CA1256802A - Contraceptive synergistic association - Google Patents
Contraceptive synergistic associationInfo
- Publication number
- CA1256802A CA1256802A CA000492672A CA492672A CA1256802A CA 1256802 A CA1256802 A CA 1256802A CA 000492672 A CA000492672 A CA 000492672A CA 492672 A CA492672 A CA 492672A CA 1256802 A CA1256802 A CA 1256802A
- Authority
- CA
- Canada
- Prior art keywords
- association
- contraceptive
- contra
- ceptive
- progestogen
- 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
Links
- 230000002254 contraceptive effect Effects 0.000 title claims abstract description 21
- 239000003433 contraceptive agent Substances 0.000 title claims abstract description 19
- 230000002195 synergetic effect Effects 0.000 title claims abstract description 6
- 239000000583 progesterone congener Substances 0.000 claims abstract description 18
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960004940 sulpiride Drugs 0.000 claims abstract description 10
- 230000003028 elevating effect Effects 0.000 claims abstract description 4
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical group CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 claims description 10
- 239000000262 estrogen Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 5
- 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
- 229960002568 ethinylestradiol Drugs 0.000 claims description 4
- 230000006651 lactation Effects 0.000 claims description 4
- 229940053934 norethindrone Drugs 0.000 claims description 4
- VIKNJXKGJWUCNN-XGXHKTLJSA-N norethisterone Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 VIKNJXKGJWUCNN-XGXHKTLJSA-N 0.000 claims description 4
- ICTXHFFSOAJUMG-SLHNCBLASA-N Norethynodrel Chemical compound C1CC(=O)CC2=C1[C@H]1CC[C@](C)([C@](CC3)(O)C#C)[C@@H]3[C@@H]1CC2 ICTXHFFSOAJUMG-SLHNCBLASA-N 0.000 claims description 3
- 238000012423 maintenance Methods 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 230000000757 progestagenic effect Effects 0.000 claims description 2
- 229940124597 therapeutic agent Drugs 0.000 claims 2
- 102000003946 Prolactin Human genes 0.000 abstract description 7
- 108010057464 Prolactin Proteins 0.000 abstract description 7
- 229940097325 prolactin Drugs 0.000 abstract description 7
- GTKYLVJCMKDNTH-UHFFFAOYSA-N 2-methoxy-5-sulfamoylbenzamide Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1C(N)=O GTKYLVJCMKDNTH-UHFFFAOYSA-N 0.000 abstract description 2
- BGRJTUBHPOOWDU-UHFFFAOYSA-N sulpiride Chemical compound CCN1CCCC1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-UHFFFAOYSA-N 0.000 abstract description 2
- 230000000694 effects Effects 0.000 description 7
- 230000028327 secretion Effects 0.000 description 5
- 208000032843 Hemorrhage Diseases 0.000 description 4
- 230000000740 bleeding effect Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 description 3
- OFCFLGYUMQEVGO-UHFFFAOYSA-N 2,3-dimethoxy-5-sulfamoylbenzamide Chemical compound COC1=CC(S(N)(=O)=O)=CC(C(N)=O)=C1OC OFCFLGYUMQEVGO-UHFFFAOYSA-N 0.000 description 3
- -1 2-pyrrolidylmethyl Chemical group 0.000 description 3
- 229940054066 benzamide antipsychotics Drugs 0.000 description 3
- 150000003936 benzamides Chemical class 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229960004400 levonorgestrel Drugs 0.000 description 3
- 230000002175 menstrual effect Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 230000009471 action Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000001076 estrogenic effect Effects 0.000 description 2
- 230000012173 estrus Effects 0.000 description 2
- 229940012028 ethynodiol diacetate Drugs 0.000 description 2
- ONKUMRGIYFNPJW-KIEAKMPYSA-N ethynodiol diacetate Chemical compound C1C[C@]2(C)[C@@](C#C)(OC(C)=O)CC[C@H]2[C@@H]2CCC3=C[C@@H](OC(=O)C)CC[C@@H]3[C@H]21 ONKUMRGIYFNPJW-KIEAKMPYSA-N 0.000 description 2
- 230000035558 fertility Effects 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 208000000509 infertility Diseases 0.000 description 2
