WO2015127556A1 - Procédés et utilisations pour induire ou faciliter la défécation chez un patient en ayant besoin - Google Patents

Procédés et utilisations pour induire ou faciliter la défécation chez un patient en ayant besoin Download PDF

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WO2015127556A1
WO2015127556A1 PCT/CA2015/050143 CA2015050143W WO2015127556A1 WO 2015127556 A1 WO2015127556 A1 WO 2015127556A1 CA 2015050143 W CA2015050143 W CA 2015050143W WO 2015127556 A1 WO2015127556 A1 WO 2015127556A1
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composition
receptor agonist
subject
ht1a
pharmaceutically acceptable
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PCT/CA2015/050143
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English (en)
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Pierre Guertin
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UNIVERSITé LAVAL
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    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/33—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
    • A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • 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

Definitions

  • SCI Spinal cord injury
  • SCI may occur following a trauma (e.g, car accident, sports, falls, etc.) or a disease (e.g., multiple sclerosis, spinal stenosis, spinal vascular accidents, etc.).
  • a trauma e.g., car accident, sports, falls, etc.
  • a disease e.g., multiple sclerosis, spinal stenosis, spinal vascular accidents, etc.
  • Neurological disorders related with Parkinson's disease (PD) or aging have also been associated with comparable dysfunction of bowel control and chronic constipation induced by neural impairment.
  • SCI-related bowel problems remain considered as unmet medical needs despite the fact that patients consider those problems as top priority and concern. Indeed, 90% of SCI patients experience bowel problems including mainly severe constipation, Gl motor dysfunction, hemorrhoids, abdominal distention and altered visceral sensitivity.
  • This 20 foot-long system comprising the stomach and intestine (bowel) essentially releases hormones (e.g., gastrin, secretin, melatonin, ghrelin, etc.) for local regulation of digestion, absorption and elimination.
  • hormones e.g., gastrin, secretin, melatonin, ghrelin, etc.
  • rhythmic muscle contractions - i.e., peristalsis, defined as cyclic rostrocaudal series of coordinated contractions and relaxations of Gl smooth muscles mediated locally by two main sensorimotor reflexes using acetylcholine (ACh), noradrenaline (NA), substance P (SP), adenosine triphosphate (ATP), etc.
  • ACh acetylcholine
  • NA noradrenaline
  • SP substance P
  • ATP adenosine triphosphate
  • Bowel problems such as diarrhea, fecal incontinence, irritable bowel syndrome (IBS) or constipation typically occur when the Gl tract does not work properly. More specifically, constipation is characterized clinically as difficult or infrequent (i.e., ⁇ 3 times/wk) passage of stools. In the general population, constipation is often caused by diet problems (e.g., low fiber), lack of exercise, dairy products, stress, pregnancy, medicines such as laxatives, antacids, antidepressants, iron, pain killers or by structural abnormalities (e.g., colon polyps, cancer, diverticula, anal problems, etc.). Related-secondary complications include fissures, fecal impaction, ulceration, abdominal distension, hemorrhoids, bleeding, pain and, occasionally, septic shock and death. Chronic constipation is experienced by 60M North Americans.
  • bowel problems associated with SCI typically chronic constipation - i.e., more than 12 weeks/year
  • CNS Central Nervous System
  • Defecation requires interactions between the somatic, autonomic and central nervous systems.
  • supraspinal networks e.g., Pontine Defecation Center
  • LDC Lumbosacral Defecation Center
  • motoneurons Onuf's nucleus
  • a failure of supraspinal inputs to modulate LDC neurons may lead to reduced colorectal motility and increased constipatory problems.
  • the present description relates to a composition that may comprise: (a) a cholinesterase inhibitor; (b) a 5-HT1A receptor agonist; (c) a 5 HT1A/7 receptor agonist; (d) a 5-HT2/3 receptor agonist; (e) a beta 2 adrenergic receptor agonist; or (f) any combination of (a) to (e), and optionally a pharmaceutically acceptable excipient or carrier, for inducing or facilitating defecation in a subject.
  • the composition may comprise at least two, at least three, or at least four of (a) to (e).
  • the composition may comprise a cholinesterase inhibitor, a 5-HT1 A receptor agonist, or both a 5-HT1 A receptor agonist and a 5 HT1A/7 receptor agonist.
  • the cholinesterase inhibitor may be: (1) neostigmine; (2) physostigmine; (3) a pharmaceutically acceptable derivative (1) or (2); or (4) any combination of (1)-(3).
  • the cholinesterase inhibitor may be neostigmine or a pharmaceutically acceptable derivative thereof.
  • the 5-HT1A receptor agonist may be: (1) buspirone; (2) tandospirone; (3) cannabidiol; (4) f-15,599; (5) flesinoxan; (6) gepirone; (7) ipsapirone; (8) quetiapine; (9) trazodone; (10) yohimbine; (11) indole alkaloid; (12) asenapine; (13) vortioxetine; (14) ziprasidone; (15) a pharmaceutically acceptable derivative of any one of (1)-(14); or (16) any combination of (1)-(15).
  • the 5-HT1A receptor agonist may be buspirone, or a pharmaceutically acceptable derivative thereof.
  • the composition may comprise a 5-HT1A/7 receptor agonist.
  • the 5-HT1A/7 receptor agonist may be: (1) 8-OH-DPAT; (2) 5-CT; (3) a pharmaceutically acceptable derivative of (1) or (2); or (4) any combination of (1)-(3).
  • the 5-HT1A/7 receptor agonist may be 8-OH-DPAT, or a pharmaceutically acceptable derivative thereof.
  • the composition may comprise a 5-HT2/3 receptor agonist.
  • the 5-HT2/3 receptor agonist may be: (1) quipazine; (2) SR57227A; (3) LSD; (4) mescaline; (5) psilocin; (6) DMT; (7) 2C-B; (8) lorcaserin; (9) 2-methyl-5-HT; (10) BZP; (11) RS-56812; (12) a pharmaceutically acceptable derivative of any one of (1)-(11); or (13) any combination of (1)-(12).
  • the 5-HT2/3 receptor agonist is quipazine, or a pharmaceutically acceptable derivative thereof.
  • the composition may comprise a beta-2 receptor agonist.
  • the beta-2 receptor agonist may be: (1) clenbuterol; (2) salbutamol; (3) levosalbutamol; (4) terbutaline; (5) pirbuterol; (6) procaterol; (7) metaproterenol; (8) fenoterol; (9) bitolterol mesylate; (10) a derivative of any one of (1)-(9); or (11) any combination of (1)-(10).
  • the beta-2 receptor agonist is clenbuterol, or a derivative thereof.
  • the composition may comprise neostigmine or a pharmaceutically acceptable derivative thereof, and buspirone or a pharmaceutically acceptable derivative thereof.
  • the composition is for oral administration and comprises 2.5 to 50 mg of buspirone, and/or 5 to 150 mg of neostigmine.
  • the present description relates to the use of the composition as defined herein for acutely inducing or facilitating defecation in a subject. In some aspects, the present description relates to the use of the composition as defined herein for the manufacture of a medicament for inducing or facilitating defecation in a subject.
  • the present description relates to the use of: (a) a cholinesterase inhibitor; (b) a 5-HT1A receptor agonist; (c) a 5 HT1A/7 receptor agonist; (d) a 5-HT2/3 receptor agonist; (e) a beta-2 receptor agonist; or (f) any combination of (a) to (e), for inducing or facilitating defecation in a subject in need thereof.
  • (a) to (e) are compounds as defined herein (e.g., in Table 1, or pharmaceutically acceptable derivatives thereof).
  • the use may be for inducing or facilitating acute defecation in a subject in need thereof.
  • the subject may suffer from chronic constipation (e.g., SCI-related chronic constipation such as constipation for more than 12 weeks/year).
  • the subject may be a spinal cord injury (SCI) subject.
  • the SCI subject may be a multiple sclerosis (MS) or Parkinson's disease (PD) subject.
  • compositions described herein may be for administration by a route which is: oral; parenteral; or sublingual.
  • compositions described herein may be for daily administration to the subject.
  • the present description relates to a method for inducing or facilitating acute defecation in a subject, said method comprising administering to said subject the composition as defined herein.
  • the present description relates to a kit comprising the composition as defined herein; and a suitable container.
  • the present description relates to the use of one or more agent, wherein the agent is: a 5- HT1A receptor agonist, a 5-HT1A/7 receptor agonist, a 5HT2/3 receptor agonist, a beta-2 adrenergic receptor agonist, a cholinesterase inhibitor, and a NK2 receptor agonist for inducing or facilitating defecation in a patient in need thereof.
  • the agent is: a 5- HT1A receptor agonist, a 5-HT1A/7 receptor agonist, a 5HT2/3 receptor agonist, a beta-2 adrenergic receptor agonist, a cholinesterase inhibitor, and a NK2 receptor agonist for inducing or facilitating defecation in a patient in need thereof.
  • the present description relates to the use of a combination of one or more agent, wherein the agent is: a 5-HT1A receptor agonist, a 5-HT1A/7 receptor agonist, a 5HT2/3 receptor agonist, a beta-2 adrenergic receptor agonist, a cholinesterase inhibitor, or a NK2 receptor agonist, and a further therapeutic agent indicated for the treatment of spinal cord injuries of traumatic (car accident) or non-traumatic origin (e.g., multiple sclerosis or PD) for inducing or facilitating defecation in a patient in need thereof
  • the agent is: a 5-HT1A receptor agonist, a 5-HT1A/7 receptor agonist, a 5HT2/3 receptor agonist, a beta-2 adrenergic receptor agonist, a cholinesterase inhibitor, or a NK2 receptor agonist
  • a further therapeutic agent indicated for the treatment of spinal cord injuries of traumatic (car accident) or non-traumatic origin e.g., multiple sclerosis or
  • the present description relates to a composition that may comprise one or more agent wherein the agent is a 5-HT1A receptor agonist, 5-HT1A/7 receptor agonist, a 5HT2/3 receptor agonist, a beta-2 adrenergic receptor agonist, a cholinesterase inhibitor, or a NK2 receptor agonist and optionally a pharmaceutically acceptable excipient or carrier for inducing or facilitating defecation in a patient.
  • the agent is a 5-HT1A receptor agonist, 5-HT1A/7 receptor agonist, a 5HT2/3 receptor agonist, a beta-2 adrenergic receptor agonist, a cholinesterase inhibitor, or a NK2 receptor agonist and optionally a pharmaceutically acceptable excipient or carrier for inducing or facilitating defecation in a patient.
  • the present description relates to a method for inducing or facilitating defecation comprising administering agent, wherein the agent is: 5-HT1A receptor agonist, a 5-HT1A/7 receptor agonist, a 5HT2/3 receptor agonist, a beta-2 adrenergic receptor agonist, a cholinesterase inhibitor, or a NK2 receptor agonist to a patient in need thereof.
  • the agent is: 5-HT1A receptor agonist, a 5-HT1A/7 receptor agonist, a 5HT2/3 receptor agonist, a beta-2 adrenergic receptor agonist, a cholinesterase inhibitor, or a NK2 receptor agonist to a patient in need thereof.
  • Figure 1 Histological examination and confirmation of spinal cord transection in a mouse.
  • A A typical Th9/10 transection without staining.
  • B Another luxol blue and cresyl violet stained cord clearly showing complete transection at the site of lesion.
  • FIG. 2A and 2B Summary of drug screening studies on quantity (Fig. 2A) and incidence (Fig. 2B) of defecation activity in spinal cord transected (Tx) mice within 30 min post-administration i.p. of different classes and subclasses of agents.
  • Fig. 2A Summary of drug screening studies on quantity
  • Fig. 2B incidence
  • Fig. 2B Summary of drug screening studies on quantity
  • Fig. 2B incidence
  • defecation activity in spinal cord transected mice mice within 30 min post-administration i.p. of different classes and subclasses of agents.
  • Figure 3 Effects of 8-OH-DPAT and buspirone on the average amounts of feces expulsed (dark gray bars) and on defecation incidence (light gray bars) within 30 min post-administration s.c. in acclimated spinal cord-transected mice.
  • Figure 4 Effects of buspirone administered s.c. (1-3 mg/kg), buspirone administered p.o. (10 mg/kg), and neostigmine administered p.o. (0.5 pg/kg) on the average amounts of feces expulsed within 30 min post-administration in acclimated spinal cord-transected mice 30 min post-administration
  • Figure 5 Effects of various doses of buspirone administered s.c. or p.o. on the amount of feces expulsed in acclimated spinal cord-transected mice 30 min post-administration
  • Figure 6 Effects of various doses of neostigmine administered s.c. or p.o. on the amount of feces expulsed in acclimated spinal cord-transected mice 30 min post-administration
  • Figure 7 Effects of combination therapies containing either: clenbuterol (2.5 mg/kg) + quipazine (5 mg/kg) + 8-OH- DPAT (1 mg/kg); or buspirone (1 mg/kg) + neostigmine (0.01 pg/kg), on the average amounts of feces expulsed (dark gray bars) and on defecation incidence (light gray bars) within 30 min post-administration s.c. to acclimated spinal cord- transected mice 30 min post-administration.
  • Figure 8 Effects of combination therapies containing various doses of buspirone (1-40 mg/kg) and neostigmine (0.01-2 g/kg) administered s.c. or p.o. on the amount of feces expulsed in acclimated spinal cord-transected mice 30 min post- administration.
  • Figure 9 Effects of other drug combinations on the amount of feces expulsed in acclimated spinal cord-transected mice 30 min post-administration s.c. Groups tested include: (1) Buspirone (2.5-40 mg/kg) + 8-OH-DPAT (1-20 mg/kg); (2) Neostigmine (0.01-0.1 pg/kg) + 8-OH-DPAT (1 mg/kg); (3) Quipazine (1-5 mg/kg) + 8-OH-DPAT (1 mg/kg); (4) Clenbuterol (2.5 mg/kg) + 8-OH-DPAT (1 mg/kg); (5) Clenbuterol (2.5 mg/kg) + Quipazine (5 mg/kg) + 8-OH-DPAT (1 mg/kg); (6) Clenbuterol (0.5-2.5 mg/kg) + Quipazine (1-5 mg/kg) + GR64349 (0.5-2.5 mg/kg).
  • compositions comprising certain classes of drugs/compounds
  • compositions may generally comprise one or more of a 5-HT (5-hydroxytryptamine, serotonin) receptor agonist, a beta-2 adrenergic receptor agonist, and a parasympathomimetic agent.
  • a 5-HT (5-hydroxytryptamine, serotonin) receptor agonist e.g., 5-HT-5-hydroxytryptamine, serotonin
  • beta-2 adrenergic receptor agonist e.g., beta-2 adrenergic receptor agonist
  • parasympathomimetic agent e.g., a parasympathomimetic agent
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), "including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, un-recited elements or method steps.
  • the present description relates to a composition that may be useful for inducing or facilitating defecation in a subject in need thereof.
  • the term "patient' or "subject' means an animal including human.
  • the expression "SCI patient' or "SCI subject” means a subject that suffered a traumatic (e.g., car accident, fall, etc.) or non-traumatic (e.g., a degenerative disease such as multiple sclerosis (MS) or Parkinson's disease (PD)) spinal cord injury, or other neurological diseases affecting the CNS or spinal cord that result in the subject having bowel (defecation) problems.
  • a traumatic e.g., car accident, fall, etc.
  • non-traumatic e.g., a degenerative disease such as multiple sclerosis (MS) or Parkinson's disease (PD) spinal cord injury, or other neurological diseases affecting the CNS or spinal cord that result in the subject having bowel (defecation) problems.
  • MS multiple sclerosis
  • PD Parkinson'
  • the SCI subject may be a patient with an irreversible loss of sensation and voluntary motor control below the level of injury.
  • the SCI patient may be a paraplegic or quadriplegic patient, or an MS or PD patient.
  • MS patient' or “MS subject”, or “PD patient” or “PD subject” refers to an SCI subject suffering from an affection to the spinal cord and diagnosed with multiple sclerosis or Parkinson's Disease.
  • compositions of the present description may comprise: (a) a cholinesterase inhibitor; (b) a 5- HT1A receptor agonist; (c) a 5 HT1A/7 receptor agonist; (d) a 5-HT2/3 receptor agonist; (e) a beta 2 adrenergic receptor agonist; or (f) any combination of (a) to (e).
  • compositions defined herein may comprise a combination of at least two, at least three, at least four, at least five; between two and five, or between two and four of: (a) to (e).
  • the composition elicits acute defecation in subjects having a spinal cord injury (SCI subject).
  • one or more of (a) to (e) may be chosen from Table 1, or a pharmaceutically acceptable derivative of a compound listed In Table 1.
  • the agents of Table 1 can be used alone or in combination with each other or with pharmaceutically acceptable derivatives thereof. It is understood that when sub-classes of agonists are identified, it means that the agonist has greater affinity for the subclass of receptor mentioned than for the other receptors within that class. For example, a 5-HT2/3 receptor agonist has more affinity for serotonin receptor subtypes 2 and 3.
  • Table 1 Classes, sub-classes and representative agents
  • the composition may comprise one or more of quipazine, buspirone, 8-OH-DPAT, SR572272A, clenbuterol, or neostigmine.
  • the uses, methods, compositions and combinations may comprise a further therapeutic agent indicated for the treatment of spinal cord injuries, multiple sclerosis, or other neurological disorders where descending signaling pathways (from brain to spinal structures) may be impaired such as Parkinson's disease or aging associated also with similar bowel problems.
  • a “pharmaceutically acceptable derivative” of a compound described herein refers to a pharmaceutically suitable compound that shares at least some level of structural and functional similarity to a compound of the present description.
  • a “pharmaceutically acceptable derivative of buspirone” refers to a compound having a core chemical structure that is similar to buspirone (e.g., is chemically synthesizable or derivable from buspirone), and is able to bind to the same molecular target or targets (i.e., 5-HT1A receptor) with a similar specificity as buspirone.
