Nonulcer dyspepsia

Nonulcer dyspepsia is a common condition in clinical practice. It is a heterogeneous disorder, and no single therapeutic agent is effective in all patients. The treatment of nonulcer dyspepsia is still dissatisfactory. Eradication of Helicobacter pylori organisms has a limited role and little effect. Antisecretory therapy has a modest effect in alleviating symptoms. Prokinetic agents may be effective, but selection bias in the trials performed to date may exaggerate their benefit. Partial 5-HT₄ agonists stimulate gastric emptying and may also affect gastric accommodation. They are promising but need further study. Data are limited on 5-HT₃ antagonists and hypnotherapy. New treatment approaches are necessary for this common and often chronic condition.     

Treatment of functional dyspepsia

Opinion statement Functional dyspepsia (FD) is a common reason a patient presents with upper gastrointestinal symptoms for medical care. Although treatment of FD remains expensive, the agents are rarely used in a systematic manner; the majority of treatments are empirical and the results short lived once therapy is ceased. This is partly due to the lack of consistent pathophysiologic markers in FD, so therapy is symptom driven. This review appraises the best evidence on available interventions. A structured scheme for deciding on appropriate therapies is to consider the possible putative pathophysiologic mechanisms. Eradicating Helicobacter pylori, if present, is a first-line strategy. In patients who have symptoms suggesting excessive gastric acid secretion, particularly epigastric pain, antisecretory agents are recommended. Prokinetics may confer benefits on symptoms suggestive of upper gastrointestinal dysmotility, like fullness or early satiety. However, their use is limited due to availability issues. The expanding field of psychologic therapies provides a promising avenue of treatment. Complementary medicines are now widely use and their benefits have been suggested in recent controlled trials. Emerging treatments include cholecystokinin 1 blockers, opioid receptor agonists, and serotonergic agents, although their application in FD is in the preliminary stages.     

Current treatments in functional dyspepsia

Opinion statement By nature of the definition of functional dyspepsia (FD), organic causes have to be ruled out before therapy can be directed. However, in uninvestigated dyspepsia in the absence of alarm features, Helicobacter pylori “test and treat” or an empiric trial of acid suppression therapy for 4 to 8 weeks is reasonable. If alarm symptoms or signs are present, or if the dyspepsia symptoms first occur in those aged greater than 55 years, prompt esophagogastroduodenoscopy is mandatory to exclude serious disease and positively diagnose FD. Empiric acid suppression with H₂-receptor antagonists or proton-pump inhibitors is superior to placebo in treatment of FD, but those patients with meal-related symptoms are least likely to respond. Helicobacter pylori eradication in FD benefits a minority of cases but is worthwhile, as response may be maintained. There is increasing evidence that some prokinetics may be superior to placebo in treatment of FD, but probably only a minority respond; those with meal-related symptoms may have the best response. Antidepressant therapy may have a place in management of difficult cases, but adequate randomized controlled trials are unavailable.     

Drugs affecting serotonin receptors

A greater understanding of the various serotonin receptor subtypes has led to a clearer appreciation of the role of serotonin in gastrointestinal motility, sensation and secretion. Serotonin is definitely involved in the aetiopathogenesis of cisplatin-induced emesis and carcinoid diarrhoea. The application of serotonergic drugs in clinical therapeutics for gut disturbances is presently dominated by the use of 5-HT₃ antagonists for acute chemotherapy-induced nausea and vomiting, and the use of substituted benzamides which are 5-HT₄ agonists stimulating gut motor function through 5-HT₄ neuronal receptors. The best-studied 5-HT₄ agonist is cisapride, which has been shown to stimulate motility at several levels of the gut. Cisapride is approved for healing and maintenance treatment of reflux oesophagitis and is used in several countries for the alleviation of symptoms consistent with regional stasis, from dyspepsia to constipation.Carcinoid diarrhoea is a prototypic disease associated with deranged serotonin metabolism, and a rationale for using 5-HT₃ or 5-HT₄ antagonists is based on the recent appreciation of the important role of impaired gut motor function in carcinoid diarrhoea. In the future, greater understanding of the serotonin receptor subtypes and their role in gut disorders may lead to novel approaches to alleviate increased visceral perception of functional gastrointestinal disorders, to correct changes in colonic capacitance, or to alter gastrointestinal motility that contributes to diarrhoea or constipation. However, at the present time, it must be stressed that these uses are still at an experimental stage and that careful validation and proper controlled studies are still required.     

