Pharmacokinetics Study of Amoxycillin and Clavulanic acid (8:1)-A New Combination in Healthy Chinese Adult Male Volunteers Using the LC–MS/MS Method

New oral granules of amoxicillin and clavulanic acid in 8:1 ratio have recently been developed and approved to conduct clinical trial in China. To date, there has been no report studying the pharmacokinetic characteristics of amoxicillin and clavulanic acid in man. Therefore, it is urgent to investigate the pharmacokinetic properties of amoxicillin and clavulanic acid in man. The aim of the study was to assess the pharmacokinetic properties of amoxicillin and clavulanic acid in 8:1 with different dosage in healthy volunteers and provide support for this drug to obtain marketing authorization in China. A liquid chromatography-tandem mass spectrometry method for determining the concentration of amoxicillin and clavulanic acid in human plasma was developed and applied to this open-label, single- and multiple-dose Pharmacokinetics study. Subjects were randomized to receive a single dose of 1, 2, and 4 pouches of the test granulation of amoxicillin and clavulanic acid in 8:1 ratio (amoxicillin is 250 mg and clavulanic acid is 31.25 mg per pouch). In the single-dose phase, blood samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 5, 8, 12, and 24 h after drug administration. In the multiple-dose phase, samples were obtained before drug administration on days 1, 2, 3, and 4 to determine the C_min of amoxicillin and clavulanic acid. In the 4th day, samples were collected from 0.25 to 24 h after drug administration. Profiles of the concentration–time curves of amoxicillin and clavulanic acid were best fitted to two-compartment model. In this group of healthy Chinese subjects, the pharmacokinetics of amoxicillin fitted the linear dynamic feature at doses of 250,500 and 1,000 mg, and not obviously about clavulanic acid at doses of 31.25, 62.5, and 125 mg. The t _1/2 of single dose and multidoses were (1.45 ± 0.12) and (1.44 ± 0.26) h of amoxicillin and (1.24 ± 0.23) and (1.24 ± 0.17) of clavulanic acid, respectively; The AUC_0–24 of single dose and multidoses were (27937.85 ± 4265.59) and (24569.80 ± 3663.63) ng h mL^?1 of amoxicillin and (891.45 ± 194.30) and (679.61 ± 284.05) ng h mL^?1 of clavulanic acid, respectively; The C_max of single dose and multidoses were (8414.58 ± 1416.78) and (7929.17 ± 1291.54) ng mL^?1 of amoxicillin and (349.00 ± 89.54) and (289.00 ± 67.36) ng h mL^?1 of clavulanic acid, respectively. t _1/2, AUC_0–24, and C_max were similar after multiple-dose administration and after single-dose administration, suggesting that amoxicillin and clavulanic acid do not accumulate with multiple-dose administration of 500 and 62.5 mg, respectively.     

MicroRNA-92a Upholds Bmp Signaling by Targeting noggin3 during Pharyngeal Cartilage Formation

1. Download : Download high-res image (181KB)
2. Download : Download full-size image

Highlights? mir92a inactivation leads to loss of pharyngeal cartilages in zebrafish embryos ? mir92a is required for chondrogenic progenitor proliferation and survival ? Bmp signaling is positively regulated by mir92a in the pharyngeal region ? nog3 mRNA is degraded by mir92a to maintain Bmp activity     

Factors restraining parasitism of the invasive vine Mikania micrantha by the holoparasitic plant Cuscuta campestris

Mikania micrantha (Asteraceae) is one of the 10 most invasive weeds in the world and has caused tremendous economic and environmental losses in southern China. The dodder Cuscuta campestris (Convolvulaceae) is a native holoparasite that can parasitize and suppress M. micrantha, and thus is recommended as an effective control agent. However, the natural growth of dodder lags behind that of M. micrantha and fails to exert direct year-round suppression. To verify the effective parasitic distance, we placed a dodder seedling at a designated distance from the stem of M. micrantha and monitored coiling, haustorium formation, and survival. To verify suitable host stems for the parasite, we grew M. micrantha for more than 6 months to form stems of different sizes, taped dodder seedlings to the stems, and monitored. We used various temperatures to determine the effect on dodder seed germination and M. micrantha sprouting. The results showed that a dodder–host distance of 4 cm decreased the probability of successful parasitism to 0; dodder seedlings cannot parasitize M. micrantha stem diameters ≥0.3 cm; and the temperatures for the highest dodder seed germination and M. micrantha sprouting are 26 and 30 °C, respectively. We conclude that the lack of suitable M. micrantha parts within the dodder’s effective parasitism distance is the major cause of restricted dodder parasitism and that the lower temperature for the highest dodder germination compared to that for the highest M. micrantha sprouting may decrease the possibility of parasitism. To acquire aggressive parasitism, dodder should be manually assisted by dispersing its vegetative form.     

