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Alimentary Pharmacology & Therapeutics Review article: a critical view on impaired accommodation astherapeutic target for functional dyspepsia B . D . J . V A N D E N E L Z E N & G . E . E . B O E C K X S T A E N S Several important pathophysiological mechanisms have been identifiedin functional dyspepsia, however a complete understanding of these mechanisms and beneficial therapeutic strategies are still lacking. Based on the currently available literature we aimed at providing a critical view on one of these pathophysiological mechanisms, impaired accom- Although impaired gastric accommodation is identified as a major pathophysiological mechanism, the clinical evidence supporting its role as an important therapeutic target is currently still lacking. Treatment with fundic relaxant drugs has shown conflicting results and has been These negative findings could be explained by the fact that impaired fundic accommodation is part of a more complex disorder involvingother regions of the proximal gut or by the increasing insight that cen-tral mechanisms may play an important role. Future studies of impairedaccommodation should take these considerations into account.
Journal compilation ª 2006 Blackwell Publishing Ltddoi:10.1111/j.1365-2036.2006.02930.x 1500 B . D . J . V A N D E N E L Z E N A N D G . E . E . B O E C K X S T A E N S With the introduction of the barostat, it became possible to study subtle changes in tone, either in Functional dyspepsia (FD) is a common disorder char- response to meal intake or to a pharmacological agent.
acterized by persistent or recurrent pain or discomfort The first studies in dogs revealed that soon after meal centred in the upper abdomen without evidence of intake, the proximal stomach relaxes creating a reser- organic disease likely to explain the symptoms.1 A voir for the ingested food. As gastric emptying pro- broad variety of symptoms such as fullness, bloating, gresses, fundic tone recovers, returning to its basal early satiety, epigastric pain, nausea, weight loss, value.18, 19 Vagal cooling abolishes gastric relaxation belching and vomiting have been reported by patients illustrating that this motor pattern is vagally medi- with FD. Although symptoms can occur at any time, ated.20 In addition, in man, meal ingestion results in a patients often relate the onset or aggravation of their prolonged relaxation of the proximal stomach.15, 21–24 This relaxation is mimicked not only by distension of Several pathophysiological mechanisms underlying the duodenum and antrum, but also by infusion of FD such as delayed gastric emptying,5, 6 abnormal nutrients in the duodenum. These findings indicate antroduodenal motility,7, 8 altered sensitivity to duode- that both distension of the antrum and the duodenum nal lipid or acid exposure,9–11 visceral hypersensitiv- by the meal and activation of vagal afferents by nutri- ity12, 13 and impaired fundic accommodation14, 15 have ents in the duodenum contribute to create a reservoir been identified. However, the current knowledge of for the meal by relaxing the proximal stomach.18, 25 these pathophysiological mechanisms has not led to a As such, food will preferentially remain in the prox- complete understanding of FD. Furthermore, attempts to imal stomach preventing filling of the antrum and the develop therapeutic strategies based on this knowledge have thus far not banned dyspepsia from our midst.
Basal gastric tone is maintained by a balance Together with visceral hypersensitivity and delayed between cholinergic excitatory activity and non-adr- gastric emptying, impaired accommodation is the most energic non-cholinergic inhibitory input. The inhibi- frequently observed pathophysiological mechanism in tion of basal gastric tone is predominantly regulated patients with FD. All three mechanisms have inde- by vagal inhibitory input which stimulates the release pendently been reported in approximately 40% of the of nitric oxide (NO) as principle neurotransmitter at functional dyspeptic patients.2–4 In this paper we aim the neuromuscular junction. Animal studies have con- at providing a critical view of the current knowledge sistently shown that basal tone is decreased by vagal regarding one of these pathophysiological mechanisms stimulation and that this effect is blocked by the spe- involved in FD, namely impaired fundic accommoda- cific NO inhibitor, NG-nitro-L-arginine (L-NNA).26, 27 tion and its potential as a therapeutic target in the The use of another NO inhibitor, N-G-monomethyl-L- arginine (L-NMMA), confirmed the involvement of NOin gastric relaxation in humans.28, 29 The gastricaccommodation to a meal can be mimicked by phar- macological interventions. This can be achieved by sti- Gastric relaxation in response to meal intake was first described by Cannon and Lieb16 almost a century ago.