Serotonin and Its Role in Colonic Function and in Gastrointestinal Disorders

Serotonin (5-HT) is most commonly thought of as a neurotransmitter in the central nervous system. However, the predominant site of serotonin synthesis, storage, and release is the enterochromaffin cells of the intestinal mucosa. Within the intestinal mucosa, serotonin released from EC cells activates neural reflexes associated with intestinal secretion, motility, and sensation. Two important receptors for serotonin that are located in the neural circuitry of the intestines are the 5-HT₃ and 5-HT₄ receptors; these are the targets of drugs designed to treat gastrointestinal disorders. 5-HT₃ receptor antagonists are used to treat nausea and emesis associated with chemotherapy and for functional disorders associated with diarrhea. 5-HT₄ receptor agonists are used as promotility agents to promote gastric emptying and to alleviate constipation. Because of the importance of serotonin in normal gut function and sensation, a number of studies have investigated potential changes in mucosal serotonin signaling in pathologic conditions. Despite the inconsistencies in the current literature, changes in serotonin signaling have now been demonstrated in inflammatory bowel disease, irritable bowel syndrome, postinfectious irritable bowel syndrome, and idiopathic constipation. Emerging evidence has led to many contradictory theories regarding serotonin signaling and its roles in the pathology of gut disorders. This review summarizes the current medications affecting serotonin signaling and provides an overview of our current knowledge of the changes in serotonin that occur in pathologic conditions. Supported by NIH grant DK62267, Novartis Pharmaceuticals, and NIH P20 COBRE grant RR16435. Reprints are not available.     

Functions of peripheral 5-hydroxytryptamine receptors, especially 5-hydroxytryptamine4 receptor, in gastrointestinal motility

The multiple 5-hydroxytryptamine (5-HT, serotonin) receptor subtypes are distinguished. In this article, we described mainly the 5-HT₄ receptor of four subtypes of functional 5-HT receptors, 5-HT₁, 5-HT₂, 5-HT₃, and 5-HT₄, recognized in the gastrointestinal tract. In-vivo microdialysis experiments determined that activation of the 5-HT₄ receptor stimulated intestinal motor activity associated with a local increase in acetylcholine (ACh) release from the intestinal cholinergic neurons in the whole body of dogs. The 5-HT₄ receptor-mediated response of ACh release in the antral, corporal, and fundic strips isolated from guinea pig stomach corresponds to the presence of 5-HT₄ receptor in the myenteric plexus. In-vitro receptor autoradiograms of the stomach and colon indicate that the distribution of 5-HT₄ receptors in human tissues is similar to that in the guinea pig, although density of 5-HT₄ receptors in the myenteric plexus of human tissues is lower than that in guinea pig tissues. The 5-HT₄ receptors located in the myenteric plexus may participate in gastrointestinal motility, and thus the 5-HT₄ agonists and antagonists may be available for treatment of dysfunction of gastrointestinal motility. Received: November 22, 1999 / Accepted: March 24, 2000     

