EAA antagonists as anti-emetic drugs

This invention relates to a method and a class of pharmaceutical agents for suppressing vomiting, nausea, and other emetic symptoms. The method involves administering to a susceptible mammal a glutamate (EAA) receptor antagonist at an anti-emetically effective dose which does not cause undesirable side effects. Preferred EAA antagonists include those that do not readily cross blood-brain barriers (BBB). One suitable formulation comprises a broad-spectrum antagonist such as kynurenic acid or 7-chlorokynurenate. Other formulations include EAA antagonists that preferentially block NMDA receptors (such as D-AP5) or non-NMDA receptors (such as CNQX), or mixtures thereof that can block both classes of EAA receptors. In lab tests, the agents of this invention were shown to reduce or entirely block the effects of several emetic agents, including cisplatin. Treated animals did not vomit or exhibit lethargy or malaise and did not display any adverse side effects, while control animals consistently displayed lethargy, malaise, and vomiting.

FIELD OF THE INVENTION 
This invention is in the field of pharmacology, and relates to anti-emetic 
drugs, i.e., drugs that suppress nausea and vomiting. 
BACKGROUND OF THE INVENTION 
"Emesis" and "emetic" refer to the process commonly known as vomiting or 
retching, wherein the stomach is evacuated through the esophagus and mouth 
due to strong muscular contractions in the abdomen. Emesis is usually 
accompanied by nausea and feelings of strong malaise and discomfort. As 
used herein, emesis includes vomiting and its related symptoms, such as 
nausea and malaise. 
Emesis can be caused or aggravated by a range of factors, including food 
poisoning, irritation of the gastrointestinal tract or the nerves that 
innervate this tract, motion sickness, or severe anxiety. It can also be 
an undesired side effect of some pharmacological and medical treatments, 
especially cancer chemotherapy, and radiation therapy. When caused by food 
poisoning, emesis can be helpful and useful, since it evacuates the 
stomach and can remove toxins or detrimental microbes. However, in most 
other situations, emesis is intensely unpleasant and unhelpful. It can be 
a major problem and can even become life-threatening for people who are 
already suffering from cancer or other life-threatening illnesses, since 
it can prevent them from obtaining proper nutrition. 
The mechanisms by which vomiting is induced are complex and are not fully 
understood. However, most cases are believed to involve a reflex circuit, 
commonly called a reflex "arc," consisting of nerve cells which are linked 
in series such that when a nerve cell on the receptive end of the arc 
receives a message, it relays the message on to other nerve cells leading 
into an emesis center in the brain stem. In the emesis center, nerve cells 
which are part of the reflex circuit interpret the message and act upon 
it. For example, the message may have come from sensory cells in the inner 
ear and may pertain to excessive abnormal motion which, for reasons that 
are poorly understood, is interpreted by the emesis center as a basis for 
sending an outgoing command through nerve fibers to muscles in the 
gastrointestinal tract and abdominal wall. This initiates a coordinated 
pattern of muscle contractions that constitute the act of vomiting, 
representing the condition known as motion sickness. 
Alternatively, a message may originate in sensory receptors in the gut wall 
pertaining to a stimulus that is irritating to the gastrointestinal tract. 
This message is conveyed through nerve fibers from the gut to the emesis 
center in the brain stem and interpreted as basis for initiating the same 
outgoing command to commence the act of vomiting. The emesis center 
functions like a "central switchboard" that serves as the central hub for 
the incoming and outgoing segments of numerous reflex arcs pertaining to 
both normal and abnormal gastrointestinal motility, normal motility being 
the peristaltic wave movements of the gut wall that facilitate processing 
of food, and abnormal motility being reverse peristaltic movements that 
are first perceived as nausea and then, as they become more vigorous, as 
retching and/or vomiting. 
Under conditions of extreme anxiety or stress, messages from higher brain 
centers pertaining to a feeling of being overwhelmed or defeated are 
conveyed to the emesis center which may interpret the situation as a basis 
for emesis, perhaps as a primitive response intended to purge the organism 
of whatever is causing the stress. 
An emesis chemoreceptor trigger (ECT) zone has been identified (Borison and 
Brizzee, 1951; Borison and Wang, 1953) in the same general region of the 
brain stem where the emesis center is located. The ECT zone is located 
specifically in a region designated anatomically as the area postrema, 
which is recognized as one of several circumventricular organs (CVO's) 
that exist within the brain. CVO's are specialized brain regions that are 
distinguished from all other regions of the central nervous system (CNS) 
by the fact that they do not have blood brain barriers (BBB) to prevent 
substances circulating in the blood from freely entering these brain 
regions (Rapoport, 1976). Thus, unlike the remainder of the CNS which has 
BBB that screen substances and only allow certain agents to enter, CVO's 
are freely accessible to any substances circulating in the blood. 
It has been postulated that neurons in the area postrema ECT zone serve as 
sensors of noxious substances circulating in the blood. Thus, after such a 
substance has been ingested and begins to be absorbed into the blood, it 
will enter the area postrema ECT zone and be sensed as a harmful 
substance. That triggers a message to evacuate the gastrointestinal tract, 
thereby ridding the body of any remaining noxious substance in the gut. 
Whether the ECT zone truly functions in this manner is not well 
established. However, it appears clear that ECT neurons, like other 
neurons in the general region of the brain stem emesis center, can mediate 
the act of vomiting. 
In the study of potential anti-emetic drugs, the lab animals appropriate 
for use are ferrets, dogs, cats and monkeys, since these species have a 
vomit reflex comparable to humans. Rodents and rabbits are not used, since 
they do not have such a vomit mechanism. Ferrets have become the preferred 
specie for such research; although they are smaller, less expensive, and 
require smaller amounts of drugs (some of which are scarce and quite 
expensive) than dogs or monkeys, ferrets respond in a similar manner (by 
exhibiting active vomiting as well as malaise and lethargy) to emetic 
stimuli that induce symptoms in dogs, monkeys, and humans (Florczyk et al, 
1982). 
As used herein, terms such as "anti-emetic" and "suppression of emesis" 
apply to a pharmaceutical agent that can reduce, ameliorate, or eliminate 
one or more symptoms of at least one type of emesis. Various efforts have 
been made to develop anti-emetic drugs. However, most drugs developed to 
date are only weakly or moderately effective as anti-emetics and are 
useful for controlling only certain types of emesis. Moreover, since most 
such agents interact with many physiological systems in addition to those 
relevant to the regulation of vomiting, they tend to have undesirable side 
effects when used at doses required to suppress nausea and vomiting. 
