Identifying patients with rheumatoid arthritis with moderate disease activity at risk of significant radiographic progression despite methotrexate treatment.

OBJECTIVES: To determine the baseline factors predictive of significant radiographic progression (SRP) in patients with moderately active rheumatoid arthritis (RA) despite receiving methotrexate (MTX). METHODS: Patients from the MTX arm of the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) trial with sustained moderate RA (defined as ≥3.2 mean disease activity score in 28 joints ≤5.1 during the last 6 months of the first year) were analysed for SRP (mTSS >3.0 overall) after 2 and 3 years. Baseline predictors for SRP were identified by univariate and multivariate analyses. All variables shown to be significantly associated with SRP were categorised based on clinically relevant cut-offs and tertiles and were included in a matrix risk model. RESULTS: 228 patients were assigned MTX treatment, 210 patients were in the radiographic intention-to-treat population, and 96 of these had sustained moderate RA. SRP occurred in 25 (26%) and 33 (34%) patients after 2 and 3 years of MTX treatment, respectively. Univariate and multivariate analyses found that C reactive protein (CRP) and rheumatoid factor (RF) positivity at baseline were predictive of SRP after 2 and 3 years (p<0.05 for all). The matrix risk model showed that RF positivity and CRP levels >40 mg/L at baseline were significantly associated with SRP after 2 (p<0.05 for both; R(2)=0.24) and 3 years (p<0.05 for both; R(2)=0.22). The baseline erosion score was not found to be predictive of SRP. CONCLUSIONS: Patients with sustained moderate RA despite receiving MTX treatment are at risk of SRP, with both RF positivity and high CRP levels shown to be predictive of this.

Retreatment in patients with psoriasis achieving response with etanercept after relapse due to treatment interruption: results from the CRYSTEL study.

BACKGROUND: In clinical practice, patients with psoriasis may require intermittent therapy as part of their long-term treatment programme. Those achieving Physician's Global Assessment (PGA) of ≤ 1 (almost clear/clear) are more likely to be selected as candidates for intermittent therapy than those with a higher PGA (≥ 2; mild or worse), who may relapse sooner or have a delayed response. The objective of this analysis was to determine if patients achieving PGA ≤ 1 using intermittent etanercept (ETN) therapy could regain response (defined as PGA ≤ 2) after relapse. METHODS: In the CRYSTEL study (clinicaltrials.gov NCT00195507), patients with moderate-to-severe psoriasis were treated with ETN 50 mg twice weekly (BIW) for ≤ 12 weeks (or for an extra 12 weeks with ETN 25 mg BIW until PGA ≤ 2 was achieved). Patients who reached PGA ≤ 1 during this time were selected for this post hoc analysis (Cycle 1). Treatment was paused, and patients who relapsed (PGA > 2) were retreated with ETN 25 mg BIW until recovery (PGA ≤ 2, Cycle 2). Treatment cycles were continued for up to 54 weeks. The proportion of PGA responders and the time to attain response were calculated, and patient satisfaction was evaluated using the Patient Satisfaction Survey. RESULTS: During Cycle 1, 131 patients achieved PGA ≤ 1 within a median of 9 weeks and subsequently relapsed after treatment cessation. In Cycle 2, 119 (91%) patients attained PGA ≤ 2 within a median time of 7 weeks. The majority of patients were either 'very satisfied', 'satisfied' or 'somewhat satisfied' during both Cycle 1 (100% in total) and Cycle 2 (97% in total). CONCLUSION: Patients achieving the stringent criteria of PGA ≤ 1 with ETN therapy before ceasing treatment, and subsequently relapsing, were able to quickly regain response during retreatment. The majority of patients considered their therapy to be satisfactory.

A 24-week randomized clinical trial investigating the efficacy and safety of two doses of etanercept in nail psoriasis.

