Biomedical subjects
Publications and source records attributed to R O Day.
The formation of the methyl ester of salicyluric acid was observed during the quantitation of salicyluric acid and other salicylate metabolites in urine by high-pressure liquid chromatography. This methyl ester formation caused artificially low values for salicyluric acid and high values for salicylic acid.
Non-steroidal analgesic and anti-inflammatory drugs (NSAID) are potent inhibitors of prostaglandin synthesis in vivo at commonly achieved concentrations of these drugs. Prostaglandins of the E-series are released by exercising muscles, and their release is inhibited by indomethacin. The consequences, with respect to exercise performance, are unknown. Drugs used for hyperuricemia and gout such as colchicine, allopurinol, probenecid, and sulphinpyrazone have not been implicated in affecting exercise performance. The uricosuric drugs probenecid and sulphinpyrazone may be contraindicated in individuals who exercise heavily because of the increased danger of precipitating uric acid crystals in the kidney tubules. Muscle relaxants do not cause measurable muscle relaxation following usual oral dosage regimens. They are, however, sedatives and this property could influence exercise performance.
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Intersubject differences in the volume of distribution, whole body clearance, and steady-state plasma concentrations of salicylic acid (SA) were studied in a series of patients with rheumatoid arthritis and healthy control subjects. The measurement of the plasma concentration of SA 12 hr after an oral dose of 1.2 gm aspirin appears predictive of the success of long-term dosage of aspirin. Concentrations below 5 microgram/ml in this single-dose test were associated with failure to achieve therapeutic plasma concentrations of SA (above 150 microgram/ml during long-term therapy with approximately 4.8 gm aspirin per day. Conversely, plasma concentrations above 10 microgram/ml in the single-dose test were associated with levels above 150 microgram/ml during long-term therapy. The volume of distribution of SA correlated poorly with body weight (r = 0.51, p less than 0.01) and did not correlate significantly with plasma albumin levels. Corticosteroids appear to induce the metabolism of SA and most subjects dosed with oral corticosteroids and aspirin 4.8 gm/day did not attain plasma levels of SA above 150 microgram/ml. The clearance of SA was greater in male than in female patients. The difference appears to be of clinical significance since fewer men than women achieved therapeutic plasma concentrations of SA.
Histamine released from the mast cells in unfractionated rat peritoneal cell suspensions could be quickly and conveniently measured by an automated chemical method. There were no substances in the unfractionated peritoneal cells that interfered with the chemical histamine measurement. Organic extraction of histamine and deproteinization of samples were not necessary using the automated method. The amount of histamine released from preparations of peritoneal cells by a fixed concentration of compound 48/80 decreased with the time of preincubation of the cells but this varied between preparations. Phagocytic activity directed against the mast cells probably explained these observations. The state of nutrition of the rats and the presence or absence and/or glucose in the medium all influenced the rate of decline of viability of the mast cells.
The effect of enteric coating of aspirin tablets on the gastrointestinal blood loss associated with high dose aspirin therapy was investigated in 12 patients with rheumatoid arthritis. Occult blood loss was measured after labelling the patients' red blood cells with Cr51. Three salicylate preparations were used: enteric coated tablets of aspirin ("Rhusal", G.P. Laboratories, 7 x 650 mg per day), uncoated tablet cores of aspirin from the same batch (7 x 650 mg per day) and enteric coated tablets of sodium salicylate (7 x 600 mg and 1 x 300 mg per day). Daily blood loss during a salicylate-free period was (0.7 +/- 0.15 ml, mean +/- SE). Blood loss was significantly increased during dosage with all three salicylate preparations. Daily blood loss during dosage with the uncoated tablets of aspirin (5.3 +/- 0.3 ml) was significantly greater than during dosage with the enteric coated tablets of aspirin (2.3 +/- 0.3 ml) and enteric coated tablets of sodium salicylate (2.1 +/- 0.4 ml). The bioavailability of the salicylate preparations was studied in seven of the 12 patients. Mean plasma salicylate concentration two hours after the second daily dose during dosage with the enteric coated tablets of aspirin was 118 +/- 15 microgram/ml compared to 131 +/- 16 microgram/ml during dosage with the uncoated tablets. Urinary recoveries of the daily dosage of aspirin in the two formulations were also similar.
1 Non-steroidal anti-inflammatory drugs (NSAID) suppressed compound 48/80-induced histamine release from rat peritoneal cells in vitro in a dose-dependent manner. 2 NSAID suppressed the adenosine triphosphate (ATP) content of rat peritoneal cells in vitro and this correlated strongly with the suppression of compound 48/80-induced histamine release. 3 The correlation demonstrated suggests that the mechanism of action of NSAID in the rat peritoneal cells is via depletion of cellular ATP.
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The bioavailability and gastrointestinal site of release of enteric coated aspirin tablets ("Rhusal", G.P. Laboratories) were investigated following dosage with single tablets. A delay of one to more than eight hours was observed between dosage and the appearance of salicylate in plasma or saliva. This delay was decreased by pretreatment with metoclopramide. No aspirin or salicylate was detected in gastric aspirates. The mean urinary recovery of salicylate was equivalent to 92% of the administered dose. All these tests were consistent with the designed function of the enteric coating. The time course of concentrations of salicylate in saliva rather than in plasma was confirmed as a useful technique for the evaluation of different formulations of aspirin. The acceleration of gastric emptying by metoclopramide is a useful technique for the evaluation of enteric coated tablets.
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The sodium salt of guanylyl-3',5'-cytidine crystallizes in a monoclinic unit cell with one molecule in the asymmetric unit. Each molecule is related to another molecule by a 2-fold rotation axis which results in the formation of an antiparallel, right-handed double helix with complementary hydrogen bonding between the guanine and cytosine residues. The crystal is heavily hydrated with 36 water molecules in the unit cell. The geometry of this crystalline double helix is very similar to those which have been derived from studies of fiber x-ray diffraction patterns of double-stranded RNA, even though the latter do not yield data at atomic resolution.
Steady-state serum salicylic acid (SA) concentrations and the formation rates of salicyluric acid (SU), salicylphenolic glucuronide (SPG), salicylacyl glucuronide (SAG), and gentistic acid (GA), and the excretion rate of unchanged SA were determined in three normal subjects following the administration of a single oral dose of acetylsalicylic acid (ASA) 37 mg kg-1 and during multiple dosing with ASA 56 mg kg-1 day-1. Steady-state SA concentrations fell 23 per cent during the 4-week study period (mean +/- SD: 239 +/- 35 to 183 +/- 23 micrograms ml-1; p less than 0.05). Absorption of drug did not decrease during this time. Significant increases in the Vmax for SU and SPG formation occurred between baseline and during multiple dosing. Mean Vmax SU increased from 0.93 to 1.68 mg kg-1 h-1 (p less than 0.05) and mean Vmax SPG increased from 0.09 to 0.19 mg kg-1 h-1 (p less than 0.05). First-order rate constants for the formation of SAG and GA and for the excretion of unchanged SA did not change significantly between baseline and multiple dosing. The mechanism for the decline in CpssSA with time during high-dose SA therapy is most likely due to the induction of the formation rates of the major metabolites of SA, namely SU and SPG.