Emesis, chemotherapy-induced treatment

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

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. 

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. 

Pollard et alP from Merck required both enantiomers of 3,5-bistrifluoro-methylphenyl ethanol since the (R)-enantiomer can be incorporated into Merck s orally active NKl receptor antagonist for the treatment of chemotherapy induced emesis, while the (5)-enantiomer is used as a chiral synthon for a number of antagonists which the same company currently have under clinical evaluation. Using proteins from a library of commercially available alcohol dehydrogenases both enantiomers were obtained with ees of 99% (Figure 1.40). 

The optical purity of 91-93% was too low for downstream chemistry. The physical properties of 170 made enantiomeric enhancement by crystallization. The formation of a DABCO inclusion complex 171 in heptane and crystallization under thermodynamic control provided material that was 99% ee, 98% purity, and 79% recovery. This procedure produced 90 kg of 170, which was used to prepare an NK-1 receptor antagonist, Aprepitant (172), used for the treatment of chemotherapy-induced emesis.213... 

Serotonin (5-HT3) antagonists are the mainstay today of drug treatment of acute chemotherapy-induced emesis [123]. However, the problem of delayed emesis has yet to be solved. Apparently dronabinol has not been tested so far as an add-on drug to HT3 antagonists to prevent this condition. 

Galmiche J P et al 1998 Treatment of gastro-oesophageal reflux disease in adults. British Medical Journal 316 1720-1723 Grunberg S M, Hesketh P J 1994 Control of chemotherapy-induced emesis. New England Journal of Medicine 329 1790 Mittal R K, Balaban D H 1997 The esophagogastric junction. New England Journal of Medicine 336 924-932... 

What are the treatment options for chemotherapy-induced emesis ... 

Currently, 5-HT, antagonists have found their greatest therapeutic value in the treatment of cancer chemotherapy-induced emesis (406). Release of 5-HT from the enterochro-mafhn cells in the gastrointestinal track often results from cancer chemotherapy with cytotoxic agents, such as cisplatin (446, 447). Blockade of 5-HT, receptors in the CNS or on peripheral vagal afferent fibers prevents the initiation of the vomit reflex. 

Other Chemotypes. Several other 5-HT, antagonists have demonstrated cognition-enhancing effects in animal models. However, data from human studies have yet to be reported. (i2)-Zacopride (170 in Fig. 14.18 Synthelabo) is undergoing clinical development as a potential treatment for cancer chemotherapy-induced emesis. In atropine-treated rats, (jR)-zacopride significantly attenuated memory impairments in a spatial navi-... 

The 5-HT3 antagonists, such as ondansetron and granisetron, have found clinical utility in the treatment of emesis, particularly for radiation or chemotherapy-induced cases [46], Application to post-surgical and other forms of emesis are less well documented. S-HT, receptors have also been speculated to be involved in cognition, anxiety, migraine, and pain. However, clinical proof of their role in these states is still lacking. 

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. 

The 5-hydroxytryptamine 5-HT3 receptor antagonists are currently used in the treatment of chemotherapy and radiotherapy induced emesis. The compounds are based on the parent structure shown in Fig. 9.10, the aromatic systems include mono- and bicyclic rings, with and without heteroatoms, and with various substitution patterns. This range of structural variation makes it difficult to analyze SAR of these compounds. 

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