MXPA01004297A - 5ht1 - Google Patents

Abstract

The present invention relates to a method of treating migraine in a mammal, including a human, by administering to the mammal a 5HT1 receptor agonist, and particularly eletriptan, in combination with metoclopramide. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a 5HT1 receptor agonist and metoclopramide.

Description

AGRONISTS OF 5-HT RERCEPTORS. AND METOCLOPRAMID FOR THE TREATMENT OF MIGRAINE The present invention relates to a method for treating migraine in a mammal, including man, by administering to the mammal an agonist of 5-HT-? Receptors. combined with metoclopramide. It also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier, a 5-HT-? Receptor agonist. and metoclopramide. Examples of 5-HT-? Receptor agonists are agonists of one or more of the 5-HT-IA, 5-HT-IB, 5-HT1c, 5-HTID, 5-HT-IE, 5-HT receptors -IF. The combined use of metoclopramide and 5-HT-? Agonists (for example, eletriptan, rizatriptan, naratriptan, sumatriptan, but excluding zolmitriptan) for the acute treatment of migraine offers increased efficacy and less nausea than currently used therapies. In 1975, Volans indicated that metoclopramide helped relieve the gastric stasis that accompanies migraine attacks (See GN, Volans, British Journal of Pharmacology, (February 1975) 2 (1), 67-73, and GN, Volans , Clinical Pharmacokinetics, Oulio, 1978) 3 (4), 313-318). He studied this effect and indicated that blood levels of aspirin and acetaminophen (paracetamol), taken orally, decreased in patients suffering from a migraine attack and that these levels returned to normal values between migraine attacks. The use of metoclopramide with aspirin or acetaminophen increased the blood levels of these drugs making them more effective for the treatment of migraine. It is believed that 5-HT-? Agonists? they must exhibit substantially greater efficacy for the treatment of migraine when administered in combination with metoclopramide, given the increased blood levels of the oral agonist SHT-t and the antiemetic and antimigraine action of metoclopramide. Metoclopramide is a derivative of benzamide and, although it is related to neuroleptics, it does not have significant antipsychotic or sedan properties. Metoclopramide is a dopamine and a 5-HT3 receptor antagonist and also has some 5-HT4 agonist activity. The actions of metoclopramide include antagonisms of emesis induced by apomorphine or ergotamine. It also induces hyperprolactinemia, a characteristic of dopaminergic blocking. Metoclopramide has a relatively low affinity towards dopamine receptor 2 (D2). The combination of metoclopramide with some 5-HT-i agonists such as zolmitriptan, as described by Seaber, E.J. et al., in European Journal of Clinical Pharmacology, (1997) 53 (3-4) 229-34 and Roian, P. in Cephelalgia (October 1997); 17 Suppl 18 21-7, has had no effect or has been described because it reduces the pharmacokinetic efficacy of zolmitriptan.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutical compositions for the treatment of migraine in a mammal, including man, comprising metoclopramide, a 5-HT-? Receptor agonist. or a pharmaceutically acceptable salt thereof, excluding zolmitriptan; and a new pharmaceutically acceptable vehicle. This invention also relates to a method for treating migraine in a mammal, including man, which comprises administering to said mammal an amount of a pharmaceutical composition comprising metoclopramide, an agonist of 5-TH? (excluding zolmitriptan) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which is effective in treating migraine. This invention also relates to a method for treating migraine in a mammal, including man, which comprises administering to the aforesaid mammal metoclopramide and a 5-TH-? Receptor agonist. (excluding zolmitriptan) or a pharmaceutically acceptable salt thereof, in amounts which make the combination of these two active agents effective in the treatment or prevention of migraine. Preferred embodiments of this invention relate to pharmaceutical compositions for the treatment of migraine and to methods for treating migraine, described above, in which the 5-HT-t receptor agonist is selected from eletriptan, naratriptan, rizatriptan, sumatriptan, almotriptan, avitriptan, frovatriptan, alniditan, LY 334370, LY306258, BMS-180048 and BMS-181885. A highly preferred embodiment is the pharmaceutical combination of eletriptan and metoclopramide, in which the pharmacokinetics of eletriptan is also expected to be increased. Other embodiments of this invention relate to pharmaceutical compositions for the treatment of migraine and to methods for treating migraine, described above, in which the 5-HT-? Receptor agonist. is a