Biomedical subjects

D Guez

Publications and source records attributed to D Guez.

At least 55 records · Page 3Linked to original sources

PubMed1996

[Treatment of hypertension with indapamide 1.5 mg sustained-release form: synthesis of results].

In accordance with international recommendations on the need to decrease doses of antihypertensive drugs, a low-dose (1.5 mg) sustained-release form of indapamide was developed so as to optimize the safety/efficacy ratio, while maintaining a once-daily administration. The new formulation ensures that the active ingredient release occurs in a sustained manner over 24 hours, with mean concentrations close to the maximal concentration over a prolonged period, while avoiding peak plasma concentrations. Clinical data were obtained mainly through two European multicenter, randomized, double-blind trials, totalling 690 patients. Firstly, the antihypertensive efficacy' of the new indapamide 1.5 mg form was demonstrated by measuring blood pressure 24 hours after the last drug intake, using a mercury sphygmomanometer; the equivalence of its antihypertensive efficacy with the immediate-release form of indapamide 2.5 mg was then verified. Biochemical safety data showed better acceptability with indapamide 1.5 mg with in particular a reduction of more than 50% of the number of patients with kalemia < 3.4 mmol/l; clinical safety data confirmed the good acceptability observed with the 2.5 mg immediate-release form of indapamide since many years, especially regarding glucose and lipid neutrality. In conclusion, the 1.5 mg sustained-release form of indapamide has an improved antihypertensive efficacy/safety ratio which is in accordance with international recommendations for the usage of low doses of antihypertensive drugs and diuretics in the first-line treatment of hypertension.

Adolescent↗

PubMed1996

[Evaluation of trough/peak ratio of indapamide 1.5 mg sustained-release form assessed by ambulatory blood pressure monitoring].

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.

Adult↗

PubMed1996

Lines of therapeutics research in Alzheimer's disease.

Therapeutic research is being stepped up to light Alzheimer's disease (AD), although its heterogeneity, the insufficiency of physiopathological knowledge, and the lack of a reference treatment impede the development of a drug to combat it. However, progress has opened up many avenues. Some recent approaches that have led to therapeutic research are identification of biochemical abnormalities, identification of dysfunction in several neurotransmitter systems (cholinergic, catecholaminergic, serotonergic, and peptidergic systems), and the study of senile plaques and neurofibrillary degeneration tangles. Although some types of therapy have been used for a long time (e.g., metabolic products such as nootropes), recently developed drugs target different systems: for example, neurotransmitter systems are important for symptomatic improvements in cognitive functions. The principal improvements expected with some new anticholinesterases whose role is to increase the available amount of central acetylcholine are in memory and attention. Second, retarding neuronal degeneration by acting on amyloid plaques is another possible future therapy. Here, protease inhibitors appear to be interesting tools. Third, the endototoxin etiology of neurodegenerative illnesses remains uncertain. After the first attempts with N-methyl-D-aspartate (NMDA) antagonists that had inescapable side effects, hopes rose with some new pharmacological tools such as the AMPA/kainate antagonists. Fourth, a possible stimulation of neuronal plasticity by neurotrophic factors such as nerve growth factor (NGF) constitutes another prospected research area. Fifth, the inflammatory aspects of degenerative diseases attract the attention of many laboratories and preliminary reports are hopeful. Finally, out of the established pharmacological tools, gene therapy, though still hypothetical, may become the expected treatment in the future. Pharmacotherapy used in the most common types of dementia has until now been largely palliative and dealt with symptoms. It is nonetheless not unreasonable to look forward to the development of drugs that will be able to combat the evolution of the dementia itself, rather than its symptoms. A list of different products developed to treat AD is concluded by an evaluation of the expected results and, in particular, the orientations likely to be necessary.

Aged↗

PubMed1995

Inhibition of basic fibroblast growth factor and vasculotropin biological activities on cultured cells by almitrine.

Autonomous cell growth may result from interactions of cellular growth factors with their receptors leading to the establishment of external or internal autocrine loops which can induce tumor formation. Tumor progression above a small volume also requires an increase in blood supply. This is achieved by the release from the tumor of angiogenic growth factors which diffuse toward preexisting capillaries. The search for compounds interfering with growth factors and their receptors represents a field of investigation of increasing importance. In this report we show that almitrine interferes with the binding of basic fibroblast growth factor and vasculotropin/vascular endothelial growth factor to their receptors present on vascular endothelial cells, smooth muscle cells or retinal pigment epithelium. This molecule inhibits reversibly serum and basic growth factors stimulated cell growth and motility without affecting epidermal growth factor-stimulated proliferation.

