Interpreting Dose-Response Relation for Exposure to Multiple Sound Impulses in the Framework of Immunity

Hearing loss is a common military health problem and it is closely related to exposures to impulse noises from blast explosions and weapon firings. In a study based on test data of chinchillas and scaled to humans (Military Medicine, 181: 59-69), an empirical injury model was constructed for exposure to multiple sound impulses of equal intensity. Building upon the empirical injury model, we conduct a mathematical study of the hearing loss injury caused by multiple impulses of non-uniform intensities. We adopt the theoretical framework of viewing individual sound exposures as separate injury causing events, and in that framework, we examine synergy for causing injury (fatigue) or negative synergy (immunity) or independence among a sequence of doses. Starting with the empirical logistic dose-response relation and the empirical dose combination rule, we show that for causing injury, a sequence of sound exposure events are not independent of each other. The phenomenological effect of a preceding event on the subsequent event is always immunity. We extend the empirical dose combination rule, which is applicable only in the case of homogeneous impulses of equal intensity, to accommodate the general case of multiple heterogeneous sound exposures with non-uniform intensities. In addition to studying and extending the empirical dose combination rule, we also explore the dose combination rule for the hypothetical case of independent events, and compare it with the empirical one. We measure the effect of immunity quantitatively using the immunity factor defined as the percentage of decrease in injury probability attributed to the sound exposure in the preceding event. Our main findings on the immunity factor are: 1) the immunity factor is primarily a function of the difference in SELA (A- weighted sound exposure level) between the two sound exposure events;it is virtually independent of the magnitude of the two SELA values as long as the difference is fixed;2) the immunity factor increases monotonically from 0 to 100% as the first dose is varied from being significantly below the second dose, to being moderately above the second dose. The extended dose-response formulation developed in this study provides a theoretical framework for assessing the injury risk in realistic situations.

Dose of Telehealth to Improve Community-Based Care for Adults Living with Multiple Chronic Conditions: A Systematic Review

The purpose of this systematic review is to identify evidence of the appropriate dose of telehealth intervention services provided to community dwelling adults experiencing chronic illness or disability related to effectiveness, quality, safety, and cost. Academic Search Complete, CINAHL, MEDLINE, Cochrane, and JBI were searched using combinations of “telehealth or telemedicine or telemonitoring or telepractice or telenursing or telecare AND chronic illness or chronic disease”. Of the identified 449 articles, 47 articles met the inclusion criteria. Most study designs were quasi-experimental one group pre-test post-test (N = 16) with few Randomized Controlled Trials (N = 12). Twenty-three published articles studied the effect of telehealth for one chronic condition (49.9%) while 24 (51.1%) examined the effectiveness of telehealth for multiple chronic conditions. Measurement of telehealth outcomes varied and included efficacy, healthcare utilization, quality, adherence, cost, and safety. No standard measure of dose could be extrapolated. Length of intervention was measured and reported differently in each study. The dose of telehealth services that improve care effectiveness, quality, safety, and cost is still unknown for community dwelling adults experiencing chronic illness. The findings from this systematic review do indicate that longer duration of telehealth services (51 weeks), regardless of modality, produced positive outcomes as opposed to those with shorter durations (37 - 38 weeks) that produced neutral or mixed results. Collecting and reporting data related to clinical workflow such as dose of intervention specific to disease and type of modality is recommended. Rigorous study design including standard measurement at the RCT and Comparative Effectiveness level is still needed.

Biologically-Effective-Dose of Tolpyralate and Tolpyralate plus Atrazine for Control of Multiple-Herbicide-Resistant Waterhemp [<i>Amaranthus tuberculatus</i>(Moq.) J. D. Sauer] in Corn

