WO2009018824A1 - Utilisation d'une composition contenant au moins un bêta-bloquant pour le traitement de troubles du sommeil - Google Patents

Utilisation d'une composition contenant au moins un bêta-bloquant pour le traitement de troubles du sommeil Download PDF

Info

Publication number
WO2009018824A1
WO2009018824A1 PCT/DK2008/000249 DK2008000249W WO2009018824A1 WO 2009018824 A1 WO2009018824 A1 WO 2009018824A1 DK 2008000249 W DK2008000249 W DK 2008000249W WO 2009018824 A1 WO2009018824 A1 WO 2009018824A1
Authority
WO
WIPO (PCT)
Prior art keywords
treatment
insomnia
composition
nebivolol
bisoprolol
Prior art date
Application number
PCT/DK2008/000249
Other languages
English (en)
Inventor
Søren TULLIN
Birger Jan Oslen
Original Assignee
Tullin Soeren
Birger Jan Oslen
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 Tullin Soeren, Birger Jan Oslen filed Critical Tullin Soeren
Priority to EP08758258A priority Critical patent/EP2285365A4/fr
Priority to US12/864,450 priority patent/US20110015261A1/en
Publication of WO2009018824A1 publication Critical patent/WO2009018824A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • insomniacs rely on sleeping tablets and other sedatives to get rest. All sedative drugs have the potential of causing psychological dependence where the individual cannot psychologically • accept that they can sleep without drags. Certain classes of sedatives such as benzodiazepines and newer nonbenzodiazepine drugs can also cause physical dependence which manifests in withdrawal symptoms if the drug is not carefully titrated down.
  • Nonbenzodiazepine prescription drugs including the nonbenzodiazepines Zolpidem and zopiclone appear to cause both psychological dependence and physical dependence, and can also cause the same memory and cognitive disturbances as the benzodiazepines along with morning sedation.
  • Some antidepressants such as mirtazapine, trazodone and doxepin have a sedative effect, and are prescribed off label to treat insomnia.
  • the major drawback of these drags is that they have antihistaminergic, anticholinergic and antiadrenergic properties which can lead to many side effects. Some also alter sleep architecture.
  • Melatonin has proved effective for some insomniacs in regulating the sleep/waking cycle, but lacks definitive data regarding efficacy in the treatment of insomnia.
  • Melatonin agonists including Ramelteon (Rozerem), seem to lack the potential for abuse and dependence.
  • This class of drugs has a relatively mild side effect profile and lower likelihood of causing morning sedation.
  • the antihistamine diphenhydramine is widely used in nonprescription sleep aids. While it is available over the counter, the effectiveness of these agents may decrease over time and the incidence of next-day sedation is higher than for most of the newer prescription drags. Dependence does not seem to be an issue with this class of drags.
  • insomniacs use herbs such as valerian, chamomile, lavender, hops, and passion-flower. Valerian has undergone multiple studies and appears to be modestly effective. Cannabis has also been suggested as a treatment for insomnia.
  • Alcohol may have sedative properties
  • the REM sleep suppressing effects of the drug prevent restful, quality sleep.
  • middle-of-the-night awakenings due to polyuria or other effects from alcohol consumption are common, and hangovers can also lead to morning grogginess.
  • insomnia As can be seen from this short review of the current medical treatments for insomnia, there is a huge unmet medical need for an efficacious treatment of insomnia (and other sleep disturbances) which does not cause psychological/physical dependence, morning sedation, neurological/cognitive side effects and/or many other side effects.
  • the current invention addresses this unmet medical need by providing a novel safe and efficacious treatment for insomnia (and other sleep disturbances), without any of the side effects of the current treatments.
