NZ737615B2 - Methods of treatment of non-histaminic pruritus in mammals - Google Patents
Methods of treatment of non-histaminic pruritus in mammals Download PDFInfo
- Publication number
- NZ737615B2 NZ737615B2 NZ737615A NZ73761516A NZ737615B2 NZ 737615 B2 NZ737615 B2 NZ 737615B2 NZ 737615 A NZ737615 A NZ 737615A NZ 73761516 A NZ73761516 A NZ 73761516A NZ 737615 B2 NZ737615 B2 NZ 737615B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- pruritus
- norketotifen
- inhibitors
- histaminergic
- histamine
- Prior art date
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
Abstract
Described herein are methods of treating a mammal in need of treatment for non-histaminic pruritus by administering to the mammal in need thereof a therapeutically effective amount of RS-norketotifen, an isomer, or a pharmaceutically acceptable salt thereof, thereby reducing the desire to scratch in the mammal. Non-histaminergic types of pruritus are resistant to treatment with selective histamine H-1-, H-2- and H-4-receptor inhibitors. In certain aspects, the non-histaminergic pruritus is associated with a dermal disorder, a nerve disorder, or a systemic disorder. the mammal. Non-histaminergic types of pruritus are resistant to treatment with selective histamine H-1-, H-2- and H-4-receptor inhibitors. In certain aspects, the non-histaminergic pruritus is associated with a dermal disorder, a nerve disorder, or a systemic disorder.
Description
METHODS OF TREATMENT OF NON—HISTAMINIC PRURITUS IN MAMIVIALS TECHNICAL FIELD The embodiments disclosed herein relate to methods of norketotifen-treatment of pruritus that is mediated through non-histaminergic pruritic mechanisms in mammals.
BACKGROUND Pruritus is also called itch. Pruritus (like pain) is not a disease, but a symptom of a disease (condition, disorder) that causes the expression of us. Thus, pruritus (like pain) is a warning signal, telling the patient that some underlying disorder is present. The terms tion", "disease", and der" are synonyms and are often called "underlying conditionH H 7 underlying disease" or "underlying disorder" in connection with pain or pruritus.
Pruritus is an unpleasant sensation that elicits the desire to h. Acute pruritus is a frequent experience in most mammalian species and can usually be abolished by scratching at the area of the itching. Chronic pruritus can be debilitating and scratching provides no or very little ; actually, scratching most often exacerbates the problem. As used herein, the terms "pruritus H H 7 pruritic", "itch", "itching" etc. refer to chronic pruritus. us is experienced by many mammals, including humans. us in humans can be caused by various ying diseases, such as for example dermatological disorders, neurological disorders, systemic disorders and by drugs with pruritic side effects.
Pruritus in dogs is also common and usually caused by parasites, various allergens or underlying diseases. Canine pruritus is rarely successfully treated with antihistamines. Thus pruritic dogs almost exclusively suffer from non-histaminergic itch. Pruritus in cats is usually caused by parasites or allergens or other ions. Cats react to itchiness in similar ways as dogs. Thus, both cats and dogs are scratching, licking and biting. However, contrary to dogs, up to 50 percent of cats with us seem to have histamine-sensitive types of pruritus, while the remaining pruritic cats suffer from non-histaminergic forms of pruritus.
Pruritus in horses is very common and is one of the most common reasons for horse owners to seek help from veterinarians. A horse with itchy skin will rub up t fences, stalls, trees, or other objects while attempting to scratch the itch. The horse may excessively bite or lick its skin to the point of causing bleeding or damage to the skin. The most common causes of allergic itching in horses are insect bites, food allergies ing allergens in horse feed, and g due to seasonal allergens. Pruritus in horses is seldom treated successfully with antihistamines, indicating that pruritus in horses y is non-histaminergic pruritus.
The lack of success of stamines in treating pruritus suggests that treatments for non-histaminergic pruritus are needed across species.
Patients ing from histamine-induced pruritus can be d with inhibitors (inverse agonists) of histamine H—l receptors, such as for example desloratadine or diphenhydramine, or by histamine H-2 receptor inhibitors, such as for e cimetidine and ranitidine, or — when they become commercially available — by ine H-4 receptor inhibitors, such as for example JNJ 7777120. Such treatments, however, are ineffective in the treatment of non-histaminergic pruritus.
Human patients suffering from non-histaminergic pruritus usually try tions, such as corticosteroids, antiepileptic drugs, opioid receptor antagonists, antidepressants or local anesthetics to relive itch, however, such medications are relatively unsuccessful. In addition, the anti-epileptic drug gabapentin, which s signals transmitting pain and pruritus to the brain, may offer some relief for human patients who can withstand the severe adverse events caused by this drug.
What is needed are treatments for staminergic pruritus that are both effective and free from debilitating side effects.
In one aspect, disclosed herein is a method of treating a mammal in need of treatment for non-histaminergic pruritus, comprising orally or topically administering to the mammal in need thereof a therapeutically effective amount of RS-norketotifen or a pharmaceutically able salt thereof In specific embodiments, administration of the therapeutically effective amount of norketotifen or a pharmaceutically acceptable salt thereof is expected to avoid systemic adverse drug effects, because the orally administered amount of RS-norketotifen lates in the skin where pruritus is expressed as a symptom for numerous underlying diseases. In certain aspects, the non-histaminergic pruritus is associated with a dermal disorder, a psychological er, a mental disorder, a nerve disorder, or a systemic disorder.
In another , a method of treating a mammal in need of treatment for non-histaminergic pruritus is described and comprises orally administering to the mammal in need thereof a therapeutically effective amount of a biophase-selective inhibitor of non- inergic pruritus, wherein the biophase-selective non-histaminergic antipruritic drug is norketotifen, or an isomer of norketotifen, or a ceutically acceptable salt of racemic or isomeric norketotifen.
DETAILED DESCRIPTION us (itch) is a sensation that causes the desire or reflex to scratch. Pain and pruritus have anatomical and physiological similarities, but while pain evokes a withdrawal reflex, pruritus creates a scratching reflex. Therefore scratching is a symptom caused by an ying disease (condition, er). Often multiple hes are evoked, usually called "bouts of scratches".