Drugs classified as anti-histaminics, such as dimenhydrinate (trade name 
Dramamine), and anticholinergics, such as scopalamine, have been used for 
years to prevent motion sickness or the related condition, vertigo 
(dizziness), which is a prominent symptom of Meniere's disease. However, 
these agents are relatively ineffective unless taken before a boat or 
airplane ride or other motion begins, or before the onset of vertigo in 
Meniere's disease. In addition, they are not effective in suppressing 
nausea and vomiting caused by other factors (Goodman and Gilman, 1975). 
Several approaches have been employed for ameliorating nausea and vomiting 
associated with cancer chemotherapy. Traditionally, phenothiazines such as 
compazine and butyrophenones such as haloperidol have been used because it 
has been thought that dopamine receptors in brain stem regions associated 
with the emesis center are involved in vomiting, and these agents block 
dopamine receptors. Results with these agents have been disappointing; 
they are only weakly active as anti-emetics and must be used at high doses 
which stimulate numerous dopamine receptors throughout the brain. This 
results in severe side effects such as abnormal motor movements, muscle 
rigidity, and tremors. 
Over the past decade, another type of dopamine antagonist, metoclopramide 
(trade name Reglan) has emerged as the agent of choice for suppressing 
emesis associated with cancer chemotherapy. Although it represents a 
moderate improvement over prior therapies, it is only partially effective 
even when used at doses associated with the same disagreeable side effects 
that other dopamine receptor antagonists typically cause. Recent evidence 
suggests that the anti-emetic properties of metoclopramide may be 
explained, not by an effect at dopamine receptors, but rather by an effect 
at serotonin receptors. Serotonin is the common name for 
5-hydroxytryptamine, 5-HT, and the 5-HT system is often called the 
serotonergic system. Serotonin receptors are divided into three classes; 
one class is referred to as 5-HT M receptors. Metoclopramide, in addition 
to being a dopamine antagonist, is able to antagonize 5-HT M receptors 
(Miner and Sanger, 1986). Metoclopramide is only a weak 5-HT M receptor 
antagonist, which explains why it has been an effective anti-emetic only 
when used at high doses. 
Recent evidence suggests that certain other agents within the 5-HT M 
antagonist class, such as BRL 43694 (which is a more powerful and 
selective 5-HT M receptor antagonist than metoclopramide), may prove more, 
useful for controlling nausea and vomiting caused by cancer drug therapy. 
BRL 43694 was shown to be effective in preventing or reducing the severity 
of emesis in ferrets treated with cisplatin (Bermudez et al., 1988). 
Cisplatin is an effective cancer chemotherapy drug; it is also a preferred 
agent for animal testing of anti-emetic drugs, since it is a particularly 
strong emetic agent in both humans and certain animals such as the ferret. 
Very recently, Cassidy and colleagues (1988) conducted a human clinical 
trial in which BRL 43694 was administered to 20 cancer patients to test 
its ability to counteract the emetic properties of various drugs being 
used to treat cancer. The authors considered the results generally 
promising in that 7 patients experienced neither nausea nor vomiting, 4 
had mild nausea, and 9 patients had both nausea and vomiting but it 
appeared to be delayed in onset. It is too early to predict whether BRL 
43694, or other agents in its class, will represent a substantial 
improvement over other anti-emetics currently available. A limitation of 
the study by Cassidy et al is that there was no control group to establish 
the expected incidence of nausea and vomiting in patients receiving 
identical cancer chemotherapy without an anti-emetic. Moreover, only 5 of 
the 20 patients received cisplatin; the others received cancer drugs that 
are not as strong in emetic properties as cisplatin. Of the 5 patients 
that received cisplaten, 4 suffered from nausea and vomiting. 
While it seems likely that 5-HT M receptor antagonists such as BRL 43694 
will prove more effective than anti-emetics previously available for 
cancer chemotherapy patients, there is still a pressing need for 
additional agents that are more effective by themselves, or that can be 
used in conjunction with 5-HT M receptor antagonists to provide better 
anti-emetic therapy. This goal could best be achieved by finding new 
agents that prevent nausea and vomiting by a different mechanism than that 
underlying the anti-emetic properties of the 5-HT M receptor antagonists 
or other currently available anti-emetics. 
It is believed that the locus of action of 5-HT M receptor antagonists is 
at the level of the gastrointestinal tract (Hawthorn et al., 1988). 
Enterochromaffin cells in the gut are thought to be irritated (stimulated) 
by cancer chemotherapy agents, which results in the release of large 
amounts of 5-HT from these cells. The 5-HT stimulates 5-HT M receptors 
which are present on nerve endings in the gut wall. This stimulus is 
communicated through nerve fibers to the emetic center in the brain stem 
which, as described above, serves as a central switchboard for receiving 
such messages and responding by initiating a vomit response. By blocking 
the 5-HT M receptors in the gut, 5-HT M receptor antagonists appear to 
prevent the message from being relayed from the gut to the emesis center 
in the brain stem. Therefore, the emesis reflex circuit is broken in its 
initial segment. 
It has also been suggested that the 5-HT M antagonists might act directly 
upon neurons in the brain stem emesis center (Hawthorn et al 1988). 
However, there is no evidence to substantiate this proposal, since it has 
not been possible to demonstrate that there are any 5-HT M receptors in 
this or any other part of the CNS. 
As will be discussed below, in seeking to develop more effective 
anti-emetics, it would be particularly advantageous if a means could be 
found for interrupting various types of emesis reflex arcs at the level or 
location of the central switchboard. Since differing reflex arcs 
pertaining to different types of emetic stimuli apparently pass through a 
common point or region in the emesis center in the brain stem, a selective 
blockade involving that region might be effective in blocking more than 
one type of emesis reflex. Since this would involve an action by a drug 
within the CNS, any such action should be regionally selective for the 
brain stem emesis center and should not involve interactions throughout 
the remainder of the CNS where unwanted side effects might be generated. A 
method and a pharmacological agent for achieving this type of anti-emetic 
therapy is the subject of the invention described herein. 
Years ago, it was discovered that two common amino acids, glutamate (the 
ionized or salt form of glutamic acid, abbreviated Glu) and aspartate (the 
ionized or salt form of aspartic acid, abbreviated Asp) induce vomiting 
when present in the blood in high concentrations. The emetic properties of 
Glu and Asp in humans were first discovered when protein hydrolysates 
containing high concentrations of these two amino acids were administered 
intravenously for nutritional purposes to patients who could not take food 
by mouth. It was found that the hydrolysate solution could not be 
administered rapidly, or it triggered vomiting. Subsequent studies 
identified the responsible agents as Glu and Asp (Unna and Howe, 1945; 
Madden et al., 1945; Levey et al., 1949). Over the past decade, Glu and 
Asp, which are present in high concentration in the CNS, have become 
recognized as major neurotransmitters that account for the vast majority 
of the excitatory neurotransmitter activity in the mammalian CNS (reviewed 
by Olney, 1989). 