BACKGROUND: Nail psoriasis is common in patients with psoriasis and can seriously affect their quality of life. Current treatments are limited and there is no standard course of therapy. OBJECTIVES: To assess the efficacy and safety of etanercept (ETN) on nail psoriasis in patients with moderate-to-severe psoriasis. METHODS: Patients with moderate-to-severe plaque psoriasis, who had previously failed at least one form of systemic therapy for nail psoriasis, were randomized to receive open-label ETN 50 mg twice weekly (BIW) for 12 weeks followed by once weekly (QW) for 12 weeks (BIW/QW group) or ETN 50 mg QW for 24 weeks (QW/QW group). The primary endpoint was the mean improvement in the Nail Psoriasis Severity Index (NAPSI; score range 0-8) over 24 weeks in the target fingernail with the most severe abnormalities. RESULTS: Seventy-two patients received one or more doses of ETN (38 BIW/QW; 34 QW/QW) and 69 patients were included in the modified intent-to-treat population. At baseline, mean (standard error) target fingernail NAPSI score was 6.0 (0.3) in the BIW/QW group and 5.8 (0.3) in the QW/QW group. At week 24, mean target fingernail NAPSI score had decreased significantly by -4.3 [95% confidence interval (CI) -4.9 to -3.7; P < 0.0001] in the BIW/QW group and by -4.4 (95% CI -5.0 to -3.7; P < 0.0001) in the QW/QW group. Improvement in NAPSI showed significant correlation with Psoriasis Area and Severity Index improvement. ETN was well tolerated with no unexpected safety findings. CONCLUSIONS: Both ETN regimens were effective at treating nail psoriasis in this patient population.

Clinical and ultrasound-based composite disease activity indices in rheumatoid arthritis: results from a multicenter, randomized study.

OBJECTIVE: To evaluate the metrologic properties of composite disease activity indices in rheumatoid arthritis (RA), utilizing information derived from clinical, gray-scale (GS), and power Doppler (PD) ultrasound examinations, and to assess the classification of patients according to disease activity using such indices. METHODS: This ancillary study utilized data from a multicenter, prospective, randomized, parallel-group study conducted in subjects with moderate RA randomized to receive etanercept and methotrexate (ETN + MTX) or usual care (various disease-modifying antirheumatic drugs [DMARDs]). In multimodal indices, the 28 swollen joint count was either supplemented or replaced by clinically nonswollen joints in which the presence of synovitis was detected either by GS and/or PD and was calculated according to the Disease Activity Score in 28 joints (DAS28) or the Simplified Disease Activity Index (SDAI). Reliability, external validity, and discriminative capacity were calculated at baseline/screening by intraclass correlation coefficient, Pearson's correlation, and standardized response mean, respectively. RESULTS: Data from 62 patients (mean ± SD age 53.8 ± 13.2 years, mean ± SD disease duration 8.8 ± 7.7 years, mean ± SD disease activity 4.6 ± 0.5 [DAS28] and 20.9 ± 5.9 [SDAI]) were analyzed, with 32 receiving ETN + MTX and 30 receiving DMARDs. The metrologic properties were at least as good for GS- and/or PD-based indices as for their clinical counterparts. Using GS- and PD-supplemented indices, an additional 67.8% and 32.3% of patients (DAS28-derived and SDAI-derived indices, respectively) could be classified as having high disease activity at the screening visit. CONCLUSION: Multimodal indices incorporating ultrasound and clinical data had similar metrologic properties to their clinical counterparts; certain indices allowed for a significantly larger number of patients to be classified to either high or moderate disease activity at the screening visit.

Comparison of patient satisfaction with two different etanercept delivery systems. A randomised controlled study in patients with rheumatoid arthritis.

