Comparison of the effects of fasting morning, fasting evening and fed bedtime administration of tenatoprazole on intragastric pH in healthy volunteers: a randomized three-way crossover study.

BACKGROUND: The effectiveness of proton pump inhibitors is influenced by meals and administration time. AIM: To compare the effects on intragastric acidity of times of dosing of tenatoprazole, a novel imidazopyridine-based proton pump inhibitor with a prolonged plasma half-life. METHODS: This randomized three-period crossover study included 12 Helicobacter pylori-negative healthy subjects, who received tenatoprazole 40 mg either fasting at 7.00 AM, fasting at 7.00 PM or fed at 9.30 PM for 7 days, with a 2-week washout between periods. Twenty-four hour intragastric pH was monitored on day 7 of each period. RESULTS: On day 7, median 24-h pH was 4.7, 5.1 and 4.7 after breakfast, dinner and bedtime dosing, respectively (P = 0.11), whereas night-time pH was 4.2, 5.0 and 4.4 (P = 0.13). The mean 24-h percentage of time over pH 4 was 62, 72 and 64 after breakfast, dinner and bedtime dosing, respectively (N.S.), and 54, 68 and 56 during night-time (P = 0.06). Nocturnal acid breakthrough incidence decreased from 100% at baseline to 83%, 55% and 75% after 7.00 AM, 7.00 PM and 9.30 PM dosing, respectively (P = 0.18), and its mean duration dropped from 6.2 to 2.8, 1.0 and 2.2 h, respectively (P < 0.05). CONCLUSION: Seven-day administration of tenatoprazole provides a prolonged duration of acid suppression, especially during the night-time, with little effect of food or time of dosing.

A comparative study of the early effects of tenatoprazole 40 mg and esomeprazole 40 mg on intragastric pH in healthy volunteers.

BACKGROUND: Tenatoprazole is a novel proton pump inhibitor with a seven-hour plasma half-life. AIM: To compare the effects of tenatoprazole 40 mg and esomeprazole 40 mg on intragastric acidity during the first 48 h in healthy volunteers. METHODS: This randomized two-period crossover study included 24 Helicobacter Pylori-negative subjects; tenatoprazole 40 mg or esomeprazole 40 mg daily were given before breakfast for two consecutive days, with a 2-week wash-out between the administration periods. Intragastric pH was monitored for 48 h. RESULTS: Over 48 h, tenatoprazole 40 mg exerted a more potent acid inhibition than esomeprazole 40 mg (median pH: 4.3 vs. 3.9, P < 0.08; per cent of time above pH 4: 57% vs. 49%, P < 0.03; proportion of subjects with at least half of the time above pH 4: 71% vs. 46%). These differences resulted from better night-time acid control with tenatoprazole 40 mg than esomeprazole 40 mg (first night median pH: 4.2 vs. 2.9, P < 0.0001; second night: 4.5 vs. 3.2, P < 0.0001). The duration of nocturnal acid breakthroughs was significantly reduced during both nights. In contrast, no significant difference was detected during the daytime periods between both regimens. CONCLUSION: Over the first 48 h, tenatoprazole 40 mg achieves a better overall and night-time control of gastric pH than esomeprazole 40 mg. The translation of better early control of acidity into clinical benefits deserves further studies.

Influence of the quality of tibial plateau alignment on the reproducibility of computer joint space measurement from Lyon schuss radiographic views of the knee in patients with knee osteoarthritis.

RATIONALE: The quality of medial tibial plateau (MT-Plateau) alignment is one of the key elements for accuracy and sensitivity to change of knee radiography in knee osteoarthritis (OA). AIM: To evaluate the influence of the quality of the MT-Plateau alignment on the reproducibility of joint space width (JSW) measurement in knee radiographs. METHODS: One hundred and twenty-seven knee radiographs (99 OA), performed using a standardized radiographic procedure (Lyon schuss (LS) view). Evaluation of the quality of MT-Plateau alignment. Computerized measurement of the JSW, twice, 1-month apart, using a semi-automated and an automated method of measurement. Assessment of the reproducibility of repeated measurements: calculation of intra-observer coefficient of correlation, smallest detectable difference (SDD) and coefficient of variation (CV). RESULTS: MT-Plateau alignment was satisfactory in 99 radiographs (77.9%). Reproducibility was excellent in both satisfactory and non-satisfactory radiographs, irrespective of the method of measurement used. The automated measurement was more reproducible than the semi-automated one (CV 1.15% and 3.23%). SDD and CV were better in satisfactory than in non-satisfactory MT-Plateau aligned radiographs. CONCLUSION: These results confirm that computer measurement of the medial tibio-femoral JSW, from LS digitized radiographs, is highly reproducible, irrespective of the quality of the radiograph. However, the quality of the MT-Plateau alignment influences the reproducibility of JSW measurement. The automated measurement was more reproducible than the semi-automated one.

