Systematic review: ageing and gastro-oesophageal reflux disease symptoms, oesophageal function and reflux oesophagitis

Background Gastro‐oesophageal reflux disease (GERD) is thought to become more prevalent with age. Aim To assess systematically how age affects the prevalence of GERD and its oesophageal complications. Methods Systematic PubMed searches were used to identify population‐based studies on the age‐related prevalence and incidence of GERD, and clinical studies on age‐related changes in oesophageal complications in GERD. Results Nine population‐based studies and seven clinical studies met the inclusion criteria. Four of seven prevalence studies observed no significant effect of age on GERD symptom prevalence, two did not report on statistical significance and one observed a significant age‐related increase in symptom prevalence. The two population‐based endoscopic surveys showed no significant effect of age on reflux oesophagitis prevalence. Clinical studies in patients with GERD showed an increase in reflux oesophagitis severity and a decrease in heartburn severity with age, and age‐related increases in oesophageal acid exposure and anatomical disruption of the gastro‐oesophageal junction. Conclusions Epidemiological studies do not show an increase in GERD symptom prevalence with age. However, in individuals with GERD, ageing is associated with more severe patterns of acid reflux and reflux oesophagitis; despite this, symptoms associated with GERD become less severe and more nonspecific with ageing. Thus, the real prevalence of GERD may well increase with age.     

Effects of ABT-229, a motilin agonist,on acid reflux,oesophageal motility and gastric emptying in patients with gastro-oesophageal reflux disease

AIM: The effect of ABT-229, a new macrolide with no antibacterial activity, on gastro-oesophageal reflux, oesophageal motility and gastric emptying in patients with gastro-oesophageal reflux disease was investigated. METHODS: Twenty-one patients were treated with a placebo and ABT-229 (2.5, 5 or 10 mg b.d.) in a randomized, incomplete crossover study design. Ambulatory 24-h pH manometry was performed and gastric emptying was assessed by the 13C-octanoic acid breath test on the seventh day of treatment. RESULTS: A significant decrease was found in the mean (+/- s.e.) percentage of reflux time (intra-oesophageal pH < 4) for ABT-229 5 mg b.d. and 10 mg b.d., but not for 2.5 mg b.d., compared with placebo. For ABT-229 5 mg, it was 8.5 +/- 0.5% vs. 10.7 +/- 0.7% (P < 0.038) and, for ABT-229 10 mg, it was 6.6 +/- 0.5% vs. 8.4 +/- 0.5% (P < 0.019). There were no significant differences in any of the analysed manometric parameters. In addition, the gastric half-emptying time for all doses of ABT-229 did not differ significantly from that after placebo. CONCLUSIONS: ABT-229 is able to reduce slightly, but significantly, acid reflux in patients with gastro-oesophageal reflux disease. This effect does not appear to be due to a measurable improvement in oesophageal motility or gastric emptying.     

Efficacy of a motilin receptor agonist (ABT-229) for the treatment of gastro-oesophageal reflux disease

BACKGROUND: ABT-229 is a potent motilin agonist without significant antibiotic activity. It has been shown to improve gastric emptying in humans and to increase lower oesophageal sphincter pressure in cats. AIM: To assess the efficacy of four different doses of ABT-229 (1.25 mg, 2.5 mg, 5 mg, 10 mg b.d.) compared to placebo in the treatment of gastro-oesophageal reflux disease, and to determine its safety in patients with gastro-oesophageal reflux disease. METHODS: In a double-blind, multicentre study, 324 patients with heartburn were randomized to receive four different doses of ABT-229 or placebo for 8 weeks. The efficacy was evaluated by Patient Symptom Questionnaire, daily diary, endoscopy and global evaluation of efficacy. RESULTS: There were no statistically significant improvement scores for any of the ABT-229 treatment groups vs. the placebo group in any of the efficacy parameters. Reflux symptom scores were significantly worse after treatment in the dyspeptic group. ABT-229 appeared to be well tolerated and safe in total daily doses up to 20 mg. CONCLUSION: ABT-229 appears to have limited, if any, clinical utility in the treatment of gastro-oesophageal reflux disease.     

