CN1047974A - Compositions and methods for effecting contraception - Google Patents
Compositions and methods for effecting contraception Download PDFInfo
- Publication number
- CN1047974A CN1047974A CN90103090A CN90103090A CN1047974A CN 1047974 A CN1047974 A CN 1047974A CN 90103090 A CN90103090 A CN 90103090A CN 90103090 A CN90103090 A CN 90103090A CN 1047974 A CN1047974 A CN 1047974A
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- Prior art keywords
- melatonin
- analog
- progestogen
- compositions
- day
- Prior art date
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- Pending
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- 239000000203 mixture Substances 0.000 title claims description 18
- 238000000034 method Methods 0.000 title abstract description 30
- 229960003987 melatonin Drugs 0.000 claims abstract description 97
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- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 claims abstract description 96
- 239000000583 progesterone congener Substances 0.000 claims abstract description 59
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- 239000000262 estrogen Substances 0.000 claims abstract description 27
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- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 claims description 4
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Images
Classifications
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A method of effecting contraception in a female comprising administering an egg suppressing amount of melatonin or a melatonin analog to a row. The melatonin or melatonin analog is administered with a progestin and/or an estrogen, as desired.
Description
The present invention relates to a kind of method that suppresses women's volleyball's ovum.Specifically, the present invention relates to a kind of method that suppresses to ovulate by the analog of using the ovulation melatonin (N-acetyl group-5-methoxytryptamine) of amount of suppression or a kind of melatonin.With the need, the analog of this melatonin or melatonin also can with a kind of progestogen and/or a kind of estrogen combined administration.
Research and development in the human contraception field is placed on the aspect that physics and chemical obstacle are set in the transfer to sperm always, for example, vaginal foam, barrier film, intrauterine utensil, and condom, and be placed on the oral contraceptive aspect that contains one or more steroid hormones.Oral contraceptive is developed, and it plays good effect to contraception, has more than 5,000 ten thousand women using oral contraceptive at present in the world.In general, oral contraceptive is a mode of taking estrogen and progestogen (being also referred to as progesterone) and usefulness.In the part of these instructions about how to take medicine, be called and use instructions about how to take medicine, take consistent all the time a kind of estrogen and a kind of progestogen every day in medicining cycle.In other taking method, be called the order instructions about how to take medicine, the dosage of estrogen or progestogen or both dosage increase or reduce at intermenstrual period.Some order taking method provides two stages or two phases controls (referring to United States Patent (USP) 3969502).Some other taking method provides the combination (referring to for example United States Patent (USP) 4628051, United States Patent (USP) 4390531) of three stages of component or three phases, the third taking method of also knowing be in menstrual cycle every day only take one or more progestogen.
Hormone in the oral contraceptive is both in the central nervous system, also work in the tissue of urogenital tract, to suppress reproductive function.The main position of effect is hypothalamus and hypophysis, preventing lutropin (LH) at the surge in mid-term in cycle, and therefore stops ovulation.The basic concentration of lutropin (LH) and follicle stimulating hormone (FSH) and the plasma content of estrogen and progestogen are suppressed by the user of oral contraceptive.In essence, those are worked by the change of hormone contents that pregnancy causes these contraceptives by causing simulation.This effect is to depend on what of dosage, and these common oral contraceptives be to minimum will taking 21 days of women's cycle, and will take whole 28 days to 30 days of one-period in some cases.
Oral contraceptive also produces a directly effect to urogenital tract.They change structure and the physical and chemical composition and the mucous denseness of neck in uterus, thereby change the ability that implant ovum in the uterus.
Oral contraceptive has shown other benefit of taking out of except that stoping pregnancy.Compare with user not, demonstrated the danger that the women who takes oral contraceptive has lower trouble pelvic inflammation (PID), dystopy pregnancy, uterus carcinoma and benign breast disease.The most important thing is effect present and also have minimizing ovarian cancer incidence rate with the type contraceptive.Oral contraceptive also can alleviate common menoxenia, comprises menoxenia, premenstrual tension, severe loss of blood and cramp.
