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21.
R. C. Small J. P. Boyle K. R. Elliott R. W. Foster A. J. Watt 《British journal of pharmacology》1989,97(4):1174-1181
1. AH 21-132 is being investigated as a potential chemotherapeutic agent for bronchial asthma. The present experiments were designed to determine whether AH 21-132 shares the activity of theophylline as an antagonist at adenosine A1 receptors and to assess its potency as a relaxant in intestinal smooth muscle. 2. In the transmurally-stimulated guinea-pig ileum, theophylline (1 mM), but not AH 21-132 (1 and 10 microM), antagonized twitch depression induced by adenosine. Higher concentrations (100 microM and 1 mM) of AH 21-132 themselves had a depressant effect. Neither theophylline (1 mM) nor AH 21-132 (1 and 10 microM) antagonized twitch depression induced by noradrenaline. 3. AH 21-132 (100 microM and 1 mM) depressed maximum contractions of ileum induced by both acetylcholine (ACh) and histamine. 4. In ileum treated with hyoscine (1 microM), AH 21-132 (greater than 10 microM) caused a concentration-dependent depression of the log concentration-effect curve for potassium chloride. 5. Simultaneous extracellular electrophysiological and mechanical recording from taenia caeci showed that AH 21-132 (100 microM-1 mM) inhibited spontaneous tension waves and their associated bursts of electrical spike activity. 6. Intracellular electrophysiological recording from taenia caeci showed that the mechano-inhibitory effect of 1 mM AH 21-132 was accompanied by abolition of spontaneous spike activity. Following spike abolition, the membrane potential assumed a value very close to that observed during periods of electrical quiescence prior to drug exposure. 7. AH 21-132 inhibited the activity of cyclic AMP-dependent and cyclic GMP-dependent phosphodiesterases derived from homogenates of ileal smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
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23.
Pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase.
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R. M. McMillan K. E. Spruce G. C. Crawley E. R. Walker S. J. Foster 《British journal of pharmacology》1992,107(4):1042-1047
1. This paper describes the pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase which is undergoing clinical evaluation. 2. ICI D2138 potently inhibited leukotriene synthesis in murine peritoneal macrophages (IC50 = 3 nM) and human blood (IC50 = 20 nM). In human and dog blood, ICI D2138 did not inhibit thromboxane B2 synthesis at a concentration of 500 microM, thus the selectivity ratio (cyclo-oxygenase: 5-lipoxygenase) was greater than 20,000. In contrast, zileuton (a 5-lipoxygenase inhibitor also undergoing clinical evaluation) exhibited a selectivity ratio of 15-100. 3. ICI D2138 potently and dose-dependently inhibited ex vivo leukotriene B4 (LTB4) synthesis by rat blood with ED50 values of 0.9, 4.0 and 80.0 mg kg-1 p.o. at 3, 10 and 20 h respectively after dosing. Similar activity was observed for inhibition of LTB4 production in a zymosan-inflamed rat air pouch model. Zileuton produced ED50 values of 5 and 20 mg kg-1 at 3 and 10 h respectively. 4. Oral administration of 1, 3 or 10 mg kg-1 ICI D2138 to dogs produced maximal inhibition of ex vivo LTB4 synthesis by blood for 5, 9 and 31 h respectively. A dose of 5 mg kg-1 p.o. of zileuton caused maximal inhibition of LTB4 for 24 h. 5. Oral administration of 10 mg kg-1 ICI D2138 caused total inhibition of LTB4 production in zymosan-inflamed rabbit knee joint. 6. Topical administration of ICI D2138 to rabbit skin caused a dose-related inhibition of arachidonic acid-induced plasma extravasation with an ID30 of 1.08 nmol per site.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
24.
The Melanesians of the North Solomons are exposed to intense equatorial sunlight and yet have a very low incidence of skin cancer. This study reveals no proven cases of basal cell carcinoma in these people, and demonstrates the rarity of squamous cell carcinoma and melanoma arising in normal pigmented skin. Most, if not all squamous cell carcinomas, arise in skin damaged by tropical ulceration, burns or osteomyelitis. Melanoma arises from the unpigmented skin of the sole of the foot. North Solomon Islanders are very deeply pigmented. Presumably, dense cutaneous melanin in normal undamaged skin provides the highly effective protection against solar carcinogenesis which these people enjoy. Chronic or recurrent skin ulceration with subsequent repair, scarring and loss of pigment is the precursor to almost all non-melanoma skin cancer in these people. Most of these cancers could be prevented by split thickness skin grafting of chronic ulcers, and protection of ulcerated, depigmented and scarred skin from solar radiation. 相似文献
25.
H M Foster 《The Australian and New Zealand journal of surgery》1988,58(1):47-50
A series of 227 consecutive laparoscopies performed over 3 years at a provincial hospital in the North Solomons Province is presented. There were no deaths due to the procedure and morbidity was 2.4%. Positive findings were revealed in 89% of patients, allowing rapid decisions to be made regarding patient management: a vital consideration in a busy surgical unit with limited resources. Laparoscopy provides an efficient, safe, rapid and direct approach to many abdominal problems encountered in general surgery, particularly liver disease, blunt abdominal trauma, intraperitoneal infection and neoplasia. 相似文献
26.