Effects of 5-HT(4) receptor agonist prokinetic agents on the action potential parameters of isolated rabbit myocardium

The effects of TS-951, a novel gastrointestinal prokinetic agent with 5-HT(4) receptor agonistic action, on the action potential parameters of isolated rabbit Purkinje fiber, ventricular muscle and sinoatrial node, and on the spontaneously beating rates of isolated rabbit right atria were compared with those of cisapride. TS-951 had no effect on the action potential parameters in both rabbit Purkinje fiber and ventricular muscle preparations. However, cisapride significantly prolonged action potential duration (APD) in both preparations. Both TS-951 and cisapride produced a negative chronotropic effect in rabbit right atria; TS-951 and cisapride at 3 x 10(-5) mol/l reduced the beating rate by about 20 and 40%, respectively. In the sinoatrial node preparations, TS-951 (3 x 10(-5) mol/l) as well as cisapride (10(-6) mol/l) prolonged cycle length and APD and reduced the diastolic depolarization rate. These results indicate that TS-951 does not appear to possess electrophysiological features leading to cardiotoxicity such as QT prolongation and, thus, torsades de pointes in common with cisapride.     

Solid form selection of zwitterionic 5-HT4 receptor agonist

From discovery synthesis of a zwitterionic pharmaceutical compound, 4-{[4-({[(3-isopropyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)carbonyl]amino}methyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-carboxylic acid (compound A), two anhydrous ZW-I and ZW-II and two hydrate forms ZW-III and ZW-IV were identified. Although stable form ZW-I was chemically stable at 70 °C/75% RH for 10 days, it was transformed to hydrate form ZW-IV under ambient conditions within a few days, taking up water from atmospheric moisture. In order to select a solid form for further investigation, solid-state characterization, salt screening on 96-well plate, stable polymorph and hydrate screening and physical stability were performed. Based on the results of the salt screening, besylate, camsylate, hemi-edisylate, hemifumarate, monosuccinate salts of compound A were prepared, and their polymorphism and chemical and physical stability were evaluated. From the viewpoint of stability and manufacturability, a stable form of besylate salt (BSA-I), which had two anhydrous forms BSA-I and BSA-II and hydrate form BSA-III, was selected as a solid form. BSA-I was quite stable at high relative humidity and provided significant improvement of physical stability compared with ZW-I.     

Clinical pharmacokinetics of tegaserod,a serotonin 5-HT(4) receptor partial agonist with promotile activity

Tegaserod, a selective serotonin (5-hydroxytryptamine; 5-HT) 5-HT(4) receptor partial agonist, is indicated in patients with irritable bowel syndrome (IBS) who identify abdominal pain or discomfort and constipation as their predominant symptoms. Tegaserod at dosages of 1 to 12 mg/day exerts pharmacodynamic actions in the upper and the lower gastrointestinal tract, accelerating small bowel and colonic transit in patients with IBS. Tegaserod is rapidly absorbed following oral administration; peak plasma concentrations (C(max)) are reached after approximately 1 hour. Absolute bioavailability is about 10% under fasted conditions. Food reduces the bioavailability of tegaserod by 40 to 65% and the C(max) by 20 to 40%. Systemic exposure to tegaserod is not significantly altered at neutral gastric pH compared with the fasted state (pH 2). Tegaserod is approximately 98% bound to plasma proteins, primarily to alpha(1)-acid glycoprotein, and has a volume of distribution at steady-state of 368 +/- 223L. Tegaserod is metabolised mainly via two pathways. The first is a presystemic acid-catalysed hydrolysis in the stomach followed by oxidation and conjugation which produces the main metabolite of tegaserod, 5-methoxyindole-3-carboxylic acid glucuronide (M 29.0). This metabolite has negligible affinity for 5-HT(4) receptors and is devoid of promotile activity. The second is direct glucuronidation which leads to generation of three isomeric N-glucuronides. The plasma clearance of tegaserod is 77 +/- 15 L/h, with an estimated terminal half-life of 11 +/- 5 hours following intravenous administration. Approximately two-thirds of the orally administered dose of tegaserod is excreted unchanged in faeces, with the remainder excreted in urine, primarily as M 29.0. The pharmacokinetics of tegaserod are dose-proportional over the range 2 to 12mg given twice daily for 5 days, with no relevant accumulation. The pharmacokinetics of tegaserod in patients with IBS are comparable to those in healthy individuals, and similar between men and women. No dosage adjustment is required in elderly patients or those with mild to moderate hepatic or renal impairment. Tegaserod should not be used in patients with severe hepatic or renal impairment. No clinically relevant drug-drug interactions with tegaserod have been identified. In vivo drug-drug interaction studies with theophylline [a cytochrome P450 (CYP) 1A2 prototype substrate], dextromethorphan (a CYP2D6 prototype substrate), digoxin, warfarin and oral contraceptives have indicated no clinically relevant interactions and no requirement for dosage adjustment.     

