Biomedical subjects
Publications and source records attributed to R O Day.
Acute gout is a well known complication of the commencement of allopurinol therapy. Prophylaxis is needed for some months, even after serum urate levels have returned to normal. Colchicine is usually preferable to NSAIDs for this purpose, being cheaper, and better tolerated, especially in patients with peptic ulcer, gastrointestinal bleeding or dyspepsia or who are taking anticoagulants.
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After a single oral dose of (R,S)-ibuprofen (1200 mg) to five healthy volunteers, paired plasma and blister fluid concentrations of drug were determined by a stereospecific HPLC assay. A pharmacokinetic model that incorporated blister fluid as a separate peripheral compartment adequately characterized the data. The plasma concentrations were consistently higher for (S)-ibuprofen than (R)-ibuprofen in both plasma and blister fluid. No significant difference in the elimination half-life of the enantiomers was observed. Similar to synovial fluid, there were relatively small fluctuations in blister fluid concentrations of both enantiomers. Blister fluid, similar to synovial fluid, therefore behaves pharmacokinetically as a peripheral compartment for drug distribution. This use of skin blisters, which can be sampled repetitively, may therefore prove to be a valuable experimental technique in pharmacokinetic and pharmacodynamic studies of drugs, especially in patients in whom synovial fluid is not available for sampling.
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Nailfold capillaries in 28 patients with OA affecting the distal interphalangeal joints were compared to 23 age- and sex-matched controls without OA. Patients with OA showed a significantly lower density of capillaries in their nailfolds and significantly more capillary morphological abnormalities including haemorrhage, 'drop out', dilatation and irregularity. There was a trend for OA patients to have warmer fingers with reduced finger to brachial blood pressure ratios. There were significant correlations between nailfold capillary numbers and average joint tenderness and between capillary morphological changes and joint swelling. These results reveal a relationship between interphalangeal joint OA and nailfold capillary abnormalities and density. As changes in microcirculation may be pertinent to the pathogenesis of OA, further studies which could explore possible causal relationships are warranted.
1. Nine healthy subjects each received three doses of 155 mg rac-hydroxychloroquine, as a tablet, an oral solution and by intravenous infusion, in a randomised cross-over design study, 30 min after a standard high fat breakfast. 2. Four methods of deconvolution were used to assess the absolute bioavailability of the tablet and oral solution doses. These were the delta function method, the staircase approximation method, and two least squares methods using a single first-order input and a sequential first-order input. The mean (+/- s.d.) fraction absorbed estimated by the four methods was 0.64 +/- 0.14 after the tablet and 0.87 +/- 0.30 after the oral solution. Wide intersubject variability was observed (0.50-0.91 for the tablet; 0.30-1.37 for the solution). 3. The mean (+/- s.d.) absorption half-life was 3.7 +/- 2.0 h for the tablet and 3.3 +/- 1.6 h for the solution, suggesting that absorption following the tablet dose was not rate-limited by dissolution. 4. The in vivo dissolution rate, extent of release and lag-time were determined using cube-root law and first-order input functions. Dissolution was found to be rapid, after a significant lag-time, but incomplete in some subjects. 5. The rate and extent of absorption was similar to that reported previously for fasted subjects. The lag-time before absorption commenced in fed subjects (1.65 +/- 0.46 h) showed a significant three-fold increase over that reported previously in fasting subjects (0.63 +/- 0.33 h), but this difference is not likely to be of clinical significance.
1. The aim of this study was to establish a simple and reliable experimental pain model that could distinguish the analgesic effects of non-steroidal anti-inflammatory drug (NSAID) treatment from placebo in human volunteers. 2. The reproducibility and reliability over time of subject pain ratings was compared using cutaneous electrical stimuli applied to either the thenar eminence or the ear lobe at varying intensities and modes. Subjects were asked to respond firstly, when the stimulus became clearly sharp and painful ('first pain') and secondly, when the sensation became deep and burning and no further increase in stimulus intensity could be tolerated ('second pain'). 3. Constant voltage stimuli were found to be more reproducible than constant current stimuli. Both phasic (intermittent) and tonic (continuous) stimulation modalities produced 'first' and 'second pain' sensations. The latter sensation was more reproducible, and was perceived as a burning pain which is akin to clinical pain. 4. Analgesics from the NSAID class were found to attenuate reliably only 'second pain' sensations. The analgesic effects of ibuprofen (ibuprofen vs placebo: 0.12 +/- 0.09 vs 0.02 +/- 0.07 volt h(-1), P = 0.03; 95% confidence interval for differences (CI): 0.03-0.18) and diflunisal (diflunisal vs placebo: 0.29 +/- 0.40 vs 0.005 +/- 0.27 volt h(-1), P = 0.0001; CI: 0.168-0.407), respectively, could be distinguished from placebo.
