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1.  A Standardized Kudzu Extract (NPI-031) Reduces Alcohol Consumption in Non Treatment-Seeking Male Heavy Drinkers 
Psychopharmacology  2012;226(1):65-73.
OBJECTIVE
We previously demonstrated that short-term treatment with a standardized kudzu extract (NPI-031) reduced alcohol drinking by men and women in a natural setting. The present study was conducted in non treatment-seeking heavy drinkers to assess the safety and efficacy of four weeks of kudzu extract in an outpatient setting.
METHOD
This randomized between-subject, double-blind, placebo-controlled study involved two weeks of baseline, four weeks of treatment and two weeks of follow-up. Seventeen men (21–33 years) who reported drinking 27.6 ± 6.5 drinks/week with a diagnosis of alcohol abuse/dependence took either kudzu extract (250 mg isoflavones, t.i.d.) or matched placebo on a daily basis. They reported alcohol consumption and desire to use alcohol using a wrist actigraphy device; twice weekly laboratory visits were scheduled to monitor medication adherence and adverse events.
RESULTS
Medication adherence was excellent and there were no adverse events, changes in vital signs, blood chemistry, renal or liver function. There was no effect on alcohol craving, but kudzu extract significantly reduced the number of drinks consumed each week by 34–57%, reduced the number of heavy drinking days and significantly increased the percent of days abstinent and the number of consecutive days of abstinence.
CONCLUSIONS
A standardized formulation of kudzu extract produced minimal side effects, was well-tolerated and resulted in a modest reduction in alcohol consumption in young non treatment-seeking heavy drinkers. Additional studies using treatment-seeking alcohol-dependent persons will be necessary to determine the usefulness of this herbal preparation in reducing alcohol use in other populations.
doi:10.1007/s00213-012-2884-9
PMCID: PMC3562758  PMID: 23070022
2.  The Isoflavone Puerarin Reduces Alcohol Intake in Heavy Drinkers: A Pilot Study 
Drug and alcohol dependence  2012;126(1-2):251-256.
Background
Isoflavone compounds naturally occurring in the root of the kudzu plant have been used historically to treat alcohol-related problems. A pilot study was conducted to assess the effects of one primary isoflavone - puerarin- for its ability to modify alcohol intake in humans.
Methods
Ten (10) healthy adult volunteers were administered puerarin (1200 mg daily) in a double-blind, placebo-controlled, crossover design experiment for one week prior to an afternoon drinking session lasting 1.5 hours. Participants had access to up to six bottles of their preferred brand of beer in addition to juice and water. A time course of drinking, sip volumes, and total amount consumed were recorded.
Results
Participants consumed on average 3.5 (± 0.55) beers when treated with placebo and 2.4 (± 0.41) beers when treated with puerarin. In contrast to drinking following placebo treatment when 3 participants drank 5 beers and 1 participant drank all 6 beers, none drank 5 or 6 beers when treated with puerarin. Drinking topography also changed. When treated with puerarin, participants decreased sip size, took more sips to finish a beer, and took longer to consume each beer. Additionally, after finishing a beer, latency to opening the next beer was increased.
Conclusions
This study is the first demonstration that a single isoflavone found in the kudzu root can alter alcohol drinking in humans. These results suggest that alcohol consumption patterns are influenced by puerarin administration and this botanical medication may be a useful adjunct in the treatment of excessive alcohol intake.
doi:10.1016/j.drugalcdep.2012.04.012
PMCID: PMC3430804  PMID: 22578529
isoflavone; alcohol consumption; binge drinking; humans
3.  Microarray Analysis Reveals the Molecular Basis of Antiarthritic Activity of Huo-Luo-Xiao-Ling Dan 
Rheumatoid arthritis (RA) is a chronic inflammatory disease of autoimmune origin. Huo-luo-xiao-ling dan (HLXL) is an herbal mixture that has been used in traditional Chinese medicine over several decades to treat chronic inflammatory diseases including RA. However, the mechanism of the anti-arthritic action of this herbal remedy is poorly understood at the molecular level. In this study, we determined by microarray analysis the effects of HLXL on the global gene expression profile of the draining lymph node cells (LNC) in the rat adjuvant arthritis (AA) model of human RA. In LNC restimulated in vitro with the disease-related antigen mycobacterial heat-shock protein 65 (Bhsp65), 84 differentially expressed genes (DEG) (64 upregulated and 20 downregulated) versus 120 DEG (94 upregulated and 26 downregulated) were identified in HLXL-treated versus vehicle (Water)-treated rats, respectively, and 62 DEG (45 upregulated and 17 downregulated) were shared between the two groups. The most affected pathways in response to HLXL treatment included immune response, inflammation, cellular proliferation and apoptosis, and metabolic processes, many of which are directly relevant to arthritis pathogenesis. These results would advance our understanding of the mechanisms underlying the anti-arthritic activity of HLXL.