  • Beta-blockers are notorious for causing sleep disturbances and nightmares, presumably because they inhibit the nocturnal Melatonin secretion ("Treatment with beta-adrenoceptor blockers reduces plasma melatonin concentration". PJ. Cowen et al., Br J Clin Pharmacol, Vol. 19 (2), 258- 260, 1985).. Analysis of the melatonin metabolite 6-sulfatoxy-melatonin (aMT6s) in urine from healthy volunteers, has e.g.
  • beta-blockers S-Propranolol (40 mg dose) and S- Atenolol (50 mg dose) cause an impressive 80-90% decrease in the nocturnal aMT6s secretion 12 hours after taking the drug ("Influence of beta-blockers on melatonin release".
  • Melatonin plays a role in sleep induction and exerts various effects on circadian rhythm, it seems plausible that the sleep disturbances caused by beta-blockers are at least partly caused by their effects on the Melatonin levels.
  • Nebivolol can improve the quality of sleep in patients with hypertension
  • Nebivolol is Different From Atenolol in Terms of Impact Onto Sleep.
  • A. Erdem et al The Anatolian Journal of Clinical Investigaton, Vol. 1(1), 25-29, 2007.
  • the authors conclude that "the improvement of sleep quality in the Nebivolol group might well be due to simply blood pressure control and lack of central side effect of the drug".
  • hypertension is associated with poor quality of sleep (Prejbisz et al., Blood Pressure. Vol. 15, 213-219, 2006).
  • anti-hypertensive drugs have also been shown to improve the quality of sleep in patients with hypertension.
  • the ACE inhibitor Captopril has e.g. been shown to improve the quality of sleep in patients with hypertension ("Quality of Life and Antihypertensive Therapy in Men — A Comparison of Captopril with Enalapril". M.A. Testa et al., The New England Journal of Medicine Vol. 328, 907-913, 1993 ).
  • the beneficial effect of the antihypertensive 3 rd generation beta-blocker Nebivolol on sleep quality in patients with hypertension is accordingly most likely caused by the blood pressure reduction induced by the drug.
  • norepinephrine-deficient mice exhibit normal sleep-wake states but have shorter sleep latency after mild stress and low doses of amphetamine", M.S. Hunsley and R.D. Palmiter, Sleep, Vol. 26 (5), 521-526, 2003).
  • poor sleep in stressed elderly caregivers, is associated with an increased plasma norepinephrine concentration.
  • aMT6s refers to the melatonin metabolite: 6-sulfatoxy-melatonin.
  • Quality of Sleep might be measured by employing the Pittsburgh Sleep Quality Index ("The Pittsburgh Sleep Quality Index: A New Instrument for Psychiatric Practice and Research", DJ. Buysse et al., Psychiatry Res Vol. 28, 193-213, 1989)
  • Stress refers to:
  • An emotionally disruptive or upsetting condition occurring in response to adverse external influences and capable of affecting physical health which can be characterized by increased heart rate, a rise in blood pressure, muscular tension, irritability, insomnia and depression.
  • Examples of stressful life events include, but are not limited to: Death of spouse, Divorce, Marital separation, Jail term or death of close family member, Personal injury or illness, Loss of job due to termination, Marital reconciliation or retirement, Pregnancy and Change in financial state (negative).
  • beta-blocker refers to:
  • Antagonists full or partial of beta-adrenergic receptors.
  • Some beta-blockers antagonize one specific subtype of beta-adrenergic receptors (e.g. a beta 1 selective beta-blocker which selectively antagonizes the beta-1 adrenergic receptor), whereas other beta-blockers are non-selective.
  • beta-blocker refers to all types of antagonists of beta- adrenergic receptors, regardless of whether the beta-blocker antagonize one, two or more beta- adrenergic receptors and regardless of whether they affect other processes.
  • beta- blockers include, but are not limited to: Acebutolol, Atenolol, Betaxolol, Bisoprolol, Bucindolol, Carteolol, Carvedilol, Celiprolol, Esmolol, Labetalol, Metoprolol, Nadolol, Nebivolol, Penbutolol, Pindolol, Propranolol, Timolol.
  • beta 1 selective beta-blocker refers to:
