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951.
Purpose. Chitosan has recently been demonstrated to effectively enhance the absorption of hydrophilic drugs such as peptides and proteins across nasal and intestinal epithelia (1–3). In this study, the effect of the chemical composition and molecular weight of chitosans on epithelial permeability and toxicity was investigated using monolayers of human intestinal epithelial Caco-2 cells as a model epithelium.
Methods. Eight chitosans varying in degree of acetylation (DA) and molecular weight were studied. The incompletely absorbed hydrophilic marker molecule 14C-mannitol was used as a model drug to assess absorption enhancement. Changes in intracellular dehydrogenase activity and cellular morphology were used to assess toxicity.
Results. Chitosans with a low DA (1 and 15%) were active as absorption enhancers at low and high molecular weights. However, these chitosans displayed a clear dose-dependent toxicity. Chitosans with DAs of 35 and 49% enhanced the transport of 14C-mannitol at high molecular weights only, with low toxicity. One chitosan (DA = 35%; MW = 170kD) was found to have especially advantageous properties such as an early onset of action, very low toxicity, and a flat dose-absorption enhancement response relationship.
Conclusions. The structural features of chitosans determining absorption enhancement are not correlated with those determining toxicity, which makes it possible to select chitosans with maximal effect on absorption and minimal toxicity. 相似文献
952.
Steroid-sensitive proteins, growth hormone and somatomedin C in prostatic cancer: effects of parenteral and oral estrogen therapy 总被引:1,自引:0,他引:1
Reinhard Stege Nils Frhlander Kjell Carlstrm ke Pousette Bo Von Schoultz 《The Prostate》1987,10(4):333-338
The effects of parenteral and parenteral plus oral estrogen therapy on the serum levels of sex hormone binding globulin (SHBG), pregnancy-associated alpha 2-macroglobulin (alpha 2-PAG), growth hormone (GH), and somatomedin C (SmC) were studied in 26 patients with prostatic cancer. Intramuscular polyestradiol phosphate treatment, yielding a mean serum level of estradiol-17 beta of 1,446 pM and a mean testosterone level of 4.5 nM, had no significant effects on alpha 2-PAG, GH, and SmC and increased SHBG levels only marginally. Combined treatment with intramuscular polyestradiol phosphate and oral ethinyl estradiol greatly increased SHBG and alpha 2-PAG levels and caused elevated GH and decreased SmC levels. The route of estrogen administration is probably of major importance for the hormonal effects on hepatic activity as reflected by SHBG and alpha 2-PAG levels. Bypassing the portal circulation might be advantageous with respect to liver-related side effects of estrogen therapy. GH and SmC might act as mediators of estrogen effects on the human liver. 相似文献
953.
Two groups of 48 hr/hr mice (24 males, 24 females) were pretreated i.p. with 0.03 nmol of a synthetic epidermal mitosis-inhibiting pentapeptide (EPP), pGlu-Glu-Asp-Ser-GlyOH, dissolved in bovine serum albumin solution (BSA) at -6, -3 and 0 h before a topical skin application of 1 mg N-methyl-N-nitrosourea (MNU) in 100 microliters reagent-grade acetone. A control group was pretreated with three solvent injections only -6, -3 and 0 h before application. The results were also compared with a large, historical control group of 333 animals treated once with 1 mg MNU and without any pretreatment. The production of benign and malignant skin tumours was recorded and the results were assessed statistically. There was no statistically significant difference between the large control group without pretreatment and the actual control group pretreated with BSA. Pretreatment with EPP led to significant enhancement of the number of tumour-bearing animals with time and to a very significant increase in the total number of tumours. The group pretreated with EPP also developed more malignant skin tumours. The results are in agreement with earlier findings after i.p. pretreatment with crude skin extracts, hydroxyurea, or when MNU was applied in relation to diurnal rhythms in epidermal cell proliferation. They are also consistent with the assumption that EPP is one of the active growth-inhibitory substances in the epidermal extracts, and support the hypothesis that epidermal basal cells may be more sensitive to MNU-induced carcinogenesis when the rate of cell proliferation is low, because then more cells are in late G1 or early S phase where MNU binding to DNA may be relatively strong. 相似文献
954.
Entire diaphyseal bones from adult dogs were repeatedly loaded in torsion. The residual deformation after unloading from the non-linear deformation range was found to decrease with time. Acoustic-emission signals typical for micro-cracking were registered not only during loading in the non-linear deformation range but also during the initial phase of the following unloading. The initial torque and twist required for further micro-cracking decreased for every subsequent load-cycle, i.e. with the amount of cracking already formed. These observations are indications of visco-elastic properties of bone material. 相似文献
955.