Modern maize hybrids in Northeast China exhibit increased yield potential and resource use efficiency despite adverse climate change

The impact of global changes on food security is of serious concern. Breeding novel crop cultivars adaptable to climate change is one potential solution, but this approach requires an understanding of complex adaptive traits for climate‐change conditions. In this study, plant growth, nitrogen (N) uptake, and yield in relation to climatic resource use efficiency of nine representative maize cultivars released between 1973 and 2000 in China were investigated in a 2‐year field experiment under three N applications. The Hybrid‐Maize model was used to simulate maize yield potential in the period from 1973 to 2011. During the past four decades, the total thermal time (growing degree days) increased whereas the total precipitation and sunshine hours decreased. This climate change led to a reduction of maize potential yield by an average of 12.9% across different hybrids. However, the potential yield of individual hybrids increased by 118.5 kg ha^?1 yr^?1 with increasing year of release. From 1973 to 2000, the use efficiency of sunshine hours, thermal time, and precipitation resources increased by 37%, 40%, and 41%, respectively. The late developed hybrids showed less reduction in yield potential in current climate conditions than old cultivars, indicating some adaptation to new conditions. Since the mid‐1990s, however, the yield impact of climate change exhibited little change, and even a slight worsening for new cultivars. Modern breeding increased ear fertility and grain‐filling rate, and delayed leaf senescence without modification in net photosynthetic rate. The trade‐off associated with delayed leaf senescence was decreased grain N concentration rather than increased plant N uptake, therefore N agronomic efficiency increased simultaneously. It is concluded that modern maize hybrids tolerate the climatic changes mainly by constitutively optimizing plant productivity. Maize breeding programs in the future should pay more attention to cope with the limiting climate factors specifically.     

Combination of Intratumoral Invariant Natural Killer T Cells and Interferon-Gamma Is Associated with Prognosis of Hepatocellular Carcinoma after Curative Resection

Purpose

To investigate the prognostic value of intratumoral invariant natural killer T (iNKT) cells and interferon-gamma (IFN-γ) in hepatocellular carcinoma (HCC) after curative resection.

Experimental Design

Expression of TRAV10, encoding the Vα24 domain of iNKT cells, and IFN-γ mRNA were assessed by quantitative real-time polymerase chain reaction in tumor from 224 HCC patients undergoing curative resection. The prognostic value of these two and other clinicopathologic factors was evaluated.

Results

Either intratumoral iNKT cells and IFN-γ alone or their combination was an independent prognostic factor for OS (P = 0.001) and RFS (P = 0.001) by multivariate Cox proportional hazards analysis. Patients with concurrent low levels of iNKT cells and IFN-γ had a hazard ratio (HR) of 2.784 for OS and 2.673 for RFS. The areas under the curve of iNKT cells, IFN-γand their combination were 0.618 vs 0.608 vs 0.654 for death and 0.591 vs 0.604 vs 0.633 for recurrence respectively by receiver operating characteristic curve analysis. The prognosis was the worst for HCC patients with concurrent low levels of iNKT cells and IFN-γ, which might be related with more advanced pTNM stage and more vascular invasion.

Conclusions

Combination of intratumoral iNKT cells and IFN-γ is a promising independent predictor for recurrence and survival in HCC, which has a better power to predict HCC patients’ outcome compared with intratumoral iNKT cells or IFN-γ alone.     

Residential Exposure to 50 Hz Magnetic Fields and the Association with Miscarriage Risk: A 2-Year Prospective Cohort Study

Objective

The hypothesis of whether exposure to extremely low-frequency magnetic fields (ELF-MF) may increase miscarriage risk is controversial. A 2-year prospective cohort study was designed to study the association between exposure to 50 Hz magnetic fields (MF) and the miscarriage risk for women residing in the area of the Pearl-River Delta of China.

Method

Two towns with densely distributed power supply constructions were selected as the study sites. From 2010 to 2012, 552 women in the region who were at approximately 8 weeks of gestation or who planned to have a baby within 1 year were selected as candidate subjects. Exposure to MF was estimated by measurements at their front doors and in the alley in front of the subjects’ houses. The average exposure level was used as a cutoff point to define the exposed group. Clinical miscarriage was diagnosed by local obstetricians. Staffs from the local population and family planning service stations were responsible for the follow-up interviews every 2 months.