  • Beta-blockers where the IC50 for inhibition of the effect of noradrenaline on the beta 1 adrenergic receptor in a functional assay (e.g. cellular cAMP production) is at least 5 times less than for any other adrenergic receptor.
  • a functional assay e.g. cellular cAMP production
  • daytime urine refers to:
  • patient refers to: A person suffering from insomnia or another sleep disorder.
  • the term"elderly is intended to mean humans from 65 years and above.
  • the ternV'adults is intended to mean humans from 18 to 64 years.
  • the temT children is intended to mean humans from 0 to 17 years.
  • insomnia refers to:
  • Insomnia is not defined by the number of hours of sleep a person gets or how long it takes to fall asleep. Individuals vary normally in their need for, and their satisfaction with, sleep. Insomnia may cause problems during the day, such as tiredness, a lack of energy, difficulty concentrating, and irritability.
  • Types of Insomnia Primary insomnia is associated with complaint in initiating, maintaining or non-restoratively sleep, not exclusively occurring due to another mental disorder, physiological effects of a substance or a general medical condition.
  • insomnia is associated with complaint in initiating, maintaining or non-restoratively sleep, occurring due to another mental disorder, physiological effects of a substance or a general medical condition.
  • Insomnia can be classified as transient (short term), intermittent (on and off), and chronic (constant). Insomnia lasting from a single night to a few weeks is referred to as transient. If episodes of transient insomnia occur from time to time, the insomnia is said to be intermittent. Insomnia is considered to be chronic if it occurs on most nights and lasts a month or more.
  • causes of Insomnia Certain conditions seem to make individuals more likely to experience insomnia. Examples of these conditions include: advanced age (insomnia occurs more frequently in those over age 60); female gender; and a history of depression. If other conditions (such as stress, anxiety, a medical problem, or the use of certain medications) occur along with the above conditions, insomnia is more likely.
  • Transient and intermittent insomnia generally occur in people who are temporarily experiencing one or more of the following: stress, environmental noise, extreme temperatures, a change in the surrounding environment, sleep/wake schedule problems such as those due to jet lag, or medication side effects.
  • Chronic insomnia is more complex and often results from a combination of factors, including underlying physical or mental disorders.
  • One of the most common causes of chronic insomnia is depression.
  • Other underlying causes include arthritis, kidney disease, heart failure, asthma, sleep apnea, narcolepsy, restless leg syndrome, Parkinson disease, and hyperthyroidism.
  • chronic insomnia may also be due to behavioral factors, including the misuse of caffeine, alcohol, or other substances; disrupted sleep/wake cycles as may occur with shift work or other nighttime activity schedules; and chronic stress.
  • Behaviors that perpetuate insomnia in some people include: expecting to have difficulty sleeping and worrying about it, ingesting excessive amounts of caffeine, drinking alcohol or smoking cigarettes before bedtime, excessive napping in the afternoon or evening, and irregular or continually disrupted sleep/wake schedules. These behaviors may prolong existing insomnia, and they can also be responsible for causing the sleeping problem in the first place. Stopping these behaviors may eliminate the insomnia altogether.
  • sed herein sleep disorder include:
  • DSPS Delayed sleep phase syndrome
  • Narcolepsy The condition of falling asleep spontaneously and unwillingly at inappropriate times.
  • Parasomnias Include a variety of disruptive sleep-related events.
  • PLMD Periodic limb movement disorder
  • PLMD Sudden involuntary movement of arms and/or legs during sleep, for example kicking the legs. Also known as nocturnal myoclonus. See also Hypnic jerk, which is not a disorder. PLMD sufferers often do not also have RLS.
  • Rapid eye movement behavior disorder (RBD): Acting out violent or dramatic dreams while in REM sleep.