Serotonin Agonists and Antagonists in Obstructive Sleep Apnea

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a prevalent disorder associated with substantial cardiovascular and neurobehavioral morbidity. Yet this is a disorder for which there are no widely effective pharmacotherapies. The pathophysiology of obstructive sleep apnea namely, normal respiration in waking with disordered breathing only in sleep, suggests that this disorder should be readily amenable to drug therapy. Over the past 10 years, we have gained tremendous insight into the neurochemical mechanisms involved in state-dependent control of respiration. It is apparent from this work that there are many potential avenues for pharmacotherapies, including several seemingly conflicting directions for serotonergic therapies.Serotonin delivery is reduced to upper airway dilator motor neurons in sleep, and this contributes, at least in part, to sleep-related reductions in dilator muscle activity and upper airway obstruction. The dilator motor neuron post-synaptic serotonin receptors are 5-HT_2A and 5-HT_2C subtypes, and in adults the presynaptic 5-HT receptor in motor nuclei is 5-HT_1B, an inhibitory receptor. Serotonin receptors are also found within central respiratory neuronal groups, and these receptor subtypes include 5-HT_1A (inhibitory) and 5-HT₂ receptors. Peripherally, stimulation of 5-HT_2A, 5-HT_2C and 5-HT₃ receptor subtypes have an inhibitory effect on respiration via action at the nodose ganglion. Many of these receptor subtypes and their signal transduction pathways may be affected by oxidative stress in obstructive sleep apnea. These alterations will make finding drug therapies for sleep apnea more challenging, but not insurmountable. Future directions are suggested for elucidating safe, well-tolerated serotonergic drugs for this disorder.Tryptophan was one of the first serotonergic drugs tested for OSAHS. This drug was withdrawn from the market as a result of reports linking tryptophan use with eosinophilic myalgia syndrome and life-threatening pulmonary hypertension. Newer drugs with serotonergic activity tested in persons with sleep-disordered breathing include buspirone, fluoxetine and paroxetine. Trials are presently being conducted to evaluate the effects of 5-HT_2A and 5-HT₃ antagonists on OSAHS. Many of the drugs tested have not shown significant improvement in sleep apnea. However, with continued effort to elucidate the pharmacology of neurochemical control of state-dependent changes in respiratory control, the availability of pharmacological therapy for this disorder is not too far away.     

Emerging Pharmacologic Therapies for Irritable Bowel Syndrome

New therapies are being developed for irritable bowel syndrome (IBS). These advances are based on understanding pathophysiology or the development of medications with greater selectivity in classes of agents with known efficacy. Prucalopride, the newest European Medicines Agency-approved 5-hydroxytryptamine receptor 4 (5-HT₄) agonist, is effective in the treatment of chronic constipation with improved cardiovascular safety relative to older 5-HT₄ drugs; similarly, ramosetron, the 5-hydroxytryptamine receptor 3 (5-HT₃) antagonist, appears efficacious in diarrhea-predominant IBS. Secretagogues with different mechanisms of action target apical domains in enterocytes that are involved in chloride secretion, such as chloride channels, the cystic fibrosis transmembrane regulator, and guanylate cyclase C. As a class, such secretagogues have high efficacy and safety for constipation. With more data obtained from phase 2 and 3 trials, we expect other classes of medications, including bile acid modulators, anti-inflammatory agents, visceral analgesics, and newer centrally acting agents to be efficacious and enter the armamentarium for the treatment of IBS in the future.     

The Impact of Dyspepsia Definition on Prevalence Estimates: Considerations for Future Researchers

Background: The role of Helicobacter pylori infection in functional dyspepsia is still controversial, and subgroups of patients with functional dyspepsia who may benefit from H. pylori eradication should be identified. Patients with functional dyspepsia and antrum‐predominant H. pylori‐positive chronic gastritis, it has been argued, have fewer symptoms after eradication therapy. In the present study, we analysed the clinical significance of antrum‐predominant gastritis on the long‐term prognosis of functional dyspepsia. Methods: Consecutive unselected dyspeptic patients were investigated in primary care and the patients with functional dyspepsia were enrolled in this long‐term follow‐up study. Altogether 182 patients were recruited: 65 with normal histology of the stomach, 36 with antrum‐predominant gastritis, 21 with corpus‐predominant gastritis and 60 with pangastritis. Patients' medical histories were reviewed after 6 to 7 years, with total number and outcome of repeated investigations analysed. At the end of follow‐up, all patients were invited for voluntary gastroscopy. Results: At the end of follow‐up, the proportion of asymptomatic patients ranged from 21% (normal histology) to 26% (antrum‐predominant gastritis). No statistically significant differences between groups appeared in regard to re‐visits or to proportion of patients examined by sigmoideo‐ or colonoscopy during follow‐up. Patients with antrum‐predominant gastritis less often underwent upper endoscopy. Peptic ulcer was more frequent (P?=?0.05) in patients with antrum gastritis than in other groups, but no other differences existed among any organic gastrointestinal findings. No significant differences between subgroups appeared among the 30% of patients using drugs for upper abdominal complaints during the previous year. Conclusions: Functional dyspepsia has an excellent long‐term prognosis. Antrum‐predominant gastritis in functional dyspepsia seems to carry an increased risk for peptic ulcer, and for this group in particular, H. pylori eradication should be considered. This finding requires confirmation in future studies performed in primary care.     

