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1.
《Journal of pharmaceutical sciences》2019,108(7):2500-2504
Accurately predicting the hepatic clearance of compounds using in vitro to in vivo extrapolation (IVIVE) is crucial within the pharmaceutical industry. However, several groups have recently highlighted the serious error in the process. Although empirical or regression-based scaling factors may be used to mitigate the common underprediction, they provide unsatisfying solutions because the reasoning behind the underlying error has yet to be determined. One previously noted trend was intrinsic clearance-dependent underprediction, highlighting the limitations of current in vitro systems. When applying these generated in vitro intrinsic clearance values during drug development and making first-in-human dose predictions for new chemical entities though, hepatic clearance is the parameter that must be estimated using a model of hepatic disposition, such as the well-stirred model. Here, we examine error across hepatic clearance ranges and find a similar hepatic clearance-dependent trend, with high clearance compounds not predicted to be so, demonstrating another gap in the field. 相似文献
2.
研究了凉粉草胶多糖在20-40℃之间特性粘度对温度的敏感性,计算得其稀溶液的临界线团交叠值C^*[η]平均为1.13,半稀释区斜率b为0.8~1.2,与其他多糖进行了比较。结果表明:凉粉草胶多糖的特性粘度在所测温度区域内的变化不敏感;凉粉草胶多糖在水溶液中,分子链构象可能为刚性杆状结构。 相似文献
3.
Dr. S. Søresen H. J. Kirkeby H. Stødkilde-Jørgensen J. C. Djurhuus 《Neurourology and urodynamics》1986,5(1):5-16
The pressure variations at the maximal urethral closure pressure (MUCP) were continuously recorded in healthy female volunteers by means of a two-point microtip transducer catheter for one hour. Before the investigation a normal voiding was assured objectively and bladder instability was excluded. All women showed pressure variations both at the MUCP and more distally. The pressure variations, from 3 to 66 cm H2O, showed rhythmicity and three frequency ranges could be identified. Slow pressure waves with a frequency of one in eight to 19 minutes were observed. Relatively fast-pressure waves were observed (one every one to four minutes) and relatively fast-frequency pressure waves were observed (rate: one to eight per minute). The pressure variations of the urethra seem to be an aspect of normal urethral physiology possibly contributing to continence and urinary tract infection prevention. 相似文献
4.
Scales of depression,ill-being and the quality of life—is there any difference? An assay in taxonomy
N. de Leval 《Quality of life research》1995,4(3):259-269
The application of a model based on the three time dimensions of past, present and future can be used to generate an alternative taxonomy for the classification of depression, ill-being and quality of life. In relation to time, depression can be defined as the passage from a healthy past to a painful present, ill-being as the painful present of the individual and the quality of life (QOL) as the degree to which the subject's present life is commensurate with his aspirations. Such an approach opens up conceptual and methodological areas of research which will allow the construction of a new type of scale. Depression scales should be constructed with two time dimensions: past and present; ill-being scales only refer to the present and QOL scales should have two time dimensions: present and future. It would be possible to combine these three scales into a single scale with three dimensions. Such a scale would enable depression and ill-being to be quantified, accurately diagnosed and monitored. The relative importance of principal symptoms could be assessed, facilitating the choice of therapy and follow-up methods. 相似文献
5.
Peripheral eosinophil counts as a marker of disease activity in intrinsic and extrinsic asthma 总被引:1,自引:0,他引:1
C. S. ULRIK 《Clinical and experimental allergy》1995,25(9):820-827
Background: Recently it has been suggested that the bronchospasm and hyperresponsiveness phenomena observed in asthma are secondary to the actions of the eosinophils; the purpose of this study was to evaluate the relationship between the peripheral number of eosinophils and various markers of disease activity in a group of asthmatics examined in childhood (mean age 10 years) and early adulthood (mean age 21 years). Methods: The relationship between eosinophil count and pulmonary function (FEV1), respiratory symptoms, bronchial responsiveness to histamine and diurnal variation in peak expiratory flow rate (PEF) was studied in 70 subjects with bronchial asthma, of whom 24 had intrinsic and 46 extrinsic asthma. Self-reported symptoms of asthma were graded on a scale from 0 to 5, where 0 = no symptoms within the preceding 12 months and 5 = daily including nocturnal symptoms, and histamine responsiveness was analysed by means of the dose-response slope (DRS). Results: In both childhood and adulthood, a direct correlation was found between blood eosinophil count and symptom score (r= 0.69, P< 0.001 and r= 0.58, P < 0.001, respectively), whereas inverse correlations were observed between number of eosinophils and FEV, % predicted (r= .0.75, P < 0.001 and r= 0.80, P < 0.001. respectively). Furthermore, in adulthood, eosinophil count was found to be significantly correlated to hisiamine responsiveness (log DRS) (r= 0.65, P < 0.001) and diurnal PEF variation (r= 0.81, P < 0.001); these correlations were also noted after dividing the subjects into intrinsic and extrinic asthmatics. In both groups of subjects a significant inverse correlation was also found between histamine responsiveness and pre challenge FEV1% predicted. The eosinophil count in childhood was weakly correlated to the symptom score in adulthood (r= 0.29, P < 0.02). Conlusions: This study showed a relationship between eosinophil count and seventy of asthmatic symptoms, level of pulmonary function, histamine responsiveness and diurnal variation in PEF in both intrinsic and extrinsic asthma; suggesting that the peripheral eosinophil count reflects asthmatic activity, and possibly the degree of inflammation in the airways, in both children and adults. Furthermore, a low number of eosinophils in childhood might be related to a relatively favourable prognosis with regard to symptoms of asthma in early adulthood. 相似文献
6.