Table 1 lists diseases causing pruritus, of which diseases marked with (*) are always or most often caused by staminic mechanisms. ation that concerns clinical use of histamine H—4 inhibitors in Table 1 refers to anticipated use since no orally active histamine H-4 or inhibitors have yet obtained regulatory approved for clinical use.
Table 1. Examples of underlying conditions that cause pruritus in human patients and effects of antihistaminic drugs on the various forms of us A. Examples of Dermatological Disorders Causing Chronic Pruritus une Atepie dermatitis _ hi staminergie (Halt) er nenuhistaniinergic (*7: d1sorders Dermatitis hereetitbrmis — antihistamineuresistant (*) Derinatemyesitis — most often antihistamineuiesistant (*) Peninhigeiti — antihistamine are ineffective (*) Psoriasis — histaminei‘gie (Hm-4) or non—histamineigie U") Sitigten‘s syndrome s antihistamii‘ies contraindicated Genetic disorders Rarities disease « antihistamines are heing used i-iaiiey—l-iailey disease ~ ininimai eiieet of antihistamines (*) iehthyesis ~ minimal or no ett‘eet of antihistamines (*) Infections and Arthi‘eped reactit‘ins — antihistamines or cemhinatiens ef PM and l-i~2 Infestations inhibitors are used fer ing; stemids ifnatient is aiiei‘gie Derinatophytesis — n'iestiiy iiistaiiiine~tesistant (*) Bactei'iai infections — ine irii~4 inhibitors to he used iioiiieuiitis — histamine H—L‘i inhibitors to he used Fungal ini‘eetions - histamine HA inhibitors to he used impetigo and ether baeteriai infectiens _ H4 antihistamines to he used lesis _ histamine Hus inhibiteis t0 he used Scabies ~ histamine H—i-i inhibitors to he used Viral infections n histamine H—4 inhibitets to he. used Inflammatory — no or minimal effect of antihistamines (*) . Asteatesis d1sorders Atepic and nenuatepic dermatitis _ histaminei‘gie (H4) 01‘ non» histaminet‘gie (*) Contact dermatitis ~ histamine HA inhibitors to he used Liei‘ien pianus ~ antihistamines are used Lichen x chmnieus - Gen-l antihistamines are used h/iiiastocytosis _ H— l and H-2 antihistamines are used Miiiaria ~ antihistamines are used for prutitus caused by heat rash Psoriasis u Histaminergic (HA?) or nomhistaminergic (*) Scars — non—sedating antihistamines have no or niinimai etfeet (*) Urticaria ~ Gen—l antihistamine + H—Z antihistamines are used stlc Cutaneous B—ceii lymphoma — rte/minimal effect of antihistamines (*) ers ' Cutaneous T~ceil iymphoma — new/minimal effect of antihistamines (*) Leukemia cutis — not antihistamines but gabapentin (*) B. Examples of Systemic Disorders causing Chronic Pruritus Pruritus that does not respond to treatment with antihistaminic drugs mine H-1, H-2 or H-4 receptor inhibitors), is called non-histaminergic pruritus and the treatment of non-histaminergic pruritus with RS—, R- and S-norketotifen is the subject of this application. An underlying disease, such as for example atopic dermatitis or psoriasis, may express histaminergic pruritus in some patients and non-histaminergic pruritus in other patients.
Non-histaminergic pruritus can be caused by various diseases such as for example, renal failure, cholestasis, dermal and/or systemic infections, endocrine disorders, neurological ers, malignancies, psychological disorders, s medications and various dermal disorders. The diagnosis by the doctor or veterinarian may be "idiopathic pruritus" which term is misleading, since it is the underlying disease — not the symptom that is idiopathic, which means that said ying disease has not been diagnosed. Pruritus associated with idiopathic disorders, such as for example "idiopathic dermatitis" may in some patients be non-histaminergic pruritus which means that the itching is resistant to treatment with histamine inhibitory drugs. Idiopathic Dermatitis may in other ts express pruritus that is sive to treatment with histamine H, histamine H-2 and histamine H-4 receptor inhibitors. Regardless if the underlying disease has been diagnosed or not, non- histaminergic itching is often very , has a strong negative impact on the patient's quality of life and need immediate and c treatment.
In one aspect, to determine if the mammalian patient is suffering from non- histaminergic pruritus, the medical doctor or the veterinarian will test if said patient reacts positively to treatment with a selective ine H-1 receptor inhibitor, such as for e diphenhydramine or desloratadine, and a selective histamine H—2 receptor inhibitors, such as for example cimetidine or ranitidine, and a selective histamine H-4 or inhibitor, such as for e INJ7777120 or INJ 10191584. If the patients is not relieved from pruritus with these ent, the caregiving doctor or narian can conclude that the patient suffers from non-histaminic pruritus and may obtain antipruritic benefit from treatment with the eutic dose of the non-histaminergic antipruritic drug ketotifen.
Pruritus associated with psychological or mental disorders may in some human patients be associated with histaminergic pruritus, but other human patients suffer from non-histaminergic us that is associated with psychological or mental disorders.
The non-histaminergic pruritus in these patients can be associated with conditions such as for example y, depression, emotional stress, neuroses, psychological trauma and psychoses. Pruritus associated with nerve disorders may in some human patients be associated with histaminergic pruritus, but other human patients may suffer from non- histaminergic pruritus that is associated with underlying conditions that have been determined to be nerve disorders, such as for e diabetes mellitus, multiple sclerosis, neuropathic diseases, scars, and post-herpetic neuralgias.
Pruritus associated with systemic disorders may in some patients be associated with histaminergic pruritus, but other patients suffer from non-histaminergic us that is associated with various systemic disorders, such as for e anemia, diabetes, Hodgkin lymphoma, iron deficiency, chronic renal failure, systemic scleroderma, multiple sclerosis, uremia, and conditions such as pregnancy.