The biologically-effective-dose of tolpyralate, a new 4-hydroxyphenyl-pyruvate dioxygenase (HPPD)-inhibitor, applied alone or tank-mixed with atrazine, for the control of multiple-herbicide-resistant (MHR) waterhemp [Amaranthus tuberculatus (Moq.) J. D. Sauer] has not been studied in corn. Seven field experiments were conducted during a three-year period (2018, 2019, 2020) in Ontario, Canada with MHR waterhemp to determine: 1) the dose-response of MHR waterhemp to tolpyralate and tolpyralate plus atrazine, and 2) the relative efficacy of tolpyralate and tolpyralate plus atrazine to post-emergence corn herbicides, dicamba/atrazine (500/1000 g·ha−1) and mesotrione + atrazine (100 + 280 g·ha−1). Tolpyralate + atrazine (120 + 4000 g·ha−1) caused 13% corn injury at one site two weeks after application (WAA), which was observed as transient foliar chlorosis and bleaching of new leaves. At 12 WAA, the predicted dose of tolpyralate for 50% control of MHR waterhemp at Cottam and on Walpole Island was 8 and 2 g·ha−1, respectively;the predicted dose of tolpyralate + atrazine for 50% control of MHR waterhemp at Cottam and on Walpole Island was 5 + 160 and 1 + 21 g·ha−1, respectively. The difference in predicted dose at the two sites is likely due to differences in MHR density and resistance profile. Applied at the registered rate, tolpyralate (30 g·ha−1) and tolpyralate + atrazine (30 + 1000 g·ha−1) controlled MHR waterhemp similar to dicamba/atrazine and mesotrione + atrazine across sites. This study demonstrates that tolpyralate + atrazine, applied POST, provides season-long control of MHR waterhemp in corn.

Pharmacokinetics of Moclobemide Sustained Release Tablets after Multiple Oral Dose Administration in Healthy Volunteers

To investigate the pharmacokinetic characteristics of moclobemide sustainedrelease tablets after multiple oral dose administration in healthy Chinese volunteers. MethodsMoclobemide sustained release tablets were given as a multiple oral dose regimen of 300 mg oncedaily for five consecutive days to 12 healthy volunteers. The concentrations of moclobemide inplasma were determined by reversed-phase high performance liquid chromatography. The partialpharmacokinetic parameters were calculated using 3p97 pharmacokinetic program. Results Theconcentration-time profile fitted an one-compartment model best. The steady-state pharmacokineticparameters of moclobemide sustained release tablets after multiple oral doses were as follows:C_(max) was (1 950 +- 156) μg· L^(-1), T_(max) was (6.00 +-1.55) h, T_(1/2(kel)) was (3.14 +-0.12)h, AUC_(ss 0-24) was (22 836 +- 1 842) μg·h· L^(-1), MRT was (7.68+-0.36) h, CL/F_((s)) was(20.2+-2.1) L·h^(-1), and V/F_((c)) was (91.4+-9.4) L, respectively. No marked adverse events werenoted during this study. Conclusion The formulation has a sustained-release effect and goodtolerance in the healthy volunteers, which provides useful information for clinical practice.

Pharmacokinetics of Controlled Release and Immediate Release Morphine Sulphate Tablets after a Single Dose and Multiple Doses in Chinese Volunteers

The pharmacokinetics of morphine sulphate was studied in 10 Chinese healthy volunteers after a single oral dose. Blood samples were collected before and after administration of controlled release tablets (CRMS, 30 mg) and immediate release tablets (IRMS, 20 mg). The plasma concentration of morphine was determined by GC MS. The pharmacokinetic parameters of controlled release tablets and immediate release tablets were calculated∶ C max was 19.38±3.80 and 21.27±6.21 ng/ml, t max was 2.36 ±0.37 h and 0.56±0.16 h, t 1/2β was 3.53±0.87 and 3.03±0.74 h, AUC was 145.15±17.65 and 93.08±16.65 ng/ml, respectively. The steady state plasma concentration of morphine sulphate in cancer patients after multiple doses was achieved, C max of CRMS and IRMS was 27.43±0.33 ng/ml and 22.68±0.16 ng/ml, C min of CRMS and IRMS was 19.45±1.44 ng/ml and 18.14±0.49 ng/ml, respectively.

Real-Time Analytical Solutions as Series Formulas and Heaviside off/on Switch Functions for Multiple Intermittent Intravenous Infusions in One- and Two-Compartment Models

Pharmacokinetic compartment models are the only models that can extract pharmacokinetic parameters from data collected in clinical studies but their estimates lack accuracy, explanations and physiological significance. The objective of this work was to develop particular solutions to drug concentration and AUC in the form of mathematical series and Heaviside functions for repetitive intermittent infusions in the one- and two-compartment models, as a function of dose number and total time using differential calculus. It was demonstrated that the central and peripheral compartment volumes determined from regression analysis of the aminoglycoside antibiotic Sisomicin concentration in plasma represent the actual physiological body fluid volumes accessible by the drug. The drug peak time and peak concentration in the peripheral compartment were also calculated as a function of dose number. It is also shown that the time of intercompartmental momentary distribution equilibrium can be used to determine the drug’s apparent volume of distribution within any dosing interval in multi-compartment models. These estimates were used to carry out simulations of plasma drug concentration with time in the one-compartment model. In conclusion, the two-compartment open mammillary pharmacokinetic model was fully explained for the aminoglycoside antibiotic sisomicin through the new concept of the apparent volume of distribution.

