The patient is the teacher: ambulatory patient-centred student-based interprofessional education where the patient is the teacher who improves patient care outcomes.

The patient's role as the key to medical student education was enunciated by Osler in 1903 and remains central to the broader imperative of interprofessional education. Interprofessional education needs to progress from the patient's passive bedside or office role to assume a more active and primary role by his/her participation as the teacher, immersed in student education. To date, the achievements in interprofessional education have been limited, but ambulatory patient-centred learning opportunities involving direct student to patient dialogues and mixed health professional student engagement with patients as teachers are emerging within various interprofessional student clinic formats. There is good evidence that such approaches lead to actual improvements in patient outcomes.

Costs and outcomes of total hip and knee joint replacement for rheumatoid arthritis.

The objective of the study was to ascertain costs and outcomes of total joint replacement surgery for rheumatoid arthritis (RA) in Australia from the patients' perspective and to explore whether costs were affected by health status pre- or postsurgery. RA patients, scheduled for primary unilateral total knee replacement (TKR) or total hip replacement (THR) surgery at five Sydney hospitals, were approached. Preoperatively, patients retrospectively recorded expenses incurred over the previous 3 months and the health assessment questionnaire (HAQ). Postoperatively, patients completed detailed prospective cost diaries, short form (SF) 36, and HAQ every 3 months during the first postoperative year. In addition, patients were asked to complete a visual analogue measure for pain at 12 months postsurgery. Arthritis-specific cost information included prescription and nonprescription medication, visits to health professionals, tests, special equipment, alterations to the house, and use of private or community services. Thirty-one TKR and 11 THR patients provided cost data for the first postoperative year. Out-of-pocket costs and service utilization decreased over the first postoperative year for both TKR and THR patients. In addition, there was an improvement in the health status as measured by SF-36 but not the HAQ at 3 and 12 months postoperatively. The small sample size of this analysis is reflective of the current national trends of RA joint replacement surgery. Despite the low incidence of RA joint replacement surgery, it was substantiated that patients consider the positive impact on health outcomes and costs important. The generic SF-36 detected improvements in the health status of these RA patients, while total HAQ scores failed to do so. HAQ was found to be insensitive in reflecting improvements following lower limb replacement surgery. Patient out-of-pocket costs significantly decreased postoperatively; however, these costs remain substantial compared to osteoarthritis total joint replacement patients.

Probenecid-clofibrate interaction.

Clofibric acid disposition was studied in four healthy men after 1 wk of clofibrate ingestion (500 mg orally every 12 hr) with and without probenecid (500 mg orally every 6 hr). Mean (+/- SD) free clofibric acid plasma concentration in the four subjects over a dosage interval at steady state was 2.5 +/- 0.03 mg/1 before and 9.05 +/- 1.09 mg/1 after the probenecid. Probenecid reached an average plasma concentration of 71.3 mg/1. No clofibric acid glucuronide was detected in plasma during either treatment. The fractions of the dose recovered in urine as clofibric acid, clofibric acid glucuronide, and clofibric acid liberated after acid hydrolysis were not altered by probenecid. These data suggest that probenecid causes a reduction in renal and metabolic clearance of clofibric acid, probably as a result of inhibition of the conjugation of clofibric acid with glucuronide.

Diflunisal disposition and hypouricemic response in osteoarthritis.

The disposition of diflunisal was studied at daily doses of 250, 500, 750, 1000 mg/day in 24 male patients (mean age 65 yr and mean creatinine clearance 72 ml/min). Each dose was given for 14 days and diflunisal apparent oral clearance and serum urate was measured on the last day of each dosing regimen. There was a dose-dependent decrease in mean diflunisal apparent oral clearance with dose from 628 ml/hr at 250 mg/day to 426 ml/hr at 1000 mg/day, with most of the decrease occurring at the lower doses and becoming less pronounced at doses of 750 and 1000 mg/day. There was a strong positive correlation between diflunisal apparent oral clearance and creatinine clearance. Diflunisal induced a hypouricemic effect at all doses, but the responses at doses of 750 and 1000 mg/day did not differ.

A Nycodenz gradient method for the purification of neutrophils from the peripheral blood of rats.