Pruritus associated with a dermal disorders, are in many cases non-histaminic us and associated with diseases such as for example alopecia areata, asteatotic dermatitis, atopic dermatitis, cutaneous B-cell lymphoma, cutaneous T-cell lymphoma, dermatitis iformis, discoid , hand eczema, ichthyosis, mycosis fiingoides, neurodermatitis, non-atopic dermatitis, notalgia paresthetica, psoriasis, prurigo nodularis, seborrheic dermatitis, Sézary syndrome and varicose eczema.
"Atopic dermatitis" and "non-atopic dermatitis" are different es, albeit classified as two types of dermatitis. There is no pathognomonic sign that differentiates between the diseases. Patients with atopic dermatitis most often have IgE-mediated ivity to allergens and are mostly children, while ts with non—atopic dermatitis do not have IgE-mediated itis and are mostly adults. Importantly, both pruritus associated with atopic dermatitis and pruritus associated with non-atopic dermatitis are practically exclusively non-histaminic forms of pruritus.
Pruritus has been found to be the most frequent complaint (64%) among patients suffering from psoriasis. Psoriatic us does not respond to antihistaminic drugs and is a non-histaminic symptom of psoriasis.
Antihistamines are used to treat a variety of conditions, in general those that involve histamine ors. It is well known to those skilled in the art of cology that antihistamines are inverse agonists that reverse the constitutive activity of histamine ors. For the sake of city, said e agonists are herein referred to as receptor inhibitors or as antihistamines.
In order to diminish the pruritus, the ian or veterinarian will attempt to determine the underlying condition that is causing the itching and treat the underlying condition. However, in many cases, identification of the underlying condition is not possible and the underlying disease is therefore ed to as being idiopathic. In such cases, or when treatment of the underlying disease is not possible, efforts have to be made to treat the symptom (pruritus) rather than the underlying ion(s).
Without being held to belief, no diagnostic tests exist that reliably can differentiate between histaminergic and non-histaminergic types of pruritus. Therefore, diagnostic s have to be focused on the symptom tus) in a similar way as physicians or veterinarians have to determine what type of painkillers to use in a specific patient. Thus, initially, the doctor has to ask the patients or caretakers what medication the patient has used for pruritus in the past. Most important is the question whether antihistaminic drugs have been used successfully. The doctor or veterinarian may also administer antihistaminic drugs before he/she is ced that the patient is suffering from histaminergic or non-histaminergic pruritus.
One disadvantage of the orally administered drugs that are used to treat pruritus are the systemic side s that result from their administration. For example, the Generation-l antihistamines are known to cause sedation upon oral administration. Without being held to , it is believed that systemic adverse effects will be less pronounced for drugs that are selectively distributed to specific biophase organs or tissues, e.g., the skin, where the drugs may accumulate in concentrations that are higher than the systemic plasma concentration. Such drugs will reach tissue concentrations that inhibit diseases or symptoms locally in the c organs or tissues, thereby reducing the systemic exposure of the drug and the incidence of systemic side effects of the drug. Thus, it may be advantageous to use a drug that accumulates at the biophase(s) for a disease or for a specific symptom. Such compounds will selectively s their ties where they are accumulated, while avoiding the adverse effects of more evenly distributed drugs.
It has specifically been found that after oral administration, racemic norketotifen (RS-norketotifen) and both isomers thereof (R—norketotifen, S-norketotifen) accumulate in the skin. The skin is the biophase for numerous dermal diseases and for the symptom called pruritus. The cokinetic exposure parameters — area under the curve, half-lives and mean residence times — of norketotifen in the dermal biophase have been found to significantly exceed the corresponding exposure parameters in the ic circulation (See Example 6.) In one embodiment, disclosed herein is a method treating a mammal in need of ent for non-histaminergic pruritus, comprising orally or topically stering to the mammal in need thereof a therapeutically effective amount of norketotifen. In c embodiments, the biophase-selective non-histaminergic us inhibitor is RS-, R- or S- norketotifen, or ceutically acceptable salts thereof, specifically RS-norketotifen or pharmaceutically acceptable salts thereof As used herein, non—histaminergic pruritus is chronic pruritus that is resistant to treatment with selective histamine H-1, H—2 and H—4 receptor inhibitors.
In another aspect, a method of treating non-histaminic pruritus in a patient ses determining whether said patient suffers from non-histaminic pruritus, and if said determination is positive, orally administering to said patient a eutically effective amount of RS—norketotifen or a pharmaceutically able salt thereof, wherein RS- norketotifen or a pharmaceutically salt thereof decrease the itchiness in the patient, and wherein the non-histaminergic pruritus is resistant to treatment with selective histamine H-l- receptor inhibitors, histamine Hreceptor inhibitors and histamine Hreceptor inhibitors Disclosed herein is a method for treating a mammal with a type of pruritus, that is not responsive to treatment with selective anti-histaminergic drug, including selective histamine H—l receptor tors, such as for example diphenhydramine or desloratadine, or selective histamine H-2 receptor inhibitors, such as for example cimetidine or ranitidine, or selective histamine H-4 receptor tors, such as for example JNJ7777120 or INJ 101915 84.
NORKETOTIFEN otifen can be made by methods known in the art, as described in US.
Patent No. 3,682,930, the disclosure of which is hereby incorporated by reference for its teaching of the sis of norketotifen.
The norketotifen isomers can be made as described in US. Patent No. 934 and US. Patent No. 7,557,128, the disclosures of which are hereby incorporated by reference for their teaching of the synthesis of the norketotifen isomers.
Norketotifen is the active metabolite of ketotifen, which is a Generation-l (sedative) antihistamine. Ketotifen is the most sedating of all marketed antihistamines, The sedative effects of fen are strictly imiting and doses higher than the recommended dose 1 mg, bid, are rarely used. It is tly believed that approximately 0.5 mg norketotifen is formed in the body for every 1 mg of ketotifen that is systemically administered. The lism — demethylation of the piperidine nitrogen in the ketotifen le — takes place in the liver, using liver enzymes such as CYP1A2 and CYP3A4. The sedation by ketotifen is caused by the short-acting "pro-drug," which is ketotifen per se, while the therapeutic effects of the orally administered drug are almost exclusively caused by the long-acting metabolite norketotifen.
