5-methoxypsoralen and other furocoumarins as jet lag suppressants

Abstract: Disclosed is use of 5-methoxypsoralen and other furocoumarins to prevent and suppress the symptoms of jet lag.

Description: The present invention relates to a new use of 5-methoxypsoralen and related furocoumarin compounds for suppressing or preventing symptoms of the human condition known as jet lag. Jet lag is a known psychological dislocation and disruption of bodily rhythms caused by high-speed travel across several time zones, usually in a jet airplane. In the course of such travel, the body's circadian clock is disturbed by the juxtaposition of night and day, or by merely a shift (usually of three hours or more) in the normal daily schedule to which the body is accustomed. Jet lag may cause a variety of maladies ranging from temporary exhaustion, insomnia, nausea and other, including gastrointestinal ailments. Jet lag sufferers may experience a reduced desire and capacity to work or to pursue recreational activities and other normal functions usually associated with long-distance travel. It is known that melatonin (N-acety-5-methoxytryptamine) is a sleep-inducing hormone secreted by the human pineal gland. Human melatonin secretion has a diurnal cycle with highest levels during the hours of darkness, typically peaking at about 11:00 pm. (2300 hours), and reaching its lowest levels at about 7:00 am., or 0700 hours. The linear furocoumarin, 5-methoxypsoralen, or 5-MOP, is well-known for its use in the treatment of various forms of psoriasis and other dermatoses such as vitiligo, atypical eczema and fungoid mycosis, and has been recognized as being especially useful in view of its efficacy and low toxicity. 5-MOP is also known for its beneficial effects in promoting "sun-tanning," or the browning of human skin as a result of the action of ultra-violet rays on the melanocytes of the skin, as described in Goupil, "Sun Products," U.S. Patent No. 4,699,781. Other furocoumarins have also been well-known for various uses, usually in the treatment of various skin conditions. In a controlled study, 5-MOP (given orally in doses of 40 mg. to normal subjects at 2100 hours) increased the plasma level of melatonin from the second hour after administration. Increased secretion was greater after evening than after morning administration, as reported by Souetre, E. et al., "5-Methoxypsoralen Increases The Plasma Melatonin Levels In Humans," J. Invest. Derm., vol. 89:152-155 (1987). Alleviation of jet lag by melatonin administered orally to patients has been described in the British Medical Journal 292 (1986), 1170. Until the present invention, 5-MOP has not been known to constitute an effective preventive or suppressive medication for the symptoms of jet lag. OBJECTS AND SUMMARY OF THE INVENTION Accordingly, it is a broad object of the invention to provide an effective treatment for the suppression and prevention of the symptoms of jet lag. It is an object of the invention to provide a new medication which effectively reduces or eliminates the otherwise occurring psychological dislocation and disruption of bodily rhythms caused by high-speed travel across several time zones. It is a further object to provide a preventive suppressant of jet lag symptoms which is easily administered, has low toxicity, and which is inexpensively synthesized and manufactured. These and other objects and advantages of the invention will be readily understood in conjunction with the following detailed description of the invention and the preferred embodiments thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The invention relates to the use of 5-methoxypsoralen for the manufacture of a medicament for preventing and suppressing the symptoms of jet lag. 5-methoxypsoralen has the following formula: 5-methoxypsoralen, or 5-MOP, as it is generally known, may be synthesized in a variety of ways. Methods of synthesizing 5-MOP are disclosed in Nikolaiski, "5-Oxy-Substituted Derivatives of Psoralene Useful In Dermatology," U.S. Patent No. 4,217,445. The 5-methoxypsoralen is administered orally in tablets, capsules or suppositories in the usual excipients which are well known to those skilled in the manufacture of oral or parenteral dosage forms. The 5-methoxypsoralen can also be administered in an appropriate solution, suspension or emulsion. When 5-methoxypsoralen is supplied as tablets, suitable vehicles are employed having a base, for example, of lactose and Encompress®. The tablets may be formulated using conventional procedures employing solid carriers and lubricants well-known in the art. When a person travels at high-speed (i.e, at a speed greater than the rate at which bodily rhythms adjust to a new time schedule) across several time zones, jet lag may be caused as in the following example, which is illustrative only. A subject travelling east from New York, USA to Zurich, Switzerland is transported across six time zones, so that the time of day and the subject's circadian clock are displaced in time by six hours. For example, when the