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Hepatic ischemia/reperfusion (IR) injury is a critical contraindication of hepatobiliary surgery and results in severe liver damage. It is imperative to identify underlying pathophysiological mechanisms. In the current study, a rat model of liver IR was established to explore the mechanisms of sevoflurane during surgical intervention on IR. The detection of cytokines was performed using ELISA and reverse transcription-quantitative polymerase chain reaction and western blot assays were used to detect mRNA and protein expression levels, respectively. The target protein of microRNA (miR)-9-5p was identified by in vitro luciferase reporter assay. Cell apoptosis was detected by Annexin-V/propidium iodide and TUNEL staining assays. The results demonstrated that sevoflurane exerted protective effect against liver IR. Sevoflurane administration ameliorated a cytokine storm by decreasing serum levels of interleukin (IL)-1 and -6 and tumor necrosis factor (TNF)-α, and improved liver function was determined. IR-induced damage was mediated by an increase in transcription factor p65 expression and activation of the nuclear factor (NF)-κB signaling pathway, which were suppressed by sevoflurane treatment. In situ analysis predicted that NFKB3, encoding for p65, may be targeted by miR-9-5p and the hypothesis was verified by in vitro reporter assays using wild type and mutant sequences of the NFKB3 3'-untranslated region. Furthermore, pretreatment of hepatic tissue with a miR-9-5p mimic inhibited IR-associated injury as suggested by the decrease in the Suzuki score and decreased serum levels of TNF-α, IL-1 and IL-6. The results indicated that sevoflurane protected the liver from IR injury by increasing miR-9-5p expression and miR-9-5p may be a potential treatment target in IR.

Background: The relationship between protein structure and its bioactivity is one of the fundamental problems for protein engineering and pharmaceutical design. Method: A new method, called SPTD (Simulated Protein Thermal Detection), was proposed for studying and improving the thermal stability of enzymes. The method was based on the evidence observed by conducting the MD (Molecular Dynamics) simulation for all the atoms of an enzyme vibrating from the velocity at a room temperature (e.g., 25°C) to the desired working temperature (e.g., 65°C). According to the recorded MD trajectories and the coordinate deviations of the constituent residues under the two different temperatures, some new strategies have been found that are useful for both drug delivery and starch industry. Conclusion: The SPTD technique presented in this paper may become a very useful tool for pharmaceutical design and protein engineering.

Background: Adefovir dipivoxil has activity against wild-type and lamivudine-resistant hepatitis B virus (HBV) and is frequently used to manage HBV infection in transplant recipients. Calcineurin inhibitors are a central component of immunosuppressive therapy. Aims: Study GS-02-531 was an open-label, multicentre drug interaction trial to examine potential drug interactions between adefovir and tacrolimus in stable post-transplant recipients. Materials and Methods: Sixteen non-HBV-infected post-transplant recipients with median age 45.5 years (69% male, 44% Caucasian, 50% Hispanic and 6% Black) and stable hepatic and renal function on a stable daily dose of tacrolimus (2–10 mg total daily dose) were studied before (tacrolimus alone) and after co-administration of adefovir 10 mg daily for 14 days (Days 1–14). Pharmacokinetic (PK) analyses utilized non-compartmental methods. Results: The median elimination half-life of tacrolimus was 14.47 and 12.59 h for Day 0 and Day 14 respectively. The geometric mean ratios for tacrolimus on Day 14 vs Day 0 were 105.2% [90% confidence interval (90% CI): 89.8–123%] for Cmax and 106.4% (90% CI: 92.9–122%) for AUCtau. Both 90% CIs for the ratios were contained within the predefined lack of interaction bounds of 80 and 125% (i.e. within the bounds for the equivalence assessment), indicating that these PK parameters of tacrolimus are not significantly altered by co-administration of adefovir. Similarly, the observed adefovir PK parameters after 14 days of co-administration with tacrolimus were comparable to historical data in non-transplant patients receiving adefovir alone. Serum creatinine values were stable during the study period. Conclusion: There is no significant PK interaction between tacrolimus and adefovir co-administered to liver transplant recipients for 14 days.