Repeat-dose pharmacological and toxicological studies have now been performed and it has surprisingly been found that daily doses up to 20 mg/kg/day of racemic or ic norketotifen can be given chronically to dogs without causing sedation or other adverse events. Similarly, it has been found that doses up to 10 mg, bid of norketotifen in humans do not produce sedation when tested in human subjects.
Useful oral doses of racemic or isomeric norketotifen to human patients suffering from non-histaminergic pruritus are between 2 mg/day and 500 mg/day. More preferred is a daily oral dose of 2 mg/day to 40 mg/day to a human patient and most preferred is a human dose of 2 mg/day to 20 mg/day of norketotifen or an isomers thereof to human patients suffering from non—histaminergic pruritus. The doses used here refer to norketotifen free base, gh various salt forms can be used.
If not stated differently, the term norketotifen herein refers to the free base or to a salt forms thereof. The preferred salts forms are the hydrochloride salt and the hydrogen fumarate salt. [003 5] Useful oral doses of racemic or isomeric otifen to canine and feline patients suffering from non-histaminergic pruritus are between 0.5 mg/kg bodyweight and 20 mg/kg bodyweight, expressed as free base and dosed once or more times daily. [003 6] Useful oral doses of racemic or isomeric otifen to equine patients suffering from non-histaminergic pruritus are between 0.2 mg/kg bodyweight and 15 mg/kg bodyweight, expressed as free base and dosed once or more times daily. [003 7] Pharmaceutical compositions for oral administration of solid dosage forms include capsules, granules, pills, powders and s. In solid dosage forms, the active compound may be mixed with one or more pharmaceutically acceptable excipients or caniers (such as for e sodium citrate, dicalcium phosphate), fillers or extenders (such as for example starch, lactose, sucrose, glucose, ol, silicic acid), binders (such as for e carboxymethyl—cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia), humectants (such as for example glycerol), on retarding agents (such as for example paraffin), egrating agents (such as for example agar-agar, calcium carbonate, starch, c acid, silicates, sodium carbonate), tion accelerators (such as for example quaternary ammonium compounds), wetting agents (such as for example cetyl alcohol, glycerol monostearate), absorbents (such as for example kaolin, bentonite clay), lubricating agents (such as for example talc, calcium stearate, magnesium stearate, polyethylene s, sodium lauryl sulfate), and/or other excipients, such as for example buffering agents. Solid forms of capsules, granules, pills, and tablets can have coatings and/or shells (such as for example enteric coatings) known in the art. The compositions may also be designed to release the active ingredient(s) in a certain part of the gastrointestinal tract or in a controlled release, slow—release or in a d-release . The active compound(s) can also be microencapsulated with one or more of the above-mentioned excipients or other le excipients. [003 8] Liquid dosage forms for oral administration may be preferred administration forms to children suffering from pruritus. Such formulations include for example pharmaceutically acceptable ons, emulsions, sions, syrups and elixirs. The liquid dosage form may also contain excipients known to those skilled in the art of drug formulations, such as for example diluents (such as for example water, other solvents and solubilizing agents, and mixtures thereof), and emulsifiers (such as for example ethanol, isopropyl alcohol, ethyl ate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, butylene glycol, dimethyl formamide, oils, oleic acid, glycerol, polyethylene glycols, sorbitan fatty esters, and mixtures thereof An example of a Compositions for topical administration of norketotifen to the skin of all patients include creams, droplets, gels, liquids, ointments, s, sprays, suspensions, and specific delivery systems such as for examples patches and bandages. In addition to the active nd, the dermal composition may also n other excipients as known to those skilled in the art. Creams, ointments or gels or solutions may contain 10 mg/ml to 100 mg/ml of norketotifen or an isomer thereof, or a salt of said racemate or isomer, calculated as free base but administered either as a salt or as the free base, and applied once or more times daily to the affected areas. The total dose of the lly applied formulation of norketotifen or an isomer thereof will depend on the actual concentration of the active ingredient in the formulation and the size of the surface being treated. An example of a topical/dermal formulation is described in Example 5.
Pharmaceutical compositions for parenteral injections include pharmaceutically acceptable e aqueous or eous solutions, dispersions, sions, emulsions and sterile powders for reconstitution into sterile injectable solutions or sions prior to use. Various aqueous and nonaqueous carriers, diluents, solvents and vehicles may be used (such as for example water, ethanol, glycerol, glycol), as well as vegetable oils (such as for example olive oil), and organic esters (such as for example ethyl ), or mixtures of various excipients may be used. Fluidity can be maintained by use of coating material such as for example lecithin, by restricting particle size and by use of surfactants.
Parenteral compositions may also contain excipients such as preservatives, wetting agents, fying agents, dispersing agents, antibacterial agents, antifungal agents, isotonic agents, and/or absorption-delaying agents. Absorption—prolonging or absorption- slowing effects may be achieved by injecting a crystalline or amorphous suspension with low water solubility. Delayed tion may also be ed by dissolving or suspending the drug in an oil vehicle or by using injectable depot forms (ex. microencapsulated matrices of the drug in biodegradable polymers, such as polylactide—polyglycolide, polyorthoesters, polyanhydrides) or by using various types of liposomes or microemulsions to hold the drug.
Formulations for ion can be sterilized by various s.
All compositions may include other excipients as known to those skilled in the art.
The oral or dermal compositions described here can also consist of combination therapies, include otifen or an isomer or a salt thereof together with other drugs with antipruritic activity, such as for example a corticosteroid or an immune- ssant drug. Due to the antipruritic activity of norketotifen or the isomers thereof, a beneficial steroid-sparing or immune-suppressant drug-sparing effect can be obtained when treating patients suffering from various types of pruritic disorders with said combination ies.
The actual dosage levels of active ingredients in the ceutical compositions disclosed herein may be varied so as to obtain the desired therapeutic effect.
Thus the amount of drug used and the frequency of dosing varies and will depend on factors such as the stration form, the severity of the disease and other circumstances, such as for example the general health, age, and weight of the individual patient. Those skilled in the art of medicine will realize that higher or lower doses than those indicated here may be used and the doses may be given more or less frequently than suggested here.
