Wenxing Liu

The effect of staggered administration of zinc sulfate on the pharmacokinetics of oral cephalexin

AIMS To investigate the effect of zinc sulfate on pharmacokinetics of cephalexin when administered concurrently or at strategically spaced dosing times designed to avoid the potential interaction in healthy volunteers. METHODS In this study, all subjects (n= 12) were randomized to receive the following four treatments, separated by a wash-out period of 7 days: cephalexin 500mg alone, concomitantly with zinc 250mg, 3h after zinc 250mg or 3h before zinc 250mg. RESULTS All subjects completed the study safely. Zinc supplements administered concurrently with cephalexin significantly decreased the peak serum concentration (C(max) ), area under the plasma concentration-time curve from zero to infinity (AUC(0-∞) ) and the time for which the plasma concentration of the drug remained above the minimal inhibitory concentration of the pathogenic organism (T > MIC) of cephalexin [mean percentage decrease (95% confidence intervals) of 31.05% (22.09-40.01%), 27.40% (18.33-36.47%) and 22.33% (12.51-32.16%), respectively; P < 0.05] compared with administration of cephalexin alone. Also, administration of zinc 3h before cephalexin decreased the C(max) , AUC(0-∞) and T > MIC of the drug compared with administration of cephalexin alone [mean percentage decrease (95% confidence intervals) of 11.48% (3.40-19.55%), 18.12% (9.63-26.60%) and 23.75% (14.30-33.20%), respectively; P < 0.05]. In contrast, the pharmacokinetics of cephalexin was not notably altered by administration of zinc 3h after cephalexin dosing (P > 0.05). CONCLUSIONS The significant interaction between zinc and cephalexin might affect the clinical outcome of cephalexin therapy. The dosing recommendation is that zinc sulfate can be safely administered 3h after a cephalexin dose.

Preclinical pharmacokinetic analysis of felotaxel (SHR110008), a novel derivative of docetaxel, in rats and its protein binding ability in vitro

Felotaxel (SHR110008), currently under clinical investigation in phase I trial, is a new taxane with potent antitumor effects. The purpose of this research was to evaluate the pharmacokinetic profiles of felotaxel in rats and the protein binding in plasma. Data were collated from several preclinical investigations, where the plasma pharmacokinetics, tissue distribution and excretion of felotaxel were assessed after a single intravenous (i.v.) injection (5 mg/kg) to rats. Samples felotaxel concentration was determined by a LC-MS/MS method. The plasma concentration versus time data was analyzed non-compartmental model. Plasma protein binding was assessed using ultrafiltration. Pharmacokinetic properties of felotaxel were similar to the previous data from the rats. Felotaxel was rapidly distributed to normal tissues, drug concentrations in the tissues tested except the brain were two to eight times higher than those in plasma, but half-lives and mean residence times were similar. The kidneys manifested as the dominant organs with high exposure that might be responsible for elimination of felotaxel. Approximately 0.21% and 0.72% of felotaxel was excreted via the urine and feces within 24 h; 0.25% was excreted into the bile up to 12 h after a single dose. The protein binding ability of felotaxel with concentration 100-5000 ng/mL in the plasma was nearly linear. This study first provided the full absorption, distribution, and excretion characteristics of felotaxel, which would be helpful for its clinical regiment design.

Gastroprotective effects of chebulagic acid against ethanol-induced gastric injury in rats

Gastric ulcer is a major complication of gastrointestinal disease. This study focuses on the gastroprotection and potential mechanism of chebulagic acid (CA) in acute gastric ulceration induced by ethanol in rats. Specifically, in animal study, gastric ulceration was induced by ethanol, morphological features of gastric tissue were observed by ulcer score, H&E, masson and CD31 staining. CA can effectively decrease gastric injury, oxidative stress and proinflammatory cytokines. In addition, significant augment of prostaglandin E2 (PGE2) and nitric oxide (NO) was observed in the gastric tissues pretreated by CA. And CA prevented microcirculatory damage, aroused reparation of vascular architecture, and promoted collagen production, in associated with upregulated expressions of MMP-2, membrane type (MT) 1-MMP, VEGF, and transforming growth factor (TGF)-β. Taken together, these results indicated that CA had a considerable gastroprotective effect on ethanol-induced gastric injury. The underlying mechanism may be ascribed to the improvement of anti-oxidant and anti-inflammatory status as well as accelerating angiogenesis.

