Ibuprofen treatment ameliorates memory deficits in rats with collagen-induced arthritis by normalizing aberrant MAPK/NF-κB and glutamatergic pathways.

Many studies have indicated that the risk of cognitive impairment is higher in patients with rheumatoid arthritis (RA). Additionally, patients with RA may have a lower incidence of cognitive impairment with long-term use of ibuprofen. This study was aimed at investigating the impacts of RA on memory function and the mechanisms that ibuprofen may exhibit to improve memory function in rats with collagen-induced arthritis (CIA). Ibuprofen (30 mg/kg) was given twice daily to CIA rats for two weeks starting from Day 18 following the first immunization. Memory function was measured by the Morris water maze (MWM) test and long-term potentiation (LTP). The proinflammatory cytokine levels and downstream signaling pathways, including mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB), were examined. Furthermore, the glutamatergic system, including glutamate transporters/receptors and brain extracellular levels of glutamate, was investigated. The results showed that the impaired learning memory in CIA rats, examined by the MWM test and LTP, can be ameliorated by ibuprofen treatment. Along with the improvement in memory deficits, ibuprofen attenuated both neuroinflammation and the associated elevated levels of phosphorylated p38, JNK, and p65 in the hippocampus of CIA rats. In addition, the decreased excitatory amino acid transporter 2 level, the increased extracellular glutamate, and the upregulated hippocampal NMDA receptor 2B of CIA rats were all normalized by ibuprofen treatment. These findings suggest that the effect of ibuprofen on the memory improvement in CIA rats is associated with the normalization of the activated MAPK and NF-κB pathways and the aberrant glutamatergic system.

Rifamycin SV MMX for the treatment of traveler's diarrhea.

INTRODUCTION: Rifamycin SV MMX®, a non-absorbable rifamycin antibiotic formulated using the multi-matrix system, was designed to exhibit its pharmacological action on the distal small intestine and colon. Its clinical efficacy and safety profile in the treatment of traveler's diarrhea were evaluated in several clinical studies. Areas covered: This review summarizes all available evidence regarding clinical trials of the efficacy and safety profile of rifamycin SV MMX for the treatment of traveler's diarrhea. Expert opinion: Rifamycin SV MMX demonstrated an excellent pharmacokinetic profile with decreased systemic toxicity similar to rifaximin. In phase II and phase III clinical trials, concerns have been raised regarding the medicine's efficacy in terms of the time to last unformed stool and cure rate compared to current recommended antibiotics in the treatment of acute diarrhea caused by diarrheagenic Escherichia coli and invasive pathogens. The significance of the increase in MICs after the use of rifamycin SV MMX warrants further examination.

Differential changes in the pharmacokinetics of statins in collagen-induced arthritis rats.

The elevated systemic levels of cytokines in rheumatoid arthritis (RA) can change the expression of metabolic enzymes and transporters. Given that statins are lipid-lowering agents frequently used in RA patients with concurrent cardiovascular diseases, the objective of the present study was to investigate the impacts of RA on the pharmacokinetics of statins of different disposition properties in rats with collagen-induced arthritis (CIA). The expression of metabolic enzymes and transporters in tissues of CIA rats were analyzed by RT-qPCR. Statins were given to CIA rats and controls through different routes, respectively. Blood samples were collected and analyzed by UPLC/MS/MS. Isolated microsomes and hepatocytes were used to determine the metabolic and uptake clearance of statins. The results showed that, compared with controls, the mRNA levels of intestinal Cyp3a1 and hepatic Cyp2c6, Cyp2c7, Cyp3a1, Oatp1a1, Oatp1b2, Oatp1a4, and Mrp2 were markedly decreased in the CIA rats. The maximal metabolic activities of Cyp2c and Cyp3a were reduced in liver microsomes of CIA rats. When given orally or injected through hepatic portal vein, the systemic levels of fluvastatin, simvastatin, and atorvastatin, but not of rosuvastatin and pravastatin, were increased in CIA rats. The metabolic clearance of simvastatin and hepatic uptake clearance of fluvastatin and atorvastatin were decreased in CIA rats. These findings suggest that the changes in the expression of enzymes and/or transporters in CIA rats differentially affect the pharmacokinetics of statins.