Almitrine↗

PubMed1995

Effect of a new cognitive drug-enhancer S-12024-2 on EEG sleep recordings in rats.

A newly synthesized agent S-12024-2 was shown to improve some aspects of cognitive processes such as memory consolidation. The relationships between sleep and memory lead us to investigate the effects of the intraperitoneal administration of three different doses (1, 3, and 10 mg/kg) of S-12024-2 on sleep variables in the rat. The results showed that S-12024-2 (10 mg/kg) increased slow wave sleep (SWS) and decreased wakefulness during the light period of the first 24 h of sleep recording. During day 1 of sleep recording, S-12024-2 tended to increase paradoxical sleep (PS) with a maximal effect observed with 3 mg/kg. Four days after administration of S-12024-2 (3 mg/kg), PS remained significantly high. These data suggest an active role for S-12024-2 on SWS and PS, compatible with its favourable effects on memory.

Animals↗

PubMed1995

Outcome of infrainguinal endovascular revascularization procedures for limb-threatening ischemia.

This report describes the results of 96 infrainguinal endovascular revascularization procedures performed in 86 patients with limb-threatening ischemia over a 3-year period. There were 41 women and 45 men (mean age 72.9 +/- 11.9 years) including 47 patients (51.1%) with diabetes and 13 (15.1%) with renal insufficiency. All patients had severe ischemia characterized by rest pain (18.8%), ulceration (12.5%), or gangrene (68.8%). Twelve procedures were carried out in association with conventional surgical reconstruction and in eight patients with mixed ulcers a venous procedure was performed during the same session. A total of 143 arterial lesions were treated including 61 occlusions (mean length 5.9 +/- 3.5 cm) and 82 stenoses (mean length 4.6 +/- 3 cm). The following techniques were used: transluminal angioplasty in 99 cases, laser in five cases, Rotablator in 24 cases, and aspiration thrombectomy in 15 cases. Nine patients (10.5%) died in the hospital. Initial failure was observed in 32 patients, of whom 18 underwent subsequent surgical revascularization and 14 required amputation of the extremity within 2 months. Analysis of variance was used to assess the following 12 risk factors for initial failure of endovascular revascularization: sex, age, diabetes, renal insufficiency, associated surgery, treatment of multiple lesions, artery treated, type of lesion, length of lesion, quality of runoff, use of an atherotome, and stent placement. Results showed a significant correlation between initial failure and both quality of runoff (12.9% in patients with two or more patent leg arteries vs. 36.5% in patients with one or fewer patent leg arteries; p < 0.05) and type of lesion (14.5% for stenosis vs. 45.9% for occlusion). Mean follow-up was 9.98 +/- 9.9 months and 4.7% of patients were lost. Restenosis was observed during follow-up of 16 of the 74 initially successful procedures. ANOVA was used to assess the same 12 risk factors for restenosis. Results showed a significant correlation between restenosis and both sex (10.8% in women vs. 32.4% in men; p < 0.05) and age (8% for patients > 80 years of age vs. 28.6% for patients < 80 years; p < 0.05). Primary patency, secondary patency and limb salvage rates calculated according to the actuarial method were 65%, 75%, and 84%, respectively, at 6 months and 47%, 67%, and 81%, respectively, at 1 year. Limb salvage rates for the endoluminal techniques used in this study were satisfactory, especially in elderly patients with either segmental lesions or contraindications for distal bypass.

Adult↗

PubMed1995

Carotid artery mechanical properties of Dahl salt-sensitive rats.

We evaluated the mechanical properties of the carotid artery in anesthetized Dahl rats with or without long-term treatment with the diuretic compound indapamide. The mechanical properties of the carotid artery were evaluated by establishing pressure-volume curves in situ in vivo before and after total relaxation of arterial smooth muscle by potassium cyanide. Dahl salt-sensitive and salt-resistant rats were fed either a low (0.4%) or high (7%) NaCl diet for 5 weeks. In each group, half the rats received for the same period of time oral treatment with indapamide (3 mg/kg per day). Blood pressure, heart rate, and pressure-volume curves were studied at the end of the 5-week period. In untreated Dahl salt-sensitive rats, the pressure-volume curve of the carotid artery was shifted to the right compared with that in untreated Dahl salt-resistant rats. The finding was observed even after potassium cyanide and regardless of the NaCl diet (P < .01 between Dahl salt-sensitive and -resistant rats). Indapamide was able to prevent the development of hypertension in Dahl salt-sensitive rats receiving a high NaCl diet (185 +/- 7 versus 146 +/- 8 mm Hg in untreated and treated Dahl salt-sensitive rats with a high NaCl diet, P < .0005). In the other groups, indapamide had no effect on blood pressure. Indapamide treatment increased carotid arterial static compliance in Dahl salt-sensitive rats with a high or low NaCl diet and to a lesser extent in Dahl salt-resistant rats. The increase was observed even after total relaxation of carotid arterial smooth muscle by potassium cyanide.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