Relative Bioavailability Study of a Novel Prodrug of Tenofovir, Tenofovir Dipivoxil Fumarate, in Healthy Male Fasted Volunteers

AbstractBackground and Objective: Tenofovir dipivoxil fumarate (9-[(R)-2-[[bis (pivaloyloxymethoxy) phosphinoyl] methoxy] propyl] adenine fumarate) is a novel ester prodrug of tenofovir. It has been developed as an anti-hepatitis B virus clinical candidate. The purpose of this study was to determine the pharmacokinetic parameters of tenofovir dipivoxil fumarate (test) and the commercially available tenofovir disoproxil fumarate (Viread®, reference). In addition, the bioavailability of tenofovir dipivoxil fumarate was evaluated in healthy male fasted subjects after a single comparatively equivalent dose. Methods: This single-dose, randomized, two-way, open-label, crossover study was conducted at Xijing Hospital, Xi’an, China. The study drug was administered under fasted conditions. Serial blood samples were obtained over 72 hours after oral administration of each treatment. Bioavailability of the drug was assessed in accordance with the State Food and Drug Administration bioequivalence criteria. Results: Eighteen subjects were enrolled and completed the study, with all study treatments being generally well tolerated. The geometric mean ratios (90% confidence interval [CI]) for maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast), and area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) were 124.49% (90% CI 115.85, 133.79), 122.85% (90% CI 115.55, 130.62), and 122.43% (90% CI 115.71, 129.54), respectively. Conclusion: The relative bioavailability of tenofovir dipivoxil was 20% higher compared with tenofovir disoproxil fumarate; this result was consistent with the preclinical data. Background and Objective: Tenofovir dipivoxil fumarate (9-[(R)-2-[[bis (pivaloyloxymethoxy) phosphinoyl] methoxy] propyl] adenine fumarate) is a novel ester prodrug of tenofovir. It has been developed as an anti-hepatitis B virus clinical candidate. The purpose of this study was to determine the pharmacokinetic parameters of tenofovir dipivoxil fumarate (test) and the commercially available tenofovir disoproxil fumarate (Viread®, reference). In addition, the bioavailability of tenofovir dipivoxil fumarate was evaluated in healthy male fasted subjects after a single comparatively equivalent dose. Methods: This single-dose, randomized, two-way, open-label, crossover study was conducted at Xijing Hospital, Xi’an, China. The study drug was administered under fasted conditions. Serial blood samples were obtained over 72 hours after oral administration of each treatment. Bioavailability of the drug was assessed in accordance with the State Food and Drug Administration bioequivalence criteria. Results: Eighteen subjects were enrolled and completed the study, with all study treatments being generally well tolerated. The geometric mean ratios (90% confidence interval [CI]) for maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast), and area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC∞) were 124.49% (90% CI 115.85, 133.79), 122.85% (90% CI 115.55, 130.62), and 122.43% (90% CI 115.71, 129.54), respectively. Conclusion: The relative bioavailability of tenofovir dipivoxil was 20% higher compared with tenofovir disoproxil fumarate; this result was consistent with the preclinical data.

Antioxidant and pro-angiogenic effects of corilagin in rat cerebral ischemia via Nrf2 activation

