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Biomedical subjects

R O Day

Publications and source records attributed to R O Day.

At least 91 records · Page 5Linked to original sources
PubMed1992

Bioavailability of hydroxychloroquine tablets assessed with deconvolution techniques.

Four deconvolution methods (staircase, delta function, and least squares methods using single and sequential first-order input functions) were used to assess the absolute bioavailability of hydroxychloroquine tablets in nine healthy fasting volunteers. The volunteers received, in a random crossover design, a 155-mg oral tablet and a 155-mg iv infusion of racemic hydroxychloroquine. The mean fractions of the dose absorbed, calculated using the four deconvolution methods, were not statistically different (p = 0.70). The mean fraction absorbed (+/- SD) was 0.67 +/- 0.12, which was not significantly different from that reported previously in a conventional bioavailability study (p = 0.22). The mean absorption half-life was calculated to be 4.0 +/- 1.3 h. The mean lag time before absorption commenced was 0.57 +/- 0.30 h. The fraction of the dose absorbed ranged from 0.44 to 0.86. Low and/or variable bioavailability of hydroxychloroquine may be a cause of therapeutic failure in some patients. Validation of the deconvolution methods means that these techniques may now be used to assess the bioavailability of hydroxychloroquine in patients. An advantage of these methods is that samples need only be collected over the expected time period of absorption, rather than the whole time drug can be detected in the body, as is required in conventional area under the concentration-time curve ratio methods. Deconvolution studies may be completed in 2 weeks rather than the 10 months required for a conventional bioavailability study of hydroxychloroquine.

Adult↗
PubMed1992

Effect of aspirin on ulcer site blood flow in cat stomachs.

Radioactive microspheres were used to measure blood flow in the cat stomach during exposure to saline, 0.075 M HCl, and then 15 and 30 min after exposure to 20 or 40 mM aspirin in HCl. At the end of the experiment, the stomach wall was divided into ulcerated regions and adjacent nonulcerated areas. When exposed to saline, both regions had similar blood flow: 27 +/- 5 and 25 +/- 5 ml.min-1.100 g-1 (means +/- SE). Addition of acid caused a significant increase in blood flow to 41 +/- 7 ml.min-1.100 g-1 only at those sites that eventually ulcerated in the presence of aspirin. In the adjacent nonulcerated regions, blood flow was 31 +/- 5 ml.min-1.100 g-1 and was not significantly greater than the flow recorded during saline exposure. Aspirin caused ulcer site blood flow to increase dramatically to 89 +/- 12 and 122 +/- 18 ml.min-1.100 g-1 after 15 and 30 min, whereas the adjacent nonulcerated tissue rose to 40 +/- 6 and 44 +/- 5 ml.min-1.100 g-1, respectively. The ulcer site hyperemia with acid alone suggests higher mucosal permeability in these regions allowing back-diffusion of acid and injurious agents. The present data obtained in the cat do not support the notion that ischemia plays a role in initiating nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers, but rather that acute NSAID ulcers are associated initially with a hyperemia.

Animals↗
PubMed1991

Chiral inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs--II. Racemization and hydrolysis of (R)- and (S)-ibuprofen-CoA thioesters.

The inversion of 2-arylpropionic acids (2-APAs) has become the subject of much attention. It is a unique reaction specific to this group of drugs. Inversion proceeds via stereoselective activation of the R-enantiomer to its CoA thioester whereby it is then racemized and hydrolysed to release free drug. The racemization and hydrolysis processes have been examined in this study using chemically synthesized CoA thioesters of the ibuprofen enantiomers and in vitro models employing rat liver homogenate and the mitochondrial and microsomal fractions as the source of the 'racemase' enzymes. Rat liver homogenate mediated the racemization and hydrolysis of both (R)- and (S)-ibuprofen-CoA thioesters. The rat liver mitochondrial fraction similarly mediated racemization and hydrolysis of both CoA thioesters. There was less racemase activity in the rat liver microsomal fraction and the data indicated that this fraction may contain two hydrolases which act separately on the (R)- and (S)-ibuprofen-CoA thioesters. The data are further evidence that the stereoselectivity of the CoA synthetase controls the overall stereoselectivity of inversion.

Animals↗
PubMed1991

Hydrogen peroxide modulation of the respiratory burst of human neutrophils.

