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Research regarding potential other pharmacological
activity of Hydrastis canadensis (goldenseal) and/or its active
compounds berberine and hydrastine
This information has been complied in order to facilitate
the research efforts of health care professionals and others. These
statements have not been evaluated by the Food and Drug Administration and
are not intended diagnose, treat, cure, prevent, mitigate, or prevent any
disease. The information is presented with the latest publications first.
This is an ongoing work so check back often as we will update these pages as
more information becomes available. Also see the anti-parasitic and
anti-diarrhea pages. Last Updated :
Interactions between natural health products and
antiretroviral drugs: pharmacokinetic and pharmacodynamic effects.
Lee LS, Andrade AS, Flexner C.
Division of Clinical Pharmacology, Johns Hopkins University, Baltimore, MD,
Clin Infect Dis. 2006 Oct 15;43(8):1052-9.
Concurrent use of natural health products (NHPs) with antiretroviral drugs (ARVs)
is widespread among human immunodeficiency virus-infected patients. This
article reviews the clinical pharmacokinetic and pharmacodynamic
interactions between NHPs and ARVs. Many NHPs are complex mixtures and are
likely to contain organic compounds that may induce and/or inhibit drug
metabolizing enzymes and drug transporters. Although the weight of evidence
for the effects of certain NHPs varies and many studies of these products
lack scientific rigor, it has been observed that St. John's wort clearly
induces cytochrome P450 3A4 and P-glycoprotein and reduces protease
inhibitor and nonnucleoside reverse-transcriptase inhibitor concentrations,
thereby increasing the likelihood of therapeutic failure. Limited clinical
research suggests that intake of garlic and vitamin C results in reductions
in ARV concentrations. The intake of milk thistle, Echinacea species, and
goldenseal inhibits cytochrome P450 enzymes in vitro and may increase ARV
concentrations, but by clinically unimportant amounts. Intake of fish
oil reduces ARV-induced hypertriglyceridemia without significantly affecting
lopinavir concentrations. Before recommending the use of NHPs as adjuncts to
ARV use, studies should first exclude significant pharmacokinetic
interactions and ensure that ARV efficacy is maintained.
In vitro antioxidant studies on the benzyl tetra
isoquinoline alkaloid berberine.
Shirwaikar A, Shirwaikar A, Rajendran K, Punitha IS.
Biol Pharm Bull. 2006 Sep;29(9):1906-10.
Berberine is a benzyl tetra isoquinoline alkaloid which is widely used as an
antimicrobial and an antidiarrhoeal. As berberine containing plants are
virtually used in all forms of traditional medicine, our study aimed to
examine the antioxidant activity of berberine using 2,2-diphenyl
1-picrylhydrazyl (DPPH) radical scavenging, nitric oxide scavenging, lipid
peroxidation, superoxide scavenging, iron chelating activity and 2,2-azino
bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) radical scavenging methods.
The IC(50) values for all the models were calculated by regression analysis.
In all the models tested, berberine showed its ability to scavenge the free
radicals in a concentration dependent manner. The present study thereby
justifies the therapeutic potential of berberine.
Pharmacological Properties of Traditional Medicine
(XXXII): Protective Effects of Hangeshashinto and the Combinations of Its
Major Constituents on Gastric Lesions in Rats.
Kawashima K, Fujimura Y, Makino T, Kano Y.
Biol Pharm Bull. 2006 Sep;29(9):1973-5.
The protective effect of Hangeshashinto (HST) and its major constituents,
baicalin (BA), berberine (BE), saponin fraction of ginseng (GS) and
glycyrrhizin (GL) on rat gastric lesion induced by ethanol was examined to
clarify its active ingredients and action mechanism. Oral treatment with HST
at the doses of 125 and 250 mg/kg suppressed ethanol-induced gastric
lesions. The mixture of BA, BE, GL and GS (4M), each of BE, GL and GS at the
dosage corresponded to HST (125 mg/kg) also suppressed the ethanol-induced
gastric lesion in rats, but BA did not. Treatment of ethanol augmented the
activity of myeloperoxidase (MPO) in the stomach, which was significantly
suppressed by the administration of HST, BE, GL and GS. These results
suggest that the protective effect of HST on ethanol-induced gastric lesion
was depended on BE, GL and GS, by, in part, the reduction of MPO activity in
Pharmacokinetics of Berberine and Its Main Metabolites in
Conventional and Pseudo Germ-Free Rats Determined by Liquid Chromatography
Ion Trap Mass Spectrometry.
