Safety and tolerance of single oral doses of trandolapril (RU 44.570), a new angiotensin converting enzyme inhibitor.

The safety and tolerance of single oral doses of a new angiotensin converting enzyme (ACE) inhibitor, trandolapril have been examined in 90 healthy male volunteers, in a randomised, double blind, placebo-controlled study. The subjects were divided into 10 groups, each of 9 subjects and treatments (6 subjects on trandolapril and 3 on placebo per group) were allocated by unbalanced randomisation. Ten single, increasing oral doses were tested: 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 24 and 32 mg. The assessment criteria were clinical (monitoring of blood pressure, heart and respiratory rate, electrocardiogram, temperature and evaluation of behaviour and side effects) and routine laboratory tests. Blood pressure did not fall except for a slight drop in diastolic pressure during the first 4 h following the 32-mg dose. However, although an effect of the compound cannot be excluded, the reduction in blood pressure may have reflected intersubject variability. No orthostatic hypotension was observed. There was no change in the other vital signs, and in particular no increase in heart rate was observed. No serious adverse effect was encountered. The pharmacological activity of the compound was studied by assaying plasma ACE activity. Inhibition of ACE was linearly dose-dependant from 0 (placebo) to 2 mg, and above that dose, the inhibition was nearly total. ACE activity was markedly reduced within 30 min after administration of trandolapril, and maximal inhibition was observed from 2-4 h onwards, lasting for up to 24 h after dosing. For doses above 2 mg, inhibition was still 40% of the basal activity on Day 8 after dosing.

Dose-response relationship of vindeburnol based on spectral analysis of posturographic recordings.

The dose-response relationship of vindeburnol has been investigated by assessing postural activity in a population of elderly patients, using posturography, an objective method for measuring balance. A controlled double blind trial was done in two periods: during the first week each patient received placebo, and during the second week either placebo or vindeburnol 30, 60 or 90 mg/d was given. Subjects underwent three posturographic recordings at weekly intervals (prior to treatment, after one week on placebo and after one week of treatment). There was no placebo effect. A significant decrease in the sagittal and lateral energies of body sway was found after vindeburnol, which indicates an improvement in balance. The improvement was proportional to the daily dose of vindeburnol.

Assessment of the antimineralocorticoid effect of RU 28318 in healthy men with induced exogenous and endogenous hypermineralocorticism.

The antimineralocorticoid effect of a single dose of RU 28318, has been assessed in healthy men with exogenous or endogenous hypermineralocorticism. For exogenous hypermineralocorticism induced by ingestion of 9 alpha-fluorohydrocortisone (9 alpha-FHC) and aldosterone infusion, RU 28318 100 mg (9 alpha-FHC ingestion) or 200 mg (aldosterone infusion) was administered, and its effect compared with identical doses of spironolactone or a placebo. For endogenous hypermineralocorticism induced by ingestion of furosemide, RU 28318 100 and 300 mg was tested in comparison with 100 mg spironolactone or placebo. In all 3 studies, both RU 28318 and spironolactone significantly raised the urinary Na/K ratio when compared to placebo administration. No significant difference was apparent between RU 28318 and spironolactone. Thus, a single dose of RU 28318 in man has an antimineralocorticoid effect identical to those produced by the identical molar dose of spironolactone. In addition, the results show that furosemide-induced hyperaldosteronism constitutes a simple and reproducible test for assessing the antimineralocorticoid effect of a drug.

Franco-Belgian cooperative study of ursodeoxycholic acid in the medical dissolution of gallstones: a double-blind, randomized, dose-response study, and comparison with chenodeoxycholic acid.

A double-blind randomized, multicenter study was carried out to determine the efficacy and safety of ursodeoxycholic acid (UDCA) at 4 doses of 2.1 to 16.2 mg X kg-1 X day-1, and chenodeoxycholic acid (CDCA) at the dose of 16.9 mg X kg-1 X day-1, in 197 patients treated for up to 1 year for radiolucent gallstones in functioning (opacified) gallbladders. There was confirmed complete dissolution in 5.9% of patients receiving UDCA at the dose of 2.1 mg X kg-1 X day-1, 18.9% in those receiving 4.2, 28.9% in those receiving 8.4, 14.6% in those receiving 16.2, and 20.0% in patients receiving CDCA. Partial (over 50%) or complete dissolution occurred in 29.4% of patients receiving 2.1 mg X kg-1 X day-1 of UDCA, 37.8% of those receiving 4.2, 55.2% in those receiving 8.4, 48.7% in those receiving 16.2, and 50.0% in patients receiving CDCA. Complete dissolution occurred significantly more frequently in small (less than 5 mm in diameter) than in large (5 to 15 and more than 15 mm) stones. There was no significant influence of treatment on serum cholesterol and triglycerides in any of the groups. Serum aminotransferases remained normal (or lower than twice the upper normal limit) in all patients treated with UDCA. Diarrhea leading to cessation of treatment occurred in 5% of patients receiving UDCA, but was significantly less frequent than in those receiving CDCA. These results confirm that, within a 1-year period, UDCA is equally effective and induces diarrhea less frequently than CDCA, with an optimal dose (8 mg X kg-1 X day-1) approximately twice lower than that of CDCA.