Effect of ω-3 Polyunsaturated Fatty Acid on Toll-like Receptors in Patients with Severe Multiple Trauma

This study examined the effects of ω-3 polyunsaturated fatty acid（ω-3PUFA） on the expression of toll-like receptor 2（TLR2）,toll-like receptor 4（TLR4） and some related inflammatory factors in peripheral blood mononuclear cells（PBMCs） of patients with early-stage severe multiple trauma.Thirty-two patients who were admitted to the Department of Traumatic Surgery,Tongji Hospital（Wuhan,China） between May 2010 and November 2010,and diagnosed as having severe multiple trauma with a injury severity score（ISS） no less than 16,were enrolled in the study and divided into two groups at random（n=16 in each）：ω-3PUFA group and control group in which routine parenteral nutrition supplemented with ω-3PUFA or not was administered to the patients in two groups for consecutive 7 days.Peripheral blood from these patients was collected within 2 h of admission（day 0）,and 1,3,5 and 7 days after the nutritional support.PBMCs were isolated and used for detection of the mRNA and protein expression of TLR2 and TLR4 by using real-time PCR and flow cytometry respectively,the levels of NF-κB by quantum dots-based immunofluorescence assay,the levels of TNF-α,IL-2,IL-6 and COX-2 by ELISA,respectively.The results showed that the mRNA and protein expression of TLR2 and TLR4 in PBMCs was significantly lower in ω-3PUFA group than in control group 5 and 7 days after nutrition support（both P0.05）.The levels of TNF-α,IL-2,IL-6 and COX-2 were found to be substantially decreased in PBMCs in ω-3PUFA group as compared with control group at 5th and 7th day（P0.05 for all）.It was concluded that ω-3PUFA can remarkably decrease the expression of TLR2,TLR4 and some related inflammatory factors in NF-κB signaling pathway in PBMCs of patients with severe multiple trauma,which suggests that ω-3PUFA may suppress the excessive inflammatory response meditated by the TLRs/NF-κB signaling pathway.

Multiple cycles of magnetic activity in the Sun and Sun-like stars and their evolution

The wavelet transform method for high-quality time-frequency analysis is applied to sets of observations of relative sunspot numbers and stellar chromosphere fluxes of 10 Sun-like stars. Wavelet analysis of solar data shows that in a certain interval of time there are several cycles of activity with pe- riods of duration which vary considerably from each other： from quasi-biennial cycles to lO0-yr cycles. Cyclic activity was detected in almost all Sun-like stars that we examined, even those that previously were not considered as stars with cyclic activity according to analysis using a Scargle periodogram. The durations of solar and stellar cycles significantly change during the observation period.

Multiple Regression Analysis of Influencing Factors on Yield of New Sugarcane Variety Yuetang 03-373

[Objectives]The purpose of this study was to provide reference for cultivation and promotion of a new sugarcane variety Yuetang 03-373,on the basis of analyzing and summarizing the characters of the variety.[Methods]Correlation,multiple regression and path analyses were performed for the yield and yield components of Yuetang 03-373.[Results]Correlation analysis shows that cane yield was significantly correlated with millable stalk number,stalk length and stalk diameter,and among them,the correlation with millable stalk number was the strongest.Multiple regression and path analyses show that millable stalk number contributed the most to cane yield,followed by stalk length,and stalk diameter contributed the least.The regression equation of cane yield against the three yield components was y=-2.8713+1.5497x1+5.8990x2-395.4294x3(R=0.9672**).[Conclusions]Millable stalk number and stalk length were the important and major factors for high yield of Yuetang 03-373,indicating that Yuetang 03-373 is a sugarcane variety of millable stalk type.In cultivation,full play should be given to the advantage of Yuetang 03-373 in millable stalk number,as well as stalk length(plant height),in order to achieve the purpose of increasing yield.