  • Hatzfeldt Syndrome or Systemic Neuro-Epiphysial Disorder is a somnipathy mainly characterized by an irregular sleep pattern, as well as irregular behavior
  • RLS Restless legs syndrome
  • SWSD Shift work sleep disorder
  • Sleep apnea The obstruction of the airway during sleep, causing loud snoring and sudden awakenings when breathing stops.
  • Sleepwalking or somnambulism Engaging in activities that are normally associated with wakefulness (such as eating or dressing), which may include walking, without the conscious knowledge of the subject.
  • Snoring Loud breathing patterns while sleeping; sometimes this is a symptom of sleep apnea.
  • Dvsomnias A broad category of sleep disorders characterized by either hypersomnolence or insomnia.
  • the three major subcategories include intrinsic (i.e., arising from within the body), extrinsic (secondary to environmental conditions or various pathologic conditions), and disturbances of circadian rhythm.
  • MeSH Insomnia
  • bruxism is mild enough not to be a health problem; however, some people suffer from significant bruxism that can become symptomatic. Bruxism often occurs during sleep and can even occur during short naps. Bruxism is one of the most common sleep disorders: 30 to 40 million Americans grind their teeth during sleep.
  • hypertension refers to:
  • High blood pressure HTN or HPN, a medical condition in which the blood pressure is chronically elevated. It was previously referred to as arterial hypertension, but in current usage, the word “hypertension” without a qualifier normally refers to arterial hypertension.
  • Hypertension can be classified as either essential (primary) or secondary.
  • Essential hypertension indicates that no specific medical cause can be found to explain a patient's condition.
  • Secondary hypertension indicates that the high blood pressure is a result of (i.e. secondary to) another condition, such as kidney disease or certain tumors (especially of the adrenal gland).
  • hypertension is considered to be present when the seated systolic blood pressure >140 mrnHg and the seated diastolic blood pressure >90 mmHg.
  • an individual is considered non-hypertensive when the seated systolic blood pressure ⁇ 140 mrnHg or the seated diastolic blood pressure ⁇ 90 mrnHg.
  • hypertension is considered to be present when the seated systolic blood pressure >140 mrnHg and/or the seated diastolic blood pressure >80 mmHg.
  • an individual is considered non-hypertensive when the seated systolic blood pressure ⁇ 140 mmHg and the seated diastolic blood pressure ⁇ 80 mmHg.
  • 1,25 mg Bisoprolol is given 2 hours before bedtime to stressed individuals suffering from insomnia.
  • a composition comprising 1,25 mg Hypoloc (Nebivolol) and 1 mg Melatonin is given 1 hour before bedtime to individuals above 55 years of age, who are suffering from insomnia.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • Anesthesiology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition contenant des bêta-bloquants spécifiques, tels que le bisoprolol et le nébivolol, destinée au traitement de l'insomnie et/ou d'un autre trouble du sommeil. La composition doit être administrée dans une quantité telle qu'elle provoque une réduction inférieure à 40 % de la quantité de 6-sulfatoxymélatonine (aMT6s) urinaire nocturne totale. La composition peut être un traitement combiné contenant un bêta-bloquant spécifique associé à un autre médicament connu, notamment la mélatonine, ayant un effet similaire sur le traitement de l'insomnie.
PCT/DK2008/000249 2007-08-03 2008-07-04 Utilisation d'une composition contenant au moins un bêta-bloquant pour le traitement de troubles du sommeil WO2009018824A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP08758258A EP2285365A4 (fr) 2007-08-03 2008-07-04 Utilisation d'une composition contenant au moins un bêta-bloquant pour le traitement de troubles du sommeil
US12/864,450 US20110015261A1 (en) 2007-08-03 2008-07-04 Use of a composition comprising at least one beta-blocker for the treatment of sleep disorders

