Category Archives: Cancer

Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting: beyond prevention of acute emesis.

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Abstract

“Chemotherapy-induced nausea and vomiting (CINV) remains a significant problem in the care of cancer patients. Although the use of serotonin (5-HT3) receptor antagonists, as well as neurokinin-1 inhibitors, has reduced rates of acute emesis, many patients still experience acute vomiting; moreover, these agents have reduced efficacy in preventing nausea, delayed CINV, and breakthrough CINV. Nausea, in particular, continues to have a major–and often overlooked–impact on patients’ quality of life. Optimizing the treatment for CINV likely will involve combinations of agents that inhibit the numerous neurotransmitter systems involved in nausea and vomiting reflexes. Cannabinoids are active in many of these systems, and two oral formulations, dronabinol (Marinol) and nabilone (Cesamet), are approved by the US Food and Drug Administration for use in CINV refractory to conventional antiemetic therapy. Agents in this class have shown superiority to dopamine receptor antagonists in preventing CINV, and there is some evidence that the combination of a dopamine antagonist and cannabinoid is superior to either alone and is particularly effective in preventing nausea. The presence of side effects from the cannabinoids may have slowed their adoption into clinical practice, but in a number of comparative clinical trials, patients have expressed a clear preference for the cannabinoid, choosing its efficacy over any undesired effects. Improvement in antiemetic therapy across the entire spectrum of CINV will involve the use of agents with different mechanisms of action in concurrent or sequential combinations, and the best such combinations should be identified. In this effort, the utility of the cannabinoids should not be overlooked.”

http://www.ncbi.nlm.nih.gov/pubmed/17566383

Regulation of nausea and vomiting by cannabinoids.

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“Anti-emetic effects of cannabinoids in human clinical trials”

  “Considerable evidence demonstrates that manipulation of the endocannabinoid system regulates nausea and vomiting in humans and other animals. The anti-emetic effect of cannabinoids has been shown across a wide variety of animals that are capable of vomiting in response to a toxic challenge. CB1 agonism suppresses vomiting, which is reversed by CB1 antagonism, and CB1 inverse agonism promotes vomiting. Recently, evidence from animal experiments suggests that cannabinoids may be especially useful in treating the more difficult to control symptoms of nausea and anticipatory nausea in chemotherapy patients, which are less well controlled by the currently available conventional pharmaceutical agents. Although rats and mice are incapable of vomiting, they display a distinctive conditioned gaping response when re-exposed to cues (flavours or contexts) paired with a nauseating treatment. Cannabinoid agonists (Δ9-THC, HU-210) and the fatty acid amide hydrolase (FAAH) inhibitor, URB-597, suppress conditioned gaping reactions (nausea) in rats as they suppress vomiting in emetic species. Inverse agonists, but not neutral antagonists, of the CB1 receptor promote nausea, and at subthreshold doses potentiate nausea produced by other toxins (LiCl). The primary non-psychoactive compound in cannabis, cannabidiol (CBD), also suppresses nausea and vomiting within a limited dose range. The anti-nausea/anti-emetic effects of CBD may be mediated by indirect activation of somatodendritic 5-HT1A receptors in the dorsal raphe nucleus; activation of these autoreceptors reduces the release of 5-HT in terminal forebrain regions. Preclinical research indicates that cannabinioids, including CBD, may be effective clinically for treating both nausea and vomiting produced by chemotherapy or other therapeutic treatments.”

“The cannabis plant has been used for several centuries for a number of therapeutic applications, including the attenuation of nausea and vomiting. Ineffective treatment of chemotherapy-induced nausea and vomiting prompted oncologists to investigate the anti-emetic properties of cannabinoids in the late 1970s and early 1980s, before the discovery of the 5-HT3 antagonists. The first cannabinoid agonist, nabilone (Cesamet), which is a synthetic analogue of Δ9-THC was specifically licensed for the suppression of nausea and vomiting produced by chemotherapy. Furthermore, synthetic Δ9-THC, dronabinol, entered the clinic as Marinol in 1985 as an anti-emetic and in 1992 as an appetite stimulant. In these early studies, several clinical trials compared the effectiveness of Δ9-THC with placebo or other anti-emetic drugs. Comparisons of oral Δ9-THC with existing anti-emetic agents generally indicated that Δ9-THC was at least as effective as the dopamine antagonists, such as prochlorperazine.”

“There is some evidence that cannabis-based medicines may be effective in treating the more difficult to control symptoms of nausea and delayed nausea and vomiting in children. Abrahamov et al. (1995) evaluated the anti-emetic effectiveness of Δ8-THC, a close but less psychoactive relative of Δ9-THC, in children receiving chemotherapy treatment. Two hours before the start of each cancer treatment and every six hours thereafter for 24 h, the children were given Δ8-THC as oil drops on the tongue or in a bite of food. After a total of 480 treatments, the only side effects reported were slight irritability in two of the youngest children (3.5 and 4 years old); both acute and delayed nausea and vomiting were controlled.”

