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Biomedical subjects

R B Philp

Publications and source records attributed to R B Philp.

At least 37 records · Page 2Linked to original sources
PubMed1987

Failure of platelets to enhance aggregation of temperature-stabilized neutrophils: effects of warming and of drugs.

Polymorphonuclear leukocytes (PMNs) were isolated on a Ficoll-Hypaque gradient, suspended in modified Hank's buffer, and aggregated alone or in the presence of washed platelets (4 or 8/PMN). Platelets had no effect on formyl-methionyl-leucyl-phenylalanine (FMLP)-induced aggregation of PMNs that had been allowed to equilibrate at 37 degrees C for 5 min after storage at room temperature. Pretreatment of platelets with an inhibitor of cyclooxygenase (ASA) or lipoxygenase (nordihydroguaiaretic acid, NDGA) produced no significant effect whereas pretreatment with an inhibitor of both enzymes (eicosatetraynoic acid) or of phospholipase (methylprednisolone sodium succinate) caused a modest but statistically-significant inhibition of PMN aggregation which appeared to be a direct effect on PMNs rather than through platelets. The warming of PMNs from 0 degrees C or 22 degrees C to 37 degrees C produced a spontaneous, reversible aggregation within 2 or 3 min, the extent of which was dependent on the degree of temperature change. This aggregation was enhanced by the presence of platelets in a 'dose' (count) dependent fashion. This enhancement was not decreased by any of the aforementioned drugs, in fact, the aggregation was augmented by all drugs, the difference being statistically significant for NDGA. Thus different mechanisms appear to be involved in spontaneous vs FMLP-induced aggregation. The role of platelets in PMN aggregation remains to be elucidated but the importance of controlling for the effects of temperature changes in such studies is self-evident.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1986

Salicylate antagonism of acetylsalicylic acid inhibition of platelet aggregation in male and female subjects: influence of citrate concentration.

Platelets from volunteers were exposed for 1 min to sodium salicylate (SA) before and after the addition of acetylsalicylic acid (ASA) to produce greater than or equal to 50% inhibition of aggregation induced by arachidonic acid (AA) or collagen. SA:ASA concentrations = 20:1. SA protection against ASA inhibition was always observed even if ASA exposure time was 15 min, whereas reversal could not be demonstrated once exposure of platelets to ASA exceeded a minimum of 3-10 min with AA as the stimulus. Reversal was even less effective when collagen was the stimulus. An apparent, increased sensitivity to SA reversal of ASA inhibition in females disappeared when citrate concentration was adjusted to compensate for lower packed cell volume. The proposed male dependency for protection in ASA treatment of thromboembolic disorders cannot be explained on the basis of differences in the SA-ASA competition at platelet cyclooxygenase and, if collagen is an important in vivo stimulus of platelet interaction with damaged vessel wall, the antagonism of ASA by SA may not be important.

Adult↗
PubMed1986

Effects of nitrogen and helium at pressure on drug-induced stereotypy and locomotion in mice.

Stereotyped behavior was induced in mice by apomorphine (5-50 mg X kg-1 s.c.) and d-amphetamine (3-5 mg X kg-1 i.p.), and increased locomotor activity was induced by d-amphetamine (8 and 10 mg X kg-1 i.p.) and by morphine sulfate (15 and 30 mg X kg-1 i.p.). Experiments were conducted at 1, 4, and 7 ATA. All mice were myringotomized under ether anesthesia 3 d before behavioral studies to minimize disturbances due to pressure differences across the tympanic membrane during compression. Compressed air significantly increased locomotor activity induced by d-amphetamine and morphine sulfate whereas He/O2 had no effect, suggesting that the change was due to the narcotic effect of N2. Drug-induced stereotyped behavior was affected variably (usually depressed) by compressed air and not by He/O2. Since both stereotypy and locomotor activity induced by these drugs involve dopamine receptor systems, the results suggest that compressed air does not influence all such membrane receptors in like manner. Evidence for receptor plasticity is discussed.

Air Pressure↗
PubMed1985

Cyclic nucleotide phosphodiesterase inhibition by a benzoic acid derivative.