Tenatoprazole, a novel proton pump inhibitor with a prolonged plasma half-life: effects on intragastric pH and comparison with esomeprazole in healthy volunteers.

BACKGROUND: Proton pump inhibitors control gastric acidity better during the day than at night, when nocturnal acid breakthrough can occur. Tenatoprazole is a novel proton pump inhibitor with a seven-fold longer plasma half-life. Aim : To compare the effects of tenatoprazole 20 mg (T20), tenatoprazole 40 mg (T40) and esomeprazole 40 mg (E40) on intragastric acidity in healthy volunteers. METHODS: This randomized, three-period, cross-over study enrolled 18 Helicobacter pylori-negative volunteers, who received E40, T20 and T40 once daily for 7 days with a 14-day washout between periods. Twenty-four-hour gastric pH monitoring was performed on day 7. Serum gastrin was assessed on day 8. RESULTS: T40 induced a more potent acid inhibition than T20 (24-h median pH: 4.6 vs. 4.0, P < 0.01; daytime: 4.5 vs. 3.9, P < 0.01; night-time: 4.7 vs. 4.1, P < 0.05). T40 was more potent than E40 (24-h median pH: 4.6 vs. 4.2, P < 0.05; night-time: 4.7 vs. 3.6, P < 0.01); the pH > 4 holding time was higher during the night for T40 than for E40: 64.3% vs. 46.8%, P < 0.01; the nocturnal acid breakthrough duration was significantly shorter for T40 than for E40. No significant gastrin increase was observed and all drugs were well tolerated. CONCLUSION: T40 is significantly more potent than T20 and E40 during the night. The therapeutic relevance of this pharmacological advantage deserves further study.

[Clinical and radiographic status of patients in the ECHODIAH study who underwent THA Pertinence of the pain-function index for operative decision making]. / Statut clinique et radiologique des patients avec prothèse totale de hanche dans l'étude ECHODIAH.

DATA COLLECTION: The ECHODIAH study conducted to evaluate the chondromodulator effect of diacerein on the osteoarthritic hip joint has provided epidemiological data on patient symptoms at three-month intervals. Patients with degenerative hip joints evaluated their pain and handicap on visual analog scales. The Lequesne functional score was also determined. A radiographic study was performed every year. IMPROVED PREDICTIVE FACTORS: Among the 507 patients included in the study, 135 underwent total hip arthroplasty. Clinical and radiological evaluations of the operated patients demonstrated that the Lequesne functional score was the best predictive factor with an optimal cutoff at 12 points. The second best predictive factor was the radiographic measurement of the joint space.

Measurement of the radiological hip joint space width. An evaluation of various methods of measurement.

OBJECTIVE: To determine the most relevant method of measurement of the radiographic hip joint space width (JSW). DESIGN: Seventy hips were examined from 36 patients of the ECHODIAH study having had one to four X-rays of the pelvis during the 3-year course of the study. Minimum interbone distance (MIDc), mean width of both the whole joint space (MJSWL) and a region of interest of the joint space (MJSWroi) were measured using computerized analysis of digitized radiographs. MID was also measured using a graduated eyepiece (MIDge). Reproducibility of the measurement was assessed by the intraclass coefficient of correlation. Sensitivity to change was evaluated by the standardized response mean. RESULTS: The intraobserver intraclass coefficient of correlation of MIDc and MJSWroi was 0.98 and 0.94, respectively. The mean value degrees S.D. of MJSWL, MJSWroi, MIDc and MIDge was 3.3 degrees 0.9, 2.6 degrees 0.9, 2.4 degrees 0.9 and 2.6 degrees 1.2 mm, respectively. MIDge was significantly larger than MIDc (mean difference: 0.21 degrees 0.62 mm, P<0.001), in both normal and osteoarthritic hips. However, the difference between MIDge and MIDc varied largely when considering topography of femoral head migration. Whatever the method was, a significant (P<0.001) mean decrease of nearly 0.5 mm was found in osteoarthritic hips over the 3 year follow-up. The standardized response mean for MJSWL, MJSWroi, MIDge and MIDc was 0.73, 0.75, 0.79 and 0.85, respectively. Superiority of MIDc, in term of sensitivity to change, was mainly seen in osteoarthritic hips showing a superomedial or a concentric migration of the femoral head. CONCLUSION: Minimum interbone distance measured with a computer assisted method is suggested as the most suitable method for the evaluation of hip osteoarthritis (OA) progression.

