US3895110A - Methods for the treatment of psychic disturbances - Google Patents
Methods for the treatment of psychic disturbances Download PDFInfo
- Publication number
- US3895110A US3895110A US503733A US50373374A US3895110A US 3895110 A US3895110 A US 3895110A US 503733 A US503733 A US 503733A US 50373374 A US50373374 A US 50373374A US 3895110 A US3895110 A US 3895110A
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- United States
- Prior art keywords
- cyproterone
- acid
- treatment
- esters
- administered
- 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 - Lifetime
Links
- 238000000034 method Methods 0.000 title claims description 14
- 208000020016 psychiatric disease Diseases 0.000 title abstract description 6
- 229960003843 cyproterone Drugs 0.000 claims abstract description 26
- 239000002249 anxiolytic agent Substances 0.000 claims abstract description 11
- 230000000949 anxiolytic effect Effects 0.000 claims abstract description 11
- 230000003542 behavioural effect Effects 0.000 claims abstract description 6
- 230000004044 response Effects 0.000 claims abstract description 5
- DUSHUSLJJMDGTE-ZJPMUUANSA-N cyproterone Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DUSHUSLJJMDGTE-ZJPMUUANSA-N 0.000 claims abstract 2
- UWFYSQMTEOIJJG-FDTZYFLXSA-N cyproterone acetate Chemical compound C1=C(Cl)C2=CC(=O)[C@@H]3C[C@@H]3[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 UWFYSQMTEOIJJG-FDTZYFLXSA-N 0.000 claims description 38
- 229960000978 cyproterone acetate Drugs 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 11
- 230000003236 psychic effect Effects 0.000 claims description 3
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- 125000004432 carbon atom Chemical group C* 0.000 description 7
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- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
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- APRJFNLVTJWEPP-UHFFFAOYSA-N Diethylcarbamic acid Chemical compound CCN(CC)C(O)=O APRJFNLVTJWEPP-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N Gluconic acid Natural products OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 1
- 208000037490 Medically Unexplained Symptoms Diseases 0.000 description 1
- SGXDXUYKISDCAZ-UHFFFAOYSA-N N,N-diethylglycine Chemical compound CCN(CC)CC(O)=O SGXDXUYKISDCAZ-UHFFFAOYSA-N 0.000 description 1
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 1
- 206010029216 Nervousness Diseases 0.000 description 1
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- 125000002252 acyl group Chemical group 0.000 description 1
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- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- ZZHGIUCYKGFIPV-UHFFFAOYSA-N butylcarbamic acid Chemical compound CCCCNC(O)=O ZZHGIUCYKGFIPV-UHFFFAOYSA-N 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
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- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- DWLVWMUCHSLGSU-UHFFFAOYSA-N dimethylcarbamic acid Chemical compound CN(C)C(O)=O DWLVWMUCHSLGSU-UHFFFAOYSA-N 0.000 description 1
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- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
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- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 1
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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
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
Definitions
- Cyproterone (6-chloro- 1 a,2oz-methylene-4,6- pregnadien-l7a-ol-3,20-dione) and the 17-esters thereof are known, for example, from US. Pat. No. 3,234,093.
- steroids are known to exert a depressant effect on the central nervous system and possess hypnotic and/or anesthetic effects. These steroids are not useful as psychotropic agents due to their known side effects and depression of the central nervous system.
- Minor tranquilizers of the benzodiazepines type have become popular as medicinal agents having an anxiolytic and sedative effect.
- these active agents have the disadvantage that their use can cause a psychic dependency (WHO Bull. 43 Suppl., 1970, 49).
- the muscle-relaxant properties of these substances can lead to undesired side effects (AMA Drug Evaluations, American Medical Assoc. Chicago, lst ed. 1971, pp. N 47 ff.).
- the conventional anxiolytic (minor tranquilizer) and anti depressant (thymoleptic) substances have sedating properties which are undesirable during waking hours, e.g., during work or activity which requires a person to be alert.