Yet, use common oral contraceptive also to be accompanied by some danger.These danger comprise and may suffer from venous thromboembolism, cardiac ischemia disease, cerebrovascular disease and hypertension greatlyyer, and this is considered to mainly is because the estrogenic component (typically, ethinyl estradiol or norquen mestranol) in the contraceptive causes.Have been found that the danger of suffering from any of these disease, be substantially limited in the women that the age surpasses 35 years old, particularly surpass 35 years old smoking women.Take estrogenic women and also can stand other disadvantageous side effect, comprise gastrointestinal dysfunction, feel sick and weight increase.
In the effort of doing for the contraception adverse side effect relevant or possible side effect, develop and only to comprise the oral contraceptive of one or more progestogen as active component with containing the estrogen oral contraceptive.But, find that these contraceptives are generally effective not as those contraceptives that comprise a kind of estrogen and a kind of progestogen.Take a kind of common side effect that the women stood that only comprises the progestogen contraceptive and be break-through bleeding at intermenstrual period.
In view of the shortcoming and the adverse side effect of common oral contraceptive, need seek new contraceptive.Therefore, one object of the present invention just provides a kind of very effective that can bring benefit to user and avoided the contraceptive device of the adverse effect relevant with the contraceptive of current use.
According to the present invention, disclose a kind of by using effective dose melatonin or the analog of melatonin stop ovulation to realize the method for childbearing age woman contraceptive.With the need, the analog of this melatonin or melatonin can be used with a kind of progestogen and/or a kind of estrogen.In a preferred embodiment, contraceptive of the present invention adopts peroral dosage form to use.
Curve display among Figure 1A-D in women's menstrual cycle various concentration of hormone (meansigma methodss in 5 cycles) in every day her blood.
Fig. 2 A-D, the curve display among Fig. 3 A-D and Fig. 4 A-D melatonin to each the influence of concentration in these hormones in each cycle in three menstrual cycle.
Melatonin (N-acetyl group-5-methoxytryptamine) be a kind of by pineal gland (Pineal gland) synthetic and excretory hormone.The definite effect of this hormone also is not determined.Research shows, gives Syria's golden hamster injection melatonin with certain number of times in one day, and its gonad development, male testicular weight and female ovulation are had inhibitory action.The female rats of injecting certain number of times melatonin in one day has also shown the inhibitory action to ovulation.Therefore, melatonin has demonstrated and has had one of various rodent gonads basic inhibitory action.Yet, do not demonstrate a similar effects on one's body other mammal of having injected melatonin.Specifically, use melatonin (Kenneway to sheep, D.J. wait the people, J.Reproductive Fertility 73:859[1985]) and give primate (Reppert, S.M. wait the people, Endocrin 104:295[1979]) use melatonin their physiology of reproduction not to be caused direct variation.Using exogenous melatonin to the people is accompanied by the hypothesis that endogenous suppresses with the unusual melatonin rhythm and pace of moving things and studies, and for pharmacokinetics purpose (Waldhauser, F., Neuroendocrinology 39:307,313[1984]) and the rhythm and pace of moving things of waking up of the sleeping circadian rhythm breakoff phenomenon aspect relevant with the time zone variation with the back that travels by air study.
The present invention is based on and finds that melatonin that a women uses certain drug dose every day can suppress the surge of the lutropin in common menstrual cycle mid-term selectively, is enough to stop ovulation.The present invention relates to a kind ofly suppress the surge (it occur in before the ovulation and be essential to ovulation) of lutropin, to realize the method for childbearing age woman contraceptive by the melatonin of using effective prevention ovulation amount every day for the women.
Used term melatonin also comprises the analog that has the melatonin of promoting suppressioning effect when using to the women in we.The analog of this melatonin can have following general structural formula:
R wherein
1, R
3And R
4Be respectively hydrogen or a alkyl group with 1 to 4 carbon atom, R
2Be selected from hydrogen, hydroxyl or a alkoxy base with 1 to 4 carbon atom, and A or-OH, or
, R wherein
5Or hydrogen or a alkyl group with 1 to 4 carbon atom, if but A be
, R
1, R
5All be methyl, and R
2Be hydrogen, R then
3And R
4Not hydrogen.Preferred chemical compound is those R
2Be the chemical compound of hydrogen or methoxyl group, preferably R
2It is the chemical compound of hydrogen.The melatonin analog that is included in this definition comprises N-acetyl group five hydroxytryptamine, N-acetyl group, 5-hydroxyl, 6-methoxytryptamine, and 6-hydroxyl-melatonin, 5-hydroxyl tryptophol and 5-methoxyl group tryptophol, best with N-acetyl group five hydroxytryptamine.