Multicenter study of an erythro-aggregometer: quality control and standardization.

There is a need for quality assurance procedures in hemorheology, especially for clinical and pharmacological studies, which require reliable and well-calibrated instruments to be interpretable and comparable. Preliminary investigations allowed preparation of standardized SM (normal NS and hyperaggregable HS), and checking of storage conditions (in accordance with the guidelines of the SSC of ISTH) of RBC in nutritive SAG mannitol for at least 2 or 3 weeks with subsequent washings and resuspension in SM. In our study, we compared erythro-aggregometers of the same brand in 6 laboratories, using the same red blood cells (RBC) and suspending media (SM) for each series of tests. EA was measured by laser backscattering with determination of aggregation time (AT), partial dissociation threshold (PDT) and aggregation index (AI). Prior to the study, devices were set up on the same day with the same standardized blood, and calibration data were then analyzed. Within-assay precision (WAP) was assessed on 3 days for the 2 types of SM (n = 18 x 2). Between-assay precision (BAP) was assessed on 6 occasions, once every month (n = 6 x 2 x 6). Accuracy was studied with 3 series of RBC resuspended in 10 SM of "unknown" aggregability. Good agreement was observed between 5/6 centers for the 3 parameters of EA. WEP was good: CV of AT ranging from 1.4 to 2.5% for the NS and from 1.4 to 2.4% for the HS. In each center, BAP was slightly lower than WEP (CV: 8-11.8% for the NS and 3.8-4.7% for the HS over the 6-month study), with no drift, except for one center. Precision was always better with the HS than with the NS which seemed a better tool to assess it. As to accuracy, non-significant differences were generally found between centers, with similar data to the reference values. This work also stressed the importance of the RBC parameter itself in rheological data. For the first time, a protocol for standardization of EA has been developed and evaluated, permitting the Quality Control of this technique.

[Morphology and vascularization of the varicose internal saphenous vein. Comparison with the normal structure]. / Morphologie et vascularisation de la veine saphne interne variqueuse. Comparaison avec la structure normale.

After reviewing the main characteristics of the normal long saphenous vein, the histological alterations observed in varicose veins are described. Samples were obtained from 14 patients undergoing venous surgery for varicose veins with long saphenous vein incompetence. These alterations mostly involve the connective tissue prolife-rating in the middle layer and causing the separation and interruption of the muscular bundles. In addition, the vasa vasorum network through the venous wall was investigated. These vessels were normally observed in the adventitial layer and the outer third of the media. In some samples from varicose veins, vasa vasorum were increased and capillaries close to the intimal layer.

[Laser-doppler flowmetry in vivo and reactivity of the normal and abnormal venous wall]. / Mesures du flux Doppler laser in vivo et réactivité de la paroi veineuse normale et anormale.

Venous wall flux was measured using laser-Doppler flowmetry on the external surface of 24 normal veins, partially dissected during the preparation of the vein for aortocoronary bypass grafting. Measurements were performed before the final dissection of the vein when at least 3/4 of the adventitia and periadventitia tissue was still intact for a length of 3 cm. The segment of vein (10 cm) proximal to the sapheno-femoral junction was studied. Measurements were repeated on 22 varicose veins before stripping or ligation of the sapheno-femoral junction. Flux was measured with a Laserflo (Vasamedics) flowmeter. A Delrin (polycarbonate) spacer was placed between the probe and the vein wall surface. Measurements shown are the average of three minutes recording. Preliminary analysis indicates that flux appears to be lower in varicose veins in comparison with flux in the normal vein wall. However the variability of results and technical problems in flux measurements indicate the need of a larger measurement sample before confirming the observation of a decreased perfusion of the varicose venous wall.

[Measurement of oxygen tension in normal and varicose vein walls]. / Mesure de la pression en oxygène dans la paroides veines normales et variqueuses.

