Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis.

OBJECTIVES: To measure MTX polyglutamates in circulating erythrocytes (E-MTX), mononuclear cells (MNC-MTX) and polymorphs (PMN-MTX) in rheumatoid arthritis (RA) patients and to see whether these correlated with clinical efficacy and side effects. METHODS: Sixty-five patients (40F, 25M; mean age 57 yrs.) with RA (ARA revised criteria) who had been on weekly pulse MTX (2.5-37.5 mg) for at least 2 months were entered into this study. The patients were classified as responders (R), partial responders (PR) or non-responders (NR) when blood was sampled for the MTX determination. Side effects since the initiation of MTX were also recorded. MTX-polyglutamates were measured (blinded to clinical details) using an enzymatic assay. RESULTS: E-MTX in responders and partial responders were significantly higher (p < 0.001) than in non-responders. Similarly, PMN-MTX were also higher, but the difference was only significant for the R group (p = 0.0019). The differences in concentrations could not be explained on the basis of the dose, which tended to be higher in NR than in R (p = 0.085). The concommitant prednisolone dose was significantly lower in R than in NR (p = 0.001), as were the ESR and CRP (p = 0.007, and p = 0.05 respectively), but the MCV was higher (p = 0.047). E-MTX tended to be higher in patients with side effects, but this difference did not reach statistical significance (p = 0.15). CONCLUSION: The results suggest that circulating intracellular levels of MTX polyglutamates in RBC and PMN correlate with clinical efficacy but not with toxicity in patients with RA.

A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease.

BACKGROUND: Previous studies suggest a potential benefit from nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD). Prescribing NSAIDs, however, carries the risk of significant gastrointestinal adverse events. OBJECTIVES: To study whether treatment with an NSAID prevents expected decline in AD patients and evaluate whether co-administration of the gastro-protective agent, misoprostol, with an NSAID is safe in AD. METHODS: The efficacy and safety of diclofenac in combination with misoprostol (D/M) was evaluated in 41 patients with mild-moderate AD in a prospective 25-week, randomized, double-blind placebo-controlled trial. Efficacy measures comprised the Alzheimer's Disease Assessment Scale cognitive and noncognitive subsections, Global Deterioration Scale, Clinical Global Impression of Change, Mini-Mental State Examination, Instrumental Activities of Daily Living, Physical Self-Maintenance Scale, and a caregiver-rated Global Impression of Change. RESULTS: There were no group differences with any of the outcome measures in an intent-to-treat analysis. There were some nonsignificant trends for the placebo group to have deteriorated more than the D/M-treated patients. Withdrawal rates were 12 of 24 in the D/M group and 2 of 17 in the placebo group. There were no serious drug-related adverse events. CONCLUSIONS: This pilot study, with small treatment numbers, did not demonstrate a significant effect of NSAID treatment in AD, but the trends observed justify further investigations with a larger number of participants. D/M is safe in AD patients, but its tolerability is not optimal.

Effects of non-steroidal anti-inflammatory drugs (NSAIDs) on human polymorphonuclear leucocyte function in buffer and plasma.

OBJECTIVE: To elucidate the mechanism of action of a wide range of non-steroidal anti-inflammatory drugs (NSAIDs) on the respiratory burst of isolated normal PMNs in buffered saline and plasma. METHODS: The oxidative burst of PMN was assessed by luminol enhanced chemiluminescence and myeloperoxidase-mediated iodination. Cells were stimulated by the synthetic tripeptide N-formyl-methionyl-leucyl-phenylalanine (FMLP), serum coated zymosan or the phorbol ester phorbol myristate acetate (PMA). RESULTS: When using buffered saline as the suspending medium, tenoxicam, piroxicam, ibuprofen, ketoprofen and diclofenac, at concentrations achieved clinically, inhibited both PMA- and FMLP-induced luminol chemiluminescence. Tenoxicam and piroxicam in buffered saline also inhibited the iodination reaction. However, in plasma, which mimics the in vivo situation more closely, the inhibitory effect was markedly reduced. Only tenoxicam and piroxicam were found to cause the inhibition of luminol chemiluminescence at concentrations achieved clinically. CONCLUSION: If these study conditions are representative of the in vivo pathological state, the results suggest that only tenoxicam, piroxicam and possibly diclofenac sodium are likely to possess anti-inflammatory properties which are independent from effects on cyclooxygenase.

NSAIDs and faecal blood loss in elderly patients with osteoarthritis: is plasma half-life relevant?

