US20040029787A1 - Use of substances with oxytocin activity against climacteric disorders - Google Patents

Use of substances with oxytocin activity against climacteric disorders Download PDF

Info

Publication number
US20040029787A1
US20040029787A1 US10/258,013 US25801303A US2004029787A1 US 20040029787 A1 US20040029787 A1 US 20040029787A1 US 25801303 A US25801303 A US 25801303A US 2004029787 A1 US2004029787 A1 US 2004029787A1
Authority
US
United States
Prior art keywords
seq
group
oxytocin
nothing
cys
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.)
Abandoned
Application number
US10/258,013
Other languages
English (en)
Inventor
Kerstin Uvnas-Moberg
Thomas Lundeberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
EntreTech Medical AB
Original Assignee
EntreTech Medical AB
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by EntreTech Medical AB filed Critical EntreTech Medical AB
Assigned to ENTRETECH MEDICAL AB reassignment ENTRETECH MEDICAL AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: UVNAS-MOBERG, KERSTIN, LUNDEBERG, THOMAS
Publication of US20040029787A1 publication Critical patent/US20040029787A1/en
Priority to US11/345,218 priority Critical patent/US7727959B2/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • the present invention relates to the use of substances with oxytocin activity against climacteric disorders or similar symptoms due to dysfunction in the ovaries. It also relates to a pharmaceutical composition comprising at least one substance with oxytocin activity against climacteric disorders.
  • Oxytocin was one of the first peptide hormones to be isolated and sequenced. It is a nonapeptide with two cysteine residues that form a disulfide bridge between positions 1 and 6 and corresponds to the formula
  • oxytocin For a long time the only effects attributed to oxytocin were its stimulating effects on milk ejection and uterine contractions, but in the past decades it has been shown tat oxytocin exerts a wide spectrum of effects within the central nervous system, CNS. It has been suggested that oxytocin participates in the control of memory and learning processes and of various types of behaviour such as feeding, locomotion, as well as maternal and sexual behaviour. Oxytocin is also suggested to participate in the control of cardiovascular functions, thermoregulation, and pain threshold and fluid balance. There is also evidence that oxytocin is involved in the control of various immunological processes.
  • oxytocin injections cause a lowering of blood pressure and increased weight gain-long lasting effects after repetitive administration.
  • oxytocin plays an important role in the intention between mother and progeny in mammals.
  • the products may also be used prophylactic in young human beings e.g. already in new born babies or young children to prevent the development of diseases later on in life which diseases are dependent on stress conditions during the fetal life.
  • diseases may be heart/vessel diseases such as stroke, heat infarct, hypertension, and diabetes.
  • oxytocin is produced in the paraventricular nucleus, PVN, and the supraoptic nucleus, SON, of the hypothalamus. It differs by only two amino acids from vasopressin, which is also produced in these nuclei.
  • the magnocellular oxytocinergic neurones of the SON and PVN send oxons to the posterior pituitary from which oxytocin is released into the circulation. Parvocellular neurones that originate in the PVN project into multiple areas within CNS.
  • the oxytocin-producing cells are innervated by cholinergic, catecholaminergic as well as peptidergic neurones.
  • oxytocin in different tissues outside the brain, such as the uterus, ovaries, testis, thymus, adrenal medulla and pancreas has been demonstrated and oxytocin is suggested to exert local effects in these organs.
  • a parallel secretion of oxytocin into the brain regions and into the circulation occurs in response to some stimuli such as suckling, but other stimuli can cause separate activation of oxytocinergic neurones, terminating in the brain or the pituitary.
  • oxytocin derivatives i.e. compounds with a structure similar to that of oxytocin.
  • the inventors have preliminary indications that other oxytocin derivatives than oxytocin could give the effects against climacteric disorders and disorders of ovarian functions as well as parts of the oxytocin molecule.