“Chemotherapy-induced vomiting is well controlled in most patients by conventionally available drugs, nausea (acute, delayed and anticipatory) continues to be a challenge. Nausea is often reported as more distressing than vomiting, because it is a continuous sensation. Indeed, this distressing symptom of chemotherapy treatment (even when vomiting is pharmacologically controlled) can become so severe that as many as 20% of patients discontinue the treatment. Both preclinical and human clinical research suggests that cannabinoid compounds may have promise in treating nausea in chemotherapy patients.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165951/

Mechanism of action of cannabinoids: how it may lead to treatment of cachexia, emesis, and pain.

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Image result for The Journal of Supportive Oncology

“Many patients with life-threatening diseases such as cancer experience severe symptoms that compromise their health status and deny them quality of life. Patients with cancer often experience cachexia, pain, and depression,which translate into an unacceptable quality of life. The discovery of the endocannabinoid system has led to a renewed interest in the use of cannabinoids for the management of nausea, vomiting, and weight loss arising either from cancer or the agents used to treat cancer. The endocannabinoid system has been found to be a key modulator of systems involved in pain perception, emesis, and reward pathways. As such, it represents a target for development of new medications for controlling the symptoms associated with cancer. Although the cannabinoid receptor agonist tetrahydrocannabinol and one of its analogs are currently the only agents approved for clinical use, efforts are under way to devise other strategies for activating the endocannabinoid system for therapeutic uses.”

http://www.ncbi.nlm.nih.gov/pubmed/15357514

The emerging role of cannabinoid neuromodulators in symptom management.

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Abstract

“INTRODUCTION:

The cannabinoids nabilone (Cesamet) and dronabinol (Marinol) are indicated for the management of chemotherapy-induced nausea and vomiting (CINV) in cancer patients who have failed to respond adequately to conventional antiemetic therapy.

DISCUSSION:

The endocannabinoid (CB) system interacts with numerous other systems and pharmaceutical cannabinoids target ubiquitous CB1 and CB2 receptors in the central nervous system and periphery, relieving nausea and vomiting and pain.

SUMMARY:

The benefits of this novel class of medications in cancer may extend beyond CINV, as indicated by data from preclinical studies and animal models.”

http://www.ncbi.nlm.nih.gov/pubmed/17139494

Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid.

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Abstract

   “One of the endogenous transformation products of tetrahydrocannabinol (THC) is THC-11-oic acid, and ajulemic acid (AJA; dimethylheptyl-THC-11-oic acid) is a side-chain synthetic analog of THC-11-oic acid. In preclinical studies, AJA has been found to be a potent anti-inflammatory agent without psychoactive properties. Based on recent reports suggesting antitumor effects of cannabinoids (CBs), we assessed the potential of AJA as an antitumor agent. AJA proved to be approximately one-half as potent as THC in inhibiting tumor growth in vitro against a variety of neoplastic cell lines. However, its in vitro effects lasted longer. The antitumor effect was stereospecific, suggesting receptor mediation. Unlike THC, however, whose effect was blocked by both CB(1) and CB(2) receptor antagonists, the effect of AJA was inhibited by only the CB(2) antagonist. Additionally, incubation of C6 glioma cells with AJA resulted in the formation of lipid droplets, the number of which increased over time; this effect was noted to a much greater extent after AJA than after THC and was not seen in WI-38 cells, a human normal fibroblast cell line. Analysis of incorporation of radiolabeled fatty acids revealed a marked accumulation of triglycerides in AJA-treated cells at concentrations that produced tumor growth inhibition. Finally, AJA, administered p.o. to nude mice at a dosage several orders of magnitude below that which produces toxicity, inhibited the growth of subcutaneously implanted U87 human glioma cells modestly but significantly. We conclude that AJA acts to produce significant antitumor activity and effects its actions primarily via CB(2) receptors. Its very favorable toxicity profile, including lack of psychoactivity, makes it suitable for chronic usage. Further studies are warranted to determine its optimal role as an antitumor agent.”

http://www.ncbi.nlm.nih.gov/pubmed/11551521

Cannabinoids for the treatment of inflammation.

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“Cannabinoids are effective at suppressing immune and inflammation functions in leukocytes in vitro, and in animal models of acute inflammation, such as the mouse hind paw, ear and air pouch models, as well as gastrointestinal, pulmonary, myocardial, vascular, periodontal, neural, hepatic, pancreatic and arthritic inflammation models.

The non-psychoactive cannabinoid receptor CB2 is emerging as a critical target for cannabinoid regulation of inflammation, and thus CB2-selective agonists are undergoing intense investigation and research. This review discusses the evidence for cannabinoid regulation of inflammation across a range of models and highlights the most promising drug candidates.”

http://www.ncbi.nlm.nih.gov/pubmed/17520866

Cannabinoid-based drugs as anti-inflammatory therapeutics.

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“In the nineteenth century, marijuana was prescribed by physicians for maladies ranging from eating disorders to rabies. However, as newer, more effective drugs were discovered and as the potential for abuse of marijuana was recognized, its use as a therapeutic became restricted, and only recently has its therapeutic potential been re-evaluated.