Treatment of Helicobacter pylori infection: current status and future concepts.

Helicobacter pylori (H. pylori) infection is highly associated with the occurrence of gastrointestinal diseases, including gastric inflammation, peptic ulcer, gastric cancer, and gastric mucosa-associated lymphoid-tissue lymphoma. Although alternative therapies, including phytomedicines and probiotics, have been used to improve eradication, current treatment still relies on a combination of antimicrobial agents, such as amoxicillin, clarithromycin, metronidazole, and levofloxacin, and antisecretory agents, such as proton pump inhibitors (PPIs). A standard triple therapy consisting of a PPI and two antibiotics (clarithromycin and amoxicillin/metronidazole) is widely used as the first-line regimen for treatment of infection, but the increased resistance of H. pylori to clarithromycin and metronidazole has significantly reduced the eradication rate using this therapy and bismuth-containing therapy or 10-d sequential therapy has therefore been proposed to replace standard triple therapy. Alternatively, levofloxacin-based triple therapy can be used as rescue therapy for H. pylori infection after failure of first-line therapy. The increase in resistance to antibiotics, including levofloxacin, may limit the applicability of such regimens. However, since resistance of H. pylori to amoxicillin is generally low, an optimized high dose dual therapy consisting of a PPI and amoxicillin can be an effective first-line or rescue therapy. In addition, the concomitant use of alternative medicine has the potential to provide additive or synergistic effects against H. pylori infection, though its efficacy needs to be verified in clinical studies.

Inhibition of Helicobacter pylori CagA-Induced Pathogenesis by Methylantcinate B from Antrodia camphorata.

The bacterial pathogen Helicobacter pylori (Hp) is the leading risk factor for the development of gastric cancer. Hp virulence factor, cytotoxin-associated gene A (CagA) interacted with cholesterol-enriched microdomains and leads to induction of inflammation in gastric epithelial cells (AGS). In this study, we identified a triterpenoid methylantcinate B (MAB) from the medicinal mushroom Antrodia camphorata which inhibited the translocation and phosphorylation of CagA and caused a reduction in hummingbird phenotype in HP-infected AGS cells. Additionally, MAB suppressed the Hp-induced inflammatory response by attenuation of NF-κB activation, translocation of p65 NF-κB, and phosphorylation of IκB-α, indicating that MAB modulates CagA-mediated signaling pathway. Additionally, MAB also suppressed the IL-8 luciferase activity and its secretion in HP-infected AGS cells. On the other hand, molecular structure simulations revealed that MAB interacts with CagA similarly to that of cholesterol. Moreover, binding of cholesterol to the immobilized CagA was inhibited by increased levels of MAB. Our results demonstrate that MAB is the first natural triterpenoid which competes with cholesterol bound to CagA leading to attenuation of Hp-induced pathogenesis of epithelial cells. Thus, this study indicates that MAB may have a scope to develop as a therapeutic candidate against Hp CagA-induced inflammation.

Interaction between Red Yeast Rice and CYP450 Enzymes/P-Glycoprotein and Its Implication for the Clinical Pharmacokinetics of Lovastatin.

Red yeast rice (RYR) can reduce cholesterol through its active component, lovastatin. This study was to investigate the pharmacokinetic properties of lovastatin in RYR products and potential RYR-drug interactions. Extracts of three registered RYR products (LipoCol Forte, Cholestin, and Xuezhikang) were more effective than pure lovastatin in inhibiting the activities of cytochrome P450 enzymes and P-glycoprotein. Among CYP450 enzymes, RYR showed the highest inhibition on CYP1A2 and CYP2C19, with comparable inhibitory potencies to the corresponding typical inhibitors. In healthy volunteers taking the RYR product LipoCol Forte, the pharmacokinetic properties of lovastatin and lovastatin acid were linear in the dose range of 1 to 4 capsules taken as a single dose and no significant accumulation was observed after multiple dosing. Concomitant use of one LipoCol Forte capsule with nifedipine did not change the pharmacokinetics of nifedipine. Yet, concomitant use of gemfibrozil with LipoCol Forte resulted in a significant increase in the plasma concentration of lovastatin acid. These findings suggest that the use of RYR products may not have effects on the pharmacokinetics of concomitant comedications despite their effects to inhibit the activities of CYP450 enzymes and P-gp, whereas gemfibrozil affects the pharmacokinetics of lovastatin acid when used concomitantly with RYR products.

