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At least 19 recordsLinked to original sources
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↗
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↗
PubMed1992

Cytochrome P-450 mediates bioactivation of organic nitrates.

The cellular mechanism of bioactivation underlying guanylate cyclase activation by organic nitrates was investigated. In cultured rat lung fibroblasts (RFL-6 cells), the inhibitor of cytochrome P-450 proadifen (0.1 mM) decreased cyclic GMP stimulation by glyceryl trinitrate (GTN, 1-100 microM) by up to 81%. Cyclic GMP stimulation by isoidide dinitrate was inhibited to a similar degree under these conditions. However, proadifen did not affect cyclic GMP stimulation by sodium nitroprusside that spontaneously releases nitric oxide. Cyclic GMP stimulation in RFL-6 cells by GTN remained unaltered in the presence of the inhibitor of glutathione S-transferase sulfobromophthalein. In the same cell type, a 24-hr pretreatment with the inducer of cytochrome P-450 3-methylcholanthrene (10 microM) augmented cyclic GMP stimulation by GTN or isoidide dinitrate by up to 102%. Cultured porcine aortic endothelial cells were found to be without a cyclic GMP response to GTN, although sodium nitroprusside produced a marked cyclic GMP elevation in these cells. The endothelial cells remained unresponsive to GTN even in the presence of N-acetylcysteine (5 mM). Moreover, in a cell-free preparation from rat liver, glutathione-dependent biotransformation of GTN was not accompanied by activation of soluble guanylate cyclase. These findings suggest that in intact cells bioactivation of, i.e., nitric oxide formation from organic nitrates is mediated by a cytochrome P-450 enzyme system rather than by glutathione S-transferase or free thiols.

Animals↗
PubMed1976

Pharmacological assessment of 3-tert-butylsydnone.

The pharmacological effects of the mesoionic derivative, 3-tert-butylsydnone, were investigated. Administration to rats caused clonic convulsions. The CD50 of 3-tert-butylsydnone was 0.471 +/- 0.033 mmole/kg. Trimethadione, but not phenytoin sodium or proadifen hydrochloride, protected the rat from the effects of 3-tert-butylsydnone. After administration of this compound, pentobarbital sodium sleeping time was reduced in the rat, but blood pressure and ECG were unchanged in the dog. Pretreatment of the mouse with 3-tert-butylsydnone did not influence the LD50 of epinephrine hydrochloride. The action of methacholine chloride in the rat was not blocked, and the pupil of the rabbit eye was unaffected. Tests for analgesic and oxytocic activity were negative. Chronic administration of a small dose to the rat for 70 days had no effect on blood glucose, blood urea nitrogen, hemoglobin, or microhematocrit values.

Anesthesia↗
PubMed1976

Anticonvulsant activity of enzyme inhibitors in rats.

Three liver microsomal enzyme inhibitors, proadifen, 2,4-dichloro-6-phenylphenoxyethyldiethylamine, and 2,4-dichloro-6-phenylphenoxyethylamine, and a hepatotoxic agent, carbon tetrachloride, were tested for anticonvulsant activity in adult male albino rats using the maximal electroshock seizure technique. All four substances exhibited significant anticonvulsant activity 1 hr after intraperitoneal administration. This protection was absent when tested 24 hr later.

Animals↗
PubMed1992

Properties of an endogenous arachidonic acid--elicited relaxing mechanism in human placental vessels.

OBJECTIVE: Our objective was to examine the action of arachidonic acid on tone in isolated human placental arteries and veins (1 to 2 mm diameter) for mechanisms involving endothelium-derived mediators, the stimulation of guanylate cyclase, and prostaglandin and cytochrome P450 metabolites. STUDY DESIGN: Pharmacologic probes and endothelium-removal were used to examine the mechanism of relaxation to arachidonic acid (10 nmol/L to 10 mumol/L) observed in placental arteries and veins obtained after delivery from uncomplicated term pregnancies and precontracted with prostaglandin F2 alpha. RESULTS: Neither removal of the endothelium nor inhibition of prostaglandin biosynthesis with 10 mumol/L indomethacin, arginine-derived nitric oxide formation with 30 mumol/L nitro-L-arginine, or guanylate cyclase stimulation with 10 mumol/L LY83583 altered the observed relaxation to arachidonic acid in either preparation. However, this relaxation was markedly attenuated by 30 mumol/L proadifen (SKF-525A), an inhibitor of cytochrome P450, suggestive of a role for arachidonic acid metabolism by an epoxygenase or monooxygenase pathway. CONCLUSION: Human placental arteries and veins possess an endogenous mechanism of relaxation to arachidonic acid, which seems to be mediated by metabolites formed by a cytochrome P450 enzyme. This endogenous relaxation mechanism could function as a suppressor of vasospasm in the placental circulation.

