Anti-inflammatory Effects in LPS-treated RAW 264.7 Cells and the Influences on Drug Metabolizing Enzyme Activities by the Traditional Herbal Formulas, Yongdamsagan-Tang and Paljung-san

Objectives: Yongdamsagan-tang (YST) and Paljung-san (PJS) in traditional medicine and finasteride in modern medicine are used to treat benign prostatic hyperplasia (BPH). In recent, the use of combination herbal remedies with conventional drugs has been increasing. Therefore, we investigated the anti-inflammatory effects of these drugs to treat BPH and the influence of herbal formulas on finasteride metabolism.Methods: The inhibitory effects of the herbal formulas and finasteride on the production of inflammatory mediators and cytokines were determined in lipopolysaccharide (LPS)-treated RAW 264.7 cells. Additionally, the influence of herbal formulas on activities of human drug metabolizing enzymes (DMEs) was assessed using human microsomal enzymes.Results: We observed that YST, PJS and finasteride inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2) and interleukin-6 (IL-6) in RAW 264.7 cells. The half maximal inhibitory concentration (IC50) of YST on PGE2 production was calculated to be below 25 μg/mL. YST inhibited the activity of uridine diphosphateglucuronosyltransterase (UGT) 1A4 with an IC50 value of 49.35 μg/mL. The activities of cytochrome P450 (CYP) 1A2, CYP2B6, CYP2C19, CYP3A4, and UGT1A1 were inhibited by PJS (IC50 < 100 μg/mL, each). Although PJS and YST inhibited the activities of CYP3A4 and UGT1A4, respectively, these formulas may not influence the metabolism of finasteride because the IC50 values of herbal formulas on DMEs are too high to affect metabolism.Conclusions: Our results suggest that the combination of finasteride and YST or PJS might not influence their drug metabolism and that the drugs may have synergistic effects against BPH.

Reduced levels of biomarkers of exposure in smokers switching to the Carbon-Heated Tobacco Product 1.0: a controlled, randomized, open-label 5-day exposure trial

In addition to smoking cessation, for those who would otherwise continue to smoke, replacing cigarettes with less harmful alternatives can reduce the harms of smoking. Heating instead of burning tobacco reduces, or eliminates, the formation of harmful and potentially harmful constituents (HPHC) that are found in cigarette smoke. The Carbon-Heated Tobacco Product (CHTP), a heat-not-burn tobacco product, mimics the cigarette smoking ritual. This randomized, open-label, two-arm, parallel-group, short-term confinement study tested the hypothesis that the geometric means of the BoExp levels for subjects switching to CHTP 1.0 for 5 days are lower relative to those continuing to smoke cigarettes. Biomarkers of exposure (BoExp), including nicotine, urinary excretion of mutagenic constituents (Ames test), and cytochrome P450 (CYP) 1A2 activity, were measured in blood and/or 24-h urine samples during ad libitum product use. Nicotine exposure remained at similar levels in individuals using CHTP as in those continuing to smoke cigarettes. Switching to CHTP resulted in marked decreases in all other urinary BoExp (56–97%), carboxyhemoglobin (59%), urinary mutagenic constituents, and CYP1A2 activity compared with continued cigarette smoking. Our results provide evidence of decreased exposure to 15 selected HPHCs in smokers switching from cigarettes to exclusive CHTP use. Trial registration ClinicalTrials.gov: NCT02503254; Date of first registration: 20/07/2015 https://www.clinicaltrials.gov/ct2/show/NCT02503254. Study protocol Study protocol published at: https://www.clinicaltrials.gov/ProvidedDocs/54/NCT02503254/Prot_000.pdf.

Koffein, das am häufigsten konsumierte Psychostimulans: eine narrative Übersichtsarbeit

ZusammenfassungKoffein ist das weltweit am häufigsten konsumierte Psychostimulans. Es ist nahezu unbeschränkt verfügbar und unterliegt in Europa keiner staatlichen Regulation. Neben seiner primären Rolle als Inhalts- oder Zusatzstoff in zahlreichen Getränken findet es auch medizinische Verwendung in der adjuvanten Schmerztherapie, bei primärem Atemstillstand bei Neugeborenen und es ist zugelassen für die kurzfristige Beseitigung von Ermüdungserscheinungen. Der Wirkmechanismus von Koffein als Psychostimulans in typischerweise aufgenommen Dosierungen basiert vermutlich in erster Linie auf einem zentralen Antagonismus von Adenosinrezeptoren (A1- und A2A-Rezeptoren), was zu einer zentralen Hemmung der Adenosin-vermittelten Reduktion der Aktivität des dopaminergen und aufsteigenden Aktivierungssystems führt. Die Metabolisierung von Koffein ist hautsächlich abhängig von Cytochrom P450 1A2, sodass Faktoren, die die Aktivität von CYP 1A2 beeinflussen (z. B. Medikamente, Schwangerschaft), erhebliche Veränderungen der pharmakokinetischen Parameter induzieren können. Koffein führt insbesondere bei Individuen mit Schlafentzug zu einer Verbesserung der Vigilanz, Aufmerksamkeit und Reaktionszeit. Zudem kann es sportliche Ausdauerleistungen und muskuläre Kraft verbessern. Intoxikationen mit Koffein sind selten, können jedoch letal verlaufen. In üblicherweise aufgenommenen Mengen gilt Koffeingebrauch als nicht gesundheitsschädlich. Koffein weist zahlreiche, jedoch nicht alle Merkmale einer Substanz mit „Abhängigkeitspotential“ auf; Entzugssyndrome nach Beendigung einer längeren Anwendung und Toleranz sind bekannt. Im DSM-5 wird die „Koffeingebrauchsstörung“ als mögliche künftige Störung, die gegenwärtig weiterer Forschung bedarf, rubriziert. Das Koffeingebrauchsmuster von Patienten sollte im Rahmen der ärztlichen Tätigkeit berücksichtigt werden.