Multiple Ionization of Argon Induced by Carbon Ions at 20-500 keV/u Energies

We measure the multiple ionization cross-section ratios Rk1 of Ar impacted by Cw＋ （q= 1-3） ions in the energy range of 20-500 keV/u. The measured ratios Rkl increase with the projectile energy at lower energies, and reach the maximum at energies of 50-150 keV/u, then decrease for higher energies, We also use the classical over barrier ionization model to calculate the ratios Rk1, and the calculation results are in good agreement with the data, which suggest that the multiple ionization process is described by the sequential over-barrier ionization process,

Rare Aggressive Form of Multiple Myeloma with Diffuse Osteosclerosis and Elevated CA 15-3 Levels

We report the case of a 56-year-old female who had recently been examined for back and epigastric pain, and was diagnosed in the internal medicine ward as having an aggressive rare form of multiple myeloma with diffuse osteoblastic bone lesions. She also had high levels of breast tumor marker (CA 15-3), severe tumor lysis syndrome, and pleural and central nervous system involvement. A few cases of multiple myeloma with diffuse osteosclerosis that are not part of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changeshave) have been described. None of these cases were as aggressive as our case. To our knowledge it is the first report describing an elevation in CA 15-3 in conjunction with multiple myeloma.

Prediction of cavity growth rate during underground coal gasification using multiple regression analysis

During underground coal gasification （UCG）, whereby coal is converted to syngas in situ, a cavity is formed in the coal seam. The cavity growth rate （CGR） or the moving rate of the gasification face is affected by controllable （operation pressure, gasification time, geometry of UCG panel） and uncontrollable （coal seam properties） factors. The CGR is usually predicted by mathematical models and laboratory experiments, which are time consuming, cumbersome and expensive. In this paper, a new simple model for CGR is developed using non-linear regression analysis, based on data from 1 l UCG field trials. The empirical model compares satisfactorily with Perkins model and can reliably predict CGR.

Dose-Injury Relation as a Model for Uncertainty Propagation from Input Dose to Target Dose

We study a general framework for assessing the injury probability corresponding to an input dose quantity. In many applications, the true value of input dose may not be directly measurable. Instead, the input dose is estimated from measurable/controllable quantities via numerical simulations using assumed representative parameter values. We aim at developing a simple modeling framework for accommodating all uncertainties, including the discrepancy between the estimated input dose and the true input dose. We first interpret the widely used logistic dose-injury model as the result of dose propagation uncertainty from input dose to target dose at the active site for injury where the binary outcome is completely determined by the target dose. We specify the symmetric logistic dose-injury function using two shape parameters: the median injury dose and the 10 - 90 percentile width. We relate the two shape parameters of injury function to the mean and standard deviation of the dose propagation uncertainty. We find 1) a larger total uncertainty will spread more the dose-response function, increasing the 10 - 90 percentile width and 2) a systematic over-estimate of the input dose will shift the injury probability toward the right along the estimated input dose. This framework provides a way of revising an established injury model for a particular test population to predict the injury model for a new population with different distributions of parameters that affect the dose propagation and dose estimation. In addition to modeling dose propagation uncertainty, we propose a new 3-parameter model to include the skewness of injury function. The proposed 3-parameter function form is based on shifted log-normal distribution of dose propagation uncertainty and is approximately invariant when other uncertainties are added. The proposed 3-parameter function form provides a framework for extending skewed injury model from a test population to a target population in application.

Risk of Hearing Loss Caused by Multiple Acoustic Impulses in the Framework of Biovariability

We consider the hearing loss injury among subjects in a crowd with a wide spectrum of individual intrinsic injury probabilities due to biovariability. For multiple acoustic impulses, the observed injury risk of a crowd vs the effective combined dose follows the logistic dose-response relation. The injury risk of a crowd is the average fraction of injured. The injury risk was measured in experiments as follows: each subject is individually exposed to a sequence of acoustic impulses of a given intensity and the injury is recorded;results of multiple individual subjects were assembled into data sets to mimic the response of a crowd. The effective combined dose was adjusted by varying the number of impulses in the sequence. The most prominent feature observed in experiments is that the injury risk of the crowd caused by multiple impulses is significantly less than the value predicted based on assumption that all impulses act independently in causing injury and all subjects in the crowd are statistically identical. Previously, in the case where all subjects are statistically identical (i.e., no biovariability), we interpreted the observed injury risk caused by multiple impulses in terms of the immunity effects of preceding impulses on subsequent impulses. In this study, we focus on the case where all sound exposure events act independently in causing injury regardless of whether one is preceded by another (i.e., no immunity effect). Instead, we explore the possibility of interpreting the observed logistic dose-response relation in the framework of biovariability of the crowd. Here biovariability means that subjects in the crowd have their own individual injury probabilities. That is, some subjects are biologically less or more susceptible to hearing loss injury than others. We derive analytically the distribution of individual injury probability that produces the observed logistic dose-response relation. For several parameter values, we prove that the derived distribution is mathematically a proper density function. We further study the asymptotic approximations for the density function and discuss their significance in practical numerical computation with finite precision arithmetic. Our mathematical analysis implies that the observed logistic dose-response relation can be theoretically explained in the framework of biovariability in the absence of immunity effect.

