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At least 19 recordsLinked to original sources
PubMed1989

Proadifen-induced production of prostacyclin by equine peritoneal macrophages.

A study was performed to determine the effect of proadifen hydrochloride on prostacyclin (prostaglandin I2 [PGI2]) and thromboxane A2 (TxA2) synthesis by equine peritoneal macrophages and the effect of proadifen on endotoxin-induced synthesis of PGI2 and TxA2 by equine macrophages. Peritoneal macrophages (2.5 x 10(6)/ml) were incubated for 6 hours in tissue culture media containing 1) nothing (nontreated control), 2) proadifen hydrochloride (20, 100, 250, and 500 mumol/L, 3) endotoxin (5 ng/ml), or 4) the calcium ionophore A23187 (0.95 mumol/L). In a second series of experiments, peritoneal macrophages were incubated with endotoxin (5 ng/ml) and proadifen (250 umol/L), for 6 hours. Concentrations of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2, the stable metabolites of PGI2 and TxA2, were determined in the incubation media by radioimmunoassay. Proadifen caused increased synthesis of PGI2 by equine macrophages, without affecting TxA2 production. The increased PGI2 production was similar to that induced by endotoxin and calcium ionophore; however, the latter 2 agents significantly stimulated TxA2 production as well (P less than 0.05). There were no significant differences among mean concentrations of 6-keto-PGF1 alpha in media from macrophages treated with 100, 250, or 500 mumol/L proadifen, but there was a significant curvilinear regression between their concentrations. The ratio of thromboxane B2 to 6-keto-PGF1 alpha was significantly lower than baseline in incubation media from macrophages exposed to proadifen, endotoxin, and calcium ionophore. Proadifen hydrochloride did not significantly change equine peritoneal macrophage production of PGI2 or TxA2 in response to endotoxin.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Effect of inflammation and proadifen on the disposition of antipyrine, lignocaine and propranolol in rat isolated perfused liver.

The effect of inflammation, induced in rats by injection of turpentine oil, on drug disposition has been evaluated in rat isolated perfused livers. The drugs studied were a low extraction drug, antipyrine, and two high extraction drugs, lignocaine and propranolol. Turpentine significantly increased the half-life of antipyrine and of propranolol, but not that of lignocaine. Proadifen (SKF 525A) significantly increased the half-life of all three drugs. Turpentine decreased the clearance of antipyrine significantly by about 50% and that of propranolol non-significantly by about 20%, but did not affect the clearance of lignocaine. Proadifen significantly decreased the clearance of all three drugs, but this was most pronounced for antipyrine. In both turpentine- and proadifen-treated rats a significant increase in volume of distribution of propranolol was observed. The results show that, as with proadifen, turpentine-induced inflammation affects the hepatic clearance of antipyrine in the rat isolated perfused liver. With both high extraction drugs, the effect of inflammation on their clearance was low or absent, in contrast to the effect of proadifen. This suggests that a possible effect of inflammation on intrinsic clearance is not large enough to influence the hepatic clearance of the high extraction drugs.

Animals↗
PubMed1979

Effect of enzyme-inducing and enzyme-inhibiting agents on drug absorption. II. Influence in proadifen on 3-O-methylglucose transport in rats.

Studies utilizing the in vitro everted rat jejunum were performed to investigate the effects of proadifen pretreatment and fasting on active and passive intestinal transfer of 3-O-methylglucose. Animals were pretreated 24 hr prior to the experiments with 100 mg of proadifen/kg ip. With mucosal concentrations of 0.1 mM 3-O-methylglucose and 14C-3-O-methylglucose, transfer to the sugar-free serosal buffer after pretreatment with proadifen was 50% greater than controls after a 24-hr fast and 120% greater than controls after a 48-hr fast. Everted intestinal segments obtained from unfasted control animals showed diminished ability to transfer the sugar derivative, with transfer rates approximately 50% less than those of segments obtained from 24-hr fasted control animals. Wet and dry tissue weights for 24- and 48 hr-fasted groups increased following proadifen pretreatment. The results suggest that proadifen enhances 3-O-methylglucose transport across the rat jejunum and also increases intestinal tissue weight.

Animals↗
PubMed1986

The effect of proadifen on the metabolism of adinazolam.

