CA2056364C - Compositions and methods of effecting contraception - Google Patents
Compositions and methods of effecting contraception Download PDFInfo
- Publication number
- CA2056364C CA2056364C CA002056364A CA2056364A CA2056364C CA 2056364 C CA2056364 C CA 2056364C CA 002056364 A CA002056364 A CA 002056364A CA 2056364 A CA2056364 A CA 2056364A CA 2056364 C CA2056364 C CA 2056364C
- Authority
- CA
- Canada
- Prior art keywords
- melatonin
- analog
- hydrogen
- progestogen
- estrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
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
Abstract
A method of effecting contraception in human females comprises administering an ovulation-inhibiting amount of melatonin or an analog of melatonin. Optionally, the melatonin or melatonin analog is administered in combination with a progestogen and/or an estrogen.
Description
Z~~~
_1_ COMPOSITIONS AND METHODS OF EFFECTING CONTRACEPTION
Field of the Inv~antion This invention relates to a method of inhibiting ovulation in human females. Mare 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.
l3ackaround of the Invention Research and development in the field of contraception in humane hoe bean in the areas of physical and chemical barriers to sperm transport, such as vaginal foams, diaphragms, intrauterine devices, and condoms, and in the ar~a of oral contraceptives containing one or more steroid hormones., t7ra1 contraceptives have been dev~loped which are highly effective in preventing contraception, and today more there fifty million women around the world use oral c:ontraceptives. Typically, the oral contraeeptivea talc~ the form of a combination of an estrogen and s progeeitogen (also known ae progeatin). In acme of th~sae regimens, known as combination regimens, a consistent dose of an eatrog~n and a grogeetogen is admini.atered daily throughout the period of administration. In other regim~ns, ref~rred to sa sequential regimens, th~ amount of estrogen or progeatogen or both is incx~eaaed or decreased during the menstrual cycle. Some sequential regimens provid~
two-stage or bi-phaaic control. (See, for example, USP 3,969,502). Others provide a three-stage or tri-phaaic combination of components. (See, for example, USP 4,628,051; US1? 9,390,531.) A third type of regimen also is known in which one or more progestog~ns is administered daily throughout the menstrual cycl~.
Th~ hormones in oral contraceptives act both within the central nervous system and in tiaau~a of the urogenital tract to inhibit reproductive function, The principal sites of action are the hypothalamus and pituitary to prevesnt the midcycle surge of luetinizing hormone (LH) and henee to prev~nt ovulation. The basal cons~ntrationa of LH and follicl~-stimulating horm~ne (ASH) and plasma levels of eatradiol sad progestmrone are suppr~as~d ~.n users of ornl contraceptiv~s. Tn essence, theae~ contraceptives work by causing changes in hormone levels that imitat~
those caused by pregnancy. This eff~ct is dos~
dependent, These conventional oral c~ntraceptivea are administered for a ani.nimum of 21 days of a woman's cyole, and in some instances for the entire ZB-30 days of the cycle.
~~~~3~!~
_1_ COMPOSITIONS AND METHODS OF EFFECTING CONTRACEPTION
Field of the Inv~antion This invention relates to a method of inhibiting ovulation in human females. Mare 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.
l3ackaround of the Invention Research and development in the field of contraception in humane hoe bean in the areas of physical and chemical barriers to sperm transport, such as vaginal foams, diaphragms, intrauterine devices, and condoms, and in the ar~a of oral contraceptives containing one or more steroid hormones., t7ra1 contraceptives have been dev~loped which are highly effective in preventing contraception, and today more there fifty million women around the world use oral c:ontraceptives. Typically, the oral contraeeptivea talc~ the form of a combination of an estrogen and s progeeitogen (also known ae progeatin). In acme of th~sae regimens, known as combination regimens, a consistent dose of an eatrog~n and a grogeetogen is admini.atered daily throughout the period of administration. In other regim~ns, ref~rred to sa sequential regimens, th~ amount of estrogen or progeatogen or both is incx~eaaed or decreased during the menstrual cycle. Some sequential regimens provid~
two-stage or bi-phaaic control. (See, for example, USP 3,969,502). Others provide a three-stage or tri-phaaic combination of components. (See, for example, USP 4,628,051; US1? 9,390,531.) A third type of regimen also is known in which one or more progestog~ns is administered daily throughout the menstrual cycl~.
Th~ hormones in oral contraceptives act both within the central nervous system and in tiaau~a of the urogenital tract to inhibit reproductive function, The principal sites of action are the hypothalamus and pituitary to prevesnt the midcycle surge of luetinizing hormone (LH) and henee to prev~nt ovulation. The basal cons~ntrationa of LH and follicl~-stimulating horm~ne (ASH) and plasma levels of eatradiol sad progestmrone are suppr~as~d ~.n users of ornl contraceptiv~s. Tn essence, theae~ contraceptives work by causing changes in hormone levels that imitat~
those caused by pregnancy. This eff~ct is dos~
dependent, These conventional oral c~ntraceptivea are administered for a ani.nimum of 21 days of a woman's cyole, and in some instances for the entire ZB-30 days of the cycle.
~~~~3~!~
Oral contraceptives also exert a direct effect on the urogenital tract. They alter the etructuxe and physical-chemical compositl.on of the endometrium and the canaistency of the cervical mucous, thus altering S the uterine capacity for tha ovum to implant.
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 (PTU), ectopic pregnancy, endometrial 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 1S can provide relief from common menstrual disorders, including irregular menses, premenstrual tension, excess blood loss and cramps.
