EP1793818A2 - Pindolol pour le traitement du syndrome et du trouble dysphorique premenstruel - Google Patents

Pindolol pour le traitement du syndrome et du trouble dysphorique premenstruel

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Publication number
EP1793818A2
EP1793818A2 EP05779646A EP05779646A EP1793818A2 EP 1793818 A2 EP1793818 A2 EP 1793818A2 EP 05779646 A EP05779646 A EP 05779646A EP 05779646 A EP05779646 A EP 05779646A EP 1793818 A2 EP1793818 A2 EP 1793818A2
Authority
EP
European Patent Office
Prior art keywords
pindolol
medicament
use according
pms
enantiomerically pure
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.)
Withdrawn
Application number
EP05779646A
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German (de)
English (en)
Inventor
Timothy Dinan
Peter Daly
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.)
NeuroCure Ltd
Original Assignee
NeuroCure Ltd
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Filing date
Publication date
Application filed by NeuroCure Ltd filed Critical NeuroCure Ltd
Publication of EP1793818A2 publication Critical patent/EP1793818A2/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to methods and compositions for the treatment of premenstrual syndrome or late luteal phase disorder and related disorders.
  • Premenstrual syndrome or late luteal phase dysphoric disorder (LLPDD) is a common complication of menstruation in otherwise healthy women.
  • PMS Premenstrual syndrome
  • LLPDD late luteal phase dysphoric disorder
  • Pre-menstrual syndrome is characterized by both affective aspects and physical symptoms.
  • the affective aspects involve in particular affective lability, depressed mood, irritability, lethargy and other features while the physical symptoms often include bloating and breast tenderness.
  • PMDD pre-menstrual dysphoric disorder
  • SSRIs selective serotonin reuptake inhibitors
  • fluoxetine and sertraline drugs show some efficacy in PMDD with luteal phase administration
  • Freeman EW Luteal Phase administration of agents for the treatment of premenstrual dysphoric disorder, CNS Drugs 2004: 18(7): 453-68.
  • SSRTs while effective at the most severe end of this spectrum, do not present a very attractive solution.
  • SSRIs typically have significant side effects which are unacceptable to many patients, including nausea and sexual dysfunction.
  • Drospirenone is a spirinolactone analogue with anti-mineralicorticoid and antiandro genie properties. This has been studied in PMS. An open label study in 326 women at baseline and cycle 6 found that statistically significant decreases from baseline were found in negative affect and water retention. (Parsey et ah, Contraception, 2000, 61:105-111.)
  • pindolol when administered as a racemate (R/S) or in the form of the S-(-) enantiomer, is an effective treatment and/or prevention of premenstrual syndrome (PMS) and symptoms associated therewith, including premenstrual tension and/or premenstrual dysphoria disorder (PMDD).
  • PMS premenstrual syndrome
  • PMDD premenstrual tension and/or premenstrual dysphoria disorder
  • one aspect of the invention relates to methods for treating and/or preventing premenstrual syndrome (PMS) comprising administering a composition comprising a therapeutically effective amount of at least one pindolol compound of the invention to a subject in need thereof, preferably during the luteal phase of the menstrual cycle.
  • PMS premenstrual syndrome
  • pindolol when administered to humans in the form of the S-(-) enantiomer, has a reduced effect on lowering blood pressure than racemic pindolol.
  • Such a pharmaceutical composition which is active at the 5HTl a site and has reduced blood pressure lowering effect is useful in the treatment of a number of conditions.
  • One further aspect of the invention relates to methods for treating and/or preventing premenstrual syndrome (PMS) comprising administering a composition comprising a therapeutically effective amount of S-(-)-pindolol to a subject in need thereof, preferably during the luteal phase of the menstrual cycle.
  • PMS premenstrual syndrome
  • PMS and PMDD in women who require or desire contraception.
  • an oral contraceptive and the CNS active drug pindolol acts in additive manner to provide highly effective relief for the physical and psychological symptoms of PMS and PMDD and in particular the most troubling affective and cognitive symptoms.
  • Women taking these drugs showed marked improvement in emotional lability, tension, anxiety and difficulties in concentration as measured by COPE (Calendar of Premenstrual Events ). Women taking these drags also showed improvement in other symptoms such as bloating, breast tenderness, headache and food cravings.
  • the invention discloses a monophasic, biphasic or triphasic oral contraceptive in combination with, e.g., once a day pindolol or S-pindolol.
  • Optimum benefit may be obtained by use of the pindolol component on a continuous 28 day cycle, i. e. the normal 7 day contraceptive placebo is combined with pindolol or S-pindolol as described herein.
