Charlie Changli Xue

Efficacy and Safety of a Chinese Herbal Medicine Formula (RCM-104) in the Management of Simple Obesity: A Randomized, Placebo-Controlled Clinical Trial

Objective. This study was to evaluate the efficacy and safety of a Chinese herbal medicine formula (RCM-104) for the management of simple obesity. Method. Obese subjects aged between 18 and 60 years were selected for 12-week, double-blind, randomized, placebo-controlled trial. Subjects were randomly assigned to take 4 capsules of either the RCM-104 formula (n = 59) or placebo (n = 58), 3 times daily for 12 weeks. Measures of BW, BMI and WC, HC, WHR and BF composition were assessed at baseline and once every four weeks during the 12 week treatment period. Results. Of the 117 subjects randomised, 92 were included in the ITT analysis. The weight, BMI and BF in RCM-104 group were reduced by 1.5 kg, 0.6 kg/m2 and 0.9% and those in the placebo group were increased by 0.5 kg, 0.2 kg/m2 and 0.1% respectively. There were significant differences in BW and BMI (P < 0.05) between the two groups. Eleven items of the WLQOQ were significantly improved in the RCM-104 group while only 2 items were significantly improved in the placebo group. Adverse events were minor in both groups. Conclusion. RCM-104 treatment appears to be well tolerated and beneficial in reducing BW and BMI in obese subjects.

Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development

Human contains 49 ATP-binding cassette (ABC) transporter genes and the multidrug resistance associated proteins (MRP1/ABCC1, MRP2/ABCC2, MRP3/ABCC3, MRP4/ABCC4, MRP5/ABCC5, MRP6/ABCC6, MRP7/ABCC10, MRP8/ABCC11 and MRP9/ABCC12) belong to the ABCC family which contains 13 members. ABCC7 is cystic fibrosis transmembrane conductance regulator; ABCC8 and ABCC9 are the sulfonylurea receptors which constitute the ATP-sensing subunits of a complex potassium channel. MRP10/ABCC13 is clearly a pseudo-gene which encodes a truncated protein that is highly expressed in fetal human liver with the highest similarity to MRP2/ABCC2 but without transporting activity. These transporters are localized to the apical and/or basolateral membrane of the hepatocytes, enterocytes, renal proximal tubule cells and endothelial cells of the blood-brain barrier. MRP/ABCC members transport a structurally diverse array of important endogenous substances and xenobiotics and their metabolites (in particular conjugates) with different substrate specificity and transport kinetics. The human MRP/ABCC transporters except MRP9/ABCC12 are all able to transport organic anions, such as drugs conjugated to glutathione, sulphate or glucuronate. In addition, selected MRP/ABCC members may transport a variety of endogenous compounds, such as leukotriene C(4) (LTC(4) by MRP1/ABCC1), bilirubin glucuronides (MRP2/ABCC2, and MRP3/ABCC3), prostaglandins E1 and E2 (MRP4/ABCC4), cGMP (MRP4/ABCC4, MRP5/ABCC5, and MRP8/ABCC11), and several glucuronosyl-, or sulfatidyl steroids. In vitro, the MRP/ABCC transporters can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and in concert with alterations in phase II conjugating or biosynthetic enzymes, classical alkylating agents, alkylating agents. Several MRP/ABCC members (MRPs 1-3) are associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer chemotherapy. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Based on currently available preclinical and limited clinical data, it can be expected that modulation of MRP members may represent a useful approach in the management of anticancer and antimicrobial drug resistance and possibly of inflammatory diseases and other diseases. A better understanding of their substrates and inhibitors has important implications in development of drugs for treatment of cancer and inflammation.

Clinically important drug interactions potentially involving mechanism-based inhibition of cytochrome P450 3A4 and the role of therapeutic drug monitoring

Cytochrome P450 (CYP) 3A4 is the most abundant enzyme of CYPs in the liver and gut that metabolizes approximately 50% currently available drugs. A number of important drugs have been identified as substrates, inducers, and/or inhibitors of CYP3A4. The substrates of CYP3A4 considerably overlap with those of P-glycoprotein. Both CYP3A4 and P-glycoprotein are subject to inhibition and induction by a number of factors. Mechanism-based inhibition of CYP3A4 is characterized by NADPH-, time-, and concentration-dependent enzyme inactivation occurring when some xenobiotics or drugs are converted by CYPs to reactive metabolites. Such an inhibition of CYP3A4 is caused by chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. To date, the identified clinically important mechanism-based CYP3A4 inhibitors mainly include macrolide antibiotics (eg, clarithromycin and erythromycin), anti-HIV agents (eg, ritonavir and delavirdine), antidepressants (eg, fluoxetine and fluvoxamine), calcium channel blockers (eg, verapamil and diltiazem), steroids and their modulators (eg, gestodene and mifepristone), and several herbal and dietary components. The inactivation of CYP3A4 by drugs often causes unfavorable and long-lasting drug-drug interactions and probably fatal toxicity, depending on many factors associated with the enzyme, drugs, and the patients. Clinicians are encouraged to have a sound knowledge of drug-induced, mechanism-based CYP3A4 inhibition; take proper cautions, and perform close monitoring for possible drug interactions when using drugs that are mechanism-based CYP3A4 inhibitors. To minimize drug-drug interactions involving mechanism-based CYP3A4 inhibition, it is necessary to choose safe drug combination regimens, adjust drug dosages appropriately, and conduct therapeutic drug monitoring for drugs with narrow therapeutic indices.

