Category Archives: Gastrointestinal Disorders

Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides.

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“The endogenous cannabinoid system (ECS) plays a crucial role in multiple physiological processes in the central nervous system and in the periphery. The discovery that selective cannabinoid (CB) receptor agonists exert a potent inhibitory action on gastrointestinal (GI) motility and pain has placed the ECS in the center of attention as a possible target for the treatment of functional GI diseases…

These data expand our understanding of the ECS function and provide a novel framework for the development of future potential treatments of functional GI disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24460851

Therapeutic potential of cannabinoid medicines.

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Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract

Acute Δ9-tetrahydrocannabinol blocks gastric hemorrhages induced by the nonsteroidal anti-inflammatory drug diclofenac sodium in mice.

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“Nonsteroidal anti-inflammatory drugs (NSAIDs), which are among the most widely used analgesics in the world, cause gastrointestinal inflammation that is potentially life-threatening.

Although inhibitors of endocannabinoid catabolic enzymes protect against gastropathy in fasted NSAID-treated mice, the gastroprotective effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana, have yet to be investigated…

 These data indicate that the phytocannabinoid Δ9-THC protects against diclofenac-induced gastric inflammatory tissue damage at doses insufficient to cause common cannabinoid side effects.”

http://www.ncbi.nlm.nih.gov/pubmed/23769745

Intractable nausea and vomiting due to gastrointestinal mucosal metastases relieved by tetrahydrocannabinol (dronabinol).

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“Four years following resection of a Clark’s level IV malignant melanoma, a 50-year-old man developed widespred metastatic disease involving the liver, bones, brain, gastrointestinal mucosa, and lungs. One week after whole brain radiation therapy, he was admitted to the hospital for nausea, vomiting, and pain.

He was treated with several antiemetic drugs, but it was not until dronabinol was added that the nausea and vomiting stopped.

Dronabinol was an effective antiemetic used in combination with prochlorperazine in nausea and vomiting unresponsive to conventional antiemetics.”

http://www.ncbi.nlm.nih.gov/pubmed/9392925

Psychoactive cannabinoids reduce gastrointestinal propulsion and motility in rodents.

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“Marijuana has been reported to be an effective antinauseant and antiemetic in patients receiving cancer chemotherapy.

Whether this is due to psychological changes, central antiemetic properties and/or direct effects on gastrointestinal (GI) function is not known. The purpose of these investigations was to determine whether the major constituents of marijuana and the synthetic cannabinoid nabilone have any effects on GI function which can be detected in rodent models of GI transit and motility. Intravenous delta 9-tetrahydrocannabinol (delta 9-THC) slowed the rate of gastric emptying and small intestinal transit in mice and in rats. Delta 9,11-THC, cannabinol and nabilone given i.v. also inhibited small intestinal transit in mice, but were less effective in reducing gastric emptying. Cannabidiol given i.v. had no effect on gastric emptying or intestinal transit. Those cannabinoids which inhibited GI transit did so at doses equal to, or lower, than those reported to produce central nervous system activity. In rats, delta 9-THC produced greater inhibition of gastric emptying and small intestinal transit than large bowel transit, indicating a selectivity for the more proximal sections of the gut. In addition, i.v. delta 9-THC decreased the frequency of both gastric and intestinal contractions without altering intraluminal pressure. Such changes probably reflect a decrease in propulsive activity, without change in basal tone.

These data indicate that delta 9-THC, delta 9,11-THC, cannabinol and nabilone (but not cannabidiol) exert an inhibitory effect on GI transit and motility in rats.”

http://www.ncbi.nlm.nih.gov/pubmed/2542532

Pharmacological synergism between cannabinoids and paclitaxel in gastric cancer cell lines.

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“Orally applicable Delta9-tetrahydrocannabinol and its synthetic derivatives have been used as antiemetic drugs during chemotherapy in cancer patients.