  • compositions which comprise a therapeutically effective amount of at least one pindolol compound of the present invention, together with one or more pharmaceutically acceptable excipients.
  • the pindolol compound can be in a racemic or enantiomerically pure form.
  • the present invention generally relates to methods and compositions for treating and/or preventing PMS, or symptoms associated therewith including premenstrual tension or premenstrual dysphoria.
  • the methods and compositions of the invention involve the use of pindolol, a known beta adrenergic blocker.
  • US Patent 6,855,729 and the current invention are related in that the drug employed in each case , pindolol or S-pindolol is the same.
  • US Patent 5,403,848 describes the use of pindolol or S-pindolol in Non-Ulcer Dyspepsia.
  • PMS and PMDD occur often in the context of a range of psychiatric co-morbidities.
  • PMS and PMDD may occur in association with major depression, cyclothymia, anxiety including generalized anxiety disorder and chronic fatigue syndrome.
  • PMS and PMDD patients may also exhibit physical symptoms such as irritable bowel syndrome, chronic fatigue, fibromyalgia, headache, pain syndromes, other genitor-urinary problems or psychosexual problems and sleep disorders.
  • somatization disorder which is essentially a form of psychiatric condition of unknown origin which involves a long term history of multiple and varying physical complaints.
  • diagnostic criteria for somatization disorder included in DSM-IY include; a history of physical complaints over many years and starting before the age of 30; at least four pain symptoms at different sites; two gastro-intestinal symptoms such as nausea or bloating; one sexual or reproductive symptom such as erectile dysfunction or irregular periods and one pseudo- neurological symptom.
  • PMS/PMDD patients fall into this category and also overlap with patients suffering from IBS and chronic fatigue syndrome/fibromyalgia.
  • the present invention is directed primarily towards PMS and PMDD patients, but also includes patients who are diagnosed as being co-morbid with PMS/PMDD and somatization disorder, IBS, chronic fatigue syndrome and/or fibromyalgia.
  • the compounds of the invention include pindolol in its racemic (BJS) form, or in its S-(-) enantiomerically pure form.
  • enantiomerically pure refers to compositions consisting substantially of a single isomer (i.e., substantially free of the opposite isomer), preferably consisting of 90%, 92%, 95%, 98%, 99%, or 100% of a single isomer.
  • an enantiomerically pure composition comprises at least 95% of a single isomer.
  • an enantiomerically pure composition comprises at least about 98% of a single isomer.
  • pindolol The chemical structure of pindolol is shown below in Formula (I), and the S-isomer is shown in Formula (Ia).
  • S-(-) enantiomer pindolol, S-pindolol, minus-pindolol, (-) pindolol, etc. are used interchangeably.
  • Pindolol is a racemic mixture consisting of both a minus enantiomer and a plus enantiomer.
  • the stereoselectivity of the enantiomers of a range of beta blockers have been studied in relation to both pharmacokinetics and pharmacodynamics.
  • Such studies as have been carried out in man involve the determination of pharmacokinetics of the enantiomers following administration of the racemate (such as those reported in the review paper: Mehvar, et al., J Pharm Pharmaceut Sci, 2001, 4(2): 185-200).
  • Such studies show minor differences between (-) and (+) pindolol in areas such pharmacokinetic parameters as AUC, Cmax and ti/ 2 hrs.
  • pindolol is a known beta adrenergic blocker, and it's preparation and synthesis in racemic or enantiomerically pure form is known in the art. Pindolol has been shown to be effective at both 5HTIa and beta adrenergic sites. Without intending to be limited by theory, it is believed that pindolol exhibits its biological properties primarily through its S-(-) enantiomer.
  • pindolol has been tested extensively as an augmentation strategy for antidepressants, the results have been mixed to date. These studies have been reevaluated in the light of recent PET studies that showed that the doses of pindolol used were too low to effect 5HTIa autoreceptor blockade (Rabiner Eugenii A et al, Am J Psychiatry, 2001, 158: 2080-2082). It was shown that in human studies the use of 2.5 mg of pindolol (the dose used in almost all of the previous SSRI studies ) did not generate any significant occupancy of 5HTIa receptors while 5.0 mg did produce a modest but significant occupancy of 19%. The dose required for effective SSRI augmentation was stated to be unknown.
  • the invention includes compounds produced by a process comprising contacting a pindolol compound of the invention with a mammalian tissue or a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products typically are identified by preparing a radio ⁇ labeled ⁇ e.g.
  • C 14 or H ⁇ pindolol compound of the invention administering it in a detectable dose (e.g., greater than about 0.5 mg/kg) to a mammal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating its conversion products from urine, blood, tumor, or other biological samples.