In eight patients with rheumatoid arthritis receiving racemic hydroxychloroquine, blood and urine concentrations of the enantiomers of hydroxychloroquine and its major metabolites were measured each month over the first 6 months of therapy. Plasma concentrations of hydroxychloroquine enantiomers were measured in five of these patients. In all patients, the blood concentration of (R)-hydroxychloroquine exceeded that of the (S)-enantiomer, the mean (R)/(S) ratio being 2.2 (range 1.6-2.9). A similar excess of (R)-hydroxychloroquine was found in the plasma, the mean (R)/(S) ratio being 1.6 (range 1.2-1.9). The mean enantiomer blood concentration ratio (R)/(S) for the metabolite desethylhydroxychloroquine was 0.45 (range 0.34-0.58) and for desethylchloroquine it was 0.56 (range 0.35-0.86) suggesting stereoselective metabolism of hydroxychloroquine. (S)-hydroxychloroquine had a mean (+/- s.d.) renal clearance from blood of 41 +/- 11 ml min-1, approximately twice that of (R)-hydroxychloroquine. The predicted unbound renal clearance was also higher for (S)-hydroxychloroquine. The clinical implications of enantioselective disposition of hydroxychloroquine are currently not known.
The prevalence and incidence of adverse drug interactions involving nonsteroidal anti-inflammatory drugs (NSAIDs) remains 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 those 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, and prescriber ignorance is likely to be a major determinant of many adverse drug interactions. Prescribing NSAIDs is relatively contraindicated for patients on oral anticoagulants due to the risk of haemorrhage, and for patients taking high-dose methotrexate due to the dangers of bone marrow toxicity, renal failure and hepatic dysfunction. Combination NSAID therapy cannot be justified as toxicity may be increased without any improvement in efficacy. Where lithium or anti-hypertensives are coprescribed with NSAIDs, close monitoring is mandatory for lithium toxicity and hypertension, respectively, and aspirin (acetylsalicylic acid) or sulindac are preferred. Phenytoin or oral hypoglycaemic agents may be administered with NSAIDs other than pyrazoles and salicylates provided that 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 triamterene should be avoided due to the risk of renal failure. High dose aspirin should be replaced by naproxen in patients on valproic acid (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. Adverse drug interactions involving NSAIDs may be limited by rational prescribing and by careful monitoring, particularly for high-risk patients, drugs and therapy periods.
The aim of the present study was to separate and characterise products formed by oxidation of uric acid by hydroxyl radicals with a view to probing for these products in vivo in clinical contexts. Aerated solutions of 200 microM uric acid, or its oxidation products, allantoin or parabanic acid, were exposed to gamma radiolysis, (52.0 Gy/min), as a source of HO. radicals, at pH 3.4 and 7.4. Aliquots were taken every 5 minutes for 20 minutes and oxidation products were separated by HPLC and analysed with a diode array detector. Identities of oxidation products were confirmed on the basis of similarity of retention times and absorbance spectra and peak purity parameters of known standards. Hydroperoxides were measured by tri-iodide formation in the 20 minute sample. Exposure of uric acid to such HO.fluxes produced a net loss of the parent compound with formation of a complex mixture of products with allantoin and parabanic acid being the predominant products at pH 3.4. The rate of uric acid degradation at physiological pH was slower and the distribution of oxidation products was different. A small but significant amount of uric acid hydroperoxide was detected at both pHs. A mechanism for uric acid oxidation under these conditions is presented.
OBJECTIVE: To determine the relationship between hydroxychloroquine concentration and effect in patients with rheumatoid arthritis (RA). METHODS: Using a cross sectional study design, drug concentration and effect were measured at one time. Forty-three patients with RA, receiving hydroxychloroquine therapy for at least 6 months and not receiving glucocorticosteroids, gold or penicillamine therapy were enrolled. The main outcome measures were hydroxychloroquine concentration and disease activity measured as degree of synovitis, pain, duration and intensity of morning stiffness, impairment of activities of daily living, patients' and physicians' subjective assessment of disease, erythrocyte sedimentation rate, and rheumatoid factor (RF). Hemoglobin and albumin concentrations were also recorded. RESULTS: Patients with none or mild intensity of morning stiffness, those with stiffness lasting less than 0.5 h and those with negative RF had significantly higher hydroxychloroquine blood concentrations than those in whom these measures indicated a more active disease (Mann-Whitney U test, p < 0.05). Similar trends were recorded for 3 other disease activity measures (p = 0.12-0.24). Analysis of all 9 individual disease activity measures indicated that the groups with less active disease had higher mean blood concentrations of hydroxychloroquine than those with measures indicating more active disease (p < 0.01). CONCLUSION: Our data provide the first evidence of a concentration-response relationship for hydroxychloroquine in RA for individual disease activity measures. However, an unweighted summed score of disease activity did not correlate significantly with drug blood concentrations. A prospective study is necessary to confirm the relationship and to determine a therapeutic concentration range.
We have previously hypothesized that a mode of action of the anti-rheumatic gold salt, aurothiomalate (AuTM), is the inhibition of DNA binding by transcription factors. Studies of the progesterone receptor (PR), which has a zinc finger structure in the DNA binding domain, were consistent with this hypothesis (1). Here we show that AuTM also markedly inhibits DNA binding by the transcription factor AP-1 and has less potent effects for AP-2, NF-1 and TFIID.