- cyproterone or a 17- ester thereof is administered systemically to a patient with a psychic disturbance of the affective or behavioral type in an amount effective to evoke an anxiolytic response.
- the preferred 17-esters of cyproterone are esters of hydrocarbon carboxylic acids of l-8 carbon atoms, preferably 2-8 carbon atoms, e.g., a monobasic alkanoic acid, e.g., formic, acetic, propionic butyric, isobutyric, oz-ethylbutyric, valeric, isovaleric, a-ethylvaleric, trimethylacetic, 2-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, enanthic, octanoic, a cyclic acid, preferably a cycloaliphatic acid, e.g., cyclopropylideneacetic, cyclobutylcarboxylic, cyclopentylcarboxylic, cyclopentylacetic, B-cyclopentylpropionic
- a preferred class of acyl groups are those of straight or branched chain monobasic alkanoic acids, preferably of 28 carbon atoms, e.g., acetyl, propionyl, butyryl, isobutyryl, of which acetyl is most preferred.
- acyl radical of the 17-ester group is not critical, as long as it is not physiologically toxic and it can be formed on the cyproterone l7-hydroxy group
- contemplated equivalents of the preferred esters described above, insofar as they can be formed are those formed with other aliphatic and aromatic unsubstituted and substituted and monobasic, dibasic and polybasic carboxylic acid, saturated or unsaturated aliphatic, araliphatic and aromatic carboxylic acids containing up to 18 and preferably up to 8 carbon atoms, e.g.,undecylic, palmitic, B-cyclohexylpropionic acid, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- dimethylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, cinnamic, naphthoic, 3-methyl-a-naphthoic, B-phenyL
- Such contemplated equivalents can also be esters with an acid containing one, two or more simple substituents in the molecule, e.g., hydroxy, halo, alkoxy, acyloxy, sulfonyloxy, amido, sulfato, nitro, mercapto and cyano, in the molecule, e.g., glycolic, lactic, citric, tartaric, d-maleic, d-glyceric, mannoic, gluconic and salicylic acid; of an amino acid, e.g., glycine, aminopropionic, diglycollamic, triglycollamic, methylglycine, dimethylglycine, diethylglycine, para-aminosalicylic, paraaminobenzoic, ethylmercaptoacetic, benzylmercaptoacetic, chloroacetic, fiuoroacetic, trichloroacetic, trifluoroacetic,
- Cyproterone acetate was tested in a placebocontrolled double blank experiment by quantitative pharmaco-electroencephalography (CEEG) and by the method of evoked potentials on humans (T.M. Itil et a]. Quantitative Pharmaco-Electroencephalography [The use of computerized cerebral biopotentials in psychotropic drug research] in Psychotropic Drug and the Human EEG, Modern Problems of Pharmacopyschiatry Series, Basel, New York: S. Karger, 1974).
- the effects and side effects were determined by various rating scales, e.g., for neurological and psychosomatic symptom spectra, by self-rating scales for sedation, fear and depression, as well as by interviews with physicians.
- the effectiveness of cyproterone acetate was proven in premenstrual anxiety and tension conditions. The effectiveness was described by physicians judgments and placed into objective form in ratings.
- the effect according to this invention occurs soon after administration, which is surprising since it is generally known from endocrine-active steroids that such effects are observed only after a longer treatment period.
- a particular advantage of the medicinal agents based on cyproterone or a l7-ester thereof in the present field of application of this invention is that, even during long-term usage, dependency does not arise and no tolerance requiring higher dosages is observed, as occurs, for example, in the case of the benzodiazepines. Additionally, even with high doses, there is no danger of impairing the functional power and reaction capacity, or of lowering the level of consciousness to produce a type of drowsiness, for example during driving or working.
- cyproterone and the l7-esters thereof even in a massive single oral dose of the order of 2 g., do not ordinarily produce adverse neurological, vegetative or other side effects, or any disturbance of consciousness. Therefore, even an overdose does not lead to serious muscle relaxation and impairment of consciousness.
