Changes of gallbladder and gastric dynamics in patients with acute hepatitis A

Transient alterations of gallbladder morphology and dynamics have been reported in patients with during acute hepatitis A. The presence of dyspepsia also suggests involvement of gastric motility. During a 60-day follow-up, we investigated gallbladder and gastric motility in relation to dyspepsia in acute viral hepatitis A patients. Twenty patients were assessed at referral (day 0) and at days 7, 21, 42 and 60 and compared with 20 healthy volunteers. Gallbladder morphology and motility and gastric motility were assessed in the fasting and postprandial period by functional ultrasonography using a liquid test meal. Dyspeptic symptoms were scored. At day 0, fasting gallbladder volume was 5.9 +/- 1.3 mL, 32.6 +/- 4.6 mL, and 21.5 +/- 1.9 mL (mean +/- SE) in patients with gallbladder sludge (n = 7), without sludge (n = 13) and controls, respectively (P < 0.05 in sludge vs. no sludge and controls; P < 0.05 in no sludge vs. controls, ANOVA). Small fasting gallbladder volume in patients with sludge increased and sludge disappeared within 7 days. At day 0, patients with sludge also had increased thickness of fasting gallbladder wall and increased serum transaminase levels compared with patients without sludge and controls. Gallbladder contraction was similar in patients and controls. However, patients had delayed gastric emptying, which positively correlated with dyspepsia score. Gallbladder morphological changes observed in the acute phase of hepatitis A are transient and are associated with hepatocellular damage. Gastric emptying is delayed during the first week of disease and is associated with dyspeptic symptoms.     

Three-dimensional sonographic evaluation of gallbladder contractility: comparison with cholescintigraphy

PURPOSE: To compare three-dimensional sonography (3D US) with quantitative cholescintigraphy for assessing gallbladder contractility. METHODS: Gallbladder radioactivity was assessed in 35 patients with suspected gallbladder disease using a gamma camera 5, 30, 60, and 90 minutes after technetium 99m (Tc-99m) DISIDA injection and 30 and 60 minutes after ingestion of a high-fat meal. Immediate gallbladder images were obtained via 3D US. Gallbladder radioactivity at 120 minutes after injection of Tc-99m DISIDA was defined as 100%, and gallbladder contractility was calculated. Gallbladder volume on 3D US was calculated using a dedicated software. Pearson correlation analysis and simple linear regression analysis were used. RESULTS: The mean gallbladder volume on 3D US was 25.3 ml after fasting and 6.6 ml after a high-fat meal. The mean gallbladder contractility index was 77.7% on cholescintigraphy (range, 18-99) and 73.4 on 3D US (range, 16.7-97.3). A linear correlation between cholescintigraphy and 3D US contractility indices was observed. The r value on Pearson analysis was 0.92 and R(2) of the coefficient of determination was 0.85. The difference in measured contractility between the 2 methods ranged from +21.5% to -15.0% (mean +/- SD, 4.4 +/- 8.7%). CONCLUSIONS: 3D US is a reliable and easy method for clinical measurement of the volume of the gallbladder and its contractility.     

The effect of sildenafil on gastric emptying in patients with end-stage renal failure and symptoms of gastroparesis

BACKGROUND: Delayed gastric emptying is a common disorder among patients with end-stage renal failure (ESRF). Pyloric relaxation, a major determinant of gastric emptying, is a nitric oxide (NO)-mediated process. NO-induced smooth muscle relaxation is mediated through its second messenger cyclic guanosine monophosphate, which is broken by tissue phosphodiesterases (PDEs). Thus the inhibition of cyclic guanosine monophosphate breakdown by PDE inhibitors can potentiate NO-mediated responses and facilitate pyloric relaxation. In an animal model of diabetes mellitus, treatment with sildenafil (a PDE-5 inhibitor) restored NO-mediated pyloric relaxation and improved gastric emptying. The aim of our study was to examine the hypothesis that sildenafil may improve gastric emptying in patients with ESRF and symptoms of gastric paresis. METHODS: We studied 12 patients with ESRF (6 men; age range, 54-80 years; 5 with diabetic nephropathy; 4 +/- 1 years receiving long-term renal replacement therapy) after either placebo or a 25-mg tablet of sildenafil (Viagra; Pfizer Inc). Gastric emptying of a solid meal (one medium-sized fried egg mixed with 37 MBq [1 mCi] technetium Tc 99m phytate plus 1 slice of bread and 150 mL of water at the end of the meal) was assessed 1 hour after dosing by use of a single-headed camera. Images were acquired every 30 seconds for 90 minutes immediately after patients ate. RESULTS: The gastric emptying rate was decreased at baseline (after placebo), to 33% +/- 6% (normal, > or =50%). Treatment with sildenafil had no effect on gastric emptying rates after 90 minutes (from 33% +/- 6% after placebo to 30% +/- 6% after sildenafil, P =.9). CONCLUSIONS: Sildenafil did not improve gastric emptying in patients with ESRF and gastric paresis. Sildenafil may have opposing effects on gastric peristalsis (causing gastric relaxation) compared with its effects on pyloric relaxation. Studies combining sildenafil with prokinetic drugs are of interest.     