Binding affinities of adinazolam and its metabolite mono-N-demethyladinazolam, U-42352, to the brain tissue are not altered by the presence of proadifen (SKF-525A) in [3H]flunitrazepam [( 3H]FNZ) binding assays in-vitro. Pretreatment of mice with proadifen significantly blocked the ability of intravenously administered adinazolam to inhibit [3H]FNZ binding in the studies ex-vivo. The binding profile of [3H]FNZ to the brain tissue was not significantly different when animals were treated with U-42352 or proadifen with U-42352. These results suggest that proadifen may block the conversion of adinazolam to its active metabolite U-42352.

Animals↗
PubMed1986

Investigation of the antimuscarinic and other actions of proadifen in-vitro.

The possibility that proadifen (SKF 525A) antagonizes endothelium-dependent relaxations to acetylcholine (ACh) in isolated blood vessel preparations via a muscarinic receptor blocking action has been investigated. In phenylephrine-contracted rat isolated aortic ring preparations (with endothelium), proadifen (10-100 microM) shifts ACh relaxant curves to the right without affecting the maximal response, yet endothelium-dependent relaxations to ATP are unaffected. At lower concentrations, proadifen (1-10 microM) antagonizes negative inotropic responses to ACh and ATP in guinea-pig left atria, antagonizes contractile responses to ACh and elevated [K+] in guinea-pig ileal preparations, displaces (-)-[3H]quinuclidinyl benzilate from muscarinic binding sites in membrane homogenates of guinea-pig ileal longitudinal muscle and reduces contractile responses to elevated [K+] in rat aortic ring preparations. It is concluded that proadifen may possess complex interactions with muscarinic receptors and Ca2+ entry blocking properties in concentrations 10-100 times lower than those reported to inhibit cytochrome P450-catalysed reactions.

Acetylcholine↗
PubMed1986

Endothelium-dependent vasodilatation in bovine coronary arteries: calcium dependence and inhibition by proadifen.

Vasodilator responses were examined in bovine coronary artery rings preconstricted with the thromboxane-mimetic, U46619. A23187 produced endothelium-dependent vasodilatation that was abolished in calcium-free solution. In contrast, endothelium-dependent vasodilatation produced by arachidonic acid was not altered in calcium-free solution. In calcium-free solution, indomethacin (10 mumol/l) did not affect arachidonate-induced relaxations whereas BW755C (100 mumol/l) reduced relaxations to low concentrations of arachidonate, and proadifen (SKF-525A, 1 mmol/l) abolished them at all concentrations. Endothelium-independent relaxations produced by glyceryl trinitrate were not affected by proadifen (1 mmol/l). It is clear that arachidonic acid bypasses a calcium-dependent step in the release of endothelium-derived relaxing factor, perhaps acting as an intermediate precursor. The data support the hypothesis that a cytochrome P-450 mono-oxygenase may also be involved.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

Proadifen-sensitive high affinity binding of 3H-alaproclate to liver membranes.

3H-Alaproclate, a selective 5-hydroxytryptamine uptake inhibitor, was found to bind to microsomal membranes from the rat liver with high affinity (KD = 3 nM) and large capacity (Bmax about 2 nmol/g liver). This binding was stereoselective since S-(-)-alaproclate was 30 times more potent than the R-(+)-enantiomer to displace the 3H-labelled racemate. Proadifen (SKF 525A), an inhibitor of cytochrome P-450, displaced the 3H-alaproclate binding with the same, high affinity (Ki = 3 nM) as alaproclate itself. Repeated treatment with phenobarbital sodium (5 x 75 mg/kg intraperitoneally) increased the number of alaproclate binding sites 7-8 times without changing the affinity. However, most of the phenobarbital induced 3H-alaproclate binding was not displaceable by proadifen, showing the presence of at least two different high affinity binding sites. The possible involvement of cytochrome P-450 in the alaproclate binding is discussed.

Alanine↗
PubMed1987

Stimulation of vascular prostacyclin by SKF 525-A (proadifen) and related compounds.