The effect of motilin agonist ABT-229 on gastro-oesophageal reflux, oesophageal motility and lower oesophageal sphincter characteristics in GERD patients

BACKGROUND: ABT-229, a motilin agonist without antibacterial activity, has been shown to enhance both lower oesophageal sphincter pressure in cats and gastric emptying in humans. AIM: To investigate the effect of oral treatment with ABT-229 10 mg b.d., ABT-229 5 mg b. d. and cisapride 10 mg q.d.s. on gastro-oesophageal reflux, lower oesophageal sphincter pressure, transient lower oesophageal sphincter relaxations and symptoms in GERD patients. METHODS: Twenty-four GERD patients completed the study. A randomized, double-blind, placebo-controlled, three-period incomplete crossover design was used with three dosing periods of 7 days. All patients received ABT-229 10 mg b.d. and placebo during two of the three periods. In the remaining period 12 patients were given ABT-229 5 mg b.d. and 12 received cisapride 10 mg q.d.s. Ambulatory 24 h recordings of oesophageal pH and pharyngeal, oesophageal, lower oesophageal sphincter and gastric pressures were performed on day 7 using an assembly incorporating a Dent sleeve connected to a portable water-perfused manometric system. RESULTS: Oesophageal acid exposure was not affected by ABT-229 or cisapride, but the incidence of reflux episodes was reduced by cisapride. None of the drugs affected oesophageal motility, lower oesophageal sphincter pressure or the incidence of transient lower oesophageal sphincter relaxations. Both ABT-229 10 mg b.d. and cisapride reduced the severity of daytime heartburn. CONCLUSION: The value of ABT-229 in the treatment of GERD appears to be limited.     

The effect of baclofen on gastro-oesophageal reflux,lower oesophageal sphincter function and reflux symptoms in patients with reflux disease

BACKGROUND: Baclofen decreases gastro-oesophageal reflux episodes in healthy subjects by reducing the incidence of transient lower oesophageal sphincter relaxations. AIM: To investigate the effect of baclofen on reflux symptoms, oesophageal pH and lower oesophageal sphincter manometry in patients with gastro-oesophageal reflux disease. METHODS: A double-blind, placebo-controlled, two-way crossover design was used to study the effect of baclofen on heartburn and regurgitation 3 h after a provocation test meal in 37 patients with gastro-oesophageal reflux disease. Additionally, in 20 of these patients, the effect of baclofen on oesophageal pH, transient lower oesophageal sphincter relaxations and basal lower oesophageal sphincter pressure was studied. RESULTS: Baclofen significantly decreased the acid reflux time and the incidence of gastro-oesophageal reflux episodes (8.3 +/- 8.8% vs. 12.4 +/- 12.0%, P = 0.03 and 10.9 +/- 7.3 per 3 h vs. 18.7 +/- 12.4 per 3 h). The incidence of transient lower oesophageal sphincter relaxations was significantly lower with baclofen than with placebo (15.1 +/- 6.4 per 3 h vs. 22.8 +/- 5.4 per 3 h, P < 0.0001). Lower oesophageal sphincter pressure and the percentage of transient lower oesophageal sphincter relaxations associated with reflux were not affected by baclofen. No significant effect on symptom scores was observed. CONCLUSIONS: Baclofen decreases post-prandial acid reflux in patients with gastro-oesophageal reflux disease by reducing the incidence of transient lower oesophageal sphincter relaxations. No effect of a single dose of baclofen on reflux symptoms could be demonstrated in this 3-h post-prandial study.     