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • a mammal such as rat, mouse, guinea pig, monkey, or to man
  • sufficient time for metabolism to occur typically about 30 seconds to 30 hours
  • isolating its conversion products from urine, blood, tumor, or other biological samples typically about 30 seconds to 30 hours
  • the metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis.
  • pindolol when administered as a racemate (R/S) or in the form of the S-(-) enantiomer, is an effective treatment and/or prevention of PMS and symptoms associated therewith including premenstrual tension or premenstrual dysphoria.
  • one aspect of the invention relates to methods for treating and/or preventing premenstrual syndrome (PMS) comprising administering a composition comprising a therapeutically effective amount of at least one pindolol compound of the invention to a subject in need thereof, preferably during the luteal phase of the menstrual cycle.
  • PMS premenstrual syndrome
  • pindolol when administered in the form of the S-(-) enantiomer, is effective in the treatment and/or prevention of a number of new indications in which the blood pressure lowering effects of the racemic form may be undesired.
  • pindolol is a known beta adrenergic blocker, and is preparation and synthesis in racemic or enantiomerically pure form is known in the art. Pindolol has been shown to be effective at both 5HTIa and beta adrenergic sites. Without intending to be limited by theory, it is believed that pindolol exhibits its biological properties primarily through its S-(-) enantiomer.
  • one aspect of the invention relates to methods for treating and/or preventing premenstrual syndrome (PMS) comprising administering a composition comprising a therapeutically effective amount of S-(-)-pindolol to a subject in need thereof, preferably during the luteal phase of the menstrual cycle.
  • PMS premenstrual syndrome
  • This invention provides for a once a day form of pindolol in combination with a once a day oral contraceptive for the treatment of symptoms of premenstrual syndrome in women who require or are desirous of contraception.
  • one aspect of the invention relates to methods for treating and/or preventing PMS and/or PMDD in a subject desirous of contraception, comprising administering a composition comprising an amount of at least one pindolol compound of the invention effective to treat and/or prevent PMS or PMDD to a subject desirous of contraception in combination with a contraceptive.
  • the pindolol compound may be administered throughout the menstrual cycle, or may be administered during the luteal phase of the menstrual cycle. Further, the pindolol compound and the contraceptive maybe administered as a single, fixed dose composition, or may be administered sequentially as separate compositions.
  • the invention provides administration of a monophasic, biphasic or triphasic oral contraceptive in combination with either racemic pindolol or S-pindolol.
  • the pindolol component may be administered on a continuous 28 day cycle, wherein the normal 7 day contraceptive placebo is combined with the racemic pindolol or S- pindolol as described herein.
  • the invention provides a combination therapy which may be utilized by subjects with an increased risk of cardiovascular events and who are desirous of contraception, such as oral contraception, transdermal "patch” contraception, or the like.
  • contraception such as oral contraception, transdermal "patch” contraception, or the like.
  • the slight decrease in blood pressure provided by the methods as described herein provide a useful reduction in risk factors in this population.
  • the invention employs once a day administration of pindolol in a fixed dose combination with a once a day oral contraceptive for the treatment of symptoms of PMS or PMDD in women who are desirous of contraception, hi a further embodiment the invention comprises a once a day form of pindolol or S-pindolol which has anti- minericorticoid properties.
  • the invention comprises a once a day administration of racemic pindolol or S-pindolol in combination with an oral contraceptive comprising oestrogen or an analogue thereof and a progestin.
  • the racemic pindolol or S-pindolol may be administered throughout the entire cycle.
  • the invention comprises a once a day form of racemic pindolol or S-pindolol in combination with a progestin only contraceptive.
  • the pindolol may be administered in combination with the contraceptive as a transdermal patch or implant.
  • the invention comprises a once a day form of racemic pindolol or S-pindolol in combination with a combined oral contraceptive containing oestrogen or a analogue and a progestin.
  • the pindolol or S-pindolol is administered throughout the entire cycle.
  • the invention comprises a once a day form of racemic pindolol or S-pindolol in combination with a progestin only contraceptive.
  • the invention comprises a once a day form of pindolol or S- pindolol which has antiminericorticoid properties.
  • the combination drug is useful in the treatment of post-menopausal symptoms.
