Effects of metoclopramide and domperidone on azygos venous blood flow in patients with cirrhosis and portal hypertension

The effects of pharmacological manipulation of the lower esophageal sphincter pressure on the esophageal circulation in patients with cirrhosis and portal hypertension were investigated in 33 patients by measuring the azygos venous blood flow, which is an index of blood flow through esophageal varices and periesophageal collaterals draining into the azygos venous system. Measurements were performed in baseline conditions and after the blind administration of metoclopramide (20 mg i.v.) (12 patients), domperidone (10 mg i.v.) (12 patients) and placebo (9 patients). Both metoclopramide and domperidone caused a significant reduction of azygos blood flow, that decreased by 11.5% (p less than 0.01) and 15.6% (p less than 0.02) respectively, while no change was observed in patients receiving placebo (+1.4%, not statistically significant). Reduction of azygos blood flow represents a selective effect of metoclopramide and domperidone on the esophageal circulation, since portal pressure, hepatic blood flow, cardiac output, heart rate and arterial blood pressure were unchanged by the administration of metoclopramide, domperidone or placebo. These results indicate that the administration of drugs that increase the lower esophageal sphincter pressure may reduce the inflow of blood into the esophageal varices in cirrhotic patients with portal hypertension.     

Early increase of lower oesophageal sphincter pressure after band ligation of oesophageal varices in cirrhotics: an intriguing phenomenon

AIM: We conducted a prospective, randomized comparison of endoscopic variceal ligation, sclerotherapy and metoclopramide injection in order to evaluate their early effect on lower oesophageal sphincter pressure. METHODS: Twenty-six patients with established cirrhosis and an episode of variceal bleeding controlled by one session of endoscopic therapy were randomized to undergo an oesophageal manometry. The patients' lower oesophageal sphincter pressure was evaluated, prior to and immediately after a single session of ligation (n = 10), a single session of sclerotherapy (n = 8) or a bolus injection of 20 mg metoclopramide hydrochloride (n = 8). RESULTS: Ligation produced a higher early increase in lower oesophageal sphincter pressure (from 12.3 +/- 2.3 to 27.8 +/- 3.0 mmHg) as compared with sclerotherapy (from 13.6 +/- 2.5 to 22.4 +/- 4.5 mmHg) or metoclopramide injection (from 14.6 +/- 3.2 to 22.5 +/- 2.9 mmHg); (P = 0.0001). CONCLUSION: Our data indicate that ligation of oesophageal varices produces an early increase in lower oesophageal sphincter pressure in cirrhotic patients.     

Pharmacological constriction of the lower oesophageal sphincter: a simple method of arresting variceal haemorrhage.

The effect of pharmacological constriction of the lower oesophageal sphincter (LOS) on oesophageal varices was investigated in an experimental study followed by a controlled clinical trial. In the experimental study intravariceal pressure was measured just above the LOS in 11 patients before and after constricting the LOS by intravenous pentagastrin. Intravariceal pressure fell from a mean of 23 (range 12-36) mmHg to 4 (range 0-7) mmHg (p less than 0.001). This marked pressure drop indicated the considerable compression of varices that occurred within the LOS. A prospective controlled clinical trial examined whether LOS constriction (effected by the longer acting metoclopramide) would compress varices sufficiently to arrest active variceal bleeding originating from the lowest 2 cm oesophagus--the area encircled by the LOS. Of 11 patients who received metoclopramide, 10 stopped bleeding compared with four of the 11 who received placebo (p less than 0.01). Pharmacological constriction of the LOS appears to offer a new and effective approach for arresting active bleeding from oesophageal varices.     

Double-blind investigation of the effects of propranolol and placebo on the pressure of esophageal varices in patients with portal hypertension

This study was aimed at investigating the effects of propranolol on esophageal variceal pressure in patients with portal hypertension. Variceal pressure was measured at endoscopy using a miniature pressure-sensitive gauge in 20 patients with portal hypertension. Measurements were obtained under baseline conditions and 20 min after double-blind administration of propranolol (0.15 mg/kg; n = 10) or an identical amount of placebo (normal saline, 0.3 ml/kg; n = 10). Under baseline conditions, variceal pressure was similar in propranolol and placebo groups (14.1 +/- 5 mm Hg vs. 14.9 +/- 6.6 mm Hg, respectively; not significant). Placebo had no significant effect on variceal pressure (baseline = 14.9 +/- 6.6 mm Hg; placebo = 15.5 +/- 6.6 mm Hg; not significant), and values after placebo administration were closely correlated with baseline values (r = 0.98; y = 1.1 + 0.97 x; p less than 0.0001). In contrast, propranolol caused a significant decrease in the pressure of esophageal varices (from 14.1 +/- 5 mm Hg to 11.3 +/- 4.4 mm Hg; p less than 0.0002). No significant changes in the size of esophageal varices were observed after propranolol or placebo administration. This study shows (a) the endoscopic pressure-gauge technique has a low variability and may be used to assess acute drug-induced changes in variceal pressure; and (b) propranolol causes significant decreases in variceal pressure in patients with portal hypertension and esophageal varices.     