time to retire to sleep arrives in Zurich at, say 11:00 p.m. (2300 hours), it is actually 5:00 p.m. (1700 hours EST) according to the subject's circadian rhythm and the natural diurnal variation in melatonin secretion. The subject is then an appropriate host for administration of a dose of 5-MOP sufficient to raise plasma melatonin levels to such level as will permit the subject to rest for an entire normal sleep period. When the subject awakes in Zurich the following morning, the body will have long since passed its peak melatonin level, as would normally be the case. Without having taken such a dose of 5-MOP, plasma melatonin levels would only recently have reached peak levels by awaking time in Zurich, and the sleep pattern would be disrupted. The situation is seen to be even more pronounced when travelling westward. When the Zurich-based traveller retires to bed in New York at 11:00 p.m., it is already 5:00 a.m. (0500 hours) according the subject's circadian clock, and plasma melatonin levels are at or near the lowest levels of the diurnal cycle. It is thus difficult for the traveller to sleep at all. By midday the next day, the subject becomes increasingly uncomfortable and begins to suffer the aforementioned maladies associated with jet lag. In this case, administration of a jet lag suppressing dose of 5-MOP at bedtime (in New York) permits the subject to extend the sleep period by prolonging the elevated plasma melatonin level. The preferred dosing method is to administer 5-MOP so as to cause registry of the thus-induced peak melatonin level at or near the normal time at which such melatonin level would be at peak if the traveller were accustomed to the local time zone. However, it is possible to vary the times and dosages of administration so that the induced melatonin level will be in registry with the normal melatonin level at some point post-administration. Determination of such dosages and timing may be easily made in accordance with clinical methods well-known to those of ordinary skill without undue experimentation. 5-MOP thus interacts with the body's hormonal system so as to effectively suppress or prevent the symptoms of jet lag. Because 5-MOP is believed to interfere with the hormonal balance, the required dosage of 5-MOP is not expected to be proportional to the host's body weight. Instead, once a minimum effective dosage is met or exceeded, the jet lag symptoms will be suppressed or prevented. Such a minimum effective dosage may be easily established according to well-known techniques and without resort to undue experimentation. Although 40 mg. doses have been found effective, of course, higher dosages of 5-MOP are also expected to be effective, albeit administration of such higher dosages would not be necessary. Preferably, 5-MOP is administered one hour before the time that the subject should go to sleep, said time being determined as described above depending on the direction of travel and the time difference between the origin and destination. 8-methoxypsoralen, a well-known isomer of 5-methoxypsoralen is also anticipated to be effective against jet lag at about the same dose levels as 5-MOP. Similarly, other furocoumarins such as are also anticipated to have the same effect. In particular, angelicin, and its derivatives (e.g., 4-methyl, 5-methyl, 5'-methyl, 4,5'-methyl, 5,5'-dimethyl) are also anticipated to be effective against jet lag in the manner described herein. In that respect, the invention also relates to the use of a member selected from the group consisting of psoralen, xanthotoxin, imperatorin, bergapten, isopimpinellin, trioxsalen, angelicin, methylated derivatives of angelicin, sphondin, isobergapten and pimpinellin for the manufacture of a medicament for preventing and suppressing the symptoms of jet lag. All of these furocoumarins are either commercially available or can be synthesized by methods well-known in the art. Phototoxicity of several furocoumarins, while a drawback, is not expected to affect the present anti-jet lag use because the presently taught administration takes place at night in the absence of sunlight and is not a long-term treatment (unlike psoriasis and other skin conditions). Of course 5-MOP has substantially reduced phototoxicity compared to other furocoumarins. Angelicin and its derivatives are likewise not phototoxic.

Claims: Use of 5-methoxypsoralen for the manufacture of a medicament for preventing and suppressing the symptoms of jet lag. Use according to claim 1, characterized in that the therapeutic amount of 5-methoxypsoralen is between 40 and 300 mg. Use of a member selected from the group consisting of psoralen, xanthotoxin, imperatorin, bergapten, isopimpinellin, trioxsalen, angelicin, methylated derivatives of angelicin, sphondin, isobergapten and pimpinellin for the manufacture of a medicament for preventing and suppressing the symptoms of jet lag.

Inventors: FORLOT PAUL, FORLOT, PAUL
Applicants: GOUPIL JEAN JACQUES, GOUPIL, JEAN-JACQUES
Application year: 1989
Main classification: A61K31
IPC codes: A61K31