The standard method by which nerve cells communicate with one another and 
perform the information processing functions of the CNS is by chemical 
neurotransmission in which a chemical transmitter molecule is released 
from a fiber ending of a neuron into the extracellular fluid. While in the 
extracellular fluid, the transmitter molecule acts upon a membrane 
receptor molecule on the external surface of another neuron. Several 
chemical transmitter systems have been identified in the mammalian CNS, 
including the dopaminergic system referred to above, in which dopamine is 
the transmitter chemical involved, and the serotonergic system, in which 
5-HT (a synonym for serotonin) is the transmitter chemical. For each 
transmitter system, several receptor subtypes have been identified. For 
example, although 5-HT M receptors have been found only outside the CNS, 
two other serotonin receptor subtypes have been clearly demonstrated 
within the CNS, and there are at least two subtypes of dopaminergic 
receptors in the CNS. The Glu and Asp transmitter systems are exclusively 
excitatory; i.e., the action of a Glu or Asp molecule at a receptor 
triggers or facilitates neuronal activity. By contrast, most other 
transmitter systems, including the dopaminergic and serotonergic systems, 
are primarily inhibitory (they suppress neuronal activity) and only 
occasionally excitatory. 
Glu and Asp are identical in their excitatory transmitter activities and, 
since Glu is found in much higher concentration in the CNS than Asp, the 
Glu/Asp excitatory transmitter system is often referred to as the Glu 
transmitter system or, alternatively, as the excitatory amino acid (EAA) 
transmitter system. Certain structural analogs of Glu and Asp, although 
not found naturally in the CNS, are also referred to as EAA's because they 
mimic the neuroexcitatory actions of Glu and Asp when brought in contact 
with EAA neuronal membrane receptors. 
Three subtypes of EAA receptors have been identified, each type being named 
after a certain Glu analog which preferentially binds to and activates 
that type of receptor. These receptor subtypes are N-methyl-D-aspartate 
(NMDA) receptors (preferentially sensitive to NMDA), kainic acid (KA) 
receptors (preferentially sensitive to KA) and quisqualic acid (Quis) 
receptors (preferentially sensitive to Quis). 
In addition to the important neurotransmitter functions performed by Glu 
and Asp, these compounds are known to have powerful neurotoxic effects 
(reviewed in Olney, 1989). This was first learned years ago when these 
compounds were administered subcutaneously to immature animals of various 
species, including monkeys, and were found to destroy neurons in specific 
brain regions, referred to above as CVO brain regions. The reason for the 
neurotoxic reaction being restricted to CVO brain regions is that Glu and 
Asp are prevented by BBB from entering other brain regions; since CVO 
regions lack BBB protection, Glu and Asp had free access to neurons in 
these regions. Subsequent research established that a neuroexcitatory 
mechanism underlies the neurotoxicity of Glu and Asp. Although Glu and Asp 
are beneficial and vitally important substances for excitatory 
neurotransmitter functions in the CNS, if EAA receptors are exposed to 
these agents in abnormally high concentrations or for prolonged periods, 
it literally excites the neuron to death. Thus, Glu and Asp are commonly 
referred to today as excitotoxins. 
Although Glu exists in high concentration in the CNS, it is normally 
confined inside neurons and is released into the extracellular fluid only 
for transmitting a nerve message from one neuron to another. For this 
purpose, it is released only in small amounts, and only long enough to 
contact an EAA synaptic receptor on the surface of another neuron, thereby 
exciting (i.e., triggering impulse conduction in) the receiving neuron. 
After impulse conduction, the excitatory action is terminated very quickly 
by rapid transport of Glu back inside the cell by an energy-dependent 
transport mechanism. Under abnormal conditions, when energy supply to the 
brain is deficient (e.g., after a stroke or cardiac arrest, or during 
perinatal asphyxia), the energy-dependent transport mechanism begins to 
fail and Glu is allowed to accumulate in abnormal concentrations at EAA 
receptors. This leads to overstimulation of neurons, which causes them to 
release more Glu. This can provoke a cascade of Glu release and neuronal 
hyperstimulation, which can lead to wholesale destruction of CNS neurons. 
The involvement of Glu and Asp in these and other possible 
neurodegenerative disorders has generated a great deal of interest in the 
development of EAA receptor antagonists as potential neuroprotective drugs 
which, by blocking EAA receptors, might be able to prevent neuronal 
degeneration under abnormal conditions such as the above. Numerous agents 
have been identified that act as specific NMDA receptor antagonists. The 
majority of these agents, such as D-2-amino-5-phosphonopentanoate (D-AP5), 
D-2-amino-7-phosphonoheptanoate (D-AP7), CGS 19755, CPP and CPP-ene 
(Olney, 1989; Boast, 1988; Herrling et al., 1989) do not readily penetrate 
blood brain barriers and, therefore, have been considered of limited 
interest as neuroprotective drugs. NMDA antagonists such as phencyclidine 
(PCP) and MK-801 which readily penetrate BBB have attracted more attention 
and, in animal experiments, have been shown to exert powerful 
neuroprotective effects in conditions such as cerebral ischemia (stroke) 
(Olney, 1989). The ability of these agents to enter brain and interact 
with NMDA receptors throughout the brain, however, makes them subject to a 
number of serious side effects, including psychotic disturbances and 
pathomorphological changes in cerebrocortical neurons (Olney, 1989; Olney 
et al., 1989). 
Fewer advances have been made in developing antagonists for the Quis and KA 
receptor subtypes. However, kynurenic acid and its chlorinated derivative, 
7-chloro-kynurenic acid, are effective broad-spectrum antagonists that 
block all three subtypes of EAA receptors (NMDA&gt;KA&gt;Quis) (Olney, 1989). 
Certain types of quinoxalinediones, including 
6,7-dinitro-quinoxaline-2,3-dion (DNQX; also referred to as FG 9041) and 
6-nitro-7-cyano-quinoxaline-2,3-dion (CNQX; also referred to as FG 9065) 
were recently described as the first available agents that block non-NMDA 
receptors substantially more powerfully than NMDA receptors (Honore et al, 
1987; also see Honore et al, 1988, and Drejer and Honore, 1988). These 
quinoxalinediones are significantly more powerful than kynurenic or 
7-chloro-kynurenic acid, but neither group has generated much interest as 
neuroprotective drugs, since they do not penetrate blood-brain barriers. 
