Effect of obesity on gastrointestinal transit, pressure and pH using a wireless motility capsule.

BACKGROUND: Despite the increasing prevalence and medical burden of obesity, the understanding of gastrointestinal physiology in obesity is scarce, which hampers drug development. AIM: To investigate the effect of obesity and food intake on gastrointestinal transit, pressure and pH. MATERIAL AND METHODS: An exploratory cross-sectional study using a wireless motility capsule (SmartPill©) was performed in 11 participants with obesity and 11 age- and gender-matched participants with normal weight (group) in fasted and fed state (visit). During the first visit, the capsule was ingested after an overnight fast. During a second visit, the capsule was ingested after a nutritional drink to simulate fed state. Linear mixed models were constructed to compare segmental gastrointestinal transit, pressure and pH between groups (obesity or control) and within every group (fasted or fed). RESULTS: Food intake slowed gastric emptying in both groups (both P < 0.0001), though food-induced gastric contractility was higher in participants with obesity compared to controls (P = 0.02). In the small intestine, a higher contractility (P = 0.001), shorter transit (P = 0.04) and lower median pH (P = 0.002) was observed in participants with obesity compared to controls. No differences were observed for colonic measurements. CONCLUSION: Obesity has a profound impact on gastrointestinal physiology, which should be taken into account for drug development.

The use of technetium-99m radiolabeled human antimicrobial peptides for infection specific imaging.

Bacterial resistance to conventional antibiotics poses a challenge medicine to search for alternatives. Cationic antimicrobial peptides (AMPs) are promising for the development of a new class of antibiotics. This review focuses on the use of technetium-99m labeled synthetic AMPs, derived from human natural cationic AMPs, for target-delivery to and in vivo detection of infection sites caused by (drug-resistant) micro-organisms. The scintigraphic approach has proven to be a reliable method for evaluating AMPs in pharmacological studies and for optimizing target-delivery of radiolabeled AMPs to pathological sites in animals and humans. In addition, the effect of alterations in amphipathicity, amino acid substitution, and dimerization on the biological performance of AMPs is reported. Radiolabeled AMPs offer good perspectives for diagnosis of infections, for monitoring therapy, and, most importantly, for the ability to discriminate between infections and sterile inflammatory processes.

Tolerance of adjuvant letrozole outside of clinical trials.

Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2-3 years of tamoxifen, or as an extended treatment after 5 years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerance in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded. In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients. Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.

The influence of the novel 5-HT1A agonist R137696 on the proximal stomach function in healthy volunteers.

As fundic dysaccommodation represents one of the pathophysiological mechanisms underlying functional dyspepsia, gastric relaxant agents may serve as a new treatment of this disorder. Previous studies have suggested the involvement of 5HT1 receptors in the control of gastric tone. Our aim was to study the effect of R137696, a novel 5HT1A agonist, on fundus sensorimotor function in healthy volunteers. The effect of single oral doses (1-2 mg) R137696 was evaluated in a double-blind, placebo-controlled manner on fasting fundic volume, visceral perception, distension-evoked symptoms and fundic compliance in 21 healthy male subjects. R137696 increased the proximal stomach volumes in a dose-dependent manner. Distention-evoked symptoms or distention and discomfort threshold were not altered by R137696. A logistic regression model, characterizing the relationships between the volume and the visual analogue scale score for dyspeptic symptoms (nausea, fullness, discomfort, pain and satiety) as a sigmoidal curve, revealed that R137696 had no effect on distension-induced discomfort, fullness, pain and satiety compared to placebo. R137696 relaxes the gastric fundus in fasting conditions but has no effect on distension-evoked dyspeptic symptoms in healthy volunteers.

A semi-blinded study comparing 2 methods of measuring nasal potential difference: Subcutaneous needle versus dermal abrasion.