The objective of this study was to investigate patients' perceptions of the acceptability of two devices delivering etanercept for rheumatoid arthritis (RA) treatment and to explore whether specific patients' attributes are associated with device preferences. Two similar multicenter, open-label, randomised, parallel-design studies were conducted in a total of 13 European countries. A total of 640 adult patients with RA were randomised to receive etanercept 50 mg once-weekly subcutaneously for 12 weeks in either a pre-filled syringe (PFS) or a pre-filled pen (PFP). Patient satisfaction at week 12 was measured on a 0- to 10-point Likert scale (primary endpoint). The study was powered to demonstrate non-inferiority of a PFP over PFS for the primary endpoint. At week 12, mean patient satisfaction was 8.3 (± 2.4) points in the pen group and 7.2 (± 2.6) points in the syringe group. Non-inferiority and even superiority of the pen over the syringe was demonstrated. In conclusion, this study showed higher patient satisfaction in the group of patients injecting etanercept with a PFP compared with the group of patients using a PFS.

Patient satisfaction with injection devices: a randomized controlled study comparing two different etanercept delivery systems in moderate to severe psoriasis.

BACKGROUND: There is limited information regarding the acceptability of injection devices for biological agents. OBJECTIVES: The primary objective of the study was to investigate patients' perceptions on the acceptability of two devices delivering etanercept. The secondary objectives of the study were to explore whether patients' attributes are associated with preferences. METHODS: This was a multicentre, open-label, randomized, parallel-design study. Adult patients with psoriasis were randomized to receive etanercept 50 mg twice-weekly subcutaneously for 12 weeks, either as a pre-filled syringe or as a pre-filled pen. The primary outcome was the patient satisfaction at week 12 with the injection device, as measured on a 0-10-point Likert scale. The study was powered to demonstrate non-inferiority of a pen over a syringe for the primary endpoint. RESULTS: A total of 421 patients were randomized. Mean patient satisfaction at week 12 was 8.9 (±1.9) points in the pen group and 7.6 (±2.6) points in the syringe group. There was a statistically significant advantage for the pen compared with the syringe. Multiple correspondence analysis showed that very satisfied patients were the oldest and had had psoriasis for a longer duration, while less satisfied patients were the most anxious and depressed. PASI 75 response was achieved by 61% of patients in the pen group and 57% in the syringe group at week 12. CONCLUSIONS: This study showed higher patient satisfaction when injecting etanercept with a pen compared with a syringe. Factors associated with lower satisfaction are younger age, anxiety and depression.

Metrologic properties of ultrasound versus clinical evaluation of synovitis in rheumatoid arthritis: results of a multicenter, randomized study.

OBJECTIVE: To evaluate the intraobserver reliability, face validity, and discriminant capacity of different global ultrasound (US) scoring systems for measuring synovitis in rheumatoid arthritis (RA). METHODS: This study was ancillary to a 52-week, multicenter, prospective, randomized, open-label, parallel-group outpatient study conducted in patients with moderate RA who were randomized to receive either etanercept combined with methotrexate or various disease-modifying antirheumatic drugs. A total of 66 different synovitis scoring systems were constructed and evaluated, including 11 different joint combinations; data derived from clinical findings, gray-scale US, and power Doppler US (PDUS); and both binary counts and semiquantitative scores. RESULTS: Due to discontinuation of the trial, only 62 patients, a subset of the initially planned number of patients, were included in this study. Reliability was found to be better for gray-scale US and PDUS than for clinical evaluation of synovitis in patients with stable disease between the screening and baseline visits (range for intraclass correlation coefficient 0.6, 0.95 for gray-scale US and 0.56, 0.93 for PDUS versus 0.31, 0.75 for clinical indices). The median (range) difference in the discriminant capacities of clinical indices versus gray-scale US and versus PDUS was 0.25 (-0.64, 0.96) and -0.025 (-0.59, 0.53), respectively, in the period from baseline to 12 weeks. No relevant differences in metrologic properties were observed regarding the number and composition of joints between the different scoring systems. Our findings suggested that a simplified scoring system referring to gray-scale US and PDUS findings might be sufficient. CONCLUSION: Our findings indicate that gray-scale US and PDUS have better reliability than generally used clinical indices for evaluating synovitis in RA. PDUS has at least as good discriminant capacity as clinical assessment of synovitis for distinguishing between treatment arms.

Similar lipid profile but improved long-term outcomes with sirolimus after cyclosporine withdrawal compared to sirolimus with continuous cyclosporine.