Influence of the 5-HT(2C) receptor antagonist SB242,084 on behaviour produced by the 5-HT(2) agonist Ro60-0175 and the indirect 5-HT agonist dexfenfluramine

Ro60-0175 has been described as a selective agonist at the 5-HT(2C) receptor, yet it has only 10- fold higher affinity at the 5-HT(2C) compared to the 5-HT(2A) subtype, and equivalent affinity for the 5-HT(2B) receptor. The selective 5-HT(2C) receptor antagonist SB242,084 (0.5 mg kg(-1) i.p.), blocked the hypoactivity and penile grooming induced by Ro60-0175 (1 mg kg(-1) s.c.). The combination of SB242,084 (0.5 mg kg(-1) i.p.) and Ro60-0175 (3 - 10 mg kg(-1)) produced a completely different pattern of behaviours including wet-dog shakes, hyperactivity and back muscle contractions. These latter effects were blocked by the selective 5-HT(2A) receptor antagonist MDL100,907 (0.5 mg kg(-1) i.p.), but not the 5-HT(2B) receptor antagonist SB215,505 (3 mg kg(-1) p.o.). The indirect 5-HT releaser/reuptake inhibitor dexfenfluramine (1 - 10 mg kg(-1) i.p.) produced a mild increase in locomotor activity, penile grooming, and occasional back muscle contractions and wet-dog shakes. Pre-treatment with SB242,084 (0.5 mg kg(-1)), blocked the incidence of penile grooming, and markedly potentiated both the dexfenfluramine-induced hyperactivity, the incidence of back muscle contractions, and to a lesser extent wet-dog shakes. Some toxicity was also evident in animals treated with dexfenfluramine (10 mg kg(-1))/SB242,084 (0.5 mg kg(-1)), but not in any other treatment groups. The hyperactivity and toxicity produced by the dexfenfluramine (10 mg kg(-1))/SB242,084 (0.5 mg kg(-1)) combination was replicated in a further study, and hyperthermia was also recorded. Both hyperthermia and toxicity were blocked by MDL100,907 (0.5 mg kg(-1)) but not SB215,505 (3 mg kg(-1)). An attenuation of the hyperlocomotor response was also observed following MDL100,907. These findings suggest that 5-HT(2C) receptor activation can inhibit the expression of behaviours mediated through other 5-HT receptor subtypes.     

Effects of a new type of 5-HT receptor agonist on male rat sexual behavior

8-Methoxy-2-(di-n-propylamino) tetralin (8-OMe-DPAT) and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) are two new drugs exerting selective actions on brain 5-HT neurotransmission. In the present experiments we have investigated the effects of these two drugs on male rat sexual behavior. It was found that both drugs reduce the number of intromissions preceding ejaculation and shorten the ejaculation latency. These effects are extremely pronounced and several animals ejaculate at the first intromission. In addition 8-OH-DPAT produced a slight reduction of the post-ejaculatory interval. There were no significant effects on latency to initiate copulation or in the number of mounts preceding ejaculation. Finally, sexual behavior was partly or completely restored in castrated male rats after injection with 8-OMe-DPAT or 8-OH-DPAT.     

Effects of mosapride citrate,a 5-HT4 receptor agonist,on colonic motility in conscious guinea pigs

It is known that 5-HT(4) receptors in the colon of guinea pigs show a distribution similar to that in humans. Thus, we examined the effects of mosapride citrate (mosapride) and cisapride, two 5-HT(4)-receptor agonists, on colonic motility in conscious guinea pigs implanted with force transducers. Mosapride and cisapride administered intragastrically at doses of 3 - 30 mg/kg significantly enhanced the colonic motility. The enhancing effect of mosapride was antagonized by atropine or GR113808, a 5-HT(4)-receptor antagonist, but not by methysergide, a 5-HT(1)- and 5-HT(2)-receptor antagonist; ondansetron, a 5-HT(3)-receptor antagonist; or CP-99994, a tachykinin NK(1)-receptor antagonist. In vitro receptor autoradiography showed that mosapride and cisapride inhibit the specific binding of [(125)I]-SB207710, a selective radioligand of 5-HT(4) receptors, in the colon of guinea pigs. These results suggest that mosapride enhances colonic motility through the 5-HT(4)-receptor activation in guinea pigs and may be useful for treating constipation in patients with colonic motility dysfunction.     