Use of conventional oral contraceptives, however, also is attended by certain risks. These risks, which include a greater chance of suffering from venous thrombaembolism, ischemic heart disease, cerebrovas~ular disease and hypertension, are believed to be largely due to the estrogen component (typically ethinyl estradiol or menstranol) in the 2S contraceptives. The risk of suffering from any of these conditions has been found to be confined primarily to women over-the age 3S, especially to Women over age 35 who smoke. Women who take estrogen also may suffer other negative side effects, including gaatraintest3.nal disturbances, nausea and weight gain, In an effort to avoid the negative side effects or possible side effects associated with oral contraceptives containing estrogen, oral contraceptives containing only one or mare progestogens as the active component have been developed, These contraceptives, however, generally have been found to be less effbctive 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:
In vfew of the drawbacks and negative side effects of conventional oral contraceptives, new contraceptives are sought. Accordingly, it is an object of the present invention to provide a contraceptive method which is highly effective and provides the benefits and avoids the adverse effects associated with contraceptives currently used.
~ummarv of the Invention In accordance with the present invention there is disclosed a method for effecting contraception in human females of child -bearing age by administering an analog of melatonin in dosages effective to prevent ovulation. Optionally, the melatonin or melatonin analog is administered fn combination with a progestogen and/or an estrogen. In a preferred embodiment, the contraceptives of this invention are administered in oral dosage form.
Brief Description of the Figures 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, IIL1~-D and IVA-D
show the effects of melatonin administration on the concentration of each of these hormones during each of three menstrual cycles.
Detailed Deacri tion of the Invent on Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland.
~'he exact role of the hormone has not yet been determined. Studies have shown that the injection of melatonin into Syrian golden hamsters at certain specific times of the day has had an inhibitory effect on the development of the gonads, the weight of the .
testes in males and on ovulation in females. Female rata injected with melatonin at certain time~ of the day also showed an inhibition of ovulation. Melatonin thus has been shown to have a primary inhibitory effect on the gonads in various rodent species. A
similar effect, however, has not been shown in other mammalian species injected with melatonin.
Specifically, the administration of melatonin to sheep (ICenneway, D.J. et al., ~ Reo~t ve Fertil;tv ZO 73x859 (1985)) and to grimatea (Reppert, g,~q,, et al., En~r~ 104:295 (1979j) did not re9ult in a direct alteration of their reproductive physiology.
Exogenous melatonin administration in humane has been studied in conjunction with a hypothesis that an Z5 abnormal melatonin rhythm is associated with endogenous depression and for pharmokinetic purposes (Waldhauser, F., Neuroendocrinoloav 39x307, 313 [1984)) and in connection with sleep-wake rhythms and ' th~ phenomenon of "jet-lag" following airplane trips 30 associated with a change in time zones.
~'he present invention is based on the discovery that pharmacological doses of melatonin administered s 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 adm.~,~istering 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.
As used herein, 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;
N' Rx \ Ra R~
Rya ~----~ CH-CH-1~
wherein R" R~ and R', individually, are hydrogen or an alkyl group having 1 to about 4 carbon atoms, Rx is selected from hydragen, hydroxy or an alkoxy group having from 1 to about 4 carbon atoms, and A is either -OH or -NH-C -Rs, wherein Rs is either hydrogen or an alkyl group having from 1 to about 4 carbon stoma, provided that if A is NH-[-Rs, and R' and Rs are both methyl and Rx is hydrogen, both of R3 end R, are not hydrogen. Preferred compounds are those in which Rx is hydrogen or methoxy, with hydrogen being most ~refexred. I~elatonin analoge encompassed within this definition include N-acetyl serotonin, N-acetyl, S-hydroxy, 6-methoxytryptamine, 6-hydroxy-melatanin, 5-hydroxytryptophol and 5-methoxytryptophol, with N-acetyl serotonin being preferred.
~~~P9~~.I~~~I
The melatonin is administered daily in dosages sufficient to suppress the uaer~s normal surge in leutinizing hormone and thus prevent ovulation.
Generally, the melatonin 3.s 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~a 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.
Th~ melatonin can be administered to women either orally, parenterally or in the form of an implant.
Administration is moat convenient when the melatonin is in oral dosage form, such as capsules, tablets, suspensions or solutions. Capsules or tablets are preferred. Capauies can b~ prepared by mixing the compound with a pharmaceutically-acceptable excipient and then filling gelatin capsules with the mixture in accordance with conventional procedures.
Alternatively, the melatonin can be mixed with one or more lubricants, such as stearic acid or magnesium atearate, flavor ameliorating agents, disintegrating elements, including potato starch and alginic acid, binders, such as gelatin and corn starch, and/or tablet bases including lacaose, corn starch and __ sucros~, and then pressed into tablets.
Ae an alternative to oral administration, the melatonin can be administered parenterally ar in the form of a solid implant. For parenteral administration, 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 accegtabl~
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. Similarly, 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.
In a preferred embodiment of this invention, the melatonin is administered in combination with a progestogen. The progeatogen is added to induce a cyclic bleeding resembling a cyclic manses bleeding and to provide the benefits currently associated with the administration of progeatogena in conventionex oral contraceptives. Any progestationally active compound is suitable for use as the progestogen companent in the present invention. Suitable ~10 progeatogens include progeaterane and derivatives thereof. The presently preferred progeatogen is norethindrone (i.e., 19-nor-17a-ethynyl-17f3-hydraxy-4-androsten-3-one) and norgeatrel (1313-ethyl-17a-ethynyl-l7fi-hydroxygon-4-en-3-one). Other progeatogena include the chlormadinone-acetate (6-chloro-17-hydroxy-pregna-4,6-diene-3,20-dione ecetat~), norethynodrel (17a-ethynyl-17-hydroxy-eatr-5(10)-en), medroxyprogeaterone acetate (17a-acetoxy-Sa-methyl-pregn-4_ene-3,20-dione), megestrol acetate (17a-acetoxy-6-methyl-pregna-4,6-diene-3,20-dione), lyneatrenol (17a-ethynyl-1713-hydroxy-eatr-4-ene), quingestrone (3-cyclopentyloxy-pregna-3,5-diene-20-one), norethindrone acetate (1713-acetoxy-17a-ethnyl-estr-4-en-3-an), ethynodivl acetate (3f3,1713-diacetoxy-I?a-ethynyl-eatr-4-ene), dimethiaterone (17f3-hydroxy-6a-methyl-17(-1-propYnyl)-androst-4-en-3-onej, deaogeatrel and levonorgestrel.