compound of formula wherein: R3, R4 and Z are independently selected from hydrogen, halo (i.e., chloro, fluoro, bromo or iodo), C1-C4 alkyl optionally substituted with one to three fluorine atoms, C1-C4 alkoxy optionally substituted with one to three fluorine atoms and (C1-C4 alkoxy) (C1-C4 alkyl) in which each of the alkyl moieties may be optionally substituted with one to three fluorine atoms, W is -CH2-O- (alkylated. or Ci-Cβ) wherein the alkyl moiety can be linear or branched, or W is -CH2NR1R2 wherein R1 and R2 are independently selected from hydrogen and straight or branched Ci-C alquilo alkyl, or R1 and R2, together with the nitrogen to which they are attached, form a four-membered saturated monocyclic ring or a saturated or unsaturated, non-aromatic monocyclic ring of five to seven members or a saturated or unsaturated saturated or unsaturated bicyclic ring of seven to ten members, which may optionally contain one or two heteroatoms in addition to the nitrogen of NR1R2, and n that said heteroatoms are independently selected from oxygen, nitrogen and sulfur, and in which one to three of the ring carbon atoms or one of the ring nitrogen atoms can be optionally and independently substituted with C 1 -C alkyl. Linear or branched C4, linear or branched C1-C4 alkoxy, (linear or branched C1-C3 alkyl) (C3-C7 cycloalkyl), hydroxy, amino, cyano, halo, aryl (straight or branched C1-C3 alkyl) or heteroaryl ( straight or branched C1-C3 alkyl), wherein said aryl is selected from phenyl and naphthyl and said heteroaryl is selected from oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrazolyl, pyrrolyl, tetrazolyl, triazolyl, thienyl, imidazolyl, pyrazinyl, pyrazolyl, indolyl, isoindolyl, cinnolinyl, pyridinyl and pyrimidinyl, with the proviso that in any ring formed by NR1R2; (a) there can not be more than one oxygen atom in the ring, (b) there can be no hydroxy, alkoxy, alkoxyalkyl, cyano, amino or alkylamino moiety attached directly to any ring nitrogen atom and (c) no carbon of the ring that is linked by a double bond to another ring carbon and no part of an aromatic ring system can be attached to an oxygen atom of the ring or to a nitrogen atom of the ring, or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION The following patents and patent applications exemplify 5-HT-? Receptor agonists. which can be used in combination with metoclopramide in the pharmaceutical compositions and methods of the invention and relate to methods of preparing the same; U.S. Patent 5,545,644 issued August 13, 1996, European Patent 776,323 issued February 11, 1998, U.S. Patent 5,618,834, dated April 8, 1997, World Patent Application PCT / EP98 / 04176, which designates the United States and was filed on July 1, 1998, European patent 503,440 granted on June 18, 1998, United States patent 4,816,470 granted on March 28, 1989, Japanese patent 9,423,197 granted on March 30, 1994, patent Canadian 1, 241,004 issued August 23, 1988, European Patent 497,512 issued September 24, 1997, U.S. Patent 5,300,506 issued April 15, 1994, European Patent Application 711, 769 published May 17, 1996, World Patent Application WO 94/2460 published February 3, 1994, United States Patent 5,541, 180 granted July 30, 1996, European Patent Application 591, 280 published April 13, 1994 e 1994, European patent 639,192 granted on May 15, 1996, European patent application 674,621 published on October 4, 1995 and European patent 486,666 granted on August 13, 1997. The aforementioned patents and patent applications are included in its whole in the present report as a reference. The following references refer to the pharmacological properties of some 5-HT-? Receptor agonists. mentioned above which are employed in preferred embodiments of this invention: Robert et al., Cephalagia, 18 (6), 406, July / August 1998; Marathe et al., Biopharm. Drug. Dispos., 19 (S), 381-394, September 1998; Saxena et al., Eur. J. Pharmacol., 351 (3), 329-339, June 26, 1998; Goldstein et al., Cephalagia, 18 (6), 410, July / August 1998; Buchan et al., Cephalagia 18 (6), 410, July / August 1998; Block et al., Cephalagia, 18 (6), 409-410, July / August 1998; Sheftell et al., Cephalagia, 18 (6), 403-404 July / August 1998; Perry et al, Drugs (New Zealand), 55 (6), 889-922, June 1998, Bamhof et al., Cephalagia (Norway), 18 (1), 33-37, January 1998; Klasson et al., Headaches (United States), 37 (10), 640-645, November / December 1997; Goldstein et al., Cephalagia (Norway), 16 (7), 497-502, November 1996; Parsons et al, J. Cardiovasc. Pharmacol. (United States), 32 (2), 220-11A, August 1998; and J. Schoenen, Curr. Opin. Neurol., 10 (3), 237-243, June 1997. These references are incorporated herein by reference in their entirety.