  • No publications describe the use of oxytocin or any other oxytocin derivatives or parts of the oxytocin molecule to have effects against climacteric disorders or other types of premature ovarian dysfunction.
  • oxytocin improves the vaginal mucosal membranes of women with postmenopausal disorders and improves the mood of such women (Example 1).
  • oxytocin normalises hormone levels and moderates weight changes (Example 2), increases motor activity and relieves somatic discomfort (Example 3), reduces hot flushes (Example 4), reduces hyperactivity in the sympathetic nervous system (Example 5), and suppresses bone loss (Example 6).
  • oxytocin or that substances with oxytocin activity may be used against climacteric disorders and ovarian dysfunction.
  • the oxytocin derivatives according to the invention are not only suitable a postmenopausal disorders but also against premenopausal, premenopausal and ovarian dysfunction.
  • the effect of oxytocin can be extended or strengthened by administration in combination with drugs increasing the release of oxytocin and/or the number or affinity of receptors, such as oestrogen, or drugs having an ⁇ 2 -agonistic effect, such as clonidine.
  • the present invention relates to the use of substances with oxytocin activity against climacteric disorders.
  • the invention also relates to a pharmaceutical composition comprising an effective concentration of at least one substance with oxytocin activity in mixture or otherwise together with at least one pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition could be used in order to improve the effects against climacteric disorders.
  • One object of the present invention is the use of a substance with oxytocin activity for the preparation of a pharmaceutical composition against climacteric disorders, such as weight changes, mood swings, hot flushes, dry and ulcerous mucous membranes, fissures, and bone loss.
  • the substance is selected from the group consisting of the following compounds:
  • X 1 is selected from the group consisting of Cys and nothing,
  • X 2 is selected from the group consisting of Tyr, Phe, and nothing,
  • X 3 is selected from the group consisting of Ile, Val, Hoph, Phe, Cha, and nothing,
  • X 4 is selected f the group consisting of Gln, Ser, Thr, Cit, Arg, and Daba,
  • X 5 is selected from the group consisting of Pro, and nothing,
  • X 6 is selected from the group consisting of Ile, Leu, nothing, Val, Hos, Daba, Thr, and Cit,
  • X 7 is selected from the group consisting of Gly, nothing, and Ala,
  • R is a chemical bond or, in the case neither of X 1 , X 2 , X 3 and X 4 represents Cys, represents nothing.
  • the cystein disulfide bridge in SEQ ID NO: 2 is only present when X 1 represents Cys, X 2 represents Tyr or Phe, and X 3 represents Ile, Val, Hoph, Phe or Cha.
  • the substance is selected from the group consisting of the following compounds:
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Ile
  • X 4 is Glu
  • X 5 is Pro
  • X 6 is Leu
  • X 7 is Gly in claim 2 and 7
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Ile
  • X 4 is Gln
  • X 5 is Pro
  • X 6 is Ile
  • X 7 is Gly in claim 2 and 7
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Ile
  • X 4 is Ser
  • X 5 is Pro
  • X 6 is Ile
  • X 7 is Gly in claim 2 and 7
  • X 1 is Cys
  • X 2 is Phe
  • X 3 is Val
  • X 4 is Arg
  • X 5 is Pro
  • X 6 is Thr
  • X 7 is Gly in claim 2 and 7
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Ile
  • X 4 is Gln
  • X 5 -X 7 is nothing in claim 2 and 7
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Ile
  • X 4 is Gln
  • X 5 is Pro
  • X 6 -X 7 is nothing in claim 2 and 7
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Ile
  • X 4 is Gln
  • X 5 is Pro
  • X 6 is Leu
  • X 7 is nothing in claim 2 and 7
  • X 1 is nothing
  • X 2 is Tyr
  • X 3 is Ile
  • X 4 is Gln
  • X 5 is Pro
  • X 6 is Leu
  • X 7 is Gly in claim 2 and 7
  • X 1 -X 2 is nothing, X 3 is Ile, X 4 is Gln, X 5 is Pro, X 6 is Leu, and X 7 is Gly in claim 2 and 7
  • X 1 -X 3 is nothing
  • X 4 is Gln
  • X 5 is Pro
  • X 6 is Leu
  • X 7 is Gly claim 2 and 7
  • X 1 -X 2 is nothing
  • X 3 is Ile
  • X 4 is Gln
  • X 5 is Pro
  • X 6 -X 7 is nothing in claim 2 and 7
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Val
  • X 4 is Thr
  • X 5 is Pro
  • X 6 is Leu
  • X 7 is Gly in claim 2 and 7 SEQ ID NO: 14 ⁇ overscore (
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Hoph
  • X 4 is Thr
  • X 5 is Pro
  • X 6 is Val
  • X 7 is Gly in claim 2 and 7 SEQ ID NO: 15 ⁇ overscore (
