Clinical trial: the effects of adding ranitidine at night to twice daily omeprazole therapy on nocturnal acid breakthrough and acid reflux in patients with systemic sclerosis--a randomized controlled, cross-over trial.

BACKGROUND: Gastro-oesophageal reflux disease (GERD) is an important problem in systemic sclerosis due to impaired salivation and oesophageal function. AIM: To determine the efficacy of adding ranitidine at bedtime to control nocturnal acid breakthrough (NAB) and GERD in patients with systemic sclerosis already prescribed high-dose omeprazole. METHODS: Patients with systemic sclerosis and GERD symptoms (n = 14) were treated with omeprazole 20 mg b.d. and either placebo or ranitidine 300 mg at bedtime for 6 weeks in a randomized, cross-over, placebo controlled study. At the end of each period a 24 h pH-study with intragastric and oesophageal pH measurement was performed. RESULTS: Pathological acid reflux occurred in eight patients with omeprazole/placebo and in seven with omeprazole/ranitidine (P = ns) with technically adequate oesophageal pH-studies (n = 13). NAB was present in eight patients with omeprazole/placebo and six with omeprazole/ranitidine (P = ns) in whom technically adequate gastric pH-studies were obtained (n = 10). The addition of ranitidine had no consistent effect on patient symptoms or quality of life. CONCLUSION: Many patients with systemic sclerosis experienced NAB and pathological oesophageal acid exposure despite high-dose acid suppression with omeprazole b.d. Adding ranitidine at bedtime did not improve NAB, GERD or quality of life in this population.

Impairment of G-protein-mediated signal transduction in the porcine coronary endothelium during rejection after heart transplantation.

BACKGROUND: Endothelial dysfunction is an early event leading to atherosclerosis. It also occurs after orthotopic heart transplantation and can be used to predict the development of intimal hyperplasia in the coronary artery wall. The present study was designed to assess the time course and specific alterations underlying endothelial dysfunction due to rejection after heart transplantation. METHODS: A porcine model of heterotopic heart transplantation was used. Preoperative serum typing for the class I antigen of the swine lymphocyte alloantigen was performed to ensure compatibility for this antigen. This permitted survival of the graft with a low grade rejection without immunosuppression. Rings (with or without endothelium) of epicardial coronary arteries of native and transplanted hearts were studied in organ chambers filled with modified Krebs-Ringer bicarbonate solution and compared 1, 30 and 60 days after transplantation. RESULTS: Myocardial contractility was normal in all grafts studied at 60 days after transplantation and all coronary arteries were patent. Myocardial biopsies showed the progression of rejection from day 1 to day 60 after implantation. All endothelium-dependent relaxations were normal one day after transplantation. Endothelium-dependent relaxations to serotonin and to the alpha 2-adrenergic agonist UK14304 (which both activate receptors coupled to Gi-proteins) and to sodium fluoride (a direct activator of G-proteins) were decreased 30 days after transplantation, while those to the calcium ionophore, A23187, and bradykinin were shifted to the right and those to ADP were normal. At 60 days, endothelium-dependent relaxations mediated by the Gi-protein pathway were decreased further while the concentration-relaxation curves to the other agonists were further shifted to the right. Endothelium-independent relaxations to the nitric oxide donor, Sin-1, were progressively reduced at 30 and 60 days, but maximal relaxations were maintained at 60 days. Histomorphometric studies showed a progressive increase in the percentage of coronary rings with intimal thickening from day 1 to day 60 after transplantation. CONCLUSIONS: The progressive endothelial dysfunction reported in this model of accelerated coronary atherosclerosis after transplantation without immunosuppression involves preferentially the pertussis-toxin-sensitive Gi-protein-mediated pathway. Endothelium-independent relaxations are decreased at 60 days, as are all other endothelium-dependent relaxations. Decreased endothelium-dependent vasodilatation may contribute to the development of coronary graft vasculopathy.

Role of the renin-angiotensin system in neointima formation after injury in rabbits.