Arachidonic Acid↗
PubMed1992

Role of lipoxygenase and cytochrome P-450 in production of endothelium-derived relaxing factors in canine femoral veins.

We wished to determine whether the metabolism of arachidonic acid, through lipoxygenase and cytochrome P-450 pathways, is involved in production of endothelium-derived relaxing factor(s) (EDRFs) in canine femoral veins. Veins were removed from anesthetized dogs and cut into rings. Endothelium was deliberately removed from some rings. In separate sets of experiments, rings were incubated with either AA861 (10(-5) M) or TMK777 (10(-6) M), inhibitors of 5-lipoxygenase, nordihydroguaiaretic acid (NDGA 3 x 10(-6) M), an inhibitor of lipoxygenase or proadifen (SKF 525A, 10(-6) M), an inhibitor of cytochrome P-450. In addition, some rings were incubated with a combination of indomethacin (10(-5) M) and NG-monomethyl-L-arginine (L-NMMA 10(-4) M) or, where appropriate, a solvent control. Concentration-response curves were obtained for acetylcholine, adenosine diphosphate, thrombin, A23187, and nitric oxide in rings contracted with a submaximal concentration of prostaglandin F2 alpha. AA861 and TMK777 did not alter endothelium-dependent relaxations to the agonists, whether with or without indomethacin and L-NMMA. However, indomethacin plus L-NMMA reduced endothelium-dependent relaxations to thrombin. These results suggest that metabolism of arachidonic acid, through lipoxygenase and cytochrome P-450 pathways, does not produce an EDRF in veins. However, thrombin receptor-activated relaxations are mediated in part by products of the cyclooxygenase pathway and nitric oxide.

Animals↗
PubMed1977

Studies on the cardiovascular effects of pindolol in DOCA/saline hypertensive rats.

1 A hypotensive response to orally administered pindolol in conscious normotensive and deoxycorticosterone acetate (DOCA)/saline hypertensive rats (DS-rats) is described. In DS-rats, pindolol (10-50 mug/kg) produced a dose-dependent fall in blood pressure and elevation of resting heart rate.2 The hypotensive response and tachycardia produced by oral pindolol (50 mug/kg) in DS-rats were prevented by propranolol (5 mg/kg), suggesting that pindolol's effects are mediated by beta-adrenoceptor stimulation.3 After mecamylamine (10 mg/kg), oral pindolol (50 mug/kg) produced a further fall in blood pressure in DS-rats, suggesting that its hypotensive effects are probably mediated in the peripheral vasculature.4 Pretreatment with oral pindolol (10 or 50 mug/kg) resulted in a reduction of neuronally-induced tachycardia in pithed DS-rats; neuronally-evoked pressor effects were also antagonized by pindolol (50 mug/kg, orally).5 Whereas pindolol, 50 mug/kg orally or intraperitoneally, produced a marked and progressive hypotensive response of rapid onset (20 min) in DS-rats the same dose intravenously produced a smaller response of delayed onset (80 minutes).6 In anaesthetized DS-rats, an equivalent degree of cardiac beta-adrenoceptor blockade was produced by pretreatment with pindolol, 50 mug/kg orally (2 h previously) or intravenously (1 h previously).7 After administration of pindolol, 2 mg/kg intravenously, to conscious DS-rats, the tachycardia produced by intravenous isoprenaline, 3 mug/kg, was almost abolished for the first 60 min of the study, whereas a hypotensive response to pindolol was delayed in onset (100 minutes).8 The hypotensive response and tachycardia produced by oral pindolol 50 mug/kg, in DS-rats were prevented by inhibition of metabolic enzyme activity by pretreatment with Proadifen (SKF 525-A), 80 mg/kg.9 The results suggest that pindolol's effects on blood pressure and heart rate in the conscious DS-rat are mediated by a metabolite(s) acting by stimulation of peripheral beta-adrenoceptors.

Administration, Oral↗
PubMed1978

The effects of agents that bind to cytochrome P-450 on hypoxic pulmonary vasoconstriction.