- Cyproterone and its l7-esters exhibits a neuropsychotropic effect of the type of the minor tranquilizers and especially anxiolytic, antidepressant (thymoleptic) and sedative activity.
- cyproterone and the l7-esters thereof possess the advantage that they overcome the deficiency of lack of dissociation between sedative and anxiolytic properties present in the known psychopharmaceuticals based on benzodiazepines.
- this invention relates to the treatment of psychic disturbances in the affective and behavioral ranges, especially anxiety and tension conditions, with and without depression, unrest and disturbances resulting from stress situations or excess stimulation, as well as pathological aggressiveness, employing cyproterone or a l7-ester thereof.
- the drugs based on cyproterone and l7-esters thereof according to the present invention can be administered subcutaneously, intramuscularly or orally with effectiveness by injection or oral administration being about equal.
- the daily dosage is 0.05 500 mg., preferably 0.1- 50 mg. This dosage can be administered in a single oral dose. It is advantageous to remain below the threshold value of endocrine effectiveness, especially under the threshold value for an antiandrogen effect in males and females of 50 to 100 mg per day.
- the formulation of the medicinal agents of this invention is accomplished in a conventional manner, by processing cyproterone and the esters thereof, especially the esters with l-8 carbon atoms, together with the vehicles, diluents and flavor-ameliorating substance, customary in galenic pharmacy, and then converting the compositions into the desired forms of application, such as, for example, tablets, dragees, capsules and solutions suitable for oral or parenteral administration.
- oily solutions such as solutions in sesame, castor and cottonseed oil.
- diluents or solubilizers such as, for example, benzyl benzoate or benzyl alcohol, can be added to increase solubility.
- cyproterone and the esters thereof can also be utilized in microencapsulated form.
- especially suitable are capsules, tablets, dragees, pills, suspensions and solutions.
- the amount of active agent in the thusformulated medicinal agents is 0.05 500 mg., preferably 0.1 50 mg., per unit dose.
- EXAMPLE I 50.0 mg. of 6-chloro-17-acetoxy-l0:,20z-methylene- 4,6-pregnadiene-3,20-dione (cyproterone acetate) is mixed homogeneously with 110.5 mg. of lactose, 59.5 mg. of corn starch, 2.0 mg. ofAerosil, 2.5 mg. of polyvinylpyrrolidone 25, and 0.5 mg. of magnesium stearate and compressed, without previous granulation, into round, biplanar tablets with a breaking notch and a final weight of 225 mg.
- EXAMPLE 2 To produce an injection solution, 100.0 mg. of cyproterone acetate is dissolved in 618.6 mg. of benzyl benzoate (USP XVII) and 353.4 mg. of castor oil (DAB [German Pharmacopoeia] 7, USP XVII); the solution is filtered under sterile conditions and filled aseptically into 3-ml. ampoules.
- USP XVII benzyl benzoate
- DAB German Pharmacopoeia] 7, USP XVII
- EXAMPLE 3 Respectively 0.1 mg. of cyproterone acetate (micronized, particle size 2-8 IL) is mixed homogeneously with mg. of lactose (DAB 7, USP XVII) and filled into hard-gelatin capsules (5 X 15 mm.).
- EXAMPLE 4 Analogously to Example 1, 10 mg. of cyproterone is compressed, with 110.5 mg. of lactose, 59.5 mg. of corn starch, 2.0 mg. ofAerosil, 2.5 mg. of polyvinylpyrrolidone 25, and 0.5 mg. of magnesium stearate, into tablets having a final weight of mg.
- EXAMPLE 5 This study was set up in a group of five very young male patients in the age range of 18-26, who are suffering from symptoms of anxiety and they were included in this study. All patients received anxiolytics or similar treatment but not systematically and no longer period of time before cyproterone acetate treatment. All patients are characterized by nervousness, restlessness, anxiety, headache, and tachycardia. Before cyproterone acetate medication, all drugs were discontinued and during the study no additional medication was allowed. The treatment period was 2 weeks and the daily dosages ranged from 1-6 mg (mean 3.7-4.7 mg) (total dosage 55-57 mg).
