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151.
Integrated oral bioavailability projection using in vitro screening data as a selection tool in drug discovery 总被引:2,自引:0,他引:2
Stoner CL Cleton A Johnson K Oh DM Hallak H Brodfuehrer J Surendran N Han HK 《International journal of pharmaceutics》2004,269(1):241-249
The objective of the analysis described herein is to examine the in vitro/in vivo relationship of estimated bioavailability values and also the applicability of the estimated in vitro bioavailability to lead candidate selection in drug discovery. To this end, in vitro ADME data from screening assays as well as in vivo rat pharmacokinetic (PK) data were compiled for 140 compounds across therapeutic areas from the Pfizer library in Ann Arbor. The compounds span a broad range of structural types, including neutral, basic, and acidic compounds. Solubility and Caco-2 permeability data from in vitro ADME screening were used to calculate the fraction dose absorbed (FDp) using the physiologically based IDEA model. In vitro metabolic stability (t(1/2)) from human and rat liver microsomal incubations was converted to an in vitro intrinsic clearance value (CL(int)'), which was then scaled up to reflect in vivo clearance (CL) and hepatic extraction as described by Obach et al. [J. Pharmcol. Exp. Ther. 283 (1997) 46]. Subsequently, the in vitro/in vivo relationship between the measured bioavailability (F(obs)) in rats and the estimated bioavailability (F(est)) from FDp and predicted CL values was examined. The observed data suggest that compounds with low estimated in vitro bioavailability (F(est)<15%) are more likely to have low in vivo bioavailability (F(obs)<30%). Therefore, the present study indicates that in vitro estimation of bioavailability is an efficient tool to eliminate compounds having low bioavailability prior to in vivo characterization and therefore can be used to reduce attrition due to poor ADME properties in drug development. 相似文献
152.
153.
Narayanan S Dalpke AH Siegmund K Heeg K Richert C 《Journal of medicinal chemistry》2003,46(23):5031-5044
A series of 21 phosphodiester oligodeoxyribonucleotides containing the core sequence 5'-GACGTT-3' or related control sequences were prepared and tested for their immunostimulatory effect on murine macrophages. The range of structural modifications tested included substituents at 3'- or 5'-termini, N3-methylation of thymidine residues, and hexaethylene glycol linkers favoring nicked or cyclic dumbbell duplexes. Lipophilic and cationic substituents at the termini failed to increase the release of TNF-alpha and nitric oxide, but two new types of modification were found that enhance the stimulation of RAW264.7 macrophages. One is the substitution of the 5'-terminal hydroxyl group with an amino group, and the other is the introduction of linkers favoring nicked duplexes. Even for sequences without linkers, UV-melting analysis and two-dimensional NMR showed that the core sequence 5'-GACGTT-3' readily forms a duplex. The cyclic derivative of the most active nicked dumbbell sequence is inactive, however. Together these results suggest a recognition of both the 5'-terminus and the core of the CpG oligonucleotides by the putative receptor(s) and provide an entry into a class of modified oligonucleotides whose activity rivals that of phosphorothioates, but consists of synthetic compounds that are single stereoisomers. 相似文献
154.
155.
Role of antimicrobials in third molar surgery: prospective, double blind,randomized, placebo-controlled clinical study 总被引:3,自引:0,他引:3
Sekhar CH Narayanan V Baig MF 《The British journal of oral & maxillofacial surgery》2001,39(2):134-137
AIM: To test the efficacy of two dosing regimens of antimicrobial prophylaxis during the removal of impacted lower third molars. DESIGN: Double blind, prospective, placebo-controlled trial. SETTING: Teaching hospital, India. SUBJECTS: 151 patients aged 19-36 having impacted lower third molars removed. METHODS: Random allocation into three groups: placebo (n= 34), metronidazole 1g orally, 1 hour preoperatively (n= 44), or metronidazole 400mg orally eight hourly for 5 days postoperatively (n= 47). Patients were recalled on the sixth postoperative day for assessment of pain scores on the second and sixth days, swelling, differences in mouth opening between preoperative and the sixth postoperative day, and the state of the wound. RESULTS: There were no significant differences in the outcome between the three groups (P= 0.09). CONCLUSION: Antimicrobial prophylaxis does not seem to reduce morbidity after removal of lower third molars. 相似文献
156.