Metabolic Activation of Herbal and Dietary Constituents and Its Clinical and Toxicological Implications: An Update

In recent years, there has been a globally increasing application of herbal medicines and dietary supplements to treat various chronic diseases and to promote health. However, there are increasing clinical reports on the organ toxicities associated with consumption of herbal medicines. This review updates the knowledge on metabolic activation of herbal components and its clinical and toxicological implications. Like many synthetic drugs undergoing metabolic activation to form reactive metabolites which are often associated with drug toxicity, it is recognized that some herbal components may also be converted to toxic, or even mutagenetic and carcinogenic metabolites by cytochrome P450s (CYPs) and less frequently by Phase II conjugating enzymes. This is exemplified by aristolochic acids (AAs) in Aristolochia spp, which undergo reduction of the nitro group by hepatic CYP1A1/2 or peroxidases in extrahepatic tissues to generate highly reactive cyclic nitrenium ions. The latter can react with macromolecules (DNA and protein), resulting in activation of H-ras oncogene and gene mutation in renal cells and finally carcinogenesis of the kidneys. Some naturally occurring flavonoids (e.g. quercetin) and alkenylbenzenes (e.g. safrole, methyleugenol and estragole) can undergo metabolic activation by sequential 1-hydroxylation and sulfation, resulting in reactive intermediates capable of forming DNA adducts and finally genotoxicity. Additional examples are pulegone present in essential oils from many mint species; and teucrin A, a diterpenoid found in germander (Teuchrium chamaedrys) used as an adjuvant to slimming dietary supplements but caused severe hepatotoxicity. Extensive pulegone metabolism generated p-cresol that was a glutathione depletory, whereas the furan ring of the diterpenoids in germander was oxidized by CYP3A4 to reactive epoxide which can inactivate hepatic CYP3A and epoxide hydrolase through covalent binding. The hepatotoxic and carcinogenic species of plant pyrrolizidine alkaloids (e.g. echimidine and jacobine), namely pyrrole-type metabolites, are generated by hepatic CYP2B6 and CYP3A4. Potential mechanisms underlying the hepatotoxicity of kava have been related to intracellular glutathione depletion and/or quinone formation. Some herbal constituents (e.g. capsaicin from chili peppers, glabridin from licorice root, oleuropein in olive oil, dially sulfone in garlic, and resveratrol found in red wine) behave as mechanism-based inhibitors of various CYPs. This may provide an explanation for some reported herb-drug interactions. In addition, the inhibition of CYPs by herbal constituents may decrease the formation of toxic metabolites and thus inhibit carcinogenesis, as CYPs play an important role in procarcinogen activation. Due to the wide use and easy availability of herbal medicines, further research should be conducted to ensure the safety and quality of herbal medicine.

Effect of acupuncture in the treatment of seasonal allergic rhinitis: a randomized controlled clinical trial.

The clinical efficacy and safety of acupuncture in the treatment of Seasonal Allergic Rhinitis (SAR) was evaluated by employing a two-phase crossover single-blind clinical trial. Thirty subjects were randomly assigned to two groups with 17 and 13 subjects respectively and treated with real or sham acupuncture (three times per week) for four consecutive weeks and then a crossover for treatments for a further four weeks without a washout period. The administration of real acupuncture treatment was guided by a syndrome differentiation according to Chinese Medicine Theory. Subjects were assessed by various criteria before, during and after the treatments. Outcome measures included subjective symptom scores using a five-point scale (FPS), relief medication scores (RMS) and adverse effect records. Twenty-six (26) subjects completed the study. There was a significant improvement in FPS (nasal and non-nasal symptoms) between the two types of acupuncture treatments. No significant differences were shown in RMS between the real acupuncture treatment group and the sham acupuncture treatment group. No side effects were observed for both groups. The results indicate that acupuncture is an effective and safe alternative treatment for the management of SAR.

Clinical drugs that interact with St. John's wort and implication in drug development.

