| Review Article |
Open Access |
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| Pharmacogenetics: Would it be a Reason for the Lack of Potency and Intrinsic Toxicity of Several Natural Medicines? |
| Tibebe Z. Woldemariam*, Nancy Wageih Hanna and David Pearson |
| Pharmaceutical and Biomedical Sciences, California Northstate University College of Pharmacy, 10811 International Drive, Rancho Cordova, CA 95670, USA |
| *Corresponding author: |
Tibebe Z. Woldemariam
Pharmaceutical and
Biomedical Sciences
California Northstate University College of Pharmacy
10811 International Drive, Rancho Cordova, CA 95670, USA
E-mail:
TWoldemariam@CalPharm.org |
|
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| Received July 13, 2012; Accepted August 08, 2012; Published August 10, 2012 |
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| Citation: Woldemariam TZ, Hanna NW, Pearson D (2012) Pharmacogenetics:
Would it be a Reason for the Lack of Potency and Intrinsic Toxicity of Several
Natural Medicines? J Proteomics Bioinform 5: 190-195. doi:10.4172/jpb.1000234 |
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| Copyright: © 2012 Woldemariam TZ, et al. This is an open-access article
distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided
the original author and source are credited. |
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| Abstract |
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| The use of natural products in drug discovery screening has declined because of the apparent disadvantages
of natural products including large-scale procurement of sufficient source material for bulk production, the lack of
potency and intrinsic toxicity of many natural products. |
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| However, very little effort has been made looking at the influence of pharmacogenetics in the efficacy and toxicity
of natural medicines. Pharmacogenomics may possibly enhance drug discovery and development from natural
sources by identifying drug targets and enhancing the subpopulation-specific drug development. |
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| Keywords |
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| Pharmacogenetics; Natural products; Drug discovery;
Natural medicines |
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| Introduction |
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| The recent availability of genomic data and our increased
understanding of the effects of genetic variations allow a thorough
evaluation of the contribution of genetic variation to efficacy or toxicity
of compounds derived from natural sources [1]. Pharmacogenomics
can identify genetic polymorphisms that predispose a small subset of
patients to adverse drug effects of natural medicines in clinical trials.
Such an approach can eliminate potential toxicities of natural products
and save them from rejection during development [2]. |
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| It is well recognized that natural products have been a source of
leads for the development of many valuable drugs currently available
for the treatment of a variety of human diseases. Conceivably, about
75% of plant-derived drugs in clinical use today came to the awareness
of pharmaceutical companies because of their vast utilization in selfcare
practices or traditional medicines [3]. |
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| The use of natural products in drug discovery screening has
declined because of the apparent disadvantages of natural products
including large-scale procurement of sufficient source material for bulk
production, the lack of potency and intrinsic toxicity of many natural
products. |
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| Nevertheless, very little effort has been made looking at the influence
of pharmacogenetics in the efficacy and toxicity of natural medicines.
For natural products that are in the early stages of drug development,
more research should be conducted to determine if gene variants are
responsible for the differences in efficacy and toxicity profiles between
patients. If genetic variants are responsible for the different responses,
pharmacogenomic tests may be used to determine who will actually
benefit from the drug. In addition, polymorphisms in the genes for
drug-metabolizing enzymes and transporters may influence the efficacy
of natural medicines mediated through these pathways. |
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| Discussion |
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| One of the major points of failure in drug development is preclinical
toxicology. A greater throughput of drug candidates that are less likely
to fail regulated toxicology studies could lower the overall cost of drug
development [4]. |
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| Some pharmaceutical companies are trying to introduce
pharmacogenetic evaluations from the very early stages of drug development in order to develop feasible pharmacogenetic tests to
reduce rejection in the drug development pipeline. The knowledge
of gene function and of their role in the disease pathway, new targets
can be derived, that might be innovative and not accessible with nongenomic
approaches [5]. |
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| Currently the lack of data makes it difficult to correlate the
compounds of interest and the genes as well as between species; we
have drawn together information on the importance of selected
natural products and their importance on the role of these agents in
modulation of various genes. |
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| Cancer Therapy |
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| There are promising areas of cancer investigation which represent
the future for therapeutic intervention, increasing treatment efficacy
and reducing drug adverse effects on the basis of genetic profiles. The
identification of candidate genes is a complex process as the majority
of anticancer drugs need to undergo an activating metabolism or are
substrates of inactivating enzymes or excretion systems. Following are
some of the compounds of interest which warrant further investigation. |
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| Resveratrol |
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| Resveratrol is a polyphenolic compound found primarily in
red wine, red grape skins, purple grape juice, mulberries, and in
smaller amounts in peanuts [6]. It exists in nature as cis- and transstereoisomers.
