EP1592424A1

EP1592424A1 - Cabergoline for the prophylactic treatment of migraine

Info

Publication number: EP1592424A1
Application number: EP04703185A
Authority: EP
Inventors: Angelo Battaglia; Maria Grazia Papini; Nicola Carfagna; Piero Barbanti
Original assignee: Pharmacia Italia SpA; Pharmacia and Upjohn SpA
Current assignee: Pfizer Italia SRL
Priority date: 2003-02-05
Filing date: 2004-01-19
Publication date: 2005-11-09
Also published as: WO2004069252A1; JP2006516596A

Abstract

The present invention relates to the use of cabergoline or its pharmaceutically acceptable salts in the preparation of a medicament for the prophylactic treatment of migraine.

Description

CABERGOLINE FOR THE PROPHYLACTIC TREATMENT OF MIGRAINE

The present invention belongs to the field of pharmaceutical chemistry and neurological medicine, and provides a method for preparing a medicament containing cabergoline for the pharmacological prophylactic treatment of migraine disorders. The pathogenetic mechanisms underlying the heterogeneous forms of migraine are complex and not yet fully understood. Clinical evidence and genetic findings support the hypothesis that dopamine could be involved in the pathophysiology of migraine. Most migraine symptoms (i.e., yawning, drowsiness, irritability and hyperactivity) reported to precede or accompany migraine attack have been linked to the hypersensitivity of post-synaptic dopamine receptors probably due to a chronic deficiency of dopamine release by presynaptic neurons, which in turn leads to the up- regulation of dopamine receptors. Thus, migraineurs show a lower threshold for dopamine receptor activation than normal subject. Genetic determinants are certainly at the basis of this hypersensitivity of dopaminergic system. In this regard, the most compelling evidence is the association between molecular variations within the dopamine D2 receptor gene and the clinical susceptibility to migraine. Several clinical studies suggest that migraine with aura is largely determined by genetic factors, whereas migraine without aura seems to be caused by a combination of both genetic and non- genetic factors. The dopaminergic system could also play a role in the headache phase, either by taking part in nociception mechanisms, or by regulating cerebral blood flow. Different treatment strategies, based on empirical ground, are currently used to treat migraine. In patients with high migraine attack frequency, prophylactic treatment is the mainstay of migraine pharmacotherapy. Prophylaxis is reserved for patients experiencing:

- > 2 attacks per month that produce disability lasting > 3 days;

- no, or inappropriate, response to symptomatic treatment or optimal abortive therapies that produce intolerable adverse effects. Current drugs used for the prophylaxis of migraine have limited efficacy and severe side effects. Circumstantial evidence indicates that dopamine agonists may be useful for prophylaxis. Unfortunately, most of these drugs lack selectivity for dopamine receptors. Also ergot alkaloids, acting as serotonin partial agonists, like methysergide and dihydroergota ine, are used in the prevention and treatment of migraines, but have several side effects.

Clearly there is a great need for better prophylactic agents. Cabergoline, generic name of l-[(6-allylergolin-8β-yl) carbonyl]-[3- (dimethylamino)propyl]-3-ethylurea, is described and claimed in US 4,526,892. Cabergoline is a long acting dopamine D2 receptor agonist currently used for the treatment of hyperprolactinemia and Parkinson's disease. Receptor binding studies indicated that the drug bound with higher affinity to D2 than Dl dopamine receptors, exhibiting 190-fold selectivity. The affinity for α-i, α₂₃ 5-HTι, or 5-HT₂ receptors was slight or negligible. The clinical efficacy, safety, and pharmacokinetic parameters of cabergoline in patients with Parkinson's disease (Mardsen CD. et al. Drugs 1998, l(sιιppll): 17-22; Wiseman LR & Fitton A, CNS Drug 1999, 12: 484-497) an d hyperprolactinemia (Biller BMK. et al. J Gin Endocrinol Metab 1996,81: 2338-2343; Colao A. et al. Ann Med 1998, 30: 452-459) have been reviewed. In particular it is reported that the long plasma half-life of cabergoline

(~ 68 h) enables the drug to be administered at least 2 days spaced intervals (i.e. a single oral doses of 0.3 to 1 mg have produced significant and prolonged suppression of serum prolactin levels for 7 to 14 days). A cluster-like headache as one of the symptoms of prolactinoma was observed by Colao et al, J. Gin. Endocrin. & Oncology, Metabolism, 82(3), 876-883, 1997 and by J. Porta-Etessam et al., J. Head and Face Pain, 41 (7), p.723, 2001. Both these last articles describe the cabergoline use in the treatment of prolactinoma, since the drug was known to be effective in tumoral hyperprolactinemia. It has been now discovered that cabergoline is effective in reducing the frequency and severity of migraine attacks in patients experiencing chronic migraine with aura (MWA) and without aura (MWOA). Therefore, it is a first object of the present invention the use of cabergoline or its pharmaceutically acceptable salts in the manufacture of a medicament for the migraine treatment. The present invention relates to the use of cabergoline or its pharmaceutically accepted salts for the manufacture of a medicament for the prophylactic treatment of migraine with and without aura, including chronic daily headache, cluster headache, chronic tension-type headache, intractable headache and migraine subtypes characterised by marked dopaminergic symptomatology.