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Phe
  • X 4 is Cit
  • X 5 is Pro
  • X 6 is Leu
  • X 7 is Gly in claim 2 and 7 SEQ ID NO: 16 ⁇ overscore (
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Cha
  • X 4 is Arg
  • X 5 is Pro
  • X 6 is Hos
  • X 7 is Ala in claim 2 and 7 SEQ ID NO: 17 ⁇ overscore (
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Val
  • X 4 is Daba
  • X 5 is Pro
  • X 6 is Cit
  • X 7 is Ala in claim 2 and 7 SEQ ID NO: 18 ⁇ overscore (
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Hoph
  • X 4 is Daba
  • X 5 is Pro
  • X 6 is Cit
  • X 7 is Ala in claim 2 and 7 SEQ ID NO: 19 ⁇ overscore (
  • X 1 is Cys
  • X 2 is Tyr
  • X 3 is Phe
  • X 4 is Arg
  • X 5 is Pro
  • X 6 is Val
  • X 7 is Ala in claim 2 and 7,
  • Daba stands for diaminobutyric acid
  • a substance with oxytocin activity refers, whenever applicable, in addition to oxytocin also to precursors, metabolic derivatives, oxytocin agonists or analogues displaying the same properties. It can be shown that a substance has oxytocin activity by performing tests showing the activity of the actual substance eg by performing a double blind cross-over randomised protocol as described in Example 1.
  • Annetocin has been isolated from the earthworm, as described in Oumi T. Ukena K, Matsushima O, Ikeda T, Fujita T, Minakata H, Nomoto K, Annetocin: an oxytocin-related peptide isolated from the earthworm, Eisenia foetida, Biochem Biophys Res Commun 1994, January 14; 198(1); 393-399.
  • Other substances with oxytocin activity could also be used, such as naturally occurring or artificially modified variants, analogues, and derivatives of oxytocin, mesotocin, isotocin, and annetocin. Such substances could be obtained by addition, insertion, elimination, or substitution of at least one amino acid in these hormones.
  • a substance with an oxytocin like activity is also understood precursors, metabolites such as metabolic derivatives e.g. metabolic degradation products, agonists, or analogues of the substances mentioned herein displaying the same properties.
  • Metabolic derivatives or metabolic degradation products may be oxytocin like peptides e.g.
  • oxytocin such as oxytocin, mesotocin, isotocin, and annetocin from which one or more amino acids has been deleted from either the carboxyl terminal end or the amino terminal end or both the carboxyl terminal and the amino terminal end, preferably 1-3 amino acids from each terminal.
  • these variants are analogues of oxytocin, mesotocin, isotocin or annetocin by immunological methods, e.g. RIA (radioimmunoassay), IRMA (radiometric methods), RIST (radioimmunosorbent test), and RAST (radioallergosorbent test).
  • the invention also includes substances having at least 50, 60, 70, 80 and most preferably 90% homology to oxytocin, and showing oxytocin activity.
  • subfragments of the oxytocin molecule could have effects against cimacteric disorders.
  • subfragments of the oxytocin molecule are the following compounds: SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12.
  • the invention also relates to the peptides mentioned above in both D- and L-form, and racemates thereof. Especially the invention relates to the L-form. By inversion of the peptide sequence thereof, the D-form could be converted to the L-form. The effect of the D- and L-forms are the same.
  • These and the peptides above can be produced by methods known to a person skilled in the art, e.g. according to Merrifield, P. B., “Solid Phase Synthesis”, Angew. Chemie, 1985, No. 97, p. 801.
  • compositions according to the invention may contain substances that extend or strengthen the effects of oxytocin. Such substances could increase the release of oxytocin and/or the member or affinity of oxytocin receptors, such as oestrogen, or drugs having an ⁇ 2 -agonistic effect, such as clonidine.
  • tat a substance with oxytocin activity is administered in an amount of 0.01-100 ng/kg body weight of the patient, in particular 0.1-10 ng/kg.
  • Another object of the invention is a pharmaceutical composition against climacteric disorders comprising an effective concentration of at least one substance with oxytocin activity in mixture or otherwise together with at least one pharmaceutically acceptable carrier or excipient. It is preferred that the substance is selected from the group consisting of compounds with the formula SEQ ID NO: 2.
  • the substance is selected from the group consisting of the following compounds: SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19.
