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91.
Prodrug research: futile or fertile? 总被引:5,自引:0,他引:5
Testa B 《Biochemical pharmacology》2004,68(11):2097-2106
The objective of this Commentary is to help clarify and illustrate what prodrugs are, what they are not, which benefits they can offer, and what their limits are. To this end, a number of criteria of classification and evaluation are presented. This is followed by a discussion of the pharmaceutical, pharmacokinetic and pharmacodynamic objectives of prodrug research. Recent examples (e.g. oseltamivir, bambuterol, capecitabine, clopidogrel and tirapazamine) are discussed in a biochemical perspective to illustrate these objectives and to demonstrate some of the therapeutic benefits afforded by successful prodrugs. Attention is also called to the fact that the in vitro and in vivo behavior of prodrug candidates may differ from that of the parent drug in ways that go beyond the original pharmaceutical, pharmacokinetic or pharmacodynamic objective being pursued. We conclude that prodrugs offer a viable strategy to disentangle pharmacodynamic and pharmacokinetic optimization. 相似文献
92.
Wallace JF Pugia MJ Lott JA Luke KE Shihabi ZK Sheehan M Bucksa JM 《Journal of clinical laboratory analysis》2001,15(5):231-235
The goal of our study was to perform a multisite evaluation of a new urine dipstick called Multistix PROtrade mark (Bayer, Elkhart, IN), which has reagent pads for the simultaneous assay of urinary albumin, protein, and creatinine. Patients' urine specimens were assayed at four sites with these dipsticks and with the familiar Bayer Multistix 10SG dipsticks for protein. The new dipstick pads for albumin are impregnated with bis (3',3"-diiodo-4',4"-dihydroxy-5',5"-dinitrophenyl)-3,4,5,6-tetrabromo-sulfonephthalein (DIDNTB) dye. These dipsticks also have a novel pad that estimates urinary creatinine using the peroxidase activity of the copper-creatinine complex. We determined the interlaboratory agreement of these dipsticks by comparing dipstick results to values obtained by quantitative analytical methods. We found that dividing the dipsticks' albumin or protein results by the creatinine concentration reduced the number of false-positive albumin or protein values observed in concentrated urines, and reduced the number of false negatives in dilute urines. The ratio of albumin to creatinine, or protein to creatinine gives a better measure of albumin or protein excretion. Compared to reading by eye, the dipstick results agreed better with the quantitative assays when they were read by a reflectometer (Bayer Clinitek). 相似文献
93.
94.
大孔树脂吸附解吸甘草多糖效果的研究 总被引:3,自引:0,他引:3
目的通过研究LSA-5B,D4020,D201等9种不同型号大孔树脂的吸附率及解吸率,确定分离纯化甘草多糖的树脂类型。方法以葡萄糖为标准品、利用紫外分光光度法,测定各树脂吸附及解吸前后的吸光度,并以甘草多糖的吸附量和解吸量为指标,对树脂进行筛选。结果在9种不同型号的大孔吸附树脂中,LSA-5B型大孔树脂的吸附和解吸性能均较好,对甘草多糖的动态吸附率为56%,动态解吸率为99%。结论在本实验条件下,LSA-5B型大孔树脂是一种较好的分离纯化甘草多糖的树脂材料。 相似文献
95.
目的观察定量毛细管速率法测定的红细胞沉降率(ESR)与红细胞压积(HCT)的相关关系,以确定其是否需要在实验前对HCT进行处理,并确定其测定结果是否需要进行校正。方法随机抽取广州市第一人民医院和广州市胸科医院住院病人标本120例(男64例,女56例),健康体检者标本100例(男50例,女50例),均采用EDTA-K_2抗凝,分别运用以定量毛细管速率法的Microtest1自动血沉仪测定ESR,用KX-21血细胞分析仪测定HCT,对数据进行直线相关分析。结果Microtest1自动血沉仪测得的健康体检男性组ESR与其HCT相关系数r=-0.257,P=0.073;女性组相关系数r=-0.209,P=0.146。病例男性组ESR与其HCT相关系数r=-0.122,P=0.376;女性组相关系数r=-0.139,P=0.342。结论定量毛细管速率法测定的ESR与HCT间,无论是病例组还是健康组,均不存在直线相关关系。采用此法测定的ESR无需调整标本的HCT,测得的ESR也无需经HCT值校正。 相似文献
96.
