Gene/Protein Disease Symptom Drug Enzyme Compound
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The subcellular distribution of free and esterified cholesterol in mouse testis and the changes occurring in cholesterol content of whole testes and cell fractions after inhibition of gonadotropins with methallibure (ICI 33, 828) and restimulation with human chorionic gonadotropin (HCG) are reported in the present paper. In subcellular fractions, the bulk of free cholesterol is associated with organelles sedimented in the microsomal fraction while esterified cholesterol is mainly stored in isolated lipid droplets. The latter compartment increases in methallibure-treated mice 2.3 fold and is remarkably depleted after administration of HCG. There is a close parallelism between the changes in esterified cholesterol content and the variation in the numbers of lipid droplets found in electron micrographs of interstitial cells of mice receiving similar treatments. By contrast no significant changes were noticed in either free cholesterol concentrations of the microsomal fractions or in the fine structure of organelles associated with this fraction. The dynamic nature of steroidogenesis in the microsomal fraction requires the existence of a free cholesterol pool with a high turnover rate for use as an intermediate in androgen synthesis. On the other hand, the large content of free cholesterol in microsomes and its stability under different conditions suggest the presence of a cholesterol compartment with a slow turnover, as a constituent of the membranes.
Cell Tissue Res 1975 Dec 29
PMID:Subcellular compartmentation of free and esterified cholesterol in the interstitial cells of the mouse testis. 17 66

We have previously shown that specific binding sites for lactogenic hormones are present at much greater levels in the liver membranes of female than of male rats. In the present studies [125I]iodo-hGH was used to study binding sites specific for lactogenic hormones in liver membranes. In male rats, a single injection of 2 mg estradiol valerate induced these binding sites. The induction was maximal by 9-12 days and was dose-dependent. Ovariectomy significantly reduced the specific binding of [125I]iodo-hGH from 9.7 +/- 0.7% in shamoperated to 6.9 +/- 0.3% in experimental rats (P less than 0.01) without a change in affinity. Fluctuations in specific binding of [125I]iodo-hGH were observed at different stages of the estrous cycle. Binding at estrus and diestrus I was significantly greater than at diestrus II and proestrus (P less than 0.05). The disappearance of binding sites following hypophysectomy was rapid, declining from 13.2 +/- 1.2% in intact rats to 6.0 +/- 0.8% and 2.2 +/- 0.4% 14 and 48 h, respectively, after surgery. In contrast, binding of insulin was slightly increased after hypophysectomy. Anti-estrogens (clomiphene, ICI 46,474, and nafoxidine) prevented the induction of binding sites in male rats given estradiol (E2). A single injection of 200 mug cycloheximide 11 days after an injection of 2 mg E2-valerate reduced binding by more than 90% in 3 h with a return to control levels by 48 h. The maximal decline in insulin binding was 54% during this entire period. These studies suggest that endogenous estrogen plays a role in regulating hepatic binding sites for lactogenic hormones. The level of these binding sites is critically dependent on the presence of an intact pituitary. The possible rapid turnover of these sites suggests that regulatory influences at the tissue level may have an important role in modulating hormone action.
Endocrinology 1975 Dec
PMID:Effects of hypophysectomy, ovariectomy, and cycloheximide on specific binding sites for lactogenic hormones in rat liver. 17 23

On four prostaglandin endoperoxide-sensitive preparations, namely human platelets in vitro, rabbit aortic strip, guinea-pig tracheal chain and pig blood pressure, ICI 79939 and its 11-oxo analogue mimicked the actions of 11,9-(epoxymethano) prostaglandin H2, and were considerably more active than either prostaglandin F2alpha or ICI 81008. It is suggested that this activity of ICI 79939 may contribute to its toxicity in experimental animals.
Br J Pharmacol 1977 Dec
PMID:Actions of 16-aryloxy analogues of prostaglandin F2alpha on preparations responsive to prostaglandin endoperoxides. 59 71