[Therapeutic benefit of a low dose of indapamide: results of a double-blind against placebo European controlled study].

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.

Adolescent↗

PubMed1995

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.

Adolescent↗

PubMed1993

Neurologic and histologic evaluation of almitrine+raubasine (Duxil) in middle cerebral artery occlusion in cats.

Impairment of energy metabolism is the fundamental mechanism leading to cell death in ischemia. Using the middle cerebral artery (MCA) occlusion model in cats, we studied the effect of Duxil (almitrine and raubasine combination), which was given either before and after or only after MCA occlusion, on ischemia in terms of neurological function and histological changes. Neurological function was assessed consecutively for 7 days after MCA occlusion using a categorical rating scale in 18 cats. Neurological function was significantly improved in treated animals than in non-treated controls regarding to the motor and sensory function, walking, posture and stepping reflex. Animals were killed on the 8th day and histological changes were examined by light and electron microscopies. Significant improvement in the morphological scores based on the light-microscopy changes were found in animals treated with Duxil compared to non-treated ones. Under the electron microscopy, the protective effects of Duxil were characterized by retaining glycogen and mitochondria. Morphological improvement was associated with the recovery of neurological function and especially profound in penumbra areas of MCA infarction. These results suggest that Duxil has a protective effect against ischemic damage induced by occlusion of MCA in cats.

Almitrine↗

PubMed1993

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.

Action Potentials↗

PubMed1993

Diuretic effects on cardiac hypertrophy in the stroke prone spontaneously hypertensive rat.

OBJECTIVE: The aim was to compare the effects of two diuretics, indapamide and hydrochlorothiazide, on cardiac hypertrophy in stroke prone spontaneously hypertensive rats (SHR-SP). METHODS: Six week old SHR-SP, on a 1% sodium chloride water intake, were treated with oral indapamide (3 mg.kg-1 x d-1) or hydrochlorothiazide (20 mg.kg-1 x d-1) over a 44 d period. The hypertrophic process was evaluated by classical indices and by the morphological analysis of myocyte cross sectional area, coronary artery thickness, and immunohistochemical analysis of interstitial fibrosis. RESULTS: In the untreated SHR-SP on 1% sodium chloride, all animals developed severe hypertension and cardiac hypertrophy when compared to normotensive salt loaded WKY by 13 weeks of age. In salt loaded SHR-SP treated with indapamide or hydrochlorothiazide, systolic blood pressure was moderately decreased by the end of the treatment when compared with untreated SHR-SP, at 259(7) and 245(7) mm Hg respectively, v 300(11) mm Hg, p < or = 0.05. Myocyte enlargement appears to be the main feature involved in the development of cardiac hypertrophy in the SHR-SP. By the end of treatment both indapamide and hydrochlorothiazide prevented the development of cardiac hypertrophy evaluated by heart weight to body weight ratio [4.69(0.07) and 4.61(0.08) respectively, v 5.39(0.13), p < or = 0.001] and myocyte hypertrophy (-33% and -21% of the SHR-SP values, p < or = 0.001). Myocardial interstitial fibrosis and perivascular fibrosis were practically absent in the two treated groups. CONCLUSIONS: Our results allow the characterisation of SHR-SP cardiac hypertrophy and indicate that the two types of chronic diuretic treatment prevent SHR-SP cardiac hypertrophy with a drug specific efficiency.

Animals↗

PubMed1993

Arterial smooth muscle cell phenotype in stroke-prone spontaneously hypertensive rats.

