AU2016216578B2 - The use of amisulpride as an anti-emetic - Google Patents

Abstract

Amisulpride is used in the therapy of nausea, vomiting or retches. The therapy may utilise a novel injectable formulation, in unit dosage form, comprising less than 50 mg amisulpride.

Description

the: wsi of mmipkm m m mmm®

FimM&Amenttm INIs Invention relates to the use of «misuipride In the therapy of haus#, vomiting and retching.

MiiffieiiMioa

Emesis: is the act of vomiting and can he deschhed as the forceful expulsion of gastrointestinal contents through the mouth brought about by the descent of the diaphragm and powerlul contractions of the abdomtnsi muscies. 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.

Vomiting, nausea, retching or any combination (hereinafter refbrrmi to as “the symptoms*} can be caused by a number of factors Including anaesthetios, :'r|jiippri.t. t^nip©r;^iemothertpg0%aphis, toxic agents, medicines, for example serotonih reuptake inhibitors, analgesics: such as morphine, antibiotics, pregnancy and motion, G ondifions which are associated with vertigo, for example Mer^iere's disease, can also cause the symptoms, Headache, caused' by for example migraine, increased Intracranial pressure or cerebral vascular haemdjfhage can also result In the symptoms. Other maladies associated with, the symptoms indude cholecystitis, chotedocholithiasis, Intestinal obstruction, acute gastroententls, perforated viscus, dyspepsiu msulfing from, for example, gastroesophogeal reflux disease, peptic ulcer disease, pastrpparesls, gastric or oescphagea! neopiasms, tnfiitrive gastric disorders (e.g. Vienetneds syndrome:, Cfohn%; disease,, aosinophsilc : gastroenteritis, sarcoidosis and amyloidosis), gastric infections, parasites, chronic gastric volvulus, chronic intestinal ischaemia, mitered gastdo modiity disorders and/orIfpoct Intoiemnce or Zpijinger-Bison syndrome, in: soma cases of the symptoms, no fiioipgy can be determined, as for example in Qycilo Vomiting Byndrome,

The symptoms may be dafihed as: acute when they are present for less: then .a week. The causes of the: symptom of short duration can be saparabie from etiologies leading to more chronic symptoms, The symptoms may be defined: as ehredld when ihtey srd present for W&t a weeks these can be continuous or internTttorfe and s a si for months or years.

Two areas of particular clinical relevance am nausea and ubmitirrg .testing from sergicai procedures (postoperative causes and vor#feg*. or PGNVJ or ehemofeerapeotic agents and' radiation therapy (chemotherapy* Induced nausea; and vomiting, m CSNV)! The -symptoms .caused· by obamaiherapeutiC: agents can be so severe that tire patient, refuses further treatment. three-: types of emesis are associated with the: use: of ohemotherapeutio agarits, be. acute emesis, delayed emesis and anticipatory emesis, PONV is a significant issue tor patients and healthcare providers, it is rated second only to pain as fee oompficailOn 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.

Bisk factors for PONV fesfed#; typirtwofiorf arSl irfere props than men to PGNV}; smoking history, odor- history of PONV or motion sickness, length of surgery, use of volatile anaesthetics and opioid ansfeesio usage. 'Certain operations seam to be: particulariy: associated with PONV, including procedures pn th| dyes and ears, laparoscopic cholecystectomy apd hysterectomy; ifeast surgery arid major PONV is: typically treated USlhg -a dopamine D2 antagonist such as droperidoi. This drug was given afeiack box warning by fee FDA in 2001 on the basis of eardiotoxloitw believed to be related to a propensily of fee dmg to block HERG channels and cause QT prolongation,

Amisulpride, an atypical antipsychotic D2 antagonist, has beneficial actions in schiSfophmnic patients. For patients ehatectedsed by predominant negative symptoms, ora! doses of 50-300 rog/day are recommended. It Is reported In fee UKPAR (Special Warninp and Preeautlens for Usef that amisulpride induces a dose dependent proiongation: of theQJ interval. >·. Amisulpride; Is marketed as Jbiiah, a: solution for Intramuscular administration,:, comprising water, feydroohldno add,: sodium chloride and amisulpride.: An ampoule contains amisuiprlde:at:260 mg/4 mi solution. US4294828 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

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. The condition may also be induced by an opioid (eg through administration of an opiate such as morphine).

In a first aspect, the present invention provides a method of therapy of a condition selected from the group consisting of post-operative nausea and vomiting (PONV), chemotherapy-induced nausea and vomiting (CINV), radiation-induced nausea and vomiting (RINV) and opioid-induced nausea and vomiting (01NV), wherein the method comprises administering an effective dose of amisulpride to a subject in need of said therapy.