BACKGROUND: According to European and US protocols, two nasal potential difference (NPD) measurement methods are considered acceptable, although they have not been formally compared: subcutaneous agar-filled needle with calomel (Ndl) and dermal abrasion with conducting cream and Ag/AgCl electrodes (Abr). We compared both in CF and healthy volunteers (HV), assessing their discriminative value and subject's preference. METHODS: Twelve classic CF and 17 HV underwent both NPD methods, performed by one operator in random order. A written questionnaire, assessing preference, was completed after each test. Tracings were coded, scored in a semi-blinded fashion and categorised as CF/non-CF. RESULTS: 110 tracings (56 Ndl/54 Abr) were collected: 42/110 scored CF and 68/110 non-CF, showing a good correlation. No significant preference for either method was reported. CONCLUSION: Both NPD methods are similar in terms of discriminative value and subject's preference, comparing classical CF and HV. For diagnosing CF, the operator's preferred NPD-method may be used.

Randomized clinical trial: a controlled pilot trial of the 5-HT4 receptor agonist revexepride in patients with symptoms suggestive of gastroparesis.

BACKGROUND: Gastroparesis is a chronic gastric disorder characterized by delayed gastric emptying without mechanical obstruction, and clinical symptoms as postprandial fullness, early satiety, bloating, nausea, vomiting, and abdominal pain. Prokinetic agents are used for the treatment of gastroparesis. Revexepride, a 5-hydroxytryptamine (serotonin) receptor (5-HT4 R) agonist, could be a good candidate drug for the gastroparesis treatment. AIM: In the current phase II, exploratory, double-blind, randomized, stratified, placebo-controlled, repeated dose trial (EudraCT number 2007-004997-23), the efficacy on gastrointestinal symptoms and gastric emptying rate, safety, and pharmacokinetic profile of three oral doses of revexepride (0.02, 0.1, and 0.5 mg administered orally t.i.d. for 4 weeks) was evaluated in trial participants (diabetic and non-diabetic) with upper gastrointestinal tract symptoms suggestive for gastroparesis. METHODS: Eighty participants, enrolled in four parallel treatment groups, were asked to score their symptom diary data, gastroparesis cardinal symptom index (GCSI), patient assessment of upper gastrointestinal disorders-symptom severity index (PAGI-SYM), quality of life questionnaires, and meal-related symptom score. Gastric emptying rate was evaluated by (13) C-octanoic acid breath test. KEY RESULTS: The severity of the symptoms assessed by means of GCSI and PAGI-SYM decreased at Week 2 and decreased further at Week 4 in all treatment groups including placebo, with similar trends in all treatment groups. Quality of life improved in all treatment groups after 4 weeks of treatment. No differences on gastric emptying rate were shown between any of the active treatment groups and placebo. Revexepride was generally safe and well-tolerated. CONCLUSIONS & INFERENCES: Four weeks of revexepride treatment did not improve symptoms or gastric emptying over placebo in patients with symptoms suggestive of gastroparesis.

Divergent role for CRF1 and CRF2 receptors in the modulation of visceral pain.

Both anti- and pro-nociceptive effects of corticotropin-releasing factor (CRF) treatment on visceral pain have been reported. Here, this dual action of CRF was differentiated by selective (in)activation of the CRF1 and CRF2 receptor prior to a visceral pain stimulus. Visceral pain was evaluated out of behavioural and visceromotor (abdominal electromyogram) responses to duodenal distension in the freely moving rat. Intraperitoneal (i.p.) CRF (50 microg kg-1) increased the distension-induced visceromotor and behavioural pain response. The pro-nociceptive effects of CRF on the behavioural response were attenuated by a selective CRF1 (CP-154526; 20 mg kg-1) but not a selective CRF2 [antiSauvagine30 (aSVG30); 100 microg kg-1] antagonist. Selective activation of the CRF2 receptor by stresscopin-related peptide (SRP; i.p. 25 microg kg-1) reduced the distension-induced visceromotor and behavioural response. Intrathecal injection of CRF (2 microg 10 microL-1) or SRP (20 microg 10 microL-1) decreased the distension-induced visceromotor and behavioural response. The antinociceptive effects of intrathecal CRF on the behavioural response were attenuated by aSVG30 (20 microg 10 microL-1) but not with CP-154526 (10 microg 10 microL-1). These findings indicate that the CRF1 receptor is involved in pro-nociception of visceral pain, whereas the CRF2 receptor is mainly involved in antinociception. This divergent role of the CRF subreceptors may explain the bimodal effects of CRF treatment on visceral nociception.