  • the combination of drospirenone plus ethinyl estradiol plus either pindolol or S- pindolol provides treatment for hot flushes associated with withdrawal of sex steroids and the small drop in blood pressure resulting from pindolol provides for a lowering of cardiovascular risk in this population.
  • the CNS effects of pindolol or S- pindolol additionally provide for treatment of anxiety in this group.
  • the invention provides a combination therapy which may be effectively utilized by women in the perimenopausal, menopausal, and post-menopausal periods. It is known that PMS is a predictor of troublesome perimenopausal, menopausal, and post-menopausal symptoms including hot flashes and depression.
  • the combination therapy is useful in the treatment of perimenopausal, menopausal, and post-menopausal symptoms.
  • drospirenone and ethinyl estradiol in combination with either racemic pindolol or S- pindolol provides treatment for hot flushes associated with withdrawal of sex steroids.
  • the small drop in blood pressure resulting from pindolol provides for a lowering of cardiovascular risk in this population.
  • the CNS effects of racemic pindolol or S- pindolol additionally provide for treatment of anxiety in this group.
  • Another aspect of the invention relates to the use of the drugs of the invention in the treatment of patients who present with PMS or PMDD and other psychiatric or somatic co ⁇ morbidities.
  • the drugs of the invention are useful in the treatment of patients who are suffering from anxiety, chronic fatigue syndrome, fibromyalgia or other pain syndromes in association with PMS or PMDD.
  • the drugs of the invention may be employed in the treatment of patients who have a dual diagnosis of PMS or PMDD in association with somatization disorder.
  • the compound(s) may be administered to the subject via any drug delivery route known in the art.
  • Specific exemplary administration routes include peripheral and central routes such as oral, ocular, rectal, buccal, topical, nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus and infusion), intracerebral, transdermal, and pulmonary.
  • the composition is administered as a transdermal patch using methods known in the art.
  • therapeutically effective amount refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent the identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect, respectively.
  • the effect can be detected by any means known in the art.
  • the precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.
  • Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • preferred therapeutically effective amounts of the compound(s) of the present invention include an initial target plasma concentration ranging from approximately 5 ⁇ g/mL to approximately 100 ⁇ g/mL, preferably from approximately 10 ⁇ g/mL to approximately 50 ⁇ g/mL , more preferably from approximately 10 ⁇ g/mL to approximately 25 ⁇ g/mL.
  • the compounds of the invention may be administered at doses that vary from 0.1 ⁇ g to 100,000 mg, depending upon the route of administration.
  • Guidance as to particular dosages and methods of delivery is provided in the literature and is generally available to practitioners in the art.
  • the dose will be in the range of about 0.1 mg/day to about 10 g/day, or about 0.5 mg to about 3 g/day, or about 1 mg to about 3 g/day, or about 1 mg to about 50 mg/day, or about 2 mg/day to about 25 mg/day, in single, divided, or continuous doses for a patient weighing between about 40 to about 100 kg (which dose may be adjusted for patients above or below this weight range, particularly children under 40 kg).
  • pindolol compound used e.g., racemic or S-(-) enantiomeric form.
  • Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Dosage amounts may be adjusted depending on whether the pindolol compound is administered as a racemic mixture or as an S-(-) enantiomerically pure form. As discussed above, it is believed that the S-(-) enantiomer of pindolol is primarily responsible for the biological activity of pindolol.
  • the dosage will generally be lower than if racemic mixtures are used.
  • Other factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy.
  • Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • compositions useful in the methods of the invention are provided.
  • the pharmaceutical compositions of the invention may be formulated with pharmaceutically acceptable excipients such as carriers, solvents, stabilizers, adjuvants, diluents, etc., depending upon the particular mode of administration and dosage form.
  • the pharmaceutical compositions should generally be formulated to achieve a physiologically compatible pH, and may range from a pH of about 3 to a pH of about 11, preferably about pH 3 to about pH 7, depending on the formulation and route of administration. In alternative embodiments, it may be preferred that the pH is adjusted to a range from about pH 5.0 to about pH 8.0.
  • the pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one pindolol compound of the present invention, together with one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition when the pharmaceutical composition is formulated as an oral tablet, the composition preferably comprises from about 0.1 mg to about 25 mg of the pindolol compound, more preferably from about 5 mg to about 25 mg.