We investigated the role of the renin-angiotensin system in neointima formation in a species in which converting enzyme inhibitors have been so far ineffective in suppressing abnormal vascular repair. The effects of converting enzyme inhibition by perindopril and selective blockade of angiotensin subtype 1 receptor by DuP 753 were assessed on neointima formation after balloon injury of rabbit carotid artery. Myointimal growth was measured by histomorphometric analysis. In rabbits treated 6 days before and for 14 days after injury, perindopril (2 mg/kg per day PO, n = 7) significantly reduced neointima formation (-51%, P < .01). DuP 753 (1 mg/d, n = 8) infused perivascularly for 14 days in the vicinity of injured carotid artery also markedly suppressed myointimal thickening (-60%, P < .01). To determine whether angiotensin subtype 2 receptor was implicated in this vascular response, we infused CGP 42112A, a specific subtype 2 receptor ligand, continuously for 14 days according to the same protocol of DuP 753 administration. CGP 42112A (1 mg/d) did not change the neointima-media ratio, indicating that angiotensin subtype 2 receptors were not involved in myointimal hyperplasia in rabbits. Thus in rabbits, the renin-angiotensin system plays a major role in neointima formation, and the protective effect of perindopril appears to be mediated mainly by inhibition of angiotensin II production, because blockade of the subtype 1 receptor reduced myointimal growth in a manner similar to that of converting enzyme inhibition and because intracarotid infusion of angiotensin II (500 ng/min) at the site of injury enhanced the vascular response (+39%, P < .05). Bradykinin (500 ng/min) administered in the same conditions as angiotensin II did not modify neointima formation.

Central vasopressin raises arterial pressure by sympathetic activation and vasopressin release.

Although central administration of arginine vasopressin (AVP) has been reported to increase arterial pressure mediated by activation of the sympathetic system, we found that peripheral blockade of sympathetic transmission did not attenuate this pressor response. To elucidate the mechanism, rats were pretreated with either phentolamine (3 mg/kg), chlorisondamine (2.5 mg/kg), a vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (AVP-X) (10 micrograms/kg), or the combinations of phentolamine and AVP-X or chlorisondamine and AVP-X. The pressor response to intracerebroventricular injection of AVP in unrestrained conscious rats was reduced but not significantly altered by intravenous injection of phentolamine or AVP-X; however, combined treatment with these agents abolished the response. To determine that the amount of central AVP leaked to the periphery did not contribute to the pressor effect, tritiated AVP and AVP (100 ng total) were injected intracerebroventricularly. Blood samples collected at 0, 3, and 30 minutes after injection showed that radioactivity in plasma was primarily metabolites and that the amount of intact AVP estimated to leak from the brain was too low to produce a pressor effect. Comparative regional hemodynamic studies between intracerebroventricular and intravenous injection of AVP performed in conscious rats instrumented with Doppler flow probes demonstrated a qualitatively similar pattern of increased resistance in the renal, mesenteric, and hindquarters beds. These data suggest that central pressor action of AVP is mediated by both activation of the sympathetic system and release of AVP.

Role of angiotensin subtype 2 receptor in neointima formation after vascular injury.

The role of angiotensin receptor subtypes 1 and 2 was assessed on neointima formation after injury in rat carotid artery. The effects of angiotensin converting enzyme inhibition by perindopril (3 mg.kg-1 x day-1 p.o.) and selective blockade of angiotensin subtype 1 receptors by DuP 753 (5 and 30 mg.kg-1 x day-1 p.o.) were compared on proliferative response to balloon injury. In rats treated 6 days before and for 14 days after injury, perindopril significantly reduced (-76%, p < 0.01) myointimal hyperplasia. In contrast, DuP 753 at 5 mg.kg-1 x day-1 did not modify the hyperplastic response to balloon catheterization. Only at 30 mg.kg-1 x day-1 was DuP 753 able to reduce neointima formation (-47%, p < 0.05). This dose was equipotent to perindopril on the renin-angiotensin system as assessed by the pressor response to angiotensin II and angiotensin I. Therefore, blockade of subtype 1 receptors was a less effective means of suppression of myointimal growth than angiotensin converting enzyme inhibition, suggesting that another angiotensin receptor subtype or converting enzyme substrates are involved in this process. For the determination of whether angiotensin subtype 2 receptors were implicated, the specific subtype 2 receptor antagonist CGP 42112A (1 mg.kg-1 x day-1) was continuously infused perivascularly for 14 days in the vicinity of the injured carotid artery. CGP 42112A was as effective in preventing neointima formation as perindopril (-73%, p < 0.01, versus -76%, p < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Antiplatelet and antithrombotic activity of SL65.0472, a mixed 5-HT1B/5-HT2A receptor antagonist.

