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Biomedical subjects

R O Day

Publications and source records attributed to R O Day.

At least 55 records · Page 3Linked to original sources
PubMed1995

Inhibition of AP-1 binding and transcription by gold and selenium involving conserved cysteine residues in Jun and Fos.

Gold(I) salts and selenite, which have diverse therapeutic and biological effects, are noted for their reactivity with thiols. Since the binding of Jun-Jun and Jun-Fos dimers to the AP-1 DNA binding site is regulated in vitro by a redox process involving conserved cysteine residues, we hypothesized that some of the biological actions of gold and selenium are mediated via these residues. In electrophoretic mobility-shift analyses, AP-1 DNA binding was inhibited by gold(I) thiolates and selenite, with 50% inhibition occurring at approximately 5 microM and 1 microM, respectively. Thiomalic acid had no effect in the absence of gold(I), and other metal ions inhibited at higher concentrations, in a rank order correlating with their thiol binding affinities. Cysteine-to-serine mutants demonstrated that these effects of gold(I) and selenite require Cys272 and Cys154 in the DNA-binding domains of Jun and Fos, respectively. Gold(I) thiolates and selenite did not inhibit nonspecific protein binding to the AP-1 site and were at least an order of magnitude less potent as inhibitors of sequence-specific binding to the AP-2, TFIID, or NF1 sites compared with the AP-1 site. In addition, 10 microM gold(I) or 10 microM selenite inhibited expression of an AP-1-dependent reporter gene, but not an AP-2-dependent reporter gene. These data suggest a mechanism regulating transcription factor activity by inorganic ions which may contribute to the known antiarthritic action of gold and cancer chemoprevention by selenium.

Amino Acid Sequence↗
PubMed1995

Adverse drug reactions and their measurement in the rheumatic diseases.

Drugs administered as therapy for rheumatological disorders are a relatively common cause of adverse events. Important data regarding the effects of drugs on patients with rheumatological conditions is being lost or rendered inaccessible because of deficiencies in classification, measurement, and collection methods for adverse drug reactions. A significant number of adverse reactions to drugs will not be known before marketing, and hence vigilance on the part of clinicians and patients in observing and documenting these reactions is paramount in building our knowledge and modifying our practice accordingly. A variety of systems and methods for detecting adverse drug reactions are described, critically evaluated, and compared for cost, potential bias, ethical concerns, and subject recruitment required for necessary statistical power. Systems need to be developed to give access to the wealth of clinical experimental data available in the individual practices of a broad spectrum of clinicians. To facilitate this, representative organizations need to make adverse drug reactions a high priority as well as contributing expertise and finance to database formulation and accessibility.

Antirheumatic Agents↗
PubMed1995

Naproxen concentrations in plasma and synovial fluid and effects on prostanoid concentrations.

OBJECTIVE: To test the hypothesis that unbound concentrations of naproxen in synovial fluid (SF) and plasma (P) are equal over a drug dosage interval at steady state or after a single dose of drug. The relationship between plasma and SF concentrations of naproxen, respectively, and prostaglandin concentrations were also examined. METHODS: Paired, sequential, total, and unbound naproxen concentrations were determined in plasma and SF in 2 groups of 6 patients. A single dose group was given naproxen 500 mg. The chronic dose group was given 500 mg bd for 7 days before collection of blood and SF samples. The effect of naproxen on prostanoid production by clotting whole blood (thromboxane B2, TXB2) and in SF (PGE2, 6-keto-PGF1 alpha) was determined by radioimmunoassay. RESULTS: Average area under the curve (AUC) of unbound (U) naproxen concentrations against time in plasma and SF were the same over a dosage interval at steady state (ratio AUCU,SF/AUCU,P, 1.12 +/- 0.18; p = 0.108), but not after a single acute dose (AUCU,SF/AUCU,P, 1.34 +/- 0.32; p = 0.044). Data from the single dose study revealed that the mean (+/- SD) of the concentrations required for 50% inhibition (EC50) of platelet derived TXB2 by total naproxen was 7.7 +/- 4.4 micrograms/ml (n = 5) and for unbound drug 25.4 +/- 22.0 ng/ml (n = 5). SF prostanoid concentrations after both acute and chronic dosing were low, as expected, but temporal and dose relationships of prostanoid concentrations with SF naproxen could not be discerned. However, this may reflect study design. CONCLUSIONS: The AUC of unbound naproxen in SF and plasma were similar at steady state. Plasma concentrations correlated with inhibition of TXB2 generation by platelets. There was sustained depression of PG concentrations in SF beyond the time suggested by plasma drug concentrations.

