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US005250529A United States Patent (19) (11) Patent Number: 5,250,529 Theoharides 45) Date of Patent: Oct. 5, 1993

54 METHOD ALLEVIATING MIGRAINE Cluster Headache,' Headache, 24:147-149, vol. 3, May HEADACHE WITH MAST CELL 1984. DEGRANULATION BLOCKINGAGENTS W. Split, et al., " (Zaditen) in the Therapy of Cluster Headache,' Rev. Roum. Med. 1983, 21 (3), pp. 75 Inventor: Theoharis C. Theoharides, 253-256. Brooklhne, Mass. W. Split, et al., “Neurologia", Neurol. Neurochir. Pol, 73) Assignee: KOS Pharmaceuticals, Inc., Miami, vol. 18, No. 2, 1984, pp. 105-109. Fla. C. I. Parodi, et al., " Prophylaxis in Mi graine", Acch. Psicol Neurol. Psichiatr., vol. 49, No. 3, 21) Appl. No.: 815,124 pp. 299-303. (22 Filed: Dec. 27, 1991 W. D. Singer, "Pharmacological Management of Post traumatic Headaches', J. Head Traum. Rehabil, vol. 4, Related U.S. Application Data No. 1, 1989, pp. 83-86. Merck Index, 11th Edition, #4771, p. 645, (63) Continuation-in-part of Ser. No. 478,164, Feb. 8, 1990, (1983). abandoned. Current Therapy, "Headache' pp. 788-793 (1981). 51 Int. Cl...... A61K 31/495; A61K 31/41; Tek, Deniz, "The Effectiveness of Nalbuphine and A61K 31/35; A61K 31/21; A61K 31/13; Hydroxyzine for Emergency Treatment of Severe A61K 31/135 Headache', Annals of Ener. Med. Mar. 1987, pp. 52 U.S. Cl...... 514/255; 514/263; 107-112. 514/381; 514/457; 514/510, 514/579; 514/650 Primary Examiner-Frederick E. Waddell 58) Field of Search ...... 514/263, 255, 557, 381, Assistant Examiner-K. Weddington 514/579, 650, 510, 457 Attorney, Agent, or Firm-Foley & Lardner (56) References Cited 57 ABSTRACT U.S. PATENT DOCUMENTS A method of preventing or alleviating a migraine head 4,599,359 7/1986 Cooper ...... 514/557 ache which comprises administering a pharmaceutically 4,794,112 12/1988 Cooper ...... 514/255 effective amount of a mast cell degranulation blocking 4,829,064 5/1989 Sunshine et al...... 514/255 agent just prior to or during the prodromal phase of the migraine in the absence of an analgesic. The agent can OTHER PUBLICATIONS also be administered in combination with a central ner International Search Report, Application No. vous system stimulant. PCT/US92/11227, including following references: W. Split, et al., "Ketotifen in the Treatment of Chronic 17 Claims, No Drawings 5,250,529 1. 2 muscular headaches, which develop gradually and METHODALLEVIATING MIGRAINE HEADACHE rarely, if ever, reach a severity comparable to that of WITH MAST CELL DEGRANULATION migraine headaches. Patients suffering from migraine BLOCKING AGENTS headaches are often so well aware of the pain that will ensue from an impending migraine that they become CROSS-REFERENCE TO RELATED apprehensive and frightened. As a result of this anxiety, APPLICATION the patients hyperventilate and/or tense their neck mus This application is a continuation-in-part of U.S. Ser. cles. Both of these effects usually lead to a muscle ten No. 07/478,164, filed Feb. 8, 1990,now abandoned, sion headache. In other words, the mere anticipation which is hereby incorporated in its entirety by refer O and fear of an impending migraine headache brings ece, about an ordinary muscular headache in virtually all migraine patients. The patients can thus suffer from two BACKGROUND OF THE INVENTION different types of affliction simultaneously. The present invention relates to a method of alleviat ing or preventing a migraine headache through the 5 B) Mast cells and migraines administration of a mast cell degranulation blocking Mast cells are normal components of the connective agent. tissue and play an important role in allergy and inflam A) Migraines mation. These cells are localized in the gastrointestinal Migraine headaches are known to produce the most mucosa, skin and lung. It is believed that mast cells are intense headache reported, which are comparable to 20 so located because these tissues are the main entry that of a brain aneurysm rupture. As many as 15% of all points for infective organisms and allergens-chemicals people, especially in industrialized societies, are suffer which trigger the body's immune response. Recently, ers, with an estimated yearly cost due to treatment and mast cells have been shown to be located at strategic work lost in the United States of America alone of points around capillaries and small blood vessels, espe almost one billion dollars. Prior to the present inven 25 tion, there has been no effective way to prevent the last cially in the brain, where they are important in regulat minute onset of the migraine headache. ing the extent of constriction or dilatation of vessels The pathophysiology of migraine headaches involves critical in