The progestogen component of these contraceptives generally is administered in the range of abaut 7.5 ug to about 2500 ~g per day, preferably in the range of about 7.5 to about 600 ug per day. lHost preferably, the progeatogen is administered in the range of about 7.5 ~g to abaut 250 ug per day. The actual amount of progeatogen provided in each daily dosage will depend l0 upon the particular progestogen chosen, its relative potency, and the method of administration selected.
For example, a lesser quantity of a more potent grogestogen may achieve the same results as a larger quantity of a less potent progestogen. As noted above, the amount of proc~estogen also can vary with the mode of administration, with lower doses typically needed for administration of an implant or intravenous injection than fox 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 mel.atonin and progestogen can be administered fox about 21 days, followed by administration of the melatonin without the progestogen for about ? day~, In a second regimen the melatonin and progestogen are administered for about 21 days, and then both are withheld for about ? days. If desired, the melatonin and progestogen alternatively can be administered each day continuausly throughout the woman's cycle for a total of about 28 days.
In a fourth suggested regimen, a combination of melatonin and progestogen is administered for about thirteen days, typically from about day 5 through day 1? of a woman's cycl~, then both the melatonin and progestogen are withheld for the remainder of her cycle.
In an alternative regimen, 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 abou t ?5 mg melatonin. Then, a second combination of melatonin and progeatogen are administered for the next ten to eleven days, during ~~~~~'!
the luteal phase of her cycle, fox a total of about twenty-one data, at dosages of about 7S0 micrograms progeetogen and about 75 mg. melatonin. In this regimen, a smaller dosage of progestogen is S adminiatered_during the first half of the woman~a cycle because an insufficieant amount of estrogen has been formed endogenously (Clue to elvw follicular growth resulting from the melatonin administration) and the administration of relatively high amounts of a progestogen can lead to break-through bleeding, gy the second half of the cycle, however, there has been a significant level of estrogen production. Hreak~-through bleeding can occur during this half of the cycle as a result of 'estrogen production peaking and is then withdrawing. Increasing the amount of progeatogen in each daily dose administered during this portion of the woman~a cycle will prevent this cause of break-.through bleeding.
In another regimen, 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 2S 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 progeatogen through the twenty-first day of the medication. Again, neither melatonin nor the progeetogen is administered for the remaining 7 days of the cycle.
In another regimen, a progeatogen 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), dust prior to the user s normal day of ovulation. If the progestogen is administered for less than the full 29 days of the cycle, no medication is administered for the remaining days. As noted above, the conventional 21-28 daily dose progestogen-only contraceptives have not been very effective. The addition of melatonin overcomes the inefficacy of administering progsstogen alone.
In any of the suggested regimens sat forth abov~, on those days in which both melatanin and a progestogen are administered, the two active components conveniently are combined and administered together, although they also can be administered separately.
In an alternative embodiment of th~ present invention, a small amount of an estrogen can be added to any of the melatonin or melatonin-progestogen regimens set forth above. The estrogen can b~ added, if desired, to stabilize the melatanin 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. l7oc-ethYnYl-3,17fi-dihydroxy-eetra-1,3,5(10)-triene) and meatranol (l7oc-ethynyl-1711-hydroxy-3-methoxy-estra-1,3,5(I0)triene). Other suitable estrogens include estradiol (3,17fi-dihydroxy-estra-1,3,5(10-triene), eatradiol(3,-16~e,17B-trihydroxy-esters-1,3,5(10)-tri~ne, estrone (3,hydroxy-estra-I,3,5(10)-triene-17-one), diethylstilbestrol, quinestradiol (3-cyclopentyloxy-l6rs,17B-dihydraxy-eetra-1,3,5-(10)-triena) and eetrone 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 ug per day and preferably in the range of about 10 ug to about 50 ug per day. As with the progestogen, the actual amount of estrogen us~.~d in a daily dosage will depend upon the particular estrogen selected and its relative potency. Ethinyl estradiol, for exampl~, hag twice the biological potency ae mestranol. Given the deletoriou~s aide effects of estrogen, desirably only the minimum amount of estrogen needed to stabilize the melatonin ie used. The estrogen cmn be combined with the melatanin and/or progeetogen in any of~the regimene suggested above. In an alternative regimen, an estrogen ie 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.
In another embodiment of this invention, melatonin can be administered as a "morning after"
pill, either by itself or in combination with an estrogen and or progestogen. In this embodiment, the melatonin is administered in daily doBee 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. If the melatonin ie 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, and flue estrogen is administered in a daily amount ranging between about 2.5 and 25 mg.
In the preferred embodiment of this invention, the contraceptive compositions of this invention are administered in oral dosage form, preferably in th.s form of pills or capsules. The pills or capsules can be packaged in any manner suitable for proper delivery and use. Preferably, 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 kite ar packages include the conventional bubble plastic package cantaining individual bubbles fox either 21 or 29 pills, depending upon the xegimen selected, in a sheet of flexible plastic. The bubbles axe sealed by a sheet of plastic which can break and release a pill when the bubble is pressed. 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 o~ her next cycle.
Appropriate notations or instructions can be placed on the dispensing kit to guide or instruct the user in the proper use o~ the oral contraceptives.
The present invention is Further described and illustrated by the following examples, which are provided for informational purposes and are not to be construed as limiting.
Ex~mole~7 The contraceptive effectiveness of melatonin was studied in a patient, referred to herein by the initials S.B., born Septemb~sr 21, 1950. In figures IA, IB, IC and ID, respectively, are shown the concentration in her blood of leutinizing hormone (LH), follicle stimulating hormone (FSH), progestrone and estradiol far each day of her cyclo, averaged over 5 consecutive cycles. As shown in the figures, this patient had s normal LH preovulatory surge and an FSH
peak followed by a poet-avulatory grogestrane rise.
