WO1990014084A1 - Utilisation de derives de melatonine afin d'effectuer la contraception - Google Patents

Utilisation de derives de melatonine afin d'effectuer la contraception Download PDF

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Publication number
WO1990014084A1
WO1990014084A1 PCT/NL1990/000073 NL9000073W WO9014084A1 WO 1990014084 A1 WO1990014084 A1 WO 1990014084A1 NL 9000073 W NL9000073 W NL 9000073W WO 9014084 A1 WO9014084 A1 WO 9014084A1
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WIPO (PCT)
Prior art keywords
melatonin
analog
progestogen
estrogen
administration
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PCT/NL1990/000073
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English (en)
Inventor
Michael Cohen
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Michael Cohen
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Publication date
Application filed by Michael Cohen filed Critical Michael Cohen
Priority to AU57206/90A priority Critical patent/AU644367B2/en
Priority to BR909007382A priority patent/BR9007382A/pt
Priority to CA002056364A priority patent/CA2056364C/fr
Publication of WO1990014084A1 publication Critical patent/WO1990014084A1/fr
Priority to MW6691A priority patent/MW6691A1/xx
Priority to NO91914468A priority patent/NO914468L/no
Priority to FI915395A priority patent/FI915395A0/fi
Priority to KR1019910701618A priority patent/KR920700637A/ko