Renal transplant recipients show an increased risk of cardiovascular disease compared with a nontransplant population. Herein we have shown an analysis of a randomized controlled trial wherein 525 patients receiving a first or second (9.7%) renal allograft from a deceased (89.1%), a living-related (7.8%), or a living-unrelated donor (3.1%) received sirolimus (SRL), cyclosporine (CsA), and steroids (ST) at the time of transplantation with randomization at 3 months after transplantation of 430 eligible patients to continue on SRL-CsA-ST or to have CsA withdrawn with increased SRL trough targets (SRL-ST group). Graft survival, patient survival, and renal function at 5 years were analyzed by average fasting total cholesterol (200 mg/dL) and triglyceride (240 mg/dL) subgroups. At 5 years, total, high-density lipoprotein (HDL), and low-density lipoprotein [LDL] cholesterol and triglyceride values were similar between the groups. Statins ( approximately 80% of patients of both groups) were most effective to lower cholesterol ( approximately 50 mg/dL; P < .001; both groups), and fibrates ( approximately 25% of patients of both groups) were most effective to decrease triglycerides ( approximately 100 mg/dL; P < .001; both groups). Renal function and blood pressure were significantly better with SRL-ST. Hypercholesterolemia and hypertriglyceridemia were associated with reduced graft survival, patient survival, and calculated GFR, but the only significant difference was lower graft survival among SRL-CsA-ST patients with hypertriglyceridemia. Cardiovascular-related deaths were reported in 3.7% and 2.8% of patients in the SRL-CsA-ST and SRL-ST groups, respectively. In conclusion, when compared with continuous SRL-CsA-ST, CsA withdrawal at 3 months followed by SRL-ST significantly improved glomerular filtration rate (GFR) and blood pressure without a further increase in lipid parameters or an incidence of untoward effects from hyperlipidemia, despite a 2-fold higher SRL exposure.

Sirolimus-based therapy with or without cyclosporine: long-term follow-up in renal transplant patients.

This open-label, phase 3b, extension trial in renal transplant recipients (Sirolimus Study 311) assessed the long-term safety of sirolimus (SRL) administered with cyclosporine (CsA) (SRL + CsA group, n = 98) or without CsA (SRL group, n = 69). Renal transplant recipients who had either completed one of seven previous SRL studies sponsored by Wyeth Research or had participated for > or =3 months and reached a protocol-designated endpoint were eligible for enrollment. Data were available for 167 patients, all of whom initially received steroids. Mean total SRL exposure was 1526 days, including previous study participation. After enrollment in the extension study, there were significantly more acute rejections in the SRL + CsA group (6.1% vs 0%, P < .05). Differences in rates of graft loss (3.1% vs 1.4%) and death (6.1% vs 1.4%) were not significantly different between SRL + CsA and SRL groups, respectively. At 48 months after transplantation, calculated GFR (53.4 vs 70.9 mL/min) and hemoglobin (124.9 vs 136.6 g/L) were significantly better in the SRL group. Lipid values were not significantly different between groups at 48 months. The incidence of treatment-emergent increased creatinine, anemia, hypertension, headache, epistaxis, abnormal kidney function, and upper respiratory infection were significantly higher in the SRL + CsA group, whereas no adverse events were significantly higher in the SRL group. Malignancies were reported more frequently (11.2% vs 0%) with SRL + CsA. Results from this extension study indicate that SRL-based therapy without CsA is a safe alternative to combination therapy with CsA, offering long-term improvement in renal function with no increased risk of late acute rejection.

Pattern of symptom improvement following treatment with venlafaxine XR in patients with generalized anxiety disorder.