In the figures, the legend PHC stands for plasma hormone concentration.
For each of three cycles the patient wes given intravenously X00 mg of melatonin in a physiological solution of glucose in saline from day 9 of her cycle for 6 consecutive days. 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.
Th~ data show three cycles wherein the adaninistration 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 th~
patient did not ovulate in ~sny of the three months if which melatonin was adminisvtered.
~xamale II
The concentrations of 1'~H, 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. 3'he average concentration of the patient'o LF3 peak was 295 ng/ml and the average of her FSH peak was 410 ng/ml. Her average progeatrone 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 progeatrone .3 ng/ml These data indicate that the patient did not ovulate during this cycle; studies have shown that a ~3 J ~ ~ ~9 ~~.
peak of LH concentration of at least 250 ng/ml ie necessary for ovulation, Example rII
A woman having a normal menstrual cycle of 28 S days with 3-5 days of moderate menstrual bleeding (150 ml. blood loss) was given intravenous injections of 350 mg melatonin in a glucose in saline solution for seven consecutive days, beginning an day 8 of her cycle. Gn days 14-28 of her cycle she was admfnistered orally 0.75 mg norethindrone per day.
The concentration of LH, FSH, progeetrone and estradiol in her blood was measured daily throughout hex cycle. She did not ovulate during this cycle (peak PHC LH was 115 ng/ml). She had a minimal 1S menstrual blood loss (t1S ml).
Exarnnle IV
A woman having a normal menstrual cycle of 30 days (12th day ovulatoz~) was given intravenous injections of 200 mg melatonin in a glucose in saline solution on each of days 7..10 of her cycle. She did n°t ovulate in his cycle, although the level of LH in hex blood was found to be not uniformly suppressed but rather erratic with levels between SO ng/ml and 180 ng/ml during the cycle. Her FSH PHG during this cycle was normal for her, her progesterone PHG was somewhat depressed, and her ~stradiol PHC throughout the cycle was normal, 1e Exa~nale y in an ongoing study, four women are taking melatonin in gelatin capaul~se. The melatonin is being administered in daily doses ranging from 30 mg. to 1000 mg. A preliminary ~valuatian 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 avulator) is given oral doses of a combination of 200 mg N-acetyl aerotonin (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 mea~uring the concentration of Lti and F'S~i in her blood on each day of her cycle.
Similar resulta.are obtained when each of 5-hydroxytryptophol, S-methoxytryptophol, 6-hydroxymelatonin and Id-acetyl, 5-hydroxy, 6-methoxytryptamine are administered with norethiaterone at the dosage levels and in accordance with cyclic schedule set forth abova.
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 (PTU), ectopic pregnancy, endometrial 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 1S can provide relief from common menstrual disorders, including irregular menses, premenstrual tension, excess blood loss and cramps.
Use of conventional oral contraceptives, however, also is attended by certain risks. These risks, which include a greater chance of suffering from venous thrombaembolism, ischemic heart disease, cerebrovas~ular disease and hypertension, are believed to be largely due to the estrogen component (typically ethinyl estradiol or menstranol) in the 2S contraceptives. The risk of suffering from any of these conditions has been found to be confined primarily to women over-the age 3S, especially to Women over age 35 who smoke. Women who take estrogen also may suffer other negative side effects, including gaatraintest3.nal disturbances, nausea and weight gain, In an effort to avoid the negative side effects or possible side effects associated with oral contraceptives containing estrogen, oral contraceptives containing only one or mare progestogens as the active component have been developed, These contraceptives, however, generally have been found to be less effbctive 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:
In vfew of the drawbacks and negative side effects of conventional oral contraceptives, new contraceptives are sought. Accordingly, it is an object of the present invention to provide a contraceptive method which is highly effective and provides the benefits and avoids the adverse effects associated with contraceptives currently used.
~ummarv of the Invention In accordance with the present invention there is disclosed a method for effecting contraception in human females of child -bearing age by administering an analog of melatonin in dosages effective to prevent ovulation. Optionally, the melatonin or melatonin analog is administered fn combination with a progestogen and/or an estrogen. In a preferred embodiment, the contraceptives of this invention are administered in oral dosage form.
Brief Description of the Figures 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, IIL1~-D and IVA-D
show the effects of melatonin administration on the concentration of each of these hormones during each of three menstrual cycles.
Detailed Deacri tion of the Invent on Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesized and secreted by the pineal gland.
~'he exact role of the hormone has not yet been determined. Studies have shown that the injection of melatonin into Syrian golden hamsters at certain specific times of the day has had an inhibitory effect on the development of the gonads, the weight of the .
testes in males and on ovulation in females. Female rata injected with melatonin at certain time~ of the day also showed an inhibition of ovulation. Melatonin thus has been shown to have a primary inhibitory effect on the gonads in various rodent species. A
similar effect, however, has not been shown in other mammalian species injected with melatonin.
Specifically, the administration of melatonin to sheep (ICenneway, D.J. et al., ~ Reo~t ve Fertil;tv ZO 73x859 (1985)) and to grimatea (Reppert, g,~q,, et al., En~r~ 104:295 (1979j) did not re9ult in a direct alteration of their reproductive physiology.
Exogenous melatonin administration in humane has been studied in conjunction with a hypothesis that an Z5 abnormal melatonin rhythm is associated with endogenous depression and for pharmokinetic purposes (Waldhauser, F., Neuroendocrinoloav 39x307, 313 [1984)) and in connection with sleep-wake rhythms and ' th~ phenomenon of "jet-lag" following airplane trips 30 associated with a change in time zones.
~'he present invention is based on the discovery that pharmacological doses of melatonin administered s 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 adm.~,~istering 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.