A Nycodenz gradient technique is described which permits the separation of functionally active polymorphonuclear neutrophils (PMN) from the peripheral blood of rats. PMN are obtained at greater than 90% purity and fractionate at a peak density of 1.0919 g/ml. The method is suitable for isolating PMN when the circulating PMN count is low (less than 20%) as in normal rats and when the count is high (greater than 30%), as a result of inducing inflammation in the subcutaneous air pouch of rats by the intra-pouch injection of peptone. The chemotactic responsiveness of rat PMN was found to be markedly less than that of human PMN when the formyl peptides were used as chemoattractants but not when zymosan-activated serum was the chemoattractant. Blood PMN from normal rats and from peptone-treated rats showed no significant difference in their response to ZAS indicating that priming of their activity by the induction of long term (8 day) inflammation was not a feature of these experiments. However, air pouch-derived PMN displayed a highly significant reduction in activity compared with their isologous blood-PMN. The Nycodenz method offers an alternative to the Percoll separation method for rat blood and will be useful when comparative studies of elicited and non-elicited PMN are required since the latter are obtained in sufficiently high yield and purity for microassays on their function to be performed.

Protective effect of enprostil against aspirin-induced gastroduodenal mucosal injury in man. Comparison with cimetidine and sucralfate.

A single-blind endoscopic study was undertaken to test the relative efficacy of enprostil, a synthetic analogue of prostaglandin E2, cimetidine, and sucralfate in the prevention of aspirin-induced gastroduodenal mucosal injury. Fifty healthy, non-smoking male volunteers completed the study after having been randomly assigned to receive two weeks of therapy with one of the following regimens: enprostil 35 micrograms twice daily; enprostil 35 micrograms in the morning; cimetidine 200 mg three times daily and 400 mg at night; sucralfate 1 g four times daily; or placebo. In the second week, aspirin (900 mg three times daily) was also administered. Endoscopies were performed before and after the aspirin phase of the study, and lesions (mucosal erosions plus submucosal hemorrhages) were counted in the stomach and duodenal bulb. All treatments were superior to placebo (p less than 0.05). The mean number of lesions in the 70-micrograms enprostil group (8.5) was significantly less than in the 35-micrograms enprostil group, (11.1), the sucralfate group (12.4), or the placebo group (16.0); the benefit over cimetidine (10.1), however, was not statistically significant. The protective effect of enprostil was greatest in the antrum, the site of maximal mucosal injury. Gastrointestinal side effects were reported in all groups, though abdominal pain and dyspepsia were noted more frequently in those taking enprostil.

Clinical pharmacokinetics of the salicylates.

The use of salicylates in rheumatic diseases has been established for over 100 years. The more recent recognition of their modification of platelet and endothelial cell function has lead to their use in other areas of medicine. Aspirin (acetylsalicylic acid) is still the most commonly used salicylate. After oral administration as an aqueous solution aspirin is rapidly absorbed at the low pH of the stomach millieu. Less rapid absorption is observed with other formulations due to the rate limiting step of tablet disintegration - this latter factor being maximal in alkaline pH. The rate of aspirin absorption is dependent not only on the formulation but also on the rate of gastric emptying. Aspirin absorption follows first-order kinetics with an absorption half-life ranging from 5 to 16 minutes. Hydrolysis of aspirin to salicylic acid by nonspecific esterases occurs in the liver and, to a lesser extent, the stomach so that only 68% of the dose reaches the systemic circulation as aspirin. Both aspirin and salicylic acid are bound to serum albumin (aspirin being capable of irreversibly acetylating many proteins), and both are distributed in the synovial cavity, central nervous system, and saliva. The serum half-life of aspirin is approximately 20 minutes. The fall in aspirin concentration is associated with a rapid rise in salicylic acid concentration. Salicylic acid is renally excreted in part unchanged and the rate of elimination is influenced by urinary pH, the presence of organic acids, and the urinary flow rate. Metabolism of salicylic acid occurs through glucuronide formation (to produce salicyluric acid), and salicyl phenolic glucoronide), conjugation with glycine (to produce salicyluric acid), and oxidation to gentisic acid. The rate of formation of salicyl phenolic glucuronide and salicyluric acid are easily saturated at low salicylic acid concentrations and their formation is described by Michaelis-Menten kinetics. The other metabolic products follow first-order kinetics. The serum half-life of salicylic acid is dose-dependent; thus, the larger the dose employed, the longer it will take to reach steady-state. There is also evidence that enzyme induction of salicyluric acid formation occurs. No significant differences exist between the pharmacokinetics of the salicylates in the elderly or in children when compared with young adults. Apart from differences in free versus albumin-bound salicylate in various disease states and physiological conditions associated with low serum albumin, pharmacokinetic parameters in patients with rheumatoid arthritis, osteoarthritis, chronic renal failure or liver disease are essentially the same.(ABSTRACT TRUNCATED AT 400 WORDS)

