Cyclic vomiting syndrome (CVS) is a disorder characterized by recurrent episodes of nausea and severe vomiting with symptom-free intervals between the episodes24. CVS has been regarded as a relatively rare disease, but now is relatively common in the pediatric population with an estimated prevalence between 1.9% and 2.3%24. CVS can develop at any age, but is mainly reported in childhood, with a mean age of 4.6-6.9 years. However, other studies suggest that 3-5% of adult patients referred to GI motility centers had CVS25. CVS is reported to be slightly more common in females than in males. Common triggering factors include stress, emotional excitement and infections. CVS typically has three phases: prodromal phase (when a patient senses an episode is coming), emetic phase, and a well phase between episodes. The diagnosis of CVS is made using the Rome III criteria that considers stereotypical episodes of vomiting lasting less than 1 week, with three or more of these episodes per year, and the absence of nausea or vomiting between episodes25. It is hypothesized that psychological or infectious stressors lead to activation of the CRF signaling system, and induce episodes of CVS through autonomic alterations that impact gut motility26. In this regard, it has long been recognized that CVS is associated with a stress-induced surge of ACTH and cortisol and that recovery corresponds to a return to normal levels27. This surge in cortisol may modulate several brain CRF or other neurotransmitter pathways to potentiate the disease symptoms. Indeed, the activation of CRF pathways in the brain has been shown to stimulate inhibitory motor nerves in the dorsal motor nucleus of the vagus, thereby triggering emesis and delayed gastric emptying28. Also, activation of CRF in other brain areas such as the paraventricular nucleus (PVN) of the hypothalamus and amygdala could influence gastrointestinal function and anxiety. In addition to increases in plasma ACTH and cortisol levels, it has also been reported that plasma CRF levels are elevated in CVS patients29. In this regard, peripheral CRF administration has been shown to inhibit gastric emptying and this effect can be blocked by peripheral administration of astressin13. Moreover, there may be communication between peripheral signals and the brain via both vagal activation and circumventricular organs such as the area postrema (AP) which is implicated in nausea and vomiting responses. Indeed, peripheral CRF administration has been shown to increase the cfos activation marker in the AP30,31 suggesting that elevated peripheral CRF levels may also modulate this pathway. During the prodromal phase various prophylactic approaches and therapies are employed to alleviate stress and the ensuing emetic phase. These include lying down in a dark, quiet environment or hot bath, high carbohydrate ingestion and/or taking anti-emetic agents, anti-anxiety agents and anti-migraine agents24. However, the effectiveness of these therapies has not been proven and oral medications are problematic if the patient progresses to the emetic phase. Astressins offer the opportunity to treat CVS by addressing the underlying stress-response in all of the stages of CVS utilizing a non-oral mode of delivery with long-lasting effects1.
1 Erchegyi et. al., (2016) J. Med. Chem., 59, 854-866
13 Martinez et. al., (1999) JPET, 290, 629-634
24 Yang, (2010) J. Neurogastroenterol. Motil., 16, 139-147
25 Shearer et. al., (2016) Frontline Gastroenterology, 0, 1-8
26 Taché, (1999) Digestive Diseases and Sciences, 44, 79S-86S
27 Wolff et. al., (1964) Am. J. Med, 36, 956-967
28 Taché et. al., (2001) Am. J. Physiol. Gastrointest. Liver Physiol., 280, G173-G77
29 Marcus et. al., (2006) Gastroenterol., 130, A4 (abstract)
30 Maillot et. al., (2003) Brain Research, 974, 70-81
31 Wang et. al., (2000) Brain Research, 855, 47-57