Betahistine, or a pharmaceutically acceptable salt thereof, and a monoamine oxidase inhibitor, for use in the treatment or prevention of one or more symptoms of vertigo in a subject

Abstract

A first aspect of the invention relates to betahistine, or a pharmaceutically acceptable salt thereof, and a monoamine oxidase inhibitor, for use in the treatment or prevention of one or more symptoms of vertigo in a subject. A second aspect of the invention relates to a method of treating or preventing one or more symptoms of vertigo in a subject, said method comprising administering to the subject (i) betahistine, or a pharmaceutically acceptable salt thereof, and (ii) a monoamine oxidase inhibitor.

Claims

1. A method of treating or preventing one or more symptoms of vertigo in a subject, said method comprising administering to a subject an effective amount of a combination of: (i) a first active agent, which is betahistine, or a pharmaceutically acceptable salt thereof; and (ii) a second active agent, which is isocarboxazid, nialamide, phenelzine, hydracarbazine, tranylcypromine, benmoxin, iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenhydrazine, safrazine, caroxazone, bifemelane, moclobemide, pirlindole, toloxatone, minaprine, or rasagiline, or a pharmaceutically acceptable salt of isocarboxazid, nialamide, phenelzine, hydracarbazine, tranylcypromine, benmoxin, iproclozide, iproniazid, mebanazine, octamoxin, pheniprazine, phenoxypropazine, pivalylbenhydrazine, safrazine, caroxazone, bifemelane, moclobemide, pirlindole, toloxatone, minaprine, or rasagiline.

2. The method according to claim 1, wherein the dosage of the first active agent in combination with the second active agent is reduced to about a third compared to the dosage of the first active agent administered in the absence of the second active agent.

3. The method according to claim 1, wherein the subject has been previously treated with the first active agent in the absence of the second active agent.

4. The method according to claim 3, wherein the subject has been previously treated with the first active agent in the absence of the second active agent for a period of at least 6 months.

5. The method of claim 1, wherein the amount of the first active agent administered is at least 48 mg per day.

6. The method of claim 1, wherein the first active agent is betahistine dihydrochloride or betahistine mesylate.

7. The method of claim 1, wherein the second active agent is rasagiline, or a pharmaceutically acceptable salt thereof.

8. The method of claim 1, wherein the first active agent is formulated for oral administration.

9. The method of claim 1, wherein the second active agent is formulated for oral administration.

10. The method of claim 1, wherein the first active agent is administered in an amount of from about 50 to about 900 mg per day.

11. The method of claim 1, wherein the first active agent is administered three times a day.

12. The method of claim 1, wherein the first active agent is administered in unit dosage form, wherein the unit dosage comprises a 24 mg tablet of betahistine dihydrochloride.

13. The method of claim 12, wherein administration of the first active agent is from 3 to 36 tablets per day.

14. The method of claim 13, wherein administration of the first active agent is from 3 to 12 tablets per day.

15. The method of claim 12, wherein administration of the first active agent in the absence of the second active agent is at least 2 tablets per day.

16. The method of claim 7, wherein the second active agent is administered in an amount of from about 1 to about 15 mg per day.

17. The method of claim 7, wherein the second active agent is administered at least once a day.

18. The method of claim 17, wherein the second active agent is administered twice a day.

19. The method of claim 1, wherein the vertigo is caused by, or associated with, Meniere's disease, vestibular neuritis, labyrinthitis, or benign paroxysmal positional vertigo.

20. The method of claim 1, wherein the administration of the first active agent and the second active agent occurs in a single formulation.

Description

BRIEF DESCRIPTION OF DRAWING

(1) The present invention is further described by way of the following non-limiting examples and FIGURES, wherein:

(2) FIG. 1 shows the daily dosage of betahistine-dihydrochloride (mg) with and without selegeline taken by 13 patients with Menière's disease (MD) during a monotherapy (left) and during the combined therapy with 5 mg/d selegiline to respond to the treatment defined by ≤1 attack per three months. The thick black line indicates the mean dosage of betahistine per day of the 13 patients. There was a significant reduction from 895.4 to 204.0 per day (mean, p<0.001, paired t-test).

EXAMPLES

(3) Materials and Methods

(4) Betahistine dihydrochloride tablets were obtained from Abbott (Vasomotol 24 mg tablets). Selegiline hydrochloride tablets were obtained from Hexal.

(5) Study Design

(6) Studies by the Applicant investigated the benefits of a high-dosage betahistine monotherapy compared with those of a lower dosage of betahistine in combination with the MAO B inhibitor (MAO-B) selegiline on the frequency of acute attacks of vertigo in patients with Menière's disease (MD).

(7) More specifically, studies investigated the effect of combination therapy in 13 subjects receiving 5 mg per day selegiline hydrochloride (either as one tablet at night, or half a tablet in the morning and half a tablet at night), in conjunction with varying amounts of betahistine dihydrochloride per day (amounts ranging from n=3 to 36, where n is the number of 24 mg tablets per day). All subjects had previously received treatment with betahistine dihydrochloride monotherapy (in amounts ranging from n=9 to 80, where n is the number of 24 mg tablets per day), and the number of vertigo attacks per month were recorded during a three month period of monotherapy prior to commencement of combination treatment. Following combination treatment, the subjects then recorded the number of vertigo attacks per month during the last two months of combination treatment.