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • This invention relates to a method of inhibiting ovulation in human females. More particularly, the invention relates to a method of inhibiting ovulation by administering an ovulation-inhibiting amount of melatonin or an analog of melatonin. Optionally, the melatonin or melatonin analog is administered in combination with a progestational and/or estrogenic agent.
  • oral contraceptives have been developed which are highly effective in preventing contraception, and today more than fifty million women around the world use oral contraceptives.
  • the oral contraceptives take the form of a combination of an estrogen and a progestogen (also known as progestin).
  • progestin also known as progestin
  • combination regimens a consistent dose of an estrogen and a progestogen is administered daily throughout the period of administration.
  • sequential regimens the amount of estrogen or progestogen or both is increased or decreased during the menstrual cycle.
  • Some sequential regimens provide two-stage or bi-phasic control. (See, for example, USP 3,969,502). Others provide a three-stage or tri- phasic combination of components. (See, for example, USP 4,628,051; USP 4,390,531.)
  • a third type of regimen also is known in which one or more progestogens is administered daily throughout the menstrual cycle.
  • the hormones in oral contraceptives act both within the central nervous system and in tissues of the urogenital tract to inhibit reproductive function.
  • the principal sites of action are the hypothalamus and pituitary to prevent the midcycle surge of luetinizing hormone (LH) and hence to prevent ovulation.
  • LH luetinizing hormone
  • FSE follicle-stimulating hormone
  • plasma levels of estradiol and progesterone are suppressed in users of oral contraceptives.
  • these contraceptives work by causing changes in hormone levels that imitate those caused by pregnancy. This effect is dose dependent.
  • These conventional oral contraceptives are administered for a minimum of 21 da. ⁇ B of a woman's cycle, and in some instances for the entire 28-30 days of the cycle.
  • Oral contraceptives also exert a direct effect on the urogenital tract. They alter the structure and physical-chemical composition of the endometriu and the consistency of the cervical mucous, thus altering the uterine capacity for the
  • Oral contraceptives have been shown to provide benefits other than the prevention of pregnancy. Compared to non-users, women who take oral contraceptives have been shown to have a lower risk of pelvic inflammatory disease (PID), ectopic pregnancy, endo etrial cancer, and benign breast disease. Most significantly, the current combination-type contraceptives also are responsible for reducing the incidence of ovarian cancer. Oral contraceptives also can provide relief from common menstrual disorders, including irregular menses, premenstrual tension, excess blood loss and cramps.
  • PID pelvic inflammatory disease
  • Oral contraceptives also can provide relief from common menstrual disorders, including irregular menses, premenstrual tension, excess blood loss and cramps.
  • oral contraceptives containing only one or more progestogens as the active component have been developed. These contraceptives, however, generally have been found to be less effective than those containing both an estrogen and a progestogen.
  • One common side effect suffered by women who take oral contraceptives which contain only progestogen is breakthrough bleeding during the menstrual cycle.
  • a method for effecting contraception in human females of child-bearing age by administering an analog of melatonin in dosages effective to prevent ovulation.
  • the melatonin or melatonin analog is administered in combination with a progestogen and/or an estrogen.
  • the contraceptives of this invention are administered in oral dosage form.
  • the graphs of Figures IA-D show the concentration of various hormones in a woman's blood stream for each day of her menstrual cycle, averaged over 5 cycles.
  • the graphs of Figures IIA-D, IIIA-D and IVA-D show the effects of melatonin administration on the concentration of each of these hormones during each of three menstrual cycles.
  • Melatonin N-acetyl-5-methoxytryptamine
  • the present invention is based on the discovery that pharmacological doses of melatonin administered daily to a female selectively suppresses the normal mid-menstrual cycle surge in leutinizing hormone sufficient to prevent ovulation.
  • the present invention is directed to a method of effecting contraception in human female of child-bearing years by daily administering to the female melatonin in dosages effective to prevent ovulation by suppressing the surge in leutinizing hormone which occurs prior to, and is required for, ovulation.
  • the term melatonin also encompasses melatonin analogs which have an ovulation inhibiting effect when administered to human females. Such melatonin analogs can have the general formula:
  • R x , R 3 and R individually, are hydrogen or an alkyl group having 1 to about 4 carbon atoms
  • R 2 is selected from hydrogen, hydroxy or an alkoxy group having from 1 to about 4 carbon atoms
  • A is either -OH or -NH-C-R 5
  • R 5 is either hydrogen or 0 an alkyl group having from 1 to about 4 carbon atoms, provided that if A is NH-C-R 5 , and R t and R 5 are both
  • R 2 is hydrogen