Protein binding of some non-steroidal anti-inflammatory drugs in rheumatoid arthritis.

The protein binding of 4 non-steroidal anti-inflammatory drugs and warfarin was investigated in 10 patients with rheumatoid arthritis and in a matched control group of patients with osteoarthritis. There were no differences between the groups in the free fractions of the 5 drugs studied. Fluorescent probe studies also showed only minor differences between groups. The results do not support previous suggestions that drug protein binding is altered in rheumatoid arthritis. Albumin concentration was positively correlated with the binding of salicylate, but not with binding of the other 4 drugs. Fatty acid concentration was directly correlated with the binding of warfarin and indomethacin. Correlations between drugs with respect to protein binding were investigated, but only that between salicylate and ibuprofen was significant.

Crystal-induced inflammation in the rat subcutaneous air-pouch.

Monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals initiated acute inflammatory reactions characterized by increased plasma extravasation and polymorphonuclear leukocyte (PMNL) accumulation in the rat subcutaneous air-pouch. Pretreatment of rats with colchicine (1 mg kg-1, s.c.) inhibited PMNL accumulation induced by either crystal type but had a greater inhibitory effect on MSU-induced plasma extravasation compared with that induced by CPPD crystals. Colchicine (1 mg kg-1, s.c.) did not reduce histamine-induced plasma extravasation in the air-pouch. The lipoxygenase product of arachidonic acid metabolism, leukotriene B4 (LTB4), was detected in MSU-induced exudates but not in CPPD-induced exudates. Pretreatment of rats with colchicine (1 mg kg-1, s.c.) inhibited LTB4 production in MSU-induced exudates.

Protein binding of GP53,633: a basic non-steroidal anti-inflammatory drug.

The protein binding of GP53,633 [2-tert. butyl-4(5)-phenyl-5(4)-(3-pyridyl)-imidazole], a basic non-steroidal anti-inflammatory drug (NSAID), has been investigated. Although GP53,633 is a base (PKa 6.4) rather than an acid, the binding in plasma or serum was totally accounted for by binding to albumin. Scatchard analysis of the binding to albumin suggested the presence of one high affinity site and a number of low affinity sites. GP53,633 and its major metabolite, CGP8716, displaced site-I fluorescent probes (DNSA and warfarin) but not the site-II probe dansylsarcosine. Binding studies by equilibrium dialysis showed that GP53,633 and its metabolite displaced site-I drugs but not site-II drugs, and 14C-GP53,633 was itself displaced by site-I but not site-II drugs. As with other site-I drugs, the binding of GP53,633 was enhanced by addition of oleic acid at molar ratios of up to 2:1 with albumin. Albumin binding of GP53,633 was markedly increased by raising the pH from 6.0 to 8.5 suggesting that only the unionised drug can bind at site-I. The data are consistent with the major part of the binding energy at site-I being due to hydrophobic interactions and also suggest that there is a cationic centre on the protein at or near site-I which precludes the binding of positively charged drugs.

A randomised, blinded, placebo-controlled, dose escalation study of the tolerability and efficacy of filgrastim for haemopoietic stem cell mobilisation in patients with severe active rheumatoid arthritis.

