US20040147510A1 - Method of treating nausea, vomiting, retching or any combination thereof - Google Patents

Method of treating nausea, vomiting, retching or any combination thereof Download PDF

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US20040147510A1
US20040147510A1 US10/757,981 US75798104A US2004147510A1 US 20040147510 A1 US20040147510 A1 US 20040147510A1 US 75798104 A US75798104 A US 75798104A US 2004147510 A1 US2004147510 A1 US 2004147510A1
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vomiting
retching
nausea
combination
caused
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Steven Landau
Cheryl Miller
Karl Thor
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Edusa Pharmaceuticals Inc
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Dynogen Pharmaceuticals Inc
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Assigned to DYNOGEN PHARMACEUTICALS, INC. reassignment DYNOGEN PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: THOR, KARL B., LANDAU, STEVEN B., MILLER, CHERYL L.
Priority to US10/846,979 priority patent/US7094786B2/en
Priority to US10/846,978 priority patent/US20040254171A1/en
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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
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • 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
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • 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
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • 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

Definitions

  • Emesis is the act of vomiting and can be described as the forceful expulsion of gastrointestinal contents through the mouth brought about by the descent of the diaphragm and powerful contractions of the abdominal muscles. Emesis is usually, but not always, preceded by nausea (the unpleasant feeling that one is about to vomit). Retching or dry heaves involves the same physiological mechanisms as vomiting, but occurs against a closed glottis, which prohibits the expulsion of gastric contents.
  • Vomiting, nausea, retching or combinations thereof can be caused by a number of factors including, but not limited to, anesthetics, radiation, cancer chemotherapeutic agents, toxic agents, odors, medicines, for example, serotonin reuptake inhibitors, analgesics such as morphine, antibiotics and antiparasitic agents, pregnancy and motion.
  • Conditions which are associated with vertigo e.g., Meniere's disease and vestibular neuronitis
  • Headache caused by, for example, migraine, increased intracranial pressure or cerebral vascular hemorrhage can also result in nausea, vomiting, retching or any combination thereof.
  • GI gastrointestinal
  • certain maladies of the gastrointestinal (GI) tract for example, cholecystitis, choledocholithiasis, intestinal obstruction, acute gastroenteritis, perforated viscus, dyspepsia resulting from, for example, gastroesophageal reflux disease, peptic ulcer disease, gastroparesis, gastric or esophageal neoplasms, infiltrative gastric disorders (e.g., Menetrier's syndrome, Crohn's disease, eosinophilic gastroenteritis, sarcoidosis and amyloidosis),gastric infections (e.g., CMV, fungal, TB and syphilis), parasites (e.g., Giardia lamblia and Strongyloides stercoralis ), chronic gastric volvulus, chronic intestinal ischemia, altered gastric motility disorders and/or food intolerance or Zollinger-Ellison syndrome can result in vomiting, nausea,
  • Nausea, vomiting and retching are defined as acute when symptoms are present for less than a week.
  • the causes of nausea, vomiting and retching of short duration are often separable from etiologies leading to more chronic symptoms.
  • Nausea, vomiting and retching are defined as chronic when symptoms are present for over a week.
  • symptoms can be continuous or intermittent and last for months or years.
  • the vomiting reflex is triggered by stimulation of chemoreceptors in the upper GI tract and mechanoreceptors in the wall of the GI tract which are activated by both contraction and distension of the gut as well as by physical damage.
  • a coordinating center in the central nervous system controls the emetic response. This center is located in the parvicellular reticular formation in the lateral medullary region of the brain.
  • Afferent nerves to the vomiting center arise from abdominal splanchnic and vagal nerves, vestibulo-labyrinthine receptors, the cerebral cortex and the chemoreceptor trigger zone (CTZ).
  • the CTZ lies adjacent in the area postrema and contains chemoreceptors that sample both blood and cerebrospinal fluid.
  • Direct links exist between the emetic center and the CTZ.
  • the CTZ is exposed to emetic stimuli of endogenous origin (e.g., hormones) as well as to stimuli of exogenous origin, such as drugs.
  • emetic stimuli of endogenous origin e.g., hormones
  • exogenous origin e.g., drugs
  • the efferent branches of cranial nerves V, VII and IX, as well as the vagus nerve and sympathetic trunk produce the complex coordinated set of muscular contractions, cardiovascular responses and reverse peristalsis that characterize vomiting.
  • the symptoms caused by the chemotherapeutic agents can be so severe that the patient refuses further treatment.
  • Three types of emesis are associated with the use of chemotherapeutic agents. The first, is acute emesis, which occurs within the first 24 hours of chemotherapy. The second, is delayed emesis which occurs 24 hours or more after chemotherapy administration. The third, is anticipatory emesis, which begins prior to the administration of chemotherapy, usually in patients whose emesis was poorly controlled during a previous chemotherapy cycle.
  • PONV is also an important patient problem and one that patients rate as the most distressing aspect of operative procedure, even above pain. Consequently, the need for an effective anti-emetic in this area is important.
  • PONV is troublesome and requires staff around to ensure that vomitus is not regurgitated, which can have very serious clinical sequelae.
  • operative procedures where it is clinically important that patients do not vomit. For example, in ocular surgery where intra-cranial ocular pressure can increase to the extent that stitches are ruptured and the operative procedure is set back in terms of success to a marked degree.
  • agents that are used clinically for the treatment of emesis. These groups include: anticholinergics, antihistamines, phenothiazines, butyrophenones, cannabinoids, benzamides, glucocorticoids, benzodiazepines and 5-HT 3 receptor antagonists.
  • tricyclic antidepressants have also been used on a limited basis.
  • the phenothiazines which include prochlorperazine and chlorpromazine, block dopamine type-2 receptors in the CTZ.
  • side effects for example, extrapyramidal symptoms, such as, dystonia and akathisia, sedation, anticholinergic effect and orthostatic hypotension make the use of the phenothiazines a less than desirable therapy.
  • Anticholinergics used in the treatment of nausea and vomiting include scopolomine (e.g., in treating motion sickness). However, drowsiness is a significant side effect.
  • Antihistamines are mainly used for motion sickness and in antiemetic combinations to reduce extrapyramidal side effects of dopamine receptor antagonists.
  • the antihistamines have modest antiemetic activity and include sedation and anticholinergic effects as the major drawbacks.
  • Butyrophenones for example, haloperidol and droperidol, work by blocking dopamine receptors in the CTZ.
  • the side effects of butyrophenones include akathisia, dystonia and hypotension.
  • Cannabinoids such as tetrahydrocannabinol and nabilone have shown limited efficacy (see, e.g. Sallan et al., N. Eng. J. Med ., 302: 135-138 (1980)).
  • the side effects include euphoria, dizziness, paranoid ideation and somnolence.
  • Benzamides include, for example, metoclopramide, cisapride and trimethobenzamide.
  • side effects which include extrapyramidal symptoms and diarrhea make the use of benzamides a less than desirable therapy.
  • Benzodiazapines include, for example, lorazepam. Side effects of the benzodiazapines include perceptual disturbances, urinary incontinence, hypotension, diarrhea, sedation and amnesia.
  • Corticosteroids such as dexamethasone and methylprednisolone are useful in combination therapy, but shown little efficacy as a single agent. Side effects include, hyperglycemia, euphoria, insomnia and rectal pain.
  • the undesirable side effects associated with the use of tricyclic antidepressants are a significant drawback for this therapy.
  • the anticholinergic properties of the tricyclic antidepressants can cause dry mouth, constipation, blurred vision, urinary retention, weight gain, hypertension and cardiac side effects, such as palpitations and arrhythmia.
  • 5-HT 3 receptors are widely distributed in the mammalian central, peripheral and enteric nervous systems.
  • the enteric nervous system resides within the walls of the gastrointestinal tract.
  • 5-HT 3 receptors have been found to play an important role in the control of vomiting in a variety of mammals including humans (Veyrat-Follet et al., Drugs 53(2): 206-234 (1997)).
  • the receptors are present in the part of the brain that is involved in controlling vomiting as well as in the gastrointestinal tract. Receptors at both locations have been shown to be involved in vomiting.
  • CTZ chemoreceptor trigger zone
  • CTZ neurotransmitters that are thought to cause emesis include, but are not limited to, dopamine, serotonin, histamine and norepinephrine.
  • 5-HT 3 receptor antagonists such as ondansetron, granisetron and tropisetron has been shown to be less effective for delayed nausea and vomiting than for acute symptoms.
  • efficacy of the 5-HT 3 receptor antagonists appears to be less pronounced for moderate emetogenic chemotherapy regimens than for cisplatin-containing regimens.
  • control over nausea appears to be significantly less than control over vomiting.
  • efficacy of the agents appears to diminish across repeated days and across repeated chemotherapy cycles (see, e.g., Morrow et al., Cancer 76(3): 343-357 (1995)).
  • the invention relates to a method of treating nausea, vomiting, retching or any combination thereof in a subject in need of treatment.
  • the method comprises administering to a subject in need of treatment a therapeutically effective amount of a compound that has 5-HT 3 receptor antagonist activity and NorAdrenaline Reuptake Inhibitor (NARI) activity.
  • NARI NorAdrenaline Reuptake Inhibitor
  • the compounds having 5-HT 3 receptor antagonist activity and NARI activity are thieno[2,3-d]pyrimidine derivatives such as those described in U.S. Pat. No. 4,695,568, the entire content of which is incorporated herein by reference.