Addition of micromolar concentrations of hydrogen peroxide (H2O2) to human neutrophils resulted in a dose-dependent luminol-enhanced chemiluminescent response. Pretreatment of neutrophils with micromolar concentrations of H2O2 altered their response to the surface acting stimulants serum-treated zymosan (STZ) and formyl-methionyl-leucyl-phenylalanine (fMLP), but not to the intracellular stimulant phorbol myristate acetate (PMA). The alterations were partially reversible by catalase, but exacerbated by superoxide dismutase. These results suggest a modulatory role for H2O2 in the respiratory burst of neutrophils.

Catalase↗
PubMed1991

The pharmacokinetics of total and unbound concentrations of tenoxicam in synovial fluid and plasma.

Tenoxicam is a nonsteroidal antiinflammatory drug with an elimination half-life of 60-80 hours; it is administered once daily. Tenoxicam concentrations were measured in plasma (10 samples) and synovial fluid (6 samples) over a 24-hour dosage interval at steady state in 10 subjects with arthritis who had been taking the drug at a dosage of 20 mg/day for at least 2 weeks. Total tenoxicam concentrations in synovial fluid were always less than those in plasma, and there was little fluctuation in plasma or synovial concentrations over the dosage interval, although there was substantial inter-subject variation in both concentrations. There was a significant relationship between the tenoxicam dosage when expressed as mg/kg of body weight and the average steady-state total concentration of tenoxicam in plasma (r = 0.80, P = 0.006); this accounted for a substantial proportion of the intersubject variation. The mean +/- SD steady-state concentrations in synovial fluid and plasma were 3.9 +/- 1.8 micrograms/ml and 9.2 +/- 3.7 micrograms/ml, respectively, yielding a mean +/- SD synovial fluid: plasma ratio of 0.43 +/- 0.12. Synovial fluid:plasma ratios of total tenoxicam correlated with synovial fluid:plasma ratios of albumin (r = 0.71, P = 0.02). The synovial fluid:plasma ratio of unbound tenoxicam was 0.90 +/- 0.3 (95% confidence interval 0.68-1.11), which was not significantly different from a value of 1 (t = -1.09, P = 0.31).

Adult↗
PubMed1991

Pharmacokinetics of the enantiomers of ibuprofen in the rabbit.

The stereoselective disposition of ibuprofen was studied in male New Zealand White (NZW) rabbits (n = 4) following an infusion (0.16 mg/kg/min) to steady-state of each of the enantiomers of ibuprofen with one week between treatments. The mean (+/- SEM) steady-state clearances of (R)-ibuprofen (15.5 +/- 1.1 ml/min/kg) and (S)-ibuprofen (13.6 +/- 1.9 ml/min/kg) were not significantly different from each other (p greater than 0.05) and exceeded the plasma clearance of indocyanine green (4.3 +/- 0.4 ml/min/kg) in a separate group of rabbits (n = 6). When the infusion rate of the enantiomers was doubled there was a significant decrease in the mean clearance of both (R)-ibuprofen (28%; p less than 0.018) and (S)-ibuprofen (24%; p less than 0.003). There was enantiospecific chiral inversion of (R)-ibuprofen to (S)-ibuprofen (fi = 0.30 +/- 0.07) as has been observed in all species so far studied for this 2-arylpropionic acid. The metabolic capacity for elimination of ibuprofen enantiomers was much greater than reported for either fenoprofen or ketoprofen and suggests that the clearance of ibuprofen enantiomers may be flow dependent in this species.

Animals↗
PubMed1991

1-Methylxanthine derived from theophylline as an in vivo biochemical probe of allopurinol effect.

The urinary 1-methyluric acid (1MU) to 1-methylxanthine (1MX) ratio has been assessed as a biochemical index of oxipurinol effect in vivo in man. Dosing with theophylline was used to produce 1MX as an intermediate metabolite in six healthy volunteers. A sigmoid Emax model was fitted to the data and gave a mean plasma oxipurinol IC50 of 3.0 +/- 1.1 mg l-1, a mean exponent n of 3.4 +/- 2.1 and a mean IC90 of 8.5 +/- 5.9 mg l-1. There was marked interindividual variability in the steepness of the plasma oxipurinol concentration response relationship, and in the plasma oxipurinol IC90 values. The study has confirmed the feasibility of using single doses of allopurinol to construct individual plasma oxipurinol concentration-response curves.