The antiplatelet and antithrombotic activity of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno [3,2-c]pyrin-4-yl) piperazin-1-yl]ethyl]-1,2-di-hydroquinoline-acetamide), a mixed 5-HT1B/5-HT2A receptor antagonist was investigated on 5HT-induced human platelet activation in vitro, and in rat, rabbit and canine platelet dependent thrombosis models. SL65.0472 inhibited 5-HT-induced platelet shape change in the presence of EDTA (IC50 values = 35, 69 and 225 nM in rabbit, rat and human platelet rich plasma (PRP)), and also inhibited aggregation induced in human PRP by 3-5 microM 5-HT + threshold concentrations of ADP (0.5-1 microM) or collagen (0.3 microg/ml) with mean IC50 values of 49 +/- 13 and 48 +/- 6 nM respectively. SL65.0472 inhibited thrombus formation when given both intravenously 5 min and orally 2 h prior to assembly of an arterio-venous (A-V) shunt in rats as from 0.1 and 0.3 mg/kg respectively. It was active in a rabbit A-V shunt model with significant decreases in thrombus weight as from 0.1 mg/kg i. v. and at 10 mg/kg p.o. The delay to occlusion in an electric current-induced rabbit femoral artery thrombosis model was increased by 251% (p <0.05) after 20 mg/kg p.o. SL65.0472 (30 microg/kg i.v.) virtually abolished coronary cyclic flow variations (7.2 +/- 1.0/h to 0.6 +/- 0.6/h, p <0.05) and increased minimum coronary blood flow (1.2 +/- 0.8 ml/min to 31.8 +/- 8.4 ml/min, p <0.05) in a coronary artery thrombosis model in the anaesthetised dog. Finally, SL65.0472 significantly increased the amount of blood lost after rat tail transection at 3 mg/kg p.o. Thus the anti-5-HT2A component of SL65.0472 is reflected by its ability to inhibit 5-HT-induced platelet activation, and platelet-rich thrombus formation.

Pharmacological profile of SL 59.1227, a novel inhibitor of the sodium/hydrogen exchanger.

1. The NHE1 isoform of the Na(+)/H(+) exchanger plays an important role in the regulation of intracellular pH and in cardiac cell injury caused by ischaemia and reperfusion. SL 59.1227 is a novel imidazolypiperidine Na(+)/H(+) antiport inhibitor which is structurally unrelated to previously described acylguanidine inhibitors such as cariporide. 2. Recovery of pH(i) following an intracellular acid load was measured in CCL39-derived PS120 variant cells, selectively expressing either NHE1 or NHE2 isoforms of the Na(+)/H(+) exchanger. pH(i) recovery was potently and selectively slowed by SL 59.1227 in NHE1-expressing cells (IC(50) 3.3+/-1.3 nM) versus NHE2-expressing cells (2.3+/-1.0 microM). The respective IC(50) values for cariporide were 103+/-28 nM (NHE1) and 73+/-46 microM (NHE2). 3. In anaesthetized rats following left coronary artery occlusion (7 min) and reperfusion (10 min) SL 59.1227 (10 - 100 microg kg(-1) min(-1) i.v.) inhibited ischaemia-mediated ventricular tachycardia (71 - 100%) and reperfusion-induced ventricular fibrillation (75 - 87%) and prevented mortality. Bolus i.v. administration of SL 59.1227 (1 mg kg(-1)) produced anti-arrhythmic effects when administered either before or during ischaemia. 4. Cardiac infarct size was determined in anaesthetized rabbits following left coronary artery occlusion (30 min) and reperfusion (120 min). Infarct size measured as a percentage of the area at risk was 36.2+/-3.4% (control group) versus 15.3+/-3.9% (SL 59.1227 0.6 mg kg(-1) i.v.). 5. SL 59.1227 is the first example of a potent and NHE1-selective non-acylguanidine Na(+)/H(+) exchanger inhibitor. It possesses marked cardioprotective properties.