The nuclear factor erythroid-2-related factor 2 (Nrf2) pathway has been considered as a potential target for neuroprotection in stroke. The aim of present study was to determine whether corilagin, a novel Nrf2 activator, can protect against ischemia-reperfusion injury and explore the underlying mechanism involved. In vivo, rats exposed to middle cerebral artery occlusion were applied to establish an ischemic stroke model. Posttreatment of corilagin significantly reduced infarct volumes and apoptotic cells as well as improved neurologic score after reperfusion, together with increased vascular density in the ischemic penumbra. Meanwhile, posttreatment with corilagin in MCAO rats significantly decreased malondialdehyde levels, restored the superoxide dismutase and glutathione activity, elevating the Nrf2, heme oxygenase-1, the vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression. However, consecutive intrathecal injection of short interference RNAs targeting Nrf2 at 24-h intervals 72 h before ischemia reduced the beneficial effects of corilagin. In primary cultured neurons, corilagin dose-dependently protected against oxygen and glucose deprivation-induced insult, but the protective effect of corilagin was attenuated by knockdown of Nrf2. In conclusion, these findings indicate that corilagin exerts protective effects against cerebral ischemic injury by attenuating oxidative stress and enhancing angiogenesis via activation of Nrf2 signaling pathway.

Acetyl-11-Keto-β-Boswellic Acid Attenuates Prooxidant and Profibrotic Mechanisms Involving Transforming Growth Factor-β1, and Improves Vascular Remodeling in Spontaneously Hypertensive Rats

Vascular remodeling is an important complication of hypertension with oxidative stress-related profibrotic pathways involved. The transforming growth factor β1 (TGF-β1) has been shown to be a potential target of vasoprotection, and has multiple roles in vascular remodeling. Acetyl-11-Keto-β-Boswellic Acid (AKBA) is one of the active principles of Boswellic acids, and shows antioxidant activity in many diseases. The study is to determine effects of AKBA on systemic oxidative stress of hypertension and vascular remodeling. In the experiments, spontaneously hypertensive rats (SHR) were used. And in vitro, fibroblast was pretreated with AKBA before Ang II stimuli. In the results, treatment of AKBA markedly reduced oxidative stress, and decreased vascular remodeling by restoring vascular wall parameters and improving vascular reactivity. AKBA dramatically reduced TGF-β1 and Smad3 expression, as shown in immunofluorescence and immunohistochemistry. In cultured fibroblast, AKBA decreased intracellular ROS levels. Cell viability and proliferation, as well as migration were inhibited by AKBA. Additionally, treatment of AKBA significantly decreased TGF-β1 secretion in culture supernatant. Expression of TGF-β1, Smad3, P-Smad3 and Smad7 were also decreased by AKBA in fibroblast. In conclusion, AKBA is able to attenuate oxidative stress and profibrotic mechanisms, and improve vascular remodeling in hypertension through TGF-β1/Smad3 pathway.

Synergistic neuroprotective effects of Danshensu and hydroxysafflor yellow A on cerebral ischemia-reperfusion injury in rats

Ischemic stroke is a common cerebrovascular disease with substantial morbidity and mortality worldwide. However, therapeutic options to minimize the cerebral ischemia-reperfusion (I/R) injury are limited. In China, combination of herb Danshen (Salvia miltiorrhiza Bge) and Honghua (Carthamus tinctorius L.) is effective for stroke treatment in patients but its underlying mechanism requires further investigation. Our study was conducted to evaluate and explore the synergistic effects of two herb ingredients Danshensu and hydroxysafflor yellow A (HSYA) on cerebral ischemia-reperfusion (I/R) injury in rats. Rats were randomly assigned to the following five groups: sham group, model group, Danshensu group, HSYA group, and Danshensu+HSYA group. Under our experimental conditions in vitro, oxygen-glucose deprivation (OGD) model was established to determine the synergistic neuroprotective effects of Danshensu and HSYA. With such methods as neurological deficits scoring, TTC, HE and TUNEL staining, and ELISA detection, the results demonstrated that administration of either Danshensu or HSYA improved neurological defects and alleviated pro-inflammatory and oxidative stress reactions. Notably, combination of Danshensu and HSYA exerted more effective results than that used alone. Furthermore, western blot analysis results showed that Danshensu and HSYA combination displayed synergistic regulation on TLR4/NF-κB and Nrf2/HO-1 pathways. Consistently, Danshensu +HSYA group exhibits better neuroprotection in primary neurons with OGD model compared with Danshensu or HSYA group. Taken together, we found for the first time that Danshensu plus HSYA could achieve remarkable synergistic neuroprotective effects on I/R injury, which is related to the anti-inflammatory and antioxidant pathways.