neurones (sumatriptan)30, 31 or by administration of This gastric accommodation response reduces meal- NO donors such as nitroglycerine.32, 33 Second, reduc- induced increase in gastric pressure and might thus tion in the cholinergic input, as shown for clonidine33 impair the development of dyspeptic symptoms. Gas- will also lead to a reduction in tone, a mechanism that tric accommodation consists of two types of relaxa- has been advocated to be useful in improving meal- relaxation. The receptive relaxation is triggered byactivation of pharyngeal and oesophageal mechanore- ceptors. When the bolus reaches the stomach, the gas- relaxation, which modulates gastric tone in response The first indication of impaired gastric accommodation to specific nutrients.17 Both reflexes contribute indis- in FD patients was derived from scintigraphic and tinguishably to the gastric accommodation response.
ultrasound studies.22, 34 These studies observed an ª 2006 The Authors, Aliment Pharmacol Ther 23, 1499–1510Journal compilation ª 2006 Blackwell Publishing Ltd R E V I E W : I M P A I R E D G A S T R I C A C C O M M O D A T I O N abnormal intragastric distribution of food in FD tes mellitus. Several studies have indicated that the patients with accumulation of the meal in the distal gastric accommodation reflex is hampered in patients stomach. Later, barostat studies revealed that the with diabetic neuropathy.42, 43 Animal studies revealed relaxation of the proximal stomach to meal intake is that one possible mechanism is impaired NOS expres- impaired in approximately 40% of the patients with FD.15, 35 Furthermore, the relaxation of the proximal Another possible underlying mechanism leading to stomach to distension of the antrum and infusion of impaired accommodation is abnormal vagal input to nutrients in the duodenum is impaired in a subgroup the nitrergic neurones. Disturbed vagal efferent func- of FD patients.36 This impaired accommodation of the tion, as evidenced by altered respiratory sinus dys- proximal stomach will lead to an abnormal meal dis- rhythmia or diminished pancreatic-polypeptide release tribution, as observed in the earlier scintigraphic and in response to the insulin-induced hypoglycaemia test ultrasound studies,22, 34 with increased filling of the has been reported in FD patients.45–48 In diabetic distal stomach. Especially as the antrum of patients patients, vagal tone was significantly correlated with with FD is hypersensitive to distension,36 impaired the maximal postprandial volume response,42, 49 fur- accommodation may significantly contribute to the ther corroborating to a possible role of altered vagal development of meal-induced symptoms. Tack et al.
input in impaired accommodation. Abnormal activa- indeed showed that the prevalence of early satiety and tion of duodenal vagal afferents by either nutrients or weight loss is significantly greater in patients with local release of hormones may also lead to impaired impaired accommodation and that the impaired caloric activation of the motor response. FD patients indeed intake in these patients can be increased by pretreat- have a less pronounced fundic relaxation in response to duodenal nutrients.36, 50 On the other hand, abnor-mal exposure of the duodenum to acid51 leads to ablunted meal-induced relaxation in healthy volunteer (HV). This finding together with the observation that duodenal acid clearance in FD is impaired, points Although impaired gastric accommodation is consid- towards a role for duodenal acid in an abnormal ered an important pathophysiological mechanism in motor response of the proximal stomach to meal the development of FD, surprisingly little is known intake.52 Finally, an abnormal response to the arrival about the aetiology of impaired gastric accommoda- of lipids in the duodenum has also been suggested to tion. Theoretically, gastric accommodation can be play an important role in the generation of dyspeptic hampered at any level of the reflex arc, both at the symptoms.9, 25 Duodenal lipids relax the proximal afferent and efferent arm of the pathway, including stomach, but to a lesser extent in patients with FD.50 Future studies are certainly warranted to further clar-ify their role in the gastric accommodation response.