 

 Recent studies in animal models and in humans have produced promising results for the treatment of various disorders – such as obesity, cancer, and spasticity and tremor due to neuropathology – with drugs based on marijuana-derived cannabinoids.

 

 Moreover, as I discuss here, a wealth of information also indicates that these drugs have immunosuppressive and anti-inflammatory properties; therefore, on the basis of this mode of action, the therapeutic usefulness of these drugs in chronic inflammatory diseases is now being reassessed.”

 

http://www.ncbi.nlm.nih.gov/pubmed/15864274

Cannabinoids as novel anti-inflammatory drugs

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Figure 1

“Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors. The discovery of Δ9-tetrahydrocannabinol (THC) as the major psychoactive principle in marijuana, as well as the identification of cannabinoid receptors and their endogenous ligands, has led to a significant growth in research aimed at understanding the physiological functions of cannabinoids. Cannabinoid receptors include CB1, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system. The fact that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids play an important role in the regulation of the immune system. Recent studies demonstrated that administration of THC into mice triggered marked apoptosis in T cells and dendritic cells, resulting in immunosuppression. In addition, several studies showed that cannabinoids downregulate cytokine and chemokine production and, in some models, upregulate T-regulatory cells (Tregs) as a mechanism to suppress inflammatory responses. The endocannabinoid system is also involved in immunoregulation. For example, administration of endocannabinoids or use of inhibitors of enzymes that break down the endocannabinoids, led to immunosuppression and recovery from immune-mediated injury to organs such as the liver. Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo can constitute a potent treatment modality against inflammatory disorders. This review will focus on the potential use of cannabinoids as a new class of anti-inflammatory agents against a number of inflammatory and autoimmune diseases that are primarily triggered by activated T cells or other cellular immune components.”

“Cannabis, commonly known as marijuana, is a product of the Cannabis sativa plant and the active compounds from this plant are collectively referred to as cannabinoids. For several centuries, marijuana has been used as an alternative medicine in many cultures and, recently, its beneficial effects have been shown in: the treatment of nausea and vomiting associated with cancer chemotherapy; anorexia and cachexia seen in HIV/AIDS patients; and in neuropathic pain and spasticity in multiple sclerosis. Cannabinoid pharmacology has made important advances in recent years after the discovery of the cannabinoid receptors (CB1 and CB2). Cannabinoid receptors and their endogenous ligands have provided an excellent platform for the investigation of the therapeutic effects of cannabinoids. It is well known that CB1 and CB2 are heterotrimeric Gi/o-protein-coupled receptors and that they are both expressed in the periphery and the CNS. However, CB1 expression is predominant in the CNS, especially on presynaptic nerves, and CB2 is primarily expressed on immune cells.”

“Cannabinoids are potent anti-inflammatory agents and they exert their effects through induction of apoptosis, inhibition of cell proliferation, suppression of cytokine production and induction of T-regulatory cells (Tregs).”

“Executive summary

  • Cannabinoids, the active components of Cannabis sativa, and endogenous cannabinoids mediate their effects through activation of specific cannabinoid receptors known as cannabinoid receptor 1 and 2 (CB1 and CB2).
  • The cannabinoid system has been shown both in vivo and in vitro to be involved in regulating the immune system through its immunomodulatory properties.
  • Cannabinoids suppress inflammatory response and subsequently attenuate disease symptoms. This property of cannabinoids is mediated through multiple pathways such as induction of apoptosis in activated immune cells, suppression of cytokines and chemokines at inflammatory sites and upregulation of FoxP3+ regulatory T cells.
  • Cannabinoids have been tested in several experimental models of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, colitis and hepatitis and have been shown to protect the host from the pathogenesis through induction of multiple anti-inflammatory pathways.
  • Cannabinoids may also be beneficial in certain types of cancers that are triggered by chronic inflammation. In such instances, cannabinoids can either directly inhibit tumor growth or suppress inflammation and tumor angiogenesis.”                      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/

News about therapeutic use of cannabis and endocannabinoid system.

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“Growing basic research in recent years led to the discovery of the endocannabinoid system with a central role in neurobiology. New evidence suggests a therapeutic potential of cannabinoids in cancer chemotherapy-induced nausea and vomiting as well as in pain, spasticity and other symptoms in multiple sclerosis and movement disorders. Results of large randomized clinical trials of oral and sublingual Cannabis extracts will be known soon and there will be definitive answers to whether Cannabis has any therapeutic potential. Although the immediate future may lie in plant-based medicines, new targets for cannabinoid therapy focuses on the development of endocannabinoid degradation inhibitors which may offer site selectivity not afforded by cannabinoid receptor agonists.”  http://www.ncbi.nlm.nih.gov/pubmed/15033046

http://www.elsevier.es/es-revista-medicina-clinica-2-linkresolver-novedades-sobre-las-potencialidades-terapeuticas-13059327

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

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Philosophical Transactions of the Royal Society B: Biological Sciences: 367 (1607)

“Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released ‘endocannabinoids’ or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive ‘multi-targeting’.”  https://www.ncbi.nlm.nih.gov/pubmed/23108552

“Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities”  http://rstb.royalsocietypublishing.org/content/367/1607/3353.long