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) vary in their degree of gastrointestinal (GI) toxicity. NSAIDs with longer half-lives are of particular concern as they may be more toxic in the elderly. AIM: To compare the GI toxicity, by measurement of faecal blood loss, of short, intermediate and long half-life NSAID treatments compared with control in elderly patients with osteoarthritis. METHODS: Twenty-three patients, mean age 69 years, with osteoarthritis requiring NSAID treatment, received treatment with diclofenac 100 mg/day, naproxen 750 mg/day and piroxicam 20 mg/day, representing a short, medium and long half-life NSAID respectively, in a double-blind, randomised, three way, cross-over block design. In each case, a three week washout control phase was followed by active treatment phases of two weeks each with three week washout between treatment phases. RESULTS: Faecal blood loss, collected over 72 hours at the end of each treatment phase, was measured by 51Cr-labelled erythrocyte method. Comparison was made of mean 24 hour faecal blood loss with each treatment compared with control using repeated measures analysis of variance. Eighteen patients completed all phases of the study. Three patients were withdrawn due to GI bleeding; two during diclofenac treatment and one during treatment with piroxicam. Mean 24 hour faecal blood loss with diclofenac (0.53 mL +/- 0.21) was not significantly different from control (0.28 mL +/- 0.06), whereas it was significantly increased with naproxen (2.76 mL +/- 2.22) and piroxicam (1.16 mL +/- 0.62), p = 0.0013. CONCLUSION: A short half-life NSAID was associated with lower GI toxicity than a medium and long half-life NSAID, as measured by faecal blood loss.

Serum interleukin-6 and interleukin-6 soluble receptor in Alzheimer's disease.

Serum levels of interleukin-6 (IL-6) and interleukin-6 soluble receptor (IL-6sR) were measured in 41 patients (23 female and 18 male, mean age 72.5 years) with Alzheimer's disease (AD) and in 32 controls (14 women and 18 men, mean age 69.2 years) using enzyme-linked immunosorbent assays (ELISA). Proportions of individuals with detectable serum IL-6 concentrations did not differ significantly between patients and controls. There was however, a significant decrease in IL-6sR levels in Alzheimer's patients when compared with controls. Our results suggest that there is a dysregulation of IL-6 and its soluble receptor in AD.

Hormonal therapy increases arterial compliance in postmenopausal women.

OBJECTIVES: This study investigated the effects of hormonal therapy on large arterial properties. BACKGROUND: Arterial stiffness is an emerging risk marker for coronary heart disease and is potentially modifiable. Postmenopausal use of hormonal therapy is associated with a lower risk of coronary heart disease. METHODS: Total systemic arterial compliance (SAC) and pulse wave velocity (PWV) were determined in 26 premenopausal and 52 postmenopausal women, 26 of whom were taking hormonal therapy. RESULTS: Arterial compliance was greater in the premenopausal group (mean +/- SEM 0.57 +/- 0.04 arbitrary compliance units [ACU]) than in the postmenopausal group not taking hormonal therapy (0.26 +/- 0.02 ACU, p = 0.001). Postmenopausal women taking hormonal therapy had a significantly increased total SAC compared with women not taking hormonal therapy (0.43 +/- 0.02 vs. 0.26 +/- 0.02 ACU, p = 0.001). PWV in the aortofemoral region in the premenopausal women was 6.0 +/- 0.2 vs. 8.9 +/- 0.3 m/s (p < 0.001) in untreated postmenopausal women. However, postmenopausal women taking hormonal therapy had a significantly lower PWV than those not taking hormonal therapy (7.9 +/- 0.2 vs. 8.9 +/- 0.3 m/s, p = 0.01). Eleven postmenopausal women had their hormone replacement therapy withdrawn for 4 weeks, resulting in a significant decrease in SAC and a significant increase in aortofemoral PWV. CONCLUSIONS: The increased SAC and decreased PWV in women receiving hormonal therapy suggest that such therapy may decrease stiffness of the aorta and large arteries in postmenopausal women, with potential benefit for age-related cardiovascular disorders. The reduction of arterial compliance with age appears to be altered with hormonal therapy.

Reduced systemic arterial compliance is associated with left ventricular hypertrophy and diastolic dysfunction in older people.

OBJECTIVES: To study the relationship between left ventricular diastolic function and systemic arterial compliance in the older population. DESIGN: Cross-sectional survey. PARTICIPANTS: A total of 67 older volunteer participants (aged 67 +/- 5.4 years). MEASUREMENTS: Systemic arterial compliance (SAC) was measured using applanation tonometry and aortic velocimetry, and diastolic function was assessed using Doppler filling. Left ventricular mass was determined echocardiographically. RESULTS: There were significant univariate correlations between diastolic filling, as measured by E/A ratio, systemic arterial compliance (0.34, P < .01), and left ventricular mass (-0.41, P < .001). In multiple regression analysis, using diastolic filling as the dependent variable and heart rate, age, left ventricular mass corrected for body surface area, systolic and diastolic blood pressures, and arterial compliance as independent variables, the major determinants of diastolic filling were heart rate, left ventricular mass, and diastolic blood pressure. Arterial compliance did not make a significant independent contribution. CONCLUSION: This study demonstrates a positive relationship between diastolic filling and arterial compliance in the older population. However, in multiple regression analysis, heart rate, diastolic blood pressure, and left ventricular mass were the independent predictors of diastolic filling (E/A), whereas arterial compliance was not. These findings imply that therapeutic modulation of aortic stiffness would not, of itself, contribute to improvement in diastolic function.