This melatonin is with the normal surge that is enough to suppress the user lutropin and therefore stop the dosage of ovulation to be used by every day.Generally, the scope of this melatonin dose every day is about 2 milligrams to about 1000 milligrams of the women of per 70 kg body weight.Preferably use about 30 milligrams to about 500 milligrams every day.
This melatonin can be used a women every day in the cycle.But, have been found that the women and just in the time about 1 day to 7 days before the normal ovulation of women, take the effect that melatonin just is enough to reach contraception in the cycle.Ovulation occurs in the 14th day of the cycle or in typical case between about the 9th day to the 17th day of women's cycle.This taking method is the best taking method of melatonin.The taking method of selected this form can influence the amount of the melatonin that uses every day, every day dosage what also change with selected application method.
Use melatonin both can to use or use by oral, non-intestinal to the women in the implant mode.When melatonin adopt peroral dosage form, during as capsule, tablet, suspension or solution, medication is a most convenient.Capsule or tablet are preferred dosage forms.Capsule can be by earlier with medicine and a kind of pharmaceutically acceptable mixed with excipients, then mixture is filled in the capsule by common step and prepares.Perhaps, this melatonin can with one or more lubricants, as stearic acid or magnesium stearate, flavoring agent, disintegrating agent, comprise potato starch and alginic acid, binding agent such as gelatin and corn starch, and/or the tablet substrate comprises that lactose, corn starch and sucrose mix mutually, are pressed into tablet then.
As oral a kind of replacement, melatonin can be used in non-intestinal mode or in the solid implant mode.Use for non-intestinal, melatonin is formed in the solution of this hormone in the physiologically acceptable diluent with a kind of pharmaceutical carrier or the injection of suspension.Carrier can comprise water or a kind of oil, and also can comprise a kind of surfactant or other pharmaceutically acceptable adjuvant with the need.Suitable oil comprises animal oil, vegetable oil, oil or artificial oil, comprises Oleum Arachidis hypogaeae semen, soybean oil, Semen Maydis oil, Oleum sesami, Oleum Ricini and mineral oil.Preferred liquid-carrier comprises water, saline solution, sugar aqueous solution and ethylene glycol such as propylene glycol or Polyethylene Glycol.
Melatonin also can be used with the form of implant, and the release that provides melatonin to hold in certain operating period to continue is provided this implant.In order to prepare this implant, melatonin can be compressed into some little cylinders, and is placed in the pharmaceutically acceptable shell material (for example a kind of can biological fall or porous polymer) by common implant technology.Similarly, melatonin can be used with a kind of vaginal suppository or storage source form, and limit kind form also will provide the lasting release of melatonin.Melatonin can with the substrate of a kind of common turunda or storage source, be a kind of pharmaceutically acceptable under body temperature liquefiable material mix mutually.
In a preferred embodiment of the invention, melatonin is used with a kind of progestogen.The adding of this progestogen be for bring out one to the periodically similar cyclic hemorrhage of menstrual bleeding, and provide with use common oral contraceptive in the relevant benefit of progestogen.Any progestogenic activity chemical compound all is applicable to as the progestogen composition among the present invention.Suitable progestogen comprise progesterone and derivant thereof.The preferred progestogen of the present invention are norethindrone (being that 19-falls-172-acetenyl-17 beta-hydroxies-4-androstene-3-ketone) and norgestrel (13 β-ethyl-17 α-acetenyl-17 beta-hydroxy steroid-4-alkene-3-ketone).Other progestogen comprise chlormadinone-acetas (6-chloro-17-hydroxyl-pregnant steroid-4,6-diene-3,20-diketone-acetas), Norethynodrel (17 α-acetenyl-17-hydroxyl-female-5(10)-alkene), medroxyprogesterone (17 α-acetate-6 Alpha-Methyl-pregnant steroid-4-alkene-3, the 20-diketone), megestrol acetas (17 α-acetate-6-methyl-pregnant steroid-4,6-diene-3, the 20-diketone), lynestrenol (17 α-acetenyl-17 beta-hydroxy-female-4-alkene), quingestrone (3-cyclopentyloxy-pregnant steroid-3,5-diene-20-ketone), norethisterone acetate (17 β-acetate-17 α-acetenyl-female-4-alkene-3-ketone), etynodiol acetas (3 β, 17 β-diacetoxyl-17 α-acetenyl-female-4-alkene), dimethisterone [17 beta-hydroxies-6 Alpha-Methyls-17(-1-propinyl)-androstane-4-alkene-3-ketone], desogestrel and levonorgestrel.