A more detailed review on the role of food in the pathogenesis of FD is reported elsewhere.2 One plausible mechanism leading to impaired gastricaccommodation is neuronal damage of the enteric neurones, either postinfectious or as part of the pro-gression of a systemic disease such as diabetes. Similar The efferent output of the vagal nerve is determined to other functional gastrointestinal disorders such as by the motor neurones in the dorsal vagal complex.53 the irritable bowel syndrome and gastroparesis,37–40 These neurones can be stimulated by microinjection of FD has been associated with acute intestinal infections L-glutamate, one of the main afferent neurotransmit- in 17% of patients.41 Tack et al. clearly illustrated that ters released in the brain stem, resulting in pro- impaired accommodation is significantly more preval- nounced gastric relaxation in mice.54 The dorsal motor ent in patients with presumed postinfectious dyspepsia nucleus of the vagal nerve not only receives afferent compared with unspecified-onset dyspepsia (67% vs.
information from the nucleus tractus solitarius (NTS).
30%; P < 0.05),41 most likely resulting from dysfunc- It also receives input from the locus coeruleus, the tion of the nitrergic neurones.41 Neuronal damage can also be afflicted by a systemic disorder such as diabe- and the anterior cingulate cortex,55 brain regions ª 2006 The Authors, Aliment Pharmacol Ther 23, 1499–1510Journal compilation ª 2006 Blackwell Publishing Ltd 1502 B . D . J . V A N D E N E L Z E N A N D G . E . E . B O E C K X S T A E N S important for regulation of arousal, emotions and auto- manner, and (ii) what is the clinical evidence that nomic or behavioural responses.56–58 At this level, impaired accommodation indeed represents an import- stress and emotions can significantly alter the auto- nomic output. It therefore seems plausible that stress oranxiety affects the vagal output to the stomach leading HO W T O S E L E C T PA T IE N T S W I T H I M P AI RE D to impaired gastric accommodation. Recent studies indeed show that experimentally induced anxietyresults in impaired meal-induced accommodation in At present, the gold standard to detect impaired gastric HV.59, 60 However, this finding needs to be confirmed accommodation is the gastric barostat, a computerized in studies with FD patients. A more detailed review of pump that measures volume changes under constant this issue is provided by Van Oudenhove et al.61 pressure in an intragastric balloon.62 This procedure ishowever invasive and stressful and above all, the pres-ence of the balloon interferes with normal gastric physiology.63, 64 Therefore, the use of other diagnostic tools to study proximal and distal stomach function The clinical relevance of impaired gastric accommoda- tion as a pathophysiological mechanism in FD wasfirst impaired accommodation is present in a substantialproportion of FD patients, is associated with early sati- As impaired accommodation has been associated with ety and weight loss, and gastric relaxation improved early satiety,15 one option would be to select patients drinking capacity in a small group of FD with based on symptoms. Tack et al. indeed provided evi- impaired accommodation.15 These considerations make dence that increasing severity of early satiety was impaired gastric accommodation an important thera- accompanied by lower tolerated nutrient drink vol- peutically target and have been the trigger to develop umes, which in turn predicted the presence of impaired new pharmacological agents aiming at relaxing the accommodation.65 Other investigators however fail to illustrate such a relationship. Bredenoord et al. conclu- Although the concept of improving gastric accom- ded that symptoms alone cannot predict physiological modation is very appealing, there are still some very disturbances such as gastric accommodation or empty- important unsolved practical issues for the clinician.
ing in patients with unexplained upper gastrointestinal First, if treatment aims at restoring fundic accommo- symptoms. Similarly, we were unable to find a rela- dation, ideally one should be able to select those tionship between symptoms and proximal stomach patients who will benefit most, i.e. patients with function. Conversely, the symptom profile evoked by a impaired accommodation. In most studies reported so drink test is comparable in FD patients with impaired far, abnormal proximal stomach function has been accommodation or visceral hypersensitivity.35 These identified by barostat studies. However, as this tech- findings, together with the fact that FD presents with a nique is time consuming, and above all invasive, it is variety of symptoms4, 35 imply that the clinician can- simply impossible to subject all patients to a barostat.
