Antiemetics clinical studies

Most of the antiemetic clinical trials in the last decade have involved metoclopramide (1) either as a single agent or in combination with other drugs. Similarly, most of the chemical modification studies have been designed to optimize antiemetic and/or gastroprokinetic properties of metoclopramide and to eliminate undesirable CNS side-effects which are the consequence of its dopamine D2 receptor blockade [1-3]. 

Clinical studies of the antiemetic/nausea efficacy of ginger... 

Clinical studies in cancer patients have also shown ondansetron to be a highly effective antiemetic drug and to be significantly more effective than metoclopramide [44-46]. As expected, there are no reports of extrapyrami-dal side-effects in patients receiving ondansetron. 

Ondansetron is the first 5-HT3-receptor antagonist to be used for the treatment of nausea and vomiting induced by cancer therapy. Its high receptor selectivity is reflected in clinical studies which show ondansetron to be a very effective antiemetic drug with few side-effects. 

In general, ketones, alcohols and ethers of formula (3) showed comparable protection against cisplatin-induced emesis in the dog and ferret with that of metoclopramide. Erythro (cis) alcohols (3c, 3g, 3i) were found to be more potent than the corresponding threo-(trans) isomers (3d, 3h, 3j). Optical isomer (.R) (3e) was found to be somewhat more potent than its (S )-enantiomer (3f) as an antagonist of cisplatin-induced emesis in the ferret. In the dog, both isomers showed similar activity. A number of heterocyclic analogues were also studied but with the exception of (3k), all were inferior in potency as antiemetic agents compared with other compounds (3) shown in Table 7.1. Lead compound, BMY 25801, batanopride, (3a) is presently under clinical investigation. 

McClennan et al. conducted a prospective 2-month intervention study to determine clinical outcomes associated with pharmacist interventions at a tertiary referral cancer institute in Australia. Clinical pharmacists documented clinical interventions and relevant patient information which were assessed by an independent pharmacist. Members of the healthcare team reviewed and discussed medical progress notes to determine outcomes. Of 674 total interventions that were documented during the study, outcomes were assessed for 10% of the interventions reported 90% of the interventions led to documented clinical benefit. Pharmacist interventions most frequently consisted of initiating changes in drug therapy associated with antiemetic, antimicrobial, and analgesic agents. 

The antiemetic effect of nabilone in the clinic is well established in numerous studies. In an early study with 113 patients undergoing cancer chemotherapy with a wide variety of anticancer drugs, 80% experienced full or partial improvement of nausea and emesis while only 36% responded to prochlorperazine treatment. Drowsiness and dizziness were reported in many cases. Euphoria (16%), dry mouth and blurred vision (4.5 %), orthostatic hypotension (1 %) and visual hallucinations (1 %) were the more serious side-effects [ 167]. This general picture has been repeated over and over again. 

Binding studies with tritiated neuroleptics have established the existence of two types of central DA receptors D[ and D2 their numbers and ratios vary in brain areas. Most interesting, however, is that both are altered in drug-naive schizophrenics. Emphasis has concentrated on the D2 subtype that seems implicated in the observable clinical responses. The role of the postsynaptic Dt receptor is not clear. It is known, however, that even though neuroleptic drugs are D,/D2 antagonists, in vitro D2 effects are achieved at 103 lower concentrations. D2 receptors are also located in central areas outside the BBB. One is the CTZ in the medulla. Presynaptic stimulation, which leads to DA inhibition there, may be the reason that many of the phenothiazine and butyrophenone neuroleptic drugs also excel as antiemetics (see comments, Table 12-11). It also explains why several DA2... 

Even before the identification of central 5-HTg receptors, 5-HTg receptor antagonists have been suggested to possess striking properties. To date, based on animal studies, several reports have shown that these drugs display anxiolytic, antipsychotic [see 3,4, 5,166,167], promnesic [72,169,170], antidepressant [136], antinociceptive [23, 171] and antiemetic [172, 173] properties, generally at low doses and without side-effects [4]. Confirmation of these results in human are necessary before drawing any definitive conclusion since, except for the antiemetic effects, data from clinical trials are few and generally limited to ondansetron. Critical reviews on the subject have recently been published [9, 235-238]. 

The small doses of apomorphine used for erectile dysfunction (2 to 3 mg) do not normally cause vomiting, but nausea does occur in about 7% of patients and the manufacturers say that interaction studies and/or clinical experience show that domperidone, ondansetron or prochlorperazine may safely be given as antiemetics in this patient group. Studies with other antiemetics have not been carried out, so at the moment concurrent use is not recommended. ... 

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