It is of interest to review the early literature pertaining to Glu and Asp 
as emetic agents, in light of other information developed more recently 
regarding their neuroexcitatory and neurotoxic properties. The fact that 
Glu and Asp, when administered subcutaneously to experimental animals, had 
neurotoxic effects on neurons confined to CVO brain regions (including the 
area postrema, which is within the same general brain region where the ECT 
zone and emetic center are located) signifies that these excitotoxins 
entered these brain regions and stimulated these neurons, initially 
causing them to fire nerve impulses excessively, and eventually causing 
them to die from excessive stimulation. It has been observed in species 
such as dogs and monkeys, which are subject to an emetic reflex similar to 
that in the human, that a toxic dose of Glu or Asp first causes the animal 
to vomit before continued excitatory stimulation destroys the area 
postrema-CVO neurons (Olney et al., 1972; Olney and Rhee., 1978). 
Based on a study of the literature, several possibilities and hypotheses 
suggested themselves to the inventor. It appeared likely that Glu and Asp 
induce emesis in monkeys and dogs (and in humans) by stimulating EAA 
receptors on the surfaces of area postrema-CVO neurons (the same receptors 
through which they kill these neurons), which implies that these neurons 
are connected to an emesis reflex circuit. This raised the question of 
whether the receptors being stimulated by subcutaneously administered Glu 
in these animal experiments functioned physiologically by receiving emetic 
messages from Glu-containing neurons in an emesis reflex circuit. If this 
were the case, then these Glu-receptive neurons might be an integral link 
in an emesis reflex circuit, and blocking such receptors with EAA 
antagonists might interrupt the emesis reflex circuit, and might prevent 
various other stimuli feeding into the emesis circuit from inducing 
emesis. Depending on how many types of emetic circuits include an 
obligatory link comprised of area postrema Glu-receptive neurons, and 
depending on the types of Glu receptors involved, numerous types of emesis 
initiated by different stimuli might be suppressed by treatment with a 
given EAA antagonist. However, if the EAA receptors on the surfaces of 
area postrema CVO neurons are there only for the purpose of interacting 
with Glu circulating in the blood, then an EAA antagonist circulating in 
the blood might block the action of circulating Glu on these neurons 
without having any effect on circuits regulating other types of emesis. 
The experiments described below were undertaken to explore the hypothesis 
that area postrema CVO neurons are part of a reflex arc from the gut to 
the brain stem and back to the gut. Based on the results of those 
experiments, it was discovered that intravenous administration of Glu 
antagonists can prevent at least some types of emesis by interrupting this 
reflex arc. 
The invention described herein entails control of nausea and vomiting by a 
mechanism that has never previously been exploited for this purpose. 
Despite considerable research in the EAA field, and despite many efforts 
to develop anti-emetic drugs, there are no published reports pertaining to 
the use of any EAA antagonists as anti-emetic drugs, nor any published 
reports indicating that EAA antagonists are able to prevent emesis of any 
kind. Therefore, the invention disclosed herein represents the discovery 
of an entirely new method for preventing nausea and vomiting, different 
from any previously described method. 
An important feature of this invention is that the locus of action of the 
EAA antagonists used as described herein is at the level of the "central 
switchboard" (the emesis center) in the brain stem, where different types 
of EAA receptors have been shown to participate in the regulation of 
emesis. Therefore, it is believed by the inventor that several different 
kinds of vomiting can be controlled by different combinations of EAA 
antagonists, and that most or all types of vomiting that are not 
adequately controlled by currently available approaches can be controlled 
by use of EAA antagonists, alone or in combination with other currently 
available drugs. 
It should be noted that other anti-emetic drugs tend to be useful for 
controlling only one type of emesis. For example, anti-histaminics are 
useful only for motion sickness, and not for emesis associated with cancer 
chemotherapy. 5-HT M receptor antagonists are not effective for motion 
sickness (Stott et al., 1989) but are somewhat effective for emesis 
associated with specific cancer chemotherapy drugs, such as cisplatin, 
that release 5-HT from enterochromaffin cells in the gut. These agents 
block the emetic stimulus at or near the beginning point, i.e., at the 
5-HT receptor site in the gut that receives the original message and sends 
it through the initial segment of the reflex arc going up to the brain 
stem. EAA antagonists also block cisplatin-induced emesis, but they do so 
at the brain stem level by preventing messages transmitted by incoming 
nerve fibers from being relayed to neurons that transmit outgoing messages 
to the abdomen, resulting in vomiting. Therefore, the action of EAA 
antagonists is not limited to a specific mechanism pertaining to the 
incoming limb of a single reflex arc, as is the case for 5-HT M 
antagonists; instead, EAA antagonists act at the central switchboard 
level, where suppression of emesis induction between incoming and outgoing 
branches of various different emesis reflex arcs appears to be possible. 
Accordingly, the use of EAA antagonists has potentially wide application 
for the control of nausea and vomiting. 
An additional special feature of this invention is that it takes advantage 
of the fact that certain Glu antagonists do not penetrate blood brain 
barriers and cannot enter most regions of the brain proper or the 
remainder of the CNS. However, they do penetrate select brain regions 
containing the specific receptors which must be blocked in order to 
effectively interrupt emesis reflex circuits. The fact that the Glu 
antagonists do not enter the brain except in the CVO regions signifies 
that they are much less likely to cause significant side effects than if 
they were able to interact with Glu receptors throughout the brain, most 
of which are directly involved in vital functions that are unrelated to 
emesis regulation. 
SUMMARY OF THE INVENTION 
This invention relates to a method and a class of pharmaceutical agents for 
suppressing vomiting, nausea, and other emetic symptoms. The method 
involves administering to a susceptible mammal a glutamate (EAA) receptor 
antagonist at an anti-emetically effective dose which does not cause 
undesirable side effects. Preferred EAA antagonists include those that do 
not readily cross blood-brain barriers (BBB). One suitable formulation 
comprises a broad-spectrum antagonist such as kynurenic acid or 
7-chlorokynurenate. Other formulations include EAA antagonists that 
preferentially block NMDA receptors (such as D-AP5) or non-NMDA receptors 
(such as CNQX), or mixtures thereof that can block both classes of EAA 
receptors. In lab tests, the agents of this invention were shown to reduce 
or entirely block the effects of several emetic agents, including 
cisplatin. Treated animals did not vomit or exhibit lethargy or malaise 
and did not display any adverse side effects, while control animals 
consistently displayed lethargy, malaise, and vomiting.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
This invention relates to a pharmacological agent or mixture administered 
to a patient suffering from nausea or vomiting, or a patient who will 
receive an emetic dosage of a chemotherapeutic drug or radiation therapy. 