Randomised clinical trial: the 5-HT4 agonist revexepride in patients with gastro-oesophageal reflux disease who have persistent symptoms despite PPI therapy.

BACKGROUND: A substantial proportion of patients with gastro-oesophageal reflux disease (GERD) have only a partial response to proton pump inhibitor (PPI) therapy. Prokinetic drugs may improve reflux symptoms by enhancing oesophageal motility and gastric emptying. AIM: To evaluate the effect of revexepride, a novel prokinetic 5-hydroxytryptamine type 4 (5-HT4 ) receptor agonist, compared with placebo, in patients with GERD who have a partial response to PPIs. METHODS: A phase 2b, double-blind, parallel-group study was conducted, in which patients were randomised to one of three revexepride treatment groups (0.1, 0.5 and 2.0 mg three times daily) or placebo (1:1:1:1 ratio). Daily e-diary data captured patients' symptoms over an 8-week treatment period. The primary efficacy outcome was the weekly percentage of regurgitation-free days in the second half of the study (weeks 5-8). RESULTS: In total, 480 patients were randomised and 477 received treatment (mean age 47.9 years; 61% women). The mean percentage of regurgitation-free days increased from baseline (range, 15.0-18.8%) to week 8 (62.3-70.5%) in all four study arms; however, there were no statistically significant differences in this change between placebo and the three treatment arms. No dose-dependent relationship in treatment effect was observed for any of the study endpoints. The incidence of treatment-emergent adverse events (TEAEs) was revexepride dose-dependent. Only one serious TEAE occurred and none resulted in death. CONCLUSIONS: Revexepride was no more effective than placebo in controlling regurgitation in patients with GERD symptoms partially responsive to PPIs. Revexepride was well tolerated. ClinicalTrials.gov Identifier: NCT01472939.

Randomized clinical trial: effect of the 5-HT4 receptor agonist revexepride on reflux parameters in patients with persistent reflux symptoms despite PPI treatment.

BACKGROUND: Approximately, 20-30% of patients with gastro-esophageal reflux disease (GERD) experience persistent symptoms despite treatment with proton pump inhibitors (PPIs). These patients may have underlying dysmotility; therefore, targeting gastric motor dysfunction in addition to acid inhibition may represent a new therapeutic avenue. The aim of this study was to assess the pharmacodynamic effect of the prokinetic agent revexepride (a 5-HT4 receptor agonist) in patients with GERD who have persistent symptoms despite treatment with a PPI. METHODS: This was a phase II, exploratory, multicenter, randomized, placebo-controlled, double-blind, parallel-group study in patients with GERD who experienced persistent symptoms while taking a stable dose of PPIs (ClinicalTrials.gov identifier: NCT01370863). Patients were randomized to either revexepride (0.5 mg, three times daily) or matching placebo for 4 weeks. Reflux events and associated characteristics were assessed by pH/impedance monitoring and disease symptoms were assessed using electronic diaries and questionnaires. KEY RESULTS: In total, 67 patients were enrolled in the study. There were no significant differences between study arms in the number, the mean proximal extent or the bolus clearance times of liquid-containing reflux events. Changes from baseline in the number of heartburn, regurgitation, and other symptom events were minimal for each treatment group and no clear trends were observed. CONCLUSIONS & INFERENCES: No clear differences were seen in reflux parameters between the placebo and revexepride groups.

A paradoxical increase in resting energy expenditure in malnourished patients near death: the king penguin syndrome.