Zuo F, Nakamura N, Akao T, Hattori M.
Drug Metab Dispos. 2006 Sep 6;
Berberine (Ber) and its main metabolites were identified and quantified
using liquid chromatography/electrospray ionization (ESI)-ion trap mass
spectrometry. Rat plasma contained the main metabolites, berberrubine (M1),
thalifendine (M2), demethyleneberberine (M3) and jatrorrhizine (M4) as free
and glucuronide conjugates after oral Ber administration. Moreover, the
original drug, the four main metabolites and their glucuronide-conjugates
were all detected in liver tissues after 0.5 h and in bile samples 1 h after
oral Ber administration. Therefore, the metabolic site seemed to be the
liver, and the metabolites and conjugates were evidently excreted into the
duodenum as bile. The pharmacokinetics of Ber and the four metabolites were
determined in conventional and pseudo germ-free rats (treated with
antibiotics) after oral administration with 40 mg.kg(-1)of Ber. The
AUC0-limt and mean transit time (MTT) values of the metabolites
significantly differed between conventional and pseudo germ-free rats. The
amounts of metabolites were remarkably reduced in the pseudo germ-free rats,
whereas levels of Ber did not obviously differ between the two groups. The
intestinal flora did not exert significant metabolic activity against Ber
and its metabolites, but it played a significant role in the enterohepatic
circulation of Ber. In this sense, the liver and intestinal bacteria
participate in the metabolism and disposition of Ber in vivo.
[Protective effects of total alkaloids from rhizoma Coptis
chinensis on alcohol-induced gastric lesion in rats]
Li B, Liu HR, Pan YQ, Jiang QS, Shang JC, Wan XH, He BC, Yang
JQ, Zhou QX.
Zhongguo Zhong Yao Za Zhi. 2006 Jan;31(1):51-4.
OBJECTIVE: To study the effects of total alkaloids(TA) from rhizoma Coptis
chinensis on alcohol-induced gastric lesion in rats and the possible
mechanisms. METHOD: The experimental gastric damges were established by
intragastric(ig) absolute ethanol, and possible protective effects of TA
given orally previously were evaluated by following parameters: gastric
damage indexes, gastric juice volume, acidity, and mucus quantity. The
contents of NO, MDA, *OH, and SOD activity were also measured in gastric
mucosa. RESULT: TA showed significantly inhibitive effects on gastric
damages induced by ig ethanol in a dose dependent manner. The effects of TA
(120 mg x kg(-1)) were stronger than that of both cimitidine(70 mg x kg(-1))
and berberine(100 mg x kg(-1)), the quantity of later was equal to TA as
calculated with berberine. TA significantly suppressed secretion of gastric
acid caused by ethanol without clear influences on gastric juice volume and
mucus secretion. TA obviously blunted ethanol-induced elevation of MDA and
*OH, as well as decrease of NO level and SOD activity from gastric mucosa.