As used herein, 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;
N' Rx \ Ra R~
Rya ~----~ CH-CH-1~
wherein R" R~ and R', individually, are hydrogen or an alkyl group having 1 to about 4 carbon atoms, Rx is selected from hydragen, hydroxy or an alkoxy group having from 1 to about 4 carbon atoms, and A is either -OH or -NH-C -Rs, wherein Rs is either hydrogen or an alkyl group having from 1 to about 4 carbon stoma, provided that if A is NH-[-Rs, and R' and Rs are both methyl and Rx is hydrogen, both of R3 end R, are not hydrogen. Preferred compounds are those in which Rx is hydrogen or methoxy, with hydrogen being most ~refexred. I~elatonin analoge encompassed within this definition include N-acetyl serotonin, N-acetyl, S-hydroxy, 6-methoxytryptamine, 6-hydroxy-melatanin, 5-hydroxytryptophol and 5-methoxytryptophol, with N-acetyl serotonin being preferred.
~~~P9~~.I~~~I
The melatonin is administered daily in dosages sufficient to suppress the uaer~s normal surge in leutinizing hormone and thus prevent ovulation.
Generally, the melatonin 3.s 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~a 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.
Th~ melatonin can be administered to women either orally, parenterally or in the form of an implant.
Administration is moat convenient when the melatonin is in oral dosage form, such as capsules, tablets, suspensions or solutions. Capsules or tablets are preferred. Capauies can b~ prepared by mixing the compound with a pharmaceutically-acceptable excipient and then filling gelatin capsules with the mixture in accordance with conventional procedures.
Alternatively, the melatonin can be mixed with one or more lubricants, such as stearic acid or magnesium atearate, flavor ameliorating agents, disintegrating elements, including potato starch and alginic acid, binders, such as gelatin and corn starch, and/or tablet bases including lacaose, corn starch and __ sucros~, and then pressed into tablets.
Ae an alternative to oral administration, the melatonin can be administered parenterally ar in the form of a solid implant. For parenteral administration, 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 accegtabl~
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. Similarly, 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.
In a preferred embodiment of this invention, the melatonin is administered in combination with a progestogen. The progeatogen is added to induce a cyclic bleeding resembling a cyclic manses bleeding and to provide the benefits currently associated with the administration of progeatogena in conventionex oral contraceptives. Any progestationally active compound is suitable for use as the progestogen companent in the present invention. Suitable ~10 progeatogens include progeaterane and derivatives thereof. The presently preferred progeatogen is norethindrone (i.e., 19-nor-17a-ethynyl-17f3-hydraxy-4-androsten-3-one) and norgeatrel (1313-ethyl-17a-ethynyl-l7fi-hydroxygon-4-en-3-one). Other progeatogena include the chlormadinone-acetate (6-chloro-17-hydroxy-pregna-4,6-diene-3,20-dione ecetat~), norethynodrel (17a-ethynyl-17-hydroxy-eatr-5(10)-en), medroxyprogeaterone acetate (17a-acetoxy-Sa-methyl-pregn-4_ene-3,20-dione), megestrol acetate (17a-acetoxy-6-methyl-pregna-4,6-diene-3,20-dione), lyneatrenol (17a-ethynyl-1713-hydroxy-eatr-4-ene), quingestrone (3-cyclopentyloxy-pregna-3,5-diene-20-one), norethindrone acetate (1713-acetoxy-17a-ethnyl-estr-4-en-3-an), ethynodivl acetate (3f3,1713-diacetoxy-I?a-ethynyl-eatr-4-ene), dimethiaterone (17f3-hydroxy-6a-methyl-17(-1-propYnyl)-androst-4-en-3-onej, deaogeatrel and levonorgestrel.
The progestogen component of these contraceptives generally is administered in the range of abaut 7.5 ug to about 2500 ~g per day, preferably in the range of about 7.5 to about 600 ug per day. lHost preferably, the progeatogen is administered in the range of about 7.5 ~g to abaut 250 ug per day. The actual amount of progeatogen provided in each daily dosage will depend l0 upon the particular progestogen chosen, its relative potency, and the method of administration selected.
For example, a lesser quantity of a more potent grogestogen may achieve the same results as a larger quantity of a less potent progestogen. As noted above, the amount of proc~estogen also can vary with the mode of administration, with lower doses typically needed for administration of an implant or intravenous injection than fox 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 mel.atonin and progestogen can be administered fox about 21 days, followed by administration of the melatonin without the progestogen for about ? day~, In a second regimen the melatonin and progestogen are administered for about 21 days, and then both are withheld for about ? days. If desired, the melatonin and progestogen alternatively can be administered each day continuausly throughout the woman's cycle for a total of about 28 days.
In a fourth suggested regimen, a combination of melatonin and progestogen is administered for about thirteen days, typically from about day 5 through day 1? of a woman's cycl~, then both the melatonin and progestogen are withheld for the remainder of her cycle.
In an alternative regimen, 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 abou t ?5 mg melatonin. Then, a second combination of melatonin and progeatogen are administered for the next ten to eleven days, during ~~~~~'!
the luteal phase of her cycle, fox a total of about twenty-one data, at dosages of about 7S0 micrograms progeetogen and about 75 mg. melatonin. In this regimen, a smaller dosage of progestogen is S adminiatered_during the first half of the woman~a cycle because an insufficieant amount of estrogen has been formed endogenously (Clue to elvw follicular growth resulting from the melatonin administration) and the administration of relatively high amounts of a progestogen can lead to break-through bleeding, gy the second half of the cycle, however, there has been a significant level of estrogen production. Hreak~-through bleeding can occur during this half of the cycle as a result of 'estrogen production peaking and is then withdrawing. Increasing the amount of progeatogen in each daily dose administered during this portion of the woman~a cycle will prevent this cause of break-.through bleeding.
In another regimen, 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 2S 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 progeatogen through the twenty-first day of the medication. Again, neither melatonin nor the progeetogen is administered for the remaining 7 days of the cycle.