Effects of serotonin (5-HT)1A and 5-HT2A receptor agonists on schedule-controlled responding in rats: drug combination studies

Rationale

Indirect-acting serotonin (5-HT) receptor agonists (e.g., selective 5-HT reuptake inhibitors [SSRI]) stimulate multiple 5-HT receptors, although the role of particular receptors as well as interaction(s) among different receptors in the therapeutic effects of SSRIs is not fully understood.

Objectives

Relatively few studies have systematically examined direct-acting agonists in combination. This study examined the 5-HT_1A receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (8-OH-DPAT; 0.01?C10.0?mg/kg) and 3-chloro-4-fluorophenyl-4-fluoro-4-([(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl)-piperidin-1-yl-methanone (F13714; 0.01?C1.0?mg/kg) and the 5-HT_2A receptor agonists 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 0.32?C10.0?mg/kg) and dipropyltryptamine (DPT; 1.0?C32.0?mg/kg), alone and in combination, in rats responding under a fixed ratio schedule of food presentation.

Results

When administered alone, each drug decreased the rate of responding in a dose-related manner with the potency order being F13714?>?8-OH-DPAT?>?DOM?>?DPT. WAY100635 (5-HT_1A receptor antagonist; 0.01?C0.1?mg/kg) attenuated the rate-decreasing effects of 8-OH-DPAT and F13714 while MDL100907 (5-HT_2A receptor antagonist; 0.01?C0.1?mg/kg) attenuated the rate-decreasing effects of DOM and DPT. Dose addition analysis showed that the interaction between 8-OH-DPAT and F13714, as well as the interaction between DOM and DPT, was additive. In contrast, the interaction between 8-OH-DPAT and DOM, as well as the interaction between F13714 and DOM, was infra-additive.

Conclusions

This study shows that for some dose combinations, agonist actions at one 5-HT receptor subtype attenuate agonist actions at another 5-HT receptor subtype; thus, the combined neuropharmacological actions and therapeutic effects of indirect-acting agonists are not likely to be adequately characterized by examining in isolation activity at particular 5-HT receptor subtypes.     

The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo

1 Tegaserod (Zelnorm) is a potent 5-hydroxytryptamine4 (5-HT4) receptor agonist with clinical efficacy in disorders associated with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5-HT2 receptors, and compared its potency in this respect to its 5-HT4 receptor agonist activity. 2 Tegaserod had significant binding affinity for human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi=7.5, 8.4 and 7.0, respectively). The 5-HT2B receptor-binding affinity of tegaserod was identical to that at human recombinant 5-HT4(c) receptors (mean pKi=8.4) in human embryonic kidney-293 (HEK-293) cells stably transfected with the human 5-HT4(c) receptor. 3 Tegaserod (0.1-3 microm) inhibited 5-HT-mediated contraction of the rat isolated stomach fundus potently (pA2=8.3), consistent with 5-HT(2B) receptor antagonist activity. Tegaserod produced, with similar potency, an elevation of adenosine 3',5' cyclic monophosphate in HEK-293 cells stably transfected with the human 5-HT4(c) receptor (mean pEC50=8.6), as well as 5-HT4) receptor-mediated relaxation of the rat isolated oesophagus (mean pEC50=8.2) and contraction of the guinea-pig isolated colon (mean pEC50=8.3). 4 Following subcutaneous administration, tegaserod (0.3 or 1 mg kg(-1)) inhibited contractions of the stomach fundus in anaesthetized rats in response to intravenous dosing of alpha-methyl 5-HT (0.03 mg kg(-1)) and BW 723C86 (0.3 mg kg(-1)), selective 5-HT2B receptor agonists. At similar doses, tegaserod (1 and 3 mg kg(-1) subcutaneously) evoked a 5-HT4 receptor-mediated increase in colonic transit in conscious guinea-pigs. 5 The data from this study indicate that tegaserod antagonizes 5-HT2B receptors at concentrations similar to those that activate 5-HT4 receptors. It remains to be determined whether this 5-HT2B receptor antagonist activity of tegaserod contributes to its clinical profile.     