The aim of this study was to determine the phenotype of smooth muscle cells in the arteries of chronically hypertensive animals and to analyze the effects of treatments known to increase the survival of the animal without a clear effect on its hypertensive state. Stroke-prone spontaneously hypertensive rats (SHRSP) kept on a 1% sodium drinking solution were untreated or treated with one of two diuretics, indapamide (3 mg/kg per day) or hydrochlorothiazide (20 mg/kg per day), from 6 to 13 weeks of age. Phenotype was characterized by the immunolabeling of arteries with antibodies raised against a cellular form (EIIIA) of fibronectin, alpha-smooth muscle actin, and nonmuscle myosin. We demonstrated that phenotypes of smooth muscle cells of the SHRSP differ from those found in Wistar-Kyoto rats. The difference in phenotype is specific for the vessel type: ie, an increased expression of nonmuscle myosin in the aorta and of both EIIIA fibronectin and nonmuscle myosin in the coronary arteries. The two diuretics (1) had no effect on blood pressure, (2) prevented or did not prevent the increase in medial thickness, and (3) prevented changes in both smooth muscle cell phenotype and ischemic tissular lesions. Taken together, the results suggest that in SHRSP the changes in the phenotype of smooth muscle cells and the thickness of arteries are unrelated events. We propose that the maintenance of the contractile phenotype of the arterial smooth muscle cells could be an essential parameter involved in the prevention of the deleterious consequences characteristic of a severe hypertensive state.

Actins↗

PubMed1993

Reactivity and sensitivity of the mesenteric artery in adult spontaneously hypertensive rats after chronic treatment with indapamide.

The effects of chronic treatment with indapamide (3 mg/kg/day) on the structure and function of the mesenteric artery were studied in two groups of spontaneously hypertensive rats (SHRs) using an experimental model of in situ localized mesenteric artery. Indapamide (n = 12) or placebo (n = 12) were given to 8-week-old rats for 4 weeks. After anesthesia and laparotomy, a segment of mesenteric artery (external diameter, 300-400 microns) was exposed for video-microscopic measurements. The diameter-pressure relationships were established under active conditions (phenylephrine, 10(-6) M) and passive conditions (potassium cyanide, KCN) for transmural pressure ranging from atmospheric pressure to 200 mm Hg. These studied arterial segments were then fixed and their wall cross-sectional areas (CSA) measured in transverse sections. Active wall stress and tension were defined as the differences in wall stresses and wall tensions calculated for active and passive conditions. Systolic arterial pressure and mesenteric CSA were decreased in treated rats (197 +/- 15 mm Hg vs. 211 +/- 12 mm Hg, p < 0.05; 16,230 +/- 1048 microns2 vs. 19,033 +/- 1082 microns2, p < 0.05). In both groups, mesenteric diameters were smaller under active than under passive conditions without significant differences in treated vs. untreated group under active conditions. The active wall tension was lower in treated (0.4 +/- 0.19 N/m) than in untreated rats (1.19 +/- 0.62 N/m, p < 0.05). However, there were no differences in active wall stress in both groups (103 +/- 47 kPa and 134 +/- 30 kPa).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Comparative effects of indapamide and hydrochlorothiazide on cardiac hypertrophy and vascular smooth-muscle phenotype in the stroke-prone, spontaneously hypertensive rat.

The effects of two diuretics, indapamide (3 mg/kg/day) and hydrochlorothiazide (20 mg/kg/day), were analyzed over a 44-day period on the cardiovascular hypertrophy of stroke-prone spontaneously hypertensive rats (SHR-SP). Untreated SHR-SP developed severe hypertension and cardiac hypertrophy when compared to normotensive Wistar-Kyoto (WKY) rats after 8 weeks on 1% sodium chloride. In diuretic-treated animals, systolic blood pressure was moderately decreased by the end of the treatment when compared with untreated SHR-SP (-13 and -18%, respectively, p < or = 0.05). Morphometric analysis of myocyte cross-sectional areas evidenced that indapamide was the most effective in preventing myocyte hypertrophy (-33%, p < or = 0.0001). Small coronary artery wall thickness was efficiently prevented in the two treated groups, but medial hypertrophy was prevented by hydrochlorothiazide only. Among markers of smooth-muscle cell phenotype (contractile or extracellular matrix proteins) EIIIA-fibronectin (FN), one FN cellular isoform, was shown to be the most sensitive marker by an immunohistochemical technic. Medial expression of EIIIA-FN, which was characteristic of SHR-SP coronary arteries, was prevented by the two treatments. The two diuretic treatments, despite similar effects on blood pressure and smooth-muscle phenotype, prevent SHR-SP cardiovascular hypertrophy with a drug-specific efficiency.

Animals↗

PubMed1993

Study of antiatherogenic properties of indapamide in a pharmacologic model.

