U.S. patent application number 17/013987 was filed with the patent office on 2021-07-29 for use of amisulpride as an anti-emetic.
The applicant listed for this patent is Acacia Pharma Ltd.. Invention is credited to Nicola COOPER, Gabriel FOX, Julian Clive GILBERT, Robert William GRISTWOOD.
Application Number | 20210228543 17/013987 |
Document ID | / |
Family ID | 1000005507859 |
Filed Date | 2021-07-29 |
United States Patent
Application |
20210228543 |
Kind Code |
A1 |
GILBERT; Julian Clive ; et
al. |
July 29, 2021 |
USE OF AMISULPRIDE AS AN ANTI-EMETIC
Abstract
Amisulpride is used in the therapy of nausea, vomiting or
retches. The therapy may utilize a novel injectable formulation, in
unit dosage form, comprising less than 50 mg amisulpride.
Inventors: |
GILBERT; Julian Clive;
(Cambridge, GB) ; GRISTWOOD; Robert William;
(Cambridge, GB) ; COOPER; Nicola; (Essex, GB)
; FOX; Gabriel; (Cambridge, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Acacia Pharma Ltd. |
Duxford |
|
GB |
|
|
Family ID: |
1000005507859 |
Appl. No.: |
17/013987 |
Filed: |
September 8, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16697986 |
Nov 27, 2019 |
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17013987 |
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16105268 |
Aug 20, 2018 |
10525033 |
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16697986 |
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15790481 |
Oct 23, 2017 |
10085970 |
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16105268 |
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15374174 |
Dec 9, 2016 |
9889118 |
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15790481 |
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14812148 |
Jul 29, 2015 |
9545426 |
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15374174 |
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14172194 |
Feb 4, 2014 |
9119836 |
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14812148 |
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13559253 |
Jul 26, 2012 |
8686019 |
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14172194 |
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PCT/GB2011/050472 |
Mar 10, 2011 |
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13559253 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 33/24 20130101; A61K 45/06 20130101; A61K 47/12 20130101; A61K
31/573 20130101; A61K 9/0019 20130101; A61K 31/282 20130101; A61K
9/0053 20130101; A61K 31/485 20130101; A61K 31/40 20130101; A61K
9/0031 20130101; A61K 31/4178 20130101 |
International
Class: |
A61K 31/40 20060101
A61K031/40; A61K 9/00 20060101 A61K009/00; A61K 31/282 20060101
A61K031/282; A61K 31/4178 20060101 A61K031/4178; A61K 31/485
20060101 A61K031/485; A61K 47/12 20060101 A61K047/12; A61K 45/06
20060101 A61K045/06; A61K 33/24 20060101 A61K033/24; A61K 31/573
20060101 A61K031/573 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 11, 2010 |
GB |
1004020.2 |
Claims
1. A pharmaceutical composition comprising amisulpride in an amount
of less than 50 mg per dose, and a pharmaceutically acceptable
carrier.
2. A method for the prevention and/or treatment of post-operative
nausea and vomiting, comprising administering amisulpride at a dose
of less than 50 mg to a subject in need thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
application Ser. No. 16/697,986, filed Nov. 27, 2019, which is a
continuation application of U.S. application Ser. No. 16/105,268,
filed Aug. 20, 2018 (now U.S. Pat. No. 10,525,033), which is a
continuation application of U.S. application Ser. No. 15/790,481,
filed Oct. 23, 2017 (now U.S. Pat. No. 10,085,970), which is a
continuation application of U.S. application Ser. No. 15/374,174,
filed Dec. 9, 2016 (now U.S. Pat. No. 9,889,118), which is a
continuation application of U.S. application Ser. No. 14/812,148,
filed Jul. 29, 2015 (now U.S. Pat. No. 9,545,426), which is a
continuation application of U.S. application Ser. No. 14/172,194,
filed Feb. 4, 2014 (now U.S. Pat. No. 9,119,836), which is a
continuation application of U.S. application Ser. No. 13/559,253,
filed Jul. 26, 2012 (now U.S. Pat. No. 8,686,019), which is a
continuation application of International Application Number
PCT/GB2011/050472, filed Mar. 10, 2011, which claims priority to
Great Britain Application No. 1004020.2, filed Mar. 11, 2010, each
of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to the use of amisulpride in the
therapy of nausea, vomiting and retching.
