Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00345 (ICI)
 5,388 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sensitised bovine granulocytes release histamine when exposed to antigen. Several anti-allergic agents, some previously shown to be active in cattle, were tested to investigate their modulation of this histamine release process. Diethylcarbamazine citrate potentiated release at low concentrations and inhibited at high concentrations. Sodium meclofenamate and PR-D-92-EA were potent inhibitors. Acetylsalicylic acid and ICI 74,917 inhibited at high concentrations. Disodium cromoglycate was relatively ineffective, although it potentiated histamine release at low concentrations.
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PMID:Modulation of antigen-induced histamine release from bovine granulocytes by several anti-allergic agents. 6 6

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.
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PMID:Quantification of the in vitro activity of some compounds with spermicidal activity. 128 67

Increases in the delivery of solute to the loop of Henle result in increased reabsorption, vasoconstriction of the afferent arteriole, and a reduction in the glomerular filtration. Although the details of this tubuloglomerular feedback (TGF) mechanism are not completely worked out, it appears certain that alterations in reabsorption by the loop of Henle are critical to its operation. In the following study, we assessed the effect of several different loop of Henle diuretics on the response of the TGF mechanism. The function of TGF was monitored by measuring the stop-flow pressure (SFP) in the early proximal tubule in response to alterations in perfusion rate through the loop of Henle. All drugs were given directly into the loop of Henle in a concentration of 10(-4) M. With control solutions, SFP fell in a sigmoidal fashion over a perfusion range of 5 to 45 nl/min. When furosemide was added to the perfusate at a dose of 10(-4) M, SFP did not change. Bumetanide had an effect similar to furosemide, but muzolimine failed to inhibit the reduction in SFP over the perfusion range. Three experimental compounds were tested. All three cause diuresis when administered orally to animals. MK447 had no effect on SFP, but its metabolite, MK447-SO4, had an effect similar to furosemide. Another compound with modest diuretic effects, ICI 207,828, actually increased the response in SFP. Two distal diuretics, hydrochlorothiazide and amiloride, had no effect on SFP. The response of SFP to all these compounds correlated with its measured effect on loop reabsorption of sodium. Furosemide, bumetanide and MK447-SO4 significantly reduced sodium reabsorption.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of loop of Henle diuretics on the tubuloglomerular feedback mechanism. 128 76

Human beta-endorphin 1-31 (beta-END) stimulated low-Km GTPase activity in a concentration-dependent and saturable manner in membranes prepared from the delta opioid receptor-containing hybrid cell line NG108-15 and from the mu opioid receptor-enriched human neuroblastoma cell line SK-N-SH. Naloxone and the delta-selective antagonist, ICI 174,864, blocked the stimulation of the GTPase activity produced by beta-END in NG108-15 cell membranes, whereas only naloxone inhibited the beta-END-induced stimulation in SK-N-SH cell membranes, suggesting that beta-END was acting through both mu and delta opioid receptors. Treatment of the cells with Bordetella pertussis toxin before the preparation of membranes blocked the stimulation of low-Km GTPase by beta-END in both cell lines. Activation of NG108-15 and SK-N-SH low-Km GTPase by beta-END was sodium-dependent, and lithium and potassium were poor promoters of this activation. These results demonstrate that beta-END stimulates the interaction of both mu and delta opioid receptors with B. pertussis toxin-sensitive G-proteins in SK-N-SH and NG108-15 cell membranes, respectively.
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PMID:Effects of beta-endorphin on mu and delta opioid receptor-coupled G-protein activity: low-Km GTPase studies. 132 14