not simply rely on presenting symptoms to predict Therefore, noninvasive techniques evaluating proximal whether or not a patient may benefit from fundic stomach function are certainly required to replace the barostat. Second, although there are several argumentsto accept that impaired fundic relaxation is associated with FD, we still have no real proof of the conceptthat correction of impaired fundic relaxation leads to Recently, a drink test was suggested as a noninvasive improvement of symptoms in patients with FD. Indi- alternative to the barostat to detect impaired accom- rectly this may question the importance of impaired modation. Tack et al. showed a good correlation accommodation as an important therapeutic target. In between a nutrient drink test at a rate of 30 mL/min the following part of this review, we addressed these and impaired accommodation as measured by the bar- two important issues: (i) How can we select patients ostat in FD patients (r ¼ 0.71, P < 0.001) (Figure 1a).
with impaired fundic accommodation in a noninvasive At a cut-off of 400 kcal, the sensitivity and specificity ª 2006 The Authors, Aliment Pharmacol Ther 23, 1499–1510Journal compilation ª 2006 Blackwell Publishing Ltd R E V I E W : I M P A I R E D G A S T R I C A C C O M M O D A T I O N Figure 1. (a) Relationship between the maximal ingested volume with a 30-mL/min drink test and meal-induced accommo-dation. A significant correlation was found (r ¼ 0.76, P < 0.01)65 (with kind permission from BMJ Publishing Group).
(b) Individual data showing the relationship between the postprandial fundic accommodation and the maximal ingestedvolume of water and Nutridrink with a 100-mL/min drink test in HV (d), MS (h) and FD (n). No significant correlationwas found66 (with kind permission from American Gastroenterological Association). It is suggested that the discrepancybetween these results derives from the difference in drinking speed (30 mL/min vs. 100 mL/min). With the rapid drink testpatients reach their maximum drinking capacity before reaching the maximal accommodation volume,67 whereas the slowdrink test is more likely to be affected by gastric emptying.66 of a slow nutrient drink test in predicting impaired the rapid drink test was inappropriately timed as accommodation were 92% and 86% respectively.
patients reached their maximum drinking capacity However, it should be emphasized that the study pop- before reaching the maximal accommodation vol- ulation consisted of patients with severe dyspepsia of ume,67 whereas a slow drink test is more likely to be which some even had received total parental nutrition.
affected by gastric emptying.66 Nevertheless, before It remains therefore questionable to what extent this accepting the slow drink test as a noninvasive tool applies to the majority of FD. We previously showed replacing the barostat, it certainly should be validated that both the water and nutrient drink test at a rate of in the majority of patients with dyspepsia seen by the 100 mL/min are good tools to evoke dyspeptic symp- general practitioner. To date, the only study available toms and are useful to discriminate healthy volunteers addressing this issue could not demonstrate a relation- from patients with FD.35 However, with this drink test ship between the findings during the drink test when we were unable to predict impaired gastric accommo- compared with single photon emission computed dation as assessed by the gastric barostat (Figure 1b).66 tomography (SPECT) scanning.68 On the other hand, The difference between these two studies may be several studies have illustrated that it is a valuable explained by the drinking rate. It was suggested that tool to elicit symptoms in FD, and thus may be ª 2006 The Authors, Aliment Pharmacol Ther 23, 1499–1510Journal compilation ª 2006 Blackwell Publishing Ltd 1504 B . D . J . V A N D E N E L Z E N A N D G . E . E . B O E C K X S T A E N S useful to evaluate the effect of drugs on symptoms, unclarities or inconsistencies however remain in the Relationship between dyspeptic symptoms and Single photon emission computed tomography, 3-D To be considered an important therapeutically target, ultrasound and magnetic resonance imaging (MRI) are there should be a clear causal relationship between relatively new methods allowing noninvasive assess- ment of gastric volume. Due to their noninvasive nat- under study. One well-designed study in 40 FD ure, these techniques are patient friendly and provide patients showed that impaired gastric accommodation more physiological data compared with the gastric measured by gastric barostat was indeed associated barostat. Their capacity to detect volume changes with symptoms of early satiety