Oxygen tension (PO2) was investigated in vivo in the long saphenous vein from 21 varicose patients (31 veins) during venous surgery and 7 patients with normal venous network undergoing popliteo-femoral by-pass. Measurement was achieved using computerized polarographic system Kimoc 6650 (Eppendorf, Hamburg) providing a microdriven stepwise progression of a needle probe. Oxygen tension profile was similar in both groups of patients. A slow PO2 decrease was observed from adventitia up to the union of the middle and inner thirds of the media where values were at the lowest then followed by a marked increased in the intima and the saphenous lumen. Oxygenation of the two external thirds of the venous wall was provided by vasa vasorum. The average minimum values in the media was significantly reduced in varicose veins compared to no-varicose veins (7,9 mmHg versus 13,4 mmHg; p < 0,05). These results indicated the key role of vasa vasorum flux in the long saphenous vein nutrition and suggest a primary or secondary deficiency in oxygen supply in varicose veins.

Fibrinolysis and hemorheology in chronic venous insufficiency: a double blind study of troxerutin efficiency.

Abnormal increase of erythrocyte aggregation and reduction of profibrinolytic activity are the two most frequent biological perturbations found in chronic venous insufficiency (CVI). A randomised, controlled, double blind trial was undertaken on 85 patients suffering from grade 1 and 2 CVI, to compare troxerutin with placebo. Two types of biological parameters were measured after 15 days of treatment. Erythrocyte aggregation as evaluated with a Myrenne erythroaggregometer by the indices M (stasis) and M1 (3s-1) progressed favorably in the troxerutin group. The values of M1 at D15 (p < 0.05), and the progression of M (p < 0.001) and M1 (p < 0.01) from D0 to D15, are significantly better in the troxerutin group. Progression of fibrinolytic activity at rest was not significantly different between the 2 groups. Conversely, the progression from D0 to D15 of the values after occlusion of euglobulin lysis time (p < 0.01), tPA (p < 0.01), and PAI activity (p < 0.05) are significantly better in the troxerutin group. The fibrinolysis capacity estimated by euglobulin lysis time (p < 0.01) and tPA (p < 0.05) also progressed favorably in the troxerutin group. These results confirm the anti-erythrocyte aggregation effect of troxerutin, and suggest a favorable effect on blood fibrinolytic activity. They could explain the positive action of this drug on stasis, capillary perfusion and trophic complications of CVL.

The affinity of troxerutin for the venous wall measured by laser scanning microscopy.

The uptake and localization of troxerutin, a trihydroxy-ethyl-rutoside, in the venous wall have been studied in patients undergoing long saphenous vein surgery. Troxerutin, an autofluorescent drug, is currently used to relieve oedema and subjective symptoms in patients with chronic venous insufficiency. In order to determine the localization of the troxerutin, a confocal scanning laser microscope has been used to record the fluorescence from vein cross sections. The quantified fluorescence was used as a measure of the local concentration of troxerutin. In order to reduce the effects of local variation, several images have been scanned from each specimen. Then the recorded data have been analysed to see how the fluorescence varies in the radial direction within the venous wall. Results showed that troxerutin was significantly accumulated in both inner and outer parts of the venous wall. Whereas inner wall troxerutin uptake resulted from direct diffusion through the lumen, the outer wall uptake proceeded likely from the vasa vasorum circulation.

Increasing erythrocyte aggregability with the progressive grades of chronic venous insufficiency: importance and mechanisms.

Erythrocyte aggregation (EA) has appeared as the most interesting parameter among rheological measurements in chronic venous insufficiency (CVI). We therefore conducted two different kinds of studies to provide further information about the distribution and mechanisms of EA in CVI. We first analysed EA values in 67 patients, classified according to 3 evolutive groups: 27 patients suffering only from subjective symptoms of venous disease (grade 1), 19 patients with varicosis and sapheno-femoral incompetence (grade 2), 21 patients with varicosis and trophic skin changes (grade 3). EA values were also measured in 22 healthy controls. Analysis of EA was performed for equal concentrations of fibrinogen and adjusted for age. EA was significantly higher in CVI. The aggregation index, related to the kinetics of aggregates formation, rose significantly even from grade 1 while compared to controls and rose further with the evolutive grades. The same trend was found with the partial dissociation threshold (i.e. red cells aggregates cohesion). As the measurements were performed at standardized hematocrit and the results expressed after fibrinogen levels adjustment, this suggests the involvement of other factors. We subsequently investigated whether red cells from CVI patients aggregate more than those of controls when suspended in the same medium. The results showed that a cellular factor is unlikely to be involved, and that an interaction between red cells and plasma proteins other than fibrinogen could also explain the increased EA in CVI.