Adult↗
PubMed1991

Aminophylline in the emergency department. Maximizing safety and efficacy.

An experimental technique designed to predict theophylline doses needed to attain therapeutic theophylline concentrations in 43 emergency department (ED) patients was compared with a standard conventional regimen in 46 ED patients. The experimental protocol utilized a computer-assisted dosage prediction program that incorporated baseline theophylline concentration rapidly obtained using a bedside assay. The standard protocol used conventional loading and infusion rates, as well as an estimate of time of last theophylline dose based on patient history. Plasma theophylline concentrations, estimated 1 and 6 hours after commencement of aminophylline therapy in each regimen, were compared. The experimental protocol was equally rapid but much more accurate in achieving targeted theophylline concentrations. Experimental dosage prediction was associated with a higher proportion of theophylline concentrations in the therapeutic range at 1 (81 percent vs 26 percent; p less than 0.001) and 6 hours (91 percent vs 37 percent; p less than 0.001). There was a trend toward fewer toxic concentrations recorded at 1 (0 percent vs 7 percent; p = 0.27) and 6 hours (0 percent vs 10 percent; p = 0.08). This protocol, which was performed quickly and without difficulty by residents in a busy hospital ED, offers an opportunity to improve the efficacy and decrease the toxicity of theophylline use in asthma emergencies.

Acute Disease↗
PubMed1991

The problems and pitfalls of NSAID therapy in the elderly (Part I).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs worldwide when grouped by generic categories and account for 3 to 9% of total prescription numbers in various countries. While NSAIDs are responsible for approximately 25% of all reported adverse drug reactions, aging may substantially increase the risk of NSAID-induced reactions. Several factors may contribute to NSAID-related toxicity in the elderly. The increase in morbidity associated with aging may result in consumption of a wide range of potent drugs, while inappropriate drug therapy and aberrant compliance are also capable of contributing to adverse drug reactions in geriatric patients. Age-related alterations in pharmacokinetics may influence the handling of NSAIDs in the elderly; in particular, dosage reduction is appropriate for azapropazone (apazone), naproxen, ketoprofen and salicylates administered to healthy aged patients, whereas the presence of renal disease may also necessitate dosage reduction of diflunisal, indomethacin, sulindac and mefenamic acid. Changes in NSAID pharmacodynamics with aging, such as increased CNS sensitivity to NSAIDs and impaired homeostasis, also predispose the elderly to NSAID-related adverse effects. It is undisputed that gastrointestinal toxicity due to NSAID therapy is a class effect. A significant association has been found between aspirin and uncomplicated gastric, but not uncomplicated duodenal ulcer, while nonaspirin NSAIDs are significantly associated with both uncomplicated gastric and duodenal ulceration. The use of NSAIDs is accompanied by a 2- to 5-fold risk of serious complications of peptic ulcer disease, i.e. haemorrhage or perforation, which increases in the elderly, particularly women. A broad range of renal side effects has been ascribed to NSAIDs, of which acute renal impairment is the most common in the elderly. Although most NSAIDs have been reported to cause hepatotoxicity, serious abnormalities of liver function are rare and are largely unpredictable. Other adverse effects due to NSAIDs have also been described, some of which (e.g. cardiovascular, CNS and haematological effects) may be more common in the elderly.

Aged↗
PubMed1991

The problems and pitfalls of NSAID therapy in the elderly (Part II).

The elderly are most susceptible to pharmacokinetic drug interactions between various NSAIDs and anticoagulants, sulphonylurea hypoglycaemic agents, certain anticonvulsants, methotrexate, digoxin, aminoglycosides and lithium. Pharmacodynamic interactions between some NSAIDs and antihypertensive drugs, anticoagulants, sulphonylurea agents and other NSAIDs are also potentially significant in the elderly. Despite the finding that mean therapeutic responses of large groups of patients have been generally equivalent for the wide range of NSAIDs studied thus far, it is also apparent that marked variability exists in the response of individual patients to different NSAIDs. Subsequent dosage increments may predispose 'nonresponders' and some less sensitive 'responders' to toxicity from NSAIDs. This interindividual variability in response to NSAIDs may be contributed to by the differing physicochemical properties of NSAIDs, physician prescribing habits and patient expectations, variations in NSAID pharmacokinetics, and the differing effects of NSAIDs other than their common ability to inhibit prostaglandin synthesis. The principles for drug prescribing in the elderly are no different from those that should be applied to the prescribing of medication in any patient. The clinician should strive to make a diagnosis and should avoid treating symptoms in isolation. Critical assessment of the indication for prescribing NSAID therapy must include consideration of the available effective and safe alternatives. If an NSAID is commenced the lowest effective dose should be the desired goal, but after an appropriate trial it is acceptable clinical practice to employ an alternative NSAID. There is no justification for combination NSAID therapy. The progress of each patient must be carefully monitored, particularly during the first few months of treatment, while periodic review of the ongoing need for the NSAID is essential.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