Nadolol for prophylaxis of gastrointestinal bleeding in patients with cirrhosis. A randomized trial

This controlled trial was designed to evaluate the prophylactic effect of nadolol on gastrointestinal bleeding in cirrhotic patients with large oesophageal varices who had never bled. Nadolol or placebo was given randomly to two groups of 53 patients. The percentage of patients free of gastrointestinal bleeding 1 year after inclusion in the study was 83 +/- 6% (mean +/- S.D.) in the nadolol group and 80 +/- 6% in the placebo group. In the nadolol and placebo groups, 40 and 47 patients, respectively, were compliant, i.e., took nadolol or placebo continuously. The percentage of patients who were free of bleeding 1 year after inclusion was 97 +/- 3% in the subgroup of compliant nadolol patients. This percentage was significantly higher than that of patients who were free of bleeding in the placebo group (P less than 0.03) as well as in the subgroup of compliant placebo patients (77 +/- 6%; P less than 0.02). We concluded that, although there was no overall significant effect of nadolol on the risk of bleeding in cirrhotic patients in good condition with large oesophageal varices, this study suggests that nadolol reduced the risk of bleeding in compliant patients.     

Effect of enalapril treatment and sclerotherapy of esophageal varices on hepatic hemodynamics in portal hypertension.

The hemodynamic effects of long-term (3 months) treatment with enalapril, a potent angiotensin converting enzyme inhibitor, were studied in 12 randomly selected patients with portal hypertension and a previous episode of hemorrhage from esophageal varices. All these patients underwent injection sclerotherapy of varices at 1-week intervals. As a control group 13 patients treated only with injection sclerotherapy and placebo were used. After 3 months the wedged hepatic venous pressure (25.5 +/- 4.8 vs. 21.3 +/- 4.8 mmHg) and the non-wedged hepatic venous pressure gradient (17.0 +/- 6.0 vs. 12.6 +/- 3.4 mmHg) were significantly lower than the basal values (p < 0.01) in the group treated with enalapril. A large decrease (> 3 mmHg) in these pressures was observed only in 50% of the patients. In the group treated with sclerotherapy+placebo this pressure reduction was not observed. Systemic hemodynamics and liver function tests did not change during the treatment. None of our patients died during the study or the next 6 months. We conclude that enalapril lowers portal pressure in patients with portal hypertension, although not in all of them, and may be used to good effect to manage patients with esophageal varices in combination with sclerotherapy.     

Terlipressin is more effective in decreasing variceal pressure than portal pressure in cirrhotic patients

BACKGROUND/AIMS: Terlipressin decreases portal pressure. However, its effects on variceal pressure have been poorly investigated. This study investigated the variceal, splanchnic and systemic hemodynamic effects of terlipressin. METHODS: Twenty cirrhotic patients with esophageal varices grade II-III, and portal pressure > or =12 mmHg were studied. Hepatic venous pressure gradient, variceal pressure and systemic hemodynamic parameters were obtained. After baseline measurements, in a double-blind administration, 14 patients received a 2mg/iv injection of terlipressin and six patients received placebo. The same measurements were repeated 60 min later. RESULTS: No demographic or biochemical differences were observed in basal condition between groups. Terlipressin produced significant decreases in intravariceal pressure from 20.9+4.9 to 16.3+/-4.7 mmHg (p<0.01, -21+/- 16%), variceal pressure gradient from 18.9+/-4.8 to 13.5+/-6.0 mmHg (p<0.01, -28+/-27%), estimated variceal wall tension from 78+/-29 to 59+/-31 mmHg x mm (p<0.01, -27+/-22%), and hepatic venous pressure gradient from 19.4+/-4.5 to 16.8+/-5 mmHg (p<0.01, -14+/-12%) at 60 min. The change in variceal pressure after 60 min of terlipressin administration was greater than the change in wedge hepatic venous pressure (-4.7 mmHg vs -0.5 mmHg, respectively, p<0.0001). Terlipressin also caused significant decreases in heart rate and cardiac index and increases in mean arterial pressure and peripheral vascular resistance. CONCLUSIONS: Our results demonstrate that terlipressin produces significant and prolonged decreases in variceal pressure and variceal wall tension and has intrinsic effects on portal pressure and systemic hemodynamics. Variceal pressure provides a better assessment of the effects of terlipressin administration on esophageal varices than hepatic venous pressure gradient.     