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. in a second aspect, the present invention provides a product comprising amisulpride and an emetogenic agent, as a combined preparation for simultaneous use in the therapy of a condition as defined herein. 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.

Description of the invention

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.

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 CHMV Mditignai routes: include sublinguai, rectal* inlranasal» tapiealif applied direotly Ip the shin, Paces; or pulmonary Inhaled, A typio&amp;i dosage, e.g. for Intravenous administration, Is from 1 to A8 mg* :&amp;g. upTo 40 mg, preferably 1 id 35 mg or, depending on Ihe pfrournstances, 5 to 3S mg, triuman doses of $<i to M mg may be effective, the drug may bsgiven once, Mice or mol'd often each bay, particularly feC^V. "b single dosage may be sufficient for PtlMV,. I will be understood, however, that the specific dose love! for any particular patientiwili depend upon a variety of factors including the agm body weight, genoral health, sex, diet, time :pf administration,: drug combination: and: the seventy of the particular condition undergoing therapy.

For intravenous ln|e:ctioo, the amisySpricie may: b# in th# forth of a #a|ii:: hydrate orsolvate. Saits include pharmaceutically accepf|b|e Salts, iprdydmple acid: addition sails derived from Inorganic or Organic: acids, such as hydmchSorirtes. hydrobrom-des. p-toiuenesuiphpnalBS, jhosphbfop, sulphates, perchlorates, acetates, triiiuoroacetstss, propionates, citrates, mslonsie% succinates, lactates, oxalates, tartrates and benzoates,

Salta may alec be formed with bases.. Such agtg from worgaple M organic bases, for example -alfiaii metei sails such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine sails, A pharmaceutical composition containing flie active Ingredient may be in any suitable form, for example aqueous or n on-aqueous solutions or suspensions, dispersible powders or granules* traafdermal pr transmyoesai patches, creams, ointments or emulsions.

The pharmaceutical compositions may be In the form of a sterile injectable aqueous of ngn-aqueous (a,g. oleaginous) solution or suspension, The sterile injectable preparation may ais© be in a sleriie injeoisbie solution or suspension in a non-toxic parenterallymepeptabie diluent or solvent for example os a:: solution in i J:~butanfdiol Among the acceptable vehicles and solvents that may be, employed are water,, phosphate buffer solution, I^hgeris solution and tsoteniq sodium chloride solution, in addition, sterile,: fixed oils ism cboveniicnaliy employed as a Solvent or suspending medium. For this purpose, any hisndlxed oil may teem ployed. including synthetic mono- anbipiycorides:, in addition, fatty solas such m oleic acid fed use in Ids preparation of injectables. Suspensions may b® formulated accc^d%tl3:1h«:kd0^niiaft usihgfHQseeuifabfe dispersing er witting agents and suspending apnts-wteich have been mentioned elsewhere.

Aqueous suspensions contain active; ingredient in admixture wild; :exclpsenis suitable ::fsr ;$te rnanufeoture of aqueous suspensions, lush excipients are suspending; agents, Ife example sodium carboxymethyioellblpse, meihylceliuiosa,: Hydrgxypiopyimetdylceiiuiose, sodium alginate, poiyfeyl-pyrtbiidone, gum trapacanth and gprh acacia, dispersing or wetting agents such as; a; naturally occurring phosphatide, for example lecithin, or condensation products of Iff; aikyiene oxide with ;titty ; acids,,, tor example polyoxyethylene Stearate,, eh OOhdehsatpn products; Of·telHyiene··'Oxide with long chain aliphatic i^liigi0hois*condensation products of ethylene ioxicte with partial esters d®nyedl;ffom fatty acids and a hexitoi such a polyoxyethylene with partial esfafs1 dCdvpd from fatty adds ;and hexitoi anhydrides, for example polyoxyethylene sorohan monooioate. The aqueous suspensions may also contain one dir more preservatives, for example ethyl or n~ propyl colouring agents, one or more flavouring agents, andl bne or more sweetening agents, such as suemse or saccharin. hlcn-adueous (s.e, oily); suspensions mayihe fermuisted by suspending the activ© in|redient in a vegetable oil, for example araehis eif, olive oil, sesame oil or coconut ©it, or in a mineral off 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 byi the: addition of an antf-oxldam such as ascorbic acid.