and weight loss.15 makes them suitable to investigate the accommodation The association between early satiety and impaired response. Gilja et al. demonstrated impaired gastric accommodation was later also demonstrated in a relaxation in FD patient by ultrasound,22 whereas Kim study using planar scintigraphy, whilst a study based et al. showed that SPECT could detect an impaired on SPECT found an association with impaired accom- volume response to food ingestion in FD patients.69 modation and weight loss.69, 74 However, other stud- For an excellent review on the value of these tech- ies using a gastric barostat or SPECT could not niques to measure gastric accommodation we refer to confirm the relationship between impaired accommo- De Schepper et al.70 In contrast to the barostat, these dation and early satiety, nor could these studies techniques rather detect the volume of the intragastric establish a correlation between gastric accommoda- content after meal intake, and not gastric tone or tion and any one of the dyspeptic symptoms in 44, relaxation. We previously showed that the positive 32 and 151 FD patients respectively.35, 69, 75 Hence it pressure applied by the barostat amplifies subtle chan- remains debatable if impaired gastric accommodation ges in tone allowing better and more adequate quanti- plays a direct role in symptom generation or that fication of gastric relaxation compared with SPECT it is part of a more complex mechanism leading to imaging. This was illustrated by a lack of correlation in glucagon-induced gastric accommodation betweenSPECT scanning and the gastric barostat.71 Therefore, Inhibition of fundic relaxation should lead to in our view, these techniques are unsuitable to evalu- ate changes in gastric tone. Nevertheless, SPECT scan-ning, MRI or 3-D ultrasound are very interesting tools When impaired gastric accommodation plays a key to study other aspects of gastric function, thus provi- role in the development of dyspeptic symptoms, it ding a more physiological view on intragastric vol- should be possible to modulate dyspeptic symptoms by ume, volume distribution and on gastric emptying pharmacological substrates affecting the fundic relaxa- tion response. Indeed, Tack et al. demonstrated thaterythromycin, sumatriptan and cisapride all affecteddrinking capacity as expected based on their known I S I M P A I R E D A C C O M M O D A T I O N AN effects on fundic accommodation.15, 65 However, an I M P O R T A N T T H E R A P E U T I C T A R G E T ? increased drinking capacity does not necessarily indi- From a pathophysiological point of view, there is cate a decrease in dyspeptic symptoms as demonstra- abundant evidence to accept that impaired accommo- ted by another study where sumatriptan influenced dation may contribute to the generation of dyspeptic drinking capacity but failed to affect dyspeptic symp- toms after a drink test.35 Other studies even reported a increased fundic pressure, shown to be related to decrease in meal or fat-induced dyspeptic symptoms symptoms especially in the presence of visceral hyper- after blocking the gastric accommodation response by sensitivity.73 In addition, the meal will be pushed either L-NMMA, a NO synthase inhibitor28 or dexlox- towards the less compliant antrum leading to overfill- iglumide, a cholecystokinin (CCK) antagonist that ing and consequently dyspeptic symptoms.36 Several ª 2006 The Authors, Aliment Pharmacol Ther 23, 1499–1510Journal compilation ª 2006 Blackwell Publishing Ltd R E V I E W : I M P A I R E D G A S T R I C A C C O M M O D A T I O N Abnormal
function
Abnormal
function
Figure 2. (a) A casual relationship between an abnormal function and a symptom. Correction of the abnormal functionwould lead to symptom improvement. (b) The abnormal function as an epiphenomenon sharing a common underlyingcause with the symptoms. Correction of the abnormal function would not lead to symptom improvement.
agents on proximal stomach function has been evalu- Impaired accommodation: a pathophysiological ated. However, the evidence that these agents indeed reduce symptoms is very scarce and will be discussed In general, there are at least two ways by which symp- toms can be related to an abnormal motor patternsuch as impaired accommodation. The symptom can either be a direct result of the mechanism under studyor be indirectly related to it by sharing a common Nitric oxide has been identified as the principle neuro- underlying cause (Figure 2). In the latter, the abnormal transmitter involved in gastric relaxation.78, 79 Admin- motor pattern is not causally related to the symptom istration of NO donors relaxes the proximal stomach but should rather be considered an epiphenomenon.