EXAMPLES The invention is further illustrated by the following non-limiting examples. e 1. Non-histaminergic antipruritic activity: Chloroquine-induced pruritus in mice The ive was to study non-histaminergic antipruritic effects of norketotifen in mice. Chloroquine induces non—histaminergic pruritus in mice.
After fasting for 1.5 hours, mice were administered a single oral dose of the test articles. Sixty minutes after oral dosing, a subcutaneous injection of CQ, 10 mg/kg was administered into the previously shaved rostral part of the back at the interscapular level.
Immediately after the CQ injection, the bouts of scratching were counted for 40 minutes by laboratory personnel who were unaware of the drug treatment.
Table 2. Antipruritic ty in mice; chloroquine-induced pruritus . . Bouts / 40 min Protection Test Art1c es (one s1ng e ora1 l 1 dose) Mean: SEM Vehicle for norketotifen, solone 16 260 i 35 and atadine Norketotifen HF3 mg/kg I 171i36 — Norketotifen HF 30 mg/kg n_" Norketotifen HF 100 mg/kg "—— Prednisolone 30 mg/kg "-— atadine 30 mg/kg "-— Vehicle for JNJ 7777120 8 201 i 34 -- INJ 0 30 mg/kg HF = hydrogen te (salt) # one outlier was excluded * Means P S 0.05; ** *** means P S 0001; means P 3 0.0001 Protection was calculated as t of vehicle events The results demonstrate that single oral doses of norketotifen reduced CQ- induced pruritus in mice. Single—dose prednisolone also reduced CQ-induced pruritus. The histamine H-1 receptor inhibitors desloratadine and JNJ7777120 (H-4) did not inhibit chloroquine-induced pruritus, which confirms reports of poor or no antipruritic activity of ine H-1 receptor inhibitors in human malaria patients administered chloroquine.
The finding that norketotifen is a potent inhibitor of chloroquine—induced pruritus is sing since ketotifen has been described as not having inhibitory activity against chloroquine-induced pruritus.
Example 2. Non-histaminergic antipruritic activity: Chloroquine-induced pruritus in dogs The objective was to study non-histaminergic antipruritic effects of norketotifen in dogs. Chloroquine induces non—histaminergic pruritus in dogs.
A new method for testing non-histaminergic antipruritic drug activities in dogs was developed. Chloroquine (CQ) was used as staminergic pruritogen. After fasting for 2 hours, beagle dogs were dosed po with es containing the test article. One single dose of norketotifen was administered to the dogs. Immediately thereafter, quine was given intravenously into a cephalic vein (2 mg/kg over 5 minutes). Starting 3 hours after the chloroquine injection, pruritic events (Biting, Licking and Scratching) were counted for 60 minutes. All test articles were administered in gelatin capsules. The pruritic events were counted by laboratory personnel who were unaware of the drug treatment of the animals.
After administration to dogs, CQ induced pruritus that was decreased by norketotifen and prednisolone. Separate chloroquine tests demonstrated the lack of antipruritic activity of the histamine H—l antagonist desloratadine.
Table 3. Antipruritic activity in dogs; quine-induced pruritus Pruritic Events All ic Test e N Protection Biting Licking Scratching Events Vehicle Control #) 40 i 8 Norketotifen 5 mg/kg I. 37 i 6 Norketotifen 10 mg/kg n. 20 i 4 Norketotifen 20 mg/kg n 4 :: 2 17 i 4 solone 10 mg/kg I. 41 i 6 #) one outlier was ed. tion was calculated as percent of e events.
Means :: SEM * P S 0.05, ** P S 0.01, *** P 3 0.001 when compared with the Vehicle Control group.
The results demonstrate that norketotifen decreased chloroquine-induced pruritus, within three hours after a single oral dose of the compound. Prednisolone is known to inhibit pruritus in dogs with AD and is also known to reduce chloroquine-induced pruritus in malaria patients. The uritic activity of prednisolone in this study validated this test method.
Justification of the model: CQ induces pruritus by activating 3 (Mas- related G—protein Ankyrin) receptors, which are expressed in dermal, afferent dendrites of dorsal root ganglia. The -activated calcium channels TRPAl (Transient Receptor Potential Ankyrin l) and TRPVl (Transient Receptor Potential Vanilloid l) are the downstream targets for MrgprA3 and at least one of TRPAl and TRPVl is currently believed to be ed for chronic itch that is caused by non-histaminergic atopic dermatitis. IL-3l receptors are co-localized with the receptors TRPAl and TRPVl and the IL-31 dependence is obvious from the fact that IL-3 1- induced pruritus is d in receptor knockout mice. Thus, CQ-induced pruritus is a well- justified dog model for tests of effects of drugs on non-histaminergic AD—pruritus. Without being held to , inhibition of the MrgprA3 / TRPAl axis may be a clinically relevant non- histaminergic mode of action of norketotifen.
Example 3. Non-histaminergic antipruritic activity: Leukotriene-induced pruritus in mice [005 5] Antipruritic effects were tested in vivo in CD-1 mice and the leukotriene precursor 5-HPETE was used as the ogen to induce non-histaminergic pruritus. The animals were dosed orally with norketotifen HF, 10 mg/kg, and sixty minutes thereafter, 5- HPETE (5 ug in 50 [LL saline with 0.1% l) was injected intradermally into the previously clipped area of the l part of the back of the mice. Starting immediately after the 5-HPETE injections, the bouts of scratchings were counted for 40 s. Protection against pruritus was calculated in % of the vehicle effect.
The test results (Table 4) demonstrated that norketotifen HF, 10 mg/kg, po reduced 5-I-lPETE-induced pruritus in mice by about 40%.
Separate E tests demonstrated the e of antipruritic activity of the histamine H—l antagonist desloratadine.
Table 4. Antipruritic activity in mice; SHPETE-induced pruritus Means i SEM.
Test Article Bouts / Protection N 40 min (%) Vehicle for Norketotifen 58.6 i HF* 5.0 Norketotifen HF 10 34.2 i 42 mg/kg 9.1 * * * HF = hydrogen fumarate salt >WP S 0.05 It was found that 5-HPETE is a potent r of non-histaminergic pruritus.