Helicobacter Pylori

Opinion Statement All infected patients with a peptic ulcer should be treated for H. pylori. The role of treating H. pylori in patients with undiagnosed dyspepsia or non-ulcer dyspepsia, those taking nonsteroidal anti-inflammatory medications, or with a family history of gastric cancer remains controversial. Triple therapies consisting of a proton pump inhibitor or ranitidine bismuth citrate and two antibiotics are the current standard of therapy for H. pylori. In general, dual therapies should no longer be used to treat H. pylori. Bismuth triple therapy consisting of bismuth, tetracycline, and metronidazole is a less expensive alternative to proton pump inhibitor-or ranitidine bismuth citrate-based triple therapies. However, bismuth triple therapy is hampered by frequent side effects and the need for qid dosing. In Europe, a 7-day course of therapy appears to be adequate. In the United States, 10-14 days of therapy are currently recommended. Metronidazole resistance in H. pylori strains varies geographically, and negatively influences the effectiveness of therapies containing this antibiotic. Clarithromycin resistance is relatively infrequent at the current time but may be rising in countries where this antibiotic is in use. If a patient remains infected after a course of therapy for H. pylori, the second treatment should avoid the antibiotics used initially.     

The spectrum of gastric disease associated with <Emphasis Type="Italic">Helicobacter pylori</Emphasis> and other infectious gastritides

Helicobacter pylori is the most frequent infection of the stomach worldwide. Some of the people infected with H. pylori develop symptoms of dyspepsia that correlate with pathologic evidence of gastritis and peptic ulcers. In addition, H. pylori has been associated with preneoplastic lesions and with two neoplasias: intestinal-type gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. Rarely, gastric pathology can also be caused by other infectious agents, including fungi, other bacteria, parasites, and viruses. This review describes H. pylori-associated pathology and pathologies related to other infectious agents.     

Kyoto global consensus report on Helicobacter pylori gastritis and its impact on Chinese clinical practice

The Kyoto global consensus report on Helicobacter pylori (H. pylori) gastritis has had a great effect on the field of H. pylori studies worldwide. For the first time H. pylori gastritis was defined entirely as an infectious disease and H. pylori‐associated dyspepsia as a new category of organic dyspepsia apart from functional dyspepsia, together with a proposed diagnostic algorithm. Accordingly, the report states that the eradication of H. pylori should be regarded as the first‐line treatment for dyspepsia. Moreover, H. pylori eradication before the development of pre‐neoplastic changes is recommended to reduce the risk of more serious complications of H. pylori gastritis. Despite the recommendations of this new global consensus, the task of transforming them into feasible and practical recommendations for individual countries will require them to become region‐specific, which requires further discussion.     

Review: Eradication of Helicobacter pylori. Problems and recommendations

The successful isolation of Helicobacter pylori from the stomachs of patients with gastritis and peptic ulcer has revolutionized our concepts of the pathogenesis of gastritis, peptic ulcer, gastric cancer and gastric B cell lymphoma. Eradication of H. pylori heals gastritis and H. pylori-related peptic ulcer. After a successful cure of H. pylori infection, virtually no recurrence of duodenal ulcer is seen. However, treatment to cure the infection has proved difficult. Numerous clinical trials have been attempted, but as yet no ideal regimen has been identified. Monotherapies have many drawbacks and should be avoided. Dual therapies combining a proton pump inhibitor (PPI) and an antimicrobial agent provide higher eradication rates than those involving two antimicrobial agents. Bismuth-based triple therapies are more effective than dual therapies in eradicating H. pylori infection. However, poor compliance and frequent adverse effects have made these combinations less favourable in clinical practice. Proton pump inhibitor-based triple therapies have shown more consistent and higher eradication rates with a short duration of treatment, good patient compliance, fewer side effects, prompt symptom relief and fast ulcer healing. Results from PPI-based quadruple therapies are promising; however, large multicentre clinical trials are needed to confirm the effect and the complex regimen again may compromise compliance outside of the clinical trial setting. Eradication of H. pylori infection is cost-effective in the long-term management of peptic ulcer disease compared with maintenance therapy with antisecretory drugs.     