BACKGROUND: The metabolic expression of extreme starvation on the verge of death is unknown in humans. OBJECTIVE: The objective was to compare the resting energy expenditure (REE) of 5 extremely malnourished dying patients [body mass index (in kg/m(2)): 9.77 +/- 0.1] with that of 16 less-malnourished anorexia nervosa (AN) patients. DESIGN: REE was measured by indirect calorimetry and body composition was measured by anthropometry and dual-frequency bioelectrical impedance analysis. Fasting serum insulin, thyroid hormone, and catecholamine concentrations were also determined. RESULTS: At the start of refeeding, REE was high in each of the 5 extremely malnourished dying patients, whereas it was low in the 16 AN patients (mean +/- SD: 5174 +/- 391 kJ/d compared with 3844 +/- 619 kJ/d; P < 0.05). The high REE value in the 5 extremely malnourished dying patients was associated with almost no fat mass (FM), high urinary nitrogen loss (16.4 +/- 2.9 g/d), low serum fatty acid concentrations (0.36 +/- 0.23 mmol/L), and low or normal serum insulin, thyroid hormone, and catecholamine concentrations. During the first 2-4 wk of refeeding, REE and nitrogen loss decreased, whereas fatty acid concentrations increased in each of the 4 surviving patients; REE and urinary nitrogen output increased in the 16 AN patients. CONCLUSION: In malnourished persons near death, there is an increase in REE and in protein catabolism. The reason for this increase is unknown but could relate to consumption of the last mobilizable muscle mass and to diseased cellular membranes.

Telemetric animal model to evaluate visceral pain in the freely moving rat.

Several research groups have measured the visceromotor response to visceral distension by electromyography (EMG) in the conscious restraint, wrapped or lightly anaesthetized rat. Our aim was to develop a more physiological and stress-free technique that enables the simultaneous measurement of duodenal distension-induced visceromotor and cardiovascular responses in the conscious, freely moving rat. A telemetry transmitter, consisting of a bipolar electrode pair and arterial catheter, was chronically implanted into the rat to measure abdominal EMG, mean arterial pressure (MAP) and heart rate (HR). Furthermore, a balloon catheter was chronically implanted in the duodenum to deliver volume-fixed staircase (0.1-0.6 ml) or phasic (0.1, 0.3, 0.5 ml) distensions. The area under the curve (AUC; mVs) and maximal amplitude (EMG(max); mV) during distension were analyzed. The model was validated by pre-treatment with morphine (0.3, 1.5 and 3 mg/kg, intraperitoneally). Staircase and phasic distension produced a volume-dependent increase in AUC and EMG(max), HR and MAP. Pre-treatment with morphine inhibited the distension-induced visceromotor response, i.e. abdominal contractions, increase in AUC and EMG(max). These findings indicate that telemetry is an adequate tool to measure visceromotor and cardiovascular responses to averse, noxious duodenal distension continuously and simultaneously in the rats home cage, without additional handling-related or restraint-induced stress. The presented animal visceral model is intended for studying acute and chronic analgesic properties of new pharmaceutical compounds.

A nitric oxide synthase activity is involved in the modulation of acetylcholine release in Aplysia ganglion neurons: a histological, voltammetric and electrophysiological study.

The role of nitric oxide or related molecules as neuromodulators was investigated in the buccal and the abdominal ganglia of the mollusc Aplysia californica. In a first step we showed that reduced nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry and specific nitric oxide synthase immunohistochemistry labelled the same neurons and fibres in both ganglia, pointing to the presence of a neuronal nitric oxide synthase. In a second step, we performed voltammetric detection of nitric oxide-related molecules using a microcarbon electrode in a reduction mode. A peak identified as N-nitroso-L-arginine was detected at -1.66 V in both ganglia. The identification of this compound as a product of endogenous nitric oxide synthase activity was reinforced by the fact that its peak amplitude was decreased in the presence of NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthase, and increased with its substrate, L-arginine. An additional proof of a nitric oxide synthase activity was the detection of nitrites and nitrates in high concentrations (millimolar range) by capillary electrophoresis. We also showed that these nitric oxide-related molecules modulated acetylcholine release at two identified synapses in these ganglia. L-Arginine decreased acetylcholine release at the inhibitory synapse (buccal ganglion), whereas it increased acetylcholine release at the excitatory synapse (abdominal ganglion). The nitric oxide synthase inhibitors, N omega-nitro-L-arginine and NG-monomethyl-L-arginine, had opposite effects. Moreover, the exogenous nitric oxide donor, 3-morpholinosydnonimine hydrochloride mimicked the effects of L-arginine on both inhibitory and excitatory cholinergic synapses. The identification of two cholinergic synapses where nitric oxide affects acetylcholine release in opposite ways provides a useful tool to study the cellular mechanisms through which nitric oxide-related molecules modulate transmitter release.