Little further work has established the nature and importance of variability in response to NSAIDs despite the phenomenon being identified by Huskisson in 1976. The following questions remain unanswered: the proportion of individuals who display marked variability in responses to different NSAIDs; reproducibility of individual responses over repeated exposures; the influence of various musculoskeletal disorders on the level of variability in response; and the importance of pharmacokinetic or pharmacodynamic mechanisms. Data continue to accumulate that there is a weak relationship between concentration of NSAIDs in plasma and degree of efficacy in RA and now OA and acute pain states, as well as with the incidence of toxicity, notably GI bleeding. The efficacy relationship may resemble a rectangular hyperbola with a steep slope upwards. None of the proposed mechanisms of action of NSAIDs additional to the universal ability to inhibit prostaglandin synthesis, which have been suggested as possible causes of response differences between drugs, has been linked rigourously to responses in individual patients. Systematic work linking clinical responses to pharmacokinetic parameters and pharmacodynamic mechanisms is required to understand variability of responses to NSAID therapy.
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OBJECTIVE: To assess the impact of a hospital based educational campaign on the prescription and use of hypnotic and sedative drugs. DESIGN: Two three-month cross-sectional surveys were performed. The first was to obtain a baseline evaluation of hypnotic and sedative drug use within the hospital, and the second was to evaluate the success of an educational intervention designed to promote more rational prescribing and use of these drugs. SETTING: St Vincent's Hospital, Sydney, a tertiary referral hospital. PATIENTS: Five patients were randomly selected each day from the hospital's admission list (only psychiatric patients were excluded); 296 patients were interviewed for the first survey and 299 for the second. A minimum six-day admission was necessary for inclusion in the study. Early discharges resulted in 214 patients remaining in each survey group. INTERVENTION: Campaigns were developed for hospital staff and for patients. A booklet and video were produced. The intervention commenced several months after the initial survey and continued throughout the second. MAIN OUTCOME MEASURE: A change in the prescription, administration and use of hypnosedatives. RESULTS: The education of staff had a considerable impact on the administration of these drugs by nursing staff and their prescribing by medical staff. The education of patients resulted in an increase in drug knowledge but had little impact on the use of hypnosedatives in hospital. However, a postal survey conducted three months after discharge from hospital showed a significant reduction (P less than 0.005) in hypnotic and sedative drug use among patients exposed to the educational campaign. CONCLUSION: The importance of continuing education in promoting more rational drug use is highlighted by the study. But the question of the best time and place for an intervention to achieve maximum impact has yet to be answered.
Propylthiouracil (PTU) has been demonstrated to reduce alcohol-induced hepatocyte damage and severe alcoholic liver disease. Although the mechanism by which the drug operates is yet to be elucidated, there is evidence that PTU may act as an antioxidant. The present study examines the reaction of PTU with oxygen free radicals and the ability of PTU to directly inhibit peroxidation of a model membrane system. PTU reacted directly with hydroxyl radicals produced by gamma-radiolysis. The rate constant for the PTU/hydroxyl radical reaction as determined by steady state competition kinetics with p-nitrosodimethylaniline was 8 x 10(9) L/mol/sec. PTU was less reactive towards superoxide generated by the xanthine/xanthine oxidase system, having a small but significant inhibitory effect on superoxide-induced reduction of cytochrome c only at a concentration of 200 microM. The ability of PTU to protect lipids from peroxidative changes was tested in membranes prepared from linoleic acid. The rate of peroxidation induced by 40 degrees heat decreased from 0.078 to 0.024 mM hydroperoxide/hr in the presence of 0-50 microM PTU. However, this trend was reversed at PTU concentrations above 50 microM. These data suggest that the protective effects of PTU against liver damage may be due to scavenging reactions with hydroxyl radicals in particular and/or its antioxidant potential.
The effects of the enantiomers of ibuprofen (0.25 and 0.50 mmol/kg b.w.) and flurbiprofen (0.01, 0.03, and 0.06 mmol/kg b.w.) on the beta-oxidation of palmitate were investigated in the rat. The mean cumulative exhalation of 14CO2 after ip administration of [U-14C]palmitic acid was significantly reduced over 6 h by ibuprofen at the higher dose but not at the lower dose for either enantiomer. There was no difference between the enantiomers, the reduction over 6 h being 31.3 and 33.0% for (R)- and (S)-ibuprofen, respectively. There was also a significant inhibition of beta-oxidation by flurbiprofen at all 3 doses. Again, there was no stereoselectivity evident in this inhibition. Flurbiprofen was much more potent than ibuprofen in eliciting this effect, the 0.01mmol/kg dose giving a similar reduction in beta-oxidation as observed for the 0.50 mmol/kg dose of ibuprofen. The data support the hypothesis that inhibition of the in vivo beta-oxidation of palmitate by ibuprofen and flurbiprofen is primarily via a nonstereoselective noncoenzyme A-dependent mechanism.