EFFECT OF METOCLOPRAMIDE ON PLASMA VASOPRESSIN IN MAN

The effect of metoclopramide, a dopamine blocker, on arginine vasopressin (AVP) secretion was investigated in normal males. After a bolus injection of metoclopramide (10 mg), all subjects (n = 7) demonstrated an increase of 80.3% (from 0.71 +/- 0.12 (Mean +/- S.E.) to 1.28 +/- 0.24 pg/ml, P less than 0.005) in plasma AVP at 15 min. In controls (n = 7) plasma AVP levels did not change after saline injection (2 ml). Because plasma osmolality and blood pressure did not change, the elevation of plasma AVP levels induced by treatment with metoclopramide may be due to its central effect as a dopamine inhibitor. Although plasma AVP levels increased again at 90 and 120 min after a bolus injection of metoclopramide, accompanying falls in blood pressure (4-5%) make the interpretation concerning the contribution of dopamine to AVP secretion in a late phase uncertain. In summary, plasma AVP levels were shown to be significantly increased by a metoclopramide bolus, suggesting that AVP secretion is under tonic inhibition by dopamine.     

GABA-ergic and dopaminergic mechanisms in gonadotrophin secretion in males--effects of baclofen and metoclopramide

The GABA analogue, baclofen, and the dopamine antagonist, metoclopramide, were studied with respect to their effects on basal and LRH-induced LH and FSH release in 6 normal male volunteers. Basal gonadotrophin secretion was unchanged following the administration of baclofen or metoclopramide given alone or in combination. LRH-stimulated LH release was significantly blunted after metoclopramide administration in the baclofen pre-treated volunteers. Serum LH concentration (mean +/- SD) in the control phase was 30.1 +/- 17.2 mIU/ml and was 19.4 +/- 9.6 mIU/ml after baclofen plus metoclopramide (P less than 0.02). LRH-stimulated values, however, were unaffected by baclofen or metoclopramide when the drugs were given alone. LRH-stimulated FSH release was not significantly influenced by baclofen or metoclopramide given alone or in combination. Basal Prl secretion increased significantly when baclofen and metoclopramide were given separately and in combination. Basal Prl concentration (mean +/- SD) increased from 14 +/- 2 ng/ml to 18.7 +/- 4.8 ng/ml after baclofen and to 111.5 +/- 31.9 ng/ml after metoclopramide (P less than 0.01). The rise in serum Prl concentration, however, was not significantly different when measured after metoclopramide alone (111 +/- 31.9 ng/ml) or after metoclopramide and baclofen (112 +/- 33.3 ng/ml). It is proposed that GABA and dopamine exert opposing effects on LH secretion in normal men.     

DOPAMINE BLOCKADE INHIBITS STARVATION KETOSIS IN MAN

The effects of dopamine blockade on the endocrine and metabolic response to starvation have been investigated by administration of metoclopramide, 30 mg daily, or placebo to five normal subjects fasted for sixty hours on two occasions. Blood glucose and alanine concentrations fell with starvation and metoclopramide had no further effect. Concentrations of the other gluconeogenic precursors, lactate and pyruvate, were also unaffected by metoclopramide. The rise in circulating ketone body concentrations with fasting was impaired by metoclopramide, significantly from 44 h onwards (blood total ketone body concentration at 60 h, 3.42 +/- 0.94 mmol/l with placebo; 2.08 +/- 0.67 mmol/l with metoclopramide, P less than 0.05). Blood glycerol and plasma non-esterified fatty acids (NEFA) levels rose with starvation, and metoclopramide had no further effect. Serum insulin concentrations remained low with fasting, while circulating glucagon and growth hormone levels rose. Similar changes were noted with both metoclopramide and placebo. Serum prolactin concentrations during starvation were elevated two to four fold by metoclopramide. The inhibitory effect of dopamine blockade on ketosis thus occurred despite hyperprolactinaemia, and did not result from measurable alterations in insulin, glucagon or growth hormone secretion. The data suggest a stimulatory role for endogenous dopamine on starvation ketonaemia in man.     