doi:10.1155/2013/524746
PMCID: PMC3745855  PMID: 23983789
4.  Chinese Herbal Formula Huo-Luo-Xiao-Ling Dan Protects against Bone Damage in Adjuvant Arthritis by Modulating the Mediators of Bone Remodeling 
Huo-luo-xiao-ling dan (HLXL) is an herbal mixture that has long been used in traditional Chinese medicine for the treatment of rheumatoid arthritis (RA) and other inflammatory disorders. Despite the availability of potent conventionally used drugs for RA, their limited efficacy in a proportion of patients coupled with their high cost and severe adverse effects has necessitated the search for novel therapeutics for this debilitating disease. Further, the control of both inflammation and bone damage is essential for effective management of arthritis. The aim of our study was to evaluate the efficacy of HLXL against arthritic bone damage in adjuvant arthritis (AA) model of RA. Our results show that HLXL treatment suppressed inflammatory arthritis and reduced bone and cartilage damage in the joints of arthritic Lewis rats. HLXL-induced protection against bone damage was mediated primarily via inhibition of mediators of osteoclastic bone remodeling (e.g., receptor activator of nuclear factor kappa-B ligand; RANKL), skewing of RANKL/osteoprotegerin (OPG) ratio in favor of antiosteoclastic activity, reduction in the number of osteoclasts in the arthrodial joint's bone, and inhibition of cytokine production and MMP activity. Our results suggest that HLXL might offer a promising alternative/adjunct treatment for both inflammation and bone damage in RA.
doi:10.1155/2013/429606
PMCID: PMC3670518  PMID: 23762133
5.  Effects of transcutaneous electric acupoint stimulation on drug use and responses to cue-induced craving: a pilot study 
Chinese Medicine  2012;7:14.
Background
Transcutaneous electric acupoint stimulation (TEAS) avoids the use of needles, and instead delivers a mild electric current at traditional acupoints. This technique has been used for treating heroin addiction, but has not been systematically tested for other drugs of abuse. This study aims to investigate the effects of TEAS on drug addiction.
Methods
Volunteers who were either cocaine-dependent (n = 9) or cannabis-dependent (n = 11) but were not seeking treatment for their dependence participated in a within-subject, single-blind study. Treatment consisted of twice daily 30-minute sessions of TEAS or sham stimulation for 3.5 days. The active TEAS levels were individually adjusted to produce a distinct twitching response in the fingers, while the sham stimulation involved 2 minutes of stimulation at threshold levels followed by 28 minutes of stimulation below the detection levels. The participants recorded their drug use and drug cravings daily. At 1 hour after the last morning session of TEAS or sham stimulation, a cue-induced craving EEG evaluation was conducted. Event-related P300 potentials (ERPs) were recorded, sorted, and analyzed for specific image types (neutral objects, non-drug-related arousing images, or drug-related images).
Results
TEAS treatment did not significantly reduce the drug use or drug cravings, or significantly alter the ERP peak voltage or latency to peak response. However, the TEAS treatment did significantly modulate several self-reported measures of mood and anxiety.
Conclusion
The results of this pilot study with a limited sample size suggest that the acupoint stimulation techniques and protocol used in this trial alone do not significantly reduce cravings for or use of cocaine or cannabis. The findings that TEAS modulates mood and anxiety suggest that TEAS could be used as an adjunct in a multimodal therapy program to treat cocaine and cannabis dependence if confirmed in a full randomized controlled clinical trial.