BACKGROUND OF THE INVENTION
[0003] Emesis is the act of vomiting and can be described as the
forceful expulsion of gastrointestinal contents through the mouth
brought about by the descent of the diaphragm and powerful
contractions of the abdominal muscles. Emesis is usually, but not
always, preceded by nausea. Retching (or dry heaves) involves the
same physiological mechanisms as vomiting, but occurs against a
closed glottis. Nausea may be defined as a desire to vomit but
which is not associated with expulsive muscular movement.
[0004] Vomiting, nausea, retching or any combination (hereinafter
referred to as "the symptoms") can be caused by a number of factors
including anesthetics, radiation, cancer chemotherapeutic agents,
toxic agents, medicines, for example serotonin reuptake inhibitors,
analgesics such as morphine, antibiotics, pregnancy and motion.
Conditions which are associated with vertigo, for example Meniere's
disease, can also cause the symptoms. Headache, caused by for
example migraine, increased intracranial pressure or cerebral
vascular haemorrhage can also result in the symptoms. Other
maladies associated with the symptoms include cholecystitis,
choledocholithiasis, intestinal obstruction, acute gastroenteritis,
perforated viscus, dyspepsia resulting from, for example,
gastroesophageal reflux disease, peptic ulcer disease,
gastroparesis, gastric or oesophageal neoplasms, infiltrive gastric
disorders (e.g. Menetrier's syndrome, Crohn's disease, eosinophilic
gastroenteritis, sarcoidosis and amyloidosis), gastric infections,
parasites, chronic gastric volvulus, chronic intestinal ischaemia,
altered gastric motility disorders and/or food intolerance or
Zollinger-Ellson syndrome. In some cases of the symptoms, no
etiology can be determined, as for example in Cyclic Vomiting
Syndrome.
[0005] The symptoms may be defined as acute when they are present
for less than a week. The causes of the symptoms of short duration
can be separable from etiologies leading to more chronic symptoms.
The symptoms may be defined as chronic when they are present for
over a week; these can be continuous or intermittent, and last for
months or years.
[0006] Two areas of particular clinical relevance are nausea and
vomiting resulting from surgical procedures (post-operative nausea
and vomiting, or PONV) or chemotherapeutic agents and radiation
therapy (chemotherapy-induced nausea and vomiting, or CINV). The
symptoms caused by chemotherapeutic agents can be so severe that
the patient refuses further treatment. Three types of emesis are
associated with the use of chemotherapeutic agents, i.e. acute
emesis, delayed emesis and anticipatory emesis.
[0007] PONV is a significant issue for patients and healthcare
providers. It is rated second only to pain as the complication most
feared by patients, and contributes significantly to anxiety and
patient distress. Vomiting can have an adverse impact on surgical
wound sites, especially upper GI tract surgery.
[0008] Risk factors for PONV include type of surgery, gender (women
are more prone than men to PONV), smoking history, prior history of
PONV or motion sickness, length of surgery, use of volatile
anesthetics and opioid analgesic usage. Certain operations seem to
be particularly associated with PONV, including procedures on the
eyes and ears, laparoscopic cholecystectomy and hysterectomy,
breast surgery and major abdominal and gynaecological surgery.
[0009] PONV is typically treated using a dopamine D2 antagonist
such as droperidol. This drug was given a black box warning by the
FDA in 2001 on the basis of cardiotoxicity, believed to be related
to a propensity of the drug to block HERG channels and cause QT
prolongation.
[0010] Amisulpride, an atypical antipsychotic D2 antagonist, has
beneficial actions in schizophrenic patients. For patients
characterised by predominant negative symptoms, oral doses of
50-300 mg/day are recommended. It is reported in the UKPAR (Special
Warnings and Precautions for Use) that amisulpride induces a dose
dependent prolongation of the QT interval.
[0011] Amisulpride is marketed as Solian, a solution for
intramuscular administration, comprising water, hydrochloric acid,
sodium chloride and amisulpride. An ampoule contains amisulpride at
200 mg/4 ml solution.
[0012] U.S. Pat. No. 4,294,828 discloses amisulpride and related
compounds having anti-apomorphine and anti-serotonin activity.
