Antiemetics cannabinoids

Cannabinoids As the active ingredient in marijuana, Cannabinoids act on the cerebral cortex and are prescribed for cancer patients who do not respond to other antiemetics. Cannabinoids are contraindicated for patients who have glaucoma and psychiatric disorders. These include ... 

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... 

HU-210 is (8.1) among the most potent cannabinoids known. Its enantiomer HU-211 (8.2) does not bind to the cannabinoid receptor and lacks psychotropic side effects (as long as optical purity is guaranteed). In animal models it shows analgesic and antiemetic activity. It also shows neuroprotec-tive effects after brain injury and was tested in humans as anti-traiuna agent, where it did not meet the expectations in a clinical phase III trial. 

Standardised preparations of cannabinoid agonists are available for therapeutic use in some countries [238]. Dronabinol (Marinol ), an oral preparation of A -THC (67), is used clinically as an appetite stimulant in AIDS patients and an antiemetic in cancer chemotherapy. A synthetic analogue of (67), nabilone (Cesamet ), (381), is also used to suppress nausea and vomiting in cancer chemotherapy. 

Cannabinoids have antiemetic activity when used alone or in combination with other antiemetics.5 Dronabinol and nabilone are commercially available oral formulations used for preventing and treating refractory CINV.5,10 Dronabinol is also used to treat anorexia and weight loss associated with human immunodeficiency virus (HIV) infection. Cannabinoids are thought to exert their antiemetic effect centrally, although the exact mechanism of action is unknown.1,10 Sedation, euphoria, hypotension, ataxia, dizziness, and vision difficulties can occur with cannabinoids. 

Levitt M. Cannabinoids as antiemetics in cancer chemotherapy. In Mechoulam R, ed. Cannabinoids as Therapeutic Agents. Boca Raton, FL CRC Press, 1986 73-79. 

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... 

Much debate has been waged over medicinal uses of cannabis. Several therapeutic uses have been proposed, including antiemetic, analgesic, appetite stimulant, and muscle relaxant. A synthetic cannabinoid, dronabinol (Marinol) has been marketed for clinical treatment of appetite loss, nausea, and vomiting. Although synthetic, it is identical to the main psychoactive chemical constituent of cannabis (A9-THC). 

THC is effective in several chemotherapy regimens, including methotrexate and the doxorubicin/cyclophosphamide/fluorouracil combination. Cisplatin treatment, however, is more resistant. Side effects of THC are generally well tolerated, and use may be limited in the elderly or with higher doses. Nabilone is a synthetic cannabinoid that is more effective than prochlorperazine in chemotherapy-induced emesis, including cisplatin. Its side effects are similar to THC. Levonantradol is another synthetic cannabinoid with antiemetic effects, and may be administered orally or intramuscularly. The side effect of dysphoria may limit its use. 

Vincent BJ, McQuiston DJ, Einhorn LH, Nagy CM, Brames MJ. (1983). Review of cannabinoids and their antiemetic effectiveness. Drugs. 25(suppl 1) 52-62. 

The synthetic cannabinoids dronabinol and nabilone have antinau-seant/antiemetic effects that may benefit AIDS and cancer patients. 

Increased appetite is frequently attributed to smoking marijuana. Cannabinoids are effective antiemetics, particularly in treating emesis arising during chemotherapy. A -THC has been reported to be as effective as codeine as an analgesic, although pronounced behavioral effects occur with analgesic doses. 

The resin secreted by Cannabis indica and Cannabis sativa, varieties of hemp, is known variously as marijuana, hashish or bhang and is abused as a hallucinogenic drug. It appears however to have some beneficial properties and is currently under test as an antiemetic in cancer therapy. The secretion contains a number of interrelated oxygen heterocycles, some of which are shown in Scheme 281, which attempts to indicate their biosynthetic relationships (70MI22401). The cannabinoids are probably derived from a monoterpene unit based on p-menthane and 5-n-pentylresorcinol (olivetol), acting the part of a polyketide. 2,2-Dimethylchromene biosynthesis also requires the intervention of an isoprene fragment. 