migraines. vasoconstriction (the closing or tightening of arteries, Each mast cell contains up to 500 secretory granules, which reduces blood flow) and vasodilation (the open 30 each storing more than 20 potent biological compounds. ing of the vessels to increase blood flow). It appears that Mast cells secrete the contents of these granules, i.e., a variety of stimuli, such as intense light, noise, anxiety, degranulate, when triggered by various specific and exertion, cold, heat, hormones, food additives and cer non-specific mechanisms. Degranulation is defined as tain foods, result in constriction of extracranial vessels. the release of any or all mediators from any or all secre The vasoconstriction is followed by a sequential or 35 tory granules, whether in parallel, differentially or se reflex powerful vasodilation, which subsequently lectively. spreads to intracranial vessels. It is during this phase The degranulation of mast cells in response to various that a patient feels an intense, throbbing headache. In agents is a biological consequence of the activation of creased levels of norepinephrine, , bradykinin one or more receptors which are located on the surface and substance P, as well as products of tissue anoxia are 40 of the mast cell. The best known receptor is immuno considered to be the endogenous pain producing mole globulin E (IgE), which is involved in allergic reaction cules accompanied by direct sensory nervestimulation, s-the only well-understood pathological process in because of stretching due to vasoconstriction and vaso volving mast cells to date. In the reaction, IgE binds dilation. strongly to mast cells through its Fc receptor. When The phases of a migraine headache have been sepa 45 mast cell-bound IgE reacts with an antigen, the latter rated into the prodrome, aura and acute painful head bridges two or more IgE and causes mast cell degranu ache stages. The prodrome is the primary stage of a lation with subsequent release of mediators, either migraine attack characterized by an alteration of mood, stored or synthesized during mast cell degranulation. energy or passive functions. This stage can occur for There is also evidence that such as hours before the onset of the headache. The mood alter 50 acetylcholine and neuropeptides, all of which are mole ations include euphoria, loquaciousness, unprovoked cules released from neurons in the nervous system, and apathy, depression, inertia, drowsiness, irritability, re female sex hormones, such as estradiol and progester petitive yawning, aggression and heightened sensitivity one, may also trigger mast cell degranulation through to various levels of sound (sonophobia). Nausea and specific receptors, especially in response to stress. Other vomiting, as well as paresthesias in the extremities, may 55 known triggers include viruses, bacterial toxins, , also accompany these symptoms. such as aspirin, and curare, contrast media The aura or second stage has been defined by the used in radiology, extreme heat, cold, solar radiation, onset of fear of light (photophobia) and visual disturb hyperosmotic media and pressure. It is, therefore, ances brought on by a reduction of cerebral blood flow clearly important to block mast cell degranulation in due to vasospasm. 60 response to these stimuli. The headache phase is vascular with distension and The compounds released by the mast cells following increased pulsation of cranial arteries. Increased vascu degranulation are known to cause many biological pro lar permeability is associated with the release of pep cesses which are part of the overall response of the tides, especially bradykinin and substance P, as well as body to invasion by infective organisms (inflammatory molecules such as and serotonin, which cause response) or aliergens. Examples of such processes are local pain when they reach perivascular nerve endings. vasoconstriction or vasodilation, and inflammation. Migraine headaches develop suddenly, and reach Compounds released by mast cell degranulation maximal intensity very quickly, in contrast to ordinary which may be associated with migraines include: hista 5,250,529 3 . 4 mine, kinins, prostaglandin E2 and vasoactive intestinal effects, especially hypotension. They have not been peptide, which are vasodilatory, as well as serotonin, reported to have any direct action on their own against prostaglandin F2a and leukotrienes, which are vasocon migraine pain in the form and method they have been strictive. In addition, histamine, kinins, prostaglandins used to date. and serotonin can cause pain directly. 