The relationship between pulmonary arterial pressure (Ppa) and blood (Q) was determined during normoxia and hypoxia in ventilated pig lungs perfused in situ with the animal's own blood. Hypoxia shifted the Ppa-Q relationship to the right and decreased its slope, indicating pulmonary vasoconstriction. Carbon monoxide (11.5% in the inspired gas) and metyrapone ditartrate (10 mg/min into the perfusate) caused vasodilation when oxygenation was normal and reduced the vasoconstriction caused by hypoxia. Since the only pharmacological property CO and metyrapone are thought to have in common at the concentrations employed is the ability to bind to the heme iron of cytochrome P-450, these results are consistent with the hypothesis that desaturation of this cytochrome leads to pulmonary vasoconstriction. Prostaglandin F2alpha, infused into the pulmonary artery at 0.01 mg/min, when oxygenation was normal, had effects on the Ppa-Q relationship similar to those of hypoxia. The F2alpha response was also reduced by CO and metyrapone, suggesting either that P-450 was involved in the F2alpha response or that CO and metyrapone were toxic to pulmonary vascular smooth muscle. Proadifen hydrochloride (1 mg/min), which is thought to bind to the protein moiety of P-450 also reduced the hypoxic response, but was a vasoconstrictor during normoxia and did not affect the F2alpha response.

Animals↗
PubMedDate not supplied

Circadian variations of phenacetin metabolism in rats in vivo and in vitro.

The metabolism of phenacetin in vivo and in vitro at different periods of day was investigated in rats. In rats maintained on standard LD conditions the disappearance rate of phenacetin from blood and activity of phenacetin O-deethylase in liver were the highest in the morning and the lowest in the evening. Continuous illumination, adrenalectomy, phenobarbital or proadifen abolished this difference. It is postulated that these circadian changes of microsomal metabolism of phenacetin in rats liver are not fully responsible for the rhythmical changes in the antipyretic action of this drug that was observed previously. The mechanisms of this phenomenon are discussed.

Adrenalectomy↗
PubMed1992

Differential effects of cytochrome P-450 induction on ligand binding to sigma receptors.

The identity of the sigma receptor as a form of cytochrome P-450 was investigated in rats treated with 3-methylcholanthrene or phenobarbital. The density of [3H]N,N'-di(o-tolyl)guanidine (DTG) binding to sigma 2 receptors in hepatic subcellular fractions increased following both treatments, while [3H](+)-pentazocine binding to sigma 1 receptors was unchanged. Furthermore, proadifen and piperonyl butoxide inhibited [3H](+)-pentazocine and [3H]DTG binding with low potency. The low affinity of cytochrome P-450 inhibitors for sigma receptors, the similar degree of enhancement of [3H]DTG binding by agents with disparate cytochrome P-450 induction profiles and the lack of change in [3H](+)-pentazocine binding are inconsistent with the identity of the sigma receptor as a cytochrome P-450.

Animals↗
PubMed1979

Equilibrium binding of [3H]tubocurarine and [3H]acetylcholine by Torpedo postsynaptic membranes: stoichiometry and ligand interactions.

Studies are presented of the equilibrium binding of [3H]-d-tubocurarine (dTC) and [3H]acetylcholine (AcCh) to Torpedo postsynaptic membranes. The saturable binding of [3H]dTC is characterized by two affinities: Kd1 = 33 +/- 6 nM and Kd2 = 7.7 +/- 4.6 microM, with equal numbers of binding sites. Both components are completely inhibited by pretreatment with excess alpha-bungarotoxin or 100 microM nonradioactive dTC and competitively inhibited by carbamylcholine with a KI = 100 nM, but not affected by the local anesthetics dimethisoquin, proadifen, and meproadifen. The biphasic nature of [3H]dTC binding was unaltered in solutions of low ionic strength and by preparation of Torpedo membranes in the presence of N-ethylmaleimide, a treatment which yields dimeric AcCJ receptors. dTC competitively inhibits the binding of [3H]AcCH and decreases the fluorescence of 1-(5-dimethylaminonaphthalene-1-sulfonamido)ethane-2-trimethylammonium (Dns-Chol) in a manner quantitatively consistent with its directly measured binding properties. It decreases the initial rate of 3H-labeled Naja nigricollis alpha-toxin binding by 50% at 60 nM with an apparent Hill coefficient of 0.58. The stoichiometry of total dTC, AcCh, and alpha-neurotoxin binding sites in Torpedo membranes was determined by radiochemical techniques and by a novel fluorescence assay utilizing Dns-Chol as an indicator, yielding ratios of 0.9 +/- 0.1:0.9 +/- 0.2:1, respectively. The biphasic equilibrium binding function is not unique to dTC since other ligands inhibited [3h]acCh binding in a biphasic manner with apparent inhibition constants as follows: gallamine triethiodide (K11 = 2 microM, K12 = 1 mM); Me2dTC (K11 = 500 nM, K12 = 10 microM); decamethonium (K11 = 100 nM, K12 = 1.6 microM). Carbamylcholine, however, inhibited [3H]AcCh binding with a single KI = 100 nM. The observed competition between those ligands and [3H] AcCh cannot be completely accounted for by competitive interaction with two different affinities, and the deviations are discussed in terms of the positive cooperativity of the [3H] AcCh binding function itself. It is concluded that dTC binds only to the AcCh sites in Torpedo membranes and that those sites display two affinities for dTC but only one for AcCh.