SKF 525-A (proadifen), a well-known inhibitor of drug metabolism and cytochrome P-450 activity, stimulated the release of prostacyclin (PGI2) from the rabbit aorta in vitro. The threshold concentration producing a detectable effect was 20 microM; the time course of SKF 525-A action exhibited particular features--progressive onset, long duration and slow reversibility--distinct from those of other stimuli (ADP, ionophore A23187 f.i.). The PGI2-stimulating activity of SKF 525-A was characterized by specific structural requirements: activity was abolished by the deletion of the terminal propyl group and increased by its elongation into an isobutyl group; chlorination of the phenyl groups increased the potency. SKF 525-A increased the production of PGI2 by cultured endothelial cells from bovine aorta and human umbilical vein, but had no effect on cultured smooth muscle from the bovine aortic media. Stimulation of PGI2 release could be explained by an increased availability of free arachidonic acid, which was probably independent from cytochrome P-450 inhibition. In human platelets, SKF 525-A inhibited prostaglandin and thromboxane production induced by A23187, thrombin and ADP. Simultaneous stimulation of endothelial PGI2 and inhibition of platelet TxA2 represents an original pharmacological profile: SKF 525-A might thus constitute the prototype of a new class of antiplatelet drugs.

Animals↗
PubMed1989

Development of desensitization during repetitive end-plate activity and single end-plate currents in frog muscle.

1. The amplitudes of end-plate currents (EPCs) in short trains of fifteen to seventeen EPCs at 10 Hz were depressed in the presence of 10 microM-proadifen when acetylcholinesterase (AChE) was inhibited. 2. The proadifen-induced EPC depression was voltage-dependent and the effect was more pronounced at negative membrane potentials. 3. In the presence of proadifen, the mean amplitude of miniature end-plate currents (MEPCs) was reduced by 36% 5 s after the EPC train as compared with MEPCs before the train. 4. Without proadifen, but with inhibited AChE, an increase of temperature from 20 to 26 degrees C and elevation of external Ca2+ from 1.8 to 2.5 mM led to EPC amplitude depression in the train, which was also potential-dependent. 5. After AChE inhibition, proadifen (10 microM) progressively shortened MEPC decay without significant reduction of amplitude up to 40 min of exposition. MEPCs were not affected by proadifen when AChE was active. 6. It is concluded that these postsynaptic effects of proadifen can be explained neither by its action on the resting acetylcholine receptors (AChR) nor on open ion channels but are due to its desensitization-promoting action.

Animals↗
PubMed1990

Further studies on the high-affinity binding of 3H-alaproclate to membranes from rat liver and some other tissues.

The high affinity binding of 3H-alaproclate to membranes in liver homogenates from naive rats and those treated with phenobarbital sodium, 75 mg/kg intraperitoneally, alaproclate hydrochloride, 40 mg/kg intraperitoneally proadifen hydrochloride, 40 mg/kg intraperitoneally once daily for 7 days and killed 24 hr after the last injection was examined. The treatment increased the normal number of alaproclate binding sites (Bmax: 1.1 nmol/g tissue, KD: 0.6 nM) by factors of about 10, 4 and 6, respectively. About 80% of the binding was localized to the microsomal fraction in both normal and phenobarbital treated rats. Ninety % of the alaproclate displaceable binding in a microsomal preparation of the normal liver was inhibited by low (nM) concentrations of proadifen whereas only about 20% in the liver preparations from phenobarbital treated rats was inhibited by low concentrations of proadifen. Thus, the main part of the induced binding sites was insensitive to proadifen. The same was found for the alaproclate and proadifen-induced alaproclate binding sites. The stereoselectivity of alaproclate enantiomers for binding to the normal and the induced binding sites was different: the S-(-) form was 100 times more potent than the R-(+)- enantiomer in inhibiting binding of racemic alaproclate to the normal sites, whereas the latter form was 3 times more potent than the former in inhibiting the binding to the phenobarbital-induced proadifen insensitive binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1987

Stereoselective high-affinity binding of 3H-alaproclate to membranes from rat cerebral cortex.

The binding of 3H-alaproclate, a selective 5-hydroxytryptamine uptake inhibitor, to membranes prepared from the rat cerebral cortex was investigated by a filtration technique. It was found that 3H-alaproclate bound with high affinity to three or four different sites and to one low affinity site. The binding to two of these sites was displaceable by 1 microM proadifen (SKF 525A), an inhibitor of drug metabolism. From iterative nonlinear regression analysis the KD-values of these sites were calculated to about 1 and 28 nM and the Bmax values 1.5 and 19 pmol/g wet tissue, respectively. The high affinity binding that was not displaceable by proadifen but by 10 microM alaproclate had KD-values of 1 nM and 6 nM and Bmax-values of 0.4 and 2 pmol/g wet tissue. The low affinity binding that was not displaceable by proadifen had a KD-value of about 200 nM and a Bmax-value of about 90 pmol/g tissue. The possible relationship between the proadifen sensitive high affinity binding of 3H-alaproclate and the brain cytochrome P-450 is discussed.