Trans-resveratrol appears to be the primary active
form. It is thought that resveratrol activates "sirtuins", enzymes that
regulate glucose and fat metabolism and increase cell survival. Orally,
resveratrol is used for atherosclerosis, aging skin, reducing cholesterol
levels, increasing HDL cholesterol levels, and preventing cancer. |
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| There has been interest in resveratrol for preventing cardiovascular
disease and cancer and improving mortality. |
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| Trans-resveratrol has antioxidant, anti-inflammatory, and
antimutagenic activity [7]. Resveratrol significantly reduces lipid
peroxidation and organ damage in animal models of ischemiareperfusion
[7]. |
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| Preliminary research suggests that chronic administration
of resveratrol might improve myocardial function in models of
myocardial ischemia [8]. |
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| Resveratrol might have a role in preventing Alzheimer's disease.
In vitro, resveratrol prevents beta-amyloid peptide-related reductions
in glutathione. This suggests that resveratrol might prevent oxidative
damage caused by beta-amyloid peptide [9]. |
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| Studies demonstrating health benefits of resveratrol
supplementation have not been done in humans. |
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| Preliminary evidence shows resveratrol inhibits the drug
metabolizing enzymes CYP3A4, CYP1A2, and CYP2E1 and it is not
known if this action interferes with metabolism of drugs in humans. |
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| Theoretically, resveratrol might increase levels of drugs metabolized
by these enzymes. However, interactions have not been reported in
humans [6]. |
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| Resveratrol |
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| (±)-Hesperetin |
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| • Hesperetin belongs to the flavanone class of flavonoids. |
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| • Hesperetin, in the form of its glycoside hesperidin, is the major
flavonoid in lemons and oranges |
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| • Hesperetin induces Notch1 expression in carcinoid cells,
subsequently suppressing tumor cell proliferation and bioactive
hormone production which provides support for further study
into hesperetin as a potential treatment for carcinoid cancer
[10]. |
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| • It appears to reduce cholesteryl ester and inhibit apoB
secretion by up to 80%. Hesperetin may have antioxidant, antiinflammatory,
anti-allergic, hypolipidemic, vasoprotective and
anticarcinogenic actions [11]. |
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| Hesperetin |
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| Chlorogenic acid |
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| • Isolated from the leaves and fruits of dicotyledonous plants (e.g. coffee beans). Analog of caffeic acid. Shows antioxidant,
analgesic, antipyretic and chemopreventive activity [12]. |
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| • Inhibits Bcr-Abl tyrosine kinase and triggers MAP kinases
p38–dependent apoptosis. Inhibitor of the tumor promoting
activity of phorbol esters. |
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| • But does not inhibit the 5-lipoxygenase activity of ionophorestimulated
human polymorphonuclear leukocytes. |
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| Chlorogenic acid |
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| Myristicin |
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| • Myristicin is a phenylpropene compound found in small
amounts in the essential oil of nutmeg, parsley, and dill. |
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| • Inhibits chemical carcinogenesis and induces apoptosis [13]. |
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| • Induces rat and human cytochrome P450 enzymes and
glutathione S-transferases. |
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| • Has very potent hepatoprotective activity. |
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| Myristicin |
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| Luteolin |
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| • Antioxidant flavonoid which inhibits VEGF-induced
angiogenesis [14]. |
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| • Inhibitor of the catalytic activity of phosphoinositide 3-kinase
(PI(3)K), whereas inhibition of PI(3)K by luteolin affects
apoptosis via PI(3)K/Akt (protein kinase B; PKB) pathways
and antimitotic effects via PI(3)K/p70S6K pathways. |
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| • Inhibitor of fatty acid synthase (FAS) and apoptosis inducer. |
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| Luteolin |
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| Ginger |
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| There are many traditional uses for ginger, but more recent interest
in the use of ginger focuses on the prevention and management
of nausea. Ginger may play a role in osteoarthritic pain and cancer.