- 231100000535 infertility Toxicity 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000029849 luteinization Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 230000016087 ovulation Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000000506 psychotropic effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- NSMXQKNUPPXBRG-SECBINFHSA-N (R)-lisofylline Chemical compound O=C1N(CCCC[C@H](O)C)C(=O)N(C)C2=C1N(C)C=N2 NSMXQKNUPPXBRG-SECBINFHSA-N 0.000 description 1
- BUJCVBRLTBAYCW-UHFFFAOYSA-N 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-2-(2-methoxyphenoxy)propan-1-one Chemical compound COC1=CC=CC=C1OC(CO)C(=O)C1=CC=C(O)C(OC)=C1 BUJCVBRLTBAYCW-UHFFFAOYSA-N 0.000 description 1
- LCUIMXDQQZOHJR-UHFFFAOYSA-N 4-amino-5-ethylsulfonyl-2-methoxybenzamide Chemical compound CCS(=O)(=O)C1=CC(C(N)=O)=C(OC)C=C1N LCUIMXDQQZOHJR-UHFFFAOYSA-N 0.000 description 1
- 101000904177 Clupea pallasii Gonadoliberin-1 Proteins 0.000 description 1
- 206010051909 Endometrial atrophy Diseases 0.000 description 1
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 1
- 206010027514 Metrorrhagia Diseases 0.000 description 1
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 1
- 206010047998 Withdrawal bleed Diseases 0.000 description 1
- WAHQVRCNDCHDIB-QZYSPNBYSA-N [(3s,8r,9s,10r,13s,14s,17r)-17-acetyl-17-acetyloxy-6,10,13-trimethyl-1,2,3,8,9,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-yl] 3-cyclopentylpropanoate Chemical compound O([C@@H]1C=C2C(C)=C[C@H]3[C@@H]4CC[C@]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)(OC(=O)C)C(C)=O)C(=O)CCC1CCCC1 WAHQVRCNDCHDIB-QZYSPNBYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 206010007776 catatonia Diseases 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000003756 cervix mucus Anatomy 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000003325 follicular Effects 0.000 description 1
- 230000008217 follicular development Effects 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960004616 medroxyprogesterone Drugs 0.000 description 1
- FRQMUZJSZHZSGN-HBNHAYAOSA-N medroxyprogesterone Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](O)(C(C)=O)CC[C@H]21 FRQMUZJSZHZSGN-HBNHAYAOSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004914 menses Anatomy 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001150 spermicidal effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
Landscapes
- 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)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Orthopedics, Nursing, And Contraception (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Catching Or Destruction (AREA)
- Fertilizers (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Medicinal Preparation (AREA)
- Investigation Of Foundation Soil And Reinforcement Of Foundation Soil By Compacting Or Drainage (AREA)
- Pretreatment Of Seeds And Plants (AREA)
- Curing Cements, Concrete, And Artificial Stone (AREA)
- Steroid Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention relates to a contraceptive synergistic association comprising a prolactin elevating benzamide such a SULPIRIDE or N [(1-ethyl-2-pyrroli-dinyl) methy] 2-methoxy-5-sulfamoylbenzamide, and a synthetic progestogen at low dose.
This invention relates to a contraceptive synergistic association comprising a prolactin elevating benzamide such a SULPIRIDE or N [(1-ethyl-2-pyrroli-dinyl) methy] 2-methoxy-5-sulfamoylbenzamide, and a synthetic progestogen at low dose.
Description
~2~68~
The invention concerns a contraceptive synergistic association consisting of a prolactin elevating benzamide such as SULPIRIDE or N (1-ethyl-2~pyrrolidinyl) methyl 2-methoxy 5-sulfamoyl benzamide, and a synthetic progestogen.
Sulpiride is essentially known for its psycllotropic properties.
This drug was observed to have a contraceptive effect at the usual doses employed in psychiatry (100 to 1000 mg per day). It has not been used extensively as a contraceptive, however, because of the relatively high dosage required for satisfactory protection and because clinical tests have shown that protection is incomplete during the first two months of drug administration. (D. BUVAT et al. Rev. Fr. Gynecol. Obstet. 71 (1) 53-51)-T'ne use of psychotropic substances for contraceptive purposes hashitherto been recommended only in the form of local application.
