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71.
Julia E. Ledger MSc Graham J. Watson Dr. Juliet E. Compston MD 《Digestive diseases and sciences》1986,31(4):361-368
The biliary excretion of radioactivity after intravenous [3H]25-hydroxyvitamin D3 was studied in nine patients with T-tube bile drainage. The mean +/- SD 24-hr radioactivity excretion in T-tube bile expressed as a percentage of the administered dose was 6.7 +/- 2.9%; after correction for incomplete bile collection, the value obtained was 16.0 +/- 11.1%. Chloroform solubility of biliary radioactivity increased from 27.4 +/- 8.9% to 72.9 +/- 10.1% following incubation with beta-glucuronidase. High-performance liquid chromatographic analysis of chloroform extracts of bile revealed that most of the eluted radioactivity was more polar than [3H]25-hydroxyvitamin D3. No free [3H]25-hydroxyvitamin D3 was demonstrated. Thus in man, most of the biliary radioactivity excreted following [3H]25-hydroxyvitamin D3 is in the form of water-soluble compounds, mainly glucuronides. However, our results suggest that glucuronides of metabolites other than 25-OHD3 are predominantly formed. 相似文献
72.
J A Bond G J Graham M Freshney T Dawson N Sawhney E D Williams D Wynford-Thomas 《Molecular and cellular endocrinology》1992,84(1-2):R15-R21
Normal adult human thyroid follicular cells have an extremely limited proliferative capacity in vitro. No previously studied mitogen, including thyrotropin (TSH) or epidermal growth factor (EGF), has in our hands resulted in a significant improvement over the 3-4% nuclear [3H]thymidine pulse-labelling index (LI) obtainable with 10% fetal calf serum. Here we report the detection in the conditioned medium from a sub-clone of NIH3T3 fibroblasts of a mitogenic activity capable of increasing this response up to 10-fold, to an LI of over 20%, together with an even greater relative stimulation of mitotic activity. Preliminary characterisation has excluded EGF and TGF alpha, and demonstrated that the activity is bound reversibly by heparin-Sepharose, thus pointing to a member of the heparin-binding fibroblast- or hepatocyte-growth factor families. This material should have wide practical application in facilitating primary culture of follicular cells, and may reveal new mechanisms of stromal-epithelial interaction regulating normal and neoplastic thyroid growth in vivo. 相似文献
73.
74.
J Cummings M A Graham B M Hoey J Butler A M Fry I D Hickson G Leonard R French J F Smyth 《Biochemical pharmacology》1992,44(3):433-439
GR63178A (NSC D611615) is the second pentacyclic pyrolloquinone to be evaluated clinically as an anticancer drug. Its mechanism of action is unknown but may be related either to its quinone group or planar ring system. In this report we have investigated the ability of GR63178A to bind non-covalently to DNA, inhibit topoisomerase II and undergo reduction to reactive free radical species. Using two DNA duplexes, a 12-mer oligonucleotide which is a preferred sequence for minor groove binders and a hexamer which is a preferred sequence for intercalators, no evidence of significant binding with GR63178A was found. Neither GR63178A nor GR54374X (its 9-hydroxy metabolite) inhibited purified human topoisomerase II in a decatenation assay. Free radical chemistry was studied by both pulse radiolysis and ESR spectroscopy as well as by in vitro drug incubations with NADPH-fortified rat liver microsomes and purified cytochrome P450 reductase. The one-electron reduction potential of GR63178A was -207 mV +/- 10 which is much more positive than other quinone-containing anticancer drugs such as doxorubicin, mitomycin C and mitozantrone. GR63178A underwent enzyme-catalysed quinone reduction more readily than doxorubicin but produced significantly fewer reactive oxygen species. No evidence was detected of drug-induced, radical-mediated DNA damage in vitro using pBR322 plasmid DNA. Disproportionation of the GR63178A semi-quinone free radical proceeded with a rate constant of 1 x 10(9) M-1 sec-1 under anaerobic conditions, one order of magnitude faster than doxorubicin. The preferential disproportionation of the semi-quinone may explain our inability to detect a free radical signal by ESR. The hydroquinone of GR63178A was stable and exhibited strong visible absorption with a bathochromic shift of 120 nm over the parent drug. These unusual properties may be due to the hydroquinone undergoing a form of keto-enol tautomerization. Thus, GR63178A free radical formation does not appear to result in significant drug activation. In conclusion, GR63178A is unlikely to mediate its antitumour activity by DNA binding, topoisomerase II inhibition or free radical formation in direct contrast to similar anthracycline- and anthraquinone-based anticancer drugs. 相似文献
75.
The potentiation of adrenaline-induced in vitro platelet aggregation by ADP, collagen and serotonin and its inhibition by naftopidil and doxazosin in normal human subjects.