- Cyproterone acetate was administered to 10 female patients in the age range of 25-55. All patients had clinical symptoms of anxiety, depression or psycho-physiological complaints which appear either in the premenstrual period or if already present, showed marked exacerbation after midcycle.
- the patients were medicated for two cycles, one with placebo and one with cyproterone acetate. Treatment was started immediately following the appearance of clinical symptoms and continued until a few days before the estimated date of the beginning of the next cycle. Cyproteronc acetate and placebo were given at 100 mg once a day in the morning. All patients showed a significant remission of anxiety-tension and depression during the premenstrual period.
- a method for the treatment in a affected person of psychic disturbances of the affective or behavioral type which comprises administering systemically to the af fected person an amount of cyproterone or a 17-ester thereof with a hydrocarboncarboxylic acid of l-8 carbon atoms effective to evoke an anxiolytic response.
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Abstract
Cyproterone and its 17-esters are administered to persons with a psychic disturbance of the affective or behavioral type to evoke an anxiolytic response.
Description
United States Patent Itil et al.
METHODS FOR THE TREATMENT OF PSYCHIC DISTURBANCES Inventors: Turan M. Itil, Nyack, N.Y.; Werner Martin Herrmann, Berlin, Germany Assignee: Schering Aktiengesellschaft, Berlin,
Germany Filed: Sept. 6, 1974 Appl. No.: 503,733
Foreign Application Priority Data Sept. 6, 1973 Germany 2345377 US. Cl. 424/242 Int. Cl. A61K 27/00 [451 July 15,1975
2/1966 Wiechert et al. 260/239.55 R
Primary Examiner-Stanley J. Friedman Attorney, Agemy or FirmMillen, Raptes & White [5 7 ABSTRACT Cyproterone and its l7-esters are administered to persons with a psychic disturbance of the affective or behavioral type to evoke an anxiolytic response.
5 Claims, No Drawings METHODS FOR THE TREATMENT OF PSYCHIC DISTURBANCES BACKGROUND OF THE INVENTION This invention relates to medicinal agents comprising cyproterone or a l7-ester thereof and to their use.
Cyproterone (6-chloro- 1 a,2oz-methylene-4,6- pregnadien-l7a-ol-3,20-dione) and the 17-esters thereof are known, for example, from US. Pat. No. 3,234,093.
Several steroids are known to exert a depressant effect on the central nervous system and possess hypnotic and/or anesthetic effects. These steroids are not useful as psychotropic agents due to their known side effects and depression of the central nervous system.
Minor tranquilizers of the benzodiazepines type have become popular as medicinal agents having an anxiolytic and sedative effect. However, these active agents have the disadvantage that their use can cause a psychic dependency (WHO Bull. 43 Suppl., 1970, 49). Furthermore, the muscle-relaxant properties of these substances, for example, can lead to undesired side effects (AMA Drug Evaluations, American Medical Assoc. Chicago, lst ed. 1971, pp. N 47 ff.). Also, the conventional anxiolytic (minor tranquilizer) and anti depressant (thymoleptic) substances have sedating properties which are undesirable during waking hours, e.g., during work or activity which requires a person to be alert.
It has now been found that cyproterone and the esters thereof have a broader spectrum of effectiveness, compared to conventional minor tranquilizers, with the additional advantage that they do not exhibit the above-described adverse side effects, but instead have additionally an antidepressant effect. This result has been obtained for the first time with a substance having a steroid structure.
SUMMARY OF THE INVENTION According to this invention, cyproterone or a 17- ester thereof is administered systemically to a patient with a psychic disturbance of the affective or behavioral type in an amount effective to evoke an anxiolytic response.