  • the exact amount of the pindolol compound may vary depending on the form of pindolol compound used (e.g., racemic or enantiomeric).
  • compositions of the invention may comprise a combination of pindolol compounds of the present invention, or may include a second therapeutic agent useful in the treatment of PMS or associated symptoms.
  • Therapeutic amounts of second agents are generally known in the art or may be determined by the skilled clinician.
  • the pharmaceutical compositions of the invention may comprise contraceptives, as is known in the art.
  • the compositions may comprise monophasic, biphasic or triphasic contraceptives, such as oestrogen or an analogue thereof and a progestin, or may comprise a progestin only.
  • the compositions may comprise therapeutic agents useful in the treatment of perimenopausal, menopausal, or post- menopasual symptoms, such as drospirenone and ethinyl estradio.
  • Formulations of the present invention are most typically solids, liquid solutions, emulsions or suspensions, while inhaleable formulations for pulmonary administration are generally liquids or powders, with powder formulations being generally preferred.
  • Alternative pharmaceutical compositions of the invention may be formulated as syrups, creams, ointments, tablets, and the like.
  • pharmaceutically acceptable excipient refers to an excipient for administration of a pharmaceutical agent, such as the compounds of the present invention.
  • the term refers to any pharmaceutical excipient that may be administered without undue toxicity.
  • Pharmaceutically acceptable excipients are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there exists a wide variety of suitable formulations of pharmaceutical compositions of the present invention ⁇ see, e.g., Remington's Pharmaceutical Sciences).
  • Suitable excipients may be carrier molecules that include large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids, amino acid copolymers, and inactive virus particles.
  • Other exemplary excipients include antioxidants such as ascorbic acid; chelating agents such as EDTA; carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water, saline, glycerol and ethanol; wetting or emulsifying agents; pH buffering substances; and the like. Liposomes are also included within the definition of pharmaceutically acceptable excipients.
  • compositions of the invention may be formulated in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, non-aqueous solutions, dispersible powders or granules (including micronized particles or nanoparticles), emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • compositions particularly suitable for use in conjunction with tablets include, for example, inert diluents, such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate; disintegrating agents, such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid; binding agents, such as povidone, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • inert diluents such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate
  • disintegrating agents such as croscarmellose sodium, cross-linked povidone, maize starch, or alginic acid
  • binding agents such as povidone, starch
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • compositions of the invention may be formulated as suspensions comprising a compound of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension.
  • pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.
  • Excipients suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol.
  • suspending agents such as sodium carboxymethylcellulose
  • the suspensions may also contain one or more preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin.
  • preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate
  • coloring agents such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate
  • flavoring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth; naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids; hexitol anhydrides, such as sorbitan monooleate; and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • any pindolol compound of the present invention with one or more other active agents useful in the treatment of PMS, or its associated symptoms, in a unitary dosage form, or in separate dosage forms intended for simultaneous or sequential administration to a patient in need of treatment.
  • the combination may be administered in two or more administrations.
  • the combination of active ingredients may be: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by any other combination therapy regimen known in the art.
  • the methods of the invention may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially
  • simultaneous therapy effective dosages of two or more active ingredients are administered together.
  • Various sequences of intermittent combination therapy may also be used.
  • the primary outcome measure was the mean change from the end of the placebo period in luteal phase total COPE score after three menstrual cycles of active treatment (pindolol).