The scope of using of progestogen composition every day of these contraceptives normally in about 7.5 micrograms to about 2500 micrograms, preferably every day, about 7.5 micrograms were to the scope of about 600 micrograms.Best, the amount of application of progestogen every days in about 7.5 micrograms in about 250 microgram scopes.The actual amount of progestogen depends on selected concrete progestogen in every day dosage, and it is renderd a service and selected administering mode accordingly.For example, a kind of more virtuous progestogen less amount just can reach identical effect with an a kind of low bigger amount rendeing a service progestogen.As noted above, the amount of progestogen can change with administering mode, and for implant or intravenous administering mode, generally the dosage that needs comes to such an extent that lack than oral administration.
Many kinds of taking methods are suitable for melatonin and progestogen combination medicine-feeding.For example, suppose a cycle of 28 days, the two can use melatonin and progestogen about 21 days, after this, can only use melatonin and without about 7 days of progestogen.In second kind of taking method, melatonin and progestogen can be used about 21 days, and the two all can be about 7 days then.If desired, melatonin and progestogen are selected as another kind, also can use continuously whole about 28 days of women's cycle.
In the taking method of the 4th kind of recommendation, about 13 days of melatonin and progesterone composition administration, typically from about the 5th day to the 17th day of women's cycle, then women's cycle At All Other Times in melatonin and progestogen all be stopped and use.
In another alternative taking method, melatonin and progestogen can be with the dosage combined administrations of the progestogen of about 300 micrograms and about 75 milligrams melatonin about 10 days or 11 days in follicle stage in women's cycle, then, the hybrid medicine of melatonin and progestogen can be used next 10 days to 11 days (take medicine altogether thing 21 days) at the corpus luteum in her cycle with second kind of compound mode of about 750 microgram progestogen and about 75 milligrams of melatonin doses in the stage.In this taking method, use the progestogen of a less dosage in time at the first half in women's cycle, because an estrogen in shortage forms (because the use of melatonin causes ovarian follicular growth to slow down) by endogenous approach, and uses the progestogen of higher amount can cause break-through bleeding.Yet, during to the latter half in cycle, the estrogen production of a great deal of has been arranged, as the result that estrogen production peaks and descends then, break-through bleeding can occur in during this latter half in cycle.The amount that increases the progestogen in used dosage every day during this part of women's cycle can prevent this cause of break-through bleeding.
In another kind of taking method, took melatonin about 5 to 14 days, then or be used in combination melatonin and progestogen, perhaps used progestogen separately 7 to 14 days, the two 24 days altogether, preferably about 21 days.Melatonin and progestogen did not all use in remaining 7 days of cycle.The 7th kind of taking method is included in and 5 days uses a kind of placebo, uses melatonin then about 3 to 7 days, then uses progestogen to the 21st day of the course of treatment.Similarly, neither use melatonin also not use progestogen in the residue in cycle 7 days.
In another kind of taking method, a kind of progestogen use and arrived to 28 days in about 21 days.Just (for example at the cycle interlude of user before common ovulation day, the 5th day to the 17th day of cycle) melatonin and progestogen are used about 1 to 13 day (best 3 to 5 days) together, if the use of progestogen is less than whole 28 days of cycle, in remaining those days, do not use any medicine.As what point out above, the contraceptive that only contains progestogen of 21 to 28 days common dosage is not effectively always, adds melatonin and has overcome the curative effect deficiency of only using progestogen.