DETAILED DISCUSSION The preferred 17-esters of cyproterone are esters of hydrocarbon carboxylic acids of l-8 carbon atoms, preferably 2-8 carbon atoms, e.g., a monobasic alkanoic acid, e.g., formic, acetic, propionic butyric, isobutyric, oz-ethylbutyric, valeric, isovaleric, a-ethylvaleric, trimethylacetic, 2-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethylacetic, enanthic, octanoic, a cyclic acid, preferably a cycloaliphatic acid, e.g., cyclopropylideneacetic, cyclobutylcarboxylic, cyclopentylcarboxylic, cyclopentylacetic, B-cyclopentylpropionic, cyclohexylcarboxylic, cyclohexylacetic, a carbocyclic aryl or an alkaryl acid, e.g., benzoic, 2-, 3- or 4- methylbenzoic acid.
A preferred class of acyl groups are those of straight or branched chain monobasic alkanoic acids, preferably of 28 carbon atoms, e.g., acetyl, propionyl, butyryl, isobutyryl, of which acetyl is most preferred.
Since the exact chemical nature of the acyl radical of the 17-ester group is not critical, as long as it is not physiologically toxic and it can be formed on the cyproterone l7-hydroxy group, contemplated equivalents of the preferred esters described above, insofar as they can be formed, are those formed with other aliphatic and aromatic unsubstituted and substituted and monobasic, dibasic and polybasic carboxylic acid, saturated or unsaturated aliphatic, araliphatic and aromatic carboxylic acids containing up to 18 and preferably up to 8 carbon atoms, e.g.,undecylic, palmitic, B-cyclohexylpropionic acid, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- dimethylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic, cinnamic, naphthoic, 3-methyl-a-naphthoic, B-phenyL propionic, diphenylacetic, biphenylacetic or a-naphthylacetic acid, or a dibasic alkanoic acid, e.g., oxalic, maleic, fumaric, succinic, malonic, glutaric, a-methylglutaric, B-methylglutaric, B,B-dimethylglutaric, adipic, pimelic and suberic acid, a dibasic aryl acid, especially those capable of forming a cyclic anhydride, e.g., phthalic acid, or a carbamic acid, e.g., carbamic acid, phenylcarbarnic, n-butylcarbamic, dimethylcarbamic, diethylcarbamic and allophanic acid; or of a heterocyclic acid, e.g., B-furylcarboxylic pyrrole carboxylic, B-pyrrolidylpropionic, N-methylpyrrolidyL 2-carboxylic, -0z-picolinic, nicotinic, indole-2- carboxylic, 6-hydroxyindolyl-3-acetic and N- methylmorphol'yl-2-carboxylic and pyrrolyl-2- carboxylic acidfor a sulfonic acid of 118, preferably 1-12, carbon atoms, including alkanesulfonic, e.g., methaneand ethanesulfonic, and aryl sulfonic, e.g., benzeneand p-toluenesulfonic acid.
Such contemplated equivalents can also be esters with an acid containing one, two or more simple substituents in the molecule, e.g., hydroxy, halo, alkoxy, acyloxy, sulfonyloxy, amido, sulfato, nitro, mercapto and cyano, in the molecule, e.g., glycolic, lactic, citric, tartaric, d-maleic, d-glyceric, mannoic, gluconic and salicylic acid; of an amino acid, e.g., glycine, aminopropionic, diglycollamic, triglycollamic, methylglycine, dimethylglycine, diethylglycine, para-aminosalicylic, paraaminobenzoic, ethylmercaptoacetic, benzylmercaptoacetic, chloroacetic, fiuoroacetic, trichloroacetic, trifluoroacetic, thioglycolic, m-nitrobenzoic, 2,3,4- trimethoxybenzoic, phenoxyacetic and a-naphthoxyacetic acid.
Cyproterone acetate was tested in a placebocontrolled double blank experiment by quantitative pharmaco-electroencephalography (CEEG) and by the method of evoked potentials on humans (T.M. Itil et a]. Quantitative Pharmaco-Electroencephalography [The use of computerized cerebral biopotentials in psychotropic drug research] in Psychotropic Drug and the Human EEG, Modern Problems of Pharmacopyschiatry Series, Basel, New York: S. Karger, 1974).
