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61.
In spite of significant efforts in academic and commercial laboratories, major breakthroughs in oral peptide and protein formulation have not been achieved. The major barriers to developing oral formulations for peptides and proteins include poor intrinsic permeability, lumenal and cellular enzymatic degradation, rapid clearance, and chemical and conformational stability. Pharmaceutical approaches to address these barriers, which have been successful with traditional, small, organic drug molecules, have not readily translated into effective peptide and protein formulations. The success achieved by Sandoz with cyclosporin formulations remains one clear example of what can be achieved, although it is likely that effective oral formulations for peptides and proteins will remain highly compound specific. Although the challenges are significant, the potential therapeutic benefit remains high, particularly with the increasing identification of potential peptide and protein drug candidates emerging from the biotechnology arena. Successful formulations will most likely require a systematic and careful merger of formulation and design delivery systems which maximize the potential for absorption across the epithelial cell layer. 相似文献
62.
本文定义了一类“近乎双线性”系统。可用以近似一类奇异摄动双线性系统,而且可以描述某些实际工业对象。并发现其控制器的设计较方便。文中还给出了一种简单的反馈控制器的设计方法。又对一类多输入双线性系统,提出一种设计反馈控制器的改进方案,根据Lyapunov定理得到一非线性反馈控制律。以上设计方法分别对某合成氨反应器作了应用研究,仿真结果表明了方法的有效性。 相似文献
63.
Tryptamine (TA) occurs in trace levels in the brain, but its role in the central nervous system is not clear. However, there is evidence that TA may be a neuromodulator since it binds to specific binding sites in the brain. TA was measured as a diheptafluorobutyryl derivative in rat whole brain by capillary gas chromatography—mass spectrometry using negative chemical ionization (NCI) and single ion monitoring (SIM). d4-TA was used as the internal standard. The ions m/z 532 and m/z 536 were monitored to identify TA and d4-TA, respectively and to calculate the concentration of TA in rat whole brain which was found to be 0.19 ± 0.08 ng g−1 (n = 8). The results confirm the earlier TA concentrations measured by GC—MS using positive electron impact ionization. However, NCI improved the signal/noise ratio of the method increasing its sensitivity for TA. 相似文献
64.
Berner Bret Wilson Donald R. Guy Richard H. Mazzenga Gerard C. Clarke Frank H. Maibach Howard I. 《Pharmaceutical research》1988,5(10):660-663
The relationship between pK
a and skin irritation in man is studied for a homologous series of benzoic acid derivatives, which permeate through human skin at comparable rates (15–88 µg/cm2/hr). Skin irritation and pK
a are correlated for pK
a 4. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pK
a, erythema at 24 hr appears to be the most sensitive parameter to variation in pK
a when pK
a 4. 相似文献
65.
目的探讨装潢居室空气中挥发性化合物的遗传毒性.方法采用小鼠骨髓嗜多染性红细胞微核试验和小鼠精子畸形试验检测居室装潢后空气中挥发性化合物的遗传毒性.结果该化合物对小鼠呼吸系统有明显的刺激作用,与阴性对照组比较,高、中、低剂量组的微核率、精子畸形率均有显著差异性.结论居室装潢后室内空气中挥发性化合物具有遗传毒性作用. 相似文献
66.
Lankin VZ Sherenesheva NI Konovalova GG Tikhaze AK 《Bulletin of experimental biology and medicine》2000,130(7):694-696
The effects of pretreatment with β-carotene-containing preparation carinat on the development of renal tumors in rats receiving
single intravenous injection of chemical carcinogen 3-(1-α-L-arabinopyranosyl)-1-methyl-1-nitrosourea were studied. Fourteen
months after carcinogen administration, the degree of lipid oxidation in rat kidneys 2.5-fold surpassed that in animals receiving
carinat in a dose producingin vivo antioxidant effect. Carinat decreased the total number of induced tumors and the incidence of mesenchymal renal tumors and
suppressed the development of multiple tumors. The accumulation of lipoperoxides in the kidneys during carcinogenesis is associated
with activation of free radical processes and carcinogen-induced inhibition of lipoperoxide enzymatic degradation and probably
promotes renal malignancies due to co-carcinogenic action of these compounds. The data suggest that carinat-induced suppression
of tumor development attests to antioxidant effects of β-carotene.
Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 130, No. 7, pp. 95–97, July, 2000 相似文献
67.
Franciszek Burdan Zofia Siezieniewska Ryszard Maciejewski Barbara Madej Elzbieta Radzikowska Zbigniew Wojtowicz 《Experimental and toxicologic pathology》2002,53(6):453-459
The aim of the study was to establish the influence of short-time omeprazole administration on liver function and morphology. Omeprazole was administered intraperitoneally, twice daily, for 3 days to male Wistar rats in two doses: 0.571 mg/kg and 5.71 mg/kg. Control animals were treated with physiological saline. Half of the animals were sacrificed 12 hours after the last injection. The remaining rats were raised for another 6 weeks, without any xenobiotics, and sacrificed on the 47th day of the experiment. The activity of free and bound fractions of hepatic acid phosphatase, beta-galactosidase, beta-N-acetyl-glucosaminidase, cathepsin B, D and L, lipase, and sulphatase were determined spectrophotometrically in homogenates of the liver. The liver sections were examined by light microscopy with hematoxylin-eosin, azan, and periodic acid-Schiff stains. Marginally significant (p < 0.1) differences in activity of free sulphatase fraction, and free and bound fractions of beta-galactosidase were found in animals exposed to the higher dose of omeprazole and sacrificed 12 hours after the last injection. Enzymatic profiles were normalised during the next 6 weeks. Histological evaluation revealed small degenerative and adaptive changes in all examined groups. It could be concluded that observed differences of hepatic lysosomal enzyme activities were the result of accompanied chemical-induced peritonitis as previously reported, and not a direct drug-toxic effect. 相似文献
68.