Buspirone, benzodiazepines, barbiturates and ethanol all reliably reduce the frequency of reticular-elicited hippocampal rhythmical slow activity. In the present experiments we tested a number of drugs which are not usually used for treating generalized anxiety disorders but which have been reported to have some anxiolytic properties. Clonidine (0.3 mg/kg, i.p.), baclofen (6 mg/kg, i.p.) and 8-hydroxy-di-n-propylamino tetralin (8-OH-DPAT) (2.5 mg/kg, i.p.) all reduced the frequency of rhythmical slow activity. The effect of all three drugs was reduced by the 5-hydroxytryptamine 1a antagonist pindolol (2 mg/kg, i.p.). Pindolol had no effect on the reduction in rhythmical slow activity produced by sodium amylobarbitone, as has been previously reported for the benzodiazepine chlordiazepoxide. Flumazenil (10 mg/kg, i.p.), a benzodiazepine receptor antagonist, reduced the effects of chlordiazepoxide (5 mg/kg, i.p.), but not buspirone (10 mg/kg, i.p.). A combination of the selective beta 1 adrenergic receptor antagonist metoprolol (20 mg/kg, i.p.) and the beta 2 adrenergic receptor antagonist ICI 118,551 (4 mg/kg, i.p.) did not reduce the effects of either buspirone (10 mg/kg, i.p.) or diazepam (1 mg/kg, i.p.). These data show that there are at least two separate routes through which anxiolytic agents reduce the frequency of hippocampal rhythmical slow activity. Buspirone, clonidine, baclofen and 8-OH-DPAT act via a system dependent on 5-hydroxytryptamine 1a receptor activation. Benzodiazepines act via activation of the benzodiazepine receptor and probably share with barbiturates action at the GABA-benzodiazepine-chloride ionophore complex but do not produce their effects, directly or indirectly, by 5-hydroxytryptamine 1a receptor activation.
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PMID:Pindolol antagonizes the effects on hippocampal rhythmical slow activity of clonidine, baclofen and 8-OH-DPAT, but not chlordiazepoxide and sodium amylobarbitone. 135 Jun 66

The pharmacological properties of BRL 37,344 (sodium-4-(2'-[2-hydroxy-2- (3-chloro-phenyl)ethylamino]-propyl)phenoxyacetatesesquihydrate), a beta 3-selective agonist, and CGP 12,177A) (-)-4-(3-t-butyl amino-2-hydroxypropoxy) benzimidazole-2-one], a non-selective beta-antagonist, recently characterized as a partial beta 3-agonist in rat adipose tissue, were studied in comparison with isoproterenol, a non-selective beta-agonist, in plasma membranes prepared from the livers of newborn rats. Competition binding curves obtained with [125I]iodocyanopindolol ([125I]CYP) as ligand and isoproterenol or BRL 37,344 as competitor were characterized by the presence of a high and a low affinity binding site; the high affinity binding site was no longer detectable when guanidylimidobisphosphate (GppNHp) was present in the incubation mixture. Competition curves with CGP 12,177A were monophasic and independent of GppNHp. In the presence of 10(-7) M of the beta 2-selective antagonist ICI 118,551 [erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylamino butan-2-ol], a concentration which blocks most of the beta 2-receptors, ligand binding was reduced to 32% of its maximum. Under these conditions, isoproterenol further displaced the ligand, and competition curves still displayed the high and the low affinity binding sites; BRL 37,344, however, caused no further displacement of ligand, except at the highest concentrations. This suggests that BRL 37,344 occupies only the ICI 118,551-sensitive binding sites, i.e. beta 2-receptors. Isoproterenol and BRL 37,344 both stimulated adenylate cyclase (EC 4.6.1.1) activity concentration dependently, although the stimulating effect of BRL 37,344 was about half of what was found for isoproterenol. Furthermore, BRL 37,344 inhibited concentration dependently the isoproterenol-induced stimulation of adenylate cyclase, and the inhibition was dependent on the concentration of isoproterenol. The stimulating effect of isoproterenol and BRL 37,344 on adenylate cyclase was blocked by ICI 118,551, whereas the beta 1-selective antagonist CGP 20,712A ((+/-)-(2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino)-3-[4-(1-methy l-4- trifluoromethyl-2-imidazolyl)-phenoxy]-2-propanolmethane sulphonate) was ineffective. CGP 12,177A failed to stimulate adenylate cyclase activity. From these results we suggest that BRL 37,344 acts as a beta 2-partial agonist in rat liver. The results obtained with CGP 12,177A are typical for a non-selective beta-antagonist. We therefore conclude that there is no pharmacological evidence for the presence of beta 3-receptors in livers from newborn rats.
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PMID:Pharmacological characterization of a beta 3-receptor agonist (BRL 37,344) and a partial agonist (CGP 12,177A) in neonatal rat liver plasma membranes. 136 33