Morphological heterogeneity with normal expression but altered function of G proteins in porcine cultured regenerated coronary endothelial cells.

1. Experiments were designed to investigate whether the pertussis toxin-dependent endothelial dysfunction following balloon injury is due to a reduced expression or an insufficient function of G-proteins. 2. Endothelium-dependent responses of porcine coronary arteries were examined in vitro by use of conventional organ chambers. Morphological analysis was performed by isolating and culturing the endothelial cells from these arteries. The expression of Gi-proteins in regenerated endothelial cells was measured by Western blots and immunolabelling. The function of G-proteins was assessed by measuring the GTPase activity of cultured endothelial cells. 3. Eight days following denudation, endothelial regrowth was confirmed by histological examination and by demonstrating the presence of endothelium-dependent relaxations to bradykinin and 5-hydroxytryptamine (5-HT). In primary culture, the regenerated endothelial cells displayed a 'cobblestone' pattern as seen with native endothelial cells. 4. Twenty eight days after denudation, the endothelium-dependent relaxations induced by 5-HT were impaired, but those to bradykinin were maintained. However, the latter were reduced when endothelium-dependent hyperpolarization was prevented. 5. Twenty eight days after denudation, multinucleated giant cells were present in the regenerated but not in the native cultured endothelial cell populations. These regenerated endothelial cells incorporated less tritiated thymidine than native endothelial cells. 6. The intensities of the bands on the immunoblot of the regenerated endothelial cells, when several antibodies against Gi alpha 1/alpha 2/alpha 3 were used, were the same as those obtained in native endothelial cells. The immunolabelling with the same antibodies was similar between the giant cells and the regenerated endothelial cells of normal size. The hydrolysis of GTP was lower in regenerated than in native endothelial cell membranes. 7. In conclusion, endothelium-dependent relaxations mediated by Gi-proteins are impaired in balloon denuded coronary arteries. This dysfunction following regeneration cannot be explained by a reduced expression of Gi proteins but rather reflects an abnormal function of the G-proteins in the regenerated endothelium.

Time course of coronary endothelial dysfunction in acute untreated rejection after heterotopic heart transplantation.

BACKGROUND: Endothelial dysfunction is one of the early events leading to atherosclerosis. It occurs early after orthotopic heart transplantation and precedes the appearance of accelerated graft coronary artery disease believed to stem from chronic rejection of the endothelium. Acute rejection may contribute to the development of graft vasculopathy. METHODS: To assess the time course and specific mechanisms of coronary endothelial dysfunction in acute untreated rejection, a swine model of retroperitoneal heterotopic heart transplantation was used. Large white swine (age 10 +/- 2 weeks, weight 25 +/- 5 kg) were serum-typed for class I antigen of the swine leukocyte antigen system and selected to ensure a similar degree of incompatibility. Donor hearts were preserved with normothermic blood cardioplegia and regional hypothermia; the mean ischemic time was 64 +/- 15 minutes. Myocardial contractility decreased from day 5 (normal) to day 14 (weak), but electrical activity was preserved. All coronary arteries were patent, and International Society for Heart and Lung Transplantation grade 4 rejection was present in all hearts beyond 5 days. The endothelial function of epicardial coronary arterial rings of native and transplanted hearts was studied in organ chambers filled with modified Krebs-Ringer bicarbonate solution and compared 1, 5, 9, and 14 days after transplantation. RESULTS: Maximal endothelium-independent relaxations were unaffected at all stages. Endothelium-dependent relaxations to serotonin and alpha 2-adrenergic agonist UK 14304 (which activate receptors coupled to Gi-proteins) and to sodium fluoride (a direct G-protein activator) deteriorated progressively over time. At 14 days maximal relaxations to the calcium ionophore A23187, adenosine diphosphate, and bradykinin were also reduced, but to a lesser degree than those to serotonin and sodium fluoride. Histomorphometric studies of the allograft coronary artery rings showed progressive intimal hyperplasia from day 5 to day 14, with an increase in the incidence from 29% +/- 8.3% to 61.5% +/- 12%. CONCLUSIONS: These studies show that endothelial dysfunction in untreated acute rejection after heart transplantation develops beyond 5 days and initially involves G-proteins; the dysfunction worsens over time to finally affect all endothelial mechanisms and vascular smooth muscle. The progression of the associated intimal hyperplasia parallels the alteration in endothelial function, suggesting a permissive role of the dysfunction in the development of this acute form of coronary graft vasculopathy.