Alanine↗
PubMed1978

Effect of enzyme-inducing and enzyme-inhibiting agents on drug absorption I: 3-O-methylglucose transport in rats.

The influence of preadministration of phenobarbital, benzo[alpha]pyrene, and proadifen hydrochloride on 3-O-methylglucose transfer across the everted rat small intestine was examined. The active and passive components of the sugar transport mechanism were evaluated using phlorizin, a potent inhibitor of active transport of sugars. Pretreatment of the animals with phenobarbital did not alter 3-O-methylglucose transfer characteristics. Pretreatment with intraperitoneally administered benzo[alpha]pyrene increased mucosal to serosal transfer of the sugar low (0.1 mM) sugar concentrations. Enhancement of the active transfer of 3-O-methylglucose by pretreatment with proadifen hydrochloride was noted at low sugar concentrations. The passive transfer of the sugar was reduced after pretreatment with proadifen hydrochloride.

Animals↗
PubMed1989

The reversible MAO inhibitor, brofaromine, inhibits serotonin uptake in vivo.

The inhibition of the binding of [3H]cyanoimipramine in the rat brain in vivo, with and without pretreatment with proadifen (SK & F 525 A) to prevent its metabolism, has recently been shown to reflect inhibition of 5-HT uptake. This method has been suggested to be more sensitive than other more indirect methods. We have used this method to study the reversible MAO-A inhibitor, brofaromine, which has been shown previously to inhibit 5-HT uptake into synaptosomal preparations in vitro and ex vivo at doses about 30 times higher than those that inhibited MAO-A, and a number of 5-HT uptake inhibitors. The effects of orally administered clomipramine, imipramine, citalopram, CGP 6085 A, fluoxetine and brofaromine on [3H]cyanoimipramine binding were similar to those obtained in the synaptosome ex vivo model in the absence of proadifen; ifoxetine seemed to be more potent in inhibiting [3H]cyanoimipramine binding. The effects of clomipramine, imipramine, citalopram and ifoxetine were moderately to markedly enhanced by proadifen, indicating a first-pass effect. The effect of brofaromine on [3H]cyanoimipramine binding showed a time course similar to that on MAO-A, and was not altered upon repeated treatment. The inactivity of another MAO-A inhibitor, moclobemide, suggest that the effect of brofaromine was due to true inhibition of 5-HT uptake and not to displacement of [3H]cyanoimipramine by elevated synaptic 5-HT. The possible role of inhibition of 5-HT uptake in the antidepressant effect of brofaromine is discussed.

Animals↗
PubMed1987

Defining the active site of cytochrome P-450: the crystal and molecular structure of an inhibitor, SKF-525A.

The crystal and molecular structure of the cytochrome P-450 inhibitor, SKF-525A [2-(diethylamino)ethyl 2,2-diphenylpentenoate; proadifen hydrochloride] is described. Proadifen hydrochloride crystallized from an ethyl acetate and acetic acid mixture in the space group P2(1)/c with one molecule in the asymmetric unit. Cell constants are a = 18.716(4), b = 8.906(1), c = 14.201(3), beta = 109.41(1) degrees. The structure was solved using direct methods and was refined to an R value of 0.047; weighted R of 0.061 using 3757 reflections. From the crystal and molecular structure, it is seen that SKF-525A has two principal modes of complementary interactions with the enzyme available: polar and non-polar. Polar interactions that principally involve the chloride anion, the quaternary nitrogen atom and the carbonyl oxygen atom. In particular, there are two strong hydrogen bonds, one between Cl ... H-N, 3.090(1) A, the other between O2 ... H-C111 (one of the ethyl hydrogen atoms) at 3.411(2) A. The other is through non-polar interactions involving the phenyl and alkyl groups. Comparisons between proadifen hydrochloride and other inhibitors whose atomic coordinates are available reveal common features which correlate with their function. These include groups to provide necessary intermolecular contacts and bulk, such as a phenyl group and a hydrogen bond acceptor, as well as a tetrahedral atom, which allows for substrate flexibility.

Crystallization↗
PubMed1990

Rat duodenal smooth muscle contractile responses to angiotensin II are dependent on calmodulin.

