Estimated glomerular filtration rate and albuminuria are independent predictors of cardiovascular events and death in type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study.

AIMS/HYPOTHESIS: We investigated effects of renal function and albuminuria on cardiovascular outcomes in 9,795 low-risk patients with diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. METHODS: Baseline and year 2 renal status were examined in relation to clinical and biochemical characteristics. Outcomes included total cardiovascular disease (CVD), cardiac and non-cardiac death over 5 years. RESULTS: Lower estimated GFR (eGFR) vs eGFR ≥90 ml min⁻¹ 1.73 m⁻² was a risk factor for total CVD events: (HR [95% CI] 1.14 [1.01-1.29] for eGFR 60-89 ml min⁻¹ 1.73 m⁻²; 1.59 [1.28-1.98] for eGFR 30-59 ml min⁻¹ 1.73 m⁻²; p < 0.001; adjusted for other characteristics). Albuminuria increased CVD risk, with microalbuminuria and macroalbuminuria increasing total CVD (HR 1.25 [1.01-1.54] and 1.19 [0.76-1.85], respectively; p = 0.001 for trend) when eGFR ≥90 ml min⁻¹ 1.73 m⁻². CVD risk was further modified by renal status changes over the first 2 years. In multivariable analysis, 77% of the effect of eGFR and 81% of the effect of albumin:creatinine ratio were accounted for by other variables, principally low HDL-cholesterol and elevated blood pressure. CONCLUSIONS/INTERPRETATION: Reduced eGFR and albuminuria are independent risk factors for cardiovascular events and mortality rates in a low-risk population of mainly European ancestry. While their independent contributions to CVD risk appear small when other risk factors are considered, they remain excellent surrogate markers in clinical practice because they capture risk related to a number of other characteristics. Therefore, both should be considered when assessing prognosis and treatment strategies in patients with diabetes, and both should be included in risk models.

Fibrates and microvascular complications in diabetes--insight from the FIELD study.

Fibrates are widely prescribed lipid-lowering drug in the treatment of dyslipidemia. Their main clinical effects, mediated by peroxisome proliferative activated receptor (PPAR) alpha activation, are a moderate reduction in total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, a marked reduction in triglycerides (TG) and an increase in high-density lipoprotein cholesterol (HDL-C), usually dependent of their baseline levels and dyslipidemia type. A beneficial effect on cardiovascular outcomes but also on inflammatory and thrombogenesis pathways as well as antioxidant properties have been evidenced conferring other pleiotropic effects to fibrates. Diabetic retinopathy, nephropathy and neuropathy are the major microvascular complications of Type 2 diabetes mellitus (T2DM) and their presence can accentuate the risk of cardiovascular disease. Hyperglycemia, hypertension, genetic susceptibility among other risk factors play a significant role in the development and progression of these complications. Plasma lipid abnormalities are also involved in the pathogenesis of microvascular diseases suggesting a potential benefit of lipid lowering drugs in their prevention. Clofibrate was the first fibrate in the 60's to show an improvement in the retinal hard exudation in subjects with diabetic retinopathy. Recently, in the Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) study fenofibrate treatment demonstrated a significant 30% reduction in the need for laser therapy in patients with and without known diabetic retinopathy, and more particularly in the first course of laser treatment for both macular edema and proliferative retinopathy. In addition, fenofibrate treatment was associated with less albuminuria progression and reduced risk of non traumatic distal amputations. These results, along with previous evidence of positive effects on microvascular complications, suggest that fibrates, and particularly fenofibrate, offer good opportunity to prevent the most serious complications of diabetes.

Acute and chronic effects of low dose almitrine bismesylate in the treatment of chronic bronchitis and emphysema.

