion
two, which would possibly require a dose adjustment. Otherwise, of certain xenobiotics from the blood to the intestinal lumen
the resulting effect could be detrimental if appropriate monitor- as well as to minimize the entry of drugs in the lumen into the
ing and evaluation is not done. A good example is the severe bloodstream, ultimately resulting in decreased absorption and
hypoglycemic that was observed in a female diabetic patient decreased oral bioavailability (Sharom, 2007). For drugs that are
taking chlorpropamide and a meal containing Momordica char- P-gp substrates such as glibenclamide, this effect of the efflux
antia and Allium sativum (Izzo and Ernst, 2001). transporter is one of the determinant factors in the recommended
Acacia nilotica
Annona senegalensis
Bauhinia thonningii
Carica papaya
Moringa oleifera
Solanum melongena
Vernonia amygdalina
Ximenia americana
Zingiber officinale
P-gp P-gp
Bridelia ferruginea
Catharanthus roseus
Curcuma longa
Khaya ivorensis
Mangifera indica
Morinda lucida
CYP CYP
Aframomum melegueta
Bixa orellana
Citrus aurantiifolia
Citrus aurantium
Citrullus colocynthis
Corchorus olitorius
Ipomoea batatas
Lawsonia inermis
Jatropha curcas
Momordica charantia
Lawsonia inermis
Morinda citrifolia
Momordica charantia
Morinda lucida
Morus alba
Moringa oleifera
Murraya koenigii
Phyllanthus amarus
Persea americana
Securidaca longipedunculata
Phyllanthus amarus
Senna alata
Senna alata
Fig. 7. In vitro pharmacokinetic herb–drug interactions identified based on the literature reviewed.
910 U.F. Ezuruike, J.M. Prieto / Journal of Ethnopharmacology 155 (2014) 857–924
dose of the drug to ensure that an adequate therapeutic concen- of these plants as herbal preparations (such as pharmacopoeial
tration is achieved in the bloodstream. Co-administration of the monographs) would be required to ensure the reproducibility of
drug with a herb with inhibitory effects on P-gp such as Acacia their therapeutic effects. Finally, as a means of giving credence to
nilotica, Annona senegalensis, Bauhinia thonningii, Bridelia ferrugi- the pre-clinical experimental evidence, intervention or clinical
nea, Carica papaya and Morinda lucida might result in increased studies with the standardised materials should be carried out in
plasma concentration of the drug. order to validate their usefulness in diabetes management. We
The cytochrome P450 (CYP) family of enzymes are respon- hope that in this manner the therapeutic potential of these
sible for phase 1 oxidative, peroxidative and reductive metabolic medicinal plants can be best harnessed, towards a possible
transformations of drugs, environmental chemicals and natural integration into the healthcare system.
compounds into less toxic, more water-soluble products, in order
to facilitate their excretion from the body. They are most abundant
in the liver, which is the primary site for metabolism. The activity Acknowledgments
of CYP enzymes can be modified either by induction or inhibition
as seen with the extracts of Bixa orellana and Jatropha curcas U.F. Ezuruike is grateful to the Commonwealth Scholarship
respectively. The biological activity of the xenobiotics metabolized Commission in the UK for the award of a DFID (Department for
by these enzymes can be greatly altered as a result (Rendic and International Development) sponsored Ph.D. scholarship.
Carlo, 1997). St John's wort (Hypericum perforatum) is a very good
example of a herbal product that has produced clinically signifi-
cant effects as a result of its interactions with P-gp and CYP
Appendix A. Supplementary information
enzymes (Henderson et al., 2002).
In vitro interactions have also been identified with the phase
Supplementary data associated with this article can be found in
2 metabolizing enzymes, particularly with the glutathione trans-
the online version at http://dx.doi.org/10.1016/j.jep.2014.05.055.
ferases (GSTs). As with P-gp and CYPs, such interactions can alter
the plasma concentration and the resulting therapeutic effect of
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