Endothelial effects of hemostatic devices for continuous cardioplegia or minimally invasive operations.

BACKGROUND: Improvements in myocardial protection may include the continuous delivery of normothermic blood cardioplegia. Technical aids are required for optimal visualization of the operative field during the performance of coronary anastomoses if cardioplegia is to be given continuously or during minimally invasive operations. However, the effects of the different hemostatic devices on coronary endothelial function are unknown. METHODS: We compared the effects on endothelial function of two commonly used hemostatic techniques, coronary clamping and gas jet insufflation, with those of a technique using extravascular balloon occlusion to mimic systolic luminal closure by the surrounding myocardium. The three techniques were applied for 15 minutes on porcine epicardial coronary arteries from explanted hearts. For coronary clamping, standard bulldog clamps were used. Gas jet insufflation was applied by blowing oxygen (12 L/min) tangentially at a 45-degree angle 1 cm away from a 3-mm arteriotomy. Extravascular balloon occlusion was achieved with a needle-tipped silicone loop, the midportion of which, once positioned beneath the coronary artery, was inflated to push a myocardial "cushion" against the back of the vessel until its occlusion. Control rings were taken from the same coronary artery. The endothelial function of control and instrumented arterial rings was then studied in organ chambers filled with modified Krebs-Ringer bicarbonate solution. RESULTS: Contractions to potassium chloride and prostaglandin F2 alpha and endothelium-independent relaxation to sin-1, a nitric oxide donor, were unaffected in all groups. Endothelium-dependent relaxation to serotonin was impaired after clamping and preserved after gas jet insufflation and extravascular balloon occlusion. Maximal endothelium-dependent relaxation to serotonin was as follows: for coronary clamping, 63% +/- 6% versus 87% +/- 3% in controls; for gas jet insufflation, 67% +/- 12% versus 88% +/- 7%; and for extraluminal balloon occlusion, 79% +/- 6% versus 85% +/- 5%. CONCLUSIONS: Whereas commonly used hemostatic devices may impair endothelial function, extravascular balloon occlusion appears to achieve effective hemostasis while preserving endothelial integrity.

High-resolution manometry predicts the success of oesophageal bolus transport and identifies clinically important abnormalities not detected by conventional manometry.

BACKGROUND AND AIMS: High-resolution manometry (HRM) is a recent development in oesophageal measurement; its value in the clinical setting remains a matter of controversy. (i) We compared the accuracy with which bolus transport could be predicted from conventional manometry and HRM. (ii) The clinical value of HRM was assessed in a series of patients with endoscopy-negative dysphagia in whom conventional investigations had been non-diagnostic. METHOD: (i) Control subjects and patients with endoscopy-negative dysphagia underwent concurrent HRM and video-fluoroscopy. Ninety-five records were reviewed using HRM with spatiotemporal plot and conventional line plots of the pressure data derived from the same recording. (ii) The HRM and notes of patients with endoscopy-negative dysphagia and abnormal bolus transport were analysed to identify additional information provided by the new technique. RESULTS: (i) Receiver operating characteristic analysis demonstrated that HRM predicts the presence of abnormal bolus transport more accurately than conventional manometry. (ii) HRM identified clinically important motor dysfunction not detected by manometry and radiography. These included localized disturbances of peristalsis and abnormal movement of the lower oesophageal sphincter during oesophageal spasm. CONCLUSION: The HRM predicts bolus movement more accurately than conventional manometry and identifies clinically relevant oesophageal dysfunction not detected by other investigations including conventional manometry.

Cardiovascular effects of SL65.0472, a 5-HT receptor antagonist.