Amisulpride is reported to inhibit apomorphine-induced vomiting in
the dog, thereby confirming that amisulpride is a functional D2
antagonist. It is suggested that the compounds should be
administered at doses of 50-750 mg/day, e.g. 200 mg/day.
SUMMARY OF THE INVENTION
[0013] The present invention relates to the use in man of
amisulpride for the therapy (including treatment and prophylaxis or
preventative therapy) of nausea, vomiting or retching. The
condition may have any cause, e.g. motion sickness, but amisulpride
may be particularly useful in therapy of PONV or in patients
receiving cancer chemotherapy or radiotherapy.
[0014] As will be evident from the data presented below,
amisulpride is effective as an anti-emetic agent, even when the
subject is receiving morphine or cisplatin, both agents whose
emetic effect is strong and difficult to alleviate. Surprisingly,
it is also effective at a dose well below any that has previously
been proposed for this drug. Therefore, although side-effects are
not as much of a concern when using amisulpride as in the case of
some other anti-emetic drugs, such effects can be minimised or
avoided.
[0015] Another aspect of the invention is a product comprising
amisulpride and an emetogenic agent, as a combined preparation for
separate, simultaneous or sequential use in the therapy of a
condition as defined herein.
[0016] A further aspect of the present invention is a buffered
composition suitable for injection. Yet another aspect of the
present invention is a unit dosage for injection comprising less
than 50 mg amisulpride.
DETAILED DESCRIPTION OF THE INVENTION
[0017] Amisulpride has a single chiral centre and 2 enantiomers
exist, i.e. (S-)-amisulpride and (R+)-amisulpride. Substantially
pure enantiomer or non-racemic mixtures may be used, but it may be
preferred to use racemate or (S-)-amisulpride.
[0018] For the purpose of the present invention, amisulpride may be
administered at dosages which are not associated with adverse
cardiovascular events. It is preferably administered by the
intravenous, intramuscular, subcutaneous or oral route for the
treatment of PONV, whilst for the treatment of CINV additional
routes include sublingual, rectal, intranasal, topically applied
directly to the skin, buccal or pulmonary inhaled.
[0019] A typical dosage, e.g. for intravenous administration, is
from 1 to 48 mg, e.g. up to 40 mg, preferably 1 to 35 mg or,
depending on the circumstances, 5 to 35 mg. Human doses of 2.5 to
20 mg may be effective. The drug may be given once, twice or more
often each day, particularly for CINV. A single dosage may be
sufficient for PONV. It will be understood, however, that the
specific dose level for any particular patient will depend upon a
variety of factors including the age, body weight, general health,
sex, diet, time of administration, drug combination and the
severity of the particular condition undergoing therapy.
[0020] For intravenous injection, the amisulpride may be in the
form of a salt, hydrate or solvate. Salts include pharmaceutically
acceptable salts, for example acid addition salts derived from
inorganic or organic acids, such as hydrochlorides, hydrobromides,
p-toluenesulphonates, phosphates, sulphates, perchlorates,
acetates; trifluoroacetates, propionates, citrates, malonates,
succinates, lactates, oxalates, tartrates and benzoates.
[0021] Salts may also be formed with bases. Such salts include
salts derived from inorganic or organic bases, for example alkali
metal salts such as magnesium or calcium salts, and organic amine
salts such as morpholine, piperidine, dimethylamine or diethylamine
salts.
[0022] A pharmaceutical composition containing the active
ingredient may be in any suitable form, for example aqueous or
non-aqueous solutions or suspensions, dispersible powders or
granules, transdermal or transmucosal patches, creams, ointments or
emulsions.
[0023] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or non-aqueous (e.g. oleaginous)
solution or suspension. The sterile injectable preparation may also
be in a sterile injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, phosphate buffer solution,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose, any bland fixed oil
may be employed, including synthetic mono- or diglycerides. In
addition, fatty acids such as oleic acid find use in the
preparation of injectables. Suspensions may be formulated according
to the known art using those suitable dispersing or wetting agents
and suspending agents which have been mentioned elsewhere.