This pharmacological agent or mixture comprises one or more EAA 
antagonists which are administered at an anti-emetically effective dose 
that does not cause adverse side effects. 
Preferably, glutamate antagonists used for the purpose of this invention 
should have a low ability to cross mammalian blood-brain barriers, 
compared to other EAA antagonists that are known to permeate easily across 
BBB's. Several such compounds, which have varying affinities for EAA 
receptors, are listed in Table 1; by contrast, several EAA antagonists 
that permeate easily through BBB's are listed in Table 2. 
The preferred trait of low BBB permeability reduces the extent to which 
certain anti-emetic EAA antagonists will contact EAA receptors on the 
surfaces of CNS cells (other than in the vicinity of CVO regions). That 
will, in turn, minimize any possible adverse side effects. As used herein, 
"adverse side effects" refers to adverse cellular, physiological, or 
behavioral effects that are detectable in lab animals (such as vacuole 
formation or mitochondrial dissolution in certain types of cerebrocortical 
neurons, as described in Olney et al 1989). It also refers to adverse side 
effects reported or suffered by humans, such as the psychotic effects that 
can be caused by phencyclidine, MK-801, ketamine, or tilletamine, which 
permeate easily through BBB's and therefore are not preferred for use as 
described herein. 
If a specific EAA antagonist leaks through the BBB in limited but 
significant quantities, it might still be useful as described herein, if 
it can be administered at a controlled low dosage which exerts an 
anti-emetic effect without causing adverse side effects in the remainder 
of the CNS. For example, if an EAA antagonist penetrates the area postrema 
region of the brain stem, a small amount might diffuse via the 
extracellular fluid into adjacent areas that are involved in or related to 
the emesis center, including areas that might be technically considered to 
be within the BBB-protected portion of the brain or brain stem. Such 
limited leakage may enhance the anti-emetic effectiveness of the EAA 
antagonists disclosed herein, without causing unacceptable adverse side 
effects. 
TABLE 1 
______________________________________ 
EAA antagonists that do not freely penetrate 
blood brain barriers 
EAA 
antagonist potency 
vs vs vs BBB Year first 
Antagonist 
NMDA KA Quis penetrability 
described 
______________________________________ 
CGS 19755 200* 0 0 low 1987 
CPP 200* 0 0 low 1987 
CPP-ene 200* 0 0 moderate 1989 
CGP 37849 200* 0 0 moderate 1988 
ifenprodil 
100 0 0 moderate 1988 
SL 82,0715 
50 0 0 moderate 1989 
D-AP5 40 0 0 very low 1979 
D-AP7 13 0 0 very low 1981 
.alpha.-amino adipate 
5 0 0 very low 1978 
CNQX 5 30 67 very low 1987 
DNQX 10 20 40 very low 1987 
7-Cl-kynurenate 
10 4 3 very low 1988 
kynyrenic acid 
4 1 1 very low 1983 
______________________________________ 
The antagonists listed are representative agents from each of several 
categories, none of which freely penetrates BBB; many additional agents 
with EAA antagonist properties have been described in each category. 
Antagonist potencies were established in a chick retina assay which has 
been used by Olney (1989) to screen prototypic EAA receptor agonists 
(NMDA, KA and Quis) for excitotoxic properties and EAA antagonists for 
potency in protecting the retina against the excitotoxic action of such 
agonists. The concentration of antagonist required to totally prevent the 
toxic action of an agonist was used to compare antagonists for potency. 
For purposes of illustration, the data were normalized by assigning a 
potency rating of 1 to kynurenic acid vs KA and all other values were 
adjusted accordingly. 
*These compounds have not been screened in the chick retina assay; their 
potencies are estimated based on other reported data pertaining to their 
electrophysiological antagonist properties. 
TABLE 2 
______________________________________ 
EAA antagonists that freely penetrate blood brain barriers 
EAA antagonist potency 
Year first 
Antagonist vs NMDA vs KA vs Quis 
described 
______________________________________ 
MK-801 5000 0 0 1986 
PCP 2000 0 0 1982 
tilletamine 200 0 0 1987 
procyclidine 
67 0 0 1987 
dextrorphan 40 0 0 1987 
ethopropazine 
40 0 0 1987 
dextromethorphan 
20 0 0 1986 
thiamylal 13 3 2 1988 
thiopental 7 2 2 1988 
______________________________________ 
The antagonists listed are representative agents from each of several 
categories, all of which freely penetrate BBB; many additional agents wit 
EAA antagonist properties have been described in each category. Antagonis 
potencies were established in a chick retina assay which has been used by 
Olney (1989) to screen prototypic EAA receptor agonists (NMDA, KA and 
Quis) for excitotoxic properties and EAA antagonists for potency in 
protecting the retina against the excitotoxic action of such agonists. Th 
concentration of antagonist required to totally prevent the toxic action 
of an agonist was used to compare antagonists for potency. For purposes o 
illustration, the data were normalized by assigning a potency rating of 1 
to kynurenic acid vs KA (see table 1) and all other values were adjusted 
accordingly. 
As used herein, "unacceptable" adverse side effects include side effects 
that either (1) cause permanent damage to one or more types of neuron in 
the central nervous system, or (2) are more painful or unpleasant than an 
emetic response which is being suppressed. In the animal tests done to 
date, the animals displayed no adverse side effects whatsoever, and it is 
believed that the agents of the subject invention may be able to suppress 
many types of emesis with little or no significant adverse side effects. 
However, as with any pharmacological agent (especially 
neuropharmacological agents), some adverse side effects may arise, 
especially at high dosages, and it is up to the treating physician in any 
specific case to determine whether the potential disadvantages and side 
effects are worth the benefits, based upon safety and efficacy data 
gathered during human clinical trials. In particular, the CVO regions of 
the CNS are involved in certain neuroendocrine regulatory functions which 
might be perturbed by the EAA antagonists described herein. However, any 
such effects are likely to be transient and will not cause any lasting 
problems. 
The inventor of the subject invention played a key role in discovering that 
NMDA antagonists cause pathological changes in certain types of neurons 
(Olney et al, 1989). In subsequent research, the inventor discovered that 
certain types of anti-cholinergic agents can prevent or reduce those 
pathological changes. Those agents and a method for their use are 
described in a co-pending U.S. patent application entitled "Compounds and 
Methods for Preventing Neurotoxic Side Effects of NMDA Antagonists," Ser. 