Epigallocatechin-3-Gallate Reduces Hepatic Oxidative Stress and Lowers CYP-Mediated Bioactivation and Toxicity of Acetaminophen in Rats

Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea. To investigate the effects of dietary EGCG on oxidative stress and the metabolism and toxicity of acetaminophen in the liver, rats were fed diets with (0.54%) or without EGCG supplementation for four weeks and were then injected intraperitoneally with acetaminophen (1 g/kg). The results showed that EGCG lowered hepatic oxidative stress and cytochrome P450 (CYP) 1A2, 2E1, and 3A, and UDP-glucurosyltransferase activities prior to acetaminophen injection. After acetaminophen challenge, the elevations in plasma alanine aminotransferase activity and histological changes in the liver were ameliorated by EGCG treatment. EGCG reduced acetaminophen-induced apoptosis by lowering the Bax/Bcl2 ratio in the liver. EGCG mildly increased autophagy by increasing the LC3B II/I ratio. Lower hepatic acetaminophen–glutathione and acetaminophen–protein adducts contents were observed after EGCG treatment. EGCG increased glutathione peroxidase and NAD(P)H quinone 1 oxidoreductase activities and reduced organic anion-transporting polypeptides 1a1 expression in the liver after acetaminophen treatment. Our results indicate that EGCG may reduce oxidative stress and lower the metabolism and toxicity of acetaminophen. The reductions in CYP-mediated acetaminophen bioactivation and uptake transporter, as well as enhanced antioxidant enzyme activity, may limit the accumulation of toxic products in the liver and thus lower hepatotoxicity.

Preliminary Studies on Genetic Profiling of Coffee and Caffeine Consumption

Regular coffee intake has been associated with reduced risk of developing serious chronic diseases. The hypothesis of this study is that coffee consumers present a particular pattern/trend of genotypes that ultimately will shed light on new gene targets to treat the diseases, from which regular coffee intake has preventive effects. Sixteen SNPs identified at genome-wide association studies (GWAS) on coffee and caffeine consumption were genotyped using real-time restriction-fragment length polymorphism-polymerase chain reaction (RT-PCR). The DNA samples were the same from a previous pilot study where 15 healthy volunteers donated two blood samples collected before and after drinking a standard cup of coffee and had caffeine plasma levels and CYP 1A2 genotype (rs762551) determined. The cross-examination of the data showed that six of the sixteen SNPs exhibited a negative allelic effect direction and nine of them showed a positive effect direction of which three of them had results confirmed by a recent GWAS. There is a need of a more in-depth study to understand the effects of the presence or absence of specific variant alleles as players to benefit the health of coffee consumers.

STUDY OF IN VIVO PHARMACOKINETIC DRUG INTERACTIONS OF CURCUMIN ON TACRINE

Objective: Tacrine is a potent acetylcholine esterase inhibitor (AChEI), and curcumin has been recently proven to possess AChEI, amyloid β aggregation inhibitory activity in addition to its diverse pharmacodynamic nature. Tacrine undergoes biological transformation by cytochrome P450 (CYP 1A2) to a hydroxy metabolite, which is hepatotoxic. Curcumin is known for its inhibitory nature for various metabolic enzymes along with CYP1A2. The present study was undertaken to evaluate the influence of curcumin on the disposition kinetics of tacrine and to assess its impact on dosage regimen.Methods: It was hypothesized that the simultaneous administration of curcumin and tacrine can minimize the toxicity along with increased absorption of tacrine and curcumin into the biological system during the treatment of Alzheimer’s patients.Results and Discussion: Hence, an attempt was made to develop a simple, precise, accurate, and cost-effective reversed-phase high-performance liquid chromatography method for simultaneous determination of curcumin and tacrine and also to estimate the effect of curcumin on absorption of tacrine, in rat plasma.Conclusion: Concomitant administration of curcumin with tacrine improved the parameters such as Cmax and AUC, which indicates that the curcumin would improve the absorption of tacrine.

In vitro modulation of the cytochrome P450 and ABCB1/P-glycoprotein activities of the aqueous extract of Allophylus cominia (L) Sw. leaves

Background:The aqueous extract of theMethods:Considering the herb–drug interaction, the aim of this study was to evaluate the potential effects of theResults:The extract did not decrease the cell viability after being assayed by the MTT test at up to 1500 μg/mL for 72 h. The exposure of the cultured rat hepatocytes to the product (up to 250 μg/mL) for 48 h increased the activities of CYP-1A2, 2C9, and 2E1 by 1.46-, 1.60-, and 1.51-fold, respectively, compared with the controls. The activities of CYP-2B6, 2D6, and 3A4 were not significantly altered, whereas the activity of P-gp decreased by 2- and 4-fold. In addition, the extracts at 100 and 200 μg/mL significantly increased doxorubicin cytotoxicity in these cells 24 h after treatment.Conclusions:The findings indicate that the