Previous studies have suggested that Ginkgo biloba extract (EGb761) has a protective potentiality against apoptosis of neurons or neuron-like cells induced by MPTP. In this study, the effects of EGb761 on PC12 cells injured by paraquat (PQ), a neurotoxin, were tested. The results showed that after incubation of PC12 cells with EGb761 prior to PQ exposure, the PQ-induced decrease of cell viability was significantly reversed, the collapse of mitochondrial membrane potential (MMP) was attenuated and the percentage of apoptotic cells was reduced. Moreover, EGb761 pretreatment evidently increased the numbers of tyrosine hydroxylase (TH) positive and bcl-2 positive cells and degraded the number of caspase-3 positive cells in PQ-injured PC12 cells, in comparison to the treatment with PQ alone. This study indicates that EGb761 has a neuroprotective effect on paraquat-induced apoptosis of PC12 cells. The mechanism underlying the protective effects of EGb761 in PQ-injured PC12 cells might be related to the increase of bcl-2 activation, maintenance of MMP stability and decrease of caspase-3 activation through mitochondria-dependent pathway. The results from this study provide an experimental basis for the potential use of EGb761 in treatment of Parkinson's disease.

Emtricitabine is a potent nucleoside reverse transcriptase inhibitor approved as a once-daily drug in combination with other antiretroviral agents for the treatment of HIV infection. Several phase I studies were conducted in healthy volunteers over the course of clinical development to evaluate whether pharmacokinetic drug-drug interactions exist between emtricitabine and other nucleoside antivirals that are extensively eliminated by renal excretion. Potential interactions with stavudine and famciclovir were evaluated in single-dose studies, whereas interactions with zidovudine and its major metabolite, zidovudine glucuronide, were evaluated in a multiple-dose study. Plasma pharmacokinetic profiles and, in some studies, urinary excretion data were evaluated when each drug was administered alone and in combination with emtricitabine. Safety and plasma pharmacokinetic profiles of each drug administered alone or with emtricitabine were consistent with historical data. Statistical analyses indicated that there were no significant interactions between emtricitabine and these 3 nucleoside antivirals.

A phase I study was conducted to formally evaluate the steady-state pharmacokinetics (PK) of tenofovir disoproxil fumarate (TDF) and ritonavir (RTV)-boosted saquinavir mesylate (SQV) when coadministered in healthy volunteers. Forty subjects received multiple doses of TDF (300 mg, once daily) and SQV/RTV (1,000 mg/100 mg, twice daily) alone and together under steady-state conditions in an open-label, fixed sequence design. Blood samples for tenofovir (TFV) and SQV/RTV PK were drawn over respective 24- and 12-h dosing intervals, and drug concentrations were measured by liquid chromatography-tandem mass spectrometry. Safety was assessed periodically by clinical and laboratory monitoring. Thirty-two subjects completed the study and were fully evaluable; three subjects discontinued participation in the study due to adverse events, three subjects withdrew for personal reasons, and two subjects withdrew because of inadequate venous access for blood sampling. Steady-state TFV PK were not significantly altered upon coadministration with SQV/RTV. Steady-state SQV (administered as SQV/RTV) AUC tau , C max , and C tau increased 29, 22, and 47%, respectively, upon coadministration with TDF, and all subjects achieved a C tau of >100 ng/ml. These modestly increased SQV exposures are not clinically meaningful given its clinical use with RTV already results in >10-fold-higher SQV levels. Steady-state RTV AUC tau and C max levels were not significantly altered, whereas C tau was 23% higher upon coadministration of SQV/RTV and TDF. Thus, no clinically relevant interactions between TDF and RTV-boosted SQV were observed under conditions simulating clinical practice.

The objective of the present study was to examine the time course and concentration dependence of modulation of P-glycoprotein (P-gp) activity in the blood-brain barrier (BBB) with consequent influence on substrate uptake into brain tissue. Potential P-gp inducers (rifampin and morphine) were administered subchorionically to P-gp-competent [mdr1a(+/+)] mice to induce P-gp expression in brain; the impact of rifampin pretreatment on brain penetration of verapamil also was evaluated with an in situ brain perfusion technique. In addition, the effect of single-dose rifampin on P-gp BBB transport activity was assessed with brain perfusion using verapamil and quinidine as model P-gp substrates. Chronic exposure to rifampin or morphine induced P-gp expression in mouse brain to a modest extent. However, single-dose rifampin treatment increased the brain uptake of verapamil and quinidine in mdr1a(+/+) mice in a dose- and concentration-dependent manner, consistent with P-gp inhibition. Maximum inhibition of P-gp-mediated efflux of verapamil by rifampin pretreatment in vivo (150 mg/kg) was approximately 55%, whereas there was only approximately 12% inhibition of P-gp-mediated efflux of quinidine at that rifampin dose. Coperfusion of rifampin at a concentration of 500 microM abolished P-gp-mediated efflux of verapamil at the BBB. However, only approximately 40% inhibition of P-gp-mediated efflux of quinidine was observed with coperfusion of rifampin, even at a 2-fold higher rifampin concentration (1000 microM). The present studies demonstrate that P-gp function at the BBB can be modulated by rifampin in a dose- and concentration-dependent manner. The degree to which rifampin inhibits P-gp-mediated transport is dependent on the substrate molecule.