Acetylsalicylic acid (ASA) and three structurally related benzoic acid derivatives, 2-acetylbenzoic acid (ABA), 3-methylphthalide (3-MP), and 3-hydroperoxy-3-methylphthalide (3-HMP), were tested for inhibitory effects on three human blood platelet cyclic nucleotide phosphodiesterase (PDE) activities. 3-MP caused a dose-dependent inhibition of the high and low affinity cyclic AMP PDE activities and the cyclic GMP PDE activity. 3-HMP had some inhibitory effects but only on the low affinity cyclic AMP PDE activity. ASA and ABA had no effects. This study shows that progressive structural changes in the ASA molecule can shift the pharmacological profile from a cyclooxygenase inhibitor (ASA) to an inactive compound (ABA) to a PDE inhibitor (3-MP) and back again to a cyclooxygenase inhibitor (3-HMP). It is proposed that the potent anti-inflammatory effects of 3-MP, which differ from those of ASA, are mediated through the inhibition of the cyclic nucleotide PDE system.

1-Methyl-3-isobutylxanthine↗
PubMed1985

The effects of some benzoic acid derivatives on polymorphonuclear leukocyte accumulation in vivo.

Previous studies, aimed at establishing a relationship between the inhibition of prostaglandin (PG) biosynthesis and the suppression of carrageenin-induced rat paw edema, indicated that, in a series of acetylsalicylic acid (ASA)-like compounds, there is not a good correlation between ability to inhibit platelet PG biosynthesis and anti-inflammatory activity. Some of the compounds tested had good anti-edema properties compared to ASA, but did not inhibit platelet lysate conversion of 14C-arachidonic acid (AA) to PGs. The effects of these compounds on polymorphonuclear (PMN) leukocyte accumulation in urethane-anesthetized rats were examined to extend the pharmacological profile of these agents in a search for other mechanisms of anti-inflammatory activity. 3-Methylphthalide (3-MP), an inhibitor of rat paw edema, suppressed PMN leukocyte accumulation although it is a poor inhibitor of PG cyclo-oxygenase activity. 3-Propionyloxybenzoic acid (3-PBA), an agent which increases primary platelet aggregation and arterial PGI2 production, caused increases in edema formation but decreases in PMN leukocyte accumulation. 2-Propionyloxybenzoic acid (2-PBA), which is similar to ASA in many effects, resulted in a trend towards decreased PMN leukocyte accumulation, while ASA did not. 2-Acetylbenzoic acid (ABA), an agent with anti-edema properties similar to ASA in the rat paw model but without any effect on PG biosynthesis, also caused a trend towards inhibition of PMN leukocyte accumulation. In addition to drug effects on prostaglandin biosythesis, this study indicates that drug effects on PMN leukocyte accumulation is an important determinant of anti-inflammatory potential.

Animals↗
PubMed1984

Rapid and sensitive determination of acetylsalicylic acid and its metabolites using reversed-phase high-performance liquid chromatography.

A rapid and sensitive high-performance liquid chromatographic technique was developed for the simultaneous determination of gentisic acid, salicyluric acid, acetylsalicylic acid and salicylic acid in plasma and serum. The method involved a single deproteinization step and separation using a reversed-phase column eluted with a buffered methanol (35%) mobile phase. Detection was achieved with a variable-wavelength ultraviolet detector set at 235 nm and a given chromatographic analysis could be completed in less than 10 min. The method was tested in both human and animal (rat) models given a single dose of acetylsalicylic acid.

Animals↗
PubMed1984

Antiinflammatory properties of a hydroperoxide compound, structurally related to acetylsalicylic acid.

3-Hydroperoxy-3-methylphthalide (3-HMP), a structural analog of acetylsalicylic acid (ASA), was found to have some antiinflammatory properties which are distinct from those of ASA. 3-HMP inhibits human platelet aggregation and ATP release in response to low concentrations of collagen but is less effective than ASA. 3-HMP inhibits prostaglandin and thromboxane production from exogenous [14C]arachidonic acid by human platelet lysates in vitro and does so at lower concentrations than ASA (3-HMP IC50 = 10 microM; ASA IC50 = 50 microM). 3-HMP is also more effective than ASA as an inhibitor of prostacyclin-like activity production by rings of rabbit aorta. Human polymorphonuclear (PMN) leukocyte [14C]arachidonic acid metabolism is inhibited by 3-HMP but not ASA. In urethane-anesthetized rats, 3-HMP (10 mg/kg intravenously) is effective in inhibiting PMN leukocyte accumulation in response to intrapleural carrageenan administration whereas ASA is ineffective (100 mg/kg intravenously). This hydroperoxy analog of ASA has antiinflammatory activity which may result from a combination of the ASA-like and hydroperoxide-related pharmacological properties.

Animals↗
PubMed1984

Effects of aspirin dosage and time of administration on arterial prostacyclin production and platelet aggregation in rats.