Successful administration of metoclopramide for the treatment of nausea in patients with advanced liver disease. A double-blind controlled trial

A double-blind comparison of metoclopramide versus placebo was performed on 8 cirrhotic patients with nausea (8 cases) and heartburn (3 of the 8 cases) plus mild portal-systemic encephalopathy. As metoclopramide is a dopamine antagonist and dopamine-inadequate neurotransmission has been implicated in the pathogenesis of hepatic coma, this study was also designed to evaluate the effects of metoclopramide on mental state. The study included basal, placebo, metoclopramide, and final periods; each period lasted for 2 wk. Throughout the study patients received 3 g/day of neomycin and an 1800-cal diet containing 40 g/day of mixed protein. During the placebo and metoclopramide phases patients received either two 10-mg metoclopramide capsules t.i.d. or identical placebo capsules. During the study, biweekly liver function tests and portal-systemic encephalopathy parameters were evaluated. A self-evaluation for the presence of nausea and heartburn was also obtained. To monitor the dopamine-blockade effect of metoclopramide, serum prolactin levels were measured. Metoclopramide significantly suppressed the subjective signs of nausea (7 of 8 cases) and heartburn (all cases). Serum prolactin levels were 22 +/- 21 ng/ml, 30 +/- 31 ng/ml, 110 +/- 57 ng/ml (p less than 0.01), and 18.6 +/- 2 ng/ml during basal, placebo, metoclopramide, and final periods, respectively. In spite of these signs of dopamine blockade, no deterioration in mental state, asterixis, electroencephalograms, blood ammonia levels, or psychometric testings were observed. In addition, no extrapyramidal signs were noticeable during any period of the study. One patient presented transient somnolence at the end of the metoclopramide period. We conclude that dopamine blockade is not associated with the appearance of portal-systemic encephalopathy. Metoclopramide is a safe and effective treatment for nausea and heartburn in patients with advanced liver disease.     

Metoclopramide in Gastroesophageal Reflux Disease: Rationale for its Use and Results of a Double-Blind Trial

We investigated the acute effect of metoclopramide on lower esophageal sphincter pressure, esophageal contraction amplitude, and gastric emptying and compared metoclopramide, 10 mg four times a day, to placebo in improving the symptoms and objective parameters of reflux esophagitis in 19 patients in a randomized, double-blind 4-wk outpatient trial. Orally administered metoclopramide, 10 mg, significantly accelerated gastric emptying of a semisolid meal in patients in whom it was delayed; lower esophageal sphincter pressure was significantly increased for up to 90 min, but there were no changes in esophageal contraction amplitude. During the treatment trial, metoclopramide resulted in an overall improvement in heartburn and regurgitation of 60%, significantly better than 32% improvement after placebo (p less than 0.05). Compared to baseline symptoms scores, metoclopramide significantly improved both daytime and nighttime heartburn and regurgitation. Compared to placebo-treated patients, the metoclopramide group had significantly fewer episodes of daytime heartburn and regurgitation (p less than 0.05), while nighttime symptoms significantly improved with both treatments. Mean antacid consumption was significantly reduced by metoclopramide, 61%, compared to placebo-treated patients, 21% (p less than 0.05), who were ingesting a mean of 1.9 oz of antacid daily. Endoscopic and histological improvement were similar in both groups, although histological healing occurred in three patients after metoclopramide compared with none in the placebo group. Our data suggest that: 1) gastric emptying and lower esophageal sphincter pressure were significantly improved by acute administration of oral metoclopramide; 2) metoclopramide therapy for 4 wk is significantly more effective than placebo (medium dose antacid therapy) in relieving the symptoms of gastroesophageal reflux without significantly altering objective parameters of esophagitis; 3) metoclopramide effectively addresses the diffuse upper gastrointestinal motor disturbances present in reflux esophagitis patients.     

