Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-09-27
2004-03-09
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S419000, C514S923000
Reexamination Certificate
active
06703412
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
Not Applicable
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
FIELD OF THE INVENTION
The present invention relates to treatment of common forms of sleeplessness and the use of limited dosage regimens using melatonin therefor.
BACKGROUND OF THE INVENTION
According to the National Sleep Foundation's 2002 “Sleep in America” Poll among 1004 US adults, almost seven in ten (69%) of adults experience one or more sleep problems at least a few nights a week. Furthermore, about three in ten (29%) say they experience insomnia every or almost every night. Amongst the most common forms of insomnia are awakening during the night or waking up too early and not being able to get back to sleep (experienced by 32% and 24% of adults at least a few nights per week respectively) These forms of sleeplessness are in fact more prevalent than the inability to initially fall asleep (experienced by 23% of adults).The result is that 40% of adults are so sleepy during the day that it interferes with their ability to perform their daily activities a few days per week or more, according to the study. 53% say they have driven while drowsy, with 19% admitting to have actually dozed off during driving. The National Highway Safety Administration estimates that 100,000 automobile accidents, 40,000 injuries, and 1,550 fatalities annually are related to drowsy driving.
Despite the prevalence and consequences of sleeplessness problems, the NSF study indicates that only 6% of adults take prescription sleep medications, with an equal percentage taking OTC sleep remedies a few nights a month or more. In fact, Mediamark Research Inc.'s 2000 Study among over 25,000 US adults indicates that only 4.6% have used any nonprescription sleep aid within the last six months. It is conjectured that non-treatment of this serious problem is due at least in part to the “mis-fit” between currently available non-prescription treatment options and the specific sleep problems suffered by many adults. Specifically, whereas more adults suffer from middle of the night or early morning awakening, all currently available sleep aids direct users to take the sleep medication before initially going to sleep.
In doing so, the individual must elect to take a medication for a problem—the inability to initially fall asleep—which they do not have, since most insomnia sufferers have no problem in initially falling asleep. Furthermore, they must elect to take medication before knowing whether they will or will not experience sleeplessness later during the sleep period (since the majority do not experience premature awakening on a daily basis.) In other words, all available sleep remedies do not address the more prevalent sleep problems and require dosage before knowing if the problem will be experienced at all.
An additional issue keeping insomnia sufferers from taking OTC medications are concerns about grogginess associated with the hypnotics, sedatives and antihistamines currently available for the treatment of sleeplessness. It is these properties that in fact prohibit the usage of such remedies at any time later than before the initial bedtime.
Melatonin (N-acetyl-5-methyoxytryptamine) is a neurohormone produced by the pineal gland and screted at night, reaching levels 10-40 times higher than those present in the daytime. It is lipid-soluble and released into the bloodstream and cerebrospsinal fluid as it is synthesized. The highest levels of melatonin are found in children age 5 and under, after which levels begin to decline (Zhdanova I., Lynch H,; and Wurtman R., Sleep; 1997; 20:899-907)
It has been established that endogenous melatonin onset occurs sometime after 1700 with peak levels between 0100 and 0500, and with offset occurring around 0700 or 0800. According to the phase response curve indicated by Lewy and associates (“
Melatonin shifts human circadian rhythms according to a phase response curve
” Chronobiolology Intl 1992; 9:380-92) melatonin administered at around 0200 would neither advance nor delay the circadian rhythm. Melatonin taken after that time is likely also to have minimal effects on circadian rhythms since it has been shown to phase advance better than phase delay.
Melatonin has a short biological half-life, ranging from 32-48 minutes for 2-100 mg. doses and is rapidly metabolized by the liver. (Aldhous, M., et. al.:
Plasma Concentrations of Melatonin in Man Following Oral Absorption of Different Preparations
. Br. J. Clin. Pharm.1985; 19:517-521) Doses of melatonin from very small (0.1 mg.) to huge (2 g.) have been administered to humans with no serious side effects. According to Waldhauser, Saletu and Trinchard-Lugan in “
Sleep Laboratory Investigations on Hypnotic Properties of melatonin
” (Psychopharmacology; 1990: 100:222-6), “The dose response curve for melatonin's effect on sleep is clearly different from those of currently recognized hypnotic agents. As the dose of benzodiazepine or barbiturate is increased, increasing degrees of sleepiness and eventually coma result. In contrast, melatonin doses of several grams, given to humans, can raise blood levels to concentrations that are over 1,000 times physiological levels, but never produce involuntary loss of consciousness. Indeed, some people may not even become overly sleepy.”
Melatonin is regarded as non-toxic since an LD
50
has not been determined. An early study of the toxicity of melatonin failed to produce death in mice given 800 mg ·kg −
1
(Barchas J, DaCosta F., and Spector. “
Acute Pharmacology of Melatonin
. Nature 1967; 214:919-20) One study reports that ingestion of 300 mg of melatonin daily, for four months, resulted in inhibition of ovulation in women. (Bettie C. G. et. al., J. Clin. Endocrin. Metabol. 1992;74:108-117).
The physiological effects of melatonin appear to be the regulation of the circadian biological timing system and modulation of sleep, acting on sleep propensity and core body temperature. The sleep-promoting properties of melatonin are well documented for both daytime and night time use. (Hughes, Badia: “
Sleep Promoting and Hypothermic Effects of Daytime Melatonin Administration in Humans
. Sleep 1997;20:124-31; Attenburrow, Cowen, Sharpley, “
Low Dose Melatonin Improves Sleep in Healthy Middle
-
Aged Subjects
. Psychopharmacology 1996; 126:179-81; Wurtman, Zhdanova. “
Improvement of Sleep Quality by Melatonin
” Lancet 1995;346:1491 and many other studies) In “Melatonin Administration in Insomnia” (James, Sack, Rosenthal, Mendelson, Neuropsychopharmacology 1990; 3:19-23) no sleep-related benefits are observed, however it has been argued that this is due to a “sleep ceiling effect” problem, in which sleep efficiency in the placebo condition is 91%, enabling little opportunity for improvement in the treatment condition.
One of the effects of melatonin is to reduce core body temperature, although the exact method of action is unknown (Cagnacci A., J. “
Melatonin in Relation to Physiology in Adult Humans
” Pineal Res: 1996; 21:200-13). However, the fact that melatonin impacts body temperature is important since many researchers believe melatonin may regulate the sleep/wake cycle through thermoregulatory mechanisms. It has been found that the decline in core body temperature occurs around the same time as the rise in melatonin, and that the increase in core body temperature coincides with melatonin decreases. As the dose of melatonin increases, a more reliable decrease in body temperature occurs. In a study by Dawson, Gibbon and Singh (“
The Hypothermic Effects of Melatonin on Core Body Temperature: Is More Better
?” J. Pineal Res. 1996; 20:192-7) where 0.1, 0.5, 1 and 5 mg. of melatonin were administered at 1600, lower doses produced more variability in the temperature decrease, whereas higher doses produced less variability in both time and amount of temperature decrease. Low doses of melatonin (producing blood levels within the normal physiological nighttime range) have been studied in connection with the ability to reduce the time period f
Fishman Irving M.
Krass Frederick
LandOfFree
Method of treating sleeplessness with melatonin on an acute... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method of treating sleeplessness with melatonin on an acute..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of treating sleeplessness with melatonin on an acute... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3193049