Dosing implications of a clinical interaction between grapefruit juice and cyclosporine and metabolite concentrations in patients with autoimmune diseases.

OBJECTIVE: To determine the effect of chronic grapefruit juice administration on steady state blood concentrations of cyclosporine and metabolites in patients with autoimmune diseases. METHODS: 9 patients stabilized on administration of cyclosporine (range 0.7-6.7 mg/kg/day) were given either grapefruit juice or water using randomized crossover design. Whole blood samples were collected before the morning cyclosporine dose and during the 12 h interdose interval. Cyclosporine concentrations were measured using a relatively specific assay (Emit) and total metabolite concentrations were estimated using a nonspecific assay (polyclonal Abbott-TDx). RESULTS: Exposure to grapefruit juice produced significant increases in predose cyclosporine concentrations (p < 0.01) and total metabolite concentrations (p = 0.03) and the area under the cyclosporine and metabolite blood concentration-time curves (p = 0.005, p = 0.001, respectively). One patient developed significant neurological side effects associated with a 68.9 and 214% increase in predose cyclosporine and metabolite concentrations, respectively, during grapefruit juice co-administration. CONCLUSION: Grapefruit juice causes an increase in both parent and metabolite profiles, indicating an alteration in the disposition of cyclosporine and metabolites. This interaction is of potential clinical importance in terms of mechanism, side effects, and dosing.

Effects of age on neutrophil function and its relevance to bacterial infections in the elderly.

OBJECTIVE: To determine the effect of age on neutrophil function in patients with and without acute bacterial infections. METHOD: Four groups of patients were recruited: Group 1: 15 elderly patients with infection (mean age 80.4 +/- 1.9 years), Group 2: 15 elderly control patients without infection (mean age 81.1 +/- 2.2 years), Group 3: 8 young patients with infections (mean age 26.7 +/- 2.9 years) and Group 4: 23 young controls (mean age 27.6 +/- 0.9 years). The main outcome measures included neutrophil counts and respiratory burst activation as measured by luminol enhanced chemiluminescence. RESULTS: Mean neutrophil counts were significantly higher in young patients with infections (5.04 +/- 0.96 x 10(9)/L) compared with young controls (2.63 +/- 0.33 x 10(9)/L) (p = 0.008) and in elderly with infections (6.51 +/- 0.97 x 10(9)/L) compared with elderly controls (4.1 +/- 0.88 x 10(9)/L) (p = 0.046). There was no significant difference between neutrophil counts of old and young patients (p = 0.40) or controls (p = 0.16). Mean peak luminol chemiluminescence was significantly increased in young patients (3329 +/- 284 mV) compared with young controls (1398 +/- 108 mV) and in elderly patients (2994 +/- 219 mV) compared with elderly controls (1674 +/- 197 mV) (p < 0.001). There was no significant difference between chemiluminescence activities of young and elderly controls (p = 0.41) or young and elderly patients (p = 0.14). CONCLUSION: Age is not associated with a change in neutrophil number or activity in the absence of bacterial infection. Infection in both young and elderly produces a significant increase in neutrophil number and chemiluminescence activity.

Age as a basis for healthcare rationing. Arguments against agism.

Age alone is a poor marker of disability. Decision making in medicine should be based on potential benefit to the individual. Most healthcare expenditure on the elderly is for routine care, which few could argue should be denied because of age. Healthcare reforms that encourage functional independence and community based care of the elderly are more likely to lead to cost savings than simple rationing according to age. Treatment options previously thought futile in the elderly, particularly surgical interventions and drug therapy for cardiovascular disease, have been shown to be effective in terms of improved health and cost benefit. Thus, discrimination on the basis of age (agism) is not only ethically unacceptable in a society embracing principles of justice and equity, but also unsupportable on scientific and/or economic analysis.

Extended hospital stays with increasing age: the impact of an acute geriatric unit.