In the taking method of any recommendation set forth above, in those days that melatonin and progestogen all are applied, these two kinds of active component can be easily in conjunction with and administration together, although they also can be used respectively.
Replace in the embodiment at one of the present invention, increase a spot of estrogen in the above in any melatonin that can propose or the melatonin one progestogen taking method.If desired, can add estrogen and stablize melatonin by the ovulation that prevents any leakage and take off, the ovulation that this leakage is taken off might take place when using melatonin under not having estrogenic situation.Any common estrogen can be as an appropriate ingredients of contraceptive of the present invention.The preferred estrogen of the present invention is ethinyl estradiol (i.e. 17 α-acetenyl-3,17 beta-dihydroxies-female steroid-1,3,5(10) triolefin) and norquen mestranol (17 α-acetenyl-17 beta-hydroxies-3-methoxyl group-female steroid-1,3,5-(10) triolefin).Other suitable estrogen comprises estradiol (3,17 beta-dihydroxies-female steroid-1,3,5(10)-and triolefin), estriol (3 ,-16 α, 17 β-trihydroxy-female steroid-1,3,5(10)-triolefin), estrone (3, hydroxyl-female steroid-1,3,5(10)-and triolefin-17-ketone), diethylstilbestrol/Kui estradiol (3-cyclopentyloxy-16 α, 17 beta-dihydroxies-female steroid-1,3,5(10)-triolefin) and the sulphuric acid estrone.In above-mentioned any taking method, estrogen can use in 21 days of 28 day cycle every day, but preferably only uses before normal ovulation day.General every day used about 2 micrograms to about 100 micrograms by estrogen, and preferably uses about 10 micrograms every day to about 50 micrograms.As progestogen, the estrogenic actual amount that uses in the dosage every day will depend on selected specific estrogen and its corresponding effectiveness.For example, ethinyl estradiol has the biopotency of norquen mestranol twice.Because estrogenic harmful side effect wishes only to use a spot of estrogen that melatonin needs that is used for stablizing.In any taking method of above-mentioned recommendation, estrogen can use with melatonin and/or progestogen.In the selectable taking method of another kind, estrogen was taken when the beginning in women's cycle about 5 to 13 days, before her normal ovulation, take melatonin then about 1 to 7 day (preferably about 3 to 5 days), in her courses of pharmaceuticals, used a kind of progestogen to the 21 days then.
In another embodiment of the invention, melatonin can be used as the tablet of taking after meal a kind of morning and uses, both can be separately, also can use with a kind of estrogen and/or progestogen.In this embodiment, in time of 1 to 5 day after the sexual intercourse, melatonin to be using to about 10000 milligrams dosage about 100 milligrams of every day, what a at least 2000 milligrams dosage.If melatonin uses with a kind of progestogen and/or a kind of estrogen, this progestogen preferably use with the amount ranges between 10 milligrams to 20 milligrams every day, and the use amount scope of this estrogen every day is between 2.5 to 25 milligrams.
In this preferred embodiment of the present invention, composition for contraception of the present invention is with peroral dosage form, preferably with tablet or capsular form administration.Tablet or capsule can be packaged in any mode that is suitable for suitably transportation and uses.Preferably they are packaged into the form of medicine box or medicated bag, in this medicine box or medicated bag, provide the dosage unit of every day or be configured to a kind of adjacent sequence arrangement form, make the women who takes tablet under her appropriate time of reproductive cycle, take in proper formula.Suitable medicine box or medicated bag are included in the common blistered plastics package on the flexible plastic paper, and it contains the bubble chamber one by one of 21 or 28 tablets medicines according to selected usage.These bubble chambers are sealed by one deck plastic paper, and when the extruding bubble chamber, plastic paper breaks and discharges a tablet.First day of her medication, this normally her the last menstrual cycle stop posthemorrhagic first day, the primary tablet in this order (no matter containing contraceptive or placebo) is extruded and is taken from its single bubble groove.Tablet next time in this order was taken at second day and by that analogy, up to this medicated bag sky till.New medicine box is brought into use when her the 7th day of next cycle.Suitable sign and indication can be placed on the medicine box to instruct or to indicate user to use this oral contraceptive rightly.