A COMPUTER SIMULATION OF HIGH-DOSE ION IMPLANTATION INTO AMORPHOUS MATERIALS

A computer program MACA was developed for simulating high-dose ion implantation into amorphous solids. The topology of amorphous solids was modelled by adjusting the free flight path distribution between collisions, so that the radial distribution function will characterize the short - range order and long - range disorder of amorphous targets. A simulation example is given.

Utility of the low-accelerating-dose regimen in 182 liver recipients with recurrent hepatitis C virus

AIM: To describe our experience using a low-acceleratingdose regimen(LADR) with pegylated interferon alpha-2a and ribavirin in treatment of hepatitis C virus(HCV) recurrence. METHODS: From 2003, a protocolized LADR strategy was employed to treat liver transplant(LT) recipients with recurrent HCV at our institution. Medical records of 182 adult patients with recurrent HCV treated with LADR between 1/2003 and 1/2011 were reviewed. Histopathology from all post-LT liver biopsies were reviewed in a blinded fashion. Paired recipient and donor IL28 B status were assessed. A novel technique was employed to ascertain recipient and donor IL28B(rs12979860) Gt data using DNA extracted from archival FFPE tissue from explanted native livers and donor gallbladders respectively. The primary endpoint was SVR; secondary endpoints examined include(1) patient and graft survival;(2) effect of anti-viral therapy on liver histology(fibrosis and inflammation);(3) incidence of on-treatment development of ACR, CDR, or PCH;(4) association of recipient and donor IL28 B genotype with SVR; and(5) incidence of antiviral therapy-associated adverse events(anemia, leukopenia, thrombocytopenia, depression) and hepatic decompensation.RESULTS: The overall SVR rate was 38%(29% Gt1, 67% Gt2, 86% Gt3 and 58% Gt4). HCV Gt(P < 0.0001), donor age(P = 0.003), cytomegalovirus mismatch(P = 0.001), baseline serum bilirubin(P = 0.002), and baseline viral load(P = 0.04) were independent predictors for SVR. SVR rates were significantly higher in the recipient-CC/donor-non CC pairs(P = 0.007). Neither baseline fibrosis nor change in fibrosis stage after anti-viral therapy were associated with SVR. Fibrosis progressed in 72% of patients despite SVR. Median graft survival was 91 mo. Five-year patient survival was superior in patients who achieved SVR(97% vs 82%, P = 0.001). Pre-treatment ALP ≥ 150 U/L(P = 0.01), total bilirubin ≥ 1.5 mg/d L(P = 0.001) and creatinine ≥ 2 mg/d L(P = 0.001) were independently associated with patient survival. Only 13% of patients achieving SVR died during the followup period. Treatment discontinuation and treatmentrelated mortality occurred in 35% and 2.2% of patients, respectively. EPO, G-CSF and blood transfusion were needed in 89%, 40% and 23% of patients, respectively. Overall hospitalization rate for treatment-related serious adverse events was 21%. Forty-six(25%) of the patients were deceased; among those who died, 25(54%) were due to liver-related complications, and 4 deaths(9%) occurred while receiving therapy(2 patients experienced hepatic decompensation and 2 sepsis). CONCLUSION: LADR strategy remains relevant in managing post-LT recurrent HCV where access to DAAs is limited. SVR is associated with improved survival, but fibrosis progression still occurs.