In another regimen, a progeatogen 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), dust prior to the user s normal day of ovulation. If the progestogen is administered for less than the full 29 days of the cycle, no medication is administered for the remaining days. As noted above, the conventional 21-28 daily dose progestogen-only contraceptives have not been very effective. The addition of melatonin overcomes the inefficacy of administering progsstogen alone.
In any of the suggested regimens sat forth abov~, on those days in which both melatanin and a progestogen are administered, the two active components conveniently are combined and administered together, although they also can be administered separately.
In an alternative embodiment of th~ present invention, a small amount of an estrogen can be added to any of the melatonin or melatonin-progestogen regimens set forth above. The estrogen can b~ added, if desired, to stabilize the melatanin 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. l7oc-ethYnYl-3,17fi-dihydroxy-eetra-1,3,5(10)-triene) and meatranol (l7oc-ethynyl-1711-hydroxy-3-methoxy-estra-1,3,5(I0)triene). Other suitable estrogens include estradiol (3,17fi-dihydroxy-estra-1,3,5(10-triene), eatradiol(3,-16~e,17B-trihydroxy-esters-1,3,5(10)-tri~ne, estrone (3,hydroxy-estra-I,3,5(10)-triene-17-one), diethylstilbestrol, quinestradiol (3-cyclopentyloxy-l6rs,17B-dihydraxy-eetra-1,3,5-(10)-triena) and eetrone 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 ug per day and preferably in the range of about 10 ug to about 50 ug per day. As with the progestogen, the actual amount of estrogen us~.~d in a daily dosage will depend upon the particular estrogen selected and its relative potency. Ethinyl estradiol, for exampl~, hag twice the biological potency ae mestranol. Given the deletoriou~s aide effects of estrogen, desirably only the minimum amount of estrogen needed to stabilize the melatonin ie used. The estrogen cmn be combined with the melatanin and/or progeetogen in any of~the regimene suggested above. In an alternative regimen, an estrogen ie 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.
In another embodiment of this invention, melatonin can be administered as a "morning after"
pill, either by itself or in combination with an estrogen and or progestogen. In this embodiment, the melatonin is administered in daily doBee 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. If the melatonin ie 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, and flue estrogen is administered in a daily amount ranging between about 2.5 and 25 mg.
In the preferred embodiment of this invention, the contraceptive compositions of this invention are administered in oral dosage form, preferably in th.s form of pills or capsules. The pills or capsules can be packaged in any manner suitable for proper delivery and use. Preferably, 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 kite ar packages include the conventional bubble plastic package cantaining individual bubbles fox either 21 or 29 pills, depending upon the xegimen selected, in a sheet of flexible plastic. The bubbles axe sealed by a sheet of plastic which can break and release a pill when the bubble is pressed. 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 o~ her next cycle.
Appropriate notations or instructions can be placed on the dispensing kit to guide or instruct the user in the proper use o~ the oral contraceptives.
The present invention is Further described and illustrated by the following examples, which are provided for informational purposes and are not to be construed as limiting.
Ex~mole~7 The contraceptive effectiveness of melatonin was studied in a patient, referred to herein by the initials S.B., born Septemb~sr 21, 1950. In figures IA, IB, IC and ID, respectively, are shown the concentration in her blood of leutinizing hormone (LH), follicle stimulating hormone (FSH), progestrone and estradiol far each day of her cyclo, averaged over 5 consecutive cycles. As shown in the figures, this patient had s normal LH preovulatory surge and an FSH
peak followed by a poet-avulatory grogestrane rise.
In the figures, the legend PHC stands for plasma hormone concentration.
For each of three cycles the patient wes given intravenously X00 mg of melatonin in a physiological solution of glucose in saline from day 9 of her cycle for 6 consecutive days. 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.
Th~ data show three cycles wherein the adaninistration 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 th~
patient did not ovulate in ~sny of the three months if which melatonin was adminisvtered.
~xamale II
The concentrations of 1'~H, 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. 3'he average concentration of the patient'o LF3 peak was 295 ng/ml and the average of her FSH peak was 410 ng/ml. Her average progeatrone 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 progeatrone .3 ng/ml These data indicate that the patient did not ovulate during this cycle; studies have shown that a ~3 J ~ ~ ~9 ~~.
peak of LH concentration of at least 250 ng/ml ie necessary for ovulation, Example rII
A woman having a normal menstrual cycle of 28 S days with 3-5 days of moderate menstrual bleeding (150 ml. blood loss) was given intravenous injections of 350 mg melatonin in a glucose in saline solution for seven consecutive days, beginning an day 8 of her cycle. Gn days 14-28 of her cycle she was admfnistered orally 0.75 mg norethindrone per day.
The concentration of LH, FSH, progeetrone and estradiol in her blood was measured daily throughout hex cycle. She did not ovulate during this cycle (peak PHC LH was 115 ng/ml). She had a minimal 1S menstrual blood loss (t1S ml).
Exarnnle IV
A woman having a normal menstrual cycle of 30 days (12th day ovulatoz~) was given intravenous injections of 200 mg melatonin in a glucose in saline solution on each of days 7..10 of her cycle. She did n°t ovulate in his cycle, although the level of LH in hex blood was found to be not uniformly suppressed but rather erratic with levels between SO ng/ml and 180 ng/ml during the cycle. Her FSH PHG during this cycle was normal for her, her progesterone PHG was somewhat depressed, and her ~stradiol PHC throughout the cycle was normal, 1e Exa~nale y in an ongoing study, four women are taking melatonin in gelatin capaul~se. The melatonin is being administered in daily doses ranging from 30 mg. to 1000 mg. A preliminary ~valuatian 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 avulator) is given oral doses of a combination of 200 mg N-acetyl aerotonin (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 mea~uring the concentration of Lti and F'S~i in her blood on each day of her cycle.