  • R 3 and R 4 are not hydrogen.
  • Preferred compounds are those in which R 2 is hydrogen or methoxy, with hydrogen being most preferred.
  • Melatonin analogs encompassed within this definition include N-acetyl serotonin, N-acetyl, 5- hydroxy, 6-methoxytryptamine, 6-hydroxy-melatonin, 5- hydroxytryptophol and 5-methoxytryptophol, with N- acetyl serotonin being preferred.
  • the melatonin is administered daily in dosages sufficient to suppress the user's normal surge in leutinizing hormone and thus prevent ovulation. Generally, the melatonin is administered in amounts ranging between about 2 mg and about 1000 mg per day per 70 kilograms body weight of the woman receiving the melatonin. Preferably about 30 mg to about 500 mg melatonin are administered daily.
  • the melatonin can be administered every day throughout a woman's cycle. It has been found, however, that administration of melatonin for only a 1 to about 7 day period in the cycle which immediately precedes the woman's normal day of ovulation is sufficient to achieve a contraceptive effect. Ovulation typically occurs on the fourteenth cycle day or alternatively between about the ninth and seventeenth day of a woman's cycle.
  • This regimen is preferred for administering the melatonin.
  • the type of regimen selected can affect the amount of melatonin administered daily. The amount provided in each daily dosage also can vary with the method of administration selected.
  • the melatonin can be administered to women either orally, parenterally or in the form of an implant. Administration is most convenient when the melatonin is in oral dosage form, such as capsules, tablets, suspensions or solutions. Capsules or tablets are preferred. Capsules can be prepared by mixing the compound with a pharmaceutically-acceptable excipient and then filling gelatin capsules with the mixture in accordance with conventional procedures.
  • the melatonin can be mixed with one or more lubricants, such as ⁇ tearic acid or magnesium ⁇ tearate, flavor ameliorating agents, disintegrating elements, including potato starch and alginic acid, binders, such as gelatin and corn starch, and/or tablet bases including lactose, corn starch and sucrose, and then pressed into tablets.
  • lubricants such as ⁇ tearic acid or magnesium ⁇ tearate
  • disintegrating elements including potato starch and alginic acid
  • binders such as gelatin and corn starch
  • tablet bases including lactose, corn starch and sucrose
  • the melatonin can be administered parenterally or in the form of a solid implant.
  • the melatonin is provided in injectable doses of a solution or suspension of the hormone in a physiologically acceptable diluent with a pharmaceutical carrier.
  • the carrier can comprise water or an oil and optionally also can contain a surfactant or other pharmaceutically acceptable adjuvant.
  • Suitable oils include those of animal, vegetable, petroleum or synthetic origin, including peanut, soybean, corn, sesame, castor and mineral oil.
  • Preferred liquid carriers include water, saline, aqueous sugar solutions, and glycols such as propylene glycol or polyethylene glycol.
  • the melatonin also can be administered in the form of an implant, which is formulated such that it will provide a sustained release of the melatonin over time. To make the implant, the melatonin can be compressed into small cylinders and placed inside a physiologically acceptable shell material such as a biodegradable or porous polymer in accordance with conventional implant technology.
  • the melatonin can be administered in the form of a vaginal suppository or depot, which also will provide for the sustained release of melatonin.
  • the melatonin can be mixed with a conventional suppository or depot base, i.e., a physiologically acceptable material which is meltable at body temperature.
  • the melatonin is administered in combination with a progestogen.
  • the progestogen is added to induce a cyclic bleeding resembling a cyclic menses bleeding and to provide the benefits currently associated with the administration of progestogens in conventional oral contraceptives. Any progestationally active compound is suitable for use as the progestogen component in the present invention.
  • Suitable progestogens include progesterone and derivatives thereof.
  • the presently preferred progestogen is norethindrone (i.e., 19-nor-17 ⁇ -ethynyl-17 ⁇ -hydroxy-4- androsten-3-one) and norgestrel (13 ⁇ -ethyl-17 ⁇ - ethynyl-17 ⁇ -hydroxygon-4-en-3-one) .
  • progestogens include the chlormadinone-acetate (6- chloro-17-hydroxy-pregna-4,6-diene-3,20-dione acetate), norethynodrel (17 ⁇ -ethynyl-17-hydroxy-estr- 5(10)-en), medroxyprogesterone acetate (17 ⁇ -acetoxy- 6 -methyl-pregn-4-ene-3,20-dione) , megestrol acetate (17 -acetoxy-6-methyl-pregna-4,6-diene-3,20-dione) , lynestrenol (17 ⁇ -ethynyl-17fl-hydroxy-estr-4-ene) , quingestrone (3-cyclopentyloxy-pregna-3,5-diene-20- one), norethindrone acetate (17 ⁇ -acetoxy-17 ⁇ -ethnyl- estr-4-en-3-on) , ethynodiol acetate (3 ⁇
  • the progestogen component of these contraceptives generally is administered in the range of about 7.5 ⁇ g to about 2500 ⁇ g per day, preferably in the range of about 7.5 to about 600 ⁇ g per day. Most preferably, the progestogen is administered in the range of about 7.5 ⁇ g to about 250 ⁇ g per day.