  • SEQ ID NO: 1 SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19.
  • compositions according to the invention may contain substances that extend or strengthen the effects of oxytocin. Such substances could increase the release of oxytocin and/or the number or affinity of oxytocin receptors, such as oestrogen, or drugs having an ⁇ 2 -agonistic effect such as clonidine.
  • the pharmaceutical compositions are prepared in a manner known to a person skilled in the pharmaceutical art.
  • the carrier or the excipient could be a solid, semi-solid or liquid material that could serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are known in the art.
  • the pharmaceutical composition could be adapted to oral, parenteral, intravaginal, or topical use and could be administered to the patient as tablets, capsules, suppositories, solutions, suspensions or the like.
  • compositions could be administered orally, e.g. with an inert diluent or with an edible carrier. They could be enclosed in gelatine capsules or be compressed to tablets.
  • the compounds according to the invention could be incorporated with excipients and used as tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • These preparations should contain at least 4% by weight of the compounds according to the invention, the active ingredient, but could be varied according to the special form and could, suitably, be 4-70% by weight of the unit.
  • the amount of the active ingredient that is contained in compositions is so high that a unit dosage form suitable for administration is obtained.
  • the tablets, pills, capsules, lozenges and the like could also contain at least one of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin, excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch, and the like, lubricants such as magnesium stearate or Sterotex, glidants such as colloidal silica dioxide, and sweetening agents such as saccharose or saccharin could be added or flavourings such as peppermint, methyl salicylate or orange flavouring.
  • binders such as microcrystalline cellulose, gum tragacanth or gelatin
  • excipients such as starch or lactose
  • disintegrating agents such as alginic acid, Primogel, corn starch, and the like
  • lubricants such as magnesium stearate or Sterotex
  • glidants such as colloidal silica dioxide
  • sweetening agents such as saccharose or
  • unit dosage forms could contain other different mars that modify the physical form of the unit dosage form, e.g. as coatings. Accordingly, tablets or pills could be coated with sugar, shellac or other enteric coating agents.
  • a syrup could in addition to the active ingredient contain saccharose as a sweetening agent and some preservatives, dyes and flavouring agents. Materials that are used for preparation of these different compositions should be pharmaceutically pure and non-toxic in the amounts used.
  • parenteral administration refers to the administration not trough the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, intranasal, intrapulmonary, through the tract, through eye drops, rectal or intravaginal (e.g. as a suppository, a vagitorium, a cream or an ointment), through the lactiferous rat in cattle, into an organ such as bone marrow, etc. Bone marrow may also be treated in vitro.
  • These preparations could contain at least 0.1% by weight of an active compound according to the invention but could be varied to be approximately 0.1-50% thereof by weight. The amount of the active ingredient that is contained in such compositions is so high that a suitable dosage is obtained.
  • the solutions or suspensions could also comprise at least one of the following adjuvants: sterile diluents such as water for injection, saline, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl paraben, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylene diamine tetraacetic acid, buffers such as acetates citrates or phosphates, and agents for adjustment of the tonicity such as sodium chloride or dextrose.
  • the parenteral preparation could be enclosed in ampoules, disposable syringes or multiple dosage vessels made of glass or plastic.
  • the compounds according to the invention could be incorporated in a solution, suspension, ointment, or gel. These preparations could contain at least 0.1% by weight of an active compound according to the invention but could be varied to be approximately 0.1-50% thereof by weight. The amount of the active ingredient that is contained in such compositions is so high that a suitable dosage is obtained.