No. 424,548, the contents of which are incorporated herein by reference. 
The anti-cholinergic agents tested to date and shown to be effective in 
reducing the neurotoxicity of NMDA antagonists that penetrate the BBB 
include scopolamine, atropine, benztropine, benactyzine, biperiden, 
procyclidine, trihexyphenidyl, and diphenhydramine. Those agents can be 
co-administered with an NMDA antagonist which penetrates the BBB, such as 
PCP or MK-801, and will serve as a protective agent to reduce or eliminate 
the pathological effects that would otherwise be caused by the NMDA 
antagonist. This will allow the use of NMDA antagonists to prevent brain 
damage in situations such as severe stroke, perinatal asphyxia, or other 
types of ischemia, with a higher degree of safety than was previously 
available. 
In a similar manner, the anti-cholinergic agents described in the cited 
U.S. patent application (Ser. No. 424,548) can be used as protective 
agents in the subject invention, by co-administering them with the EAA 
antagonists disclosed herein. This will provide a higher degree of safety 
against any possible adverse effects from the EAA antagonists. This might 
allow, for example, the effective but safe use of EAA antagonists that 
have "moderate" levels of BBB permeability, as indicated in Table 1. It is 
also likely that anti-cholinergic agents such as scopolamine (which is 
already used as an anti-emetic agent against certain types of emesis, 
primarily involving motion sickness) might exert a synergistic effect with 
the EAA antagonists of this invention. Based on recent discoveries, such 
as the invention described in U.S. patent application Ser. No. 424,548, it 
has become clear that there are more interactions between the two main 
excitatory systems (the EAA system and the cholinergic system) than had 
previously been recognized. Based on those discoveries, and on 
scopolamine's effectiveness against motion sickness, administering an EAA 
antagonist and an anti-cholinergic agent in combination may provide a very 
powerful anti-emesis treatment. 
In one embodiment of this invention, a single broad-spectrum EAA antagonist 
is used, such as kynurenic acid (Kyn) or an analog thereof, such as 
7-chlorokynurenate, which binds to EAA receptors. As used herein, "analog" 
is used in its conventional pharmaceutical sense; it includes molecules 
which are structurally similar to a certain molecule, differing by factors 
such as halide or alkyl group substitutions, altered placement of a 
certain moiety, etc. For example, DNQX would be regarded as an analog of 
CNQX, and D-AP7 would be regarded as an analog of D-AP5. Any such analogs, 
in order to be useful for the purposes of this invention, must be 
pharmaceutically acceptable, i.e., they must be non-toxic at effective 
doses, they must be deliverable to the intended site in a suitable 
pharmaceutical carrier, etc. 
The term "broad spectrum" refers to an EAA antagonist (or a mixture of two 
or more antagonists) which has substantial potency against NMDA receptors 
and at least one type of non-NMDA receptor (either KA or QUIS). In this 
context, the phrase "potency against" refers to the ability of an 
antagonist to prevent or reduce the effects of EAA receptor activation by 
glutamate, aspartate, or any other naturally occurring EAA transmitter 
molecules. 
In an alternate preferred embodiment of this invention, an EAA antagonist 
is used which preferentially binds to NMDA receptors, such as D-AP5; 
alternately, an EAA antagonist is used which preferentially binds to 
non-NMDA receptors, such as CNQX. In either case, only one class of 
receptor would be blocked, while the other class would remain undisturbed. 
As described in Example 1, a selective EAA antagonist which blocks only 
NMDA receptors has been shown to suppress one type of chemically induced 
emesis in lab animals, and as described in Example 2, an EAA antagonist 
has been shown to suppress a different type of chemically induced emesis 
which directly involves only the KA class of non-NMDA receptors. 
Therefore, it has been shown that at least some types of emesis can be 
caused by activating only one type of EAA receptor. It has also been shown 
that such emesis can be blocked effectively by blocking that particular 
class of receptor. 
As discussed in the Background section, the different types of emesis 
suffered by humans are not fully understood, and it is not known whether, 
or to what extent, certain types of emesis may involve activation of NMDA 
receptors but not non-NMDA receptors (or vice-versa). In general, it is 
probably preferable to treat any case of emesis with the minimal amount of 
intervention necessary to provide effective relief, especially since the 
CVO regions that will be affected are involved in various neuroendocrine 
regulatory functions. For example, if a specific type of emesis involves 
activation of NMDA receptors but not non-NMDA receptors, it probably would 
be preferable to block the NMDA receptors, without blocking the non-NMDA 
receptors which are involved in normal neuronal processes. Similarly, if 
non-NMDA receptors alone are involved in a specific type of emesis, it 
probably would be preferable to block those receptors without blocking the 
NMDA receptors. 
Therefore, the subject invention offers two major benefits. First, it 
provides a highly useful method for determining whether emesis induced by 
any type of causative agent involves (1) NMDA receptors only; (2) non-NMDA 
receptors only; or, (3) both types of receptors. Second, when any specific 
type of emesis is discovered to involve only one class of receptor (i.e., 
if it can be suppressed by a selective antagonist such as D-AP5 alone, or 
by CNQX alone), the subject invention provides a method for treating such 
cases by blocking only that class of receptor without disturbing or 
altering the normal functioning of the other class of receptors. This will 
minimize potential side effects, compared to using broad-spectrum EAA 
antagonists or mixtures that block both classes of receptors even when one 
class does not need to be blocked. 
In an alternate preferred embodiment of this invention which involves 
broad-spectrum blockage, which may be necessary in severe cases such as 
those involving chemotherapy, a mixture of two or more EAA antagonists is 
used wherein a first antagonist preferentially binds to NMDA receptors, 
and a second antagonist preferentially binds to non-NMDA receptors. One 
such mixture, which has been shown to be a highly effective anti-emetic in 
animal tests, comprises two active ingredients: (1) D-AP5, which blocks 
NMDA receptors; and (2) CNQX, which preferentially blocks non-NMDA 
receptors. CNQX is believed to have substantial affinity for both KA and 
QUIS receptors (see Table 1), as well as a lesser affinity for NMDA 
receptors. These two agents, or other NMDA and non-NMDA antagonists such 
as those listed in Table 1, can be mixed together in a single formulation. 
Alternately, they can be administered separately if desired, preferably 
within a reasonably brief span of time so that both will exert their 
effects simultaneously. 
The pharmacological agents of this invention can be administered via 
subcutaneous or intramuscular injection using a single bolus injection, 
for patients who do not need large quantities, or via intravenous infusion 
if larger quantities are needed, such as for patients receiving 
chemotherapy. If injected or infused, they should be mixed with a suitable 
carrier liquid such as sterile buffered saline. 
