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71.
1. The anti-HIV drug zidovudine (3'-azido-2',3'-dideoxythymidine; ZDV) has three important pathways of metabolism. ZDV is a prodrug and must be phosphorylated in lymphocytes in order to exert its antiviral action. However, in quantitative terms this is a minor pathway probably accounting for less than 1% of the overall metabolic profile. The predominant pathway of metabolism is glucuronidation to GZDV and the metabolite is renally excreted. A further metabolite, derived by reduction of the azido moiety is 3'-amino-3'-deoxythymidine (AMT). 2. Zidovudine glucuronidation has been characterised in human liver microsomes. A number of drugs (e.g., naproxen, indomethacin and probenecid) have been shown to inhibit the in vitro conjugation of ZDV. Some of these drugs have also been co-administered with ZDV in HIV-positive patients. Significant pharmacokinetic interactions have been demonstrated with probenecid, naproxen and fluconazole. 3. 3'-amino-3'-deoxythymidine formation is probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Peak plasma concentrations of AMT are approximately 10-15% of ZDV in patients. This is a potentially important metabolite because of its alleged cytotoxicity. 4. Measurement of intracellular ZDV phosphates in patients provides the key to our understanding of both the efficacy and toxicity of ZDV. Important recent work has demonstrated that as patients deteriorate (i.e., CD4 counts decrease below 100 x 10(6)/L), there is a corresponding increase in intracellular ZDV-monophosphate. This could have toxicological implications. 相似文献
72.
GJ Wetscher G Perdikis DH Kretchmar RG Stinson D Bagchi EJ Redmond TE Adrian RA Hinder 《Canadian Metallurgical Quarterly》1995,40(6):1297-1305
Free radical-mediated esophagitis was studied during duodenogastroesophageal reflux (mixed reflux) or acid reflux in rats. The influence of reflux on esophageal glutathione levels was also examined. Mixed reflux caused more gross mucosal injury than acid reflux. Gross mucosal injury occurred in the mid-esophagus. Total glutathione (GSH) in the esophageal mucosa of control rats was highest in the distal esophagus. The time course of esophageal GSH in rats treated by mixed reflux showed a significant decrease 4 hr after initiation of reflux, followed by a significant increase from the 12th hour on. Mucosal GSH was increased in both reflux groups after 24 hr but significantly more so in the mixed than in the acid reflux group. The free radical scavenger superoxide dismutase (SOD) prevented esophagitis and was associated with decreased GSH levels. GSH depletion by buthionine sulfoximine (BSO) prevented esophagitis and stimulated SOD production in the esophageal mucosa. It is concluded that gastroesophageal reflux is associated with oxidative stress in the esophageal mucosa. The lower GSH levels in the mid-esophagus may predispose to damage in this area. Duodenogastroesophageal reflux causes more damage than pure acid reflux. Oxidative stress leads to GSH depletion of the esophageal mucosa in the first few hours following damage but then stimulates GSH production. GSH depletion by BSO does not worsen esophagitis since it increases the esophageal SOD concentration. 相似文献
73.
Bakos E T Hegedüs Z Holló E Welker GE Tusnády GJ Zaman MJ Flens A Váradi B Sarkadi 《Canadian Metallurgical Quarterly》1996,271(21):12322-12326
The membrane topology of the human multidrug resistance-associated protein (MRP) was examined by flow cytometry phenotyping, immunoblotting, and limited proteolysis in drug-resistant human and baculovirus-infected insect cells, expressing either the glycosylated or the underglycosylated forms of this protein. Inhibition of N-linked glycosylation in human cells by tunicamycin did not inhibit the transport function or the antibody recognition of MRP, although its apparent molecular mass was reduced from 180 kDa to 150 kDa. Extracellular addition of trypsin or chymotrypsin had no effect either on the function or on the molecular mass of MRP, while in isolated membranes limited proteolysis produced three large membrane-bound fragments. These experiments and the alignment of the MRP sequence with the human cystic fibrosis transmembrane conductance regulator (CFTR) suggest that human MRP, similarly to CFTR, contains a tandem repeat of six transmembrane helices, each followed by a nucleotide binding domain, and that the C-terminal membrane-bound region is glycosylated. However, the N-terminal region of MRP contains an additional membrane-bound, glycosylated area with four or five transmembrane helices, which seems to be a characteristic feature of MRP-like ATP-binding cassette transporters. 相似文献
74.