In this study, we describe the cardiovascular effects of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno[3,2-c] pyridin-4-yl) piperazin-l-yl] ethyl]-1, 2-dihydroquinoline-1-acetamide), a novel 5-hydroxytryptamine (5-HT) receptor antagonist developed for the treatment of cardiovascular disease, in several in vivo models. The haemodynamic profile of SL65.0472 was evaluated in anaesthetised dogs. Following i.v. bolus doses of 0.03 mg/kg i.v. and 0.3 mg/kg, no significant changes in cardiac output, contractility or rate, systemic and pulmonary pressures, regional blood flows and vascular resistances or electrocardiogram were noted. After 1 mg/kg i.v. SL65.0472 significantly reduced arterial blood pressure. In conscious spontaneously hypertensive rats administration of SL65.0472 0.5 mg/kg p.o. had no effect on mean arterial blood pressure or heart rate. Vasoconstriction produced by 5-HT results primarily from the stimulation of two receptor subtypes, 5-HT(1B) and 5-HT(2A) receptors. In anaesthetised dogs SL65.0472 antagonised sumatriptan-induced decreases in saphenous vein diameter (5-HT(1B)-receptor mediated) with an ID(50) of 10.1 microg/kg i.v. (95% c.l. 8.3-12.4). In anaesthetised pithed rats SL65.0472 inhibited 5-HT pressor responses (5HT(2A)-receptor mediated) with ID(50) values of 1.38 microg/kg i.v. (95% c.l. 1.15-1.64) and 31.1 microg/kg p.o. (95% c.l. 22.6-42.6). The duration of the 5-HT(2A)-receptor antagonist effect of SL65.0472 following oral administration was evaluated in conscious rats. SL65.0472 (0.1 mg/kg p.o.) markedly inhibited 5-HT pressor responses 1 and 6 h after administration. Therefore, in vivo, SL65.0472 potently antagonises vasoconstriction mediated by 5-HT(1B) and 5-HT(2A) receptors but has minimal direct haemodynamic effects.

The pharmacological basis and pathophysiological significance of the heart rate-lowering property of diltiazem.

The calcium channel blocker diltiazem lowers heart rate in man and this property probably contributes to its clinical effectiveness in ischaemic heart disease and hypertension. This review examines the pharmacological basis of diltiazem's heart rate-lowering activity and considers its pathophysiological significance. The points discussed include the potent direct inhibitory effect of diltiazem on the sinus node and the frequency-dependence of this action. In addition, the well-balanced tissue selectivity profile of diltiazem and its ability to modulate cardiac reflex responsiveness contribute by counteracting the potential for reflex tachycardia.

The arterial wall: a new pharmacological and therapeutic target.

In recent years, two key concepts having numerous interrelationships were advanced for the understanding of various cardiovascular diseases: the "endothelial dysfunction" and the "arterial remodelling". Both endothelial dysfunction and arterial remodelling occur in various pathologies including essential hypertension, heart failure, atherosclerosis, restenosis after angioplasty, and pulmonary hypertension, and have modified the therapeutic approach by offering new pharmacological targets: specific receptors not only at the site of the vascular smooth muscle cells but also on the endothelial cells, growth factors that stimulate proliferation of smooth muscle, and receptors and enzymes of the extra-cellular matrix. Among the various substances under research, the present review will discuss angiotensin II receptor antagonists, endothelin receptor antagonists, nitrates-NO donors, potassium channel activators, and substances interfering with proteoglycans and other components of the extra-cellular matrix.

Relative bioavailability of different butamirate citrate preparations after single dose oral administration to 18 healthy volunteers.