Adult↗
PubMed1994

Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis.

PURPOSE: A meta-analysis of randomized trials studying the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on blood pressure. DATA SOURCES AND STUDY SELECTION: Eight databases were searched, yielding 38 randomized, placebo-controlled trials and 12 randomized but not placebo-controlled trials (comparing two or more NSAIDs). DATA EXTRACTION: Pooled mean treatment effects were computed in each trial for blood pressure, weight, creatinine clearance, plasma renin activity, and daily urinary excretion of sodium and prostaglandins. Meta-analyses of these variables were done for all randomized, controlled trials; for all randomized, uncontrolled trials; and for several subgroups. DATA SYNTHESIS: When pooled, NSAIDs elevated supine mean blood pressure by 5.0 mm Hg (95% CI, 1.2 to 8.7 mm Hg) but had no effect on variables other than blood pressure. Nonsteroidal anti-inflammatory drugs antagonized the antihypertensive effect of beta-blockers (blood pressure elevation, 6.2 mm Hg; CI, 1.1 to 11.4 mm Hg) more than did vasodilators and diuretics. Among NSAIDs, piroxicam produced the most marked elevation in blood pressure (6.2 mm Hg; CI, 0.8 to 11.5 mm Hg), whereas sulindac and aspirin had the least hypertensive effect. CONCLUSIONS: Nonsteroidal anti-inflammatory drugs may elevate blood pressure and antagonize the blood pressure-lowering effect of antihypertensive medication to an extent that may potentially increase hypertension-related morbidity. Although certain NSAIDs and antihypertensive agents could be more likely to produce these effects, the underlying mechanisms require further study.

Adult↗
PubMed1994

Pharmacokinetics and pharmacodynamics of hydroxychloroquine enantiomers in patients with rheumatoid arthritis receiving multiple doses of racemate.

Hydroxychloroquine, a slow acting antirheumatic drug, is administered as the racemic mixture. Blood concentrations of the two enantiomers of hydroxychloroquine were measured in two studies, one study of eight patients, in whom blood and urine concentrations were measured during the first 6 months of therapy with rac-hydroxychloroquine, and one of 43 patients who had received rac-hydroxychloroquine therapy for at least 6 months. In the latter study rheumatoid disease activity was also measured. The pharmacokinetics of hydroxychloroquine were found to be enantioselective. The concentrations of (-)-(R)-hydroxychloroquine were higher than those of the (+)-(S)-antipode in all patients at all time points, although the ratios of the two enantiomers did display a two to three fold variability between patients. Both total and renal clearance were greater for the (+)-(S)-enantiomer. From the observational, cross-sectional study design used, it was not possible to differentiate concentration-effect relationships of the two enantiomers. The 11-fold range of drug concentrations swamped any effect of variability between patients in enantiomer proportions. Blood concentrations of both enantiomers were significantly higher in groups of patients with less active disease.

Arthritis, Rheumatoid↗
PubMed1994

Disposition and absorption of hydroxychloroquine enantiomers following a single dose of the racemate.

The disposition of hydroxychloroquine enantiomers has been investigated in nine patients with rheumatoid arthritis following administration of a single dose of the racemate. Blood concentrations of (-)-(R)-hydroxychloroquine exceed those of (+)-(S)-hydroxychloroquine following both an oral and intravenous dose of the racemate. Maximum blood concentrations of (-)-(R)-hydroxychloroquine were higher than (+)-(S)-hydroxychloroquine after oral dosing (121 +/- 56 and 99 +/- 42 ng/ml, respectively, P = 0.009). The time to maximum concentration and the absorption half-life, calculated using deconvolution techniques, were similar for both enantiomers. The fractions of the dose of each enantiomer absorbed were similar, 0.74 and 0.77 for (-)-(R)- and (+)-(S)-hydroxychloroquine, respectively (P = 0.77). The data suggest that absorption of hydroxychloroquine is not enantioselective. The stereoselective disposition of hydroxychloroquine appears to be due to enantioselective metabolism and renal clearance, rather than stereoselectivity in absorption and distribution.

Absorption↗
PubMed1994

Bioavailability of hydroxychloroquine tablets in patients with rheumatoid arthritis.