This study investigates within-subject variations and associations of salivary viscosities and flow rates in a test panel of healthy adults. After several practice sessions, unstimulated and stimulated whole saliva samples were collected 5 times daily (at 0800, 1100, 1400, 1700, and 2000 h) from 30 university students. There was a significant within-subject variation in viscosity and flow rate of unstimulated saliva (P<0.001). Intra-item correlations were significantly different for salivary flow rates (r= 0.82 for unstimulated, r= 0.88 for stimulated, P< 0.001) and viscosity of unstimulated saliva (r= 0.54, P< 0.05), but viscosity of stimulated saliva was different in this respect. Our results indicate that there is a significant within-subject variation in viscosity of unstimulated saliva. 相似文献
75.
Four women aged 30, 29, 52 and 43 years presented with what appeared to be subacute thyroiditis (De Quervain's thyroiditis). This disease is characterized by fatigue, a painful thyroid gland and thyrotoxic manifestations. The diagnosis is further based on a high erythrocyte sedimentation rate and low tracer uptake during thyroid scintigraphy. Only the first patient showed a typical course. In the second and third ones the painful thyroid was associated with nodular enlargement. Fine needle aspiration cytology was at first consistent with subacute thyroiditis but a repeated aspiration showed papillary carcinoma in the second and anaplastic carcinoma in the third patient. In the fourth one, subacute thyroiditis was accompanied by normochromic anaemia, a low serum albumin concentration and liver function disorders. She made a full recovery without treatment. Thyroid malignancies can mimic subacute thyroiditis. Persistent nodular enlargement of the thyroid is suspicious and requires careful investigation. 相似文献
76.
GJ Mancini-Samuelson V Kieweg KM Sabaj S Ghisla MT Stankovich 《Canadian Metallurgical Quarterly》1998,37(41):14605-14612
The modulation of the electron-transfer properties of human medium-chain acyl-CoA dehydrogenase (hwtMCADH) has been studied using wild-type and site-directed mutants by determining their midpoint potentials at various pH values and estimating the involved pKs. The mutants used were E376D, in which the negative charge is retained; E376Q, in which one negative charge (pKa approximately 6. 0) is removed from the active center; E99G, in which a different negative charge (pKa approximately 7.3) also is affected; and E376H (pKa approximately 9.3) in which a positive charge is present. Em for hwtMCADH at pH 7.6 is -0.114 V. Results for the site-directed mutants indicate that loss of a negative charge in the active site causes a +0.033 V potential shift. This is consistent with the assumption that electrostatic interactions (as in the case of flavodoxins) and specific charges are important in the modulation of the electron-transfer properties of this class of dehydrogenases. Specifically, these charge interactions appear to correlate with the positive Em shift observed upon binding of substrate/product couple to MCADH [Lenn, N. D., Stankovich, M. T., and Liu, H. (1990) Biochemistry 29, 3709-3715], which coincides with a pK increase of Glu376-COOH from approximately 6 to 8-9 [Rudik, I., Ghisla, S., and Thorpe, C. (1998) Biochemistry 37, 8437-8445]. From the pH dependence of the midpoint potentials of hwtMCADH two mechanistically important ionizations are estimated. The pKa value of approximately 6.0 is assigned to the catalytic base, Glu376-COOH, in the oxidized enzyme based on comparison with the pH behavior of the E376H mutant, it thus coincides with the pK value recently estimated [Vock, P., Engst, S., Eder, M., and Ghisla, S. (1998) Biochemistry 37, 1848-1860]. The pKa of approximately 7.1 is assigned to Glu376-COOH in reduced hwtMCADH. Comparable values for these pKas for Glu376-COOH in pig kidney MCADH are pKox = 6.5 and pKred = 7.9. The Em measured for K304E-MCADH (a major mutant resulting in a deficiency syndrome) is essentially identical to that of hwtMCADH, indicating that the disordered enzyme has an intact active site. 相似文献
77.