Viloxazine hydrochloride (ICI 58,834, VIVALAN) a chemically novel antidepressant, shows selective inhibition of noradrenaline uptake into mouse heart in vivo and into rat brain in vitro. The noradrenaline uptake inhibitory activity resides primarily in one of the two optically active isomers, and it is suggested that in the conformation adopted for uptake by noradrenaline, the aryl and the amino groups are trans. In a comparison of in vivo and in vitro potency, tri- and tetracyclic antidepressants exhibit a good correlation. However, viloxazine possesses higher in vivo activity than would be expected from in vitro studies. The latter finding cannot be readily explained on the basis of known pharmacokinetic or metabolic factors.
Eur J Pharmacol 1978 Dec 01
PMID:Effects of viloxazine, its optical isomers and its major metabolites on biogenic amine uptake mechanisms in vitro and in vivo. 72 46

1. Atenolol (ICI 66.082, Tenormin) is a new beta-adrenoreceptor-blocking agent, devoid of intrinsic sympathomimetic and membrane-stabilizing properties. It does not cross the blood-brain barrier. 2. Atenolol given to hypertensive patients in initial open trials reduced arterial blood pressure significantly. 3. A double-blind comparison between atenolol and placebo in forty-five patients with essential hypertension demonstrated that atenolol gave a statistically significant reduction of blood pressure (delta 28/15 mmHg, P less than 0-005). 4. The optimum anti-hypertensive dose of atenolol in patients with mild to moderately severe essential hypertension was 200 mg daily. 5. Atenolol was compared with propranolol in thirty patients with essential hypertension. No statistically significant differences of anti-hypertensive effect were observed between the two drugs. 6. Long-term results (up to 2 years) in 117 hypertensive patients indicate that drug tolerance is good. No serious toxic effects were observed. 7. In four of twelve hypertensive patients with obstructive airways disease atenolol had to be withdrawn owing to deterioration of ventilatory function.
Clin Sci Mol Med Suppl 1976 Dec
PMID:Clinical evaluation of atenolol in hypertension. 79 59

To investigate the role of neutrophil proteases in the pathogenesis of mucus hypersecretion in bronchiectasis, we collected sputum samples from seven patients with bronchiectasis and measured their secretagogue activity by examining secretion of radiolabeled macromolecules by bovine airway submucosal gland cells incubated with sputum supernatants. There was marked secretagogue activity in bronchiectasis sputum, reaching a maximum of 1,963 +/- 292% (mean +/- SEM) above baseline at 1:15 dilution. Addition of ICI 200,355 (10(-5) M), a selective human neutrophil elastase inhibitor, decreased the secretory response markedly (72.53 +/- 5.89% reduction). The combination of aprotinin, an inhibitor of cathepsin G, and ICI 200,355 caused significantly more reduction in the secretory response than ICI 200,355 alone (89.12 +/- 3.8 versus 72.53 +/- 5.89% reduction, p < 0.05). We conclude that bronchiectasis sputum causes a large secretory response from tracheal submucosal glands due mostly to neutrophil proteases.
Am Rev Respir Dis 1992 Dec
PMID:Mucus hypersecretion in bronchiectasis. The role of neutrophil proteases. 128 Sep 28

The release of substance P (SP) from spinal dorsal horn slices is partially inhibited by micromolar concentrations of selective delta-opioid receptor agonists. In the present study, we have examined the effect of nanomolar concentrations of [D-Pen2,D-Pen5]enkephalin (DPDPE, delta-opioid receptor agonist) and low micromolar of concentrations morphine on K(+)-evoked SP release from rat trigeminal nucleus caudalis (TNC) slices. DPDPE and morphine inhibited SP release with an apparent maximal effect at 3 nM and at 3 microM, respectively. DPDPE and morphine produced U-shaped concentration-response curves that were completely autoinhibited at 100 nM DPDPE and 1 microM morphine. The inhibition of SP release produced by 3 nM DPDPE and 3 microM morphine was blocked by the opioid receptor antagonists naloxone (30 nM; non-selective) and ICI 174,864 (0.3 microM; delta-selective) but not by nor-binaltorphimine (3 nM n-BNI; kappa-selective), naloxonazine (1 nM; micro 1-selective) or beta-funaltrexamine (20 nM beta-FNA; mu-selective). These findings indicate that delta-opioid receptor-mediated inhibition of SP release from TNC can be achieved by nanomolar concentrations of selective delta-opioid receptor agonists. Activation of delta-opioid receptors by morphine might be involved in the residual analgesia observed after mu 1-opioid receptor blockade and in the analgesia produced by high doses of morphine.
Eur J Pharmacol 1992 Dec 08
PMID:Delta-opioid-receptor activation by [D-Pen2,D-Pen5]enkephalin and morphine inhibits substance P release from trigeminal nucleus slices. 128 3

