Itopride hydrochloride (itopride), a gastrokinetic drug, has recently been evaluated for its clinical usefulness in functional dyspepsia. We investigated effects of itopride on human plasma gastrin-, somatostatin-, motilin-, and cholecystokinin (CCK)-like immunoreactive substances (IS); adrenocorticotropic hormone (ACTH)-immunoreactive substances (IS), and cortisol under stress conditions in healthy subjects. A single administration of itopride caused significant increases in plasma somatostatin- and motilin-IS levels compared to placebo. Itopride significantly decreased plasma CCK-IS, and suppressed the ACTH-IS level compared to placebo. We hypothesize that itopride may have an accelerating gastric emptying effect, and a modulatory effect on the hypothalamo-pituitary-adrenal axis and autonomic nervous functions. These effects might be beneficial in stress-related diseases, suggesting that itopride has clinicopharmacological activities.

The pathophysiology of acid-peptic disease may be thought of as an imbalance between aggressive factors (acid, pepsin and Helicobacter pylori infection) and local mucosal defenses; the secretion of bicarbonate, mucus and prostaglandins. Although treatment most often is directed at the reduction of aggressive factors, it can be directed at strengthening mucosal defenses of the stomach and the duodenum with so-called cytoprotective agents.Cetraxate hydrochloride (cetraxate), introduced in 1976 as an anti-ulcer drug with a mucosal protective effect, produces a dose-related increase in gastric mucosal blood flow, 1) and raises plasma calcitonin gene-related peptide and substance P levels, which are powerful vasoactive substances.2) Ecabet sodium (ecabet) and sulpiride have similar effects to cetraxate; an improvement of the gastric mucosal microcirculation and acceleration of bicarbonate secretion. 3,4) Gastric mucosal injury is greatly influenced by mental and/or physiological stress. The hypothalamo-pituitaryadrenal (HPA) axis is activated when stress is present. Corticotropin-releasing hormone (CRH) is secreted from the hypothalamus and stimulates the pituitary. From the pituitary, adrenocorticotropic hormone (ACTH), which stimulates adrenal and accelerates cortisol secretion, is secreted. ACTH and cortisol suppress the secretion of CRH (negative feedback) to normalize the HPA axis. Therefore, we believe that ACTH and cortisol may be indicators of stress.ACTH is a peptide containing 39 amino acids, and ACTHlike immunoreactive substance (IS) is found in tissues other than the pituitary gland (i.e., brain, adrenal gland, gastrointestinal tract, pancreas, thyroid gland, and placenta). The secretion of ACTH is controlled by a circadian rhythm mechanism and negative feedback from plasma cortisol and neurogenic stimulation.5) The peptide acts to secrete glucocorticoid and rises under stress. 6) Cortisol, commonly used to indicate the level of stress, is secreted by the zona fasciculate of the adrenal cortex and its secretion is dependent on the ACTH level.In general, venipuncture for blood sampling is thought to be a stress factor that can increase circulating ACTH and cortisol levels. 7) Repetitive blood sampling places subjects under artificial stress and venipuncture as a stressor is useful for the evaluation of the pharmacological effects of drugs. 8)To determine whether cytoprotective drugs can improve HPA axis abnormalities, which might be closely related to the genesis of peptic ulcers, we investigated the effects on stress-related hormone levels (ACTH-IS and cortisol) under continual stress after administration of cetraxate, ecabet and sulpiride. MATERIALS AND METHODSMaterials Cetraxate (Neuer capsule; Daiichi Seiyaku Co., Ltd., Tokyo, Japan), ecabet (Gastrom granules; Tanabe Seiyaku Co., Ltd., Osaka, Japan) and sulpiride (Dogmatyl capsule; Fujisawa Pharmaceuticals Co., Ltd., Osaka, Japan) were used. Lactose (Merck Hoei Co., Ltd., Osaka, Japan) was used as placebo.Synthetic human ACTH (1-10) was purchased from ...