OBJECTIVES: To examine the association between increasing age and extended length of hospitalisation, and the impact of an acute geriatric unit on this association. DESIGN: Retrospective analysis of concurrently collected data of patients admitted to three general medical units, one of which was an acute geriatric unit. SETTING: Alfred Hospital, Melbourne (a tertiary referral teaching hospital), between 1 July 1993 to 30 June 1994. PATIENTS: Those classified into the same diagnosis-related groups (DRGs) as the 15 most common DRGs of the acute geriatric unit. OUTCOME MEASURE: Incidence of patients with extended lengths of stay ("high outliers"), analysed by age, medical unit and DRG. RESULTS: Of 3499 patients discharged from the hospital with the 15 study DRGs, 303 patients (8.6%) were from the acute geriatric unit, and 274 and 300 patients (7.8% and 8.5%) were from the two other general medical units, respectively. Patients in the acute geriatric unit were significantly older (median age group, 75-79; age range, 18-98) than patients in all other hospital units (median age group, 60-64; age range, 18-97) (P < 0.0001). Analysis of patients with respiratory and cardiovascular DRGs admitted to all general medical units compared with specialty units showed this age discrepancy was even more marked for patients aged over 85. There was an increased likelihood (P < 0.001) of an extended length of stay for patients aged over 55. The incidence of high outliers for comparable DRGs was lower for patients cared for by the acute geriatric unit, compared with general medical units. In the acute geriatric unit, unlike the overall trend, the proportion of high outliers did not increase with age. CONCLUSIONS: The specialised management of acute geriatric medical units can counteract the trend towards increased incidence of high outliers with increasing age, despite significantly older patients.

Aminoglycoside dosing: one, two or three times a day?

The safety and efficacy of conventional aminoglycoside dosing regimens have been proven in clinical trials. Higher doses at longer intervals may be more effective if they result in higher peak serum levels of the drug, but few trials of "once-a-day" dosing have shown improved clinical outcome. The clinical safety of allowing trough serum levels to fall below the minimum inhibitory concentration is not established. Literal "once-a-day" dosing will result in drug accumulation and toxicity in patients with reduced renal clearance, and in potential lack of efficacy and the emergence of antibiotic-resistant organisms in those with increased renal clearance. However, modified "once-a-day" dosing, with the interval determined by the individual's renal clearance rate (hence avoiding subtherapeutic trough levels), will avoid these problems.

Second-line agents for rheumatoid arthritis.

Second-line agents (disease-modifying agents or slow-acting antirheumatoid drugs) are well established for synovitis that persists despite treatment with non-steroidal anti-inflammatory agents. Indications for their use in the elderly are similar to those in younger people, but the elderly are at higher risk of adverse reactions. Therefore, lower doses, more cautious patient selection and more frequent monitoring for adverse reactions are recommended. Low dose corticosteroids are often effective in the elderly and obviate the need for second-line agents.

Gout: 'a disease of plenty'.

Gout is a syndrome caused by an inflammatory response to the formation of monosodium urate monohydrate crystals which develop secondary to hyperuricaemia. Acute and chronic forms occur. Hyperuricaemia may be due to environmental and/or genetic factors. It most commonly affects middle-aged males. This article discusses the management of both acute and chronic gout.

Fluoxetine induced dyskinesia.

A case of fluoxetine induced dyskinesia in an elderly woman with previous use of low dose haloperidol is described. In contrast to neuroleptic induced tardive dyskinesia it was characterised by a rapid onset after commencing fluoxetine and rapid resolution on cessation. In the case discussion we describe other cases of fluoxetine induced extrapyramidal syndromes and possible mechanisms.

Relevance of pharmacokinetics and pharmacodynamics.

Appropriate and rational use of drugs in the elderly is a matter of growing medical and social concern. The elderly as a group are particularly prone to adverse drug reactions. Such reactions have often been due to inappropriate drug prescribing, based on incomplete recognition and knowledge of changes in drug handling with age and pathological states associated with ageing. Recognition of such changes with modification of prescribing practice may lead to benefits by minimising the incidence of adverse drug reactions. This article discusses the current knowledge of age-related changes in drug absorption, distribution, clearance and sensitivity and some implications of these changes for clinical therapeutics in the elderly.

Interaction of cisplatin with other cytotoxics and non-steroidal anti-inflammatory drugs.

This study investigated a possible interaction between cisplatin, other cytotoxics and non-steroidal anti-inflammatory drugs. Experiments were performed in quadruplicate. Plasma was spiked with cisplatin with or without another cytotoxic or non-steroidal anti-inflammatory drug. The results were analysed by Student's t-test and a p value of less than 0.05 was accepted as statistically significant. No interaction between cisplatin and the other cytotoxics was demonstrated. However, an increase in free cisplatin was noted when mixed with indomethacin (p = 0.019). No interaction with the other non-steroidal anti-inflammatory drugs was demonstrated.

Pain management for the elderly.

Pain management for the elderly is based on the same principles as for all other age groups. There is no evidence that the elderly patient and the young patient perceive pain differently. Pain management should aim at achieving a specific diagnosis and a specific treatment with the appropriate choice of analgesic used in the optimal regimen and should give attention to all other factors contributing to the patient's suffering. Geriatric medicine uses an essentially multidisciplinary approach to treatment of medical problems, and this doctrine should apply to treatment of pain.