Results with a new quantitative, reproducible, comparative method for assessing sperm immobilizing activity of spermicides are provided. The Hamilton Thorn Motility Analyzer is a computer-assisted system using image capture analysis and phase contrast optics. The compounds studied were nonoxynol-9 (nonylphenoxypolyethoxyethanol, Triton N101, Sigma, UK), benzalkonium chloride (Sigma, UK), dioctylsodium sulphosuccinate (sodium docusate, Cyanamid, UK), Menfegol (p-menthanylphenyl polyoxyethylene, Eisai Pharma-Chem Europe Ltd) and chlorhexidine gluconate (ICI, UK). Test materials were dissolved in Tyrode's solution containing glucose, except for chlorhexidine which was diluted in 290 mM sucrose. All tests were read at 1 minute. Results, expressed in ED50s were: nonoxynol, 0.134 mg/ml; sodium docusate, 0.308; Menfegol, 0.104; benzalkonium chloride, 0.135; and chlorhexidine, 1.032. When the percent motility was plotted against exposure time, the biguanide antiseptic chlorhexidine immobilized sperm much faster than did the detergent spermicides. This method is considered superior than previous standards, the Sander-Cramer test and the IPPF Approved test, because it allows comparison of relative spermicidal activity between different agents. Since local concentrations of intravaginal spermicides tend to be much higher than the ED50s found here, it is likely that other factors such as local distribution and dispersion of the spermicide are of more practical importance.
Contraception 1992 Dec
PMID:Quantification of the in vitro activity of some compounds with spermicidal activity. 128 67

The antiestrogen tamoxifen has been successfully used to control estrogen receptor (ER) and progesterone receptor positive breast cancer. However, the development of antiestrogen resistance is frequently observed in patients following long term treatment. We have studied the development of antiestrogen resistance in vitro and established an antiestrogen resistant variant of MCF-7 cells (clone 5C) after long term culture in estrogen free medium. The growth of clone 5C cells was not altered by either estradiol-17 beta or the antiestrogens 4-hydroxytamoxifen and ICI 164,384. Estrogen-stimulated progesterone receptor and reporter gene expression were markedly reduced in 5C cells compared to wild type MCF-7 cells. Only minor alteration in the levels of ER and no alteration in the affinity of ER for ligand were found in 5C cells. No mutation of ER cDNA in 5C cells was detected by polymerase chain reaction and DNA sequencing. This study demonstrates that change(s) in ER-mediated gene expression rather than the amino acid sequence of the ER itself may be associated with the development of at least one form of antiestrogen resistance.
Mol Cell Endocrinol 1992 Dec
PMID:An estrogen receptor positive MCF-7 clone that is resistant to antiestrogens and estradiol. 130

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. Zileuton was approximately 40 times less potent.7. Oral anti-inflammatory activity was assessed in an arachidonic acid-induced mouse ear oedema model in animals treated with indomethacin to block pro-inflammatory prostanoids. ICI D2138, given orally, caused dose-dependent inhibition of oedema with an approximate ID50 of 1.8 mg kg'. Zileuton was approximately 10 times less potent.8. ICI D2138 caused a dose-dependent inhibition of antigen-induced broncho-constriction in guineapigs with an approximate ID50 of 0.1 mg kg-', i.v. Zileuton was approximately 10 times less potent.9. In view of the pharmacological profile described here, ICI D2138 has the potential to provide improved clinical efficacy compared to existing lipoxygenase inhibitors such as zileuton.
Br J Pharmacol 1992 Dec
PMID:Pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase. 133 48


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