Population pharmacokinetic characteristics of sirolimus in healthy Chinese subjects and renal transplant patients.

AIM: To identify the factors affecting the pharmacokinetics (PKs) of sirolimus in healthy Chinese subjects and renal transplant patients. METHODS: A population PK model of sirolimus was constructed using dense data from 22 healthy volunteers and sparse data from 105 renal transplant patients. RESULTS: The data were well described by a two-compartment model with first-order absorption. The estimates of absorption rate constant (Ka), clearance (CL/F), and central volume of distribution (V2/F) were 0.24 h(-1), 8.81 L/h, and 676 L, respectively. The CL/F in renal transplant patients was 45.5% lower than that in healthy subjects. Based on the final model, CL/F decreased significantly with increasing cyclosporine (CsA) daily dose and age. A decrease of 7.3% in CL/F for every 100-mg increase in the CsA daily dose and a decrease of 34.2% in CL/F for every 20-year increase in age was observed. Moreover, V2/F increased significantly with increasing serum creatinine in our study. However, the range of serum creatinine concentration and the interindividual variability for V2/F are large. CONCLUSION: This is the first study to characterize the population PKs of sirolimus using a two-compartment model in healthy Chinese subjects and renal transplant patients. A decrease of 7.3% in the sirolimus CL/F for every 100-mg increase in the CsA daily dose and a decrease of 34.2% in the sirolimus CL/F for every 20-year increase in age was observed, which allowed us to better optimize sirolimus dosing regimens in Chinese renal transplant patients.

Genome sequencing of high-penicillin producing industrial strain of Penicillium chrysogenum.

BACKGROUND: Due to the importance of Penicillium chrysogenum holding in medicine, the genome of low-penicillin producing laboratorial strain Wisconsin54-1255 had been sequenced and fully annotated. Through classical mutagenesis of Wisconsin54-1255, product titers and productivities of penicillin have dramatically increased, but what underlying genome structural variations is still little known. Therefore, genome sequencing of a high-penicillin producing industrial strain is very meaningful. RESULTS: To reveal more insights into the genome structural variations of high-penicillin producing strain, we sequenced an industrial strain P. chrysogenum NCPC10086. By whole genome comparative analysis, we observed a large number of mutations, insertions and deletions, and structural variations. There are 69 new genes that not exist in the genome sequence of Wisconsin54-1255 and some of them are involved in energy metabolism, nitrogen metabolism and glutathione metabolism. Most importantly, we discovered a 53.7 Kb "new shift fragment" in a seven copies of determinative penicillin biosynthesis cluster in NCPC10086 and the arrangement type of amplified region is unique. Moreover, we presented two large-scale translocations in NCPC10086, containing genes involved energy, nitrogen metabolism and peroxysome pathway. At last, we found some non-synonymous mutations in the genes participating in homogentisate pathway or working as regulators of penicillin biosynthesis. CONCLUSIONS: We provided the first high-quality genome sequence of industrial high-penicillin strain of P. chrysogenum and carried out a comparative genome analysis with a low-producing experimental strain. The genomic variations we discovered are related with energy metabolism, nitrogen metabolism and so on. These findings demonstrate the potential information for insights into the high-penicillin yielding mechanism and metabolic engineering in the future.

Tomitella cavernea sp. nov., an actinomycete isolated from soil.