  • the administration could be facilitated by applying touch, pressure, massage, heat, warms, or infrared light on the skin, which leads to enhanced skin permeability.
  • Hirvonen, J., Kalia, Y N, and Gay, R H. Transdermal delivery of peptides by iontophoresis. Nat Biotechnol December 1996; 14(13): 1710-1713 describes how to enhance the transport of a drug via the skin using the driving force of an applied electric field.
  • iontophoresis is effected at a slightly basic pH.
  • administration forms are inhalation through the lungs, buccal administration via the mouth, enteral administration via the small intestine, and local administration with a release, preferably a slow release, of the active substance eg in the form of a ring. All these administration forms could be effected by means known by a person skilled in the art.
  • FIG. 1 is a bar graph showing the plasma concentration of insulin in ovariectomised rats administered subcutaneously with saline (NaCl) and oxytocin.
  • FIG. 2 is a bar graph showing the plasma concentrations of corticosterone and growth hormone (GH) in ovariectomised rats subjected to subcutaneous treatment.
  • Group A refers to rats treated with oestrogen, progesterone, and oxytocin.
  • Group B refers to rats treated with oestragen and progesterone.
  • Group C refers to rats treated with oxytocin.
  • Group D refers to rats treated with saline.
  • FIG. 3 shows the weight change in ovariectomised rats in response to consecutively given subcutaneous treatments with oxytocin compared to controls receiving saline.
  • FIG. 4 shows the somatic discomfort relieving effect for ovariectomised rats given intravaginal treatments with oxytocin compared to controls receiving saline.
  • mice Female sexually mature Sprague-Dawley rats weighing 250-300 g were used (B & K Universal Sollentuna, Sweden). The rats were housed 5 to each cage with free access to food and tap water at 20 ⁇ 2° C. and with a 12 h light/12 h dark cycle for at least 3 weeks before and throughout the experimental period.
  • All rats were fed standard chow feed containing 7.1 g/kg of calcium and 5 g/kg of phosphorus; the energy content of the feed was 3100 kcal/kg.
  • a control group of 15 rats were not manipulated but fed the stud diet (control group, mean initial weight 269 ⁇ 31 g).
  • a experimental group of 15 rats was ovariectomized at 120 days of life and given oxytocin for 10 days 1.0 mg/kg sc. (OVX+Oxy group, mean initial weight 277 ⁇ 32 g).
  • a group of 15 rats underwent ovariectomy (OVX group, mean initial weight 282 ⁇ 27 g). The OVX group did not receive oxytocin and was fed the standard diet.
  • the ovariectomy was performed as in previous studies [Rico H, Amo C, Revilla M, Arribas I, Gonzalez-Riola J, Villa L F, Rodriguez-Puyol M Etidronate versus Clodronate in the prevention of postovariectomy bone loss.
  • the manipulated rats were controlled to observe the development of intestinal function, alterations, and infection or dehiscence of surgical sutures. All rats received water ad libitum.
  • the rats were kept for 30 days in the animal laboratory of department of Physiology and Pharmacology, Karolinska Institutet Living conditions (12 hours of light and 12 hours of darkness; mean room temperature 22° C.), habitat, and diet met current guidelines of the European Union. Weight was measured with a precision biomedical balance.
  • Ovariectomy means removal of an ovary or ovaries and can eg be effected according to Merchentaler, I., Funkhouser, J. M., Carver, J. N, Lundeen, S. G., Ghosh, K, Winneker, R. C. The effect of estrogens and antiestrogens in a rat model for hot flush. Maturitas, Nov 16, 1998; 30(3): 307-316.
  • the treatment was effected by a gynaecologist who inspected the mucous membranes. After a treatment lasting 2-3 days, the mucous membranes had improved in that they looked like those in a female woman. They were all perfused with blood and all ulcers had disappeared.
  • Atrophic mucous membranes have formerly been treated with oestrogen cream or gel with oestradiol or oestrone as an active substance. Then, a certain improvement is observed after a treatment of approximately 2 weeks, but the improvement is not as complete as after the preliminary observations with the oxytocin gel. Furthermore, the improvement is often preceded by a period with local itch and irritation. No mood improvement has been observed after a local oestrogen treatment.