Previously we reported that electrically-induced carotid artery thrombosis in anesthetized rats was prevented by 3.3 or 10 mg/kg aspirin (ASA) given i.v. 10 min before injury but not by 1.7, 20 or 100 mg/kg and protection was lost by delaying injury to 20 min (Haemostasis 13:42, 1983). Here, collagen-induced platelet aggregation and arterial prostacyclin-generating activity, measured by RIA for 6 keto-PGF1 alpha and by human platelet aggregation bioassay, were studied ex vivo after i.v. ASA to anesthetized rats. In all cases where platelet aggregation was inhibited less than 50%, no protection had been observed (1.7 mg/kg at 10 min, 3.3 at 20 min, 20 at 10 min). In the two cases where protection had been observed, platelet aggregation was inhibited by about 75% or more and in one, prostacyclin activity was about 50% of normal (3.3 mg/kg at 10 min). Thus in five of six dose-time combinations tested, antithrombotic protection could be explained by a requirement for about 50% of normal prostacyclin activity and about 75% of inhibition of collagen aggregation. Aberrant findings are discussed in the light of knowledge of salicylate/aspirin competition for cyclooxygenase.

Animals↗
PubMed1984

The effects of an ASA-like hydroperoxide compound on adenosine diphosphate induced platelet aggregation.

A hydroperoxide compound structurally related to acetylsalicylic acid, 3-hydroperoxy-3-methylphthalide, inhibits both the first and second phases of adenosine diphosphate induced, biphasic, human platelet aggregation. This occurs over the same concentration range (0.05-0.5 mM) that acetylsalicylic acid inhibits second phase aggregation and the release reaction only. The complete inhibition of adenosine diphosphate induced aggregation is a unique pharmacological property for an acetylsalicylic-acid-like compound.

Adenosine Diphosphate↗
PubMed1984

The effects of high doses of aspirin and related benzoic acid derivatives on arterial thrombosis in male rats.

The antithrombotic effects of four compounds structurally related to aspirin (acetylsalicylic acid, ASA) were examined in a rat model of arterial thrombosis and compared to ASA. ASA had antithrombotic activity, but only at high doses (200 mg/kg), when carotid artery thrombosis was induced 15 min after intravenous drug administration. Lower doses were associated with augmented thrombus formation in some animals. 2-Propionyloxybenzoic acid, which has in vitro activities similar to ASA, caused similar in vivo effects, but was antithrombotic at 100 mg/kg. 3-Propionyloxybenzoic acid, which augments platelet function in vitro, and 3-methylphthalide, which inhibits biphasic adenosine diphosphate-induced platelet aggregation, had no statistically significant effects. 2-Acetoxybenzoic acid, which is a weak platelet aggregation and prostaglandin biosynthesis inhibitor, had antithrombotic activity at 100 and 200 mg/kg and was not associated with augmented thrombosis at lower doses as found with ASA. The pattern of antithrombotic activity of this series of compounds does not reflect in vitro effects on prostaglandin biosynthesis and indicates alternative mechanisms of antithrombotic activity.

Animals↗
PubMed1983

Low-dose aspirin (ASA) renders human platelets more vulnerable to inhibition of aggregation by prostacyclin (PGI2).

Pre-treatment of human, platelet-rich plasma with concentrations of aspirin that produced 50% or less inhibition of aggregation induced by collagen, arachidonic acid or adenosine diphosphate, significantly increased the % inhibition of platelet aggregation by a low concentration of authentic prostacyclin or by prostacyclin-like activity generated by incubation of rat aorta rings in human platelet-poor plasma. Similarly a single aspirin tablet (325 mg) taken orally by human volunteers significantly increased the sensitivity of their platelets to inhibition of aggregation by authentic prostacyclin (8.1 X 10(-10) M) for 2-48 h after ingestion. Statistical significance was lost at 72 h but the trend was still evident. These results support the contention that low doses of aspirin may be efficacious in the therapy of arterial thromboembolism since this could preserve some arterial prostacyclin-generating activity which might be sufficient to inhibit adhesion and aggregation of the aspirin-treated platelets.

Adult↗
PubMed1983

The influence of dose, time of administration, body temperature and salicylate kinetics on the antithrombotic action of acetylsalicylic acid in male rats.