The present invention will be by following example further instruction and elaboration, and these examples just give information on the situation, and are not limitation of the present invention.
Example 1
The contraception effectiveness of melatonin is born in 21 days the patient who is abbreviated as S.B here of nineteen fifty JIUYUE at one and is studied on one's body.Figure I A, I B, I C and I D have shown the lutropin (LH) in her cycle every day of the blood, follicle stimulating hormone (FSH), the concentration of progesterone and estradiol (meansigma methodss in 5 cycles of continuing) respectively.Just as seen in these figures, this patient has the preovulatory surge of a normal lutropin and the peak value of follicle stimulating hormone, then is the rising of a progesterone after the ovulation.In these figure, symbol PHC represents blood plasma hormone concentration.
For each cycle in three cycles of patient, gave the 300mg melatonin of her intravenous injection glucose saline in continuous 6 days from her beginning in the 9th day in cycle.Figure II A, II B, II C and II D have shown the administering effect of (January nineteen eighty-three) melatonin in first cycle.These figure have demonstrated an anovulatory cycle after the injection.Figure III A, III B, III C, III D have shown the administering effect of (May nineteen eighty-three) melatonin in second period, and figure IV A-IV D has shown the administering effect of (in November, 1984) melatonin in the 3rd cycle.These have also shown an anovulatory cycle of injection melatonin.
These data show take the surge that melatonin causes the normal preovulatory lutropin of patient in three cycles and be suppressed.These data have shown that also the limit of follicle stimulating hormone (FSH) and the preceding estradiol of ovulation suppresses and the obvious minimizing of progesterone content.The inhibition of lutropin is the anovular important symbol of any given day patient in three months of use melatonin.
Example 2
The plasma concentration of a patient's lutropin (LH), follicle stimulating hormone (FSH), progesterone and estradiol is measured in every day of three menstrual cycle of patient.Determine the mean concentration of each hormone of every day in the cycle.The mean concentration of patient's lutropin peak value is the 295ng/ milliliter, and the mean concentration of her follicle stimulating hormone peak value is the 410ng/ milliliter.The average progesterone content of the corpus luteum stage in she during peak value is the 14.5ng/ milliliter in cycle, and the mean concentration of her estradiol peak value is the 0.6ng/ milliliter.The peak value of patient's lutropin occurs in the 15th day of she in cycle.
Give the 500 milligram melatonins of her intravenous injection in glucose saline every day of the 7th day to the 12nd day in cycle of patient, as in the previous, measures the plasma concentration of her four hormones from start to finish in her cycle.Melatonin is taken in discovery, and to influence hormone concentration as follows:
The blood plasma hormone peak concentration:
Lutropin (LH) 110ng/ml
Follicle stimulating hormone (FSH) 295ng/ml
Estradiol 0.4ng/ml
Progesterone 0.3ng/ml
This patient of these data representations is not ovulation in this one-period, and research shows that the lutropin peak concentration is at least 250ng/ml and just may ovulates.
Example 3
One have 28 days common menstrual cycle and have 3 to 5 days appropriate menstrual bleeding (losing blood about 50 milliliters) the women, gave the 350 milligram melatonins of her intravenous injection glucose saline in continuous 7 days from her beginning in the 8th day of cycle.In her the 14th day to the 28th day of cycle, every day oral 0.75 milligram of norethindrone.The concentration of measuring lutropin, follicle stimulating hormone, progesterone and estradiol in her blood every day in her cycle.In this one-period she do not ovulate (peak value of lutropin plasma concentration is 115ng/ml).She has a minimum menstrual blood loss (about 15 milliliters).
Example 4
Women with 30 days normal menstrual cycles (ovulation in the 12nd day) gives the 200 milligram melatonins of her intravenous injection in dextrose in saline solution in the 7th to the 10th day the every day in her cycle.She does not ovulate in her cycle, although find that the lutropin content in her blood is not suppressed equably, but is fluctuating between 50ng/ml and 180ng/ml during her cycle quite brokenly.In this cycle, the plasma concentration of her follicle stimulating hormone is normal to her, and how many her progesterone plasma concentration has been suppressed a bit, and her estradiol plasma concentration all is normal in the whole cycle.