A Gram-staining-positive, aerobic, non-spore-forming, irregular rod-shaped actinobacterium, designated YIM C00895(T), was isolated from a soil sample collected from Jiuxiang Scenic Region, Yunnan province, south-west China. The strain was able to grow at 10-28 °C, pH 6.0-10.0 and 0-11% NaCl (w/v). Phylogenetic analysis based on 16S rRNA (95.3%) gene sequences revealed the highest similarity to Tomitella biformata AHU1821(T). The whole-cell hydrolysates of strain YIM C00895(T) contained meso-diaminopimelic acid, arabinose and galactose, indicating chemotype IV. The muramic acids in the peptidoglycan were glycolated. The polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannosides and an unidentified glycolipid. MK-9(H2) was the predominant menaquinone. The major fatty acids were C14 : 0, C16 : 0, C16 : 1 and C18 : 1ω9c and tuberculostearic acid (10-methyl C18 : 0) was present in relatively small amounts (4.5%). TLC analysis of its cellular mycolic acids showed a similar profile to Tomitella biformata DSM 45403(T). The DNA G+C content of the strain was 67.5 mol%. The results of physiological and biochemical tests allowed strain YIM C00895(T) to be differentiated phenotypically from Tomitella biformata DSM 45403(T). On the basis of evidence from this polyphasic study, the novel species Tomitella cavernea sp. nov. is proposed. The type strain of Tomitella cavernea is YIM C00895(T) ( = DSM 45788(T)  = JCM 18542(T)).

Trivaric acid, a potent depside human leukocyte elastase inhibitor.

Human leukocyte elastase (HLE) is a serine protease implicated in several inflammatory diseases, and represents a major target for anti-inflammatory drug development. In the present study, nordivaricatic acid (1), divarinyl divarate (2), and trivaric acid (3), three depsides isolated from the culture of a soil derived fungal strain were identified as inhibitors of HLE. Two didepsides 1 and 2 showed low inhibitory activity. In contrast, trivaric acid, a para-tridepside, exhibited highly potent inhibitory activity with an IC(50) value of 1.8 µM and a K(i) of 0.6 µM. Kinetic investigations with trivaric acid showed that this inhibition is reversible, competitive pattern. Further studies on the selectivity of three depsides toward serine proteases showed that they did not inhibit chymotrypsin, trypsin and thrombin even at 150 µM.

Risk Assessment and Potential Analysis of the Agricultural Use of Sewage Sludge in Central Shanxi Province.

The agricultural use of sewage sludge has become an economic disposal method used worldwide. However, heavy metals contained in sewage sludge have become the crucial limiting factors for this way of disposal. This study showed that regulatory limit values are not enough to determine whether sewage sludge is suitable for agricultural use; risk assessment and potential analysis should be applied. Correlation analysis and hierarchical cluster analysis (HCA) should also be performed to identify heavy metals' sources and show their influence on sewage sludge utilization. Samples were collected from 13 wastewater treatment plants (WWTPs) located in central Shanxi Province. Results indicated that the mean contents of heavy metals in sewage sludge were all less than the limit threshold of China. According to the monomial potential ecological risk coefficient (), the agricultural use of sewage sludge had low ecological risks for all heavy metals, except for Hg and Cd. Based on the potential ecological risk index (RI), only three stations had moderate risk, other nine stations all had higher potential risk. The mean potentials by all heavy metals were all beyond 10 years, which is the limit of the maximum application time specified by China. Combining all heavy metals, only one station's potential was less than 10 years. Although the contents of heavy metals were all within the threshold values, large quantities of sewage sludge are not suitable for agricultural use. Coal-related industries, which were the main sources of Hg and Cd, greatly affected the agricultural use of sewage sludge.

Comparison of the Potential Ecological and Human Health Risks of Heavy Metals from Sewage Sludge and Livestock Manure for Agricultural Use.