A9-Tetrahydrocannabinol is the major psychoactive cannabinoid in marijuana (Cannabis sativa). Its synthetic form, dronabinol, became available in the U.S. in 1985 as an antiemetic for patients receiving emetogenic chemotherapy. However, it is seldom used as a first-line antiemetic because of its psychoactive effects, and its use is usually limited to patients who have a low tolerance or minimal response to other antiemetic drugs (see Chapter 18). 

There are two features of the cannabinoids which may ultimately be of therapeutic importance. THC lowers intraocular pressure, which may be of benefit in the treatment of glaucoma. There is also evidence that THC is a moderately effective antiemetic agent. Such a discovery has led to the development of nabilone, a synthetic cannabinoid, as an antiemetic agent, but its use is limited because of the dysphoria, depersonalization, memory disturbance and other effects which are associated with the cannabinoids. Whether the bronchodilator action of THC will ever find therapeutic application in the treatment of asthma remains an open question. 

Cannabinoids Marijuana derivatives, including dronabinol [droe NAB i nol] and nabilone, are effective against moderately emetogenic chemotherapy. However, they are seldom first-line antiemetics because of their serious side effects, including dysphoria, hallucinations, sedation, vertigo, and disorientation. In spite of their psychotropic properties (see p. 105), the antiemetic action of cannabinoids may not involve the brain synthetic cannabinoids having no psychotropic activity, nevertheless are antiemetic. 

In our 1987 review, we summarized the research and clinical experience in this area [1], Surprisingly, in spite of the enormous public interest in medical marijuana and countless articles in the daily press and magazines focused predominantly on this aspect of marijuana use, little progress has been reported on the antiemetic activity of cannabinoids in the last decade. Plasse et al. have reviewed the clinical experience gained over 7 years with dronabinol (d9-THC) in antiemetic treatment [117]. With doses of 7 mg/m2 or below, complete response was noted in 36% of the patients, 32% showed partial response and 32% showed no response. However, 65% displayed drowsiness and dizziness and 12% had dysphoric effects. Combination treatment of dronabinol with prochlorperazine (a dopamine receptor blocker widely used as an antipsychotic drug with antiemetic effects) was more effective than each drug alone [118]. 

The antiemetic activity of cannabinoids is not mediated, at least not with all cannabinoids, via either CB or CB2. We found that HU-211 (4), a non-psychotropic cannabinoid, which does not bind significantly to either CBj or CB2, is a potent antiemetic agent in pigeons administered cisplatin [119]. Unexpectedly, addition of low doses of cupric ions potentiated the activity of HU-211. The activity of HU-211 was U shaped 2.5 mg/kg HU-211 (with 0.8 mg/kg CuCl2) reduced the amount of vomitus by 97% at higher... 

The mechanism of cannabinoid antiemetic activity is not well understood. As pointed out above, it does not seem to involve CB, or CB2. Fan has shown that anandamide and some synthetic cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons [61]. These receptors are known to mediate emetic activity. However, we have found that HU-211 does not bind to 5-HT3 receptors (unpublished observations). Hence, although cannabinoids may act, in part at least, through this serotonin receptor, this mode of action does not account for the total activity. 

Cannabis is one of the oldest and most widely used drugs in the world. In different Western countries the possible therapeutic use of cannabinoids as antiemetics in patients with cancer or in patients with multiple sclerosis has become an issue, because of the prohibition of cannabis, and has polarized opinion about the seriousness of its adverse effects (1,2). 

Nabilone is a synthetic cannabinoid and has properties similar to tetrahydrocannabinol (the active constituent of marijuana) which has an antiemetic action. It is used to relieve nausea or vomiting caused by cytotoxic drugs. Adverse effects include somnolence, dry mouth, decreased appetite, dizziness, euphoria, dysphoria, postural hypotension, confusion and psychosis. These may be reduced if prochlorperazine is given concomitantly. 

Droleptan " droperidol. dromostanolone propionate drostanolone. dronabinol [inn. usan] (NSC 134454 Deltanyne " Marinol ) is a constituent of marijuana. It is the (6aR,10aR)-(-)-trans-form of A -tetrahydrocannabinol. It is a cannabinoid receptor agonist and has euphoric, mild psychotropic (hallucinogenic) and ANTIEMETIC properties. 

---