Sonographic evaluation of gallbladder kinetics: in vitro and in vivo comparison of different methods to assess gallbladder emptying.

In an in vitro study, 10 gallbladders of adult pigs and 6 gallbladders of lambs, all removed immediately after slaughtering, were stimulated in a water bath by electric means to induce active contraction. Gallbladder emptying was followed by ultrasonography employing five measurement procedures: (1) gallbladder width, (2) longitudinal planimetry, (3) transverse planimetry, (4) ellipsoid method, and (5) sum of cylinders method. In an in vivo investigation, gallbladder emptying of 30 volunteers (12 healthy subjects, 18 diabetics) was evaluated in the same way after ingestion of a fatty meal. Gallbladder width was found to be unsuitable to estimate the decrease in gallbladder volume due to a nonlinear relation of the parameters. Longitudinal planimetry tended to be less valid than transverse planimetry in assessing gallbladder volume reduction. The most valid estimation of gallbladder volume decreases was obtained by the two three-dimensional procedures. However, in neither in vitro nor in vivo could a significant difference between the sum of cylinders method and the ellipsoid method in determining relative volume reduction be established. We conclude that a three-dimensional measurement procedure should be used for valid assessments of gallbladder motility. However, according to our data there is no advantage in using the time-consuming sum of cylinders method compared to the simple ellipsoid method.     

Effect of rectal distension on gallbladder emptying and circulating gut hormones

BACKGROUND: Abnormalities of upper gut motility, including a delay of gastric emptying and small bowel transit, found in patients with constipation may be secondary to factors originating in the colon or rectum as a result of faecal stasis. The aim was to determine if stimulation of mechanosensory function by rectal distension affects postprandial gallbladder emptying and release of gastrointestinal peptides participating in control of upper gut motility. MATERIALS AND METHODS: Eight healthy volunteers were studied with an electronic barostat and a plastic bag positioned in the rectum. Intrabag pressure was maintained at minimal distension pressure + 2 mmHg on one occasion and on a pressure that induced a sensation of urge on the other. Gallbladder volume and plasma concentrations of cholecystokinin (CCK), pancreatic polypeptide (PP) and peptide YY (PYY) were measured before and after ingestion of a 450-kcal mixed liquid meal. RESULTS: Rectal distension enhanced maximum gallbladder emptying from 66 +/- 7% to 78 +/- 5% (P < 0.05). Distension tended to increase integrated plasma PYY from 77 +/- 30 pM min to 128 +/- 40 pM min in the first hour after the meal (P = 0.08) and it suppressed integrated plasma PP from 1133 +/- 248 pM min to 269 +/- 284 pM min in the second hour (P < 0.05). Integrated plasma CCK concentrations were not significantly affected. CONCLUSION: Mechanosensory stimulation of the rectum enhances postprandial gallbladder emptying and influences postprandial release of gut hormones involved in the regulation of gastrointestinal motility in healthy subjects. These mechanisms may play a role in the pathogenesis of the upper gastrointestinal motor abnormalities observed in constipated patients.     