However, there is limited clinical information to support these uses.
It is also used for discontinuing selective serotonin reuptake inhibitor
(SSRI) drug therapy [15]. Over 400 different compounds have been
identified in ginger. The main components are [6]-gingerol and [6]-shogaol; however, the pharmacologically active compounds [6]
- and [10]-dehydrogingerdione and [6] - and [10]-gingerdione have
also been identified. Active constituents of ginger include gingerol,
gingerdione, shogaol, and sesquiterpene and monoterpene volatile oils. |
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| 6-Gingerol 6-Shogaol |
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| Ginseng |
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| Ginseng is popularly used for its adaptogenic, antineoplastic,
immunomodulatory, cardiovascular, CNS, endocrine, and ergogenic
effects, but these uses have not been confirmed by clinical trials. |
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| Most traditional ginseng herbal preparations contain saponin
(ginsenosides) glycoside. Ginseng root is standardized on content
of ginsenosides. Most of the pharmacological effects of ginseng are
attributed to ginsenosides [16]. Ginsenosides have been shown to
interact with numerous membrane proteins such as ion channels,
transporters and receptors, which lead to a broad range of physiological
activities. Ginsenoside Rg1 affects the expressions of genes involved
in vascular constriction, cell adherence, coagulation, cell growth
and signal transduction in TNF-α stimulated human umbilical vein
endothelial cells (HUVECs). Ginsenoside Rg1 regulates sets of genes in
endothelial cells and protects endothelial cells from TNF-α activation. |
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| Ginsenoside Rg1 |
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| S-adenosyl-L-methionine (SAMe) |
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| S-adenosyl-L-methionine (SAMe), a popular alternative to
conventional antidepressants, appears to affect levels of dopamine,
norepinephrine, and serotonin. Imaging studies suggest that it affects
brain activity similar to conventional antidepressants [17]. SAMe is
effective for depression, but so far, there is no reliable evidence that it
works for anxiety disorders. Don't recommend it. |
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| S-adenosyl-L-methionine (SAMe) |
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| Sedatives, Hypnotics, and Anxiolytics |
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| There is a lot of interest in herbal alternatives for their use as
sedatives, hypnotics, and anxiolytics. |
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| Kava |
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| Kava tea has a long history of use among Pacific Islanders for a
calming effect and promotes sociability. In North America, kava extract
capsules are being used for their calming effects and as a treatment for
anxiety. Kava extracts are thought to have a variety of effects including
anxiolytic, sedative, anticonvulsant, and analgesic. Kava does not seem
to affect benzodiazepine receptors, but it might increase the effects of
GABA by increasing GABA binding sites [18]. |
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| Kava has been safely used in short-term clinical trials. But
hepatotoxicity can occur in some patients after as little as 3-4 weeks of
use, even in normal doses. Slow metabolizers or those patients deficient
in cytochrome P450 2D6 are theorized to be more susceptible [18].The
compounds of utmost pharmacological interest in Kava extracts are the
substituted a -pyrones or kava pyrones, commonly called kavalactones.
Fifteen lactones have been isolated from kava rootstock. The following
six compounds are present in the highest concentrations and account
for approximately 96 percent of the lipid resin: yangonin, methysticin,
dihydromethysticin, kavain, dihydrokavain, and demethoxyyangonin
(5, 6-dehydrokavain) [19,20]. Structures for the three major
kavalactones are shown below. |
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| Kavain methysticin 10-methoxyyangonin |
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| In vitro and in vivo analysis carried out on hepatic and intestinal
CYP enzymes of rat, have demonstrated that ginkgolic acids were
shown to be potent inhibitors of CYP1A2, CYP2C9 and CYP2C19.