  • the actual amount of progestogen provided in each daily dosage will depend upon the particular progestogen chosen, its relative potency, and the method of administration selected. For example, a lesser quantity of a more potent progestogen may achieve the same results as a larger quantity of a less potent progestogen.
  • the amount of progestogen also can vary with the mode of administration, with lower doses typically needed for administration of an implant or intravenous injection than for oral administration.
  • a number of regimens are suitable for administering a combination of melatonin and a progestogen. For example, assuming a 28 day cycle, both the melatonin and progestogen can be administered for about 21 days, followed by administration of the melatonin without the progestogen for about 7 days.
  • the melatonin and progestogen are administered for about 21 days, and then both are withheld for about 7 days.
  • the melatonin and progestogen alternatively can be administered each day continuously throughout the woman's cycle for a total of about 28 days.
  • a combination of melatonin and progestogen is administered for about thirteen days, typically from about day 5 through day 17 of a woman's cycle, then both the melatonin and progestogen are withheld for the remainder of her cycle.
  • a combination of melatonin and progestogen are administered for about 10 or eleven days, during the follicular phase of a woman's cycle, at dosages of about 300 micrograms of progestogen and about 75 mg melatonin. Then, a second combination of melatonin and progestogen are administered for the next ten to eleven days, during the luteal phase of her cycle, for a total of about twenty-one days, at dosages of about 750 micrograms progestogen and about 75 mg. melatonin.
  • a smaller dosage of progestogen is administered during the first half of the woman's cycle because an insufficient amount of estrogen has been formed endogenously (due to slow follicular growth resulting from the melatonin administration) and the administration of relatively high amounts of a progestogen can lead to break-through bleeding.
  • the second half of the cycle there has been a significant level of estrogen production. Break ⁇ through bleeding can occur during this half of the cycle as a result of estrogen production peaking and then withdrawing. Increasing the amount of progestogen in each daily dose administered during this portion of the woman's cycle will prevent this cause of break-through bleeding.
  • the melatonin is administered for about 5-14 days, followed by administration of either a combination of melatonin and progestogen or progestogen alone for about 7-14 days for a combined total of about 24, preferably about 21, days. Neither the melatonin nor the progestogen is administered for the remaining 7 days of the cycle.
  • a seventh regimen comprises administering a placebo for the first 5 days, then administering melatonin for about 3-7 days, followed by administration of the progestogen through the twenty-first day of the medication. Again, neither melatonin nor the progestogen is administered for the remaining 7 days of the cycle.
  • a progestogen is administered for about 21 to about 28 days.
  • Melatonin is administered in combination with the progestogen for about 1-13 days (preferably to about 3-5 days) at mid- cycle (e.g., days 5-17 of the cycle), just prior to the user's normal day of ovulation. If the progestogen is administered for less than the full 28 days of the cycle, no medication is administered for the remaining days.
  • the conventional 21-28 daily dose progestogen-only contraceptives have not been very effective.
  • the addition of melatonin overcomes the inefficacy of administering progestogen alone.
  • the two active components conveniently are combined and administered together, although they also can be administered separately.
  • an estrogen in an alternative embodiment of the present invention, can be added to any of the melatonin or melatonin-progestogen regimens set forth above.
  • the estrogen can be added, if desired, to stabilize the melatonin by preventing any escape ovulation that might possibly occur if the melatonin is administered in the absence of an estrogen.
  • Any conventional estrogen can be employed as a suitable component of the contraceptive compositions of the present invention.
  • the presently preferred estrogens are ethinyl estradiol (i.e.
  • estradiol 3,17 ⁇ -dihydroxy-estra-l,3,5(10-triene) , estradiol(3,-16 ⁇ ,17 ⁇ -trihydroxy-estera-l,3,5(10)- triene, estrone (3,hydroxy-estra-l,3,5(10)-triene-17- one), diethylstilbestrol, quinestradiol (3- cyclopentyloxy-16 ⁇ ,17 ⁇ -dihydroxy-estra-l,3,5-(10)- triene) and estrone sulfate.
  • the estrogen can be administered daily throughout 21 days of the 28 day cycle in any of the regimens set forth above, but preferably it is administered only prior to the normal day of ovulation.
  • the estrogen generally is administered in the range of about 2 ⁇ g to about 100 ⁇ g per day and preferably in the range of about 10 ⁇ g to about 50 ⁇ g per day.
  • the actual amount of estrogen used in a daily dosage will depend upon the particular estrogen selected and its relative potency.
  • Ethinyl estradiol for example, has twice the biological potency as mestranol.
  • the estrogen can be combined with the melatonin and/or progestogen in any of the regimens suggested above.