5 For example, meperidine hydrochloride (Deme Histamine and the other mediators are secreted from rol (E)) has been used in combination with the anti-hista the granules of mast cells during degranulation of mast mine hydroxyzine (in the form of hydroxyzine pamo cells due to activation of specific surface receptors. The ate), Hydroxyzine has been thought to limit some of the histamine and other mediators then bind to specific undesirable side actions of meperidine, such as hypoten receptors on the surface of endothelial cells on vessels, O sion and anaphylaxis, and to potentiate the effect of the neurons or other tissues. Vasodilation and chemoattrac . tion permits lymphocytes to leave the circulation and The effectiveness of hydroxyzine perse in the symp enter the tissue, where they cause additional mast cell tomatic treatment of migraines was questioned in a degranulation and other responses. The process of de recent study. In Tek et al., The Effectiveness of Nalbu granulation continues, eventually involving many mast 15 phine and Hydroxyzine for the Emergency Treatment of cells. Severe Headache, Annals of Emergency Medicine 16: Mast cell degranulation thus contributes to the symp 308-313 (March, 1987), it was concluded that intramus toms experienced by migraineurs during the aural and cular administration of nalbuphine or hydroxyzine (50 acute headache phase of the disease. mg) or a combination of the two during severe migraine C) Treatment 20 is no more effective than a placebo in the treatment of A variety of pharmacological agents has been em pain associated with classic migraine. However, in this ployed in the prior art in attempting to treat individuals study, the migraine pain was treated well after occur suffering from migraine headaches. The pharmacologi rence of the acute headache phase. Moreover, the dos cal agents previously used generally counteracted the 25 age of hydroxyzine used by Tek was 50 mg per patient, symptoms of a migraine after, rather than before, occur the normal dose used in combination with a narcotic rence of the acute migraine headache phase, specifically analgesic. by antagonizing the effects of serotonin or its utilization Although not reported in the literature, high doses of at the brain stem and forebrain synapses. hydroxyzine (over 100mg) alone have been used on an Examples of symptomatic treatments suggested by 30 ad hoc basis for the symptomatic treatment of migraine the prior art include use of extracranial vasoconstric headaches after the pain has occurred despite the fact tors, typically ergot alkaloids such as , and that hydroxyzine used alone in smaller doses (50mg) . In addition, it was reported that the vaso had been reported (e.g., by Tek et al.) to be ineffective constrictor Sumatriptan has been reported to be effec in the treatment of migraine. tive in the treatment of migraine by inhibiting the re 35 In Wild, U.S. Pat. No. 4,017,614, the lease of serotonin by the nerve cells in the brain (Mos was administered with an analgesic after the kowitz et al., "Evidence that Serotonin 1-like Heterore onset of the aura. Buclizine was, however, indicated to ceptors Block Neuropeptide Release and Neurogenic be ineffective if administered individually, and at high Plasma Extravasation to Mediate the Actions of Ergot doses was reported to trigger a headache. Alkaloid and Sumatriptan (GR43175) in Migraine Opioid analgesics, such as morphine, are known to Headaches," XVth International Symposium on Cere make the migraine worse, as are high doses of non-opi bral Blood Flow and Metabolism, BRAIN-91, Abstract oid analgesics, such as aspirin, ibuprofen, acetamino 14 (Jun. 1-6, 1991)). However, if vasoconstrictors or phen and the like. This undesirable effect is found with serotonin are taken before the migraine, they all analgesics. Concurrent administration of high doses may precipitate the migraine, and they are contraindi 45 of analgesics along with certain can also cated in coronary heart disease and in pregnancy. trigger rather than inhibit mast cell degranulation (see, Chronic prophylactic administration of certain drugs e.g., Wojnar et al., J. Allergy Clin. Immunol., vol. 66, has been tried using 5-hydroxytryptamine (5-HT, sero No. 1, pp. 37-45 (July 1980); Masini et al., Agents and tonin) antagonists such as and cyprohep Actions, vol. 18, (1986), pp. 85-88). The deleterious tadine, vasodilators such as papaverine, beta-adrenergic 50 effects of high dosages of analgesics is known in the blockers, such as , nadolol, timololorateno literature (see, e.g., Goth, A., Effects of drugs on mast lol; anti-depressants, such as ; cells, Adv. Pharmacol. 