Inhibition of DNA binding and transcriptional activity of a nuclear receptor transcription factor by aurothiomalate and other metal ions.

The antirheumatic gold salt aurothiomalate (AuTM) has cellular actions that are consistent with modulation of gene expression. We have tested the hypothesis that an important mode of action of AuTM is inhibition of binding of certain transcription factors to regulatory elements in DNA. The chemistry of transcription factors containing the zinc finger motif makes them candidates for such an interaction with AuTM. In this regard, the interaction of a steroid hormone receptor, the progesterone receptor (PR), with its DNA response element (PRE) was chosen as a suitable model. Nuclear extracts of T-47D human breast cancer cells rich in PR were incubated with radiolabeled PRE, and binding was determined by gel retardation assay. Preincubation of nuclear extract with AuTM caused a concentration-dependent inhibition of binding of PR to PRE (IC50, approximately 3 microM). Other metal ions inhibited binding at higher concentrations, in a rank order correlating with their binding affinity for thiols. Thiomalic acid had no effect in the absence of gold in this system. To test the effect of AuTM on PR-mediated transcription, we transfected the progestin-inducible expression vector pMSG-CAT into T-47D cells. Transfected cells were incubated in the absence or presence of AuTM and treated with the synthetic progestin ORG2058, to induce chloramphenicol acetyl transferase (CAT) activity. With 10 and 100 microM AuTM, there was inhibition to 67 +/- 3% (p = 0.012) and 42 +/- 8% (p = 0.008) of CAT specific activity, respectively, compared with controls. These results demonstrate that AuTM can regulate gene expression and that inhibition of binding of a transcription factor to its response element is a likely mechanism. This provides a molecular model for further study of the antirheumatic action of gold salts.

Cell Nucleus↗
PubMed1990

A functional psychosis precipitated by quinidine.

A 62-year-old man with a syndrome of gradually progressive cognitive deterioration accompanied by paranoid features is described. He had been taking quinidine since 1974 for a recurring supraventricular tachyarrhythmia. Examination revealed a suspicious man with widespread patchy cognitive deficits but no focal neurological signs. An exhaustive range of investigations gave unremarkable results. Within 24 hours of cessation of quinidine there was a dramatic improvement in his mental state and, after a further four days, he had returned essentially to normal with no demonstrable cognitive deficits. Several months later he suffered a recrudescence with prominent paranoid and depressive features which gradually settled after commencement of pimozide and dothiepin. It is likely that these events reflect a recurring functional psychosis which was precipitated or exacerbated in the first instance by quinidine. This represents a significant complication of quinidine therapy which has been largely unrecognized. Therapy with quinidine should be considered as a potential contributing factor in any patient with dementia or a functional psychosis who is also taking this drug.

Cognition Disorders↗
PubMed1990

Stereoselective disposition of ibuprofen and flurbiprofen in rats.