Sewage sludge and livestock (chicken, swine and cattle) manure samples were collected from the Yanmenguan Cattle Herbivorous Livestock Area to compare the potential ecological and human health risks caused by heavy metals contained in them. In this study, the Class II level of Quality Control of Imported Organic Fertilizers is selected as the limit standard value of heavy metals. Based on the mean content values, no heavy metal in cattle manure was higher than the limit standard value; the content of Cu in swine manure was higher than the limit of Cu; the content of Zn in sewage sludge, chicken manure and swine manure were all higher than the limit of Zn; and the content of Cr in sewage sludge and chicken manure were all higher than the limit of Cr. Results indicated that sewage sludge and livestock manure all had high contents of Zn, Cu and Cr. The mean pollution index (PI) suggested that Cu, Zn, As and Cr in sewage sludge and livestock manures all induced potential ecological risks. According to the mean Nemerow's synthetic pollution index (PN) values, swine manure had the highest potential ecological risk for agricultural use. Daily exposure to Cu, Zn and Cr was higher than other heavy metals from sewage sludge and livestock manures, and heavy metal exposure was always higher for children than adults, with ingestion as the main pathway. Non-carcinogenic risk was caused mainly by Cu and Cr, based on the higher hazard quotient (HQ) values for adults and children. There was no non-carcinogenic risk for all people, except exposure of Cu from swine manure for children, which was 1.76 times higher than the threshold value of 1. According to the mean hazard index (HI) values, only swine manure had a non-carcinogenic risk for children. As the carcinogenic risk index (Risk) values were continuously greater for As than Cd, As had a higher carcinogenic risk than Cd. There was no carcinogenic risk for any single heavy metal, although As exposure from sewage sludge was found to have an inapparent carcinogenic risk for both adults and children. Regarding the RISK value, sewage sludge had an unacceptable carcinogenic risk for adults and children, and swine manure had an unacceptable risk for children only. In general, for both non-carcinogenic and carcinogenic risks, ingestion was the main pathway, and children were more sensitive than adults. Comparing the four kinds of organic waste, cattle manure was the safest for agricultural use in terms of ecological and human health risks. In multiple comparisons, swine manure was significantly different regarding potential ecological risk and non-carcinogenic risk, and sewage sludge was significantly different regarding carcinogenic risk.

Disposal Situation of Sewage Sludge from Municipal Wastewater Treatment Plants (WWTPs) and Assessment of the Ecological Risk of Heavy Metals for Its Land Use in Shanxi, China.

Land use of sewage sludge is the primary disposal method in Shanxi, accounting for 42.66% of all. To determine the ecological risk of heavy metals in sewage sludge, contents of seven heavy metals in sewage sludge from 9 municipal waste water treatment plants (WWTPs) that had the highest application for land use were determined. The order of the measured concentrations was: Zn > Cr > Cu > Ni > Pb > As > Cd, and all heavy metals contents were within the threshold limit values of the Chinese Control Standards for Pollutants in Sludge from Agriculture Use (GB4284-84). Four indices were used to assess the pollution and the ecological risk of heavy metals. By the mean values of the geoaccumulation index (Igeo), heavy metals were ranked in the following order: Cd > Zn > Cu > As > Cr > Ni > Pb. The values showed that the pollution of Zn in station 3 and Cd in station 1, 2, 3, 4, 8 and 9 were heavily; Cu in station 8 and 9, Zn in station 1, 2, 4, 8 and 9 and Cd in station 5 and 7 were moderately to heavily, and the accumulation of other heavy metals were not significant. The single-factor pollution index (PI) suggested that none of the stations had heavy metals contamination, except for Cu in station 9, Zn in station 3 and 8, and Cd in station 1 and 9, which were at a moderate level. According to the results of the Nemerow's synthetic pollution index (PN), sewage sludge from all stations was safe for land use with respect to heavy metals contamination, except for stations 3, 8 and 9, which were at the warning line. The monomial potential ecological risk coefficient (Eri) revealed that heavy metals ecological risks in most stations were low. However, station 9 had a moderate risk for Cu; station 6 had a moderate risk, stations 5 and 7 had high risk, other stations had very high risk for Cd. According to the results of the potential ecological risk index (RI), station 1, 8 and 9 had high risk; station 2, 3, 4, 5 and 7 had a moderate risk, and station 6 had a low risk. The preliminary results indicated that the potential risk of land exposure to heavy metals in sewage sludge was relatively low, with Zn and Cd as the main contributor to the ecological risk for the applying of sewage sludge on land. Additionally, stations 3, 8 and 9 require more attention regarding the land applications related to heavy metals pollution.

Comparison of Health Risk Assessments of Heavy Metals and As in Sewage Sludge from Wastewater Treatment Plants (WWTPs) for Adults and Children in the Urban District of Taiyuan, China.