连续口服D-聚甘酯片的Ⅰ期临床安全性、耐受性研究

目的:评价健康志愿者连续口服国家一类新药D-聚甘酯片的安全性和耐受性。方法:29名18～55岁健康受试者,男女不限。将受试者随机分配至100,200,400,500,600和700mg剂量组,连续口服不同剂量D-聚甘酯片。各组观察指标为临床症状、生命体征和血常规、血沉、尿常规、肝、肾功能、电解质等实验室检查,并监测心电图、脑电图。结果:服药后各组受试者体征和实验室检查结果与给药前比较没有区别。个别受试者出现轻微不适及一过性肌酸激酶、丙氨酸氨基转移酶和天冬氨酸氨基转移酶增高,提示D-聚甘酯片有可能导致肌肉受损。结论:健康受试者对D-聚甘酯片连续口服有很好耐受性。最大剂量至500mg仍比较安全。

自动固相微萃取(SPM E)GC-MS、GC-MS-MS法检测环境水中有机磷杀虫剂的研究

固相微萃取(solid-phase microextraction,SPME)是20世纪90年代发展起来的一种样品前处理技术,与传统的液-液提取、液-固提取相比,SPME更适用于提取、浓缩液态或气态的挥发性和半挥发性物质,SPME技术可将采样、萃取、浓缩和样本引入集中于一个步骤完成,尤其随着自动SPME与GC-MS等联用技术的日益完善,使SPME技术优点得到更充分的发挥.……

多次小剂量^(188)Re-CL58放射免疫治疗的临床研究

采用FDG-PET显像方法及动态观察血清中肿瘤标志物的变化监测^(188)Re-CL58(或^(131)I-HAb18)对临床病例进行多次小剂量治疗的疗效,及其对造血系统和肝、肾等器官的毒副作用。结果显示;治疗后PET显像显示病灶部位的^(18)F标记的脱氧葡萄糖(FDG)标准化摄取值(SUV)均有不同程度下降,对于小转移灶SUV下降明显甚至降至正常,且治疗后血清中肿瘤标志物CEA、AFP水平均有不同程度下降或下降至正常水平。多次小剂量^(188)Re-CL58治疗后CD_4^+细胞升高、CD_8^+细胞减少以及CD_4^+/CD_8^+比例升高。对白细胞、血小板、血色素的影响不明显,对肝、肾功能均无明显损害。随访至半年,循环系统中均未检测到HAMA。因此,多次小剂量^(188)Re-CL58(或^(131)I-HAb18)治疗对于实体瘤的小转移灶有明显的治疗作用;能解除机体的免疫抑制,放射免疫治疗仅引起造血系统的轻度抑制;多次小剂量RIT能避免产生HAMA。

大鼠多次给予染料木素甲氧基封端的聚乙二醇-乳酸羟基乙酸共聚物胶束的药动学研究

目的讨论染料木素(GEN)甲氧基封端的聚乙二醇-乳酸羟基乙酸共聚物(MePEG-PLGA)胶束多次给药在健康大鼠体内的药动学行为。方法将24只健康Wistar大鼠按体重分成四组,每组6只,分别为GEN乳剂组,GEN胶束低、中、高剂量组。每组分别多次尾静脉注射GEN乳剂和GEN胶束,乳剂剂量为40 mg/kg,胶束剂量分别为20、40、60 mg/kg。采用高效液相色谱法(HPLC)测定给药后不同时间点血浆中GEN浓度。结果GEN乳剂组和GEN胶束组最小血药浓度(Cmin)、半衰期(t1/2)、药时曲线下面积(AUC0~t)、清除率(CL)、波动系数(DF)比较,差异均有高度统计学意义(P<0.01);GEN胶束低、中和高3个剂量组主要药动学参数Tmax、t1/2、CL、表观分布容积(Vd)和DF比较,差异无统计学意义(P>0.05)。与GEN胶束低剂量组比较,GEN胶束中剂量组最大血药浓度(Cmax)、AUC0~t升高,与GEN胶束低、中剂量组比较,GEN胶束高剂量组Cmax、AUC0~t升高,差异均有高度统计学意义(均P<0.01)。GEN胶束各剂量组AUC0~t、AUC0-∞、Cmax、平均稳态浓度(Cav)随给药剂量增大而增加,差异有高度统计学意义(P<0.01),AUC0-t、AUC0-∞、Cmax、Cav与剂量呈线性关系(r>0.97)。在相同剂量下,单次和多次给药后的主要药动学参数Cmax、t1/2、AUC0~t、CL、Vd、MRT0~t差异无统计学意义(P>0.05)。结论GEN胶束能明显延迟GEN在大鼠体内滞留时间,提高生物利用度,且血药浓度与剂量呈线性关系,多次给药后在大鼠体内不存在蓄积现象。