Similar resulta.are obtained when each of 5-hydroxytryptophol, S-methoxytryptophol, 6-hydroxymelatonin and Id-acetyl, 5-hydroxy, 6-methoxytryptamine are administered with norethiaterone at the dosage levels and in accordance with cyclic schedule set forth abova.
Claims (35)
1. A method of effecting contraception which comprises the administration of a melatonin analog having an ovulation-inhibiting effect in human females to a human female of child-bearing years on a schedule and at dose levels sufficient to prevent ovulation wherein the analog has the general formula wherein R1, R3 and R4, individually are hydrogen or an alkyl group having 1 to 4 carbon atoms, R2 is hydrogen, hydroxy or an alkoxy group having from 1 to 4 carbon atoms, and A is selected from hydroxy and , wherein R5 is either hydrogen or an alkyl group having from 1 to 4 carbon atoms, provided, however, that if A is , R2 is hydrogen and R1 and R5 are both methyl, both of R3 and R4 are not hydrogen.
2. The method of claim 1, wherein R2 is selected from hydrogen and methoxy.
3. The method of claim 2, wherein R2 is hydrogen.
4. The method of claim 3, wherein A is -OH.
5. The method of claim 4, wherein the analog is 5-hydroxytryptophol.
6. The method of claim 4, wherein the analog is 5-methoxytryptophol.
7. The method of claim 1, wherein A is .
8. The method of claim 7, wherein the analog is N-acetylserotonin.
9. The method of claim 7, wherein the analog is N-acetyl-5-hydroxy-6-methoxytryptamine.
10. The method of claim 7, wherein the analog is 6-hydroxymelatonin.
11. The method of claim 1 wherein the daily dosage level of melatonin analog ranges from 2 mg to 1000 mg per 70 kg body weight of the female.
12. The method of claim 11 wherein the daily dosage level is from 30 mg to 500 mg per 70 kg body weight.
13. The method of claim 1, wherein a progestogen is administered in combination with the melatonin analog.
14. The method of claim 13 wherein the dosage level of meltonin analog is from 2 mg to 1000 mg per 70 kg body weight and the dosage level of the progestogen is from 7.5 µg to 2500 µg per 70 kg body weight on each day of administration.
15. The method of claim 14, wherein the dosage level of progestogen is from 7.5 µg to 600 µg per 70 kg body weight on each day of administration.
16. The method of claim 15 wherein the progestogen is selected from the group consisting of norethindrone, norgestrel, chlormadinone-acetate, norethynodrel, medroxyprogesterone acetate, megestrolacetate lynestrenol, quingestrone, norethindrone acetate, ethynodiol acetate, levonorgestrel, desogestral and dimethisterone.
17. The method of claim 1, wherein an estrogen is administered in combination with the melatonin analog.
18. The method of claim 17 wherein the dosage level of melatonin analog is from 2 mg to 1000 mg per 70 kg of body weight of the female and the dosage level of estrogen is 2 µg to 100 µg per 70 kg of body weight on each day of administration.
19. The method of claim 18 wherein the dosage level of melatonin analog is from 30 mg to 500 mg per 70 kg of body weight and the dosage level of estrogen is 10 µg to 50 µg per 70 kg of body weight on each day of administration.
20. The method of claim 17, wherein a progestogen is administered in combination with the melatonin analog and the estrogen.
21. The method of claim 20 wherein the dosage level of melatonin analog is from 2 mg to 1000 mg per 70 kg body weight, the dosage level of progestogen is 7.5 µg to 2500 µg per 70 kg body weight, and the dosage level of estrogen is 2 µg to 100 µg per 70 kg body weight on each day of administration.
22. The method of claim 17 or 20 wherein the estrogen is selected from the group consisting of ethinyl estradiol, mestranol, estradiol, estrone, estriol, diethylstilbestrol, quinestradiol and estrone sulfate.
23. The method of claim 1 wherein the method of administration is oral.
24. The method of claim 1 wherein the method of administration is by intravenous injection in a physiologically suitable carrier.
25. The method of claim 1 wherein the method of administration is by implant.
26. A composition for effecting contraception in a human female of child-bearing age which comprises a contraceptively effective combination of an analog of melatonin having ovulation-inhibiting effects in human females and a progestogen, wherein the analog has the general formula wherein R1, R3 and R4, individually are hydrogen or an alkyl croup having 1 to 4 carbon atoms, R2 is hydrogen, hydroxy or an alkoxy group having from 1 to 4 carbon atoms, and A
is selected from hydroxy and , wherein R5 is either hydrogen or an alkyl group having from 1 to 4 carbon atoms, provided, however, that if A is , R2 is hydrogen and R1 and R5 are both methyl, both of R3 and R4 are not hydrogen.
is selected from hydroxy and , wherein R5 is either hydrogen or an alkyl group having from 1 to 4 carbon atoms, provided, however, that if A is , R2 is hydrogen and R1 and R5 are both methyl, both of R3 and R4 are not hydrogen.
27. A composition for effecting contraception in a human female of child-bearing age which comprises a contraceptively effective combination of an analog of melatonin having an ovulation-inhibiting effect in human females and an estrogen, wherein the analog has the general formula wherein R1, R3 and R4, individually are hydrogen or an alkyl group having 1 to 4 carbon atoms, R2 is hydrogen, hydroxy or an alkoxy group having from 1 to 4 carbon atoms, and A
is selected from hydroxy and , wherein R5 is either hydrogen or an alkyl group having from 1 to 4 carbon atoms, provided, however, that if A is , R2 is hydrogen and R1 and R5 are both methyl, both of R3 and R4 are not hydrogen.
is selected from hydroxy and , wherein R5 is either hydrogen or an alkyl group having from 1 to 4 carbon atoms, provided, however, that if A is , R2 is hydrogen and R1 and R5 are both methyl, both of R3 and R4 are not hydrogen.