Harry L June Rancia Cummings William J A Eiler Katrina L Foster Peter F McKay Regat Seyoum Marin Garcia Shannan McCane Collette Grey Stephanie E Hawkins Dynesha Mason 《Neuropsychopharmacology》2004,29(2):285-299
The exact opioid-sensitive receptors participating in EtOH-seeking behaviors remains unclear. Previous studies have reported higher densities of micro-opioid receptor binding in the nucleus accumbens (NACC) of P relative to NP rats; however, no differences were seen in delta-receptor binding. In contrast to the NACC, substantially lower levels of micro-receptor binding have been observed in the ventral tegmental area (VTA) of both P and NP rats, albeit no line differences have been observed. In the present study, opioid receptors in the NACC, VTA, and hippocampus were evaluated for their capacity to regulate both EtOH- and saccharin-motivated behaviors in the genetically selected alcohol-preferring (P) rat. To accomplish this, nalmefene, an opiate antagonist with preferential binding affinity for the micro-opioid receptor was unilaterally or bilaterally infused during concurrent availability of 1 h daily EtOH (10% v/v) and saccharin (0.025 or 0.050% w/v) solutions. Rats performed under a two-lever fixed ratio (FR) schedule in which four responses on one lever produced the EtOH solution, and four on a second lever produced the saccharin solution. The results demonstrated that when responding maintained by both EtOH and saccharin are matched at basal levels, unilateral (1-60 microg) or bilateral (0.5-10 microg) microinjections of nalmefene into the NACC produced selective dose-dependent reductions on responding maintained by EtOH. Unilateral (40, 60 microg) and bilateral (10 microg) VTA infusions were also observed to selectively reduced EtOH responding; however, greater nalmefene doses were required and the magnitude of suppression on EtOH responding was markedly less compared with the NACC. The greater sensitivity of nalmefene to suppress EtOH responding in the NACC is likely due to the greater number of opioid receptors in the NACC relative to the VTA. Only bilateral infusion of the 40 microg dose in the NACC and VTA suppressed responding maintained by both EtOH and saccharin. In contrast, intrahippocampal infusions dose dependently suppressed EtOH- and saccharin-maintained responding over a range of doses (1-20 microg). The present study provides evidence that nalmefene suppresses EtOH-motivated behaviors via blockade of opioid receptors within the NACC and VTA, and under various dose conditions both reinforcer and neuroanatomical specificity can be observed. 相似文献
27.
OBJECTIVE: The purpose of the present study was to investigate the cerebral correlates of varying ages of emotional memories using quantitative electroencephalography. BACKGROUND: Recollection of emotional memories has often been used as a method of inducing emotional arousal in studies seeking to investigate the cerebral correlates of emotional arousal. However, the specific effects of the ages of the memories recalled on resulting changes in cerebral activity have not been investigated. METHOD: A total of 16 female undergraduates were asked to recollect an angry memory while quantitative electroencephalography was recorded. Following recollection, they were further asked to indicate the age of the memory recalled. RESULTS: The results indicated that significant correlations existed between ages of angry memories and changes in the magnitude of low beta (13 to 21 Hz) and high beta (21 to 32 Hz) at the right frontal, left temporal, and bilateral parietal regions of the brain. CONCLUSIONS: The results support an integration of the spreading activation and parallel distributed processing models of memory in predicting the cerebral effects of varying ages of emotional memories. Further, given the present findings, it may be important for investigators to determine the ages of the memories recalled so as to control or otherwise account for the effects of this potentially confounding variable. 相似文献
28.
29.
The possibility that regulation of Ca2+ levels in brain nerve terminals is altered as the brain ages was examined in synaptosomes from adult and aged Fischer 344 rats. Free intrasynaptosomal [Ca2+]i was monitored with fura-2 as synaptosomes were depolarized with KCl, veratridine and ibotenic acid. With all three depolarizing agents, synaptosomes from aged animals reached higher free Ca2+ levels, and the maximal Ca2+ increases (delta Ca2+) estimated from computer assisted-fitting of the curves, ranged from 35% to 80% greater in synaptosomes from aged animals. The total Ca2+ content of the brain and of synaptosomes was also found to be considerably higher in aged than in adult animals. These results suggest that the aging process in brain is accompanied by alterations in both dynamic aspects of Ca2+ handling in nerve endings and the overall content of Ca2+ in the brain and synaptic terminals. 相似文献
30.
R Vassilopoulou-Sellin P L Foster C O Oyedeji N A Samaan 《Metabolism: clinical and experimental》1988,37(1):38-45
Cartilage sulfation (somatomedin) inhibitors (CSI) from rat liver produce reversible inhibition of cartilage growth. After gel filtration Sephadex G-200, CSI appear to have MW approximately 100,000 and they are urea- and trypsin-labile factors. To explore further the mechanism of CSI action, we used the chick pelvic rudiment bioassay and studied the effect of CSI on the incorporation on 35S-sulfate (proteoglycan synthesis), 14C-leucine (protein synthesis), 3H-uridine (RNA synthesis), and 3H-thymidine (DNA synthesis). Normal rat serum (NRS) significantly stimulated the incorporation of all four isotopes, as expected. After a 24-hour incubation, CSI significantly blunted cartilage stimulation by NRS regarding total isotope uptake (1), 35S-sulfate (NRS, 96 +/- 8 mcg/100 mg cartilage dry weight; NRS + CSI, 48 +/- 4, mean +/- SEM, n = 29, P less than .05); and (2) 14C-leucine (NRS, 2,089 +/- 172 cpm/mg dry weight; NRS + CSI, 1,102 +/- 141, n = 18, P less than .05); and (3) 3H-uridine (NRS, 6,711 +/- 832 cpm/mg; NRS + CSI, 3,227 +/- 425 cpm/mg, n = 18, P less than .05); but not (4) 3H-thymidine (NRS, 3,540 +/- 620 cpm/mg; NRS + CSI 3,249 +/- 285, n = 19). The inhibition of 35S-sulfate and 14C-leucine uptake by CSI was dose-dependent and reversible. For 35S-sulfate, uptake by cartilage incubated with CSI alone for 40 hours was 13 +/- 3 micrograms/100 mg; with CSI for 16 hours then fresh medium with NRS for 24 hours uptake was 39 +/- 12, P less than .05.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献