Dietary resistant starch and chronic inflammatory bowel diseases 总被引:5,自引:0,他引:5
Jacobasch G Schmiedl D Kruschewski M Schmehl K 《International journal of colorectal disease》1999,14(4-5):201-211
These studies were performed to test the benefit of resistant starch on ulcerative colitis via prebiotic and butyrate effects.
Butyrate, propionate, and acetate are produced in the colon of mammals as a result of microbial fermentation of resistant
starch and other dietary fibers. Butyrate plays an important role in the colonic mucosal growth and epithelial proliferation.
A reduction in the colonic butyrate level induces chronic mucosal atrophy. Short-chain fatty acid enemas increase mucosal
generation, crypt length, and DNA content of the colonocytes. They also ameliorate symptoms of ulcerative colitis in human
patients and rats injected with trinitrobenzene sulfonic acid (TNBS). Butyrate, and also to a lesser degree propionate, are
substrates for the aerobic energy metabolism, and trophic factors of the colonocytes. Adverse butyrate effects occur in normal
and neoplastic colonic cells. In normal cells, butyrate induces proliferation at the crypt base, while inhibiting proliferation
at the crypt surface. In neoplastic cells, butyrate inhibits DNA synthesis and arrests cell growth in the G1 phase of the
cell cycle. The improvement of the TNBS-induced colonic inflammation occurred earlier in the resistant starch (RS)-fed rats
than in the RS-free group. This benefit coincided with activation of colonic epithelial cell proliferation and the subsequent
restoration of apoptosis. The noncollagenous basement membrane protein laminin was regenerated initially in the RS-fed group,
demonstrating what could be a considered lower damage to the intestinal barrier function. The calculation of intestinal short-chain
fatty acid absorption confirmed this conclusion. The uptake of short-chain fatty acids in the colon is strongly inhibited
in the RS-free group, but only slightly reduced in the animals fed with RS. Additionally, RS enhanced the growth of intestinal
bacteria assumed to promote health. Further studies involving patients suffering from ulcerative colitis are necessary to
determine the importance of RS in the therapy of a number of intestinal diseases and the maintenance of health.
Accepted: 11 August 1999 相似文献
97.
研究龙马酶(EC 3. 1. 1. 3)固定化载体、固定化条件和固定化酶的性质。方法:固定化采用吸附法。结果:固定化最适条件:酶液PH9.0,吸附时间1.5 h,酶浓度1.5 g/100 ml,在此条件下固定化酶活力53 u/g载体,活力回收率71%。固定化酶的最适作用温度和pH较游离酶高,范围较游离酶广,耐热性、酸碱稳定性比游离酶好。结论:固定化酶性能比游离酶得到提高。 相似文献
98.
Fattinger K Benowitz NL Jones RT Verotta D 《European journal of clinical pharmacology》2000,56(4):305-310
Objective: Several xenobiotics, including cocaine, are dosed by the nasal route for systemic effects. The aim of this study was to
estimate and compare cocaine input into the systemic circulation after oral and nasal dosing, and to determine the relevance
of local absorption through the nasal mucosa.
Methods: Cocaine was administered to healthy volunteers through the intravenous, oral, and nasal routes. Cocaine serum concentrations
were measured at frequent intervals. From these data, the gastrointestinal, nasal, and nasal mucosa input rate functions were
determined using nonparametric, subject-specific population deconvolution.
Results: After oral dosing, cocaine input into systemic circulation increased slowly and peaked around 45 min after ingestion. The
median systemic bioavailability after oral dosing was 33%. After nasal dosing, drug input was substantial even during the
first minute and showed two peaks at 10 min and 45 min after ingestion. Since the second peak after nasal dosing closely resembled
drug input after oral administration, we hypothesized that, after nasal administration, a part of the dose is swallowed and
thereafter absorbed gastrointestinally. The data from the sessions with nasal cocaine administration were reanalyzed assuming
the same shape for gastrointestinal drug input as after oral dosing. The fraction absorbed through the nasal mucosa was estimated
to be 19% (95% CI: 11–26%). The fraction absorbed through the nasal mucosa contributed 31% (95% CI: 23–37%) of total systemic
cocaine exposure.