The focus of regenerative medicine is rebuilding damaged tissues by cell transplantation or implantation of bioartificial tissues. In either case, therapies focus on adult stem cells (ASCs) and embryonic stem cells (ESCs) as cell sources. Here we review four topics based on these two cell sources. The first compares the current performance of ASCs and ESCs as cell transplant therapies and the drawbacks of each. The second explores somatic cell nuclear transfer (SCNT) as a method to derive ESCs that will not be immunorejected. The third topic explores how SCNT and ESC research has led to the ability to derive pluripotent ESCs by the dedifferentiation of adult somatic cells. Lastly, we discuss how research on activation of intrinsic adult stem cells and on somatic cell dedifferentiation can evolve regenerative medicine from a platform consisting of cell transplantation to one that includes the chemical induction of regeneration from the body's own cells at the site of injury. Developmental Dynamics 237:3648–3671, 2008. © 2008 Wiley‐Liss, Inc. 相似文献
69.
Yoshino H Futakuchi M Cho YM Ogawa K Takeshita F Imai N Tamano S Shirai T 《Clinical & experimental metastasis》2005,22(5):441-447
Previously, we established the in vivo lung metastasis model of rat HCC induced by two hepatocarcinogens, diethylnitrosamine (DEN) and N-nitrosomorpholine (NMOR)
at a dose of 120 ppm. This model allows us to investigate modifying factors leading to the inhibition of metastasis formation.
However, low survival rates made the evaluation of metastasis formation difficult. The current experiments were conducted
to modify the experimental protocol to improve survival and to establish a better animal metastasis model. Lower doses of
NMOR (80 or 40 ppm in drinking water) were given to F344 rats for 14 weeks after DEN treatment. Survival rates in the 80 ppm
group and in the 40 ppm group were 57% and 81%, respectively and these values were significantly higher than that in 120 ppm.
Incidences of lung metastasis in the 40 ppm group steadily increased up to 67% by week 36 while that in the 80 ppm increased
sharply up to 86% by week 24. Severity of lung metastases in the 40 ppm group at week 36 was mild compared with the 80 ppm
group at week 24. In the second experiment, in order to characterize HCC development and lung metastasis in the 40 ppm group,
rats given DEN and then followed with 40 ppm NMOR were killed sequentially. Development of HCC was observed at week 14 and
reached 100% incidence at week 20. First lung metastatic lesions were evident at week 22, and incidence of lung metastasis
reached 100%. Tumor cells were identified in the blood at week 20 by RT-PCR. The current study revealed that 40 ppm NMOR for
14 weeks after DEN treatment developed HCC without lung metastases at week 22, then HCC with a frequent lung metastasis at
week 40. Thus, it can be said that this system is a more appropriate model for elucidation of mechanisms of metastasis and
also for analysis of factors to inhibit natural metastasis. 相似文献
70.
The objective of this study is to determine whether pentachlorophenol (PCP) alters benzo[a]pyrene (B[a]P)-induced DNA adduct formation in infant and adult B6C3F1 male mice. Mice were exposed intraperitoneally to 55 microg B[a]P/g body weight (BW) alone and in combination with several doses of PCP in DMSO. The 32P-postlabeling assay was used to analyze for (+/-) anti-7,8-diol-9,10-epoxide-B[a]P-N(2)deoxyguanosine (BPDE-N(2)G) adducts formed in liver and lung DNA. Hepatic DNA also was analyzed for 8-hydroxy-2'-deoxyguanosine (8-OHdG) base damage in mice exposed to PCP. 8-OHdG was not detected at any dose of PCP in infant or adult mice. PCP exhibited an antagonistic effect on BPDE-N(2)G accumulation in infant mice exposed to B[a]P in combination with 50 microg PCP/g BW at both 12 and 24 hr. Comparatively, BPDE-N(2)G adducts were increased in adult mice exposed to binary mixtures at 24 hr in both hepatic and lung DNA (P < 0.05). Multiple comparison analysis between infant and adult mice revealed that adduct levels in infants exposed to B[a]P alone or in combination with PCP were not different from those observed in adult mice exposed to B[a]P. However, a significant increase in adducts was observed in adult mice exposed to a combination of B[a]P and PCP compared to that in all other treatment groups (P < 0.05). These results suggest that PCP alters the metabolism of B[a]P in both infant and adult mice through different mechanisms, and that infants are not susceptible to the potentiating effects of PCP observed in adult mice. 相似文献