BACKGROUND: The efficacy of anxiolytic drugs in generalized anxiety disorder (GAD) is conventionally assessed by evaluating changes in the total score of psychometric scales such as the Hamilton Rating Scale for Anxiety (HAM-A). The purpose of this pooled analysis of data was to evaluate the efficacy of venlafaxine extended release (XR) on individual items of the HAM-A and the Brief Scale for Anxiety (BSA). METHOD: Data were pooled from 5 studies of patients with GAD who were treated with either venlafaxine XR or placebo for 8 weeks (N = 2,021) and up to 6 months (N = 767). Individual items of the HAM-A and the BSA were examined. and, using the mean changes from baseline to endpoint, an effect size for each item was calculated by dividing the difference between baseline and endpoint values for each item by the standard deviation of this difference. The effect sizes determined for the venlafaxine group were compared with those for the placebo group. Items from each scale that are concordant with the DSM-IV diagnostic criteria for GAD were selected for further examination, and the specific effect sizes of each item were expressed after controlling for placebo effects. RESULTS: The effect size of the majority of the 14 items of the HAM-A scale and the 10 items of the BSA scale associated with treatment with venlafaxine XR was greater than with placebo at both 8 weeks and 6 months. Furthermore, the effect sizes at 6 months were generally greater than at 8 weeks in venlafaxine XR-treated patients. Effect sizes associated with venlafaxine XR were greatest for the HAM-A items that were most closely related to diagnostic symptoms of GAD, namely anxious mood, tension, intellectual functioning, and behavior at interview at both 8 weeks and 6 months. Similarly, GAD-related BSA items of inner tension, worrying over trifles, hostile feelings, and muscular tension were associated with the greatest improvements with venlafaxine XR at both time-points. CONCLUSION: The HAM-A and BSA items that most closely corresponded to DSM-IV diagnostic criteria for GAD showed the largest improvement during treatment with venlafaxine XR. This indicates that the specific symptoms of GAD can be treated effectively with venlafaxine XR, both in the short and longer term.

Case-control study of the risk factors for age related macular degeneration. France-DMLA Study Group.

AIM: A case-control study was initiated to determine the risk factors for the development of age related macular degeneration (AMD). METHODS: Study participants, who were all white, aged 50-85 years, and were recruited from private ophthalmology practices. Each practitioner enrolled patients with bilateral AMD, who were then matched with controls for sex and age. Environmental factors and systemic and ocular histories were screened. All patients had bilateral red-free fundus photographs and fluorescein angiography. Photographs were classified into pigment epithelium alterations, drusen, geographic atrophy, and exudative AMD. Statistical analysis included the identification of risk factors for AMD. A multivariate analysis was performed at the end of the study. Analysis included the entire study population and was carried out for each stage of AMD. RESULTS: 1844 controls were compared with 1844 patients with AMD. Mean age was 71 years for controls and 72 for cases. Logistic regression identified six major risk factors for AMD (whole population): arterial hypertension (odds ratio (OR) = 1.28), coronary disease (OR = 1.31), hyperopia (OR = 1.33), light coloured irises (OR = 1.22), and lens opacities or previous cataract surgery (OR = 1.55). The significance of vascular risk factors was increased for late stages of AMD, especially the atrophic forms (coronary disease, OR = 3.19). CONCLUSIONS: This large case-control study confirms some of the risk factors previously identified and may contribute to the determination of methods for prevention of AMD.

[Evaluation of trough/peak ratio of indapamide 1.5 mg sustained-release form assessed by ambulatory blood pressure monitoring]. / Evaluation du rapport vallée/pic de l'indapamide 1,5 mg comprimé enrobé a libération prolongée par la mesure ambulatoire de la pression artérielle.

Because of the high variability of casual blood pressure measurements. ABPM has become a complementary clinical tool for evaluating antihypertensive treatment. Nevertheless, there is still a lack of practical guidelines to interpret the data. A review of the literature shows that ABPM efficacy data are analyzed differently, especially the trough-to-peak ratio proposed by the Food and Drug Administration. Published trough-to-peak ratios are widely disparate due to the diversity of the calculation methods which are most often not justified. Thus inappropriate comparisons of these results can easily produce incorrect conclusions. The aim of this review is to select, through the literature, basic methodological requirements commonly agreed on for accurate assessment of trough-to-peak ratio, and to apply them to the ABPM data on indapamide, a diuretic related to the thiazides. Six methodological requirements commonly agreed on at this time are the following: 1. study design: placebo-controlled study with a placebo run-in period; 2. patients selection: compliance with the study protocol, record obtained before and after treatment for each patient; 3. population analysis: whole and responder population: 4. quality control of the records: 5. placebo effect subtraction; 6. global and individual calculation with the indication of median values. Given that, no T/P ratio, especially for a diuretic, has yet been calculated according to these requirements, the above methodological points were taken into account for the T/P calculation of indapamide, from a placebo-controlled dose-finding study involving 285 patients.

