Cancer emesis

Dronabinol (tetrahydrocannabinol), the active principle from cannabis and synthetic cannabinoids, nabilone and levonantradol are effective in treating nausea and vomiting in cancer chemotherapy. The mode of action is unclear but appears to involve cannabinoid CBi receptors. Cannabinoids have been shown to reduce acetylcholine release in the cortex and hippocampus, and have been suggested to inhibit medullary activity by a cortical action. Inhibition of prostaglandin synthesis and release of endorphins may also be involved in the antiemetic effect. A review of trials of dronabinol, nabilone or levonantradol concluded that while the cannabinoids were superior to placebo or dopamine receptor antagonists in controlling emesis... 

The Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (2006) Prevention of chemotherapy- and radiotherapy-induced emesis results of the Perugia International Antiemetic Consensus Conference. Ann Oncol 17 20-28... 

Aapro MS 5-HT3 receptor antagonists an overview of their present status and future potential in cancer therapy-induced emesis. Drugs 42 551-568, 1991... 

The present review covers progress in medical chemistry, basic mechanisms of emesis, role of serotonergic mechanism, and treatment of cancer-chemotherapy-induced emesis. 

Metoclopramide, administered at doses higher than those required to inhibit apomorphine-induced emesis, was more effective than haloperidol in antagonizing cisplatin-induced emesis in dogs [80]. This was observed despite the fact that metoclopramide was considerably weaker than haloperidol as a D2-dopamine antagonist [43]. Subsequently, antiemetic efficacy of metoclopramide administered at high doses has been reported in cancer patients... 

The following overview is limited to control of emesis induced by cancer chemotherapy and presents more important developments in the last decade. The reader is referred to more extensive reviews and monographs on this subject [30, 37, 122-126]. 

These compounds alone do not have significant antiemetic activity. Their main value is the adjunct use with other agents to decrease anxiety and anticipatory emesis in cancer patients [129]. 

Metoclopramide may be considered as a prototype 5-HT3 antagonist because its antiemetic efficacy both in animals and man could not be adequately explained by D2-dopamine blockade. In fact, metoclopramide was considerably weaker as a D2-antagonist than haloperidol or domperidone and yet it was effective against emesis induced by anticancer agents both in animals [43, 80] and cancer patients [135]. 

Chapter 7 outlines the basic mechanism and treatment of emesis, and in particular, that induced by chemotherapy of cancer. Finally, the chemistry, pharmacology and clinical applications of antagonists of the platelet-activating factor (PAF), an important mediator of many physiological and pathological conditions, are reviewed in Chapter 8. 

Cannabinoid CBj Human cDNA Motor function, memory, analgesia, convulsion, Parkinson s disease, emesis, glaucoma, pain, cancer Modulation of neurotransmitter release, sleep disturbance, weight loss, antiemetic activity locomotor disfunction, bronchodilatation, neuroprotection, memory loss... 

Costall B, Naylor RJ. (1992). Neuropharmacology of emesis in relation to clinical response. BrJ Cancer. 19 S2-7, discussion S7-8. 

Reddy, G.K., Gralla, R.J. and Hesketh, P.J., Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis. Support. Cancer Ther., 2006, 3, 140-142. 

Prevention of chemotherapy-induced emesis Infuse slowly IV over not less than 15 minutes, 30 minutes before beginning cancer chemotherapy repeat every 2 hours for 2 doses, then every 3 hours for 3 doses. 

Ondansetron, other 5-HT3 antagonists 5-HT3 blockade in gut and CNS with shorter duration of binding than alosetron Extremely effective in preventing chemotherapy-induced and postoperative nausea and vomiting First-line agents in cancer chemotherapy also useful for postop emesis Usually given IV but orally active in prophylaxis. 4-9 h duration of action very low toxicity but may slow colonic transit... 

Aprepitant NKj-receptor blocker in CNS Interferes with vomiting reflex no effect on 5-HT, dopamine, or steroid receptors Effective in reducing both early and delayed emesis in cancer chemotherapy Given orally IV fosaprepitant available fatigue, dizziness, diarrhea CYP interactions... 

Ondansetron, granisetron, topisetron, and batanopride are antagonists of the 5HT3 receptor, and are considered effective in controlling cancer-chemotherapy-induced emesis. Clozapine, an effective antipsychotic agent (neuroleptics) with little or no extrapyramidal... 

The 5-HT3 receptors are found in both the peripheral nervous system and central nervous system (CNS), where they mediate last synaptic transmission at synapses (3). In the CNS, they are located predominantly at intemeurones, where they modulate the release of a range of neurotransmitters (4-9). There is some evidence that 5-HT3 receptors play roles in brain reward mechanisms and in neurological phenomena such as anxiety, psychosis, nociception, and cognitive function (10,11), and in the first few years following the discovery of these receptors, there was also much interest in the therapeutic potential of 5-HT3 receptor antagonists for antipsychotic, antinociceptive, and other psychiatric disorders (12-15). This potential has not yet been realized, but there is still active research in this area (16), and their current major therapeutic target is against emesis in cancer chemotherapy and irritable bowel syndrome (17,18). 

Finally, the ability of aprepitant to block emesis, a therapeutically relevant endpoint for the ultimate clinical application of the drug, as discussed below, was tested in the presence of several emetogens in the ferret. This species is believed to be a valid animal model for cancer chemotherapy-induced emesis in humans. Aprepitant (1) effectively blocked retching and vomiting due to cisplatin, apomorphine, and morphine at a dose of 3.0 mg/kg p.o. and 0.3 mg/kg i.v. (in the case of cisplatin).8... 

Corred answer = E. THC is sometimes used to treat the severe emesis caused by cancer chemotherapeutic agents. 

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