  • the compounds having 5-HT 3 receptor antagonist activity and NARI activity are represented by structural Formula I:
  • R 1 and R 2 independently represent hydrogen, halogen or a C 1 -C 6 alkyl group; or R 1 and R 2 together with the carbon atoms to which they are attached form a cycloalkylene group having 5 to 6 carbon atoms;
  • R 3 and R 4 independently represent hydrogen or a C 1 -C 6 alkyl group
  • R 5 is hydrogen, C 1 -C 6 alkyl
  • m is an integer from about 1 to about 3
  • X is halogen and R 6 is a C 1 -C 6 alkyl group
  • Ar is a substituted or unsubstituted phenyl, 2-thienyl or 3-thienyl group
  • n is 2 or 3; or a pharmaceutically acceptable salt thereof.
  • the compound having 5-HT 3 receptor antagonist activity and NARI activity is represented by the formula:
  • MCI-225 MCI-225 or DDP-225.
  • the chemical name of the structure set forth in the formula is: 4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine.
  • the nausea, vomiting, retching or any combination thereof can be caused by anesthetics, radiation, cancer chemotherapeutic agents, toxic agents, odors, medicines, pregnancy and motion.
  • the nausea, vomiting, retching or any combination thereof can be caused by administration of general anesthetics associated with surgical procedures.
  • the nausea, vomiting, retching or any combination thereof can be caused by administration of chemotherapeutic agents, radiation therapy or a combination thereof.
  • the nausea, vomiting, retching or any combination thereof can be caused by conditions which are associated with vertigo.
  • the nausea, vomiting, retching or any combination thereof can be caused by Meniere's disease or vestibular neuronitis.
  • the nausea, vomiting, retching or any combination thereof can be caused by headache.
  • the headache is a result of migraine, increased intracranial pressure or cerebral vascular hemorrhage.
  • the nausea, vomiting, retching or any combination thereof can be caused by maladies of the gastrointestinal (GI) tract.
  • the malady of the gastrointestinal tract is selected from the group consisting of cholecystitis, choledocholithiasis, intestinal obstruction, acute gastroenteritis, perforated viscus, dyspepsia and Zollinger-Ellison syndrome.
  • the vomiting, nausea, retching or any combination thereof can be of undetermined etiology.
  • the nausea, vomiting, retching or any combination thereof can be characterized as Cyclic Vomiting Syndrome.
  • the invention further relates to a method of treating nausea, vomiting, retching or any combination thereof in a subject in need thereof, comprising coadministering to said subject a therapeutically effective amount of a 5-HT 3 receptor antagonist and a therapeutically effective amount of a NARI.
  • the invention further relates to a method of treating nausea, vomiting, retching or any combination thereof in a subject in need thereof, comprising coadministering to said subject a first amount of a 5-HT 3 receptor antagonist and a second amount of a NARI, wherein the first and second amounts together comprise a therapeutically effective amount.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof caused by anesthetics, radiation, cancer chemotherapeutic agents, toxic agents, odors, medicines, pregnancy and motion.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof caused by administration of general anesthetics associated with surgical procedures.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof caused by administration of chemotherapeutic agents, radiation therapy or a combination thereof.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof caused by conditions which are associated with vertigo.
  • the nausea, vomiting, retching or any combination thereof can be caused by Meniere's disease or vestibular neuronitis.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof caused by headache.
  • the headache is a result of migraine, increased intracranial pressure or cerebral vascular hemorrhage.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof caused by maladies of the gastrointestinal (GI) tract.
  • the malady of the gastrointestinal tract is selected from the group consisting of cholecystitis, choledocholithiasis, intestinal obstruction, acute gastroenteritis, perforated viscus, dyspepsia and Zollinger-Ellison syndrome.
  • the coadministration can be used to treat vomiting, nausea, retching or any combination thereof, of undetermined etiology.
  • the nausea, vomiting, retching or any combination thereof can be characterized as Cyclic Vomiting Syndrome.
  • the invention relates to a method of treating nausea, vomiting, retching or any combination thereof in a subject in need thereof comprising administering a therapeutically effective amount of a NARI.
  • the NARI is characterized by the substantial absence of anticholinergic effects.
  • the nausea, vomiting, retching or any combination thereof can be caused by anesthetics, radiation, cancer chemotherapeutic agents, toxic agents, odors, medicines, pregnancy and motion.
  • the nausea, vomiting, retching or any combination thereof can be caused by administration of general anesthetics associated with surgical procedures.
  • the nausea, vomiting, retching or any combination thereof can be caused by administration of chemotherapeutic agents, radiation therapy or a combination thereof.
  • the nausea, vomiting, retching or any combination thereof can be caused by conditions which are associated with vertigo.
  • the nausea, vomiting, retching or any combination thereof can be caused by Meniere's disease or vestibular neuronitis.
  • the nausea, vomiting, retching or any combination thereof can be caused by headache.
  • the headache is a result of migraine, increased intracranial pressure or cerebral vascular hemorrhage.
  • the nausea, vomiting, retching or any combination thereof can be caused by maladies of the gastrointestinal (GI) tract.
  • the malady of the gastrointestinal tract can be selected from the group consisting of cholecystitis, choledocholithiasis, intestinal obstruction, acute gastroenteritis, perforated viscus, dyspepsia and Zollinger-Ellison syndrome.
  • the vomiting, nausea, retching or any combination thereof can be of undetermined etiology.
  • the nausea, vomiting, retching or any combination thereof can be characterized as Cyclic Vomiting Syndrome.
  • the invention further relates to pharmaceutical compositions useful for the treatment of a nausea, vomiting, retching or any combination thereof.
  • the pharmaceutical composition comprises a first amount of a 5-HT 3 receptor antagonist compound and a second amount of a NARI compound.
  • the pharmaceutical compositions of the present invention can optionally contain a pharmaceutically acceptable carrier.
  • the 5-HT 3 receptor antagonist and the NARI can each be present in the pharmaceutical composition in a therapeutically effective amount.
  • said first and second amounts can together comprise a therapeutically effective amount.
  • the pharmaceutical composition can be used to treat vomiting, nausea, retching or combinations thereof caused by a number of factors including, but not limited to, anesthetics, radiation, cancer chemotherapeutic agents, toxic agents, odors, medicines, for example, serotonin reuptake inhibitors, analgesics such as morphine, antibiotics and antiparasitic agents, pregnancy and motion.
  • anesthetics e.g., radiation, cancer chemotherapeutic agents, toxic agents, odors, medicines, for example, serotonin reuptake inhibitors, analgesics such as morphine, antibiotics and antiparasitic agents, pregnancy and motion.
  • vertigo e.g., Meniere's disease and vestibular neuronitis
  • Headache caused by, for example, migraine, increased intracranial pressure or cerebral vascular hemorrhage can also result in nausea, vomiting, retching or any combination thereof.
  • GI gastrointestinal
  • certain maladies of the gastrointestinal (GI) tract for example, cholecystitis, choledocholithiasis, intestinal obstruction, acute gastroenteritis, perforated viscus, dyspepsia resulting from, for example, gastroesophageal reflux disease, peptic ulcer disease, gastroparesis, gastric or esophageal neoplasms, infiltrative gastric disorders (e.g., Menetrier's syndrome, Crohn's disease, eosinophilic gastroenteritis, sarcoidosis and amyloidosis) gastric infections (e.g., CMV, fungal, TB and syphilis), parasites (e.g., Giardia lamblia and Strongyloides stercoralis ), chronic gastric volvulus, chronic intestinal ischemia, altered gastric motility and/or food intolerance or Zollinger-Ellison syndrome can result in vomiting, nausea,
  • the invention further relates to use of a compound that has 5-HT 3 receptor antagonist activity and NARI activity for the manufacture of a medicament for treating nausea, vomiting, retching or any combination thereof.
  • the invention also relates to the use of a pharmaceutical composition comprising a first amount of a 5-HT 3 receptor antagonist compound and a second amount of a NARI compound for the manufacture of a medicament for the treatment of a nausea, vomiting, retching or any combination thereof.
  • the pharmaceutical composition used for the manufacture of a medicament for treating nausea, vomiting, retching or any combination thereof can optionally contain a pharmaceutically acceptable carrier.
  • the 5-HT 3 receptor antagonist and the NARI can each be present in the pharmaceutical composition in a therapeutically effective amount or said first and second amounts can together comprise a therapeutically effective amount. Further, the invention relates to the use of a NARI for the manufacture of a medicament for treating nausea, vomiting, retching or any combination thereof.
  • FIG. 1 is a bar graph of cisplatin-induced retches per hour versus time (hours) post administration of cisplatin in male ferrets treated with a 5 mg/kg dose of cisplatin and vehicle.
  • FIG. 2 is a bar graph of cisplatin-induced vomits per hour versus time (hours) post administration of cisplatin in male ferrets treated with a 5 mg/kg dose of cisplatin and vehicle.
  • FIG. 3 is a bar graph of the total number of cisplatin-induced emetic events (retches and vomits combined) in male ferrets treated with cisplatin at a dose of 5 mg/kg followed by ondansetron at 5 mg/kg or 10 mg/kg or vehicle alone.
  • FIG. 4 is a bar graph of the effect of ondanseton on the latency of the first cisplatin-induced emetic event (retch or vomit) in male ferrets treated with cisplatin at a dose of 5 mg/kg followed by ondansetron at 5 mg/kg or 10 mg/kg or vehicle alone.
  • FIG. 5 is a bar graph of the total number of cisplatin-induced emetic events (retches and vomits combined) in male ferrets treated with cisplatin at a dose of 5 mg/kg followed by a single dose of MCI-225 (1 mg/kg, 10 mg/kg or 30 mg/kg), two 30 mg/kg doses at 3 hour intervals or vehicle alone.
  • FIG. 6 is a bar graph of the effect of ondansetron on the latency of the first cisplatin-induced emetic event (retch or vomit) in male ferrets treated with cisplatin at a dose of 5 mg/kg followed by a single dose of MCI-225 (1 mg/kg, 10 mg/kg or 30 mg/kg), two 30 mg/kg doses at 3 hour intervals or vehicle alone.