Results

Four hundred and thirteen pregnant women were selected for the cohort study. The average residential exposure to MF was 0.099 µT. No significantly increased risk of miscarriage was found to be associated with the average front-door exposure (p>0.05). However, miscarriage risk was found to be significantly associated with maximum alley exposure (p=0.001). The relative risk (RR) of miscarriage from maximum alley exposure was 2.35 (95% C.I.: 1.18-4.71). In addition, Cox regression analysis showed that the adjusted hazard ratio of maximum alley exposure for miscarriage was 1.72 (95% C.I.:1.10-2.69).

Conclusion

Although the miscarriage incidence was shown to be positively associated with the maximum alley MF exposure, the association between miscarriage risk and the exposure to MF was not confirmed in the study. The results of this study are of interest concerning MF exposure assessment and pregnancy outcomes.     

Are Platelet-Rich Products Necessary during the Arthroscopic Repair of Full-Thickness Rotator Cuff Tears: A Meta-Analysis

Background

Platelet-rich products (PRP) are widely used for rotator cuff tears. However, whether platelet-rich products produce superior clinical or radiological outcomes is controversial. This study aims to use meta-analysis to compare clinical and radiological outcomes between groups with or without platelet-rich products.

Methods

The Pubmed, Embase, and Cochrane library databases were searched for relevant studies published before April 20, 2013. Studies were selected that clearly reported a comparison between the use or not of platelet-rich products. The Constant, ASES, UCLA, and SST scale systems and the rotator cuff retear rate were evaluated. The weighted mean differences and relative risks were calculated using a fixed-effects model.

Results

Seven studies were enrolled in this meta-analysis. No significant differences were found for the Constant scale (0.73, 95% CI, −1.82 to 3.27, P = 0.58), ASES scale (−2.89, 95% CI, −6.31 to 0.53, P = 0.1), UCLA scale (−0.79, 95% CI, −2.20 to 0.63, P = 0.28), SST scale (0.34, 95% CI, −0.01 to 0.69, P = 0.05), and the overall rotator cuff retear rate (0.71, 95% CI, 0.48 to 1.05, P = 0.08). Subgroup analysis according to the initial tear size showed a lower retear rate in small- and medium-sized tears (0.33, 95% CI, 0.12 to 0.91, P = 0.03) after platelet-rich product application but no difference for large- and massive-sized tears (0.86, 95% CI, 0.60 to 1.23, P = 0.42).

Conclusion

In conclusion, the meta-analysis suggests that the platelet-rich products have no benefits on the overall clinical outcomes and retear rate for the arthroscopic repair of full-thickness rotator cuff tears. However, a decrease occurred in the rate of retears among patients treated with PRP for small- and medium-sized rotator cuff tears but not for large- and massive-sized tears.

Level of Evidence

Level II     

Polymorphisms of Genes in Neurotransmitter Systems Were Associated with Alcohol Use Disorders in a Tibetan Population

Studies of linkage and association in various ethnic populations have revealed many predisposing genes of multiple neurotransmitter systems for alcohol use disorders (AUD). However, evidence often is contradictory regarding the contribution of most candidate genes to the susceptibility of AUD. We, therefore, performed a case-control study to investigate the possible associations of genes selected from multiple neurotransmitter systems with AUD in a homogeneous Tibetan community population in China. AUD cases (N = 281) with an alcohol use disorder identification test (AUDIT) score ≥10, as well as healthy controls (N = 277) with an AUDIT score ≤5, were recruited. All participants were genotyped for 366 single nucleotide polymorphisms (SNPs) of 34 genes selected from those involved in neurotransmitter systems. Association analyses were performed using PLINK version 1.07 software. Allelic analyses before adjustment for multiple tests showed that 15 polymorphisms within seven genes were associated with AUD (p<0.05). After adjustment for the number of SNPs genotyped within each gene, only the association of a single marker (rs10044881) in HTR4 remained statistically significant. Haplotype analysis for two SNPs in HTR4 (rs17777298 and rs10044881) showed that the haplotype AG was significantly associated with the protective effect for AUD. In conclusion, the present study discovered that the HTR4 gene may play a marked role in the pathogenesis of AUD. In addition, this Tibetan population sample marginally replicated previous evidence regarding the associations of six genes in AUD.