Smooth muscle 5-HT2A receptors mediating contraction of porcine isolated proximal stomach strips.

1. The aim of this study was to characterize the 5-HT receptors involved in the 5-HT-induced contraction of longitudinal muscle (LM) strips of porcine proximal stomach. This was done in a classical organ bath set-up for isotonic measurement. 2. The concentration-contraction curve to 5-HT was not modified by 5-HT(3) and 5-HT(4) receptor antagonism. Methysergide, ketanserin and mesulergine antagonized the curve to 5-HT. Concomitantly, increasing concentrations of ketanserin and mesulergine progressively revealed a biphasic nature of the 5-HT curve. Ketanserin antagonized the low-affinity receptor while it did not modify the high-affinity receptor. 3. Tetrodotoxin did not influence the concentration-contraction curve to 5-HT neither in the absence nor presence of ketanserin, indicating that nerves are not involved. 4. Ketanserin competitively antagonized the monophasic concentration-response curve to alpha-Methyl-5-HT, yielding a Schild slope that was not significantly different from unity. After constraining the Schild slope to unity, a pK(B) estimate of 8.23+/-0.90 was obtained. This affinity estimate of ketanserin closely approximates previously reported affinities at 5-HT(2A) receptors. 5. In the presence of ketanserin (0.1 microM; exposing the high-affinity receptor), a wide range of 5-HT receptor antagonists covering all 5-HT receptors known, was tested. Only methysergide and ritanserin inhibited the response to 5-HT, thus expressing affinity for the high-affinity receptor. This did not reveal the identity of the receptor involved. 6 It can be concluded that 5-HT induces pig proximal stomach (LM) contraction via 5-HT(2A) receptors located on smooth muscle. A ketanserin-insensitive phase of contractions could not be characterized between the actually known classes of 5-HT receptors with the pharmacological tools that were used.

Pharmacological characterization of the 5-HT receptors mediating contraction and relaxation of canine isolated proximal stomach smooth muscle.

1. We aimed to characterize 5-HT receptors mediating contraction and relaxation to 5-HT in dog proximal stomach longitudinal muscle (LM) strips. 2. Of the tryptamine analogues tested, 5-HT was the most potent contractile agent at basal length, while 5-CT was the most potent relaxant of PGF(2alpha)-induced contraction. Neither the contractions to 5-HT, nor the relaxations to 5-CT were influenced by tetrodotoxin, illustrating that action potential propagation is not involved. 3. The 5-HT-induced contraction was antagonized by mesulergine (0.03 to 0.3 microM) and ketanserin (2 - 20 nM), but the antagonism was not of a simple competitive nature, indicating multiple receptor involvement. Ketanserin (3 to 30 nM) and mesulergine (30 nM) competitively antagonized the alpha-Me-5-HT-induced contraction (pK(B): 8.83+/-0.09 and pA(2): 8.25+/-0.06 respectively). These affinity values are in line with literature affinities of ketanserin and mesulergine at 5-HT(2A) receptors in various bioassays. 4. The 5-CT-induced inhibition of PGF(2alpha)-induced contraction was competitively antagonized by mesulergine (pK(B) estimate: 8.52+/-0.12) and by the selective 5-HT(7) receptor antagonist SB-269970 (pK(B) estimate: 9.36+/-0.14). Both pK(B) estimates are in line with literature affinities of these compounds for 5-HT(7) receptors. Mesulergine (30 nM) and SB-269970 (10 nM) shifted the relaxant curve to 5-HT parallel to the right in the presence of ketanserin (0.3 microM) (pA(2) estimates of 8.08+/-0.10 and 8.75+/-0.14 respectively), indicative of 5-HT(7) receptor involvement. 5. It is concluded that 5-HT induces dog proximal stomach (LM) contraction via smooth muscle 5-HT(2A) receptors and relaxation via smooth muscle 5-HT(7) receptors.