Purpose. This study assessed the influence of mdr1a P-glycoprotein (P-gp) gene disruption, gender and concentration on initial brain uptake clearance (Clup) of morphine, quinidine and verapamil.

Purpose. Previous studies have suggested that P-glycoprotein (P-gp)modulates opioid antinociception for selected μ-and δ-agonists. Thisstudy was undertaken to assess morphine antinociception in micelacking the mdr1a gene for expression of P-gp in the CNS.

This study was performed to evaluate cytokines in donor-site wound fluids and to determine their effect on wound healing. A film dressing was applied to the donor-site wound of 24 patients immediately after a split-thickness skin graft was taken. On the 5th day after treatment, 2-3 ml of the fluid retained under the film dressing was collected by means of puncture with a syringe. Growth factors and cytokines considered to accelerate wound healing were present in relatively large amounts in the exudate. Very low concentrations of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were detected by a commercially-available enzyme-linked immunosorbant assay (ELISA) kit. However, the presence of both growth factors in wound fluid could not be confirmed because of the possible cross-reactivity of the antibodies to other EGF and FGF family growth factors. In contrast, platelet derived growth factor (PDGF), interleukin-6 (IL-6), transforming growth factor-alpha (TGF-alpha) and TGF-beta were present in relatively large amounts. The finding that certain cytokines coexist in a balanced state under the film dressing suggests that epithelization can proceed, since an adequate balance would insure proper regulation by the cytokine network. Our present study increases the likelihood that film or hydrocolloid dressings will be used more frequently in the future for treatment of burn wounds, ulcers or donor-site wounds since these dressings were shown to be more capable than ointments of retaining cytokines, particularly intrinsic growth factors secreted at the wound site.

Oxidative stress can induce apoptosis and decrease activities of osteoblasts. 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), is a potent antioxidant derived from a Chinese herb Polygonum multiflorum Thunb. To evaluate the protective effect provided by TSG to osteoblastic MC3T3-E1 cells, the cells were pretreated with TSG for 24h before being treated with 0.3mM hydrogen peroxide (H(2)O(2)) for 24 h, then some markers of osteoblast function and oxidative damage of the cells were examined. Our data demonstrated that TSG significantly (P< 0.05) increased cell survival, alkaline phosphatase (ALP) activity, calcium deposition, and the mRNA expression of ALP, collagen I (COL-I) and osteocalcin (OCN) in the presence of H(2)O(2). In addition, TSG decreased the production of receptor activator of nuclear factor-κB ligand (RANKL), interleukin-6 (IL-6), intracellular reactive oxygen species and malondialdehyde (MDA) of osteoblastic MC3T3-E1 cells induced by H(2)O(2). Taken together, these results demonstrated that the protective effect provided by TSG to osteoblastic MC3T3-E1 cells was mediated, at least in part, via inhibition of the release of bone-resorbing mediators and oxidative damage of the cells. Our results indicated that TSG may be effective in providing protection against osteoporosis associated with oxidative stress.

The study evaluated whether a liquid suspension of adefovir dipivoxil (ADV) is effective and safe when dose adjusted based on varying degrees of renal impairment in patients with chronic hepatitis B. Patients had stable mild, moderate, or severe renal impairment or end-stage renal disease. Twenty-eight patients were enrolled: 10 (mild), 12 (moderate), and 6 severe renal impairment or end-stage renal disease with hemodialysis. Statistical testing demonstrated that daily dosages of ADV liquid suspension at 10 mg and 5 mg in the mild and moderate renal impairment groups, respectively, were clinically similar to ADV 10-mg tablets. However, the antiviral effect observed with the 5-mg/d dose was clearly numerically less than that observed with the 10-mg/d dose. Steady-state adefovir plasma exposures after administration of the ADV liquid suspension were generally within the ranges observed in patients with normal renal function. Treatment with ADV liquid suspension for up to 48 weeks was generally well tolerated. The daily dose-adjustment approach was not clearly safer or more efficacious than the dosing-interval adjustment. Therefore, the results do not support daily ADV dosing using a liquid suspension over the current strategy of adjustment of the ADV dosing interval in patients with impaired renal function.