  • an estrogen is administered at the beginning of a woman's cycle for about 5-13 days, followed by the administration of melatonin for about 1-7 days (preferably for about 3-5 days) prior to her normal day of ovulation, then a progestogen is administered through about the twenty-first day of her medication.
  • melatonin can be administered as a "morning after" pill, either by itself or in combination with an estrogen and or progestogen.
  • the melatonin is administered in daily doses of about 100 mg. to about 10,000 mg., preferably a dose of at least 2000 mg., over a 1-5 day post-coital period.
  • the melatonin is administered in combination with a progestogen and/or an estrogen
  • the progestogen preferably is administered in a daily amount ranging between about 10 mg and 20 mg
  • the estrogen is administered in a daily amount ranging between about 2.5 and 25 mg.
  • the contraceptive compositions of this invention are administered in oral dosage form, preferably in the form of pills or capsules.
  • the pills or capsules can be packaged in any manner suitable for proper delivery and use.
  • they are packaged in the form of a pharmaceutical kit or package in which the daily unit dosage forms are provided or arranged in a contiguous, sequential order which will enable the women taking the pills to take the proper formulation at the appropriate time in her reproductive cycle.
  • Suitable kits or packages include the conventional bubble plastic package containing individual bubbles for either 21 or 28 pills, depending upon the regimen selected, in a sheet of flexible plastic. The bubbles are sealed by a sheet of plastic which can break and release a pill when the bubble is pressed.
  • the first pills in the sequence On the first day of her medication, which is generally the first day after the cessation of bleeding from her last menstrual period the first pills in the sequence, whether it contains the contraceptive or a placebo, is removed from its individual slot and taken. The next pills in the sequence is taken the next day and so on thereafter until the dispenser is empty. A new dispenser is begun on day seven of her next cycle. Appropriate notations or instructions can be placed on the dispensing kit to guide or instruct the user in the proper use of the oral contraceptives.
  • Figures IIA, IIB, IIC and IID show the effects of the melatonin administration during the first cycle (January, 1983).
  • the figures show an anovulatory cycle following the injections.
  • Figures IIIA-IIID show the results of melatonin administration in the second cycle (May, 1983) and Figures IVA-IVD show the results of melatonin administration in the third cycle (November, 1984). These figures also show an anovulatory cycle following melatonin injection.
  • the data show three cycles wherein the administration of melatonin resulted in a suppression of the patient's normal pre-ovulatory surge of LH.
  • the data also illustrates that there was a marginal suppression of FSH and pre-ovulatory estradiol and a significant reduction in progestrone levels.
  • the LH suppression is a sufficient indication that the patient did not ovulate in any of the three months if which melatonin was administered.
  • the concentrations of LH, FSH, progestrone and estradiolin a patient's plasma were measured daily throughout three of the patient's menstrual cycles. The average concentration of each hormone for each day of the cycle was determined. The average concentration of the patient's LH peak was 295 ng/ml and the average of her FSH peak was 410 ng/ml. Her average progestrone level at the peak of the leuteal phase of her cycle was 14.5 ng/ml, and the average concentration of her estradiol peak was 0.6 ng/ml. The patient's peak in LH occurred on the fifteenth day of her cycle.
  • the patient was given an intravenous injection of 500 mg melatonin in a glucose in saline solution on each of days 7 through 12 of her cycle.
  • the concentration of the four hormones in her plasma was measured throughout this cycle as before.
  • the administration of melatonin was found to affect the hormone concentrations as follows: peak PHC LH 110 ng/ml FSH 295 ng/ml estradiol .4 ng/ml progestrone .3 ng/ml
  • a woman having a normal menstrual cycle of 28 days with 3-5 days of moderate menstrual bleeding ( ⁇ 50 ml. blood loss) was given intravenous injections of 350 mg melatonin in a glucose in saline solution for seven consecutive days, beginning on day 8 of her cycle.
  • On days 14-28 of her cycle she was administered orally 0.75 mg norethindrone per day.
  • the concentration of LH, FSH, progestrone and estradiol in her blood was measured daily throughout her cycle. She did not ovulate during this cycle (peak PHC LH was 115 ng/ml). She had a minimal menstrual blood loss ( ⁇ 15 ml).
  • melatonin In an ongoing study, four women are taking melatonin in gelatin capsules. The melatonin is being administered in daily doses ranging from 30 mg. to 1000 mg. A preliminary evaluation indicates a satisfactory uptake of the melatonin from the gastrointestinal tract without negative side effects (such as diarrhea or nausea).
  • Example VI A woman having a normal menstrual cycle of 30 days (12th day ovulator) is given oral doses of a combination of 200 mg N-acetyl serotonin (5-hydroxy-N- acetyltryptamine) and 7.5 ⁇ g norethisterone on each of days 7-30 of her cycle. The dosage is found to effectively block ovulation, as evidenced by measuring the concentration of LH and FSH in her blood on each day of her cycle.
  • N-acetyl serotonin 5-hydroxy-N- acetyltryptamine