(8) The 13 patients in this observational study fulfilled the current diagnostic criteria of MD [48]. Patients with the diagnosis of other peripheral or central vestibular disorders, such as vestibular migraine, benign paroxysmal positional vertigo, paroxysmal brainstem attacks, or functional dizziness, were not included. Patients suffering from known contraindications or hypersensitivity to betahistine, such as bronchial asthma, pheochromocytoma, or treatment with other antihistaminic drugs, ulcer of the stomach or duodendum, or severe dysfunction of liver or kidney were also not treated with betahistine. Patients with known contraindications (e.g., use of meperidine or other opioids, tricyclic antidepressants or non-selective MAOIs, selective serotonin re-uptake inhibitors) or hypersensitivity to selegiline were not treated with this agent [51].

(9) Based on the results of the BEMED trial (showing that betahistine 48 mg tid is evidently not effective) the study initially started with a dosage of 96 mg tid in all patients. During the three- to six-monthly follow-up examinations the daily dosages were adjusted according to the patient's response (approach: “titration” of attacks of vertigo). Patients had been treated for at least 18 months with high dosages of betahistine-dihydrochloride and had ≤1 attacks for at least three months.

(10) An initial dosage of 5 mg/day selegiline hydrochloride was chosen (approved dosage for Parkinson's disease is 5 to 10 mg/d). In parallel the dosage of betahistine was reduced to about a tenth of the initial dosage. The design of the observational study was approved by the local ethics committee. Follow-up examinations were after 1 month and then every 3 months to check the efficacy of the treatment and the side-effects and to adjust the betahistine dosage if necessary. Ideally, the objective was to achieve ≤1 attack per three months.

(11) Preliminary Results

(12) Patient characteristics were as follows: n=13, 7 females, 6 males; age range 40 to 75 yrs; mean age 58.9 yrs. Further details are shown in Table 1.

(13) Based on the negative results of the BEMED trial, the patients started on a dosage of betahistine of 96 mg tid. Then the dosage was adjusted according to the number of attacks of vertigo per three months. The daily betahistine-dihydrochloride dosage eventually required to achieve a treatment response (≤1 attack for three months) ranged from 216 to 1920 mg (mean 895.4 mg/d, FIG. 1), i.e. 9 to 80 24-mg tablets per day (mean 37.3). This was well tolerated except for some fullness of the stomach in 4 patients which responded well to the proton-pump inhibitor pantoprazole (20 to 40 mg per day).

(14) After informing the patients that theoretically the betahistine dosage can be reduced when a patient also takes selegiline, the dosage was first reduced to about 10% of the initial dosage for three months. Finally, after the combination with 5 mg/d selegiline, the dosage needed to achieve the same benefit for at least three months was 3 to 36 24-mg tablets (mean 8.5), i.e. 72 to 864 mg/d (mean 204.9 mg/d, p<0.001, paired t-test). One patient transiently stopped the treatment with selegiline, another one reduced the dosage to 2.5 mg per day and the attacks re-occurred after 2 to 4 weeks. Six out of 13 patients reported transient fullness of the head or too much blood in the head during the combined treatment; in two of them this disappeared when switching to selegiline 2.5 mg bid.

(15) Of the 13 subjects tested, 10 were completely free from vertigo attacks during the last four months of combination treatment. One patient suffered only 1 vertigo attack per month during the last two months of combination treatment. Two patients suffered only one attack during the last 3 months of combination treatment. One subject also noted an improvement in tinnitus symptoms. Four subjects commented that they were very happy with the treatment. Other side effects included slight nausea (1 subject).

(16) In the longer term (>9 months), one patient had to increase the selegiline dosage to 5 mg twice per day because the attacks had re-occurred (up to three attacks per month); after increasing the selegiline dosage they experienced ≤1 attack per month. Eleven patients are still on selegiline treatment (5 mg per day), one is on 2.5 mg selegiline per day, one patient stopped selegiline because they were free of attacks for more than six months.

(17) The major finding of this observational study in 13 patients is that the combination of a lower dosage of betahistine and the MAO inhibitor selegiline (5 mg/d) has the same benefit as very high dosages of betahistine (of up to 1920 mg/d). This benefit can be explained by an increase of the blood concentrations of betahistine due to reduction of the normally almost complete first-pass effect (99%) of betahistine, leading to plasma concentrations of less than 0.5 ng/ml [52].

(18) Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.

REFERENCES

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(20) TABLE-US-00001 TABLE 1 Clinical characteristics and dosages Dosage of betahistine Dosage of (monotherapy) required betahistine in that the patient had a combination with significant effect before 5m selegiline the combined treatment (n of 24-mg Patient Sex, age, diagnosis (n of 24-mg tablets) tablets) 1 Female, 74 yrs, bilateral MD 80 36 2 Female, 69 yrs, MD, right 30 3 3 Female, 73 yrs, bilateral MD 9 3 4 Male, 43 yrs, bilateral MD 36 6 5 Female, 40 yrs, MD, right 60 18 6 Male, 51 yrs, bilateral MD 24 3 7 Male, 43 yrs, MD, left 30 12 8 Male, 52 yrs, MD, right 18 3 9 Male, 70 yrs, MD, right 50 3 10 Male, 57 yrs, bilateral MD 40 6 11 Male, 52 yrs, MD, left 30 9 12 Female, 67 yrs, MD, right 18 3 13 Female, 75 yrs, MD, left 60 6 MD = Menière's Disease