Regression of left ventricular hypertrophy in patients with essential hypertension. Results of 6 month treatment with indapamide.

Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity in hypertensive patients. The effects of diuretics on LVH have raised controversies, but recent studies suggest that diuretics are able to reduce LVH in hypertensive patients, mainly through a reduction in ventricular diameter. The present multicenter open study was designed to test the effects of indapamide, a widely used nonthiazide diuretic, on LVH in patients with essential hypertension. Patients had to have mild-to-moderate essential hypertension (supine diastolic blood pressure [sDBP] 95 to 115 mm Hg) with echocardiographic evidence of LVH (left ventricular mass index [LVMI] > 130 g/m2 for men and > 110 g/m2 for women). After a 2 week placebo run-in period, eligible patients underwent a 6 month treatment with 2.5 mg indapamide daily. All echograms were performed by the same investigator before and after 6 months of indapamide. Clinical and biological acceptability and quality of life (visual analog scale) were also studied. One hundred and thirty patients were included in the study and 112 completed the trial. Indapamide induced a significant reduction i systolic and diastolic blood pressures. Indapamide induced a marked reduction in posterior wall thickness (from 12.1 +/- 2.0 to 11.2 +/- 1.6 mm) and in interventricular wall thickness (from 12.7 +/- 1.7 to 11.8 +/- 1.9 mm; each P < .001) and a slight decrease in left ventricular diameter (P = .049). This resulted in a 13% reduction in LVMI (from 161.9 +/- 37.9 to 140.7 +/- 33.8 g/m2, P < .001). Left ventricular fractional shortening remained unchanged. There was no significant relation between changes in LVMI and changes in systolic, diastolic, or mean blood pressure. No significant adverse clinical or biological effects were reported during the study. The increased score of the visual analog scale indicated that overall well-being was improved (P < .001). Our study indicates that indapamide, in addition to blood pressure control, is able to reduce LVH. This effect was achieved mainly through a reduction in wall thicknesses rather than in internal cavity diameter.

An equivalence study of the safety and efficacy of a fixed-dose combination of perindopril with indapamide versus fixed-dose combinations of captopril with hydrochlorothiazide and enalapril with hydrochlorothiazide in the treatment of hypertension.

OBJECTIVE: The aim of this multicenter, randomly allocated, double-blind, parallel-group study was to evaluate the equivalence of three fixed-dose combination drugs in mild to moderate hypertension: perindopril + indapamide (4 + 1.25 mg), captopril + hydrochlorothiazide (50 + 25 mg) and enalapril + hydrochlorothiazide (20 + 12.5 mg). PATIENTS AND METHODS: After a single-blind, 4-week, placebo run-in phase, 527 patients (mean +/- SD age 54.5 +/- 1.2 years) with a supine diastolic blood pressure of 101.2-101.7 mmHg were randomly assigned to one of the three treatments for 8 weeks. The main evaluation criteria were diastolic blood pressure and serum potassium concentration. Equivalence was assessed on an intention-to-treat basis, using Schuirmann's method, which involves performing two one-tailed statistical tests on the data. Thirty-five patients were withdrawn from the study but there were no differences between groups in the reasons for withdrawal. RESULTS: Diastolic blood pressure decreased by between 13.1 and 14.2 mmHg in the three groups. The 90% confidence intervals for the differences between perindopril + indapamide and the other treatments were -1.1, +1.7 mmHg for captopril + hydrochlorothiazide and -0.4, +2.6 mmHg for enalapril + hydrochlorothiazide. Schuirmann's test was highly statistically significant (P<0.001 for perindopril + indapamide versus captopril + hydrochlorothiazide; P<0.002 for perindopril + indapamide versus enalapril + hydrochlorothiazide), so that the two one-sided hypotheses that the treatments were not equivalent were rejected at the nominal level of alpha = 0.05. Similarly, the safety of the treatments was equivalent in terms of serum potassium. The 90% confidence intervals of the differences between perindopril + indapamide and the other treatments were -8.7, -1.6% for captopril + hydrochlorothiazide (P = 0.004) and -1.5, +2.7% for enalapril + hydrochlorothiazide (P<0.001). CONCLUSIONS: We conclude that the safety and efficacy of perindopril + indapamide, captopril + hydrochlorothiazide and enalapril + hydrochlorothiazide were equivalent after 8 weeks of treatment in patients with mild to moderate hypertension.