A localized atheromatous plaque was induced in rabbits after transmural electrical stimulation of the carotid and a cholesterol-rich diet (1.33% cholesterol) for 4 weeks. This model was used to investigate the antiatherogenicity of indapamide. The treatment given per os started 14 days before the stimulation period. Animals were divided into six groups: group 1 (control) received gelatin 2%, group 2 received hydrochlorothiazide at 20 mg/kg/day, group 3 was treated with flunarizine at 25 mg/kg/day, and groups 4, 5, and 6 received indapamide at 0.3, 1, and 3 mg/kg/day, respectively. During the experimental period, all rabbits showed similar weight gain, regardless of the treatment. Image analysis showed an antiatherogenic effect for indapamide (0.3 mg/kg/day) characterized by a reduction in the number of cell layers (NCL; 10.5 +/- 1.8 vs. 18.0 +/- 2.9; p < 0.05) and in the intima/media area ratio (I/M; 17.5 +/- 4.5 vs. 42.7 +/- 7.0%; p < 0.01). Indapamide appeared to be more active than the reference drug flunarizine (NCL = 14.2 +/- 2.5, N.S.; I/M = 24.5 +/- 4.3, p < 0.05). The maximum effect occurred at the lowest dose tested (0.3 mg/kg/day). The reason for the loss of antiatherogenic activity of indapamide at higher doses is discussed. Hydrochlorothiazide did not show any effect on the formation of the atheromatous plaque.

Animals↗

PubMed1993

Indapamide inhibits human platelet aggregation in vitro: comparison with hydrochlorothiazide.

Among antihypertensive drugs with diuretic properties, indapamide was shown to inhibit platelet growth factors production in diabetic hypertensive patients, suggesting an antiplatelet activity. The present study aimed to demonstrate the antiaggregating properties of indapamide. The effect of indapamide on platelet function was compared in vitro to that of hydrochlorothiazide. Indapamide (100 microM) inhibited the second wave of adenosine diphosphate-induced aggregation and inhibited collagen-induced aggregation of platelet rich plasma by 50%. Using isolated platelets, indapamide also inhibited aggregation induced by low doses of thrombin (70% inhibition with 0.035 U/ml). This inhibition was dose-dependent and was still observed in presence of high thrombin concentrations, although the inhibition was moderate. Inhibitory effect of indapamide was more pronounced on the release reaction. Indapamide inhibited the thrombin-induced release of serotonin from dense granules by up to 80%. Hydrochlorothiazide at the same concentrations had no effect on platelet aggregation, and the inhibitory effect on the secretion was inconsistent and never exceeded 30%. By contrast, when the aggregation inducer was arachidonic acid, indapamide had no effect either on aggregation or on thromboxane formation, indicating that it was not acting on arachidonic catabolism. Calcium mobilization evoked by thrombin stimulation and measured with the fluorescent dye Indo 1 was also reduced in presence of indapamide by 30%. Myosin light chain and pleckstrin phosphorylation induced by thrombin were also reduced. These results demonstrate that indapamide inhibits platelet responses by inhibiting calcium mobilization. The anti-aggregating properties of indapamide could contribute to normalize the hyperresponsiveness of platelets from hypertensive patients.

Adenosine Diphosphate↗

PubMed1993

[Regulation of osteoclastic resorption by prostanoids in vivo].

Prostanoids, and particularly prostaglandins (PGs) E, are potent mediators of bone resorption. However the actual role(s) of these agents in osteoclastic resorption is (are) not yet known. In an attempt to approach the role of prostanoids in the events leading to resorption itself, we used two different animal models. We showed that indomethacin, an inhibitor of prostanoid biosynthesis, drastically reduced osteoclastic resorption at the dose of 7 mg/kg/d in the two models. This effect was dose-dependent as resorption inhibition increased by increasing the dose of indomethacin. However the effect was already significant at the lower dose (2 mg/kg/d). The total number of osteoclasts in the site was according by reduced, showing the involvement of the prostanoids in the events preceding and/or regulating the fusion of the mononucleated preosteoclasts into multinucleated osteoclasts. The calculation of the ratio active/inactive osteoclasts indicated that the activation (i.e. access to the bone surface) of the osteoclast, was prostanoid-dependent; indeed the ratio systematically decreased in the indomethacin-treated animals in the two models. We also observed that the inhibition was not sustained in time as resorption recovered, probably through the starting of PG-independent metabolic pathways. However this starting was rather slow and these pathways apparently were less affective than the PG-dependent ones since the intrinsic activity of the differentiated osteoclasts was significantly reduced.

Animals↗