OBJECTIVES: Study of the acute and chronic effects of low-dose almitrine therapy in stable hypoxaemic patients with chronic bronchitis and emphysema. METHODS: A low daily dose of 75 mg almitrine bismesylate was administered for six months in 23 patients with chronic bronchitis and emphysema. Nine patients (group 1) were placed on oral almitrine bismesylate 25 mg t.i.d. after they had received a single intravenous dose of 60 mg almitrine three months earlier. Fourteen additional patients, seven receiving almitrine (group 2) and seven placebo (group 3) were randomized for a 6 month double-blind evaluation of both acute and chronic effects of 75 mg almitrine on pulmonary gas exchange and on pulmonary haemodynamics. All patients were followed-up with regular measurements of blood gases, body plethysmography and with evaluation of peripheral nerve function. RESULTS: Acute effects of almitrine were a significant increase in arterial oxygen tension by 14 mmHg after intravenous (p < 0.001) and by 15 mmHg after oral administration (p < 0.001), amelioration of hypercapnia, a slight transient increase in mean pulmonary artery pressure from 26 +/- 7 to 29 +/- 6 mmHg (NS) and a decrease of shunt due to improvement in ventilation/perfusion mismatching. In contrast, no acute changes in blood gases and pulmonary pressures were seen in the placebo group. A combination of almitrine with oxygen (8-10 L/min) was most effective in amelioration of hypoxaemia and shunt. With chronic almitrine therapy, the improvements in gas exchange persisted without elevation of pulmonary artery pressure (26 +/- 8 mmHg), whereas a negative trend in change of blood gases and pulmonary artery pressure occurred in the placebo treated group (NS). No significant changes in external ventilation, other spirometric parameters or adverse effects concerning peripheral nerve function were seen after almitrine or placebo treatment. The elimination of almitrine was fitted to a three compartment model and the terminal half-life in the patient population was found to be 32 +/- 29 days after intravenous dosing. CONCLUSION: Acute and six-month almitrine bismesylate therapy at a low daily dose of 75 mg is found to be safe, even in severely compromised patients, with regard to pulmonary haemodynamics and peripheral nerve function. The agent is beneficial to pulmonary gas exchange, with reduction of hypercapnia, of intrapulmonary shunt and also with regard to sustained elevation of arterial oxygen tension. A combination with inhaled oxygen seems especially efficacious.

[Treatment of arterial hypertension. Efficacy of nitrendipine 20 mg/day]. / Traitement de l'hypertension artérielle. Efficacité de la nitrendipine 20 mg/j.

The effectiveness and acceptability of nitrendipine, given as a single 20 mg tablet in the morning, were evaluated in general practice in 6.058 hypertensive patients. Visits were planned after 2, 6 and 12 weeks of treatment. Eighty-nine percent completed the 12-week study, 95 percent of them receiving 20 mg of nitrendipine once daily. Adverse events were observed in 26 percent of the patients, mainly during the first two weeks, when flushing and peripheral edema occurred in 9 and 7 percent of the patients respectively. Both led to withdrawal of 4 percent of the patients included over 3 months. A supine diastolic blood pressure below 90 mmHg was achieved in 65 percent of the patients, irrespective of age, sex, activity, smoking habits, and presence of diabetes or previous antihypertensive therapy. This large-scale study further established the effectiveness of nitrendipine as monotherapy given once daily in most hypertensive patients. Eight out of 10 patients felt they had benefited from the treatment. The investigators were satisfied with the results in 66 percent of the patients. They considered that the main advantage of nitrendipine was ease of use.

Effectiveness of nitrendipine, 20 mg once daily in the management of hypertension in general practice.

The effectiveness of nitrendipine, given as a single 20 mg tablet in the morning, was evaluated in general practice in 6,058 hypertensive patients. They filled in a questionnaire on their activities and previous antihypertensive treatment, if any. Visits were planned after 2, 6, and 12 weeks. Then, patients and general practitioners gave their assessment of the treatment. Eighty-four percent completed the 12-week study while receiving 20 mg of nitrendipine once daily. Adverse events were observed in 26% of the patients, mainly during the first 2 weeks, where flushing and peripheral edema occurred in 9 and 7% of the patients, respectively. Both led to withdrawal of 4% of the included patients over 3 months. A supine diastolic blood pressure below 90 mm Hg was achieved in 65% of the patients, irrespective of age, sex, activity, smoking habits, and presence of diabetes or previous antihypertensive therapy. In conclusion, this large-scale study further established the effectiveness of nitrendipine as monotherapy given once daily in most hypertensive patients. Eight patients in 10 felt they had benefited from the treatment. The investigators were satisfied with the results in 66% of the patients. They considered that the main advantage of nitrendipine was ease of use.

A double-blind, randomized, comparative study of nitrendipine and enalapril in elderly hypertensive patients.