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N A Alarayyed B R Graham B N Prichard C C Smith 《British journal of clinical pharmacology》1995,39(4):369-374
1. Aggregation in platelet-rich plasma from normotensive men was induced by adrenaline (0.25-16 microM), ADP (0.25-16 microM), collagen (0.25-8 micrograms ml-1) or serotonin (10 microM) alone, or by previously sub-threshold concentrations of adrenaline (0.03-1 microM) in combination with sub-threshold concentrations of serotonin (2.5 microM), ADP (0.5 microM) or collagen (0.125 micrograms ml-1). The effects of the alpha 1-adrenoceptor blockers naftopidil and doxazosin on platelet aggregation were investigated. 2. The dose-response curves for collagen and ADP were unaffected by either drug. However, naftopidil (40 microM) inhibited serotonin-induced platelet aggregation (23.9%, 95% confidence interval (CI) 10.7 to 37.1%; P < 0.01) and caused a slight shift to the right of the adrenaline dose-response curve with a mean increase in the EC50 value of 0.5 microM (95% CI 0.07 to 0.93 microM; P < 0.05). Doxazosin had no effect on serotonin or adrenaline-induced aggregation. 3. A marked potentiation of the aggregation induced by subthreshold concentrations of adrenaline resulted from the prior addition of low concentrations of ADP, collagen or serotonin. 4. These potentiated responses were inhibited in a dose-dependent manner by naftopidil and to a lesser extent doxazosin. The maximum inhibitions (%) produced by naftopidil (40 microM) on the responses of adrenaline potentiated by ADP were 58.3% (95% CI 36.8 to 79.8%; P < 0.001), serotonin 58.9% (95% CI 40.0 to 77.8%; P < 0.001), and collagen 70.9% (95% CI 52.5 to 89.3%; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
76.
77.
78.
Ralph Worfolk Graham R. Barnes 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》1992,90(3):589-598
Summary Independent target and background motions have been used to generate conflicting activity within the pursuit and optokinetic systems. Subjects were required to pursue a small target against a structured background which moved independently. Selective enhancement of the response to the target generated high-gain active pursuit which dominated the eye movements. Passive eye movements induced during relative target and background motion are not normally directly quantifiable due to their low gain. By reducing the gain of the active pursuit optokinetically induced eye movements were enhanced and quantified. Three techniques are described for degrading active pursuit: tachistoscopic, eccentric and pseudorandom methods of target presentation. Our results demonstrate the synchronous input of active and passive eye movement drives to the oculomotor system and illustrate their interaction. 相似文献
79.
LIMITATIONS OF RADIOTHERAPY IN THE DEFINITIVE TREATMENT OF SQUAMOUS CARCINOMA OF THE TONSILLAR FOSSA
Christopher J. O'Brien Geeta K. Castle Graham N. Stevens G. Mac Halliday John K. Donovan Kenneth K. Lee Nicholas A. Packham Maurice J. Peat 《ANZ journal of surgery》1992,62(9):709-713
Between 1970 and 1990, 104 patients with squamous cell carcinoma (SCC) of the tonsil were treated. The median age was 58 years and 80% of patients were males. Distribution among clinical stages was: stage I, 19 patients; stage II, 12 patients; stage III, 23 patients; and stage IV, 48 patients. More than 70% of patients had initial radiotherapy as definitive treatment irrespective of stage, reflecting the treatment philosophy over much of this period. The overall survival rate was 26% at 5 years, with survival being significantly affected by T stage, clinical stage and age. Clinical node status did not significantly affect survival rates. Good local control of T1N0 cancers was achieved with radiotherapy alone, but patients with more advanced cancers did poorly. We have now moved away from a non-selective policy and use initial surgery combined with postoperative radiotherapy in most patients, reserving radiotherapy alone for mainly early tonsil cancers. 相似文献
80.
Michael J. LaRouere John J. Zappia Harvey I. Wilner Malcolm D. Graham Larry B. Lundy 《Skull base》1994,4(1):21-25
Four patients with grade C or D1 glomus jugulare tumors who underwent preoperative highly selective embolization followed by infratemporal fossa removal of their tumors were compared to three patients undergoing surgery alone with respect to intraoperative blood loss, operative time, cranial nerve palsy, length of hospitalization, and perioperative complications. Embolized patients demonstrated a marked reduction in blood loss (650 vs 1375 cc) compared with the nonembolized group. Operative time was shortened (by 51 minutes). Facial nerve function did not appear related to embolization but was directly related to intraoperative nerve manipulation. Hospital stay, perioperative complications, and lower cranial nerve palsies were not related to embolization. 相似文献