5:47-78 (1967)). calcium channel antagonists, such as and Verapamil, and , such as or SUMMARY OF THE INVENTION phenelzine. Certain of these drugs, however, have se 55 It is an object of the present invention to provide a were side effects. For example, propranolol and nifedi method of preventing or alleviating migraine headaches pine inhibit the function of the heart, and while the that can be carried out prior to or during the prodrome former causes impotence, the latter can precipitate a phase. headache. Amitriptyline casues a drop in blood pres Another object of the present invention is to provide sure, sedation, behavioral changes and weight gain. a method that avoids undesirable chronic prophylactic Anti- have been used in combination with administration. analgesics (narcotic and/or non-narcotic). In particular, In accomplishing the foregoing objectives, there has anti-histamines have been used in the treatment of mi been provided, in accordance with one aspect of the graines after the onset of pain, in combination with a present invention, a method of preventing or all (RViat narcotic analgesic. The use of antihistamines in this 65 ing a migraine headache which comprises the step of manner was considered desirable because they are se administering to a patient a -pharmaceutically effective dating, they may reduce nausea, and they may potenti amount of a mast cell degranulation blocking agent just ate the action of analgesics, while minimizing their side prior to or during the prodrome phase in the absence of 5,250,529 5 an analgesic administered prior to the onset of the acute Chlorotetracycline migraine phase. Cyclosporin A In a preferred embodiment, the mast cell degranula Tetracyclic pyridone-2-carboxylic acid tion blocking agent is hydroxyzine. Antihormones which are estrogen or progestin receptor In another preferred embodiment, the mast cell de 5 antagonists granulation blocking agent is administered in combina Estrogen receptor antagonists tion with a pharmaceutically effective amount of a cen Clomiphene tral nervous system stimulant such as caffeine, which Tamoxifen also permits better absorption. Progestin receptor antagonists Other objects, features and advantages of the present O invention will become apparent to those skilled in the Arachidonic acid metabolites art from the following detailed description. It is to be Leukotriene D4 understood, however, that the detailed description and Lipoxin B specific examples, while indicating preferred embodi Phospholipase A2 ments of the present invention, are given by way of 15 Prostaglandin D2 illustration and not limitation. Many changes and modi Prostaglandin E1 fications within the scope of the present invention may Prostaglandin E2 be made without departing from the spirit thereof, and ATPase inhibitors the invention includes all such modifications. Ethancrynic acid 20 OETALED DESCRIPTION OF THE Ouabain PREFERRED EMBODIMENTS Quercetin Calcium entry blockers The method of the present invention prevents or Diltiazem alleviates the migraine headache by inhibiting the re Nifedipine lease from mast cells of the vasoactive (i.e., vasocon 25 Nimodipine strictive and vasodilatory) and nociceptive compounds Verapamil which are involved in the precipitation of the migraine. 2'-Carboxylatochromon-5-yl-2-hydroxy It has been found that administration of mast cell block propanederivatives ing agents, especially those which interfere with the cell Bis(acetoxymethyl) cromoglycate receptor activation mechanisms in the primary prodro 30 Disodium cromoglycate mal stage, will prevent or alleviate the onset of the two Nedocromil later stages in the migraine process. Central nervous system stimulants By "prevention or alleviation' is meant the follow Methyl Xanthines: ing: assuming that the fully developed migraine head 3-Isobutyl-1-methylxanthine ache is associated with the activation of a specific num 35 Aminophylline ber of mast cells, the development thereof can involve Caffeine sequential activation of a certain percentage of this total Enprophylline at a time. If the mast cell degranulation blocking agent Theophylline is administered to the patient before the beginning of the Histamine-1 receptor antagonists containing ring struc activation process, the result will be prevention of the 40 ture migraine. However, if the blocking agent is adminis Piperidines tered during the activation process, but before all of the necessary mast cells are activated, then the result will be alleviation of the migraine. In other words, since all of Burfroline the necessary mast cells will not be activated, the full 45 migraine headache will not develop and the resulting Doxantrozole pain, which has yet to develop, will be less severe than Forskolin would be the case if the blocking agent were not admin Ketotifen istered. The reduction in severity of the impending