Effect of somatostatin on postprandial gallbladder relaxation

Although the inhibitory effect of somatostatin (SST) on gallbladder contraction is well known, the influence of SST on gallbladder motility during the late postprandial or relaxation phase has not been studied. We therefore investigated the effect of SST on gallbladder relaxation and gut hormone release during the late postprandial phase. Eight healthy volunteers participated in two experiments performed in random order during continuous infusion of either SST or saline (placebo) starting 2 h after meal ingestion. At regular intervals, gallbladder volumes were measured (ultrasonography) and blood samples were taken for determination of plasma cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY (PYY) and neurotensin levels (radioimmunoassay). Postprandial gallbladder contraction was similar in both experiments: 68 ± 4% vs. 66 ± 4%. During SST infusion, postprandial gallbladder contraction was significantly (P<0·01) reduced (2874 ± 813% *240 min) compared with saline (9391 ± 1595% *240 min). Plasma CCK, PP, PYY and neurotensin levels were in the same range in the early postprandial phase but were significantly reduced during SST infusion compared with placebo (late postprandial phase). Plasma levels of CCK correlated with gallbladder volumes during both the contraction and relaxation phase (r=0·68, P=0·01 and r=0·61, P=0·008, respectively). SST enhances gallbladder relaxation and reduces hormone secretion in the late postprandial phase. The results point to an association between CCK and gallbladder volume not only during the postprandial contraction phase but also during the relaxation phase.     

Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in humans. Implications for the physiology of CCK.

To explore the physiology of cholecystokinin (CCK) in humans, we investigated the effect on gallbladder contraction and gastric emptying of a recently developed CCK receptor antagonist, MK-329. In a double-blind, four-period crossover study eight subjects received single doses of 0.5, 2, or 10 mg MK-329, or placebo, followed by an intravenous infusion of CCK-8 (30 pmol/kg.h). In placebo-treated subjects gallbladder volumes decreased on average to 43% of initial volumes after 2 h of CCK infusion. MK-329 caused a dose-dependent inhibition of CCK-stimulated gallbladder contraction with 10 mg producing complete blockade (P less than 0.01, cf. placebo). Gallbladder contraction and gastric emptying rates after a mixed meal were then measured in a two-period crossover study. Subjects received placebo or 10 mg of MK-329 2 h before eating. Gastric emptying of both solids and liquids was measured simultaneously by gamma scintigraphy. In placebo-treated subjects plasma CCK levels increased postprandially to 2.3 pM, gallbladder volumes decreased 68.4 +/- 3.8% (SE), and the times for 50% emptying of liquids and solids from the stomach were 58 +/- 10 and 128 +/- 8 min, respectively. In MK-329-treated subjects there was a marked elevation in peak CCK levels to 13.8 pM (P less than 0.01, cf. placebo), and gallbladder contraction was completely inhibited. Solid and liquid emptying rates were unaffected. These findings demonstrate that (a) MK-329 is a potent, orally active antagonist of CCK in humans, and (b) CCK is the major regulator of postprandial gallbladder contraction. These data also support the concept of negative feedback regulation of CCK secretion and suggest that mechanisms other than CCK play a dominant role in the regulation of postprandial gastric emptying rates.     

Emergency Medicine Resident Performed Bedside Ultrasonography of the Gallbladder in Non-Fasted Healthy Volunteers

Background: Gallbladder ultrasonography is a commonly performed test in the emergency department. It is unknown whether a non-fasting state alters the visualization of the gallbladder by emergency medicine (EM) residents. Objectives: We conducted this study to determine whether EM residents are able to visualize the gallbladder in volunteers who have recently consumed a fatty meal. Methods: This study used a prospective, single-blinded, randomized controlled design. Initial scans were performed on fasting volunteers. A fatty meal was then consumed. Thirty minutes after eating, a different resident, who was unaware of whether the volunteer had eaten or fasted, performed a second scan. To control for operator bias, 10% of subjects remained fasting between scans. Student's paired-samples t-test, Pearson's chi-squared, and McNemar test were determined as appropriate. Results: A total of 92 scans from 46 volunteers were analyzed. EM residents were able to visualize the gallbladder in all 40 pre-prandial scans (100%) and all 40 post-prandial scans (100%). Gallbladder area as measured in the longitudinal axis decreased 20% from a mean baseline of 11.58 ± 4.86 cm² (95% confidence interval [CI] 11.17–12.98) to 9.2 ± 5.04 cm² (95% CI 7.74–10.66, p = 0.0009) after food intake. Total time to scan for the fasting volunteers (110.2 s, 95% CI 84.34–136) did not change significantly from non-fasting volunteers (129.7 s, 95% CI 110.29–149.01, p = 0.153). Conclusions: EM residents are able to visualize the gallbladder in non-fasted healthy volunteers.     