The term "treating", as used herein, refers to delaying or reversing, or alleviating or preventing the disorder or ailment or one or more symptoms of said disorder or ailment to which the term "treating" is applied. . The term "treatment", as used herein, refers to the act of treating a disorder or ailment, having to deal with the meaning defined above. This invention relates to methods for treating migraine in which metoclopramide and the 5-HT-? Receptor agonist are administered together as part of the same pharmaceutical composition, as well as to methods in which these two agents are separately administered. assets as part of an appropriate dosing regimen designed to reap the benefits of combination therapy. The appropriate dosage regimen, amount of each dose administered and intervals between doses of the active agents will depend on the 5-HT-? Receptor agonist. which is used, type of pharmaceutical formulations used, characteristics of the patient being treated and the severity of the migraine. Generally, to perform the methods of this invention, the 5-HT-? Receptor agonist. an average adult 70 kg man will be administered orally in an amount ranging from about 1 to about 400 mg per day, in a single dose or in divided doses, and metoclopramide will be administered in an amount ranging from about to approximately 125 mg per day, in a single dose or in divided doses. Metoclopramide will generally be administered in amounts ranging from about 20 to about 80 mg per day, depending on the severity of the headache and the route of administration. Metoclopramide can be administered orally, intranasally, intravenously, as rectal suppositories or by using an "instant" formulation (that is, allowing the medication to dissolve in the mouth without the use of water). The following table exemplifies preferred dosage ranges of certain 5-HTα receptor agonists. and metoclopramide, when used in combination.

The 5-HT-? Receptor agonists which are employed in the pharmaceutical compositions and methods of this invention, and their pharmaceutically acceptable salts, can be administered alone or in combination with pharmaceutically acceptable carriers or diluents. They can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Said compounds can be administered orally, buccally, intranasally, parenterally (for example, intravenously, intramuscularly or subcutaneously) or rectally, or in a form suitable for administration by inhalation or insufflation. For oral administration, the pharmaceutical compositions may take the form, for example, of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients, as binding agents (eg, pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose), fillers (e.g. , lactose, microcrystalline cellulose or calcium phosphate), lubricants (e.g., magnesium stearate, talc or silica), disintegrants (e.g., potato starch or sodium starch glycolate) or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form, for example, of solutions, syrups or suspensions, or they can be presented as a dry product to be reconstituted with water or with another suitable vehicle before use. Said liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, as suspending agents (for example, sorbitol syrup, methylcellulose or hydrogenated edible fats), emulsifying agents (for example, lecithin or gum arabic), non-aqueous vehicles (for example, example, almond oil, fatty esters or ethyl alcohol) and preservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid). For buccal administration, the composition may take the form of tablets or lozenges formulated in a conventional manner.