1. Isolated duodenal segments were pretreated with either of the calmodulin inhibitors proadifen or trifluoroperazine and the subsequent contractile force and frequency response to angiotensin II monitored. 2. Both proadifen and trifluoroperazine decreased the spontaneous contractile force and frequency in isolated perfused duodenal segments and attenuated the force generation following exposure to angiotensin II. Proadifen and trifluoroperazine also altered the qualitative behaviour of duodenal segments. 3. These results suggest that the action of angiotensin II on duodenal smooth muscle motility is dependent on calmodulin. Furthermore, the change in qualitative behaviour of duodenal segments following treatment with calmodulin inhibitors suggest that the function of intrinsic intestinal neurons is also altered.

Angiotensin II↗
PubMed1988

Mechanisms of action of lipoxygenase and cytochrome P-450-mono-oxygenase inhibitors in blocking endothelium-dependent vasodilatation.

1. Acetylcholine, ionophore A23187 and melittin induced endothelium-dependent relaxations of preconstricted strips of rabbit aorta. These relaxations are likely to be mediated by endothelium-derived relaxing factor (EDRF). 2. Relaxations in response to acetylcholine (1 microM) were inhibited by the following lipoxygenase inhibitors, with the approximate IC50 values indicated in parentheses: gossypol (1.5 microM), nordihydroguairetic acid (NDGA, 5 microM), AA 861 (20 microM), phenidone (30 microM), quercetin (40 microM), BW 755C (300 microM), and piriprost (500 microM); with cirsiliol 50% inhibition was not achieved. Acetylcholine-induced relaxations were also blocked by the cytochrome P-450-mono-oxygenase inhibitors proadifen (SKF 525A, 4 microM), metyrapone (300 microM), and cimetidine (300 microM); 7,8 benzoflavone had no effect up to 100 microM. 3. The more potent inhibitors were also tested against relaxations induced by A23187 (0.1 microM) and melittin (1 microM) and produced partial inhibition of these relaxations. 4. The mechanism of action of the more potent inhibitors was investigated in a bioassay system. EDRF was produced in columns filled with cultured human endothelial cells. The factor was bioassayed with endothelium denuded segments of rabbit femoral artery. When added to effluent of the column, NDGA, AA861, proadifen and metyrapone inhibited the EDRF-induced vasodilatation, whereas gossypol had no effect. Gossypol, however, blocked EDRF production when infused through the column. 5. The more potent inhibitors were also tested to determine their effect on purified soluble guanylate cyclase. While gossypol, NDGA and proadifen had no appreciable effects, basal and nitroprusside (50 microM)-stimulated guanylate cyclase activity was inhibited by AA861 and metyrapone. 6. These data suggest that many of the above compounds inhibit EDRF by mechanisms other than lipoxygenase- or cytochrome P-450-mono-oxygenase inhibition.

Acetylcholine↗
PubMed1991

1-(2-pyrimidinyl)-piperazine may alter the effects of the 5-HT1A agonist in the learned helplessness paradigm in rats.

The 5-HT1A agonists buspirone, gepirone and ipsapirone have been shown to possess antidepressive-like properties in several animal models of depression as well as in clinical studies. These compounds are metabolized to 1-(2-pyrimidinyl)-piperazine (1-PP) in rats and humans. In the learned helplessness paradigm, buspirone exhibits a biphasic action: at low or moderate doses it shows an antidepressant-like effect but this action progressively disappears as the doses are increased. In order to establish whether 1-PP affects the reversal of helpless behaviour induced by the 5-HT1A agonists at high doses in rats, we have investigated its role in the learned helplessness. Thus, 1-PP has been evaluated alone (0.06-4 mg/kg/day) or in combination with a selective 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg/day) which is not metabolized to 1-PP and buspirone (0.5 mg/kg/day). In addition, buspirone at a higher dose (2 mg/kg/day) has also been examined in the presence of proadifen which inhibits oxidative metabolism. Our results show that i) daily injections of 1-PP did not reverse helpless behaviour, ii) the reversal of helpless behaviour by 8-OH-DPAT or active dose of buspirone was antagonized by daily coadministration of 1-PP, iii) in rats pretreated with proadifen, the highest "inactive" dose of buspirone induces a reversal of helpless behaviour. These results strongly suggest that up to a certain concentration 1-PP can impair the effects of the parent drug in the learned helplessness.

8-Hydroxy-2-(di-n-propylamino)tetralin↗