Reference may be made, for example, to international patent applications to COI~IF,R (pub'Lications of PCT 81/03~21 and 83/00086) which describe prepnrations Eor Intra-va~Lna] or Lntra-uterlne use, colllprLsLng a pSyCllOtrOp:lC der:Lva~ Lve SllCh ns a pllenotll:LazLIle or be'nYodinzepLIle whLcll is associated with a L'oam, jelly, or other conventional pharm~aceutical vehicle for external use.
The principle involves replacing the usual spermicidal compound (or combining it) with a psychotropic substance which penetrates the spermatozoon membrane and inhibits spermatozoon activation by calmoduline, thus blocking the spermatozoon's fertilizing action.
It is known to use synthetic progestogens for contraceptive purposes. A distinction is made between three types of use thereof :
1) Da:ily use at very low doses ____ ____ At low doses, progestogens modify the cervical mucus and thus prevent spermatozoa from entering the cervix. Use of progestogens at these doses, however, also interferes with gonadotrophin secretion ~FSH
and LH), giving rise to the following therapeutic disadvantages :
- incomplete contraceptive effect, particularly at the beginning of treatment - intermittant breack-through bleeding - suppression of withdrawal bleeding, obtained with intermittantly administered treatment required to preserve the psychological comfort of recurring "menstrual" cycles.
~5~ D2 Norgestrel (at a rate of 30 ~g per day) or Norethindrone (at a rate of 300 ~g per day) may be cited as examples of daily low-dose progestagen therapy.
The invention concerns a contraceptive synergistic association consisting of a prolactin elevating benzamide such as SULPIRIDE or N (1-ethyl-2~pyrrolidinyl) methyl 2-methoxy 5-sulfamoyl benzamide, and a synthetic progestogen.
Sulpiride is essentially known for its psycllotropic properties.
This drug was observed to have a contraceptive effect at the usual doses employed in psychiatry (100 to 1000 mg per day). It has not been used extensively as a contraceptive, however, because of the relatively high dosage required for satisfactory protection and because clinical tests have shown that protection is incomplete during the first two months of drug administration. (D. BUVAT et al. Rev. Fr. Gynecol. Obstet. 71 (1) 53-51)-T'ne use of psychotropic substances for contraceptive purposes hashitherto been recommended only in the form of local application.
Reference may be made, for example, to international patent applications to COI~IF,R (pub'Lications of PCT 81/03~21 and 83/00086) which describe prepnrations Eor Intra-va~Lna] or Lntra-uterlne use, colllprLsLng a pSyCllOtrOp:lC der:Lva~ Lve SllCh ns a pllenotll:LazLIle or be'nYodinzepLIle whLcll is associated with a L'oam, jelly, or other conventional pharm~aceutical vehicle for external use.
The principle involves replacing the usual spermicidal compound (or combining it) with a psychotropic substance which penetrates the spermatozoon membrane and inhibits spermatozoon activation by calmoduline, thus blocking the spermatozoon's fertilizing action.
It is known to use synthetic progestogens for contraceptive purposes. A distinction is made between three types of use thereof :
1) Da:ily use at very low doses ____ ____ At low doses, progestogens modify the cervical mucus and thus prevent spermatozoa from entering the cervix. Use of progestogens at these doses, however, also interferes with gonadotrophin secretion ~FSH
and LH), giving rise to the following therapeutic disadvantages :
- incomplete contraceptive effect, particularly at the beginning of treatment - intermittant breack-through bleeding - suppression of withdrawal bleeding, obtained with intermittantly administered treatment required to preserve the psychological comfort of recurring "menstrual" cycles.
~5~ D2 Norgestrel (at a rate of 30 ~g per day) or Norethindrone (at a rate of 300 ~g per day) may be cited as examples of daily low-dose progestagen therapy.
2) Use for 21 days per cycle at high doses The contraceptive effect achieved by progestagens administered according to this treatment schedule results from inhibition of gonadrotrophin secretion, as for example with 2 mg of ethynodiol diacetate daily for 21 days. Such treatment has disadvantages and may induce :
- severe endometrial atrophy, with remitting metrorrhagia or absence of "menstruation" between courses of treatment - the clinical tolerance of the method is judged too highly uncertain
- severe endometrial atrophy, with remitting metrorrhagia or absence of "menstruation" between courses of treatment - the clinical tolerance of the method is judged too highly uncertain
3) Use in "de~ot'' Eorm Contraception is flchieved by monthly in~ections oE
medroxyproge~terone ocetate (known or e~ample under the t:rflde nnme D~PO~ OVRRA ). I'rog~s~erone admlnLqtered ln thls wny presellts tlle following dlsadvantclges wh:lch are non-reversible as long as the effect of the injectisn persists :
- disappearance of the "menstrual" cycle - irregular or prolonged bleeding - uncertainty with respect to the time at which fertility is restored after treatment is discontinued It is also well known that a mlmber of contraceptive preparations combine a progestogen and an oestrogen (generally ethinyl-oestradiol).
The oestrogens contained in such combinations, however, are considered to cause certain metabolic disturbances and hepatic or thrombo-embolic accidents, and consequently, this type of contraception is not feasible in all situations due to the risks of oestrogen therapy or its contra-indication in certain patients.
Therefore, in accordance with the present invention, a synergistic association of drugs is proposed which provides effective contraception from the onset of treatment at low dose levels, thereby enabling a considerable reduction in side effects. This therapeutic association is composed oE :
~s~
1) A benzamide ____ selected because of its weak effect on the central nervous system and because of its strong peripheral and, in particular, endocrinian effects ; such benzamides selected among those having no catatonic effect are characterized by their potency at low doses to inhibit oestrus, which consequently reflects their strong impact on the hypothalamo-hypophysial axis.
Reference may be made for example to Sulpiride (1) which, at a dose of 1 mg/kg increases the number of days of dioestrus by more than 200 %.
Other benzamides are illustrated in Table I :
(2) N-(1-allyl 2-pyrrolidylmethyl) 2,3-dimethoxy 5-sulfamoyl benzamide (3) N-(l-ethyl 2-pyrrolidylmethyl) 2-methoxy 4-amino 5-ethylsulfonyl benzamide
medroxyproge~terone ocetate (known or e~ample under the t:rflde nnme D~PO~ OVRRA ). I'rog~s~erone admlnLqtered ln thls wny presellts tlle following dlsadvantclges wh:lch are non-reversible as long as the effect of the injectisn persists :
- disappearance of the "menstrual" cycle - irregular or prolonged bleeding - uncertainty with respect to the time at which fertility is restored after treatment is discontinued It is also well known that a mlmber of contraceptive preparations combine a progestogen and an oestrogen (generally ethinyl-oestradiol).
The oestrogens contained in such combinations, however, are considered to cause certain metabolic disturbances and hepatic or thrombo-embolic accidents, and consequently, this type of contraception is not feasible in all situations due to the risks of oestrogen therapy or its contra-indication in certain patients.
Therefore, in accordance with the present invention, a synergistic association of drugs is proposed which provides effective contraception from the onset of treatment at low dose levels, thereby enabling a considerable reduction in side effects. This therapeutic association is composed oE :
~s~
1) A benzamide ____ selected because of its weak effect on the central nervous system and because of its strong peripheral and, in particular, endocrinian effects ; such benzamides selected among those having no catatonic effect are characterized by their potency at low doses to inhibit oestrus, which consequently reflects their strong impact on the hypothalamo-hypophysial axis.
Reference may be made for example to Sulpiride (1) which, at a dose of 1 mg/kg increases the number of days of dioestrus by more than 200 %.
Other benzamides are illustrated in Table I :
(2) N-(1-allyl 2-pyrrolidylmethyl) 2,3-dimethoxy 5-sulfamoyl benzamide (3) N-(l-ethyl 2-pyrrolidylmethyl) 2-methoxy 4-amino 5-ethylsulfonyl benzamide
(4) N-~l-allyl 2-pyrrolidylmethyl) 2-methoxy ~-amino 5-methyl sulFamoyl benæamlde
(5) N-(1-methyl 2-pyrrolldylme~llyl) 2-methoxy ~I-amlno 5~ hy.lslll.Eony,l bcnæ.lmlde 2) A progestogen preferably selected from Norgestrel, Ethynodiol diacetate~
Medroxyprogesterone and Norethindrone.
In breast-feeding mothers, lactation determines a period of infertility with total ovarian inactivity, which is very marked initially. Subsequently, suckling frequency decreases (with a consequent reduction in suckling-induced stimuli) resulting in a period of relative infertility with resumption oE ovarian activity characterized by an abnormal luteal phase. The mechanism of such infertilily is still subject of discussion, but the rise in prolactin secondary to suckling has been suggested as one of the causes.
Prolactin may act on the hypothalamus by suppressing the positive feedback of oestrogens responsible for ovulation, and inversely by facilitating negative feedback on gonadotrophin secretion. Prolactin may act directly on the ovary and inhibit the action of gonadotrophins on follicular growth resulting in subsequently abnor~al luteal phases, characterized by poor follicular development (Mc~eilly et al. J. Reprod.
Fert. (1982) 65, 559-569).
4 ~Z5~
The hypofertility caused by certain benzamides is probably partly due to their hyperprolactinemic effect. However, it may be that their oestrus blocking effect does not only depend on the serum concentration of prolactin but also on inhibition of LH-RH secretion. Such a mechanism has been put forward by Hermand et coll. (L'Encephale 1975 - I, 375-382).
These observations and the known inhibiting effect of progestogens on gonadotrophin secretion gave rise of the idea of assvciating a prolactin elevating benzamide at a low doses with a progestogen.
Clinical results demonstrated the synergistic effect of such an association making it possible to use smaller doses of each of the constituents. The daily dosage of Sulpiride ranges from 5 to 25 mg (average 10 mg) associated with 5 to 250 ~g of Norethisterone (taken as an example of a progestogen) which at maximum, equals half the usual daily doses, offers complete contraceptual protec~ion with an increased margin o~ safety. Such an assocLation wonld be o~ part:Lc-llar interest as a ~s~ar~er plLl" admLnistered Lor 1 to ~ months at the begLnnLng oE
contr;lcel~loll, aLIaylrlg ~he dLsndvan~nget; oE the prevlollsly de~L3cribed contraceptives tln particular ens~lrlng :Lmmediate contraceptlon and avolding frequent breackthrough bleeding). Subsequently conventional purely-progestogenic contraception would be utilised once ovulation was completely inhibited.
The present invention is also of interest because of the possibility of using it in populatlons where the nursing period are prolonged, as in the case of female populations in developing countries.
It is noteworthy that the oestro-progestogenic contraception that is presently recommended gradually reduces lactation and paradoxically causes premature restoral of fertility which, along with the frequent poor compliance of patients taking oestro-progestrogenic contraception, results in an increase in birth rate.
In that context, an association which provides both reliable contraception and the maintenance of lactation would appear of special interest, particularly since breast-feeding and increased intervals between births constitute two main factors in the struggle against infantile mortality in developing nations.
5 ~2~6 51~ ~
A further development of the invention affords an additional advantage. The addition of a very small amount of oestrogen to the drug association according to the invention results in a "physiological pill"
i.e. a pill which conserves the impression of a normal menstrual cycle, whereby several days of "menstrual" bleeding occur in the week-long interim between 3-week treatment cycles. Consequently, in addition to the total contraceptive protection, offered by such an association at markedly reduced doses of the compounds involved (no more than 15 ~g of ethinyl-oestradiol compared to 30 ~g found in the lowest dosed commercially available contraceptive) the patient has the benefit of the psychological comfort of having regular "menses" and will as a result be more likely to comply to therapy. A synthetic progestogen with intrinsic oestrogenic activity, such as LYNESTROL, could be used as the progestogenic agent, eliminating the need for an oestrogen compound.
The following examples are proposed in order to illustrate the invention but without limiting it :
Example 1 : use of a progestogen The EollowLng are :introcluced into an Lnert tablet or capsule, using a manulacturlng process l~nown per se :
NorethLsterone 150 ~Ig Sulpiride 10 mg excipient qs 500 mg Example 2 : use of a progestogen with oestrogenic activity Lynestrol 250 ~g Sulpiride 10 mg excipient qs 500 mg Example 3 : use of a progestogen and an oestrogen Norgestrel 15 ~g Sulpiride 10 mg Ethinyl-oestradiol 15 ~g excipient qs 500 mg All the usual pharmaceutical forms, including capsules and tablets among others, suitable for containing the substances according to the invention, may be used for the application thereof.