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Abstract

Un procédé servant à la contraception chez la femme comporte l'administration d'une quantité de mélatomine, ou d'un analogue de mélatonine, inhibitrice de l'ovulation. La mélatonine, ou l'analogue de mélatonine, peut éventuellement être administrée en association avec un progestatif et/ou un ÷strogène.
PCT/NL1990/000073 1989-05-17 1990-05-17 Utilisation de derives de melatonine afin d'effectuer la contraception WO1990014084A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU57206/90A AU644367B2 (en) 1989-05-17 1990-05-17 Use of melatonin derivatives for effecting contraception
BR909007382A BR9007382A (pt) 1989-05-17 1990-05-17 Composicoes e metodos de efetuar a contracepcao
CA002056364A CA2056364C (fr) 1989-05-17 1990-05-17 Compositions et methodes pour la contraception
MW6691A MW6691A1 (en) 1989-05-17 1991-11-13 Composition and methods of effecting contraception
NO91914468A NO914468L (no) 1989-05-17 1991-11-14 Anvendelse av melatoninderivater for prevensjon
FI915395A FI915395A0 (fi) 1989-05-17 1991-11-15 Anvaendningen av melatoninderivat foer att foerhindra befruktning.
KR1019910701618A KR920700637A (ko) 1989-05-17 1991-11-16 피임을 위한 멜라토닌 유도체의 용도

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US35301989A 1989-05-17 1989-05-17
US353,019 1989-05-17

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WO1990014084A1 true WO1990014084A1 (fr) 1990-11-29

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EP (1) EP0472628A1 (fr)
JP (1) JPH05500207A (fr)
KR (1) KR920700637A (fr)
CN (1) CN1047974A (fr)
CA (1) CA2056364C (fr)
DD (1) DD300071A5 (fr)
EG (1) EG19554A (fr)
FI (1) FI915395A0 (fr)
HU (2) HUT60134A (fr)
MW (1) MW6691A1 (fr)
NZ (1) NZ233697A (fr)
OA (1) OA09562A (fr)
PT (1) PT94074A (fr)
WO (1) WO1990014084A1 (fr)
ZA (1) ZA903811B (fr)

Cited By (2)

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Publication number Priority date Publication date Assignee Title
US5508039A (en) * 1991-10-18 1996-04-16 Alza Corporation Controlled transdermal administration of melatonin
WO2003068741A1 (fr) * 2002-02-13 2003-08-21 Meiji Dairies Corporation Derives d'indole substitues avec des alcools a longue chaine et medicaments contenant ceux-ci

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JP4745491B2 (ja) * 2000-10-11 2011-08-10 株式会社明治 インドール長鎖アルコール及びこれを含有する医薬
CN111849934B (zh) * 2019-04-26 2022-06-03 西南大学 粤桑大十n-乙酰-5羟色胺氧甲基转移酶及其应用

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US4614807A (en) * 1984-10-04 1986-09-30 Eli Lilly And Company 6,7-dihalomelatonins
EP0281242A1 (fr) * 1987-02-02 1988-09-07 Eli Lilly And Company Bêta-alkylmélatonines
WO1988007370A1 (fr) * 1987-03-23 1988-10-06 Applied Medical Research, Ltd. Compositions et procede de contraception et de prevention du cancer de la poitrine