The variations of constituents of gingko (ginkgolides, biobalides, and
flavone glycosides) and their bioavailability could explain the disparity
in findings, in addition to species variability in drug metabolism. |
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| Alzheimer's Disease (AD) |
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| During the course of conventional drug treatment for Alzheimer’s
disease, fewer than 20% of patients are reasonable responders.
Pharmacogenomics studies have shown that the therapeutic response is
genotype specific as pharmacogenomics factors account for more than
60% of drug variability in drug disposition. Some natural medicines
tend to inhibit acetylcholinesterase activity. |
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| Huperzine A |
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| Huperzine A is an alkaloid isolated from Huperzia serrata (Chinese
club moss). It is a specific acetylcholinesterase inhibitor with a longer
duration of action than donepezil (Aricept) or tacrine (Cognex) [21,22].
It also has N-methyl-D-aspartate (NMDA) receptor antagonist
properties in animal models similar to memantine (Namenda) [23]. It
protects cells against hydrogen peroxide, β-amyloid protein, glutamate,
ischemia and staurosporine-induced cytotoxicity and apoptosis.
Prospective agent for the treatment of Alzheimer‘s disease. |
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| No clinical research has evaluated huperzine A in patients with
moderate to severe Alzheimer's disease. There is some clinical evidence that huperzine A can improve cognitive and behavioral function
in Alzheimer's patients [23]. Most studies have included only small
numbers of patients and for short treatment periods. More evidence of
long-term safety and effectiveness gas not been established yet. |
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| Huperzine A ((+/-)-Selagine) |
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| Rosmarinic acid |
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| Rosmarinic acid is an ester of caffeic acid, and 3,
4-dihydroxyphenyllactic acid. It is a major ingredient of the culinary
herb sage (Salvia officinalis) and lemon balm (Melissa officinalis), a
plant that has shown promising signs of therapeutic activity in patients
with Alzheimer’s disease [24]. Main activities of rosmarinic acid
include antioxidant, anti inflammatory, antimutagen, antibacterial, and
antiviral properties [25]. Currently research studies are underway at
CNUCOP on pharmacokinetic and mechanistic aspects of rosmarinic
acid that target its use in the treatment of alzheimer’s disease [26]. |
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| Rosmarinic acid |
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| Gotu kola |
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| Gotu kola, Centella asiatica, a plant grown in India and southern
Africa. The three asiaticoside derivatives in Gotu kola extract show
some neuroprotective effects. In vitro, the asiatosides, asiatic acid,
asiaticoside 6, and SM2 are able to block cell death induced by betaamyloid
[27]. But, there is no evidence yet that it helps patients with
Alzheimer's disease. |
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| Asiatic acid |
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| Hyperlipidemia |
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| Some natural medicines are thought to have some pharmacological
effects that are similar to statins. |
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| Garlic |
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| Garlic is one of the most vigorously researched supplements
around. Garlic contains a variety of organosulfur constituents with
biological activity. The active constituents in garlic are thought to
inhibit cholesterol synthesis by blocking enzymes such as HMGCoA
reductase, squalene epoxidase, and glucose-6-phosphate
dehydrogenase [28]. The research studies which claimed these activities
were generally were often small, flawed, and inconsistently designed. |
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| However more recent research has been consistent in the opposite
direction. These studies show that a variety of garlic preparations do not
significantly reduce cholesterol levels [29]. Some garlic preparations
can induce cytochrome P450 3A4. Some studies have shown no effect
of garlic on drug metabolism. Preparations that give a higher amount
of the constituent allicin appear to be more likely to cause interactions
[30]. |
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| Allicin (S-Allyl acrylo-1-sulphinothioate) |
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| Artichoke extract |
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| Artichoke extract contains cynaroside and its derivative luteolin.