[Therapeutic benefit of a low dose of indapamide: results of a double-blind against placebo European controlled study]. / Bénéfice thérapeutique d'une faible dose d'indapamide: résultats d'une étude européenne contrôlée en double aveugle contre placebo.

Indapamide is a diuretic prescribed in the treatment of hypertension at the dosage of 2.5 mg per day. In accordance with international recommendations concerning the need to use low doses of antihypertensives, a new lower-dose form of indapamide has been developed to achieve the best safety/efficacy ratio by decreasing the incidence of hypokalemia. A new pharmaceutical sustained-release (SR) form was developed to give a smooth pharmacokinetic profile in comparison with the indapamide instant release (IR) form. The aim of this study was to determine the lowest new dosage of the SR form producing similar hypertensive efficacy as the LR form, and decreasing the percentage of patients with a serum potassium concentration below 3.4 mmol/l. This multicenter study was designed as a single-blind, run-in, placebo period of 1 month, followed by a double-blind, active treatment period of 2 months, using parallel groups: 285 patients with essential uncomplicated mild-to-moderate hypertension (95 mmHg < or = supine diastolic blood pressure (sDBP) < or = 114 mmHg) were included and randomly treated by either IR indapamide (2.5 mg) or SR indapamide (1.5, 2.0, 2.5 mg). After 2 months of active treatment, the one-way analysis of variance on the principal criterion (difference in sDBP between M2 and M0) revealed a significant treatment effect (p = 0.016). The mean drop in sDBP (+/- standard deviation) was 5.8 mmHg (+/- 8.6) after 2 months of placebo; 10.1 mmHg (+/- 7.0) after indapamide IR 2.5 mg; and 11.0 mmHg (+/- 9.4), 8.9 mmHg (+/- 9.4), and 10.5 mmHg (+/- 8.5) after indapamide SR 1.5 mg, 2 mg, and 2.5 mg, respectively. The difference between the placebo and indapamide treatment was significant (p < or = 0.05). No significant difference was detected between the various indapamide treatments, i.e., no difference between the IR and SR formulations, no difference between the various dosages of the SR form, and therefore no dose/effect relationship in the dose interval tested (SR 1.5, 2, and 2.5 mg). The incidence of patients with a serum potassium concentration less than 3.4 mmol/l was lower with indapamide SR 1.5 mg (11%) than with indapamide 2.5 mg, SR 2 mg, and SR 2.5 mg, respectively: 29%, 18% and 14%. These results show the interest of a low dose of indapamide in improving the safety while producing the same antihypertensive efficacy.

Clinical and electrophysiological study of the peripheral nervous system in the elderly.

The effect of age on the peripheral nervous system was investigated by clinical examination and neurophysiological studies in 59 subjects aged 60-103 years and 23 young subjects. A full laboratory screen for factors which, though clinically silent, may constitute risk factors (RFs) for peripheral neuropathy was also performed in the elderly subjects. Our findings show that the presence of RFs affects exceptionally the electrophysiological parameters in a statistically significant way. The age-dependent changes in nerve conduction parameters were well predicted by non-linear models. The simultaneous electromyographical study demonstrates the re-innervation capacity of the motor system.