Gallbladder and gastric motility in patients with idiopathic slow-transit constipation

OBJECTIVE: Idiopathic slow-transit constipation (STC) has been suggested to be a pangastrointestinal motility disorder. We investigated scintigraphically whether motility in the gallbladder and stomach was impaired in slow-transit constipation. METHODS: Twenty-four patients with STC were studied. Colon transit time, gallbladder motility, and solid-phase gastric emptying were measured by scintigraphy. RESULTS: Gallbladder dysmotility was observed in 8 of 18 (44.4%) patients. Mean gallbladder ejection fraction was 41.6 +/- 13.6% (range, 16.3-67.0%). Gastric emptying was delayed in 9 of 18 (50%) patients. Mean solid-phase gastric half-emptying time was 75 minutes. STC may be associated with impaired function of other gastrointestinal organs. Approximately half of patients with STC presented gallbladder or gastric dysmotility. CONCLUSION: STC may not be a pure colonic abnormality; it may be a component of a pangastrointestinal tract motility disorder involving several organs.     

A model for the comparison of pharmacologic agents influencing gallbladder contraction

Investigations on pharmacologic effects on gallbladder contraction must take into consideration the spontaneous motility of the gallbladder. In 20 healthy subjects, we measured the area of the gallbladder sonographically over 10 h at hourly intervals. The spontaneous motility expressed as a coefficient of variation varied between 1.6 and 13% (mean value, 6.3%). Afterwards, we checked the cholecystokinetic action of ceruletide and fatty meal in eight subjects. Here, an alteration of the area by four times the previously found coefficient of variation was defined as significant. A significant contraction occurred earlier after ceruletide administration than after a fatty meal (10 min as compared to 20 min). This lasted longer (40 min. vs. 25 min) and led to a very much more marked reduction in area (69% as compared to 53%). These differences were significant on a 5% level. The end of the contraction did not differ (50 min as compared to 45 min). We conclude that drugs which affect gallbladder contraction can be compared with consideration of spontaneous motility.     

No adverse hemodynamic interaction between sildenafil and red wine

OBJECTIVE: Our objective was to investigate the hemodynamic interaction between sildenafil and red wine. Sildenafil citrate (Viagra), a phosphodiesterase type 5 inhibitor, is an effective treatment for male erectile dysfunction that potentiates nitric oxide-mediated vasodilation. Alcohol is a commonly used recreational substance with complex vascular effects, which may, in part, be mediated by nitric oxide. Thus there is potential for an adverse hemodynamic interaction. METHODS: Eight healthy men received either 100 mg sildenafil, alcohol (750 mL red wine, 13.5% by volume), or the combination, in a 4-way, double placebo-controlled, randomized crossover study. Blood pressure, heart rate, and cardiac index were measured every 15 minutes up to 180 minutes. RESULTS: Results are expressed as mean +/- SEM. Red wine increased cardiac index (by 15% +/- 8%, P = .04) and heart rate (by 27% +/- 5%, P < .0001). Mean arterial pressure initially increased by approximately 5% and then fell by a maximum of approximately 7%. Sildenafil reduced peripheral vascular resistance (by 24% +/- 8%, P = .03) and mean arterial pressure (by 7% +/- 3%, P = .03) with no effect on cardiac index or heart rate. CONCLUSIONS: There is no clinically important hemodynamic interaction between sildenafil and alcohol (red wine).     

Does jejunal feeding activate exocrine pancreatic secretion?