BACKGROUND The main clinical symptoms of Parkinson's disease (PD) are resting tremor, muscle rigidity, bradykinesia, and so on. There is no effective treatment for PD yet, and dyskinesia symptoms affect the life qualities of PD patients. The therapy used for reinforcing kidney and activating blood circulation in treatment of PD can achieve good clinical effects. OBJECTIVE To evaluate the efficacy and safety of Bushen Huoxue Granule (BSHXG), a compound traditional Chinese herbal medicine for reinforcing kidney and activating blood circulation in treatment of PD. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS A multi-center, randomized, double-blind, placebo-controlled clinical study was undertaken. A total of 120 PD patients from Outpatient Department of General Hospital of People's Liberation Army, Guangdong Provincial Hospital of Traditional Chinese Medicine, and Xijing Hospital and Tangdu Hospital in Xi'an, were randomly divided into BSHXG group and placebo group. There were 55 cases in BSHXG group, for 5 cases lost to follow-up, and 51 cases in placebo group, for 1 case was excluded and 8 cases lost to follow-up. The patients in two groups were all treated for three months. MAIN OUTCOME MEASURES The movement scale, exercise testing, and muscle tension were observed before and after treatment to make a comprehensive evaluation for clinical efficacy. One month follow-up was also made. RESULTS At three different times (one, two and three months) after treatment, the score of Unified Parkinson's Disease Rating Scale (UPDRS) III, rise time of 10-meter back and forth exercise and resting muscle tension in BSHXG group were improved as compared with before treatment (P

The approved antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate, were considered good candidates for a fixed-dose combination product that could be administered as a single pill once daily (qd), thereby simplifying existing treatment regimens and promoting patient adherence. As both drugs are extensively renally eliminated, a randomized, 3-way crossover study was conducted in 19 healthy volunteers to formally evaluate the potential pharmacokinetic interaction when the drugs are administered alone and together (ie, 200 mg emtricitabine qd for 7 days, 300 mg tenofovir disoproxil fumarate qd for 7 days, and 200 mg emtricitabine plus 300 mg tenofovir disoproxil fumarate qd for 7 days) with no washout between treatments. Steady-state pharmacokinetic parameters (AUC(tau), C(max), and C(min)) of emtricitabine and tenofovir (as tenofovir disoproxil fumarate) in combination were essentially equivalent versus each drug alone, providing a pharmacokinetic rationale for combining these products in emtricitabine/tenofovir disoproxil fumarate fixed-dose tablets.

Green tea, owing to its beneficial effect on health, is becoming more and more popular worldwide. (-)-Epigallocatechin-3-gallate (EGCG), the main ingredient of green tea polyphenols, is a known protective effect on injured neurons in neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease. Paraquat (PQ) is a widely used herbicide that possesses a similar structure to MPP(+) and is toxic to mesencephalic dopaminergic neurons. In the present study, PQ-injured PC12 cells were chosen as an in vitro cell model of Parkinson's disease and the neuroprotective effects of EGCG were investigated. The results showed that EGCG attenuated apoptosis of PC12 cells induced by PQ. The possible mechanism may be associated with maintaining mitochondrial membrane potential, inhibiting caspase-3 activity and downregulating the expression of pro-apoptotic protein Smac in cytosol. The present study supports the notion that EGCG could be used as a neuroprotective agent for treatment of neurodegenerative diseases.

Objectives: To evaluate the pharmacodynamics and safety of escalating doses of amdoxovir (DAPD) monotherapy administered to treatment-naive and experienced HIV-1 -infected patients over 15 days. Design: Ninety patients with plasma HIV-1 RNA levels between 5000 and 250 000 copies/ml were randomized to DAPD 25, 100, 200, 300 or 500 mg twice daily or 600 mg once daily monotherapy [antiretroviral therapy (ART)-naive and ART-experienced] or to add DAPD 300 or 500 mg twice daily to existing ART. After 15 days of dosing, patients were followed for an additional 7 days. Methods: Antiviral activity was compared between treatment arms using log 10 HIV-1 RNA based on average area under the curve minus baseline to day 15. Safety and tolerability was analyzed by incidence of grade 1 to 4 clinical and laboratory adverse events. Results: In ART-naive patients receiving short-term DAPD monotherapy, a median reduction in plasma HIV-1 RNA of 1.5 log 10 copies/ml at the highest doses was observed. In ART-experienced patients, the reduction in viral load observed at each dose was less than that observed in treatment-naive patients (reduction of 0.7 log 10 at 500 mg twice daily). The incidence of adverse events was similar across groups with the majority of adverse events reported as mild or moderate in severity. Steady-state plasma concentrations of DAPD and dioxolane guanosine followed linear kinetics. Conclusions: DAPD was well tolerated and produced antiviral activity in treatment-naive and in some treatment-experienced patients. In ART-experienced patients, the antiviral activity was significant in those with no thymidine-analogue mutations and higher baseline CD4+ cell counts.