Compositions fm injection are typically aqueous, and comprisa a Puffer, erg. citrate buffe© No other Ingredients may tee mpulred. The pH of such a composition may be, for example: from 4 te fee-g, 8, dispersible powders and granules suitable for preparation of an; aqueous suspension; by the add ition of water provide The. active ingredient In admixture; with a dispersing or wailing agent, suspending agent, and one or more preservatives. Suitable dispersingmr wetting agents; and suspending «gents are known,

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.

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.

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.

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.

It may also be advantageous to co-administer amisulpride with drugs which are associated with emesis in man, for example certain opioids including an opiate such as 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.

By way of example, amisulpride and an emetogenic agent may be administered to a subject in combination, simultaneously or sequentially. For example, amlsulpride is given: before treatment With, .sat, morphine or a chemotherapeutic agent such as aspfatin. As indicated shove, the route of .administration may depend on the condition Doing treated.

As indicated above, there ere various causes of emesis. Examples of conditions that may be treated by the use of emisuipride include anaesthetics, radiation, cancer chemotherapeutic agents, toxic agents, medicines, for example seroton;n reupiake inhibitors, analgesics such as morphine, antlhiolcs* pregnancy, motion, conditions which arc associated with vertigo, for example 'Meniere’s disease, headache, caused by for exampie migraine, increased intracranial pressure or cerebral vascular haemorrhage,:: choiecystitis, choiedoohoiithiasis, ibtestmai obstruction, acute gastroenteritis,;, perferafed viscus. dyspepsia msulfng front,; for example igastrpesephogeaf: reflux: disease, ipeptic utcer disease, |astroparasis, gastric or Pesgphageai neoplasms, inflinve gastrio disorders; (e.g. Menetriers syndrome, Drbhnts disease, eosinophilic gastroenteritis, sarectbosls and amyloidosis),- gastric Infections, parasites, chronic gastric voivuius, chronic intestinal ischaemia, altered gastric motility disorders and/effood intolerance and Zoilinger-Eilson syndrome, the feiiowihg studies provide evidence on which the invention Is based. The preeiinicai evidence for efficacy against vomiting in PPNV and DlfW involves studies inTeftets, whilst efficacy against nausea can he demonsfmtad in patients receiving a general anaesthetic procedure.

Skbyl

Amisufpdde, white powder, was dissolved in dimothyfsuifoxide and then diluted in physiological saline.

Dor vehicle control physioiogical saline was used for s,c. administration (apornorphine experiments) and 8.3% DM SO in physioiogioai saline was used foriv. administration (morphine, cispiatin),

Dropenciol was bissoived; in DMSO then diluted in lactic acid! in phploiogica! saline, to a final DMSD concentration of 7,S%.

Apornorphine hydrochloride hemlhydrotos, white powder, was dissolved in physiological saline.

Morphine hylroehtpnde, white powder, was dissOived In physiological saline.

Cisplatlnum i! diamine dichteride, yeilawpcwdsm^^^ in 0.2% hydroxymethyiceiiulose in physiological saline.

The method used to test sntismetic activity predinicaily follows that described by Gardner eial. (Brit J. Pharmacol., 116: 3158-3163, 1985) and uses ferrets.

Sixty minutes before administration ©f the test substance, ferrets are placed fodpdMdual' stafoless steel cages (43 x 5b x 14 cm) :#h a grid floor. Then, tbe animais ere challenged with apomorphine fo.25 rngtlrg ate,), moraine (0.4 mg/Kg iip.V or cisplatin (10 m§/k| lip.) and :fmrnediat|iy observed, oder at least a 2-hour period. Parameters mcbfoed ineiodes number of ferrets showing retches and vomltst latency to first retching; latency to first vomiting^ number of retches; vorniting (number of vomits): number of emesis periods and moan duration of emesis periods. Retching is defined as a rhythmic respiratory movement against a closed giottis> while vomiting Is defined as a forced expulsion of upper g|strointestinal contents.

Where apomorphin© is used as the emetogen, amisuipride (or vehteie) wap administered suboiitarteousiy (sm. 31 minutes before administration of apomorphine). Animals (6 per group) weredroated with vehicle or amisuipride at fo 11. or 100 pg/itg The observation period was 2 Hours after apombfobine aoimirnstf aiiotn.

Where morphine ;s usedfos the ameiogerp amisuipride (n-Siper group) or vehicle (h~3) is administered Intravenously 5 minutes before the administration of morphine. The observation period is 2 hours after administration of the morphine.