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US4614807A (en) * 1984-10-04 1986-09-30 Eli Lilly And Company 6,7-dihalomelatonins
EP0281242A1 (fr) * 1987-02-02 1988-09-07 Eli Lilly And Company Bêta-alkylmélatonines
WO1988007370A1 (fr) * 1987-03-23 1988-10-06 Applied Medical Research, Ltd. Compositions et procede de contraception et de prevention du cancer de la poitrine

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British Journal of Hospital Medicine, Vol. 25, No. 3, March 1981, (London, GB), P.E. MULLEN et al.: "The Endocrinology of the Human Pineal", pages 248, 253-256, see page 254, paragraph: "The Pineal and Reproduction *
British Journal of Hospital Medicine, Vol. 25, No. 3, March 1981, (London, GB), R.J. REITER et al.: "The Pineal Gland: Another Perspective", page 741, see column 1 *
J. Clin. Endocrinol. & Metab., Vol. 42, No. 1, 1976, (Philadelphia, Us), L. WETTERBERG et al.: "Human Serum Melatonin Changes during the Menstrual Cycle", pages 185-188, see page 187: "Discussion" *
J. Gynaecol. Endocrinol., Vol. 2, Nos. 1-2, 1986, (Padova, IT), A TURI et al.: "Circadian Rhythm of Serum Melatonin and Menstrual Cycle: pages 31-34 see Abstract; figure 2; "Discussion" *
Journal of Clinical Endocrinology and Metabolism, Vol. 63, No. 2, 1986, The Endocrine Society, (Philadelphia, US), G.E. WEBLEY et al.: "The Circadian Pattern of Melatonin and its Positive Relationship with Progesterone in Women", pages 323-328, see the whole article *
Journal of Medicinal Chemistry, Vol. 22, No. 1, 1979, American Chemical Society, (Washington, US), M.E. FLAUGH et al.: "Synthesis and Evaluation of the Antiovulatory Activity of a Variety of Melatonin Analogues", pages 63-69, see the whole article, especially table 1 *
Psychoneuroendocrinology, Vol. 5, No. 2, 1980, Pergamon Press Ltd. (Oxford, GB), W.B. CUTLER et al.: "The Psychoneuroendocrinology of the Ovulatory Cycle of Woman: A Review", pages 89-111, see page 98, paragraph 1.4.4 *
The Lancet, Vol. 1, No. 7909, 29 March 1975, (London, GB), R.J. REITER et al.: "The Pineal Gland: Another Perspective", page 741, see column 1 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5508039A (en) * 1991-10-18 1996-04-16 Alza Corporation Controlled transdermal administration of melatonin
WO2003068741A1 (fr) * 2002-02-13 2003-08-21 Meiji Dairies Corporation Derives d'indole substitues avec des alcools a longue chaine et medicaments contenant ceux-ci
US7407983B2 (en) 2002-02-13 2008-08-05 Meiji Dairies Corporation Indole derivatives substituted with long-chain alcohols and medicaments containing them
US7902249B2 (en) 2002-02-13 2011-03-08 Meiji Dairies Corporation Indole derivatives substituted with long-chain alcohols and medicaments containing them

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DD300071A5 (de) 1992-05-21
EG19554A (en) 1995-06-29
FI915395A0 (fi) 1991-11-15
MW6691A1 (en) 1993-07-14
CN1047974A (zh) 1990-12-26
EP0472628A1 (fr) 1992-03-04
PT94074A (pt) 1991-01-08
OA09562A (en) 1993-01-31
CA2056364C (fr) 2002-08-20
HUT60134A (en) 1992-08-28
HU905255D0 (en) 1992-01-28
NZ233697A (en) 1996-12-20
KR920700637A (ko) 1992-08-10
HU210342A9 (en) 1995-03-28
ZA903811B (en) 1991-03-27
CA2056364A1 (fr) 1990-11-18

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