BACKGROUND: The upper small bowel is of pivotal importance for the stimulation of exocrine pancreatic secretion in response to a meal. We hypothesize that more distal delivery of nutrients into the small intestine will result in less activation of pancreatic secretion. MATERIALS AND METHODS: Eight healthy subjects (3 male, 5 female; age 23 +/- 1 years) participated in two experiments, performed in random order. Subjects were intubated with a 4-lumen tube. Duodenal outputs of pancreatic enzymes and bilirubin were measured by aspiration using a recovery marker. The distal opening was used for continuous administration of a mixed liquid meal and located at either the ligament of Treitz or 60 cm further distally. Gallbladder volume was measured and blood samples were drawn for determination of gastrointestinal hormones. The duration of each experiment was 4 h; with 1 h fasting and 3 h continuous administration of nutrients. RESULTS: During proximal jejunal feeding, pancreatic enzyme output increased significantly over basal levels. No significant increase over basal levels was observed during distal jejunal feeding. Bilirubin output and gallbladder contraction were significantly (P < 0.05) reduced during distal compared to proximal jejunal feeding. No significant differences were found in plasma levels of CCK, PYY and neurotensin between proximal and distal jejunal feeding. CONCLUSION: Continuous feeding in the distal jejunum does not stimulate exocrine pancreatic secretion but maintains gallbladder contraction, although to a lesser extent. These effects are not related to hormonal changes but probably reduced activation of the enteropancreatic reflexes.     

The effect of sildenafil on nitric oxide-mediated vasodilation in healthy men

BACKGROUND: Sildenafil, a treatment for erectile dysfunction, is a specific phosphodiesterase type 5 (PDE 5) inhibitor that enhances nitric oxide (NO)-mediated vasodilation in the corpus cavernosum by inhibiting cyclic guanosine monophosphate breakdown. Since PDE 5 is widely expressed in the vasculature, we examined the hypothesis that sildenafil could enhance NO-mediated vasodilation in other vascular beds and improve endothelial function. METHODS: NO-mediated responses to acetylcholine (endothelium-dependent) and nitroglycerin (endothelium-independent) were measured in healthy men in the dorsal hand vein (n = 13), after the administration of either sildenafil 50 mg or placebo. Flow-mediated dilation of the brachial artery and forearm postischemic reactive hyperemia were measured before and after sildenafil 50 mg, isosorbide dinitrate 5 mg, and placebo in a double-blind, randomized, crossover study (n = 11). RESULTS: In the hand vein, sildenafil administration increased sensitivity to local nitroglycerin. The 50% effective dose decreased approximately 4-fold from 13.5 ng/min (range, 6.9-26.6 ng/min) to 2.7 ng/min (range, 1.1-6.4 ng/min) (P =.025). Sildenafil decreased the maximum venoconstriction induced by phenylephrine from 81% +/- 3% to 74% +/- 3% (P =.025). Sildenafil did not significantly affect the maximal venodilatory response to acetylcholine (35% +/- 7% after placebo versus 32% +/- 8% after sildenafil) (P =.7). In the arterial vasculature, flow-mediated dilation before (2.4% +/- 1%) and after (2.8% +/- 1.4%) sildenafil (P =.8) and postischemic reactive hyperemia area under the curve before (1807 +/- 393 mL. min. s/100 mL) and after (1467 +/- 257 mL. min. s/100 mL) sildenafil were not different (P =.8). Resting heart rate, blood pressure, and resting brachial artery diameter were unchanged after sildenafil administration. Isosorbide dinitrate, an endothelium-independent vasodilator, caused a significant increase in resting brachial artery diameter from 0.53 +/- 0.01 cm to 0.56 +/- 0.02 cm (P =.005), without altering flow-mediated dilation. CONCLUSIONS: In healthy men sildenafil increased sensitivity to nitroglycerin, an exogenous NO donor, approximately 4-fold but did not affect endothelium-dependent, NO-mediated responses in either the hand vein or forearm vasculature. Differential vascular responses to sildenafil may localize its enhancement of endogenous NO-mediated vasodilation to vascular beds such as the corpus cavernosum.     

Effects of cilomilast, a selective phosphodiesterase 4 inhibitor, on esophageal motility and pH, and orocecal and colonic transit: two single-center, randomized, double-blind, placebo-controlled, two-part crossover studies in healthy volunteers