CONCLUSION: It is suggested that the TA is a potent protective agent against
ethanol-induced gastric damages. The mechanism of actions may be related
with inhibiting the secretion of gastric acid and blunting the increase of
MDA and *OH, as well as the decrease of NO level and SOD activity from
Effects of berberine on the blood concentration of
cyclosporin A in renal transplanted recipients: clinical and pharmacokinetic
Wu X, Li Q, Yu A, Zhong M
Eur J Clin Pharmacol. 2005 Aug 26;
OBJECTIVE: To study the effects of berberine (BBR) on the blood
concentration and pharmacokinetics of cyclosporin A (CsA) in
renal-transplant recipients.METHODS: In a randomized and controlled clinical
trial, 52 renal-transplant recipients were treated with CsA and 0.2 g BBR
three times daily for 3 months, while another 52 subjects received CsA
without BBR co-administration. Blood trough concentration of CsA and
biochemistry indexes for hepatic and renal functions were determined. For
the pharmacokinetic study, six renal-transplant recipients were included
with a 3-mg/kg dosage of CsA twice daily before and after oral
co-administration of 0.2 g BBR three times daily for 12 days.RESULTS: The
trough blood concentrations and the ratios of concentration/dose of CsA in
the BBR-treated group increased by 88.9% and 98.4%, respectively, compared
with those at baseline (P<0.05). As for the BBR-free group, they rose by
64.5% and 69.4%, respectively, relative to those at baseline (P<0.01).
Nevertheless, the final blood concentrations and the ratios of
concentration/dose of CsA in BBR-treated patients were still 29.3% and
27.8%, respectively, higher than those in BBR-free patients (P<0.05). No
significant effects on liver or renal functions were observed under
coadministration of BBR. After co-administration of BBR in six patients for
12 days, the mean AUC of CsA was increased by 34.5% (P<0.05). The mean time
taken to reach the peak blood concentration (t(max)) and the mean half-life
(t(1/2)) of CsA were increased by 1.7 h and 2.7 h, respectively (P<0.05).
The average percentage increases in the steady-state drug concentration
(C(ss)) and minimum blood concentration (C(min)) were 34.5% and 88.3%,
respectively (P<0.05). In addition, the average percentage decrease in CL/F
was 40.4% (P<0.05) and the peak-to-through fluctuation index was
significantly reduced (P<0.01).CONCLUSION: The BBR can markedly elevate
the blood concentration of CsA in renal-transplant recipients in both
clinical and pharmacokinetic studies. This combination may allow a
reduction of the CsA dosage. The mechanism for this interaction is most
likely explained by inhibition of CYP3A4 by BBR in the liver and/or small
Acetaldehyde-induced interleukin-1beta and tumor necrosis
factor-alpha production is inhibited by berberine through nuclear
factor-kappaB signaling pathway in HepG2 cells.
Hsiang CY, Wu SL, Cheng SE, Ho TY
J Biomed Sci.
2005 Aug 19;:1-11
Alcoholic liver disease (ALD) is one of the most common liver diseases in
the world. Increased levels of proinflammatory cytokines, including
interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha),
have been correlated with the patients affected by ALD. However, the direct
effect of alcohol in the induction of IL-1beta and TNF-alpha has not been
clarified. In this study, we demonstrated that acetaldehyde, the metabolic
product of ethanol, was able to induce IL-1beta and TNF-alpha production in
HepG2 cells. Nuclear factor-kappaB (NF-kappaB), the transcription factor
involved in the regulation of cytokine production, was also activated by
acetaldehyde through inhibitory kappaB-alpha (IkappaB-alpha) phosphorylation
and degradation. However, the NF-kappaB inhibitors, such as aspirin,
cyclosporin A and dexamethasone, inhibited both the acetaldehyde-induced
NF-kappaB activity and the induced cytokine production. Therefore, these
data suggested that acetaldehyde stimulated IL-1beta and TNF-alpha
production via the regulation of NF-kappaB signaling pathway. By screening
297 controlled Chinese medicinal herbs supervised by Committee on Chinese
Medicine and Pharmacy at Taiwan, we found that Coptis chinensis (Huang-Lien)
and Phellodendron amurense (Huang-Po) were capable of inhibiting
acetaldehyde-induced NF-kappaB activity. Berberine, the major ingredient of
these herbs, abolished acetaldehyde-induced NF-kappaB activity and cytokine
production in a dose-dependent manner. Moreover, its inhibitory ability was
through the inhibition of induced IkappaB-alpha phosphorylation and
degradation. In conclusion, we first linked the acetaldehyde-induced
NF-kappaB activity to the induced proinflammatory cytokine production in
HepG2 cells. Our findings also suggested the potential role of berberine in
the treatment of ALD.