The invention, therefore, is useful whenever is desirable to reduce and/or prevent headache recurrence episodes that are physically or psychologically disabling and/or unresponsive to symptomatic treatment. A preferred method involves repeated administrations per os of cabergoline or of a pharmaceutically acceptable salt thereof to a patient in need of such treatment, in an amount effective to reduce the frequency and severity of headache attack. In general, an effective amount is that of a pharmaceutical preparation that alone or together with further doses or co -administration of other agents, produces the desired response. Cabergoline is effective at relatively low doses and by virtue of its long plasma half-life, it may be safely and effectively be administered as a single dose at 2-3 days spaced intervals through slow dose titration. Thus, difficulties created by multiple dosing and patient's compliance are completely avoided. The use of cabergoline is particularly favourable for the following reasons: a) lack of sedation and weight gain, often present with drugs commonly used in migraine prevention such as flunarizine, valproate and amitriptyline, b) potential increased efficacy in menstrual migraine; c) very convenient way of administration, as only 1 to 3 doses per week are needed, with an improvement in the pharmacological compliance of the patients.

The optimum dose for each patient, as always, must be set by the physician by taking into account patient's size, concomitant drug treatments, severity of the migraine attacks and all the other circumstances complained by the patient. Other therapeutic agents may be added to supplement the compound. No adverse toxicological effects have been established for the compositions or methods of the invention in the above dosage. The compound is particularly selective, having few, if any, physiological effects besides those on dopamine function, and therefore is free of side effects and unwanted activities. In the method of the invention, the active medicament is preferably prepared in a suitable pharmaceutical composition form for oral administration, such as tablets, capsules, suspension and the like according to the conventional technology and would include one or more excipient. The active compound may also be administered, if there is any reason to do so in a particular circumstance, in other non-oral pharmaceutical forms, such as injectable solutions, depot injections, suppositories and the like.

The preferred doses of cabergoline for the prophylaxis of migraine disorders range from about 0.25 to about 2.5 mg, given as a single oral or non-oral dose once, twice or three times weekly.

More preferably, cabergoline is used at the dose of 1 mg per week for the migraine prophylactic treatment.

EXAMPLE

An open study on 20 subjects affected by migraine with aura (MWA) and/or without aura (MWOA) was performed at the Department of Neurological Sciences, University "La Sapienza", Rome (M/F: 3/17; age: 33.2 ± 12.1 yrs; MWOA: 18 pts; MWOA + MWA: 2). Patients with a diagnosis of MWOA and/or MWA from at least 6 months, migraine attack frequency ranging from 3 to 8 /month and age ranging from 18 to 65 years were included.

Patients with concomitant medical or neuropsychiatric illness, drug or alcohol abuse, pregnancy or breast-feeding and hypersensitivity to dopamine agonists were excluded. At baseline, each patient received a diary card to record the frequency, intensity and duration of the attacks. After 4 weeks of run-in, each patient was given cabergoline according to the following schedule of administration: a) 0.25 mg 2 times a week (Monday and Thursday) the first week; b) 0.50 mg 2 times a week for the following 16 weeks; c) 2 down-titration weeks at the dose of 0.25 mg 2 times a week. During the first 10 days of treatment, the patients were pre-treated with domperidone at the dose of 10 mg b.i.d. The primary end-point of the study was the reduction of the frequency of the attacks.

The actual results of this example are as follows: Nineteen patients completed the study. One patient dropped-out for vomiting. Twelve patients (63.2%) presented a reduction of the frequency of the attacks at the end of the treatment. Of these, 7 presented a frequency reduction > 50%. In the remaining patients the frequency of the attacks was unchanged in 6 (31.5%) and worsened in 1 (5.3%). On the whole the reduction of the number of migraine attacks was statistically significant (P< 0.05, paired data Student's "t" test). A trend to a reduction of pain intensity and attack duration was also observed. Among patients who completed the study, 3 individuals (15.8%) presented the following adverse events which were referred as mild and transient in nature: nausea (2 pts), asthenia (1 pt) and hypotension(l pt).

The following table one summarizes the results.

Table I-Prophylactic efficacy of cabergoline in patients affected by migraine with

(MWA) and without aura (MWOA)

*P <0.05 (paired Student's "t" test)

Claims

1. Use of cabergoline or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the pharmacological prophylaxis of migraine.

2. Use according to claim 1, wherein the migraine is a chronic human migraine disorder with and/or without aura.

3. Use according to claim 2, wherein the migraine is chronic daily headache, clusterlike headache, chronic tension-type headache, intractable headache.

4. Use according to claim 1, wherein migraine is predominantly characterised by a dopaminergic component.

5. Use according to any of claims 1 to 4, wherein the medicament is administered orally.

6. Use according to claim 5, in which the medicament is a tablet, a capsule, a suspension, or the like.

7. Use according to any of the preceding claims, in which cabergoline or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 0.25 to about 2.5 mg/patient.

8. Use according to claim 7, in which the cabergoline or a pharmaceutically acceptable salt thereof is administered once, twice or thrice a week.

9. Use according to claim 7, in which cabergoline or a pharmaceutically salt thereof is administered at the dose of 1 mg per week.

10. Use according to any of claims 1 to 4, wherein the medicament is not administered orally.

11. Use according to claim 10, in which the medicament is a injectable solution, a depot injection, a suppository or the like.

12. Use according to claim 11, in which cabergoline or a pharmaceutically acceptable salt thereof is administered at a dose ranging from about 0.25 to about 2.5 mg/patient.

13. Use according to claim 11, in which cabergoline or a pharmaceutically acceptable salt thereof is administered once, twice or thrice a week.

14. Use according to any of the preceding claims, characterized in that cabergoline or its pharmaceutically salt is used in combination with other therapeutic agents.