Eighteen volunteers have been treated with different oral formulations of butamirate citrate according to 2 randomized 2-way crossover designs. In the first study (study I) the test preparation was a syrup (Demotussol Hustensirup, Demopharm), and the reference preparation was a syrup already marketed (Sinecod Sirup, Zyma SA). A test preparation (Demotussol Tabletten) was compared to a solution (Demotussol Hustentropfen) in the second study (study II). Within the 2 study periods the volunteers received single 45 mg doses of the test and the reference formulation, respectively. Blood samples have been drawn immediately prior to each administration and at 17 sampling points within 96 h after dosing. A wash-out period of 1 week was maintained between successive drug doses. The plasma concentration of one of the main metabolites, 2-phenylbutyric acid, was determined by a validated reversed-phase HPLC method with UV detection, with a lower limit of quantification of 50 ng/ml. The following mean values have been obtained in study I (syrup preparations) for the test: AUC0-infinity 46.9 micrograms x h/ml, Cmax of 1.77 micrograms/ml at 1.1 h, t1/2 28 h and after administration of the reference: AUC0-infinity 50.4 micrograms x h/ml, Cmax 1.86 micrograms/ml, tmax 1.5 h, t1/2 26 h. In study II the following mean values have been obtained for the test preparation (tablet): AUC0-infinity 54.7 micrograms x h/ml, Cmax of 1.88 micrograms/ml at 1.1 h, t1/2 27 h and for the reference (solution): AUC0-infinity 54.5 micrograms x h/ml, Cmax 1.94 micrograms/ml, tmax 1.1 h, t1/2 26 h. Both preparations have been proven to be bioequivalent to their corresponding references regarding extent and rate of absorption.

[Non-hypertensive desoxycorticosterone treatment enhances the progression of atherosclerosis in WHHL rabbit]. / La déoxycorticostérone à dose non hypertensive accélère la progression de l'athérosclérose chez le lapin WHHL.

Coexistence of hypertension and lipid disorders enhances the development of atherosclerosis. However it is still unclear whether this promoting effect of hypertension results only from hemodynamic changes or whether part of it is mediated by humoral or neurogenic factors independently of blood pressure alteration. The aim of this study is to determine whether mineralocorticoids, which are known to be involved in the pathogenesis of hypertension, can influence the atherosclerotic process in Watanabe heritable hyperlipidemic rabbits (WHHL) independently of pressure changes. For this purpose, DOCA (200 or 400 mg/kg) or vehicle were implanted subcutaneously for 4 weeks in 3 months old WHHL or New Zealand (NZ) rabbits, without nephrectomy and with a fluid intake solution of 1% NaCl +0.2% KCl. DOCA treatment, independently of hemodynamic changes, significantly increases the size of atherosclerotic lesions in parallel with the aortic cholesterol esters content in the arch and thoracic aorta of WHHL rabbits. Plasmatic and aortic cholesterol and triglyceride content remains unchanged by DOCA treatment. Alteration of endothelial function usually found in WHHL rabbits is accentuated only for the dose of 400 mg/kg. Aortic sensitivity to serotonin is not altered, but the maximal contraction to this agonist is decreased in both strains by mineralocorticoid treatment. These results indicate the importance of non-hemodynamic factors related to hypertension which are implicated also in atherogenesis and support the clinical observations that a reduction of arterial pressure in hypertensive atherosclerotic patients is not sufficient to reduce the progression of this vascular disease.

[Arterial wall: a new pharmacological and therapeutic target?]. / La paroi artérielle: une nouvelle cible pharmacologique et thérapeutique?

In recent years, endothelial dysfunction and arterial remodelling in various cardiovascular diseases have emerged as two key concepts, with numerous interrelationships. Both endothelial dysfunction and arterial remodelling occur in various pathologies including heart failure, atherosclerosis, restenosis after angioplasty, and pulmonary hypertension, and have modified the therapeutic approach by offering new pharmacological targets: specific receptors not only at the site of the vascular smooth muscle cells but also on the endothelial cells, growth factors that stimulate proliferation of smooth muscle, and receptors and enzymes of the extracellular matrix. Among the various substances under research, the present review will discuss angiotensin II receptor antagonists, endothelin receptor antagonists, nitrates-NO donors, potassium channel activators, and substances interfering with proteoglycans and other components of the extracellular matrix.

Physiology of the oesophageal transition zone in the presence of chronic bolus retention: studies using concurrent high resolution manometry and digital fluoroscopy.