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  • Indole Compounds (AREA)

Abstract

Selon l'invention, on a découvert que le pindolol constitue un traitement hautement efficace pour le PMS et/ou le PMDD. L'invention concerne généralement des méthodes et des compositions pour traiter et/ou pour prévenir le PMS, ou des symptômes associés au PMS, notamment une tension prémenstruelle ou une diyphorie prémenstruelle. Les méthodes et les compositions de l'invention concernent également l'utilisation de pindolol, un bloqueur bêta-adrénergique connu, combiné à des contraceptifs connus.
EP05779646A 2004-09-17 2005-09-19 Pindolol pour le traitement du syndrome et du trouble dysphorique premenstruel Withdrawn EP1793818A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US61061004P 2004-09-17 2004-09-17
US65494305P 2005-02-23 2005-02-23
US68671805P 2005-06-01 2005-06-01
PCT/IB2005/002769 WO2006030306A2 (fr) 2004-09-17 2005-09-19 Methodes et compositions pour le traitement du syndrome premenstruel (pms) et d'un trouble dysphorique premenstruel (pmdd)

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EP1793818A2 true EP1793818A2 (fr) 2007-06-13

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EP (1) EP1793818A2 (fr)
JP (1) JP2008513430A (fr)
AU (1) AU2005283829A1 (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8716325B2 (en) 2006-12-05 2014-05-06 Psioxus Therapeutics Limited Treatment of cachexia

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DE69942009D1 (de) 1998-10-15 2010-03-25 Imp Innovations Ltd Verbindungen für die behandlung von gewichtsverlust
JP2012526832A (ja) * 2009-05-13 2012-11-01 スノビオン プハルマセウトイカルス インコーポレイテッド トランスノルセルトラリン及びセロトニン受容体１ａ作動剤／拮抗剤を含む組成物及びその使用

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EP0714663A3 (fr) * 1994-11-28 1997-01-15 Lilly Co Eli Potentialisation d'un médicament par un antagoniste du récepteur sérotonine 1A
GB9714675D0 (en) * 1997-07-11 1997-09-17 Smithkline Beecham Plc Novel composition
WO2003065970A2 (fr) * 2001-02-20 2003-08-14 Royal College Of Surgeons Ie Traitement de la fibromyalgie et du syndrome de fatigue associe au moyen d'antagonistes ou d'agonistes partiels de recepteurs 5ht1a

Non-Patent Citations (1)

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Title
See references of WO2006030306A2 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8716325B2 (en) 2006-12-05 2014-05-06 Psioxus Therapeutics Limited Treatment of cachexia

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AU2005283829A1 (en) 2006-03-23
JP2008513430A (ja) 2008-05-01
WO2006030306A8 (fr) 2007-10-04
WO2006030306A3 (fr) 2006-09-08
WO2006030306A2 (fr) 2006-03-23

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