  • a rat having its ovaries removed also gains weight compared to untreated rats. Rats treated with oxytocin for 10 days do not gain weight as much despite of the fact that they do not eat less (see FIG. 3).
  • Table I shows the forward locomotion of ovariectomised rats (rats R1-R7) after intravaginal oxytocin administration compared to saline administered control rats (rats B1-B7).
  • forward locomotion is meant successive interruptions of photocells in the lower rows when the animal is moving in the same direction, i.e. initially, the location of the animal is defined by the photocell being interrupted, the next interruption indicates that the animal is moving, and successive interruptions are registered as locomotion, as long as the animal moves along the same vector (for further details, see Carter, S. Oxytocin and sexual behavior. Neurosci. Biobehav. Rev. 16:131-144; 1992).
  • the total experimental time is 30 minutes per rat, and the values in table I show the forward locomotion for the first 15 minutes, for the whole experimental time, and for the last 15 minutes.
  • TABLE I Minutes 1-15 Minutes 16-30 Minutes 1-30 Control B1 23.9 24.6 24.2 B2 24.7 15.9 22.1 B3 27.4 22.5 25.5 B4 24.5 9.5 22.6 B5 31.3 16.8 26.7 B6 30.6 22.5 27.6 B7 27.3 16.5 24.3
  • AVERAGE 27.10 18.33 24.71 SD 2.97 5.22 2.03 Oxytocin R1 30.7 20.3 27.7 R2 27.8 19.8 25.3 R3 28.8 17.7 25.1 R4 28.6 23.2 26.3 R5 32.2 21.6 28.7 R6 32.3 15.3 27.7 R7 31 23 27.6 AVERAGE 30.20 20.13 26.91 SD 1.81 2.86 1.36 T-test 0.04* 0,44 ns 0.03*
  • oxytocin Besides increased motor activity, oxytocin also gives rise to relief of somatic discomfort.
  • One way of applying somatic discomfort to an organism is to subject a part of it to a high temperature.
  • This relief effect of oxytocin was investigated in a tail-flick test.
  • the tails of ovariectomised rats were immersed in water at 51° C.
  • the latency time from the immersion of the tails to the withdrawal thereof were measured for rats treated with oxytocin ( ⁇ ) and rats treated with saline ( ⁇ ).
  • the test sessions were accomplished three times with a period of 15 minutes between the sessions.
  • an intravaginal administration of oxytocin increases the latency time.
  • a longer latency time means that the rat could stand the somatic discomfort better such as increased temperature ta it otherwise would do.
  • ovariectomised rats 300-350 g were treated with oxytocin for 8 days subcutaneously. Rats were addicted to morphine by implanting a morphine pellet (75 mg each) subcutaneously on days 3 and 5 of treatment. On the last day of treatment, an infrared thermistor was placed above the tail of each animal and morphine addiction was withdrawn by naloxone injection (1.0 mg/kg, subcutaneously). Temperature measurements were taken for 1 h under ketamine (80 mg/kg. intramuscularly) anaesthesia. In general, vehicle treated rats showed a 5-6° C. elevation of their tail skin temperature with the peak occurring about 15 ml after naloxone injection. Repeated oxytocin treatment 1.0 mg/kg subcutaneous oxytocin or 0.1 m g subcutaneous 17-alpha-ethinyloestradiol (EA) significantly inhibited the temperature increase (flashes).
  • EA 17-alpha-ethinyloestradiol
  • PCOS polycystic ovary syndrome
  • EV oestradiol valerate
  • PCOS Polycystic ovary syndrome
  • Osteoclasts are large multinuclear cells associated with the absorption and removal of bone and are, accordingly, implicated in bone loss.
  • An object of the invention is, therefore, to counteract the action of osteoclasts. As shown in the present Example, administration of oxytocin suppresses bone loss in rats and, hence, counteracts the action of osteoclasts.
  • F-BMC means femur bone mineral content
  • F-BMD means femur bone mineral density
  • V-BMC means 5 th lumbar vertebral bone mineral content
  • V-BNMD means 5 th lumbar vertebral bone mineral density
  • OVX means ovariectomized rats
  • OVX+Oxy means oxytocin-treated ovariectomized rats. TABLE II Values for each parameter in three groups of rats Controls OVX OVX + Oxy Initial weight (g) 269 ⁇ 31 282 ⁇ 27 277 ⁇ 32 Final weight (g) 312 ⁇ 22 331 ⁇ 25 334 ⁇ 31 Femur (mm) 34.6 ⁇ 0.5 32.8 ⁇ 1.4 35.5 ⁇ 1.3 Femur (mg) 729 ⁇ 54 669 ⁇ 74 712 ⁇ 42 F-BMC (mg) 399 ⁇ 36 282 ⁇ 42 335 ⁇ 37 F-BMD (mg/cm 2 ) 145 ⁇ 16 117 ⁇ 17 131 ⁇ 18 F-BMC/BW (mg/g) 1.38 ⁇ 0.05 0.93 ⁇ 0.08 1.12 ⁇ 0.09 Vertebra (mm) 7.2 ⁇ 0.4 6.4 ⁇ 0.9 6.9 ⁇ 0.6 Vertebra (mg) 269