28. A composition for effecting contraception in a human female of child-bearing age which comprises a contraceptively effective combination of an analog of melatonin having ovulation-inhibiting effects in human females, a progestogen and an estrogen, wherein the analog has the general formula wherein R1, R3 and R4, individually are hydrogen or an alkyl group having 1 to 4 carbon atoms, R2 is hydrogen, hydroxy or an alkoxy group having from 1 to 4 carbon atoms, and A
is selected from hydroxy and , wherein R5 is either hydrogen or an alkyl group having from 1 to 4 carbon atoms, provided, however, that if A is , R2 is hydrogen and R1 and R5 are both methyl, both of R3 and R4 are not hydrogen.
is selected from hydroxy and , wherein R5 is either hydrogen or an alkyl group having from 1 to 4 carbon atoms, provided, however, that if A is , R2 is hydrogen and R1 and R5 are both methyl, both of R3 and R4 are not hydrogen.
29. The composition of claim 25 or 28 wherein the progestogen is selected from the group consisting of norethindrone, norestrel, chlormadinone-acetate, norethynodrel, medroxyprogesterone acetate, megestrol acetate, lynestrenol, quingestrone, norethindrone acetate, ethynodiol acetate, levonorgestrel, desogestrel and dimethisterone.
30. The composition of claim 27 or 28 wherein the estrogen is selected from the group consisting of ethinyl estradiol, mestranol, estradiol, estrone, estriol, diethylstilbestrol, quinestradiol and estrone sulfate.
31. The composition of claim 30, wherein the melatonin analog is N-acetyl serotonin.
32. The composition of claim 30, wherein the melatonin analog is 5-hydroxytryptophol.
33. The composition of claim 30, wherein the melatonin analog is 5-methoxytryptophol.
34. The composition of claim 30, wherein the melatonin analog is 6-hydroxymelatonin.
35. The composition of claim 30, wherein the melatonin analog is N-acetyl-5-hydroxy-6-methoxytryptamine.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35301989A | 1989-05-17 | 1989-05-17 | |
| US353,019 | 1989-05-17 | ||
| PCT/NL1990/000073 WO1990014084A1 (en) | 1989-05-17 | 1990-05-17 | Use of melatonin derivatives for effecting contraception |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2056364A1 CA2056364A1 (en) | 1990-11-18 |
| CA2056364C true CA2056364C (en) | 2002-08-20 |
Family
ID=23387406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002056364A Expired - Fee Related CA2056364C (en) | 1989-05-17 | 1990-05-17 | Compositions and methods of 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) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2116036A1 (en) * | 1991-10-18 | 1993-04-29 | F. Eugene Yates | 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 |
| WO2003068741A1 (en) | 2002-02-13 | 2003-08-21 | Meiji Dairies Corporation | Indole derivatives substituted with long-chain alcohols and medicaments containing them |
| CN111849934B (en) * | 2019-04-26 | 2022-06-03 | 西南大学 | Tue-sang-Dodecan-5-hydroxytryptamine oxygen methyltransferase and application thereof |
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 ZA ZA903811A patent/ZA903811B/en unknown
- 1990-05-17 WO PCT/NL1990/000073 patent/WO1990014084A1/en not_active Application Discontinuation
- 1990-05-17 EP EP90908689A patent/EP0472628A1/en not_active Withdrawn
- 1990-05-17 PT PT94074A patent/PT94074A/en not_active Application Discontinuation
- 1990-05-17 CN CN90103090A patent/CN1047974A/en active Pending
- 1990-05-17 JP JP2508079A patent/JPH05500207A/en active Pending
- 1990-05-17 HU HU905255A patent/HUT60134A/en unknown
- 1990-05-17 CA CA002056364A patent/CA2056364C/en not_active Expired - Fee Related
-
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
Also Published As
| Publication number | Publication date |
|---|---|
| MW6691A1 (en) | 1993-07-14 |
| HUT60134A (en) | 1992-08-28 |
| HU905255D0 (en) | 1992-01-28 |
| WO1990014084A1 (en) | 1990-11-29 |
| JPH05500207A (en) | 1993-01-21 |
| OA09562A (en) | 1993-01-31 |
| KR920700637A (en) | 1992-08-10 |
| HU210342A9 (en) | 1995-03-28 |
| CA2056364A1 (en) | 1990-11-18 |
| EG19554A (en) | 1995-06-29 |
| CN1047974A (en) | 1990-12-26 |
| PT94074A (en) | 1991-01-08 |
| FI915395A0 (en) | 1991-11-15 |
| EP0472628A1 (en) | 1992-03-04 |
| ZA903811B (en) | 1991-03-27 |
| NZ233697A (en) | 1996-12-20 |
| DD300071A5 (en) | 1992-05-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0354921B1 (en) | Use of melatonin for the manufacture of a contraceptive composition | |
| EP1446128B1 (en) | Use of estrogenic compounds in combination with progestogenic compounds in hormone-replacement therapy | |
| EP1390041B1 (en) | Drug delivery system comprising a tetrahydroxylated estrogen for use in hormonal contraception | |
| US7732430B2 (en) | Drug delivery system comprising a tetrahydroxilated estrogen for use in hormonal contraception | |
| CZ288062B6 (en) | Preparation for woman contraception | |
| CA2056364C (en) | Compositions and methods of effecting contraception | |
| EP0479867B1 (en) | Compositions useful as contraceptives in males | |
| HU194494B (en) | Process for producing synergistic contraceptive compositions | |
| AU644367B2 (en) | Use of melatonin derivatives for effecting contraception | |
| NZ244997A (en) | Use of melatonin derivatives for contraception | |
| RU2067001C1 (en) | Method for reducing risk to acquire mammary gland carcinoma | |
| IL94411A (en) | Compositions comprising an analog of melatonin in combination with progestogen and/or estrogen for effecting contraception |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed | ||
| MKLA | Lapsed |
Effective date: 20060517 |