doi:10.1186/1749-8546-7-14
PMCID: PMC3412709  PMID: 22682006
6.  Modified Huo-Luo-Xiao-Ling Dan Suppresses Adjuvant Arthritis by Inhibiting Chemokines and Matrix-Degrading Enzymes 
Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting the joints that can lead to deformities and disability. The prolonged use of conventionally used drugs is associated with severe adverse reactions. Therefore, safer and less expensive therapeutic products are continually being sought. Huo-Luo-Xiao-Ling dan (HLXL), a traditional Chinese herbal mixture, and its modified versions possess anti-arthritic activity. In this paper, we examined the influence of modified HLXL on two of the key mediators of arthritic inflammation and tissue damage, namely, chemokines and matrix-metalloproteinases (MMPs) in the rat adjuvant-induced arthritis (AA) model of RA. We treated arthritic Lewis rats with HLXL (2.3 g/kg) by daily gavage beginning at the onset of AA. The control rats received the vehicle. At the peak phase of AA, rats were sacrificed and their draining lymph node cells (LNC) and spleen adherent cells (SAC) were tested. The HLXL-treated rats showed a significant reduction in the levels of chemokines (RANTES, MCP-1, MIP-1α, and GRO/KC), MMPs (MMP 2 and 9), as well as cytokines (IL-6 and IL-17) that induce them, compared to the control vehicle-treated rats. Thus, HLXL controls arthritis in part by suppressing the mediators of immune pathology, and it might offer a promising alternative/adjunct treatment for RA.
doi:10.1155/2012/589256
PMCID: PMC3310235  PMID: 22474510
7.  Novel coumarin glycoside and phenethyl vanillate from Notopterygium forbesii and their binding affinities for opioid and dopamine receptors 
Bioorganic & medicinal chemistry  2007;16(6):3218-3223.
Bioactivity-guided fractionation of Notopterygium forbesii has resulted in the isolation of one new coumarin glycoside and one new phenethyl vanillate, together with seventeen known compounds. The structures of these compounds were characterized by spectroscopic methods. These compounds were evaluated for their binding affinities to the opioid and dopamine receptors, and falcarindiol showed weak binding affinities to opioid receptors and moderate affinity for D1 receptor (Ki = 192±6 nM).
doi:10.1016/j.bmc.2007.12.021
PMCID: PMC2366027  PMID: 18166466
Notopterygium forbesii; Coumarin; Falcarindiol; Opioid receptor; Dopamine receptor
8.  Synthesis of deacetyl-1,10-didehydrosalvinorin G 
Tetrahedron letters  2008;49(11):1782-1785.
To unambiguously confirm the actual product in autoxidation of salvinorin A under basic conditions, deacetyl-1,10-didehydrosalvinorin G was synthesized from salvinorin C via intermediate salvinorin H. Furthermore, oxidation of salvinorin D with manganese dioxide gave salvinorin G in good yield.
doi:10.1016/j.tetlet.2008.01.065
PMCID: PMC2390901  PMID: 19279674
Salvinorin A; Oxidation; Manganese dioxide; Synthesis
9.  2-Methoxymethyl-Salvinorin B Is a Potent κ Opioid Receptor Agonist with Longer Lasting Action in Vivo Than Salvinorin A 
Salvinorin (Sal) A is a naturally occurring, selective κ opioid receptor (KOPR) agonist with a short duration of action in vivo. Pharmacological properties of a C(2) derivative, 2-methoxy-methyl (MOM)-Sal B, were characterized. MOM-Sal B bound to KOPR with high selectivity and displayed ~3-fold higher affinity than U50,488H [(trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate] and Sal A. It acted as a full agonist at KOPR in guanosine 5′-O-(3-[35S]thio)triphosphate binding and was ~5- and ~7-fold more potent than U50,488H and Sal A, respectively. In Chinese hamster ovary cells stably expressing KOPR, all three κ agonists internalized or down-regulated KOPR to similar extents, with MOM-Sal B being the most potent. In mice, MOM-Sal B (0.05–1 mg/kg s.c.) caused immediate and dose-dependent immobility lasting ~3 h, which was blocked by norbinaltorphimine. In contrast, ambulation in a Y-maze was increased when rats received MOM-Sal B (1–5 mg/kg s.c.). In addition, MOM-Sal B (0.5–5 mg/kg i.p.) produced antinociception (hot-plate test) and hypothermia in a dose-dependent manner in rats. MOM-Sal B was more potent than U50,488H in both tests and more efficacious than U50,488H in the hot-plate test. These latter two in vivo effects were blocked by norbinaltorphimine, indicating KOPR-mediated actions. Sal A at 10 mg/kg elicited neither antinociception nor hypothermia 30 min after administration to rats. In summary, MOM-Sal B is a potent and efficacious KOPR agonist with longer lasting in vivo effects than Sal A.
doi:10.1124/jpet.107.132142
PMCID: PMC2519046  PMID: 18089845
10.  Revised structure of deacetyl-1,10-didehydrosalvinorin G 
Tetrahedron letters  2007;48(31):5461-5464.