Tegaserod: a serotonin 5-HT4 receptor agonist for treatment of constipation-predominant irritable bowel syndrome

Activation of serotonin 5-HT(4) receptors has been proposed as treatment for irritable bowel syndrome, a common, complex and distressing gastrointestinal disorder. Abnormal intestinal motility and sensitivity in irritable bowel syndrome patients can result in diarrhea, constipation, abdominal pain, bloating, headache and fatigue; these and other symptoms can lead to exacerbation of psychological stress, which may in turn induce further physiological abnormalities and patient discomfort. The serotonin agonist tegaserod binds with high affinity to 5-HT(4) receptors and has demonstrated potent pharmacological effects on the mid- and distal gut. Tegaserod has been safely employed in clinical trials where it has demonstrated efficacy in normalizing intestinal function, thereby improving irritable bowel syndrome symptoms.     

The effect of sildenafil on segmental oesophageal motility and gastro-oesophageal reflux

BACKGROUND: Sildenafil is an inhibitor of type 5 phosphodiesterase. It relaxes or inhibits contraction of smooth muscle by increasing cellular concentrations of cyclic guanosine monophosphate. Multichannel intraluminal impedance manometry/pH allow the precise evaluation of oesophageal bolus transit and acid/non-acid reflux. AIM: To investigate the effect of sildenafil on segmental oesophageal motor function and gastro-oesophageal reflux. METHODS: Eight healthy volunteers underwent multichannel intraluminal impedance manometry baseline, and 15, 30 and 45 min before and after a 50-mg dose of sildenafil successively. The subjects underwent 2-h multichannel intraluminal impedance/pH studies on two separate days after either water or sildenafil ingestion. RESULTS: Sildenafil decreased the resting lower oesophageal sphincter pressure and prolonged the duration of lower oesophageal sphincter relaxation for the 45 min following its ingestion. At 15 min, distal onset velocity, total bolus transit time, bolus presence time and segmental transit time were delayed in the mid to distal oesophagus. At 30 min, distal onset velocity was restored but bolus presence time and bolus presence time were still delayed in distal smooth muscle segment. At 45 min, total bolus transit time and distal onset velocity were restored but bolus presence time and segmental transit time were delayed more in the transition zone. Sildenafil did not alter the reflux. CONCLUSION: Sildenafil alters lower oesophageal sphincter function and oesophageal bolus transit, but not induce gastro-oesophageal reflux.     

Full substitution of the discriminative cue of a 5-HT(1A/1B/2C) agonist with the combined administration of a 5-HT(1B/2C) and a 5-HT(1A) agonist

The present study examined whether animals attend to the individual components of the cue produced by a drug that stimulates different 5-hydroxytryptamine (5-HT) receptor populations, using a drug discrimination task based on the conditioned taste aversion (CTA) procedure. The training drug was indorenate (5-methoxytryptamine beta-methylcarboxylate) (INDO) that has been described as a 5-HT(1A/2C/1B) agonist able to exert discriminative control in both operant and CTA procedures. The principal objective was to examine generalization with the combined administration of agonists for the different receptor sites that may mimic the mechanism of action of the training drug. Male Wistar rats, deprived of water, were trained to discriminate INDO from saline; during the drug trials, the administration of INDO preceded saccharin-LiCl pairings, while, during the saline trials, the administration of saline preceded the saccharin-saline pairings. In generalization tests, INDO, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT(1A) agonist), 1-(3-trifluoromethylphenyl)piperazine (TFMPP, a 5-HT(1B) agonist), alpha-methyl-5-HT (a 5-HT(2C) agonist) or 2-methyl-5-HT (a 5-HT(3) agonist), were administered alone or in combination. The results showed that 8-OH-DPAT, TFMPP and alpha-methyl-5-HT produced dose-dependent generalization, up to 88% in the case of 8-OH-DPAT. The combined administration of the following pairs of drugs, 8-OH-DPAT+TFMPP or 8-OH-DPAT+ alpha-methyl-5-HT, at doses that produced only 15-55% generalization when administered alone, produced greater than 80% generalization to INDO. However, the single administration of 2-methyl-5-HT produced only saline-like responding and its combined administration with 8-OH-DPAT did not modify the generalization produced by the single administration of 8-OH-DPAT. These results suggest that animals attend to the individual components of the drug cue; in the case of INDO, which has three elements, each mediated by a different receptor subpopulation (5-HT(1A), 5-HT(1B) and 5-HT(2C) ), the separate stimulation of at least two receptor subpopulations was 'interpreted' by the subject as the presence of the training drug.     