  • the invention relates to methods of treating nausea, vomiting, retching or any combination thereof.
  • Monoamine neurotransmitters such as noradrenaline (also referred to as norepinephrine), serotonin (5-hydroxytryptamine, 5-HT) and dopamine are known and disturbances in these neurotransmitters have been indicated in many types of disorders, such as depression. These neurotransmitters travel from the terminal of a neuron across a small gap referred to as the synaptic cleft and bind to receptor molecules on the surface of a second neuron. This binding elicits intracellular changes that initiate or activate a response or change in the postsynaptic neuron. Inactivation occurs primarily by transport of the neurotransmitter back into the presynaptic neuron, which is referred to as reuptake. These neurons can be found both in the Central Nervous System (CNS) and in the Enteric Nervous System (ENS).
  • CNS Central Nervous System
  • ENS Enteric Nervous System
  • NARI NorAdrenaline Reuptake Inhibitor
  • an agent e.g., a molecule, a compound
  • a NARI can inhibit binding of a ligand of a noradrenaline transporter to said transporter and/or inhibit transport (e.g., uptake or reuptake of noradrenaline).
  • transport e.g., uptake or reuptake of noradrenaline
  • NERI NorAdrenergic Reuptake Inhibitor and NorEpinephrine Reuptake Inhibitor
  • noradrenaline transporter refers to naturally occurring noradrenaline transporters (e.g., mammalian noradrenaline transporters (e.g., human ( Homo sapiens ) noradrenaline transporters, murine (e.g., rat, mouse) noradrenaline transporters)) and to proteins having an amino acid sequence which is the same as that of a corresponding naturally occurring noradrenaline transporter (e.g., recombinant proteins).
  • the term includes naturally occurring variants, such as polymorphic or allelic variants and splice variants.
  • the NARI can inhibit the binding of a ligand (e.g., a natural ligand such as noradrenaline, or other ligand such as nisoxetine) to a noradrenaline transporter.
  • a ligand e.g., a natural ligand such as noradrenaline, or other ligand such as nisoxetine
  • the NARI can bind to a noradrenaline transporter.
  • the NARI can bind to a noradrenaline transporter, thereby inhibiting binding of a ligand to said transporter and inhibiting transport of said ligand.
  • the NARI can bind to a noradrenaline transporter, and thereby inhibit transport.
  • NARI activity is determined using the radioligand uptake assay described above, according to the procedure detailed in Eguchi et al., Arzneim .- Anlagen/Drug Res ., 47(12): 1337-47 (1997).
  • rats are decapitated and the cortical, hypothalamic, hippocampal and striatal tissues are rapidly dissected.
  • the tissues are homogenized (Potter homogenizer with Teflon pestle) in 10 volumes of ice cold 0.32 mol/L sucrose.
  • the P 2 fraction is obtained by centrifugation at 1000 ⁇ g for 10 minutes and 11500 ⁇ g for 20 minutes and suspended in Krebs-Ringer phosphate buffer, pH 7.4 (124 mmol/L NaCl, 5 mmol/L KCl, 20 mmol/L Na 2 HPO 4 , 1.2 mmol/L KH 2 PO 4 , 1.3 mmol/L MgSO 4 , 0.75 mmol/L CaCl 2 , 10 mmol/L glucose).
  • the [ 3 H]NA uptake assays are performed on the cortical and hypothalamic synaptosomes.
  • the assay tubes contain radiolabled noradrenaline, [ 3 H]NA, in a volume of 0.2 mL, compounds at 5 or more concentrations in a volume of 0.1 mL, and the oxygenated buffer described above in a volume of 0.5 mL. After 5 minutes preincubation at 37° C., uptake is initiated by the addition of the synaptosomal fraction in volume of 0.2 mL. The final concentration of [ 3 H]NA in the incubation mixtures is 0.25 ⁇ mol/L. The reaction is stopped after 5 minutes by filtration through Whatman GF/B glass fiber filter under a vacuum with a cell harvester.
  • the filter is rinsed three times with 4 mL of saline and placed in a scintillation vial containing 10 mL of Atomlight (Du Pont/NEN Research Products). Radioactivity is measured by liquid scintillation spectrometry. For determination of non-specific uptake, incubations are performed at 4° C. without the addition of test compounds. IC 50 values are calculated by nonlinear regression analysis. Inhibitor constants, Ki values, are calculated from the IC 50 values using the Cheng-Prusoff equation.
  • NARI compounds suitable for use in the invention have a Ki value for NARI activity of about 500 nmol/L or less, such as about 250 nmol/L or less, for example, about 100 nmol/L or less. It is preferred that the Ki value for NARI activity be about 100 nmol/L or less. It is understood that the exact value of the Ki for a particular compound can vary depending on the assay conditions employed for determination (e.g., radioligand and tissue source). As such, it is preferred that the NARI activity be assessed essentially according to the radioligand binding assay described in Eguchi et al., Arzneim .- Anlagen/Drug Res ., 47(12): 1337-47 (1997) and discussed in detail above.
  • NARI compounds possess one or more characteristics selected from the group consisting of:
  • Selective inhibition of noradrenaline reuptake as compared to inhibition of serotonin or dopamine reuptake can be determined by comparing the Ki values for the respective reuptake inhibitions.
  • the inhibition constants for serotonin and dopamine reuptake can be determined as described above for nordrenaline, but employing the appropriate radioligand and tissue for the activity being assessed (e.g., [ 3 H] 5-HT for serotonin, using e.g., hypothalamic or cortical tissue and [ 3 H]DA for dopamine (DA), using e.g., striatal tissue).
  • a preferred method of determining serotonin reuptake inhibition and dopaminergic reuptake inhibition is described in Eguchi et al., Arzneim .- Anlagen/Drug Res ., 47(12): 1337-47 (1997). Specifically, rats are decapitated and the cortical, hypothalamic, hippocampal and striatal tissues are rapidly dissected. The tissues are homogenized (Potter homogenizer with Teflon pestle) in 10 volumes of ice cold 0.32 mol/L sucrose.
  • the P 2 fraction is obtained by centrifugation at 1000 ⁇ g for 10 minutes and 11500 ⁇ g for 20 minutes and suspended in Krebs-Ringer phosphate buffer, pH 7.4 (124 mmol/L NaCl, 5 mmol/L KCl, 20 mmol/L Na 2 HPO 4 , 1.2 mmol/L KH 2 PO 4 , 1.3 mmol/L MgSO 4 , 0.75 mmol/L CaCl 2 , 10 mmol/L glucose).
  • the [ 3 H]5-HT uptake assays are performed on the cortical, hypothalamic and hippocampal synaptosomes, and the [ 3 H]DA uptake assays are performed on striatal synaptosomes.
  • the assay tubes contain the appropriate radiolabled ligand (i.e., [ 3 H]5-HT or [ 3 H]DA), in a volume of 0.2 mL, compounds at 5 or more concentrations in a volume of 0.1 mL, and the oxygenated buffer described above in a volume of 0.5 mL. After 5 minutes preincubation at 37° C., uptake is initiated by the addition of the synaptosomal fraction in volume of 0.2 mL. The final concentration of [ 3 H]DA in the striatal incubation mixtures is 0.4 ⁇ mol/L.
  • radiolabled ligand i.e., [ 3 H]5-HT or [ 3 H]DA
  • the final concentrations of [ 3 H]5-HT in the cortical, hypothalamic and hippocampal synaptosome incubation mixtures are 0.02 ⁇ mol/L, 0.04 ⁇ mol/L and 0.08 ⁇ mol/L.
  • the reaction is stopped after 5 minutes ([ 3 H]5-HT) or 3 minutes [ 3 H]DA by filtration through Whatman GF/B glass fiber filter under a vacuum with a cell harvester.
  • the filter is rinsed three times with 4 mL of saline and placed in a scintillation vial containing 10 mL of Atomlight (Du Pont/NEN Research Products). Radioactivity is measured by liquid scintillation spectrometry.
  • IC 50 values are calculated by nonlinear regression analysis. Inhibition constants, Ki values, are calculated from the IC 50 values using the Cheng-Prusoff equation.
  • the ratio of the activities can be determined.
  • Selective inhibition of noradrenaline reuptake as compared to inhibition of serotonin reuptake and/or dopaminergic reuptake refers to a compound having a Ki value for inhibition of serotonin (re)uptake and/or dopamine (re)uptake which is about 10 times or more than the Ki for inhibition of noradrenaline (re)uptake.
  • the ratio, Ki inhibition of serotonin (re)uptake/Ki inhibition of noradrenaline (re)uptake is about 10 or more, such as about 15 or more, about 20 or more, for example, about 30, 40 or 50 or more.
  • the ratio, Ki inhibition of dopamine (re)uptake/Ki inhibition noradrenaline (re)uptake is about 10 or more, such as about 15 or more, about 20 or more, for example, about 30, 40 or 50 or more.
  • the Ki values for comparison are determined according to the method of Eguchi et al., discussed in detail above. It is most preferred, that the Ki values for NARI activity and inhibition of serotonin reuptake activity, which are compared to determine selective inhibition are determined according to the method of Eguchi et al. using a synaptosomal preparation from rat hypothalamic tissue. Further, it is most preferred, that the Ki values for NARI activity and inhibition of dopamine reuptake activity, which are compared to determine selective inhibition are determined according to the method of Eguchi et al. using a synaptosomal preparation from rat hypothalamic tissue for inhibition of noradrenaline uptake and from rat striatal tissue for inhibition of dopamine uptake.
  • the NARI is characterized by the substantial absence of anticholinergic effects.