OBJECTIVE: To compare oral misoprostol 400 microg with placebo in the routine management of the third stage of labour. DESIGN: A double-blind placebo controlled trial. Setting The labour ward of an academic hospital in Johannesburg, South Africa with 7000 deliveries per annum. PARTICIPANTS: Low-risk women expected to deliver vaginally. METHODS: Women in labour were randomly allocated to receive either misoprostol 400 microg orally or placebo after the birth. Conventional oxytocics were given immediately if blood loss was thought to be more than usual. Postpartum blood loss in the first hour was measured by collection in a special flat plastic bedpan. Side effects were recorded. MAIN OUTCOME MEASURES: Measured blood loss > or = 1000 ml within the first hour after birth. Use of additional oxytocics. RESULTS: The groups were well matched. Measured blood loss > or = 1000 ml occurred in 15/250 (6%) after misoprostol and 23/250 (9%) after placebo (relative risk 0.65; 95% confidence interval 0.35-1.22). The difference may have been reduced by the greater use of conventional oxytocics in the placebo group, which was statistically significant for intravenous oxytocin infusion (2.8% vs 8.4%, relative risk 0.33, 95% confidence interval 0.14-0.77). Shivering was more common in the misoprostol group (19% vs 5%, relative risk 3.69; 95% confidence interval 2.05-6.64). CONCLUSIONS: Shivering has been shown in this study to be a specific side effect of misoprostol administered orally in the puerperium. No serious side effects were noted. Misoprostol shows promise as a method of preventing postpartum haemorrhage. Because of the potential benefits for childbearing women, particularly those in developing countries, further research to determine its effects with greater certainty should be expedited. 相似文献
78.
H Fujioka R Thakur GJ Wang K Mizuno G Balian SR Hurwitz 《Canadian Metallurgical Quarterly》1998,37(3-4):205-218
The effects of surgical repair versus non-repair on cell morphology and type X collagen expression were investigated using a rat model of Achilles tendon avulsion. The animals were divided into four groups. In Group 1, tendon was reattached to the original attachment site by suturing through a drill hole in the calcaneus; in Group II, tendon was not reattached and a drill hole was not made; in Group III, tendon was not reattached but a drill hole was made; and the animals in Group IV were sham operated. In Group I (tendon reattached), at 2 weeks postoperatively, many hypertrophic chondrocytes appeared at the reattachment site adjacent to bone and type X collagen was detected immunologically both in the cells and in the extracellular matrix. After 4 weeks, the cells at the original site of attachment were arranged in rows along the newly formed tendon fibers and were stained with type X collagen antibody. By contrast, when tendon was not reattached (Groups II and III), a gap between the original attachment site and the tendon stump was observed through the entire postoperative period. At 8 weeks, the original attachment site was covered by fibrocartilaginous tissue and tendon became attached to the calcaneal fibrocartilage area, which is proximal to the original attachment site. Type X collagen was detected in the cells which were adjacent to bone. In Group IV (sham operation), there were no changes in histology or type X collagen distribution, either at the attachment site or in tendon and bone, compared with the non-operated control rats. These results suggest that surgical reattachment of tendon to the original site is important to help reorganize cells during the repair process. Type X collagen was identified immunohistochemically in the cells adjacent to bone in all the groups, suggesting that it may play a role in maintaining distinct areas of calcified and non-calcified fibrocartilage. 相似文献
79.
JG Gribben GJ Freeman VA Boussiotis P Rennert CL Jellis E Greenfield M Barber VA Restivo X Ke GS Gray 《Canadian Metallurgical Quarterly》1995,92(3):811-815
The regulation of T cell-mediated immune responses requires a balance between amplification and generation of effector function and subsequent selective termination by clonal deletion. Although apoptosis of previously activated T cells can be induced by signaling of the tumor necrosis factor receptor family, these molecules do not appear to regulate T-cell clonal deletion in an antigen-specific fashion. We demonstrate that cross-linking of the inducible T-cell surface molecule CTLA4 can mediate apoptosis of previously activated human T lymphocytes. This function appears to be antigen-restricted, since a concomitant signal T-cell receptor signal is required. Regulation of this pathway may provide a novel therapeutic strategy to delete antigen-specific activated T cells. 相似文献
80.
PR Davis-Searles AS Morar AJ Saunders DA Erie GJ Pielak 《Canadian Metallurgical Quarterly》1998,37(48):17048-17053
Proteins denature at low pH because of intramolecular electrostatic repulsions. The addition of salt partially overcomes this repulsion for some proteins, yielding a collapsed conformation called the A-state. A-states have characteristics expected for the molten globule, a notional kinetic protein folding intermediate. Here we show that the addition of neutral sugars to solutions of acid-denatured equine ferricytochrome c induces formation of the A-state in the absence of added salt. We characterized the structure and stability of the sugar-induced A-state with circular dichroism spectropolarimetry (CD) and NMR-monitored hydrogen-deuterium exchange experiments. We also examined the stability of the sugar-induced A-state as a function of sugar size and concentration. The results are interpreted using several models and we conclude that the stabilizing effect is consistent with increased steric repulsion between the protein and the sugar solutions. 相似文献