Additive neuroprotective effects of minocycline with creatine in a mouse model of ALS 总被引:13,自引:0,他引:13
The known neuroprotective effects of minocycline and creatine in animal models of amyotrophic lateral sclerosis (ALS) led us to examine whether the combination of these agents would result in increased neuroprotection. As previously reported, we confirmed in ALS mice that either minocycline or creatine treatment results in improvement in motor performance and extended survival. We report that combination of minocycline and creatine resulted in additive neuroprotection, suggesting this to be a novel potential strategy for the treatment of ALS. To our knowledge, this is the first report demonstrating additive neuroprotection of a combinatorial approach in a mouse model of ALS. Adding relevancy to our findings, minocycline and creatine, are relatively safe, cross the blood-brain barrier, and are currently available for human evaluation. 相似文献
157.
Patient satisfaction is an important outcome measure independent of other outcomes. Its measurement is important to assess the effectiveness of a programme and to gain insight into the patients'' perception of the programme. In this study conducted in a large rehabilitation centre it was found that majority of patients express satisfaction with care inspite of perceived discomfort. Various demographic factors, severity or duration of the disability or the level of rehabilitation do not influence patient satisfaction. Patients express more concern with aspects such as delay in issue of the prosthesis, or hotel component of the hospital services. Patients did not appear too concerned about the level of information provided. Patient satisfaction is an individual reaction to the overall care process and is influenced by the initial expectation level of the patient. Emotional response of the patient appears to be more important determinant of patient satisfaction than the cognitive evaluation. Periodical assessment of patient satisfaction should be an important component of any programme evaluation exercise.KEY WORDS: Amputation, Patient satisfaction, Programme evaluation, Prosthesis, Quality of care, Rehabilitation 相似文献
158.
DNA mismatch repair (MMR) has been shown to play a role in the cytotoxicity of ionizing radiation (IR), as cell lines established from MMR-deficient mice exhibit higher clonogenic survival after IR than do cell lines from wild-type littermates. To test whether this tolerance phenotype would render MMR-deficient animals hypermutable to IR, we compared IR mutagenesis of Pms2-deficient versus wild-type transgenic mice carrying a lambda shuttle vector for mutation detection. In Pms2 nullizygous animals, the mutation frequency in the supFG1 reporter gene was increased from 210 x 10(-5) in untreated animals to 734 x 10(-5) after 6 Gy of IR (an increase of 524 mutants per 10(5)), whereas the frequency in wild-type mice increased from 1.9 x 10(-5) to 10.2 x 10(-5) (an increase of only 8.3 mutants per 10(5)). Similarly, when the lambda cII gene was used as a reporter, the mutation frequency in nullizygous mice was increased from 16.3 x 10(-5) to 42.3 x 10(-5) after IR (an increase of 26.0 x 10(-5)), whereas the frequency in wild-type mice increased from 2.4 x 10(-5) to 9.4 x 10(-5) (an increase of only 7.0 x 10(-5)). The pattern of IR-induced mutations in the MMR-deficient animals was notable for single bp deletions and insertions in mononucleotide repeat sequences, along with a slight increase in transversions. Overall, these results suggest that MMR-deficiency confers hypermutability to IR, and that much of this hypermutability can be attributed to induced instability of simple sequence repeats. Hence, MMR influences not only the survival but also the mutability of cells in response to IR. 相似文献
159.
Cementum attachment protein enriches putative cementoblastic populations on root surfaces in vitro 总被引:3,自引:0,他引:3
BarKana I Narayanan AS Grosskop A Savion N Pitaru S 《Journal of dental research》2000,79(7):1482-1488
We tested the capacity of cementum attachment protein (CAP) to recruit putative cementoblastic populations to root surfaces in vitro by determining the phenotypic expression of periodontal ligament cloned cell populations. The clones were derived from cells that attached to either CAP-coated (experimental) or uncoated (control) root slices. Root slices were co-cultured with primary human periodontal ligament cells. Cloned and parent populations were analyzed for their capacity to express alkaline phosphatase (AP), osteopontin, bone sialoprotein (BSP), and CAP and to form mineralized tissue in vitro. The percentage of CAP- and BSP-positive clones was significantly higher in the experimental clones than in the controls. The percentage of cells positive for AP, BSP, and CAP was higher in the experimental clones than in their control counterparts. Mineralized tissue formation was observed only in the cell populations derived from the CAP-coated root slices. These results indicate that CAP is capable of recruiting putative cementoblastic populations on root slices in vitro and therefore might play an important role in cementogenesis during periodontal homeostasis and wound healing. 相似文献
160.