St. Johns wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs that have distinctive chemical structure, mechanism of action and metabolic pathways. This review highlights and updates the knowledge on clinical interactions of prescribed drugs with SJW and the implication in drug development. A number of clinically significant interactions of SJW have been identified with conventional drugs, including anticancer agents (imatinib and irinotecan), anti-HIV agents (e.g. indinavir, lamivudine and nevirapine), anti-inflammatory agents (e.g. ibuprofen and fexofenadine), antimicrobial agents (e.g. erythromycin and voriconazole), cardiovascular drugs (e.g. digoxin, ivabradine, warfarin, verapamil, nifedipine and talinolol), central nervous system agents (e.g. amitriptyline, buspirone, phenytoin, methadone, midazolam, alprazolam, and sertraline), hypoglycaemic agents (e.g. tolbutamide and gliclazide), immuno-modulating agents (e.g. cyclosporine and tacrolimus), oral contraceptives, proton pump inhibitor (e.g. omeprazole), respiratory system agent (e.g. theophylline), statins (e.g. atorvastatin and pravastatin). Both pharmacokinetic and pharmacodynamic components may play a role in the interactions of drugs with SJW. For pharmacokinetic changes of drugs by SJW, induction of cytochrome P450s (e.g. CYP2C9 and 3A4) and P-glycoprotein (P-gp) are considered the major mechanism. Thus, it is not a surprise that many drugs that interact with SJW are substrates of CYP3A4, CYP2C9 and P-gp. A comprehensive understanding of clinical drugs that interact with SJW has important implications in drug development. New drugs may be designed to minimize interactions with SJW; and new SJW formulations may be designed to avoid drug interactions. Further clinical and mechanistic studies are warranted to explore the interaction of SJW with other important drugs and the potential clinical impact.

A numerical study of spray particle deposition in a human nasal cavity

Particle depositional studies from nasal sprays are important for efficient drug delivery. The main influences on deposition involve the nasal cavity geometry and the nasal spray device of which its parameters are controlled by the product design. It is known that larger particle sizes (≫ 10 μm) at a flow rate of 333 ml/s impact in the anterior portion of the nose, leaving a significant portion of the nasal cavity unexposed to the drugs. Studies have found correlations for the spray cone angles and particle sizes with deposition efficiencies. This study extends these ideas to incorporate other parameters such as the insertion angle of the nasal spray and the injected particle velocity to observe its effect on deposition. A numerical method utilizing a particle tracking procedure found that the most important parameter was the particles Stokes number which affected all other parameters on the deposition efficiency.

Panax ginseng in Randomised Controlled Trials: A Systematic Review

Panax ginseng C.A. Meyer is a common herb with many purported health benefits. However, there is no conclusive evidence supporting its use in the treatment of any particular disease. We conducted a systematic review to evaluate randomised controlled trials. Four English databases were searched with no publication date restriction. Included studies evaluated P. ginseng in patients with any type of disease or in healthy individuals. We assessed the quality of studies using the Cochrane risk of bias tool. Of the 475 potentially relevant studies, 65 met the inclusion criteria. These studies examined P. ginsengs effects on psychomotor performance (17 studies), physical performance (ten), circulatory system (eight), glucose metabolism (six), the respiratory system (five), erectile dysfunction (four), immunomodulation (four), quality of life/mood (four), antioxidant function (two), cancer (two), menopausal symptoms (two) and dry mouth (one). The risk of bias was unclear in most studies. Authors evaluated adverse events in 40 studies, with 135 minor events and no serious adverse events reported. P. ginseng shows promising results for improving glucose metabolism and moderating the immune response. This may have implications for several diseases including type 2 diabetes and chronic respiratory conditions. Further studies are needed to explore P. ginsengs potential as an effective treatment for these and other health conditions. Copyright

Ear acupressure for smoking cessation: a randomised controlled trial.

This study investigated the efficacy and safety of ear acupressure (EAP) as a stand-alone intervention for smoking cessation and the feasibility of this study design. Adult smokers were randomised to receive EAP specific for smoking cessation (SSEAP) or a nonspecific EAP (NSEAP) intervention which is not typically used for smoking cessation. Participants received 8 weekly treatments and were requested to press the five pellets taped to one ear at least three times daily. Participants were followed up for three months. Primary outcome measures were a 7-day point-prevalence cessation rate confirmed by exhaled carbon monoxide and relief of nicotine withdrawal symptoms (NWS). Intention-to-treat analysis was applied. Forty-three adult smokers were randomly assigned to SSEAP (n = 20) or NSEAP (n = 23) groups. The dropout rate was high with 19 participants completing the treatments and 12 remaining at followup. One participant from the SSEAP group had confirmed cessation at week 8 and end of followup (5%), but there was no difference between groups for confirmed cessation or NWS. Adverse events were few and minor.

Herbal medicine for dementia: A systematic review

This systematic review aimed to assess the effectiveness and safety of herbal medicines (HM) for treating dementia. Databases in English and Chinese were searched from their inceptions to February 2007. References in reviews and randomized controlled trials (RCTs) were screened by hand. Trials comparing orally administered HM with placebo, no intervention or other therapy were considered. Trials on Ginkgo biloba and its extracts were excluded to avoid duplication of existing reviews. Pairs of authors independently applied eligibility criteria, extracted data and assessed methodological quality using the Jadad Scale. Thirteen RCTs met the inclusion criteria of three or above on this scale. Six trials compared herbal medicine with placebo, one with no treatment, and the remainder with pharmaceutical intervention. Meta‐analyses were performed on common cognitive performance outcome measures. All studies reported HM had significant effects in improving symptoms. In studies that employed active controls, HM was at least as effective as the pharmaceutical intervention. Meta‐analyses found HM more effective than no treatment or placebo and at least equivalent to control interventions, although the overall effect was small. No severe adverse events were reported. These trials provide overall positive evidence for the effectiveness and safety of certain HMs for dementia management. Copyright