Where cfsplailn is used as the emetogen. amisuipride (rteb per group) or Vehicle. (0^6) is administered intravenously -at least B -minutes^ before: the: administration of elspiatln. The observation period is. up :te 72 hours,: which allows effects m eariy and late phase emesis fo bo obseived,

Apomorphin© In tbe vehicle control group induced emesis; in the ferrets over tho 2 hour observation period (14.8±4,8 retches, 1.040.5 vomits, 3,340J emesis periods). Retches and vomits occurred 319453 and! 6214308: seconds after administration respectively. Amisuipnde given at 1 pgteg, 30 minutes before apemorphine, decreased the emetic efects of apomorphlne as compared: with··.thi©'ve:h]cl:a· control group retches, ό±0 vomits and 1811$! spbsls periods). :ΑπΊί|ϋΙρη|θ::Βΐ IQ and 110 pg/kg totally inhibited the app^pfiphjhe emeSis.,;: This demonstrates that, as might be expected: amisuioride blocks dopamine 02 racepin-s.

Morphine in the vehicle control group Induces emesis in the ferrets over the :2 hour observation period. Amtsulpnde reduces the emeticefects induced by morphine, in dosa-dependent manner, as compared control group. The E.DS0 for amtsulprlde against rnorphine emesis is calculated. These data Indicate that; emlsulpride has efficacy against r«Qfphihedoduced; emesis and that Is: effective when admimstered via the intravenous routs.

More specifically, morphine id the control group: induced the occurrence of 'retches and vomits m &amp; |retches) and. 4 (vomits} cf 6 animals, the mean (£ s,e.rm}: values were 33:114,7 retches* 1,810,7 vomits and 7.51TS emesis periods..: fetches and vomits occurred after 213*24: and 3?4±6.4 seconds respectively. Amisulodds was given at :3,: :6 and 12 m0k§ before morphine. Amisuipride at 3 mg/kg produced small decreases in retches: itc 28,7*7,1 m<$ emesis periods,to 5:2114 and abolished the Incidence of vomits, Amispipbde given at 0 mg/kg decreased the Incidence of ail 3 parameters* retches to 1.?,.8*6.8 (approximately a 30% decrease), vomits to 0.6*0:3 fa ?2% decmase) and emesis periods to IJili (a 58% decrease). The data from the first 2 dose levels demonstrate a dose related reduction in emesis with amssufpnde, Amlsufpride given at 12 mg/kg had no effect on retches 31.7*11.2, but sllli produced a reduction In vomits to 0,81-0,4 and slight reduction in emesis periods to 5.711.5.

These data demonstrate that amisulpFfde blocks rnorphlnedhducsd emesis, and also that the drug may be less effective at higher dosages, it Is reasonabjete deduce that; a dose of less than 50 mg will be effective In a human subject.

Clsplafin In the vehicle control group Induces emesis over the 72 hour period. Amisuiprlde reduces the emetic effects of; ptsplatlo.: In dose -dependent manner, as compared with the vehicle control group, having an effect on both early and late stages.

More spesiflipliy, #ste; am reported; from: m experiment in which the observation period was ::S: hours following elspiatih challenge, Cisplafln induced thebcbutrhnce of retches and vomits in f and 5:;of':i animate tested respectively, Thdtetiean incidences were 7Θ,8*22.2: retches, 3uD:*1>1 vomits and emetic periods. Retches sod vomits occurred after 85 minutes 6 seconds*? minutes: 53 seconds and 86 minutes 39 seconds*)0 minutes 28 seconds respectively amisuipnde 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 Q,2*0.2 fa 33% decrease) and emesis periods 3.7±2.0 (a 65% decrease). At 0,6 mg/kg the Incidence of retches was 62.5*51:8, vomits Hfft.l and emesis periods 3.7±i.3. It was noted in this group that oh#: animal had en early, exaggerated;: response to psplaiin. At: 2>;0: mg/kg the Incidence of retches was :3.3*2<5, vomits 0,2±o.2 adduemesle periods O,8*0>3, t::|s dear the! amfsuipride at 0.6 mg/kg (with one animal excl:ud8d);:Snd::i:m|/kg Is' 3 inφ% MM mg/kg the incidences were i:d ,7±3.8 retches, 1.2*1.0 vomits and 3.7.t1.3 emesis periods.