BACKGROUND: Phase IIb studies have reported that cilomilast, a selective phosphodiesterase 4 inhibitor being developed for the treatment of chronic obstructive pulmonary disease, is associated with gastrointestinal (GI) adverse effects (AEs) in a small proportion (approximately 5%) of individuals. OBJECTIVES: The aims of these 2 studies were to investigate the effects of cilomilast 15 mg BID on: (1) lower esophageal sphincter pressure (LESP) and esophageal body motility and pH (study 1); and (2) orocecal and whole-gut transit times (OCTT and WGTT, respectively) (study 2) in healthy volunteers. METHODS: These 2 randomized, double-blind, placebo-controlled, 2-part crossover studies were conducted at the Neurogastroenterology Unit, Wythenshawe Hospital, Manchester, United Kingdom (study 1) and GlaxoSmithKline, Harlow, United Kingdom (study 2). In study 1, subjects were randomly assigned to receive either cilomilast (15 mg BID) or matched placebo (control) for 7 days (13 doses; subjects were not given the evening dose on day 7), and in study 2, cilomilast (15 mg BID) or matched placebo (control) for 9 days (18 doses) in each of 2 treatment periods. After study drug administration, combined esophageal motility and pH were recorded for 2 hours before and 4 hours after the administration of a standardized meal (2400 kJ [573 kcal]). Sequences of 6 consecutive 5-mL water swallows (separated by 20 seconds) were carried out 60 and 90 minutes (fasting) and 150, 180, 210, 240, 300, and 360 minutes (fed) after study drug administration. OCTT was determined from the increase in breath hydrogen after the meal. WGTT was determined from the time taken to excrete at least 16 of 20 ingested radiopaque markers, ingested as 2 capsules, each containing 10 radiopaque markers, with 240 mL of water. AEs were elicited at specified times throughout each session using nonleading questions, spontaneously reported AEs, and diary cards. RESULTS: Study 1 enrolled 20 subjects (11 men, 9 women; age range, 20-52 years). Study 2 enrolled 16 subjects (10 men, 6 women; age range, 19-48 years). No clinically significant differences in the amplitude (mean difference in postprandial-preprandial AUC0-t/t, 6.09 mm Hg; 95% CI, -10.66 to 22.84), duration (difference, -0.08 second; 95% CI, -0.54 to 0.37), or velocity of propagation (difference, 0.90 cm/s; 95% CI, -0.66 to 2.46) of esophageal contractions, LESP (difference, -0.39 mm Hg; 95% CI, -5.23 to 4.45), or preprandial or postprandial percentage time pH<4 (median differences: preprandial, 0.47% [95% CI, -0.45 to 1.27]; postprandial, -0.005% [95% CI, -1.30 to 6.27]) were found with cilomilast compared with placebo. No significant differences in OCTT (difference, -0.37 hour; 95% CI, -1.59 to 0.84) or WGTT (difference, -2.96 hours; 95% CI, -20.76 to 14.84) were found with cilomilast compared with controls. In both studies, the most frequently reported AEs with cilomilast use were nausea (8/18 in study 1 and 3/16 in study 2) and headache (8/18 in study 1 and 6/16 in study 2); however, these were generally of mild to moderate intensity. Overall, GI AEs did not correlate with changes in GI motility. CONCLUSION: The results of these 2 studies suggest that cilomilast was not associated with significant changes in esophageal motility and pH or GI transit in these healthy volunteers.     

Psychomotor performance in healthy young adult volunteers receiving lormetazepam and placebo: a single-dose, randomized, double-blind, crossover trial

BACKGROUND: Lormetazepam is a hypnotic benzodiazepine currently used in the treatment of insomnia. When this agent is used appropriately, its pharmacologic properties predict a high therapeutic index with a good tolerability profile. OBJECTIVE: The primary aim of this study was to compare the effects on psychomotor performance of lormetazepam and placebo in healthy young adult subjects. A secondary objective was to evaluate the clinical tolerability of lormetazepam. METHODS: This was a randomized, double-blind,placebo-controlled, crossover study in healthy young adult volunteers. All volunteers received single doses of lormetazepam 1 mg and placebo, with a 1-week interval between doses. The primary study variables were visual simple reaction time (VSRT) and visual choice reaction time (VCRT), measured before dosing with lormetazepam or placebo and at 20, 60, 120, 180, 240, and 360 minutes after dosing using a standard computerized apparatus. To increase the sensitivity of the results, visual reaction times were also recorded using a validated mobile computerized device. Secondary variables were the duration and quality of sleep on the night before each study session, rated by subjects using a 100-mm visual analog scale; the Epworth Sleepiness Scale for daytime drowsiness; and the Critical Flicker Fusion Threshold test. Spontaneously reported adverse events were recorded and monitored throughout the study. RESULTS: The study included 18 healthy young adult volunteers (12 women, 6 men; mean [SD] age, 26.7 [2.8] years [range, 21-30 years]; mean body weight, 58 [9.5] kg). There were no significant differences in either VSRT or VCRT after administration of lormetazepam or placebo. Independent of study drug but consistent with the accepted range of variability between the 2 devices, overall reaction times were significantly shorter with the use of the mobile device compared with the standard apparatus (P < 0.01). Analysis of the results showed no sequence effects or other evidence of learning. There were no changes in the secondary study variables after administration of the test drugs. Administration of lormetazepam was associated with dizziness in 2 subjects, in 1 case occurring in association with somnolence. These adverse events were mild and subsided spontaneously 3 hours after drug intake. After administration of placebo, 1 subject reported slight somnolence 60 minutes after dosing that persisted through 180 minutes. CONCLUSION: In this small, selected group of healthy young adult subjects, a single dose of lormetazepam 1 mg did not affect psychomotor performance, assessed in terms of visual reaction times, compared with placebo.     