A new drug design targeting the adenosinergic system for Huntington's disease.

BACKGROUND: Huntington's disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide expansion in the Huntingtin (Htt) gene. The expanded CAG repeats are translated into polyglutamine (polyQ), causing aberrant functions as well as aggregate formation of mutant Htt. Effective treatments for HD are yet to be developed. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report a novel dual-function compound, N(6)-(4-hydroxybenzyl)adenine riboside (designated T1-11) which activates the A(2A)R and a major adenosine transporter (ENT1). T1-11 was originally isolated from a Chinese medicinal herb. Molecular modeling analyses showed that T1-11 binds to the adenosine pockets of the A(2A)R and ENT1. Introduction of T1-11 into the striatum significantly enhanced the level of striatal adenosine as determined by a microdialysis technique, demonstrating that T1-11 inhibited adenosine uptake in vivo. A single intraperitoneal injection of T1-11 in wildtype mice, but not in A(2A)R knockout mice, increased cAMP level in the brain. Thus, T1-11 enters the brain and elevates cAMP via activation of the A(2A)R in vivo. Most importantly, addition of T1-11 (0.05 mg/ml) to the drinking water of a transgenic mouse model of HD (R6/2) ameliorated the progressive deterioration in motor coordination, reduced the formation of striatal Htt aggregates, elevated proteasome activity, and increased the level of an important neurotrophic factor (brain derived neurotrophic factor) in the brain. These results demonstrate the therapeutic potential of T1-11 for treating HD. CONCLUSIONS/SIGNIFICANCE: The dual functions of T1-11 enable T1-11 to effectively activate the adenosinergic system and subsequently delay the progression of HD. This is a novel therapeutic strategy for HD. Similar dual-function drugs aimed at a particular neurotransmitter system as proposed herein may be applicable to other neurotransmitter systems (e.g., the dopamine receptor/dopamine transporter and the serotonin receptor/serotonin transporter) and may facilitate the development of new drugs for other neurodegenerative diseases.

Interaction of flavonoids and intestinal facilitated glucose transporters.

The intestinal facilitated glucose transporter, GLUT2, is a high-turnover transport system and is important to handle the large transepithelial substance flux. Since intestinal GLUT2 is normally located at the basolateral side, glucose uptake in the presence of flavonoids was measured using basolateral membrane vesicles (BLMV) isolated from the rat jejunum to investigate the interaction between flavonoids and intestinal facilitated glucose transporters. In addition, basolateral uptake of flavonoids was studied in Caco-2 cells. As a result, in the BLMV study most flavonoids (glycosides or aglycones) at 0.1 mM inhibited glucose uptake in BLMV; epicatechin gallate (ECG) showed the highest inhibitory activity (about 33%), followed by quercetin 3-O-glucoside (Q3G), fisetin and gossypin (about 25-28% inhibition). The dose-response study showed that the IC50 values for ECG and Q3G on glucose uptake in BLMV were 294+/-89 microM and 357+/-52 microM, respectively. Kinetic analyses showed that ECG and Q3G competitively inhibited glucose uptake in BLMV with inhibition constants (Ki) of 332+/-42 microM and 404+/-45 microM, respectively. In Caco-2 cells, basolateral uptake of Q3G was significantly inhibited by phloretin, a GLUT2 inhibitor (0.40+/-0.05 vs. 0.24+/-0.03 nmole/mg protein without aand with phloretin, respectively). On the other hand, phloretin did not show inhibitory activity on basolateral uptake of ECG in Caco-2 cells (1.26+/-0.05 vs. 1.22+/-0.07 nmole/mg protein without and with phloretin, respectively). The data showed that the intestinal facilitated glucose transporter recognizes a variety of flavonoids with or without conjugation. In addition, GLUT2 can be responsible for the transport of Q3G across the intestinal basolateral membrane.