Autologous haemopoietic stem cell transplantation (HSCT) represents a potential therapy for severe rheumatoid arthritis (RA). As a prelude to clinical trails, the safety and efficacy of haemopoietic stem cell (HSC) mobilisation required investigation as colony-stimulating factors (CSFs) have been reported to flare RA. A double-blind, randomised placebo-controlled dose escalation study was performed. Two cohorts of eight patients fulfilling strict eligibility criteria for severe active RA (age median 40 years, range 24-60 years; median disease duration 10.5 years, range 2-18 years) received filgrastim (r-Hu-methionyl granulocyte(G)-CSF) at 5 and 10 microg/kg/day, randomised in a 5:3 ratio with placebo. Patients were unblinded on the fifth day of treatment and those randomised to filgrastim underwent cell harvesting (leukapheresis) daily until 2 x 10(6)/kg CD34+ cells (haemopoietic stem and progenitor cells) were obtained. Patients were assessed by clinical and laboratory parameters before, during and after filgrastim administration. RA flare was defined as an increase of 30% or more in two of the following parameters: tender joint count, swollen joint count or pain score. Efficacy was assessed by quantitation of CD34+ cells and CFU-GM. One patient in the 5 microg/kg/day group and two patients in the 10 microg/kg/day group fulfilled criteria for RA flare, although this did not preclude successful stem cell collection. Median changes in swollen and tender joint counts were not supportive of filgrastim consistently causing exacerbation of disease, but administration of filgrastim at 10 microg/kg/day was associated with rises in median C-reactive protein and median rheumatoid factor compared with placebo. Other adverse events were well recognised for filgrastim and included bone pain (80%) and increases in alkaline phosphatase (four-fold) and lactate dehydrogenase (two-fold). With respect to efficacy, filgrastim at 10 microg/kg/day was more efficient with all patients (n = 5) achieving target CD34+ cell counts with a single leukapheresis (median = 2.8, range = 2.3-4.8 x 10(6)/kg, median CFU-GM = 22.1, range = 4.2-102.9 x 10(4)/kg), whereas 1-3 leukaphereses were necessary to achieve the target yield using 5 microg/kg/day. We conclude that filgrastim may be administered to patients with severe active RA for effective stem cell mobilisation. Flare of RA occurs in a minority of patients and is more likely with 10 than 5 microg/kg/day. However, on balance, 10 microg/kg/day remains the dose of choice in view of more efficient CD34+ cell mobilisation.

Problems of antiarthritic therapy in the elderly.

Rheumatic diseases are prevalent in the elderly population, resulting in high morbidity caused mainly by lack of mobility. Consequently, the use of antirheumatic drugs in older persons is extensive. This review outlines some of the hazards encountered in the use of antirheumatic drugs in the elderly. Analgesics such as propoxyphene and acetaminophen are useful adjuncts to the treatment of arthritic pain, but propoxyphene has been associated with respiratory depression, and renal clearance of acetaminophen is reduced in elderly subjects. Salicylates may cause deafness, and like the other nonsteroidal anti-inflammatory drugs, may cause salt and water retention resulting in congestive cardiac failure. Phenylbutazone should not be used because of the risk of blood dyscrasia, and indomethacin has been reported as interfering with the antihypertensive effect of beta-blockers. Chloroquine levels may be raised in patients with impaired renal function, and there is increased risk of retinal damage with the drug in elderly subjects. Injectable gold compounds and penicillamine are not contraindicated in the elderly, because they are just as efficacious as in younger persons for the treatment of rheumatoid arthritis. Toxicity due to gold compound is not increased in the elderly, but skin rashes and abnormalities of taste do occur more commonly in elderly patients treated with penicillamine. Corticosteroids do not affect disease progression and therefore should be used only in acute severe disease for short periods of time. As in the younger population, treatment of gout in the elderly is dependent on renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of antirheumatic medication during pregnancy and in the puerperium.

Patients with rheumatic diseases will want to take as few medications as possible while they are conceiving, pregnant, or breast feeding. The guidelines above can be used to balance the risk of a drug effect on the fetus or neonate with the effect of provoking a flare in disease activity by ceasing the drug. Where no information on drug concentration in pregnancy or lactation exists, guidelines can be developed from knowledge of the drug's inherent metabolism. In most of the rheumatic diseases, disease activity can be reduced to a minimum using the smallest possible dose of drugs with known behaviors in pregnancy and lactation and thus providing minimal risk to mother and fetus.

Estradiol, estrone, and gonadotropin levels after use of vaginal estradiol.

The vaginal absorption of 0.5-mg tablets of micronized estradiol was evaluated in postmenopausal women. In a single-dose study, one hour after insertion, a 5.3-fold rise in mean serum estradiol levels and 1.5-fold rise in mean serum estrone levels were observed. Mean levels of luteinizing hormone and follicle-stimulating hormone were significantly depressed. In a three-week alternate-day regimen, mean serum levels of estradiol were consistently two to three times greater than those of estrone 12 hours after insertion. Vaginal absorption of micronized estradiol tablets into the systemic circulation was found to be rapid and efficient. The vaginal route was acceptable and well tolerated by patients. In addition, the major conversion of estradiol to estrone that follows oral or sublingual administration was reduced. The vagina may be a preferred alternate route for estrogen replacement therapy in selected patients.

Progress towards optimal trial end-points in rheumatoid arthritis.

Trials in rheumatoid arthritis have been difficult to perform and interpret due to disagreement over what to measure. This paper reviews the most frequently used measures and their validity against the background of the Outcome Measures in Rheumatology (OMERACT) consensus conferences. These conferences have resulted in the adoption of a core set of end-points to be used as a minimum in all clinical trials in rheumatoid arthritis. These are known as the World Health Organization/International League of Associations for Rheumatology (WHO/ILAR) core set. This set of measures comprises: pain;patient global assessmentphysical disability;swollen joints;tender joints;acute phase reactants;physician (assessor) global assessment; and, in studies of 1 or more years duration,radiographs of joints. Other developments include a renewed interest in aggregate end-points (indices) such as response criteria, and in the measurement of adverse effects and economic costs. In sum, measurement methodology in rheumatoid arthritis has been improved in time to take advantage of expected important advances in treatment.

Azapropazone - its place in the management of rheumatoid conditions.

The authors review the trials carried out on azapropazone in rheumatoid arthritis and other rheumatoid conditions. They comment that in terms of efficacy azapropazone would appear to be a useful non-steroidal anti-inflammatory analgesic which compares favourably with other established antirheumatic agents against which it has been tested. Its main advantages are its low incidence of side-effects and the fact that in the majority of the trials reported azapropazone treatment was preferred by patients to that with other agents.

Flurbiprofen-aspirin interaction: a double-blind crossover study.

Fifteen patients with seropositive rheumatoid arthritis were treated for 2-weeks periods with 150 mg flurbiprofen daily and with flubriprofen in the same dosage plus 3 g aspirin daily, the treatments being administered in random allocation. The results showed that there were no significant differences clinically between the two treatments. Serum levels of flurbiprofen were measured during both treatment periods in 4 patients. During the flurbiprofen and aspirin period there was a full in the serum levels of flurbiprofen was unchanged. No obvious reduction in clinical efficacy was apparent.

Night-time indomethacin in rheumatoid arthritis.

Indomethacin is commonly prescribed at night to relieve morning stiffness in patients with rheumatoid arthritis. Pharmacokinetic and pharmacodynamic interactions are frequently described with non-steroidal anti-inflammatory drugs, and the rationale of using more than one of these agents at the same time is questionable. A randomized crossover trial was carried out in 14 patients to compare the effects of 100 mg indomethacin at night with those of placebo when added to a baseline regimen of stabilized salicylate therapy with a slow-release preparation. Each treatment was given for 2 weeks. The results suggest that the addition of indomethacin produced no significant benefit in terms of reduction in the duration of morning stiffness or on the overall daily pain score.

Tenoxicam compared with diclofenac in patients with ankylosing spondylitis.

A randomized study was performed on 24 patients with ankylosing spondylitis to compare the efficacy and tolerability of 20 mg tenoxicam daily with 50 mg diclofenac twice daily. There were 6 withdrawals from the group taking tenoxicam and 4 from the diclofenac group. Depression in 1 patient taking tenoxicam was the only significant adverse event. Both drugs were otherwise well tolerated. Tenoxicam and diclofenac were rated as good or excellent by 27% and 55% of patients, respectively. Global assessment, pain and duration of morning stiffness were improved with both drugs but this improvement was not statistically significant and there was no statistically significant difference between the two groups. This study confirms that tenoxicam is effective and well tolerated but larger numbers would be required to detect a small difference between groups.