Acetylcholinesterase inhibitors from the aerial parts of
Kim DK, Lee KT, Baek NI, Kim SH, Park HW, Lim JP, Shin TY,
Eom DO, Yang JH, Eun JS.
Arch Pharm Res. 2004 Nov;27(11):1127-31.
In a bioassay-guided search for acetylcholinesterase inhibitors from Korean
natural resources, four isoquinoline alkaloids, corynoxidine (1), protopine
(2), palmatine (3), and berberine (4) have been isolated from the methanolic
extract of the aerial parts of Corydalis speciosa. Structures of these
compounds were elucidated on the basis of spectroscopic techniques. These
compounds inhibited acetylcholinesterase activity in a dose-dependent
manner, and the IC50 values of compounds 1-4 were 89.0, 16.1, 5.8, and 3.3
Hepatobiliary excretion of berberine.
Tsai PL, Tsai TH.
Drug Metab Dispos. 2004 Apr;32(4):405-12.
Berberine is a bioactive herbal ingredient isolated from the roots and bark
of Berberis aristata or Coptis chinensis. To investigate the detailed
pharmacokinetics of berberine and its mechanisms of hepatobiliary excretion,
an in vivo microdialysis coupled with high-performance liquid chromatography
was performed. In the control group, rats received berberine alone; in the
drug-treated group, 10 min before berberine administration, the rats were
injected with cyclosporin A (CsA), a P-glycoprotein (P-gp) inhibitor;
quinidine, both organic cation transport (OCT) and P-gp inhibitors; SKF-525A
(proadifen), a cytochrome P450 inhibitor; and probenecid to inhibit the
glucuronidation. The results indicate that berberine displays a linear
pharmacokinetic phenomenon in the dosage range from 10 to 20 mg kg(-1),
since a proportional increase in the area under the concentration-time curve
(AUC) of berberine was observed in this dosage range. Moreover, berberine
was processed through hepatobiliary excretion against a concentration
gradient based on the bile-to-blood distribution ratio (AUC(bile)/AUC(blood));
the active berberine efflux might be affected by P-gp and OCT since
coadministration of berberine and CsA or quinidine at the same dosage of 10
mg kg(-1) significantly decreased the berberine amount in bile. In addition,
berberine was metabolized in the liver with phase I demethylation and phase
II glucuronidation, as identified by liquid chromatography/tandem mass
spectrometry. Also, the phase I metabolism of berberine was partially
reduced by SKF-525A treatment, but the phase II glucuronidation of berberine
was not obviously affected by probenecid under the present study design.
Effects of (1R,9S)-beta-hydrastine on l-DOPA-induced
cytotoxicity in PC12 cells.
Yin SY, Lee JJ, Kim YM, Jin CM, Yang YJ, Kang
MH, Kai M, Lee MK.
Eur J Pharmacol. 2004 Mar
(1R,9S)-beta-Hydrastine in lower concentrations of 10-50 microM inhibits
dopamine biosynthesis in PC12 cells. In this study, the effects of
(1R,9S)-beta-hydrastine on L-DOPA (L-3,4-dihydroxyphenylalanine)-induced
cytotoxicity in PC12 cells were investigated. (1R,9S)-Hydrastine at
concentrations up to 250 microM did not reduce cell viability. However, at
concentrations higher than 500 microM it caused cytotoxicity in PC12 cells,
as determined with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide (MTT) assay, TUNEL (terminal deoxynucleotidyltransferase dUTP
nick-end labeling) method and flow cytometry. Exposure of PC12 cells to
cytotoxic concentrations of (1R,9S)-beta-hydrastine (500 and 750 microM) in
combination with L-DOPA (20, 50 and 100 microM) after 24 or 48 h resulted in
a significant decrease in cell viability compared with the effects of
(1R,9S)-beta-hydrastine or L-DOPA alone, and apoptotic cell death was
observed. However, the decrease in cell viability induced by
(1R,9S)-beta-hydrastine was not prevented by the antioxidant N-acetyl-L-cysteine,
indicating that it is not mediated by membrane-based oxygen free radical
damage. These data suggest that (1R,9S)-beta-hydrastine has a mild
cytotoxic effect and at higher concentration ranges aggravates L-DOPA-induced
cytotoxicity in PC12 cells.