Nine patients with RA received two doses of 155 mg racemic hydroxychloroquine each, as a tablet and by i.v. infusion, in a randomized cross-over design study. Blood concentrations over the first 32 h following each dose were determined. Bioavailability was estimated using a sequential exponential least squares deconvolution method. The mean fraction absorbed from the tablet was 0.79 (range 0.39 to 1.27). The mean absorption lag-time was 1.3 h (range 0.5 to 3.7 h) and the mean time for 50% absorption was 4.3 h (range 1.9 to 10.3 h). Mean rate and extent of hydroxychloroquine absorption were not significantly different from that previously reported for healthy volunteers, although the interindividual variability in absorption parameters was greater in the patient group. Variability in the extent of absorption would lead to differences in steady-state hydroxychloroquine concentrations between patients, potentially contributing to the variability in response observed in clinical practice.

Adult↗
PubMed1994

Neither cimetidine nor probenecid affect the pharmacokinetics of tenoxicam in normal volunteers.

The effect of pretreatment with cimetidine (1 g day-1, 7 days) and of probenecid (1 g twice daily, 4 days) on the pharmacokinetics of tenoxicam (single oral dose, 20 mg) was studied in six healthy volunteers. Cmax was increased significantly when tenoxicam was given with probenecid (2.8 micrograms ml-1 alone, 3.5 micrograms ml-1 after probenecid; P < 0.005). No other pharmacokinetic parameters were altered significantly by either drug. It is concluded that neither cimetidine nor probenecid affects the pharmacokinetics of tenoxicam in a clinically important way.

Administration, Oral↗
PubMed1994

The stereoselective disposition of the enantiomers of ibuprofen in blood, blister and synovial fluid.

1. A sensitive, stereospecific assay using gas chromatography-mass spectrometry (GC/MS) was established to measure the concentrations of the enantiomers of ibuprofen in small volumes (50 microliters) of blister fluid. 2. The concentrations of the enantiomers in blister fluid, assessed in eight patients, were similar to those in synovial fluid, both fluids behaving as peripheral compartments with respect to plasma. 3. The mean rate constants of transfer of R-ibuprofen into (0.14 +/- 0.06 h-1) and out of (0.20 +/- 0.04 h-1) blister fluid were not significantly different from those for synovial fluid (0.19 +/- 0.12 h-1, 0.34 +/- 0.11 h-1, respectively). Similarly, the mean rate constants of transfer of S-ibuprofen into (0.22 +/- 0.07 h-1) and out of (0.27 +/- 0.08 h-1) blister fluid were not significantly different from those for synovial fluid (0.29 +/- 0.10, 0.36 +/- 0.11 h-1). However, the correlations were poor between the transfer constants for each of the enantiomers between plasma, and both blister and synovial fluid (P > 0.2). 4. The complex rate constant of transfer of S-ibuprofen into blister fluid (0.22 +/- 0.07 h-1) was greater than that of R-ibuprofen (0.14 +/- 0.07 h-1), which may be explained by the lesser protein binding of the S-enantiomer.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1994

Clinical response to non-steroidal anti-inflammatory drugs in urate-crystal induced inflammation: a simultaneous study of intersubject and intrasubject variability.

1. It is well known that an individual subject often responds preferentially to a particular nonsteroidal anti-inflammatory drug (NSAID) and clinical response to these drugs is characterised by considerable variability between individuals. Variability in response has often been attributed to the episodic nature of musculoskeletal disease. Few studies have studied intrasubject variability in response to these drugs using a multiple crossover design. A major difficulty has been the lack of objective, validated measures of inflammation sensitive to NSAIDs. The primary aim of the present study was to test the utility of urate-crystal induced inflammation as a tool to predict NSAID response in humans. 2. An inflammatory reaction was established in twenty-five healthy subjects with intradermal injection of urate crystals on four separate occasions separated by 1 week. Each subject was randomly assigned to receive either ibuprofen on two of these occasions (800 mg four times over 36 h) or matched placebo on the other two occasions using a double-blind, cross-over design. Decrease in the area under the wheal size-time curve was used to indicate anti-inflammatory response. 3. Peak inflammatory response was observed at about 32 h and had dissipated by 56 h post-urate injection. The logarithmic mean wheal area was significantly lower after ibuprofen (mean +/- s.e. mean; 6.74 +/- 0.09) compared with placebo (6.96 +/- 0.07 mm h); a difference of 20% (95% confidence interval for difference: 1 to 35%; P < 0.05). 4. There was marked intra- and intersubject variability in response to ibuprofen over the four treatment periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Risks and benefits of drugs used in the management and prevention of gout.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are now commonly used for the treatment of acute gout, but caution is required in view of their adverse effects, especially in the elderly. Colchicine is still an effective acute agent, but care must be taken to monitor toxicity. Intra-articular glucocorticosteroid therapy is useful and very safe; oral steroids and corticotrophin (adrenocorticotrophic hormone) may have a small role in acute therapy and seem safe when used over short time spans. Low dose colchicine may have a cost and toxicity advantage over NSAIDs in the prophylaxis of gout when commencing therapy aimed at reducing elevated plasma urate concentrations. Allopurinol is more frequently used than uricosuric agents such as probenecid, and toxicity may be largely avoided by tailoring dosage schedules according to renal function.