Moreover, the effects and side effects were determined by various rating scales, e.g., for neurological and psychosomatic symptom spectra, by self-rating scales for sedation, fear and depression, as well as by interviews with physicians. In clinical tests, the effectiveness of cyproterone acetate was proven in premenstrual anxiety and tension conditions. The effectiveness was described by physicians judgments and placed into objective form in ratings. In the practical application of cyproterone and the esters thereof, the effect according to this invention occurs soon after administration, which is surprising since it is generally known from endocrine-active steroids that such effects are observed only after a longer treatment period. In the case of cyproterone acetate, in its previous applications for its known effects, such effects were known to occur only after weeks of treatment. Whereas, the desired psychotropic effects of cyproterone or its l7-esters, occur within hours after administration.
A particular advantage of the medicinal agents based on cyproterone or a l7-ester thereof in the present field of application of this invention is that, even during long-term usage, dependency does not arise and no tolerance requiring higher dosages is observed, as occurs, for example, in the case of the benzodiazepines. Additionally, even with high doses, there is no danger of impairing the functional power and reaction capacity, or of lowering the level of consciousness to produce a type of drowsiness, for example during driving or working.
Furthermore, it is also advantateous that cyproterone and the l7-esters thereof, even in a massive single oral dose of the order of 2 g., do not ordinarily produce adverse neurological, vegetative or other side effects, or any disturbance of consciousness. Therefore, even an overdose does not lead to serious muscle relaxation and impairment of consciousness.
During the further development of psychopharmaceuticals based on benzodiazepines, a dissociation between the sedative and anxiolytic properties was sought.
With cyproterone and its l7-esters, a class of compounds has been found for the first time which has the typical activity profile of an anxiolytic agent, but does not have any significant sedating properties.
Cyproterone and its l7-esters exhibits a neuropsychotropic effect of the type of the minor tranquilizers and especially anxiolytic, antidepressant (thymoleptic) and sedative activity.
Accordingly, cyproterone and the l7-esters thereof possess the advantage that they overcome the deficiency of lack of dissociation between sedative and anxiolytic properties present in the known psychopharmaceuticals based on benzodiazepines.
In its method of use aspect, this invention relates to the treatment of psychic disturbances in the affective and behavioral ranges, especially anxiety and tension conditions, with and without depression, unrest and disturbances resulting from stress situations or excess stimulation, as well as pathological aggressiveness, employing cyproterone or a l7-ester thereof.
In medical practice, the drugs based on cyproterone and l7-esters thereof according to the present invention can be administered subcutaneously, intramuscularly or orally with effectiveness by injection or oral administration being about equal. The daily dosage is 0.05 500 mg., preferably 0.1- 50 mg. This dosage can be administered in a single oral dose. It is advantageous to remain below the threshold value of endocrine effectiveness, especially under the threshold value for an antiandrogen effect in males and females of 50 to 100 mg per day.
The formulation of the medicinal agents of this invention is accomplished in a conventional manner, by processing cyproterone and the esters thereof, especially the esters with l-8 carbon atoms, together with the vehicles, diluents and flavor-ameliorating substance, customary in galenic pharmacy, and then converting the compositions into the desired forms of application, such as, for example, tablets, dragees, capsules and solutions suitable for oral or parenteral administration.
Especially suitable for injections are oily solutions, such as solutions in sesame, castor and cottonseed oil.
If desired, diluents or solubilizers, such as, for example, benzyl benzoate or benzyl alcohol, can be added to increase solubility. To obtain a protracted effect, cyproterone and the esters thereof can also be utilized in microencapsulated form. For oral application, especially suitable are capsules, tablets, dragees, pills, suspensions and solutions. The amount of active agent in the thusformulated medicinal agents is 0.05 500 mg., preferably 0.1 50 mg., per unit dose.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the specification and claims in any way whatsoever.