Nitric oxide is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens in vitro.

1. In the guinea-pig colon ascendens, 5-hydroxytryptamine (5-HT) induces contractions, mediated by 5-HT2, 5-HT3 and 5-HT4 receptors, and relaxations, through a 5-HT1 receptor subtype, that triggers the release of an inhibitory neurotransmitter. Nitric oxide (NO) is one of the main candidates of NANC inhibitory neurotransmission in the gut. The aim of this study was to establish whether NO is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens. 2. Antagonists to block the contractile responses to 5-HT via 5-HT2, 5-HT3 and 5-HT4 receptors were present throughout the experiments and methacholine was administered to precontract the strips. Under these conditions, 5-HT concentration-dependently induced relaxations from 10 nM onwards (EC50 = 258 (172-387) nM). The relaxations were inhibited by metergoline (10 nM) and methiothepine (100 nM) and abolished by tetrodotoxin (TTX, 320 nM). Guanethidine (3.2 microM) did not affect them. 3. NG-nitro-L-arginine (L-NNA) inhibited the responses to 5-HT (IC50 = 18.7 (13.3-26.3) microM); at the highest 5-HT concentration a maximum inhibition of about 75% was observed with 320 microM L-NNA. This inhibition was reversed with L-arginine. Relaxations to glyceryl trinitrate (GTN) were not inhibited by L-NNA. 4. Haemoglobin (32 microM) inhibited the relaxations to 5-HT and GTN, but not those to isoprenaline (Iso). Methylene blue (10 microM) inhibited the relaxations to 5-HT but did not affect those caused by GTN or Iso. 5. It is concluded that 5-HT induces relaxations that involve NO.We also confirmed that 5-HT induces these relaxations via (a) 5-HT, receptor subtype(s), located on neurones.

In vivo characterization of 5-HT1A receptor-mediated gastric relaxation in conscious dogs.

Accumulating data have been published emphasizing the important role of 5-hydroxytryptamine (5-HT) receptors in proximal stomach relaxation. However, a proper in vivo characterization of 5-HT receptors mediating gastric relaxation is still missing. In the current study, we focus on the in vivo characterization of 5-HT1A receptors mediating relaxation of the proximal stomach in conscious dogs. Beagle dogs were equipped with a gastric fistula. In the conscious state, volume changes within an intragastric bag were measured at constant pressure by means of a barostat. Results are presented as the maximum volume increase after treatment (mean+/-s.e.m.). All drugs were injected intravenously. The 5-HT1A receptor agonist flesinoxan (10, 50, 100 and 150 microg kg-1) induced a dose-dependent relaxation of the canine proximal stomach (50+/-10, 230+/-51, 290+/-38 and 275+/-33 ml, respectively; n=9-11). The selective 5-HT1A receptor antagonist WAY-100635 dose-dependently inhibited the flesinoxan-induced relaxation. NG-nitro-l-arginine methyl ester did not affect this relaxation, suggesting that nitrergic nerves are not involved. After supradiaphragmatic vagotomy, the baseline of the intragastric volume was larger compared to that before vagotomy (317+/-50 vs 142+/-28 ml, respectively; n=5). Compensation for this by either reduction of the intraballoon pressure or infusion of a contractile dose of bethanechol did not establish a condition in which flesinoxan was able to relax the stomach. In contrast, nitroprusside induced a significant gastric relaxation when tone was increased by bethanechol. It is concluded that flesinoxan induces proximal gastric relaxation in conscious dogs via 5-HT1A receptors. The response is mediated through a vagal pathway without involvement of nitrergic nerves.