Lodoxamide trimethamine migraine headache constitutes "alleviation' of the mi 50 Loperamide graine. Myricetin Particularly preferred are certain histamine-1 recep tor antagonists, antihormones and polyamines, espe cially those specific compounds set forth below. As to Proxicromil the H-1 receptor antagonists, even more especially pre 55 Terfenadine ferred are azelastine, azatadine, hydroxyzine and keto tifen, based on their potency in inhibiting cranial mast 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine cell secretion as distinct from mast cells present else 1-(1-Hydroxy-5-isoquinolinylsulfonyl) where in the body. A particularly suitable mast cell degranulation blocking agent is hydroxyzine and the pharmaceutically acceptable, non-toxic salts of hy Hydroxyzine droxyzine. N-(optionally substituted benhydryl)-N'-(option Some of the classes of drugs which inhibit mast cell ally substituted)piperazines degranulation and examples of such classes are the fol Tertiary Alkylamines lowing: 65 Pyrilamine Anthralinic acid derivatives N-(3,4-dimethoxycinnamoyl)anthranilic acids Peptides Antibiotics L-Asp-Ser-Asp-Pro-Arg 5,250,529 7 8 Forssman antibody All the members of the foregoing classes may not Interleukin-1 necessarily inhibit mast cell degranulation. However, Lymphocyte Inhibitory Factor (LIF) the ability of any individual members to inhibit mast cell Substance P-receptor antagonist degranulation can be determined by the test set forth Phenothiazines below. Chlorocyclazine First, mast cells from rats (peritoneal cavity) or hu mans (chronic peritoneal dialysis fluid) are purified; otherwise, rat basophilic leukemia (RBL) cells are kept in culture. Any of these mast cells are then exposed to Trifluoroperazine O various concentrations of inhibitory compounds to Polyamines allow binding of the inhibitor to the receptor sites be Putrescine fore testing their efficacy with respect to inhibition of Spermidine mast cell degranulation. They are then used as such or Spermine washed free of unbound before exposure to stimuli Proteoglycans 15 known to induce degranulation. Compounds which are Heparin inhibitory prevent the stimulus from causing degranula Quinoline derivatives tion by binding to specific receptors or inactivating a 1,3-oxazolo,4,5-hlquinolines crucial step in the degranulation process. 2-Carboxypyrimidoquinolines It is important to note that some H-receptor antago 3-Aminoquinolines 20 nists actually cause mast cell degranulation and thus Steroids must be avoided (see Pini et al., Degranulation of Rat Cortisone Mesentery Mast Cells by Antihistamines: Influence of Danocrine Ionization. Agents and Actions, vol. 8/5:491-96 (1978)). Examples are given in Table 1 below. Diethylstilbestrol 25 Prednisone TABLE 1 Testosterone ANTI-HISTAMINES WHICH CAUSE MAST Thiophene derivatives CELE DEGRANULATION 1-Methyl-2(1,3,4-oxadiazol-2(3H)-one-5-yl) Compound ED20 for Histamine Release 30 Clorphenyramine 10-3 M 5 x 10-4 M Toxins 10-3 M Diphtheria toxin Promethazine 0-4 M Pertussis toxin ED20 = effective dose causing 20% secretion. Tricyclic M = molar concentration. Amitriptyline 35 The mast cell degranulation inhibitor in the dosage administered preferably are capable of passing the Miscellaneous compounds blood-brain barrier in an effective amount. The ability 2-Substituted 3-dimethylamino-5,6-methylenedioxy of the mast cell degranulation blocking agent to pass the dines blood-brain barrier in effective amounts can be deter 2-o-Propoxyphenyl-8-azapurin-6-one mined by calculating the percentage of a particular 2-Ethoxyethyl-5-chloro-benzoxazole-2-carboxylate agent that reaches the brain when administered by a 5-Amino-4-imidazolecarboxyamide riboside conventional route to experimental animals by methods 5-Chlorobenzoxazole-2-carboxcylic acid 45 known in the literature, especially utilizing radiolabeled 7-Methyl-5-propyl-s-triazole(1,5c)pyrimidine-2- agents. amine The instant invention is predicated on the early and 7-(2-Hydroxyethoxy)-9-oxoxanthene-2-carboxylic rapid inhibition of the mast cell degranulation process acid to prevent or alleviate the migraine headache. To effect 9-Chloro-5-oxo-7-(1H-tetrazol-5yl)-5H-1]ben SO this early intervention, dosage forms for the delivery of Zopyrano (2,3-bpyridine sodium salt pentahydrate hydroxyzine necessitate those that achieve high blood Aniloride levels of the drug very rapidly. These dosage forms are Cloxacepride adapted for a variety of conventional routes of adminis Deoxycoformycin tration, including oral, parenteral and transepithelial, Dipyridamole 55 such as sublingual, or transmucosal, transdermal, intra Fistein nasal and rectal. Flufenamic acid The mast cell degranulation blocking agent is