EXAMPLE I 50.0 mg. of 6-chloro-17-acetoxy-l0:,20z-methylene- 4,6-pregnadiene-3,20-dione (cyproterone acetate) is mixed homogeneously with 110.5 mg. of lactose, 59.5 mg. of corn starch, 2.0 mg. ofAerosil, 2.5 mg. of polyvinylpyrrolidone 25, and 0.5 mg. of magnesium stearate and compressed, without previous granulation, into round, biplanar tablets with a breaking notch and a final weight of 225 mg.
EXAMPLE 2 To produce an injection solution, 100.0 mg. of cyproterone acetate is dissolved in 618.6 mg. of benzyl benzoate (USP XVII) and 353.4 mg. of castor oil (DAB [German Pharmacopoeia] 7, USP XVII); the solution is filtered under sterile conditions and filled aseptically into 3-ml. ampoules.
EXAMPLE 3 Respectively 0.1 mg. of cyproterone acetate (micronized, particle size 2-8 IL) is mixed homogeneously with mg. of lactose (DAB 7, USP XVII) and filled into hard-gelatin capsules (5 X 15 mm.).
EXAMPLE 4 Analogously to Example 1, 10 mg. of cyproterone is compressed, with 110.5 mg. of lactose, 59.5 mg. of corn starch, 2.0 mg. ofAerosil, 2.5 mg. of polyvinylpyrrolidone 25, and 0.5 mg. of magnesium stearate, into tablets having a final weight of mg.
EXAMPLE 5 This study was set up in a group of five very young male patients in the age range of 18-26, who are suffering from symptoms of anxiety and they were included in this study. All patients received anxiolytics or similar treatment but not systematically and no longer period of time before cyproterone acetate treatment. All patients are characterized by nervousness, restlessness, anxiety, headache, and tachycardia. Before cyproterone acetate medication, all drugs were discontinued and during the study no additional medication was allowed. The treatment period was 2 weeks and the daily dosages ranged from 1-6 mg (mean 3.7-4.7 mg) (total dosage 55-57 mg).
In two patients complete remission with the improvement of symptoms of anxiety, somatic symptoms, headache was observed (Patient 2 and 3). In one patient a moderate degree of improvement was observed in dosages 3-4 mg daily (Patient 4). When the dosage was increased patient got restless. In two other patients (Patient l and 5), only slight improvement was observed in symptoms such as restlessness, parasthesia, difficulty in swallowing, tachycardia, and insomnia.
EXAMPLE 6 Cyproterone acetate was administered to 10 female patients in the age range of 25-55. All patients had clinical symptoms of anxiety, depression or psycho-physiological complaints which appear either in the premenstrual period or if already present, showed marked exacerbation after midcycle.
The patients were medicated for two cycles, one with placebo and one with cyproterone acetate. Treatment was started immediately following the appearance of clinical symptoms and continued until a few days before the estimated date of the beginning of the next cycle. Cyproteronc acetate and placebo were given at 100 mg once a day in the morning. All patients showed a significant remission of anxiety-tension and depression during the premenstrual period.
The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
What is claimed is:
l. A method for the treatment in a affected person of psychic disturbances of the affective or behavioral type which comprises administering systemically to the af fected person an amount of cyproterone or a 17-ester thereof with a hydrocarboncarboxylic acid of l-8 carbon atoms effective to evoke an anxiolytic response.
2. A method according to claim 1 wherein cyproterone is administered.
3. A method according to claim 2 wherein the cyproterone is administered orally.
4. A method according to claim 1 wherein cyproterone acetate is administered.
5. A method according to claim 4 wherein the cyproterone acetate is administered orally.
Claims (5)
1. A METHOD FOR THE TREATMENT IN A AFFECTED PERSON OF PSYCHIC DISTURBANCES OF THE AFFECTIVE OR BEHAVIORAL TYPE WHICH COMPRISES ADMINISTERING SYSTEMICALLY TO THE AFFECTED PERSON AN AMOUNT OF CYPROTERONE OR A 17-ESTER THEREOF WITH A HYDROCARBONCARBOXYLIC ACID OF 1-8 CARBON ATOMS EFFECTIVE TO EVOKE AN ANXIOLYTIC RESPONSE.