Managing dyspepsia

The prevalence of dyspepsia in the general population is as high as 40%, and its management represents a considerable financial burden to the health care system. Causes of dyspepsia amenable to medical therapy include peptic ulcer and functional dyspepsia, and testing for Helicobacter pylori and treating positive individuals is beneficial in both conditions. Individuals presenting for the first time with uninvestigated dyspepsia, age greater than 50 years, or alarm features require upper gastrointestinal (GI) endoscopy to exclude gastroesophageal malignancy. Upper GI endoscopy for younger individuals without alarm features is not cost-effective compared with the “test and treat” approach. Test and treat and empirical acid-suppression using a proton pump inhibitor (PPI) have similar costs and effects. Recent evidence suggests that empirical acid suppression commencing with antacids is as effective as PPI. Screening and treatment of H. pylori in PPI users and the community may reduce the costs of managing dyspepsia.     

Functional dyspepsia: drugs for new (and old) therapeutic targets

The therapeutic management of functional dyspepsia remains a major challenge for the gastroenterologist. Current therapies available are based on putative underlying pathophysiologic mechanisms, including gastric acid sensitivity, slow gastric emptying and Helicobacter pylori infection, but only a small proportion of patients achieve symptomatic benefit from these therapeutic approaches. Relatively novel mechanistic concepts under testing include impaired gastric accomodation, visceral hypersensitivity, and central nervous system dysfunction. Serotonergic modulators (e.g. the 5-HT4 agonist tegaserod, the 5-HT3 antagonist alosetron and the 5-HT1P agonist sumatriptan), CCK-1 antagonists (e.g. dexloxiglumide), opioid agonists (e.g. asimadoline), N-methyl-D-aspartate (NMDA) receptor antagonists (e.g dextromethorphan), neurokinin antagonists (e.g. talnetant), capsaicin-like agents and antidepressants are among the agents currently under investigation. It seems unlikely, however, that targeting a single mechanism with an individual drug will result in complete symptom remission in most cases.     

Treatment of Non-Ulcer Dyspepsia: a Meta-Analysis of Placebo-Controlled Prospective Studies

Background: Dyspeptic symptoms are commonly reported complaints in clinical practice and are mostly the result of functional disorders. Empirical treatment with histamine H₂-receptor blockers or gastroprokinetics for 2-4 weeks has frequently been proposed as first line management of these patients. The clinical trials which support the use of these agents, show a high variation in clinical success rate and benefit of these treatments. Methods: The available clinical trials were evaluated, pooled where appropriate and subjected to a meta-analysis with the principal goal to provide valid treatment recommendations for patients with non-ulcer dyspepsia. In the present meta-analysis 19 studies on gastroprokinetics (cisapride, domperidone) and 10 studies on histamine H₂-receptor antagonists (cimetidine, ranitidine) were included. Results: Based on these studies, a total of 1540 patients were evaluated for histamine H₂-receptor antagonists (verum n = 786, placebo n = 754) and 1235 patients for gastroprokinetics (verum n = 616, placebo n = 619). The probability for treatment success compared to placebo was 0.2026 (0.1261; 0.2791) for histamine H₂-receptor antagonists and 0.4029 (0.3042; 0.5069) for gastroprokinetics. Conclusions: Based on these data both treatments are significantly more effective than placebo in the symptomatic treatment of non-ulcer dyspepsia, with gastroprokinetics (cisapride, domperidone) being more effective than histamine H₂-receptor antagonists (cimetidine, ranitidine).     

Helicobacter pylori: testing and treatment

Helicobacter pylori is an important pathogen worldwide. Accurate diagnosis and appropriate therapy is important in clinical practice. Invasive tests that accurately identify current infection include the biopsy urease test and histology. The best noninvasive tests for diagnosis include the urea breath test and stool antigen testing. Proton pump inhibitor therapy can lead to false-negative H. pylori test results, and treatment should be stopped for 1–2 weeks prior to testing if possible. In the setting of bleeding peptic ulcer disease, urea breath testing is recommended to rule out a false-negative biopsy test result if needed. The current recommendations for when to test for H. pylori vary around the world. Well-accepted indications include active and past ulcer disease, and gastric-mucosa associated lymphoid tissue lymphoma. There is no universal agreement regarding whether all patients with functional dyspepsia should be tested and treated, although this is an evidence-based recommendation. There is also evidence that H. pylori eradication prevents peptic ulcer disease in those starting NSAIDs long term. Primary treatment remains triple therapy with 10–14 days probably being superior to shorter courses of therapy. Quadruple therapy is recommended if standard triple therapy fails. Salvage therapies with levofloxacin, rifabutin or furazolidone have been identified. Novel approaches to treatment include sequential therapy and use of adjuvants.     

