Rafael Segal

The effect of mini-dose aspirin on renal function and uric acid handling in elderly patients

OBJECTIVE Aspirin is known to have a bimodal effect on the renal handling of uric acid (UA). High dosages (>3 gm/day) are uricosuric, while low dosages (1-2 gm/day) cause UA retention. Although very-low-dose (mini-dose) aspirin is used increasingly as a platelet aggregation inhibitor, no studies have been published on whether aspirins renal effects occur at dosages of <0.5 gm/day. The aim of the present study was to evaluate the effects of commonly used mini-dosages of aspirin on renal function and UA handling in elderly patients. METHODS The study included 49 elderly inpatients (age 61-94). Patients were excluded if they had renal failure, hyperuricemia, gout, or a history of bleeding, or if they were receiving anticoagulants, aspirin, or nonsteroidal antiinflammatory drugs. Previous medications and diet were kept unchanged. Aspirin was administered as follows: 75 mg/day (week 1), 150 mg/day (week 2), 325 mg/day (week 3), and 0 mg/day (week 4). Baseline and weekly samples of blood and urine were evaluated for UA, creatinine, blood urea nitrogen, creatinine clearance, UA excretion, UA clearance, and plasma levels of aspirin. RESULTS At the lowest dosage, aspirin caused a 15% decrease in the rate of UA excretion (P = 0.045 by t-test), which was associated with a slight but significant increase in serum levels of UA (P = 0.009). These effects on UA levels were gradually reduced with increasing dosages of aspirin (multivariate analysis of variance with repeated measures showed no statistically significant difference in the rate of UA excretion between weeks 1-3 and week 0 [baseline], but the difference in serum UA levels for the same comparison was statistically significant [P = 0.038]). Generally, creatinine and UA clearance rates paralleled each other during aspirin treatment. However, 1 week after aspirin was discontinued, creatinine clearance remained decreased while UA clearance returned to baseline. Plasma aspirin concentrations were low and variable. However, patients with above-median aspirin levels had significantly greater changes in serum creatinine levels, urinary UA excretion rates, and UA clearance rates following the first week of aspirin treatment. Hypoalbuminemia and concomitant treatment with diuretics enhanced the effects of aspirin on renal function and UA retention. CONCLUSION Mini-dose aspirin, even at a dosage of 75 mg/day, caused significant changes in renal function and UA handling within 1 week in a group of elderly inpatients, mainly in those with preexisting hypoalbuminemia. Given the widespread (and often unmonitored) use of mini-dose aspirin, especially among the elderly, these findings call for clinician alertness as well as for further studies to clarify the mechanisms underlying these phenomena.

Methotrexate : mechanism of action in rheumatoid arthritis

Most studies of immune function in rheumatoid arthritis (RA) patients treated with methotrexate (MTX) show only marginal effects on humoral or cellular immune responses. These include measurements of lymphocyte subsets, proliferative responses to mitogens, immunoglobulin production, rheumatoid factor and immune complexes. The mechanism of action of MTX in RA might be more antiinflammatory than immunosuppressive. This is supported by the rapid clinical response to drug treatment and by data from in vitro and animal studies. The inhibition of interleukin-1 (IL-1) activity or other inflammatory cytokines by MTX may play an important role in the antiinflammatory effect of MTX. MTX effects in RA are not fully understood and further studies are needed to clarify its mechanism of action. MTX has crucial effects on the cascade of events initiated by some cytokines (IL-1, IL-6, tumor necrosis factor), which plays a major role in RA and other inflammatory diseases.