The 5-HT-? Receptor agonists of the invention and its salts can be formulated for parenteral administration by injections, including the use of conventional catheterization or infusion techniques. Injectable formulations may be presented in the form of unit doses, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in aqueous or oily vehicles and may contain formulatory agents, such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle (eg, sterile pyrogen water) before use. The 5-HT-? Receptor agonists of this invention and its salts can also be formulated in rectal compositions, such as retention enemas or suppositories which, for example, contain conventional suppository bases, such as butter or cocoa or other glycerides. For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently provided in the form of solution or suspension from a pump spray container that the patient expresses or pumps or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant (for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In case of a pressurized aerosol, the dosage unit can be determined by providing a valve that provides a measured quantity. The pressurized container or the nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, of gelatin) can be formulated for use in an inhaler or insufflator, which contain a mixed powder of a compound of the invention and a suitable powder base, such as lactose or starch. Preferably the aerosol formulations for the treatment of migraine in an adult adult man are made so that each measured dose or "hit" of aerosol contains from 20 to 1,000 μg of the compound of the invention. The total daily dose with an aerosol will generally be in the range of about 100 μg to 10 mg. The administration can be several times a day, for example, 2, 3, 4, or 8 times, giving, for example, 1, 2 or 3 doses each time. Can the activity of 5-HT receptor agonist be measured? of a compound or salt by in vitro binding assays to receptors described for the 5-HT1A receptor using rat cortex as a source of receptors and [3H] 8-OH-DPAT as radioligand. [D. Hoyer et al., Europ. J. Pharmacol., 118, 13 (1985)] and Os described for the 5-HT? D receptor using cow tail tissue as a source of receptors and [3H] 5-HT as radioligand [R.E. Heuring and S. J. Peroutka, J. Neuroscience, 7, 894 (1987)]. The in vitro activity of a compound at the 5-HT ?D receptor binding site can be determined according to the following method. Cow's tail tissue is homogenized and suspended in 20 volumes of a buffer containing 50 mM TRIS (tris [hydroxymethyl] aminomethane hydrochloride) with a pH of 7.7. The homogenate is then centrifuged at 45,000 g for 10 minutes. The supernatant is discarded and the resulting pellet is resuspended in approximately 20 volumes of 50 mM TRIS hydrochloride buffer at pH 7.7. This suspension is then pre-incubated for 15 minutes at 37 ° C, after which the suspension is centrifuged again at 45,000 g for 10 minutes and the supernatant is discarded. The resulting pellet (approximately 1 gram) is resuspended in 150 ml of a 15 mM TRIS hydrochloride buffer containing 0.01 percent ascorbic acid with a final pH of 7.7 and also containing 10 mM pargyline and calcium chloride (CaC) 4 mM. Keep the suspension on ice for at least 30 minutes before using it. The inhibitor is then incubated, control or vehicle according to the following method. To 50 ml of a 20 percent solution of dimethyl sulfoxide (DMSO) and 80 percent distilled water is added 200 ml of tritiated 5-hydroxy-triptamine (2 nM) in a 50 mM TRIS hydrochloride buffer containing 0.01 percent of ascorbic acid with a pH of 7.7 and which also contains 10 mM pargyline and 4 mM calcium chloride plus 100 nM of 100 nM mesylergin and 8-hydroxy-DPAT (dipropylaminotetralin). 750 ml of cow tail tissue is added to this mixture and vortexed to ensure homogenization of the suspension. The suspension is then incubated for 30 minutes at 25 ° C in a shaking water bath. After the incubation is completed, the suspension is filtered using glass fiber filters (e.g., Whatman GF / B filters). The pellet is then washed three times with 4 ml of a 50 mM TRIS hydrochloride buffer at pH 7.7. The pellet is then placed in a scintillation vial with 5 ml of scintillation fluid (Aquasol 12) and left to stand overnight. The percent inhibition for each dose of the compound can be calculated. From the inhibition percentage values, the IC 50 value can be calculated afterwards. The ability of a compound or salt to bind 5-HT-IA receptors can be determined according to the following method. The rat brain cortex tissue is homogenized and divided into 1 gram samples which are diluted with 10 volumes of 0.32 M sucrose solution. The suspension is then centrifuged at 900 g for 10 minutes, the supernatant is separated and the centrifuge again at 70,000 g for 15 minutes. The supernatant is discarded and the pellet is resuspended in 10 volumes of 15 mM TRIS hydrochloride at pH 7.5. The suspension is allowed to incubate at 37 ° C for 15 minutes. After the pre-incubation is completed, the suspension is centrifuged at 70,000 g for 15 minutes and the supernatant is discarded. The resulting tissue pellet is resuspended in a buffer of 50 mM TRIS hydrochloride at pH 7.7 containing 4 mM calcium chloride and 0.01 percent ascorbic acid. The tissue is preserved at -70 ° C until the moment of the experiment. The tissue can be thawed immediately before use, diluted with 10 ml of pargyline and kept on ice. The tissue is then incubated according to the following method. Fifty microliters of control, inhibitor or vehicle are prepared at various dosages (final concentration of DMSO: 1 percent). To this solution is added 200 ml of tritiated DPAT at a concentration of 1.5 nM in a buffer of 50 mM TRIS hydrochloride at pH 7.7 containing 4 mM calcium chloride, 0.01 percent ascorbic acid and pargyline. 