Norketotifen inhibited 5-HPETE -induced pruritus within one hour after the oral administration of a single dose of 10 mg/kg norketotifen to mice.
Justification of the model: It has been shown that HPETE and other lipoxygenase products directly activate the TRPAl and TRPVl ligand-activated m channels on dorsal root ganglia, which may n the non—histaminergic pruritic activity of 5-HPETE.
Example 4. Non-histaminergic antipruritic activity: 1L-31 induced pruritus in mice sed dermal concentration of the pruritogenic cytokine lL-31 with concomitant non-histaminergic pruritus is found in the skin of human and canine patients with atopic dermatitis (AD). It is well known that us of patients suffering from AD is not inhibited by histamine H—1 inhibitors, like desloratadine, although Generation-1 antihistamines, like diphenhydramine, may offer some pruritic relief for AD-patients, due to their soporific activity.
The present studies were med in mice, using murine IL31 as the pruritogen to induce staminergic pruritus. The mice were dosed orally (po) with a test article, exactly 60 min before murine IL31 at a dose of 1.0 [Lg/30 gram mouse was injected subcutaneously (sc) into a previously depilated area on the rostral part of the back of mice.
IL31 was dissolved in ate buffered saline (PBS) with 0.1% bovine serum albumin (BSA). The injected volume was 0.1 se. The bouts of scratchings were counted, starting 30 min after the injection of 1L-31 and lasting for a total of 120 min. The bouts of scratchings were counted by laboratory personnel, who were not aware of the pretreatment of the animals.
Separate 1L-31 tests using the methodology bed above demonstrated the absence of antipruritic activity of the histamine H-1 antagonist desloratadine 10 mg/kg, po.
The test results trated antipruritic activity of norketotifen and the reference compound oclacitinib, is shown in Table 5.
Table 5. Non-histaminergic antipruritic activity in mice; 1L3 l-induced pruritus Pruritic Bouts Protection Test Article N Mean :: SEM (1%) —n — Norketotifen HF 10 mg/kg n 93-__ 10 * = Oclacitinib maleate 10 mg/kgm means PS 005 when compared with Vehicle. HF = hydrogen fumarate (salt) It was concluded that a single dose of norketotifen potently inhibited IL—3 l-induced pruritus by non-histaminergic mechanisms within one hour after oral administration.
IL-31 is a non-histaminergic and highly pruritic cytokine that is a key mediator for pruritus that is caused by both ic dermatitis and non-allergic dermatitis. High concentrations of the potently pruritic cytokine IL-3l have been found not only in the skin from patients with atopic dermatitis and non-atopic dermatitis but also in the skin from patients suffering from alopecia areata, mycosis fiingoides, notalgia paresthetica, prurigo nodularis, psoriasis and Sézary syndrome, all of which are dermal diseases causing pruritus. Thus, pruritus sed in patients suffering from these diseases suffer from lL-3 l-mediated, non-histaminergic pruritus.
The m is that few drugs inhibit the pruritogenic effects of IL-3 1. The only presently known IL-31 selective inhibitor is OSMR—L-GLP, which is a fusion protein ting of 720 amino acids. In addition, while antibodies to IL-31 and the lL-3l receptor can be expected to selectively upt the IL-3l ogenic pathway, these molecules are also proteins that will have to be injected. Thus, the currently ble selective lL-31 inhibitors are not suitable for oral or topical administration. Oclacitinib, which is a Janus kinase inhibitor, inhibits the ogenic effects of IL-3 1, however, it has only been approved for veterinary use in dogs. It has now surprisingly been found that norketotifen inhibits IL-31—mediated pruiitus (See Table 5).
Example 5. Topical stration of norketotifen The objective of this study was to determine if norketotifen is absorbed after topical (dermal) application.
A lanolin/ethanol cram ning 1.0% norketotifen HF was prepared as follows: A solution containing 2.5% of RS-norketotifen hydrogen filmarate, calculated as free base free base in ethanol was ed. Lanolin was weighed and liquefied by submerging a vessel ning lanolin in hot water. While the lanolin was a liquid, it was rapidly mixed (by vortexing) with the 2.5% of RS-norketotifen solution in ethanol to result in a 1.0% solution. The ethanol/lanolin solution was allowed to solidify resulting in a cream which consisted of 1.0% RS- norketotifen in 60% lanolin/40% ethanol.
About 10 mg of either norketotifen cream or a vehicle cream was applied to both ears of mice and left for 30 s. The cream was then removed and a solution of 1% of the known pro-inflammatory compound croton oil in acetone was applied to both ears. After the acetone had dried (10 seconds), the cream containing the test article (or vehicle) was reapplied and the animals were returned to their cages. At 0, 30, 60, 90 and 120 minutes following the croton oil administration, groups of four animals were etized with halothane and euthanized. Cream was wiped off from the ears and ears were removed and weighed.
The effects of the test article are shown in Table 6. All results represent mean ear weights (:: S.E.M.) from 8 ears. The weight ofthe croton oil treated ears was increased by about percent within 90 s. There was complete inhibition of the croton oil-induced ation after a single dermal dose of otifen. It was concluded that norketotifen was rapidly absorbed after topical/dermal application. The very rapid onset (<30 min) indicates that the skin is the biophase for the anti-pruritic activity of norketotifen.
Table 6. Effects of norketotifen cream on dermal inflammation in mice.
Time after Croton Oil Average Ear Weight (mg) :: S.E.M.
Application (min) Vehicle RS-Norketotifen 0 (predose) 35 :: 1 36 i 1 3O 41 i l 36 i 1 60 41 :: 1 37 i 2 90 46 :t 2 36 :1: 2 It was concluded that norketotifen was rapidly absorbed after topical/dermal application. The very rapid onset (<30 min) indicates that the skin is the biophase for the anti- pruritic activity of norketotifen.
Example 6. Dermal Drug Accumulation after Oral Drug Administration The objective of this study was to determine pharmacokinetic properties of otifen after oral administration, Five male beagle dogs, weighing 11.2 - 13.9 kg (2 - 4 years old) were used in the study. All animals were administered gelatin capsules containing oral doses of the test article 8.0 mg/kg/day as a hydrogen filmarate salt, equal to 5.6 mg/kg/day of the free base.