Positive anti-cyclic citrullinated proteins and rheumatoid factor during active lung tuberculosis

Objectives: To determine the prevalence of anti-cyclic citrullinated proteins (anti-CCP) and IgM rheumatoid factor (RF) in sera of patients with TB compared with healthy controls. Patients and methods: 47 consecutive patients with recently diagnosed active pulmonary TB and 39 healthy controls were studied. Data were collected by questionnaire on clinical features of the disease, duration of symptoms, fever, cough, arthralgia, myalgia, sicca symptoms. Serum samples were collected from patients before starting treatment for TB and frozen at −20°C. Anti-CCP and IgM RF were evaluated by ELISA. Results: The mean (SD) duration of TB related symptoms was 4.4 (1.7) months, 73% had fever, 94% a cough. Rheumatic symptoms were relatively rare: arthralgia (4%), myalgias (4%), eye and mouth dryness (2% and 9%, respectively). Mean (SD) levels of anti-CCP were significantly increased in patients with TB compared with controls: 44.9 (51) IU v 20 (7.3) IU (p = 0.002). Serum levels >40 U were found in 15/47 (32%) patients compared with 1/39 (2.6%) controls (p = 0.002). Mean (SD) serum levels of IgM RF were significantly increased in patients with TB: 17.8 (19) v 4.3 (5) (p<0.0001). IgM RF was positive (>6 IU) in 29/47 (62%) patients v 1/39 (2.6%) controls (p<0.0001). Conclusions: A significant proportion of patients with active TB have an increased titre of anti-CCP and IgM RF.

Molecular analysis of HLA-B27 haplotypes in Caucasoids. Frequencies of B27-Cw in Jewish and Spanish populations.

PCR in combination with SSO probes was used to analyze the polymorphism in exons 2 and 3 of HLA-B27 subtypes and HLA-C-related alleles in two genetically distant Caucasian groups: Spanish and Jewish populations. AS patients and healthy B27 donors from both populations were analyzed in order to ascertain B27-Cw haplotypes. Three different ancestral haplotypes were found to be represented in both populations: B*2705/Cw*0102, B*2705/Cw*02022, and B*2702/Cw*02022. The B*2705 (92.5%) was the most frequent allele found in the Spanish population, carried by B*2705/Cw*0102 (60.9%) and B2705/Cw*02022 (30.4%) haplotypes. In contrast, B*2702 (59.4%) was the most prevalent allele found in the Jewish population and was carried by the B*2702/Cw*02022 (63.3%) haplotype. No different allelic and haplotypic distributions were among healthy and AS patients in either Spanish or Jewish populations. The differences found in the distribution of B27 haplotypes among Spanish and Jewish Caucasian populations are consistent with the genetic distance of these ethnic groups. When the Jewish population was subdivided into Ashkenazi (A) and non-Ashkenazi (NA) groups, no significant differences were observed in the distribution of B*2702/Cw*02022 haplotype. Minor differences were observed in the underrepresented B*2705 haplotypes. The present results reflect the ancestral affinities of A and NA Jewish populations. A possible HLA-B27 evolutive pathway in Caucasians is proposed according to the data available for the B27/Cw ancestral haplotypes in Spanish and Jewish groups.

Increased incidence of urinary tract infection in patients with rheumatoid arthritis and secondary Sjögren's syndrome.

The incidence of lower urinary tract infection in 120 women with rheumatoid arthritis and secondary Sjögrens syndrome was evaluated retrospectively. Thirty one patients (26%) had secondary Sjögrens syndrome. Recurrent urinary tract infection was significantly more common in these patients (11/31) than in patients without Sjögrens syndrome (4/89). Habitual leucocyturia was also more common in patients with secondary Sjögrens syndrome (18/31) than in patients with rheumatoid arthritis without Sjögrens syndrome (8/89). Of seven patients with vaginal sicca symptoms, six had recurrent urinary tract infection. Urinary 24 hour mucopolysaccharide excretion in 20 patients with Sjögrens syndrome was similar to the excretion in 10 patients without Sjögrens syndrome. These results show that recurrent urinary tract infection is significantly more common in women with rheumatoid arthritis and secondary Sjögrens syndrome. A local deficit in protective urinary mucosal secretion or other immune mechanisms may be responsible for this susceptibility.