[Rheological parameters in hemorrhoid pathology]. / Etude des paramètres rhéologiques dans la pathologie hémorroïdaire.

The authors studied erythrocyte aggregation in 62 patients suffering from hemorrhoidal disease, distributed on the basis of proctoscopy findings between three groups (recent uncomplicated congestive attack, recent thrombosed hemorrhoid, stage IIb or III chronic prolapse). This hemorheological parameter is a sensitive marker of circulatory stasis. Values measured were compared with those obtained in 21 healthy subjects. Erythrocyte aggregation index was significantly higher in patients than in controls (31.6 +/- 6.8 versus 27.7 +/- 4.4) (p < 0.05). This difference was due essentially to increased values in patients with acute hemorrhoid problems. A parallel increase in blood fibrinogen was found in these same patients. Hemorheological changes could predispose to worsening of venous stasis in the hemorrhoidal circulation and participate in the onset or spread of thrombotic processes.

[Microcirculation and rheology]. / Microcirculation et rhéologie.

Microvessels, especially in the skin and muscles are organized in functional units. These units are controlled by the adrenergic system and hormones but also have autonomous metabolic and myogenic regulatory systems independent of vasomotion. Microcirculatory blood flow is affected by special rheologic properties: a low arteriolar haematocrit rises to the systemic level in the venules. The flow rate in the venules is low, and together with the raised haematocrit, explains the microvenular sensitivity to hyperviscosity. Capillarovenular microangiopathy, recently described by standard and fluorescent capillaroscopy, develops during chronic venous insufficiency. The capillary loops appear dilated and knotted together with fibrous deposits and pericapillary oedema. Venous hyperpressure is the cause of this microangiopathy. Together these phenomena disrupt normal haemodynamics and physiology of the microcirculatory unit: baseline hyperhaemia, lowered vasomotor and vasomotion reactivity, development of rheologic disorders (haemoconcentration, hyperfibrinogenaemia, erythrocyte agregation) and decreased fibrinolysis. Modifications in the transcapillary exchange is related to hypoxia and is aggravated by depressed lymphatic drainage. The main consequence is oedema. Inflammation, a characteristic of these microangiopathies could occur when the endothelium is activated by the hypoxia. The classical mediators of inflammation would activate interactions between the different cells: endothelium, granulocytes, monocytes and platelets. Several pharmacological models have been developed for the analysis of these data including exploration of the permeability and capillary resistance and rheological analysis. Objective observation of the microangiopathy with capillaroscopy, together with modern haemodynamical, biological and pharmacological methods are essential for a better understanding of microvascular disorders in chronic venous insufficiency.

[Quality control in clinical hemorheology: preliminary study by three centers]. / Contrôle de qualité en hémorhéologie clinique: étude préliminaire sur trois centres.

Clinical or pharmacological trials require reproducible laboratory tests. The aim of this work was to investigate the conditions of quality control of two laboratory tests, blood viscosity and red cell aggregation used for hemorheology trials in three centers. The results showed that viscosity measurements require 2 standards. For red cell aggregation, the control suspension standardized media (normal an pathological aggregation) showed a good intercentre reproducibility of the dissociation thresholds but a wide variability of aggregation times. Complementary studies in 5 or 6 centres are planned in order to define national standards of quality control.

Red blood cell aggregation and microcirculation in rat cremaster muscle.

Using intravital microscopy of the rat cremaster muscle, we studied the effects of changing red blood cell (RBC) aggregation on RBC arteriolar velocity and perfused capillary density (PCD). To modify RBC aggregation, 2 and/or 10% dextran (molecular weights 40,000, 70,000 or 480,000) or fresh rat plasma was infused into adult male rats via a normovolemic hemodilution procedure. The high-molecular-weight dextrans (70,000 and 480,000) both induced RBC hyperaggregation associated with similar dose-dependent decreases in RBC arteriolar velocity (30 and 40% for dextran concentrations of 2 and 10%, respectively) and in PCD (35 and 37%, respectively, for the two concentrations). Conversely, with 40,000 molecular weight dextran or plasma, we observed a 30% increase in RBC arteriolar velocity, but no change in PCD or hyperaggregation. Intravenous injection of the antiaggregating drug troxerutin (10(-3) M), either before or after 2% dextran 70,000, significantly inhibited the effects of this dextran on RBC arteriolar velocity and on PCD. We conclude that RBC hyperaggregation can lead to changes in both arteriolar velocity and PCD and may, therefore, impair tissue oxygenation.