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Medicines Containing Plant Substances (AREA)
US10/258,013 2000-04-18 2001-04-18 Use of substances with oxytocin activity against climacteric disorders Abandoned US20040029787A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/345,218 US7727959B2 (en) 2000-04-18 2006-02-02 Use of substances with oxytocin activity against climacteric disorders

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE0001440A SE0001440D0 (sv) 2000-04-18 2000-04-18 A drug against climacteric disorders
SE0001440-7 2000-04-18
PCT/SE2001/000854 WO2001078758A1 (en) 2000-04-18 2001-04-18 Use of substances with oxytocin activity against climacteric disorders

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/345,218 Division US7727959B2 (en) 2000-04-18 2006-02-02 Use of substances with oxytocin activity against climacteric disorders

Publications (1)

Publication Number Publication Date
US20040029787A1 true US20040029787A1 (en) 2004-02-12

Family

ID=20279369

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/258,013 Abandoned US20040029787A1 (en) 2000-04-18 2001-04-18 Use of substances with oxytocin activity against climacteric disorders
US11/345,218 Expired - Fee Related US7727959B2 (en) 2000-04-18 2006-02-02 Use of substances with oxytocin activity against climacteric disorders

Family Applications After (1)

Application Number Title Priority Date Filing Date
US11/345,218 Expired - Fee Related US7727959B2 (en) 2000-04-18 2006-02-02 Use of substances with oxytocin activity against climacteric disorders

Country Status (8)

Country Link
US (2) US20040029787A1 (es)
EP (1) EP1406649B9 (es)
AT (1) ATE387213T1 (es)
AU (1) AU2001248994A1 (es)
DE (1) DE60133050T2 (es)
ES (1) ES2302728T3 (es)
SE (1) SE0001440D0 (es)
WO (1) WO2001078758A1 (es)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0100684D0 (sv) * 2001-02-28 2001-02-28 Kerstin Uvnaes Moberg New subject-matter
JO2937B1 (en) 2004-08-11 2016-03-15 فيرينغ.بي.في Tight muscles of the peptide vascular tensioner receptor
RU2415149C2 (ru) 2006-02-10 2011-03-27 Ферринг Б.В. Пептидные соединения
US9050286B2 (en) 2007-08-14 2015-06-09 Ferring B.V. Use of peptidic vasopression receptor agonists
CA2698754A1 (en) * 2007-09-11 2009-03-19 Dorian Bevec Use of a peptide as a therapeutic agent
WO2009033820A2 (en) * 2007-09-11 2009-03-19 Mondobiotech Laboratories Ag Use of a peptide as a therapeutic agent
AU2008303955A1 (en) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Use of melanocyte-stimulating hormone release-inhibiting factor as a therapeutic agent in the treatment of Pseudomonas aeruginosa infection
US20100190722A1 (en) * 2007-09-11 2010-07-29 Dorian Bevec Substance p and thyrotropin releasing hormone for therapeutic applications
RU2010114013A (ru) * 2007-09-11 2011-10-20 Мондобайотек Лабораториз Аг (Li) Применение нейротрофического фактора для холинергических нейронов сетчатки (nfrcn) и хорионического гонадотропина бета (109-145) в качестве терапевтических средств
SE536091C2 (sv) * 2011-04-14 2013-04-30 Pep Tonic Medical Ab Farmaceutisk komposition innehållande oxytocin eller fragment eller varianter därav och åtminstone en icke-jonisk cellulosaeter
EP2908840A1 (en) * 2012-10-12 2015-08-26 Peptonic Medical AB Novel use of a composition comprising oxytocin
SE1750680A1 (en) 2017-05-30 2018-12-01 Peptonic Medical Ab Composition for treating or preventing climacteric disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040176284A1 (en) * 2001-02-28 2004-09-09 Kerstin Uvnas-Moberg Use of oxytocin for the preparation of a pharmaceutical composition against cancer in situ and cervicitis

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4889844A (en) * 1985-10-22 1989-12-26 Silvetti Sr Anthony N Fructose containing wound healing preparation
US5457128A (en) * 1992-03-28 1995-10-10 Dott Limited Company Topical preparation for healing wounds of the skin
MY117988A (en) * 1995-10-03 2004-08-30 Nor Ind Inc Cleaning compositions for oil and gas well, lines, casings, formations and equipment and methods of use
US5753266A (en) * 1996-12-03 1998-05-19 Youssefyeh; Parvin Safflower seed powder compositions for the treatment of rheumatoid based arthritic diseases
SE9701162D0 (sv) * 1997-03-27 1997-03-27 Karolinska Innovations Ab New use II
SE9803272D0 (sv) * 1998-09-25 1998-09-25 Kerstin Uvnaes Moberg A drug for cell regeneration
US6333313B1 (en) * 1998-10-29 2001-12-25 Board Of Regents, The University Of Texas System Clinical use of oxytocin alone or in combination to treat bone disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040176284A1 (en) * 2001-02-28 2004-09-09 Kerstin Uvnas-Moberg Use of oxytocin for the preparation of a pharmaceutical composition against cancer in situ and cervicitis

Also Published As

Publication number Publication date
ATE387213T1 (de) 2008-03-15
ES2302728T3 (es) 2008-08-01
EP1406649B1 (en) 2008-02-27
AU2001248994A1 (en) 2001-10-30
WO2001078758A1 (en) 2001-10-25
DE60133050D1 (de) 2008-04-10
US7727959B2 (en) 2010-06-01
EP1406649A1 (en) 2004-04-14
SE0001440D0 (sv) 2000-04-18
US20060148685A1 (en) 2006-07-06
EP1406649B9 (en) 2008-10-15
DE60133050T2 (de) 2009-02-26

Similar Documents

Publication Publication Date Title
US7727959B2 (en) Use of substances with oxytocin activity against climacteric disorders
Catzeflis et al. Neuropeptide Y administered chronically into the lateral ventricle profoundly inhibits both the gonadotropic and the somatotropic axis in intact adult female rats
JPH10500423A (ja) アヘン剤拮抗物質およびカルシウム塩を含む薬剤組成物、エンドルフィン介在病状の治療のためのこれらの使用法
KR930003332B1 (ko) 항이뇨제 ddavp의 경구 투여용 제제의 제조방법
RU2297218C2 (ru) Способы и материалы для лечения тестостероновой недостаточности у мужчин
CA2480626A1 (en) Enhancement of endogenous gonadotropin production
PT809654E (pt) Analogos da calcitonina do salmao, sua preparacao, uso medicinal e uso como agentes amaliticos
ES2267531T3 (es) Uso de lh administrado en la fase folicular media o tardia para el tratamiento de mujeres anovulatorias.
Bosch-Marcé et al. Aquaretic effect of the κ-opioid agonist RU 51599 in cirrhotic rats with ascites and water retention
ES2247710T3 (es) Antagonista de gonadotropina.
TW577735B (en) Pharmaceutical combined preparation and its use in the treatment of gynaecological disorders
NO324357B1 (no) Anvendelse av et ostroprogestagenhormonpreparat ved fremstillingen av et medikament for behandling av ostrogenforstyrrelser og osteoporose hos postmenopausale kvinner, samt anvendelse av et farmasoytisk preparat ved fremstilling av et medikament for a stoppe ovulasjon
EP1370277B1 (en) Use of oxytocin for the preparation of a pharmaceutical composition against cancer in situ and cervicitis
EP1115416B1 (en) Use of substances with oxytocin activity in order to create cell regeneration
HUT59007A (en) Process for producing novel pharmaceutical preparations of improved absorption containing somatostatine
Caldara et al. Inhibition of gastrin secretion by sulpiride treatment in duodenal ulcer patients
US4870054A (en) Treatment for osteoporosis using GRF or a biologically active analog thereof
BG63363B1 (bg) Използване на антагонист на gnrh за получаване нафармацевтичен състав за лечение на гонадостероидно зависими заболявания
WO2007068039A1 (en) Treatment of weight gain in estrogen deficient mammals
EP1432434A2 (en) Use of substances with oxytocin activity for the preparation of a pharmaceutical composition against inflammation
Ottesen et al. Influence of pregnancy and sex steroids on concentration, motor effect and receptor binding of VIP in the rabbit female genital tract
US5484768A (en) Treatment of male infertility by administration of a muellerian inhibiting substance and surgery and/or hormonal treatment
US7714105B2 (en) Use of fragments of oxytocin for the preparation of a pharmaceutical composition in order to create eustasis
EP0538394B1 (en) Treatment of male infertility
ES2628709T3 (es) Composición para controlar y mejorar la gametogénesis femenina y masculina.

Legal Events

Date Code Title Description
AS Assignment

Owner name: ENTRETECH MEDICAL AB, SWEDEN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:UVNAS-MOBERG, KERSTIN;LUNDEBERG, THOMAS;REEL/FRAME:014255/0857;SIGNING DATES FROM 20021028 TO 20021118

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION