Randomized Pharmacodynamic and Pharmacogenetic Trial of Dronabinol Effects on Colon Transit in Irritable Bowel Syndrome-Diarrhea

Table of Contents







Introduction to Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is one of the most popular gastrointestinal disabilities in the regular community globally, with an incidence varying from 5%-20% [3]. It is a chronic bowel syndrome wherein the defecation or a shift in gastrointestinal behaviors is linked to stomach pain or irritation. It is detected more often in females than males and individuals younger than 50 years old [17]. It includes natural symptoms such as an allergy to lactose and feckless diarrhea. However, Drossman, Whitehead, and Camilleri stated that in Europe and the United States, gastrointestinal motility has been proven as a significant field of study [5]. Moreover, Manning confirmed that IBS had a diverse series of effects from many other natural disorders, like bowel tumours or inflammatory bowel disease [12]. Furthermore, recognizing IBS pathogenicity is necessary as the established pathophysiological functions of IBS are continuing to be targeted by today's modern pharmacotherapy agents [13]. IBS is categorized as either diarrhea-predominant (IBS-D), constipation-predominant (IBS-C), or mixed model (IBS-M) or pain prevalent, as per the WHO DMS-IV code specification for IBS and its subgroups [14]

The main objective of this study is to determine the colonic transition effect of a Cannabinoid receptor1 agonist in IBS patients. The report is focusing on different aspects: background, a summary of the article, evaluation by considering its strength and limitations, and discussion related to the same. Finally, it concludes the paper.

Background of Irritable Bowel Syndrome

Severe constipation is handled based on the removal of any organic disorder. For the first-line treatment, over-the-counter (OTC) medicines such as osmotic or stimulant painkillers, fiber, and prokinetics are required in IBS-C. But a significant percentage of patients remained symptomatic. Sonu, Triadafilopoulos and Gardner discussed that for lessening indigestion, modern pharmacological products like lubiprostone and naloxegol possess improvement over placebo [16]. But they are not independent of adverse events (AEs) like stomach discomfort or diarrhea. However, many researchers suggested that reverse agonists of the cannabinoid receptor (CB) have appeared possible sources for IBS-C therapy [7].

A number of gastrointestinal behaviours, like pain control, irritation, and colonic motility, are manipulated by cannabinoid receptors. Moreover, many researchers reported two different categories of cannabinoid receptors that are G-protein-coupled, CB1, and CB2 [10]. Moreover, Begg mentioned that a third cannabinoid receptor, as though uncloned, may exist [2]. CB1 immunoreactivity is found in the typical colonic epithelium, soft muscles, and myenteric cortex, while plasma cells possess both CB1 and CB2 receptors [19]. However, Hillard demonstrates that the endocannabinoid structure (ECS) comprises of CB1 and CB2 receptors [8]. The ECS also consists of anandamide and 2-arachidonyl glycerol that are the binding sites of such receptors, and monoacylglycerol lipase (MGLL) and fatty acid amide hydrolase (FAAH) (the receptor-inactivating enzymes).

Mallat further mentioned that it communicates within its routes and also with all the inflammatory channels [11]. The gene expressing CB1 is cannabinoid receptor 1 (CNR1). There was a strong correlation between the CNR1 rs806378 gene and the syndrome phenotype, with IBS-D colonic transit (quickest colonic transport) and pressure feeling but not pain throughout colonic rupture [4]. Moreover, Hinds discussed that in the human colonic curved organ, the stimulation of CB1 receptors paired with cholinergic sensory nerves prevents excitatory impulse distribution [9]. Without modifying intraluminal load or cortical tones in rodents, ECS prevents gastrointestinal and small intestinal transmission [15].

However, Esfandyari introduced dronabinol (DRO), a non - selective CB receptor agonist, stimulates gastrointestinal, and colonic digestion in healthy individuals [6]. It is a delta-9-tetrahydrocannabinol ('9-THC) synthetic. It undertakes significant hepatic first-pass activation, mainly by enzyme hydrolysis, forming both active and unresponsive metabolism. The influence of 7.5 mg DRO on colonic tone and phasic motility was detected, which also caused adverse symptoms of sleepiness, nausea, and blurred vision. Amongst healthier people, the 5 mg DRO dose seems to be more acceptable. Genetic variation in endocannabinoid metabolites in the FAAH genome was correlated with effects and colonic transition in people with irritable bowel syndrome (IBS) with diarrhea (IBS-D). Therefore, it is necessary to analyze the possible impacts of genetic variants in DRO therapy.

Summary of Irritable Bowel Syndrome

We presumed that DRO restricts colonic movement in IBS and that difference in the genomes for the CB1 receptor (CNR1) and FAAH, the rate-limiting destruction inhibitor of the endocannabinoid anandamide, attenuate the inhibitory activity. In this article, we have evaluated the impact of an oral placebo, DRO 2.5 mg, and DRO 5 mg on gastrointestinal, small intestine, and colonic migration in the cannabinoid (CB)-naive IBS-D patients. It has been done during two successive days of twice-daily management and investigates the possible impacts of genetic differences in CNR1 and FAAH on the transition outcomes of DRO therapy.

This article makes use of DRO pharmacogenetics that directed us to prefer a study layout that demanded just 2 days of therapy to examine the intense symptoms of DRO, compared to 7-10 days of rehabilitation that might demand steady-state drug doses as shown in figure 1.

 The appropriate techniques like qualifications records, monitoring surveys, and medical assessment during the previous month has been conducted by all participants. Also, Gastric, small intestine, and colonic movement scintigraphic measures were used on days 1 and 2 and finished with a 48-hour fasting analysis on day 3, if no medicine were provided. For the evaluation of such measures, standardized radioscintigraphy has been used and also, the specific nucleotide polymorphisms CNR1 rs806378 and FAAH rs324420 were analyzed using it. To resolve the effect of pharmacogenetics on the transition approach to DRO, two gene factors (FAAH and CB1) were suggested.

36 IBS-D representatives were allocated to twice per day PLA (n = 13), DRO 2.5 mg (n = 10), or DRO 5 mg (n = 13) for 2 days (double-blind, secret management). A maximum of 13 helpers earned randomized placebo BID, 10 obtained 2.5 mg BID for DRO, and 13 collected 5 mg BID for DRO. Due to an unexpected incident, one patient in the DRO 5 mg category abandoned treatment, and such results were ascertained in compliance with the statistical analysis strategy. However, the table in Figure. 2 outlines the patient statistics through rehabilitation teams.

No pharmacodynamic effects were reported for gastric (P = 0.88), small intestine (P = 0.76) and colonic transition (overall P = 0.23; 2.5 mg DRO vs placebo, P = 0.16; 5 mg DRO vs placebo, P = 0.53) (Figure 3). Related to the slowing impact of the 2.5- and 5-mg DRO doses in the CNR1 rs806378 CT / TT genotype category, possible genotype-associated differential therapeutic impacts were discussed by contrasting placebo with the joint DRO dose sets. The statistical slowing of colonic transition at 24 h and the post-pre shift in the colonic movement at 24 h were supported in the placebo-related CT / TT genotype population (Figure 4).

Evaluation of Irritable Bowel Syndrome

Bashashati demonstrated that CB stimulation with the inhibitors of the CB1 and CB2 receptor and the regulator of FAAH, AM3506, can influence visceral feeling or gastrointestinal transit and colonic fecal production in endotoxin-exposed mice [1]. In human trials, the results on irritation or visceral experiences were also discouraging. However, our analysis shows the ability of CB agents in IBS-D to attenuate colonic activity.

The strong points of our research encompass the standardized procedures used for evaluating gastrointestinal and colonic transit, the clinical importance of the measurement employed as the main result (colonic GC24). Also, the incorporation of pharmacogenetic review used to determine if genetic variability in CB signalling or metabolism will regulate DRO's influence.

The limitations of this research are the measurement over 2 days with just four DRO doses and the non-selective presence of DRO for CB1 and CB2 receptors. However, in our work, the study of genotype-dependent differential drug results was constrained by the sample size and by the larger than usual variance found in delta GC24. In our work, there was only a 52% intensity to recognize the 'gene-by-treatment interactions (Figure 4). However, the standard power needed for detecting gene-by-treatment correlations is roughly 80%. Thus, we need nearly 40 patients per therapeutic group by considering the common distribution of genotypes for every group to attain 80 percent energy in GC24 of 1.44.

Discussion on Irritable Bowel Syndrome

Our research demonstrates that colonic transition is not greatly impacted by the non-selective CB receptor agonist, DRO. Furthermore, in a subgroup of IBS-D patients, DRO can suppress colonic transit, depending on a particular gene deviation in CB1. In diarrhea-predominant IBS patients, a specific CB1 agonist could have the ability as a treatment.

Future research studies are required to determine the beneficial purpose of specific CB receptor agonists in IBS. Also, the application of stratification focused on the genetic variant CNR1 rs806378 or the utilization of gene variability as a control variable in the interpretation of outcomes can improve medical trials. A further CB pharmacogenetics research can assist to recognise a group of patients with IBS-D who are more prone to recover from CB agonist therapy.

References for Irritable Bowel Syndrome

[1] Bashashati M, Storr MA, Nikas SP, Wood JT, Godlewski G, Liu J, Ho et al. Inhibiting fatty acid amide hydrolase normalizes endotoxin-induced enhanced gastrointestinal motility in mice. British Journal of Pharmacology. 2012;165(5):1556–1571. Available from: https://doi.org/10.1111/j.1476-5381.2011.01644.x

[2] Begg M, Pacher P, Batkai S, Osei-Hyiaman D, Offertaler L, Mo FM L et al. Evidence for novel cannabinoid receptors. Pharmacology & Therapeutics. 2005;106(2):133–145. Available from: https://doi.org/10.1016/j.pharmthera.2004.11.005

[3] Brandt LJ, Chey W, Foxx-Orenstein AE, Schiller LR, Schoenfeld P, Spiegel B et al. An Evidence-Based Position Statement on the Management of Irritable Bowel Syndrome. The American Journal of Gastroenterology. 2009;1(4):S1-S35. Available from: 10.1038/ajg.2008.122.

[4] Camilleri M, Kolar G J, Vazquez-Roque MI, Carlson P, Burton DD, Zinsmeister AR. Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits. American Journal of Physiology. 2013;304(5):G553–G560. Available from: https://doi.org/10.1152/ajpgi.00376.2012

[5] Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology. 1997;112(6):2120–2137. Available from: https://doi.org/10.1053/gast.1997.v112.agast972120

[6] Esfandyari T, Camilleri M, Busciglio I, Burton D, Baxter K, Zinsmeister AR. Effects of a cannabinoid receptor agonist on colonic motor and sensory functions in humans: a randomized, placebo-controlled study. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2007; 293(1): G137–G145. Available from: https://doi.org/10.1152/ajpgi.00565.2006

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[8] Hillard C J. Biochemistry and pharmacology of the endocannabinoids arachidonylethanolamide and 2-arachidonylglycerol. Prostaglandins & Other Lipid Mediators. 2000;61(1-2):3–18. Available from: https://doi.org/10.1016/s0090-6980(00)00051-4

[9] Hinds NM, Ullrich K, Smid SD. Cannabinoid 1 (CB1) receptors coupled to cholinergic motorneurones inhibit neurogenic circular muscle contractility in the human colon. British Journal of Pharmacology. 2006;148(2):191–199. Available from: https://doi.org/10.1038/sj.bjp.0706710

[10] Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacological Reviews. 2002;54(2):161-202. Available from: https://doi.org/10.1124/pr.54.2.161

[11] Mallat A, Teixeira-Clerc F, Deveaux V, Manin S, Lotersztajn S. The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings. British Journal of Pharmacology. 2011;163(7):1432–1440. Available from: https://doi.org/10.1111/j.1476-5381.2011.01397.x

[12] Manning AP, Thompson WG, Heaton KW, Morris AF. Towards positive diagnosis of the irritable bowel. British Medical Journal. 1978; 2(6138):653–654. Available from: https://doi.org/10.1136/bmj.2.6138.653

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[15] Shook JE, Burks TF. Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents. The Journal of Pharmacology And Experimental Therapeutics. 1989;249(2):444–449.

[16] Sonu I, Triadafilopoulos G, Gardner J. Persistent constipation and abdominal adverse events with newer treatments for constipation. BMJ Open Gastroenterology. 2016;3. Available from: https://doi.org/10.1136/bmjgast-2016-000094

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[18] Wong BS, Camilleri M, Eckert D, Carlson P, Ryks M, Burton D et al. Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea. Neurogastroenterology and Motility : The Official Journal of The European Gastrointestinal Motility Society. 2012;24(4):358–e169. Available from: https://doi.org/10.1111/j.1365-2982.2011.01874.x

[19] Wright K, Rooney N, Feeney M, Tate J, Robertson D, Welham M, et al. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology. 2005;129(2):437–453. Available from: https://doi.org/10.1016/j.gastro.2005.05.026

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