Toward modulation of the endocannabinoid system for treatment of gastrointestinal disease: FAAHster but not “higher”

Cannabis has been used to treat various afflictions throughout the centuries, including nausea, vomiting, and pain. It has also been used recreationally for its psychotropic properties, which can include a pleasurable ‘high’ feeling and a decrease in anxiety and tension; however, other may experience dysphoria. Changes in cognition and psychomotor performance are also well‐known with cannabis use. In recent years, our understanding of the endocannabinoid system (ECS) has progressed dramatically; the objective of identifying agents which may allow modulation of the ECS without significant psychotropic side effects may be possible. Inhibition of fatty acid amide hydrolase (FAAH), an important enzyme for the degradation of anandamide and other endogenous cannabinoids, is a promising target to achieve this goal. In this issue of Neurogastroenterology and Motility, Fichna and colleagues report on a novel selective FAAH inhibitor, PF‐3845, with potent antinociceptive and antidiarrheal effects in a mouse model. In this context, we briefly review the components of the ECS, discuss pharmacologic targets for indirect cannabinoid receptor stimulation, and describe recent research with cannabinoids for gut disorders.     

Efficacy and tolerability of renzapride in irritable bowel syndrome: a meta-analysis of randomized,controlled clinical trials including 2528 patients

Introduction

By targeting different subtypes of 5-hydroxytryptamine (5HT) receptors in the gastrointestinal (GI) tract, several drugs have been introduced for the management of irritable bowel syndrome (IBS). Renzapride is a full agonist for 5HT4 receptor and an antagonist to 5HT2b and 5HT3 receptors which is thought a promising therapeutic agent for constipation predominant IBS (C-IBS) patients due to its accelerating effect on the GI tract. In this meta-analysis, our aim was to evaluate the efficacy and tolerability of renzapride in the management of IBS.

Material and methods

A search was done from 1992 to February 2013 for placebo-controlled trials that investigated the efficacy of renzapride in IBS.

Results

Relative risk (RR) for clinical efficacy in IBS patients treated for 5 weeks or less comparing renzapride to placebo was 1.07 (95% CI = 0.89–1.29, p = 0.38). This value for IBS patients treated for more than 5 weeks was 1.04 (95% CI = 0.78–1.239, p = 0.77). The RR for clinical efficacy in IBS patients treated with renzapride (4 mg) for 5 weeks or less and more than 5 weeks in comparison to placebo was 1.2 (95% CI = 0.97–1.48, p = 0.1) and 1.16 (95% CI = 0.98–1.37, p = 0.08), respectively, which were statistically non-significant but clinically important. The analysis of tolerability demonstrated that amongst different reported adverse effects, renzapride caused diarrhea more than placebo (RR = 1.61 with a 95% CI = 1.16–2.24, p = 0.004). The RR for withdrawals from renzapride compared to placebo was 1.58 (95% CI = 1.26–2.07, p = 0.0007).

Conclusions

Renzapride is not superior to placebo in relieving IBS symptoms and causes significant incidences of diarrhea and drop-outs due to adverse effects in treated patients vs. placebo. Thus, this medicine might be a cost burden to patients without providing good effectiveness.     

Mucormycosis in COVID-19 patients

Mucormycosis, commonly known as ‘Black Fungus’ which was then a rare fungal infection, has suddenly come to light post the COVID-19- pandemic, more so during the second wave in India. It thus becomes important not only for the medical fraternity but also the general population to build awareness about the same. The present review will focus on the pathophysiology, etiology, outcomes of some case studies, and current treatment methods of mucormycosis infection. Major focus of the current article is on rhino-orbital-cerebral mucormycosis. All the studies included in the present review article was extracted from the PubMed database.     

Nutrition in Patients with Lactose Malabsorption,Celiac Disease,and Related Disorders

Lactose malabsorption (LM), celiac disease (CD), non-celiac gluten sensitivity (NCGS), and irritable bowel syndrome (IBS) are conditions associated with food triggers, improvement after withdrawal, treatment with dietary restriction, and subsequent nutritional detriments. LM occurs when there is incomplete hydrolysis of lactose due to lactase deficiency and frequently produces abdominal symptoms; therefore, it can cause lactose intolerance (LI). A lactose-restricted diet is frequently recommended, although it can potentially lead to nutrient deficiencies. Furthermore, lactose is an essential component of fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs) and is subsequently associated with intolerance to these compounds, especially in IBS. LM commonly presents in CD. Nutritional deficits are common in CD and can continue even on a gluten-free diet (GFD). Conditions triggered by gluten are known as gluten-related disorders (GRDs), including CD, wheat allergy, and NCGS. IBS can also be associated with a gluten sensitivity. A GFD is the treatment for CD, GRDs, and gluten sensitive IBS, although compliance with this restricted diet can be difficult. Strict dietary therapies can have a negative effect on quality of life. This review aims to provide an overview of the difficult nutritional elements of these disorders, which are critical for medical providers to recognize when managing these patients.     