Both of these constituents seem to block HMG-CoA reductase, similar
to statins [31]. Artichoke extract seems to be safe for most patients. But
some people can experience flatulence after starting artichoke extract. |
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| Cynaroside Luteolin |
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| Hypertension |
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| Pomegranate juice |
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| Researchers are also taking an interest in studying pomegranate
juice for prostate cancer, high cholesterol, atherosclerosis, COPD,
hypertension, and other potential uses. But for all these uses, research
is just in its infancy. |
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| For hypertension, some research shows that pomegranate can
reduce the activity of ACE by about 36% [32]. Clinical research is
contradictory, some research shows modest reductions in systolic blood
pressure after drinking 50 mL/day for up to a year [33]. Other research
shows no benefit after drinking 240 mL/day for 3 months. Ellagic acid
was found to be the major active ingredient in the pomegranate juice. |
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| Ellagic acid |
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| Allergy and Asthma |
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| Approximately 89% of patients with asthma use some form of
alternative medicine. About a quarter of these patients use an herbal or
other natural medicine [34]. |
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| Over 160 natural ingredients have identified that are used or
promoted for treating or preventing asthma. Of these, only about
25 have been clinically studied for treating asthma. Several of these
natural medicines have effects on inflammatory mediators with some
similarities to leukotriene modifiers or corticosteroids. |
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| Butterbur |
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| Butterbur is best known as a remedy for allergies, but it is
also promoted for asthma and many other respiratory conditions. Butterbur and the butterbur constituent "petasin" appear to decrease
synthesis of leukotrienes in vitro [35,36]. Although butterbur has
substantial clinical research supporting its use for allergic rhinitis, there
is no reliable clinical research that it is effective for asthma. Butterbur
naturally contains unsaturated pyrrolizidine alkaloids (UPAs), which
are hepatotoxic, carcinogenic, and mutagenic. |
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| Petasin |
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| Limitations of Classical Natural Products Discovery
Processes |
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| In spite of the success of natural products with their structural
diversity and tremendous value as therapeutics, drug discovery for
natural products faces many challenges. Several of these real and
perceived limitations of natural products include their chemical
complexity; bioavailability problems and poor water solubility and lack
of sufficient solubility enhancement studies; the difficulty and timeconsuming
nature of screening of mixtures of compounds in natural
product extracts; the apparently common occurrence of synergistic
actions between different components in an extract and solubility
issue once the compounds in question are isolated in pure form;
adulterations and poor reproducibility between different batches of
extracts; and the uncertainty of being able to obtain resupplies of an
interesting extract in large quantities. |
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| Future Perspectives |
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| The US National Institutes of Health (NIH) and executives from
the drug companies announced 3rd May 2012 that 24 drugs abandoned
during development by three major pharmaceutical companies will
become available to scientists seeking novel therapeutic uses under
the notion ‘Teach old drugs new tricks’. It is a good news for the
natural products drug discovery groups, academics, non-profit groups,
biotechnology companies and others. Several natural compounds
that were tested during clinical stages of drug development but were
abandoned because they didn’t work for the intended purpose or
because of lack of sufficient data will have a better chance with this
current approach. Based on preliminary research data, majority
of natural products databases downgrade commonly used natural
medicines to a rating of ‘Possibly Ineffective’ for most of useful
indications used by consumers. Pharmacogenomic factors were not
looked at for almost all the natural agents abandoned during the
clinical trials. Pharmacogenomics could be a reason for the lack of
potency and intrinsic toxicity of several natural medicines? It is hoped
that new approach with improved and effective application of natural
products will improve the drug discovery process. |
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| Conclusion |
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| From the above examples it is clear that there are number of natural
products that can prevent or cure numerous life threatening diseases by
interacting with genes. It is obvious that optimizing the assessment of
natural products as drug leads requires multidisciplinary collaboration
to recuperate the usefulness of commonly used natural medicines
and compounds originated from plants, plants tissue culture, soil and
marine microorganisms which didn’t make it to later stages of drug
development [36]. |
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| With a view to promoting more effective and safe natural
medicines, clinical studies need to be reviewed in order to include
pharmacogenomic studies of natural products. It may be that
some abandoned natural agents can offer improved outcomes with
relatively little investment and cost. More open discussion on how
pharmacogenetics can improve existing therapies is vital if this is to
become a reality in the future research endeavor. There is hope that
those compounds which passed through preclinical testing and
through phase I safety trials in humans, but were abandoned later for
lack of efficacy will come into life in the future. |
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