Robert H. Smallwood George W. Mihaly Richard A. Smallwood Denis J. Morgan 《Journal of pharmacokinetics and pharmacodynamics》1988,16(5):529-542
For substances eliminated from blood by the liver, the effect of a change in unbound fraction of drug (fu
b
)on steady state total (C
b
)and unbound (Cu
b
)blood concentrations has hitherto only been considered for the two limiting cases, i.e., at the upper and lower extremes of hepatic intrinsic clearance (CL
int
).For a substance of very low CL
int
,if fu
b
changes, C
t
will change and Cu
b
will remain constant, whereas if CL
int
isvery high, Cu
b
will change and C
b
will remain constant.The present study defines the effects of a change in fu
b
on C
b
and Cu
b
over the whole CL
int
range. Computer simulations were undertaken which predicted that, for a given change in fu
b
,absolute and relative changes in C
b
would decreasenonlinearly with increasing CL
int, twhile the relative change in Cu
b would increasewith CL
int
.The absolute change in Cub
would be independent of CL
int
.Significant changes in Cb and Cu
b would be observed at intermediate values of CL
int not just at the high and low extremes. These theoretical predictions were investigated experimentally in the isolated perfused rat liver by examining the effects of a change in fu
b of sodium taurocholate a substance with intermediate CL
int
(such that at fu
b
=0.27,hepatic extraction ratio=0.71) induced by concurrent administration of sodium oleate. Sodium 24-
14
C-taurocholate (specific activity 52 Ci/mmol) was infused into the reservoir in a recycling system at 30 mol/hr for 105 min (n=6). At 45 min a bolus dose of sodium oleate (50 mmol) was administered to the reservoir, followed by a constant infusion of 143 mmol/hr for 1 hr. Following the administration of oleate, taurocholate fu
b fell promptly by 55% (0.27–0.12). There was a relative increase of taurocholate C
b of 22.7% and a relative decrease in Cu
b of 45.4%, in accordance with the simulations (p<0.05). We conclude that important changes in unbound steady-state concentration, the pharmacologically active moiety, can occur upon changes in unbound fraction with compounds of intermediate hepatic intrinsic clearance.This study was supported by the National Health and Medical Research Council of Australia. 相似文献
7.
F. Walberg E. Dietrichs T. Nordby 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》1984,56(2):377-383
Summary The medullary projection from the mesencephalic trigeminal nucleus has been studied in cats where the wheat germ agglutinin-horseradish peroxidase complex has been used as a retrograde and anterograde tracer. All injections were made at the level of the caudal pole of the inferior olive and show that it is especially the lateral part of nucleus parvicellularis of the reticular formation which is the main area for termination of the fibres. In addition, it can not be excluded that the descending fibres also reach the medialmost part of the spinal trigeminal sensory nucleus (pars magnocellularis and the adjoining pars gelatinosa). All three cell types of the mesencephalic trigeminal nucleus are labelled, the large globular, the small globular and the polygonal cells. Some of these cells are only faintly labelled. The observations confirm previous studies of the intrinsic trigeminal connections, but show that when the wheat germ agglutinin-horseradish peroxidase complex is used as a tracer, the origin as well as the termination for the intrinsic fibres (also the commissural) can be studied in the same section. The use of this sensitive tracer also shows new details within the intrinsic connections. The findings are discussed with special reference to the recent observations by Ruggiero et al. (1982). These authors found that in rabbit and rat there is a more restricted termination for the descending mesencephalic trigeminal fibres. The discrepancies between the observations seem to indicate that there are species differences as regards the connections between the mesencephalic trigeminal nucleus and the nuclei in the lower part of the brain stem. 相似文献
8.
Optimum support properties for protein separations by high-performance size exclusion chromatography
Optimum chromatographic properties of high performance size exclusion chromatography (HPSEC) of proteins, such as resolution, molecular weight accuracy and recovery, are obtained on packings and columns with tailor-made physical and chemical structures, employed at properly adjusted eluent compositions and operation conditions. SEC-theory suggests that a broad molecular weight fractionation range and high linearity of the log-linear calibration plot can be achieved by the use of two packings (10- and 80-nm pore size, characterized by a pore-size distribution (psd) equal to or less than 1 decade and by equal internal column porosity (p)), rather than a single 30- to 50-nm pore-size packing with a wide psd. Favourably high-phase ratios of (p)/(o)/ 1.0 for HPSEC columns were accomplished with a minimum interstitial column porosity (o) and a high value for the internal column porosity (p) (the specific pore volume, nu(p), multiplied by the packing density, varrho(p).) Ligands such as diol, N-acetoxyamino and oligomeric ether with a propyl- or propoxy-spacer bonded to the silica at the highest density appear to provide high mass recovery and bioactivity as well as chemical stability. Such packings, available in 3-5 mum particle size ranges of narrow distribution, packed into columns 6 mm i.d. and 500 mm in length, offer the best compromise with respect to resolution, speed and pressure drop. More careful studies are required to explain the effects of protein conformational changes and interconversions during elution on HPSEC columns. 相似文献
9.
介绍了复旦大学附属华山医院与多年来合作伙伴、多家企业医院协商,在双方自愿的前提下,组建以神经外科为主,神经内外科、放射科紧密合作,以神经外科作为主要治疗手段的集团医院的具体做法。指出,组建集团医院不仅是数量的发展,更主要的是质量的提高。必须注重内涵建设,注重可持续发展的后劲。与此同时,必须转变观念,正确处理好相关学科之间的关系。 相似文献
10.
对低温,低压,高活性的A301氨合成催化剂的本征动力学进行了研究,实验采用等温积分反应器,在320-480度,6.0MPa-10.0MPa,5000h^-1--30000h^-1的条件下测定了反应器出口氨浓度,建立了Temkin形式的动力学方程,获得了反应的活化能及指前因子。 相似文献