admin Nylidrin hydrochloride istered in a pharmaceutically effective amount. The p-Bromophenacyl dosage range for pharmaceutical effectiveness can be Pinozide determined by reference to standard laboratory tests for Salbutamol sulfate inhibition of mast cell degranulation and by the dosages Particularly useful known mast cell degranulation used for such agents in other conditions. The pharma blocking agents are certain anti-histamines (H1-receptor ceutically effective dose of the mast cell degranulation antagonists) such as hydroxyzine, azelastine, azatadine, blocking agent can be approximated by its ID20, which cetirizine, cyproheptadine, ketotifen, oxatomide and 65 is defined as the dose necessary to cause 20% inhibition terfenadine. Hi -receptor antagonists are defined as in mast cells when applied to mast cells stimulated in having "affinity" (i.e., binding tightly) to the histamine vitro. The ID20 of selected inhibitors of the anti-hista 1 receptor at concentrations of 5x 10-5M or lower. mine category is as follows: 5,250,529 9 O TABLE 2 teral administration orally or through mucus mem ANTIHISTAMINES WHICH INHIBITRAT MAST CELL branes such as intranasal, sublingual, buccal, rectal, as DEGRANULATION IN VITRO well as transdermal. A transdermal route is preferred Antihistamines ID20 for Histamine Release for convenience, comfort, safety and avoidance of first Azatadine 10-7 M pass metabolism. Cyproheptadine 5 x 10-6 M Forms suitable for oral administration include tablets, Hydroxyzine 5 x 10-5 M dispersible powders, granules, capsules, syrups, elixirs Ketotifen 10-5 M Oxatomide 0-7 M and suspensions. Terfenadine 5 x 10-6 M Compositions for oral use contain one or more con O Ido are inhibitory dose causing 20% inhibition. ventional adjuvants, such as sweetening agents, flavor M is molar concentration. ing agents, coloring agents and preserving agents, in order to provide a presentable and palatable prepara The dosage of mast cell degranulation blocking agent tion. Tablets may contain the active ingredients in a for use in mammals can be calculated from the effective mixture with conventional pharmaceutically acceptable dose data by experimental selection. In general, the 15 ID20 is tested at 0.05 mg to 50 mg per kilogram body excipients. These include inert carriers, such as calcium weight of the animal. carbonate, sodium carbonate, lactose, and talc; granu The mast cell degranulation blocking agent can be lating and disintegrating agents, such as starch and al administered in the form of the active agent itself or as ginic acid; binding agents such as starch, gelatin acacia; a pharmaceutically acceptable salt of the active agent. 20 and, lubricating agents, such as magnesium stearate, The term "pharmaceutically acceptable salt' means a stearic acid and talc. Tablets may be uncoated or coated non-toxic, substantially non-irritating salt of the com by known techniques to delay disintegration and ab pound used. Typical salts include those containing a sorption in the gastrointestinal tract thereby providing a cation which is an alkali metal or alkaline earth metal, sustained action over a longer period of time. Similarly, such as sodium, potassium, calcium, magnesium or am 25 suspensions, syrups and elixirs may contain active ingre monium. Suitable cations for the salt include sulphate, dients in mixture with any of the conventional excipi Phosphate, tartrate and citrate. Other acceptable salts ents utilized in the preparation of such compositions. are those with non-toxic organic acids such as fatty This includes suspending agents such as methylcellu acids of one to six carbon atoms. lose, tragacanth and sodium alginate; wetting agents Hydroxyzine is a preferred mast cell degranulation 30 such as lecithin, polyoxyethylene stearate or polyoxy blocking agent because it also possesses other character ethylene sorbidan monoleate; and preservatives. Cap istics which are helpful in treating migraine. It is known sules may contain the active ingredients alone or an to be a mild , a tranquilizer, an anti-emetic and admixture with an inert solid carrier, such as calcium an inhibitor of neuronally-derived mast cell triggers. carbonate, calcium phosphate or kaolin. These pharma Finally, since hydroxyzine panoate, a salt of hydroxy 35 ceutical compositions may contain up to 90% of active zine, is lipophilic, i.e. more soluble in lipid solvents than ingredients in combination with the carrier or adjuvant. water, it allows chemicals, in this case hydroxyzine Preferably, the compounds are put up in unit dosage pamoate, to cross the vascular wall and the blood-brain forms particularly for oral administration. Such forms barrier. may contain the active