These data demonstrate that amlsuiprfee blocks dlsptatln-ihduced emesis, and also Indicate that the drug may be loss effective at higher: dosages; Again, it is reasonable to deduce: that a dose of less than 50 mg: will he effective in a human subject,: A® indicated shove, dropeddol is a known agent: for the treatment of AoteV. In a comparative experiment, dropehdoi was given 5 minutes before cispiatio (using the methods described above) In 3 animals and It was found that, based on the incidence of nausea and vomiting, amisuipnde at 0,8 mg/kg (with one animal whioh had the exaggerated response exeludedjand 2 ntg/kg Is more-effective than droperideiiald: mg/kg, A formuiation of the Invention was prepared* suitable for intravenous administration, it is a :2/5: mg/mi citrate-buffered solution (nominal pH 6.0):;of amlsujpride, Tbercompqsitlon fsglven/helow,

... ,...., ; Lmdtrgosng fouUna

The stfecte of amsselphde are stueied sh ' V f , = -. jla: study :pf sffcaey at a: suroerv in S randomised, controlled, opencaoer ps ,, ..... vomiting. me primary prophyiastfi M ,....., , .... f , ,,., . 24-hour period posh endposni is the incidence of nausea and vom^ng φ ope raison. The ~ ^ '*

endpoints are tie nauseaand vornitlhg rales and:sevenly U over ®"2 hours, 2¾ feonrs and :0-24 hoars posi-Dpefaton· ! v ! * -h> Oi rescue medication and safety/adverse events are s<wa-?>-’'V- T''~ data domPnstrate the effect of amisulpode against fw nausea as renAL.g andrstebind associated with P:C*N% ......... . . .. tide specification the word "compneeh or such ** ©r' ’'Wifi N understood to imply Lu,.uJ~n u, element, integer or step* or group of elements*. integers &amp; Sieps: bu, hos. the exclusion of any: other etesoenf, integer or step, or group of eiemente, integers or steps. •Ail puhifeatioiis mentioned in this specification are herein incorporated by reference. Any discussion of documents, sefs: materials, devices, articles: or tie like which has fe^eAdiudedi in present speefflestatt is soieiy for the purpose ol Providing acorPext for the present invention, ft is not to he· taken es an admission that, any oral! of these metiers form part of the prior art base or wers: commoss general knowledge in. the field relevant to -the present, invention: as if existed. In Australia; or elsewhere before the priority date of each claim ofthiseppitcation,

Itrwili be appreciated iby persons skilled In the art that numemus variations and/or modifications may be meda to the ^invention as shown in the specific embodiments without: departing from the spirit or scope: of the invention astteroadly: described, The: prmmh embodlrnents are, therefore, to he considered in all respects es illustrative and not restrictive.

Claims (21)

1. THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

   1. A method of therapy of opioid-induced nausea and vomiting (OINV), wherein the method comprises administering an effective dose of amisulpride to a subject in need of said therapy.
2. 2. A method according to claim 1, wherein the opioid is an opiate.
3. 3. A method according to claim 2, wherein the opiate is morphine.
4. 4. A method according to any one of the preceding claims, wherein the amisulpride is administered by intravenous injection or subcutaneous injection.
5. 5. A method according to any one of claims 1 to 3, wherein the amisulpride is administered by oral, transdermal, sublingual or inhaled administration.
6. 6. A method according to any one of the preceding claims, wherein the subject is human.
7. 7. A method according to any one of the preceding claims, wherein the amisulpride is administered in the form of a unit dose comprising less than 50 mg amisulpride.
8. 8. A method according to claim 7, wherein the unit dose comprises 1 to 35 mg amisulpride.
9. 9. A method according to claim 8, wherein the unit dose of 1 to 35 mg is given once or twice daily to a human subject.
10. 10. A method according to any one of the preceding claims, wherein the amisulpride is administered in combination with another anti-emetic drug.
11. 11. A method according to claim 10, wherein the another anti-emetic drug is a 5-HT3 antagonist.
12. 12. A method according to claim 11, wherein the another anti-emetic drug is ondansetron.
13. 13. A method according to claim 10, wherein the another anti-emetic drug is dexamethasone.
14. 14. The use of amisulpride in the manufacture of a medicament for treating opioid-induced nausea and vomiting (OINV).
15. 15. The use of claim 14, wherein the medicament also comprises another anti-emetic drug.
16. 16. The use of claim 15, wherein the another anti-emetic drug is a 5-HT3 antagonist.
17. 17. The use of claim 16, wherein the another anti-emetic drug is ondansetron.
18. 18. The use of claim 15, wherein the another anti-emetic drug is dexamethasone.
19. 19. The use of any one of claims 14 to 18, wherein the medicament comprises a unit dose of less than 50 mg amisulpride.
20. 20. The use of claim 19, wherein the unit dose comprises 1 to 35 mg amisulpride.
21. 21. The use of claim 20, wherein the unit dose of 1 to 35 mg is given once or twice daily to a human subject.