  • substantial absence of anticholinergic effects refers to a compound which has an IC 50 value for binding to muscarinic receptors of about 1 ⁇ mol/L or more.
  • the IC 50 value for binding to muscarinic receptors can be determined using a suitable assay, such as an assay which determines the ability of a compound to inhibit the binding of suitable radioligand to muscarinic receptors.
  • the binding assays for determination of binding to muscarinic receptors can be performed on tissue isolated from the rat cerebral cortex.
  • the preferred radiolabeled ligand is [ 3 H]QNB (3-quinuclidinyl benzilate) which is present in a final concentration of 0.2 nmol/L.
  • the test compound is added at various concentrations and the resulting mixtures are incubated for 60 minutes at 37° C.
  • the reaction is terminated by rapid vacuum filtration onto glass fiber filter. Radioactivity trapped on the filter is measured by scintillation spectrometry.
  • Non-specific binding is determined using 100 ⁇ mol/L atropine.
  • IC 50 values can be calculated by nonlinear regression analysis.
  • the NARI compound can be selected from venlafaxine, duloxetine, buproprion, milnacipran, reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.
  • the NARI compound can be selected from reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.
  • Serotonin also referred to as 5-hydroxytryptamine (5-HT)
  • 5-HT 5-hydroxytryptamine
  • 5-HT 5-hydroxytryptamine
  • 5-HT 7 seven subtypes of serotonin receptors are recognized and delineated into seven families, 5-HT, through 5-HT 7 . These subtypes share sequence homology and display some similarities in their specificity for particular ligands.
  • a review of the nomenclature and classification of the 5-HT receptors can be found in Neuropharm ., 33: 261-273 (1994) and Pharm. Rev ., 46:157-203 (1994).
  • 5-HT 3 receptors are ligand-gated ion channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization have been found to affect the regulation of visceral pain, colonic transit and gastrointestinal secretions. Antagonism of the 5-HT 3 receptors has the potential to influence sensory and motor function in the gut.
  • 5-HT 3 receptor refers to naturally occurring 5-HT 3 receptors (e.g., mammalian 5-HT 3 receptors (e.g., human ( Homo sapiens ) 5-HT 3 receptors, murine (e.g., rat, mouse) 5-HT 3 receptors)) and to proteins having an amino acid sequence which is the same as that of a corresponding naturally occurring 5-HT 3 receptor (e.g., recombinant proteins).
  • the term includes naturally occurring variants, such as polymorphic or allelic variants and splice variants.
  • the term 5-HT 3 receptor antagonist refers to an agent (e.g., a molecule, a compound) which can inhibit 5-HT 3 receptor function.
  • a 5-HT 3 receptor antagonist can inhibit binding of a ligand of a 5-HT 3 receptor to said receptor and/or inhibit a 5-HT 3 receptor-mediated response (e.g., reduce the ability of 5-HT 3 to evoke the von Bezold-Jarisch reflex).
  • the 5-HT 3 receptor antagonist can inhibit binding of a ligand (e.g., a natural ligand, such as serotonin (5-HT 3 ), or other ligand such as GR65630) to a 5-HT 3 receptor.
  • a ligand e.g., a natural ligand, such as serotonin (5-HT 3 ), or other ligand such as GR65630
  • the 5-HT 3 receptor antagonist can bind to a 5-HT 3 receptor.
  • the 5-HT 3 receptor antagonist can bind to a 5-HT 3 receptor, thereby inhibiting the binding of a ligand to said receptor and a 5-HT 3 receptor-mediated response to ligand binding.
  • the 5-HT 3 receptor antagonist can bind to a 5-HT 3 receptor, and thereby inhibit a 5-HT 3 receptor-mediated response.
  • 5-HT 3 receptor antagonists can be identified and activity assessed by any suitable method, for example, by a method which assesses the ability of a compound to inhibit radioligand binding to 5-HT 3 receptor (see, for example, Eguchi et al., Arzneim .- Anlagen/Drug Res ., 47(12): 1337-47 (1997) and G. Kilpatrick et al., Nature , 330: 746-748 (1987)) and/or by their effect on the 5-HT 3 -induced von Bezold-Jarisch (B-J) reflex in the cat or rat (following the general methods described by Butler et al., Br. J. Pharmacol ., 94: 397-412 (1988) and Ito et al., J. Pharmacol. Exp. Ther ., 280(1): 67-72 (1997), respectively).
  • 5-HT 3 receptor antagonist activity of a compound can be determined according to the method described in Eguchi et al., Arzneim .- Anlagen/Drug Res ., 47(12): 1337-47 (1997).
  • the reaction is terminated by rapid vacuum filtration onto glass fiber filter. Radioactivity trapped on the filter is measured by scintillation spectrometry. Non-specific binding is determined using 1 ⁇ mol/L of MDL-7222 (endo-8-methyl-8-azabicyclo [3.2.1]oct-3-yl-3,5-dichlorobenzoate.
  • IC 50 values are calculated by nonlinear regression analysis. The affinity constants, Ki values, are calculated from the IC 50 values using the Cheng-Prusoff equation.
  • Compounds having 5-HT 3 receptor antagonist activity which are suitable for use in the invention have an affinity for 5-HT 3 receptor (Ki) of not more than about 250 times the Ki of ondansetron for 5-HT 3 receptor.
  • Ki affinity for 5-HT 3 receptor
  • This relative activity to ondansetron Ki of test agent for 5-HT 3 receptor/Ki of ondansetron for 5-HT 3 receptor
  • the relative activity of the 5-HT 3 receptor antagonist activity be not more than about 200 times that of ondansetron, for example, not more than about 150 times that of ondansetron, such as not more than about 100 times that of ondansetron, for example, not more than about 50 times that of ondansetron.
  • the compound having 5-HT 3 receptor antagonist activity has a relative activity to ondansetron of not more than about 10.
  • the 5-HT 3 receptor antagonist can be selected from indisetron, YM-114 ((R)-2,3-dihydro-1-[(4,5,6,7-tetrahydro-1H-benzimidazol-5-yl-)carbonyl]-1H-indole), granisetron, talipexole, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620 ([3(S)-endo]-4-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1-]oct-3-yl-2[(1-methyl-2-butynyl)oxy]benzamide), lintopride, KAE-393, itasetron, zatosetron, dolasetron, ( ⁇
  • the 5-HT 3 receptor antagonist can be selected from indisetron, granisetron, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, cilansetron, itasetron, zatosetron, and dolasetron.
  • the invention relates to a method of treating nausea, vomiting, retching or any combination thereof in a subject in need of treatment.
  • the method comprises administering to a subject in need of treatment a therapeutically effective amount of a compound that has 5-HT 3 receptor antagonist activity and NARI activity.
  • the compounds having 5-HT 3 receptor antagonist activity and NARI activity are thieno[2,3-d]pyrimidine derivatives such as those described in U.S. Pat. No. 4,695,568, the entire content of which is incorporated herein by reference.
  • R 1 and R 2 independently represent hydrogen, halogen or a C 1 -C 6 alkyl group; or R 1 and R 2 together with the carbon atoms to which they are attached form a cycloalkylene group having 5 to 6 carbon atoms;
  • R 3 and R 4 independently represent hydrogen or a C 1 -C 6 alkyl group
  • R 5 is hydrogen, C 1 -C 6 alkyl
  • m is an integer from about 1 to about 3, X is halogen and R 6 is a C 1 -C 6 alkyl group;
  • Ar is a substituted or unsubstituted phenyl, 2-thienyl or 3-thienyl group
  • n is 2 or 3; or a pharmaceutically acceptable salt thereof.
  • Substituted phenyl, 2-thienyl or 3-thienyl group refers to a phenyl, 2-thienyl or 3-thienyl group in which at least one of the hydrogen atoms available for substitution has been replaced with a group other than hydrogen (i.e., a substituent group).
  • a substituent group can be present on the phenyl, 2-thienyl or 3-thienyl ring. When multiple substituents are present, the substituents can be the same or different and substitution can be at any of the substitutable sites on the ring.
  • Substituent groups can be, for example, a halogen atom (fluorine, chlorine, bromine or iodine); an alkyl group, for example, a C 1 -C 6 alkyl group such as a methyl, ethyl, propyl, butyl, pentyl or hexyl group; an alkoxy group, for example, a C 1 -C 6 alkoxy group such as methoxy, ethoxy, propoxy, butoxy; a hydroxy group; a nitro group; an amino group; a cyano group; or an alkyl substituted amino group such as methylamino, ethylamino, dimethylamino or diethylamino group.
  • a halogen atom fluorine, chlorine, bromine or iodine
  • an alkyl group for example, a C 1 -C 6 alkyl group such as a methyl, ethyl, propyl, butyl
  • Alkyl group refers to a straight chain or branched alkyl group.
  • C 1 -C 6 alkyl group refers to a straight-chain or branched alkyl group having from one to six carbon atoms.
  • the C 1 -C 6 alkyl group can be a strain-chain alkyl such as methyl, ethyl, propyl, etc.
  • the alkyl group can be branched for example, an isopropyl or t-butyl group.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • the compounds having 5-HT 3 receptor antagonist activity and NARI activity are represented by Formula I, wherein R 1 is a C 1 -C 6 alkyl group and Ar is a substituted phenyl. In this embodiment, it is preferred that the phenyl group is substituted with a halogen.
  • the compounds having 5-HT 3 receptor antagonist activity and NARI activity are represented by Formula I, wherein n is 2, R 1 is a C 1 -C 6 alkyl group and Ar is a substituted phenyl.
  • the phenyl group is substituted with a halogen and the alkyl group of R 1 is a methyl group.