[0024] Aqueous suspensions contain the active ingredient in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents such as a naturally occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxyethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such a polyoxyethylene with partial esters
derived from fatty acids and hexitol anhydrides, for example
polyoxyethylene sorbitan monooleate. The aqueous suspensions may
also contain one or more preservatives, for example ethyl or
n-propyl p-hydroxybenzoate, one or more colouring agents, one or
more flavouring agents; and one or more sweetening agents, such as
sucrose or saccharin.
[0025] Non-aqueous (i.e. oily) suspensions may be formulated by
suspending the active ingredient in a vegetable oil, for example
arachis oil, olive oil, sesame oil or coconut oil, or in a mineral
oil such as liquid paraffin. The oily suspensions may contain a
thickening agent, for example beeswax, hard paraffin or cetyl
alcohol. These compositions may be preserved by the addition of an
anti-oxidant such as ascorbic acid.
[0026] Compositions for injection are typically aqueous, and
comprise a buffer, e.g. citrate buffer. No other ingredients may be
required. The pH of such a composition may be, for example from 4
to 7, e.g. 5.
[0027] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are known.
[0028] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally occurring gums, for example gum
acacia or gum tragacanth, naturally occurring phosphatides, for
example soya bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate.
[0029] The active agent may also be administered in the form of
suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the
rectum to release the drug. Such materials are cocoa butter and
polyethylene glycols.
[0030] For topical delivery, transdermal and transmucosal patches,
creams, ointments, jellies, solutions or suspensions may be
employed. For sub-lingual delivery, fast dissolving tablet
formulations may be used, as well as a number of the presentations
described above. For oral administration, amisulpride may be
administered as tablets, capsules or liquids.
[0031] It may be advantageous to co-administer amisulpride with
other classes of drug which can add additional benefits of efficacy
and/or, by titrating dosages downwards, result in fewer
side-effects. These include, but are not limited to,
antihistamines, 5-HT3 antagonists including granisetron,
ondansetron, palonosetron, dolasetron, and tropisetron,
dexamethasone, aprepitant and other neurokinin-1 receptor
antagonists and drugs such as nabilone.
[0032] It may also be advantageous to co-administer amisulpride
with drugs which are associated with emesis in man, for example
certain opioids including morphine. Amisulpride, at an appropriate
concentration determined by one of skill, can be formulated with
the drug in question, for example morphine, in a dosing system such
as an infusion bag or other appropriate dosage form.
[0033] By way of example, amisulpride and an emetogenic agent may
be administered to a subject in combination, simultaneously or
sequentially. For example, amisulpride is given before treatment
with, say, morphine or a chemotherapeutic agent such as cisplatin.
As indicated above, the route of administration may depend on the
condition being treated.
[0034] As indicated above, there are various causes of emesis.
Examples of conditions that may be treated by the use of
amisulpride include anesthetics, radiation, cancer chemotherapeutic
agents, toxic agents, medicines, for example serotonin reuptake
inhibitors, analgesics such as morphine, antibiotics, pregnancy,
motion, conditions which are associated with vertigo, for example
Meniere's disease, headache, caused by for example migraine,
increased intracranial pressure or cerebral vascular haemorrhage,
cholecystitis, choledocholithiasis, intestinal obstruction, acute
gastroenteritis, perforated viscus, dyspepsia resulting from, for
example, gastroesophageal reflux disease, peptic ulcer disease,
gastroparesis, gastric or oesophageal neoplasms, infiltrive gastric
disorders (e.g. Menetrier's syndrome, Crohn's disease, eosinophilic
gastroenteritis, sarcoidosis and amyloidosis), gastric infections,
parasites, chronic gastric volvulus, chronic intestinal ischaemia,
altered gastric motility disorders and/or food intolerance and
Zollinger-Ellson syndrome.
[0035] The following studies provide evidence on which the
invention is based. The preclinical evidence for efficacy against
vomiting in PONV and CINV involves studies in ferrets, whilst
efficacy against nausea can be demonstrated in patients receiving a
general anesthetic procedure.
Study 1
[0036] Amisulpride, white powder, was dissolved in
dimethylsulfoxide and then diluted in physiological saline.
[0037] For vehicle control, physiological saline was used for s.c.
administration (apomorphine experiments) and 8.3% DMSO in
physiological saline was used for intravenous (i.v.) administration
(morphine, cisplatin).