750 ml of tissue are then added to this solution and the resulting suspension is vortexed to ensure homogeneity. The suspension is then incubated for 30 minutes at 37 ° C in a shaking water bath. The solution is then filtered and washed twice with 4 ml of 10 mM TRIS hydrochloride at pH 7.5 containing 154 p.M sodium chloride. The percentage of inhibition is calculated for each dose of the compound, control or vehicle. The values of! C5o- can be calculated from the inhibition percentage values. The agonist and antagonist activities of compounds can be determined in 5-HT-IA and 5-HT-ID receptors using a single saturating concentration in accordance with the next method. Hartley male guinea pigs are decapitated and 5-HT1A receptors are dissected from the hippocampus while 5-HT1D receptors are obtained by slicing at 350 mM with a Mcllwain tissue cutter and dissecting the black substance from the appropriate slices. Individual tissues are homogenized in 5 mM HEPES buffer containing 1 mM EGTA (pH 7.5) using a manual glass-teflon® homogenizer and centrifuged at 35,000 g for 10 minutes at 4 ° C. The pellets are resuspended in 100 mM HEPES buffer containing 1 mM EGTA (pH 7.5) to a final concentration of 20 mg (hippocampus) or 5 mg (substantia nigra) of tube protein. The following agents are added so that the reaction mixture in each tube contains 2.0 mM MgCl2., 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM IBMX, 10 mM phosphocreatine, 0.31 mg / ml creatine phosphokinase, 10 mM GTP and 0.5-1 microcuries of [32 P] -ATP (Ci / mmoles; NEG-003- New England Nuclear). Incubation is initiated by adding (in triplicate) tissue to siliconized microcentrifuge tubes at 30 ° C for 15 minutes. Each tube receives 20 ml of tissue, 10 ml of drug or buffer (final concentration 10X), 10 ml of agonist or buffer 32 nM (final concentration 10X), 20 ml of forskolin (final concentration 3 mM) and 40 ml of the mixture of the preceding reaction. The incubation is terminated by adding 100 ml of 2% SDS, 1.3 mM cAMP, 45 mM ATP solution containing 40,000 dpm of [3 H] -cAMP (30 Ci / mmole, NET-275 - New England Nuclear) to follow the recovery of cAMP from the columns. The separation of [32 P] -ATP and [32 P] -cAMP is performed using the method of Solomon et al., Analytical Biochemistry, 58, 541-548 (1974). The radioactivity is quantified by liquid scintillation counting. Maximum inhibition is defined by 10 mM (R) -8-OH-DPAT for 5-HT1A receptors and by 320 mM 5-HT for 5-HT? D receptors. The percentages of inhibition by the test compounds are then calculated with respect to the inhibitory effect of (R) -d-OH-DPAT for 5-HT? A and 5-HT receptors for 5-HTID- receptors. The inverse of agonist-induced inhibition of the adenylate cyclase activity stimulated by forskolin with respect to the 32 nM agonist effect. The antagonist activity induced by 5-HT-ID receptor agonists induced in guinea pigs according to the following method can be tested in vivo with the compounds. The subjects of the experiment are Hartley male guinea pigs weighing 250-275 grams on arrival and 300-600 grams at the time of testing. The guinea pigs are housed in standard laboratory conditions with a lighting schedule of 7 in the morning to 7 in the evening for at least seven days before the experimentation. They have available water and food ad libitum until the time of the trial. The compounds of the invention can be administered as solutions in a volume of 1 ml / kg. The used vehicle vs depending on the solubility of the compound. The test compounds are typically administered orally (po) sixty minutes or subcutaneously (sc) zero minutes before a 5-HTID receptor agonist, such as [3- (1-methylpyrrolidin-2-ylmethyl) - 1 H-indol-5-yl] - (3-nitropyridin-3-yl) amine, which can be prepared as described in PCT publication WO 93/11106 published on June 10, 1993 and which it is administered subcutaneously at a dose of 5.6 mg / kg. Before taking a first reading of the temperature, each guinea pig is placed in a transparent plastic shoebox containing wood shavings and a metal grate floor and allowed to acclimate to the environment for 30 minutes. After each temperature reading the animals are returned to the same box. Before each temperature measurement, each animal is held firmly with one hand for a period of 30 seconds. A digital thermometer with a small animal probe is used for temperature measurements. The probe is made of semi-flexible nylon with a tip of epoxy resin. The probe is inserted 6 cm into the rectum and held there for 30 seconds or until a stable reading is obtained. Then the temperatures are recorded. In oral experiments, a reference reading "before the drug" is made at the minute -90, the test compound is administered at the minute -60 and an additional reading is made at the minute -30. The 5-HT-ID receptor agonist is then administered at minute 0 and the temperatures are taken 30, 60, 120 and 240 minutes later. In subcutaneous experiments, a reference reading "before the drug" is made at the minute -30. The test compound and the 5-HT-ID receptor agonist are administered simultaneously and temperatures are taken 30, 60, 120 and 240 minutes later. Data are analyzed by bidirectional analysis of vnts with repeated measurements in Newman-Keuls post hoc analysis. It can determine the agonist activity of 5-HT? by in vitro receptor binding assays as described for the 5-HT? A receptor using rat cortex as sources of receptors and [3H] -8-OH-DPAT as radioligand [D. Hoyer et al., Eur. J.Pharm., 118, 13 (1985)] and as described for the 5-HTID receptor using cow tail tissue as a source of receptors and [3 H] serotonin as radioligand [R.E. Heuring and S.J. Peroutka, J. Neuroscience, 7, 894 (1987)]. Of the active compounds tested, all exhibited an IC50 of 1 mM or less in any of the assays. Compounds and salts can be evaluated as antimigraine agents by testing the extent to which they mimic sumatriptan by contracting a saphenous vein strip isolated from a dog [P.P.A. Humphrey et al., Br. J. Pharmacol., 94, 1128 (1998)]. This effect can be blocked by metiotepine, a known serotonin antagonist. It is known that sumatriptan is useful in the treatment of migraine and produces a selective increase in carotid vascular resistance in the anesthetized dog. Fenwick et al., British Journal of Pharmacology, 96, 83 (1989) have suggested that this is the basis of their efficacy.