We investigated alterations in myocardial beta- and beta 1-adrenergic receptor (BAR and B1AR) number during hyperdynamic state induced by endotoxin or cytokines. [METHODS] Twenty-nine Japanese White rabbits were divided into 2 groups. Hearts were removed 18 h after intraperitoneal administration of sterile saline (SAL) or E. coli endotoxin (LPS; 50 micrograms/kg) (Group E, n = 12), or 3 h after intravenous injection of SAL or cytokines (interleukin 1-beta; 5 micrograms/kg followed by 25 ng/kg/min for 2 h, or tumor necrosis factor; 5 micrograms/kg) (Group C, n = 17). BAR and B1AR numbers were determined in myocardial membranes from rabbit left ventricles with techniques of radioactive ligand binding study. We used [3H] dihydroalprenolol (3H-DHA) as radioactive ligand, and specific 3H-DHA binding to BARs was defined as the difference between the presence and the absence of 10 microM propranolol. B1AR number was assessed through the specific binding of 3H-DHA in the presence of ICI 118, 551 (5 x 10(-8) M), a highly selective beta 2-adrenergic receptor antagonist. In Group E, mean arterial blood pressure (MAP), heart rate (HR), and cardiac output (CO) (by thermodilution) were measured under pentobarbital sodium anesthesia before excision of hearts. [RESULTS] In Group E, CO was significantly (p less than 0.05) increased in rabbits injected with LPS (E-LPS) as compared with that in rabbits injected with SAL (E-SAL) (E-LPS; 0.75 +/- 0.02 l.min-1, E-SAL; 0.61 +/- 0.05 l.min-1, mean +/- SEM). MAP and HR were slightly decreased in E-LPS but not significantly. Maximum binding (Bmax) of 3H-DHA to BARs was significantly (p less than 0.05) decreased by 18% in myocardial membranes from E-LPS compared to E-SAL (E-LPS; 48.2 +/- 4.3 fmol/mg protein, E-SAL; 58.9 +/- 2.9 fmol/mg protein, mean +/- SEM). Similarly, Bmax of 3H-DHA to B1ARs was decreased by 18% in E-LPS, although no statistical significance was detected. In Group C, both BAR and B1 AR number was slightly, but not significantly decreased 3 h after administration of cytokines. [CONCLUSION] These data suggest that down regulation of cardiac BARs may occur during hyperdynamic stage of endotoxic shock.
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PMID:[Alterations in number of rabbit myocardial beta-adrenergic receptors in endotoxic shock: down regulation in hyperdynamic sepsis model and effects of cytokines administration]. 166 39

Dopexamine hydrochloride (DPX) is a dopamine analog and it possesses agonistic action at DA-1 receptors and beta 2-adrenoceptors. It also is a weak agonist at DA-2 receptors. In the present study, we have examined the anatomical localization of DPX binding sites in rat kidney and their functional significance in terms of the renal effects of this compound. In receptor-ligand binding studies, [3H]-DPX was found to bind specifically to sections of rat kidney in a time (maximum binding at 60 min), temperature (optimal temperature 25 degrees C) and concentration (highest specific/non-specific ratio at 2 nmol/l) dependent manner. Autoradiographic studies revealed the presence of [3H]-DPX binding sites in renal tubules, glomerulus and various layers of small and large blood vessels. Inhibition studies with SCH 23390, ICI 118.551 and 1-sulpiride showed that DPX binds primarily to DA-1 receptors in tubules, only to beta 2-adrenoceptors in glomerulus and to beta 2-adrenoceptors, DA-1 and DA-2 receptors in blood vessels. Also, DPX caused concentration related increases in cyclic AMP levels in rat kidney membrane particles, which could be completely abolished by a combined presence of SCH 23390 and propranolol suggesting that both binding sites of DPX are linked to adenylate cyclase. In functional studies DPX (1 microgram/kg.min for 30 min) produced a modest fall in blood pressure, pronounced tachycardia and slight but significant increase in renal blood flow (11%). These responses were accompanied by increases in urine output (97%), urinary sodium excretion (89%), and fractional excretion of sodium (132%). There was no change in glomerular filtration rate. Propranolol pretreatment abolished DPX-induced hypotension and tachycardia but seemed to potentiate the natriuretic responses to DPX. On the other hand, SCH 23390, a DA-1 receptor antagonist completely abolished DPX-induced hypotension, natriuresis and diuresis without affecting tachycardia. These results indicate that (1) DPX binds predominantly to DA-1 receptors in renal tubules, to beta 2-adrenoceptors in glomerulus and to beta 2-adrenoceptors, as well as DA-1 and DA-2 receptors in renal blood vessels (2) DPX stimulates cAMP formation in the kidney by activating both DA-1 and beta 2-adrenoceptors and (3) DPX produces natriuresis and diuresis by selectively activating DA-1 receptors located on renal tubules.
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PMID:Biochemical, autoradiographic and pharmacological evidence for the involvement of tubular DA-1 receptors in the natriuretic response to dopexamine hydrochloride. 167 60