We conducted a randomized, double-blind, double-placebo study in two groups of elderly hypertensive patients aged over 60 years to compare nitrendipine to enalapril, given once daily over 4 months, as monotherapy with 20 mg tablets. Clinic blood pressure was measured monthly and 24 h ambulatory monitoring was obtained at day 0 and day 120. Fifty-two patients entered the study (22 in the nitrendipine group, 30 in the enalapril group); 4 patients in both groups were dropped from the study because they withdrew their consent to participate. Three patients under nitrendipine and five patients under enalapril were not included in the analysis of data because of insufficient follow-up. The two groups were comparable on final analysis. The clinical blood pressure was similarly reduced in both groups at 24 h postdose (172/97 to 157/85 mm Hg on nitrendipine vs. 177/98 to 154/86 mm Hg on enalapril). Seventy percent of the patients had their blood pressure normalized at the end of the study in the two groups. With ambulatory blood pressure recording, no 24 h blood pressure significant differences were found on day 120 when we calculated the mean of systolic blood pressure (SBP) or diastolic blood pressure (DBP) (137 +/- 12/82 +/- 9 mm Hg on nitrendipine vs. 136 +/- 16/82 +/- 11 mm Hg on enalapril), or for daytime or nighttime periods. The pulse pressure or the mean of the five highest SBP values was also similar in nitrendipine and enalapril patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Peripheral action of spironolactone: improvement in arterial elasticity.

Arterial elasticity, which can be assessed by means of a piezogram, is thought to be involved in the development of hypertension. In hypertensive patients (and with aging in normal subjects), arterial elasticity is reduced. Long-term administration of spironolactone, beta blockers, or a beta-blocker/dihydralazine combination to hypertensive patients sufficiently reduced systolic and diastolic blood pressure to about the same extent; however, only spironolactone had any effect on piezoelectric indexes of arterial elasticity.

Dose-response and pharmacokinetic study with almitrine bismesylate after single oral administrations in COPD patients.

To better define the dose-effect relationship and the pharmacokinetics of almitrine, sixteen stable hypoxaemic COPD patients received random single oral administrations of almitrine bismesylate 50, 100 and 150 mg or placebo at two-week intervals in a double-blind manner. Resting ventilation, arterial blood gases and plasma almitrine levels were measured. No significant changes were seen after placebo administration. Almitrine 50 and 100 mg caused a significant dose-related improvement in arterial oxygen tension (PaO2) in thirteen of the sixteen patients. Almitrine 150 mg caused little if any additional PaO2 increment. PaO2 returned to near basal values after 24 h. Two patients responded to almitrine 100 and 150 mg only, whereas one patient did not respond at all. Mean PaO2 increases in the sixteen patients were 0.9 kPa (7 mmHg), 1.5 kPa (11 mmHg) and 1.6 kPa (12 mmHg) 3 h after 50, 100 and 150 mg, respectively. A significant mean 0.9 kPa (7 mmHg) decrease in arterial carbon dioxide tension (PaCO2) and a l.min-1 increase in ventilation were observed after almitrine 150 mg. Mean maximum almitrine plasma concentration and area under the curve correlated linearly with dose. The relationship between mean PaO2 improvement and mean almitrine plasma level was curvilinear with a flattening of the curve over plasma levels of 150 ng.ml-1. Almitrine plasma half-life was found to be 116-140 h.

Is the mode of action of almitrine bismesylate dose dependent?

In order to assess whether different doses and/or plasma levels of almitrine bismesylate (ABM) could induce preferential effects on ventilation or on lung perfusion, we performed a single-blind placebo-controlled study of ABM treatment with different dosages (0.75, 1.5 and 2.25 mg.kg-1 single oral dose) in 26 patients suffering from chronic obstructive pulmonary disease (COPD). All measurements were performed according to the same time table. At control and at three 1.5-hour intervals, we measured alveolar-arterial (A-a) differences, alveolar dead space, total ventilation and ABM plasma levels. The effect on ventilation was estimated using changes in ventilatory parameters and (A-a)O2 differences. The effect on perfusion was indirectly estimated by analysis of arterial-end-tidal (a-ET)CO2 difference and alveolar dead space. The response to treatment was significant for the 1.5- and the 2.25-mg.kg-1 ABM groups, but not for the 0.75 mg.kg-1 ABM and the placebo group. A ventilatory response was often present in both 1.5- and 2.25-mg.kg-1 ABM groups, but a nonventilatory effect was present only at the highest dose according to the Severinghaus and Stupfel concept. Only the parameters reflecting an effect of the distribution of perfusion (a-ET)CO2 difference and alveolar dead space were significantly correlated with ABM plasma levels. The results suggest that a dose-dependent effect of ABM on lung perfusion may explain the controversial data in the literature about the mode of action of ABM.