Restraint accentuates the effects of 5-HT2 receptor antagonists and a 5-HT1A receptor agonist on lordosis behavior

The effect of restraint on lordosis behavior was examined in proestrous and ovariectomized, hormone-primed rats. Restraint durations from 5 to 60 min had no effect on lordosis behavior of proestrous rats. There was also no effect of 5 min restraint on lordosis behavior of ovariectomized rats hormonally primed with 10 microg estradiol benzoate and 500 microg progesterone. However, after intraperitoneal treatment with 1.0 mg/kg ketanserin tartrate (ketanserin), 5 min of restraint significantly reduced lordosis behavior of both groups of rats. The 5-min restraint combined with 0.50 or 0.75 mg/kg ketanserin reduced lordosis to mount (L/M) ratios of ovariectomized rats, while L/M ratios of proestrous rats were inhibited only by the 1.0 mg/kg dose. Increasing the restraint duration (10 or 15 min) reduced the dose of ketanserin necessary to reduce the L/M ratios of proestrous rats. Treatment with the selective serotonin (5-HT)(2C) receptor antagonist, SB206553 (2.5 or 5.0 mg/kg), in combination with 5 min of restraint, also reduced L/M ratios of hormonally primed, ovariectomized rats. The neural sites responsible for ketanserin's additivity with restraint are unknown, but infusion of the drug into the ventromedial nucleus of the hypothalamus (VMN) did not mimic the systemic treatment. However, 5 min of restraint did enhance the effects of VMN infusion with the 5-HT(1A) receptor agonist, 8-OH-DPAT. In contrast, 8-OH-DPAT's systemic potency was not enhanced by restraint. These findings support the hypothesis that a mild stressor increases the lordosis-inhibiting effects of 5-HT(1A) receptor agonists and that 5-HT(2) receptors may protect against such disruption of lordosis behavior.     

The effects of tegaserod (HTF 919) on oesophageal acid exposure in gastro-oesophageal reflux disease

BACKGROUND: Tegaserod (HTF 919), a 5-HT4 receptor partial agonist, has prokinetic effects that might be useful in decreasing acid reflux in gastro-oesophageal reflux disease (GERD). METHODS: To investigate the potential clinical utility of tegaserod in GERD, a five-period crossover study (balanced Latin square) was designed to evaluate the efficacy of 4 b.d. doses of tegaserod vs. placebo. Four-hour manometry (1 h fasting and 3 h postprandial) with continuous recording of lower oesophageal sphincter pressure and distal oesophageal pH, was performed at the end of each 2-week treatment period in 19 patients with mild-to-moderate GERD. Recordings were scored for mean lower oesophageal sphincter pressure, number of transient lower oesophageal sphincter relaxations, and distal oesophageal acid exposure. RESULTS: Tegaserod (1 mg/day and 4 mg/day) caused a more than 50% decrease in acid exposure in the postprandial period in patients with abnormal acid exposure, although only the 1 mg/day tegaserod treatment elicited statistically significant decreasing (P < 0.05) for the entire treatment group (percentage time for which pH < 4: placebo=13%; 1 mg/day dose=5%; 4 mg/day dose=8%). A decreased number of reflux episodes was demonstrated with both the 1 mg/day and 4 mg/day tegaserod doses. There was no apparent effect on mean lower oesophageal sphincter pressure, whilst transient lower oesophageal sphincter relaxations frequency decreased in the 1-2.5 h post-dose. CONCLUSIONS: Tegaserod in a dose of 1 mg/day causes a significant decrease in postprandial oesophageal acid exposure. The reduction in oesophageal acid exposure with tegaserod treatment may result from enhanced oesophageal acid clearance, improved gastric emptying, and/or reduced transient lower oesophageal sphincter relaxations.     

Tegaserod: a new 5-HT(4) agonist in the treatment of irritable bowel syndrome

Tegaserod is a selective partial agonist acting on serotonergic type 4 receptors (5-HT(4)). Pharmacodynamic studies indicate that tegaserod is able to stimulate gut propulsion and secretion with a net prokinetic effect. In contrast to other 5-HT(4) agonists endowed with a complex pharmacological profile, tegaserod has a reliable prokinetic activity in the colon. Clinical trials show that tegaserod is effective and safe in the treatment of patients with irritable bowel syndrome. In particular, tegaserod relieves symptoms of abdominal pain, discomfort, abdominal bloating and constipation.