Conclusions: Our data suggest that the main reason addicts prefer nasal to oral cocaine dosing is faster absorption, enhancing the subjective
effects rather than higher bioavailability.
Received: 28 December 1999 / Accepted in revised form: 23 March 2000 相似文献
99.
Zusammenfassung Ausgehend von der Ähnlichkeit der Transportsysteme für Aminosäuren in Niere und Darm wurde die Frage untersucht, ob bei Rachitis mit Hyperaminoacidurie auch der Aminosäurentransport im Dünndarm gestört ist. In umgestülpten Darmsäckchen wurde die Absorption von 14C-markierten Aminosäuren bei 2 Ferkeln mit erblicher Pseudomangelrachitis und 7 klinisch gesunden Tieren gemessen. Die Versuche ergaben, daß bei bestehender aktiver Rachitis mit Hyperaminoacidurie die intestinale Aminosäurenabsorption nicht beeinträchtigt ist. Die Absorption nahm dagegen mit dem Alter der Versuchstiere signifikant ab. Das isolierte Auftreten eines Transportschadens für Aminosäuren in der Niere läßt den Schluß zu, daß dieser Defekt nicht durch direkte Einwirkung hämatogener Faktoren (erhöhter PTH-Spiegel oder Mangel an Vitamin D-Metaboliten) auf die Transportsysteme hervorgerufen wird, sondern die Folge vorgeschalteter spezifischer Effekte auf die Tubulusepithelien darstellt.
Intestinal amino acid absorption in vitamin D dependent rickets
Since structure and specifity of amino acid transport systems are basically similar in kidney and intestines it was suspected that rickets associated with hyperaminoaciduria was linked with defective intestinal amino acid uptake. Therefore amino acid absorption from everted sacs of small intestines was studied in 2 piglets suffering from vitamin D dependent rickets, and 7 healthy piglets using 14C labelled amino acids. The experiments revealed an unaffected intestinal absorption in the rachitic animals, whereas the uptake decreased significantly with increasing age of the experimental animals. The results from these studies suggest that regulatory factors in the blood system, e. g. increased level of PTH or lack of specific vitamin D metabolites, do not directly affect amino acid transport systems in kidney and intestines. It is concluded that hyperaminoaciduria has to be mediated through specific and thus far unidentified effects at the tubular cell level.
Im Rahmen des Sonderforschungsbereichs 146 Versuchstierforschung finanziell gefördert. 相似文献
100.
Shibin Mathew David Tess Woodrow Burchett George Chang Nathaniel Woody Christopher Keefer Christine Orozco Jian Lin Samantha Jordan Shinji Yamazaki Rhys Jones Li Di 《Journal of pharmaceutical sciences》2021,110(4):1799-1823
Volume of distribution at steady state (Vss) is an important pharmacokinetic parameter of a drug candidate. In this study, Vss prediction accuracy was evaluated by using: (1) seven methods for rat with 56 compounds, (2) four methods for human with 1276 compounds, and (3) four in vivo methods and three Kp (partition coefficient) scalar methods from scaling of three preclinical species with 125 compounds. The results showed that the global QSAR models outperformed the PBPK methods. Tissue fraction unbound (fu,t) method with adipose and muscle also provided high Vss prediction accuracy. Overall, the high performing methods for human Vss prediction are the global QSAR models, Øie-Tozer and equivalency methods from scaling of preclinical species, as well as PBPK methods with Kp scalar from preclinical species. Certain input parameter ranges rendered PBPK models inaccurate due to mass balance issues. These were addressed using appropriate theoretical limit checks. Prediction accuracy of tissue Kp were also examined. The fu,t method predicted Kp values more accurately than the PBPK methods for adipose, heart and muscle. All the methods overpredicted brain Kp and underpredicted liver Kp due to transporter effects. Successful Vss prediction involves strategic integration of in silico, in vitro and in vivo approaches. 相似文献