The portal pressure response to beta-blockade is greater in cirrhotic patients without varices than in those with varices

BACKGROUND & AIMS: Nonselective beta-blockers are effective in reducing portal pressure in cirrhotic patients. However, this beneficial effect is highly variable and may depend on the extent of portal system collateralization. The aim of this study was to compare portal pressure response with timolol, a nonselective beta-blocker, in cirrhotic patients with and without varices. METHODS: Portal and systemic hemodynamics were measured before and after a single oral dose of 10 mg of timolol in 50 patients with cirrhosis and portal hypertension, 15 with and 35 without esophageal varices. RESULTS: Timolol significantly decreased portal pressure in all patients (mean reduction, 20% +/- 13%; P < 0.0001). The reduction in hepatic venous pressure gradient was greater in patients without varices (-24% +/- 14%) than in those with varices (-12% +/- 8%) (P < 0.01). A decrease in the hepatic venous pressure gradient of <12 mm Hg was achieved in 7 of 12 (58%) patients without varices and a baseline pressure gradient of <12 mm Hg, but only in 3 of 15 patients with varices (20%) (P < 0.01). CONCLUSIONS: Timolol is effective in reducing portal pressure in cirrhotic patients, more so in patients without varices, suggesting that nonselective beta-blockers will be more effective in the treatment of portal hypertension when administered at early stages, before the development of varices. (Gastroenterology 1997 Jun;112(6):2012-6)     

Effect of metoclopramide on normal and delayed gastric emptying in gastroesophageal reflux patients

Gastric emptying has an important role in the pathophysiology of gastroesophageal reflux disease. We investigated the effect of metoclopramide, a gastric prokinetic agent, in gastroesophageal reflux patients with normal as well as delayed emptying. Twenty-six patients with subjective and objective evidence of gastroesophageal reflux ingested an egg salad sandwich meal labeled with 99mtechnetium-DTPA for a baseline study, and then again on a separate day after receiving oral metoclopramide, 10 mg, 30 min prior to the test meal. The mean percent isotope remaining in the stomach after 90 min improved significantly (P less than 0.001) from 70.3 +/- 3.9% (SEM) to 55.2 +/- 4.2% after metoclopramide. Fourteen (54%) had a basal emptying in the normal range of 34-69% retention of isotope at 90 min, (means +/- 2 SD), while it was slow in 12 (46%). For those with delayed basal gastric emptying, the mean retention of 88.9 +/- 2.9% at 90 min was significantly (P less than 0.005) decreased by metoclopramide to 68.6 +/- 6.1%. In those patients with a normal basal gastric emptying and a mean retention of 54.4 +/- 2.3% at 90 min, there was also significant improvement (P less than 0.025) to 43.6 +/- 3.6% after metoclopramide. These data indicate that metoclopramide increased gastric emptying in gastroesophageal reflux patients with normal as well as delayed gastric emptying. Therefore on a patient management level a trial of metoclopramide is warranted in patients with gastroesophageal reflux disease and is not limited by the gastric emptying status of the patient.     

Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis

Postprandial hyperemia is associated with a significant increase in portal pressure in cirrhosis, which may contribute to progressive dilation and rupture of gastroesophageal varices. In cirrhosis, an insufficient hepatic production of nitric oxide (NO) may impair the expected hepatic vasodilatory response to increased blood flow, further exaggerating the postprandial increase in portal pressure. This study was aimed at investigating whether low doses of an oral NO donor might counteract the postprandial peak in portal pressure. Twenty-three portal hypertensive cirrhotics, 8 of them under propranolol therapy, were randomized to receive orally 5-isosorbide mononitrate (ISMN; 10 mg; n = 11) or placebo (n = 12) and a standard liquid meal 15 minutes later. Hepatic venous pressure gradient (HVPG), mean arterial pressure (MAP), and hepatic blood flow (HBF) were measured at baseline and 15, 30, and 45 minutes after a meal. ISMN significantly attenuated the postprandial increase in portal pressure as compared with placebo (peak HVPG increase: 2.4 +/- 1.4 mm Hg vs. 5.2 +/- 2.1 mm Hg, P =.002). Percentual increases in HBF were similar in both groups. MAP decreased slightly in ISMN group (-7.5% +/-.5%; P <.01 vs. baseline). These effects were also observed in patients on chronic propranolol therapy. In conclusion, hepatic NO supplementation by low doses of ISMN effectively reduces the postprandial increase of portal pressure in cirrhosis, with only a mild effect on arterial pressure. The same was observed in patients receiving propranolol. Our results suggest that therapeutic strategies based on selective hepatic NO delivery may improve the treatment of portal hypertension.     