in humans,32, 33 and improves accommodation of the Targeting this mechanism with pharmacological agents proximal stomach to a meal. Sublingual nitroglycerine will then consequently not lead to improvement of reduced postprandial pain and nausea scores in FD.32 symptoms. Instead, the disorder giving rise to the However, the use of NO donors is generally associated abnormal motor pattern should be corrected. For with significant side effects such as reduction in blood pressure, tachycardia and headache. Especially the lat- increasingly recognized in the aetiology of functional ter may have distracted the attention leading to lower gastrointestinal disorders.76, 77 Stress or central dys- postprandial scores. In addition, these side effects ren- function may lead to abnormal processing of visceral der this class of drugs less suitable as a treatment incoming information with increased perception, lead- option for FD. An alternative for NO donors would be ing to abnormal autonomic output and impaired effer- sildenafil, a phosphodiesterase blocker that prolongs ent vagal output. The recent finding that anxiety can the relaxant properties of NO-mediated smooth muscle impair meal-induced relaxation supports this hypothe- relaxation. Pretreatment with sildenafil relaxes the sis.59 These considerations would rather plead for cen- proximal stomach in healthy volunteers.80 However, tral acting agents instead of peripherally acting fundic whether it also restores impaired gastric accommoda- tion or improves dyspeptic symptoms remains to bedetermined.
Fundic relaxation as a treatment: the clinicalevidence Since the introduction of impaired accommodation as The role of serotonin (5-HT) as a neurotransmitter of a therapeutic target, the effect of several relaxant intrinsic neurones in the vagally mediated gastric ª 2006 The Authors, Aliment Pharmacol Ther 23, 1499–1510Journal compilation ª 2006 Blackwell Publishing Ltd 1506 B . D . J . V A N D E N E L Z E N A N D G . E . E . B O E C K X S T A E N S relaxation was first described in mouse and guinea-pig could not establish an effect of SSRIs on gastric by Bulbring and Gershon.81 5-HT1 receptor activation volumes94, 95 or fasting compliance.94, 95 In HV, i.v.
by f.e. sumatriptan relaxes the proximal stomach citalopram even inhibits gastric accommodation,96 in both animals and man by releasing NO.30, 82, 83 suggesting that effects on symptom improvement of In humans, sumatriptan induces an immediate and this type of drugs is more likely mediated by their profound relaxation of the gastric fundus15, 31, 84 and effects on the central nervous system.
patients with early satiety.15 It should be emphasized though that caloric intake during the drink test wasstill only half of the amount ingested by healthy con- Another approach to influence gastric accommoda- trols, and the effect on dyspeptic symptoms was not tion is through the sympathetic innervation. Cloni- evaluated. Other investigators failed to confirm the dine, an a2 receptor agonist, has been shown to effect of sumatriptan on meal intake in HV and FD relax the proximal stomach, enhance accommodation patients with impaired accommodation and sumatrip- and to reduce gastric sensations.33 However, the tan did not affect postprandial symptoms.35, 85 Buspi- effects on gastric accommodation were only present rone, a 5-HT1 agonist, improved meal-induced gastric at lower doses (<0.1 mg), whereas the effect on gas- accommodation in 18 FD patients and reduced meal- tric discomfort became prominent at the higher dose related symptoms by 50%.86 Buspirone however is a (0.1 mg). Other distension-evoked symptoms were potent anxiolytic drug which may have greatly contri- not affected by clonidine. Therefore, as the authors state, their data suggest a specific effect on afferent Recently, the effect of a new specific 5-HT1a receptor nociceptive pathways, rather than an effect mediated agonist R137696, shown to relax the proximal stom- by relaxation of the stomach. Similar to these find- ach of HV,87 was evaluated in a randomized placebo- ings, clonidine (0.5 mg) only improved postprandial belching in a study with eight FD patients and did however failed to improve fundic accommodation and dyspeptic symptoms.88 Tachyphylaxis or inadequate indicate that the gastric relaxant capacity of cloni- dosing may however have contributed to the negative dine is not related to an improvement in dyspeptic Other 5-HT agonists such as tegaserod, a partial 5-HT4 agonist, failed to enhance meal-induced gastric although there was a significant effect on meal- In general, the