 However, it is not well known how cannabinoids influence the effects of chemotherapeutic agents on malignant tumors. In this study, we investigated how the endogenous cannabinoid anandamide (AEA) changes the effect of paclitaxel on gastric cancer cell lines.

 In the human gastric cancer cell line, HGC-27, which express cannabinoid receptor 1 (CB1), AEA stimulated proliferation at concentrations under 1 microM, while it strongly suppressed proliferation through the induction of apoptosis at 10 microM. This bimodal effect was reproduced by a selective CB1 agonist, arachidonyl-2-chloroethylamide, although the effects were less marked. When AEA was used with paclitaxel, AEA at 10 microM synergistically enhanced the cytotoxic effect of paclitaxel, whereas it showed no significant effect at lower concentrations. Flow cytometric analysis revealed that addition of 10 microM AEA synergistically enhanced paclitaxel-induced apoptosis, possibly through the activation of caspase-3, -8, and -9.

Our results suggest that cannabinoids could be a good palliative agent for cancer patients receiving paclitaxel.”

http://www.ncbi.nlm.nih.gov/pubmed/19394652

Effect of a synthetic cannabinoid agonist on the proliferation and invasion of gastric cancer cells.

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“Although cannabinoids are associated with antineoplastic activity in a number of cancer cell types, the effect in gastric cancer cells has not been clarified. In the present study, we investigated the effects of a cannabinoid agonist on gastric cancer cell proliferation and invasion.

The cannabinoid agonist WIN 55,212-2 inhibited the proliferation of human gastric cancer cells in a dose-dependent manner and that this effect was mediated partially by the CB(1) receptor. We also found that WIN 55,212-2 induced apoptosis and down-regulation of the phospho-AKT expression in human gastric cancer cells. Furthermore, WIN 55,212-2 treatment inhibited the invasion of gastric cancer cells, and down-regulated the expression of MMP-2 and VEGF-A through the cannabinoid receptors.

Our results open the possibilities in using cannabinoids as a new gastric cancer therapy.”

http://www.ncbi.nlm.nih.gov/pubmed/20336665

Antiproliferative mechanism of a cannabinoid agonist by cell cycle arrest in human gastric cancer cells.

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“For gastric cancers, the antineoplastic activity of cannabinoids has been investigated in only a few reports and knowledge regarding the mechanisms involved is limited. We have reported previously that treatment of gastric cancer cells with a cannabinoid agonist significantly decreased cell proliferation and induced apoptosis.

Here, we evaluated the effects of cannabinoids on various cellular mediators involved in cell cycle arrest in gastric cancer cells. AGS and MKN-1 cell lines were used as human gastric cancer cells and WIN 55,212-2 as a cannabinoid agonist.

 …Cell cycle arrest preceded apoptotic response. Thus, this cannabinoid agonist can reduce gastric cancer cell proliferation via G1 phase cell cycle arrest, which is mediated via activation of the MAPK pathway and inhibition of pAKT.”

http://www.ncbi.nlm.nih.gov/pubmed/21312237

Cannabinoid Receptor Agonist as an Alternative Drug in 5-fluorouracil-resistant Gastric Cancer Cells.

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“Fluorouracil is the main chemotherapeutic drug used for gastrointestinal cancers, which suffers the important problem of treatment resistance. There is little information whether cannabinoid agonists can be used as an alternative drug for fluorouracil-resistant gastric cancer cells. In this study, we investigated the effects of a cannabinoid agonist, WIN-55,212-2, on 5-fluorouracil (5-FU)-resistant human gastric cancer cells, to examine whether the cannabinoid agonist may be an alternative therapy.

These results indicate that a cannabinoid agonist may, indeed, be an alternative chemotherapeutic agent for 5-FU-resistant gastric cancer.”

http://www.ncbi.nlm.nih.gov/pubmed/23749906

The endocannabinoid system and its therapeutic exploitation.

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Image result for Nat Rev Drug Discov.

“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.”  http://www.ncbi.nlm.nih.gov/pubmed/15340387

http://www.nature.com/nrd/journal/v3/n9/full/nrd1495.html