Some EAA antagonists can be swallowed in capsule, liquid, or emulsion form 
without suffering an unacceptable reduction in activity; the preferred 
dosage for oral administration is usually increased compared to injection. 
If necessary to protect an orally administered EAA antagonist against 
degradation in the stomach, the antagonist can be placed in a capsule with 
a coating that does not dissolve until the capsule reaches the small 
intestines. 
The utility and effectiveness of several EAA antagonists as anti-emetic 
agents have been demonstrated in animal tests described in the Examples. 
In a series of tests described in Example 1, NMDA (an EAA agonist which 
activates the NMDA class of EAA receptors) was administered to dogs. It 
induced vomiting. That emetic response was blocked by subcutaneous (SC) 
injection of D-AP5, a competitive antagonist which does not penetrate the 
BBB and which has high affinity for NMDA receptors but not for KA or QUIS 
receptors. Since neither NMDA nor D-AP5 can cross the BBB, these two 
results indicate the following: 
(1) NMDA receptors on cells outside the BBB are involved in at least some 
types of emetic response and can causes emesis even if non-NMDA receptors 
are not activated; and, 
(2) a competitive antagonist which blocks NMDA receptors only on cells that 
are not protected by the blood-brain barrier, such as cells in the CVO 
regions of the CNS, can block an NMDA receptor mediated emetic response. 
In Example 2, kainic acid (KA), an agonist which triggers the KA class of 
non-NMDA receptors, was used to induce vomiting in dogs. That response was 
blocked by kynurenic acid (Kyn), an EAA antagonist which does not 
penetrate the BBB, but which acts at both NMDA and non-NMDA receptors. 
In Example 3, glutamate was administered to dogs. It activated both NMDA 
and non-NMDA receptors in the CVO regions (but not inside the remainder of 
the CNS, since glutamate does not penetrate the BBB). An emetic response 
occurred, which could not be blocked by D-AP5 even at relatively high 
doses. However, the emetic response could be blocked by Kyn. These 
results, together with the results of Example 2, suggest that both NMDA 
and non-NMDA receptors may play a role in some types of EAA-mediated 
emesis. In order to prevent that type of emesis, both types of receptors 
must be blocked by a broad-spectrum EAA antagonist, or by a mixture of 
antagonists which, acting together, have broad-spectrum activity. 
The preliminary results involving dogs led to a more extensive series of 
tests involving ferrets. As described in Example 4, experiments were 
performed on ferrets using cisplatin, a chemotherapeutic drug which has a 
powerful emetic effect. Four ferrets (a control group) received cisplatin. 
All four displayed persistent malaise and obviously did not feel well; 
none were playful, and none sought or ate any food. One control animal did 
not vomit, but the other three vomited repeatedly during the observation 
period. Nine test animals were treated with cisplatin, and with Kyn at 
varying doses either by bolus (one-shot) injection or by continuous IV 
infusion. All of the ferrets treated by continuous infusion displayed 
playful behavior, sought and ate food, did not appear ill, and did not 
vomit. Three of the ferrets treated by bolus injection vomited once or 
twice and showed transient malaise; however, only one appeared to be as 
ill as the control animals. 
In late 1987, Honore et al reported that a newly discovered compound, CNQX, 
could block non-NMDA receptors with high affinity. CNQX does not cross the 
BBB. The inventor obtained a sample of CNQX (Ferrosan Pharmaceuticals, 
Denmark) and determined, in an in vitro assay using retinas from chick 
embryos (Olney et al, 1986), that it is approximately 30 times more 
powerful than Kyn in blocking non-NMDA receptors. 
Since suitable agents such as D-AP5 are already available that can block 
NMDA receptors without crossing the BBB, a mixture of CNQX and D-AP5 was 
tested to see whether the mixture had anti-emetic properties. In these 
tests, described in Example 5, the dosage of cisplatin was increased to 10 
mg/kg IV, since only 3 out of 4 of the control animals vomited when 8 
mg/kg was used in Example 4. This increased the stringency of the test. 
Five control animals (ferrets) were treated. All five displayed repeated 
vomiting, with 5 to 10 vomiting episodes each within the first 2 hours. 
All appeared ill throughout the 5 hour observation period. 
Five test animals were treated by intravenous infusion of a mixture of CNQX 
and D-AP5. All 5 were completely free of vomiting throughout the 5 hour 
observation period. Some were playful and sought and ingested food and 
water; some appeared somnolent during part of the observation period, but 
none displayed any clear discomfort. There was no indication of any 
significant side effects. This result confirms that vomiting and nausea 
induced by a powerful emetic agent can be prevented by drugs that exert 
blocking activity against both NMDA and non-NMDA receptors, even though 
the drugs used do not cross the blood-brain barriers. 
As mentioned above, it appears that the emesis center in the brain stem 
mediates various emetic reflex arcs that initially involve non-EAA 
receptors, such as dopamine, serotonin, histamine, or cholinergic 
receptors. Based on the experimental results described herein, coupled 
with previous information, it appears that EAA receptors in the emesis 
center are involved as integral components of various different types of 
arcs. Since there may be many segments in a reflex circuit, analogous to 
successive links in a chain, both EAA receptors and non-EAA receptor 
systems may be integral components of any given circuit. The important 
requirement for achieving an anti-emetic effect with EAA antagonists of 
this invention is that there be an EAA receptor link in the circuit which 
lies outside the BBB, so that it can be contacted by EAA antagonists 
circulating in the blood. Regardless how many other transmitter receptors 
participate in any given reflex arc, if an EAA antagonist blocks 
transmission through an EAA link in the circuit, it will prevent the 
initial stimulus from leading to an emetic response. 
In addition, EAA antagonists, when used as described herein, will allow 
researchers to study and evaluate the roles that glutamate, aspartate, and 
EAA receptors play in emesis that is initially triggered by various emetic 
factors. 
It should also be recognized that extensive research is actively being done 
on EAA antagonists, and reports have appeared during each of the past few 
years identifying EAA antagonists with varying combinations of receptor 
affinities and BBB permeabilities. Several such compounds which have 
appeared recently are listed in Tables 1 and 2. Other EAA antagonists will 
surely be discovered in the future, including various compounds that do 
not penetrate the BBB in high quantities. Such antagonists can be screened 
for anti-emetic activity using no more than routine experimentation. 