The impact of hemiparalysis on the expression of osteoarthritis

OBJECTIVE Primary generalized osteoarthritis (OA), the most prevalent joint disease, is usually symmetric. Sporadic case reports mention decreased OA manifestations in limbs in which there are neurologic deficits, but no systematic research has been published. The aim of the present study was to examine these observations in a planned and controlled survey in a group of patients with OA. METHODS Seventy-five geriatric patients with a history of stroke and hemiparalysis were studied clinically and radiographically (hand radiographs; graded according to a modified Altman method) for the presence and the degree of OA in the hands. Detailed clinical and radiologic scores were calculated for each hand. Demographic, occupational, and neurologic data were collected. Patients with other joint or neurologic conditions were excluded. A group of 55 elderly patients without stroke were similarly studied (controls). Scores in the paralyzed hand were compared with those in the nonparalyzed hand in the stroke patients and subgroups (by Students paired t-test and Wilcoxon test). Scores in the dominant hands were compared with those in the nondominant hands in stroke patients and control subjects (by Students paired t-test and Mann-Whitney test). Correlation between the degree of neurologic damage and OA asymmetry (Pearsons correlation coefficient) was also sought. RESULTS Paralyzed hands showed significantly fewer OA changes than nonparalyzed hands, both clinically and radiologically. This trend, accentuated in patients with more severe paralysis, disappeared in those with mild residual paresis. Asymmetry of OA was more pronounced in patients with flaccid, compared with spastic, paralysis. The degree of paralysis and loss of muscle strength correlated with the degree of OA asymmetry. Women had significantly higher OA scores than men. In the control group, dominant hands had higher OA scores, but this finding was concealed among hemiparalyzed patients. Lifetime gross occupational load and present grip strength did not correlate with the degree of OA. CONCLUSION In elderly patients, hemiparalysis reduces ipsilateral hand expression of OA, while OA is accentuated (or increased) in the dominant hand of patients without paralysis. This first systematic study confirms the findings of previous case reports and lends support to the role of biomechanical factors in the development of OA.

Methotrexate in rheumatoid arthritis: a prospective study in Israeli patients with immunogenetic correlations.

In a prospective open study 44 Israeli patients with rheumatoid arthritis were treated with weekly low dose methotrexate (MTX) for up to 36 months. Nine patients withdrew from the study: six because of side effects and three due to inefficacy. One patient died of septicaemia following septic arthritis. Significant improvement, graded by Ritchie articular index, grip strength, physicians global assessment, erythrocyte sedimentation rate (ESR), and platelet counts, was noticed in response to treatment. Seronegative patients had a better clinical response. Transient gastrointestinal symptoms were common and correlated with increases of serum aspartate transaminase (AST). HLA-DR1 and DR7 were significantly associated with increased serum AST concentrations.

Therapeutic drug monitoring of theophylline in frail elderly patients: oral compared with nasogastric tube administration.

Summary Treating debilitated elderly patients through nasogastric tube (NGT) can change the pharmacokinetic characteristics of drugs, mainly those that are slow released (SR). The purpose of this study was to compare pharmacokinetic parameters between patients who receive SR theophylline orally and those who receive it through NGT. Patients and Methods The authors studied elderly patients in the geriatric ward receiving SR theophylline for chronic obstructive lung disease. In 17 patients fed by NGT (group I), theophylline was removed from the capsule and mixed with 10 mL of water. Group II included 15 patients who swallowed the drug orally. Theophylline blood levels were measured, as were peak concentration (Cmax), time to peak (Tmax), and area under the serum concentration-time curves (AUC). Results The mean daily dose was not statistically different between the two groups: 320 ± 130 (200–500) mg/d in group I and 360 ± 85 (200–500) mg/d in group II, given twice daily. All pharmacokinetic measurements were lower in group I as compared with group II: trough theophylline blood levels were 3.78 ± 3.2 (0.5–10.77) &mgr;g/mL versus 8.63 ± 4.6 (0–15.61) &mgr;g/mL (P = 0.002); Cmax was 6.53 ± 4.1 (1.3–13.33) &mgr;g/mL versus 10.51 ± 3.30 (4.3–16.28) &mgr;g/mL (P = 0.0058), and AUC was 50.04 ± 38.59 (11–112) &mgr;g/h/mL versus 80.37 ± 28.8 (23–148) &mgr;g/h/ml (P = 0.024). Conclusions Patients receiving the drug through NGT had variability and unexpectedly low blood levels. Therefore, the pharmacokinetic parameters of SR preparations should be evaluated before their administration through NGT.