Portal pressure, presence of gastroesophageal varices and variceal bleeding

This study was performed to examine the relationships between portal pressure measurements and the presence of esophagogastric varices, the size of varices and the occurrence of hemorrhage from varices in 93 patients with alcoholic cirrhosis, using standardized measurements of portal pressure by hepatic vein catheterization. The mean hepatic vein pressure gradient (HVPG) was significantly higher in 49 patients who had bled from varices than in 44 cirrhotic patients who had not (20.4 +/- 5.1 vs. 16.0 +/- 5.2; p less than 0.001). None of the 49 patients who had bled from varices had an HVPG less than 12 mm Hg. Among the 87 patients who had been examined by endoscopy for varices, all 72 with varices had an HVPG greater than 12 mm Hg. Six of 15 cirrhotic patients without varices had HVPG less than 12 mm Hg. The mean HVPG in the 15 patients without varices (15.1 +/- 6.8 mm Hg) was lower than the 72 patients with varices (19.3 +/- 4.8 mm Hg; p less than 0.01). Of the 72 patients with varices, 40 had large varices, 28 had small varices, and in four patients variceal size could not be assessed adequately. The mean HVPG was similar in the patients with large or small varices (19.8 +/- 4.8 vs. 18.3 +/- 5.0 mm Hg; p greater than 0.10). There was a positive relationship between the presence of large varices and the occurrence of bleeding from varices.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage

This study evaluated the clinical application of a pressure-sensitive gauge that allows the noninvasive measurement of the pressure of esophageal varices at endoscopy. The study was performed in 70 patients with cirrhosis and portal hypertension. Among them, 47 had bled from the varices and 23 had varices but had not bled. In addition to measurements of variceal pressure, the size of the varices was estimated semiquantitatively at endoscopy. This allowed an estimate of the tension on the wall of the varices as the product of the transmural pressure and the estimated radius of the varices. Most patients had a standard hemodynamic evaluation of portal hypertension, with measurements of wedged and free hepatic venous pressures, and of azygos blood flow. These were performed within 24 h of the variceal pressure measurements. Variceal pressure was significantly higher in bleeders than in nonbleeders (15.7 +/- 2.8 vs. 12.1 +/- 2.6 mmHg, p less than 0.001) in spite of a similar portal pressure in both groups (20.1 +/- 5.1 vs. 20.4 +/- 7.6 mmHg, NS). More than 60% of the bleeders, but only 22% of the nonbleeders had a variceal pressure greater than or equal to 15 mmHg (p less than 0.005). Among nonbleeders, variceal pressure was higher in patients with large varices (13.9 +/- 2 mmHg, n = 9) than in those with small varices (10.9 +/- 2.4 mmHg, n = 14) (p less than 0.01). Estimates of variceal wall tension further exaggerated the differences between bleeders and nonbleeders (66.1 +/- 22.6 vs. 32.0 +/- 19.8 mmHg.mm, p less than 0.001). More than 50% of bleeders, but just 9% of nonbleeders had an estimated variceal tension greater than 50 mmHg.mm (p less than 0.001). Our findings support the role of an increased variceal pressure in the pathogenesis of variceal hemorrhage, and suggest that this noninvasive technique can be valuable in assessing the risk of variceal hemorrhage in patients with portal hypertension.     

A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis

BACKGROUND & AIMS: Beta-blockers are extensively used to prevent variceal bleeding in patients with large esophageal varices. It is not established if beta-blockers delay the growth of small varices. METHODS: A total of 161 patients with cirrhosis and small esophageal varices (F1 according to the classification of Beppu et al.) without previous bleeding were enrolled. A total of 83 patients were randomized to nadolol (dose adjusted to decrease resting heart rate by 25%; mean dose given, 62 +/- 25 mg/day) and 78 to placebo. The principal end point was occurrence of large esophageal varices (F2 or F3 according to the classification of Beppu et al.). Endoscopic examination was performed after 12, 24, 36, 48, and 60 months of follow-up. Mean follow-up was 36 months. RESULTS: The 2 groups were well matched for demographic and clinical characteristics. During the study period, 9 patients randomized to nadolol and 29 randomized to placebo had growth of esophageal varices. At the end of follow-up, the cumulative risk was 20% versus 51% (P < 0.001) (absolute risk difference, 31%; 95% confidence interval, 17%-45%). When possible confounding factors were taken into account, treatment was a significant factor predicting growth of varices (odds ratio, 4.0; 95% confidence interval, 1.95-8.4). The cumulative probability of variceal bleeding was also lower in patients randomized to nadolol (P = 0.02). Survival was not different (P = 0.33). Adverse effects resulting in withdrawal of drug occurred in 9 in the nadolol group and one in the placebo group (P = 0.01). CONCLUSIONS: This study suggests that beta-blocker prophylaxis of variceal bleeding in patients with compensated cirrhosis should be started when small esophageal varices are present.     