Example 5
In an ongoing research, four women take the melatonin capsule.The dosage range of melatonin use every day is 30 milligrams to 1000 milligrams.Preliminary assessment has shown that melatonin is absorbed satisfactorily by the intestines and stomach and do not have a disadvantageous side effect (for example diarrhoea or feel sick).
Example 6
Women with 30 days normal menstrual cycles (ovulation in the 12nd day), the 7th day to the 30th day the every day in she in cycle oral a kind of 200 milligrams N-acetyl-5-hydroxytryptamine (5-hydroxy-n-acetyl group tryptamines) with the oral agents of the norethindrone combination of 7.5 micrograms.By finding that in her lutropin and the follicle stimulating hormone concentration of measurement every day in her blood in cycle this dosage has stoped ovulation effectively.
When 5-hydroxyl tryptophol, 5-methoxyl group tryptophol, when 6-hydroxyl melatonin and N-acetyl group, 5-hydroxyl, 6-methoxytryptamine use with norethindrone and according to dosage level that proposes above and periodicity timetable respectively, can obtain similar result.
Claims (11)
1, a kind of compositions that realizes childbearing age woman contraceptive comprises a kind of to ovulate effective contraception combination of the analog of inhibited melatonin and a kind of progestogen of women.
2, a kind of compositions that realizes childbearing age woman contraceptive comprises a kind of analog and a kind of estrogenic effective contraception combination that women's ovulation is had inhibiting melatonin.
3, a kind of compositions that realizes childbearing age woman contraceptive comprises a kind of analog and a kind of progestogen and a kind of estrogenic effective contraception combination that the women is had the inhibiting melatonin of ovulation.
4, a kind of as claim 1 or 3 described compositionss, it is characterized in that these progestogen are selected from norethindrone, norgestrel, chlormadinone acetate, Norethynodrel, medroxyprogesterone, megestrol crystal aerugo, lynestrenol, quingestrone, norethisterone acetate, etynodiol acetas, levonorgestrel, desogestrel and dimethisterone.
5, a kind of as claim 2 or 3 described compositionss, it is characterized in that this estrogen is to be selected from ethinyl estradiol, norquen mestranol, estradiol, estrone, estriol, diethylstilbestrol, Kui estradiol and sulphuric acid estrone.
6, a kind of as the described compositions of claim 1,2 and 3, it is characterized in that the analog of melatonin has following general structural formula l:
R wherein
1, R
3And R
4Be respectively hydrogen or a groups with 1 to 4 carbon atom, R
2Be hydrogen, hydroxyl or a alkoxy grp with 1 to 4 carbon, A be from hydroxyl or
7, a kind of compositions as claimed in claim 6, the analog that it is characterized in that this melatonin is N-acetyl group-five hydroxytryptamine.
8, a kind of compositions as claimed in claim 6, the analog that it is characterized in that this melatonin are 5-hydroxyl tryptophols.
9, a kind of compositions as claimed in claim 6, the analog that it is characterized in that this melatonin are 5-methoxyl group tryptophols.
10, a kind ofly require 6 described compositionss as claim, the analog that it is characterized in that this melatonin is a 6-hydroxyl melatonin.