  • compositions may include any pharmaceutically acceptable salts, pro-drugs, metabolites, esters, ethers, hydrates, polymorphs, solvates, complexes, enantiomers or adducts of a compound described herein which, upon administration to a subject, is capable of providing (directly or indirectly) the parent compound.
  • compositions as defined herein may be used for acutely inducing or facilitating defecation in a subject (e.g., an SCI subject), for the manufacture of a medicament for same, or in a method for treating a subject having bowel (defecation) problems (e.g., chronic constipation).
  • defecation refers to the process of disposing fecal matter from the anus to the outside of the body.
  • inducing or facilitating means an increase in defecation frequency and/or an increase in fecal matter amount disposed in patients with constipation problems.
  • the use and methods as described herein may be used to induce or facilitate daily defecation (e.g., once daily).
  • acutely inducing or facilitating means a rapid increase, within 30 minutes upon administration of a composition described herein, in defecation frequency and/or an increase in fecal matter amount disposed in subjects with constipation problems.
  • the compositions, uses and methods of the present description can be used to induce or facilitate acute defecation (e.g., within 30 minutes of administration).
  • therapeutically effective amounts of the cholinesterase inhibitor, 5-HT1A receptor agonist, 5 HT1A/7 receptor agonist, 5-HT2/3 receptor agonist, or beta 2 adrenergic receptor agonist are used in the uses, methods, compositions and combinations described herein.
  • the expression "therapeutically effective amount' refers to that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought be a researcher or clinician.
  • the therapeutically acceptable amount is the amount required to elicit or induce the increase defecation in the patient or subject (e.g., acute defecation).
  • the present description is intended to include all pharmaceutically acceptable ionized forms (e.g., salts) and solvates (e.g., hydrates) of the compounds, regardless of whether such ionized forms and solvates are specified, since it is well known in the art to administer pharmaceutical agents in an ionized or solvated form. It is also noted that, unless a particular stereochemistry is specified, recitation of a compound is intended to encompass all possible stereoisomers (e.g., enantiomers or diastereomers depending on the number of chiral centers), independent of whether the compound is present as an individual isomer or a mixture of isomers.
  • the present description also relates to pharmaceutically acceptable salts compounds recited herein.
  • pharmaceutically acceptable salts are meant those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toleune p sulphonic, tartaric, acetic, trifluoroacetic, citric, methanesulphonic, formic, benzoic, malonic, naphthalene 2 sulphonic and benzenesulphonic acids. Salts derived from amino acids are also included (e.g.
  • Salts derived from appropriate bases include alkali metals (e.g. sodium, lithium, potassium) and alkaline earth metals (e.g. calcium, magnesium).
  • alkali metals e.g. sodium, lithium, potassium
  • alkaline earth metals e.g. calcium, magnesium
  • polymorphism is an ability of a compound to crystallize as more than one distinct crystalline or "polymorphic" species.
  • a polymorph is a solid crystalline phase of a compound with at least two different arrangements or polymorphic forms of that compound molecule in the solid state.
  • Polymorphic forms of any given compound are defined by the same chemical formula or composition and are as distinct in chemical structure as crystalline structures of two different chemical compounds. It will be appreciated that the amount of compounds required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition for which treatment is required and the age and condition of the patient and will be ultimately at the discretion of the attendant physician.
  • the desired dose may conveniently be presented in a single dose or as divided dose administered at appropriate intervals, for example as two, three, four or more doses per day (e.g., one or more unitary doses).
  • the compositions as described herein may be a fixed-dose combination.
  • the compositions described herein may comprise between 1 and 500 mg of the compounds listed in Table 1 , or pharmaceutically acceptable derivatives thereof.
  • persons of skill in the art will be able to select the proper dosages of each compound to acutely trigger defecation, depending on a number of factors such as the potency or toxicity of the compound, the desired route of administration, and the age and/or weight of the subject.
  • compositions described herein for oral administration may comprise between 2.5 and 50 mg of a 5-HT1A receptor agonist (e.g., buspirone), or between 15 and 150 mg of a cholinesterase inhibitor (e.g., neostigmine).
  • a 5-HT1A receptor agonist e.g., buspirone
  • a cholinesterase inhibitor e.g., neostigmine
  • the compounds may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical composition.
  • the present description thus further relates to a pharmaceutical combination or composition of the compounds as described herein or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the compounds described herein may be prepared as dosage forms for once or twice daily administration.
  • dosage forms may be immediate release dosage forms that can be taken by a subject "on-demand" in order to acutely elicit defecation.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • the compositions may, where appropriate, be conveniently presented in discrete dosage units (e.g., unitary dosages) and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired composition.
  • compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • Tablets and capsules for oral administration may contain conventional excipients, such as binding agents, fillers, lubricants, disintegrants, or wetting agents.
  • the tablets may be coated according to methods well known in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, nonaqueous vehicles (which may include edible oils), or preservatives.
  • the compounds may also be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • parenteral administration e.g., by injection, for example bolus injection or continuous infusion
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
  • the compounds may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • transdermal patches may contain penetration enhancers such as linalool, carvacrol, thymol, citral, menthol and t-anethole.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • compositions suitable for topical administration in the mouth include lozenges comprising active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • compositions suitable for rectal administration wherein the carrier is a solid are for example presented as unit dose suppositories.
  • suitable carriers include cocoa butter and other materials commonly used in the art, and the suppositories may be conveniently formed by admixture of the active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the compounds or combinations may be used as a liquid spray or dispersible powder or in the form of drops.
  • Drops may be formulated with an aqueous or non-aqueous base also comprising one more dispersing agents, solubilizing agents or suspending agents. Liquid sprays are conveniently delivered from pressurized packs.
  • the compounds or combinations are conveniently delivered from an insufflator, nebulizer or a pressurized pack or other convenient means of delivering an aerosol spray.
  • Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the compounds or combinations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the powder composition may be presented in unit dosage form in, for example, capsules or cartridges or e.g. gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
  • an acceptable carrier or "a pharmaceutically acceptable excipient or carrier” means a vehicle for the combinations and compounds described herein that can be administered to a subject without adverse effects.
  • Suitable carriers known in the art include, but are not limited to, gold particles, sterile water, saline, glucose, dextrose, or buffered solutions.
  • Carriers may include auxiliary agents including, but not limited to, diluents, stabilizers (e.g., sugars and amino acids), preservatives, wetting agents, emulsifying agents, pH buffering agents, viscosity enhancing additives, colors and the like.
  • the present description relates to a kit comprising compositions defined herein; and a suitable container.
  • Preoperative care included lactate-Ringer's solution (1 mL, administered subcutaneously (s.c.)), analgesic (buprenorphine; 0.1 mg/kg, s.c,
  • Tx transection
  • the inner vertebral walls were explored and entirely scraped several times with scissor tips in order to disrupt any small fibres which had not been previously severed. Opened skin areas were sutured and animals were placed for a few hours on heating pads. Postoperative care included administration of lactate-Ringer's solution (2 x 1 mL/day, s.c), buprenorphine (0.2 mg/kg/day, s.c.) and BaytrilTM (5 mg/kg/day) for four consecutive days. Bladders were also emptied manually for four days or until a spontaneous return of some micturition. Animals were left in their cages with food and water ad libitum.
  • Complete Tx was confirmed by 1) mainly flaccid hindlimbs and 2) post-mortem examination of the lesioned area using either coronal or longitudinal sections of the spinal cord stained with luxol blue and cresyl violet.
  • panel A shows a typical Th9/10 transection without staining
  • panel B shows another luxol blue and cresyl violet-stained cord clearly showing complete transection at the site of lesion.
  • Tests with agents (drugs) administered separately by intraperitoneal injection (i.p.) were generally performed 7 days post-Tx. Drug selection was based upon known corresponding receptor family classes and subclasses in the spinal cord. For each compound, corresponding low and high doses were chosen based on binding affinity data available and evidence of central-mediated effects in the literature (see selected dose ranges below and in the Results section of this example).
  • defecation activity was assessed as follows. Fecal pellets expulsed during a 30 min- period of observation were monitored. Incidence was calculated as the number of tested animals in which at least one episode (i.e., at least one fecal pellet) of defecation was found during the 30 min period post-administration.
  • mice that underwent a complete spinal transection thoracically were tested (see Fig.1).
  • Figure 2A shows the effects of different classes of compounds (e.g., cathecolaminergic, monoaminergic, or peptidergic compounds) administered i.p. on the quantity (in mg) of defecation elicited in 30 minutes.
  • compounds e.g., cathecolaminergic, monoaminergic, or peptidergic compounds
  • Figure 2B shows the results (% incidence of defecation) from further experiments in which drugs were administered separately i.p. to non-acclimated spinal cord-transected mice in different groups (8-10 spinal cord transected mice tested per group with drug administration occurring 7-28 days post-Tx).
  • Dosages tested ranged generally between 0.1 and 5 mg/kg, except for neostigmine (0.00001-0.1 mg/kg), L-DOPA (25-100 mg/kg), carbidopa (5-25 mg/kg), and NMDA (10-75 mg/kg), for which either lower or higher doses have been shown to elicit centrally-mediated actions.
  • mice underwent acclimation
  • Preoperative care included lactate-Ringer's solution (1 mL, s.c), analgesic (buprenorphine; 0.1 mg/kg, s.c, Schering-Plough, Pointe-Claire, QC), and antibiotic (BaytrilTM; 5 mg/kg, s.c, Bayer, Toronto, ON).
  • lactate-Ringer's solution 1 mL, s.c
  • analgesic buprenorphine
  • s.c Schering-Plough, Pointe-Claire, QC
  • antibiotic Bactasthoracic level
  • Spinal transection at the low-thoracic level was performed under complete anesthesia with 2.5% isoflurane.
  • the spinal cord was completely transected (Tx) intervertebral ⁇ using microscissors (no.
  • mice Upon arrival at the animal care facilities, animals were housed as groups of 3 or 4 mice per cage with free access to food and water. Basic acclimation began with 4 days in these conditions. Four (4) days before experiments, we placed each group in a circular PlexiglasTM arena (diameter of 60 cm) for 30 minutes, which would we used to observe the animals following drug administration. Generally, the results showed that during the first 15 min, most mice were particularly active at exploring that new environment. Then, exploration and corresponding locomotor activity decreased progressively for the remaining 15 min. Towards the third day, complete immobility and grooming was even found during the first 15 min suggesting that less stress was experienced by the animals when placed in the PlexiglasTM arena.
  • each group was acclimated again for 10 minutes in the PlexiglasTM arena prior to administrations. It was found that acclimation is critically important to reduce as much as possible the effects of stress on fecal pellet production which, otherwise, would lead to false positive results and lack of reproducibility. Then each animal was tested separately. Following administration of sterile water (control) or a drug, the animal was examined for 30 min during which fecal pellets were removed from the arena using forceps as they were being produced.
  • mice were administered separately.
  • corresponding low and high doses were chosen based on binding affinity data available or evidence of central-mediated effects in the literature.
  • Animal groups consisted generally of at least 8 spinal cord-transected (Tx) mice per group (drug or drug combination) or subgroup (dose).
  • Drug solutions were prepared each day of experiments a few hours before testing using sterile water.
  • Parenteral or oral administrations consisted of a bolus injection.
  • 0.5-1 ml_ of solution was injected in the back area of the animal.
  • 0.2 ml_ of solution was delivered by gavage using a bended needle for that purpose.
  • defecation activity was assessed as follows. Fecal pellets expressed during a 30 min- period of observation were recorded. Incidence (expressed as a percentage) was calculated as the number of tested animals in which at least one episode of defecation was found during the 30 min period post-administration. Intensity (number of feces generated per animal), and total ejected feces (amounts in mg) were also monitored.
  • Results were reported either as percentages (incidences) or as amounts of feces (average amount of feces expulsed in mg per animal). For each group, we performed unpaired T tests, using GraphPad PrismTM 5.0 software, in which results were expressed as mean ⁇ SEM. P values ⁇ 0.05 were considered statistically significant.
  • Figure 3 shows the effects of 8-OH-DPAT and buspirone on the average amounts of feces expulsed (dark gray bars) and on defecation incidence (light gray bars) within 30 min post-administration s.c. in Tx mice. More specifically, Fig. 3 shows that, within physiological dose ranges, 8-OH-DPAT (0.5-5 mg/kg) induced an average of 74.3 ⁇ 21.9 mg feces per animal, and buspirone (1-3 mg/kg) elicited an average of 71.4 ⁇ 11.7 mg of feces per animal, which are both greater (P ⁇ 0.05) than the control (water).
  • Figure 4 shows the effects of buspirone administered s.c. (1-3 mg/kg), buspirone administered p.o. (10 mg/kg), and neostigmine administered p.o. (0.5 g/kg) on the average amounts of feces expulsed within 30 min post- administration in Tx mice. In each case, the average amounts of feces expulsed were greater (p ⁇ 0.05) than control (water).
  • mice were spinal cord transected and administered buspirone either subcutaneously (s.c.) or orally (p.o.) and evaluated for defecation within 30 min post-administration, as generally described in Example 2.1.
  • Figure 5 shows the effects of various doses of buspirone administered s.c. or p.o. to Tx mice.
  • buspirone 5-HT1 A agonist
  • 1 week post-Tx averages of 110.2 ⁇ 19.9 mg and 99.3 ⁇ 11.6 mg of feces per animal were expulsed, respectively, within 30 min post-administration.