In comparison with the NMR data of salvinorin A and its 8-epimer, the published structure of deacetyl-1,10-didehydrosalvinorin G was revised to its 8-epimer. The stereochemistry of 8-epi-deacetyl-1,10-didehydrosalvinorin G was further confirmed by NOESY and chemical synthesis.
doi:10.1016/j.tetlet.2007.05.179
PMCID: PMC2390872  PMID: 18665199
Salvinorin A; Epimer; NMR; Revised structure
11.  Inhibition of highly productive HIV-1 infection in T cells, primary human macrophages, microglia, and astrocytes by Sargassum fusiforme 
Background
The high rate of HIV-1 mutation and increasing resistance to currently available antiretroviral (ART) therapies highlight the need for new antiviral agents. Products derived from natural sources have been shown to inhibit HIV-1 replication during various stages of the virus life cycle, and therefore represent a potential source of novel therapeutic agents. To expand our arsenal of therapeutics against HIV-1 infection, we investigated aqueous extract from Sargassum fusiforme (S. fusiforme) for ability to inhibit HIV-1 infection in the periphery, in T cells and human macrophages, and for ability to inhibit in the central nervous system (CNS), in microglia and astrocytes.
Results
S. fusiforme extract blocked HIV-1 infection and replication by over 90% in T cells, human macrophages and microglia, and it also inhibited pseudotyped HIV-1 (VSV/NL4-3) infection in human astrocytes by over 70%. Inhibition was mediated against both CXCR4 (X4) and CCR5 (R5)-tropic HIV-1, was dose dependant and long lasting, did not inhibit cell growth or viability, was not toxic to cells, and was comparable to inhibition by the nucleoside analogue 2', 3'-didoxycytidine (ddC). S. fusiforme treatment blocked direct cell-to-cell infection spread. To investigate at which point of the virus life cycle this inhibition occurs, we infected T cells and CD4-negative primary human astrocytes with HIV-1 pseudotyped with envelope glycoprotein of vesicular stomatitis virus (VSV), which bypasses the HIV receptor requirements. Infection by pseudotyped HIV-1 (VSV/NL4-3) was also inhibited in a dose dependant manner, although up to 57% less, as compared to inhibition of native NL4-3, indicating post-entry interferences.
Conclusion
This is the first report demonstrating S. fusiforme to be a potent inhibitor of highly productive HIV-1 infection and replication in T cells, in primary human macrophages, microglia, and astrocytes. Results with VSV/NL4-3 infection, suggest inhibition of both entry and post-entry events of the virus life cycle. Absence of cytotoxicity and high viability of treated cells also suggest that S. fusiforme is a potential source of novel naturally occurring antiretroviral compounds that inhibit HIV-1 infection and replication at more than one site of the virus life cycle.
doi:10.1186/1742-6405-3-15
PMCID: PMC1481599  PMID: 16725040
12.  Boswellia carterii Extract Inhibits TH1 Cytokines and Promotes TH2 Cytokines In Vitro 
Traditional herbal formulas used to treat inflammatory arthritis in China and India include Boswellia carterii or Boswellia serrata. They both contain boswellic acids (BAs) which have been shown to exhibit anti-inflammatory and antiarthritic properties. This study tests the hypothesis that mixtures of BAs derived from B. carterii have immunomodulatory properties. B. carterii plant resin obtained from China was prepared as an ethanol extract, and the presence of seven BAs was confirmed by column chromatography, high-performance liquid chromatography, and UV laser desorption/ionization tandem mass spectroscopy. The extract was then tested for its ability to alter in vitro production of TH1 cytokines (interleukin-2 [IL-2] and gamma interferon) and TH2 cytokines (IL-4 and IL-10) by murine splenocytes. Delivery of the resin extract using ethanol as a solvent resulted in significant cellular toxicity not seen with the addition of ethanol alone. By contrast, delivery of the resin extract using a sesame oil solvent resulted in a dose-dependent inhibition of TH1 cytokines coupled with a dose-dependent potentiation of TH2 cytokines. These results indicate that a purified mixture of BAs from B. carterii plant resin exhibits carrier-dependent immunomodulatory properties in vitro.
doi:10.1128/CDLI.12.5.575-580.2005
PMCID: PMC1112084  PMID: 15879017

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