[0038] Droperidol was dissolved in DMSO then diluted in lactic acid
in physiological saline, to a final DMSO concentration of 7.5%.
[0039] Apomorphine hydrochloride hemihydrates, white powder, were
dissolved in physiological saline.
[0040] Morphine hydrochloride, white powder, was dissolved in
physiological saline.
[0041] Cisplatinum II diamine dichloride, yellow powder, was
dispersed in 0.2% hydroxymethylcellulose in physiological
saline.
[0042] The method used to test antiemetic activity preclinically
follows that described by Gardner et al. (Brit. J. Pharmacol., 116:
3158-3163, 1995) and uses ferrets.
[0043] Sixty minutes before administration of the test substance,
ferrets are placed in individual stainless steel cages
(40.times.50.times.34 cm) with a grid floor. Then, the animals are
challenged with apomorphine (0.25 mg/kg s.c.), morphine (0.4 mg/kg
i.p.) or cisplatin (10 mg/kg i.p.) and immediately observed over at
least a 2-hour period. Parameters recorded include: number of
ferrets showing retches and vomits; latency to first retching;
latency to first vomiting; number of retches; vomiting (number of
vomits); number of emesis periods and mean duration of emesis
periods. Retching is defined as a rhythmic respiratory movement
against a closed glottis, while vomiting is defined as a forced
expulsion of upper gastrointestinal contents.
[0044] Where apomorphine is used as the emetogen, amisulpride (or
vehicle) was administered subcutaneously (s.c. 30 minutes before
administration of apomorphine). Animals (6 per group) were treated
with vehicle or amisulpride at 1, 10, or 100 .mu.g/kg given
sub-cutaneously. The observation period was 2 hours after
apomorphine administration.
[0045] Where morphine is used as the emetogen, amisulpride (n=6 per
group) or vehicle (n=6) is administered intravenously 5 minutes
before the administration of morphine. The observation period is 2
hours after administration of the morphine.
[0046] Where cisplatin is used as the emetogen, amisulpride (n=6
per group) or vehicle (n=6) is administered intravenously at least
5 minutes before the administration of cisplatin. The observation
period is up to 72 hours, which allows effects on early and late
phase emesis to be observed.
[0047] Apomorphine in the vehicle control group induced emesis in
the ferrets over the 2 hour observation period (14.8.+-.4.8
retches, 1.0.+-.0.5 vomits, 3.3.+-.0.9 emesis periods). Retches and
vomits occurred 319.+-.53 and 621.+-.308 seconds after
administration respectively. Amisulpride given at 1 .mu.g/kg, 30
minutes before apomorphine, decreased the emetic effects of
apomorphine as compared with the vehicle control group (6.0.+-.2.2
retches, 0.+-.0 vomits and 1.5.+-.0.6 emesis periods). Amisulpride
at 10 and 100 .mu.g/kg totally inhibited the apomorphine emesis.
This demonstrates that, as might be expected, amisulpride blocks
dopamine D2 receptors.
[0048] Morphine in the vehicle control group induces emesis in the
ferrets over the 2 hour observation period. Amisulpride reduces the
emetic effects induced by morphine, in dose-dependent manner, as
compared with the vehicle control group. The ED50 for amisulpride
against morphine emesis is calculated. These data indicate that
amisulpride has efficacy against morphine-induced emesis and that
is effective when administered via the intravenous route.
[0049] More specifically, morphine in the control group induced the
occurrence of retches and vomits in 6 (retches) and 4 (vomits) of 6
animals, the mean (.+-.s.e.m.) values were 33.8.+-.4.7 retches,
1.8.+-.0.7 vomits and 7.5.+-.1.5 emesis periods. Retches and vomits
occurred after 213.+-.24 and 374.+-.64 seconds respectively.
Amisulpride was given at 3, 6 and 12 mg/kg before morphine.
Amisulpride at 3 mg/kg produced small decreases in retches to
28.7.+-.7.1 and emesis periods to 5.2.+-.1.4 and abolished the
incidence of vomits. Amisulpride given at 6 mg/kg decreased the
incidence of all 3 parameters, retches to 17.8.+-.6.8
(approximately a 50% decrease), vomits to 0.5.+-.0.3 (a 72%
decrease) and emesis periods to 3.3.+-.1.1 (a 56% decrease). The
data from the first 2 dose levels demonstrate a dose related
reduction in emesis with amisulpride. Amisulpride given at 12 mg/kg
had no effect on retches 31.7.+-.11.2, but still produced a
reduction in vomits to 0.8.+-.0.4 and slight reduction in emesis
periods to 5.7.+-.1.5.