11, a kind of compositions as claimed in claim 6, the analog that it is characterized in that this melatonin are N-acetyl group, 5-hydroxyl, 6-methoxytryptamine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35301989A | 1989-05-17 | 1989-05-17 | |
| US353,019 | 1989-05-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1047974A true CN1047974A (en) | 1990-12-26 |
Family
ID=23387406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN90103090A Pending CN1047974A (en) | 1989-05-17 | 1990-05-17 | Compositions and methods for effecting contraception |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0472628A1 (en) |
| JP (1) | JPH05500207A (en) |
| KR (1) | KR920700637A (en) |
| CN (1) | CN1047974A (en) |
| CA (1) | CA2056364C (en) |
| DD (1) | DD300071A5 (en) |
| EG (1) | EG19554A (en) |
| FI (1) | FI915395A0 (en) |
| HU (2) | HUT60134A (en) |
| MW (1) | MW6691A1 (en) |
| NZ (1) | NZ233697A (en) |
| OA (1) | OA09562A (en) |
| PT (1) | PT94074A (en) |
| WO (1) | WO1990014084A1 (en) |
| ZA (1) | ZA903811B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111849934A (en) * | 2019-04-26 | 2020-10-30 | 西南大学 | Yuesang Da Shi N-acetyl-5-hydroxytryptamine oxygen methyltransferase and its application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU660336B2 (en) * | 1991-10-18 | 1995-06-22 | Alza Corporation | Device for the transdermal administration of melatonin |
| JP4745491B2 (en) * | 2000-10-11 | 2011-08-10 | 株式会社明治 | Indole long-chain alcohol and medicine containing the same |
| EP1474390B1 (en) * | 2002-02-13 | 2009-07-22 | Meiji Dairies Corporation | Indole derivatives substituted with long-chain alcohols and medicaments containing them |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4614807A (en) * | 1984-10-04 | 1986-09-30 | Eli Lilly And Company | 6,7-dihalomelatonins |
| ZA88498B (en) * | 1987-02-02 | 1989-10-25 | Lilly Co Eli | Alkylmelatonins |
| US4855305A (en) * | 1987-03-23 | 1989-08-08 | Applied Medical Research | Compositions and methods of effecting contraception utilizing melatonin |
-
1990
- 1990-05-15 NZ NZ233697A patent/NZ233697A/en unknown
- 1990-05-16 EG EG28990A patent/EG19554A/en active
- 1990-05-16 DD DD340729A patent/DD300071A5/en unknown
- 1990-05-17 JP JP2508079A patent/JPH05500207A/en active Pending
- 1990-05-17 WO PCT/NL1990/000073 patent/WO1990014084A1/en not_active Application Discontinuation
- 1990-05-17 CA CA002056364A patent/CA2056364C/en not_active Expired - Fee Related
- 1990-05-17 ZA ZA903811A patent/ZA903811B/en unknown
- 1990-05-17 HU HU905255A patent/HUT60134A/en unknown
- 1990-05-17 CN CN90103090A patent/CN1047974A/en active Pending
- 1990-05-17 EP EP90908689A patent/EP0472628A1/en not_active Withdrawn
- 1990-05-17 PT PT94074A patent/PT94074A/en not_active Application Discontinuation
-
1991
- 1991-11-13 MW MW6691A patent/MW6691A1/en unknown
- 1991-11-15 FI FI915395A patent/FI915395A0/en not_active Application Discontinuation
- 1991-11-16 KR KR1019910701618A patent/KR920700637A/en not_active Application Discontinuation
-
1992
- 1992-02-14 OA OA60142A patent/OA09562A/en unknown
-
1994
- 1994-08-29 HU HU94P/P00017P patent/HU210342A9/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111849934A (en) * | 2019-04-26 | 2020-10-30 | 西南大学 | Yuesang Da Shi N-acetyl-5-hydroxytryptamine oxygen methyltransferase and its application |
| CN111849934B (en) * | 2019-04-26 | 2022-06-03 | 西南大学 | Yuesang Da Shi N-acetyl-5-hydroxytryptamine oxygen methyltransferase and its application |
Also Published As
| Publication number | Publication date |
|---|---|
| FI915395A0 (en) | 1991-11-15 |
| EG19554A (en) | 1995-06-29 |
| CA2056364A1 (en) | 1990-11-18 |
| ZA903811B (en) | 1991-03-27 |
| DD300071A5 (en) | 1992-05-21 |
| JPH05500207A (en) | 1993-01-21 |
| CA2056364C (en) | 2002-08-20 |
| PT94074A (en) | 1991-01-08 |
| HUT60134A (en) | 1992-08-28 |
| WO1990014084A1 (en) | 1990-11-29 |
| OA09562A (en) | 1993-01-31 |
| EP0472628A1 (en) | 1992-03-04 |
| HU905255D0 (en) | 1992-01-28 |
| KR920700637A (en) | 1992-08-10 |
| NZ233697A (en) | 1996-12-20 |
| HU210342A9 (en) | 1995-03-28 |
| MW6691A1 (en) | 1993-07-14 |
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| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |