Camicinal Hydrochloride

Among the myriad of non-communicable diseases plaguing mankind, diabetes mellitus has established itself as the important if not the most prominent disorder. Diabetes mellitus brings with it the spectre of serious often life-threatening micro- and macrovascular complications. Diabetes mellitus hardly spares any organ systems—some are impacted more than others. While the more prominent complications, such as cardiovascular disease, nephropathy and retinopathy, have taken centre stage in terms of early diagnosis and treatment, some equally distressing complications have been left in relative neglect. One of these lesser-known complications is diabetic gastroparesis (DGP). The prevalence of DGP is quite high. A recent meta-analysis looking at the global prevalence of DGP reported an overall prevalence of 9.3%.[1] The data from the United States indicate that this disease is not very common in North America, which indirectly implies that other areas of the world have a much higher prevalence of gastroparesis.[2] The prevalence of DGP was reported to be 19% in Brazil, 13.79% in Thailand and an astonishingly high 40% in a study from China.[1] In a larger study from the UK, Asians formed the second-largest ethnic group among patients with gastroparesis.[3] The data on DGP from Asian countries, however, are limited. It is suspected that the DGP has a high prevalence in Asia but is being under-reported due to a lack of awareness among physicians, a paucity of diagnostic equipment and a dearth of effective treatment options.[4] In a survey of gastroenterologists from various Asian countries, only 24.2% and 54.2% could correctly identify the definition and diagnostic gold standards of gastroparesis, respectively.[5] The probable high prevalence and lack of awareness in healthcare workers indicate that a lot needs to be performed to improve the diagnosis and management of this disease. The typical symptoms of DGP include early satiety, bloating, nausea, vomiting, postprandial fullness and weight loss. Interestingly, persistent nausea and vomiting seen in gastroparesis may not always result in weight loss. Many patients with idiopathic gastroparesis expend much fewer calories than they consume, resulting in weight gain.[6] Whether this is also true in DGP is not yet known. Still, patients with DGP and type 2 diabetes mellitus (T2DM) are more likely to be overweight or obese when compared to those with type 1 diabetes mellitus (T1DM) or idiopathic gastroparesis.[3] The presence of obesity or lack of weight loss should not deter the physician from suspecting DGP. DGP, apart from these typical symptoms, also impairs the quality of life in patients with diabetes.[7] Furthermore, the mortality rates of patients with DGP are higher than those without it.[8] It is unclear whether this is entirely due to comorbidities or due to a direct effect of DGP. Therefore, timely diagnosis of DGP has potential benefits beyond mere symptom control. Although autonomic neuropathy is considered to be the chief mechanism behind DGP, there is enough evidence to suggest that other mechanisms, such as loss of enteric neurons, intestinal pacemaker cells (interstitial cells of Cajal) and smooth muscle dysfunction, also play a role in DGP. These events are mediated by a variety of pathways, including apoptosis, ischaemia and inflammation.[9] This implies that the mere absence of autonomic neuropathy should not prevent the clinician from considering a diagnosis of DGP. The definitive diagnosis of DGP requires delayed gastric emptying by scintigraphy, but the limited availability of this investigation in primary- and secondary–level healthcare facilities hinders the diagnosis. The categorisation used by Jung et al.,[8] which proposed entities such as "possible gastroparesis," "probable gastroparesis" and "definitive gastroparesis," may be useful in increasing the recognition of these disorders and helping direct referral to higher centres in selected cases. The traditional treatment options for DGP include the use of anti-emetic and gastric motility-enhancing drugs, along with dietary modifications. Better glycaemic control may also help in improving the symptoms of DGP. The use of a small–particle low-fat and fibre diet or a liquid diet can help alleviate symptoms. The commonly used drugs are metoclopramide, domperidone, levosulpiride and erythromycin. While these drugs do reduce symptoms, their use is limited by adverse effects.[10-12] Ghrelin receptor analogues, such as ulimorelin, have been tried in DGP but have met with little success.[13,14] A newer ghrelin agonist, relamorelin, has shown better results and is currently undergoing phase 3 trials.[15] A trial of 5-hydroxytryptamine 4 (5HT-4) agonist (velusetrag) reported improvement in gastric emptying although only the lowest dose showed improvement in symptoms.[16] More studies with ghrelin receptor analogues are underway. A neurokinin-1 antagonist (tradipitant) is also under investigation.[17] Camicinal, a small-molecule motilin agonist, has also shown promise in initial studies.[18] These ongoing investigations, notwithstanding the search for safer and more potent therapies for DGP, are far from over. In this issue, Singh et al.[19] have furthered this search by studying an indigenous plant called Pistacia lentiscus. Pistacia lentiscus has been earlier reported to have some benefits in gastrointestinal disorders, including improvement in gut motility.[20,21] Singh et al. have found that the stem extract of Pistacia lentiscus improved gastric emptying and symptoms of DGP to an extent comparable to levosulpiride without causing any significant adverse effects. Metabolic parameters such as glycaemia and low-density lipoprotein (LDL) levels were improved in the Pistacia lentiscus group as compared to levosulpiride. The findings of Singh et al. are promising and open up a new avenue for the therapy of DGP. If the results are replicated in other studies, Pistacia lentiscus stem extract can become a safe yet effective agent in the present armamentarium against DGP. The increased recognition of DGP by doctors involved in the care of patients with diabetes mellitus is the need of the hour. It will not only enable patients to get access to the available treatment options but also fuel research in this relatively neglected area. It would be prudent to hope that more effective and safe therapeutic options for DGP emerge in the future.

Motilin is a 22-amino-acid gastrointestinal (GI) hormone and is involved in the regulation of GI motility through binding to GPR38, the motilin receptor which is expressed on smooth muscle cells in the GI tract. Therefore, GPR38 agonists are expected to be novel gastrointestinal prokinetic agents for the treatment of functional gastrointestinal disorders such as gastroparesis and chronic constipation. We identified a series of N-methylanilide derivatives as novel non-macrolide GPR38 agonists. Among them, 12 di-l-tartrate (DS-3801b) was selected as a clinical candidate for further evaluation.