[0050] These data demonstrate that amisulpride blocks
morphine-induced emesis, and also that the drug may be less
effective at higher dosages. It is reasonable to deduce that a dose
of less than 50 mg will be effective in a human subject.
[0051] Cisplatin in the vehicle control group induces emesis over
the 72 hour period. Amisulpride reduces the emetic effects of
cisplatin, in dose-dependent manner, as compared with the vehicle
control group, having an effect on both early and late stages.
[0052] More specifically, data are reported from an experiment in
which the observation period was 3 hours following cisplatin
challenge. Cisplatin induced the occurrence of retches and vomits
in 7 and 5 of 9 animals tested respectively. The mean incidences
were 79.8.+-.22.2 retches, 3.0.+-.1.1 vomits and 10.7.+-.2.8 emetic
periods. Retches and vomits occurred after 85 minutes 6
seconds.+-.7 minutes 53 seconds and 86 minutes 39 seconds.+-.10
minutes 28 seconds respectively amisulpride was given at 0.2, 0.6,
2 and 6 mg/kg. At 0.2 mg/kg the incidence of retches was
23.3.+-.10.8 (a 71% decrease in mean value), of vomits 0.2.+-.0.2
(a 93% decrease) and emesis periods 3.7.+-.2.0 (a 65% decrease). At
0.6 mg/kg the incidence of retches was 62.5.+-.59.0, vomits
1.3.+-.1.1 and emesis periods 3.7.+-.1.3. It was noted in this
group that one animal had an early, exaggerated response to
cisplatin. At 2.0 mg/kg the incidence of retches was 3.3.+-.2.5,
vomits 0.2.+-.0.2 and emesis periods 0.5.+-.0.3. It is clear that
amisulpride at 0.6 mg/kg (with one animal excluded), and 2 mg/kg is
better than droperidol at 3 mg/kg. At 6 mg/kg the incidences were
11.7.+-.3.8 retches, 1.2.+-.1.0 vomits and 3.7.+-.1.3 emesis
periods.
[0053] These data demonstrate that amisulpride blocks
cisplatin-induced emesis, and also indicate that the drug may be
less effective at higher dosages. Again, it is reasonable to deduce
that a dose of less than 50 mg will be effective in a human
subject.
[0054] As indicated above, droperidol is a known agent for the
treatment of PONV. In a comparative experiment, droperidol was
given 5 minutes before cisplatin (using the methods described
above) in 3 animals and it was found that, based on the incidence
of nausea and vomiting, amisulpride at 0.6 mg/kg (with one animal
which had the exaggerated response excluded) and 2 mg/kg is more
effective than droperidol at 3 mg/kg.
Study 2
[0055] A formulation of the invention was prepared, suitable for
intravenous administration. It is a 2.5 mg/ml citrate-buffered
solution (nominal pH 5.0) of amisulpride. The composition is given
below.
TABLE-US-00001 Quantity (g) per vial Component % w/v (10 mL fill)
Amisulpride 0.25 0.025 Citric acid monohydrate 0.935 0.0935
Trisodium citrate dihydrate 1.632 0.1632 Sodium chloride 0.18 0.018
Hydrochloric acid dilute qs qs Sodium hydroxide qs qs Water for
injection To 100 To 10 mL
[0056] The effects of amisulpride are studied in patients
undergoing routine surgery in a randomised, controlled, open-label
phase IIa study of efficacy of a single dose as prophylaxis of
post-operative nausea and vomiting. The primary endpoint is the
incidence of nausea and vomiting in the 24-hour period
post-operation. The drug is administered at the time of the
operation. The secondary endpoints are the nausea and vomiting
rates and severity (measured separately) over 0-2 hours, 2-6 hours
and 6-24 hours post-operation. In addition, the use of rescue
medication and safety/adverse events, are recorded. The data
demonstrate the effect of amisulpride against the nausea as well as
the vomiting and retching associated with PONV.
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