Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-08-20
2000-06-06
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31445
Patent
active
060719265
DESCRIPTION:
BRIEF SUMMARY
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. Pharmacological 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, ie., 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 GH levels, i.e., 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 (Mendel
REFERENCES:
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 suppresses both sleep and growth hormone secreation in the rat," Brain Research, 557:149-153, 1991.
Copinschi Georges
Van Cauter Eve
ARCH Development Corporation
Spivack Phyllis G.
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