Effect of a dopaminergic agonist, piribedil (Trivastal 50 mg LP), on visual and spatial integration in elderly subjects.

Dopamine acts as a neuromodulator in the retina. Dopaminergic deficiency of any origin, as observed in elderly subjects, is associated with altered visual performances, and more specifically with altered perception of contrasts. The goal of this study was to compare contrast vision in elderly subjects and young subjects (first phase, n = 20), then to compare this function in elderly subjects before and after 3 months of treatment with a dopaminergic agonist, piribedil (Trivastal 50 mg LP), administered once daily (second phase, n = 20). The perception of contrast was analysed using a test measuring sensitivity to colour contrast yielding threshold values for sensitivity to contrast in eight spatial frequencies and three colours (red, green, blue) and in two directions (horizontal and vertical). The results of the first phase of the study demonstrated that elderly subjects showed a decrease in contrast perception in comparison with young subjects, primarily in the high frequency range, and over the full range of stimulation for direction and colour. In the second phase, elderly subjects, in comparison with young subjects, showed altered visual contrast, again in the high frequency range, but also in the low frequency range for horizontal simulation with red and blue. After 3 months of treatment with piribedil the mean contrast sensitivity threshold, over the entire frequency range, had significantly increased (P less than 0.05) for all stimulations, apart for red in the vertical direction. These results underline the value of treatment with a dopaminergic agonist, piribedil in visual disturbances in patients with dopaminergic deficiency (Parkinson patients or elderly subjects).

A hybrid device for measurement of left ventricular heat production.

The presented hybrid system allows precise temperature measurements in various sites of the circulation, from the acquisition and preprocessing of dilution curves. From haemodynamic data and left ventricular heat production, an in situ estimate of left heart efficiency is made available. A simplifying hypothesis allows the determination of total left ventricular heat production from three data inputs: (1) the coronary sinus blood flowrate, (2) the thermal coronary veno-arterial difference, (3) the ratio of thermodilution curves areas recorded in the aortic root and the coronary sinus, following a rapid injection in the left ventricular cavity of cold isotonic glucose. Experiments were performed on anaesthetized, artificially ventilated, closed-chest dogs, into which five catheters and probes had been inserted.

Computer determination of thoracic gas volume using plethysmographic "thoracic flow".

Plotting a line to the variables obtained during a panting maneuver, i.e. thoracic volume and mouth pressure, is the conventional way of computing plethysmographic thoracic gas volume (TGV). This procedure is reliable if the magnitude of the thoracic volume changes is large compared to the drift on the signal; this is one of the major problems in volumetric plethysmography. We propose replacing the thoracic volume signal (Vt) by its time derivative (Vt) and similarly mouth pressure (Pm) with its time derivative (Pm). Drift is thus ruled out, and the magnitude of Vt is preserved when the subject fails to carry out noticeable changes in thoracic volume during the panting, since even then the speed of these changes in thoracic volume remains high. The use of Vt and Pm appeared to be necessary when a minicomputer was connected to a pressure-compensated flow plethysmograph to obtain an automatic calculation of TGV. A regression-line technique applied to signals obtained during the panting was used to find the slope of the relation and thus TGV. However, this slope can only be predicted with less than 5% error if the correlation coefficient is very high (i.e., above 0.99). The analysis of 121 recordings from patients showed that the mean r was only 0.954 when Vt and Pm were used. It increased to 0.993 with Vt and Pm. For the same recordings the comparison of hand-calculated TGV and computer-derived TGV showed a much better agreement for the Vt-Pm method (standard error of the estimate (SEE) = 0.14 liter) than for the Vt-Pm method (SEE = 0.34 liter). These results emphasize that, in contrast to the manual technique, the computer does not adequately handle even a small drift of the thoracic signal. The proposed time-derivative method is therefore useful for a hand calculation, but essential to a reliable computer determination of thoracic gas volume