Acetylcholine↗
PubMed1992

Platelet activating factor inhibits Cl and K transport in the medullary thick ascending limb.

Since the kidney medulla was reported to generate platelet activating factor (PAF), we investigated a possible effect of this agent on the reabsorptive function of in vitro microperfused medullary thick ascending limbs from mouse kidney (mTAL). PAF, 10(-7) M in the bath, significantly decreased the net chloride flux (JCl) from 48.8 +/- 7.1 to 27.4 +/- 5.7 pmol/min. This effect was reversible, blocked by the antagonist BN 50730, and not reproduced by the inactive metabolite lyso-PAF. PAF inhibited the transepithelial potential difference with a threshold at 10(-9) M. In the presence of isoproterenol, the PAF-induced decrease of JCl was not significantly different from that observed in basal conditions; moreover, PAF did not modify the adenylate cyclase activity in isolated mTALs, either in basal condition or under stimulation by isoproterenol. The effect of PAF on JCl was not prevented by mepacrine, NDGA associated with proadifen, or adenosine desaminase. When the apical Na-K-2Cl cotransport was blocked by furosemide or bumetanide, a net K secretion occurred (-1.1 +/- 0.2 pmol/min), which was significantly decreased by PAF (-0.06 +/- 0.3 pmol/min). Moreover, it was verified on isolated mTALs that PAF did not modify the Na,K-ATPase activity. It is concluded that PAF inhibits the reabsorptive function of the mTAL, as indicated by the decrease of Cl reabsorption and K secretion. This effect could not be accounted for by adenosine or arachidonic acid metabolite action, and was not mediated by an inhibition of the adenylate cyclase activity.

Absorption↗
PubMed1992

Modulation of (+)-[3H]pentazocine binding to guinea pig cerebellum by divalent cations.

The ability of cations to modulate the binding of the sigma 1 receptor-selective ligand (+)-[3H]pentazocine to guinea pig cerebellum was investigated. Di- and trivalent cations biphasically inhibited (+)-[3H]pentazocine binding, revealing multiple affinity states. The rank order of potency of these cations (based on the high affinity component of inhibition) was Zn2+ > Co2+ >> La3+ = Ni2+ = Cd2+ = Mn2+ = Gd2+ > Ba2+ = Sr2+ >> Mg2+ > Ca2+. The inhibition of 1,3-[3H]di(2-tolyl)guanidine binding to the sigma 2 receptor by these cations differed qualitatively and quantitatively from their effects on (+)-[3H]pentazocine binding. Although monovalent cations decreased the Kd for (+)-[3H]pentazocine binding, divalent cations split (+)-[3H]pentazocine binding into low and high affinity components. The Bmax of the high affinity component decreased with increasing divalent cation concentrations. Both mono- and divalent cations significantly reduced the rate of association of (+)-[3H]pentazocine with the sigma 1 receptor without altering the dissociation rate. (+)-[3H]Pentazocine binding was not altered by guanine nucleotides or by treatment with cholera or pertussis toxins. However, nonselective cation channel blockers (cinnarizine, hydroxyzine, prenylamine, amiodarone, and proadifen) potently inhibited (+)-[3H]pentazocine binding. These results indicate that physiologically relevant concentrations of divalent cations allosterically modulate (+)-[3H]pentazocine binding to the sigma 1 receptor, to reveal multiple affinity states. These sites do not represent sigma 1 to sigma 2 subtype interconversion or ternary complex formation with guanine nucleotide-binding proteins. However, the rank order of cation potency and the inhibition of binding by cation channel blockers is consistent with a potential role for sigma receptors as constituents of cation channels.

Animals↗
PubMedDate not supplied

Propoxyphene bioavailability: an evaluation of ten products.

Ten commercial products containing 65 mg propoxyphene hydrochloride have been evaluated for their relative bioavailability in human subjects in a complete crossover study. No statistically significant (P greater than 0.05) differences were observed between the products in terms of plasma levels 1, 2, 3, 4, 6, 8, and 12 hours after administration; peak plasma levels; time to achieve peak plasma level; and area under the plasma level-time curve. Individual subjects exhibited considerable differences in the propoxyphene plasma levels, which were similar to the variability observed by others. The average estimated half-life of 3.61 hours was consistent with previously reported values, although it may have underestimated the true value because the low plasma levels remaining after 12 hours were not quantitated.

Adult↗