The animals were dosed once daily for four utive weeks followed by daily observations for an additional two-week washout period. Multiple plasma samples and skin es were taken from each dog on Day 1 and Day 28 of drug administration. The plasma and skin samplings were performed at se, and at 2, 6, 12 and 24 hours post-dose.
Plasma and skin samples were also taken ittently at predetermined intervals during the 28-days dosing period and up to the last day of the study, which was Day 42. Blood s were taken from v. cephalica antebrachii. Skin es were taken from the area between the mid ventral to lateral abdominal areas, using a 6 mm (diameter) skin biopsy device (Acu- Punch®, Acuderm® Inc., Fort Lauderdale, FL . Multiple plasma and biopsy samples were obtained from each of 4 or 5 dogs. Subcutaneous fat deposits were carefully trimmed from the skin samples and the skin samples were weighed. The plasma samples and skin biopsy samples were analyzed using validated LC/MS/MS methodology. All pharmacokinetic es were performed using Pharsight WinNonlin® Professional v5.2.1 software.
As shown in Table 7, there was a pronounced dermal accumulation of otifen after oral drug administration.
Table 7: Pharmacokinetic (PK) Parameters on Day 28 of Dosing.
S-BPI S-BPI RS-BPI PK Parameter Plasma Skin Skin 1627 25710 1658 20376 3286 54187 162.7 7.7 157.0 10.5 167.6 MRT (hr) 159.0 14.1 159.1 12.8 169.3 AUC0.0O = Area under the plasma concentration (or skin concentration) vs. time curves t1/2 = Plasma or skin half-life MRT = Mean residence time S-BPI = S-norketotifen; R—BPI = R—norketotifen; RS—BPI = total norketotifen Since norketotifen is a potent inhibitor of pruritus, and since the skin is the biophase for that activity, the dermal accumulation of norketotifen will further improve the anti-pruritic activity of this drug, while simultaneously sing the risk for systemic adverse events.
Example 7. Exemplary oral dosage formulations Formulations for oral administration of norketotifen (such as for e tablets, capsules and syrups) have been developed.
Table 8. Tablet formulations Ingredient Amount per tablet Amount per batch otifen 10 mg 100 g MCC * 30 mg 300 g Lactose 70 mg 700 g Calcium stearate 2 mg 20 g FD&C Blue #1 Lake ** 0.03 mg 300 mg * MCC = microcrystalline cellulose; ** FD&C Blue No 1 Aluminum Lake is a FDA- approved color for tablets The active ingredient is blended with the lactose and the microcrystalline cellulose until a uniform blend is formed. The blue lake is added and further blended.
Finally, the calcium stearate is blended in, and the resulting mixture is ssed into tablets using for example a 9/32-inch (7 mm) w concave punch. Tablets of other strengths may be prepared by altering the ratio of active ient to the excipients or to the final weight of the tablet.
Those skilled in the art realize that oral formulations can be in the form of, for example, a tablet, a capsule, a dog-treat, a cat-treat, a syrup or another form of liquid formulations.
Example 8. Exemplary topical/dermal dosage ations Topical/dermal solutions, topical/dermal ointments, topical/dermal emulsions and ldermal creams are examples of topical/dermal administration forms of RS- norketotifen. Preservative excipients will not be needed since norketotifen ations are self-preserving.
Table 9 Examples of topical/dermal solutions ations containing norketotifen.
Sodium phosphate dibasic 0.473 — 0.160 Sodium phosphate 0.460 monobasic, drate If needed, the viscosity can be adjusted by a viscosity-modifying agent to obtain the red viscosity. The final acidity can be adjusted by adjusting the concentrations of buffering agents or by adding an acid or a base.
The topical/dermal solution formulations were prepared by adding the excipients, one at a time to an appropriate amount of water, followed by mixing until dissolved. Once all excipients had been added and dissolved, norketotifen was added to the solution of excipients and mixed continuously until dissolved. The acidity of the topical/dermal solutions was measured and adjusted by modifying the buffer system or by adding an acid or a base solution to the desired pH. If needed, viscosity and tonicity were adjusted as indicated above.
The use of the terms "a" and "an" and "the" and similar referents (especially in the context of the ing claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or y contradicted by context.
The terms first, second etc. as used herein are not meant to denote any particular ordering, but simply for convenience to denote a plurality of, for example, layers.
The terms "comprising77 CL 37 (C 7 having 7 including", and ining" are to be construed as open-ended terms (i.e., meaning "including, but not limited to") unless otherwise noted.
Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated , and each separate value is incorporated into the specification as if it were individually d herein. The endpoints of all ranges are included within the range and independently combinable.
All s described herein can be performed in a le order unless otherwise indicated herein or otherwise clearly contradicted by context.
The use of any and all examples, or exemplary language (e. g., "such as"), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.
No language in the specification should be construed as indicating any non- claimed element as essential to the practice of the ion as used herein.
The term "antihistamine" as used herein refers to histamine H-l receptor inhibitors unless stated differently.
The terms ation-l antihistamine" and "Gen-l antihistamine" as used herein refers to antihistamines that commonly express sedative effects The terms "Generation-2 antihistamine" and Gen—2 antihistamine" as used herein refers to antihistamines that commonly do not s sedative effects The term "patient" as used herein refers to human patients, canine patients, feline patients and equine patients unless stated differently.
As used herein, the term "biophase" refers to the site(s) in the body of patients, where a drug ses its eutic activity.
For the sake of simplicity the terms "dermatitis" and "eczema" are used inter- changeably and used as synonyms herein.
The terms "disease", "condition" and "disorder" are synonyms and are used interchangeably herein.
The terms "atopic" and "allergic" are synonyms and are used interchangeably herein.
The terms "histaminic" and "histaminergic" are synonyms and are used interchangeably herein.
The terms "non-histaminic" and istaminergic" are synonyms and are used interchangeably herein While the invention has been described with reference to a preferred embodiment, it will be tood by those skilled in the art that various s may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many cations may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.