~;~56i~
The duration of use will depend on the physician's prescription, but in general, a maximum of 3 months is recommended when the invention is to be used as a precursor to conventional ;pure-progestogenic contraception, whether the latter is administered daily (capsules or tablets) or as a long term depot injection (e.g. a monthly injection).
TABLE I
Compound administered Increase in the number days of dioestrus at 1 mg/kg 1 + 231 %
2 + 168 %
3 -t 251 %
-~ 16~ %
157 %
Medroxyprogesterone and Norethindrone.
In breast-feeding mothers, lactation determines a period of infertility with total ovarian inactivity, which is very marked initially. Subsequently, suckling frequency decreases (with a consequent reduction in suckling-induced stimuli) resulting in a period of relative infertility with resumption oE ovarian activity characterized by an abnormal luteal phase. The mechanism of such infertilily is still subject of discussion, but the rise in prolactin secondary to suckling has been suggested as one of the causes.
Prolactin may act on the hypothalamus by suppressing the positive feedback of oestrogens responsible for ovulation, and inversely by facilitating negative feedback on gonadotrophin secretion. Prolactin may act directly on the ovary and inhibit the action of gonadotrophins on follicular growth resulting in subsequently abnor~al luteal phases, characterized by poor follicular development (Mc~eilly et al. J. Reprod.
Fert. (1982) 65, 559-569).
4 ~Z5~
The hypofertility caused by certain benzamides is probably partly due to their hyperprolactinemic effect. However, it may be that their oestrus blocking effect does not only depend on the serum concentration of prolactin but also on inhibition of LH-RH secretion. Such a mechanism has been put forward by Hermand et coll. (L'Encephale 1975 - I, 375-382).
These observations and the known inhibiting effect of progestogens on gonadotrophin secretion gave rise of the idea of assvciating a prolactin elevating benzamide at a low doses with a progestogen.
Clinical results demonstrated the synergistic effect of such an association making it possible to use smaller doses of each of the constituents. The daily dosage of Sulpiride ranges from 5 to 25 mg (average 10 mg) associated with 5 to 250 ~g of Norethisterone (taken as an example of a progestogen) which at maximum, equals half the usual daily doses, offers complete contraceptual protec~ion with an increased margin o~ safety. Such an assocLation wonld be o~ part:Lc-llar interest as a ~s~ar~er plLl" admLnistered Lor 1 to ~ months at the begLnnLng oE
contr;lcel~loll, aLIaylrlg ~he dLsndvan~nget; oE the prevlollsly de~L3cribed contraceptives tln particular ens~lrlng :Lmmediate contraceptlon and avolding frequent breackthrough bleeding). Subsequently conventional purely-progestogenic contraception would be utilised once ovulation was completely inhibited.
The present invention is also of interest because of the possibility of using it in populatlons where the nursing period are prolonged, as in the case of female populations in developing countries.
It is noteworthy that the oestro-progestogenic contraception that is presently recommended gradually reduces lactation and paradoxically causes premature restoral of fertility which, along with the frequent poor compliance of patients taking oestro-progestrogenic contraception, results in an increase in birth rate.
In that context, an association which provides both reliable contraception and the maintenance of lactation would appear of special interest, particularly since breast-feeding and increased intervals between births constitute two main factors in the struggle against infantile mortality in developing nations.
5 ~2~6 51~ ~
A further development of the invention affords an additional advantage. The addition of a very small amount of oestrogen to the drug association according to the invention results in a "physiological pill"
i.e. a pill which conserves the impression of a normal menstrual cycle, whereby several days of "menstrual" bleeding occur in the week-long interim between 3-week treatment cycles. Consequently, in addition to the total contraceptive protection, offered by such an association at markedly reduced doses of the compounds involved (no more than 15 ~g of ethinyl-oestradiol compared to 30 ~g found in the lowest dosed commercially available contraceptive) the patient has the benefit of the psychological comfort of having regular "menses" and will as a result be more likely to comply to therapy. A synthetic progestogen with intrinsic oestrogenic activity, such as LYNESTROL, could be used as the progestogenic agent, eliminating the need for an oestrogen compound.
The following examples are proposed in order to illustrate the invention but without limiting it :
Example 1 : use of a progestogen The EollowLng are :introcluced into an Lnert tablet or capsule, using a manulacturlng process l~nown per se :
NorethLsterone 150 ~Ig Sulpiride 10 mg excipient qs 500 mg Example 2 : use of a progestogen with oestrogenic activity Lynestrol 250 ~g Sulpiride 10 mg excipient qs 500 mg Example 3 : use of a progestogen and an oestrogen Norgestrel 15 ~g Sulpiride 10 mg Ethinyl-oestradiol 15 ~g excipient qs 500 mg All the usual pharmaceutical forms, including capsules and tablets among others, suitable for containing the substances according to the invention, may be used for the application thereof.
~;~56i~
The duration of use will depend on the physician's prescription, but in general, a maximum of 3 months is recommended when the invention is to be used as a precursor to conventional ;pure-progestogenic contraception, whether the latter is administered daily (capsules or tablets) or as a long term depot injection (e.g. a monthly injection).
TABLE I
Compound administered Increase in the number days of dioestrus at 1 mg/kg 1 + 231 %
2 + 168 %
3 -t 251 %
-~ 16~ %
157 %
Claims (9)
1. A novel contraceptive association with a synergistic effect comprising a prolactine elevating benzamide and a progestogen, in small quantities, possi-bly associated with an oestrogen.
2. According to Claim 1, a contraceptive association wherein the benzamide is Sulpiride.
3. According to Claim 2, a contraceptive association comprising from 5 to 25 mg of Sulpiride per unit dose.
4. According to Claims 1 to 3, a contra-ceptive association containing from 5 to 250 µg of Norethisterone.
5. According to Claim 1, a contra-ceptive association wherein the oestrogen is ethinyl-oestradiol.
6. According to Claim 1, a contraceptive association containing an oestrogen in a quantity of less than 30 µg per unit dose.
7. According to Claim 1, a contraceptive association wherein the progestogen is Lynestrol.
8. As a new therapeutic agent, a contra-ceptive association according to Claim 1, which can be used as a temporary precursor to conventional pure progestogenic contraception.
9. As a new therapeutic agent, a contra-ceptive association according to Claim 1, which can be used during lactation without affecting maintenance thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP84402033A EP0177654B1 (en) | 1984-10-10 | 1984-10-10 | Synergistic contraceptive mixture |
| EP84402033.9 | 1984-10-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1256802A true CA1256802A (en) | 1989-07-04 |
Family
ID=8192919
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000492672A Expired CA1256802A (en) | 1984-10-10 | 1985-10-10 | Contraceptive synergistic association |
Country Status (28)
| Country | Link |
|---|---|
| US (1) | US4639439A (en) |
| EP (1) | EP0177654B1 (en) |
| JP (1) | JPS6193119A (en) |
| AT (1) | ATE43499T1 (en) |
| BE (1) | BE903341A (en) |
| CA (1) | CA1256802A (en) |
| CH (1) | CH665953A5 (en) |
| DD (1) | DD238921A5 (en) |
| DE (2) | DE3478398D1 (en) |
| DK (1) | DK164442C (en) |
| FI (1) | FI83593C (en) |
| FR (1) | FR2571254B1 (en) |
| GB (1) | GB2165750B (en) |
| GR (1) | GR852428B (en) |
| HU (1) | HU194494B (en) |
| IL (1) | IL76470A0 (en) |
| IN (1) | IN162049B (en) |
| IS (1) | IS1393B6 (en) |
| LU (1) | LU86106A1 (en) |
| MA (1) | MA20544A1 (en) |
| NO (1) | NO169322C (en) |
| NZ (1) | NZ213652A (en) |
| OA (1) | OA08115A (en) |
| PH (1) | PH21798A (en) |
| PT (1) | PT81217B (en) |
| ZA (1) | ZA857524B (en) |
| ZM (1) | ZM7385A1 (en) |
| ZW (1) | ZW17785A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2617297B2 (en) * | 1986-04-28 | 1997-06-04 | 三菱電機株式会社 | Magnetic image reproducing device |
| US5595985A (en) | 1989-03-10 | 1997-01-21 | Endorecherche Inc. | Combination therapy for prophylaxis and/or treatment of benign prostatic hyperplasia |
| US5372996A (en) * | 1989-03-10 | 1994-12-13 | Endorecherche, Inc. | Method of treatment of androgen-related diseases |
| ATE230994T1 (en) * | 1989-07-07 | 2003-02-15 | Endorech Inc | METHOD OF TREATING ANDROGEN-RELATED DISEASES |
| DE69034148T2 (en) * | 1989-07-07 | 2005-06-30 | Endorecherche Inc., Ste-Foy | Combination therapy for the prophylaxis and / or treatment of benign prostatic hyperplasia |
| AU5856090A (en) * | 1989-07-07 | 1991-02-06 | Endorecherche Inc. | Androgen derivatives for use in the inhibition of sex steroid activity |
| UA35589C2 (en) * | 1992-05-21 | 2001-04-16 | Андорешерш Інк. | INHIBITORS OF TESTOSTERONE 5-<font face="Symbol">a</font>-REDUCTASE activity, pharmaceutical composition and a method for inhibiting activity of testosterone 5-<font face="Symbol">a</font>-REDUCTASE |
| US6995139B2 (en) * | 2001-04-20 | 2006-02-07 | Debiopharm S.A. | Cyclic undecapeptide pro-drugs and uses thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4067975A (en) * | 1975-08-04 | 1978-01-10 | Yu Ruey J | Treatment of psoriasis with 6-aminonicotinamide and thionicotinamide |
| CA1199273A (en) * | 1982-07-15 | 1986-01-14 | Ctibor Schindlery | Anti-inflammatory composition |
-
1984
- 1984-10-10 EP EP84402033A patent/EP0177654B1/en not_active Expired
- 1984-10-10 DE DE8484402033T patent/DE3478398D1/en not_active Expired
- 1984-10-10 AT AT84402033T patent/ATE43499T1/en not_active IP Right Cessation
-
1985
- 1985-09-18 IS IS3043A patent/IS1393B6/en unknown
- 1985-09-23 IL IL76470A patent/IL76470A0/en not_active IP Right Cessation
- 1985-09-23 IN IN739/MAS/85A patent/IN162049B/en unknown
- 1985-09-27 PT PT81217A patent/PT81217B/en not_active IP Right Cessation
- 1985-09-30 FI FI853768A patent/FI83593C/en not_active IP Right Cessation
- 1985-09-30 FR FR858514432A patent/FR2571254B1/en not_active Expired - Fee Related
- 1985-09-30 NZ NZ213652A patent/NZ213652A/en unknown
- 1985-09-30 ZA ZA857524A patent/ZA857524B/en unknown
- 1985-09-30 BE BE1/011343A patent/BE903341A/en not_active IP Right Cessation
- 1985-10-02 LU LU86106A patent/LU86106A1/en unknown
- 1985-10-03 DE DE19853535396 patent/DE3535396A1/en not_active Withdrawn
- 1985-10-07 ZM ZM73/85A patent/ZM7385A1/en unknown
- 1985-10-07 ZW ZW117/85A patent/ZW17785A1/en unknown
- 1985-10-08 GR GR852428A patent/GR852428B/el unknown
- 1985-10-08 JP JP60225948A patent/JPS6193119A/en active Pending
- 1985-10-08 MA MA20768A patent/MA20544A1/en unknown
- 1985-10-08 DD DD85281523A patent/DD238921A5/en not_active IP Right Cessation
- 1985-10-09 CH CH4351/85A patent/CH665953A5/en not_active IP Right Cessation
- 1985-10-09 OA OA58697A patent/OA08115A/en unknown
- 1985-10-09 GB GB8524891A patent/GB2165750B/en not_active Expired
- 1985-10-09 HU HU853921A patent/HU194494B/en not_active IP Right Cessation
- 1985-10-09 PH PH32904A patent/PH21798A/en unknown
- 1985-10-09 DK DK461485A patent/DK164442C/en not_active IP Right Cessation
- 1985-10-09 NO NO854009A patent/NO169322C/en unknown
- 1985-10-10 CA CA000492672A patent/CA1256802A/en not_active Expired
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