Posterior callosal infarction. Clinicopathological correlations.

Clinicoanatomical observations on a patient with partial interhemispheric disconnection associated with complete ischaemic destruction of the splenium and of the posterior part of the body of the corpus callosum are presented. Neuropathological examination of the areas containing degenerated white matter indicated that the lesions affected the transcallosal fibres that link the cortex of the occipital lobes and the superior parietal lobules (SPL). The white matter situated in the temporal lobes was intact. This suggests that in man, and contrary to what has been described in the monkey, the callosal pathway followed by the temporal fibres is rostral to the one followed by the parietal or at least by the SPL fibres. The most prominent disconnection syndrome elements were left tactile anomia (in spite of a rather good tactile-motor integration between the hemispheres), left visual anomia, agraphia of the left hand and 'diagnostic' apraxia. The fact that the anterior part of the corpus callosum was intact accounts for the preservation of interhemispheric transfer of somatic sensory information and for the absence of left extinction during the dichotic listening test. An attempt is made to give a more detailed explanation of the results obtained during the different tests.

Almitrine bismesylate: a long-term placebo-controlled double-blind study in COAD--Vectarion International Multicentre Study Group.

701 patients, age 61.9 +/- 8.3 yr (mean +/- SD), with hypoxaemic chronic obstructive airways disease (COAD) were entered into a one yr placebo-controlled double-blind study to determine the effect of oral almitrine bismesylate on arterial blood gas tensions and clinical condition. Initial arterial O2 tension (PaO2) was 7.6 +/- 0.8 kPa (57.0 +/- 6.2 mmHg) and arterial CO2 tension (PaCO2) was 6.0 +/- 0.9 kPa (45.2 +/- 6.7 mmHg). Forced expiratory volume in one second (FEV1) was 0.87 +/- 0.35 l and forced vital capacity (FVC) was 2.31 +/- 0.72 l. 163 patients, evenly distributed between treated and untreated groups, were receiving long-term O2 therapy; other conventional therapy was continued. In a stabilization period before treatment, excellent reproducibility of blood gas tensions and spirometry was achieved. In the placebo group (P; n = 357), little change in physiological measurements or clinical assessment was recorded, 90 patients (25%) were lost from the study, mostly due to deterioration of their respiratory disease or to death; 3.4% withdrew for adverse reactions. The almitrine group (A; n = 344), received 100-200 mg per day orally in two divided doses, depending on the improvement in PaO2 achieved. On entry to the study their blood gas tensions, lung function tests, clinical assessment, history of hospitalization and frequency of right heart failure were not significantly different from the placebo group. After one yr of treatment, PaO2 rose from 7.6 +/- 0.8 kPa (57.4 +/- 6.1 mmHg) to 8.5 +/- 1.3 kPa (63.7 +/- 9.7 mmHg), p less than 0.001 compared with the placebo group. Red cell count decreased p less than 0.001 compared with the placebo group and FEV1 increased from 0.92 l to 0.95 l, p less than 0.001 compared with the placebo group. Dyspnoea, assessed on a 100 mm analog scale was unchanged in the almitrine group as a whole, but some individual patients withdrew on account of breathlessness. A smaller proportion of patients in group A were hospitalized and had episodes of right heart failure during the study than in group P (p less than 0.05). Vital signs, biochemistry and ECG characteristics did not change. 139 patients (40%) in this group did not complete the study, 35 (10%) through deterioration of respiratory symptoms or death (4.9%); 43 (12.5%) withdrew because of adverse reactions, either drug-related or not. The most frequent adverse reactions were gastro-intestinal, central nervous system disturbances, increased dyspnoea and peripheral paraesthesiae.(ABSTRACT TRUNCATED AT 400 WORDS)

Study of the local graft versus host reaction in the rat. I. Evidences for a donor-related "rat effect".

The local graft versus host reaction (GVHR) observed in the hybrid F1 LBN rat was chosen to evaluate the immunologic effect induced by allogeneic transfusion of Brown Norway blood to the Lewis rat. Study of the kinetics of this GVHR with immunized as well as with nonimmunized cells shows an "individual rat effect" which is shown by a variability of the popliteal lymph node weight from one recipient to another. When spleen cells from different Lewis donors are pooled this effect disappears which indicates that it is related to the donor's rather than to the F1 recipient's cells. To even out variation between individual donors, cells from a number of donors should be pooled to allow better interpretation of experimental protocols using this GVHR.