Influence of goldenseal root on the pharmacokinetics of
Sandhu RS, Prescilla RP, Simonelli TM, Edwards DJ.
J Clin Pharmacol. 2003 Nov;43(11):1283-8.
Goldenseal root was identified as the most potent inhibitor of CYP3A4 in a
study that tested 21 popular herbal products for in vitro inhibitory
activity. The purpose of this investigation was to examine the influence of
goldenseal root on the disposition of the CYP3A4 substrate indinavir in
humans. Using a crossover study design, the pharmacokinetics of indinavir
were characterized in 10 healthy volunteers before and after 14 days of
treatment with goldenseal root (1140 mg twice daily). Indinavir was given as
a single 800-mg oral dose, and blood samples were collected for 8 hours
following the dose. No statistically significant differences in peak
concentration (11.6 vs. 11.9 mg/L) or oral clearance (26.8 vs. 23.9 mg*h/L)
were observed following treatment with goldenseal root. Half-life and time
to reach peak concentration were also unchanged by goldenseal. These
results suggest that patients being treated with indinavir can safely take
goldenseal root and that interactions with other drugs metabolized by CYP3A4
in the liver are unlikely.
Potentiation of nerve growth factor-induced neurite
outgrowth in PC12 cells by a Coptidis Rhizoma extract and protoberberine
Shigeta K, Ootaki K, Tatemoto H, Nakanishi T, Inada A, Muto
Biosci Biotechnol Biochem. 2002 Nov;66(11):2491-4.
A methanol extract of Coptidis Rhizoma effectively enhanced the outgrowth of
neurite in PC12 cells induced by nerve growth factor (NGF). Following
solvent partition and preparative HPLC, berberine was isolated as the major
active compound. Berberine enhanced the proportion of neurite-bearing cells
in a dose-dependent manner without cytotoxicity. Its structural relatives,
palmatine and coptisine, showed a slightly weaker NGF-enhancing effect than
berberine. These three alkaloids inhibited acetylcholinesterase activity at
a level comparable to that of physostigmine, but this inhibition was not
responsible for the potentiation of NGF-induced neurite outgrowth. It is
demonstrated for the first time that protoberberine alkaloids potentiated
the NGF-induced differentiation of neural cells.
Monoamine oxidase inhibitors from rhizoma of Coptis
Kong LD, Cheng CH, Tan RX.
Planta Med. 2001 Feb;67(1):74-6.
Three protoberberine alkaloids jatrorrhizine, berberine and palmatine were
isolated from the monoamine oxidase (MAO) inhibitory fraction of the
methanol extract of Coptis chinensis rhizoma. Jatrorrhizine was shown to
inhibit non-competitively both MAO-A and -B from rat brain mitochondria with
the IC50 values of 4 and 62 microM, respectively. Berberine only
competitively inhibited MAO-A with an IC50 values of 126 microM whereas
palmatine exhibited, up to 200 microM, no inhibition on any type of the
enzyme. The structure-activity relationship was briefly discussed.
An in vitro evaluation of human cytochrome P450 3A4
inhibition by selected commercial herbal extracts and tinctures.
Budzinski JW, Foster BC, Vandenhoek S, Arnason JT.
Phytomedicine. 2000 Jul;7(4):273-82.