Effect of adrenoceptor agonists on striated muscle strips of the canine oesophagus.

1. Acute psychological stress, which could be related to the release of a large amount of catecholamines, may cause oesophageal motility disorders. Therefore, the aim of our study was to elucidate the influence of adrenoceptor agonists on the striated muscle portion of the oesophagus by use of isolated strips from dogs. 2. Contractions were evoked in isolated striated muscle strips by electrical field stimulation (1 pulse min-1, 1 ms/pulse, submaximal voltage). The effects induced by administration of adrenoceptor agonists alone or in the presence of antagonists were tested to determine the nature of the adrenoceptors on this muscle preparation. 3. The administration of both the natural adrenoceptor agonists, adrenaline and noradrenaline, and the synthetic beta-adrenoceptor agonists, isoprenaline (beta 1 + beta 2), dobutamine (beta 1) or ritodrine (beta 2), enhanced the amplitude of the contractions induced by electrical stimulation in a concentration-dependent manner. The maximum responses were 82.6 (adrenaline), 66.2 (noradrenaline), 86.2 (isoprenaline), 34.6 (dobutamine) and 80.8% (ritodrine). The EC20 values obtained were respectively 2 nM, 0.2 microM, 0.91 nM, 3 microM and 80 nM. The administration of the alpha 1-adrenoceptor agonist, phenylephrine, also enhanced the contractile response in a concentration-dependent manner (EC20 value = 0.3 microM) and the maximum response was 64.6%, but the administration of the alpha 2-adrenoceptor agonist, clonidine, did not influence the contractile response. These data suggest the involvement of beta 2- and possibly alpha 1-adrenoceptors in the responses of these adrenoceptor agonists. 4 The selective P2-adrenoceptor antagonist ICI 118551 (3-100nM) shifted the concentration-effect curves for noradrenaline, phenylephrine and ritodrine to the right in a concentration-dependent manner.ICI 118551 (3 nM) also shifted the concentration-effect curves for adrenaline and isoprenaline to the right, but increasing the concentration of ICI 118551 did not cause any further antagonist activity until a concentration of 100 nM, when a further rightward shift was obtained.5. The selective alpha 1-adrenoceptor antagonist, prazosin (30-300 nM), did not affect the increased contractile responses induced by adrenaline, noradrenaline, phenylephrine, isoprenaline or ritodrine.6. In conclusion, it appears that beta2-adrenoceptors are present in the striated muscle portion of the canine oesophagus, where they mediate an enhancement of contractile responses evoked by electrical stimulation. The alpha l-agonist, phenylephrine, appears to interact with beta2-adrenoceptors on this preparation.beta 3-Adrenoceptors have already been demonstrated in smooth muscle from various parts of the gastrointestinal tract, and our study does not exclude the possibility that there is an additional population of beta 3-receptors in the canine striated muscle part of the oesophagus.

Influence of rhein anthrone on peristaltic reflex of guinea-pig isolated ileum: involvement of prostaglandins.

1 The influence of rhein anthrone on the peristaltic reflex was studied with a modified Trendelenburg technique in a range from 10(-8) M to 4 x 10(-5) M, on a normal and reversed guinea-pig ileum segment. Rhein anthrone had no significant effects on longitudinal muscle tension, intraluminal pressure or volume displacement when tested on the normal segment in doses up to 10(-5) M. When applied to the mucosal side (reversed segment), rhein anthrone produced a dose-dependent increase of longitudinal muscle tension (significant from 10(-7) M), of intraluminal pressure (significant from 3 x 10(-6) M) and of volume displacement (significant from 10(-7) M). The data show that rhein anthrone possesses in vitro activity which is dependent on contact with the mucosa. 2 The action of rhein anthrone on the reversed segment was inhibited by BW755C (a dual inhibitor of cyclo-oxygenase and lipoxygenase), by indomethacin and by SC19220 (an antagonist of prostaglandin E2 (PGE2) and PGF2 alpha). The effects remaining on longitudinal muscle tension, intraluminal pressure and volume displacement, calculated as percentage (mean +/- s.e.mean) of the initial value, were respectively: 13 +/- 8; 23 +/- 13; 112 +/- 5 for BW755C; 66 +/- 19; 51 +/- 8; 53 +/- 8 for indomethacin and 27 +/- 12; 13 +/- 7; 50 +/- 5 for SC19220. It is concluded that arachidonic acid metabolites, especially PGE2 and PGF2 alpha are involved in the effects of rhein anthrone on the reversed segment.