Hidden anti-nuclear antibodies in rheumatic diseases.

Hidden anti-nuclear antibodies are demonstrated by immunofluorescence using smears of rat nuclei as substrate and rat liver section technique when sera are incubated with penicillamine. The non-detection of hidden anti-nuclear antibodies by tissue sections in the absence of a splitting agent may be due to the formation of high molecular weight complexes between rheumatoid factors and anti-nuclear antibodies. These high molecular weight complexes containing anti-nuclear antibodies do not have access to tissue nuclear antigens, but can react directly with free nuclei. It is postulated that anti-nuclear antibodies may represent the early pathway of both rheumatoid arthritis and connective tissue diseases. The demonstration of hidden anti-nuclear antibodies in seropositive sera indicates that rheumatoid factors may have a protective effect. It may explain dissimilarities observed in the clinico-immunological profile of rheumatoid arthritis and systemic lupus erythematosus. The splitting effect of penicillamine observed in vitro may be similar in vivo. It can explain clinical improvement and immunological side effects observed in rheumatoid arthritis patients treated with this drug.

Interactions between IgM antiglobulins and IgG antinuclear antibodies. Some aspects of D-penicillamine activities.

In this report we describe an in vitro masking action of IgM rheumatoid factor (IgM-RF) towards IgG antinuclear antibodies (IgG-ANA) which can be recovered by using D-penicillamine (DP) as an unmasking agent. The mechanism of this masking effect was elucidated by using smears of rat free nucleus as substrate, instead of the classical rat liver cryostat sections technique. It was postulated that the 'inhibition' of IgG-ANA by IgM-RF may be due to the formation of high molecular weight complexes (HMWC); this would be the same in vivo. Allowing the formation of HMWC which can be removed from the circulation, IgM-RF may have a protective effect by preventing or minimizing systemic lesions. Therefore, IgM-RF may be considered as a defence response against potentially noxious ANA or antigen-antibody complexes. Induced nephropathy and the high frequency of detection of ANA observed in rheumatoid arthritis (RA) patients treated by DP may be the result of the dissociating effect of this drug on HMWC, in which the activity of pre-existing ANA is hidden when rat liver sections are used for its detection.

[Lymphocyte subpopulations in adjuvant arthritis of rats. Effects of corticoids and gamma irradiation]. / Etude des sous-populations de lymphocytes dans la polyarthrite à adjuvant de rat. Effet des corticoïdes et del l'irradiation gamma.

Experimental model of human chronic inflammatory arthritis, adjuvant arthritis may be induced only in several strains of inbred Rats: it is well developed in LEW and practically absent in WAG. After adjuvant injection, the PHA-stimulable lymphocytes subpopulation quite disappears from the blood, if polyarthritis is well developed. These cells are probably capted in the tissues implicated in immunological conflict. On the contrary, the ConA-stimulable subpopulation is enhanced in both strains after adjuvant injection, earlier and more intense in WAG than in LEW and that phenomenon is probably linked to a stimulation of suppressor T lymphocytes. Treatment with prednisone or gamma rays inhibits partially and delays the appearance of arthritis in LEW, acting essentially on ConA-stimulable subpopulation.

Gout and hyperlipidaemia. Effect of overweight on the levels of circulating lipids.

A study of the serum lipids in 90 patients with gout and 90 controls matched for age and weight index demonstrated that in gout there was a significant elevation of the mean serum levels of cholesterol (282 +/- 55 mg/100 ml), triglycerides (183 +/- 161 mg/100 ml) and phospholipids (270 +/- 61 mg/100 ml) compared with the controls whose mean values were respectively 243 +/- 41 mg, 95 +/- 53 mg and 245 +/- 36 mg. Hyperlipidaemia of mixed type was the most common lipid defect in the patients with gout; there was no difference in the frequency of pure hypercholesterolaemia (without hypertriglyceridaemia) between gout and the controls. The frequency of anomalies of blood lipid levels in gout does not result from (or not solely from) obesity since patients with gout and controls were matched for their weight and height. There was a correlation between the serum lipid levels and obesity in the controls but this was not demonstrable in the patients with gout.

Immunochemical study on serum proteins in systemic sclerosis.

Forty one patients with systemic sclerosis were studied after separation into three groups according to Barnett's classification. A multi-dimensional statistical analysis eight serum proteins revealed a difference between control patients and patients with type I and type II scleroderma. Type I scleroderma was characterised by a rise in alpha 2 macroglobulin and in the C4 fraction of complement, whilst in type II scleroderma all the proteins studied were raised, with the exception of CO complement, which was normal, and transferrin which was markedly decreased.

[Proof, by a double-blind study, of the efficacy of synoviorthesis by erbium-169 in rheumatoid arthritis of the fingers]. / Preuve, par étude en double aveugle, de l'efficacitré des synoviorthèses par l'erbium-169 dans l'arthrite rhumatoïde des doigts

A double-blind study (201 metacarpo and interphalangeal joints) on the effectiveness of the synoviorthesis shows the significant value of the 169-Erbium, compared with intra-articular placebo or corticotherapy. The treatment gives an improvement in 58% of the cases (p less than 0.01) (stade 1:80,7%), by destruction of the rheumatoid pannus, begins after 3 months and develops for one year and more.

Immunofluorescence of synovial membrane multifactorial analysis of the results.

Synovial membrane taken by needle biopsy from the knee joint of 61 patients with various rheumatic diseases were studied using immunofluorescence methods. Staining techniques and their controls were detailed. Classical statistical tests and principal components multifactorial analysis of the data emphasized some differences between the pathological groups. Connective tissue diseases seemed to be characterized by plasma cells fluorescence and mixed immunoglobulins and complement deposits. These were mostly localized to extracellular spaces in sero-positive rheumatoid arthritis and to blood vessels in sero-negative rheumatoid arthritis and systemic lupus erythematosus. On the contrary, isolated immunoglobulins without complement were mostly found in the other inflammatory arthritis, while negative results were obtained in non inflammatory arthropathy. Immunoglobulin classes did not seem to have any diagnostic value. On the contrary, rheumatoid factor was specific for rheumatoid arthritis, whatever the serological pattern was, and it was particularly frequent in patients suffering from rheumatoid arthritis associated with a Sj5AOGREN SYNDROME. A strict relationship between classical histological findings and immunofluorescence results was not always found; so, immunological methods can be aquivocal.

Adjuvant-induced arthritis in four inbred strains of rats. An in vitro study of peripheral T and B lymphocytes.

The lymphoblastic response (LTT) to non-specific mitogens (PHA, PWM and ConA) of peripheral lymphocytes was investigated at days 0, 7, 14, 21 and 28 after adjuvant injection in four strains of inbred rats: Wistar (WAG), Long Evans (LE), Lewis (LEW) and Brown Norway (BN). LTT was assessed by using 18 hours H3 TdR incorporation in 5 days cultures of whole blood (micromethod). The statistical treatment of data, using principal components multifactorial analysis and analysis of variance showed a striking difference between strains. In control animals the responses to PHA and PWM were correlated and were higher in LE and WAG than in LEW and BN (BN=LEW less than LE=WAG). The response to ConA was independent of that to the other mitogens. It was generally low, but significantly higher in LEW and BN than in WAG and LE. In adjuvant-injected animals the responses to PHA and PWM were still correlated, but modified compared to control: in LE and LEW, but not in WAG and BN, a marked decrease of the response was found, reaching a minimum value within days 7 and 14. In the same time the response to ConA increased in the four strains, later in LE than in the others. However the intensity of the ConA response varied from one strain to another: it was constantly low in LE and WAG compared to LEW and BN. So the most striking modification of LTT were observed in LE and LEW, which both developed the most severe arthritis. However these different behaviours after adjuvant injection were not explained by the initial level of LTT to the different mitogens. These data suggest that the development of intense arthritis is associated with the proliferation and the release into the blood stream of a lymphocyte subpopulation, which exhibits a low response to PHA and PWM and a high response to ConA. These LTT modifications are not paralleled by quantitative variations of B-cells assessed by surface Ig immunofluorescent staining and EAC rosetting.

Soluble complexes and antiglobulin factors detection by immunofluorescence and immunoadsorption in rheumatoid sera.

In this report is was demonstrated that in rheumatoid factors (RF) positive sera, 19 S IgM rheumatoid factor can form soluble complexes with different proteins (IgG, albumin) of sera. In these complexes the antiglobulin activity of IgM is not inhibited. When immunofluorescence and immunoadsorption procedures are used for the detection of antiglobulin activities of rheumatoid sera, the proteins which are bound to IgM rheumatoid factor, even if they are devoid of any antiglobulin character, may be revealed simultaneously with IgM. Moreover in some cases the detection of IgM may be hindered, while the linked proteins remain detectable. In these conditions, these complexes in RF positive sera may give false negative results for IgM rheumatoid factor, and may give rise to artefactual appearance of IgG and other proteins (albumin antiglobulin-like activities. This paper points out that before investigating IgG and IgA antiglobulin activities, IgM rheumatoid factor should be previously eliminated, for example by immunoadsorption.

Hyperbasophilic immunoblasts in circulating blood in chronic inflammatory rheumatic and collagen diseases.

The number of large circulating hyperbasophilic mononuclear cells - referred to as hyperbasophilic immunoblasts (HBI)- is often increased in collagen disease and rheumatoid arthritis (RA) and grossly reflects the degree of disease activity. In contrast, in psoriatic arthropathy the percentage of (HBI) is within the normal range. HBI are mainly involved in immune reactions and may provide a valuable routine test for the assessment of the latter in disease states and for the predicition of relapse in chronic collagen diseases. Immunofluorescent techniques applied to samples from active autoimmune diseases have shown that a number of HBI are Ig-producing B-blasts. Moreover, in a few cases these intracytoplasmic immunoglobulins exhibited a rheumatoid factor-like activity, a finding which promises to yield additional information on the immunopathogenesis of RA.