ingredient separately, for exam Hydroxyzine can be administered in dosages of about ple in separate layers. Oral administration is often pre 0.1 to about ten (10) milligrams (mg) per kg or about 8 ferred if the mast cell degranulation inhibiting agent is mg to about 800 mg for 80 kilograms (kg) of body orally active. For patients who experience nausea or weight of the subject per day. When the hydroxyzine is vomiting, sublingual administration is preferred. to be administered transmucosally, it is convenient to The agents can be administered in sustained release use hydroxyzine in the form of a pamoate salt. 45 form or in divided dosages. Dosages per 80 kilograms bodyweight per day for In the case of mast cell degranulation inhibiting several preferred blocking agents are given in Table 3 agents which are substantially destroyed or deactivated below. upon oral administration, or where a more immediate TABLE 3 50 response is desired or prolonged duration of activity is DOSAGES OF PREFERRED BLOCKINGAGENTS desired, the mast cell degranulation blocking agents of Agent Dosage(mg)/80 kg/day this invention can also be administered transdermally or Azatadine 0.4-8 via other body membranes such as rectally, sublingually Azelastine 0.4-8 or buccally. Similarly, the compositions of this inven Cyproheptadine 0.4-40 Hydroxyzine 8-800 55 tion are administered by those routes with carriers Ketotifen 0.2-SO known for such administration. Oxatonide 6-60 An advantage of the inventive method is that the use Terfenadine 6400 of the mast cell degranulation blocking agents as de scribed does not involve a narrow therapeutic window The mast cell degranulation blocking agent can be 60 in the sense that increasing the dosage leads to precipita administered by known methods for drug administra tion, rather than prevention/alleviation, of the mi tion. The agents are typically administered as pharma graine. ceutical compositions in combination with pharmaceu The mast cell degranulation blocking agent is admin tically acceptable carriers. Such compositions may be istered without the concomitant administration of an prepared from conventional materials by procedures 65 effective amount of an analgesic. By the foregoing is well known in the art. meant that an analgesic is not administered just prior to The compositions of this invention may be adapted or during the prodome when the mast cell degranula for oral or parenteral administration, as well as for en tion blocking agent is first administered. Rather, the 5,250,529 11 12 administration of an analgesic is deferred until later if not relieved during those ten years by a variety of nar and when the migraine pain actually occurs. cotic and non-narcotic analgesics, and often related to The term an "analgesic' refers to a substance known her menstrual cycle, was administered sublingually to exert an analgesic effect in standard laboratory test, hydroxyzine in the form of the pamoate ester. Her pro typically the mouse hot plate test. drome was characterized by nausea and photophobia The mast cell degranulation blocking agent can be and typically lasted roughly hour. During the pro administered alone or in conjunction with other thera drome of the migraine, she took 50 mg hydroxyzine peutic agents, provided those therapeutic agents do not pamoate sublingually in the absence of any other anal directly or indirectly promote mast cell degranulation. gesic. In each and every case, the migraine failed to One preferred conjunct to the administration of a mast 10 appear as determined by the absence of severe headache cell degranulation blocking agent is the administration and disappearance of nausea and photophobia. The of a xanthine-like central nervous system stimulant, for patient was occasionally left with a mild, dull ache (i.e., example, a methylxanthine such as caffeine. Such com a residual muscle tension headache) which was well pounds are potent stimulants of the central nervous tolerated. system. In particular, the use of a central nervous sys 15 ten stimulant such as caffeine results in vasoconstric EXAMPLE 4 tion and adenosine receptor blocking action, which also reduces mast cell degranulation since the latter is aug Treatment mented by adenosine which is released during anoxia. A female patient, age 26, with a four-year history of Caffeine also increases the absorption of drugs when 20 migraine headaches occurring at irregular intervals and co-administered. unrelieved during those four years by narcotic or non These compounds also affect the actions of the heart, narcotic analgesics, was administered hydroxyzine in cause relaxation of bronchial smooth muscles and re the form of the pamoate ester