Antihypertensive effect of valsartan 80 mg and hydrochlorothiazide 12.5 mg evaluated by ambulatory blood pressure monitoring

OBJECTIVE: The aim of the study was to evaluate by ambulatory blood pressure measurement (ABPM) the 24 hours antihypertensive efficacy of the fixed combination therapy, valsartan 80 mg + hydrochlorothiazide 12.5 mg (V + H), once daily, after 6 weeks of treatment, in patients with mild to moderate hypertension. STUDY DESIGN: It was a French, multicenter, double blind, randomized trial in parallel groups comparing V + H and placebo. After an initial two weeks placebo period, patients were assigned to receive either V + H or placebo for six weeks. Were eligible those with clinical arterial blood pressure, measured by sphygmomanometer, between 160/95 and 209/114 mmHg after monotherapy. A 26 hours ABPM, with Spacelabs 90,207, was done at J0 and J42 (one measurement every 15 minutes, in day time and at night). Responders were defined as a fall in day diastolic blood pressure > or = 5 mmHg and/or day diastolic blood pressure < 90 mmHg with ABPM. RESULTS: 123 of the 138 randomized patients had two interpretative measurements. Their average age was 59 + 10 years. 57% (78) of them were males and their average ABPM before treatment was 143 +/- 15/88 +/- 11 mmHg. With V + H, the reduction of the systolic and the diastolic blood pressure measured by ABPM, was significantly more important than with placebo (SBP: -15.4 +/- 10.9 mmHg versus -0.6 +/- 7.7 mmHg, p < 0.001; DBP: -9.1 +/- 7 mmHg versus -0.4 +/- 5.4 mmHg, p < 0.001). Pulse pressure (PP) was also significantly reduced with the combination therapy V + H, but it was not modified with placebo (-6.3 + 5.5 mmHg versus -0.2 + 4.1 mmHg, p < 0.001). ABPM responder rate was 73% with V + H versus 24% with placebo (p < 0.001). Trough/peak ratio was 80.3% for systolic blood pressure and 57.3% for diastolic blood pressure. The combination V + H was as well tolerated as placebo. CONCLUSION: The fixed combination V + H used for treatment of hypertension, after failure of monotherapy, is very effective in reducing pulse pressure, systolic and diastolic blood pressure, over 24 hours, homogeneously, and is as well tolerated as placebo.     

Unique cardioprotective action of the new calcium antagonist mibefradil

BACKGROUND: Mibefradil is a calcium antagonist with few negative inotropic effects at therapeutic concentrations. METHODS AND RESULTS: The effect of mibefradil on infarct size (IS) was compared with those of placebo, amlodipine, and verapamil in 64 anesthetized pigs. In placebo pigs, after 90 minutes of ischemia and 120 minutes of reperfusion, IS (by triphenyl tetrazolium chloride staining) was 15.3+/-10.8% (SD) of the area at risk. Mibefradil (0.60 mg/kg IV) reduced heart rate and left ventricular (LV) pressure, and IS was 1. 9+/-3.9% (P<0.05 versus placebo). Verapamil (0.15 mg/kg IV) also decreased heart rate, LV pressure, and IS (6.1+/-4.2%, P<0.05 versus placebo). Amlodipine (0.20 mg/kg IV) did not alter heart rate, LV pressure, or IS (9.9+/-5.4%, P=NS versus placebo). When heart rate was maintained constant by left atrial pacing and LV pressure was adjusted to that of the placebo group by an intra-aortic balloon, mibefradil still decreased IS (3.8+/-3.0%, P<0.05 versus placebo), but verapamil did not (11.6+/-8.3%, P=NS versus placebo). With glibenclamide infusion, mibefradil no longer reduced IS (13.1+/-4.3% versus 17.8+/-5.6% with glibenclamide alone, P=NS). CONCLUSIONS: The IS-limiting effect of mibefradil, in contrast to that of verapamil, was not dependent on favorable hemodynamics but was abolished by glibenclamide, suggesting a direct cardioprotective action of mibefradil.