A single orally administered dose of almitrine improves pulmonary gas exchange during exercise in patients with chronic air-flow obstruction.

To verify if the improvement in gas exchange observed at rest with almitrine in patients with chronic air-flow obstruction is maintained at exercise, we studied 10 patients on a randomized, crossover, double-blind exercise protocol. After assessment of steady state of their disease, patients with FEV 1 less than 1.5 L.s-1 and PaCO2 less than 70 mmHg cycled 8 to 11 min at 80% of their previously determined maximal O2 uptake. Blood gases, arterial lactate (La), expired ventilation, (VE), O2 uptake (Vo2), Co2 production (VCO2), heart rate (HR), and arterial blood pressure (BP) were measured at rest, at mid-exercise, at end-exercise, and at 2, 14, 15, and 35 min of recovery. We found that at all stages of the study PaO2 was significantly higher in those who had received almitrine than in those who had received placebo; the mean increment was 11.9 torr at rest, 8.9 at end-exercise, and 13.7 at 15 min of recovery. Changes in PaCO2 and arterial (H+) were the opposite of those in PaO2; at end-exercise PaCO2 was 5.9 torr lower in those who had received almitrine, and pH was 7.36 versus 7.32 in those who had received placebo. No significant difference was found at all stages of the study between drug and placebo with respect to VE, VO2, VCO2, HR, and BP. But the ventilatory equivalent for oxygen, VE/VO2, was slightly higher in those who had received almitrine than in those who had received placebo during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

A one-year double-blind placebo-controlled study of the efficacy and safety of almitrine bismesylate in hypoxic COLD patients. Monitoring progress status on 490 patients entered into the VIMS study before January 1st, 1984.

The aim of the VIMS group is to verify the efficacy and acceptability of almitrine bismesylate (ABM) taken orally in the treatment of chronic obstructive bronchitis, by an international long-term study, one year controlled against placebo. This study includes more than 800 out-patients in 70 centres in 12 countries. 490 patients entered the study before 1/1/84, after the first 9 months of the inclusion period. 60% of patients are treated in France, 20% in the U.K. and Ireland and 20% in Belgium, Denmark, Italy, Switzerland. Their mean FEV1 is 0.87 liters, their mean PaO2 is 57 mmHg. The study protocol foresees two control visits separated by a 3 week interval before entry into the study in order to verify the stability of the patients on the basis of clinical, spirometric and gazometric data; the variation in PaO2 is less than or equal to 6 mmHg in more than 90% of the patients. The severity of the disease is assessed by the existence of an hospitalisation during the year preceeding the study in 55% of the patients, the necessity of oxygenotherapy at home for at least 12hr/day in 1/3 of them. The treatment of the latter was attributed separately at random to seek in a prospective manner the interest of associating O2 and ABM. During the study, the mortality of the patients included is 6% and about 70% of the patients completed the study period. The survey of adverse reactions and reasons for treatment interruption is progressively established by close collaboration between the investigators and monitors, to comply with the directives of pharmacosurveillance for severe and polymedicated patients. The analysis of the results to be carried out at the end of the study after verification and correction by the investigators, should enable us to enhance our knowledge of the clinical and gazometric parameters in patients with chronic obstructive disease followed for one year and treated by conventional means (control group) and the activity of ABM in order to confirm its therapeutic value in the treatment of chronic obstructive bronchitis.

[Idiopathic nephrotic syndrome and the HLA allele. Prevalence of age-related DR7]. / Syndrome néphrotique idiopathique et allèle HLA. Prévalence de DR7 liée à l'âge.

High prevalence of HLA DR7 was well documented in idiopathic nephrotic syndrome (INS) of childhood. Our data in 43 INS, child and adult patients, did not show any significant difference from control group, specially for HLA DR7. Moreover a significant difference occurred when the data was compared in child and adult INS patients. HLA DR7 was more frequent when the nephrotic syndrome appeared before 15 years old. There was no correlation between the presence of HLA DR7 and those of allergy history or increased serum IgE level, on the opposite with previous data. The presence of DR7 would favor its onset at an earlier age. Alternatively, the difference in DR7 prevalence could be an additional argument for considering that the corticosensitivity and negative histological criteria might collect, under the same name, different glomerulopathies.