Sleep quality improvement using a growth hormone secretagogue

Details Sleep quality improvement using a growth hormone secretagogue Sleep quality improvement using a growth hormone secretagogue

2000-01-27

2001-11-06

Spivack, Phyllis G. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06313133

ABSTRACT:

I. FIELD OF THE INVENTION
The present invention relates to the fields of sleep medicine, gerontology and hormonal disorders. In particular, the invention addresses sleep deficiencies that are associated with depressed levels of growth hormone and prolactin.
II. RELATED ART
In young adults, sleep is associated with marked hormonal changes, including increased release of growth hormone (GH) and prolactin (PL). A pulse of GH occurs shortly after sleep onset in association with the first episode of slow-wave sleep (SWS) and often represents 50-100% of the total daily GH output. Sleep onset is associated with a marked increase in PL secretion. PL levels return to low daytime values after morning awakening. There is good evidence to indicate that the nocturnal release of GH and PL contributes to the maintenance and quality of sleep.
In older adults, sleep is disturbed with more awakenings, less SWS and less rapid eye movement (REM) sleep. The most dramatic change is the decrease in SWS, which often represents less than 5% of the sleep period time or, sometimes, disappears entirely in aged individuals. Simultaneously, growth hormone secretion also is markedly decreased, both during sleep and wakefulness. Since sleep-related GH secretion represents the major part of total GH secretion, the reduction or absence of SWS in the elderly plays a major role in contributing to the overall decline in GH secretion. The absence of activation of the GHRH-GH axis in early sleep also may be involved in the fragmentation, shallowness and reduced duration of mid and late sleep. Nocturnal prolactin release also is markedly decreased in old age and this alteration may play an important role in diminished sleep quality.
Conversely, the effects of GH secretion on sleep can be pronounced. Pharmnacological doses of GH may increase the duration of rapid-eye movement (REM) sleep in normal subjects In animals, injections of GHRH stimulate REM and non-REM sleep, while inhibition of endogenous GHRH suppresses both sleep and GH secretion. In normal young men, intravenous injections of GHRH may induce marked increases in SW sleep and/or REM sleep, and decreases the amount of wake. These somnogenic effects are dependent on the dosage and timing of administration. The mechanisms by which these hypnotic effects are effected have not been elucidated. Animal data also have suggested involvement of PL in sleep regulation and have indicated that PL may enhance REM sleep.
The implications of reduced GH secretion may be inferred from the findings in untreated GH-deficient adults, i.e., subjects who have no GH secretion due to either a congenital defect or pituitary disease. Pathologic states found in such individuals include increased cardiovascular mortality, reduced exercise capacity, reduced muscle strength, subnormal kidney function, defective sweat and temperature regulation, reduced energy expenditure and basal metabolic rate, abnormal thyroid hormone metabolism, increased fat mass, decreased lean body mass, upper body obesity and reduced bone mineral content. All of these abnormal conditions can be partially corrected by expensive GH replacement therapy with synthetic human GH. Most of the aforementioned abnormalities also are present in elderly adults who, incidentally, also have very low levels of GH secretion. Clinical trials with elderly subjects have shown the beneficial effects of GH replacement therapy, similar to that observed in GH-deficient subjects. The implication of reduced PL secretion in old age has not yet been defined.
Unfortunately, treatment with GH injections results in an unphysiological profile of circulating GM levels, ie., continuously elevated levels as compared to the intermittent pulses that characterize normal GH secretion, and this may be responsible for the development of the undesirable side effects which have been observed in long term treatments, including joint problems (carpal tunnel syndrome), water retention and impaired glucose tolerance.
The older population also is the primary user of hypnotics (Mendelson, 1987), although it is widely accepted that chronic hypnotic use has generally deleterious effects (Prinz, 1995). Commercially available hypnotics, including the benzodiazepines, improve sleep efficiency but do not consistently increase either SW or REM sleep (Gaillard, 1994).
An alternative to these approaches is the development of growth hormone secretagogues or compounds that stimulate release of prolactin. The ability of such secretagogues to provide the same physiologic benefits as natural GH and/or prolactin secretion, however, remains largely untested. Thus, there remains a need for alternatives in therapies in subjects exhibiting reduced GH and prolactin levels.
III. SUMMARY OF THE INVENTION
Therefore, it is an object of the present invention to provide methods of improving the sleep quality in persons having hormonally-related alterations in sleep. More particularly, it is an object of the present invention to identify individuals with age-related sleep disorders and, by increasing the levels of GH and prolactin secretion, improve the sleep quality of these individuals.
In fulfilling these objects, there is provided a method of improving sleep quality comprising the steps of (a) identifying a subject having age-related sleep disorder; and (b) administering to said subject an amount of the drug N-[1(R){[1,2-dihydro-1-methanesulfonylspiro-(3H-indole-3,4′-piperidin)-1′yl]carbonyl}-2-(phenylmethoxy)-ethyl]-2-amino-2-methylpropanamide methanesulfonate.
In one embodiment, the subject is at least about forty years old and, in another embodiment, the subject is at least about fifty years old and, in still another embodiment, the subject is at least about sixty years old. In still another embodiment, the subject is experiencing difficulty sleeping. And in still another embodiment, the administration occurs one hour prior to retiring, more preferably within one-half hour of retiring.
In another embodiment, the effective amount of the drug is 1.0-50.0 grams. In yet other embodiments, the effective amount of the drug is 5.0 mg., 10.0 mg. or 25.0 mg. The dosing preferably is oral.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.


REFERENCES:
patent: WO 94/13696 (1994-06-01), None
patent: WO 97/41879 (1997-11-01), None
Mendelson et al., “The Effect of Growth Hormone Administration on Human Sleep: a Dose-Response Study”, Biological Psychiatry, 15(4): 613-618, 1980.
Obal Jr. et al., “Inhibition of Growth Hormone-Releasing Factor Supresses Both Sleep and Growth Hormone Secreation in the Rat”, Brain Research, 557: 149-153, 1991.
Kerkhofs et al., Am. J. Physiol., 264(4, Pt. 1), E594-E598 (abstract), 1993.

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