  • the compounds having 5-HT 3 receptor antagonist activity and NARI activity are represented by Formula I, wherein R 1 is a C 1 -C 6 alkyl group or a halogen and Ar is an unsubstituted phenyl. Further, when R 1 is an alkyl group and Ar is an unsubstituted phenyl, R 2 can also be a hydrogen or a C 1 -C 6 alkyl group.
  • the compounds having 5-HT 3 receptor antagonist activity and NARI activity are represented by Formula I, wherein n is 2, R 1 is a C 1 -C 6 alkyl group and Ar is an unsubstituted phenyl.
  • R 1 is a C 1 -C 6 alkyl group and Ar is an unsubstituted phenyl
  • R 2 can be hydrogen or a C 1 -C 6 alkyl group.
  • the compound having 5-HT 3 receptor antagonist activity and NARI activity is represented by structural Formula II:
  • MCI-225 MCI-225 or DDP-225.
  • the chemical name of the structure set forth in the formula is: 4-(2-fluorophenyl)-6-methyl-2-(1-piperazinyl)thieno[2,3-d]pyrimidine.
  • the method further comprises administering a therapeutically effective amount of an (i.e., one or more) additional therapeutic agent.
  • Compounds having 5-HT 3 receptor antagonist activity and NARI activity are useful for treating nausea, vomiting, retching or any combination thereof by virtue of the dual therapeutic modes of action which they can exhibit. That is, the unique ability to modulate the function of both the 5-HT 3 receptor and the noradrenaline reuptake mechanism can provide an enhanced treatment regimen for the subject undergoing treatment.
  • compounds having 5-HT 3 receptor antagonist activity and NARI activity possess one or more characteristics selected from the group consisting of:
  • the specific compound MCI-225 has been shown to be a selective NARI and a 5-HT 3 receptor antagonist with substantially no anticholinergic activity.
  • MAO-A Monoamine Oxidase-A
  • MAO-B Monoamine Oxidase-B
  • the receptors tested included, ⁇ 1 , ⁇ 2 , ⁇ 1 , ⁇ 2 , 5-HT 1 , 5-HT 1A , 5-HT 1c , 5-HT 2 , 5-HT 3 , 5-HT 4 , 5-HT 6 , 5-HT 7 , D 1 , D 2 , Muscarinic, M 1 , M 2 , M 3 , Nicotonic, H 1 , H 2 , GABA-A, GABA-B, BZP, Opiate non-selective, Opiate ⁇ , Opiate ⁇ , Opiate ⁇ , CRF (Corticotropin Releasing Factor) and glucocorticoid.
  • the IC 50 values determined for MCI-225, for these additional receptors were all greater than 1 ⁇ mol/L.
  • the nausea, vomiting, retching or any combination thereof can be caused by anesthetics, radiation, cancer chemotherapeutic agents, toxic agents, odors, medicines, pregnancy and motion.
  • the nausea, vomiting, retching or any combination thereof can be caused by administration of general anesthetics associated with surgical procedures.
  • the nausea, vomiting, retching or any combination thereof can be caused by administration of chemotherapeutic agents, radiation therapy or a combination thereof.
  • the nausea, vomiting, retching or any combination thereof can be caused by conditions which are associated with vertigo.
  • the nausea, vomiting, retching or any combination thereof can be caused by Meniere's disease or vestibular neuronitis.
  • the nausea, vomiting, retching or any combination thereof can be caused by headache.
  • the headache can be a result of migraine, increased intracranial pressure or cerebral vascular hemorrhage.
  • the nausea, vomiting, retching or any combination thereof can be caused by maladies of the gastrointestinal (GI) tract.
  • the malady of the gastrointestinal tract can be selected from the group consisting of cholecystitis, choledocholithiasis, intestinal obstruction, acute gastroenteritis, perforated viscus, dyspepsia and Zollinger-Ellison syndrome.
  • the vomiting, nausea, retching or any combination thereof can be of undetermined etiology.
  • the nausea, vomiting, retching or any combination thereof can be characterized as Cyclic Vomiting Syndrome.
  • the invention further relates to a method of treating nausea, vomiting, retching or any combination thereof in a subject in need thereof, comprising coadministering to said subject a therapeutically effective amount of a 5-HT 3 receptor antagonist and a therapeutically effective amount of a NARI.
  • the invention further relates to a method of treating nausea, vomiting, retching or any combination thereof in a subject in need thereof, comprising coadministering to said subject a first amount of a 5-HT 3 receptor antagonist and a second amount of a NARI, wherein the first and second amounts together comprise a therapeutically effective amount.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof can be caused by anesthetics, radiation, cancer chemotherapeutic agents, toxic agents, odors, medicines, pregnancy and motion.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof can be caused by administration of general anesthetics associated with surgical procedures.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof caused by administration of chemotherapeutic agents, radiation therapy or a combination thereof.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof caused by conditions which are associated with vertigo.
  • the nausea, vomiting, retching or any combination thereof can be caused by Meniere's disease or vestibular neuronitis.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof caused by headache.
  • the headache is a result of migraine, increased intracranial pressure or cerebral vascular hemorrhage.
  • the coadministration can be used to treat nausea, vomiting, retching or any combination thereof caused by maladies of the gastrointestinal (GI) tract.
  • the malady of the gastrointestinal tract is selected from the group consisting of cholecystitis, choledocholithiasis, intestinal obstruction, acute gastroenteritis, perforated viscus, dyspepsia and Zollinger-Ellison syndrome.
  • the coadministration can be used to treat vomiting, nausea, retching or any combination thereof, of undetermined etiology.
  • the nausea, vomiting, retching or any combination thereof can be characterized as Cyclic Vomiting Syndrome.
  • the coadministration methods further comprise administering a therapeutically effective amount of an (i.e., one or more) additional therapeutic agent.
  • the 5-HT 3 receptor antagonist can be selected from indisetron, YM-114 ((R)-2,3-dihydro-1-[(4,5,6,7-tetrahydro-1H-benzimidazol-5-yl-)carbonyl]-1H-indole), granisetron, talipexole, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620 ([3(S)-endo]-4-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1-]oct-3-yl-2[(1-methyl-2-butynyl)oxy]benzamide), lintopride, KAE-393, itasetron, zatosetron, do
  • the 5-HT 3 receptor antagonist can be selected from indisetron, granisetron, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, cilansetron, itasetron, zatosetron, and dolasetron.
  • the NARI compound can be selected from venlafaxine, duloxetine, buproprion, milnacipran, reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.
  • the NARI compound can be selected from reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.
  • the NARI compound possesses one or more characteristics selected from the group consisting of:
  • the invention relates to a method of treating nausea, vomiting, retching or any combination thereof in a subject in need thereof comprising administering a therapeutically effective amount of a NARI.
  • the NARI is characterized by the substantial absence of anticholinergic effects.
  • the NARI possesses selective inhibition of noradrenaline reuptake as compared to inhibition of serotonin reuptake and/or selective inhbition of noradrenaline reuptake as compared to inhibition of dopamine reuptake.
  • the nausea, vomiting, retching or any combination thereof can be caused by anesthetics, radiation, cancer chemotherapeutic agents, toxic agents, odors, medicines, pregnancy and motion.
  • the nausea, vomiting, retching or any combination thereof can be caused by administration of general anesthetics associated with surgical procedures.
  • the nausea, vomiting, retching or any combination thereof can be caused by administration of chemotherapeutic agents, radiation therapy or a combination thereof.
  • the nausea, vomiting, retching or any combination thereof can be caused by conditions which are associated with vertigo.
  • the nausea, vomiting, retching or any combination thereof can be caused by Meniere's disease or vestibular neuronitis.
  • the nausea, vomiting, retching or any combination thereof can be caused by headache.
  • the headache can be a result of migraine, increased intracranial pressure or cerebral vascular hemorrhage.
  • the nausea, vomiting, retching or any combination thereof can be caused by maladies of the gastrointestinal (GI) tract.
  • the malady of the gastrointestinal tract can be selected from the group consisting of cholecystitis, choledocholithiasis, intestinal obstruction, acute gastroenteritis, perforated viscus, dyspepsia and Zollinger-Ellison syndrome.
  • the vomiting, nausea, retching or any combination thereof is of undetermined etiology.
  • the nausea, vomiting, retching or any combination thereof is Cyclic Vomiting Syndrome.
  • the method further comprises administering a therapeutically effective amount of an (i.e., one or more) additional therapeutic agent.
  • the method can further comprise administering a corticosteroid.
  • the invention further relates to pharmaceutical compositions useful for the treatment of a nausea, vomiting, retching or any combination thereof.
  • the pharmaceutical composition comprises a first amount of a 5-HT 3 receptor antagonist compound and a second amount of a NARI compound.
  • the pharmaceutical compositions of the present invention can optionally contain a pharmaceutically acceptable carrier.
  • the 5-HT 3 receptor antagonist and the NARI can each be present in the pharmaceutical composition in a therapeutically effective amount.
  • said first and second amounts can together comprise a therapeutically effective amount.
  • the pharmaceutical composition further comprises an (i.e., one or more) additional therapeutic agent.
  • the pharmaceutical composition can be used in the treatment of a nausea, vomiting, retching or any combination thereof in a subject in need of treatment.
  • the invention relates to a method of treating nausea, vomiting, retching or any combination thereof in a subject in need of treatment comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition as described herein.
  • An additional therapeutic agent suitable for use in the methods and pharmaceutical compositions described herein can be, but is not limited to, for example: an anticholinergic (e.g., scopolomine); an antihistamine (e.g., dimenhydrinate and diphenhydramine); a phenothiazine (e.g., prochlorperazine and chlorpromazine); a butyrophenone (haloperidol and droperidol); a cannabinoid (e.g., tetrahydrocannabinol and nabilone); a benzamide (e.g., metoclopramide, cisapride and trimethobenzamide); a glucocorticoid (e.g., dexamethasone and methylprednisolone); a benzodiazepine (e.g., lorazepam); or any combination thereof.