(R)-2-Arylpropionates are often inverted to the pharmacologically active S-enantiomers in vivo, although there is significant interspecies variability in inversion. In order to provide a basis for determining the biochemical consequences of this unique process using rats as a model, it was important to establish the pharmacokinetic disposition of the enantiomers of ibuprofen, a drug well inverted in man and flurbiprofen, a drug apparently poorly inverted in man. Rats were dosed i.v. with a single dose of (R)- or (S)-ibuprofen (20 mg/kg), (R,S)-ibuprofen (40 mg/kg), (R)- or (S)-flurbiprofen (10 mg/kg), or (R,S)-flurbiprofen (20 mg/kg). Each treatment group consisted of six animals. Serial blood samples were withdrawn over a period of 6 h for ibuprofen and 10 h for flurbiprofen. These drugs were assayed in plasma by a stereospecific HPLC assay. The pharmacokinetics of the ibuprofen and flurbiprofen enantiomers were evaluated using a two-compartment open model with conversion of the R- to S-enantiomers in the central compartment. There was 50 +/- 4% inversion of (R)-ibuprofen, a figure similar to that observed in man and (R)-ibuprofen had a higher clearance (12.6 +/- 1.3 ml/min/kg) than (S)-ibuprofen (7.7 +/- 0.7 ml/min/kg; P less than 0.01). The clearance of (R)-flurbiprofen after racemate (2.3 +/- 0.1 ml/min/kg) was higher than its clearance when administered alone (1.7 +/- 0.2 ml/min/kg; P less than 0.01), indicating a pharmacokinetic interaction between the enantiomers (most probably at plasma protein binding sites). A corresponding difference was not observed for ibuprofen. There was a small amount of inversion of (R)-flurbiprofen as determined by area analysis (4.5 +/- 1.6%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Compliance with criteria necessary for effective drug concentration monitoring.

Drug concentration monitoring (DCM) has become a widely used tool in clinical medicine. However, optimal benefit from this service is most likely if there is close adherence to specific guidelines governing the initiation of, interpretation of, and clinical response to each DCM request. This study was designed to identify deficiencies in the clinical utilization of the DCM service at St. Vincent's Hospital, Sydney, and to test the effect of an intervention process designed to correct these deficiencies. Audit criteria describing appropriate indications for DCM, clinical data required to interpret DCM results, and actions to be taken in response to a result outside the therapeutic range were used to assess the performance of DCM. The results obtained from the baseline survey were used to devise educational material for the resident medical staff and to assist in the revision of the DCM request form. There was a clinically and statistically significant increase in the number of DCM results that satisfied the audit criteria after the intervention process.

Drug Therapy↗
PubMed1990

D-penicillamine and D-penicillamine-protein disulphide in plasma and synovial fluid of patients with rheumatoid arthritis.

1. The plasma pharmacokinetics of D-penicillamine (D-pen) and D-penicillamine-albumin disulphide (D-pen-alb) were examined over a dosage interval in six patients with rheumatoid arthritis. In two of these, 24 h synovial fluid profiles of D-pen and D-pen-alb were also obtained. 2. D-pen was undetectable in plasma at the beginning of the study. The peak concentration (5.4 +/- 1.2 microM) occurred at between 45 min and 2 h and the mean elimination half-life was 0.6 h. D-pen-alb, however, was present at a mean plasma concentration of 19.1 microM prior to dosage, peaked at 26.2 microM and was eliminated with a half-life of 40 h. 3. D-pen concentrations in synovial fluid rose more slowly and peaked lower than in plasma. D-pen-alb was present in synovial fluid of the patients at 50.1% and 83.6%, respectively, of the simultaneous plasma concentration prior to dosage. Concentrations varied during the study interval, corresponding to changes in plasma concentrations. 4. These results demonstrate that D-pen forms stable conjugates with protein in treated patients. The presence of D-pen-alb in relatively high concentrations throughout the dosage interval contrasts with the low concentrations and rapid elimination of D-pen. Both D-pen and D-pen-alb were also shown to be present at the putative site of drug action (the inflamed synovial joint) in concentrations lower than those in plasma.

Adult↗
PubMed1989

Chiral inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs--1. In vitro studies of ibuprofen and flurbiprofen.

The mechanism of inversion of the enantiomers of 2-arylpropionic acids was investigated in vitro using tissue homogenates. Crude rat liver homogenate was shown to mediate the inversion of R to S-ibuprofen, but not inversion of the S to the R-enantiomer. Inversion required CoA and ATP as cofactors. In contrast, R-ibuprofen was not inverted by homogenates of kidney or small intestine and there was no inversion of the enantiomers of flurbiprofen by any of these tissue homogenates. Long-chain acyl-CoA synthetase was partially purified from rat liver microsomes and bound to Matrex Gel Red A. R-Ibuprofen was shown to be a substrate for this enzyme while S-ibuprofen and R and S-flurbiprofen were not substrates. These data are consistent with the hypothesis that the stereospecificity of inversion is controlled by the acyl-CoA synthetase. R-Ibuprofen-CoA did not racemize in either buffer solution (pH 7.4) or human plasma consistent with the hypothesis that racemization of the CoA thioesters is mediated enzymatically.

Animals↗