In a first aspect, the invention relates to a method of treating a non-human mammal in need of treatment for non-histaminic pruritus, comprising orally administering to the mammal in need thereof a therapeutically ive amount of RS-norketotifen, R- norketotifen, S-norketotifen, or a pharmaceutically acceptable salt thereof, thereby ng the desire to scratch in the mammal, wherein the non-histaminergic pruritus is resistant to treatment with selective histamine Hreceptor inhibitors, histamine ceptor inhibitors and histamine Hreceptor inhibitors, and wherein the staminergic pruritus is associated with a dermal disorder, a nerve er, or a systemic disorder.
In a second aspect, the invention relates to use of a therapeutically ive amount of RS-norketotifen, R-norketotifen, S-norketotifen, or a pharmaceutically acceptable salt f in the manufacture of a medicament for treating a subject in need of treatment for non-histaminic pruritus, wherein the medicament is formulated for oral administration to the subject in need thereof, thereby reducing the desire to scratch in the t, wherein the staminergic pruritus is resistant to treatment with selective histamine Hreceptor inhibitors, histamine Hreceptor inhibitors and histamine H receptor inhibitors, and wherein the non-histaminergic us is associated with a dermal disorder, a nerve disorder, or a systemic disorder.
Claims (13)
1. A method of ng a non-human mammal in need of treatment for nonhistaminic pruritus, comprising orally administering to the mammal in need thereof a therapeutically effective amount of ketotifen, R-norketotifen, S-norketotifen, or a pharmaceutically acceptable salt thereof, thereby ng the desire to scratch in the mammal, wherein the staminergic pruritus is resistant to treatment with selective histamine ceptor inhibitors, histamine Hreceptor inhibitors and histamine H receptor inhibitors, and wherein the non-histaminergic pruritus is associated with a dermal disorder, a nerve disorder, or a systemic disorder.
2. The method of claim 1, n the non-histaminergic pruritus is associated with a dermal disorder that is asteatotic itis, cutaneous T-cell lymphoma, discoid eczema, hand eczema, alopecia areata, atopic dermatitis, cutaneous B-cell lymphomas, dermatitis herpetiformis, ichthyosis, idiopathic itis, mycosis fungoides, non-atopic dermatitis, notalgia hetica, psoriasis, prurigo nodularis, heic dermatitis, Sézary syndrome or varicose eczema.
3. The method of claim 1 or claim 2, wherein said mammal is a dog.
4. The method of claim 1 or claim 2, wherein said mammal is a cat.
5. The method of claim 1 or claim 2, wherein said mammal is a horse.
6. The method of any one of claims 1 to 5, wherein the nerve disorder is diabetes us, multiple sclerosis, neuropathic diseases, scars, or post-herpetic gia.
7. The method of any one of claims 1 to 5, wherein the systemic disorder is anemia, diabetes, iron deficiency, chronic renal failure, ic scleroderma, multiple sclerosis, or uremia.
8. The method of any one of claims 1 to 7, further comprising prior to orally administering, determining whether said mammal suffers from non-histaminic pruritus and if said determination is positive, then orally administering to said mammal a therapeutically effective amount of RS-norketotifen, R-norketotifen, S-norketotifen, or a pharmaceutically acceptable salt thereof, wherein RS-norketotifen, R-norketotifen, S- norketotifen, or a pharmaceutically salt thereof decrease the itchiness in the mammal, and wherein the non-histaminergic us is resistant to treatment with selective histamine H- 1-receptor inhibitors, ine Hreceptor inhibitors and histamine Hreceptor inhibitors.
9. Use of a therapeutically effective amount of RS-norketotifen, R- otifen, S-norketotifen, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a subject in need of treatment for non-histaminic pruritus, wherein the medicament is formulated for oral administration to the subject in need thereof, thereby reducing the desire to scratch in the subject, n the nonhistaminergic us is resistant to treatment with selective histamine Hreceptor tors, histamine Hreceptor inhibitors and histamine Hreceptor inhibitors, and wherein the staminergic pruritus is associated with a dermal disorder, a nerve disorder, or a systemic er.
10. The use of claim 9, wherein the non-histaminergic pruritus is associated with a dermal disorder that is asteatotic dermatitis, ous T-cell lymphoma, discoid eczema, hand eczema, alopecia areata, atopic dermatitis, cutaneous B-cell lymphomas, dermatitis herpetiformis, ichthyosis, idiopathic dermatitis, mycosis fungoides, non-atopic dermatitis, notalgia paresthetica, psoriasis, prurigo nodularis, seborrheic dermatitis, Sézary syndrome or varicose eczema.
11. The use of claim 9 or claim 10, wherein the nerve disorder is diabetes mellitus, multiple sclerosis, athic diseases, scars, or erpetic neuralgia.
12. The use of claim 9 or claim 10, wherein the systemic disorder is anemia, diabetes, iron deficiency, chronic renal failure, systemic scleroderma, multiple sclerosis, or uremia.
13. The use of any one of claims 9 to 12, further sing prior to orally administering, determining whether said subject s from non-histaminic pruritus and if said ination is positive, then orally administering to said subject a therapeutically effective amount of ketotifen, R-norketotifen, etotifen, or a pharmaceutically acceptable salt thereof, wherein RS-norketotifen, R-norketotifen, S-norketotifen, or a pharmaceutically salt thereof decrease the itchiness in the subject, and wherein the nonhistaminergic pruritus is resistant to treatment with selective histamine Hreceptor inhibitors, histamine Hreceptor inhibitors and histamine Hreceptor inhibitors. Bridge Pharma, Inc. By the eys for the Applicant SPRUSON & FERGUSON Per:
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Application Number | Priority Date | Filing Date | Title |
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US14/736,626 | 2015-06-11 | ||
US14/736,626 US9345697B2 (en) | 2013-08-06 | 2015-06-11 | Methods of treatment of non-histaminic pruritus |
PCT/US2016/033177 WO2016200578A1 (en) | 2015-06-11 | 2016-05-19 | Methods of treatment of non-histaminic pruritus in mammals |
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NZ737615B2 true NZ737615B2 (en) | 2021-08-03 |
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