2. A method according to claim 1 wherein cyproterone is administered.
3. A method according to claim 2 wherein the cyproterone is administered orally.
4. A method according to claim 1 wherein cyproterone acetate is administered.
5. A method according to claim 4 wherein the cyproterone acetate is administered orally.
Applications Claiming Priority (1)
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DE19732345377 DE2345377A1 (en) | 1973-09-06 | 1973-09-06 | PHARMACEUTICAL PREPARATION I |
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US503733A Expired - Lifetime US3895110A (en) | 1973-09-06 | 1974-09-06 | Methods for the treatment of psychic disturbances |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6165504A (en) * | 1998-09-23 | 2000-12-26 | Barr Laboratories, Inc. | Methods for treating hot flashes and improving the quality of life of castrated prostatic cancer patients |
US6613758B1 (en) | 1999-04-02 | 2003-09-02 | Barr Laboratories, Inc. | Method for treating osteoporosis in castrated prostatic cancer patients |
WO2009049030A1 (en) * | 2007-10-09 | 2009-04-16 | Triton Biopharma, Llc | Method to use compositions having antidepressant anxiolytic and other neurological activity and compositions of matter |
US20100260860A1 (en) * | 2008-10-10 | 2010-10-14 | Ahmed Salah U | Methods for Treating Vasomotor Symptoms in Castrated Prostatic Cancer Patients with Low Dose Cyproterone Acetate |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2880276A1 (en) * | 2005-01-05 | 2006-07-07 | Lefebvre Dominique Caparros | USE OF ANTI-ANDROGENES IN THE TREATMENT OF AGGRESSIVE OR IMPULSIVE BEHAVIORS INDUCED BY DISEASES OF THE CENTRAL NERVOUS SYSTEM |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3234093A (en) * | 1961-04-29 | 1966-02-08 | Schering Ag | 6-chloro-1, 2alpha-methylene-delta6-17alpha-hydroxyprogesterone compounds and compositions |
-
1973
- 1973-09-06 DE DE19732345377 patent/DE2345377A1/en not_active Withdrawn
-
1974
- 1974-09-06 US US503733A patent/US3895110A/en not_active Expired - Lifetime
- 1974-09-06 GB GB3912274A patent/GB1474749A/en not_active Expired
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3234093A (en) * | 1961-04-29 | 1966-02-08 | Schering Ag | 6-chloro-1, 2alpha-methylene-delta6-17alpha-hydroxyprogesterone compounds and compositions |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6165504A (en) * | 1998-09-23 | 2000-12-26 | Barr Laboratories, Inc. | Methods for treating hot flashes and improving the quality of life of castrated prostatic cancer patients |
US6613758B1 (en) | 1999-04-02 | 2003-09-02 | Barr Laboratories, Inc. | Method for treating osteoporosis in castrated prostatic cancer patients |
WO2009049030A1 (en) * | 2007-10-09 | 2009-04-16 | Triton Biopharma, Llc | Method to use compositions having antidepressant anxiolytic and other neurological activity and compositions of matter |
US20100260860A1 (en) * | 2008-10-10 | 2010-10-14 | Ahmed Salah U | Methods for Treating Vasomotor Symptoms in Castrated Prostatic Cancer Patients with Low Dose Cyproterone Acetate |
US8288342B2 (en) | 2008-10-10 | 2012-10-16 | Teva Women's Health, Inc. | Methods for treating vasomotor symptoms in castrated prostatic cancer patients with low dose cyproterone acetate |
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GB1474749A (en) | 1977-05-25 |
DE2345377A1 (en) | 1975-03-20 |
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