Abstract: To compare the human health risk of heavy metals and As in sewage sludge between adults and children, samples were collected from five wastewater treatment plants (WWTPs) located in the urban district of Taiyuan, the capital of Shanxi. Heavy metals and As in sewage sludge can be ranked according to the mean concentration in the following order: Cu > Cr > Zn > Pb > As > Hg > Cd. Compared with the concentration limit set by different countries, the heavy metals contents in sewage sludge were all within the standard limits, except for the content of As, which was higher than the threshold limit established by Canada. A health risk assessment recommended by the United States Environmental Protection Agency (USEPA) was used to compare the non-cancer risk and cancer risk between adults and children. Based on the mean and 95% upper confidence limit (UCL) of the average daily dose (ADD), heavy metals and As can be ranked in the order of Cu > Cr > Zn > Pb > As > Hg > Cd for adults, and Cu > Cr > Zn > Pb > Hg > As > Cd for children. Moreover, results of ADDingest and ADDinhale indicated that ingestion was the main pathway for heavy metals and As exposure for both adults and children, and the sum of ADD implied that the exposure to all heavy metals and As for children was 8.65 and 9.93 times higher, respectively, than that for adults according to the mean and 95% UCL. For the non-carcinogenic risk, according to the hazard quotient (HQ), the risk of Cu, Hg and Cr was higher than the risk of Zn and Pb. The hazard index (HI) for adults was 0.144 and 0.208 for the mean and 95% UCL, which was less than the limit value of 1; for children, the HI was 1.26 and 2.25, which is higher than the limit value of 1. This result indicated that children had non-carcinogenic risk, but adults did not. Furthermore, ingestion was the main pathway for non-carcinogenic risk exposure by the HQingest and HQinhale. For the carcinogenic risk, Cd and As were classified as carcinogenic pollutants. The values of RISK for the mean and 95% UCL for adults and children all exceeded the limit value of 1 × 10-5, which implied that adults and children had a carcinogenic risk, and this risk was higher for children than for adults. The results of RISK for As and Cd implied that As was the main pollutant for carcinogenic risk. Moreover, the results of RISKingest and RISKinhale indicated that ingestion was the main pathway. Uncertainty analysis was performed, and the risk ranges of it were greater than certainty analysis, which implied that uncertainty analysis was more conservative than certainty analysis. A comparison of the non-carcinogenic risk and carcinogenic risk for adults and children indicated that children were more sensitive and vulnerable than adults when exposed to the same pollutant in the environment.

Evaluation and Source Apportionment of Heavy Metals (HMs) in Sewage Sludge of Municipal Wastewater Treatment Plants (WWTPs) in Shanxi, China.

Heavy metals (HMs) in sewage sludge have become the crucial limiting factors for land use application. Samples were collected and analyzed from 32 waste water treatment plants (WWTPs) in the Shanxi Province, China. HM levels in sewage sludge were assessed. The multivariate statistical method principal component analysis (PCA) was applied to identify the sources of HMs in sewage sludge. HM pollution classes by geochemical accumulation index I(geo) and correlation analyses between HMs were also conducted. HMs were arranged in the following decreasing order of mean concentration: Zn > Cu > Cr > Pb > As > Hg > Cd; the maximum concentrations of all HMs were within the limit of maximum content permitted by Chinese discharge standard. I(geo) classes of HMs pollution in order from most polluted to least were: Cu and Hg pollution were the highest; Cd and Cr pollution were moderate; Zn, As and Pb pollution were the least. Sources of HM contamination in sewage sludge were identified as three components. The primary contaminant source accounting for 35.7% of the total variance was identified as smelting industry, coking plant and traffic sources; the second source accounting for 29.0% of the total variance was distinguished as household and water supply pollution; the smallest of the three sources accounting for 16.2% of the total variance was defined as special industries such as leather tanning, textile manufacturing and chemical processing industries. Source apportionment of HMs in sewage sludge can control HM contamination through suggesting improvements in government policies and industrial processes.