Sergi Ferré Robert Schwarcz Xi Ming Li Per Snaprud Sven Ove Ögren Kjell Fuxe 《Psychopharmacology》1994,116(3):279-284
Stimulation of adenosine A2 receptors (with the selective adenosine A2 agonist CGS 21680) in rat striatal membrane preparations, produces a decrease in both the affinity of D2 receptors and the transduction of the signal from the D2 receptor to the G protein. This intramembrane A2-D2 interaction might be responsible for the behavioural depressant effects of adenosine agonists and for the behavioural stimulant effects of adenosine antagonists such as caffeine and theophylline. Dopamine denervation induces an increase in the intramembrane A2-D2 interaction, which may underlie the observed higher sensitivity to the behavioural effects induced by adenosine antagonists found in these animals. The present study was designed to examine if chronic treatment with haloperidol, which also produces dopamine receptor supersensitivity, is also associated with an increase in the intramembrane A2-D2 interaction in the neostriatum and with a higher sensitivity to the behavioural effects induced by adenosine antagonists. The data showed that: (i) haloperidol pretreatment causes a higher binding of the D2 antagonist [3H] raclopride in striatal membrane preparations due to an increase in the number of D2 receptors without changes in their affinity for the antagonist (increase in Bmax without changes in kd); (ii) GCS 21680 decreases the affinity of dopamine for the D2 receptor, by increasing the equilibrium dissociation constants of high (Kh) and low affinity (K1) dopamine D2 binding sites and increases the proportion of high affinity binding sites (Rh); (iii) a low dose of CGS 21680 (3 nM), which is ineffective in membrane preparations from neostriatum of nontreated animals, is effective in membranes from the striatum of haloperidol-pretreated animals; (iv) the nonselective adenosine antagonist theophylline (20 mg/kg SC) causes a higher motor activation in rats pretreated with haloperidol. The possible relevance of these results for the pathophysiology and treatment of tardive dyskinesias is discussed. 相似文献
956.
Kalervo Kiianmaa Kurt Andersson Kjell Fuxe 《Pharmacology, biochemistry, and behavior》1979,10(4):603-608
Selective lesions of the ascending dopamine pathways were made by bilateral injection of the neurotoxin 6-OHDA (8 μg/4 μl). Catecholamine fluorescence histochemistry revealed a marked degeneration of the ascending mesostriatal and mesolimbic dopamine systems, while the hypothalamic dopamine and noradrenaline nerve terminals were unaffected. After recovery of feeding and drinking behaviors the voluntary ethanol intake was not different from that of the controls. The time of ethanol-induced narcosis and the extent of ethanol-induced hypothermia were not affected. In contrast, in a tilting-plane test conducted two months after the operation, ethanol impaired the performance of the 6-OHDA-treated rats significantly less than that of the controls. This finding suggests a role for the ascending dopamine neurons to the forebrain in the intoxicating effect of ethanol. 相似文献
957.
Liv Endresen Arne Bakka Anne Glennås Kjell Magne Tveit Hans Erik Rugstad 《Toxicology and applied pharmacology》1983,67(2):274-283
Cultured cells can be adapted to large concentrations of the toxic cadmium ion, apparently by induction of synthesis of the Cd-binding protein metallothionein (MT). One human epithelial line derived from normal skin (HE100) and one murine fibroblast line, derived from L cells (C1 1D100), were used to study the stability of Cd resistance, the MT levels following omission of Cd, and the inducibility of MT synthesis in cells on reexposure to Cd. In the murine cells there was no significant loss of resistance during a 4-week period either after cultivation in vitro or after growing the cells in nude mice. In the human cells a decrease (50%) in resistance was noted the first week after Cd omission. After removing Cd from the cells, a rapid decrease in MT content was demonstrated. After 3 weeks of cultivation only trace amounts were left in both cell lines. However, approximately 60% (HE100) and 80% (C1 1D100) of the previous levels were demonstrated after reexposure to maximum tolerable doses for 24 hr. The data indicate that the degree of stability of Cd resistance is dependent on the capacity in cells for an immediate de novo synthesis of large amounts of MT on reexposure to Cd. The animal experiments demonstrate that Cd resistance is maintained even after growing the cells in vivo. 相似文献
958.
Kjell Berostrom Karl-Henrik Gustavson Hakan Jorulf 《Journal of Medical Imaging and Radiation Oncology》1972,16(2):155-158
Thanatophoric dwarfism is a recently identified fatal form of achondroplasia which can be differentiated from the usual form of the disease. A newborn male infant with this disease, where the diagnosis was made in utero, is described. Roentgenological critera for the diagnosis are extremely flat vertebral bodies, extremely short and bowed tubular bones and a small thorax with short, broad ribs. The mode of inheritance and the importance of a correct diagnosis are discussed. 相似文献
959.
Passive transfer (PK) tests were performed with a reaginic serum on a recipient reacting with an immediate and a more prolonged reaction when specificity challenged. Both reactions are thought to be mediated by IgE immunology. Ketotifen, a cycloheptathiophene derivative, and clemastine, given to the recipient in maximal clinical doses for 3 days, inhibited the immediate reaction. Ketotifen had a very slight effect also on the prolonged reaction. The results indicate that the in vivo effects of ketotifen in the human system are due not so much to mast cell inhibitory mechanisms, but more to post-release antihistaminic and some anti-inflammatory properties. 相似文献
960.
Kjell Tullus Omar Fituri Lars G. Burman Bengt Wretlind Annelie Brauner 《Pediatric nephrology (Berlin, Germany)》1994,8(3):280-284
Interleukin-6 (IL-6) and interleukin-8 (IL-8) are important mediators of the inflammatory response in serious bacterial infections. We studied the levels of these two cytokines (standardised for urinary creatinine) in the urine of infants and children during and 6 weeks after acute pyelonephritis and in non-renal febrile controls and healthy children without apparent infection. IL-6 was detected in the urine of 52% of children with pyelonephritis compared with 15% of other children (P<0.001). The median urinary IL-6 level in acute pyelonephritis was 4 pg/mol compared with undetectable levels in the control group (P<0.001). IL-8 was detected in 98% of children with pyelonephritis and 42% of other children (P<0.001). The median concentration of IL-8 was 188 pg/mol in pyelonephritis; it was undetectable in controls (P<0.001). IL-8 levels were higher in children less than 1 year of age (P<0.001). 相似文献