Distinct contraction waves (CWs) exist above and below the transition zone (TZ) between the striated and smooth muscle oesophagus. We hypothesize that bolus transport is impaired in patients with abnormal spatio-temporal coordination and/or contractile pressure in the TZ. Concurrent high resolution manometry and digital fluoroscopy were performed in healthy subjects and patients with reflux oesophagitis; a condition associated with ineffective oesophageal contractility and clearance. A detailed analysis of space-time variations in bolus movement, intra-bolus and intra-luminal pressure was performed on 17 normal studies and nine studies in oesophagitis patients with impaired bolus transit using an interactive computer based system. Compared with normal controls, oesophagitis patients had greater spatial separation between the upper and lower CW tails [median 5.2 cm (range 4.4-5.6) vs 3.1 cm (2.2-3.7)], the average relative pressure within the TZ region (TZ strength) was lower [30.8 mmHg (28.3-36.5) vs 45.8 mmHg (36.1-55.7), P < 0.001], and the risk of bolus retention was higher (90%vs 12%; P < 0.01). The presence of bolus retention was associated with a wider spatial separation of the upper and lower CWs (>3 cm, the upper limit of normal; P < 0.002), independent of the presence of oesophagitis. We conclude that bolus retention in the TZ is associated with excessively wide spatial separation between the upper and lower CWs and lower TZ muscle squeeze. These findings provide a physio-mechanical basis for the occurrence of bolus retention at the level of the aortic arch, and may underlie impaired clearance with reflux oesophagitis.

Blockade of cannabinoid CB1 receptors improves renal function, metabolic profile, and increased survival of obese Zucker rats.

Obesity is a major risk factor in the development of chronic renal failure. Rimonabant, a cannabinoid CB1 receptor antagonist, improves body weight and metabolic disorders; however, its effect on mortality and chronic renal failure associated with obesity is unknown. Obese Zucker rats received either rimonabant or vehicle for 12 months and were compared to a pair-fed but untreated group of obese rats. Mortality in the obese rats was significantly reduced by rimonabant along with a sustained decrease in body weight, transient reduction in food intake, and an increase in plasma adiponectin. This was associated with significant reduction in plasma total cholesterol, low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, glucose, norepinephrine, plasminogen activator inhibitor 1, and preservation of pancreatic weight and beta-cell mass index. The cannabinoid antagonist attenuated the increase in proteinuria, urinary N-acetylglucosaminidase excretion, plasma creatinine, and urea nitrogen levels while improving creatinine clearance. Renal hypertrophy along with glomerular and tubulointerstitial lesions were reduced by rimonabant. Although the drug did not modify hemodynamics, it normalized the pressor response to angiotensin II. Our study suggests that in a rat model of chronic renal failure due to obesity, rimonabant preserves renal function and increases survival.

The anti-obesity effect of rimonabant is associated with an improved serum lipid profile.

We investigated the effects of chronic treatment with the CB1 receptor antagonist rimonabant (10 mg/kg/day p.o. for 10 weeks) in mice with established obesity (5-month high-fat diet). Untreated obese mice showed a weight gain of 46% (45.0 +/- 0.6 g vs. 30.8 +/- 0.5 g) compared with age-matched animals fed a standard diet. Rimonabant treatment, commencing after 5-month high-fat diet, produced a marked and sustained decrease in body weight (34.5 +/- 0.8 g vs. 47.2 +/- 0.5 g in the high-fat vehicle group, p < 0.001). The anti-obesity effect of rimonabant was similar to that obtained by switching obese mice from high-fat diet to standard laboratory diet during 10 weeks (final weight 33.7 +/- 0.6 g) and was associated with only transient (14 days) reduction in energy intake. Serum leptin, insulin and glucose levels were markedly elevated in obese animals. Rimonabant treatment significantly reduced these elevations (leptin -81%, insulin -78%, glucose -67%, p < 0.001 in all cases vs. high-fat vehicle group). In addition, rimonabant treatment modestly but significantly increased serum adiponectin levels (+18%, p < 0.05 vs. high-fat vehicle group). Obese mice demonstrated abnormal serum lipid profiles. Although rimonabant did not modify high-density lipoprotein cholesterol (HDLc) and had modest effects on total cholesterol, it significantly reduced triglycerides and low-density lipoprotein cholesterol (LDLc) and, notably, increased the HDLc/LDLc ratio (12.4 +/- 0.8 vs. 7.9 +/- 0.2 in high-fat vehicle group, p < 0.001). Therefore, in a model of established obesity, chronic rimonabant treatment produces a marked and sustained decrease in body weight (equivalent to that achieved by dietary change) which is associated with favourable modifications in serum biochemical and lipid profiles.