Acetylsalicylic acid (ASA), given i.v. to male rats 10 min before electrical injury to the carotid artery, was found to reduce rate and extent of thrombosis at 3.3 and 10.0 mg/kg but not at 1.7, 20 or 100 mg/kg, indicating a narrow, low-dose window for antithrombotic effect. ASA was more effective in rats in which body temperature was allowed to fall greater than 0.5 degrees C but protection was lost if injury was delayed 15 min or more after ASA administration. Serum salicylate studies did not support the view that loss of protection was due to competition between salicylate and ASA for cyclooxygenase-binding sites. ASA was also protective at 200 mg/kg i.v., possibly through non-specific toxic effects.

Animals↗
PubMed1982

Structure-activity studies of aspirin and related compounds on platelet aggregation, arachidonic acid metabolism in platelets and artery, and arterial prostacyclin activity.

A series of benzoic acid derivatives was tested for specificity of action on human platelet function and platelet prostaglandin (PG) synthesis versus prostacyclin (PGI2) production by rat and rabbit aorta rings. None of the agents tested was more specific for one system than the other. ASA was more potent than 2-propionyloxybenzoic acid (2-PBA) in inhibiting platelet function and platelet PG synthesis although the potencies of these agents were comparable in inhibiting PGI2 synthesis. 3-Propionyloxybenzoic acid (3-PBA) caused increased activity in both systems while 2-acetylbenzoic acid (ABA) had only minor effects. A cyclical derivative, 3-methylphthalide (3-MP), inhibited both platelet function and PGI2 synthesis although it did not inhibit cyclo-oxygenase activity, suggesting a novel mechanism of action. Thus only minor changes in the ASA molecule could be effected without significant changes in pharmacological activity. The investigation of novel agents such as 3-MP may lead to a better understanding of arachidonate metabolism in different tissues and possibly to the development of more tissue-specific drugs.

Adenosine Diphosphate↗
PubMed1981

Relationship of inhibition of prostaglandin synthesis in platelets to anti-aggregatory and anti-inflammatory activity of some benzoic acid derivatives.

The relationships between inhibition of platelet prostaglandin (PG) synthesis and aggregation, and suppression inflammation were investigated with a number of benzoic acid (aspirin-like) chemicals. The compounds studied were 2-acetylbenzoic acid (ABA), 3-methylphthalide (3-MP), 3-propionyloxybenzoic acid (3-PBA) and 2-propionyloxybenzoic acid (2-PBA). At 0.5--0.6 mM, 3-MP inhibited the second phase of ADP-induced aggregation in human platelets, and reduced collagen-induced aggregation by 50%. Previous studies have shown 2-PBA to inhibit aggregation at similar concentrations. In contrast, ABA required 10 times higher concentrations, and low concentrations actually potentiated aggregation. Inhibition of PG synthesis from 14C-arachidonic acid (AA) by human platelets was shown for 2-PBA, but not to 3-BPA, or ABA. At high concentration (1 mM), 3-MP showed modest inhibitory activity. Significant inhibition of AA aggregation was produced by ASA (83%), 2-PBA (76%) and 3-MP (69%), an order reflecting their inhibition of PG synthesis, where ABA and 3-PBA did not inhibit AA aggregation. Carrageenin-induced edema of the rat paw was suppressed by 3-MP, ABA and 2-PBA; all being roughly equipotent with aspirin. In contrast, 3-PBA did not suppress edema. Following oral administration of the drugs to rats, PG synthesis from labeled AA by rat platelets showed similar profiles to effects of the drugs on PG synthesis in human platelets. This suggests that biotransformation or species differences are not explanations for the observed differences in activity in the various test systems. The results indicate that, in a related series of chemicals there is not a good correlation between ability to inhibit platelet PG synthesis, anti-aggregatory activity and anti-inflammatory activity. Multiple mechanisms of action, differing sensitivities of various tissue PG synthetases, or unidentified factors could be involved.

Animals↗
PubMed1981

Non-interference by salicylate with aspirin inhibition of arterial thrombosis in rats.

Several authors have reported that salicylate blocks and reverses aspirin inhibition of prostaglandin synthesis by platelets and arterial wall. Male rats were given sodium salicylate 15 or 100 mg/kg i.v. 2 min before receiving aspirin, 10 mg/kg i.v. Right and left carotid arteries were injured electrically before and after drug administration and thrombus generation recorded by measuring downstream temperature. Significant antithrombotic effect of aspirin was observed in all cases regardless of prior salicylate administration and the results were similar to those obtained with aspirin alone. Thus competition between salicylate and aspirin as reported in vitro does not appear to significantly affect the in vivo antithrombotic action of aspirin in this model.

Animals↗