Claims (6)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition for the treatment of migraine, comprising eletriptan, metoclopramide, and a pharmaceutically acceptable carrier.

2. The use of a pharmaceutical composition as claimed in claim 1, for the manufacture of a medicament for treating migraine in a mammal.

3. The use of a) metoclopramide and b) eletriptan, for the manufacture of a first and second medication, respectively, to treat migraine in a mammal.

4. The use as claimed in claim 3, wherein the first and second drugs comprising eletriptan and! A metoclopramide are administered separately according to a dosage regimen that makes the combination of active agents administered separately be effective in the treatment of migraine

5. The use as claimed in claim 3, wherein the second medicament provides from about 1 mg to about 400 mg of eletriptan for the mammal per day, and the first The medicament provides from about 5 mg to about 125 mg of metoclopramide to the mammal per day.

6. The use of a) the 5-HT receptor agonist, excluding zolmitriptan, or a pharmaceutically acceptable salt thereof and b) a metoclopramide for the manufacture of a first and second medication respectively for treating migraine in a mammal, wherein the first medicament comprising the 5-HT-? receptor agonist. or its pharmaceutically acceptable salt is administered orally and the second medicament comprising metoclopramide is administered intravenously. 7 - The use of eletriptan with metoclopramide for the manufacture of a medicament for increasing the pharmacokinetics of eletriptan for the treatment of migraine in a mammal.