Effects of cholestyramine on gallbladder and gastric emptying in obese and lean subjects

Abstract. Gallbladder stasis is frequent in obese subjects and may contribute to their increased risk for gallstone formation. The bile salt sequestrant cholestyramine acutely enhances postprandial gallbladder emptying in lean subjects, through dis-inhibition of a negative feedback between intraluminal bile salts and CCK release. In this study the effect of cholestyramine on both gallbladder and gastric antrum dynamics were studied by realtime ultrasonography in 12 obese and 15 lean subjects. For the acute study, on different days, subjects ingested a liquid meal (two egg yolks plus water 200 mL, 50 kJ) or a meal with 4g cholestyramine. Gallbladder emptying was impaired in obese patients who had significantly larger fasting gallbladder volume (39.4 ± 6.9 vs. 21.6 ± l.7mL, P <0.02), larger residual volume (12.3 ± 1.8 vs. 4.0 ± 0.5ml, P < 0.0006) and slower emptying time ( T /2: 33 ± 2 vs. 21 ± 2 min, P < 0.05) than lean subjects. Integrated antral emptying was also less in obese than lean subjects (5521 ± 578 vs. 7908 ± 491 % 120min^-1, P <0.02). Cholestyramine enhanced postprandial gallbladder emptying in both obese and lean subjects. Gastric emptying was delayed with cholestyramine in lean but not obese subjects. For the chronic study, after 1 month therapy with cholestyramine (4 g every 2 days), the motility tests were repeated in nine obese subjects. Gallbladder and gastric responses to a test meal, with or without cholestyramine, were preserved. We conclude that both gallbladder and antral emptying of a liquid test meal are impaired in obese subjects. Gallbladder emptying improves after acute administration of a low dose cholestyramine with test meal. This effect is sustained after 1 month treatment with a low dose of cholestyramine and does not interfere with gastric emptying of obese patients. Cholestyramine may improve gallbladder hypomotility in obese people.     

Sildenafil citrate as a phosphodiesterase inhibitor has an antioxidant effect in the blood of men

Background and objective: Sildenafil citrate enhances the action of nitric oxide by preventing the hydrolysis of cGMP, and is widely used to treat erectile dysfunction. We investigated the effects of sildenafil citrate administration on lipid peroxidation and antioxidant redox enzymes in blood of healthy men. Method: Thirty healthy male subjects were divided equally into two groups. The first group was used as the control. A single dose of sildenafil citrate was administrated orally to subjects constituting the second group. Blood samples were obtained at 0, 2, 6 and 24 h after intake of the single dose of 100 mg sildenafil citrate or placebo. Results and discussion: The dose of sildenafil citrate resulted in significant increase in the erythrocyte superoxide dismutase and catalase activities at 6 and 24 h. Plasma lipid peroxidation levels decreased slightly. There was no statistical difference in erythrocyte glutathione peroxidase activity between the placebo and sildenafil citrate groups. Conclusion: Treatment of blood with 100 mg sildenafil citrate has protective effects on oxidative stress by inhibiting free radical formation and by supporting antioxidant redox systems.     