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
DKPA20070116 2007-08-03
DKPA200701116 2007-08-03
DKPA200701332 2007-09-17
DKPA200701332 2007-09-17
DKPA200800182 2008-02-11
DKPA200800182 2008-02-11
DKPA200800625 2008-05-02
DKPA200800625 2008-05-02
DKPA200800932 2008-07-04
DK200800932A DK200800932A (en) 2007-08-03 2008-07-04 Use of a composition comprising at least one beta-blocker for the treatment of sleep disorders

Publications (1)

Publication Number Publication Date
WO2009018824A1 true WO2009018824A1 (fr) 2009-02-12

Family

ID=40364301

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2008/000249 WO2009018824A1 (fr) 2007-08-03 2008-07-04 Utilisation d'une composition contenant au moins un bêta-bloquant pour le traitement de troubles du sommeil

Country Status (2)

Country Link
DK (1) DK200800932A (fr)
WO (1) WO2009018824A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5496560A (en) * 1993-10-13 1996-03-05 Pharmed Dr. Liedtke Gmbh Borderline active dosage forms of beta blockers
WO1997031629A1 (fr) * 1996-02-29 1997-09-04 Eli Lilly And Company Traitement des troubles du sommeil
US6638963B1 (en) * 1990-12-04 2003-10-28 Oregon Health And Science University Methods for treating circadian rhythm disorders
US20050021092A1 (en) * 2003-06-09 2005-01-27 Yun Anthony Joonkyoo Treatment of conditions through modulation of the autonomic nervous system
US20050143378A1 (en) * 2003-12-29 2005-06-30 Yun Anthony J. Treatment of conditions through pharmacological modulation of the autonomic nervous system

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6638963B1 (en) * 1990-12-04 2003-10-28 Oregon Health And Science University Methods for treating circadian rhythm disorders
US5496560A (en) * 1993-10-13 1996-03-05 Pharmed Dr. Liedtke Gmbh Borderline active dosage forms of beta blockers
WO1997031629A1 (fr) * 1996-02-29 1997-09-04 Eli Lilly And Company Traitement des troubles du sommeil
US20050021092A1 (en) * 2003-06-09 2005-01-27 Yun Anthony Joonkyoo Treatment of conditions through modulation of the autonomic nervous system
US20050143378A1 (en) * 2003-12-29 2005-06-30 Yun Anthony J. Treatment of conditions through pharmacological modulation of the autonomic nervous system

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2285365A4 *

Also Published As

Publication number Publication date
DK200800932A (en) 2009-02-04

Similar Documents

Publication Publication Date Title
Neubauer Sleep problems in the elderly
Ancoli-Israel et al. Diagnosis and treatment of sleep disorders in older adults
Vitiello et al. Sleep disturbances in patients with Alzheimer’s disease: epidemiology, pathophysiology and treatment
O'Donnell Insomnia in cancer patients
Dauvilliers Insomnia in patients with neurodegenerative conditions
Fetveit Late‐life insomnia: A review
Roth Dementia and sleep
Thaxton et al. Sleep disturbances and their management in patients with brain injury
US20110015261A1 (en) Use of a composition comprising at least one beta-blocker for the treatment of sleep disorders
Folks et al. Sedative hypnotics and sleep
Marasinghe Sleep disorders in elderly
WO2009018824A1 (fr) Utilisation d'une composition contenant au moins un bêta-bloquant pour le traitement de troubles du sommeil
National Heart, Lung, and Blood Institute Working Group on Insomnia Insomnia: Assessment and management in primary care
Chaudhry Managing insomnia efficiently
Wilson et al. Insomnia: guide to diagnosis and choice of treatment
Ayalon et al. Normal sleep in aging
Saaresranta et al. Practical Approach for the Diagnosis and Management of Insomnia During Menopausal Transition
Millman Sleep and aging
Roehrs et al. Sleep and sleep disorders
Truter Evidence based pharmacy practice: insomnia: clinical
Gothi Restless legs syndrome: Common yet an under recognized entity
Setiati et al. Insomnia in geriatrics
Doghramji et al. Clinical management of insomnia
Vimmerová-Lattová Endocrine and Metabolic Aspects of Various Sleep Disorders
Bramble et al. Sleep Disorders

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08758258

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2008758258

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 12864450

Country of ref document: US