  • the additional therapeutic agent is a glucocorticoid (e
  • Emesis and vomiting are synonymous and can be described as the forceful expulsion of gastrointestinal contents through the mouth brought about by the descent of the diaphragm and powerful contractions of the abdominal muscles. Emesis is usually, but not always, preceded by nausea.
  • Nausea as used herein, is the unpleasant feeling that one is about to vomit.
  • Retching or dry heaves involves the same physiological mechanisms as vomiting, but occurs against a closed glottis, which prohibits the expulsion of gastric contents.
  • Nausea, vomiting, retching or combinations thereof can be caused by a number of factors including, but not limited to, anesthetics, radiation, cancer chemotherapeutic agents, toxic agents, odors, medicines, for example, serotonin reuptake inhibitors, analgesics such as morphine, antibiotics and antiparasitic agents, pregnancy and motion.
  • Conditions which are associated with vertigo e.g., Meniere's disease and vestibular neuronitis
  • Headache caused by, for example, migraine, increased intracranial pressure or cerebral vascular hemorrhage can also result in nausea, vomiting, retching or any combination thereof.
  • GI gastrointestinal
  • certain maladies of the gastrointestinal (GI) tract for example, cholecystitis, choledocholithiasis, intestinal obstruction, acute gastroenteritis, perforated viscus, dyspepsia resulting from, for example, gastroesophageal reflux disease, peptic ulcer disease, gastroparesis, gastric or esophageal neoplasms, infiltrative gastric disorders (e.g., Menetrier's syndrome, Crohn's disease, eosinophilic gastroenteritis, sarcoidosis and amyloidosis) gastric infections (e.g., CMV, fungal, TB and syphilis), parasites (e.g., Giardia lamblia and Strongyloides stercoralis ), chronic gastric volvulus, chronic intestinal ischemia, altered gastric motility and/or food intolerance or Zollinger-Ellison syndrome can result in vomiting, nausea,
  • Nausea, vomiting and retching are defined as acute when symptoms are present for less than a week.
  • the causes of nausea, vomiting and retching of short duration are often separable from etiologies leading to more chronic symptoms.
  • Nausea, vomiting and retching are defined as chronic when symptoms are present for over a week.
  • symptoms can be continuous or intermittent and last for months or years.
  • Dyspepsia refers to pain or discomfort centered in the upper abdomen that can also include bloating, early satiety, postprandial fullness, nausea, anorexia, heartburn, regurgitation, and burping or belching. Generally, the symptoms of dyspepsia arise from the upper luminal GI tract. Dyspepsia can be caused by a number of foods, medications, systemic disorders and diseases of the luminal GI tract.
  • Subject refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent or murine species.
  • mammals including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent or murine species.
  • therapeutically effective amount refers to an amount sufficient to elicit the desired biological response.
  • the desired biological response is a reduction (complete or partial) in vomiting, nausea, retching or any combination thereof resulting from any cause.
  • Chemotherapeutic agents include, but are not limited to, for example alkylating agents, e.g. cyclophosphamide, carmustine, lomustine, and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C, and bleomycin; antimetabolites, e.g. cytarabine, methotrexate, and 5-fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine, and vincristine; and others such as cisplatin, dacarbazine, procarbazine, and hydroxyurea; and combinations thereof.
  • alkylating agents e.g. cyclophosphamide, carmustine, lomustine, and chlorambucil
  • cytotoxic antibiotics e.g. dactinomycin, doxorubicin, mitomycin-C, and bleomycin
  • SRI serotonin reuptake inhibitor
  • analgesics, antibiotics, antiparasitic agents, and serotonin reuptake inhibitors can cause nausea, vomiting, retching or a combination thereof.
  • a serotonin reuptake inhibitor is any compound which inhibits the uptake of serotonin.
  • the nausea, vomiting, retching or any combination thereof is associated with the onset of SRI therapy. When the SRI is dosed on an as needed basis (prn), each dose can be considered the onset of therapy and can cause nausea, vomiting, retching or any combination thereof.
  • SRIs include selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline and the rapid onset SSRI dapoxetine.
  • SSRIs selective serotonin reuptake inhibitors
  • certain SSRIs are known to exhibit 5-HT 1A receptor activities (e.g., antagonist or partial agonist activity at the 5-HT 1A receptor).
  • 5-HT 1A receptor activities e.g., antagonist or partial agonist activity at the 5-HT 1A receptor.
  • Compounds which have combined SSRI and 5-HT 1A receptor activities include those described in WO 99/02516 and WO 02/44170, the contents of which are incorporated herein by reference. These compounds are represented by the Formulas III, IV and V:
  • Z is —CO—, —CH(OR 6 )— or —C(NOR 7 )—;
  • R 1 is hydrogen, C 1 -C 6 alkyl, halogen or —O—R 12 ;
  • R 2 and R 3 independently represent hydrogen, C 1 -C 6 alkyl, halogen, nitro or —O—R 6 or R 2 and R 3 are together —CR 8 ⁇ CR 9 -CR 10 ⁇ CR 11 ;
  • R4 and R5 independently represent hydrogen, alkyl, halogen, haloalkyl, —OR, 12 , nitro, —NR 13 R 14 , —COR 12 , —CO 2 R 12 ; —SO 2 NR 13 R 14 ; —SO 2 R 12 , —SR 12 , cyano, —CONR 13 R 14 ;
  • R 6 is hydrogen, C 1 -C 6 alkyl, —CO 2 R 12 , —C(O)NR 13 R 14 , naphthyl or phenyl;
  • R 7 is hydrogen or C 1 -C 6 alkyl
  • R 8 , R 9 , R 10 and R 11 are independently hydrogen, C 1 -C 6 alkyl, halogen, —OR 12 , nitro, cyano, —NR 13 R 14 , —COR 12 , —CO 2 R 12 , SO 2 NR 13 R 14 , —SO 2 R 12 , —SR 12 , or —CONR 13 R 14 ;
  • R 12 is hydrogen, Cl-C 6 alkyl or phenyl
  • R 13 and R 14 are independently hydrogen, C 1 -C 6 alkyl or phenyl or R 13 and R 14 form a ring of 5 or 6 members; or a pharmaceutically acceptable salt or solvate or any isomer (geometric or optical) or polymorph thereof.
  • n 1,2 or 3;
  • Z is —C(O) or —CHOH
  • R 1 is hydrogen, C 1 -C 6 alkyl, halogen —OR 2 , nitro, cyano, —NR 3 R 4 , —COR 2 , —CO 2 R 2 , —O—COR 2 , —SO 2 NR 3 R 4 , —SO 2 R 2 , —SR 2 or —CONR 3 R 4 ;
  • R 2 is hydrogen, C 1 -C 6 alkyl or phenyl
  • R 3 and R 4 are independently hydrogen, C 1 -C 6 alkyl or phenyl or R 3 and R 4 together form a morpholine, thiomorphone or piperazine ring;
  • Ar is an optionally substituted bicyclic system formed by a benzocondensed heterocyclic ring with 5, 6 or 7 ring atoms, saturated or unsaturated and containing 1, 2 or 3 heteroatoms selected from N, O or S; or a pharmaceutically acceptable salt or solvate or any isomer (geometric or optical) or polymorph thereof.
  • the compounds for use in the method of the invention can be formulated for oral, transdermal, sublingual, buccal, parenteral, rectal, intranasal, intrabronchial or intrapulmonary administration.
  • the compounds can be of the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate).
  • binding agents e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose
  • fillers e.g., cornstarch, lactose, microcrystalline cellulose or
  • the tablets can be coated using suitable methods and coating materials such as OPADRY® film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY® OY Type, OY-C Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY® White, 32K18400).
  • OPADRY® film coating systems available from Colorcon, West Point, Pa. (e.g., OPADRY® OY Type, OY-C Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OPADRY® White, 32K18400).
  • Liquid preparation for oral administration can be in the form of solutions, syrups or suspensions.
  • the liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxy benzoates or sorbic acid
  • the compounds for use in the method of the invention can be in the form of tablets or lozenges formulated in a conventional manner.
  • the compounds for use in the method of the invention can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents can be used.
  • the compounds for use in the method of the invention can be in the form of suppositories.
  • tablets can be formulated in conventional manner.
  • the compounds for use in the method of the invention can be formulated in a sustained release preparation.
  • the compounds can be formulated with a suitable polymer or hydrophobic material which provides sustained and/or controlled release properties to the active agent compound.
  • the compounds for use the method of the invention can be administered in the form of microparticles for example, by injection or in the form of wafers or discs by implantation.
  • Additional dosage forms of this invention include dosage forms as described in U.S. Pat. No. 6,340,475, U.S. Pat. No. 6,488,962, U.S. Pat. No. 6,451,808, U.S. Pat. No. 6,340,475, U.S. Pat. No. 5,972,389, U.S. Pat. No. 5,582,837, and U.S. Pat. No. 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. patent application Ser. No. 20030147952, U.S. patent application Ser. No. 20030104062, U.S. patent application Ser. No. 20030104053, U.S. patent application Ser. No. 20030044466, U.S.
  • Additional dosage forms of this invention also include dosage forms as described in PCT Patent Application WO 03/35041, PCT Patent Application WO 03/35040, PCT Patent Application WO 03/35029, PCT Patent Application WO 03/35177, PCT Patent Application WO 03/35039, PCT Patent Application WO 02/96404, PCT Patent Application WO 02/32416, PCT Patent Application WO 01/97783, PCT Patent Application WO 01/56544, PCT Patent Application WO 01/32217, PCT Patent Application WO 98/55107, PCT Patent Application WO 98/11879, PCT Patent Application WO 97/47285, PCT Patent Application WO 93/18755, and PCT Patent Application WO 90/11757.
  • the dosage forms of the present invention include pharmaceutical tablets for oral administration as described in U.S. patent application Ser. No. 20030104053.
  • suitable dosage forms of the present invention can combine both immediate-release and prolonged-release modes of drug delivery.
  • the dosage forms of this invention include dosage forms in which the same drug is used in both the immediate-release and the prolonged-release portions as well as those in which one drug is formulated for immediate release and another drug, different from the first, is formulated for prolonged release.
  • This invention encompasses dosage forms in which the immediate-release drug is at most sparingly soluble in water, i.e., either sparingly soluble or insoluble in water, while the prolonged-release drug can be of any level of solubility.
  • the prolonged-release portion of the dosage form can be a dosage form that delivers its drug to the digestive system continuously over a period of time of at least an hour and preferably several hours and the drug is formulated as described in in U.S. patent application Ser. No. 20030104053.
  • the immediate-release portion of the dosage form can be a coating applied or deposited over the entire surface of a unitary prolonged-release core, or can be a single layer of a tablet constructed in two or more layers, one of the other layers of which is the prolonged-released portion and is formulated as described in U.S. patent application Ser. No. 20030104053.
  • the supporting matrix in controlled-release tablets or controlled release portions of tablets is a material that swells upon contact with gastric fluid to a size that is large enough to promote retention in the stomach while the subject is in the digestive state, which is also referred to as the postprandial or “fed” mode.
  • This is one of two modes of activity of the stomach that differ by their distinctive patterns of gastroduodenal motor activity.
  • the “fed” mode is induced by food ingestion and begins with a rapid and profound change in the motor pattern of the upper gastrointestinal (GI) tract. The change consists of a reduction in the amplitude of the contractions that the stomach undergoes and a reduction in the pyloric opening to a partially closed state.
  • the result is a sieving process that allows liquids and small particles to pass through the partially open pylorus while indigestible particles that are larger than the pylorus are retropelled and retained in the stomach.
  • This process causes the stomach to retain particles that are greater than about 1 cm in size for about 4 to 6 hours.
  • the controlled-release matrix in these embodiments of the invention is therefore selected as one that swells to a size large enough to be retropelled and thereby retained in the stomach, causing the prolonged release of the drug to occur in the stomach rather than in the intestines. Disclosures of oral dosage forms that swell to sizes that will prolong the residence time in the stomach are found in U.S. Pat. No. 6,448,962, U.S. Pat. No. 6,340,475, U.S.
  • coadministration refers to administration of a first amount of a 5-HT 3 receptor antagonist compound and a second amount of a NARI compound to treat nausea, vomiting, retching or any combination thereof.
  • Coadministration encompasses administration of the first and second amounts of the compounds of the coadministration in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each.
  • coadministration also encompasses use of each compound in a sequential manner in either order.
  • coadministration involves the separate administration of the NARI and 5-HT 3 receptor antagonist, the compounds are administered sufficiently close in time to have the desired therapeutic effect.
  • the therapeutically effective amount or dose of (a) a compound having dual therapeutic modes of action (i.e., 5-HT 3 receptor antagonist activity and NARI activity); (b) a 5-HT 3 receptor antagonist and NARI in combination; or (c) a NARI alone, will depend on the age, sex and weight of the patient, the current medical condition of the patient and the nature of the nausea, vomiting, retching or any combination thereof being treated. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • continuous dosing refers to the chronic administration of a selected active agent.
  • as-needed dosing also known as “pro re nata” “prn” dosing, and “on demand” dosing or administration is meant the administration of a therapeutically effective dose of the compound(s) at some time prior to commencement of an activity wherein suppression of nausea, vomiting, retching or any combination thereof would be desirable. Administration can be immediately prior to such an activity, including about 0 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours prior to such an activity, depending on the formulation.
  • drug administration or dosing is on an as-needed basis, and does not involve chronic drug administration.
  • as-needed administration can involve drug administration immediately prior to commencement of an activity wherein suppression of nausea, vomiting, retching or any combination thereof would be desirable, but will generally be in the range of from about 0 minutes to about 10 hours prior to such an activity, preferably in the range of from about 0 minutes to about 5 hours prior to such an activity, most preferably in the range of from about 0 minutes to about 3 hours prior to such an activity.
  • a suitable dose of the 5-HT 3 receptor antagonist can be in the range of from about 0.001 mg to about 500 mg per day, such as from about 0.01 mg to about 100 mg, for example, from about 0.05 mg to about 50 mg, such as about 0.5 mg to about 25 mg per day.
  • the dose can be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage can be the same or different.
  • a suitable dose of the NARI compound can be in the range of from about 0.001 mg to about 1000 mg per day, such as from about 0.05 mg to about 500 mg, for example, from about 0.03 mg to about 300 mg, such as about 0.02 mg to about 200 mg per day.
  • the dose can be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage can be the same or different.
  • a suitable dose of the compound having both 5-HT 3 receptor antagonist and NARI activity can be in the range of from about 0.001 mg to about 1000 mg per day, such as from about 0.05 mg to about 500 mg, for example, from about 0.03 mg to about 300 mg, such as from about 0.02 mg to about 200 mg per day.
  • a suitable dose of the compound having both 5-HT 3 receptor antagonist and NARI activity can be in the range of from about 0.1 mg to about 50 mg per day, such as from about 0.5 mg to about 10 mg per, day such as about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg per day.
  • the dose per day can be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day. When multiple dosages are used, the amount of each dosage can be the same or different. For example a dose of 1 mg per day can be administered as two 0.5 mg doses, with about a 12 hour interval between doses.
  • the amount of compound dosed per day can be administered every day, every other day, every 2 days, every 3 days, every 4 days, every 5 days, etc.
  • a 5 mg per day dose can be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, etc.
  • the compounds for use in the method of the invention can be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.
  • each dosage can typically contain from about 0.001 mg to about 1000 mg, such as from about 0.05 mg to about 500 mg, for example, from about 0.03 mg to about 300 mg, such as about 0.02 mg to about 200 mg of the active ingredient.
  • the compounds for use in the method of the invention can be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose. Dosing can be on demand by the subject.
  • each dosage can typically contain from about 0.001 mg to about 1000 mg, such as from about 0.05 mg to about 500 mg, for example, from about 0.03 mg to about 300 mg, such as about 0.02 mg to about 200 mg of the active ingredient.
  • each dose can typically contain from about 0.001 mg to about 1000 mg, such as from about 0.05 mg to about 500 mg, for example, from about 0.03 mg to about 300 mg, such as about 0.02 mg to about to about 200 mg of the NARI and typically can contain from about 0.001 mg to about 500 mg, such as from about 0.01 mg to about 100 mg, for example, from about 0.05 mg to about 50 mg, such as about 0.5 mg to about 25 mg of the 5-HT 3 receptor antagonist.
  • each dose can typically contain from about 0.001 mg to about 1000 mg, such as from about 0.05 mg to about 500 mg, for example, from about 0.03 mg to about 300 mg, such as 0.02 to about to about 200 mg of the active ingredient.
  • the invention further includes a kit for treating nausea, vomiting, retching or any combination thereof.
  • the kit comprises at least one compound having both 5-HT 3 receptor antagonist activity and NARI activity (e.g., a single compound) and an instruction insert for administering the compound according to the method of the invention.
  • the kit can comprise a first compound which is a 5-HT 3 receptor antagonist and a second compound which is a NARI and an instruction insert for administering the compounds according to the method of the invention.
  • the first and second compounds can be in separate dosage forms or combined in a single dosage form.
  • the term pharmaceutically acceptable salt refers to a salt of the administered compounds prepared from pharmaceutically acceptable non-toxic acids including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoric.
  • Appropriate organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like.
  • 5-HT 3 receptor antagonists NARIs and single compounds having both NARI and 5-HT 3 antagonist activities can be identified, for example, by screening libraries or collections of molecules using suitable methods.
  • Another source for the compounds of interest are combinatorial libraries which can comprise many structurally distinct molecular species.
  • Combinatorial libraries can be used to identify lead compounds or to optimize a previously identified lead.
  • Such libraries can be manufactured by well-known methods of combinatorial chemistry and screened by suitable methods.
  • the invention also relates to a method of processing a claim under a health insurance policy submitted by a claimant seeking reimbursement for costs associated with the treatment of nausea, vomiting, retching or any combination thereof, as described herein.
  • the method of processing a claim under a health insurance policy submitted by a claimant seeking reimbursement for costs associated with treatment of nausea, vomiting, retching or any combination thereof comprises coadministering to a subject a first amount of a 5-HT 3 receptor antagonist and a second amount of a noradrenaline reuptake inhibitor, wherein the first and second amounts together comprise a therapeutically effective amount comprising: reviewing said claim; determining whether said treatment is reimbursable under said insurance policy; and processing said claim to provide partial or complete reimbursement of said costs.
  • the nausea, vomiting, retching or any combination thereof is caused by an anesthetic, radiation, a cancer chemotherapeutic agent, a toxic agent, an odor, a medicine, pregnancy or motion.
  • the medicine is selected from the group consisting of an analgesic, an antibiotic, an antifungal or a serotonin reuptake inhibitor.
  • the nausea, vomiting, retching or any combination thereof is caused by a condition which is associated with vertigo.
  • the nausea, vomiting, retching or any combination thereof is caused by headache.
  • the nausea, vomiting, retching or any combination thereof is caused by a malady of the gastrointestinal (GI) tract.