Introduction : Dolutegravir (DTG) is an HIV integrase strand transfer inhibitor approved for use in combination with other antiretrovirals for the treatment of HIV-infection in adults and adolescents. Metformin is a drug frequently used in diabetic HIV-infected patients, which requires titration to optimize dosing. In vitro , DTG inhibits organic cation transporter 2 (OCT2) and multidrug and toxin extrusion transporter 1 (MATE 1) which are known to be involved in the disposition of metformin. The objective of this study was to assess the drug interaction between DTG and metformin. Materials and Methods : This was an open-label, parallel-group, three-period crossover study in healthy adult subjects. Eligible subjects were enrolled into one of the two treatment cohorts (15 subjects/cohort). Subjects received metformin 500 mg q12h for 5 days in Period 1; metformin 500 mg q12h plus DTG 50 mg q24h (Cohort 1) or 50 mg q12h (Cohort 2) for 7 days in Period 2; and metformin 500 mg q12h for 10 days in Period 3. There were no washout periods between treatments. All doses of study drug were taken with a moderate-fat meal. Serial plasma PK samples and safety assessments were obtained throughout the study. Non-compartmental PK analysis was performed and geometric least squares (GLS) mean ratios and 90% confidence intervals (CI) were generated by the mixed effect model for within-subject treatment comparisons for each cohort. Results : Fourteen and thirteen subjects completed study in Cohort 1 and Cohort 2, respectively. Plasma exposures of metformin were significantly increased when co-administered with DTG (Table 1). There were no apparent changes in metformin half-life and tmax. Increased metformin plasma exposure returned to normal levels observed in Period 1 after DTG was discontinued in Period 3. No Grade 3 or 4 adverse events (AEs), deaths or serious AEs were reported during the study. Most frequently reported drug-related AEs were headache (9), loose stools (8), and nausea (7). All AEs were mild or Grade 1 with the exception of one Grade 2 headache. Conclusions : Co-administration of DTG and metformin was well tolerated, yet significantly increased metformin plasma exposure; effects were DTG dose dependent. Though metformin has a wide therapeutic index and alone is not associated with hypoglycemia, close monitoring is recommended when co-administering metformin and DTG. Dose adjustments of metformin may be considered. (Published: 2 November 2014) Citation : Abstracts of the HIV Drug Therapy Glasgow Congress 2014 Zong J et al. Journal of the International AIDS Society 2014, 17(Suppl 3) :19584 http://www.jiasociety.org/index.php/jias/article/view/19584 | http://dx.doi.org/10.7448/IAS.17.4.19584

Daclatasvir (DCV) is an NS5A replication complex inhibitor recently approved for chronic hepatitis C virus treatment. To assess drug interactions between the HIV integrase strand transfer inhibitor dolutegravir (DTG) and DCV, subjects were randomized into 1 of 2 sequences in an open-label, 3-period, crossover study. Subjects received either DTG 50 mg once daily or DCV 60 mg once daily for 5 days in periods 1 and 2 and DTG 50 mg plus DCV 60 mg once daily for 5 days in period 3, with no washout between periods 2 and 3. Between periods 1 and 2, there was a washout period of at least 7 days. The geometric least-squares mean ratios (90 % confidence intervals) of DCV area under the concentration-time curve over a dosing interval (AUC0-τ), maximum observed concentration (Cmax), and concentration at the end of the dosing interval (Cτ) were 0.978 (0.831–1.15), 1.03 (0.843–1.25), and 1.06 (0.876–1.29), respectively, when DCV was administered with DTG compared with DCV alone. Compared with DTG alone, coadministration of DTG with DCV increased DTG AUC0-τ, Cmax, and Cτ by approximately 33, 29, and 45 %, respectively. DCV plasma exposure was not meaningfully affected by DTG. Coadministration of DTG with DCV resulted in slight increases in DTG AUC0-τ, Cmax, and Cτ. Accumulated safety and tolerability data in humans receiving DTG to date suggests this effect is not considered clinically significant. DTG and DCV can be coadministered without dose adjustment. Registered on March 6, 2014 with ClinicalTrials.gov; registration number: NCT02082808 and as Study ID: 201102 on the ViiV Clinical Study Registry.