Effects of Amlodipine on the Oral Bioavailability of Cephalexin and Cefuroxime Axetil in Healthy Volunteers

In this study, the authors compared the effects of amlodipine (AML) on the bioavailability of cephalexin (LEX) and cefuroxime axetil (CXM). Twenty‐four healthy men were randomized to 4 treatments according to a crossover design with a 14‐day washout. After an overnight fast, they were administered orally LEX 500 mg alone, LEX 500 mg 2 hours after oral administration of AML 5 mg, CXM 500 mg alone, and CXM 500 mg 2 hours after oral administration of AML 5 mg. All participants completed the whole study without side effects being observed. Pharmacokinetic data were analyzed by noncompartmental modeling with WinNonlin software. The geometric mean (GM) ratios were 1.38 (90% confidence interval [CI], 1.32‐1.45) for the area under the concentration‐time curve (AUC) for LEX and 1.27 (1.18‐1.36) for the maximum concentration of drug in serum (Cmax) for LEX followed by AML versus alone. In contrast, no significant differences were found in the pharmacokinetic parameters of CXM between treatments (P < .05). They authors conclude that AML possesses an enhancement effect in β‐lactam antibiotic bioavailability (in this case, LEX), and this interaction may be specific to the peptidomimetic β‐lactam antibiotics.

In vitro assessment of cytochrome P450 inhibition and induction potential of felotaxel (SHR110008).

The purpose of this study was to assess the potential inhibitory and inductive effects of felotaxel on cytochrome P450 isozymes in vitro. The inhibitory effects of felotaxel on various CYP isozymes were determined in human liver microsomes. In addition, the ability of felotaxel to induce CYP enzymes in cultured human hepatocytes was evaluated. Results showed that felotaxel did not inhibit CYP1A2-, CYP2C9-, CYP2C19-, CYP2E1-, CYP2D6-, CYP2B6-, CYP2C8-, and mediated activities in human liver microsomes up to a concentration of 100 μM, while the inhibition (<30% inhibition) of CYP3A4 activities was observed at 100 μM felotaxel. In vitro felotaxel did not induce CYP1A2, CYP2C19, or CYP3A4/5 activities in cultured human hepatocytes. In present study, felotaxel has been identified as a potent inhibitor of metabolic activity of CYP3A4. Therefore, clinically relevant pharmacokinetic drug-drug interactions are likely to occur between felotaxel and co-administered substrates of these CYP3A4 isozymes. These findings provided some useful information for safe and effective use of felotaxel in clinical practice.

Investigation into the underlying molecular mechanisms of hypertensive nephrosclerosis using bioinformatics analyses

Hypertensive nephrosclerosis (HNS) is a major risk factor for end-stage renal disease. However, the underlying pathogenesis of HNS remains to be fully determined. The gene expression profile of GSE20602, which consists of 14 glomeruli samples from patients with HNS and 4 normal glomeruli control samples, was obtained from the Gene Expression Omnibus database. Gene ontology (GO) and pathway enrichment analyses were performed in order to investigate the functions and pathways of differentially expressed genes (DEGs). Pathway relation and co-expression networks were constructed in order to identify key genes and signaling pathways involved in HNS. In total, 483 DEGs were identified to be associated with HNS, including 302 upregulated genes and 181 downregulated genes. Furthermore, GO analysis revealed that DEGs were significantly enriched in the small molecule metabolic process. In addition, pathway analysis also revealed that DEGs were predominantly involved in metabolic pathways. The tricarboxylic acid (TCA) cycle was identified as the hub pathway in the pathway relation network, whereas the sorbitol dehydrogenase (SORD) and cubulin (CUBN) genes were revealed to be the hub genes in the co-expression network. The present study revealed that the SORD, CUBN and albumin genes as well as the TCA cycle and metabolic pathways are involved in the pathogenesis of HNS. The results of the present study may contribute to the determination of the molecular mechanisms underlying HNS, and provide insight into the exploration of novel targets for the diagnosis and treatment of HNS.