Oro-cecal transit time: influence of a subsequent meal

BACKGROUND: Small intestinal and oro-cecal transit time (OCTT) is determined for clinical diagnostics and research purposes. Experimental protocols used vary with respect to the inclusion of a subsequent meal during the test period. This study was conducted to elucidate whether the ingestion of a subsequent meal during the test period influences the OCTT of the test meal. MATERIALS AND METHODS: The OCTT of a liquid test meal, measured with the lactose-[(13)C]ureide breath test, was compared between four groups of healthy volunteers (n = 36) who consumed the subsequent meal at different time points. Also, the OCTT was determined twice in eight subjects; a subsequent meal was ingested after 180 min (test A) and after 360 min (test B). RESULTS: An apparently meal-related increase in median OCTT was observed. The OCTT of the eight volunteers measured in test A (210; 210-349 median; quartiles) was significantly shorter than that found in test B (345; 300-375 min, P = 0.016). As result of the ingestion of the subsequent meal at 180 min the OCTT was shortened by 90; 64-116 min in 7/8 subjects. CONCLUSION: These data indicate that the ingestion of a subsequent meal affects the OCTT of a liquid test meal. This phenomenon could be explained by the increased intestinal motility in response to a meal, and should be taken into account when designing protocols for measurements of the OCTT and in the interpretation of small intestinal absorption studies.     

Effect of sustained-release isosorbide dinitrate on post-prandial gastric emptying and gastroduodenal motility in healthy humans

Nitric oxide (NO) is an inhibitory neurotransmitter released by non-adrenergic and non-cholinergic neurons that innervate the smooth muscles of the gastrointestinal tract. We examined whether NO, derived from a sustained-release preparation of isosorbide dinitrate, influenced gastric emptying and gastroduodenal motility after a meal. Eleven healthy volunteers participated in a double-blind, placebo-controlled, cross-over study. Each subject ingested 40 mg isosorbide dinitrate orally as a sustained-release formulation or oral placebo, in random order. Gastric emptying and gastroduodenal motility were measured using scintigraphic and manometric techniques. Isosorbide dinitrate did not change the area under the curve of gastric retention versus time, and did not influence the frequency of antral contractions as assessed at 15-min intervals or the integrated duodenal motility index, as recorded over consecutive 15-min periods. A 40 mg single dose of sustained-released isosorbide dinitrate does not seem to alter gastric emptying or gastroduodenal motility after a meal.     

Randomized dose ranging study of the reduction of fasting and postprandial glucose in type 2 diabetes by nateglinide (A-4166).

OBJECTIVE: This randomized crossover double-blind placebo-controlled study aimed to assess the efficacy of nateglinide (A-4166), a novel phenylalanine-derived insulin secretagogue, in type 2 diabetic subjects while fasting and 5 min before a standard meal. RESEARCH DESIGN AND METHODS: A single dose of nateglinide (60, 120, or 180 mg) or placebo was given to eight diet-treated overnight-fasted type 2 diabetic patients and to seven patients 5 min before a standard breakfast. Plasma glucose, radioimmunoassay insulin, and nateglinide were measured at baseline and for a further 180 min. RESULTS: The time-averaged 180-min postdose mean decrease in fasting plasma glucose concentration was greater after nateglinide (1.8 mmol/l; 95% CI 1.5-2.0) than after placebo (0.7 mmol/l; 95% CI 0.3-1.2) (P < 0.001). Hypoglycemia did not develop in any of the subjects. Insulin concentrations increased 1.5-, 1.8-, and 1.9-fold with the 60-, 120-, and 180-mg doses, respectively (P < 0.001), peaking approximately 30 min after the dose. Nateglinide concentrations peaked after approximately 30 min, decreasing to 21% of peak by 180 min. In the meal test, the mean increase (2.9 mmol/l, 2.3-3.6) in plasma glucose over 180 min after placebo was reduced by 1.8 mmol/l (P < 0.001) with the two higher doses of nateglinide. CONCLUSIONS: A single dose of nateglinide administered to diet-treated type 2 diabetic patients with fasting hyperglycemia increased insulin secretion and reduced fasting glucose without hypoglycemia. Administered 5 min before a meal, nateglinide reduced the postprandial glucose excursion by 64%. With its rapid onset and short duration of action, nateglinide is a promising oral prandial therapy in type 2 diabetes.