  • the difference between both groups treated with buspirone p.o. (2.5 mg/kg or 10 mg/kg) was not statistically significant (p > 0.05).
  • Figure 6 shows the effects of various doses of neostigmine administered s.c. or p.o. to Tx mice.
  • neostigmine cholinesterase inhibitor
  • the difference between both groups treated with neostigmine s.c. (0.01 g/kg or 0.1 g/kg) was not statistically significant (p > 0.05).
  • mice were spinal cord transected and administered different combinations of buspirone and neostigmine either subcutaneously (s.c.) or orally (p.o.) and evaluated for defecation within 30 min post-administration, as generally described in Example 2.1.
  • Figure 7 shows the effects of combination therapies containing: (1) clenbuterol (2.5 mg/kg) + quipazine (5 mg/kg) + 8-OH-DPAT (1 mg/kg); or (2) buspirone (1 mg/kg) + neostigmine (0.01 pg/kg), on the average amounts of feces expulsed (dark gray bars) and on defecation incidence (light gray bars) within 30 min post-administration s.c. More specifically, the combination of buspirone + neostigmine resulted in an average of 123.0 ⁇ 16.0 mg of feces per animal being expulsed within 30 min post-administration.
  • Figure 8 shows the effects of combination therapies containing various doses of buspirone (1-40 mg/kg) and neostigmine (0.01-2 g/kg) administered s.c. or p.o. at 1-5 weeks post-Tx.
  • Table 3 Note that the defecation effects elicited at relatively low doses of buspirone and neostigmine are comparable to the level of defecatory activity found in intact (non-Tx) mice (see Table 2, last row). Indeed, fecal pellet production ranging between 130 and 141 mg was found at lower doses, even upon p.o. administration, with peaks that could reach 185 mg of feces in some case.
  • Table 3 Average amount of fecal pellets expulsed per animal within 30 min post-administration s.c. or p.o.
  • Figure 9 shows the effects of other drug combinations delivered via s.c. administration in Tx mice. Mice received 0.5 ml_ s.c. of the drug combinations described in Table 4 at 1 , 2, 3 or 4 weeks post-Tx.
  • Table 3 Average amount of fecal pellets expressed per animal within 30 min post-administration s.c. or p.o.

Abstract

La présente invention concerne des compositions pour déclencher la défécation aiguë chez des sujets ayant une lésion de la moelle épinière (sujets atteints de LME). Les compositions peuvent comprendre d'une manière générale un ou plusieurs éléments parmi un agoniste du récepteur 5-HT (5-hydroxytryptamine, de la sérotonine), un agoniste du récepteur bêta-2 adrénergique, et un agent parasympathomimétique. Plus spécifiquement, les compositions peuvent comprendre un ou plusieurs éléments parmi : un inhibiteur de la cholinestérase ; un agoniste du récepteur 5-HT1A ; un agoniste du récepteur 5-HT1A/7 ; un agoniste du récepteur 5-HT2/3 ; et un agoniste du récepteur bêta-2 adrénergique. Des utilisations et procédés destinés à déclencher la défécation aiguë chez des sujets en ayant besoin sont également décrits.
PCT/CA2015/050143 2014-02-28 2015-02-27 Procédés et utilisations pour induire ou faciliter la défécation chez un patient en ayant besoin WO2015127556A1 (fr)

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US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
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US11471439B2 (en) 2017-02-09 2022-10-18 Caamtech, Inc. Compositions and methods comprising a combination of serotonergic drugs
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11724985B2 (en) 2020-05-19 2023-08-15 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use
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US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11471439B2 (en) 2017-02-09 2022-10-18 Caamtech, Inc. Compositions and methods comprising a combination of serotonergic drugs
US11974984B2 (en) 2017-02-09 2024-05-07 Caamtech, Inc. Compositions and methods comprising a combination of serotonergic drugs
US11819475B2 (en) 2017-02-09 2023-11-21 Caamtech, Inc. Compositions comprising a serotonergic tryptamine compound
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US11724985B2 (en) 2020-05-19 2023-08-15 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use
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US11834410B2 (en) 2020-05-19 2023-12-05 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use
US11958807B2 (en) 2020-05-19 2024-04-16 Cybin Irl Limited Deuterated tryptamine derivatives and methods of use
US11680043B2 (en) 2021-02-10 2023-06-20 Eleusis Therapeutics Us, Inc. Pharmaceutically acceptable salts of psilocin and uses thereof
US11312684B1 (en) 2021-02-10 2022-04-26 Eleusis Therapeutics Us, Inc. Pharmaceutically acceptable salts of psilocin and uses thereof

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