Compounds which perform effectively as anti-emetics can be further 
analyzed to determine whether they cause adverse effects in animals, and 
if so, at what dosages, using the methods described herein and in Olney et 
al 1989. EAA antagonists which have a wide margin of safety between the 
anti-emetic effective dosage, and the dosage that causes significant 
adverse side effects, can be used as described herein for the purposes of 
this invention, subject to human clinical testing to ensure that any side 
effects are acceptably small. Such antagonists may have higher affinities 
for one or more classes of EAA receptors, and as such, they may comprise 
patentable improvements over the antagonists known today. However, such 
improvements will fall within the teachings of this invention and the 
coverage of the claims, if they are used as anti-emetic agents in the 
manner and for the purposes described herein. 
EXAMPLES 
Example 1: Emesis Induction by NMDA; Blockage by D-AP5 
NMDA, an EAA agonist which does not penetrate the BBB and which activates 
NMDA receptors but not non-NMDA receptors, was administered intravenously 
(IV) to dogs at doses in the vicinity of 5 mg/kg. The vomit reflex in dogs 
is sensitive and rapidly transient, and vomiting can be induced by NMDA at 
dosages that cause no lasting symptoms. Therefore, each dog (all were 
young adults) was used for more than one experiment. Typically, one or 
more tests would be done using NMDA to determine an effective dosage for 
an individual dog. After the dose was established, an experiment was 
conducted on a subsequent day in which the dog also received 2 mg/kg D-AP5 
subcutaneously (SC), along with the NMDA. On the day after that, NMDA was 
administered alone, to ensure that the emetic response was unchanged and 
the dog had not developed tolerance or sustained damage to the 
emesis-mediating reflexes. 
The D-AP5 blocked the emesis response in all dogs. Since D-AP5 cannot cross 
the BBB, these results indicate the following: 
(1) NMDA receptors on cells outside the BBB are involved in at least some 
types of emetic response and can causes emesis even if non-NMDA receptors 
are not activated; and, 
(2) a competitive antagonist which blocks NMDA receptors only on cells 
outside the BBB, such as cells in the CVO regions of the CNS, can block an 
NMDA receptor-mediated emetic response. 
Example 2 Emesis Induction by KA; Blockaqe by Kyn 
Kainic acid (KA), an EAA agonist which triggers the KA class of non-NMDA 
receptors, was administered to dogs at dosages in the vicinity of 0.5 
mg/kg SC. On certain days, the dogs also received kynurenic acid (Kyn), an 
EAA antagonist that does not readily penetrate the BBB. All of the animals 
suffered an emetic response when KA was administered without Kyn; however, 
emesis was blocked by 50 mg/kg Kyn SC. 
These results indicate that: 
1. some types of emesis are mediated by non-NMDA EAA receptors on cells 
outside the BBB, even if NMDA receptors are not directly triggered; and, 
2. an antagonist that blocks KA receptors only on cells outside the BBB can 
block a KA receptor-mediated emetic response. 
Example 3: Emesis Induction by Glutamate 
Glutamate was administered to dogs (150 mg/kg IV). It activated both NMDA 
and non-NMDA receptors in the CVO regions, but not inside the remainder of 
the CNS, since glutamate does not penetrate the BBB. An emetic response 
was observed in all animals. This response could not be blocked by D-AP5, 
even at doses up to 25 mg/kg SC. However, it could be blocked by Kyn, a 
broad-spectrum EAA antagonist that blocks both NMDA and non-NMDA 
receptors, at a dosage of 75 mg/kg SC. These results indicate that both 
NMDA and non-NMDA receptors can play a role in some types of emesis, and 
both categories of receptors must be blocked in order to prevent those 
types of emesis. 
Example 4: Emesis Induction by Cisplatin; Blockage by Kyn 
Four ferrets (a control group) received 8 mg/kg IV cisplatin, a 
chemotherapeutic drug which has a powerful emetic effect. All four control 
animals displayed persistent malaise and obviously did not feel well; none 
was playful, and none sought or ate any food. One control animal did not 
vomit, but the other three vomited repeatedly during the observation 
period (five hours; most vomiting occurred during the first two hours). 
Nine ferrets were treated with cisplatin (8 mg/kg IV), and with Kyn, either 
by bolus (one-shot) injection using 150 mg/kg, or by continuous IV 
infusion using 50 mg/kg/hour. All of the ferrets treated by continuous 
infusion displayed playful behavior, sought and ate food, did not appear 
ill, and did not vomit. Three of the ferrets treated by bolus injection 
vomited once or twice and showed transient malaise; however, only one 
appeared to be as ill as the control animals. 
Example 5: Emesis Induction by Cisolatin; Blockage by D-AP5/CNQX 
Honore et al 1987 and 1988 reported that CNQX, which does not cross the 
BBB, could block non-NMDA receptors with high affinity. The inventor 
obtained a sample from Ferrosan Pharmaceuticals of Denmark and determined, 
in an assay using chick retinas (Olney et al 1986) that it is 
approximately 30 times more powerful than Kyn in blocking non-NMDA 
receptors. 
Since suitable agents such as D-AP5 are available that can block NMDA 
receptors without crossing the BBB, a mixture of CNQX and D-AP5 was tested 
to see whether a mixture of an NMDA antagonist and a non-NMDA antagonist 
would have anti-emetic properties. The dosage of cisplatin was increased 
to 10 mg/kg IV, since only 3 out of 4 of the control animals vomited when 
8 mg/kg was used as described in Example 4. This increased the stringency 
of the test. 
Five control animals (ferrets) were treated. All five displayed 5 to 10 
vomiting episodes each within the first 2 hours, and all appeared ill 
throughout the observation period, which lasted five hours. 
Five test animals were treated by cisplatin, 10 mg/kg IV, followed by 
intravenous infusion of a mixture of 15 mg/kg/hr CNQX and 5 mg/kg/hr 
D-AP5. All 5 were completely free of vomiting throughout the 5 hour 
observation. Some were playful and sought and ingested food and water; 
some appeared somnolent during part of the observation period, but none 
displayed any clear discomfort. There was no indication of any significant 
side effects. This result confirms that vomiting and nausea induced by a 
powerful emetic agent can be prevented by EAA antagonists that do not 
cross the blood-brain barriers. 
Thus, it has been demonstrated that various types and mixtures of EAA 
antagonists can reduce or eliminate at least some types of emesis. Judging 
from lab animal behavior, these pharmacological agents also reduced or 
eliminated nausea, and did not cause any adverse side effects. This 
invention therefore satisfies all of the objectives set forth above. 
As will be recognized by those skilled in the art, various modifications 
can be made to the specific embodiments described here. Such changes, if 
they do not depart from the scope and teachings of the subject invention, 
are deemed to be covered by this invention, which is limited only by the 
claims below. 
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