sublingually. Her pro duce the release of secretory products of a number of drome was shown by generalized malaise and photo other endocrine and exocrine tissues. In addition, the 25 phobia and sonophobia, i.e., intolerance to intense light caffeine counterbalances the sedative effect present or sound, respectively. Her prodrome typically lasted with some of the mast cell degranulation blocking one to two hours. During the prodrome of the migraine, agents, which is particularly useful in patients who wish she took 50 mg of hydroxyzine panoate powder in an to maintain a normal life-style. inert carrier sublingually in the absence of any other Besides caffeine, other xanthine compounds exerting 30 analgesic. In each and every case, the migraine failed to a pattern of actions similar to that of caffeine, such as appear as determined by the absence of severe headache aminophylline, are also useful. (Although theophylline and disappearance of photophobia and phonophobia. and theobromine can be used, their use is limited by The patient was infrequently left with a dull ache (resid their toxicity.) ual muscle tension headache) which was well tolerated. The caffeine that can be administered with the mast 35 What is claimed is: cell degranulation blocking agent is administered in the 1. A method of alleviating a migraine headache pharmaceutically effective amount. A pharmaceutically which comprises the step of administering to a patient a effective amount denotes a dosage from 5 to 50 milli pharmaceutically effective amount of a mast cell de grams per kilogram body weight. granulation blocking agent only during the prodrome The following non-limiting examples further illus phase in the absence of an analgesic administered prior trate the invention. to the onset of the acute migraine phase. EXAMPLE 1. 2. A method as claimed in claim 1, wherein said mast cell degranulation blocking agent is administered paren Hydroxyzine Injection terally, orally, intranasally, sublingually, buccally, rec A sterile solution of hydroxyzine hydrochloride, with 45 tally or transdermally. sodium metabisulfate, in water for injection is provided 3. A method as claimed in claim 1, wherein said mast in one (1.0) ml ampules containing 50 mg of hydroxy cell degranulation blocking agent is selected from the zine panoate. group consisting of mast cell degranulation blocking EXAMPLE 2 agents having histamine-i receptor antagonist activity. 50 4. A method as claimed in claim 3, wherein said mast Tablets cell degranulation blocking agent is selected form the Preferred embodiment for rapidly disintegrating tab group consisting of azatadien, azelastine, cetirizine, lets are as follows: cyproheptadien, doxantrozole, etodroxizine, forskolin, hydroxyzine, ketotifen, oxatomide and terfenadine. 55 5. A method as claimed in claim 4, wherein said mast Sublingual Tablet: cell degranulation blocking agent is hydroxyzine. Ingredients ng/tablet 6. A method as claimed in claim 5, wherein said hy Hydroxyzine Pamoate 50 mg droxyzine is in the form of a pharmaceutically accept Milk sugar (12 mesh granular) 25 mg able salt. Starch 20 mg Talc 8 mg 7. A method as claimed in claim 5, wherein said hy Magnesium Stearate 0.4 mg droxyzine is administered in an amount from about 0.05 to 50 milligrams per kilogram body weight of said pa tient. EXAMPLE 3 8. A method as claimed in claim 7, wherein said hy 65 droxyzine is administered in the form of hydroxyzine Treatment panoate. A female patient, age 29, with a ten-year history of 9. A method as claimed in claim 8, wherein said hy migraine headaches occurring once every three months, droxyzine pamoate is administered transmucosally. 5,250,529 13 14 14. A method as claimed in claim 4, wherein said mast 10. A method as claimed in claim i, wherein said mast cell degranulation blocking agent is ketotifen. cell degranulation blocking agent is a polyamine. 15. A method as claimed in claim 14, wherein said 11. A method as claimed in claim 10, wherein said ketotifen is administered in an amount from about 0.005 polyamine is spermine. to 0.5 milligrams per kilogram body weight of said patient. 12. A method as claimed in claim 1, wherein said mast 16. A method as claimed in claim 1, wherein said mast cell degranulation blocking agent is administered in cell degranulation blocking agent is the estrogen recep conjunction with a pharmaceutically effective amounta tor antagonist tamoxifen. O 17. A method as claimed in claim 1, wherein said mast central nervous system stimulant. cell degranulation blocking agent is the ATPase inhibi 13. A method as claimed in claim 12, wherein said tor quercetin. stimulant is caffeine. k

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