Low fasting glucose‐to‐estimated average glucose ratio was associated with superior response to insulin degludec/aspart compared with basal insulin in patients with type 2 diabetes

Aims/IntroductionThe benefits of once‐daily insulin degludec/aspart (IDegAsp) compared with basal insulin in type 2 diabetes patients have not been established.Materials and MethodsThis was a retrospective observational study. From a basal insulin cohort from three referral hospitals, patients were enrolled who initiated once‐daily IDegAsp. A control group maintaining basal insulin was selected by propensity score matching. Glycated hemoglobin (HbA1c) changes over a period of 6 months and associated clinical factors were evaluated.ResultsThe IDegAsp group and the control group comprised of 87 patients, respectively. Baseline HbA1c was comparable between the two groups (8.7 ± 0.9 vs 8.6 ± 0.9%, mean and standard deviation). After 6 months with matched insulin doses, HbA1c in the IDegAsp group was lower than that in the control group (8.1 ± 1.0 vs 8.4 ± 1.1%, P = 0.029). Among baseline variables, fasting plasma glucose (FPG) and fasting C‐peptide in the IDegAsp were lower than that in the control (FPG 124.2 ± 38.4 vs 148.0 ± 50.6 mg/dL, P < 0.001). Considering that the lower FPG despite the comparable HbA1c could be related with the efficacy of IDegAsp, subgroup analysis was carried out according to a ratio of FPG‐to‐estimated average glucose, which is calculated from HbA1c. When compared with each control group, the superiority of IDegAsp in the reduction of HbA1c was significant only in the patients with a lower FPG‐to‐estimated average glucose ratio (0.49 ± 0.09), but not in those with a higher FPG‐to‐estimated average glucose ratio (0.79 ± 0.20).ConclusionsWe observed that IDegAsp was more effective than basal insulin in patients with an FPG lower than predicted by HbA1c, which might be related with insulin deficiency and postprandial hyperglycemia in patients on basal insulin therapy.     

P38 MAPK激活在高血糖致大鼠微血管通透性增高过程中的作用

目的研究P38 MAPK信号传导通路在糖尿病大鼠微血管内皮细胞通透性增高中的作用机制。方法SD雄性大鼠,腹腔注射链脲佐菌素(STZ 55 mg/kg)制备糖尿病模型。分正常组、糖尿病组、溶剂对照组、MKK6b(A)组和MKK6b(E)组。溶剂组:给予相同容量的柠檬酸缓冲液;MKK6b(A)组:在糖尿病模型基础上,实验前24 h尾静脉注射MKK6b(A)2.5 mL/kg;MKK6b(E)组:在实验前24 h给正常大鼠尾静脉注射MKK6b(E)2.5 mL/kg。用荧光强度检测微血管通透性;用荧光染色法观察微血管内皮细胞骨架蛋白的形态。结果糖尿病大鼠的微血管通透性明显高于正常组;注射MKK6b(E)可以增高大鼠微血管的通透性,而注射MKK6b(A)后微静脉的高通透性则被抑制。结论P38 MAPK信号转导系统参与介导了糖尿病微血管通透性增高的反应过程。     

Stress hyperglycemia is associated with in‐hospital mortality in patients with diabetes and acute ischemic stroke

Background and ObjectiveStress hyperglycemia may occur in diabetic patients with acute severe cerebrovascular disease, but the results regarding its association with stroke outcomes are conflicting. This study aimed to examine the association between stress‐induced hyperglycemia and the occurrence of in‐hospital death in patients with diabetes and acute ischemic stroke.Research Design and MethodsAll data were from the Chinese Stroke Center Alliance (CSCA) database and were collected between 2016 and 2018 from >300 centers across China. Patients’ demographics, clinical presentation, and laboratory data were extracted from the database. The primary endpoint was in‐hospital death. The ratio of fasting blood glucose (FBG) to HbA1c was calculated, that is, the stress‐induced hyperglycemia ratio (SHR), to determine stress hyperglycemia following acute ischemic stroke.ResultsA total of 168,381 patients were included. The mean age was 66.2 ± 10.7, and 77,688 (43.0%) patients were female. The patients were divided into two groups: survivors (n = 167,499) and non‐survivors (n = 882), as well as into four groups according to their SHR quartiles (n = 42,090–42,099/quartile). There were 109 (0.26%), 142 (0.34%), 196 (0.47%), and 435 (1.03%) patients who died in the Q1, Q2, Q3, and Q4 quartiles, respectively. Compared with Q1 patients, the death risk was higher in Q4 patients (odds ratio (OR) = 4.02) (adjusted OR = 1.80, 95% confidence interval [CI] = 1.10–2.92, p = 0.018 after adjustment for traditional cardiovascular risk factors). The ROC analyses showed that SHR (AUC = 0.667, 95% CI: 0.647–0.686) had a better predictive value for mortality than that of fasting blood glucose (AUC = 0.633, 95% CI: 0.613–0.652) and HbA1c (AUC = 0.523, 95% CI: 0.504–0.543).ConclusionsThe SHR may serve as an accessory parameter for the prognosis of patients with diabetes after acute ischemic stroke. Hyperglycemia in stroke patients with diabetes mellitus is associated with a higher risk of in‐hospital death.