Serial dilutions of 21 commercial ethanolic herbal extracts and tinctures,
and 13 related pure plant compounds have been analyzed for their in vitro
cytochrome P450 3A4 (CYP3A4) inhibitory capability via a fluorometric
microtitre plate assay. Roughly 75% of the commercial products and 50% of
the pure compounds showed significant inhibition of CYP3A4 metabolite
formation. For each herbal product and pure compound exhibiting
dose-dependency, the inhibition values were used to generate median
inhibitory concentration (IC50) curves using linear regression. Among the
commercial extracts, Hydrastis canadensis (goldenseal), Hypericum
perforatum (St. John's wort), and Uncaria tomentosa (cat's claw) had the
lowest IC50 values at < 1% full strength, followed by Echinacea
angustifolia roots, Trifolium pratense (wild cherry), Matricaria chamomilla
(chamomile), and Glycyrrhiza glabra (licorice), which had IC50 values
ranging from 1%-2% of full strength. Dillapiol, hypericin, and naringenin
had the lowest IC50 values among the pure plant compounds at < 0.5 mM;
dillapiol was the most potent inhibitor at 23.3 times the concentration of
the positive CYP3A4 inhibitor ketoconazole. Utilizing high-throughput
screening methodologies for assessing CYP3A4 inhibition by natural products
has important implications for predicting the likelihood of potential
herbal-drug interactions, as well as determining candidates for further
(+)-Hydrastine, a potent competitive antagonist at
mammalian GABAA receptors.
Huang JH, Johnston GA.
Br J Pharmacol. 1990 Apr;99(4):727-30.
1. (+)-Hydrastine is a
phthalide isoquinoline alkaloid, isolated from Corydalis stricta. It has the
same 1S,9R configuration as the competitive GABAA receptor antagonist
bicuculline and is the enantiomer of the commercially available
(-)-hydrastine. 2. (+)-Hydrastine (CD50 0.16 mg kg-1, i.v.) was twice as
potent as bicuculline (CD50 0.32 mg kg-1, i.v.) as a convulsant in mice.
This action was stereoselective in that (+)-hydrastine was 180 times as
potent as (-)-hydrastine. 3. (+)-Hydrastine was a selective antagonist at
bicuculline-sensitive GABAA receptors in the guinea-pig isolated ileum. It
did not influence phaclofen-sensitive GABAB receptors or acetylcholine
receptors in this tissue. (+)-Hydrastine was a competitive antagonist of
GABAA responses (pA2 6.5) more potent than bicuculline (pA2 6.1). 4. When
tested against the binding of [3H]-muscimol to high affinity GABAA binding
sites in rat brain membranes, (+)-hydrastine (IC50 2.37 microM) was 8 times
more potent than bicuculline (IC50 19.7 microM). 5. As an antagonist of the
activation of low affinity GABAA receptors as measured by the stimulation by
GABA of [3H]-diazepam binding to rat brain membranes, (+)-hydrastine (IC50
0.4 microM) was more potent than bicuculline (IC50 2.3 microM). 6.
(+)-Hydrastine, 10 nM to 1 mM, did not inhibit the binding of [3H]-(-)-baclofen
to GABAB binding sites in rat brain membranes.
Berberine sulfate blocks adherence of Streptococcus
pyogenes to epithelial cells, fibronectin, and hexadecane.
Sun D, Courtney HS, Beachey EH.
Antimicrob Agents Chemother. 1988
Berberine sulfate is an alkaloid extracted from the roots and bark of
various plants and possesses antibacterial, antifungal, and antiprotozoal
activities. Most studies have focused on the bacteriostatic or bactericidal
activities of this compound. In this study, we report that berberine sulfate
is bacteriostatic for streptococci and that sub-MICs of berberine blocked
the adherence of streptococci to host cells, immobilized fibronectin, and
hexadecane. Concentrations of berberine below its MIC caused an eightfold
increase in release of lipoteichoic acid from the streptococci. Higher
concentrations of berberine directly interfered with the adherence of
streptococci to host cells either by preventing the complexing of
lipoteichoic acid with fibronectin or by dissolution of such complexes once
they were formed. Thus, berberine sulfate interferes with the adherence
of group A streptococci by two distinct mechanisms: one by releasing the
adhesin lipoteichoic acid from the streptococcal cell surface and another by
directly preventing or dissolving lipoteichoic acid-fibronectin complexes.
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