Adrenocorticotropic Hormone↗
PubMed1994

NSAID-related adverse drug interactions with clinical relevance. An update.

The prevalence and incidence of adverse drug interactions involving NSAIDs remain unknown. To identify those proposed drug interactions of greatest clinical significance, it is appropriate to focus on interactions between commonly used and/or commonly coprescribed drugs, interactions for which there are numerous well documented case reports in reputable journals, interactions validated by well designed in vivo human studies and interactions affecting high-risk drugs and/or high-risk patients. While most interactions between NSAIDs and other drugs are pharmacokinetic, NSAID-related pharmacodynamic interactions may be considerably more important in the clinical context. However, prescriber ignorance is likely to be a major determinant of many adverse drug interactions. Adverse drug interactions involving NSAIDs may be restricted by rational prescribing and by careful monitoring, particularly high-risk patients, drugs and therapy periods. Prescribing NSAIDs is relatively contra-indicative for patients on oral anticoagulants due to hemorrhage and for patients taking high dose methotrexate due to bone marrow toxicity, renal failure and hepatic dysfunction. Combination NSAID therapy cannot be justified since toxicity may be increased without any improvement in efficacy. Where lithium or antihypertensives are coprescribed with NSAIDs, aspirin or sulindac are preferred and close monitoring is mandatory for lithium toxicity and hypertension respectively. Phenytoin or oral hypoglycemic agents may be administered with NSAIDs other than pyrazoles and salicylates, provided, the patients are monitored carefully at the initiation and cessation of NSAID treatment. Digoxin, aminoglycosides and probenecid may be coprescribed with NSAIDs but close monitoring is required, particularly for high-risk patients such as the elderly. Indomethacin and triamterine should be avoided due to the risk of renal failure, high dose aspirin should be replaced by naproxen in patients on sodium valproate and care is required when corticosteroids are administered to patients taking salicylates long term in high dosage. Interactions between NSAIDs and antacids or cholestyramine are generally avoidable by administering these drugs at different times.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1994

Evaluation of the accuracy and reproducibility of ambulatory blood pressure monitoring in the very elderly using the Takeda TM-2420.

The accuracy and reproducibility of ambulatory blood pressure monitoring (ABPM) were evaluated in the healthy elderly (> or = 75 years) using the Takeda TM-2420 ambulatory BP monitor (A & D Mercury, Australia). Accuracy was assessed from 90 standardised sphygmomanometer and simultaneously recorded TM-2420 BP measurements in 28 subjects with a BP range of 60-210 mmHg. Reproducibility was determined in 19 subjects who underwent four separate days of ABPM by calculating the standard deviation of the mean differences between pairs of recording days (sdd) and the coefficient of reliability (R). Adaptation was also assessed using R. Of 3471 BP measurements in 19 subjects over 76 recording days, 76% were valid readings. The TM-2420 overestimated simultaneously recorded sphygmomanometer measurements with a bias (mean difference, d +/- sdd) of 13.9 +/- 13.9 mmHg for SBP and 7.5 +/- 6.4 mmHg for DBP. The mean sdd between pairs of recording days was greater for SBP (20.0) than for DBP (9.4) but R was very high for both SBP (0.914) and DBP (0.904). Adaptation effects were not detected. ABPM with the TM-2420 is highly reproducible in the elderly. The TM-2420 performs acceptably in 'field' testing and as it overestimates cuff measurements consistently, appropriate adjustment of recorded TM-2420 BP should be possible in elderly individuals.

Aged↗