clinical evidence of a role for fundic induced gastric volume increase in a subgroup of FD relaxation as therapeutic strategy in FD is rather lim- patients with normal gastric emptying.89 A recent ited. Several factors could have contributed: one study showed a significant effect on gastric accommo- plausible explanation could be that fundic relaxant dation with tegaserod in a small group (n ¼ 12) of drugs also relax the distal stomach leading to delayed HV.91 In FD patients however, tegaserod had no gastric emptying80, 97 and an increase in antral diam- effect on gastric accommodation and showed no bene- eter.84 As mentioned earlier, antral distension is ficial effect on the satisfactory relief of dyspeptic already present in FD patients34, 98, 99 and the less compliant antrum was shown to be sensitive to disten-sion.36, 100 Sumatriptan has been shown to increaseantral area in HV84 which may perhaps explain why Selective serotonin reuptake inhibitor (SSRI) sumatriptan and R137696 had no effect on dyspeptic Based on the concept that 5-HT is involved in vagally symptoms. This would suggest that the ideal drug mediated relaxation,92 several studies focused on the should relax the proximal stomach but increase tone use of SSRI to prolong endogenous 5-HT availability in order to improve gastric accommodation. Although Other explanations include receptor tachyphylaxis paroxetine increased gastric accommodation after food or the use of inappropriate doses. Receptor tachyphy- intake, the difference between the paroxetine and pla- laxis is a well-known problem of 5-HT receptor agon- cebo group was small.93 Furthermore, other studies ists101, 102 and may well explain the negative results ª 2006 The Authors, Aliment Pharmacol Ther 23, 1499–1510Journal compilation ª 2006 Blackwell Publishing Ltd R E V I E W : I M P A I R E D G A S T R I C A C C O M M O D A T I O N after long-term use. In addition, patients with FD may relaxation, the aetiology of this pathophysiological require higher doses of the drug under study compared mechanism remains largely unknown, and both central with HV. In the R137696, application of 2 mg did not and peripheral factors may be involved. The relation- result in an increase in meal-induced accommoda- ship between dyspeptic symptoms and a pathophysio- tion,88 whereas this dose resulted in a significant logical mechanism such as impaired accommodation is obviously very complex. Although impaired gastric Finally, the weak causal relationship between dys- accommodation is identified as a major pathophysio- peptic symptoms and impaired accommodation would logical mechanism, the clinical evidence for impaired provide another explanation for the disappointing accommodation as an important therapeutic target is results on fundic relaxant therapy. If impaired accom- currently still lacking. Treatment with fundic relaxant modation only moderately contributes to symptom drugs thus far has shown conflicting results and has generation, treatment should perhaps aim preferen- been rather disappointing in general. These negative tially at other more important mechanisms (Figure 2).
findings could be explained by the fact that impaired Whether this hypothesis is valid and whether central fundic accommodation is part of a more complex dis- mechanisms or peripheral mechanisms are involved as order involving other regions of the proximal gut or the underlying mechanism clearly remains to be eluci- by the increasing insight that central mechanisms may Although we understand more and more about the B.v.d.E. is supported by a grant from Janssen Research neural pathways involved in meal-induced fundic imal duodenum in dyspeptic patients.
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VII. Access to Drugs and Formularies This section covers: • Pharmacy networks • Formularies • Cost-containment strategies • Transition policies Each Part D plan has a network of pharmacies from which an enrollee can routinely access his or her Part D drugs. Additionally, each Part D plan covers the prescription drugs that it places on a formulary, or list of covered d

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Title Incremental Cost-Effectiveness (ICE) Statistical Inference from Two Unbiased SamplesAuthor Bob Obenchain <wizbob@att.net>Maintainer Bob Obenchain <wizbob@att.net>Description Given two unbiased samples of patient level data on cost and effectivenessfor a pair of treatments, make head-to-head treatment comparisons by (i) generating thebivariate bootstrap resampling distribution

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