Management of adverse clinical events by duty physicians in a nursing home

Background and aims: The nature of adverse clinical events (ACE) during duty hours (16:00-08:00 and holidays), as well as the way they are addressed by duty physicians (DP) in a nursing home (NH) are the subject of this study. Methods: Data, including medical details concerning ACEs and the resultant referrals to hospital, were collected prospectively during 183 consecutive days in a 90-bed NH. Results: Ninety-six residents experienced 370 ACEs, representing an average of one for every 44.5 patient days. The highest rate of events was during evening hours (18:00–21:00). The most prevalent ACE was fever (32%). Most cases (53%) were treated by the DPs on site. No intervention was needed in 19% of cases, whereas 28% of ACEs (104 cases) were referred to the Emergency Room (ER) of a general hospital. Sixty-six percent of these were actually admitted. The rate of ER referral of residents was one for every 158 patient days. About 40% of the referred patients had been discharged from hospital the previous week. High fever was the commonest cause for referral: 47%. During the working hours of the study period, the rate of referral by the staff physician was only 1 for every 915 patient days. Only 17% of these had high fever. Conclusions: Evening rounds by staff physicians, strengthening of working relations with hospital physicians, as well as fostering intravenous treatment in NHs, are suggested as means for reducing hospital transfers. A standardized method for the reporting of ACEs and referrals to hospitals should be adopted in order to facilitate comparisons between NHs and to evaluate its use as a quality indicator.

Pharmacokinetics of ciprofloxacin in hospitalized geriatric patients: comparison between nasogastric tube and oral administration.

Objectives: Drug administration to debilitated elderly patients on enteral feeding through a nasogastric tube (NGT) can modify the pharmacokinetic characteristics of the drug and influence its therapeutic blood concentration. The aim of this study was to evaluate the pharmacokinetics of ciprofloxacin administered through an NGT and to compare it with those of a group of patients receiving the drug orally. Methods: Twenty patients in stable clinical and hemodynamic condition from the long-term care ward of a geriatric multilevel hospital were studied. Patients in group 1 (n = 10) had oropharyngeal dysphagia and received food and medications, including ciprofloxacin, by NGT. Group 2 (n = 10) included age- and disease-matched orally fed patients from the same department receiving ciprofloxacin orally. Blood samples for ciprofloxacin concentration were taken at steady state, before drug administration, time 0, and at 1, 2, 3, 4, 6, 8, and 10 hours after drug administration. Ciprofloxacin was measured using liquid chromatography with tandem mass spectrometric detection. The mean daily dose was the same in both the groups: 1000 mg (500 mg twice daily). Results: Pharmacokinetic parameters of ciprofloxacin were not significantly different between the 2 groups: trough concentrations were 1.24 ± 0.95 &mgr;g/mL (0.25–3.67 &mgr;g/mL) versus 1.30 ± 0.61 &mgr;g/mL (0.21–2.36 &mgr;g/mL) (P = 0.76); Cmax 3.30 ± 2.16 &mgr;g/mL (1.54–8.62 &mgr;g/mL) versus 4.24 ± 1.99 &mgr;g/mL (2.24–9.02 &mgr;g/mL) (P = 0.356); tmax 2.8 ± 1.5 versus 3.1 ± 2.8 hours (P = 0.799); and AUC0–10 20.2 ± 12.1 &mgr;g·h−1·mL−1 (9–51.07 &mgr;g·h−1·mL−1) versus 24.4 ± 13.0 &mgr;g·h−1·mL−1 (5.57–52.48 &mgr;g·h−1·mL−1) (P = 0.493), in the oral fed versus NGT, respectively. Conclusions: Ciprofloxacin pharmacokinetic parameters are not significantly different between patients receiving the drug through NGT compared with those who received it orally, and therefore, in frail elderly patients, this route of administration can be considered.