  • GI gastrointestinal
  • the invention also relates to a method for processing a claim under a health insurance policy submitted by a claimant seeking reimbursement for costs associated with treatment of nausea, vomiting, retching or any combination thereof, wherein said treatment comprises coadministering to a subject a therapeutically effective amount of a 5-HT 3 receptor antagonist and a therapeutically effective amount of a noradrenaline reuptake inhibitor comprising: reviewing said claim; determining whether said treatment is reimbursable under said insurance policy; and processing said claim to provide partial or complete reimbursement of said costs.
  • the nausea, vomiting, retching or any combination thereof is caused by an anesthetic, radiation, a cancer chemotherapeutic agent, a toxic agent, an odor, a medicine, pregnancy or motion.
  • the medicine is selected from the group consisting of an analgesic, an antibiotic, an antifungal or a serotonin reuptake inhibitor.
  • the nausea, vomiting, retching or any combination thereof is caused by a condition which is associated with vertigo.
  • the nausea, vomiting, retching or any combination thereof is caused by headache.
  • the nausea, vomiting, retching or any combination thereof is caused by a malady of the gastrointestinal (GI) tract.
  • GI gastrointestinal
  • the invention also relates to a method for processing a claim under a health insurance policy submitted by a claimant seeking reimbursement for costs associated with treatment of nausea, vomiting, retching or any combination thereof, wherein said treatment comprises administering to a subject a therapeutically effective amount of a compound having 5-HT 3 receptor antagonist activity and noradrenaline reuptake inhibitor activity comprising: reviewing said claim; determining whether said treatment is reimbursable under said insurance policy; and processing said claim to provide partial or complete reimbursement of said costs.
  • the compound having 5-HT 3 receptor antagonist activity and noradrenaline reuptake inhibitor activity is MCI-225.
  • the nausea, vomiting, retching or any combination thereof is caused by an anesthetic, radiation, a cancer chemotherapeutic agent, a toxic agent, an odor, a medicine, pregnancy or motion.
  • the medicine is selected from the group consisting of an analgesic, an antibiotic, an antifungal or a serotonin reuptake inhibitor.
  • the nausea, vomiting, retching or any combination thereof is caused by a condition which is associated with vertigo.
  • the nausea, vomiting, retching or any combination thereof is caused by headache.
  • the nausea, vomiting, retching or any combination thereof is caused by a malady of the gastrointestinal (GI) tract.
  • GI gastrointestinal
  • the invention further relates to a method for processing a claim under a health insurance policy submitted by a claimant seeking reimbursement for costs associated with treatment of nausea, vomiting, retching or any combination thereof, wherein said treatment comprises administering to a subject a therapeutically effective amount of a noradrenaline reuptake inhibitor, wherein the noradrenaline reuptake inhibitor characterized by the substantial absence of anticholinergic effects comprising: reviewing said claim; determining whether said treatment is reimbursable under said insurance policy; and processing said claim to provide partial or complete reimbursement of said costs.
  • the nausea, vomiting, retching or any combination thereof is caused by an anesthetic, radiation, a cancer chemotherapeutic agent, a toxic agent, an odor, a medicine, pregnancy or motion.
  • the medicine is selected from the group consisting of an analgesic, an antibiotic, an antifungal or a serotonin reuptake inhibitor.
  • the nausea, vomiting, retching or any combination thereof is caused by a condition which is associated with vertigo.
  • the nausea, vomiting, retching or any combination thereof is caused by headache.
  • the nausea, vomiting, retching or any combination thereof is caused by a malady of the gastrointestinal (GI) tract.
  • GI gastrointestinal
  • the activity of compounds as anti-emetics can be demonstrated by any suitable model.
  • the extent to which compounds can reduce the latency or the number of retches and/or vomits induced by emetogens e.g., cisplatin which is a typically used emetogenic trigger in suitable animal models
  • the dog e.g., beagles
  • the piglet or in the ferret can be assessed.
  • suitable methods are described in Tatersall et al. and Bountra et al., European Journal of Pharmacology , 250: (1993) R5 and 249:(1993) R3-R4 and Milano et al., J. Pharmacol. Exp. Ther ., 274(2): 951-961 (1995).
  • both the test compound and cisplatin are prepared and administered.
  • the cisplatin is a representative emetogenic trigger for vomiting.
  • Emesis is induced in groups of 6 male ferrets weighing about 2 kg, by intravenous administration of cisplatin at a suitable dose (e.g., 10 mg/kg). The onset of emesis is noted. Over a period of 2 hours the number of vomits/retches (episodes) is recorded. Behavioral changes characteristic of emesis are also noted.
  • test compound is administered to groups of 6 male ferrets weighing about 2 kg, by intravenous administration at suitable doses immediately prior to administration of cisplatin as described above. The animals are observed for 3 hours.
  • MCI-225 The ability of MCI-225 to reduce retching and vomiting in an accepted model of cytotoxin-induced emesis in the ferret was assessed. Specifically, the experiments described herein investigated the effect of MCI-225 on retching and vomiting induced by cisplatin. Ondansetron was used as a positive control in the model, in view of its known antiemetic activity.
  • a cisplatin solution was prepared by adding preheated (70° C.) saline to cisplatin powder (Sigma-Aldrich Co.) and stirring or sonicating at 40° C. until dissolved.
  • ferrets received an intraperitoneal (i.p.) injection of cisplatin (5 mg/kg in 5 mL) followed in about 2 minutes by i.p. injection of a single dose of MCI-225 or ondansetron (Rudd and Naylor, Eur. J. Pharmacol ., 322: 79-82 (1997)).
  • MCI-225 or ondansetron (Rudd and Naylor, Eur. J. Pharmacol ., 322: 79-82 (1997)).
  • Dose-response effects of MCI-225 dosed at 1, 10 and 30 mg/kg i.p. in a 0.5 mL/kg solution or ondansetron dosed at 5 and 10 mg/kg i.p. in a 0.5 mL/kg solution were studied.
  • Each animal received a single-dose drug treatment.
  • three animals received an initial dose (30 mg/kg i.p.) and a second MCI-225 injection (30 mg/kg i.p.) 180 minutes following the initial dose.
  • Control animals were treated with cisplatin followed by vehicle alone (propanediol dosed in a 0.5 mL/kg solution). All groups were randomized.
  • Cisplatin induced an emetic response in 100% of the animals receiving vehicle.
  • the mean response was characterized by a total number of 42.8 ⁇ 8.1 events (both retches and vomits), which occurred during the observation period.
  • the mean latency of the first response was 133 ⁇ 22 min post-cisplatin administration.
  • the time-course of acute emetic events appearing in response to cisplatin is summarized in FIG. 1 (retches) and FIG. 2 (vomits).
  • the effect of ondansetron was accompanied by an increase in the latency of the first emetic response following cisplatin treatment.
  • Table 1 (*p ⁇ 0.05). and presented graphically in FIG. 3 and FIG. 4. TABLE 1 No.
  • N 10 Vehicle 42.8 ⁇ 8.1 3.3 ⁇ 0.8 46.1 ⁇ 7.8 133 ⁇ 22
  • N 7 Ondansetron 11.2 ⁇ 7.0 0.3 ⁇ 0.2 11.5 ⁇ 7.2 288 ⁇ 4 (5 mg/kg)
  • N 7 Ondansetron 2.4 ⁇ 1.6 0.0 ⁇ 0.0 2.4 ⁇ 1.6* 313 ⁇ 32 (10 mg/kg)
  • N 10 Vehicle 42.8 ⁇ 8.1 3.3 ⁇ 0.8 46.1 ⁇ 7.8 133 ⁇ 22
  • N 10 MCI-225 30.4 ⁇ 9.1 2.5 ⁇ 0.7 32.9 ⁇ 9.8 186 ⁇ 35 (1 mg/kg)
  • N 10 MCI-225 22.9 ⁇ 10.3 2.6 ⁇ 1.0 25.5 ⁇ 11.1 192 ⁇ 57 (10 mg/ kg)
  • N 11 MCI-225 3.3 ⁇ 2.2 0.7 ⁇ 0.5 ⁇ 2.6* 287 ⁇ 38 (30 mg/ kg)
  • N 3 MCI-225 0.0 ⁇ 0.0 0.0 ⁇ 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 360 ⁇ 0 (30 mg/kg b.i.d)
  • MCI-225 is effective at reducing retching and vomiting in an accepted animal model of emesis, using a similar dose range as the positive control (ondansetron).
  • MCI-225 can be used in the treatment of nausea, vomiting, retching or any combination thereof in a subject.

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RU2608458C2 (ru) * 2009-05-20 2017-01-18 Инсерм (Энститю Насьональ Де Ля Сантэ Э Де Ля Решерш Медикаль) Антагонисты серотониновых 5-нт3-рецепторов для применения при лечении вестибулярных нарушений с повреждениями
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EP1567163A4 (fr) 2006-01-18
DE602004005814T2 (de) 2008-01-10
WO2004062624A2 (fr) 2004-07-29
US20040254171A1 (en) 2004-12-16
JP2006516977A (ja) 2006-07-13
PL378369A1 (pl) 2006-04-03
DE602004005814D1 (de) 2007-05-24
ES2285407T3 (es) 2007-11-16
BRPI0406748A (pt) 2005-12-20
CA2512022A1 (fr) 2004-07-29
EP1567163A2 (fr) 2005-08-31
ATE359079T1 (de) 2007-05-15
AU2004204827A1 (en) 2004-07-29
KR20050094843A (ko) 2005-09-28
WO2004062624A3 (fr) 2005-04-07
EP1567163B1 (fr) 2007-04-11
US7094786B2 (en) 2006-08-22
US20040254172A1 (en) 2004-12-16
AU2004204827B2 (en) 2006-06-29
NZ541009A (en) 2007-09-28
MXPA05007379A (es) 2006-02-10

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