Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-14
2001-10-16
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06303595
ABSTRACT:
The present invention pertains to the treatment of sleep apneas. Sleep apnea is defined as the cessation of breathing during sleep. It comprises a spectrum of respiration-related disorders with varying severity and morbidity, involving periods, during sleep, in which airflow is disturbed. The usual classification of sleep apneas distinguishes obstructive, central, and mixed apneas, depending on the presence or absence of respiratory efforts during the periods in which airflow has ceased. In the case of the obstructive sleep apnea syndrome, which is the most familiar apnea, sporadic recurring collapse of the patient's upper airway occurs during sleep. If the collapse is complete, there is no air exchange at the nose and the mouth, and breathing is interrupted. The usual result is a partial arousal from sleep, and a return to normal breathing. The patient in most instances does not have any knowledge or memory of these apnea episodes, but finds himself constantly suffering from fatigue and daytime sleepiness for no apparent reason. These recurrent apnea episodes with resultant hypoxemia and fragmented sleep can have serious neurologic and cardiac consequences. While the obstructive sleep apnea is a physical blockade, central sleep apnea is defined as a neurological disorder, causing cessation of all respiratory effort during sleep, usually with decreases in blood oxygen saturation. The effects of both types of apneas are highly similar. Mixed apnea is a combination of the previous two. An episode of mixed sleep apnea usually starts with a central component and then becomes obstructive in nature.
The sleep apnea syndrome today is regarded as a serious problem, as it occurs widely, and there is a true lack of an effective treatment. Surgical and mechanical interventions have been suggested and tried as treatments, as has oxygen administration during sleep, but none of these are recognised to be very suitable. Pharmacological intervention has also been tried, but with little success. In fact, several kinds of respiratory stimulants, theophylline, antidepressants, and progestogens have been used to treat sleep apneas, but none of these has been found to be very effective.
It is an object of the present invention to provide an effective medicine against sleep apneas. To this end, the invention is a method for the treatment of an animal, for example, a mammal including a human patient, suffering from sleep apnea, comprising administering an effective amount of mirtazapine. The invention also involves the use of mirtazapine for the manufacture of a medicament for the treatment of sleep apnea.
Without wishing to be bound by theory, the applicant, with the hindsight of the unexpected effect of the invention, believes that it is the particular serotonergic profile of mirtazapine which is responsible for the efficacy against sleep apnea.
It should be noted that in a 1992 scientific publication (The Journal of Pharmacology and Experimental Therapeutics, Vol. 260 No. 2, pages 917-924), the pharmacological characterisation of the receptors mediating 5-HT (serotonin)—induced apnea has been investigated by studying the inhibitory effects of exogenous 5-HT on respiration and phrenic nerve activity in anaesthetised rats. This study supports the nowadays recognised potential importance of serotonin receptors in respiration, and indicates, int.al., that 5-HT and 2methyl-5-HT provoked central apneas are antagonised by ondansetron (GR 38032 F), which is a selective 5HT
3
antagonist.
The invention resides in the finding that an effective medicine against sleep apneas is provided on the basis of the compound mirtazapine. This compound displays a combined serotonergic antagonistic activity to the effect that it simultaneously is a combined 5HT2A, 5HT2C and 5HT3 antagonist. The invention in general pertains to the use of this compound for manufacturing a medicament for treating sleep apneas, Surpisingly, the compound is not only useful as a therapy against sleep apneas of the central type, but also against sleep apneas of the obstructive and mixed types.
Mirtazapine is known, e.g. from U.S. Pat. No. 4,062,848. The compound containing a centre of chirality, it may exist as different enantiomers and enantiomeric mixtures. The present invention includes the use of any particular enantiomer alone, or in a mixture with one or more stereoisomers, in any proportion including racemic mixtures. The present invention includes any salts of the compound, such as acid addition salts, for example, hydrochloric, fumaric, maleic, citric or succinic acid, these acids being mentioned only by way of illustration and without implied limitation. These compounds can be prepared in accordance with U.S. Pat. No. 4,062,848, incorporated herein by reference.
In a preferred embodiment, the aforementioned compound is combined with a selective serotonin reuptake inhibitor (SSRI). SSRI's, and pharmaceutically acceptable salts thereof, are known and have been available since the early 1980s. They include zimelidine, fluoxetine and fluvoxamine. Other SSRI's are for example citalopram, cericlamine, femoxetine, ifoxetine, cyanodothiepin, sertraline, paroxetine, and litoxetine. SSRI's are known to the skilled person, and may be prepared by any method known in the art. For example, fluoxetine or pharmaceutically acceptable salts thereof, can be prepared in accordance with U.S. Pat. No. 4,314,081, incorporated herein by reference.
A further benefit of mirtazapine, is that it also has antidepressant and anxiolytic properties, which helps to overcome secondary symptoms of which sleep apnea patients may suffer. Moreover mirtazapine improves the quality of sleep in general, which up to date has not been achieved with treatments of sleep apnea.
The compounds used according to the invention are to be administered in dosages of from 0.01 to 30 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 5 mg per kg body weight. In most instances, the preferred dosage of mirtazapine is 5 to 45 mg per day, and more preferably 15-30 mg. The SSRI dose may vary depending on the potency and efficacy of the specific active substance, but will generally be in the range of from 5 to 300 mg per day. E.g. citalopram and paroxetine will have a suitable dose of 40-50 mg, while the doses for fluvoxamine and sertraline will be 200-300 mg per day. In general, a suitable dose of an SSRI or a pharmaceutically acceptable salt thereof for administration to a human will be in the range of 0.01 to 50 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 3 mg per kilogram body weight per day. The preferred SSRI is fluoxetine which, administered in a dose within the range of 0.01 to 10 mg per kilogram body weight of the recipient per day, preferably in the range of 0.1 to 1 mg per kilogram body weight per day, together with the above preferred dose of mirtazapine forms the best choice for providing a highly effective medicament for the treatment of sleep apneas of the obstructive and mixed types.
The method of treatment of sleep apneas wherein the compounds according to the invention are administered for therapy to an animal e.g. a mammal including a human, may be carried out in conventional manner, using all kinds of methods, including parenteral, peroral or rectal administration. Administration in the form or oral dosage units, such as tablets or capsules, is preferred. In the method of the invention according to which the aforementioned compounds are used for manufacturing a medicine, the compound can be mixed with all kinds of pharmaceutically acceptable carriers, depending on the method of administration intended. For the preferred, peroral, method of administration, the active compound is taken up in known manner in a composition from which granules or tablets are prepared.
The term “dosage unit” generally refers to physically discrete units suitable as unitary dosages for humans, each containing a predetermined quantity of active material calculated to produce the desired effect, fo
Akzo Nobel N.V.
Reamer James H.
Sullivan Michael G.
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