Effect of radiation therapy after radical prostatectomy on serum prostate-specific antigen measured by an ultrasensitive assay.

OBJECTIVES: To study prospectively the impact of adjuvant radiation therapy on the serum level of prostate-specific antigen (PSA), as measured by an ultrasensitive Yang Proscheck assay in patients with detectable serum PSA and a negative metastatic survey after radical prostatectomy for T1 or T2 prostate cancer. METHODS: Seventeen patients had a detectable serum PSA (2.40 +/- 2.1 ng/mL; range, 0.5 to 10) by the Yang polyclonal assay 2 to 71 months after radical prostatectomy for P2N0 (2 patients) or P3N0 (15 patients) prostate cancer. Metastatic workup (bone and computed tomography scan) was negative; 9 of 17 patients had a local recurrence documented by a positive biopsy of the vesicourethral anastomosis. All patients were treated by external radiotherapy, receiving 65 Gy on the prostate fossa over 5 weeks for an assumed low volume residual disease. Patients were followed up by determination of serum PSA every 3 months, using the Yang ultrasensitive assay for a mean duration of 14.4 months. RESULTS: In 17.6% of the patients (3 of 17) PSA became undetectable (less than 0.05 ng/mL) after radiotherapy. Radiotherapy had no impact on PSA in 35.3% (6 of 17). PSA decreased after radiation therapy within 6 months in 47.1% (8 of 17) and for up to 12 months in 2 patients, with a nadir of 0.28 ng/mL. All patients in this group experienced a secondary rise in PSA a mean of 10.6 months (range, 6 to 18 months) after radiotherapy. CONCLUSIONS: External radiotherapy has a limited impact on residual disease after radical prostatectomy, as assessed by its impact on PSA.

Systematic biopsies accurately predict extracapsular extension of prostate cancer and persistent/recurrent detectable PSA after radical prostatectomy.

OBJECTIVES: To determine if methodic analysis of systematic echo-guided biopsies associated with prostatic-specific antigen (PSA) and PSA density can accurately predict the actual pathologic stage of prostate cancer (Ca P). METHODS: One hundred patients with clinically localized (T1, T2) Ca P who underwent radical prostatectomy (RP) were preoperatively staged by digital rectal examination (DRE), measurement of serum PSA (Yang Pros-check) and PSA density (PSAD), and transrectal echo-guided systematic biopsies (three in each lobe aiming to sample prostatic capsule) to evaluate T stage, Gleason grade, number of positive biopsies, and presence of cancer in the periprostatic tissues. Radical prostatectomy specimens were processed following the McNeal method. The PSA levels were measured every month for 2 years. RESULTS: Extracapsular disease was detected on the specimen in 45% of the patients, persistent/recurrent detectable PSA in 47% (mean follow-up 18 months). Clinical stage T2 B, presence of Gleason grade 4, PSA > 25 ng/mL, PSAD > 0.6, number of positive biopsies > 66% of the total number of cores taken had a positive predictive value (PPV), respectively, of 72%, 66%, 80%, and 87%. Periprostatic tissue was evaluable on the core biopsies in 77% of the cases. Presence of cancer in the periprostatic fat on the core biopsies had a PPV of 94% for extracapsular disease/biological recurrence. CONCLUSIONS: The presence of extracapsular cancerous tissue on prostatic core biopsies accurately predicts extracapsular extension of Ca P. Therefore, care should be taken when performing prostate biopsies to sample the prostate capsule and surrounding tissues to obtain a more accurate staging of the disease. The second best predictor of extracapsular disease is the percentage of positive biopsies.