ICI 207,828, an aminomethylphenol pyrazine derivative, produces water diuretic effects with only minimal alterations in kaliuresis in dogs and rats after oral and parenteral administration. In the dog, ICI 207,828 reached maximum activity at a dose of 10 mg/kg, p.o. This was comparable to that of hydrochlorothiazide (HCTZ) at a dose of 5 mg/kg, p.o. or higher. In the rat, a dose of 30 mg/kg, p.o. of ICI 207,828 was comparable to the maximum of water diuretic and saluretic response obtained with HCTZ at a dose of 10 mg/kg, p.o. Based upon studies using in vitro amphibian models of the mammalian nephron, ICI 207,828 appeared to act on both the thick ascending limb of the loop of Henle and the late distal nephron. In the toad bladder preparation, ICI 207,828 inhibited Na+ transport when placed on either the mucosal (amiloride-like) or serosal (thiazide-like or loop diuretic-like) sides. This compound also inhibited Cl- transport in the toad cornea preparation (loop diuretic-like). ICI 207,828 did not change plasma K+ significantly in dogs dosed for 14 days at doses having diuretic effects (5 and 10 mg/kg, p.o., daily). In contrast, HCTZ consistently decreased plasma K+, whereas amiloride increased it significantly. ICI 207,828 demonstrated antihypertensive effects in spontaneously hypertensive rats. At 30 mg/kg, p.o., b.i.d., ICI 207,828 and HCTZ produced approximately equal antihypertensive activities during a 3 1/2-day treatment period. The pharmacological profile of ICI 207,828 indicates that this compound is a potent eukalemic diuretic and antihypertensive agent in animals.
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PMID:Renal and antihypertensive effects of a novel eukalemic diuretic, ICI 207,828. 173 94

ICI 207,828 is a novel eukalemic diuretic in animals that is comparable in effect to hydrochlorothiazide. We used micropuncture and microperfusion techniques to determine the site(s) of action of this compound in the rat nephron. Either furosemide (FUR) or ICI 207,828 were perfused through the loop of Henle in situ. Both compounds caused significant reduction in water and electrolyte reabsorption by the loop. The effect of ICI 207,828 was significantly less than that of FUR. Both amiloride and ICI 207,828 were perfused, in situ, through the superficial distal tubule. ICI 207,828 had an effect similar to amiloride. Sodium and water reabsorption and potassium secretion were inhibited. In free-flow micropuncture studies, ICI 207,828, infused continuously i.v., had little effect on electrolyte and water reabsorption by the superficial proximal tubule. This compound significantly inhibited water and electrolyte reabsorption by the loop of Henle. Distal tubule secretion of potassium was inhibited. In addition, fractional potassium reabsorption beyond the superficial, late distal tubule was inhibited by ICI 207,828. From these results, we conclude that ICI 207,828 significantly inhibits electrolyte and water transport by the loop of Henle and distal tubule, and at sites beyond the superficial distal tubule such as either the collecting duct system or juxtamedullary nephrons. The reduction in distal potassium secretion, in concert with reduced loop of Henle and postdistal reabsorption, results in no net potassium loss in the urine, thus rendering this compound eukalemic.
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PMID:Evaluation of the renal site of action of a novel, eukalemic diuretic, ICI 207,828. 173 95


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