Role of impaired gastric accommodation to a meal in functional dyspepsia

Background Aims: Impaired accommodation of the proximal stomach to a meal has been reported in functional dyspepsia, but its relevance to symptoms is unclear. The aim of this study was to test the hypothesis that impaired gastric accommodation causes early satiety. Methods: A gastric barostat was used to study postprandial fundus relaxation in 35 healthy subjects and 40 patients with functional dyspepsia. Gastric emptying, Helicobacter pylori status, sensitivity to gastric distention, and a dyspepsia symptom score were obtained from all patients. In addition, the effect of sumatriptan, a fundus-relaxing 5-hydroxytryptamine₁ agonist, on gastric accommodation and on early satiety in dyspeptic patients was studied. Results: Impaired gastric accommodation to a meal was found in 40% of the patients. In univariate analysis, this was associated with early satiety and weight loss but not with hypersensitivity to gastric distention, presence of H. pylori, or delayed gastric emptying. In a multivariate analysis, only early satiety was associated with impaired gastric accommodation. Sumatriptan restored gastric accommodation, thereby significantly improving meal-induced satiety. Conclusions: Impaired relaxation of the proximal stomach to a meal is present in a high proportion of patients with functional dyspepsia. It is associated with symptoms of early satiety. Restoring gastric accommodation with a fundus-relaxing drug improves early satiety.GASTROENTEROLOGY 1998;115:1346-1352     

Antiplatelet therapy for atherothrombotic disease: How can we improve the outcomes?

Platelets play a key role in hemostasis but are also responsible for the formation of pathogenic thrombi underlying the acute clinical manifestations of vascular atherothrombotic disease. Platelets are activated by multiple pathways, including adenosine diphosphate (ADP), thromboxane A₂ (TXA₂), and thrombin, ultimately leading to formation of platelet-rich thrombi that occlude the arterial lumen, resulting in ischemia and cardiovascular events. Current oral antiplatelet agents inhibit the TXA₂ (aspirin [ASA]) and ADP platelet activation pathways (P2Y₁₂ ADP receptor antagonists) and have demonstrated clinical efficacy for the reduction of morbidity and mortality in patients with atherothrombotic disease. However, these agents are associated with residual risk for thrombotic events, bleeding risk, and variability in response. Thus, there is a strong clinical need for novel antiplatelet therapies that decrease the risk of thrombotic events without exposing patients to increased risk of bleeding. This review describes the clinical safety and efficacy of ASA and P2Y₁₂ ADP receptor antagonists, the limitations of current antiplatelet therapy, and novel therapies in development, including newer P2Y₁₂ ADP receptor antagonists and protease-activated receptor (PAR-1) inhibitors.     

Treatment of irritable bowel syndrome

Opinion statement Irritable bowel syndrome (IBS) is an extremely common cause of consultation, and at present is diagnosed on the basis of symptoms and a few simple exclusion tests. Exclusion diets can be successful, but many patients have already attempted and failed such treatments before consulting. Anxiety and somatization may be an important driver of consultation. Patients’ concerns should be understood and addressed. Those with prominent psychiatric disease may benefit from psychotherapy. Hypnotherapy benefits symptoms in those without psychologic disturbance, but its availability is limited. Antidepressants are effective in improving both mood and IBS symptoms globally, and the evidence is particularly good for tricyclic antidepressants. Although antispasmodics are currently the most commonly prescribed drugs, most responses (75%) are due to the placebo effect and not specific to the drug. Bulk laxatives such as ispaghula can increase stool frequency and help pain, but bloating may be aggravated. Loperamide is effective treatment for urgency and loose stools, but less effective for bloating and pain. 5-HT₃ antagonists such as alosetron improve urgency, stool consistency, and pain in diarrhea-predominant-IBS. The 5-HT₄ agonist tegaserod shows modest benefit in constipation-predominant IBS, improving stool frequency, consistency, and bloating as well as global improvement. There are many new drugs, such as cholecystokinin, neurokinin, and corticotropin receptor antagonists, in development.